 Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
专利摘要:
The present invention relates to novel compounds having HCV protease inhibitory activity, and methods of making such compounds. In another aspect, the present invention relates to a pharmaceutical composition comprising the compound and a method of using the same to treat a disease associated with HCV protease. 公开号:KR20030025277A 申请号:KR10-2003-7000784 申请日:2001-07-19 公开日:2003-03-28 发明作者:삭세나아닐케이.；기리자발라반비요르무필；러비레이몬드지.；자오에드윈이.；베넷프랭크；맥코믹진핑엘.；왕하이얀；파이크러셀이.；보겐스테판엘.；찬틴-야우；류위-청；쥬쟈오닝；은조로게에프.죠지；아라사판아쇼크；파레크테잘엔.；갱굴리아쉬트케이.；첸케빈엑스.；벤카트라만스리칸쓰；바카로헨리에이.；핀토패트릭에이.；산타남바마；우완리；헨드라타시스카；후앙유후아；켐프스콧제프리；레비오딜에스터；림-윌비마르구에리타；타무라수잔와이. 申请人:쉐링 코포레이션；코르바스 인터내셔날, 인코포레이티드； IPC主号:
专利说明:
Novel peptides as NS3-serine protease inhibitors of hepatitis C virus} [2] Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus that is closely influenced as a major inducer of non-A, non-B hepatitis (NANBH), particularly blood-related NANBH (BB-NANBH). See International Publications WO 89/04669 and EP 381 216. NANBH has other forms of liver disease such as alcoholism and primary biliary cirrhosis, as well as other types of virus-induced liver diseases such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) induced liver disease. [3] Recently, HCV proteases required for polypeptide processing and viral replication have been identified, cloned and expressed (see, eg, US Pat. No. 5,712,145). These approximately 3000 amino acid polyproteins are available from nucleocapsid protein (C), envelope proteins (E1 and E2) and some non-structural proteins (NS1, 2, from amino terminus to carboxy terminus). 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 N-terminal amino acids; And (b) an RNA-dependent ATPase domain at the C-terminus of the protein. NS3 proteases are considered members of the chymotrypsin family because of their similar protein sequence, overall three-dimensional structure and catalysis mechanism. Other chymotrypsin-like enzymes are elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA and PSA. Since HCV NS3 serine protease is involved in the proteolysis of the polypeptide (polyprotein) at NS3 / NS4a, NS4a / NS4b, NS4b / NS5a and NS5a / NS5b junctions, it has been associated with producing four viral proteins during viral replication. There is. As such, HCV NS3 serine protease has become an interesting target in antiviral chemotherapy. [4] The NS4a protein, approximately 6 kda polypeptide, was found to be a cofactor for the serine protease activity of NS3. Self-cleaving of NS3 / NS4a linkages by NS3 / NS4a serine protease occurs intramolecularly (ie cis), while other cleavage sites are processed intermolecularly (ie trans). [5] Analysis of the natural cleavage site for HCV protease revealed cysteine in P1 and serine in P1 ', and these residues were strictly conserved within NS4a / NS4b, NS4b / NS5a and NS5a / NS5b junctions. . The NS3 / NS4a linkage contains threonine at P1 and serine at P1 '. Cys → Thr substitutions in NS3 / NS4a are considered because they require cis processing rather than trans processing at the linkages. See, eg, Pizzi et al. (1994) Proc. Natl. Acad. Sci (USA) 91 : 888-892, Failla et al. (1996) Folding & Design 1 : 35-42. NS3 / NS4a cleavage sites also allow for mutagenesis better than other sites. See Kollykhalov et al. (1994) J. Virol. 68 : 7525-7533. It has also been found that acidic residues within the top of the region of the cleavage site are required for efficient cleavage. Komoda et al. (1994) J. Virol. 68 : 7351-7357. [6] Inhibitors of HCV proteases that have been reported include antioxidants (WO 98/14181), certain peptides and peptide homologs (WO 98/17679); Landro et al. (1997) Biochem. 36 : 9340-9348, Ingallinella et al. (1998) Biochem. 37 : 8906-8914, Llinas-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8 : 1713-1718], an inhibitor based on the 70 amino acid polypeptide Eglin c [Martin et al. (1998) Biochem. 37 : 11459-11468], an inhibitor affinity selected from human pancreatic secretory trypsin inhibitor (hPSTI-C3) and minibody repertoires (MBip) [Dimasi et al. (1997) J. Virol. 71 : 7461-7469], cV H E2 [“camelized” variable domain antibody fragment] [Martin et al. (1997) Protein Eng. 10 : 607-614] and α1-antichymotrypsin (ACT) (Elzouki et al. (1997) J. Hepat. 27 : 42-28. Ribozymes have been recently reported designed to selectively destroy hepatitis C virus RNA (BioWorld Today 9 (217) : 4 (November 10, 1998)). [7] See also PCT Publication 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 2 February 18, 1999), Boehringer Ingelheim Canada Ltd. [8] HCV has a close effect on cirrhosis and induction of hepatocellular carcinoma. At present, it is very difficult to predict patients with HCV infection. HCV infection is more difficult to treat than other forms of hepatitis because there is no difference in immunity or illness associated with HCV infection. Current data indicate that survival after four years of diagnosis of cirrhosis is less than 50%. The survival rate after 5 years of patients diagnosed with resectable localized hepatocellular carcinoma is 10-30%, while the survival rate after 5 years of patients diagnosed with nonresectable localized hepatocellular carcinoma is less than 1%. [9] A. described for the synthesis of bicyclic homologues of inhibitors of HCV NS3 protease [A. Marchetti et al, Synlett, S1, 1000-1002 (1999). The compounds described in this document have the following formula: [10] [11] In addition, a method for producing specific α-ketoamides, α-ketoesters and α-diketones containing allyl and ethyl functional groups is described in W. Han et al., Bioorganic & Medicinal Chem. Lett, (2000) 10, 711-713. [12] See also WO 00/09558 (Assignee: Boehringer Ingelheim Limited; published February 24, 2000), which describes peptide derivatives of the formula: [13] [14] [Wherein various elements are defined in the above documents]. Examples of compounds of this series are as follows: [15] [16] See also WO 00/09543 (A assignee: Boehringer Ingelheim Limited; published February 24, 2000), which describes peptide derivatives of the formula: [17] [18] [Wherein various elements are defined in the above documents]. Examples of compounds of this series are as follows: [19] [20] Current treatments for hepatitis C include interferon-α (INF α ) and a combination of ribavirin and interferon (Bermeguer et al. (1998) Proc. Assoc. Am. Physicians 110 (2) : 98-112]. These therapies have a low response duration and frequently cause side effects. Hoofnagle et al. (1997) N. Engl. J. Med. 336 : 347. At present, no vaccine is available for HCV infection. [21] Currently pending US patent application Ser. No. 60 / 194,607, filed on April 5, 2000; 60 / 198,204, filed April 19, 2000; 60 / 220,110, filed Jul. 21, 2000; 60 / 220,109, filed Jul. 21, 2000; 60 / 220,107, filed Jul. 21, 2000; 60 / 254,869, filed December 12, 2000; And 60 / 220,101, filed Jul. 21, 2000, describe various types of peptides and / or other compounds as NS3-serine protease inhibitors of hepatitis C virus. [22] New treatments and treatments for HCV infection are needed. Accordingly, it is an object of the present invention to provide compounds useful for treating, preventing or alleviating one or more symptoms of hepatitis C. [23] It is a further object of the present invention to provide a method of treating, preventing or alleviating one or more symptoms of hepatitis C. [24] It is a further object of the present invention to provide a method for modulating the activity of serine proteases, in particular HCV NS3 / NS4a serine protease, using the compounds provided herein. [25] It is another object of the present invention to provide a method of modulating the processing of an HCV polypeptide using a compound provided herein. [26] Summary of the Invention [27] In many embodiments, the present invention provides a novel class of inhibitors of HCV proteases, pharmaceutical compositions containing one or more of the compounds, methods of making pharmaceutical formulations comprising one or more of the compounds, and one or more of hepatitis C. Provided are methods for treating, preventing or alleviating symptoms. Also provided are methods of modulating the interaction of HCV polypeptides with HCV proteases. Among the compounds provided herein, compounds which inhibit HCV NS3 / NS4a serine protease activity are preferred. Herein are compounds of formula (I), and enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrugs, and pharmaceuticals of such compounds or prodrugs thereof Acceptable salts or solvates are described: [28] [29] In the above formula, [30] Y is 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, provided that Y is optionally substituted by X 11 or X 12 ; [31] X 11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl or heteroarylalkyl, provided that 11 may be optionally further substituted by X 12 ; [32] X 12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carboalkoxy, Carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano or nitro, provided that alkyl, alkoxy and aryl are optionally added by residues independently selected from X 12 Optionally substituted; [33] R 1 is COR 5 or B (OR) 2 , and R 5 is H, OH, OR 8 , NR 9 R 10 , CF 3 , C 2 F 5 , C 3 F 7 , CF 2 R 6 , R 6 , or COR 7 , R 7 is H, OH, OR 8 , CHR 9 R 10 or NR 9 R 10 , and R 6 , R 8 , R 9 and R 10 are H, alkyl, aryl, heteroalkyl, heteroaryl, cyclo Alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH (R 1 ′ )] p COOR 11 , [CH (R 1 ′ )] p CONR 12 R 13 , [CH (R 1 ′ )] p SO 2 R 11 , [CH (R 1 ′ )] p COR 11 , [CH (R 1 ′ )] p CH (OH) R 11 , CH (R 1 ′ ) CONHCH (R 2 ′ ) COOR 11 , CH (R 1 ′ CONHCH (R 2 ' ) CONR 12 R 13 , CH (R 1' ) CONHCH (R 2 ' ) R', CH (R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) COOR 11 , CH ( R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) CONR 12 R 13 , CH (R 1' ) CONHCH (R 2 ' ) CONHCH (R 3' ) CONHCH (R 4 ' ) COOR 11 , CH ( R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) CONHCH (R 4' ) CONR 12 R 13 , CH (R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) CONHCH (R 4' ) CONHCH (R 5 ′ ) COOR 11 , and CH (R 1 ′ ) CONHCH (R 2 ′ ) CONHCH (R 3 ′ ) CONHCH (R 4 ′ ) CONHCH (R 5 ′ ) CONR 12 R 13 to Tack and, R 1 ', R 2' , R 3 ', R 4', R 5 ', R 11, R 12, R 13 and R' is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, Independently selected from the group consisting of alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; [34] Z is selected from O, N, CH or CR; [35] W may be present or absent, and when W is present, W is selected from C═O, C═S, C (═N—CN) or SO 2 ; [36] Q can be present or absent, and when Q is present, Q is CH, N, P, (CH 2 ) p , (CHR) p , (CRR ') p , O, NR, S or SO 2 , When Q is absent, M can also be present or absent; When Q and M are absent, A is directly linked to L; [37] A is O, CH 2 , (CHR) p , (CHR-CHR ') p , (CRR') p , NR, S, SO 2 or a bond; [38] E is CH, N or CR, or a double bond to A, L or G; [39] G may be present or absent, and when G is present, G is (CH 2 ) p , (CHR) p , or (CRR ′) p , and when G is absent, J is present and E is present in G Directly linked to a carbon atom in formula (I) as linked; [40] J may be present or absent, and when J is present, J is (CH 2 ) p , (CHR) p , (CRR ′) p , SO 2 , 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; [41] L can be present or absent, if L is present, L is CH, CR, O, S or NR, and if L is absent, M can be present or absent and L is present and M is present When M is directly and independently linked to E, J is directly and independently linked to E; [42] M may be present or absent, and when M is present, M may be O, NR, S, SO 2 , (CH 2 ) p , (CHR) p , (CHR-CHR ') p , or (CRR') p ; [43] p is a number from 0 to 6; [44] R, R ', R 2 , R 3 and R 4 are H; C 1 -C 10 alkyl; C 2 -C 10 alkenyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (Cycloalkyl) alkyl and (heterocycloalkyl) alkyl, wherein the cycloalkyl is made from 3 to 8 carbon atoms, 0 to 6 oxygen, nitrogen, sulfur or phosphorus atoms, the alkyl having 1 to 6 carbon atoms ; Aryl; Heteroaryl; Alkyl-aryl; And alkyl-heteroaryl, independently selected from the group consisting of [45] The alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally chemically substituted, and the term "substituted" is alkyl, alkenyl, alkynyl , Aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, sia O, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide and hydroxamate, optionally chemically substituted by one or more residues selected from the group consisting of; [46] Further, the unit NCGELJN represents a five or six membered cyclic ring structure, provided that the unit NCGELJN represents a five membered cyclic ring structure, or N, C, G, E, L, J, N, A When the bicyclic ring structure in formula (I) comprising Q, M represents a 5-membered cyclic ring structure, such 5-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring. [47] Among the above-mentioned definitions for the various residues of formula (I), the preferred groups for the various residues are as follows: [48] Preferred definitions for R 1 are COR 5 , R 5 is H, OH, COOR 8 or CONR 9 R 10 and R 8 , R 9 and R 10 are as defined above. Also preferred residues for R 1 are COCONR 9 R 10 , R 9 is H, R 10 is H, R 14 , [CH (R 1 ′ )] p COOR 11 , [CH (R 1 ′ )] p CONR 12 R 13 , [CH (R 1 ′ )] p SO 2 R 11 , [CH (R 1 ′ )] p SO 2 NR 12 R 13 , [CH (R 1 ′ )] p COR 11 , CH (R 1 ' ) CONHCH (R 2' ) COOR 11 , CH (R 1 ' ) CONHCH (R 2' ) CONR 12 R 13 or CH (R 1 ' ) CONHCH (R 2' ) (R '), R 14 is H , Alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, aryl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl. [49] Among the above-mentioned definitions for R 10, preferred moieties for R 10 is H, R 14, CH (R 1 ') COOR 11, CH (R 1') CH (R 1 ') COOR 11, CH (R 1') CONR 12 R 13 , CH (R 1 ' ) CH (R 1' ) CONR 12 R 13 , CH (R 1 ' ) CH (R 1' ) SO 2 R 11 , CH (R 1 ' ) CH (R 1' ) SO 2 NR 12 R 13 , CH (R 1 ' ) CH (R 1' ) COR 11 , CH (R 1 ' ) CONHCH (R 2' ) COOR 11 , CH (R 1 ' ) CONHCH (R 2' ) CONR 12 R 13 or CH (R 1 ′ ) CONHCH (R 2 ′ ) (R ′), R 1 ′ is H or alkyl, R 2 ′ is phenyl, substituted phenyl, hetero atom-substituted phenyl, thio Phenyl, cycloalkyl, piperidyl or pyridyl. [50] More preferred residues are as follows: R 1 ′ is H; R 11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α, α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; R 'is hydroxymethyl or CH 2 CONR 12 R 13 and NR 12 R 13 is [51] [52] It is selected from the group consisting of; [53] U 6 is H, OH or CH 2 OH; [54] R 14 is preferably H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but 3-enyl, OMe, cyclopropylmethyl; [55] R 2 ' is preferably [56] [57] Independently selected from the group consisting of; [58] U 1 and U 2 may be the same or different and H, F, CH 2 COOH, CH 2 COOMe, CH 2 CONH 2 , CH 2 CONHMe, CH 2 CONMe 2 , azido, amino, hydroxyl, substituted amino , Substituted hydroxyl; [59] U 3 and U 4 may be the same or different and are selected from O and S; [60] U 5 is alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryl Oxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or combinations thereof. [61] Preferred residues for R 2 are as follows: [62] [63] [64] Preferred residues for R 3 are as follows: [65] [66] [67] In the above formula, [68] R 31 is = OH or O-alkyl; [69] Y 19 is [70] [71] Is selected from; [72] Y 20 is selected from the following residues: [73] [74] The most preferred residues for R 3 are as follows: [75] [76] Some other preferred residues are as follows: Z is N; R 4 is H; W is C = O. In addition, when R 4 is absent, the residue ZCR 3 in Formula I can be represented by the following structure: [77] [78] Preferred residues for Y are as follows: [79] [80] ** [81] [82] [83] [84] In the above formula, [85] Y 11 is selected from H, COOH, COOEt, OMe, Ph, OPh, NHMe, NHAc, NHPh, CH (Me) 2 , 1-triazolyl, 1-imidazolyl and NHCH 2 COOH; [86] Y 12 is selected from H, COOH, COOMe, OMe, F, Cl or Br; [87] Y 13 is the residue [88] [89] Is selected from; [90] Y 14 is selected from MeSO 2 , Ac, Boc, iBoc, Cbz or Alloc; [91] Y 15 and Y 16 are independently selected from alkyl, aryl, heteroalkyl and heteroaryl; [92] Y 17 is CF 3 , NO 2 , CONH 2 , OH, COOCH 3 , OCH 3 , OC 6 H 5 , C 6 H 5 , COC 6 H 5 , NH 2 or COOH; [93] Y 18 is COOCH 3 , NO 2 , N (CH 3 ) 2 , F, OCH 3 , CH 2 COOH, COOH, SO 2 NH 2 or NHCOCH 3 ; [94] Y is more preferably represented by: [95] [96] [97] [98] Y 17 is CF 3 , NO 2 , CONH 2 , OH, NH 2 or COOH; [99] Y 18 is F, COOH. [100] More preferred residues for Y are as follows: [101] [102] As shown in Formula I, the following units represent cyclic ring structures