Method of treating interferon non-responders using HCV protease inhibitor

CROSS-REFERENCE TO PRIORITY APPLICATION

0001This application claims benefit of priority from U.S. provisional patent application Ser. No. 60/686926 filed Jun. 2, 2005.

FIELD OF THE INVENTION

0002The present invention relates to methods of treating a wide variety of diseases or disorders associated with hepatitis C virus (“HCV”) by inhibiting HCV protease (for example HCV NS3/NS4a serine protease).

BACKGROUND OF THE INVENTION

0003HCV has been implicated in cirrhosis of the liver and in induction of hepatocellular carcinoma. The prognosis for patients suffering from HCV infection is currently poor. 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 indicates a less than 50% survival rate at four years post cirrhosis diagnosis. Patients diagnosed with localized resectable hepatocellular carcinoma have a five-year survival rate of 10-30%, whereas those with localized unresectable hepatocellular carcinoma have a five-year survival rate of less than 1%.

0004Current therapies for hepatitis C include interferon-α (INF_{<u style="single">α</u>}) and combination therapy with ribavirin and interferon. See, e.g., Beremguer et al. (1998) <i>Proc. Assoc. Am. Physicians </i>110(2):98-112. These therapies suffer from a low sustained response rate and frequent side effects. See, e.g., Hoofnagle et al. (1997) <i>N. Enql. J. Med. </i>336:347. Currently, no vaccine is available for HCV infection.

0005Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH)(see, International Patent Application Publication No. WO 89/04669 and European Patent Application Publication No. EP 381 216). NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biliar cirrhosis.

0006Recently, an HCV protease necessary for polypeptide processing and viral replication has been identified, cloned and expressed; (see, e.g., U.S. Pat. No. 5,712,145). This approximately 3000 amino acid polyprotein 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 an approximately 68 kda protein, 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 RNA-dependent ATPase domain at the C-terminus of the protein. The NS3 protease is considered a member of the chymotrypsin family because of similarities in protein sequence, overall three-dimensional structure and mechanism of catalysis. Other chymotrypsin-like enzymes are elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA and PSA. The HCV NS3 serine protease is responsible for proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating four viral proteins during viral replication. This has made the HCV NS3 serine protease an attractive target for antiviral chemotherapy.

0007It has been determined that the NS4a protein, an approximately 6 kda polypeptide, is a co-factor for the serine protease activity of NS3. Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine protease occurs intramolecularly (i.e., cis) while the other cleavage sites are processed intermolecularly (i.e., trans).

0008Analysis of the natural cleavage sites for HCV protease revealed the presence of cysteine at P1 and serine at P1′ and that these residues are strictly conserved in the NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions. The NS3/NS4a junction contains a threonine at P1 and a serine at P1′. The Cys→Thr substitution at NS3/NS4a is postulated to account for the requirement of cis rather than trans processing at this junction. See, e.g., Pizzi et al. (1994) <i>Proc. Natl. Acad. Sci </i>(<i>USA</i>) 91:888-892, Failla et al. (1996) <i>Folding </i>&amp; <i>Design </i>1:35-42. The NS3/NS4a cleavage site is also more tolerant of mutagenesis than the other sites. See, e.g., Kollykhalov et al. (1994) <i>J. Virol. </i>68:7525-7533. It has also been found that acidic residues in the region upstream of the cleavage site are required for efficient cleavage. See, e.g., Komoda et al. (1994) <i>J. Virol. </i>68:7351-7357.

0009Inhibitors of HCV protease that have been reported include antioxidants (see, International Patent Application Publication No. WO 98/14181), certain peptides and peptide analogs (see, International Patent Application Publication No. WO 98/17679, Landro et al. (1997) <i>Biochem. </i>36:9340-9348, Ingallinella et al. (1998) <i>Biochem. </i>37:8906-8914, Llinàs-Brunet et al. (1998) <i>Bioorg. Med. Chem. Lett. </i>8:1713-1718), inhibitors based on the 70-amino acid polypeptide eglin c (Martin et al. (1998) <i>Biochem. </i>37:11459-11468, inhibitors affinity selected from human pancreatic secretory trypsin inhibitor (hPSTI-C3) and minibody repertoires (MBip) (Dimasi et al. (1997) <i>J. Virol. </i>71:7461-7469), cV_HE2 (a “camelized” variable domain antibody fragment) (Martin et al.(1997) <i>Protein Eng. </i>10:607-614), and α1-antichymotrypsin (ACT) (Elzouki et al.) (1997) <i>J. Hepat. </i>27:42-28). A ribozyme designed to selectively destroy hepatitis C virus RNA has recently been disclosed (see, <i>BioWorld Today </i>9(217): 4 (Nov. 10, 1998)).

0010Reference is also made to the PCT Publications, No. WO 98/17679, published Apr. 30,1998 (Vertex Pharmaceuticals Incorporated); WO 98/22496, published May 28, 1998 (F. Hoffmann-La Roche AG); and WO 99/07734, published Feb. 18, 1999 (Boehringer Ingelheim Canada Ltd.).

0011Pending and copending U.S. patent applications, Ser. No. 60/194,607, filed Apr. 5, 2000, and Ser. No. 60/198,204, filed Apr. 19, 2000, Ser. No. 60/220,110, filed Jul. 21, 2000, Ser. No. 60/220,109, filed Jul. 21, 2000, Ser. No. 60/220,107, filed Jul. 21, 2000, Ser. No. 60/254,869, filed Dec. 12, 2000, Ser. No. 60/220,101, filed Jul. 21, 2000, Ser. No. 60/568,721 filed May 6, 2004, and WO 2003/062265, disclose various types of peptides and/or other compounds as NS-3 serine protease inhibitors of hepatitis C virus.

0012There is a need for new treatments and therapies for HCV infection to provide methods of treatment useful in the treatment or prevention or amelioration of one or more symptoms of hepatitis C, methods for modulating the activity of serine proteases, particularly the HCV NS3/NS4a serine protease, and methods of modulating the processing of the HCV polypeptide using the compounds provided herein.

0013There is a need for inventive treatments for patients having one more more symptoms associated with the presence of HCV and 1) in whom previous treatment with interferon has been ineffective and/or 2) in whom the HCV is of Genotype 1, namely, Genotype 1a or Genotype 1b.

SUMMARY OF THE INVENTION

0014The present invention provides a method of treating, preventing or ameliorating one or more symptoms associated with hepatitis C virus (HCV) in a patient in whom either the HCV is of Genotype 1 and/or the patient was previously treated with interferon and the previous interferon therapy was ineffective to treat the one or more symptoms associated with HCV, comprising administering to such a patient an effective amount of at least one HCV protease inhibitor compound of formulae I-XXVI set forth below.

0015In one embodiment, the inhibitor is a compound of structural formula I <chemistry id="CHEM-US-00002" num="2"><img file="US2007004635A1_D0001.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof;

0016wherein:

0017Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be optionally substituted with X¹¹or X¹²;

0018X¹¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X¹¹may be additionally optionally substituted with X¹²;

0019X¹²is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X¹²;

0020R¹is COR⁵or B(OR)₂, wherein R⁵is H, OH, OR⁸, NR⁹R¹⁰, CF₃, C₂F₅, C₃F₇, CF₂R⁶, R⁶, or COR⁷wherein R⁷is H, OH, OR⁸, CHR⁹R¹⁰, or NR⁹R¹⁰, wherein R⁶, R⁸, R⁹and R¹⁰are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R^1′)]_pCOOR¹¹, [CH(R^1′)] _pCONR¹²R¹³, [CH(R^1′)]_pSO₂R¹¹, [CH(R^1′)]_pCOR¹¹, [CH(R^1′)]_pCH(OH)RCH(R^1′)CONHCH(R^2′)COO R¹¹, CH(R^1′)CONHCH(R^2′)CONR¹²R¹³, CH(R^1′)CONHCH(R^2′)R′, CH(R^1′)CONHCH(R^2′)CONHCH(R^3′)COO R¹¹, CH(R^1′)CONHCH(R^2′)CONHCH(R^3′) CONR¹²R¹³, CH(R^1′)CONHCH(R^2′)CONHCH(R^3′) CONHCH(R^4′)COO R¹¹, CH(R^1′)CONHCH(R^2′) CONHCH(R^3′)CONHCH(R^4′)CONR¹²R¹³, CH(R^1′)CONHCH(R^2′) CONHCH(R^3′)CONHCH(R^4′)CONHCH(R^5′)COO R¹¹and CH(R^1′)CONHCH(R^2′) CONHCH(R^3′)CONHCH(R^4′)CONHCH(R^5′) CONR¹²R¹³, wherein R^1′, R^2′, R^3′, R^4′, R^5′, R¹¹, R¹², R¹³, and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;

0021Z is selected from O, N, CH or CR;

0022W may be present or absent, and if W is present, W is selected from C═O, C═S,

0023C(═N—CN), or SO₂;

0024Q may be present or absent, and when Q is present, Q is CH, N, P, (CH₂)_p, (CHR)_p, (CRR′)_p, O, NR, S, or SO₂; and when Q is absent, M may be present or absent;

0025when Q and M are absent, A is directly linked to L;

0026A is O, CH₂, (CHR)_p, (CHR—CHR′)_p, (CRR′)_p, NR, S, SO₂or a bond;

0027E is CH, N, CR, or a double bond towards A, L or G;

0028G may be present or absent, and when G is present, G is (CH₂)_p, (CHR)_p, or (CRR′)_p; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to;

0029J may be present or absent, and when J is present, J is (CH₂)_p, (CHR)_p, or (CRR′)_p, SO₂, NH, NR or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J;

0030L may be present or absent, and when L is present, L is CH, CR, O, S or NR; and

0031when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;

0032M may be present or absent, and when M is present, M is O, NR, S, SO₂, (CH₂)_p, (CHR)_p(CHR—CHR′)_p, or (CRR′)_p;

0033p is a number from 0 to 6; and

0034R, R′, R², R³and R⁴are independently selected from the group consisting of H; C₁-C₁₀alkyl; C₂-C₁₀alkenyl; C₃-C₈cycloalkyl; C₃-C₈heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;

0035wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;

0036further wherein said unit N—C-G-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N—C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic_ring.

0037In another embodiment, the inhibitor is a compound of formula II: <chemistry id="CHEM-US-00003" num="3"><img file="US2007004635A1_D0002.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0038Z is O, NH or NR¹²;

0039X is alkylsulfonyl, heterocyclylsulfonyl, heterocyclylalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkyaminocarbonyl, heterocyclylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl moiety, with the proviso that X may be additionally optionally substituted with R¹²or R¹³;

0040X¹is H; C₁-C₄straight chain alkyl; C₁-C₄branched alkyl or; CH₂-aryl (substituted or unsubstituted);

0041R¹²is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that R¹²may be additionally optionally substituted with R¹³.

0042R¹³is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro moiety, with the proviso that the alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from R¹³. P1a, P1b, P2, P3, P4, P5, and P6 are independently:

0043H; C1-C10 straight or branched chain alkyl; C2-C10 straight or branched chain alkenyl;

0044C3-C8 cycloalkyl, C3-C8 heterocyclic; (cycloalkyl)alkyl or (heterocyclyl)alkyl, wherein said cycloalkyl is made up of 3 to 8 carbon atoms, and zero to 6 oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of 1 to 6 carbon atoms;

0045aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein said alkyl is of 1 to 6 carbon atoms;

0046wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyl and (heterocyclyl)alkyl moieties may be optionally substituted with R¹³, and further wherein said P1a and P1b may optionally be joined to each other to form a spirocyclic or spiroheterocyclic ring, with said spirocyclic or spiroheterocyclic ring containing zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and may be additionally optionally substituted with R¹³; and

0047P1′ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, aryl, aryl-alkyl, heteroaryl, or heteroaryl-alkyl; with the proviso that said P1′ may be additionally optionally substituted with R¹³.

0048In another embodiment, the inhibitor is a compound of formula III <chemistry id="CHEM-US-00004" num="4"><img file="US2007004635A1_D0003.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein: G, J and Y may be the same or different and are independently selected from the group consisting of the moieties: H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be additionally optionally substituted with X¹¹or X¹²;

0049X¹¹is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X¹¹may be additionally optionally substituted with X¹²;

0050X¹²is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X¹²;

0051R¹is COR⁵or B(OR)₂, wherein R⁵is selected from the group consisting of H, OH, OR⁸, NR⁹R¹⁰, CF₃, C₂F₅, C₃F₇, CF₂R⁶, R⁶and COR⁷wherein R⁷is selected from the group consisting of H, OH, OR⁸, CHR⁹R¹⁰, and NR⁹R¹⁰, wherein R⁶, R⁸, R⁹and R¹⁰may be the same or different and are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, CH(R^1′)COOR¹¹,CH(R^1′)CONR¹²R¹³,CH(R^′)CONHCH(R^2′)COOR¹¹, CH(R^1′)CONHCH(R^2′)CONR¹²R¹³,CH(R^1′)CONHCH(R^2′)R′,CH(R^1′)CONHCH(R^2′)CO NHCH(R^3′)COOR¹¹,CH(R^1′)CONHCH(R^2′)CONHCH(R^3′)CONR¹²R¹³, CH(R^1′)CONHCH(R^2′)CONHCH(R^3′)CONHCH(R^4′)COOR¹¹,CH(R^1′)CONHCH(R^2′)C ONHCH(R^3′)CONHCH(R^4′)CONR¹²R¹³,CH(R^1′)CONHCH(R^2′)CONHCH(R^3′)CONHC H(R^4′)CONHCH(R^5′)COOR¹¹,and CH(R^1′)CONHCH(R^2′)CONHCH(R^3′)CONHCH(R^4′) CONHCH(R^5′) CONR¹²R¹³, wherein R^1′, R^2′, R^3′, R^4′, R^5′, R¹¹, R¹², R¹³, and R′ may be the same or different and are independently selected from a group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;

0052Z is selected from O, N, or CH;

0053W may be present or absent, and if W is present, W is selected from C═O, C═S, or SO₂; and

0054R, R′, R², R³and R⁴are independently selected from the group consisting of H; C1-C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro; oxygen, nitrogen, sulfur, or phosphorus atoms (with said oxygen, nitrogen, sulfur, or phosphorus atoms numbering zero to six); (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;

0055wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamide, sulfoxide, sulfone, sulfonylurea, hydrazide, and hydroxamate.

0056In another embodiment, the inhibitor is a compound of formula IV <chemistry id="CHEM-US-00005" num="5"><img file="US2007004635A1_D0004.tif" /></chemistry>

0057or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0058Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be optionally substituted with X¹¹or X¹²;

0059X¹¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X¹¹may be additionally optionally substituted with X¹²;

0060X¹²is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X¹²;

0061R¹is selected from the following structures: <chemistry id="CHEM-US-00006" num="6"><img file="US2007004635A1_D0005.tif" /></chemistry>

0062wherein k is a number from 0 to 5, which can be the same or different, R¹¹denotes optional substituents, with each of said substituents being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, hydroxy, thio, alkylthio, arylthio, amino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro, with the proviso that R¹¹(when R¹¹≈H) may be optionally substituted with X¹¹or X¹²;

0063Z is selected from O, N, CH or CR;

0064W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or S(O₂);

0065Q may be present or absent, and when Q is present, Q is CH, N, P, (CH₂)_p, (CHR)_p, (CRR′)_p, O, N(R), S, or S(O₂); and when Q is absent, M may be present or absent;

0066when Q and M are absent, A is directly linked to L;

0067A is O, CH₂, (CHR)_p, (CHR—CHR′)_p, (CRR′)_p, N(R), S, S(O₂) or a bond;

0068E is CH, N, CR, or a double bond towards A, L or G;

0069G may be present or absent, and when G is present, G is (CH₂)_p, (CHR)_p, or (CRR′)_p; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to;

0070J may be present or absent, and when J is present, J is (CH₂)_p, (CHR)_p, or (CRR′)_p, S(O₂), NH, N(R) or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J;

0071L may be present or absent, and when L is present, L is CH, C(R), O, S or N(R); and

0072when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;

0073M may be present or absent, and when M is present, M is O, N(R), S, S(O₂), (CH₂)_p, (CHR)_p(CHR—CHR′)_p, or (CRR′)_p;

0074p is a number from 0 to 6; and

0075R, R′, R², R³and R⁴can be the same or different, each being independently selected from the group consisting of H; C₁-C₁₀alkyl; C₂-C₁₀alkenyl; C₃-C₈cycloalkyl; C₃-C₈heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally substituted, with said term “substituted” referring to substitution with one or more moieties which can be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;

0076further wherein said unit N—C-G-E-L-J-N represents a five-membered cyclic ring structure or six-membered cyclic ring structure with the proviso that when said unit N-C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of said five-membered cyclic ring.

0077In another embodiment, the inhibitor is a compound of formula V <chemistry id="CHEM-US-00007" num="7"><img file="US2007004635A1_D0006.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester of said compound wherein:

0078(1) R¹is —C(O)R⁵or —B(OR)₂;

0079(2) R⁵is H, —OH, —OR⁸, —NR⁹R¹⁰, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —CF₃, —C₂F₅, C₃F₇, —CF₂R⁶, —R⁶, —C(O)R⁷or NR⁷SO₂R⁸;

0080(3) R⁷is H, —OH, —OR⁸,or —CHR⁹R¹⁰;

0081(4) R⁶, R⁸, R⁹and R¹⁰are independently selected from the group consisting of H: alkyl, alkenyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, R¹⁴, —CH(R^1′)CH(R^1′)C(O)OR¹¹,[CH(R^1′)]_pC(O)OR¹¹,—[CH(R^1′)]_pC(O)NR¹²R¹³,—[CH(R^1′)]_pS(O₂)R¹¹,—[CH(R^1′)]_pC(O)R¹¹,—[CH(R^1′)]_pS(O₂)NR¹²R¹³, CH(R^1′)C(O)N(H)CH(R^2′)(R′), CH(R^′1)CH(R^1′)C(O)NR¹²R¹³, —CH(R^1′)CH(R^1′)S(O₂)R¹¹, CH(R^1′)CH(R^1′)S(O₂)NR¹²R¹³, —CH(R^1′)CH(R^1′)C(O)R¹¹, —[CH(R^1′)]_pCH(OH)R¹¹, CH(R^1′)C(O)N(H)CH(R^2′)C(O)OR¹¹, C(O)N(H)CH(R^2′)C(O)OR¹¹, —C(O)N(H)CH(R^2′)C(O)R¹¹,CH(R^1′)C(O)N(H)CH(R^2′) C(O)NR¹²R¹³, —CH(R^1′)C(O)N(H)CH(R^2′)R′,CH(R^1′)C(O)N(H)CH(R^2′)C(O)N(H) CH(R^3′)C(O)OR¹¹,CH(R^1′)C(O)N(H)CH(R^2′)C(O)CH(R^3′)NR¹²R¹³,CH(R^1′)C(O)N(H)CH (R^2′)C(O)N(H)CH(R^3′)C(O)NR¹²R¹³, CH(R^1′)C(O)N(H)CH(R^2′)C(O)N(H)CH(R^3′)C(O)N(H)CH (R^4′)C(O)OR¹¹, H(R^1′)C(O)N(H)CH(R^2′)C(O)N(H)CH(R^3′)C(O)N(H)CH(R^4′)C(O)NR¹²R¹³, CH(R^1′)C(O)N(H)CH(R^2′) C(O)N(H)CH(R^3′)C(O)N(H)CH(R^4′)C(O)N(H)CH(R^5′)C(O)OR¹¹, and CH(R^1′)C(O)N(H)CH(R^2′)C(O)N(H)CH(R^3′)C(O)N(H)CH(R^4′)C(O)N(H)CH(R^5′) C(O)NR¹²R¹³;

0082wherein R^1′, R^2′, R^3′, R^4′, R^5′, R¹¹R¹²and R¹³can be the same or different, each being independently selected from the group consisting of: H, halogen, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, heterocycloalkyl, aryl-alkyl and heteroaralkyl; or

0083R¹²and R¹³are linked together wherein the combination is cycloalkyl, heterocycloalkyl, ary or heteroaryl;

0084R¹⁴is present or not and if present is selected from the group consisting of: H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, allyl, alkyl-heteroaryl, alkoxy, aryl-alkyl, alkenyl, alkynyl and heteroaralkyl;

0085(5) R and R′ are present or not and if present can be the same or different, each being independently selected from the group consisting of: H, OH, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₃-C₈cycloalkyl, C₃-C₈heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, amino, amido, arylthioamino, arylcarbonylamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl, (aryl)alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl, heteroaryl, (alkyl)aryl, alkylheteroaryl, alkyl-heteroaryl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms;

0086(6) L′ is H, OH, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;

0087(7) M′ is H, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl or an amino acid side chain;

0088or L′ and M′ are linked together to form a ring structure wherein the portion of structural Formula 1 represented by <chemistry id="CHEM-US-00008" num="8"><img file="US2007004635A1_D0007.tif" /></chemistry><br /> is represented by structural Formula 2: <chemistry id="CHEM-US-00009" num="9"><img file="US2007004635A1_D0008.tif" /></chemistry><br /> wherein in Formula 2:

0089E is present or absent and if present is C, CH, N or C(R);

0090J is present or absent, and when J is present, J is (CH₂)_p, (CHR—CHR′)_p, (CHR)_p, (CRR′)_p, S(O₂), N(H), N(R) or O; when J is absent and G is present, L is directly linked to the nitrogen atom marked position 2;

0091p is a number from 0 to 6;

0092L is present or absent, and when L is present, L is C(H) or C(R); when L is absent, M is present or absent; if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;

0093G is present or absent, and when G is present, G is (CH₂)_p, (CHR)_p, (CHR—CHR′)_por (CRR′)_p; when G is absent, J is present and E is directly connected to the carbon atom marked position 1;

0094Q is present or absent, and when Q is present, Q is NR, PR, (CR═CR), (CH₂)_p, (CHR)_p, (CRR′)_p, (CHR—CHR′)_p, O, NR, S, SO, or SO₂; when Q is absent, M is (i) either directly linked to A or (ii) an independent substituent on L, said independent substituent bing selected from —OR, —CH(R)(R′), S(O)_0-2R or —NRR′ or (iii) absent; when both Q and M are absent, A is either directly linked to L, or A is an independent substituent on E, said independent substituent bing selected from —OR, —CH(R)(R′), S(O)_0-2R or —NRR′ or A is absent;

0095A is present or absent and if present A is O, O(R), (CH₂)_p, (CHR)_p, (CHR—CHR′)_p, (CRR′)_p, N(R), NRR′, S, S(O₂), —OR, CH(R)(R′) or NRR′; or A is linked to M to form an alicyclic, aliphatic or heteroalicyclic bridge;

0096M is present or absent, and when M is present, M is halogen, O, OR, N(R), S, S(O₂), (CH₂)_p, (CHR)_p(CHR—CHR′)_p, or (CRR′)_p; or M is linked to A to form an alicyclic, aliphatic or heteroalicyclic bridge;

0097(8) Z′ is represented by the structural Formula 3: <chemistry id="CHEM-US-00010" num="10"><img file="US2007004635A1_D0009.tif" /></chemistry>

0098wherein in Formula 3, Y is selected from the group consisting of: H, aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl, heteroalkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, and Y is unsubstituted or optionally substituted with one or two substituents which are the same or different and are independently selected from X¹¹or X¹²;

0099X¹¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, and X¹¹is unsubstituted or optionally substituted with one or more of X¹²moieties which are the same or different and are independently selected;

0100X¹²is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, heteroarylcarbonyl, sulfonylurea, cycloalkylsulfonamido, heteroaryl-cycloalkylsulfonamido, heteroaryl-sulfonamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl are unsubstituted or optionally independently substituted with one or more moieties which are the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl;

0101Z is O, N, C(H) or C(R);

0102R³¹is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino or heterocycloalkylamino, and R³¹is unsubstituted or optionally substituted with one or two substituents which are the same or different and are independently selected from X¹³or X¹⁴;

0103X¹³is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, and X¹³is unsubstituted or optionally substituted with one or more of

0104X¹⁴moieties which are the same or different and are independently selected; X¹⁴is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, heteroarylcarbonyl, cycloalkylsulfonamido, heteroaryl-cycloalkylsulfonamido, heteroarylsulfonamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, and said alkyl, alkoxy, and aryl are unsubstiuted or optionally independently substituted with one or more moieties which are the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl;

0105W may be present or absent, and if W is present, W is C(═O), C(═S), C(═N—CN), or S(O₂);

0106(9) X is represented by structural Formula 4: <chemistry id="CHEM-US-00011" num="11"><img file="US2007004635A1_D0010.tif" /></chemistry>

0107wherein in Formula 4, a is 2, 3, 4, 5, 6, 7, 8 or 9; b, c, d, e and f are 0, 1, 2, 3, 4 or 5;

0108A is C, N, S or O;

0109R²⁹and R^29′ are independently present or absent and if present can be the same or different, each being independently one or two substituents independently selected from the group consisting of: H, halo, alkyl, aryl, cycloalkyl, cycloalkylamino, cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxyl, C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkyiheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁and Y₂can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; or

0110R²⁹and R^29′ are linked together such that the combination is an aliphatic or heteroaliphatic chain of 0 to 6 carbons;

0111R³⁰is present or absent and if present is one or two substituents independently selected from the group consisting of: H, alkyl, aryl, heteroaryl and cylcoalkyl;

0112(10) D is represented by structural Formula 5: <chemistry id="CHEM-US-00012" num="12"><img file="US2007004635A1_D0011.tif" /></chemistry><br /> wherein in Formula 5, R³², R³³and R³⁴are present or absent and if present are independently one or two substituents independently selected from the group consisting of: H, halo, alkyl, aryl, cycloalkyl, cycloalkylamino, spiroalkyl, cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxyl, —C(O)O-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocyclenyl, Y¹Y₂N-alkyl-, Y¹Y₂NC(O)— and Y¹Y₂NSO₂—, wherein Y₁and Y₂can be the same or different and are independently selected from the group consisting of 30 hydrogen, alkyl, aryl, and aralkyl; or

0113R³²and R³⁴are linked together such that the combination forms a portion of a cycloalkyl group;

0114g is 1, 2, 3, 4, 5, 6, 7, 8 or 9; h, i, j, k, l and m are 0, 1, 2, 3, 4 or 5; and

0115A is C, N, S or O,

0116(11) provided that when structural Formula 2: <chemistry id="CHEM-US-00013" num="13"><img file="US2007004635A1_D0012.tif" /></chemistry>

0117W′ is CH or N, both the following conditional exclusions (i) and (ii) apply: conditional exclusion (i): Z′ is not —NH—R³⁶, wherein R³⁶is H, C₆or 10 aryl, heteroaryl, —C(O)—R³⁷, —C(O)OR³⁷or —C(O)NHR³⁷, wherein R³⁷is C_1-6alkyl or C_3-6cycloalkyl; and

0118conditional exclusion (ii): R¹is not —C(O)OH, a pharmaceutically acceptable salt of —C(O)OH, an ester of —C(O)OH or —C(O)NHR³⁸wherein R³⁸is selected from the group consisting of C_1-8alkyl, C_3-6cycloalkyl, C_{6 to 10}aryl or C_7-16aralkyl.