which may be five or six membered ring structures: [103] [104] When such cyclic rings represent five-membered rings, it is essential for the present invention that these five-membered cyclic rings do not contain carbonyl groups as part of the cyclic ring structure. Preferably, the 5-membered ring has the structure: [105] [106] Wherein R and R 'are as defined above. [107] Preferred for the 5-membered cyclic ring structure is the following structure: [108] [109] Wherein R 20 is selected from the following residues: [110] [111] Furthermore, the 5-membered ring, together with its two adjacent exocyclic carbonyls, can be represented as follows: [112] [113] Wherein R 21 and R 22 may be the same or different and are independently selected from the following residues: [114] [115] A five-membered ring structure [116] [117] Some preferred examples for [118] [119] Additionally, the unit in formula (I) [120] [121] Can be represented by the following structures b and c: [122] [123] The preferred definition for b is: [124] [125] [126] in c, G and J are independently selected from the group consisting of (CH 2 ) p , (CHR) p , (CHR—CHR ′) p, and (CRR ′) p ; A and M are independently selected from the group consisting of O, S, SO 2 , NR, (CH 2 ) p , (CHR) p , (CHR—CHR ′) p and (CRR ′) p ; Q is CH 2 , CHR, CRR ', NH, NR, O, S, SO 2 , NR, (CH 2 ) p , (CHR) p and (CRR') p . [127] The preferred definition for c is: [128] [129] [130] The cyclic ring structure [131] [132] When presented as, the most preferred examples thereof are as follows: [133] [134] [135] [136] Units listed below [137] [138] Some preferred residues for are: [139] [140] [141] Unless stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Thus, for example, the term alkyl (including the alkyl portion of alkoxy) refers to monovalent groups derived from straight or branched chain saturated hydrocarbons by removing a single atom having 1 to 8, preferably 1 to 6 carbon atoms. Refer. [142] Aryl represents carbocyclic groups having 6 to 14 carbon atoms and at least one benzenoid ring, with all available and substitutable aromatic carbon atoms of these carbocyclic groups being considered as possible contact points. Preferred aryl groups are phenyl, 1-naphthyl, 2-naphthyl and indanyl, with phenyl and substituted phenyl being especially preferred. [143] Aralkyl refers to residues containing aryl groups linked through lower alkyl. [144] Alkylaryl refers to a moiety containing lower alkyl linked through an aryl group. [145] Cycloalkyl represents an optionally substituted saturated carbocyclic ring having 3 to 8, preferably 5 or 6 carbon atoms. [146] Heterocyclics are saturated and unsaturated cyclic organic groups having one or more O, S and / or N atoms that block the carbocyclic ring structure consisting of one ring or two fused rings, in addition to the heteroaryl groups defined below. Wherein each ring is 5-, 6- or 7-membered, and may or may not have a double bond lacking non-local pi electrons, wherein the ring structure is 2-8, preferably 3-6 Having 2 carbon atoms, for example, 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl. [147] Halogen represents fluorine, chlorine, bromine and iodine. [148] Heteroaryl refers to a cyclic organic group having at least one O, S and / or N that blocks the carbocyclic ring structure and having a sufficient number of non-local pi electrons to provide aromatic character, which is an aromatic heterocyclyl group Has 2 to 14, preferably 4 or 5 carbon atoms, for example 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- , 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl and the like. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; Such heteroaryl groups may be optionally substituted. Additionally, unless otherwise defined, the terms "substituted or unsubstituted" or "optionally substituted" as mentioned above are optionally chemically suitably substituted by residues belonging to R 12 or R 13 . Refers to. As used herein, “prodrug” refers to a drug precursor compound that, after being administered to a patient, releases the drug in vivo through some chemical or physiological process (eg, when brought to physiological pH or enzymes). Through action, the prodrug is converted into the desired drug form). [149] The present invention also includes tautomers, rotamers, enantiomers and other optical isomers, and prodrugs of the compounds of formula (I) as well as pharmaceutically acceptable salts, solvates and derivatives thereof. [150] A further aspect of the invention is a pharmaceutical composition which contains as an active ingredient a compound of formula (I) (or a salt, solvate or isomer thereof) together with a pharmaceutically acceptable carrier or excipient. [151] The invention also provides methods for the preparation of compounds of formula (I) and for treating diseases such as HCV, AIDS (acquired immune deficiency syndrome) and related diseases. Such methods of treatment include administering to a patient with the disease a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising such a compound of formula (I). [152] Also provided is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of HCV, AIDS and related diseases. [153] Also described herein are methods of treating a hepatitis C virus related disease, including administering an effective amount of one or more compounds of the invention. [154] Also described herein are methods of modulating the activity of HCV proteases, including contacting hepatitis C virus (HCV) protease with one or more compounds of the invention. [155] Also described herein are methods of treating, preventing or alleviating one or more symptoms of hepatitis C, including administering an effective amount of one or more compounds of the present invention. HCV protease is an NS3 or NS4a protease. Compounds of the present invention inhibit this protease. They also coordinate the processing of hepatitis C virus (HCV) polypeptides. [1] The present invention is directed to novel hepatitis C virus ("HCV") protease inhibitors, pharmaceutical compositions containing one or more such inhibitors, methods of making said inhibitors, and methods of using said inhibitors to treat hepatitis C and related diseases. It is about. The present invention particularly relates to novel peptide compounds as inhibitors of HCV NS3 / NS4a serine protease. [156] In one aspect, the invention relates to a compound of formula (I), or a pharmaceutically acceptable derivative thereof, wherein the various definitions are as set forth above, as inhibitors of HCV protease, in particular HCV NS3 / NS4a serine protease. [157] Representative compounds of the invention that exhibit excellent HCV protease inhibitory activity are listed in the following Tables 1-5 along with their activity [K i * value (nanomol, nM)]. Some compounds as well as additional compounds are additionally described in the claims. [158] TABLE 1 [159] Compound and HCV Protease Serial Assay Results [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] HCV Continuous Test Ki * Range: [170] Category A = 1-100 nM; Category B = 101-1,000 nM; Category C> 1000 nM. [171] Several types of compounds of the present invention and methods of synthesizing various types of compounds of formula (I) of the present invention are listed below and presented in the following schemes, and are illustrated in the Examples. [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] Depending on the structure, the compounds of the present invention may form pharmaceutically acceptable salts with organic or inorganic acids, or organic or inorganic bases. Examples of suitable acids for forming such salts are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid, and other inorganic acids well known to those skilled in the art and Carboxylic acid. Suitable bases for salt formation with bases are, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide and the like. [210] In another embodiment, the present invention provides a pharmaceutical composition comprising the peptide of the present invention as an active ingredient. Such pharmaceutical compositions generally additionally comprise a pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as a carrier material). Due to their HCV inhibitory activity, the pharmaceutical compositions are useful for treating hepatitis C and related diseases. [211] In another aspect, the present invention provides a method of preparing a pharmaceutical composition comprising the compound of the present invention as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredient is typically in the intended dosage form, i.e. oral tablet, capsule (solid filled, semi solid filled or liquid filled), constituent powder, oral gel, Appropriately selected for elixirs, dispersible granules, syrups, suspensions and the like and consistent with conventional pharmaceutical practice, will be administered with a suitable carrier material. For example, in oral dosage forms in the form of tablets or capsules, the active drug component may be incorporated into any oral, nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate. , Dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid) and the like. Moreover, if desired, suitable binders, lubricants, disintegrating agents and coloring agents may be incorporated into the mixture. Powders and tablets may comprise about 5 to about 95% of the compositions of the present invention. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia gum, sodium alginate, carboxymethylcellulose, polyethylene glycols and waxes. As lubricants for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like can be mentioned. Disintegrants include starch, methylcellulose, guar gum and the like. [212] Sweetening, flavoring and preservatives may optionally be included. Some of the terms mentioned above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below. [213] In addition, the compositions of the present invention may be formulated in sustained release form to provide a rate controlled release of one or more of these ingredients or active ingredients to optimize therapeutic effects, ie, HCV inhibitory activity and the like. Dosage forms suitable for sustained release include layered tablets containing a controlled release polymeric matrix impregnated with layers or active ingredients that exhibit varying disintegration rates, and tablets or capsules containing the impregnated or encapsulated porous polymeric matrix. do. [214] Liquid form preparations include solvents, suspensions and emulsions. As an example, mention may be made of parenteral water for injection or water-propylene glycol solutions, or additions of sweetening and whitening agents for oral solvents, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. [215] Aerosol formulations suitable for inhalation may include solids and solvents in powder form, which may be combined with pharmaceutically acceptable carriers such as inert compressed gas (eg nitrogen). [216] To prepare suppositories, low melting waxes, such as mixtures of fatty acid glycerides, for example cocoa butter, are first melted and dispersed homogeneously by stirring or similarly mixing the active ingredients therein. This molten homogeneous mixture is then poured into a mold of conventional size and solidified by cooling. [217] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solvents, suspensions and emulsions. [218] Compounds of the invention can also be delivered transdermally. Such transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in transdermal patches of the matrix or reservoir type as are conventional in the art for this purpose. [219] Preferably, the compound is administered orally, intravenously or subcutaneously. [220] Preferably, the pharmaceutical agent is present in unit dosage form. In this form, the formulation is subdivided into unit doses of suitable size, containing suitable amounts of the active ingredient, eg, an amount effective to achieve the desired. [221] The amount of active composition of the invention in unit dose formulations is generally from about 1.0 mg to about 1,000 mg, preferably from about 1.0 mg to about 950 mg, more preferably from about 1.0 mg to about 500 mg, typically depending on the particular application. It can be varied or adjusted from about 1 to about 250 mg. The actual dosage used may be determined according to the age, sex, weight of the patient and the severity of the disease to be treated. Such techniques are well known to those skilled in the art. [222] In general, human oral dosage forms containing the active ingredient may be administered once or twice daily. Dosage and frequency of administration will be adjusted at the discretion of the attending physician. In the case of oral administration, the recommended daily dosage regimen is from about 1.0 mg / day to about 1,000 mg / day in a single dose or divided into several doses. [223] Some useful terms are described below: [224] Capsules refer to special containers or enclosures made of methyl cellulose, polyvinyl alcohol, or modified gelatin or starch for holding or containing a composition comprising the active ingredient. Hard shell capsules are typically made of a blend of relatively high gel strength bone and pork skin gelatin. The capsule itself may contain small amounts of dyes, whitening agents, plasticizers and preservatives. [225] Tablets refer to compressed or molded solid dosage forms containing the active ingredient with suitable diluents. Tablets can be made by compressing a mixture or granulated product obtained by wet granulation, dry granulation or densification. [226] Oral gels refer to the active ingredient dispersed or solubilized in a hydrophilic semisolid matrix. [227] Constituent powders refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juice. [228] Diluents refer to substances that typically make up the major part of a composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; Starch derived from wheat, corn, rice and potatoes; And cellulose, such as microcrystalline cellulose. The amount of diluent in the composition is about 10 to 90%, preferably about 25 to about 75%, more preferably about 30 to about 60%, even more preferably about 12 to about based on the total weight of the composition May range from 60%. [229] Disintegrants refer to substances added to the composition to assist in disruptive separation (disintegration) of the medicament to help release it. Suitable disintegrants include starch; "Cold water soluble" modified starches such as sodium carboxymethyl starch; Natural and synthetic gums such as locust bean, karaya, guar, tragacand and agar; Cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; Microcrystalline cellulose and crosslinked microcrystalline cellulose such as sodium croscarmellose; Alginates such as alginic acid and sodium alginate; Clays such as bentonite; And effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 15 weight percent, more preferably from about 4 to about 10 weight percent, based on the total weight of such composition. [230] A binder refers to a material that binds or "glues" the powders together and makes them adherent by forming granules, so that they act as "adhesives" in the formulation. The binder adds the adhesive strength already available in the diluent or bulk agent. Suitable binders include sugars such as sucrose; Starch derived from wheat, corn, rice and potatoes; Natural gums such as acacia, gelatin and tragacand; Derivatives of seaweeds such as alginic acid, sodium alginate and ammonium calcium alginate; Cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; Polyvinylpyrrolidone; And minerals such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight percent, preferably from about 3 to about 10 weight percent, more preferably from about 3 to about 6 weight percent, based on the total weight of the composition. [231] Lubricant refers to a substance added to the dosage form in order to compress the tablets, granules, etc. and then release the formulation 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 glycol and d'l-leucine. Lubricants are typically added at the very last step before compression, since they must be present on the granule surface and must be present between the granules and the tablet compaction. The amount of lubricant in the composition may range from about 0.2 to about 5 weight percent, preferably from about 0.5 to about 2 weight percent, more preferably from about 0.3 to about 1.5 weight percent based on the total weight of the composition. [232] A glidant refers to a substance that prevents caking and improves the flow characteristics