0119In another embodiment, the inhibitor is a compound of formula VI <chemistry id="CHEM-US-00014" num="14"><img file="US2007004635A1_D0013.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester of said compound, wherein: Cap and P′ are independently H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy or heterocyclylamino, wherein each of said alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy or heterocyclylamino can be unsubstituted or optionally independently substituted with one or two substituents which can be the same or different and are independently selected from X¹and X²;

0120X¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl, and X¹can be unsubstituted or optionally independently substituted with one or more of X²moieties which can be the same or different and are independently selected;

0121X²is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, keto, ester or nitro, wherein each of said alkyl, alkoxy, and aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl and heteroarylalkyl;

0122W may be present or absent, and when W is present W is C(═O), C(═S), C(═NH), C(═N—OH), C(═N—CN), S(O) or S(O₂);

0123Q may be present or absent, and when Q is present, Q is N(R), P(R), CR═CR′, (CH₂)_p, (CHR)_p, (CRR′)_p, (CHR—CHR′)_p, O, S, S(O) or S(O₂); when Q is absent, M is (i) either directly linked to A or (ii) M is an independent substituent on L and A is an independent substituent on E, with said independent substituent being selected from —OR, —CH(R′), S(O)_0-2R or —NRR′; when both Q and M are absent, A is either directly linked to L, or A is an independent substituent on E, selected from —OR, CH(R)(R′), —S(O)_0-2R or —NRR′;

0124A is present or absent and if present A is —O—, —O(R) CH₂—, —(CHR)_p—, —(CHR—CHR′)_p—, (CRR′)_p, N(R), NRR′, S, or S(O₂), and when Q is absent, A is —OR, —CH(R)(R′) or —NRR′ ; and when A is absent, either Q and E are connected by a bond or Q is an independent substituent on M;

0125E is present or absent and if present E is CH, N, C(R);

0126G may be present or absent, and when G is present, G is (CH₂)_p, (CHR)_p, or (CRR′)_p; when G is absent, J is present and E is directly connected to the carbon atom marked position 1;

0127J may be present or absent, and when J is present, J is (CH₂)_p, (CHR—CHR′)_p, (CHR)_p, (CRR′)_p, S(O₂), N(H), N(R) or O; when J is absent and G is present, L is directly linked to the nitrogen atom marked position 2;

0128L may be present or absent, and when L is present, L is CH, N, or CR; when L is absent, M is present or absent; if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;

0129M may be present or absent, and when M is present, M is O, N(R), S, S(O₂), (CH₂)_p, (CHR)_p, (CHR—CHR′)_p, or (CRR′)_p;

0130p is a number from 0 to 6;

0131R, R′ and R³can be the same or different, each being independently selected from the group consisting of: H, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₃-C₈cycloalkyl, C₃-C₈heterocyclyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, arylthioamino, arylcarbonylamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl, heteroalkenyl, alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl, heteroaryl, alkyl-aryl, alkylheteroaryl, alkyl-heteroaryl and (heterocyclyl)alkyl;

0132R and R′ in (CRR′) can be linked together such that the combination forms a cycloalkyl or heterocyclyl moiety; and

0133R¹is N(R) or O.

0134In another embodiment, the inhibitor is a compound of formula VII <chemistry id="CHEM-US-00015" num="15"><img file="US2007004635A1_D0014.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof, wherein,

0135M is O, N(H), or CH₂;

0136n is 0-4;

0137R¹is —OR⁶, —NR⁶R⁷or <chemistry id="CHEM-US-00016" num="16"><img file="US2007004635A1_D0015.tif" /></chemistry>

0138where R⁶and R⁷can be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino, arylamino and alkylamino;

0139R⁴and R⁵can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl and cycloalkyl; or alternatively R⁴and R⁵together form part of a cyclic 5- to 7-membered ring such that the moiety <chemistry id="CHEM-US-00017" num="17"><img file="US2007004635A1_D0016.tif" /></chemistry><br /> is represented by <chemistry id="CHEM-US-00018" num="18"><img file="US2007004635A1_D0017.tif" /></chemistry><br /> where k is 0 to 2;

0140X is selected from the group consisting of: <chemistry id="CHEM-US-00019" num="19"><img file="US2007004635A1_D0018.tif" /></chemistry>

0141where p is 1 to 2, q is 1-3 and P²is alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino or cycloalkylamino; and

0142R³is selected from the group consisting of: aryl, heterocyclyl, heteroaryl, <chemistry id="CHEM-US-00020" num="20"><img file="US2007004635A1_D0019.tif" /></chemistry>

0143where Y is O, S or NH, and Z is CH or N, and the R⁸moieties can be the same or different, each R⁸being independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and alkyloxy.

0144In another embodiment, the inhibitor is a compound of formula formula VIII: <chemistry id="CHEM-US-00021" num="21"><img file="US2007004635A1_D0020.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof, wherein,

0145M is O, N(H), or CH₂;

0146R¹is —OR⁶, —NR⁶R⁷or <chemistry id="CHEM-US-00022" num="22"><img file="US2007004635A1_D0021.tif" /></chemistry>

0147where R⁶and R⁷can be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino, arylamino and alkylamino;

0148P₁is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl haloalkyl;

0149P₃is selected from the group consisting of alkyl, cycloalkyl, aryl and cycloalkyl fused with aryl;

0150R⁴and R⁵can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl and cycloalkyl; or alternatively R⁴and R⁵together form part of a cyclic 5- to 7-membered ring such that the moiety <chemistry id="CHEM-US-00023" num="23"><img file="US2007004635A1_D0022.tif" /></chemistry><br /> is represented by <chemistry id="CHEM-US-00024" num="24"><img file="US2007004635A1_D0023.tif" /></chemistry><br /> where k is 0 to 2;

0151X is selected from the group consisting of: <chemistry id="CHEM-US-00025" num="25"><img file="US2007004635A1_D0024.tif" /></chemistry>

0152where p is 1 to 2, q is 1 to 3 and p²is alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamino or cycloalkylamino; and

0153R³is selected from the group consisting of: aryl, heterocyclyl, heteroaryl, <chemistry id="CHEM-US-00026" num="26"><img file="US2007004635A1_D0025.tif" /></chemistry><br /> where Y is O, S or NH, and Z is CH or N, and the R⁸moieties can be the same or different, each R⁸being independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and alkyloxy.

0154In another embodiment, the inhibitor is a compound of formula formula IX: <chemistry id="CHEM-US-00027" num="27"><img file="US2007004635A1_D0026.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof, wherein,

0155M is O, N(H), or CH₂;

0156n is 0-4;

0157R¹is —OR⁶, —NR⁶R⁷or <chemistry id="CHEM-US-00028" num="28"><img file="US2007004635A1_D0027.tif" /></chemistry>

0158where R⁶and R⁷can be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, amino, arylamino and alkylamino;

0159R⁴and R⁵can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl and cycloalkyl; or alternatively R⁴and R⁵together form part of a cyclic 5- to 7-membered ring such that the moiety <chemistry id="CHEM-US-00029" num="29"><img file="US2007004635A1_D0028.tif" /></chemistry><br /> is represented by <chemistry id="CHEM-US-00030" num="30"><img file="US2007004635A1_D0029.tif" /></chemistry><br /> where k is 0 to 2;

0160X is selected from the group consisting of: <chemistry id="CHEM-US-00031" num="31"><img file="US2007004635A1_D0030.tif" /></chemistry>

0161where p is 1 to 2, q is 1 to 3 and P²is alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, dialkylamino, alkyamino, arylamino or cycloalkulamino; and

0162R³is selected from the group consisting of: aryl, heterocyclyl, heteroaryl, <chemistry id="CHEM-US-00032" num="32"><img file="US2007004635A1_D0031.tif" /></chemistry>

0163where Y is O, S or NH, and Z is CH or N, and the R⁸moieties can be the same or different, each R⁸being independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and alkyloxy.

0164In another embodiment, the inhibitor is a compound of formula X: <chemistry id="CHEM-US-00033" num="33"><img file="US2007004635A1_D0032.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0165R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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;

0166A and M can be the same or different, each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected to each other such that the moiety: <chemistry id="CHEM-US-00034" num="34"><img file="US2007004635A1_D0033.tif" /></chemistry><br /> shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0167E is C(H) or C(R);

0168L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0169R, R′, R², and R³can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to each other such that NRR′ forms a four to eight-membered heterocyclyl;

0170and Y is selected from the following moieties: <chemistry id="CHEM-US-00035" num="35"><img file="US2007004635A1_D0034.tif" /></chemistry><br /> wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷and R¹⁸can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately, R¹⁵and R¹⁶are connected to each other to form a four to eight-membered cycloalkyl, heteroaryl or heterocyclyl structure, and likewise, independently R¹⁷and R¹⁸are connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl;

0171wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties 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, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0172In one embodiment, the inhibitor is a compound of Formula XI: <chemistry id="CHEM-US-00036" num="36"><img file="US2007004635A1_D0035.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0173R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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;

0174A and M can be the same or different, each being independently selected from R, NR⁹R¹⁰, SR, SO₂R, and halo; or A and M are connected to each other (in other words, A-E-L-M taken together) such that the moiety: <chemistry id="CHEM-US-00037" num="37"><img file="US2007004635A1_D0036.tif" /></chemistry><br /> shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0175E is C(H) or C(R);

0176L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0177R, R′, R², and R³can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to each other such that NR⁹R¹⁰forms a four to eight-membered heterocyclyl;

0178Y is selected from the following moieties: <chemistry id="CHEM-US-00038" num="38"><img file="US2007004635A1_D0037.tif" /></chemistry>

0179wherein Y³⁰and Y³¹are selected from <chemistry id="CHEM-US-00039" num="39"><img file="US2007004635A1_D0038.tif" /></chemistry>

0180X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O) and SO₂;

0181G is NH or O; and

0182R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, T₃and T₄can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately, R¹⁷and R¹⁸are connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl;

0183wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties 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, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0184In another embodiment, the inhibitor is a compound of formula XII: <chemistry id="CHEM-US-00040" num="40"><img file="US2007004635A1_D0039.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0185R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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;

0186A and M can be the same or different, each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected to each other such that the moiety: <chemistry id="CHEM-US-00041" num="41"><img file="US2007004635A1_D0040.tif" /></chemistry><br /> shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0187E is C(H) or C(R);

0188L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0189R, R′, R², and R³can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to each other such that NRR′ forms a four to eight-membered heterocyclyl;

0190and Y is selected from the following moieties: <chemistry id="CHEM-US-00042" num="42"><img file="US2007004635A1_D0041.tif" /></chemistry><br /> wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately, (i) either R¹⁵and R¹⁶are connected to each other to form a four to eight-membered cyclic structure, or R¹⁵and R¹⁹are connected to each other to form a four to eight-membered cyclic structure, and (ii) likewise, independently, R¹⁷and R¹⁸are connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl;

0191wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl, aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0192In another embodiment, the inhibitor is a compound of Formula XIII: <chemistry id="CHEM-US-00043" num="43"><img file="US2007004635A1_D0042.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0193R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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;

0194A and M can be the same or different, each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected to each other (in other words, A-E-L-M taken together) such that the moiety: <chemistry id="CHEM-US-00044" num="44"><img file="US2007004635A1_D0043.tif" /></chemistry><br /> shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0195E is C(H) or C(R);

0196L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0197R, R<b>40</b> , R², and R³can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to each other such that NRR′ forms a four to eight-membered heterocyclyl;

0198and Y is selected from the following moieties: <chemistry id="CHEM-US-00045" num="45"><img file="US2007004635A1_D0044.tif" /></chemistry><br /> wherein G is NH or O, and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹and R²⁰can be the same or different, each being independently selected from the group consisting of H, C₁-C₁₀alkyl, C₁-C₁₀heteroalkyl, C₂-C₁₀alkenyl, C₂-C₁₀heteroalkenyl, C₂-C₁₀alkynyl, C₂-C₁₀heteroalkynyl, C₃-C₈cycloalkyl, C₃-C₈heterocyclyl, aryl, heteroaryl, or alternately: (i) either R¹⁵and R¹⁶can be connected to each other to form a four to eight-membered cycloalkyl or heterocyclyl, or R¹⁵and R¹⁹are connected to each other to form a five to eight-membered cycloalkyl or heterocyclyl, or R¹⁵and R²⁰are connected to each other to form a five to eight-membered cycloalkyl or heterocyclyl, and (ii) likewise, independently, R¹⁷and R¹⁸are connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl,

0199wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0200In another embodiment, the inhibitor is a compound of Formula XIV: <chemistry id="CHEM-US-00046" num="46"><img file="US2007004635A1_D0045.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0201R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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;

0202A and M can be the same or different, each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, and halo;

0203or A and M are connected to each other such that the moiety: <chemistry id="CHEM-US-00047" num="47"><img file="US2007004635A1_D0046.tif" /></chemistry><br /> shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0204E is C(H) or C(R);

0205L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0206R, R′, R², and R³can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately R and R′ in NRR′ are connected to each other such that NRR′ forms a four to eight-membered heterocyclyl;

0207and Y is selected from the following moieties: <chemistry id="CHEM-US-00048" num="48"><img file="US2007004635A1_D0047.tif" /></chemistry><br /> wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷and R¹⁸can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or alternately, (i) R¹⁵and R¹⁶are connected to each other to form a four to eight-membered cyclic structure, and (ii) likewise, independently R¹⁷and R¹⁸are connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl;

0208wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl, aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0209In another embodiment, the inhibitor is a compound of Formula XV: <chemistry id="CHEM-US-00049" num="49"><img file="US2007004635A1_D0048.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0210R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can be the same or different, each being independently selected from the group consisting of H, alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, arylalkyl-, and heteroarylalkyl; E and J can be the same or different, each being independently selected from the group consisting of R, OR, NHR, NRR⁷, SR, halo, and S(O₂)R, or E and J can be directly connected to each other to form either a three to eight-membered cycloalkyl, or a three to eight-membered heterocyclyl moiety;

0211Z is N(H), N(R), or O, with the proviso that when Z is O, G is present or absent and if G is present with Z being O, then G is C(═O);

0212G may be present or absent, and if G is present, G is C(═O) or S(O₂), and when G is absent, Z is directly connected to Y;

0213Y is selected from the group consisting of: <chemistry id="CHEM-US-00050" num="50"><img file="US2007004635A1_D0049.tif" /></chemistry><chemistry id="CHEM-US-00051" num="51"><img file="US2007004635A1_D0050.tif" /></chemistry>

0214R, R⁷, R², R³, R⁴and R⁵can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-, wherein each of said heteroalkyl, heteroaryl and heterocyclyl independently has one to six oxygen, nitrogen, sulfur, or phosphorus atoms;

0215wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl moieties can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyi, halo, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate.

0216In another embodiment, the inhibitor is a compound of Formula XVI: <chemistry id="CHEM-US-00052" num="52"><img file="US2007004635A1_D0051.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0217R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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 R⁹and R¹⁰in NR⁹R¹⁰are connected to each other such that NR⁹R¹⁰forms a four to eight-membered heterocyclyl, and likewise independently alternately R⁹and R¹⁰in CHR⁹R¹⁰are connected to each other such that CHR⁹R¹⁰forms a four to eight-membered cycloalkyl;

0218R²and R³can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

0219Y is selected from the following moieties: <chemistry id="CHEM-US-00053" num="53"><img file="US2007004635A1_D0052.tif" /></chemistry><chemistry id="CHEM-US-00054" num="54"><img file="US2007004635A1_D0053.tif" /></chemistry>

0220wherein G is NH of O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴and R²⁵can be the same or different, each being independently selectedly from the group cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷and R¹⁸are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R¹⁵and R¹⁹are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R¹⁵and R¹⁶are connected to each other to form a four to eight-membered heterocyclyl; (iv) likewise independently R¹⁵and R²⁰are connected to each other to form a four to eight-membered heterocyclyl; (v) likewise independently R²²and R²³are connected to each other to form a three to eight-membered cycloalkyl or a four to eight-membered heterocyclyl; and (vi) likewise independently R²⁴and R²⁵are connected to each other to form a three to eight-membered cycloalkyl or a four to eight-membered heterocyclyl;

0221wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties 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, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0222In another embodiment, the inhibitor is a compound of Formula XVII: <chemistry id="CHEM-US-00055" num="55"><img file="US2007004635A1_D0054.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0223R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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;

0224A and M can be the same or different, each being independently selected from R, OR, NHR, NRR′, SR, SO₂R, and halo; or A and M are connected to each other such that the moiety: <chemistry id="CHEM-US-00056" num="56"><img file="US2007004635A1_D0055.tif" /></chemistry><br /> shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0225E is C(H) or C(R);

0226L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0227R, R′, R², and R³can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in NRR′ are connected to each other such that NRR′ forms a four to eight-membered heterocyclyl;

0228Y is selected from the following moieties: <chemistry id="CHEM-US-00057" num="57"><img file="US2007004635A1_D0056.tif" /></chemistry><br /> wherein Y³⁰is selected from <chemistry id="CHEM-US-00058" num="58"><img file="US2007004635A1_D0057.tif" /></chemistry>

0229X is selected from O, NR¹⁵, NC(O)R¹⁶, S, S(O) and SO₂;

0230G is NH or O; and

0231R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, T₁, T₂, and T₃can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately, R¹⁷and R¹⁸are connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl;

0232wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties 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, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0233In another embodiment, the inhibitor is a compound of Formula XVIII: <chemistry id="CHEM-US-00059" num="59"><img file="US2007004635A1_D0058.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:

0234R⁸is selected from the group consisting of alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, heteroarylalkyl-, and heterocyclylalkyl;

0235R⁹is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and cycloalkyl;

0236A and M can be the same or different, each being independently selected from R, OR, N(H)R, N(RR′), SR, S(O₂)R, and halo; or A and M are connected to each other (in other words, A-E-L-M taken together) such that the moiety: <chemistry id="CHEM-US-00060" num="60"><img file="US2007004635A1_D0059.tif" /></chemistry>

0237shown above in Formula I forms either a three, four, five, six, seven or eight-membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl;

0238E is C(H) or C(R);

0239L is C(H), C(R), CH₂C(R), or C(R)CH₂;

0240R and R′ can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryl-alkyl-; or alternately R and R′ in N(RR′) are connected to each other such that N(RR′) forms a four to eight-membered heterocyclyl;

0241R²and R³can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

0242Y is selected from the following moieties: <chemistry id="CHEM-US-00061" num="61"><img file="US2007004635A1_D0060.tif" /></chemistry><chemistry id="CHEM-US-00062" num="62"><img file="US2007004635A1_D0061.tif" /></chemistry>

0243wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹and R²⁰can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷and R¹⁸are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R¹⁵and R¹⁹are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R¹⁵and R¹⁶are connected to each other to form a four to eight-membered heterocyclyl; and (iv) likewise independently R¹⁵and R²⁰are connected to each other to form a four to eight-membered heterocyclyl;

0244wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, spiro-linked cycloalkyl, and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0245In another embodiment, the inhibitor is a compound of Formula XIX: <chemistry id="CHEM-US-00063" num="63"><img file="US2007004635A1_D0062.tif" /></chemistry><br /> wherein:

0246Z is selected from the group consisting of a heterocyclyl moiety,

0247N(H)(alkyl), —N(alkyl)₂, —N(H)(cycloalkyl), —N(cycloalkyl)₂, —N(H)(aryl, —N(aryl)₂, —N(H)(heterocyclyl), —N(heterocyclyl)₂, —N(H)(heteroaryl), and —N(heteroaryl)₂;

0248R¹is H, OR⁸, NR⁹R¹⁰, or CHR⁹R¹⁰, wherein R⁸, R⁹and R¹⁰can 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 R⁹and R¹⁰in NR⁹R¹⁰are connected to each other such that NR⁹R¹⁰forms a four to eight-membered heterocyclyl, and likewise independently alternately R⁹and R¹⁰in CHR⁹R¹⁰are connected to each other such that CHR⁹R¹⁰forms a four to eight-membered cycloalkyl;

0249R²and R³can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

0250Y is selected from the following moieties: <chemistry id="CHEM-US-00064" num="64"><img file="US2007004635A1_D0063.tif" /></chemistry><chemistry id="CHEM-US-00065" num="65"><img file="US2007004635A1_D0064.tif" /></chemistry>

0251wherein G is NH or O; and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰and R²¹can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R¹⁷and R¹⁸are independently connected to each other to form a three to eight-membered cycloalkyl or heterocyclyl; (ii) likewise independently R¹⁵and R¹⁹are connected to each other to form a four to eight-membered heterocyclyl; (iii) likewise independently R¹⁵and R¹⁶are connected to each other to form a four to eight-membered heterocyclyl; and (iv) likewise independently R¹⁵and R²⁰are connected to each other to form a four to eight-membered heterocyclyl;

0252wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties 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, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.

0253In another embodiment, the inhibitor is a compound of formula XX <chemistry id="CHEM-US-00066" num="66"><img file="US2007004635A1_D0065.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein: a is 0 or 1; b is 0 or 1; Y is H or C_1-6alkyl;

0254B is H, an acyl derivative of formula R₇—C(O)— or a sulfonyl of formula R₇—SO2 wherein

0255R7 is (i) C_1-10alkyl optionally substituted with carboxyl, C_1-6alkanoyloxy or C_1-6alkoxy; <ul id="ul0001" list-style="none"><li id="ul0001-0001" num="0000"><ul id="ul0002" list-style="none"><li id="ul0002-0001" num="0256"> (ii) C_3-7cycloalkyl optionally substituted with carboxyl, (C_1-6alkoxy)carbonyl or phenylmethoxycarbonyl; </li><li id="ul0002-0002" num="0257"> (iii) C₆or C₁₀aryl or C_7-16aralkyl optionally substituted with C_1-6alkyl, hydroxy, or amino optionally substituted with C_1-6alkyl; or </li><li id="ul0002-0003" num="0258"> (iv) Het optionally substituted with C_1-6alkyl, hydroxy, amino optionally substituted with C_1-6alkyl, or amido optionally substituted with C_1-6alkyl; </li></ul></li></ul>

0259R₆, when present, is C_1-6alkyl substituted with carboxyl;

0260R₅, when present, is C_1-6alkyl optionally substituted with carboxyl;

0261R₄is C_1-10alkyl, C_3-7cycloalkyl or C_4-10(alkylcycloalkyl);

0262R₃is C_1-10alkyl, C_3-7cycloalkyl or C_4-10(alkylcycloalkyl);

0263R₂is CH₂—R₂₀, NH—R₂₀, 0-R₂₀or S—R₂₀, wherein R₂₀is a saturated or unsaturated C_3-7cycloalkyl or C_4-10(alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R₂₁, or R₂₀is a C₆or C₁₀aryl or C_7-16aralkyl optionally mono-, di- or tri-substituted with R₂₁,

0264or R₂₀is Het or (lower alkyl)-Het optionally mono-, di- or tri-substituted with R₂₁, wherein each R₂₁is independently C_1-6alkyl; C_1-6alkoxy; amino optionally mono- or di-substituted with C_1-6alkyl; sulfonyl; NO₂; OH; SH; halo; haloalkyl; amido optionally mono-substituted with C_1-6alkyl, C₆or C₁₀aryl, C_7-16aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C₆or C₁₀aryl, C_7-16aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R₂₂;

0265wherein R₂₂is C_1-6alkyl; C_1-6alkoxy; amino optionally mono- or di-substituted with C_1-6alkyl; sulfonyl; NO₂; OH; SH; halo; haloalkyl; carboxyl; amide or (lower alkyl)amide;

0266R₁is C_1-6alkyl or C_2-6alkenyl optionally substituted with halogen; and W is hydroxy or a N-substituted amino.

0267In the above-shown structure of the compound of Formula XX, the terms P6, P5, P4, P3, P2 and P1 denote the respective amino acid moieties as is conventionally .known to those skilled in the art.

0268In another embodiment, the inhibitor is a compound of formula XXI <chemistry id="CHEM-US-00067" num="67"><img file="US2007004635A1_D0066.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0269B is H, a C₆or C₁₀aryl, C_7-16aralkyl; Het or (lower alkyl)- Het, all of which optionally substituted with C_1-6alkyl; C_1-6alkoxy; C_1-6alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C_1-6alkyl; amido; or (lower alkyl)amide;

0270or B is an acyl derivative of formula R₄—C(O)—; a carboxyl of formula R₄—O—C(O)—; an amide of formula R₄—N(R₅)—C(O)—; a thioamide of formula R₄—N(R₅)—C(S)—; or a sulfonyl of formula R₄—SO2 wherein

0271R₄is (i) C_1-10alkyl optionally substituted with carboxyl, C_1-6alkanoyl, hydroxy, C_1-6alkoxy, amino optionally mono- or di-substituted with C_1-6alkyl, amido, or (lower alkyl) amide;

0272(ii) C_3-7cycloalkyl, C_3-7cycloalkoxy, or C_4-10alkylcycloalkyl, all optionally substituted with hydroxy, carboxyl, (C_1-6alkoxy)carbonyl, amino optionally mono- or di-substituted with C_1-6alkyl, amido, or (lower alkyl) amide;

0273(iii) amino optionally mono- or di-substituted with Cl-₆alkyl; amido; or (lower alkyl)amide;

0274(iv) C₆or C₁₀aryl or C_7-16aralkyl, all optionally substituted with C_1-6alkyl, hydroxy, amido, (lower alkyl)amide, or amino optionally mono- or di-substituted with C_1-6alkyl; or

0275(v) Het or (lower alkyl)-Het, both optionally substituted with C_1-6alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C_1-6alkyl;

0276R₅is H or C_1-6alkyl;

0277with the proviso that when R₄is an amide or a thioamide, R₄is not (ii) a cycloalkoxy;

0278Y is H or C_1-6alkyl;

0279R₃is C_1-8alkyl, C_3-7cycloalkyl, or C_4-10alkylcycloalkyl, all optionally substituted with hydroxy, C_1-6alkoxy, C_1-6thioalkyl, amido, (lower alkyl)amido, C₆or C₁₀aryl, or C_7-16aralkyl;

0280R₂is CH₂—R₂₀, NH—R₂₀, O—R₂₀or S—R₂₀, wherein R₂₀is a saturated or unsaturated C_3-7cycloalkyl or C_4-10(alkylcycloalkyl), all of which being optionally mono-, di- or tri-substituted with R₂₁, or R₂₀is a C₆or C₁₀aryl or C_7-14aralkyl, all optionally mono-, di- or tri-substituted with R₂₁,

0281or R₂₀is Het or (lower alkyl)-Het, both optionally mono-, di- or tri-substituted with R₂₁,

0282wherein each R₂₁is independently C_1-6alkyl; C_1-6alkoxy; lower thioalkyl; sulfonyl; NO₂; OH; SH; halo; haloalkyl; amino optionally mono- or di-substituted with C_1-6alkyl, C₆or C₁₀aryl, C_7-14aralkyl, Het or (lower alkyl)-Het; amido optionally mono-substituted with C_1-6alkyl, C₆or C₁₀aryl, C_7-14aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C₆or C₁₀aryl, C_7-14aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R₂₂;

0283wherein R₂₂is C_1-6alkyl; C_3-7cycloalkyl; C_1-6alkoxy; amino optionally mono- or di-substituted with C_1-6alkyl; sulfonyl; (lower alkyl)sulfonyl; NO₂; OH; SH; halo; haloalkyl; carboxyl; amide; (lower alkyl)amide; or Het optionally substituted with C_1-6alkyl;

0284R1 is H; C_1-6alkyl, C_3-7cycloalkyl, C_2-6alkenyl, or C_2-6alkynyl, all optionally substituted with halogen.

0285In another embodiment, the inhibitor is a compound of formula XXII <chemistry id="CHEM-US-00068" num="68"><img file="US2007004635A1_D0067.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein

0286W is CH or N,

0287R²¹is H, halo, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-6cycloalkoxy, hydroxy, or N(R²³)₂, wherein each R²³is independently H, C_1-6alkyl or C_3-6cycloalkyl;

0288R²²is H, halo, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, C_1-6thioalkyl, C_1-6alkoxy, cycloalkoxy, C_2-7alkoxyalkyl, C_3-6cycloalkyl, C_{6 or 10}aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Het being substituted with R²⁴, wherein R²⁴is H, halo, C_1-6alkyl, C_3-6cycloalkyl, C_1-6alkoxy, C_3-6cycloalkoxy, NO₂, N(R²⁵)₂, NH—C(O)—R²⁵or NH—C(O)—NH—R²⁵, wherein each R²⁵is independently: H, C_1-6alkyl or C_3-6cycloalkyl;

0289or R²⁴is NH—C(O)—OR²⁶wherein R²⁶is C_1-6alkyl or C_3-6cycloalkyl;

0290R³is hydroxy, NH₂, or a group of formula —NH—R³¹, wherein R³¹is C_{6 or 10}aryl, heteroaryl, —C(O)—R³², —C(O)—NHR³²or —C(O)—OR³², wherein R³²is C_1-6alkyl or C_3-6cycloalkyl;

0291D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N—R⁴¹, wherein R⁴¹is H, C_1-6alkyl, C_3-6cycloalkyl or —C(O)—R⁴², wherein R⁴²is C_1-6alkyl, C_3-6cycloalkyl or C_{6 or 10}aryl; R⁴is H or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, hydroxy, halo, amino, oxo, thio and C 1-6 thioalkyl, and A is an amide of formula —C(O)—NH—R⁵, wherein R⁵is selected from the group consisting of: C_1-8alkyl, C_3-6cycloalkyl, C_{6 or 10}aryl and C_7-16aralkyl;

0292or A is a carboxylic acid.

0293In another embodiment, the inhibitor is a compound of formula XXIII <chemistry id="CHEM-US-00069" num="69"><img file="US2007004635A1_D0068.tif" /></chemistry><br /> a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0294R⁰is a bond or difluoromethylene;

0295R¹is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;

0296R²and R⁹are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;

0297R3, R5 and R7 are each independently: <ul id="ul0003" list-style="none"><li id="ul0003-0001" num="0000"><ul id="ul0004" list-style="none"><li id="ul0004-0001" num="0298"> optionally substituted (1, 1- or 1,2-)cycloalkylene; or </li><li id="ul0004-0002" num="0299"> optionally substituted (1,1- or 1,2-) heterocyclylene; or </li><li id="ul0004-0003" num="0300"> methylene or ethylene), substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group, and wherein the methylene or ethylene is further optionally substituted with an aliphatic group substituent; or; </li></ul></li></ul>

0301R4, R6, R8 and R¹⁰are each independently hydrogen or optionally substituted aliphatic group; <chemistry id="CHEM-US-00070" num="70"><img file="US2007004635A1_D0069.tif" /></chemistry><br /> is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R⁹-L-(N(R⁸)—R⁷—C(O)—)_nN(R⁶)—R⁵—C(O)—N moiety and to which the —C(O)—N(R⁴)—R³—C(O)C(O)NR²R¹moiety is attached; L is —C(O)—, —OC(O)—, —NR¹⁰C(O)—, —S(0)₂—, or —NR¹⁰S(0)₂—; and n is 0 or 1,

0302provided when <chemistry id="CHEM-US-00071" num="71"><img file="US2007004635A1_D0070.tif" /></chemistry><br /> is substituted <chemistry id="CHEM-US-00072" num="72"><img file="US2007004635A1_D0071.tif" /></chemistry><br /> then L is —OC(O)— and R⁹is optionally substituted aliphatic; or at least one of R³, R⁵and R⁷is ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group and wherein the ethylene is further optionally substituted with an aliphatic group substituent; or R⁴is optionally substituted aliphatic.

0303In another embodiment, the inhibitor is a compound of formula (XXIV) <chemistry id="CHEM-US-00073" num="73"><img file="US2007004635A1_D0072.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:

0304W is: <chemistry id="CHEM-US-00074" num="74"><img file="US2007004635A1_D0073.tif" /></chemistry>

0305m is 0 or 1;

0306each R¹is hydroxy, alkoxy, or aryloxy, or each R¹is an oxygen atom and together with the boron, to which they are each bound, form a 5-7 membered ring, wherein the ring atoms are carbon, nitrogen, or oxygen;

0307each R²is independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl, or two R²groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a 5-7 membered monocyclic heterocyclic ring system; wherein any R²carbon atom is optionally substituted with J;

0308J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J¹groups;

0309J¹is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino, alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoaikyl, halo, cyano, nitro, formyl, sulfonyl, or sulfonamido;

0310L is alkyl, alkenyl, or alkynyl, wherein any hydrogen is optionally substituted with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom is optionally substituted with sulfhydryl or hydroxy;

0311A¹is a bond;

0312R⁴is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups;

0313R⁵and R⁶are independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionally substituted with 1-3 J groups;

0314X is a bond, —C(H)(R7)-, -0-, —S—, or —N(R8)-;

0315R⁷is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, and is optionally substititued with 1-3 J groups;

0316R⁸is hydrogen alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aralkanoyl, heterocyclanoyl, heteroaralkanoyl, —C(O)R¹⁴, —SO₂R¹⁴, or carboxamido, and is optionally substititued with 1-3 J groups; or R⁸and Z, together with the atoms to which they are bound, form a nitrogen containing mono- or bicyclic ring system optionally substituted with 1-3 J groups;

0317R¹⁴is alkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl, or heteroaralkyl;

0318Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, —S(0)₂-, or —S(O)(NR⁷)—, wherein R⁷is as defined above;

0319Z is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —OR², or —N(R²)₂, wherein any carbon atom is optionally substituted with J, wherein R²is as defined above;

0320A²is a bond or <chemistry id="CHEM-US-00075" num="75"><img file="US2007004635A1_D0074.tif" /></chemistry>

0321R⁹is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups;

0322M is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl, optionally substituted by 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom;

0323V is a bond, —CH₂—, —C(H)(R¹¹)—, -0-, —S—, or —N(R¹¹)—;

0324R¹¹is hydrogen or C_1-3alkyl;

0325K is a bond, -0-, —S—, —C(O)—, —S(O)—, —S(0)₂-, or —S(O)(NR¹¹)—, wherein R¹¹is as defined above;

0326T is —R², -alkyl-R, -alkenyl-R¹², -alkynyl-R¹², —OR¹², —N(R¹²)2, —C(O)R¹², —C(═NOalkyl)R¹², or <chemistry id="CHEM-US-00076" num="76"><img file="US2007004635A1_D0075.tif" /></chemistry>

0327R¹²is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylidenyl, or heterocycloalkylidenyl, and is optionally substituted with 1-3 J groups, or a first R¹²and a second R¹², together with the nitrogen to which they are bound, form a mono- or bicyclic ring system optionally substituted by 1-3 J groups;

0328R¹⁰is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 hydrogens J groups;

0329R¹⁵is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally substituted with 1-3 J groups; and

0330R¹⁶is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.

0331In another embodiment, the inhibitor is a compound of formula XXV <chemistry id="CHEM-US-00077" num="77"><img file="US2007004635A1_D0076.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof;

0332wherein

0333E represents CHO or B(OH)2;

0334R¹represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, heteroaryllower alkyl, lower alkenyl or lower alkynyl;

0335R²represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower alkyl; and

0336R³represents hydrogen or lower alkyl;

0337or R²and R³together represent di- or trimethylene optionally substituted by hydroxy;

0338R⁴represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryllower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lower cycloalkyl;

0339R⁵represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl or lower cycloalkyl;

0340R⁶represents hydrogen or lower alkyl;

0341R⁷represent lower alkyl, hydroxydower alkyl, carboxylower alkyl, aryl-iower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl;

0342R⁸represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl or aryl-lower alkyl; and

0343R⁹represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl.

0344In another embodiment, the inhibitor is a compound of formula XXVI <chemistry id="CHEM-US-00078" num="78"><img file="US2007004635A1_D0077.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof; wherein

0345B is an acyl derivative of formula R₁₁—C(O)— wherein R₁₁is CI-10 alkyl optionally substituted with carboxyl; or R₁₁is C₆or C₁₀aryl or C_7-16aralkyl optionally substituted with a C_1-6alkyl;

0346a is 0 or 1;

0347R₆, when present, is carboxy(lower)alkyl;

0348b is 0 or 1;

0349R₅, when present, is C_1-6alkyl, or carboxy(lower)alkyl;

0350Y is H or C_1-6alkyl;

0351R₄is C_1-10alkyl; C_3-10cycloalkyl;

0352R₃is C1-10 alkyl; C_3-10cycloalkyl;

0353W is a group of formula: <chemistry id="CHEM-US-00079" num="79"><img file="US2007004635A1_D0078.tif" /></chemistry>

0354wherein R₂is C-_1-10alkyl or C_3-7cycloalkyl optionally substituted with carboxyl; C₆or C₁₀aryl; or C_7-16aralkyl; or

0355W is a group of formula: <chemistry id="CHEM-US-00080" num="80"><img file="US2007004635A1_D0079.tif" /></chemistry>

0356wherein X is CH or N; and

0357R₂′ is C_3-4alkylene that joins X to form a 5- or 6-membered ring, said ring optionally substituted with OH; SH; NH2; carboxyl; R₁₂; OR₁₂, SR₁₂, NHR₁₂or NR₁₂R₁₂′ wherein R₁₂and R₁₂′ are independently:

0358cyclic C_3-16alkyl or acyclic C_1-16alkyl or cyclic C_3-16alkenyl or acyclic C_2-16alkenyl, said alkyl or alkenyl optionally substituted with NH₂, OH, SH, halo, or carboxyl; said alkyl or alkenyl optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N; or

0359R₁₂and R₁₂′ are independently C₆or C₁₀aryl or C_7-16aralkyl optionally substituted with C_1-6alkyl, NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl; said aryl or aralkyl optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N;

0360said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with a second 5-, 6-, or 7-membered ring to form a cyclic system or heterocycle, said second ring being optionally substituted with NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl; C₆or C₁₀aryl, or heterocycle; said second ring optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N;

0361Q is a group of the formula: <chemistry id="CHEM-US-00081" num="81"><img file="US2007004635A1_D0080.tif" /></chemistry>

0362wherein Z is CH or N;

0363X is 0 or S;

0364R₁is H, C_1-6alkyl or C_1-6alkenyl both optionally substituted with thio or halo;

0365and

0366when Z is CH, then R₁₃is H; CF₃; CF₂CF₃; CH₂—R₁₄; CH(F)R₁₄; CF₂—R₁₄; NR₁₄R₁₄′; S—R₁₄; or C0-NH—R₁₄wherein R₁₄and R₁₄′ are independently hydrogen, cyclic C_3-10alkyl or acyclic C_1-10alkyl or cyclic C_3-10alkenyl or acyclic C_2-10said alkyl or alkenyl optionally substituted with NH₂, OH, SH, halo or carboxyl; said alkyl or alkenyl optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N; or

0367R₁₄and R₁₄′ are independently C₆or C₁₀aryl or C_7-16aralkyl optionally substituted with C_1-6alkyl, NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl or substituted with a further C_3-7cycloalkyl, C₆or C₁₀aryl, or heterocycle; said aryl or aralkyl optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N;

0368said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with a second 5-, 6-, or 7-membered ring to form a cyclic system or heterocycle, said second ring being optionally substituted with NH₂, OH, SH, halo, carboxyl or carboxy(lower)alkyl or substituted with a further C_3-7cycloalkyl, C₆or C₁₀aryl, or heterocycle; said second ring optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N;

0369or R₁₄and R₁₄′ are independently C_1-4alkyl which when joined together with N form a 3 to 6-membered nitrogen-containing ring which is optionally fused with a further C_3-7cycloalkyl, C₆or C₁₀aryl or heterocycle;

0370with the proviso that when Z is CH, then R₁₃is not an α-amino acid or an ester thereof;

0371when Z is N, then R₁₃is H; carboxy; C_1-6alkyl optionally substituted with carboxy; CH₂—R₁₄; CHR₁₄R₁₄′; CH(F)—R₁₄; O—R₁₄; NR₁₄R₁₄′ or S—R₁₄wherein R₁₄and R₁₄′ are as defined above; or

0372Q is a phosphonate group of the formula: <chemistry id="CHEM-US-00082" num="82"><img file="US2007004635A1_D0081.tif" /></chemistry>

0373wherein R₁₅and R_1-6are independently C_6-20aryloxy; and R₁is as defined above.

0374In the above-shown structure of the compound of Formula XXVI, the terms P6, P5, P4, P3, P2 and P1 denote the respective amino acid moieties as is conventionally known to those skilled in the art. Thus, the actual structure of the compound of Formula XXVI is: <chemistry id="CHEM-US-00083" num="83"><img file="US2007004635A1_D0082.tif" /></chemistry>

0375In another embodiment, the compound is selected from the group consisting of: <chemistry id="CHEM-US-00084" num="84"><img file="US2007004635A1_D0083.tif" /></chemistry><chemistry id="CHEM-US-00085" num="85"><img file="US2007004635A1_D0084.tif" /></chemistry><chemistry id="CHEM-US-00086" num="86"><img file="US2007004635A1_D0085.tif" /></chemistry><chemistry id="CHEM-US-00087" num="87"><img file="US2007004635A1_D0086.tif" /></chemistry><chemistry id="CHEM-US-00088" num="88"><img file="US2007004635A1_D0087.tif" /></chemistry><chemistry id="CHEM-US-00089" num="89"><img file="US2007004635A1_D0088.tif" /></chemistry><chemistry id="CHEM-US-00090" num="90"><img file="US2007004635A1_D0089.tif" /></chemistry><chemistry id="CHEM-US-00091" num="91"><img file="US2007004635A1_D0090.tif" /></chemistry><chemistry id="CHEM-US-00092" num="92"><img file="US2007004635A1_D0091.tif" /></chemistry><chemistry id="CHEM-US-00093" num="93"><img file="US2007004635A1_D0092.tif" /></chemistry><chemistry id="CHEM-US-00094" num="94"><img file="US2007004635A1_D0093.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0376Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.”

BRIEF DESCRIPTION OF THE FIGURES

0377<figref idref="DRAWINGS">FIG. 1</figref> is a graph showing the effect on HCV-RNA viral load after the compound of Formula la is administered to HCV Genotype 1 non-responder patients for 14 days;

0378<figref idref="DRAWINGS">FIG. 2</figref> is a graph showing mean HCV-RNA changes after 7 days of treatment with 200 mg TID of the compound of Formula la alone, or weekly treatment with PEG-Intron (1.5 mcg/kg/wk) alone for 2 weeks, or combination therapy for 14 days; and <figref idref="DRAWINGS">FIG. 3</figref> is a flow diagram which identifies a 6-arm screening study for “non-responders” as defined herein.

DETAILED DESCRIPTION

0379The present invention provides a method of treating, preventing or ameliorating one or more symptoms associated with hepatitis C virus (HCV) in a patient in whom either the HCV is of Genotype 1 and/or the patient was previously treated with interferon and the previous interferon therapy was ineffective to treat the one or more symptoms associated with HCV, comprising administering to such a patient an effective amount of at least one compound of formulae I-XXVI set forth below either alone or in simultaneous or sequential combination with (i) an interferon or pegylated interferon and/or (ii) an antiviral agent including but not limited to ribavirin and/or an immunomodulatory agent. The inventive methods are particularly useful to treat “non-responder” patients for whom “non-responder” is defined to mean “failure to achieve 2 log drop versus baseline viral load despite at least twelve weeks of PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day).” In practice, the application of this definition accommodates a 0.5 log variation of the definition, so that if an individual patient achieves as high as a 2.5 log drop versus baseline, or anywhere between 2 and 2.5 log drop versus baseline viral load despite at least twelve weeks of PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day), it is within the discretion of the investigator to denominate the patient as a “non-responder” on a case by case basis.

0380The treatments of the present invention are useful for treating patients for whom treatment for one or more symptoms associated with HCV Genotype 1 (Genotypes 1a or 1b) is indicated, and/or patients for whom previous interferon therapy has proved ineffective. The methods for treating such patients, as described above, embrace the administration of an effective amount of at least one of the compounds described hereinabove either alone or in simultaneous or sequential combination with interferon and/or an antiviral agent including but not limited to ribavirin and/or an immunomodulatory agent. The inventive methods are particularly useful to treat “non-responder” patients for whom “non-responder” is defined to mean “a patient who experiences failure to achieve at least about a 2 log drop versus baseline viral load despite at least twelve weeks' treatment with PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day).”

0381By “ineffective,” in the context of patients having had previous interferon therapy which proved to be ineffective, the definition of “ineffective” is failure to achieve at least about a 2 log drop versus baseline viral load despite at least twelve weeks of therapy including interferon alone or in combination with other active agents in which the interferon is administered at about 1.5 mcg/kg/week. This definition of “ineffective” further embraces that if the interferon is given in combination therapy, the combination active agent may be ribavirin, or a wide variety of other agents, as well as either the presence or absence of viral rebound after the treatment period deemed to be “ineffective.” The data particularly suggest that the compound of Formula la is effective to restore the ability of interferon to reduce the one or more symptoms associated with HCV even in patients in whom previous interferon therapy was ineffective, when the compound of Formula Ia and interferon were given in combination.

0382As a general matter, the HCV protease inhibitors of the present invention can be given alone—for example as formulated above-or in combination with other agents. As non-exclusive examples, the following describes certain dosing possibilities and recommended dosages for the HCV protease inhibitors given alone or in combination with other active agents. The HCV protease inhibitor can be administered in combination with interferon alpha, PEG-interferon alpha conjugates or consensus interferon simultaneously or sequentially (i.e., concurrently or consecutively) at certain below-described recommended dosages. The commercially available forms of interferon alpha include interferon alpha 2a and interferon alpha 2b and also pegylated forms of both aforementioned interferon alphas. The recommended dosage of INTRON-A interferon alpha 2b (commercially available from Schering-Plough Corp.) as administered by subcutaneous injection at 3MIU(12 mcg)/0.5 mL/TIW is for 24 weeks or 48 weeks for first time treatment. The recommended dosage of PEG-INTRON interferon alpha 2b pegylated (commercially available from Schering-Plough Corp.) as administered by subcutaneous injection at 1.5 mcg/kg/week, within a range of 40 to 150 mcg/week, is for at least 24 weeks. The recommended dosage of ROFERON A inteferon alpha 2a (commercially available from Hioffmann-La Roche) as administered by subcutaneous or intramuscular injection at 3MIU(11.1 mcg/mL)/TIW is for at least 48 to 52 weeks, or alternatively 6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks. The recommended dosage of PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La Roche) as administered by subcutaneous injection at 180 mcg/1 mL or 180 mcg/0.5 mL is once a week for at least 24 weeks. The recommended dosage of INFERGEN interferon alphacon-1 (commercially available from Amgen) as administered by subcutaneous injection at 9 mcg/TIW is for 24 weeks for first time treatment and up to 15 mcg/TIW for 24 weeks for non-responsive or relapse treatment. Optionally, ribavirin, a synthetic nucleoside analogue with activity against a broad spectrum of viruses including HCV, can be included in combination with the interferon and the HCV protease inhibitor. The recommended dosage of ribavirin is in a range from 600 to 1400 mg per day for at least 24 weeks (commercially available as REBETOL ribavirin from Schering-Plough or COPEGUS ribavirin from Hoffmann-La Roche).

0383The present methods thus embrace treating the above described patients with at least one HCV protease inhibitor of formulae I-XXVI, with the HCV protease inhibitor being administered alone or in combination with one or more other active agents. Most generally, when combination therapy is used the combination therapy will include, in addition to the HCV protease inhibitor active agent, one or more of an antiviral agent and/or an immunomodulatory agent and specifically can include interferon (in the various forms as described above) and/or ribavirin.

0384In one embodiment, the patients include those having symptoms associated with HCV of Genotype 1, namely, Genotype 1a or Genotype 1b. The genotypes 1a and 1b of HCV are both well known to one skilled in the art at this writing. As a non-limiting example, Holland, J. et al., “Hepatitis C Genotyping by Direct Sequencing of the Product . . . ,” Pathology, vol. 30, pp.192-195 (1998), identify in Table 2 that the sequences of Genotype 1a and Genotype 1b of HCV are already well known as corroborated by the Genbank/EMBL identification provided for each Genotype, respectively, namely, M62321 and D90208. Other literature provides comparable classification information regarding HCV genotypes 1a and 1b, including without limitation Simmonds, K A et al., J. Clin. Microbiol., 31(6), 1493-1503 (1993). In theory, without any intention of being bound by the theory, either Genotype 1a or Genotype 1b HCV and/or patients infected therewith are in some way generally often (but not always) resistant to interferon therapy either given alone or in combination with ribavirin. It should be noted, however, that some patients in whom interferon therapy is ineffective and/or some “non-responder” patients do not have symptoms associated with HCV Genotype 1 (1a/1b). Conversely, some patients in whom association with HCV Genotype 1 (1a/1b) is noted do not evince an ineffective or non-response reaction to interferon therapy at all. For this reason, the present invention must be understood to be applicable to patients in whom either or both of the following conditions apply: one or more symptoms associated with HCV Genotype 1 (i.e., Genotype 1a or Genotype 1b) and/or the ineffective nature of previous interferon therapy.

0385Sample descriptions of various embodiments of the above-described therapies include, without limitation, as to the targeted patient described above:

03861. Administering an HCV protease inhibitor of the present invention to a patient in whom previously administered interferon therapy was ineffective;

03872. Administering an HCV protease inhibitor to a patient in whom previously administered combined interferon/ribavirin therapy was ineffective;

03883. Administering an HCV protease inhibitor to a patient who previously exhibited one or more symptoms-or was susceptible to one or more symptoms-associated with either HCV Genotype l a or HCV Genotype 1b;

03894. Administering an HCV protease inhibitor to a patient for the purpose of decreasing viral load by 0.5-14 log versus baseline after 24 weeks of treatment, more preferably after twelve weeks of treatment, more preferably to achieve a 5-8 log drop and most preferably to achieve undetectible levels of HCV, with “undetectible” being defined as &lt;100 copies of the HCV per mL of patient tissue or blood;

03905. Administering an HCV protease inhibitor to a patient for the purpose of decreasing viral load by 1-4 logs versus baseline, although 2 log decrease or greater is preferred;

03916. Administering an HCV protease inhibitor to a patient alone or in combination with other therapeutic agents in a dosing regimen involve once, twice, three or four times daily administration in doses of up to 1000 mg and more typically 100, 200 or 400 mg per dose;

03927. Administering an HCV protease inhibitor to a patient in combination (simultaneously or sequentially) with interferon for the purpose of restoring interferon response in the patient and further wherein the interferon is administered in the amount of 40-250 mcg per week, more preferably 40-150 mcg per week, most preferably 1.5 mcg/kg/week and further wherein in addition to the interferon an antiviral agent or an immunomodulatory agent is administered as well; and

03938. Administering an HCV protease inhibitor to a patient in combination (simultaneously or sequentially) with both interferon and ribavirin in the dosages of 40-250 mcg per week and 600-1400 mg per day, respectively, and more preferably 1.5 mcg/kg/week interferon and 10.6 mg/kg/day ribavirin.

0394Suitable compounds of formula I are disclosed in PCT International publication WO03/062265 published Jul. 31, 2003. Non-limiting examples of certain compounds disclosed in this publication include: <chemistry id="CHEM-US-00095" num="95"><img file="US2007004635A1_D0094.tif" /></chemistry><chemistry id="CHEM-US-00096" num="96"><img file="US2007004635A1_D0095.tif" /></chemistry><chemistry id="CHEM-US-00097" num="97"><img file="US2007004635A1_D0096.tif" /></chemistry><chemistry id="CHEM-US-00098" num="98"><img file="US2007004635A1_D0097.tif" /></chemistry><chemistry id="CHEM-US-00099" num="99"><img file="US2007004635A1_D0098.tif" /></chemistry><chemistry id="CHEM-US-00100" num="100"><img file="US2007004635A1_D0099.tif" /></chemistry><chemistry id="CHEM-US-00101" num="101"><img file="US2007004635A1_D0100.tif" /></chemistry><chemistry id="CHEM-US-00102" num="102"><img file="US2007004635A1_D0101.tif" /></chemistry><chemistry id="CHEM-US-00103" num="103"><img file="US2007004635A1_D0102.tif" /></chemistry><chemistry id="CHEM-US-00104" num="104"><img file="US2007004635A1_D0103.tif" /></chemistry><chemistry id="CHEM-US-00105" num="105"><img file="US2007004635A1_D0104.tif" /></chemistry><chemistry id="CHEM-US-00106" num="106"><img file="US2007004635A1_D0105.tif" /></chemistry><chemistry id="CHEM-US-00107" num="107"><img file="US2007004635A1_D0106.tif" /></chemistry><chemistry id="CHEM-US-00108" num="108"><img file="US2007004635A1_D0107.tif" /></chemistry><chemistry id="CHEM-US-00109" num="109"><img file="US2007004635A1_D0108.tif" /></chemistry><chemistry id="CHEM-US-00110" num="110"><img file="US2007004635A1_D0109.tif" /></chemistry><chemistry id="CHEM-US-00111" num="111"><img file="US2007004635A1_D0110.tif" /></chemistry><chemistry id="CHEM-US-00112" num="112"><img file="US2007004635A1_D0111.tif" /></chemistry><chemistry id="CHEM-US-00113" num="113"><img file="US2007004635A1_D0112.tif" /></chemistry><chemistry id="CHEM-US-00114" num="114"><img file="US2007004635A1_D0113.tif" /></chemistry><chemistry id="CHEM-US-00115" num="115"><img file="US2007004635A1_D0114.tif" /></chemistry><chemistry id="CHEM-US-00116" num="116"><img file="US2007004635A1_D0115.tif" /></chemistry><chemistry id="CHEM-US-00117" num="117"><img file="US2007004635A1_D0116.tif" /></chemistry><chemistry id="CHEM-US-00118" num="118"><img file="US2007004635A1_D0117.tif" /></chemistry><chemistry id="CHEM-US-00119" num="119"><img file="US2007004635A1_D0118.tif" /></chemistry><chemistry id="CHEM-US-00120" num="120"><img file="US2007004635A1_D0119.tif" /></chemistry><chemistry id="CHEM-US-00121" num="121"><img file="US2007004635A1_D0120.tif" /></chemistry><chemistry id="CHEM-US-00122" num="122"><img file="US2007004635A1_D0121.tif" /></chemistry><chemistry id="CHEM-US-00123" num="123"><img file="US2007004635A1_D0122.tif" /></chemistry><chemistry id="CHEM-US-00124" num="124"><img file="US2007004635A1_D0123.tif" /></chemistry><chemistry id="CHEM-US-00125" num="125"><img file="US2007004635A1_D0124.tif" /></chemistry><chemistry id="CHEM-US-00126" num="126"><img file="US2007004635A1_D0125.tif" /></chemistry><chemistry id="CHEM-US-00127" num="127"><img file="US2007004635A1_D0126.tif" /></chemistry><chemistry id="CHEM-US-00128" num="128"><img file="US2007004635A1_D0127.tif" /></chemistry><chemistry id="CHEM-US-00129" num="129"><img file="US2007004635A1_D0128.tif" /></chemistry><chemistry id="CHEM-US-00130" num="130"><img file="US2007004635A1_D0129.tif" /></chemistry><chemistry id="CHEM-US-00131" num="131"><img file="US2007004635A1_D0130.tif" /></chemistry><chemistry id="CHEM-US-00132" num="132"><img file="US2007004635A1_D0131.tif" /></chemistry><chemistry id="CHEM-US-00133" num="133"><img file="US2007004635A1_D0132.tif" /></chemistry><chemistry id="CHEM-US-00134" num="134"><img file="US2007004635A1_D0133.tif" /></chemistry><chemistry id="CHEM-US-00135" num="135"><img file="US2007004635A1_D0134.tif" /></chemistry><chemistry id="CHEM-US-00136" num="136"><img file="US2007004635A1_D0135.tif" /></chemistry><chemistry id="CHEM-US-00137" num="137"><img file="US2007004635A1_D0136.tif" /></chemistry><chemistry id="CHEM-US-00138" num="138"><img file="US2007004635A1_D0137.tif" /></chemistry><chemistry id="CHEM-US-00139" num="139"><img file="US2007004635A1_D0138.tif" /></chemistry><chemistry id="CHEM-US-00140" num="140"><img file="US2007004635A1_D0139.tif" /></chemistry><chemistry id="CHEM-US-00141" num="141"><img file="US2007004635A1_D0140.tif" /></chemistry><chemistry id="CHEM-US-00142" num="142"><img file="US2007004635A1_D0141.tif" /></chemistry><chemistry id="CHEM-US-00143" num="143"><img file="US2007004635A1_D0142.tif" /></chemistry><chemistry id="CHEM-US-00144" num="144"><img file="US2007004635A1_D0143.tif" /></chemistry><chemistry id="CHEM-US-00145" num="145"><img file="US2007004635A1_D0144.tif" /></chemistry><chemistry id="CHEM-US-00146" num="146"><img file="US2007004635A1_D0145.tif" /></chemistry><chemistry id="CHEM-US-00147" num="147"><img file="US2007004635A1_D0146.tif" /></chemistry><chemistry id="CHEM-US-00148" num="148"><img file="US2007004635A1_D0147.tif" /></chemistry><chemistry id="CHEM-US-00149" num="149"><img file="US2007004635A1_D0148.tif" /></chemistry><chemistry id="CHEM-US-00150" num="150"><img file="US2007004635A1_D0149.tif" /></chemistry><chemistry id="CHEM-US-00151" num="151"><img file="US2007004635A1_D0150.tif" /></chemistry><chemistry id="CHEM-US-00152" num="152"><img file="US2007004635A1_D0151.tif" /></chemistry><chemistry id="CHEM-US-00153" num="153"><img file="US2007004635A1_D0152.tif" /></chemistry><chemistry id="CHEM-US-00154" num="154"><img file="US2007004635A1_D0153.tif" /></chemistry><chemistry id="CHEM-US-00155" num="155"><img file="US2007004635A1_D0154.tif" /></chemistry><chemistry id="CHEM-US-00156" num="156"><img file="US2007004635A1_D0155.tif" /></chemistry><chemistry id="CHEM-US-00157" num="157"><img file="US2007004635A1_D0156.tif" /></chemistry><chemistry id="CHEM-US-00158" num="158"><img file="US2007004635A1_D0157.tif" /></chemistry><chemistry id="CHEM-US-00159" num="159"><img file="US2007004635A1_D0158.tif" /></chemistry><chemistry id="CHEM-US-00160" num="160"><img file="US2007004635A1_D0159.tif" /></chemistry><chemistry id="CHEM-US-00161" num="161"><img file="US2007004635A1_D0160.tif" /></chemistry><chemistry id="CHEM-US-00162" num="162"><img file="US2007004635A1_D0161.tif" /></chemistry><chemistry id="CHEM-US-00163" num="163"><img file="US2007004635A1_D0162.tif" /></chemistry><chemistry id="CHEM-US-00164" num="164"><img file="US2007004635A1_D0163.tif" /></chemistry><chemistry id="CHEM-US-00165" num="165"><img file="US2007004635A1_D0164.tif" /></chemistry><chemistry id="CHEM-US-00166" num="166"><img file="US2007004635A1_D0165.tif" /></chemistry><chemistry id="CHEM-US-00167" num="167"><img file="US2007004635A1_D0166.tif" /></chemistry><chemistry id="CHEM-US-00168" num="168"><img file="US2007004635A1_D0167.tif" /></chemistry><chemistry id="CHEM-US-00169" num="169"><img file="US2007004635A1_D0168.tif" /></chemistry><chemistry id="CHEM-US-00170" num="170"><img file="US2007004635A1_D0169.tif" /></chemistry><chemistry id="CHEM-US-00171" num="171"><img file="US2007004635A1_D0170.tif" /></chemistry><chemistry id="CHEM-US-00172" num="172"><img file="US2007004635A1_D0171.tif" /></chemistry><chemistry id="CHEM-US-00173" num="173"><img file="US2007004635A1_D0172.tif" /></chemistry><chemistry id="CHEM-US-00174" num="174"><img file="US2007004635A1_D0173.tif" /></chemistry><chemistry id="CHEM-US-00175" num="175"><img file="US2007004635A1_D0174.tif" /></chemistry><chemistry id="CHEM-US-00176" num="176"><img file="US2007004635A1_D0175.tif" /></chemistry><chemistry id="CHEM-US-00177" num="177"><img file="US2007004635A1_D0176.tif" /></chemistry><chemistry id="CHEM-US-00178" num="178"><img file="US2007004635A1_D0177.tif" /></chemistry><chemistry id="CHEM-US-00179" num="179"><img file="US2007004635A1_D0178.tif" /></chemistry><chemistry id="CHEM-US-00180" num="180"><img file="US2007004635A1_D0179.tif" /></chemistry><chemistry id="CHEM-US-00181" num="181"><img file="US2007004635A1_D0180.tif" /></chemistry><chemistry id="CHEM-US-00182" num="182"><img file="US2007004635A1_D0181.tif" /></chemistry><chemistry id="CHEM-US-00183" num="183"><img file="US2007004635A1_D0182.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0395In one embodiment, the HCV protease inhibitor is selected from the group consisting of <chemistry id="CHEM-US-00184" num="184"><img file="US2007004635A1_D0183.tif" /></chemistry><br /> and pharmaceutically acceptable salts or solvates thereof.