of the granulate, thereby allowing the flow to be smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricant in the composition may range from about 0.1 to about 5 weight percent, preferably from about 0.5 to about 2 weight percent based on the total weight of the composition. [233] Colorants are excipients that color the composition or dosage form. Such excipients may include food grade pigments and food grade pigments adsorbed onto suitable adsorbents such as clay or aluminum oxide. The amount of such colorant may range from about 0.1 to about 5 weight percent, preferably from about 0.1 to about 1 weight percent, based on the total weight of the composition. [234] Bioavailability refers to the rate and extent at which an active drug component or therapeutic moiety is absorbed into the systemic circulation from the administered dosage form, as compared to a standard or control. [235] Conventional methods of making tablets are known. Suitable methods include dry methods such as direct compression and compaction of granules produced by densification, or wet methods or other special procedures. Conventional methods of preparing other dosage forms, such as capsules, suppositories, and the like, are also well known. [236] Another aspect of the invention relates to the use of the above-mentioned pharmaceutical composition for treating a disease such as hepatitis C. The method comprises administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a patient in need of the treatment having the disease (s). [237] In another embodiment, the compounds of the present invention can be used to treat HCV in humans in combination with a monotherapy modality or combination therapy modalities (eg, dual combinations, triple combinations, etc.), eg, antiviral agents and / or immunomodulators. have. Examples of such antiviral agents and / or immunomodulators include Ribavirin (source: Schering-Plough Corporation, Madison, New Jersey) and Levovirin ™ (source: ICN Pharmaceuticals, Costa Mesa, California), VP 50406 ™. (Source: Viropharma, Incorporated, Exton, Pennsylvania), ISIS 14803 ™ (Source: ISIS Pharmaceuticals, Carlsbad, Calfornia), Heptazyme ™ (Source: Ribozyme Pharmaceuticals, Boulder, Colorado), VX 497 ™ (Source: Vertex Pharmaceuticals, Cambridge, Massachusetts), Thymosin ™ (Source: SciClone Pharmaceuticals, San Mateo, California), Maxamine ™ (Source: Maxim Pharmaceuticals, San Diego, California), Mycophenolate mofetil) (source: Hoffman-LaRoche, Nutley, New Jersey), interferon (eg, interferon-alpha, PEG-interferon alpha conjugate), and the like. "PEG-interferon alpha conjugate" is an interferon alpha molecule covalently attached to a PEG molecule. Examples of PEG interferon alpha conjugates include interferon alfa-2a (Roferon ™) in the form of pegylated interferon alfa-2a (e.g., marketed under the trademark Pegasys ™) from Hoffman-LaRoche, Nutley, New Jersey ), Pegylated interferon alpha-2b (eg, commercially available under the trade name PEG-Intron ™) in the form of interferon alpha-2b (Intron ™) from Schering-Plough Corporation, Interferon alpha-2c (Berofor Alpha ™) (Source: Boehringer Ingelheim, Ingelheim, Germany) or Consensus Interferon (Infergen ™) (Source: Amgen, Thousand Oaks, California) as defined by the determination of the consensus sequence of native interferon alpha. [238] As mentioned above, the present invention also includes tautomers, rotamers, enantiomers and other stereoisomers of the compounds. Thus, as is known to those skilled in the art, some of the compounds of the present invention may exist in suitable isomeric forms. Such variants are also considered to be within the scope of the present invention. [239] Another aspect of the invention relates to a process for the preparation of the compounds described herein. Such compounds can be prepared by several techniques known in the art. An example of a representative method is shown in the following scheme. Although the following exemplary schemes describe methods for preparing some representative compounds of the present invention, any suitable substitution of both natural and non-natural amino acids may form the desired compound based on such substitutions. It should be recognized. Such variants are also considered to be within the scope of the present invention. [240] The abbreviations used in the description of the following schemes, preparation examples and examples are as follows: [241] THF: tetrahydrofuran [242] DMF: N, N-dimethylformamide [243] EtOAc: ethyl acetate [244] AcOH: acetic acid [245] HOOBt: 3-hydroxy-1,2,3-benzotriazine-4 (3H) -one [246] EDCl: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride [247] NMM: N-methylmorpholine [248] ADDP: 1,1 '-(Azodicarboville) dipiperidine [249] DEAD: diethylazodicarboxylate [250] MeOH: Methanol [251] EtOH: Ethanol [252] Et 2 O: diethyl ether [253] DMSO: Dimethyl Sulfoxide [254] HOBt: N-hydroxybenzotriazole [255] PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate [256] DCM: Dichloromethane [257] DCC: dicyclohexylcarbodiimide [258] TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy [259] Phg: Phenylglycine [260] Chg: cyclohexylglycine [261] Bn: Benzyl [262] Bzl: Benzyl [263] Et: ethyl [264] Ph: Phenyl [265] iBoc: isobutoxycarbonyl [266] iPr: Isopropyl [267] t Bu or Bu t : tert-butyl [268] Boc: tert-butyloxycarbonyl [269] Cbz: benzyloxycarbonyl [270] Cp: cyclopentyldienyl [271] Ts: p-toluenesulfonyl [272] Me: methyl [273] HATU: O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate [274] DMAP: 4-N, N-dimethylaminopyridine [275] Bop: Benzotriazol-1-yl-oxy-tris (dimethylamino) hexafluorophosphate. [276] General Manufacturing Schemes: [277] The following scheme describes the synthesis of intermediate building blocks: [278] [279] [280] [281] [282] [283] [284] [285] [286] [287] [288] [289] [290] [291] [292] [293] [294] [295] [296] [297] [298] [299] Preparation of Intermediates: [300] Preparation Example 1: [301] Step 1: Compound (1.1) [302] [303] Compound (1.08) (3.00 g, 12.0 mmol) in DMF (15 ml) and CH 2 Cl 2 (15 ml) at −20 ° C. (SL Harbeson et al., J. Med. Chem. 37 No. 18 (1994) 2918-2929] was added HOOBt (1.97 g, 12.0 mmol), N-methyl morpholine (4.0 ml, 36.0 mmol) and EDCl (2.79 g, 14.5 mmol) and stirred for 10 minutes. Then, HCl.H 2 N-Gly-OBn (2.56 g, 13.0 mmol) is added. The resulting solution is stirred at −20 ° C. for 2 hours, then kept in the refrigerator overnight, concentrated to dryness and diluted with EtOAc (150 ml). The EtOAc solution was then washed twice with saturated NaHCO 3 , H 2 O, 5% -H 3 PO 4 , brine, dried over Na 2 SO 4 , filtered and concentrated to dryness to give compound (1.09) (4.5). g, 94%) is obtained. LRMS m / z MH + = 395.1. [304] Step B: Compound (1.1) [305] [306] A solution of compound (1.09) (7.00 g, 17.8 mmol) in anhydrous ethanol (300 ml) is stirred at room temperature under hydrogen atmosphere in the presence of Pd-C (300 mg, 10%). Monitor the reaction progress with tlc. After 2 hours, the mixture is filtered through a pad of celite and the resulting solution is concentrated in vacuo to yield 1.1 (5.40 g, quant.). LRMS m / z MH + = 305.1. [307] Preparation Example 2 [308] Step A: Compound (1.3) [309] [310] Compound (1.1) (1 equiv), Compound (1.2) (Source: Novabiochem, Catalog No. 04-12-5147) (1.03 equiv), HOOBt (1.03 equiv), N- from Preparation Example 1, Step B above. A mixture of methylmorpholine (2.2 equiv) and dimethylformamide (70 ml / g) is stirred at -20 ° C. EDCl (1.04 equiv) is added and the reaction is stirred for 48 h. The reaction mixture is poured into 5% aqueous KH 2 PO 4 and extracted with ethyl acetate (2 ×). The combined organics are washed with cold 5% aqueous K 2 CO 3 and then with 5% aqueous KH 2 PO 4 followed by brine and the organic layer is dried over anhydrous MgSO 4 . The mixture is filtered, then evaporated, the filtrate is dried under vacuum and the residue is triturated with Et 2 O-hexane and filtered to give the title compound (1.3) (86% yield). [311] C 25 H 39 N 3 0 7 (493.60), mass spectrum (FAB) M + 1 = 494.3. [312] Step B: Compound (1.4) [313] [314] Compound (1.3) (3.0 g) from Preparation Example 2, Step A was treated with 4N HCl / dioxane (36 ml) and stirred at room temperature for 7 minutes. The mixture is poured into 1.5 L of cold (5 ° C.) hexanes, stirred and left to cool for 0.5 h. The mixture is suction-filtered under a dry atmosphere and the collected solids are further dried to give the title compound 1.4 (2.3 g, 88% yield). [315] [316] Preparation Example 3 [317] Compound (1.5) [318] [319] Compound (1.3) from Preparation Example 2, Step A was treated essentially in the same manner as in Preparation Example 7, Step A, to give Compound (1.5). [320] Preparation Example 4 [321] Compound (1.6) [322] [323] Compound (1.5) from Preparation Example 3 was treated essentially in the same manner as in Preparation Example 2, Step B to give Compound (1.6). [324] Preparation Example 5 [325] Step A: Compound (2.09) [326] [327] Dimethylamine hydrochloride (1.61 g, 19.7 mmol), N-Boc-phenylglycine, Compound (2.08) (4.50 g, 17.9 mmol, Bachem Co) in dry DMF (200 ml) and CH 2 Cl 2 (150 ml) at −20 ° C. # A-2225) add NMM (5.90 ml, 53.7 mmol) to a solution of HOOBt (3.07 g, 18.8 mmol) and EDCl (4.12 g, 21.5 mmol). After stirring for 30 minutes at this temperature, the reaction mixture is kept overnight in the freezer (18 hours). It is then warmed to rt and EtOAc (450 ml), brine (100 ml) and 5% H 3 PO 4 (100 ml) are added. After separating the layers, the organic solution was washed with 5% H 3 PO 4 (100 ml), saturated aqueous sodium bicarbonate solution (2 × 150 ml), water (150 ml) and brine (150 ml), dried (MgSO 4 ) and filtered And then concentrated in vacuo to afford 2.09 (4.86 g) as a white solid which is used without further purification. [328] Step B: Compound (2.1) [329] [330] Compound (2.09) (4.70 g, crude) from Preparation Example 5, Step A is dissolved in 4N HCl (60 ml, 240 mmol) and the resulting solution is stirred at room temperature. The progress of this reaction is monitored by TLC. After 4 hours, the solution is concentrated in vacuo to afford compound 2.1 as a white solid, which is used in the next step without further purification. LRMS m / z MH + = 179.0. [331] Preparation Example 6 [332] Step A: Compound (2.2) [333] [334] Compound (2.2) is prepared in the same manner as in Preparation Example 2, Step A, using phenylglycine N, N-dimethylamide hydrochloride instead of phenylglycine t-butyl ester hydrochloride: Mass spectrum (FAB) M + 1 = 465.3. [335] Step B: Compound (2.3) [336] [337] Compound (2.2) (1.85 g) from Step A is reacted with 4N HCl / dioxane (50 ml) at room temperature for 1 hour. The mixture is evaporated in vacuo in a 20 ° C. water bath, triturated under isopropyl ether, filtered and dried to give 2.3 (1.57 g, 98% yield): C 18 H 28 N 4 O 4 HCl , Mass spectrum (FAB) M + 1 = 365.3. [338] Preparation Example 7 [339] Step A: Compound (2.4) [340] [341] A solution of compound (2.2) (2.0 g) from Preparation Example 5, step A in dichloromethane (60 ml) was treated with dimethylsulfoxide (3.0 ml) and 2,2-dichloroacetic acid (0.70 ml). The stirred mixture is cooled to 5 ° C. and then 1M dicyclohexylcarbodiimide / dichloromethane solution (8.5 ml) is added. The cold bath is taken out and the mixture is stirred for 22 hours. Then 2-propanol (0.5 ml) is added and stirred for a further hour. The mixture is filtered and then washed with ice cold 0.1 N NaOH (50 ml), ice cold 0.1 N HCl (50 ml), 5% aqueous KH 2 PO 4 , and saturated brine. The organic solution is dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated and chromatographed on silica gel eluting with ethyl acetate to give compound 2.3 (1.87 g, 94% yield): C 23 H 34 N 4 O 6 , mass spectrum (FAB) M + 1 = 463.3. [342] Step B: Compound (2.5) [343] [344] Compound (2.5) is prepared in essentially the same manner as in Preparation Example 2, step B. [345] Preparation Example 8 [346] Step A: Compound (3.1) [347] [348] In the flask, N-Cbz-hydroxyproline methyl ester (Source: Bachem Biosciences, Incorporated, King of Prussia, Pennsylvania), compound (3.01) (3.0 g), toluene (30 ml) and ethyl acetate (30 ml) are combined. The mixture is stirred vigorously and then a solution of NaBr / water (1.28 g / 5 ml) is added. To this is added 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO, 17 mg; source: Aldrich Chemicals, Milwaukee, Wisconsin). This stirred mixture is cooled to 5 ° C. and then the prepared oxidant solution (commercial bleach, Clorox® (18 ml), NaHCO 3 (2.75 g), and water to make up 40 ml) is added dropwise over 0.5 hour. To this was added 2-propanol (0.2 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic extracts are combined, washed with 2% sodium thiosulfate and then with saturated brine. The organic solution is dried over anhydrous MgSO 4 , filtered and the filtrate is evaporated in vacuo to give a pale yellow gum (2.9 g, 97% yield) suitable for subsequent reactions: C 14 H 15 NO 5 (277.28), mass Spectrum (FAB) M + 1 = 278.1. [349] Step B: Compound (3.2) [350] [351] Compound (3.1) (7.8 g) from Step A was dissolved in dichloromethane (100 ml) and cooled to 15 ° C. To this mixture, first, 1,3-propanedithiol (3.1 ml) is added, followed by freshly distilled boron trifluoride etherate (3.7 ml). The mixture is stirred at rt for 18 h. While stirring vigorously, a K 2 CO 3 / water (2 g / 30 ml) solution is added carefully, followed by saturated NaHCO 3 (10 ml). The organic layer is separated from the aqueous layer (pH about 7.4), washed with water (10 ml) and then brine. The organic solution is dried over anhydrous MgSO 4 , filtered and evaporated in vacuo. The residue is eluted with toluene and then chromatographed on silica gel, eluting with a hexane-Et 2 O gradient (2: 3 to 0: 1) to give a brown oil (7.0 g, 68% yield): C 17 H 21 NO 4 S 2 (367.48), mass spectrum (FAB) M + 1 = 368.1. [352] Step C: Compound (3.3) [353] [354] The solution of compound (3.2) (45 g) from step B in acetonitrile (800 ml) at 20 ° C. is treated in one step with freshly distilled iodotrimethylsilane (53 ml). The reaction is stirred for 30 minutes and then poured into a solution of freshly prepared di-t-butyldicarbonate (107 g), ethyl ether (150 ml) and diisopropylethylamine (66.5 ml). The mixture is stirred for 30 minutes and then washed with hexane (2 x 500 ml). Ethyl acetate (1000 ml) is added to the lower acetonitrile layer, which is then washed with 10% aqueous KH 2 PO 4 (2 × 700 ml) and brine. The filtrate is evaporated in vacuo in a 25 ° C. water bath and taken up in fresh ethyl acetate (1000 ml) and washed successively with 0.1N HCl, 0.1N NaOH, 10% aqueous KH 2 PO 4 and brine. The organic solution is dried over anhydrous MgSO 4 , filtered and evaporated in vacuo. The residue (66 g) was eluted with hexane (2 L), then eluted with Et 2 O / hexane (55:45, 2 L) and chromatographed on silica gel (2 kg), eluting with Et 2 O (2 L) to give an organic gum Which is slowly crystallized upon standing (28 g, 69% yield): C 14 H 23 NO 4 S 2 (333.46), mass spectrum (FAB) M + 1 = 334.1. [355] Step D: Compound (3.4) [356] [357] The solution of compound (3.3) (11 g) from step C above in dioxane (150 ml) at 20 ° C. is treated with IN aqueous LiOH (47 ml) and stirred for 30 h. The mixture is concentrated in vacuo in a 30 ° C. water bath to halve the volume. The remainder is diluted with water (300 ml) and extracted with Et 2 O (2 × 200 ml). The aqueous layer is acidified to pH about 4 with 12N HCl (3-4 ml), extracted with ethyl acetate and washed with brine. The organic solution is dried over anhydrous MgSO 4 , filtered and evaporated in vacuo to give 3.4 (8.1 g, 78%): C 13 H 21 NO 4 S 2 (319.44), mass spectrum (FAB) M + 1 = 320.1. [358] Step E: Compound (3.5) [359] [360] To a solution of compound (3.3) (1 g) from Step C above in dioxane (5 ml) is added 4N HCl-dioxane solution (50 ml). The mixture is stirred vigorously for 1 hour. The mixture is evaporated in vacuo in a 25 ° C. water bath. The residue was triturated with Et 2 O and filtered to afford the title compound (0.76 g, 93% yield): C 9 H 15 NO 2 S 2 HCl (269.81), mass spectrum (FAB) M + 1 = 234.0. [361] Preparation Example 9 [362] Step A: Compound (3.6) [363] [364] While propane dithiol is replaced with ethane dithiol, essentially the same procedure as in Preparation Example 8, step B is carried out to give compound (3.6). [365] Step B: Compound (3.7) [366] [367] Compound (3.7) is obtained by essentially following the same procedure as in Preparation Example 8, Step C, replacing compound (3.2) with compound (3.6). [368] Step C: Compound (3.8) [369] [370] Subsequently, the same procedure as Preparation Example 8, Step D was carried out while replacing Compound (3.3) with Compound (3.7), to obtain Compound (3.8). [371] Step D: Compound (3.9) [372] [373] Compound (3.3) is replaced with compound (3.7) while essentially following the same procedure as in Preparation Example 8, Step E to give compound (3.9). [374] Preparation Example 10 [375] Step A: Compound (4.1) [376] [377] Essentially following the same procedure as in Preparation Example 2, Step A, Compound (4.1) was prepared: C 33 H 48 N 4 O 9 S 2 (708.89). [378] Step B: Compound (4.2) [379] [380] Essentially following the same procedure as in Preparation Example 2, Step B, Compound (4.2) was prepared: Mass spectrum (FAB) M + 1 = 609.3. [381] Step C: Compound (4.3) [382] [383] Essentially following the same procedure as in Preparation Example 2, Step A, compound (4.3) was prepared: C 41 H 61 N 5 O 10 S 2 (708.89), mass spectrum (FAB) M + 1 = 709.3. [384] Step D: Compound (4.4) [385] [386] In essentially the same manner as in Preparation Example 7, Step A, Compound (4.4) was prepared. [387] Preparation Example 11 [388] Step A: Compound (4.5) [389] [390] In essentially the same manner as in Preparation Example 2, Step A, Compound (4.5) was prepared. [391] Step B: Compound (4.6) [392] [393] Essentially the same procedure as Preparation Example 2, Step B, was carried out to prepare Compound (4.6). [394] Step C: Compound (4.7) [395] [396] Essentially the same procedure as Preparation Example 2, Step A, was carried out to react Compound (4.9) from Preparation Example 12 with Compound (4.6) from Step B above to prepare Compound (4.7). [397] Step D: Compound (4.8) [398] [399] In essentially the same manner as in Preparation Example 7, Step A, Compound (4.8) was prepared. [400] Preparation Example 12 [401] Compound (4.9) [402] [403] A solution of L-cyclohexylglycine (4.02) (1.0 equiv), dimethylformamide (20 ml / g) and diisopropylethylamine (1.1 equiv) at 5 ° C. was converted to isobutyl chloroformate (4.01) (1.1 equiv) Process. The cold bath is taken out and stirred for 6 hours. The reaction mixture is poured into 5% aqueous KH 2 PO 4 and extracted with ethyl acetate (2 ×). The combined organics are washed with cold 5% aqueous K 2 CO 3 and then with 5% aqueous KH 2 PO 4 followed by brine and the organic layer is dried over anhydrous MgSO 4 . The mixture is filtered and the filtrate is evaporated in vacuo and the residue is chromatographed if necessary or triturated with Et 2 O-hexane and filtered to give the title compound (4.9): C 13 H 23 NO 4 (257.33). [404] Preparation Example 13 [405] Compound (13.1) [406] [407] L-cyclohexylglycine (4.02) was replaced with LO-benzylthreonine (13.02). Wang et al., J. Chem. Soc., Perkin Trans. 1, (1997) No. 5, 621-624, essentially following the same procedure as in Preparation Example 12, to prepare compound 13.3: C 16 H 23 NO 5 (309.36), mass spectrum (FAB) M + 1 = 310.2. [408] Preparation Example 14 [409] [410] Compound (4.8) (1.0 g) from Preparation Example 11, Step D was reacted with a solution of trifluoroacetic anhydride-dichloromethane (1: 1, 50 ml) for 2 hours. This solution is diluted with xylene (100 ml) and evaporated in vacuo. The residue was triturated with Et 2 O and filtered to give the title compound (5.1) (0.9 g): C 37 H 53 N 5 O 9 S 2 (775.98), mass spectrum (FAB) M + 1 = 776.5. [411] Step B: Compound (5.2) [412] [413] Perform essentially the same manner as in Preparation Example 2, Step A, where compound (5.1) is reacted with ammonia (0.5M, 1,4-dioxane solution) to give the title compound (5.2): C 37 H 54 N 6 O 8 S 2 (774.99), Mass Spectrum (FAB) M + 1 = 775.4. [414] Preparation Example 15 [415] [416] A mixture of compound (5.1) (0.15 g), N, N-dimethylamine (0.12 ml of 2M THF solution), dimethylformamide (10 ml) and PyBrOP coupling reagent (0.11 g) from Preparation Example 14, step A was prepared. After cooling to 5 ° C., diisopropylethylamine (DIEA or DIPEA, 0.12 ml) is added. The mixture is stirred cold for 1 minute and then at room temperature for 6 hours. The reaction mixture is poured into cold 5% aqueous H 3 PO 4 (50 ml) and extracted with ethyl acetate (2 ×). The combined organics are washed with cold 5% aqueous K 2 CO 3 and then with 5% aqueous KH 2 PO 4 followed by brine. The organic solution is dried over anhydrous MgSO 4 , filtered and then evaporated in vacuo. The residue is chromatographed on silica gel eluting with MeOH-CH 2 Cl 2 to afford the title compound (5.3): C 39 H 58 N 6 O 8 S 2 (803.05), mass spectrum (FAB) M + 1 = 803.5 . [417] Preparation Example 16 [418] Step A: Compound (6.2) [419] [420] Essentially following the same procedure as Preparation Example 2, Step A, compound (6.1) hydroxyproline benzyl ester hydrochloride was reacted with compound (4.9) from Preparation Example 12 to give the title compound (6.2): C 25 H 36 N 2 O 6 (460.56), mass spectrum (FAB) M + 1 = 461.2. [421] Step B: Compound (6.3) [422] [423] Essentially following the same procedure as in Preparation Example 8, Compound (6.3) was prepared: C 25 H 34 N 2 O 6 (458.55), Mass Spectrum (FAB) M + 1 = 459.2. [424] Step C: Compound (6.4) [425] [426] A mixture of compound (6.3) (1 g), 10% Pd / C (0.05 g) and EtOH (100 ml) from step B is stirred under 1 atmosphere H 2 for 6 hours. This mixture was filtered and evaporated to dryness in vacuo to afford the title compound (6.4) (0.77 g): C 18 H 28 N 2 O 6 (368.42), mass spectrum (FAB) M + 1 = 369.2. [427] Preparation Example 17 [428] Step A: Compound (7.1) [429] [430] In essentially the same manner as in Preparation Example 2, Step A, Compound (6.4) from Preparation Example 16, Step C was reacted with Compound (2.3) from Preparation Example 6, Step B to give Compound (7.1) Obtained: C 36 H 54 N 6 0 9 (714.85), mass spectrum (FAB) M + 1 = 715.9. [431] Step B: Compound (7.2) [432] [433] Essentially the same procedure as in Preparation Example 7, Step A, Compound (7.1) was reacted to give Compound (7.2): C 36 H 52 N 6 O 9 (712.83), mass spectrum (FAB) M + 1 = 713.5. [434] Step C: Compound (7.3) [435] [436] Essentially following the same procedure as in Preparation Example 8, Step B, the compound (7.2) from Step B was reacted with 1,4-butanedithiol to give the title compound (7.3): C 40 H 60 N 6 O 8 S 2 (817.07), mass spectrum (FAB) M + 1 = 817.5. [437] Using the procedure mentioned above, the attached compound of Table 2 is prepared. As is generally recognized in all tables attached herein as well as in the examples and schemes herein, all open-terminal nitrogen atoms exhibiting unfilled valences in the chemical structures in the examples and tables refer to NH, or Or in the case of terminal nitrogen, -NH 2 . Similarly, all open-ended oxygen atoms that exhibit unfilled valences in the chemical formulas in the examples and tables refer to -OH. [438] Solid Phase Synthesis: [439] General procedure for solid phase coupling reaction: [440] This synthesis is carried out in a reaction vessel constructed from a polypropylene syringe cartridge equipped with a polypropylene frit at the bottom. Fmoc-protected amino acids are coupled under standard solid phase techniques. Each reaction vessel is loaded with 100 mg (approximately 0.03 mmol) of starting Fmoc-Sieber resin. This resin is washed with 2 ml fractions of DMF (twice). The Fmoc protecting group is removed by treatment with 2 ml of a 20% v / v solution of piperidine in DMF for 20 minutes. This resin is washed with 2 ml fractions of DMF (4 times). 0.1 mmol of Fmoc-amino acid, 0.1 mmol of HATU [O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate] and DIPEA (N, N-di Coupling is carried out in DMF (2 ml) using 0.2 mmol of isopropylethylamine). After shaking for 2 hours, the reaction vessel is dehydrated and the resin is washed with 2 ml fractions of DMF (4 times). The coupling cycle is then repeated using Fmoc-amino acids or capping groups. [441] General procedure for solid phase des-martin oxidation reaction: [442] This synthesis is carried out in a reaction vessel made from a polypropylene syringe cartridge equipped with a polypropylene frit at the bottom. The resin-bound hydroxy compound (approximately 0.03 mmol) is treated with a solution of 0.12 mmol of des-martin periodinan and 0.12 mmol of t-BuOH in 2 ml of DCM for 4 hours. The resin was added to DCM, 2 ml fraction of 20% v / v solution of iPrOH in THF, 50% v / v solution of THF in water (4 times), 50% v / v solution of THF (4 times) and DCM 50% v / v Wash with solution (4 times). [443] Preparation Example 18 [444] Preparation of N-Fmoc-2 ', 3'-dimethoxyphenylglycine [Compound (901)] [445] [446] To a solution of potassium cyanide (1.465 g, 22.5 mmol) and ammonium carbonate (5.045 g, 52.5 mmol) in water (15 ml) was added a solution of 2,3-dimethoxybenzaldehyde 901A (2.5 g, 15 mmol) in ethanol (15 ml). do. The reaction mixture is heated at 40 ° C. for 24 hours. The volume of this solution is reduced to 10 ml by evaporation under reduced pressure. Concentrated hydrochloric acid (15 ml) is added and compound 901B is obtained as a white precipitate. The compound is isolated by filtration of 901B (2.2 g, 9.3 mmol). Compound 901B is dissolved in 10% w / w aqueous sodium hydroxide solution (15 ml) and the resulting solution is heated at reflux for 24 h. Concentrated hydrochloric acid is added and the pH is adjusted to neutral (pH 7). The resulting solution, containing compound 901C, is evaporated under reduced pressure. The residue is dissolved in 5% w / w aqueous sodium bicarbonate solution (150 ml). The solution was cooled to 0 ° C. in an ice bath and a solution of 9-fluorenylmethyl succinimidyl carbonate (2.7 g, 8 mmol) in 1,4-dioxane (30 ml) and 1,4-dioxane (30 ml) was zeroed out. It is added at ℃. The reaction mixture is warmed to room temperature and stirred at room temperature for 24 hours. 1,4-dioxane is evaporated under reduced pressure. The aqueous solution is washed with diethyl ether. Concentrated hydrochloric acid is added and the pH is adjusted to acidic (pH 1). Ethyl acetate is added and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to afford the desired compound 901 as a white foamy solid (3.44 g, 7.9 mmol). MS (LCMS-electron spray) 434.1 MH + . [447] Preparation Example 19 [448] Compound (801) [449] [450] To a solution of N-Fmoc-phenylalanine 801A (5 g, 12.9 mmol) in dry DCM (22 ml) cooled to -30 ° C. in a dry ice-acetone bath, N-methylpyrrolidine (1.96 ml, 16.1 mmol) and methyl chloroform Mates (1.2 ml, 15.5 mmol) are added sequentially. The reaction mixture was stirred at -30 ° C. for 1 hour, N, O-dimethylhydroxylaminehydrochloride (1.51 g, 15.5 mol) and N-methylpyrrolidine (1.96 ml, 16.1 mmol) in dry DCM (8 ml). ) Is added. The reaction mixture is allowed to warm to room temperature and stirred overnight at room temperature. Toluene is added and the organic layer is washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to afford compound 801B (4 g, 9.29 mmol). [451] To a solution of Red-Al (6.28 ml, 21.4 mmol) in dry toluene (8 ml) cooled to -20 ° C. in a dry ice-acetone bath was added a solution of compound 801B (4 g, 9.29 mmol) in toluene (12 ml). . The reaction mixture is stirred at -20 ° C for 1.5 hours. The organic layer is washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the crude product 801C is used for the next reaction without further purification. [452] To a solution of compound 801C (approximately 9.29 mmol) in hexane (15 ml) was a solution of potassium cyanide (24 mg, 0.37 mmol) and tetrabutylammonium iodide (34 mg, 0.092 mmol) in water (4 ml), and acetone cyanohydrin ( 1.27 ml, 13.9 mmol) is added sequentially. The reaction mixture is stirred at room temperature for 24 hours. Ethyl acetate is added and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to afford compound 801D (2.4 g, 6.03 mmol). [453] To a solution of compound 801D (2.4 g, 6.03 mmol) in 1,4-dioxane (11 ml) is added concentrated hydrochloric acid (11 ml). The reaction mixture is heated at 80 ° C. for 3 hours. Ethyl acetate (25 ml) and water (25 ml) are added. The organic layer is washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to afford the desired compound 801 as a white effervescent solid (2 g, 4.8 mmol). MS (LCMS-electron spray) 418.1 MH + . [454] Scheme 8 [455] [456] Example 301J: [457] Scheme 8: compound 301J [458] [459] Resin-bound compounds 301B, 301C, 301D, 301E, 301F and 301G are prepared according to the general procedure for solid phase coupling reactions starting with 100 mg (0.03 mmol) of Fmoc-Sieber resin. The resin bound compound 301G is oxidized to the resin bound compound 301H according to the general procedure for solid phase des-martin oxidation reaction. The resin bound compound 301H is treated with 4 ml of a 2% v / v solution of TFA in DCM for 5 minutes. The filtrate is added to 1 ml of AcOH and the solution is concentrated by vacuum centrifugation to give compound 301J (0.0069 g, 29% yield). MS (LCMS-electron spray) 771.2 MH + . [460] Using the solid phase synthesis techniques mentioned above, the compounds in Table 3 are prepared using the following residues for the various functional groups in the compound of Formula 1: [461] [462] [463] [464] [465] [466] [467] [468] [469] [470] TABLE 3 [471] Compounds Prepared By Solid Phase Synthesis [472] [473] [474] [475] [476] [477] [478] [479] [480] [481] [482] [483] [484] [485] [486] [487] [488] [489] [490] [491] [492] [493] [494] [495] [496] [497] [498] [499] [500] [501] [502] [503] [504] [505] [506] [507] [508] [509] [510] [511] Additional compounds prepared and their activity (Ki *) ranges are shown in the attached Tables 4 and 5. The procedure used to prepare the compounds of Tables 4 and 5 is summarized below. [512] I) Synthesis of Intermediates for the Compounds in Tables 4 and 5 [513] Example I Synthesis of 4,4-Dimethyl Proline Methyl Ester (H-Pro (4,4-diMe) -OMe) [514] [515] Step 1: Synthesis of tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (Boc-PyroGlu (4-methyl) -OtBu): [516] [517] 1M solution of lithium hexamethyldisilazide in THF (42 ml) to a solution of tert-butyl N-tert-butoxycarbonyl-pyroglutamate (11.5 g, 40 mmol) in THF (200 ml) with stirring at −78 ° C. , 42 mmol) is added dropwise over 5 minutes. After 30 minutes, methyl iodide (3.11 ml, 50 mmol) is added. After 2 h at −78 ° C., the cooling bath is removed and 50% saturated aqueous ammonium chloride (200 ml) is added. The solution is stirred for 20 minutes and then extracted with ether (3 x 200 ml). The combined organic layers are washed with brine (200 ml), dried (Na 2 SO 4 ), filtered and concentrated. The residue is chromatographed with 1: 1 ethyl acetate / hexanes to give Boc-PyroGlu (4-methyl) -OtBu (10.6 g, 35.4 mmol, 88%) as a mixture of isomers (2: 1 cis to trans). [518] Step 2: Synthesis of tert-butyl N-tert-butoxycarbonyl-4,4-dimethyl-L-pyroglutamate (Boc-PyroGlu (4,4-dimethyl) -OtBu): [519] [520] To tetrahydrofuran in a solution of tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (1.2 g, 4.0 mmol) in tetrahydrofuran (20 ml) with stirring at −78 ° C. 1M solution of lithium hexamethyldisilazide (4.4ml, 4.4mmol) was added dropwise over 5 minutes. After 30 minutes, methyl iodide (0.33 ml, 5.2 mmol) is added. After 3 h at −78 ° C., the cooling bath is removed and 50% saturated aqueous ammonium chloride (40 ml) is added. The solution is stirred for 20 minutes and then extracted with ether (2 x 50 ml). The combined organic layers were washed with water (2 x 25 ml), saturated sodium bicarbonate (2 x 25 ml), brine (50 ml), dried (Na 2 SO 4 ), filtered and concentrated to Boc-PyroGlu (4,4- Dimethyl) -OtBu (0.673 g, 54%) is obtained. [521] Step 3: Synthesis of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline (Boc-Pro (4,4-dimethyl) -OtBu): [522] [523] Modifications of known procedures [Pedregal, C .; Ezquerra, J .; Escribano, A .; Carreno, M.C .; Garcia Ruano, J.L. Tetrahedron Letters 1994, 35 (13), 2053-2056. [524] Lithium triethylbo in tetrahydrofuran to a solution of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylpyroglutamate (2.0 mmol) in tetrahydrofuran (5 ml) with stirring at −78 ° C. 1M solution of low hydride (2.4 ml, 2.4 mmol) was added dropwise over 5 minutes. After 30 minutes, the cooling bath is taken out and saturated aqueous sodium bicarbonate (5 ml) is added. The reaction mixture is immersed in an ice water bath and 30% aqueous hydrogen peroxide (10 drops) is added. The solution is stirred at 0 ° C. for 20 minutes and then the reaction mixture is concentrated in vacuo to remove tetrahydrofuran. The aqueous solution is diluted with water (10 ml) and extracted with dichloromethane (3 x 40 ml). The organic layer is dried (Na 2 