0396The compound of formula la has recently been separated into its isomer/diastereomers of Formulas lb and Ic. In one embodiment, the HCV protease inhibitor is selected from the group consisting of the compound of Formula Ic and pharmaceutically acceptable salts or solvates thereof as a potent inhibitor of HCV NS3 serine protease. <chemistry id="CHEM-US-00185" num="185"><img file="US2007004635A1_D0184.tif" /></chemistry><br /> The chemical name of the compound of Formula Ic is (1R,2S,5S)-N-[(t S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide.

0397Processes for making compounds of Formula I are disclosed in U.S. Patent Publication Nos. 2005/0059648, 2005/0020689 and 2005/0059800, incorporated by reference herein.

0398Non-limiting examples of suitable compounds of formula II and methods of making the same are disclosed in WO02/08256 and in U.S. Pat. No. 6,800,434, at col. 5 through col. 247, incorporated herein by reference.

0399Non-limiting examples of suitable compounds of formula IlIl and methods of making the same are disclosed in International Patent Publication WO02/08187 and in U.S. Patent Publication 2002/0160962 at page 3, paragraph 22 through page 132, incorporated herein by reference.

0400Non-limiting examples of suitable compounds of formula IV and methods of making the same are disclosed in International Patent Publication WO03/062228 and in U.S. Patent Publication 2003/0207861 at page 3, paragraph 25 through page 26, incorporated herein by reference.

0401Non-limiting examples of suitable compounds of formula V and methods of making the same are disclosed in U.S. patent application Ser. No. 10/948,367 filed Sep. 23, 2004, and the preparation of the compounds are detailed in the experimental section of this application set forth hereinbelow.

0402Non-limiting examples of suitable compounds of formula VI and methods of making the same are disclosed in U.S. Patent Publication Ser. No. 2005/0085425 at page 3, paragraph 0023 through page 139, incorporated herein by reference.

0403Compounds of formula VII-IX are disclosed in U.S. Patent Application Ser. No. 10/993,394 filed Nov. 19, 2004, and the preparation of the compounds are detailed in the experimental section of this application set forth hereinbelow.

0404Non-limiting examples of certain compounds of formula VII disclosed in U.S. patent application Ser. No. 10/993,394 are: <chemistry id="CHEM-US-00186" num="186"><img file="US2007004635A1_D0185.tif" /></chemistry><chemistry id="CHEM-US-00187" num="187"><img file="US2007004635A1_D0186.tif" /></chemistry><chemistry id="CHEM-US-00188" num="188"><img file="US2007004635A1_D0187.tif" /></chemistry><chemistry id="CHEM-US-00189" num="189"><img file="US2007004635A1_D0188.tif" /></chemistry><chemistry id="CHEM-US-00190" num="190"><img file="US2007004635A1_D0189.tif" /></chemistry><chemistry id="CHEM-US-00191" num="191"><img file="US2007004635A1_D0190.tif" /></chemistry><chemistry id="CHEM-US-00192" num="192"><img file="US2007004635A1_D0191.tif" /></chemistry><chemistry id="CHEM-US-00193" num="193"><img file="US2007004635A1_D0192.tif" /></chemistry><chemistry id="CHEM-US-00194" num="194"><img file="US2007004635A1_D0193.tif" /></chemistry><chemistry id="CHEM-US-00195" num="195"><img file="US2007004635A1_D0194.tif" /></chemistry><chemistry id="CHEM-US-00196" num="196"><img file="US2007004635A1_D0195.tif" /></chemistry><chemistry id="CHEM-US-00197" num="197"><img file="US2007004635A1_D0196.tif" /></chemistry><chemistry id="CHEM-US-00198" num="198"><img file="US2007004635A1_D0197.tif" /></chemistry><chemistry id="CHEM-US-00199" num="199"><img file="US2007004635A1_D0198.tif" /></chemistry><chemistry id="CHEM-US-00200" num="200"><img file="US2007004635A1_D0199.tif" /></chemistry><chemistry id="CHEM-US-00201" num="201"><img file="US2007004635A1_D0200.tif" /></chemistry><chemistry id="CHEM-US-00202" num="202"><img file="US2007004635A1_D0201.tif" /></chemistry><chemistry id="CHEM-US-00203" num="203"><img file="US2007004635A1_D0202.tif" /></chemistry><chemistry id="CHEM-US-00204" num="204"><img file="US2007004635A1_D0203.tif" /></chemistry><chemistry id="CHEM-US-00205" num="205"><img file="US2007004635A1_D0204.tif" /></chemistry><chemistry id="CHEM-US-00206" num="206"><img file="US2007004635A1_D0205.tif" /></chemistry><chemistry id="CHEM-US-00207" num="207"><img file="US2007004635A1_D0206.tif" /></chemistry><chemistry id="CHEM-US-00208" num="208"><img file="US2007004635A1_D0207.tif" /></chemistry><chemistry id="CHEM-US-00209" num="209"><img file="US2007004635A1_D0208.tif" /></chemistry><chemistry id="CHEM-US-00210" num="210"><img file="US2007004635A1_D0209.tif" /></chemistry><chemistry id="CHEM-US-00211" num="211"><img file="US2007004635A1_D0210.tif" /></chemistry><chemistry id="CHEM-US-00212" num="212"><img file="US2007004635A1_D0211.tif" /></chemistry><chemistry id="CHEM-US-00213" num="213"><img file="US2007004635A1_D0212.tif" /></chemistry><chemistry id="CHEM-US-00214" num="214"><img file="US2007004635A1_D0213.tif" /></chemistry><chemistry id="CHEM-US-00215" num="215"><img file="US2007004635A1_D0214.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0405Nonlimiting examples of certain compounds of formula VIII disclosed in U.S. patent application Ser. No. 10/993,394 are: <chemistry id="CHEM-US-00216" num="216"><img file="US2007004635A1_D0215.tif" /></chemistry><chemistry id="CHEM-US-00217" num="217"><img file="US2007004635A1_D0216.tif" /></chemistry><chemistry id="CHEM-US-00218" num="218"><img file="US2007004635A1_D0217.tif" /></chemistry><chemistry id="CHEM-US-00219" num="219"><img file="US2007004635A1_D0218.tif" /></chemistry><chemistry id="CHEM-US-00220" num="220"><img file="US2007004635A1_D0219.tif" /></chemistry><chemistry id="CHEM-US-00221" num="221"><img file="US2007004635A1_D0220.tif" /></chemistry><chemistry id="CHEM-US-00222" num="222"><img file="US2007004635A1_D0221.tif" /></chemistry><chemistry id="CHEM-US-00223" num="223"><img file="US2007004635A1_D0222.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0406Nonlimiting examples of certain compounds of formula IX disclosed in U.S. patent application Ser. No. 10/993,394 are: <chemistry id="CHEM-US-00224" num="224"><img file="US2007004635A1_D0223.tif" /></chemistry><chemistry id="CHEM-US-00225" num="225"><img file="US2007004635A1_D0224.tif" /></chemistry><chemistry id="CHEM-US-00226" num="226"><img file="US2007004635A1_D0225.tif" /></chemistry><chemistry id="CHEM-US-00227" num="227"><img file="US2007004635A1_D0226.tif" /></chemistry><chemistry id="CHEM-US-00228" num="228"><img file="US2007004635A1_D0227.tif" /></chemistry><chemistry id="CHEM-US-00229" num="229"><img file="US2007004635A1_D0228.tif" /></chemistry><chemistry id="CHEM-US-00230" num="230"><img file="US2007004635A1_D0229.tif" /></chemistry><chemistry id="CHEM-US-00231" num="231"><img file="US2007004635A1_D0230.tif" /></chemistry><chemistry id="CHEM-US-00232" num="232"><img file="US2007004635A1_D0231.tif" /></chemistry><chemistry id="CHEM-US-00233" num="233"><img file="US2007004635A1_D0232.tif" /></chemistry><chemistry id="CHEM-US-00234" num="234"><img file="US2007004635A1_D0233.tif" /></chemistry><chemistry id="CHEM-US-00235" num="235"><img file="US2007004635A1_D0234.tif" /></chemistry><chemistry id="CHEM-US-00236" num="236"><img file="US2007004635A1_D0235.tif" /></chemistry><chemistry id="CHEM-US-00237" num="237"><img file="US2007004635A1_D0236.tif" /></chemistry><chemistry id="CHEM-US-00238" num="238"><img file="US2007004635A1_D0237.tif" /></chemistry><chemistry id="CHEM-US-00239" num="239"><img file="US2007004635A1_D0238.tif" /></chemistry><chemistry id="CHEM-US-00240" num="240"><img file="US2007004635A1_D0239.tif" /></chemistry><chemistry id="CHEM-US-00241" num="241"><img file="US2007004635A1_D0240.tif" /></chemistry><chemistry id="CHEM-US-00242" num="242"><img file="US2007004635A1_D0241.tif" /></chemistry><chemistry id="CHEM-US-00243" num="243"><img file="US2007004635A1_D0242.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0407Compounds of formula X are disclosed in U.S. patent application Ser. No. 11/065,572 filed Feb. 24, 2005 and the preparation of the compounds are detailed in the experimental section of this application set forth hereinbelow.

0408Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/065,572 filed Feb. 24, 2005 are: <chemistry id="CHEM-US-00244" num="244"><img file="US2007004635A1_D0243.tif" /></chemistry><chemistry id="CHEM-US-00245" num="245"><img file="US2007004635A1_D0244.tif" /></chemistry><chemistry id="CHEM-US-00246" num="246"><img file="US2007004635A1_D0245.tif" /></chemistry><chemistry id="CHEM-US-00247" num="247"><img file="US2007004635A1_D0246.tif" /></chemistry><chemistry id="CHEM-US-00248" num="248"><img file="US2007004635A1_D0247.tif" /></chemistry><chemistry id="CHEM-US-00249" num="249"><img file="US2007004635A1_D0248.tif" /></chemistry><chemistry id="CHEM-US-00250" num="250"><img file="US2007004635A1_D0249.tif" /></chemistry><chemistry id="CHEM-US-00251" num="251"><img file="US2007004635A1_D0250.tif" /></chemistry><chemistry id="CHEM-US-00252" num="252"><img file="US2007004635A1_D0251.tif" /></chemistry><chemistry id="CHEM-US-00253" num="253"><img file="US2007004635A1_D0252.tif" /></chemistry><chemistry id="CHEM-US-00254" num="254"><img file="US2007004635A1_D0253.tif" /></chemistry><chemistry id="CHEM-US-00255" num="255"><img file="US2007004635A1_D0254.tif" /></chemistry><chemistry id="CHEM-US-00256" num="256"><img file="US2007004635A1_D0255.tif" /></chemistry><chemistry id="CHEM-US-00257" num="257"><img file="US2007004635A1_D0256.tif" /></chemistry><chemistry id="CHEM-US-00258" num="258"><img file="US2007004635A1_D0257.tif" /></chemistry><chemistry id="CHEM-US-00259" num="259"><img file="US2007004635A1_D0258.tif" /></chemistry><chemistry id="CHEM-US-00260" num="260"><img file="US2007004635A1_D0259.tif" /></chemistry><chemistry id="CHEM-US-00261" num="261"><img file="US2007004635A1_D0260.tif" /></chemistry><chemistry id="CHEM-US-00262" num="262"><img file="US2007004635A1_D0261.tif" /></chemistry><chemistry id="CHEM-US-00263" num="263"><img file="US2007004635A1_D0262.tif" /></chemistry><chemistry id="CHEM-US-00264" num="264"><img file="US2007004635A1_D0263.tif" /></chemistry><chemistry id="CHEM-US-00265" num="265"><img file="US2007004635A1_D0264.tif" /></chemistry><chemistry id="CHEM-US-00266" num="266"><img file="US2007004635A1_D0265.tif" /></chemistry><chemistry id="CHEM-US-00267" num="267"><img file="US2007004635A1_D0266.tif" /></chemistry><chemistry id="CHEM-US-00268" num="268"><img file="US2007004635A1_D0267.tif" /></chemistry><chemistry id="CHEM-US-00269" num="269"><img file="US2007004635A1_D0268.tif" /></chemistry><chemistry id="CHEM-US-00270" num="270"><img file="US2007004635A1_D0269.tif" /></chemistry><chemistry id="CHEM-US-00271" num="271"><img file="US2007004635A1_D0270.tif" /></chemistry><chemistry id="CHEM-US-00272" num="272"><img file="US2007004635A1_D0271.tif" /></chemistry><chemistry id="CHEM-US-00273" num="273"><img file="US2007004635A1_D0272.tif" /></chemistry><chemistry id="CHEM-US-00274" num="274"><img file="US2007004635A1_D0273.tif" /></chemistry><chemistry id="CHEM-US-00275" num="275"><img file="US2007004635A1_D0274.tif" /></chemistry><chemistry id="CHEM-US-00276" num="276"><img file="US2007004635A1_D0275.tif" /></chemistry><chemistry id="CHEM-US-00277" num="277"><img file="US2007004635A1_D0276.tif" /></chemistry><chemistry id="CHEM-US-00278" num="278"><img file="US2007004635A1_D0277.tif" /></chemistry><chemistry id="CHEM-US-00279" num="279"><img file="US2007004635A1_D0278.tif" /></chemistry><chemistry id="CHEM-US-00280" num="280"><img file="US2007004635A1_D0279.tif" /></chemistry><chemistry id="CHEM-US-00281" num="281"><img file="US2007004635A1_D0280.tif" /></chemistry><chemistry id="CHEM-US-00282" num="282"><img file="US2007004635A1_D0281.tif" /></chemistry><chemistry id="CHEM-US-00283" num="283"><img file="US2007004635A1_D0282.tif" /></chemistry><chemistry id="CHEM-US-00284" num="284"><img file="US2007004635A1_D0283.tif" /></chemistry><chemistry id="CHEM-US-00285" num="285"><img file="US2007004635A1_D0284.tif" /></chemistry><chemistry id="CHEM-US-00286" num="286"><img file="US2007004635A1_D0285.tif" /></chemistry><chemistry id="CHEM-US-00287" num="287"><img file="US2007004635A1_D0286.tif" /></chemistry><chemistry id="CHEM-US-00288" num="288"><img file="US2007004635A1_D0287.tif" /></chemistry><chemistry id="CHEM-US-00289" num="289"><img file="US2007004635A1_D0288.tif" /></chemistry><chemistry id="CHEM-US-00290" num="290"><img file="US2007004635A1_D0289.tif" /></chemistry><chemistry id="CHEM-US-00291" num="291"><img file="US2007004635A1_D0290.tif" /></chemistry><chemistry id="CHEM-US-00292" num="292"><img file="US2007004635A1_D0291.tif" /></chemistry><chemistry id="CHEM-US-00293" num="293"><img file="US2007004635A1_D0292.tif" /></chemistry><chemistry id="CHEM-US-00294" num="294"><img file="US2007004635A1_D0293.tif" /></chemistry><chemistry id="CHEM-US-00295" num="295"><img file="US2007004635A1_D0294.tif" /></chemistry><chemistry id="CHEM-US-00296" num="296"><img file="US2007004635A1_D0295.tif" /></chemistry><chemistry id="CHEM-US-00297" num="297"><img file="US2007004635A1_D0296.tif" /></chemistry><chemistry id="CHEM-US-00298" num="298"><img file="US2007004635A1_D0297.tif" /></chemistry><chemistry id="CHEM-US-00299" num="299"><img file="US2007004635A1_D0298.tif" /></chemistry><chemistry id="CHEM-US-00300" num="300"><img file="US2007004635A1_D0299.tif" /></chemistry><chemistry id="CHEM-US-00301" num="301"><img file="US2007004635A1_D0300.tif" /></chemistry><chemistry id="CHEM-US-00302" num="302"><img file="US2007004635A1_D0301.tif" /></chemistry><chemistry id="CHEM-US-00303" num="303"><img file="US2007004635A1_D0302.tif" /></chemistry><chemistry id="CHEM-US-00304" num="304"><img file="US2007004635A1_D0303.tif" /></chemistry><chemistry id="CHEM-US-00305" num="305"><img file="US2007004635A1_D0304.tif" /></chemistry><chemistry id="CHEM-US-00306" num="306"><img file="US2007004635A1_D0305.tif" /></chemistry><chemistry id="CHEM-US-00307" num="307"><img file="US2007004635A1_D0306.tif" /></chemistry><chemistry id="CHEM-US-00308" num="308"><img file="US2007004635A1_D0307.tif" /></chemistry><chemistry id="CHEM-US-00309" num="309"><img file="US2007004635A1_D0308.tif" /></chemistry><chemistry id="CHEM-US-00310" num="310"><img file="US2007004635A1_D0309.tif" /></chemistry><chemistry id="CHEM-US-00311" num="311"><img file="US2007004635A1_D0310.tif" /></chemistry><chemistry id="CHEM-US-00312" num="312"><img file="US2007004635A1_D0311.tif" /></chemistry><chemistry id="CHEM-US-00313" num="313"><img file="US2007004635A1_D0312.tif" /></chemistry><chemistry id="CHEM-US-00314" num="314"><img file="US2007004635A1_D0313.tif" /></chemistry><chemistry id="CHEM-US-00315" num="315"><img file="US2007004635A1_D0314.tif" /></chemistry><chemistry id="CHEM-US-00316" num="316"><img file="US2007004635A1_D0315.tif" /></chemistry><chemistry id="CHEM-US-00317" num="317"><img file="US2007004635A1_D0316.tif" /></chemistry><chemistry id="CHEM-US-00318" num="318"><img file="US2007004635A1_D0317.tif" /></chemistry><chemistry id="CHEM-US-00319" num="319"><img file="US2007004635A1_D0318.tif" /></chemistry><chemistry id="CHEM-US-00320" num="320"><img file="US2007004635A1_D0319.tif" /></chemistry><chemistry id="CHEM-US-00321" num="321"><img file="US2007004635A1_D0320.tif" /></chemistry><chemistry id="CHEM-US-00322" num="322"><img file="US2007004635A1_D0321.tif" /></chemistry><chemistry id="CHEM-US-00323" num="323"><img file="US2007004635A1_D0322.tif" /></chemistry><chemistry id="CHEM-US-00324" num="324"><img file="US2007004635A1_D0323.tif" /></chemistry><chemistry id="CHEM-US-00325" num="325"><img file="US2007004635A1_D0324.tif" /></chemistry><chemistry id="CHEM-US-00326" num="326"><img file="US2007004635A1_D0325.tif" /></chemistry><chemistry id="CHEM-US-00327" num="327"><img file="US2007004635A1_D0326.tif" /></chemistry><chemistry id="CHEM-US-00328" num="328"><img file="US2007004635A1_D0327.tif" /></chemistry><chemistry id="CHEM-US-00329" num="329"><img file="US2007004635A1_D0328.tif" /></chemistry><chemistry id="CHEM-US-00330" num="330"><img file="US2007004635A1_D0329.tif" /></chemistry><chemistry id="CHEM-US-00331" num="331"><img file="US2007004635A1_D0330.tif" /></chemistry><chemistry id="CHEM-US-00332" num="332"><img file="US2007004635A1_D0331.tif" /></chemistry><chemistry id="CHEM-US-00333" num="333"><img file="US2007004635A1_D0332.tif" /></chemistry><chemistry id="CHEM-US-00334" num="334"><img file="US2007004635A1_D0333.tif" /></chemistry><chemistry id="CHEM-US-00335" num="335"><img file="US2007004635A1_D0334.tif" /></chemistry><chemistry id="CHEM-US-00336" num="336"><img file="US2007004635A1_D0335.tif" /></chemistry><chemistry id="CHEM-US-00337" num="337"><img file="US2007004635A1_D0336.tif" /></chemistry><chemistry id="CHEM-US-00338" num="338"><img file="US2007004635A1_D0337.tif" /></chemistry><chemistry id="CHEM-US-00339" num="339"><img file="US2007004635A1_D0338.tif" /></chemistry><chemistry id="CHEM-US-00340" num="340"><img file="US2007004635A1_D0339.tif" /></chemistry><chemistry id="CHEM-US-00341" num="341"><img file="US2007004635A1_D0340.tif" /></chemistry><chemistry id="CHEM-US-00342" num="342"><img file="US2007004635A1_D0341.tif" /></chemistry>

0409Compounds of formula XI are disclosed in U.S. application Ser. No. 11/065,509 filed Feb. 24, 2005. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0410Non-limiting examples of certain compounds disclosed in U.S. application Ser. No. 11/065,509 are: <chemistry id="CHEM-US-00343" num="343"><img file="US2007004635A1_D0342.tif" /></chemistry><chemistry id="CHEM-US-00344" num="344"><img file="US2007004635A1_D0343.tif" /></chemistry><chemistry id="CHEM-US-00345" num="345"><img file="US2007004635A1_D0344.tif" /></chemistry><chemistry id="CHEM-US-00346" num="346"><img file="US2007004635A1_D0345.tif" /></chemistry><chemistry id="CHEM-US-00347" num="347"><img file="US2007004635A1_D0346.tif" /></chemistry><chemistry id="CHEM-US-00348" num="348"><img file="US2007004635A1_D0347.tif" /></chemistry><chemistry id="CHEM-US-00349" num="349"><img file="US2007004635A1_D0348.tif" /></chemistry><chemistry id="CHEM-US-00350" num="350"><img file="US2007004635A1_D0349.tif" /></chemistry><chemistry id="CHEM-US-00351" num="351"><img file="US2007004635A1_D0350.tif" /></chemistry><chemistry id="CHEM-US-00352" num="352"><img file="US2007004635A1_D0351.tif" /></chemistry><chemistry id="CHEM-US-00353" num="353"><img file="US2007004635A1_D0352.tif" /></chemistry><chemistry id="CHEM-US-00354" num="354"><img file="US2007004635A1_D0353.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0411Compounds of formula XII are disclosed in U.S. patent application Ser. No. 11/065,531 filed Feb. 24, 2005. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0412Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/065,531 are: <chemistry id="CHEM-US-00355" num="355"><img file="US2007004635A1_D0354.tif" /></chemistry><chemistry id="CHEM-US-00356" num="356"><img file="US2007004635A1_D0355.tif" /></chemistry><chemistry id="CHEM-US-00357" num="357"><img file="US2007004635A1_D0356.tif" /></chemistry><chemistry id="CHEM-US-00358" num="358"><img file="US2007004635A1_D0357.tif" /></chemistry><chemistry id="CHEM-US-00359" num="359"><img file="US2007004635A1_D0358.tif" /></chemistry><chemistry id="CHEM-US-00360" num="360"><img file="US2007004635A1_D0359.tif" /></chemistry><chemistry id="CHEM-US-00361" num="361"><img file="US2007004635A1_D0360.tif" /></chemistry><chemistry id="CHEM-US-00362" num="362"><img file="US2007004635A1_D0361.tif" /></chemistry><chemistry id="CHEM-US-00363" num="363"><img file="US2007004635A1_D0362.tif" /></chemistry><chemistry id="CHEM-US-00364" num="364"><img file="US2007004635A1_D0363.tif" /></chemistry><chemistry id="CHEM-US-00365" num="365"><img file="US2007004635A1_D0364.tif" /></chemistry><chemistry id="CHEM-US-00366" num="366"><img file="US2007004635A1_D0365.tif" /></chemistry><chemistry id="CHEM-US-00367" num="367"><img file="US2007004635A1_D0366.tif" /></chemistry><chemistry id="CHEM-US-00368" num="368"><img file="US2007004635A1_D0367.tif" /></chemistry><chemistry id="CHEM-US-00369" num="369"><img file="US2007004635A1_D0368.tif" /></chemistry><chemistry id="CHEM-US-00370" num="370"><img file="US2007004635A1_D0369.tif" /></chemistry><chemistry id="CHEM-US-00371" num="371"><img file="US2007004635A1_D0370.tif" /></chemistry><chemistry id="CHEM-US-00372" num="372"><img file="US2007004635A1_D0371.tif" /></chemistry><chemistry id="CHEM-US-00373" num="373"><img file="US2007004635A1_D0372.tif" /></chemistry><chemistry id="CHEM-US-00374" num="374"><img file="US2007004635A1_D0373.tif" /></chemistry><chemistry id="CHEM-US-00375" num="375"><img file="US2007004635A1_D0374.tif" /></chemistry><chemistry id="CHEM-US-00376" num="376"><img file="US2007004635A1_D0375.tif" /></chemistry><chemistry id="CHEM-US-00377" num="377"><img file="US2007004635A1_D0376.tif" /></chemistry><chemistry id="CHEM-US-00378" num="378"><img file="US2007004635A1_D0377.tif" /></chemistry><chemistry id="CHEM-US-00379" num="379"><img file="US2007004635A1_D0378.tif" /></chemistry><chemistry id="CHEM-US-00380" num="380"><img file="US2007004635A1_D0379.tif" /></chemistry><chemistry id="CHEM-US-00381" num="381"><img file="US2007004635A1_D0380.tif" /></chemistry><chemistry id="CHEM-US-00382" num="382"><img file="US2007004635A1_D0381.tif" /></chemistry><chemistry id="CHEM-US-00383" num="383"><img file="US2007004635A1_D0382.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or esther thereof.