SO 4 ), filtered and concentrated. The residue is dissolved in dichloromethane (20 ml) and triethylsilane (310 μl, 2.0 mmol), then cooled to −78 ° C. and boron trifluoride diethyl etherate (270 μl, 2.13 mmol) is added dropwise. Stirring is continued for 30 minutes, at which time additional triethylsilane (310 μl, 2.0 mmol) and boron trifluoride diethyl etherate (270 μl, 2.13 mmol) are added. After 2 h of stirring at -78 ° C, the cooling bath is removed and saturated aqueous sodium bicarbonate (4 ml) is added. After 5 minutes, the mixture is extracted with dichloromethane (3 x 40 ml). The organic layer is dried (Na 2 SO 4 ), filtered and concentrated to give Boc-Pro (4,4-dimethyl) -OtBu. [525] Step 4: Synthesis of 4,4-dimethylproline (H-Pro (4,4-dimethyl) -OH): [526] [527] A solution of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) is stirred at room temperature for 5 hours. This solution is concentrated and dried under high vacuum and then taken to the next step without further purification. [528] Step 5: Synthesis of N-tert-butoxycarbonyl 4,4-dimethylproline (Boc-Pro (4,4-dimethyl) -OH): [529] [530] To a solution of 4,4-dimethylproline trifluoroacetic acid salt (1.5 mmol) in dioxane (7 mL), acetonitrile (12 mL) and diisopropylethylamine (700 μL, 4 mmol), di- in acetonitrile (5 mL). A solution of tert-butyl-dicarbonate (475 mg, 2.18 mmol) is added. After stirring for 12 hours at room temperature, the solution is concentrated in vacuo, dissolved in saturated aqueous sodium bicarbonate (50 ml) and washed with diethyl ether (3 × 40 ml). The aqueous layer is acidified to pH 3 with citric acid and then extracted with dichloromethane (3 x 40 ml). The combined organic layers are dried over sodium sulphate, filtered and concentrated. [531] Step 6: Synthesis of 4,4-dimethylproline methyl ester hydrochloride salt (HCl.H-Pro (4,4-dimethyl) -OMe): [532] [533] Thionylchloride (448 L, 6.18 mmol) is added dropwise to a solution of Boc-Pro (4,4-diMe) -OH (0.5 g, 2.06 mmol) in anhydrous methanol (8 ml) and the reaction is stirred at room temperature for 6 hours. . The reaction mixture is concentrated to anhydrous solid (377 mg, 95%). [534] Example II: General procedure for the synthesis of N-tert-butoxycarbonyl-4-alkyl-4-methyl proline: [535] [536] Compounds in which the R groups are alkyl and benzyl are synthesized according to the following steps 1-4: [537] Step 1: Synthesis of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methyl-L-pyroglutamate: [538] [539] Tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (10.2 g, mmol) in tetrahydrofuran (170 ml) (see Example I, Step 1) with stirring at −78 ° C. 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (37.5 ml, 37.5 mmol) was added dropwise over 5 minutes. After 40 minutes, an alkyl halide (61.4 mmol) is added. After 3 h at −78 ° C., the cooling bath is removed and 50% saturated aqueous ammonium chloride (200 ml) is added. The solution is stirred for 20 minutes and then extracted with ether (2 x 200 ml). The combined organic layers are diluted with hexane (150 ml), washed with saturated sodium bicarbonate (100 ml), water (2 x 100 ml) and brine (100 ml), dried (Na 2 SO 4 ), filtered and concentrated. The residue was flash chromatographed using 20% ethyl acetate in hexanes to give pure tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methyl-L-pyroglutamate. [540] Step 2: Synthesis of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methylproline: [541] [542] Modifications of known procedures [Pedregal, C .; Ezquerra, J .; Escribano, A .; Carreno, M. C .; Garcia Ruano, J.L. Tetrahedron Letters 1994, 35 (13), 2053-2056. [543] Lithium tri in tetrahydrofuran in a solution of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methylpyroglutamate (16.6 mmol) in tetrahydrofuran (40 ml) with stirring at −78 ° C. 1M solution of ethylborohydride (20ml, 20mmol) was added dropwise over 10 minutes. After 120 minutes, the cooling bath is warmed to -25 ° C, at which time saturated aqueous sodium bicarbonate (40 ml) is added. The reaction mixture is immersed in an ice water bath and 30% aqueous hydrogen peroxide (4 ml) is added. The solution is stirred at 0 ° C. for 10 minutes and then the reaction mixture is concentrated in vacuo to remove tetrahydrofuran. The aqueous solution is diluted with water (300 ml) and extracted with dichloromethane (3 × 200 ml). The organic layer is dried (sodium sulfate), filtered and concentrated. The residue is dissolved in dichloromethane (100 ml) and triethylsilane (2.6 ml, mmol), then cooled to -78 ° C and boron trifluoride diethyl etherate (2.2 ml, mmol) is added dropwise. Stirring is continued for 1 hour, at which time additional triethylsilane (2.6 ml, mmol) and boron trifluoride diethyl etherate (2.2 ml, mmol) are added. After 4 h of further stirring at -78 ° C, the cooling bath is removed and saturated aqueous sodium bicarbonate (30 ml) and water (150 ml) are added. After 5 minutes, the mixture is extracted with dichloromethane (3 x 200 ml). The organic layer is dried (Na 2 SO 4 ), filtered and concentrated. [544] Step 3: Synthesis of 4-alkyl-4-methylproline: [545] [546] A solution of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methylproline in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) is stirred at room temperature for 5 hours. Toluene is added and the solution is concentrated and dried under high vacuum. [547] Step 4: Synthesis of N-tert-butoxycarbonyl 4-alkyl-4-methylproline: [548] [549] To a solution of 4-alkyl-4-methylproline trifluoroacetic acid salt (1.5 mmol) in dioxane (7 ml), acetonitrile (12 ml) and diisopropylethylamine (700 μl, 4 mmol) in acetonitrile (5 ml) A solution of di-tert-butyl-dicarbonate (475 mg, 2.18 mmol) is added. After stirring for 12 hours at room temperature, the solution is concentrated in vacuo, dissolved in saturated aqueous sodium bicarbonate (50 ml) and washed with diethyl ether (3 × 40 ml). The aqueous layer is acidified to pH 3 with 1N hydrochloric acid and then extracted with dichloromethane (3 × 40 ml). The combined organic layers are dried (Na 2 SO 4 ), filtered and concentrated. The residue is purified by flash chromatography using 1: 1 ethyl acetate / hexanes with 1% acetic acid. [550] Example III Synthesis of N-tert-butoxycarbonyl 4-propyl-4-methylproline: [551] [552] A solution of N-tert-butoxycarbonyl-4-allyl-4-methylproline (400 mg, 1.48 mmol) in methanol (20 ml) (see Example II, step 4) and 10% Pd on carbon for 4 hours at 50 psi Hydrogenate. This mixture is filtered and then concentrated. [553] Example IV Synthesis of Boc-4-cyclohexylproline: [554] [555] A commercial solution of Boc-4-phenylproline (750 mg) and 5% Rh on carbon (750 mg) in methanol (15 ml) was hydrogenated at 50 psi for 24 hours. The mixture is filtered and concentrated to yield 730 mg of product. [556] Example V Preparation of Fluorenylmethoxycarbonyl-Pro (4-spirocyclopentane) carboxylic Acid [557] [558] Step 1: Synthesis of Boc-pyroglutamic acid (4-allyl) -tert-butylester: [559] [560] To a cooled (-78 ° C) solution of commercially available N-Boc-tert-butyl pyroglutamate (10 g, 35.1 mmol) in THF (175 ml) was charged lithium hexamethyldisilazide (36.8 ml, 36.8 mmol) over 5 minutes. Add. Stirring is continued for 30 minutes. A solution of allyl bromide (6.1 ml, 70.2 mmol) in THF (39 ml) is added dropwise to the first solution. After 2 hours at −78 ° C., the reaction is quenched by the slow addition of saturated ammonium chloride (50 ml) solution. The reaction mixture is then diluted with ethyl acetate and the layers are separated. The organic layer is dried over sodium sulfate and then concentrated. Flash column chromatography with 2: 8 ethyl acetate: hexanes affords the product (6 g, 53%): [561] [562] Step 2: Synthesis of N-Boc-pyroglutamic acid (4,4-diallyl) -tert-butylester [563] [564] N-Boc-pyroglutamic acid (4-allyl) -tert-butyl ester (2.68 g, 8.24 mmol) obtained in step 1 above was subjected to a second alkylation reaction with allyl bromide under similar conditions. Flash chromatography with 15:85 ethyl acetate: hexanes provided 2.13 g (71%) of product as a clear oil. [565] Step 3: Synthesis of Boc-Pro (4,4-diallyl) -tert-butylester: [566] [567] Part a : Lithium triethylborohydride in a cooled (-78 ° C) solution of Boc-PyroGlu (4,4-diallyl) -tert-butylester (2.13 g, 5.83 mmol) in tetrahydrofuran (14 ml) Ride (1M in tetrahydrofuran, 7.29 ml, 7.29 mmol) is added over 5 minutes. After 2 hours at −78 ° C., the reaction is warmed to 0 ° C. and the reaction is quenched by the slow addition of saturated sodium bicarbonate solution (20 ml) and 30% hydrogen peroxide (20 drops). Stirring is continued for 20 minutes. Tetrahydrofuran is removed under reduced pressure and the remaining dark white residue is diluted with water (80 ml) and extracted three times with dichloromethane. The organic layer is dried, filtered and then concentrated and taken to the next step without further purification. [568] Part b: To the product obtained in part (a) in dichloromethane (14 ml) triethylsilane (931 μl, 5.83 mmol) was added followed by boron trifluoride diethyl etherate (776 μl, 6.12 mmol). . After 30 minutes, additional triethylsilane (931 μl, 5.83 mmol) and boron trifluoride diethyl etherate (776 μl, 6.12 mmol) were added and the reaction stirred at −78 ° C. for 3 more hours and saturated sodium bicarbonate The reaction is quenched by the slow addition of solution and water. The reaction mixture is extracted with dichloromethane and the organic layer is dried, filtered and concentrated. Flash column chromatography on 15% ethyl acetate in hexanes gave 1.07 (57%) of a colorless oil: [569] [570] Step 4: Synthesis of Boc-Pro (4-spirocyclopentene) -tert-butylester: [571] [572] 5% bis (tricyclohexylphosphine) benzylidene ruthenium IV dichloride (Grubbs catalyst) in Boc-Pro (4,4-diallyl) -tert-butylester (1.07 g, 3.31 mmol) in dichloromethane (66 ml) ) Is added and the mixture is heated at reflux for 1.5 h. The reaction mixture is concentrated and the remaining residue is purified by flash column chromatography with 15% ethyl acetate in hexanes. Obtained a yellow oil (0.57 g, 53%): [573] [574] Step 5: Synthesis of Boc-Pro (4-spirocyclopentane) -tert-butylester: [575] [576] A solution of Boc-Pro (4-spirocyclopentene) -tert-butylester (1.12 g) in methanol (18 ml), water (4 ml) and acetic acid (4 ml) was placed in a Parr shaker and placed on carbon Hydrogenate at 35 psi for 3 hours in the presence of 10% palladium (300 mg). The catalyst is filtered off and the filtrate is concentrated to a colorless oil (1.26 g): [577] [578] Step 6: Synthesis of Fmoc-Pro (4-spirocyclopentane) -carboxylic acid: [579] [580] Boc-Pro (4-spirocyclopentane) -tert-butylester (1.26 g, 3.9 mmol) is treated with dichloromethane (10 ml) and trifluoroacetic acid (15 ml) for 3 hours. The reaction mixture is concentrated and the yellow oil obtained is dissolved in water (6 ml). Fluorenylmethyl succinyl carbonate (1.45 g, 4.3 mmol) dissolved in dioxane (6 ml) was added dropwise and potassium carbonate (2.16 g, 15.6 mmol) was added dropwise. The reaction is stirred for 18 hours and then concentrated. The remaining residue is diluted with saturated sodium bicarbonate solution (10 ml) and washed with diethyl ether (3 x 10 ml). The aqueous layer is then acidified to pH about 1 with 1N sodium bisulfate solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated to yield a beige foam (1.3 g, 100%). [581] Example VI Synthesis of Boc-Pro (4t-NH (Fmoc))-OH [582] [583] Step 1: N αSynthesis of -tert-butoxycarbonyl-cis-4-chloro-L-proline benzyl ester: [584] [585] Commercial N-tert-butoxycarbonyl-trans-4-hydroxy-proline (8.79 g, 38 mmol), potassium carbonate (13.0 g, 94 mmol), benzyl bromide (4.5 ml, 38 mmol) and dimethylformamide (150 ml) The mixture is stirred for 18 hours. Ethyl acetate (100 ml) was added followed by filtration. 1M HCl (100 ml) is added to clear the white turbid filtrate. The layers are separated and the aqueous layer is extracted with additional ethyl acetate (2 x 100 ml). The combined organic layers are washed with water (2 x 50 ml), dried (sodium sulfate), filtered and concentrated. Toluene is added to the crude benzyl ester and the solution is filtered and then concentrated. Dichloromethane (70 ml) and carbon tetrachloride (70 ml) were added followed by triphenylphosphine (21.11 g, 80 mmol). The reaction mixture is stirred for 10 hours, quenched with ethanol (7 ml) and stirred for another 5 hours. The solution is concentrated to approximately 100 ml, then dichloromethane (40 ml) is added followed by ether (200 ml) with stirring. The solution was cooled for 4 hours, filtered and concentrated to give a tan oil which was purified by flash chromatography using ether / hexane / dichloromethane 2: 2: 1 to give the title compound (9.13 g, 26.9 mmol, 71%) is obtained as a white solid. [586] Step 2: N αSynthesis of -tert-butoxycarbonyl-trans-4-azido-L-proline benzyl ester: [587] [588] A solution of N α -tert-butoxycarbonyl-cis-4-chloro-L-proline benzyl ester (9.0 g, 26.5 mmol) and sodium azide (7.36 g, 113 mmol) in dimethylformamide (270 ml) was added to 75 Heat at C for 2 days. Water (100 ml) is added and the reaction mixture is extracted with ethyl acetate (3 × 100 ml). The combined organic layers are washed with water (3 x 50 ml), dried (sodium sulfate), filtered and concentrated. The oil is purified by flash chromatography using ethyl acetate / hexanes 1: 1 to afford the title compound (8.59 g, 24.8 mmol, 94%). [589] Step 3: Synthesis of Boc-Pro (4t-NH (Fmoc))-OH: [590] [591] A mixture of N α -tert-butoxycarbonyl-trans-4-azido-L-proline benzyl ester (8.59 g, 24.8 mmol) and 10% palladium on carbon (900 mg) in ethanol (500 ml) Hydrogenation reaction at 50 psi for 14 hours. The mixture is filtered, concentrated, dissolved in methanol (60 ml), refiltered and concentrated to give a colorless oil. This oil was dissolved in water (53 ml) containing sodium carbonate (5.31 g, 50.1 mmol) and a solution of fluorenylmethyl succinyl carbonate (8.37 g, 29.8 mmol) in dioxane (60 ml) was added over 40 minutes. do. The reaction mixture is stirred at rt for 17 h, then concentrated to remove dioxane and diluted with water (200 ml). This solution is washed with ether (3 x 100 ml). The pH of the aqueous solution is adjusted to 2 by adding citric acid (warning! Foaming!) And water (100 ml). The mixture is extracted with dichloromethane (400 ml, 100 ml, 100 ml) and the combined organic layers are dried (sodium sulfate), filtered and concentrated to afford the title compound. [592] Example VII: Synthesis of N-t-butoxycarbonyl-4-trans- (N-fluorenylmethyloxycarbonyl aminomethyl) -L-proline (Boc-Pro (4t-MeNHFmoc) -OH) [593] [594] Step 1: Synthesis of tert-butoxycarbonyl cis-4-hydroxy-L-proline benzyl ester (Boc-Pro (4-cis-OH) -OBn): [595] [596] To a mixture of cis-hydroxy-L-proline (5 g, 38.1 mmol) in benzene (45 ml) and benzyl alcohol (45 ml) p-toluenesulfonic acid monohydrate (7.6 g, 40.0 mmol) is added. The reaction mixture is heated at 125 ° C. for 20 hours while water is removed using a Dean-Stark trap. The solution is filtered while keeping hot and then ether (150 ml) is added. The solution is cooled at room temperature for 3 hours and then at 4 ° C. for 3 hours. The resulting solid is collected, washed with ether (100 ml) and dried under vacuum for 1 hour to give 13.5 g of a white solid. This solid was dissolved in dioxane (40 ml) and diisopropylethylamine (7.6 ml), and then di-tert-butyl-dicarbonate (10 g, 45.8 mmol) was added over 5 minutes using an ice bath. Maintain a constant reaction temperature. After 10 h at rt, the reaction mixture is poured into cold water (200 ml) and extracted with ethyl acetate (3 × 200 ml). The combined organic layers are washed with water (3 x 100 ml) and saturated aqueous sodium chloride (50 ml), dried (sodium sulfate), filtered and concentrated. This crude product is purified by flash chromatography using 40-60% ethyl acetate in hexanes to give the title compound (10.04 g, 31.24 mmol, 82%). [597] Step 2: Synthesis of N-t-butoxycarbonyl cis-4-mesyloxy-L-proline benzyl ester (Boc-Pro (4-cis-OMs) -OBn): [598] [599] To a solution of Boc-Pro (4-cis-OH) -OBn (8.45 g, 26.3 mmol) in pyridine (65 ml) at 0 ° C. is added dropwise over 7 minutes methanesulfonyl chloride (3.4 ml, 44 mmol). The reaction mixture is allowed to warm to room temperature over 2 hours and then stirred overnight. A 10% aqueous solution in pyridine (20 ml) is added over 15 minutes and the reaction mixture is concentrated. The residue is dissolved in water and extracted with ethyl acetate (2 x 200 ml). The combined organic