0413Compounds of formula XIII are disclosed in U.S. patent application Ser. No. 11/065,647 filed Feb. 24, 2005. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0414Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/065,647 are: <chemistry id="CHEM-US-00384" num="384"><img file="US2007004635A1_D0383.tif" /></chemistry><chemistry id="CHEM-US-00385" num="385"><img file="US2007004635A1_D0384.tif" /></chemistry><chemistry id="CHEM-US-00386" num="386"><img file="US2007004635A1_D0385.tif" /></chemistry><chemistry id="CHEM-US-00387" num="387"><img file="US2007004635A1_D0386.tif" /></chemistry><chemistry id="CHEM-US-00388" num="388"><img file="US2007004635A1_D0387.tif" /></chemistry><chemistry id="CHEM-US-00389" num="389"><img file="US2007004635A1_D0388.tif" /></chemistry><chemistry id="CHEM-US-00390" num="390"><img file="US2007004635A1_D0389.tif" /></chemistry><chemistry id="CHEM-US-00391" num="391"><img file="US2007004635A1_D0390.tif" /></chemistry><chemistry id="CHEM-US-00392" num="392"><img file="US2007004635A1_D0391.tif" /></chemistry><chemistry id="CHEM-US-00393" num="393"><img file="US2007004635A1_D0392.tif" /></chemistry><chemistry id="CHEM-US-00394" num="394"><img file="US2007004635A1_D0393.tif" /></chemistry><chemistry id="CHEM-US-00395" num="395"><img file="US2007004635A1_D0394.tif" /></chemistry><chemistry id="CHEM-US-00396" num="396"><img file="US2007004635A1_D0395.tif" /></chemistry><chemistry id="CHEM-US-00397" num="397"><img file="US2007004635A1_D0396.tif" /></chemistry><chemistry id="CHEM-US-00398" num="398"><img file="US2007004635A1_D0397.tif" /></chemistry><chemistry id="CHEM-US-00399" num="399"><img file="US2007004635A1_D0398.tif" /></chemistry><chemistry id="CHEM-US-00400" num="400"><img file="US2007004635A1_D0399.tif" /></chemistry><chemistry id="CHEM-US-00401" num="401"><img file="US2007004635A1_D0400.tif" /></chemistry><chemistry id="CHEM-US-00402" num="402"><img file="US2007004635A1_D0401.tif" /></chemistry><chemistry id="CHEM-US-00403" num="403"><img file="US2007004635A1_D0402.tif" /></chemistry><chemistry id="CHEM-US-00404" num="404"><img file="US2007004635A1_D0403.tif" /></chemistry><chemistry id="CHEM-US-00405" num="405"><img file="US2007004635A1_D0404.tif" /></chemistry><chemistry id="CHEM-US-00406" num="406"><img file="US2007004635A1_D0405.tif" /></chemistry><chemistry id="CHEM-US-00407" num="407"><img file="US2007004635A1_D0406.tif" /></chemistry><chemistry id="CHEM-US-00408" num="408"><img file="US2007004635A1_D0407.tif" /></chemistry><chemistry id="CHEM-US-00409" num="409"><img file="US2007004635A1_D0408.tif" /></chemistry><chemistry id="CHEM-US-00410" num="410"><img file="US2007004635A1_D0409.tif" /></chemistry><chemistry id="CHEM-US-00411" num="411"><img file="US2007004635A1_D0410.tif" /></chemistry><chemistry id="CHEM-US-00412" num="412"><img file="US2007004635A1_D0411.tif" /></chemistry><chemistry id="CHEM-US-00413" num="413"><img file="US2007004635A1_D0412.tif" /></chemistry><chemistry id="CHEM-US-00414" num="414"><img file="US2007004635A1_D0413.tif" /></chemistry><chemistry id="CHEM-US-00415" num="415"><img file="US2007004635A1_D0414.tif" /></chemistry><chemistry id="CHEM-US-00416" num="416"><img file="US2007004635A1_D0415.tif" /></chemistry><chemistry id="CHEM-US-00417" num="417"><img file="US2007004635A1_D0416.tif" /></chemistry><chemistry id="CHEM-US-00418" num="418"><img file="US2007004635A1_D0417.tif" /></chemistry><chemistry id="CHEM-US-00419" num="419"><img file="US2007004635A1_D0418.tif" /></chemistry><chemistry id="CHEM-US-00420" num="420"><img file="US2007004635A1_D0419.tif" /></chemistry><chemistry id="CHEM-US-00421" num="421"><img file="US2007004635A1_D0420.tif" /></chemistry><chemistry id="CHEM-US-00422" num="422"><img file="US2007004635A1_D0421.tif" /></chemistry><chemistry id="CHEM-US-00423" num="423"><img file="US2007004635A1_D0422.tif" /></chemistry><chemistry id="CHEM-US-00424" num="424"><img file="US2007004635A1_D0423.tif" /></chemistry><chemistry id="CHEM-US-00425" num="425"><img file="US2007004635A1_D0424.tif" /></chemistry><chemistry id="CHEM-US-00426" num="426"><img file="US2007004635A1_D0425.tif" /></chemistry><chemistry id="CHEM-US-00427" num="427"><img file="US2007004635A1_D0426.tif" /></chemistry><chemistry id="CHEM-US-00428" num="428"><img file="US2007004635A1_D0427.tif" /></chemistry><chemistry id="CHEM-US-00429" num="429"><img file="US2007004635A1_D0428.tif" /></chemistry><chemistry id="CHEM-US-00430" num="430"><img file="US2007004635A1_D0429.tif" /></chemistry><chemistry id="CHEM-US-00431" num="431"><img file="US2007004635A1_D0430.tif" /></chemistry><chemistry id="CHEM-US-00432" num="432"><img file="US2007004635A1_D0431.tif" /></chemistry><chemistry id="CHEM-US-00433" num="433"><img file="US2007004635A1_D0432.tif" /></chemistry><chemistry id="CHEM-US-00434" num="434"><img file="US2007004635A1_D0433.tif" /></chemistry><chemistry id="CHEM-US-00435" num="435"><img file="US2007004635A1_D0434.tif" /></chemistry><chemistry id="CHEM-US-00436" num="436"><img file="US2007004635A1_D0435.tif" /></chemistry><chemistry id="CHEM-US-00437" num="437"><img file="US2007004635A1_D0436.tif" /></chemistry><chemistry id="CHEM-US-00438" num="438"><img file="US2007004635A1_D0437.tif" /></chemistry><chemistry id="CHEM-US-00439" num="439"><img file="US2007004635A1_D0438.tif" /></chemistry><chemistry id="CHEM-US-00440" num="440"><img file="US2007004635A1_D0439.tif" /></chemistry><chemistry id="CHEM-US-00441" num="441"><img file="US2007004635A1_D0440.tif" /></chemistry><chemistry id="CHEM-US-00442" num="442"><img file="US2007004635A1_D0441.tif" /></chemistry><chemistry id="CHEM-US-00443" num="443"><img file="US2007004635A1_D0442.tif" /></chemistry><chemistry id="CHEM-US-00444" num="444"><img file="US2007004635A1_D0443.tif" /></chemistry><chemistry id="CHEM-US-00445" num="445"><img file="US2007004635A1_D0444.tif" /></chemistry><chemistry id="CHEM-US-00446" num="446"><img file="US2007004635A1_D0445.tif" /></chemistry><chemistry id="CHEM-US-00447" num="447"><img file="US2007004635A1_D0446.tif" /></chemistry><chemistry id="CHEM-US-00448" num="448"><img file="US2007004635A1_D0447.tif" /></chemistry><chemistry id="CHEM-US-00449" num="449"><img file="US2007004635A1_D0448.tif" /></chemistry><chemistry id="CHEM-US-00450" num="450"><img file="US2007004635A1_D0449.tif" /></chemistry><chemistry id="CHEM-US-00451" num="451"><img file="US2007004635A1_D0450.tif" /></chemistry><chemistry id="CHEM-US-00452" num="452"><img file="US2007004635A1_D0451.tif" /></chemistry><chemistry id="CHEM-US-00453" num="453"><img file="US2007004635A1_D0452.tif" /></chemistry><chemistry id="CHEM-US-00454" num="454"><img file="US2007004635A1_D0453.tif" /></chemistry><chemistry id="CHEM-US-00455" num="455"><img file="US2007004635A1_D0454.tif" /></chemistry><chemistry id="CHEM-US-00456" num="456"><img file="US2007004635A1_D0455.tif" /></chemistry><chemistry id="CHEM-US-00457" num="457"><img file="US2007004635A1_D0456.tif" /></chemistry><chemistry id="CHEM-US-00458" num="458"><img file="US2007004635A1_D0457.tif" /></chemistry><chemistry id="CHEM-US-00459" num="459"><img file="US2007004635A1_D0458.tif" /></chemistry><chemistry id="CHEM-US-00460" num="460"><img file="US2007004635A1_D0459.tif" /></chemistry><chemistry id="CHEM-US-00461" num="461"><img file="US2007004635A1_D0460.tif" /></chemistry><chemistry id="CHEM-US-00462" num="462"><img file="US2007004635A1_D0461.tif" /></chemistry><chemistry id="CHEM-US-00463" num="463"><img file="US2007004635A1_D0462.tif" /></chemistry><chemistry id="CHEM-US-00464" num="464"><img file="US2007004635A1_D0463.tif" /></chemistry><chemistry id="CHEM-US-00465" num="465"><img file="US2007004635A1_D0464.tif" /></chemistry><chemistry id="CHEM-US-00466" num="466"><img file="US2007004635A1_D0465.tif" /></chemistry><chemistry id="CHEM-US-00467" num="467"><img file="US2007004635A1_D0466.tif" /></chemistry><chemistry id="CHEM-US-00468" num="468"><img file="US2007004635A1_D0467.tif" /></chemistry><chemistry id="CHEM-US-00469" num="469"><img file="US2007004635A1_D0468.tif" /></chemistry><chemistry id="CHEM-US-00470" num="470"><img file="US2007004635A1_D0469.tif" /></chemistry><chemistry id="CHEM-US-00471" num="471"><img file="US2007004635A1_D0470.tif" /></chemistry><chemistry id="CHEM-US-00472" num="472"><img file="US2007004635A1_D0471.tif" /></chemistry><chemistry id="CHEM-US-00473" num="473"><img file="US2007004635A1_D0472.tif" /></chemistry><chemistry id="CHEM-US-00474" num="474"><img file="US2007004635A1_D0473.tif" /></chemistry><chemistry id="CHEM-US-00475" num="475"><img file="US2007004635A1_D0474.tif" /></chemistry><chemistry id="CHEM-US-00476" num="476"><img file="US2007004635A1_D0475.tif" /></chemistry><chemistry id="CHEM-US-00477" num="477"><img file="US2007004635A1_D0476.tif" /></chemistry><chemistry id="CHEM-US-00478" num="478"><img file="US2007004635A1_D0477.tif" /></chemistry><chemistry id="CHEM-US-00479" num="479"><img file="US2007004635A1_D0478.tif" /></chemistry><chemistry id="CHEM-US-00480" num="480"><img file="US2007004635A1_D0479.tif" /></chemistry><chemistry id="CHEM-US-00481" num="481"><img file="US2007004635A1_D0480.tif" /></chemistry><chemistry id="CHEM-US-00482" num="482"><img file="US2007004635A1_D0481.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0415Compounds of formula XIV are disclosed in U.S. patent application Ser. No. 11/064,673 filed Feb. 24, 2005. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0416Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/064,673 are: <chemistry id="CHEM-US-00483" num="483"><img file="US2007004635A1_D0482.tif" /></chemistry><chemistry id="CHEM-US-00484" num="484"><img file="US2007004635A1_D0483.tif" /></chemistry><chemistry id="CHEM-US-00485" num="485"><img file="US2007004635A1_D0484.tif" /></chemistry><chemistry id="CHEM-US-00486" num="486"><img file="US2007004635A1_D0485.tif" /></chemistry><chemistry id="CHEM-US-00487" num="487"><img file="US2007004635A1_D0486.tif" /></chemistry><chemistry id="CHEM-US-00488" num="488"><img file="US2007004635A1_D0487.tif" /></chemistry><chemistry id="CHEM-US-00489" num="489"><img file="US2007004635A1_D0488.tif" /></chemistry><chemistry id="CHEM-US-00490" num="490"><img file="US2007004635A1_D0489.tif" /></chemistry><chemistry id="CHEM-US-00491" num="491"><img file="US2007004635A1_D0490.tif" /></chemistry><chemistry id="CHEM-US-00492" num="492"><img file="US2007004635A1_D0491.tif" /></chemistry><chemistry id="CHEM-US-00493" num="493"><img file="US2007004635A1_D0492.tif" /></chemistry><chemistry id="CHEM-US-00494" num="494"><img file="US2007004635A1_D0493.tif" /></chemistry><chemistry id="CHEM-US-00495" num="495"><img file="US2007004635A1_D0494.tif" /></chemistry><chemistry id="CHEM-US-00496" num="496"><img file="US2007004635A1_D0495.tif" /></chemistry><chemistry id="CHEM-US-00497" num="497"><img file="US2007004635A1_D0496.tif" /></chemistry><chemistry id="CHEM-US-00498" num="498"><img file="US2007004635A1_D0497.tif" /></chemistry><chemistry id="CHEM-US-00499" num="499"><img file="US2007004635A1_D0498.tif" /></chemistry><chemistry id="CHEM-US-00500" num="500"><img file="US2007004635A1_D0499.tif" /></chemistry><chemistry id="CHEM-US-00501" num="501"><img file="US2007004635A1_D0500.tif" /></chemistry><chemistry id="CHEM-US-00502" num="502"><img file="US2007004635A1_D0501.tif" /></chemistry><chemistry id="CHEM-US-00503" num="503"><img file="US2007004635A1_D0502.tif" /></chemistry><chemistry id="CHEM-US-00504" num="504"><img file="US2007004635A1_D0503.tif" /></chemistry><chemistry id="CHEM-US-00505" num="505"><img file="US2007004635A1_D0504.tif" /></chemistry><chemistry id="CHEM-US-00506" num="506"><img file="US2007004635A1_D0505.tif" /></chemistry><chemistry id="CHEM-US-00507" num="507"><img file="US2007004635A1_D0506.tif" /></chemistry><chemistry id="CHEM-US-00508" num="508"><img file="US2007004635A1_D0507.tif" /></chemistry><chemistry id="CHEM-US-00509" num="509"><img file="US2007004635A1_D0508.tif" /></chemistry><chemistry id="CHEM-US-00510" num="510"><img file="US2007004635A1_D0509.tif" /></chemistry><chemistry id="CHEM-US-00511" num="511"><img file="US2007004635A1_D0510.tif" /></chemistry><chemistry id="CHEM-US-00512" num="512"><img file="US2007004635A1_D0511.tif" /></chemistry><chemistry id="CHEM-US-00513" num="513"><img file="US2007004635A1_D0512.tif" /></chemistry><chemistry id="CHEM-US-00514" num="514"><img file="US2007004635A1_D0513.tif" /></chemistry><chemistry id="CHEM-US-00515" num="515"><img file="US2007004635A1_D0514.tif" /></chemistry><chemistry id="CHEM-US-00516" num="516"><img file="US2007004635A1_D0515.tif" /></chemistry><chemistry id="CHEM-US-00517" num="517"><img file="US2007004635A1_D0516.tif" /></chemistry><chemistry id="CHEM-US-00518" num="518"><img file="US2007004635A1_D0517.tif" /></chemistry><chemistry id="CHEM-US-00519" num="519"><img file="US2007004635A1_D0518.tif" /></chemistry><br /> pharmaceutically acceptable salt, solvate or ester thereof.

0417Compounds of formula XV are disclosed in U.S. patent application Ser. No. 11/007,910 filed Dec. 9, 2004. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0418Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/007,910 are: <chemistry id="CHEM-US-00520" num="520"><img file="US2007004635A1_D0519.tif" /></chemistry><chemistry id="CHEM-US-00521" num="521"><img file="US2007004635A1_D0520.tif" /></chemistry><chemistry id="CHEM-US-00522" num="522"><img file="US2007004635A1_D0521.tif" /></chemistry><chemistry id="CHEM-US-00523" num="523"><img file="US2007004635A1_D0522.tif" /></chemistry><chemistry id="CHEM-US-00524" num="524"><img file="US2007004635A1_D0523.tif" /></chemistry><chemistry id="CHEM-US-00525" num="525"><img file="US2007004635A1_D0524.tif" /></chemistry><chemistry id="CHEM-US-00526" num="526"><img file="US2007004635A1_D0525.tif" /></chemistry><chemistry id="CHEM-US-00527" num="527"><img file="US2007004635A1_D0526.tif" /></chemistry><chemistry id="CHEM-US-00528" num="528"><img file="US2007004635A1_D0527.tif" /></chemistry><chemistry id="CHEM-US-00529" num="529"><img file="US2007004635A1_D0528.tif" /></chemistry><chemistry id="CHEM-US-00530" num="530"><img file="US2007004635A1_D0529.tif" /></chemistry><chemistry id="CHEM-US-00531" num="531"><img file="US2007004635A1_D0530.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0419Compounds of formula XVI are disclosed in U.S. patent application Ser. No. 11/064,757 filed Feb. 24, 2005. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0420Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/064,757 are: <chemistry id="CHEM-US-00532" num="532"><img file="US2007004635A1_D0531.tif" /></chemistry><chemistry id="CHEM-US-00533" num="533"><img file="US2007004635A1_D0532.tif" /></chemistry><chemistry id="CHEM-US-00534" num="534"><img file="US2007004635A1_D0533.tif" /></chemistry><chemistry id="CHEM-US-00535" num="535"><img file="US2007004635A1_D0534.tif" /></chemistry><chemistry id="CHEM-US-00536" num="536"><img file="US2007004635A1_D0535.tif" /></chemistry><chemistry id="CHEM-US-00537" num="537"><img file="US2007004635A1_D0536.tif" /></chemistry><chemistry id="CHEM-US-00538" num="538"><img file="US2007004635A1_D0537.tif" /></chemistry><chemistry id="CHEM-US-00539" num="539"><img file="US2007004635A1_D0538.tif" /></chemistry><chemistry id="CHEM-US-00540" num="540"><img file="US2007004635A1_D0539.tif" /></chemistry><chemistry id="CHEM-US-00541" num="541"><img file="US2007004635A1_D0540.tif" /></chemistry><chemistry id="CHEM-US-00542" num="542"><img file="US2007004635A1_D0541.tif" /></chemistry><chemistry id="CHEM-US-00543" num="543"><img file="US2007004635A1_D0542.tif" /></chemistry><chemistry id="CHEM-US-00544" num="544"><img file="US2007004635A1_D0543.tif" /></chemistry><chemistry id="CHEM-US-00545" num="545"><img file="US2007004635A1_D0544.tif" /></chemistry><chemistry id="CHEM-US-00546" num="546"><img file="US2007004635A1_D0545.tif" /></chemistry><chemistry id="CHEM-US-00547" num="547"><img file="US2007004635A1_D0546.tif" /></chemistry><chemistry id="CHEM-US-00548" num="548"><img file="US2007004635A1_D0547.tif" /></chemistry><chemistry id="CHEM-US-00549" num="549"><img file="US2007004635A1_D0548.tif" /></chemistry><chemistry id="CHEM-US-00550" num="550"><img file="US2007004635A1_D0549.tif" /></chemistry><chemistry id="CHEM-US-00551" num="551"><img file="US2007004635A1_D0550.tif" /></chemistry><chemistry id="CHEM-US-00552" num="552"><img file="US2007004635A1_D0551.tif" /></chemistry><chemistry id="CHEM-US-00553" num="553"><img file="US2007004635A1_D0552.tif" /></chemistry><chemistry id="CHEM-US-00554" num="554"><img file="US2007004635A1_D0553.tif" /></chemistry><chemistry id="CHEM-US-00555" num="555"><img file="US2007004635A1_D0554.tif" /></chemistry><chemistry id="CHEM-US-00556" num="556"><img file="US2007004635A1_D0555.tif" /></chemistry><chemistry id="CHEM-US-00557" num="557"><img file="US2007004635A1_D0556.tif" /></chemistry><chemistry id="CHEM-US-00558" num="558"><img file="US2007004635A1_D0557.tif" /></chemistry><chemistry id="CHEM-US-00559" num="559"><img file="US2007004635A1_D0558.tif" /></chemistry><chemistry id="CHEM-US-00560" num="560"><img file="US2007004635A1_D0559.tif" /></chemistry><chemistry id="CHEM-US-00561" num="561"><img file="US2007004635A1_D0560.tif" /></chemistry><chemistry id="CHEM-US-00562" num="562"><img file="US2007004635A1_D0561.tif" /></chemistry><chemistry id="CHEM-US-00563" num="563"><img file="US2007004635A1_D0562.tif" /></chemistry><chemistry id="CHEM-US-00564" num="564"><img file="US2007004635A1_D0563.tif" /></chemistry><chemistry id="CHEM-US-00565" num="565"><img file="US2007004635A1_D0564.tif" /></chemistry><chemistry id="CHEM-US-00566" num="566"><img file="US2007004635A1_D0565.tif" /></chemistry><chemistry id="CHEM-US-00567" num="567"><img file="US2007004635A1_D0566.tif" /></chemistry><chemistry id="CHEM-US-00568" num="568"><img file="US2007004635A1_D0567.tif" /></chemistry><chemistry id="CHEM-US-00569" num="569"><img file="US2007004635A1_D0568.tif" /></chemistry><chemistry id="CHEM-US-00570" num="570"><img file="US2007004635A1_D0569.tif" /></chemistry><chemistry id="CHEM-US-00571" num="571"><img file="US2007004635A1_D0570.tif" /></chemistry><chemistry id="CHEM-US-00572" num="572"><img file="US2007004635A1_D0571.tif" /></chemistry><chemistry id="CHEM-US-00573" num="573"><img file="US2007004635A1_D0572.tif" /></chemistry><chemistry id="CHEM-US-00574" num="574"><img file="US2007004635A1_D0573.tif" /></chemistry><chemistry id="CHEM-US-00575" num="575"><img file="US2007004635A1_D0574.tif" /></chemistry><chemistry id="CHEM-US-00576" num="576"><img file="US2007004635A1_D0575.tif" /></chemistry><chemistry id="CHEM-US-00577" num="577"><img file="US2007004635A1_D0576.tif" /></chemistry><chemistry id="CHEM-US-00578" num="578"><img file="US2007004635A1_D0577.tif" /></chemistry><chemistry id="CHEM-US-00579" num="579"><img file="US2007004635A1_D0578.tif" /></chemistry><chemistry id="CHEM-US-00580" num="580"><img file="US2007004635A1_D0579.tif" /></chemistry><chemistry id="CHEM-US-00581" num="581"><img file="US2007004635A1_D0580.tif" /></chemistry><chemistry id="CHEM-US-00582" num="582"><img file="US2007004635A1_D0581.tif" /></chemistry><chemistry id="CHEM-US-00583" num="583"><img file="US2007004635A1_D0582.tif" /></chemistry><chemistry id="CHEM-US-00584" num="584"><img file="US2007004635A1_D0583.tif" /></chemistry><chemistry id="CHEM-US-00585" num="585"><img file="US2007004635A1_D0584.tif" /></chemistry><chemistry id="CHEM-US-00586" num="586"><img file="US2007004635A1_D0585.tif" /></chemistry><chemistry id="CHEM-US-00587" num="587"><img file="US2007004635A1_D0586.tif" /></chemistry><chemistry id="CHEM-US-00588" num="588"><img file="US2007004635A1_D0587.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0421Compounds of formula XVII are disclosed in U.S. patent application Ser. No. 11/064,574 filed Feb. 24, 2005. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0422Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/064,574 are:

0423Non-limiting examples of certain compounds disclosed in U.S. patent application Ser. No. 11/064,574 are: <chemistry id="CHEM-US-00589" num="589"><img file="US2007004635A1_D0588.tif" /></chemistry><chemistry id="CHEM-US-00590" num="590"><img file="US2007004635A1_D0589.tif" /></chemistry><chemistry id="CHEM-US-00591" num="591"><img file="US2007004635A1_D0590.tif" /></chemistry><chemistry id="CHEM-US-00592" num="592"><img file="US2007004635A1_D0591.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0424Compounds of formula XVIII are disclosed in U.S. Provisional Patent Application Ser. No. 60/605,234 filed Aug. 27, 2004. The preparation of these compounds is disclosed in the experimental section of this application set forth hereinbelow.

0425Non-limiting examples of certain compounds disclosed in U.S. Provisional Patent Application Ser. No. 60/605,234 are: <chemistry id="CHEM-US-00593" num="593"><img file="US2007004635A1_D0592.tif" /></chemistry><chemistry id="CHEM-US-00594" num="594"><img file="US2007004635A1_D0593.tif" /></chemistry><br /> or a pharmaceutically acceptable salt, solvate or ester thereof.

0426Compounds of formula (XX) have been disclosed in U.S. Pat. No. 6,767,991 at col. 3, line 48 through col. 147, incorporated herein by reference.

0427Compounds of formula (XXI) have been disclosed in U.S. Patent Publication Nos. 2002/0016442, 2002/0037998 and U.S. Pat. Nos. 6,268,207, 6,323,180 at col. 3, line 28 through col. 141, line 60, U.S. Pat. No. 6,329,379 at col. 3, line 28 through col. 147, line 27, U.S. Pat. No. 6,329,417 at col. 3, line 25 through col. 147, line 30, U.S. Pat. No. 6,410,531 at col. 3, line 28 through col. 141, U.S. Pat. No. 6,534,523 at col. 3, line 34 through col. 139, line 29, and U.S. Pat. No. 6,420,380 at col. 3, line 28 through col. 141, line 65, each incorporated herein by reference.

0428Compounds of formula (XXII) have been disclosed in PCT International Patent Publication WO00/59929 published on Oct. 12, 2000, U.S. Patent Publication No. 2004/0002448 and U.S. Patent No. 6,608,027 at col. 4 through col. 137, incorporated herein by reference.

0429Compounds of formula (XXIII) have been disclosed in PCT International Patent Publication WO02/18369 published on Mar. 7, 2002.

0430Compounds of formula (XXIV) have been disclosed U.S. Patent Publication Nos. 2002/0032175, 2004/0266731 and U.S. Patent No. 6,265,380 at col. 3, line 35 through col. 121 and U.S. Pat. No. 6,617,309 at col. 3, line 40 through col. 121, each incorporated herein by reference.

0431Compounds of formula (XXV) have been disclosed U.S. Pat. No. 5,866,684 at col. 1 through col. 72 and U.S. Pat. No. 6,018,020 at col. 1 through col. 73, each incorporated herein by reference.

0432Compounds of formula (XXVI) have been disclosed in U.S. Pat. No. 6,143,715 at col. 3, line 6 through col. 62, line 20, incorporated herein by reference.

0433Isomers of the various compounds of the present invention (where they exist), including enantiomers, stereoisomers, rotamers, tautomers and racemates are also contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of the present invention. Isomers may also include geometric isomers, e.g., when a double bond is present. Polymorphous forms of the compounds of the present invention, whether crystalline or amorphous, also are contemplated as being part of this invention. The (+) isomers of the present compounds are preferred compounds of the present invention.

0434Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are also within the scope of this invention.

0435It will be apparent to one skilled in the art that certain compounds of this invention may exist in alternative tautomeric forms. All such tautomeric forms of the present compounds are within the scope of the invention. Unless otherwise indicated, the representation of either tautomer is meant to include the other. For example, both isomers (1) and (2) are contemplated: <chemistry id="CHEM-US-00595" num="595"><img file="US2007004635A1_D0594.tif" /></chemistry><br /> wherein R′ is H or C_1-6unsubstituted alkyl.

0436Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, <i>Pro</i>-<i>drugs as Novel Delivery Systems </i>(1987) 14 of the A.C.S. Symposium Series, and in <i>Bioreversible Carriers in Drug Design, </i>(1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

0437For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

0438Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

0439If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³wherein Y²is (C₁-C₄) alkyl and Y³is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N-or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴is H or methyl and y⁵is mono-N— or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

0440“Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H₂O.

0441One or more compounds of the invention may also exist as, or optionally converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, <i>J. Pharmaceutical Sci., </i>93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, <i>AAPS Pharm Sci Tech., </i>5(1), article 12 (2004); and A. L. Bingham et al, <i>Chem. Commun., </i>603-604 (2001). A typical, non-limiting, process involves dissolving a compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

0442“Effective amount” or “therapeutically effective amount” is meant to describe an amount of a compound or a composition of the present invention effective in inhibiting HCV protease, and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a suitable subject.

0443The compounds of the present invention form salts that are also within the scope of this invention. Reference to a compound of the present invention herein is understood to include reference to salts, esters and solvates thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the various formulae of the present invention may be formed, for example, by reacting a compound of the present invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al, <i>Journal of Pharmaceutical Sciences </i>(1977) 66(1) 1-19; P. Gould, <i>International J. of Pharmaceutics </i>(1986) 33 201-217; Anderson et al, <i>The Practice of Medicinal Chemistry </i>(1996), Academic Press, New York; in <i>The Orange Book </i>(Food &amp; Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), <i>Handbook of Pharmaceutical Salts: Properties, Selection, and Use, </i>(2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.

0444Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like.

0445Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

0446All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention. All acid and base salts, as well as esters and solvates, are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

0447Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping 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, C_1-4alkyl, or C_1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C_1-20alcohol or reactive derivative thereof, or by a 2,3-di (C_6-24)acyl glycerol.

0448In such esters, unless otherwise specified, any alkyl moiety present preferably contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters preferably contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters preferably comprises a phenyl group.

0449In another embodiment, this invention provides pharmaceutical compositions comprising the inventive peptides as an active ingredient. The pharmaceutical compositions generally additionally comprise a pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials). Because of their HCV inhibitory activity, such pharmaceutical compositions possess utility in treating hepatitis C and related disorders.

0450Another embodiment of the invention discloses the use of the pharmaceutical compositions disclosed above for treatment of diseases such as, for example, hepatitis C and the like. The method comprises administering a therapeutically effective amount of the inventive pharmaceutical composition to a patient having such a disease or diseases and in need of such a treatment.

0451In yet another embodiment, the compounds of the invention may be used for the treatment of HCV in humans in monotherapy mode or in a combination therapy (e.g., dual combination, triple combination etc.) mode such as, for example, in combination with antiviral and/or immunomodulatory agents. Examples of such antiviral and/or immunomodulatory agents include Ribavirin (from Schering-Plough Corporation, Madison, N.J.) and Levovirin™ (from ICN Pharmaceuticals, Costa Mesa, Calif.), VP ₅₀₄₀₆™ (from Viropharma, Incorporated, Exton, Pa.), ISIS 14803™ (from ISIS Pharmaceuticals, Carlsbad, Calif.), Heptazyme™ (from Ribozyme Pharmaceuticals, Boulder, Colo.), VX 497™ (from Vertex Pharmaceuticals, Cambridge, Mass.), Thymosin™ (from SciClone Pharmaceuticals, San Mateo, Calif.), Maxamine™ (Maxim Pharmaceuticals, San Diego, Calif.), mycophenolate mofetil (from Hoffman-LaRoche, Nutley, N.J.), interferon (such as, for example, interferon-alpha, PEG-interferon alpha conjugates) and the like. “PEG-interferon alpha conjugates” are interferon alpha molecules covalently attached to a PEG molecule. Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (Roferon™, from Hoffman La-Roche, Nutley, N.J.) in the form of pegylated interferon alpha-2a (e.g., as sold under the trade name Pegasys™), interferon alpha-2b (Intron™, from Schering-Plough Corporation) in the form of pegylated interferon alpha-2b (e.g., as sold under the trade name PEG-Intron™), interferon alpha-2c (Berofor Alpha™, from Boehringer Ingelheim, Ingelheim, Germany) or consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen™, from Amgen, Thousand Oaks, Calif.).

0452The HCV protease inhibitor can be administered in combination with interferon alpha, PEG-interferon alpha conjugates or consensus interferon concurrently or consecutively at recommended dosages for the duration of HCV treatment in accordance with the methods of the present invention. The commercially available forms of interferon alpha include interferon alpha 2a and interferon alpha 2b and also pegylated forms of both aforementioned interferon alphas. The recommended dosage of INTRON-A interferon alpha 2b (commercially available from Schering-Plough Corp.) as administered by subcutaneous injection at 3MIU(12 mcg)/0.5 mL/TIW is for 24 weeks or 48 weeks for first time treatment. The recommended dosage of PEG-INTRON interferon alpha 2b pegylated (commercially available from Schering-Plough Corp.) as administered by subcutaneous injection at 1.5 mcg/kg/week, within a range of 40 to 150 mcg/week, is for at least 24 weeks. The recommended dosage of ROFERON A inteferon alpha 2a (commercially available from Hoffmann-La Roche) as administered by subcutaneous or intramuscular injection at 3MIU (11.1 mcg/mL)/TIW is for at least 48 to 52 weeks, or alternatively 6 MIU/TIW for 12 weeks followed by 3 MIU/TIW for 36 weeks. The recommended dosage of PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La Roche) as administered by subcutaneous injection at 180 mcg/1 mL or 180 mcg/0.5 mL is once a week for at least 24 weeks. The recommended dosage of INFERGEN interferon alphacon-1 (commercially available from Amgen) as administered by subcutaneous injection at 9 mcg/TIW is for 24 weeks for first time treatment and up to 15 mcg/TIW for 24 weeks for non-responsive or relapse treatment. Optionally, Ribavirin, a synthetic nucleoside analogue with activity against a broad spectrum of viruses including HCV, can be included in combination with the interferon and the HCV protease inhibitor. The recommended dosage of ribavirin is in a range from 600 to 1400 mg per day for at least 24 weeks (commercially available as REBETOL ribavirin from Schering-Plough or COPEGUS ribavirin from Hoffmann-La Roche).

0453A preferred dosage for the administration of a compound of the present invention is about 0.001 to 500 mg/kg of body weight/day of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof. Alternatively, the broadest range of dosing for the compound of the present invention would be 50 mg to 3000 mg over a 24 hour period, which at doses TID would be 50-1000 mg per dose. Narrower ranges per dose could be 50-800 mg, 50-600 mg, 50-400 mg, or 50-200 mg per dose, with the 400 mg/TID being the dose of the most preferred embodiment.

0454The phrases “effective amount” and “therapeutically effective amount” mean that amount of a compound of the present invention, and other pharmacological or therapeutic agents described herein, that will elicit a biological or medical response of a tissue, a system, or a subject (e.g., animal or human) that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more of the presently claimed diseases such as HCV related diseases. The formulations or compositions, combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body of, for example, a mammal or human.

0455For administration of pharmaceutically acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.

0456As described above, this invention includes combinations comprising an amount of at least one compound of the presently claimed methods or a pharmaceutically acceptable salt or ester thereof, and an amount of one or more additional therapeutic agents listed above (administered together or sequentially) wherein the amounts of the compounds/ treatments result in desired therapeutic effect.

0457When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for illustration purposes, a compound of the present invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).

0458If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. Compounds of the present invention may also be administered sequentially with known therapeutic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the present invention may be administered either prior to or after administration of the known therapeutic agent. Such techniques are within the skills of persons skilled in the art as well as attending physicians.

0459The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays for measuring HCV viral activity or cathepsin activity, such as are well know to those skilled in the art.

0460While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers, adjuvants or vehicles thereof and optionally other therapeutic agents. Each carrier, adjuvant or vehicle must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the mammal in need of treatment.

0461Accordingly, this invention also relates to pharmaceutical compositions comprising at least one compound utilized in the presently claimed methods, or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.

0462In yet another embodiment, the present invention discloses methods for preparing pharmaceutical compositions comprising the inventive compounds as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.

0463Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. 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 noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

0464Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. HCV inhibitory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

0465Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

0466Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.

0467For preparing 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 dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

0468Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

0469The compounds of the invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

0470Preferably the compound is administered orally, intravenously or subcutaneously.

0471Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.

0472More particularly, the above-described compounds exhibit HCV inhibitory activity and are thus referenced herein as HCV protease inhibitors. The present formulations thus comprise at least one HCV protease inhibitor together with one or more pharmaceutically acceptable adjuvants and optionally other therapeutic agents and pharmaceutically acceptable carriers and excipients. Each excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the mammal in need of treatment. In one embodiment, the adjuvant is at least one pharmaceutically acceptable surfactant or at least one pharmaceutically acceptable acidifying agent or both. When desired or needed, suitable carriers and other excipients (such as binders, glidents, lubricants, and disintegrants) may also be incorporated in the formulation. Surfactants may be present in the pharmaceutical formulations of the present invention in an amount of about 0.1 to about 10% by weight or about 1 to about 5% by weight. Acidifying agents may be present in the pharmaceutical formulations of the present invention in a total amount of about 0.1 to about 10% by weight or about 1 to 5% by weight. The formulations of the present invention may be administered orally, intravenously, subcutaneously, or transdermally. The pharmaceutical formulation in a unit dosage form may contain about 1 mg to about 1000 mg of the HCV protease inhibitor. Other unit dosage forms may contain from about 50 mg to about 800 mg, or from about 50 mg to about 600 mg, or from about 50 mg to about 400 mg, or from about 50 mg to about 200 mg according to the particular application. In one embodiment, the unit dosage form is a tablet containing about 200 mg of the active compound. The dosage range, generally, over 24 hours will range between 50 mg to 3,000 mg of the HCV protease inhibitor. The use of HCV protease inhibitors thus formulated is accordingly particularly useful to treat patients exhibiting one or more symptoms associated with hepatitis C virus (HCV) when the patient exhibits symptoms associated with HCV Genotype 1 (i.e., Genotype 1 a or Genotype 1 b); and/or previous interferon therapy in the patient was ineffective.

0473Some useful terms are described below:

0474Capsule—refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.

0475Tablet—refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.

0476Oral gel—refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.

0477Powder for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.

0478Diluent—refers to substances that usually make up the major 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 potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.

0479Disintegrant—refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; “cold water soluble” modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

0480Binder—refers to substances that bind or “glue” powders together and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.

0481Lubricant—refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic 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 at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.

0482Glident—material that prevents caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0. 1 % to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

0483Coloring agents—excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.

0484Bioavailability—refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.

0485Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.

0486For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), <i>Remington's Pharmaceutical Sciences, </i>18th Edition, (1990), Mack Publishing Co., Easton, Pa.

0487The term pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a subject by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.

0488Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

0489Preferably the compound is administered orally.

0490Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

0000The Following Experimental Section Applies for the Preparation of the Compounds of Formula XI:

0491Abbreviations which are used in the descriptions of the schemes, preparations and the examples that follow are: <ul id="ul0005" list-style="none"><li id="ul0005-0001" num="0492"> THF: Tetrahydrofuran </li><li id="ul0005-0002" num="0493"> DMF: N,N-Dimethylformamide </li><li id="ul0005-0003" num="0494"> EtOAc: Ethyl acetate </li><li id="ul0005-0004" num="0495"> AcOH: Acetic acid </li><li id="ul0005-0005" num="0496"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one </li><li id="ul0005-0006" num="0497"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0005-0007" num="0498"> NMM: N-Methylmorpholine </li><li id="ul0005-0008" num="0499"> ADDP: 1,1′-(Azodicarbobyl)dipiperidine </li><li id="ul0005-0009" num="0500"> EAD: Diethylazodicarboxylate </li><li id="ul0005-0010" num="0501"> MeOH: Methanol </li><li id="ul0005-0011" num="0502"> EtOH: Ethanol </li><li id="ul0005-0012" num="0503"> Et₂O: Diethyl ether </li><li id="ul0005-0013" num="0504"> DMSO: Dimethylsulfoxide </li><li id="ul0005-0014" num="0505"> HOBt: N-Hydroxybenzotriazole </li><li id="ul0005-0015" num="0506"> PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate </li><li id="ul0005-0016" num="0507"> DCM: Dichloromethane </li><li id="ul0005-0017" num="0508"> DCC: 1,3-Dicyclohexylcarbodiimide </li><li id="ul0005-0018" num="0509"> TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy </li><li id="ul0005-0019" num="0510"> Phg: Phenylglycine </li><li id="ul0005-0020" num="0511"> Chg: Cyclohexylglycine </li><li id="ul0005-0021" num="0512"> Bn: Benzyl </li><li id="ul0005-0022" num="0513"> Bzl: Benzyl </li><li id="ul0005-0023" num="0514"> Et: Ethyl </li><li id="ul0005-0024" num="0515"> Ph: Phenyl </li><li id="ul0005-0025" num="0516"> iBoc: isobutoxycarbonyl </li><li id="ul0005-0026" num="0517"> iPr: isopropyl </li><li id="ul0005-0027" num="0518"> tBu or But: tert-Butyl </li><li id="ul0005-0028" num="0519"> Boc: tert-Butyloxycarbonyl </li><li id="ul0005-0029" num="0520"> Cbz: Benzyloxycarbonyl </li><li id="ul0005-0030" num="0521"> Cp: Cyclopentyldienyl </li><li id="ul0005-0031" num="0522"> Ts: p-toluenesulfonyl </li><li id="ul0005-0032" num="0523"> MCPBA: 3-chloroperbenzoic acid. </li><li id="ul0005-0033" num="0524"> Me: Methyl </li><li id="ul0005-0034" num="0525"> HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate </li><li id="ul0005-0035" num="0526"> DMAP: 4-N,N-Dimethylaminopyridine </li><li id="ul0005-0036" num="0527"> Bop: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate </li><li id="ul0005-0037" num="0528"> PCC: Pyridiniumchlorochromate </li></ul>

0529Other abbreviations are commonly used abbreviations Such as according to the guidelines published by <i>Journal of Organic Chemistry. </i>

General Schemes for Preparation of Target Compounds

0530Compounds of the present invention were synthesized using the general schemes (Methods A-E) described below.

0000Method A

0531Deprotection of the N-Boc functionality of 1.01 under acidic conditions provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine under peptide coupling methodology (Louis A Carpino et al. “Preparation of uronium and immonium salts for peptide coupling”, WO 2002094822, pp. 76) to afford 1.03. N-Boc deprotection followed by treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the appropriate P₁—P∝ primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffatt, or Dess-Martin's) resulted in the target compound 1.08. <chemistry id="CHEM-US-00596" num="596"><img file="US2007004635A1_D0595.tif" /></chemistry><chemistry id="CHEM-US-00597" num="597"><img file="US2007004635A1_D0596.tif" /></chemistry><br /> Method B

0532Peptide coupling of the acid 1.06 with the appropriate P₁—P′ secondary amide moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's) resulted in the target compound 1.10.

0000Method C

0533In another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.03 with the appropriate P₁—P′ amide moiety afforded the hydroxyl amide 1.11. Oxidation (Moffatt or Dess-Martin's) resulted in the keto-amide 1.12. Deprotection of the N-Boc using either formic acid or 4 M HCl in dioxane gave the formate or hydrochloride salt 1.13. Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target compound 1.14. <chemistry id="CHEM-US-00598" num="598"><img file="US2007004635A1_D0597.tif" /></chemistry><br /> Method D

0534In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 1.14. <chemistry id="CHEM-US-00599" num="599"><img file="US2007004635A1_D0598.tif" /></chemistry><br /> Method E

0535In yet another variation, the dipeptide hydrochloride salt 1.04 was converted to the 4-nitrophenyl carbamate as described above. Treatment with an amine (or amine hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis and further elaboration as described in Methods A/B provided the target compounds 1.14. <chemistry id="CHEM-US-00600" num="600"><img file="US2007004635A1_D0599.tif" /></chemistry><br /> The Following Experimental Section Applies for the Preparation of the Compounds of Formula XII:

0536Abbreviations which are used in the descriptions of the schemes, preparations and the examples that follow are: <ul id="ul0006" list-style="none"><li id="ul0006-0001" num="0537"> THF: Tetrahydrofuran </li><li id="ul0006-0002" num="0538"> DMF: N,N-Dimethylformamide </li><li id="ul0006-0003" num="0539"> EtOAc: Ethyl acetate </li><li id="ul0006-0004" num="0540"> AcOH: Acetic acid </li><li id="ul0006-0005" num="0541"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one </li><li id="ul0006-0006" num="0542"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0006-0007" num="0543"> NMM: N-Methylmorpholine </li><li id="ul0006-0008" num="0544"> ADDP: 1,1′-(Azodicarbobyl)dipiperidine </li><li id="ul0006-0009" num="0545"> DEAD: Diethylazodicarboxylate </li><li id="ul0006-0010" num="0546"> MeOH: Methanol </li><li id="ul0006-0011" num="0547"> EtOH: Ethanol </li><li id="ul0006-0012" num="0548"> Et₂O: Diethyl ether </li><li id="ul0006-0013" num="0549"> DMSO: Dimethylsulfoxide </li><li id="ul0006-0014" num="0550"> HOBt: N-Hydroxybenzotriazole </li><li id="ul0006-0015" num="0551"> PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate </li><li id="ul0006-0016" num="0552"> DCM: Dichloromethane </li><li id="ul0006-0017" num="0553"> DCC: 1,3-Dicyclohexylcarbodiimide </li><li id="ul0006-0018" num="0554"> TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy </li><li id="ul0006-0019" num="0555"> Phg: Phenylglycine </li><li id="ul0006-0020" num="0556"> Chg: Cyclohexylglycine </li><li id="ul0006-0021" num="0557"> Bn: Benzyl </li><li id="ul0006-0022" num="0558"> Bzl: Benzyl </li><li id="ul0006-0023" num="0559"> Et: Ethyl </li><li id="ul0006-0024" num="0560"> Ph: Phenyl </li><li id="ul0006-0025" num="0561"> iBoc: isobutoxycarbonyl </li><li id="ul0006-0026" num="0562"> iPr: isopropyl </li><li id="ul0006-0027" num="0563">^tBu or Bu^t: tert-Butyl </li><li id="ul0006-0028" num="0564"> Boc: tert-Butyloxycarbonyl </li><li id="ul0006-0029" num="0565"> Cbz: Benzyloxycarbonyl </li><li id="ul0006-0030" num="0566"> Cp: Cylcopentyldienyl </li><li id="ul0006-0031" num="0567"> Ts: p-toluenesulfonyl </li><li id="ul0006-0032" num="0568"> Me: Methyl </li></ul>

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

0000<ul id="ul0007" list-style="none"><li id="ul0007-0001" num="0569"> DMAP: 4-N,N-Dimethylaminopyridine </li><li id="ul0007-0002" num="0570"> BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate </li><li id="ul0007-0003" num="0571"> PCC: Pyridiniumchlorochromate </li></ul>

General Schemes for Preparation of Target Compounds

0572Compounds of the present invention were synthesized using the general schemes (Methods A-E) described below.

0000Method A:

0573Deprotection of the N-Boc functionality of 1.01 under acidic conditions provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine under peptide coupling methodology to afford 1.03. N-Boc deprotection followed by treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the appropriate P₁—P′ primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffatt or related process—T. T. Tidwell, <i>Synthesis, </i>1990, 857; or Dess-Martin's—<i>J. Org. Chem., </i>1983, 48, 4155) resulted in the target compound 1.08. <chemistry id="CHEM-US-00601" num="601"><img file="US2007004635A1_D0600.tif" /></chemistry><chemistry id="CHEM-US-00602" num="602"><img file="US2007004635A1_D0601.tif" /></chemistry><br /> Method B

0574Peptide coupling of the acid 1.06 with the appropriate P₁—P′ secondary amide moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's) resulted in the target compound 1.10. <chemistry id="CHEM-US-00603" num="603"><img file="US2007004635A1_D0602.tif" /></chemistry><br /> Method C

0575In another variation, peptide coupling of the N-Boc-P₂—P₃-acid 1.17 with the appropriate P₁—P′ amide moiety afforded the hydroxyl amide 1.11. Oxidation (Moffaft or Dess-Martin's) resulted in the keto amide 1.12. Deprotection of the N-Boc functionality gave the hydrochloride salt 1.13. Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target compound 1.14. <chemistry id="CHEM-US-00604" num="604"><img file="US2007004635A1_D0603.tif" /></chemistry><br /> Method D

0576In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 1.14. <chemistry id="CHEM-US-00605" num="605"><img file="US2007004635A1_D0604.tif" /></chemistry><br /> Method E

0577In yet another variation, the dipeptide hydrochloride salt 1.03 was converted to the 4-nitrophenyl carbamate as described above. Treatment with an amine (or amine hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis and further elaboration as described in Methods A/B provided the target compounds 1.14. <chemistry id="CHEM-US-00606" num="606"><img file="US2007004635A1_D0605.tif" /></chemistry><br /> The Following Experimental Section Applies for the Preparation of the Compounds of Formula XIII: <br /> Abbreviations Which are Used in the Descriptions of the Schemes, Preparations and the Examples that Follow are: <ul id="ul0008" list-style="none"><li id="ul0008-0001" num="0578"> THF: Tetrahydrofuran </li><li id="ul0008-0002" num="0579"> DMF: N,N-Dimethylformamide </li><li id="ul0008-0003" num="0580"> EtOAc: Ethyl acetate </li><li id="ul0008-0004" num="0581"> ACOH: Acetic acid </li><li id="ul0008-0005" num="0582"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin4(3H )-one </li><li id="ul0008-0006" num="0583"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0008-0007" num="0584"> NMM: N-Methylmorpholine </li><li id="ul0008-0008" num="0585"> ADDP: 1,1′-(Azodicarbobyl)dipiperidine </li><li id="ul0008-0009" num="0586"> DEAD: Diethylazodicarboxylate </li><li id="ul0008-0010" num="0587"> DIAD: Diisopropylazodicarboxylate </li><li id="ul0008-0011" num="0588"> MeOH: Methanol </li><li id="ul0008-0012" num="0589"> EtOH: Ethanol </li><li id="ul0008-0013" num="0590"> Et₂O: Diethyl ether </li><li id="ul0008-0014" num="0591"> DMSO: Dimethylsulfoxide </li><li id="ul0008-0015" num="0592"> HOBt: N-Hydroxybenzotriazole </li><li id="ul0008-0016" num="0593"> PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate </li><li id="ul0008-0017" num="0594"> DCM: Dichloromethane </li><li id="ul0008-0018" num="0595"> DCC: 1,3-Dicyclohexylcarbodiimide </li><li id="ul0008-0019" num="0596"> TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy </li><li id="ul0008-0020" num="0597"> Phg: Phenylglycine </li><li id="ul0008-0021" num="0598"> Chg: Cyclohexylglycine </li><li id="ul0008-0022" num="0599"> Bn: Benzyl </li><li id="ul0008-0023" num="0600"> Bz: Benzyl </li><li id="ul0008-0024" num="0601"> Et: Ethyl </li><li id="ul0008-0025" num="0602"> Ph: Phenyl </li><li id="ul0008-0026" num="0603"> iBoc: isobutoxycarbonyl </li><li id="ul0008-0027" num="0604"> iPr: isopropyl </li><li id="ul0008-0028" num="0605">^tBu or Bu^t: tert-Butyl </li><li id="ul0008-0029" num="0606"> Boc: tert-Butyloxycarbonyl </li><li id="ul0008-0030" num="0607"> Cbz: Benzyloxycarbonyl </li><li id="ul0008-0031" num="0608"> Cp: Cylcopentyldienyl </li><li id="ul0008-0032" num="0609"> Ts: p-toluenesulfonyl </li><li id="ul0008-0033" num="0610"> Me: Methyl </li><li id="ul0008-0034" num="0611"> Ms or Mesyl: Methane sulfonyl </li></ul>

HATU: O-(7-azabenzotriazol-2-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

0000<ul id="ul0009" list-style="none"><li id="ul0009-0001" num="0612"> DMAP: 4-N,N-Dimethylaminopyridine </li><li id="ul0009-0002" num="0613"> Bop: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate </li><li id="ul0009-0003" num="0614"> PCC: Pyridiniumchlorochromate </li><li id="ul0009-0004" num="0615"> DIBAL-H: diisopropyl aluminum hydride </li><li id="ul0009-0005" num="0616"> rt or RT: Room temperature </li><li id="ul0009-0006" num="0617"> quant.: Quantitative yield </li><li id="ul0009-0007" num="0618"> h or hr: hour </li><li id="ul0009-0008" num="0619"> min: minute </li><li id="ul0009-0009" num="0620"> TFA: Trifluoroacetic acid </li></ul>

General Schemes for Preparation of Target Compounds

0621Compounds of the present invention were synthesized using the general schemes (Methods A-E) described below.