layers are washed with water (2 x 50 ml), saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium chloride (50 ml), dried (sodium sulfate), filtered and concentrated. The resulting residue is dissolved in toluene (100 ml) and concentrated to remove traces of pyridine. The residue was dried in vacuo for 30 min to afford the title compound (10.7 g, 102%) which was used in the next step without purification. [600] Step 3: N-t-butoxycarbonyl trans-4R-cyano-L-proline benzyl ester (Boc-Pro (4-trans-CN) -OBn): [601] [602] A solution of Boc-Pro (4-cis-OMs) -OBn (10.7 g, 26.3 mmol) and tetrabutylammonium cyanide (15.0 g, 56 mmol) in dimethylformamide (100 ml) was 28 hours in an oil bath at 55 ° C. Heat during. After cooling, water (150 ml) is added and the mixture is extracted with ethyl acetate (3 x 200 ml). The combined organic layers are washed with water (3 x 100 ml) and saturated aqueous sodium chloride (100 ml), dried (sodium sulfate), filtered and concentrated. The resulting residue is purified by flash chromatography (1: 1 ether / hexanes) and then recrystallized from ethyl acetate / hexanes to give the title compound (2.40 g, 7.26 mmol, 28%). [603] Step 4: N-t-butoxycarbonyl-4-trans- (N-fluorenylmethyloxycarbonyl aminomethyl) -L-proline (Boc-Pro (4t-MeNHFmoc) -OH): [604] [605] A mixture of the compound of step 3 (2.31 g, 7 mmol), water (10 ml), methanol (85 ml) and 10% palladium on carbon (700 mg) is hydrogenated at 50 psi for 11 hours using a Parr hydrogenation apparatus. This mixture is filtered and then concentrated. Water (15 ml) and sodium carbonate (1.5 g, 14.2 mmol) are added to the residue. A solution of fluorenylmethyl succinyl carbonate (2.36 g, 7.0 mmol) in dioxane (17 ml) is added over 5 minutes and stirring is continued at room temperature for 28 hours. The reaction is concentrated in vacuo to 15 ml volume and water (100 ml) is added. The solution is washed with ether (3 x 75 ml). The pH of the aqueous solution is adjusted to 2 by adding citric acid (approximately 20 g, warning! Effervescent!) And water (100 ml). The mixture is extracted with dichloromethane (4 x 100 ml) and the combined organic layers are dried (sodium sulfate), filtered and concentrated. The crude product contains most of the impurities that require three steps of purification. This crude product is dissolved in dichloromethane (50 ml) and trifluoroacetic acid (50 ml), stirred for 5 hours and then concentrated. The residue is purified by preparative reversed phase HPLC. Pure 4- (N-fluorenylmethyloxycarbonyl aminomethyl) proline trifluoroacetate salt (1.887 g, 3.93 mmol) was added to dioxane (10 ml), acetonitrile (20 ml) and diisopropylethylamine (1.4 ml). , 8 mmol). To this reaction mixture is added a solution of di-tert-butyldicarbonate (1.1 g, 5 mmol) in dioxane (5 ml). After stirring for 18 hours, the pH of the solution is adjusted to 2 by addition of citric acid (Warning: effervescent!) And water (100 ml). The mixture is extracted with ethyl acetate (3 x 150 ml) and the combined organic layers are washed with saturated aqueous sodium chloride (100 ml), dried (sodium sulfate), filtered and concentrated. The crude product is dissolved in saturated aqueous sodium bicarbonate (100 ml) and washed with ether (3 × 75 ml). The aqueous layer is adjusted to pH 3 by addition of citric acid and then extracted with dichloromethane (4 x 100 ml). The combined organic layers are dried (sodium sulfate), filtered and concentrated to give the title compound (1.373 g, 2.94 mmol, 42%). [606] Example VIII Synthesis of 3,4-isopropylideneprolino [607] [608] Step 1: Cyclopropaneation reaction [Tetrahedron Lett. 1993, 34 (16), 2691 and 2695]: [609] [610] To a stirred solution of isopropyltriphenyl-phosphonium iodide (4.14 g, 9.58 mmol) in tetrahydrofuran (60 ml) at 0 ° C., n-butyllithium (1.6 M in hexane, 5.64 ml, 9.02 mmol) for 5 minutes Apply across. After 30 minutes, enamide [(5R, 7S) -5-phenyl-5,6,7,7a-tetrahydro-6-oxapyrrolidin-3-one] in tetrahydrofuran (40 ml) (1.206 g, 6.0 mmol) (see J. Org. Chem. 1999, 64 (2), 547) for the synthesis of enamide starting materials) is added over 10 minutes. After 10 minutes more, the cooling bath is taken out and the reaction mixture is stirred at room temperature for 4 hours. The reaction is poured into water (400 ml) and extracted with diethyl ether (400 ml) and ethyl acetate (2 × 400 ml). The combined organic extracts are dried over sodium sulfate, filtered and concentrated to give the desired crude product. The residue is purified by flash chromatography eluting with 3: 5: 2 ethyl acetate / hexanes / methylene chloride to afford the pure cyclopropaneated product (750 mg, 3.08 mmol, 51%). [611] Step 2: Synthesis of 3,4-isopropylideneprolino P [3,4- (diMe-cyclopropyl)]-alcohol) See J. Org. Chem. (1999) 64 (2), 330: [612] [613] A mixture of the product obtained in step 1 (1.23 g, 5.06 mmol) and lithium aluminum hydride (1.0 M in THF, 15 ml, 15 mmol) is heated under reflux for 5 hours. After cooling to 0 ° C., the remaining aluminum hydride is carefully quenched by dropwise addition of saturated aqueous sodium sulfate (1.5 ml) over 15 minutes. The mixture is diluted with ethyl acetate (40 ml) and then filtered through celite. The filtrate is dried over sodium sulphate, filtered and concentrated to give crude N-benzyl aminoalcohol (1.25 g) which is taken to the next step without further purification. A solution of crude N-benzyl aminoalcohol (1.25 g, 5.06 mmol) in 1: 1 acetic acid / ethyl acetate (30 ml) with 10% Pd / C (1 g) was hydrogenated at 50 psi for 16 hours using a Parr hydrogenation unit. React. The reaction mixture is filtered to remove the carbonaceous catalyst and the filtrate is concentrated. The residue is dissolved in water (30 ml) and the pH is adjusted to 13 with 50% NaOH. The mixture is extracted with ether (3 x 60 ml). The combined extracts are dried over sodium sulphate, filtered and concentrated to give crude aminoalcohol (485 mg, 3.43 mmol). This material is taken to the next step without further purification. [614] Example IX: Synthesis of iBoc-G (Chx) -Pro (3,4-isopropylidene) -carboxylic acid [615] [616] Step 1: Synthesis of isobutyloxycarbonyl-cyclohexylglycine (iBoc-G (Chx) -OH): [617] [618] Potassium carbonate is added to a solution of commercial cyclohexylglycine hydrochloride (15 g, 77.4 mmol) in acetonitrile (320 ml) and water (320 ml). Isobutylchloroformate (11.1 ml, 85.1 mmol) is added to the clear solution over 15 minutes and the reaction is stirred for 17 hours. Acetonitrile is removed under reduced pressure and the remaining aqueous layer is extracted twice with ether (100 ml). The aqueous layer is then acidified to pH 1 with 6N hydrochloric acid and extracted with dichloromethane (3 × 300 ml). The organic layer is dried over sodium sulfate, filtered and concentrated to yield 18.64 g (94%) of product as a white solid. [619] Step 2: Synthesis of isobutyloxycarbonyl-cyclohexylglycyl-3,4-isopropylideneproline (iBoc-G (Chx) -P [3,4- (diMe-cyclopropyl)]-OH) [620] [621] a) coupling step [622] To a solution of iBoc-G (Chx) -OH (890 mg, 3.45 mmol) in acetonitrile (20 ml) was added HATU (1.33 g, 3.5 mmol), HOAt (476 mg, 3.5 g) was added, followed by diisopropylethylamine (2.5 ml, 14 mmol) is added. After 2 minutes, 3,4-isopropylideneprolinol (485 mg, 3.43 mmol) is added and the reaction mixture is stirred overnight. Saturated aqueous sodium bicarbonate is added and then extracted with ether and ethyl acetate. The combined organic layers are dried, filtered and concentrated. The residue was purified by flash chromatography, eluting with 1: 1 ethyl acetate / hexanes to give pure dipeptide alcohol iBoc-G (Chx) -3,4-isopropylideneprolinol (870 mg, 2.3 mmol, 67%). do. [623] b) Jones oxidation step [624] Jones reagent (300 μL) was added to a solution of dipeptide alcohol iBoc-G (Chx) -3,4-isopropylideneprolinol (100 mg, 0.26 mmol) in acetone (2 mL) over 5 minutes with stirring at 0 ° C. Add dropwise (Jones reagent: prepared from concentrated sulfuric acid (11.5 ml) and chromium trioxide (13.4 g) diluted with water to a total volume of 50 ml. After stirring for 3 hours at 0 ° C., isopropanol (500 μl) is added and stirring is continued for 10 minutes. The reaction mixture is diluted with water (20 ml) and extracted with ethyl acetate (3 x 70 ml). The combined organic layers are dried, filtered and concentrated to give dipeptide iBoc-G (Chx) -3,4-isopropylideneproline (100 mg, 0.25 mmol, 96%). [625] Example X: Synthesis of N-Cbz-3,4-methanoproline: [626] [627] Step 1: Synthesis of N-benzyl-3,4-methanoprolinol: [628] [629] Benzylidene starting material [J. Org. Chem. 1999, 64 (2), 547] (4.6 g, 21.4 mmol) and a lithium aluminum hydride (1.0 M in THF, 64 ml, 64 mmol) are heated under reflux for 5 hours. After cooling to 0 ° C., the remaining aluminum hydride is carefully quenched by dropwise addition of saturated aqueous sodium sulfate (5 ml) over 15 minutes. The mixture is diluted with ethyl acetate (200 ml) and then filtered through celite. The filtrate is dried over sodium sulfate, filtered and concentrated to give crude N-benzyl aminoalcohol (3.45 g) which is taken to the next step without further purification. [630] Step 2: Synthesis of N-benzyloxycarbonyl-3,4-methanoprolinol (CBz-P (3,4-CH2) -ol): [631] [632] A solution of crude N-benzyl aminoalcohol (3 g, 14.76 mmol) in methanol (120 ml) and concentrated HCl (1.5 ml) is hydrogenated with 10% Pd / C (300 mg) for 16 hours at 50 psi. The reaction mixture is filtered to remove the carbonaceous catalyst and the filtrate is concentrated. The residue is dissolved in water / dioxane (100 ml) and diisopropylethylamine (3.2 ml) is added. Benzyl chloroformate (2.76 ml, 16.2 mmol) is added and the reaction is stirred overnight. The reaction mixture is concentrated, dissolved in 1M HCl (100 ml) and extracted with ethyl acetate (3 × 200 ml). The combined organic layers are dried over magnesium sulphate, filtered and concentrated. The residue is purified by flash chromatography using 1: 3 ethyl acetate / hexanes to give N-Cbz-3,4-methanoprolinol (2.4 g). [633] Step 3: Synthesis of N-benzyloxycarbonyl-3,4-methanoproline (CBz-P (3,4-CH2) -OH): [634] [635] To a solution of N-CBz-3,4-methanoprolinol (2.2 g, 8.90 mmol) in acetone (68 ml) was added dropwise over 5 minutes to Jones reagent (6.6 ml) with stirring at 0 ° C. Prepared from concentrated sulfuric acid (11.5 ml) and chromium trioxide (13.4 g) diluted with water to a volume of 50 ml. After stirring for 3 hours at 0 ° C., isopropanol (11 ml) is added and stirring is continued for 10 minutes. The reaction mixture is diluted with water (400 ml) and extracted with ethyl acetate (3 x 500 ml). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to give N-Cbz-3,4-methanoproline (2.25 g, 96%). [636] Example XI Synthesis of Boc- (6S-carboethoxymethano) proline [637] [638] Published process [Marinozzi, M .; Nataini, B .; Ni, M. H .; Costantino, G .; According to Pellicciari R. IL Farmaco (1995) 50 (5), 327-331, the synthesis of the title compound is carried out. [639] Example XII: Synthesis of Boc-3-morpholine carboxylic acid [640] [641] Published courses [Kogami Y., Okawa, K. Bull. Chem. Soc. Jpn. (1987) 60, 2963-2965, the synthesis of the title compound is carried out. [642] Example XIII Synthesis of N-tert-butoxycarbonyl 2-aza-3S-hydroxycarbonyl- [2,2,2] -bicyclooctane: [643] [644] Crude 2-aza-2- (1-phenylethyl) -3S-methoxycarbonyl- [2,2,2] -bicyclooct-5-ene (10 mmol) in methanol (30 ml) [Tetrahedron (1992) 48 (44) 9707-9718] and a solution of 10% Pd (1 g) on carbon are acidified with 12N HCl and then hydrogenated at 50 psi for 16 hours using a Parr hydrogenation apparatus. The reaction mixture is filtered to remove the carbonaceous catalyst and the filtrate is concentrated. The residue is dissolved in concentrated HCl and stirred overnight. The solution is concentrated and redissolved in acetonitrile (50 ml). Diisopropylethylamine (3.5 ml) and di-tert-butyldicarbonate (1 g) are added. The reaction mixture is stirred for 24 hours and then concentrated. The residue is dissolved in CH 2 Cl 2 and 5% aqueous sulfuric acid. The reaction mixture is extracted with CH 2 Cl 2 and the combined organic layers are concentrated. The residue is dissolved in 10% saturated sodium bicarbonate, extracted with diethyl ether (2x) and acidified with 5% aqueous sulfuric acid. The aqueous layer is extracted with ethyl acetate (2x). The combined ethyl acetate layers were dried filtered and concentrated to afford N-tert-butoxycarbonyl 2-aza-3S-hydroxycarbonyl- [2,2,2] -bicyclooctane (650 mg). [645] Example XIV: Synthesis of isobutyloxycarbonyl-cyclohexylglycyl-4,4-dimethyl proline (iBoc-G (Chx) -P (4,4-dimethyl) -OH) [646] [647] Step 1: Synthesis of iBoc-G (Chx) -P (4,4-dimethyl) -OMe: [648] [649] In a solution of iBoc-G (Chx) -OH (Example IX, Step 1) (377 mg, 1.95 mmol) in acetonitrile (7 ml), HCl-HN-Pro (4,4-dimethyl) -OMe (Example I, Step 6) (377 mg, 1.95 mmol), N-hydroxybenzotriazole (239 mg, 1.75 mmol), TBTU (845 mg, 2.63 mmol) and diisopropylethylamine (1.35 ml, 7.8 mmol) were added successively. The reaction mixture is stirred at rt for 18 h. The reaction mixture is concentrated and the remaining residue is dissolved in ethyl acetate. The organic layer is washed twice with saturated sodium bicarbonate solution, 1N hydrochloric acid solution and 10 ml fractions of brine. The organic layer is dried over sodium sulfate, filtered and concentrated to give a white solid (612 mg, 79%). [650] Step 2: Synthesis of iBoc-G (Chx) -P (4,4-dimethyl) -OH: [651] [652] The methyl ester (612 mg, 1.54 mmol) obtained in step 1 above in methanol (6 ml) is saponified in the presence of 2M lithium hydroxide (1.16 ml) for 3 hours. Methanol is removed under reduced pressure, the remaining residue is diluted with ethyl acetate and acidified to pH 2 with 1N hydrochloric acid. The layers are separated and the organic layer is washed with water and brine, dried over sodium sulphate, filtered and concentrated. [653] Example XV: Synthesis of L-phenylglycine Dimethylamide [654] [655] Step 1: Synthesis of N-benzyloxycarbonyl-L-phenylglycine dimethylamide (CBz-Phg-NMe2) [656] [657] N-benzyloxycarbonyl-L-phenylglycine (25 g, 88 mmol) is dissolved in THF (800 ml) and cooled to -10 ° C. N-methylmorpholine (9.7 ml, 88 mmol) and isobutylchloroformate (11.4 ml, 88.0 mmol) are added and the mixture is stirred for 1 minute. Dimethylamine (100 ml, 2M in THF) is added and the reaction is allowed to warm to room temperature. The mixture is filtered and the filtrate is concentrated in vacuo to give N-benzyloxycarbonyl-L-phenylglycine dimethylamide (32.5 g) as a yellow oil. [658] [659] Step 2: Synthesis of L-phenylglycine Dimethylamide (H-Phg-NMe2) [660] The obtained N-benzyloxycarbonyl-L-phenylglycine dimethylamide (32.5 g) is dissolved in methanol (750 ml) and 10% palladium on activated carbon (3.3 g) is added. This mixture is hydrogenated on a Parr apparatus under 35 psi hydrogen for 2 hours. The reaction mixture is filtered, the solvent is removed in vacuo, and the residue is recrystallized from methanol-hexane to give phenylglycine dimethylamide (26 g) as a gray solid. The ee of this material was determined to be> 99% by HPLC analysis of 2,3,4,6-tetra-O-acetylglucopyranosylthioisocyanate derivative. [661] Example XVI: Synthesis of (1-methylcyclohexyl) glycine: [662] [663] Step 1: 1-methyl-1-hydroxymethylcyclohexane [664] [665] To a solution of 1-methyl-1-hydroxycarbonylcyclohexane (10 g, 70 mmol) in tetrahydrofuran (300 ml) at 0 ° C., 1M diborane (200 ml, 200 mmol) of tetrahydrofuran strain was added over 90 minutes. The cooling bath is taken out and the reaction mixture is stirred for 2 days at room temperature. The remaining borane is quenched by the slow addition of saturated sodium bisulfate (10 ml) over 90 minutes while cooling. Additional saturated sodium bisulfate (200 ml) is added and after stirring for 20 minutes, the aqueous layer is removed. The organic layer is washed with water and saturated sodium chloride, dried, filtered and concentrated. The residue is purified by flash chromatography using 20% diethyl ether in hexanes to give 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol, 69%). [666] Step 2: 1-methylcyclohexylcarboxaldehyde [667] [668] Pyridine sulfur trioxide complex in dimethylsulfoxide (150 ml) in a solution of 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol) and triethylamine (20.1 ml, 144 mmol) in dichloromethane (150 ml) at 0 ° C. 22.9 g, 144 mmol) is added over 15 minutes. The cooling bath is warmed to room temperature over 2 hours, whereupon the reaction mixture is poured with