0000Method A

0622Deprotection of the N-Boc functionality of 1.01 under acidic conditions provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine under peptide coupling methodology to afford 1.03. N-Boc deprotection followed by treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the appropriate P₁—P′ primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffatt or related process—T. T. Tidwell, <i>Synthesis, </i>1990, 857; or Dess-Martin's periodinane (<i>J. Org. Chem., </i>1983, 48, 4155) resulted in the target compound 1.08. <chemistry id="CHEM-US-00607" num="607"><img file="US2007004635A1_D0606.tif" /></chemistry><chemistry id="CHEM-US-00608" num="608"><img file="US2007004635A1_D0607.tif" /></chemistry><br /> Method B

0623Peptide coupling of the acid 1.06 with the appropriate P₁—P′ secondary amide moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's) resulted in the target compound 1.10. <chemistry id="CHEM-US-00609" num="609"><img file="US2007004635A1_D0608.tif" /></chemistry><br /> Method C

0624In another variation, peptide coupling of the N-Boc-P₂—P₃-acid 1.17 with the appropriate P₁—P′ amide moiety afforded the hydroxyl amide 1.11. Oxidation (Moffatt or Dess-Martin's) resulted in the keto amide 1.12. Deprotection of the N-Boc functionality gave the hydrochloride salt 1.13. Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target compound 1.14. <chemistry id="CHEM-US-00610" num="610"><img file="US2007004635A1_D0609.tif" /></chemistry><br /> Method D

0625In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 1.14. <chemistry id="CHEM-US-00611" num="611"><img file="US2007004635A1_D0610.tif" /></chemistry><br /> Method E

0626In yet another variation, the dipeptide hydrochloride salt 1.03 was converted to the 4-nitrophenyl carbamate as described above. Treatment with an amine (or amine hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis and further elaboration as described in Methods A/B provided the target compounds 1.14. <chemistry id="CHEM-US-00612" num="612"><img file="US2007004635A1_D0611.tif" /></chemistry><br /> The Following Experimental Section Applies for the Preparation of the Compounds of Formula XIV:

0627For the procedures described below, the following abbreviations are used: <ul id="ul0010" list-style="none"><li id="ul0010-0001" num="0628"> THF: Tetrahydrofuran </li><li id="ul0010-0002" num="0629"> DMF: N,N-Dimethylformamide </li><li id="ul0010-0003" num="0630"> EtOAc: Ethyl acetate </li><li id="ul0010-0004" num="0631"> ACOH: Acetic acid </li><li id="ul0010-0005" num="0632"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin4(3H)-one </li><li id="ul0010-0006" num="0633"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0010-0007" num="0634"> NMM: N-Methylmorpholine </li><li id="ul0010-0008" num="0635"> ADDP: 1,1′-(Azodicarbobyl)dipiperidine </li><li id="ul0010-0009" num="0636"> DEAD: Diethylazodicarboxylate </li><li id="ul0010-0010" num="0637"> MeOH: Methanol </li><li id="ul0010-0011" num="0638"> EtOH: Ethanol </li><li id="ul0010-0012" num="0639"> Et2O: Diethyl ether </li><li id="ul0010-0013" num="0640"> DMSO: Dimethylsulfoxide </li><li id="ul0010-0014" num="0641"> HOBt: N-Hydroxybenzotriazole </li><li id="ul0010-0015" num="0642"> PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate </li><li id="ul0010-0016" num="0643"> DCM: Dichloromethane </li><li id="ul0010-0017" num="0644"> DCC: 1,3-Dicyclohexylcarbodiimide </li><li id="ul0010-0018" num="0645"> TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy </li><li id="ul0010-0019" num="0646"> Phg: Phenylglycine </li><li id="ul0010-0020" num="0647"> Chg: Cyclohexylglycine </li><li id="ul0010-0021" num="0648"> Bn: Benzyl </li><li id="ul0010-0022" num="0649"> Bzl: Benzyl </li><li id="ul0010-0023" num="0650"> Et: Ethyl </li><li id="ul0010-0024" num="0651"> Ph: Phenyl </li><li id="ul0010-0025" num="0652"> DMF-DMA: N,N-Dimethylformamide-dimethylacetal </li><li id="ul0010-0026" num="0653"> iBoc: isobutoxycarbonyl </li><li id="ul0010-0027" num="0654"> iPr: isopropyl </li><li id="ul0010-0028" num="0655">^tBu or Bu^t: tert-Butyl </li><li id="ul0010-0029" num="0656"> Boc: tert-Butyloxycarbonyl </li><li id="ul0010-0030" num="0657"> Cbz: Benzyloxycarbonyl </li><li id="ul0010-0031" num="0658"> Cp: Cylcopentyldienyl </li><li id="ul0010-0032" num="0659"> Ts: p-toluenesulfonyl </li><li id="ul0010-0033" num="0660"> Me: Methyl </li></ul>

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

DMAP: 4-N,N-Dimethylaminopyridine

0000<ul id="ul0011" list-style="none"><li id="ul0011-0001" num="0661"> BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate </li><li id="ul0011-0002" num="0662"> PCC: Pyridiniumchlorochromate </li><li id="ul0011-0003" num="0663"> KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethylsilylamide) </li><li id="ul0011-0004" num="0664"> NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide) </li><li id="ul0011-0005" num="0665"> LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide) </li><li id="ul0011-0006" num="0666"> 10% Pd/C: 10% Palladium on carbon (by weight). </li><li id="ul0011-0007" num="0667"> TG: Thioglycerol <br /> General Schemes for Preparation of Target Compounds </li></ul>

0668Compounds of the present invention were synthesized using the general schemes (Methods A-E) described below.

0000Method A

0669Deprotection of the N-Boc functionality of 1.01 under acidic conditions provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine under peptide coupling methodology to afford 1.03. N-Boc deprotection followed by treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the appropriate P₁—P′ primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffaft oxidation or related process—see, T. T. Tidwell, <i>Synthesis, </i>1990, 857), or Dess-Martin Periodinane—<i>J. Org. Chem., (</i>1983) 48, 4155) resulted in the target compound 1.08. <chemistry id="CHEM-US-00613" num="613"><img file="US2007004635A1_D0612.tif" /></chemistry><chemistry id="CHEM-US-00614" num="614"><img file="US2007004635A1_D0613.tif" /></chemistry><br /> Method B

0670Peptide coupling of the acid 1.06 with the appropriate P₁—P′ secondary amide moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's) resulted in the target compound 1.10. <chemistry id="CHEM-US-00615" num="615"><img file="US2007004635A1_D0614.tif" /></chemistry><br /> Method C

0671In another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.17 with the appropriate P₁—P′ amide moiety afforded the hydroxyl amide 1.11. Oxidation (Moffatt or Dess-Martin Periodinane) resulted in the keto amide 1.12. Deprotection of the N-Boc functionality gave the hydrochloride salt 1.13. Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target compound 1.14. <chemistry id="CHEM-US-00616" num="616"><img file="US2007004635A1_D0615.tif" /></chemistry><br /> Method D

0672In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 1.14. <chemistry id="CHEM-US-00617" num="617"><img file="US2007004635A1_D0616.tif" /></chemistry><br /> Method E

0673In yet another variation, the dipeptide hydrochloride salt 1.03 was converted to the 4-nitrophenyl carbamate as described above. Treatment with an amine (or amine hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis and further elaboration as described in Methods A/B provided the target compounds 1.14. <chemistry id="CHEM-US-00618" num="618"><img file="US2007004635A1_D0617.tif" /></chemistry>

0674The following experimental section applies for the preparation of the compounds of Formula XV:

0675For the procedures described below, the following abbreviations are used: <ul id="ul0012" list-style="none"><li id="ul0012-0001" num="0676"> THF: Tetrahydrofuran </li><li id="ul0012-0002" num="0677"> DMF: N,N-Dimethylformamide </li><li id="ul0012-0003" num="0678"> EtOAc: Ethyl acetate </li><li id="ul0012-0004" num="0679"> AcOH: Acetic acid </li><li id="ul0012-0005" num="0680"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one </li><li id="ul0012-0006" num="0681"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0012-0007" num="0682"> NMM: N-Methylmorpholine </li><li id="ul0012-0008" num="0683"> ADDP: 1,1′-(Azodicarbobyl)dipiperidine </li><li id="ul0012-0009" num="0684"> DEAD: Diethylazodicarboxylate </li><li id="ul0012-0010" num="0685"> MeOH: Methanol </li><li id="ul0012-0011" num="0686"> EtOH: Ethanol </li><li id="ul0012-0012" num="0687"> Et2O: Diethyl ether </li><li id="ul0012-0013" num="0688"> DMSO: Dimethylsulfoxide </li><li id="ul0012-0014" num="0689"> HOBt: N-Hydroxybenzotriazole </li><li id="ul0012-0015" num="0690"> PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate </li><li id="ul0012-0016" num="0691"> DCM: Dichloromethane </li><li id="ul0012-0017" num="0692"> DCC: 1,3-Dicyclohexylcarbodiimide </li><li id="ul0012-0018" num="0693"> TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy </li><li id="ul0012-0019" num="0694"> Phg: Phenylglycine </li><li id="ul0012-0020" num="0695"> Chg: Cyclohexylglycine </li><li id="ul0012-0021" num="0696"> Bn: Benzyl </li><li id="ul0012-0022" num="0697"> Bzl: Benzyl </li><li id="ul0012-0023" num="0698"> Et: Ethyl </li><li id="ul0012-0024" num="0699"> Ph: Phenyl </li><li id="ul0012-0025" num="0700"> iBoc: isobutoxycarbonyl </li><li id="ul0012-0026" num="0701"> iPr: isopropyl </li><li id="ul0012-0027" num="0702">^tBu or Bu^t: tert-Butyl </li><li id="ul0012-0028" num="0703"> Boc: tert-Butyloxycarbonyl </li><li id="ul0012-0029" num="0704"> Cbz: Benzyloxycarbonyl </li><li id="ul0012-0030" num="0705"> Cp: Cylcopentyldienyl </li><li id="ul0012-0031" num="0706"> Ts: p-toluenesulfonyl </li><li id="ul0012-0032" num="0707"> Me: Methyl </li></ul>

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

DMAP: 4-N,N-Dimethylaminopyridine

0000<ul id="ul0013" list-style="none"><li id="ul0013-0001" num="0708"> BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate </li><li id="ul0013-0002" num="0709"> PCC: Pyridiniumchlorochromate </li><li id="ul0013-0003" num="0710"> KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethylsilylamide) </li><li id="ul0013-0004" num="0711"> NaHMDS: Sodium Hexamethyidisilazide or Sodium bis(trimethylsilylamide) </li><li id="ul0013-0005" num="0712"> LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide) </li><li id="ul0013-0006" num="0713"> 10% Pd/C: 10% Palladium on carbon (by weight). </li></ul>

Preparative Example 1

0714<chemistry id="CHEM-US-00619" num="619"><img file="US2007004635A1_D0618.tif" /></chemistry><br /> Step A <chemistry id="CHEM-US-00620" num="620"><img file="US2007004635A1_D0619.tif" /></chemistry>

0715A solution of pyrazinecarboxylic acid 1a (3 g) in 150 mL of dry dichloromethane and 150 mL of dry DMF was stirred at 0° C. and treated with HATU (1.4 eq, 6.03 g). L-cyclohexylglycine hydrochloride 1b (1.2 eq, 6.03 g) was added in small portions. Then, N-methylmorpholine (4 eq, 10 mL, d 0.920) was added dropwise. The reaction mixture was gradually warmed to room temperature and stirred for 20 h. All the volatiles were removed under vacuum and the residue was dissolved in 500 mL of ethyl acetate. The organic layer was washed with water (100 mL), aqueous 1N HCl (100 mL), aqueous saturated sodium bicarbonate solution (100 mL), and brine (100 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 afford the product 1c as a white solid. <br /> Step B <chemistry id="CHEM-US-00621" num="621"><img file="US2007004635A1_D0620.tif" /></chemistry>

0716A solution of methyl ester 1c (6.5 g) in 270 mL of a 1:1:1 mixture of THF/MeOH/water was cooled to 0° C. and treated with lithium hydroxide monohydrate (2.5 eq, 2.45 g). The mixture was stirred and monitored by TLC (acetone/hexanes; 2:8). When all the starting material had been consumed, the reaction mixture was treated with 100 mL of aqueous 1N HCl and the mixture was concentrated on the rotavap. Dichloromethane (250 mL) was added and layers separated. The aqueous layer was extracted with dichloromethane (3×80 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the product 1d as a white solid. <br /> Step C <chemistry id="CHEM-US-00622" num="622"><img file="US2007004635A1_D0621.tif" /></chemistry>

0717The amino ester 1e was prepared following the method of R. Zhang and J. S. Madalengoitia (<i>J. Org. Chem. </i>1999, 64, 330), with the exception that the Boc group was cleaved by the reaction of the Boc-protected amino acid with methanolic HCl (4M HCl in dioxane was also employed for the deprotection).

0718(Note: In a variation of the reported synthesis, the sulfonium ylide was replaced with the corresponding phosphonium ylide). <br /> Step D <chemistry id="CHEM-US-00623" num="623"><img file="US2007004635A1_D0622.tif" /></chemistry>

0719A solution of Boc-tert-Leu 1f (Fluka, 5.0 g, 21.6 mmol) in dry CH₂Cl₂/DMF (50 mL, 1:1) was cooled to 0° C. and treated with the amine hydrochloride 1e (5.3 g, 25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The reaction was stirred at rt. for 24 h, diluted with aqueous HCl (1 M) and extracted with CH₂Cl₂. The combined organic layers were washed with aqueous 1M HCl, saturated NaHCO₃, brine, dried (MgSO₄), filtered and concentrated in vacuo and purified by chromatography (SiO₂, Acetone/Hexane 1:5) to yield 1g as a colorless solid. <br /> Step E <chemistry id="CHEM-US-00624" num="624"><img file="US2007004635A1_D0623.tif" /></chemistry>

0720A solution of methyl ester 1g (4.0 g, 10.46 mmol) was dissolved in 4M HCl in dioxane and stirred at rt. for 3 h. The reaction mixture was concentrated in vacuo to obtain the amine hydrochloride salt, 1 h which was used without purification. <br /> Step F <chemistry id="CHEM-US-00625" num="625"><img file="US2007004635A1_D0624.tif" /></chemistry>

0721A solution of acid 1d (100 mg) in 5 mL of dry dichloromethane and 5 mL of dry DMF was stirred at 0° C. and treated with HATU (1.4 eq, 202 mg). The amine hydrochloride 1 h (1.2 eq, 146 mg) was added. Then, N-methylmorpholine (4 eq, 0.17 mL, d 0.920) was also added. The reaction mixture was stirred at 0° C. overnight. All the volatiles were removed under vacuum and the residue was dissolved in 80 mL of ethyl acetate. The organic layer was washed with water (10 mL), aqueous 1N HCl (10 mL), aqueous saturated sodium bicarbonate solution (10 mL), and brine (10 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; 1:9 to 4:6) to afford the product 1i as a white solid. <chemistry id="CHEM-US-00626" num="626"><img file="US2007004635A1_D0625.tif" /></chemistry>

0722A solution of methyl ester 1i (180 mg) in 9 mL of a 1:1:1 mixture of THF/MeOH/water was cooled to 0° C. and treated with lithium hydroxide monohydrate (2.5 eq, 35 mg). The mixture was stirred and monitored by TLC (acetone/hexanes; 3:7). When all the starting material had been consumed, the reaction mixture was treated with 50 mL of aqueous 1N HCl and the mixture was concentrated on the rotavap. Dichloromethane (80 mL) was added and layers separated. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the product 1j as a white solid. <br /> Step H <chemistry id="CHEM-US-00627" num="627"><img file="US2007004635A1_D0626.tif" /></chemistry>

0723A solution of acid 1k (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 to 50° C. overnight. The reaction mixture was concentrated to half its volume and diluted with 400 mL of ethyl acetate. The organic layer was washed with water (80 mL), aqueous 1M HCl (80 mL), aqueous saturated 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 afford the product 1l as a clear oil. <br /> Step I <chemistry id="CHEM-US-00628" num="628"><img file="US2007004635A1_D0627.tif" /></chemistry>

0724A solution of amide 1l (2.2 g) in 100 mL of dry THF was cooled to ° C. Lithium aluminum hydride solution (1.3 eq) was added dropwise. The cooling bath was removed after 5 min and the mixture was allowed to reach room temperature. TLC analysis (ethyl acetate/hexanes; 2:8) showed that all the starting material had been consumed. The excess LAH was carefully quenched by addition of drops of aqueous saturated sodium hydrogen sulfate. The mixture was diluted with 200 mL of ether and aqueous saturated sodium hydrogen sulfate was added in small portions until a white solid precipitated. The mixture was filtered thru celite 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 afford the aldehyde product 1m as a colorless oil. <br /> Step J <chemistry id="CHEM-US-00629" num="629"><img file="US2007004635A1_D0628.tif" /></chemistry>

0725A solution of aldehyde 1m (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 the volatiles were removed under vacuum and the residue was chromatographed on silica gel (gradient: ethyl acetate/hexanes; 2:8 to 6:4) to afford the product 1n as a white solid. <br /> Step K <chemistry id="CHEM-US-00630" num="630"><img file="US2007004635A1_D0629.tif" /></chemistry>

0726A solution of acetate 1n (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 approximately 1 h until all the starting material had been consumed as determined by TLC analysis (ethyl acetate/hexanes; 1:1). The volatiles were removed in rotavap and the residue was diluted with dichloromethane (150 mL). The layers were separated and the aqueous layer was diluted with 30 mL of aqueous saturated sodium bicarbonate solution and extracted with dichloromethane (3×80 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the product 1p as a white solid. <br /> Step L <chemistry id="CHEM-US-00631" num="631"><img file="US2007004635A1_D0630.tif" /></chemistry>

0727The N-Boc protected amine 1p (1.5 g) was dissolved in 20 mL of 4M HCl in dioxane. The reaction mixture was stirred for about 1 h until all the starting material had been consumed. All the volatiles were removed under vacuum to afford the product 1q as a white solid. <br /> Step M <chemistry id="CHEM-US-00632" num="632"><img file="US2007004635A1_D0631.tif" /></chemistry>

0728A solution of acid 1j (50 mg) in 2 mL of dry dichloromethane and 2 mL of dry DMF was stirred at 0° C. and treated with HATU (1.4 eq, 52 mg). The amine hydrochloride 1q (1.2 eq, 26 mg) was added. Then, N-methylmorpholine (4 eq, 0.042 mL, d 0.920) was also added. The reaction mixture was stirred at 0° C. overnight. All the volatiles were removed under vacuum and the residue was dissolved in 80 mL of ethyl acetate. The organic layer was washed with water (10 mL), aqueous 1N HCl (10 mL), aqueous saturated 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 1r was used without further purification. <br /> Step N <chemistry id="CHEM-US-00633" num="633"><img file="US2007004635A1_D0632.tif" /></chemistry>

0729A solution of alcohol 1r (65 mg) in 5 mL of dry dichloromethane was treated with Dess-Martin periodinane (3 eq, 121 mg). Reaction mixture was stirred at room temperature for 45 min. The mixture was treated with aqueous 1 M sodium thiosulfate solution (10 mL) and aqueous saturated sodium bicarbonate solution (10 mL) and stirred for 15 min. The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 2:8 to 5:5) to afford the product 1 as a white solid.

0730One skilled in the art would understand that other suitable compounds of Formula XV can be prepared in a similar manner to that disclosed above.

0731The following experimental section applies for the preparation of the compounds of Formula XVI:

Preparative Example A

0732<chemistry id="CHEM-US-00634" num="634"><img file="US2007004635A1_D0633.tif" /></chemistry><br /> Step 1 <chemistry id="CHEM-US-00635" num="635"><img file="US2007004635A1_D0634.tif" /></chemistry>

0733A 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). The 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 the volatiles were removed under vacuum and the residue was taken into 100 mL of ethyl acetate. The organic layer was washed with aqueous 1 N HCl (15 mL), aqueous saturated NaHCO3 (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford the desired product A1. No further purification was carried out for the product. <br /> Step 2 <chemistry id="CHEM-US-00636" num="636"><img file="US2007004635A1_D0635.tif" /></chemistry>

0734A 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). Reaction mixture was stirred at room temperature for about 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with aqueous saturated NaHCO₃(15 mL), aqueous 1N HCl (15 mL), and brine (15 mL). The organic layer was dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone/hexanes; 2:8 to 5:5) to afford the product A2 in 84% yield. <br /> Step 3 <chemistry id="CHEM-US-00637" num="637"><img file="US2007004635A1_D0636.tif" /></chemistry>

0735The N-Boc protected amine A2 was treated with 10 mL of formic acid. The resulting solution was stirred for 2 h. All the volatiles were removed under reduced pressure. No further purification was done for the product A3. <br /> Step 4 <chemistry id="CHEM-US-00638" num="638"><img file="US2007004635A1_D0637.tif" /></chemistry>

0736To 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 0.135M soln) was slowly added. The mixture was stirred for 2 h (temp 0 to 25° C.). The reaction mixture was diluted with 60 mL of dichloromethane and washed with 15 mL of aqueous 1N HCl. Aqueous layer was back extracted with dichloromethane (2×20 mL). 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 the product A (15 mg) as a white solid in 20% yield. HRMS (FAB) calcd for C₃₇H₅₃N₆O₇[M+H] 693.3976; found 693.3987.

0737One skilled in the art would understand that other suitable compounds of Formula XVI can be prepared in a similar manner to that disclosed above.

0738The following experimental section applies for the preparation of the compounds of Formula XVII:

0739Abbreviations which are used in the descriptions of the schemes, preparations and the examples that follow are: <ul id="ul0014" list-style="none"><li id="ul0014-0001" num="0740"> THF: Tetrahydrofuran </li><li id="ul0014-0002" num="0741"> DMF: N,N-Dimethylformamide </li><li id="ul0014-0003" num="0742"> EtOAc: Ethyl acetate </li><li id="ul0014-0004" num="0743"> AcOH: Acetic acid </li><li id="ul0014-0005" num="0744"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one </li><li id="ul0014-0006" num="0745"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0014-0007" num="0746"> NMM: N-Methylmorpholine </li><li id="ul0014-0008" num="0747"> ADDP: 1,1′-(Azodicarbobyl)dipiperidine </li><li id="ul0014-0009" num="0748"> DEAD: Diethylazodicarboxylate </li><li id="ul0014-0010" num="0749"> MeOH: Methanol </li><li id="ul0014-0011" num="0750"> EtOH: Ethanol </li><li id="ul0014-0012" num="0751"> Et2O: Diethyl ether </li><li id="ul0014-0013" num="0752"> DMSO: Dimethylsulfoxide </li><li id="ul0014-0014" num="0753"> HOBt: N-Hydroxybenzotriazole </li><li id="ul0014-0015" num="0754"> PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate </li><li id="ul0014-0016" num="0755"> DCM: Dichloromethane </li><li id="ul0014-0017" num="0756"> DCC: 1,3-Dicyclohexylcarbodiimide </li><li id="ul0014-0018" num="0757"> TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy </li><li id="ul0014-0019" num="0758"> Phg: Phenylglycine </li><li id="ul0014-0020" num="0759"> Chg: Cyclohexylglycine </li><li id="ul0014-0021" num="0760"> Bn: Benzyl </li><li id="ul0014-0022" num="0761"> Bzl: Benzyl </li><li id="ul0014-0023" num="0762"> Et: Ethyl </li><li id="ul0014-0024" num="0763"> Ph: Phenyl </li><li id="ul0014-0025" num="0764"> iBoc: isobutoxycarbonyl </li><li id="ul0014-0026" num="0765"> iPr: isopropyl </li><li id="ul0014-0027" num="0766">^tBu or Bu^t: tert-Butyl </li><li id="ul0014-0028" num="0767"> Boc: tert-Butyloxycarbonyl </li><li id="ul0014-0029" num="0768"> Cbz: Benzyloxycarbonyl </li><li id="ul0014-0030" num="0769"> Cp: Cylcopentyldienyl </li><li id="ul0014-0031" num="0770"> Ts: p-toluenesulfonyl </li><li id="ul0014-0032" num="0771"> Me: Methyl </li></ul>

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

DMAP: 4-N,N-Dimethylaminopyridine

0000<ul id="ul0015" list-style="none"><li id="ul0015-0001" num="0772"> BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate </li><li id="ul0015-0002" num="0773"> PCC: Pyridiniumchlorochromate </li><li id="ul0015-0003" num="0774"> KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethylsilylamide) </li><li id="ul0015-0004" num="0775"> NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide) </li><li id="ul0015-0005" num="0776"> LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide) </li><li id="ul0015-0006" num="0777"> 10% Pd/C: 10% Palladium on carbon (by weight). </li><li id="ul0015-0007" num="0778"> TG: Thioglycerol <br /> General Schemes for Preparation of Target Compounds </li></ul>

0779Compounds of the present invention were synthesized using the general schemes (Methods A-E) described below.

0000Method A

0780Deprotection of the N-Boc functionality of 1.01 under acidic conditions provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine under peptide coupling methodology to afford 1.03. N-Boc deprotection followed by treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the appropriate P₁—P′ primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffatt oxidation or related process—see, T. T. Tidwell, Synthesis, 1990, 857), or Dess-Martin Periodinane—<i>J. Org. Chem., (</i>1983) 48, 4155) resulted in the target compound 1.08. <chemistry id="CHEM-US-00639" num="639"><img file="US2007004635A1_D0638.tif" /></chemistry><chemistry id="CHEM-US-00640" num="640"><img file="US2007004635A1_D0639.tif" /></chemistry><br /> Method B

0781Peptide coupling of the acid 1.06 with the appropriate P₁—P′ secondary amide moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's) resulted in the target compound 1.10. <chemistry id="CHEM-US-00641" num="641"><img file="US2007004635A1_D0640.tif" /></chemistry><br /> Method C

0782In another variation, peptide coupling of the N-Boc-P2-P₃-acid 1.17 with the appropriate P₁—P′ amide moiety afforded the hydroxyl amide 1.11. Oxidation (Moffatt or Dess-Martin Periodinane) resulted in the keto amide 1.12. Deprotection of the N-Boc functionality gave the hydrochloride salt 1.13. Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target compound 1.14. <chemistry id="CHEM-US-00642" num="642"><img file="US2007004635A1_D0641.tif" /></chemistry><br /> Method D

0783In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 1.14. <chemistry id="CHEM-US-00643" num="643"><img file="US2007004635A1_D0642.tif" /></chemistry><br /> Method E

0784In yet another variation, the dipeptide hydrochloride salt 1.03 was converted to the 4-nitrophenyl carbamate as described above. Treatment with an amine (or amine hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis and further elaboration as described in Methods A/B provided the target compounds 1.14. <chemistry id="CHEM-US-00644" num="644"><img file="US2007004635A1_D0643.tif" /></chemistry>

0785The following experimental section applies for the preparation of the compounds of Formula XVIII:

Example 3

Preparation of Compound of Formula 3

0786<chemistry id="CHEM-US-00645" num="645"><img file="US2007004635A1_D0644.tif" /></chemistry>

0787To a cooled solution (0° C.) of the intermediates 1.06 (75.0 mg, 0.2 mmol) and 1.09 (100.0 mg, 0.36 mmol) in DMF (5.0 mL) was added HATU (Aldrich, 76.05 mg, 0.20 mmol), followed by DIPEA (0.102 mL, 6 mmol). The reaction mixture was stirred for two days then warmed up to room temperature, diluted with ethyl acetate (40.0 mL), washed with 5% KH₂PO₄containing 0.05 vol. of 1M H₃PO₄and brine. Organic layer was dried over MgSO₄, filtered and concentrated to dryness. Residue was purified over silica gel using acetone-CH₂Cl₂(1:9 to 1:1) to get 8.0 mg of product of formula 3(6.5% yield); LCMS: (590.1).

0788One skilled in the art would understand that other suitable compounds of Formula XVIII can be prepared in a similar manner to that disclosed above.