brine (400 ml). The layers are separated and the aqueous layer is extracted with dichloromethane (200 ml). The combined organic layers are diluted with hexane (600 ml), washed with 1M HCl (2 x 150 ml), saturated sodium chloride (2 x 100 ml), dried, filtered and concentrated. The residue is purified by flash chromatography to yield 1-methylcyclohexylcarboxaldehyde (1.77 g, 13.8 mmol, 29%). [669] Step 3: Synthesis of N-formyl-N-glycosyl-1-methylcyclohexyl tert-butylamide: [670] [671] Open process [Kunz. H .; Pfrengle, W .; Ruck, K .; According to Wilfried, S. Synthesis (1991) 1039-1042, the synthesis of 2,3,4-tri-O-pivaloyl--D-arabinosylamine is performed. [672] 1-methylcyclohexylcarboxaldehyde (1.17 g, 8.34 mmol), 2,3,4-tri-O-pivaloyl--D-arabinosylamine (8.3 g in tetrahydrofuran (170 ml) at -30 ° C , 20.7 mmol), formic acid (850 μl, 22.2 mmol) and tert-butyl isocyanide (2.4 ml, 21.2 mmol) were added 0.5 M zinc chloride (41 ml, 20.57 mmol) in tetrahydrofuran. The solution is stirred at -20 [deg.] C. for 3 days and then concentrated. The residue is diluted with CH 2 Cl 2 (500 ml) and washed with saturated sodium bicarbonate (2 × 500 ml) and water (500 ml). The organic layer is dried, filtered and concentrated to afford a clean oil. Flash chromatography (20% ethyl acetate in hexanes) gave the pure product (4.3 g, 6.6 mmol, 33%). [673] Step 4: Synthesis of (1-methylcyclohexyl) glycine: [674] [675] The solution of the product obtained in step 3 (4.3 g, 6.6 mmol) in dichloromethane (30 ml) and saturated anhydrous methanolic HCl (30 ml) was stirred overnight. The solution is concentrated and the residue is dissolved in water (100 ml) and washed with pentane (2 x 100 ml). The aqueous layer is concentrated, the residue is dissolved in 6N HCl (50 ml) and heated at reflux for 30 h. Concentrate this solution to give crude (1-methylcyclohexyl) glycine hydrochloride (790 mg, 3.82 mmol, 58%). [676] Example XVII: Synthesis of (4,4-dimethylcyclohexyl) glycine [677] [678] Step 1: Synthesis of 4,4-dimethylcyclohexanone: [679] [680] A mixture of 4,4-dimethylcyclohex-2-en-1-one (12 ml, 91.2 mmol) and Degussa type 10% Pd (2 g) on carbon is hydrogenated at 40 psi for 18 hours. This mixture is filtered and concentrated [ 1 H NMR showed a 5: 3 mixture of ketones and alcohols]. The mixture is dissolved in acetone (400 ml) and cooled to 0 ° C. Jones reagent (40 ml) is added over 30 minutes and the cooling bath is removed. After 2 days, excess acetone is evaporated and the resulting residue is dissolved in water and diethyl ether. The ether layer is washed with water until colorless, dried, filtered and concentrated to give 4,4-dimethylcyclohexanone (7.4 g, 58.6 mmol, 64%). [681] Step 2: Synthesis of Methyl Enol Ether of 4,4-dimethylcyclohexylcarboxaldehyde: [682] [683] To a solution of methoxymethyl triphenylphosphonium chloride (8.6 g) in tetrahydrofuran (125 ml) at 0 ° C. is added n-butyllithium (1.6 M in hexane, 14.3 ml) over 10 minutes. After 30 minutes, the reaction mixture is cooled to −78 ° C. and a solution of 4,4-dimethylcyclohexanone (2.45 g, 19.1 mmol) in tetrahydrofuran (50 ml) is added over 20 minutes. After 1 hour, the cooling bath is taken out and the reaction is slowly warmed to 0 ° C. The reaction is diluted with saturated ammonium chloride (50 ml), ethyl acetate (100 ml) and hexane (100 ml). The organic layer is washed with water and brine, dried and filtered and then concentrated. The residue is stirred with hexane (70 ml) for 10 minutes and then filtered. The filtrate is concentrated and chromatographed with 25% ethyl acetate in hexanes to give the title compound (1.925 g, 12.5 mmol, 65%). [684] Step 3: 4,4-dimethylcyclohexylcarboxaldehyde: [685] [686] A solution of methyl enol ether (1.925 g, 12.5 mmol) of 4,4-dimethylcyclohexylcarboxaldehyde (step 2 above), tetrahydrofuran (100 ml) and 6 M HCl (20 ml) is stirred at room temperature for 4 hours. The reaction mixture is diluted with hexane, diethyl ether, brine and water. The organic layer is dried, filtered and concentrated to give 4,4-dimethylcyclohexylcarboxaldehyde (1.0 g, 7.1 mmol, 57%). [687] Step 4: Synthesis of N-formyl-N-glycosyl-4,4-dimethylcyclohexyl tert-butylamide: [688] [689] 4,4-dimethylcyclohexylcarboxaldehyde (1.17 g, 8.34 mmol), 2,3,4-tri-O-pivaloyl-α-D-arabinosylamine (3.43 in THF (70 ml) at −30 ° C. g, 8.55 mmol), 0.5 M zinc chloride (17 ml, 8.5 mmol) in tetrahydrofuran are added to a solution of formic acid (350 μl, 9.17 mmol) and tert-butyl isocyanide (990 μl, 8.76 mmol). The solution is stirred at -20 [deg.] C. for 2 days and then concentrated. The residue is diluted with dichloromethane (200 ml) and washed with saturated sodium bicarbonate (2 x 200 ml) and water (200 ml). The organic layer is dried, filtered and concentrated to afford a clean oil. Flash chromatography (20% ethyl acetate in hexanes) affords the pure product (2.1 g, 3.3 mmol, 39%). [690] Step 5: Synthesis of (4,4-dimethylcyclohexyl) glycine: [691] [692] The solution of the Ugi product (2.1 g, 3.3 mmol) obtained in step 4 above in dichloromethane (20 ml) and saturated anhydrous methanolic HCl (20 ml) is stirred overnight. The solution is concentrated and the residue is dissolved in water (100 ml) and washed with pentane (2 x 100 ml). The aqueous layer is concentrated, the residue is dissolved in 6N HCl (40 ml) and heated at reflux for 30 h. Concentrate this solution to afford crude (1-methylcyclohexyl) glycine hydrochloride (300 mg, 1.36 mmol, 41%). [693] Example XVIII: Synthesis of Boc-nVal- (CHOH) -Gly-OH [694] [695] Step 1: Preparation of Boc-Norvalinol: [696] [697] To a solution of Boc-norvaline (25.0 g, 0.115 mol) in tetrahydrofuran (461 ml) cooled to 0 ° C. is added dropwise a borane / tetrahydrofuran complex (461 ml of 1.0M solution in tetrahydrofuran). After 1 hour at 0 ° C., the solution is allowed to warm to room temperature over 1.5 hours. TLC indicates that the reaction is complete. Methanol is added to quench the reaction. The solution is concentrated to give the title compound (22.56 g, 96%) as effervescent syrup. TLC of this product indicated satisfactory purity. R f = 0.34 (40% ethyl acetate / hexanes). [698] Step 2: Preparation of Boc-Norvalinal: [699] [700] EDC (73.32 g, 382 mmol) was added to Boc-norvalinol (7.77 g, 38 mmol) in anhydrous dimethylsulfoxide (153 ml) and toluene (153 ml). After cooling the solution to 0 ° C., dichloroacetic acid (15.8 ml, 191 mmol) was added dropwise. After the addition is complete, the reaction is stirred for 15 minutes. The solution is allowed to warm to room temperature over 2 hours. The reaction mixture is concentrated to remove toluene and then dissolved in ethyl acetate. The solution is washed successively with 1N sodium bisulfate, saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to give crude Boc-norvalinal which is used directly in the next step. TLC R f = 0.84 (40% ethyl acetate / hexanes). [701] Step 3: Synthesis of Boc-nVal- (CHOH) -Gly-OEt: [702] [703] To a solution of crude Boc-norvalinal (4.18 g, 20.77 mmol) in dichloromethane (83 ml) is added ethylisocyanoacetate (2.72 ml, 24.93 mmol) and pyridine (6.72 ml, 83.09 mmol). After cooling the solution to 0 ° C., trifluoroacetic acid (4.15 ml, 41.54 mmol) is added dropwise. After stirring for 1 hour, the solution is stirred for 18 hours at room temperature, during which the solvent is evaporated under ambient conditions from the reaction mixture in an uncovered vessel. The reaction mixture is concentrated and then dissolved in ethyl acetate. The solution is washed successively with 1N sodium bisulfate, saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography, eluting with 20-40% ethyl acetate / hexanes to give 2.8 g of the title compound as a yellow syrup. Low resolution mass spectroscopy confirmed the presence of the desired product (MH + 333). [704] Step 4: Synthesis of Boc-nVal- (CHOH) -Gly-OH: [705] [706] The resulting product (Boc-nVal- (CHOH) -Gly-OEt) (1.52 g, 4.70 mmol) dissolved in ethanol (23 ml) was saponified with 1N lithium hydroxide (18.81 ml) for 2 hours at room temperature. The reaction mixture is acidified to pH about 2 with Dowex® 50 WX8 ion exchange resin, stirred for 20 minutes and then filtered. The resin is washed well with ethanol and water and the combined filtrates are concentrated to give a white foam (0.48 g, 33%). [707] Example XVIV: Synthesis of (2R, 3S, 4S, 5S) -tert-butyl N-CBz-3-amino-2-hydroxy-4,5-methylene-hexanoate [708] [709] Step 1: [710] [711] To a solution of tert-butyl diethylphosphonoacetate (4.7 ml, 20 mmol) dissolved in THF (50 ml) at −78 ° C. add 1.6 M n-butyl lithium (12.4 ml) in hexane. After 30 minutes, (1S, 2S) -2-methylcyclopropylcarboxaldehyde (1 g, 12 mmol) in diethyl ether (100 ml) [Barrett, A.G.M .; Doubleday, W.W .; Kasdorf, K .; Tustin, G. J., J. Org. Chem. (1996) 61, 3280] is added over 10 minutes. The reaction is warmed to 0 ° C. for 2 hours and then to 6 ° C. for 12 hours. The reaction was quenched with saturated ammonium chloride (20 ml), the organic layer was separated, washed with 50 ml brine, dried over sodium sulfate, filtered and concentrated to give 3.5 g of a clean oil. Flash chromatography (20% ethyl acetate in hexanes) affords pure unsaturated tert-butyl ester (1.4 g). [712] Step 2: [713] [714] To a solution of benzyl carbamate (3.55 g, 23.5 mmol) in n-propanol (24 ml) was added a solution of sodium hydroxide (900 mg, 22.7 mmol) in water (48 ml), followed by tert-butylhypochlorite (2.57 ml, 22.7 mmol) is added. After 15 minutes, the reaction was cooled to 0 ° C. and (DHQ) 2 PHAL (350 mg, 0.45 mmol) was added to n-propanol (24 ml) and then unsaturated tert-butyl ester from above in n-propanol (48 ml). (1.4 g) is added. Finally, when potassium osmate (110 mg, 0.30 mmol) in water (2 ml) was added, the solution turned dark green very quickly, which lasted for 4 hours. After 6 hours, saturated sodium sulfate (50 ml) is added and the mixture is extracted with ethyl acetate (2 x 50 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulphate, filtered and concentrated. Flash chromatography with 20% ethyl acetate in hexanes affords the desired CBz protected amino tert-butyl ester as a white solid (316 mg). [715] Step 3: [716] [717] A mixture of 32 mg 10% palladium on carbon and CBz protected amino tert-butyl ester (316 mg, 0.9 mmol) in 9 ml of methanol is hydrogenated for 8 hours. The mixture is filtered and concentrated to give free amine as a clear oil (195 mg). [718] Example XX: Synthesis of 1R, 2-dimethylpropyl chloroformate [719] [720] To a commercially available 2R-hydroxy-3-methylbutane (410 mg, 4.65 mmol) was added a solution of 20% phosgene (1 ml, 2 mmol) in toluene. The solution is stirred for 6 hours to produce chloroformate (2 mmol), which is reacted directly with the desired amine directly. S-isomers are synthesized in the same process. [721] II) Representative Solution Phase Synthesis of HCV Inhibitors [722] Example XXI: Solution Phase Synthesis of iBoc-G (Chx) -Pro (4,4-Dimethyl) -Leu- (CO) -Gly-Phg-Dimethylamide [723] [724] Step 1: Synthesis of tert-butyloxycarbonyl-leucinal (Boc-Leu-CHO): [725] [726] Triethyl amine (2 ml, 14.36 mmol) was added to a solution of Commercial Chem Tech Boc-L-Lysinol (0.78 g, 3.6 mmol) in anhydrous dichloromethane (17.5 ml) and the mixture was cooled to 0 ° C. . Dimethyl sulfoxide (17.5 ml) is added, followed by sulfur trioxide pyridine complex (2.3 g, 14.36 mmol) and the reaction is stirred for 2 hours. TLC in 1: 1 ethyl acetate: hexanes confirmed the reaction was complete. The reaction mixture is concentrated and the remaining residue is diluted with ethyl acetate. This ethyl acetate layer is washed with 1M hydrochloric acid (2 x 75 ml), followed by saturated sodium bicarbonate solution (2 x 75 ml) and brine (75 ml). The organic layer is dried (sodium sulfate), filtered and concentrated to give 775 mg of product. [727] Step 2: Synthesis of Boc-2-hydroxy-3-amino-5-methyl hexanoyl-glycine ethyl ester (Boc-Leu- (CHOH) -Gly-OEt): [728] [729] To a solution of Boc-leucine aldehyde (0.77 g, 3.59 mmol) in anhydrous dichloromethane (24 ml) was added anhydrous pyridine (1.16 ml, 14.36 mmol) and ethylisocyanoacetate (0.4 ml, 4.66 mmol). The reaction mixture is cooled to 0 ° C. and trifluoroacetic acid (0.55 ml, 7/18 mmol) is added over 2 minutes. The reaction mixture is capped and stirred at 4 ° C. for 4 days and then at room temperature for 1 day. The reaction mixture is diluted with dichloromethane (350 ml) and washed twice with 75 ml fractions each of 1 M hydrochloric acid, saturated sodium bicarbonate and brine. The organic layer is dried, filtered and then concentrated. The obtained residue is flash chromatographed on a 2 "x 6" silica gel column using 10% ethyl acetate in hexanes (800 ml) followed by 1: 1 ethyl acetate (800 ml) in hexanes. The fractions corresponding to the product are combined and concentrated to give 980 mg (79%) of the product. [730] Step 3: Synthesis of Boc-Leu- (CHOH) -Gly-OH: [731] [732] To a solution of Boc-Leu- (CHOH) -Gly-Oet (0.98 g, 2.83 mmol) in ethanol (11.3 ml) is added 2M lithium hydroxide (4.25 ml) and the reaction is stirred at room temperature for 5 hours. Ethanol is removed under reduced pressure and the aqueous layer is diluted with ethyl acetate. The organic layer is washed with 1M hydrochloric acid, then brine, dried, filtered and concentrated to give 775 mg (86%) of the product as a white solid. [733] Step 4: Synthesis of Boc-Leu- (CHOH) -Gly-Phg-dimethylamide: [734] [735] Phenylglycine dimethylamide (Example XV, obtained in step 2), EDC (0.34 g, 1.76 mmol) in a solution of Boc-Leu- (CHOH) -Gly-OH (0.37 g, 1.18 mmol) in acetonitrile (23 ml) ), N-hydroxybenzotriazole (HOBt) (0.18 g, 1.18 mmol) and diisopropylethylamine (DIEA) (0.82 ml, 4.7 mmol) are added successively and the reaction is stirred at room temperature for 18 hours. . The reaction mixture is concentrated and the remaining residue is diluted with ethyl acetate and washed twice successively with 75 ml fractions each of 1M hydrochloric acid, saturated sodium bicarbonate and brine. The organic layer is then filtered dry and concentrated. For crude product, flash chromatography on a 2 "x 6" silica gel column using 4: 1 ethyl acetate: hexane (700 ml) followed by 10% methanol (600 ml) and ethyl acetate (1000 ml) in dichloromethane. Graphy. Collect the fractions corresponding to the product and concentrate to give 445 mg (80%) of a white solid. [736] Step 5: Synthesis of H-Leu- (CHOH) -Gly-Phg-dimethylamide trifluoroacetate salt: [737] [738] To a solution of Boc-Leu- (CHOH) -Gly-Phg-dimethylamide (70 mg, 0.146 mmol) in dichloromethane (1 ml) is added trifluoroacetic acid (1 ml) and the reaction is stirred at room temperature for 1 hour. The reaction mixture is concentrated and taken to the next step without further purification. [739] Step 6: Synthesis of iBoc-G (Chx) -Pro (4,4-dimethyl) -Leu- (CHOH) -Gly-Phg-dimethylamide: [740] [741] TFA.2HN-Leu (CHOH) -Gly in a solution of iBoc-G (Chx) -P (4,4-diMe) -OH (Example XIV, Step 2) (53 mg, 0.148 mmol) in acetonitrile (3 ml). -Phg-NMe2 (61 mg, 0.148 mmol), N-hydroxybenzotriazole (HOBt) (23 mg, 0.148 mmol), TBTU (71.5 mg, 0.222 mmol) and diisopropylethyl amine (103 L, 0.593 mmol) Add it. The reaction is stirred at rt for 18 h and then concentrated. The remaining residue is dissolved in ethyl acetate and washed with 1M hydrochloric acid (2 x 5 ml), saturated sodium bicarbonate solution (2 x 5 ml) and brine (2 x 5 ml). The organic layer is then filtered dry and concentrated. The product (100 mg) is taken to the next step without further purification. [742] Step 7: Synthesis of iBoc-G (Chx) -Pro (4,4-dimethyl) -Leu- (CO) -Gly-Phg-dimethylamide: [743] [744] Commercially available des-martin reagent (Omega) in a solution of iBoc-G (Chx) -Pro (4,4-dimethyl) -Leu- (CHOH) -Gly-Phg-dimethylamide (30 mg, 0.04 mmol) in dichloromethane (1 ml). Chemical Company Inc.) (67.8 mg, 0.16 mmol) is added and the reaction is stirred at room temperature for 90 minutes. The reaction mixture is concentrated and the remaining residue is stirred in 5% sodium thiosulfate. Then it is diluted with dichloromethane and the layers are separated. The organic layer is washed with sodium thiosulfate (4 x 3 ml) and then with water and brine. The organic layer is dried over sodium sulphate, filtered and concentrated. The crude product is dissolved in hexane and isopropyl alcohol, and a normal phase Kromasil 5 silica column (Phenomenex, 250 x 21.20 mm, 100 mm pore) is eluted with a 30 minute gradient (25 ml / min) consisting of 0-25% isopropyl alcohol in hexane. Size, 5 μm gel particles). Collect the fractions