0789The following experimental section applies for the preparation of the compounds of Formula XIX:

Synthesis of Preparative Examples

Synthesis of Example 101

0790Step 1 <chemistry id="CHEM-US-00646" num="646"><img file="US2007004635A1_D0645.tif" /></chemistry>

0791To a stirred solution of the proline derivative 1.01 (3.66 mmol, prepared as described above) in dichloromethane (20 mL) and DMF (15 mL) at 0° C. was added L-boc-tert-leucine (930 mg, 4.03 mmol), DIPEA (2.02 mL, 10.98 mmol) and HATU (1.8 g, 4.76 mmol). After 15 minutes at that temperature, the reaction flask was stored in the freezer (−20° C), overnight (16 hr). The reaction mixture was diluted with dichloromethane (80 mL) and washed with saturated sodium bicarbonate solution (80 mL), 10% aq. citric acid solution (80 mL), brine (80 mL), dried (Na₂SO₄), filtered and concentrated. The crude material was purified by silica chromatography using 25/75 to 50/50 EtOAc/hexanes to provide 1.77 g of the required material, 101a. LC-MS: 518.1 (M+H)⁺. <br /> Step 2 <chemistry id="CHEM-US-00647" num="647"><img file="US2007004635A1_D0646.tif" /></chemistry>

0792To a solution of the methyl ester 101a (1.21 g, 2.34 mmol) in THF (10 mL) and MeOH (5 mL) was added aq. 1M LiOH solution (5 mL). The reaction mixture was stirred at RT for 4 h. It was then concentrated, diluted with water (50 mL) and acidified with solid citric acid (pH approximately 3) when white solid material crashed out. This solid was filtered off, washed with water and dried in vacuo to afford 970 mg of 101b. LC-MS: 504.1 (M+H)⁺. <br /> Step 3 <chemistry id="CHEM-US-00648" num="648"><img file="US2007004635A1_D0647.tif" /></chemistry>

0793The acid 101b (503 mg, 1 mmol) was coupled with intermediate 13.06 (334 mg, 1.5 mmol) using essentially procedure described above (Step 1, preparation of 101a) to provide 101c which was used without purification. MS: 672.37 (M+H)⁺. <br /> Step 4 <chemistry id="CHEM-US-00649" num="649"><img file="US2007004635A1_D0648.tif" /></chemistry>

0794To a solution of the hydroxyl compound 101c from above in dichloromethane (15 mL) was added Dess-Martin's periodinane (848 mg, 2 mmol) and the reaction mixture was stirred at RT for 5 h. At this time, the reaction mixture was diluted with dichloromethane (30 mL) and washed with 1:1 mixture of aq. 10% sodium thiosulfate solution and saturated sodium bicarbonate solution (2×25 mL each), brine (50 mL), dried (Na₂SO₄), filtered and concentrated. The crude material was purified by silica chromatography using 15/85 to 50/50 acetone/hexanes to provide 410 mg of the required material, 101d. LC-MS: 670.2 (M+H)⁺. <br /> Step 5 <chemistry id="CHEM-US-00650" num="650"><img file="US2007004635A1_D0649.tif" /></chemistry>

0795Deprotection of the N-boc functionality of 101d to provide the required material 101e was carried out as described for intermediate 1.01, Step 3 (reaction time=2 h). LC-MS: 570.1 (M+H)⁺. <br /> Step 6 <chemistry id="CHEM-US-00651" num="651"><img file="US2007004635A1_D0650.tif" /></chemistry>

0796To a solution of the amine salt 101e (60 mg, 0.1 mmol) in dichloromethane (2 mL) at 0° C. was added DIPEA (0.06 mL, 0.3 mmol) followed by the isocyanate intermediate 65.01 (0.25 M solution in toluene, 0.8 mL, 0.2 mmol). After 15 minutes at that temperature, the reaction flask was stored in the freezer (−20° C.), overnight (16 hr). The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated ammonium chloride solution (20 mL), brine (20 mL), dried (Na₂SO₄), filtered and concentrated. The crude material was purified by silica chromatography using 15/85 to 50/50 acetone/hexanes to provide the required compound 101 (53 mg); LC-MS: 872.2 (M+H)⁺.

0797One skilled in the art would understand that other suitable compounds of Formula XIX can be prepared in a similar manner to that disclosed above.

0798The following experimental section applies for the preparation of the compounds of Formulae Ia, Ib and Ic:

0000Abbreviations:

0799Abbreviations which are used in the descriptions of the schemes, preparations and the examples that follow are: <ul id="ul0016" list-style="none"><li id="ul0016-0001" num="0800"> THF: Tetrahydrofuran </li><li id="ul0016-0002" num="0801"> DMF: N,N-Dimethylformamide </li><li id="ul0016-0003" num="0802"> EtOAc: Ethyl acetate </li><li id="ul0016-0004" num="0803"> AcOH: Acetic acid </li><li id="ul0016-0005" num="0804"> HOOBt: 3-Hydroxy-1,2,3-benzotriazin4(3H)-one </li><li id="ul0016-0006" num="0805"> EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride </li><li id="ul0016-0007" num="0806"> NMM: N-Methylmorpholine </li><li id="ul0016-0008" num="0807"> MeOH: Methanol </li><li id="ul0016-0009" num="0808"> EtOH: Ethanol </li><li id="ul0016-0010" num="0809"> Et2O: Diethyl ether </li><li id="ul0016-0011" num="0810"> DMSO: Dimethylsulfoxide </li><li id="ul0016-0012" num="0811"> K^tBuO: Potassium tert-butoxide </li><li id="ul0016-0013" num="0812"> DCM: Dichloromethane </li><li id="ul0016-0014" num="0813"> Chg: Cyclohexylglycine </li><li id="ul0016-0015" num="0814"> Bn: Benzyl </li><li id="ul0016-0016" num="0815"> Et: Ethyl </li><li id="ul0016-0017" num="0816"> Ph: Phenyl </li><li id="ul0016-0018" num="0817"> iPr: isopropyl </li><li id="ul0016-0019" num="0818">^tBu or Bu^t: tert-Butyl </li><li id="ul0016-0020" num="0819"> Boc: tert-Butyloxycarbonyl </li><li id="ul0016-0021" num="0820"> Cbz: Benzyloxycarbonyl </li></ul>

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

0821BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate 10% Pd/C: 10% Palladium on carbon (by weight).

EXAMPLE

Synthesis of (1R,5S)-N-[3-Amino-1-(Cyclobutylmethyl)-2,3-Dioxopropyl]-3-[2(S)-[[[(1,1-Dimethylethyl)Amino]Carbonyl]Amino]-3,3-Dimethyl-1-Oxobutyl]-6,6-Dimethyl-3-Azabicyclo[3.1.01Hexan-2(S)-Carboxamide (Structure 1a)

0822<chemistry id="CHEM-US-00652" num="652"><img file="US2007004635A1_D0651.tif" /></chemistry><br /> Step 1. <chemistry id="CHEM-US-00653" num="653"><img file="US2007004635A1_D0652.tif" /></chemistry>

0823A stirred solution of the ketimime 1a′ (50 g, 187.1 mmol, available from Aldrich Chemical Company, Milwaukee, Wis.) under N₂in dry THF (400 mL) was cooled to −78° C. and treated with 1 M solution of K-^tBuO (220 mL, 1.15 equiv.) in THF. The reaction mixture was warmed to 0° C. and stirred for 1 h and treated with bromomethylcyclobutane (28 mL, 249 mmol). The reaction mixture was stirred at room temperature for 48 h and concentrated in vacuo. The residue was dissolved in Et₂O (300 mL) and treated with aq. HCl (2 M, 300 mL) The resulting solution was stirred at room temperature for 5 h and extracted with Et₂O (1 L). The aqueous layer was made basic to pH ˜12-14 with aq. NaOH (50%) and extracted with CH₂Cl₂(3×300 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated to give pure amine (1b′, 18 g) as a colorless oil. <br /> Step 2. <chemistry id="CHEM-US-00654" num="654"><img file="US2007004635A1_D0653.tif" /></chemistry>

0824A solution of the amine 1b′ (1 8g, 105.2 mmol) at 0° C. in CH₂Cl₂(350 mL) was treated with di-tert-butyldicarbonate (23 g, 105.4 mmol) and stirred at rt. for 12 h. After the completion of the reaction (TLC), the reaction mixture was concentrated in vacuo and the residue was dissolved in THF/H₂O (200 ml, 1:1) and treated with LiOH.H₂O (6.5 g, 158.5 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the basic aqueous layer was extracted with Et₂O. The aqueous layer was acidified with conc. HCl to pH˜1-2 and extracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo to yield 1c′ as a colorless viscous oil which was used for next step without any further purification. <br /> Step 3. <chemistry id="CHEM-US-00655" num="655"><img file="US2007004635A1_D0654.tif" /></chemistry>

0825A solution of the acid 1c′ (15.0 g, 62 mmol) in CH₂Cl₂(250 mL) was treated with BOP reagent (41.1 g, 93 mmol), N-methylmorpholine (27 mL), N,O-dimethyl hydroxylamine hydrochloride (9.07 g, 93 mmol) and stirred overnight at rt. The reaction mixture was diluted with 1 N aq. HCl (250 mL), and the layers were separated and the aqueous layer was extracted with CH₂Cl₂(3×300 ml). The combined organic layers were dried (MgSO₄), filtered, concentrated in vacuo and purified by chromatography (SiO₂, EtOAc/Hex 2:3) to yield the amide 1d (15.0 g) as a colorless solid. <br /> Step 4. <chemistry id="CHEM-US-00656" num="656"><img file="US2007004635A1_D0655.tif" /></chemistry>

0826A solution of the amide 1d (15 g, 52.1 mmol) in dry THF (200 mL) was treated dropwise with a solution of LiAlH₄(1 M, 93 mL, 93 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1h and carefully quenched at 0° C. with a solution of KHSO₄(10% aq.) and stirred for 0.5 h. The reaction mixture was diluted with aq. HCl (1 M, 150 mL) and extracted with CH₂Cl₂(3×200 mL), The combined organic layers were washed with aq. HCl (1 M), saturated NaHCO₃, brine, and dried (MgSO₄). The mixture was filtered and concentrated in vacuo to yield 1e as viscous colorless oil (14 g). <br /> Step 5. <chemistry id="CHEM-US-00657" num="657"><img file="US2007004635A1_D0656.tif" /></chemistry>

0827A solution of the aldehyde 1e (14 g, 61.6 mmol) in CH₂Cl₂(50 mL), was treated with Et₃N (10.73 mL, 74.4 mmol), and acetone cyanohydrin (10.86 g, 127.57 mmol) and stirred at room temperature for 24 hrs. The reaction mixture was concentrated in vacuo and diluted with aq. HCl (1 M, 200 mL) and extracted into CH₂Cl₂(3×200 mL). The combined organic layer were washed with H₂O, brine, dried (MgSO₄), filtered, concentrated in vacuo and purified by chromatography (SiO₂, EtOAc/Hex 1:4) to yield 1f (10.3 g) as a colorless liquid as a mixture of diastereomers. <br /> Step 6. <chemistry id="CHEM-US-00658" num="658"><img file="US2007004635A1_D0657.tif" /></chemistry>

0828Methanol saturated with HCl*, prepared by bubbling HCl gas to CH₃OH (700 ml) at 0° C., was treated with cyanohydrin 1f and heated to reflux for 24 h. The reaction was concentrated in vacuo to yield 1g, which was used in the next step without purification.

0829Alternatively 6M HCl prepared by addition of AcCl to dry methanol can also be used. <br /> Step 7. <chemistry id="CHEM-US-00659" num="659"><img file="US2007004635A1_D0658.tif" /></chemistry>

0830A solution of the amine hydrochloride 1g 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 (2 M, 200 mL) and extracted into CH₂Cl₂. The combined organic layers were dried (MgSO₄) filtered, concentrated in vacuo and purified by chromatography (EtOAc/Hex 1:4) to yield hydroxy ester 1h. <br /> Step 8. <chemistry id="CHEM-US-00660" num="660"><img file="US2007004635A1_D0659.tif" /></chemistry>

0831A solution of methyl ester 1h (3g, 10.5 mmol) in THF/H₂O (1:1) was treated with LiOH.H₂O (645 mg, 15.75 mmol) and stirred at rt. for 2 h. The reaction mixture was acidified with aq HCl (1 M, 15 mL) and concentrated in vacuo. The residue was dried in vacuum.

0832A solution of the acid in CH₂Cl₂(50 mL) and DMF (25 mL) was treated with NH₄Cl (2.94 g, 5.5 mmol), EDCl (3.15 g, 16.5 mmol), HOOBt (2.69 g, 16.5 mmol), and NMM (4.4 g, 44 mmol). The reaction mixture was stirred at room temperature for 3 d. The solvents were removed under vacuo and the residue was diluted with aq. HCl (250 mL) and extracted with CH₂Cl₂. The combined organic layers were washed with aq. saturated NaHCO₃, dried (MgSO₄) filtered concentrated in vacuo to obtain 1i, which was used as it is in the following steps. (Alternatively 1i can also be obtained directly by the reaction of 1f (4.5 g, 17.7 mmol) with aq. H₂O₂(10 mL), LiOH.H₂O (820 mg, 20.8 mmol) at 0° C. in 50 mL of CH₃OH for 0.5 h.) <br /> Step 9. <chemistry id="CHEM-US-00661" num="661"><img file="US2007004635A1_D0660.tif" /></chemistry>

0833A solution of 1i obtained in the previous step was dissolved in 4 N HCl in dioxane and stirred at rt. for 2 h. The reaction mixture was concentrated in vacuo to give 1j as a solid, which was used without further purification. <br /> Step 10. <chemistry id="CHEM-US-00662" num="662"><img file="US2007004635A1_D0661.tif" /></chemistry>

0834The amino ester 1l was prepared following the method of R. Zhang and J. S. Madalengoitia (<i>J. Org. Chem. </i>1999, 64, 330), with the exception that the Boc group was cleaved by the reaction of the Boc-protected amino acid with methanolic HCl.

0835A solution of Boc-tert-Lue 1k (Fluka, 5.0 g 21.6 mmol) in dry CH₂Cl₂/DMF (50 mL, 1:1) was cooled to 0° C. and treated with the amine 1l (5.3 g, 25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The reaction was stirred at rt. for 24 hrs, diluted with aq. HCl (1 M) and extracted with CH₂Cl₂. The combined organic layers were washed with HCl (aq, 1 M), saturated NaHCO₃, brine, dried (MgSO₄), filtered and concentrated in vacuo and purified by chromatography (SiO₂, acetone/hexane 1:5) to yield 1m as a colorless solid. <br /> Step 11. <chemistry id="CHEM-US-00663" num="663"><img file="US2007004635A1_D0662.tif" /></chemistry>

0836A solution of methyl ester 1m (4.0 g, 10.46 mmol) was dissolved in HCl (4 M solution in dioxane) and stirred at rt. for 3 h. The reaction mixture was concentrated in vacuo to obtain the amine hydrochloride salt used in the next step without further purification.

0837A solution of the amine hydrochloride salt (397 mg, 1.24 mmol) in CH₂Cl₂(10 mL) was cooled to −78° C. and treated with tert-butyl isocyanate (250 mg, 2.5 mmol) and stirred at rt. overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with aq. HCl (1M) and extracted with CH₂Cl₂. The combined organic layers were washed with aq. HCl (1M), saturated NaHCO₃and brine. The organic layers were dried, filtered and concentrated in vacuo and the residue was purified by chromatography (SiO₂, acetone/Hex 1:4) to yield 1n as a colorless solid. <br /> Step 12. <chemistry id="CHEM-US-00664" num="664"><img file="US2007004635A1_D0663.tif" /></chemistry>

0838A solution of methyl ester 1n (381 mg, 1.0 mmol) in THF/H₂O (1:1, 5 mL) was treated with LiOH.H₂O (62 mg, 1.5 mmol) and stirred at rt. for 3 h. The reaction mixture was acidified with aq. HCl and concentrated in vacuo to obtain the free acid.

0839A solution of acid (254.9 mg, 0.69 mmol) in DMF/CH₂Cl₂(1:1, 5.0 mL) was treated with amine 1j (159 mg, 0.763 mmol), EDCl (199 mg, 1.04 mmol), HOOBt (169.5 mg, 1.04 mmol) and NMM (280 mg, 2.77 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 48 h and concentrated in vacuo. The residue was diluted with aq. 1M HCl and extracted with EtOAc, The combined organic layers were extracted with aq. NaHCO₃, aq. HCl, brine, dried (MgSO₄) filtered, concentrated in vacuo to obtain 1o (470 mg) as a tan colored solid that was used in the next reaction without further purification. <br /> Step 13. <chemistry id="CHEM-US-00665" num="665"><img file="US2007004635A1_D0664.tif" /></chemistry>

0840A solution of amide 1o (470 mg, 0.9 mmol) in toluene and DMSO (1:1 20 mL) at 0° C. was treated with EDCl (1.72 g, 9.0 mmol) and dichloroacetic acid (0.37 mL, 4.5 mmol) and stirred at 0° C. for 4 hrs. The reaction mixture was diluted with CH₂Cl₂, and washed with saturated NaHCO₃, and brine. The organic layer was dried (MgSO₄), filtered, concentrated, in vacuo and purified by chromatography (SiO₂, acetone/hexanes 3:7) to yield 1a as a colorless solid. <br /> Separation of the Compound of Formula 1 Into Diastereomers of Formulas Ib and Ic: <chemistry id="CHEM-US-00666" num="666"><img file="US2007004635A1_D0665.tif" /></chemistry>

Preparative HPLC Condition for Separation

0841COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN <ul id="ul0017" list-style="none"><li id="ul0017-0001" num="0000"><ul id="ul0018" list-style="none"><li id="ul0018-0001" num="0842"> 120 Å, S-10/20; 50 mm×500 mm I.D/length </li></ul></li></ul>

0843SOLVENT A: Hexanes

0844SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol+300 mL of <ul id="ul0019" list-style="none"><li id="ul0019-0001" num="0000"><ul id="ul0020" list-style="none"><li id="ul0020-0001" num="0845"> CH₃CN+2 L of CH₂Cl₂) </li></ul></li></ul>

0846HPLC CONDITIONS: 12% of Solvent B/88% of Solvent A

0847FLOW: 120 mL/min

0848Procedure: 1 g of compound la was dissolved in 10 mL of CH₂Cl₂/25 mL of Hexanes and injected into the column. It was eluted with 120 mL/min and two peaks were independently collected and concentrated. The solid residue was further dried in high vacuum and analyzed by analytical HPLC. Since the polar (second isomer) contained 2.6% of nonpolar diastereomer (First isomer), it was purified once more to isolate the pure diastereomers.

0000Analytical Conditions for Analysis of Diastereomeric Purity

0849COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN <ul id="ul0021" list-style="none"><li id="ul0021-0001" num="0000"><ul id="ul0022" list-style="none"><li id="ul0022-0001" num="0850"> 200 Å, S-5 □M; 150 mm×3 mm length/I.D </li></ul></li></ul>

0851SOLVENT A: Hexanes

0852SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol+300 mL of <ul id="ul0023" list-style="none"><li id="ul0023-0001" num="0000"><ul id="ul0024" list-style="none"><li id="ul0024-0001" num="0853"> CH₃CN+2 L of CH₂Cl₂) </li></ul></li></ul>

0854HPLC CONDITIONS: 8.5% of Solvent B/91.5% of Solvent A

0855FLOW: 0.7 mL/min

0856Rt Nonpolar isomer (compound 1b)=13.2 min <ul id="ul0025" list-style="none"><li id="ul0025-0001" num="0000"><ul id="ul0026" list-style="none"><li id="ul0026-0001" num="0857"> Polar isomer (compound 1c)=16.1 min </li></ul></li></ul>

08582.5 mg of compound in 1 mL was used and 20 μL was injected and analyzed with a

0859U.V detector at λ=254 nm.

0000Analytical Data for Compounds 2 and 3.

0000Compound 3 [Polar Diastereomer]

0860¹H NMR (d₆-dmso, 500 MHz): δ 8.26 (d, 1 H, J=7.0 Hz), 8.00 (s, 1 H), 7.75 (s, 1 H), 5.96 (s, 1 H), 5.84 (d, 1 H, J=10 Hz), 4.96 (m, 1 H), 4.28 (s, 1H), 4.11 (d, 1 H, J=11 Hz), 3.94 (d, 1H, J=10 Hz), 3.73 (dd, 1 H, J=10 &amp; 5 Hz), 2.48 (m, 1 H), 1.95 (m, 2 H), 1.61 (m, 1 H), 1.59 (m, 1 H), 1.77(m, 1 H), 1.57 (m, 1 H), 1.74 (m, 2 H), 1.42 (dd, 1 H, J=7.5 &amp; 5 Hz), 1.28 (d, 1 H, J=7.5 Hz), 1.17 (s, 9 H), 1.01 (s, 3 H), 0.90 (s, 9 H), 0.85 (s, 3 H). ¹³C NMR (d₆-dmso, 125 MHz): δ 197.8, 170.9, 170.8, 162.8, 157.4, 59.1, 56.8, 51.8, 48.9, 47.4, 36.7, 34.0, 32.0, 30.6, 29.1, 27.8, 27.3, 27.1, 26.4, 26.1, 18.5, 17.7, 12.5. MS [FAB] 520 (55), 421 (100), 308 (75), 213 (90). HRMS calcd for C₂₇H₄₆O₅N₅[M+1]⁺520.3499; observed: 520.3505.

Compound 2 [Non-Polar Diastereomer]

0861¹H NMR (d₆-dmso, 500 MHz): δ 8.15 (d, 1 H, J=7.0 Hz), 7.96 (s, 1 H), 7.74 (s, 1 H), 5.96 (s, 1 H), 5.86 (d, 1 H, J=10 Hz), 4.85 (m, 1 H), 4.27 (s, 1H), 4.13 (d, 1 H, J=11.0 Hz), 3.97 (d, 1H, J=10 Hz), 3.76 (dd, 1 H, J=10 &amp; 5 Hz), 2.36 (m, 1 H), 1.97 (m, 2 H), 1.60 (m, 2 H), 1.78 (m, 1 H), 1.64 (m, 1 H), 1.75 (m, 2 H), 1.44 (dd, 1 H, J=7.5 &amp; 5 Hz), 1.27 (d, 1 H, J=7.5 Hz), 1.17 (s, 9 H), 1.00 (s, 3 H), 0.89 (s, 9 H), 0.82 (s, 3 H). ¹³C NMR (d₆-dmso125 MHz): δ 197.1, 171.1, 170.7, 163.0, 157.3, 59.4, 56.9, 52.1, 48.9, 47.4, 36.6, 34.0, 32.1, 30.5, 29.1, 27.9, 27.4, 26.8, 26.4, 26.1, 18.5, 17.8, 12.4. MS [FAB] 520 (40), 421 (100), 308 (60), 213 (65). HRMS calcd. for C₂₇H₄₆O₅N₅[M+1]⁺520.3499; observed: 520.3514.

0862Although the invention has been described with particularity above, the following Examples are illustrative.

EXAMPLES

Example 1

0863A rising multiple dose study was conducted in four groups of non-responder patients in which 100, 200 and 400 mg BID and 400 mg TID dosages of the compound of Formula la were administered for 14 days. For the purpose of this study “non-responder” was defined to mean “a patient exhibiting failure to achieve at least about a 2 log drop versus baseline viral load despite at least twelve weeks of PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day).” In practice, the application of this definition accommodated a 0.5 log variation of the definition, however, so that if an individual patient achieved as high as a 2.5 log drop versus baseline, or anywhere between 2 and 2.5 log drop versus baseline viral load despite at least twelve weeks of PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day), it was within the discretion of the investigator to denominate the patient as a “non-responder.” A flow diagram showing screening for non-responders is shown in <figref idref="DRAWINGS">FIG. 3</figref>.

0864The methodology used was a randomized, placebo controlled, multi-center, third-party-blind, multiple-dose study of the compound of Formula Ia in non-responders conducted in accordance with Good Clinical Practices. For the purpose of this study, it should be noted that the non-responders also were patients in whom one or more symptoms were established in association with, or the possibility of one or more symptoms was suspected of in association with, HCV Genotype 1 (either Genotype 1a or Genotype 1b) specifically.

0865Referring now to <figref idref="DRAWINGS">FIG. 1</figref>, of the above four groups of patients in Example 1 who completed the study, the greatest decrease in viral load was seen with the 400 mg TID dose. All 10 patients in the 400 mg TID group had a viral load reduction, with an average maximum reduction of 2 logs from baseline (range 1.1 to 2.7 logs). The HCV-RNA viral load returned to baseline levels in all patients following discontinuation of the 14-day treatment.

0866In order to measure viral load, the Hepatitis C virus RNA (HCV-RNA) is measured by extracting total RNA from plasma or serum samples and using an in-house real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay with a lower limit of detection of 29 International Units (IU)/mL. The amplification target is the 5′-Untranslated region (UTR) of the HCV genome. An internal RNA control is added to each sample to assess the efficiency of RNA extraction. Appropriate negative and positive controls are added in each assay run. The assay method has been validated against the WHO International Standard for HCV. The HCV-RNA amount in a sample is reported as copies of HCV-RNA per mL of sample and also as HCV IU per mL of sample. When &lt;100 copies of HCV-RNA per mL are found, the HCV-RNA is considered to be undetectible.

0867Thus monotherapy with the compound of Formula la reduced viral load in all patients treated with the monotherapy.

Example 2

0868A second study was commenced in patients having detectible levels (<100 copies per mL tissue or fluid) HCV Genotype 1 (1a or 1b) and whom were already established as non-responders from previous trials. For the purpose of this study “non-responder” was defined to mean “a patient exhibiting failure to achieve at least about a 2 log drop versus baseline viral load despite at least twelve weeks of PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day).” In practice, the application of this definition accommodated a 0.5 log variation of the definition, however, so that if an individual patient achieved as high as a 2.5 log drop versus baseline, or anywhere between 2 and 2.5 log drop versus baseline viral load despite at least twelve weeks of PEG-Intron (pegylated interferon) 1.5 mcg/kg/week plus weight based RBV (ribavirin) (>10.6 mg/kg/day), it is within the discretion of the investigator to denominate the patient as a “non-responder.”

0869A flow diagram showing screening for non-responders is shown in <figref idref="DRAWINGS">FIG. 3</figref>. The methodology of the study was a parallel group, rising, multiple-dose, 3 period crossover (within each group) study in which subjects are treated with pegylated interferon (PEG-Intron, commercially available from Schering-Plough), 1.5 mcg/kg of the compound of Formula Ia or combination treatment of PEG-Intron 1.5 mcg/kg and the compound of Formula Ia. The doses of the compound of Formula Ia used for each group were 200 mg TID or 400 mg TID.

0870Twelve patients were treated in a random sequence with each 200 mg TID dose of the compound of Formula Ia alone for 7 days, PEG-Intron once weekly for two doses, and a combination treatment of 200 mg TID of the compound of Formula la plus PEG-Intron for 14 days. Preliminary results from the 200 mg TID dose group are illustrated in <figref idref="DRAWINGS">FIG. 2</figref>.

0871Referring now to <figref idref="DRAWINGS">FIG. 2</figref>, the mean maximum HCV-RNA reduction was 0.85 logs after administration of 7 days of the compound according for Formula la alone. PEG-Intron (1.5 mcg/kg) alone once a week for two weeks showed that the maximum viral load reduction occurred 2 days after each injection, followed by an increase toward baseline 6 days after the treatment. The greatest decrease in HCV-RNA viral load was observed when the compound according to Formula la was used in combination with PEG-Intron; the average maximum reduction was 2.4 logs (with a range of 1.0 to 4.5 logs) during the two weeks of treatment. One patient's HCV-RNA viral load level decreased by 4.5 logs and became undetectible (&lt;100 copies per mL of tissue or fluid) at the end of 14 days of therapy. The reduction in HCV-RNA when the products were used in combination exhibited a pattern similar to the PEG-Intron monotherapy but with a much steeper decrease in mean viral load for each PEG-Intron response cycle. Additionally, viral load continued to decline in the second week.

0872In conclusion, for those patients who have failed the current standard of care for the treatment of HCV, namely, interferon therapy with or without ribavirin, and for whom there are no approved therapeutic options at this writing, there remains an urgent heretofore unmet medical need to offer new therapies which may eradicate HCV infection and prevent the serious sequelae (cirrhosis, hepatocellular carcinoma, liver failure and transplant) associated with persistent infection.

0873Each document (including granted patents, published patent applications, and nonpatent publications such as journal articles) referred to in this application is incorporated in its entirety by reference for all purposes.

0874It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but is intended to cover modifications that are within the spirit and scope of the invention, as defined by the appended claims.