corresponding to the product and concentrate. Lyophilization from water yields 6.7 mg of a white powder. Low resolution mass spectra confirmed the desired mass (MH + = 741.4). [745] III) Solid Phase Synthesis: [746] Solid phase synthesis is useful for preparing small amounts of certain compounds of the invention. As using conventional peptide solid phase synthesis, reactors for solid phase synthesis of peptidyl ketoamides are reactors that are permeable to solvents and dissolved reagents, but are not permeable to synthetic resins of selected mesh sizes. It consists of a container. Such reactors include sintered glass frits, glass solid phase reaction vessels equipped with polypropylene tubes or columns with frits, or Kans ™ (Irori Inc., San Diego CA) reactors. The reactor type chosen depends on the volume of solid phase resin required, and different reactor types may be used for different synthesis steps. The following procedure will be referenced in the subsequent examples: [747] Procedure A: Coupling reaction : Fmoc-amino acid (2 equivalents), HOAt (2 equivalents), HATU (2 equivalents) and di in a resin suspended in N-methylpyrrolidine (NMP) (10-15 ml / g resin) Isopropylethylamine (4 equivalents) is added. The mixture is allowed to react for 4 to 48 hours. The reaction is dehydrated and the resin is washed successively with dimethylformamide, dichloromethane, methanol, dichloromethane and diethyl ether (using 10-15 ml solvent / g resin). The resin is then dried under vacuum. [748] Procedure B: Fmoc Deprotection : Fmoc protected resin is treated with 20% piperidine (10 ml reagent / g resin) in dimethylformamide for 30 minutes. This reagent is dehydrated and the resin is washed successively with dimethylformamide, dichloromethane, methanol, dichloromethane and diethyl ether (using 10 ml solvent / g resin). [749] Procedure C: Boc deprotection : The Boc-protected resin is treated with a 1: 1 mixture of dichloromethane and trifluoroacetic acid for 20 to 60 minutes (10 ml solvent / g resin). This reagent is dehydrated and the resin is washed successively with dichloromethane, dimethylformamide, 5% diisopropylethylamine in dimethylformamide, dimethylformamide, dichloromethane and dimethylformamide (10 ml solvent / g resin). [750] Procedure D: Semicarbazone hydrolysis : The resin is suspended for 2 hours in a cut cocktail (10 ml / g resin) consisting of trifluoroacetic acid: pyruvic acid: dichloromethane: water 9: 2: 2: 1. The reaction is dehydrated and the process repeated three more times. The resin is washed successively with dichloromethane, water and dichloromethane and dried under vacuum. [751] Procedure E: HF Cleavage : The dried peptide-nVal (CO) -GO-PAM resin (50 mg) is placed in a HF vessel containing a small stirring rod. Anisole (10% of total volume) is added as a scavenger. In the presence of glutamic acid and cysteine amino acids, thioanisole (10%) and 1,2-ethanedithiol (0.2%) are also added. The HF vessel is then connected to an HF device (Immuno Dynamics) and the system is flushed with nitrogen for 5 minutes. It is then cooled to -70 ° C using a dry ice / isopropanol bath. After 20 minutes, HF is distilled to the desired volume (10 ml HF / g resin). The reaction is allowed to proceed at 0 ° C. for 1 hour 30 minutes. Work up by removing all HF with nitrogen. Dichloromethane is then added to the resin and the mixture is stirred for 5 minutes. Then 20% acetic acid in water (4 ml) is added. After stirring for 20 minutes, the resin is filtered using a fritted funnel and the dichloromethane is removed under reduced pressure. The remaining residue and mixture is washed with hexane (2x) to remove scavenger. In the meantime, the resin is immersed in 1 ml of methanol. Aqueous layer (20% HOAc) is added back to the resin and the mixture is shaken for 5 minutes and then filtered. Methanol is removed under reduced pressure and the aqueous layer is lyophilized. The peptide is then dissolved in 10-25% methanol (containing 0.1% trifluoroacetic acid) and purified by reverse phase HPLC. [752] Example XXII: Representative Solid Phase Synthesis of Hepatitis C Inhibitor (iBoc-G (Chx) -P (4t-NHSO2Ph) -nV- (CO) -G-G (Ph) -NH2) [753] [754] Step 1: Synthesis of Fmoc-nV- (dpsc) -Gly-OH: [755] A) Synthesis of allyl isocyanoacetate (next steps a-b): [756] a) Synthesis of isocyanoacetic acid potassium salt: [757] [758] Ethyl isocyanoacetate (96.6 ml, 0.88 mol) is added dropwise to a cooled solution of ethanol (1.5 L) and potassium hydroxide (59.52 g, 1.0 mol). The reaction is slowly warmed to room temperature. After 2 hours, the precipitated product is filtered on a glass funnel and washed with cold ethanol water fractions. The potassium salt of isocyanoacetic acid thus obtained is dried under vacuum to give a golden brown solid (99.92 g, 91.8%). [759] b) Synthesis of allyl isocyanoacetate: [760] [761] Allyl bromide (92 ml, 1.05 mol) is added to the product of Part a (99.92 g, 0.81 mol) dissolved in acetonitrile (810 ml). After heating at reflux for 4 hours, a dark brown solution is obtained. The reaction mixture is concentrated and the remaining residue is dissolved in ether (1.5 L) and washed three times with water (500 ml). The organic layer is dried, filtered and concentrated to give dark brown syrup. The crude product was purified by vacuum distillation at 7 mm Hg (98 C) to give a clean oil (78.92 g, 78%): [762] [763] B) Synthesis of 9-fluorenylmethoxycarbonyl-norvalinal (next steps a-c): [764] a) Synthesis of 9-fluorenylmethoxycarbonyl-L-norvaline methyl ester (Fmoc-nVal-OMe): [765] [766] Thionyl chloride (53.76 ml, 737.5 mmol) is added to a cooled solution of commercial Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml) over 1 hour. TLC in ethyl acetate taken after 1 hour confirmed that the reaction was complete (R f = 0.85). The reaction mixture is concentrated and the remaining residue is dissolved in ethyl acetate. The organic layer is washed several times with saturated sodium bicarbonate and then with 200 ml portions of brine. The organic layer is dried, filtered and concentrated to give Fmoc-norVal-OMe as a white solid (26.03 g) in quantitative yield: [767] [768] b) Synthesis of 9-fluorenylmethoxycarbonyl-norvalinol (Fmoc-nvalinol): [769] [770] Calcium chloride (16.37 g, 147.49 mmol) is added to Fmoc-nVal-OMe (26.03 g, 73.75 mmol) in tetrahydrofuran (123 ml) and methanol (246 ml). The reaction mixture is cooled to 0 ° C. and sodium borohydride (11.16 g, 294.98 mmol) is added in several batches. To the thick paste obtained, methanol (500 ml) is added and the reaction is left stirring at room temperature for 90 minutes. TLC in 2: 3 ethyl acetate: hexanes confirmed the reaction was complete (R f = 0.25). The reaction is quenched by the slow addition of water (100 ml) at 0 ° C. Methanol is removed under reduced pressure and the remaining aqueous phase is diluted with ethyl acetate. The organic layer is washed with water (3 x 500 ml), saturated sodium bicarbonate (3 x 500 ml) and brine (500 ml). The organic layer is dried over sodium sulfate, filtered and concentrated to give a white solid (21.70 g, 90.5%): [771] [772] c) Synthesis of 9-fluorenylmethoxycarbonyl-norvalinal (Fmoc-nVal-CHO): [773] [774] To a solution of Fmoc-norvalinol (21.70 g, 66.77 mmol) in dichloromethane (668 ml) was added triethylamine (37.23 ml, 267 mmol) and the solution was cooled to 0 ° C. A suspension of pyridine sulfur trioxide complex (42.51 g, 267 mmol) in dimethylsulfoxide (96 ml) is added to the cooling solution. After 1 hour, TLC in 2: 3 ethyl acetate: hexanes confirmed the reaction was complete. Dichloromethane is removed under reduced pressure and the remaining residue is dissolved in ethyl acetate and washed with water (2 x 50 ml), 1N saturated sodium bisulfate (2 x 50 ml), saturated sodium bicarbonate (2 x 50 ml) and brine (50 ml). . The organic layer is concentrated to give a white solid. The theoretical yield (21.57 g) was estimated and the reaction was taken to the next step without further purification. [775] C) Synthesis of diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt (next steps a-b): [776] a) Synthesis of Boc-Semicarbazide-4-yl Diphenylmethane [777] [778] To a solution of carbonyldiimidazole (16.2 g, 0.10 mole) in dimethylformamide (225 ml) was added dropwise a solution of t-butyl carbazate (13.2 g, 0.100 mol) in dimethylformamide (225 ml) over 30 minutes. . Diphenylmethylamine (18.3 g, 0.10 mol) is then added over 30 minutes. The reaction is left to stir at room temperature for 1 hour. Water (10 ml) is added and the mixture is concentrated to about 150 ml under reduced pressure. This solution is poured into water (500 ml) and extracted with ethyl acetate (400 ml). The ethyl acetate phase is washed twice with 75 ml each of 1N HCl, water, saturated sodium bicarbonate solution and sodium chloride and dried over magnesium sulfate. The mixture is filtered and the solution is concentrated to give 29.5 g (85% yield) of white foam. This material can be purified by recrystallization from ethyl acetate / hexanes, but it is pure enough to be used directly in the next step: Melting point 142-143 ° C .: [779] [780] b) Synthesis of diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt [781] [782] A solution of Boc-semicarbazide-4-yl diphenylmethane (3.43 g, 10 mmol) in dichloromethane (12.5 ml) is treated with 12.5 ml of trifluoroacetic acid at room temperature and stirred for 30 minutes. This solution is added dropwise to 75 ml of ether and the resulting solid (2.7 g, 80%) is collected by filtration. Melting point 182-184 ° C: [783] [784] D) Synthesis of Fmoc-nVal- (CHOH) -Gly-Oallyl: [785] [786] Allyl isocyanoacetate (step IA) (2.46 ml, 20.28 mmol) and pyridine (5.47 ml, 67.61 mmol) in a solution of Fmoc-nVal-CHO (step IB) (5.47 g, 16.90 mmol) in dichloromethane (170 ml) Add. The reaction mixture is cooled to 0 ° C. and trifluoroacetic acid (3.38 ml, 33.80 mmol) is added dropwise. The reaction is stirred at 0 ° C. for 1 hour and then at room temperature for 48 hours. TLC taken in ethyl acetate confirmed the reaction was complete. The reaction mixture is concentrated and flash chromatographed using 20% to 70% ethyl acetate in hexanes. Fractions containing the desired product are combined and concentrated to yield a white foam (6.88 g, 87.3%). TLC in 50:50 ethyl acetate shows one spot (R f = 0.37): [787] [788] E) Synthesis of Fmoc-nVal- (CO) -Gly-Oallyl: [789] [790] EDC (20.6 g, 107.7 mmol) was added to a solution of Fmoc-nVal- (CHOH) -Gly-Oallyl (step D) (5.01 g, 10.77 mmol) in dimethylsulfoxide (100 ml) and toluene (100 ml). The reaction mixture is cooled to 0 ° C. and dichloroacetic acid (4.44 ml, 53.83 mmol) is added dropwise. The reaction is stirred at 0 ° C. for 15 minutes and then at room temperature for 1 hour. After cooling back to 0 ° C., water (70 ml) is added and toluene is removed under reduced pressure. The remaining residue is diluted with ethyl acetate and washed several times with saturated sodium bicarbonate solution followed by 1N sodium bisulfate and brine. The organic layer is dried over sodium sulphate, filtered and concentrated. The theoretical yield is estimated to be 4.99 g and the reaction is taken to the next step without further purification. TLC in 50:50 ethyl acetate shows one spot (R f = 0.73). [791] F) Synthesis of Fmoc-nVal- (dpsc) -Gly-Oallyl: [792] [793] Diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt in a solution of Fmoc-nVal- (CO) -Gly-Oallyl (step E) (4.99 g, 10.75 mmol) in ethanol (130 ml) and water (42 ml) (Step IC) (7.6 g, 21.5 mmol) and sodium acetate.3H 2 O (1.76 g, 12.9 mmol) were added successively. The reaction mixture is heated at reflux for 90 minutes. The reaction was completed by TLC taken in 1: 1 ethyl acetate: hexanes. Ethanol is removed under reduced pressure and the remaining residue is dissolved in ethyl acetate and washed with 1N sodium bisulfate (2 x 10 ml), saturated sodium bicarbonate (2 x 10 ml) followed by brine (10 ml). The organic layer is dried, filtered and then concentrated. The resulting residue is purified by flash chromatography with 20-50% ethyl acetate in hexanes to give a white solid (5.76 g, 78%). TLC in 50:50 ethyl acetate: hexanes shows two spots (cis and trans isomers) (R f = 0.42 and 0.5). [794] G) Synthesis of Fmoc-nVal- (dpsc) -Gly-OH: [795] [796] Dimethone (4.62g, 32.97mmol) was added to a solution of Fmoc-nVal- (dpsc) -Gly-Oallyl (step IF) (4.53g, 6.59mmol) in tetrahydrofuran (300ml), followed by tetrakis (tri Phenylphosphine) palladium (O) catalyst (0.76 g, 0.66 mmol) is added. The reaction was confirmed by TLC 90 minutes after using 9: 1 dichloromethane: methanol. The reaction mixture is concentrated and the remaining residue is dissolved in ethyl acetate and washed three times with 50 ml fractions of 0.1 M potassium bicarbonate. The organic layer is then treated with 50 ml of sodium bisulfite and the biphasic system is stirred for 15 minutes. The phases are separated and this process is repeated two more times. The organic layer is dried, concentrated and flash chromatographed with 20-100% ethyl acetate in hexanes. Then, a 9: 1 dichloromethane: methanol solution is used. Fractions corresponding to pure product are combined and concentrated to give a white solid (3.99 g, 94%). TLC in 9: 1 dichloromethane: methanol showed two spots (cis and trans isomers): [797] [798] Step 2: Synthesis of H-Phg-MBHA Resin: [799] [800] Commercial MBHA resin (2.6 g, 1.12 mmol / g, 2.91 mmol) was transferred to a 250 ml frit solid phase reaction vessel equipped with a nitrogen inlet. It is then thoroughly washed with 30 ml fractions of dichloromethane, methanol, dimethylformamide and dichloromethane and coupled over 18 hours to commercially available Fmoc-Phg-OH (2.17 g, 5.82 mmol) according to process A with 99.82% efficiency. . The resin is then Fmoc deprotected according to procedure B. Qualitative ninhydrin assay on small aliquots resulted in a solution with dark blue resin, indicating a successful reaction. [801] Step 3: Synthesis of H-nVal (dpsc) -Gly-Phg-MBHA Resin: [802] [803] The resin obtained in step II (2.6 g, 0.8 mmol / g, 2.91 mmol) is reacted with Fmoc-nVal- (dpsc) -Gly-Oallyl (step IG) (5.82 mmol, 3.77 g) according to process A. After 18 hours, quantitative ninhydrin analysis indicated 99.91% coupling efficiency. The resin was subjected to Fmoc deprotection according to Process B. Qualitative ninhydrin assay on small aliquots resulted in a solution with dark blue resin, indicating a successful reaction. [804] Step 4: Synthesis of Boc-Pro (4t-NHFmoc) -nVal (dpsc) -Gly-Phg-MBHA Resin: [805] [806] Compound H-nVal (dpsc) -Gly-Phg-MBHA resin (step 3 above) (600 mg, 0.8 mmol / g, 0.67 mmol) was transferred to a frit-type polypropylene tube, which was followed by Boc-Pro (4t- Couple to NHFmoc) -OH (Example VI, Step 3) (610 mg, 1.34 mmol). After 18 hours, quantitative ninhydrin analysis indicated 99.96% coupling efficiency. [807] Step 5: Boc-Pro (4t-NH 2Synthesis of) -nVal (dpsc) -Gly-Phg-MBHA Resin: [808] [809] Resin from the previous step (Boc-Pro (4t-NHFmoc) -nVal (dpsc) -Gly-Phg-MBHA resin) was Fmoc deprotected according to procedure B. Qualitative ninhydrin assay on small aliquots resulted in a solution with dark blue resin, indicating a successful reaction. [810] Step 6: Boc-Pro (4t-NHSO 2Synthesis of Bn) -nVal (dpsc) -Gly-Phg-MBHA Resin: [811] [812] 2,4,6- in resin (Boc-Pro (4t-NH 2 ) -nVal (dpsc) -Gly-Phg-MBHA resin) (0.2 g, 0.22 mmol) obtained from the previous step suspended in NMP (2 ml). Collidine (0.24 ml, 1.79 mmol) and benzenesulfonyl chloride are added and the reaction is shaken for 18 hours. The solvent is dehydrated and the resin is washed thoroughly with 2 ml fractions of dichloromethane, methanol, dimethylformamide and dichloromethane. Qualitative ninhydrin analysis showed colorless beads and solutions, indicating a successful reaction. [813] Step 7: Fmoc-G (Chx) -Pro (4t-NHSO 2Synthesis of Bn) -nVal (dpsc) -Gly-Phg-MBHA Resin [814] [815] The Boc deprotection process is carried out in accordance with Process C, targeting the resin obtained in the previous step (Boc-Pro (4t-NHSO 2 Bn) -nVal (dpsc) -Gly-Phg-MBHA resin). Fmoc-G (Chx) (0.17 g, 0.45 mmol) is then coupled according to procedure A. After 18 hours, qualitative ninhydrin assay showed colorless beads and quantitative ninhydrin assay showed 99.79% coupling efficiency. [816] Step 8: iBoc-G (Chx) -Pro (4t-NHSO 2Synthesis of Bn) -nVal (dpsc) -Gly-Phg-MBHA Resin [817] [818] Fmoc deprotection is carried out in accordance with Process B, targeting the resin obtained in the previous step (Fmoc-G (Chx) -Pro (4t-NHSO 2 Bn) -nVal (dpsc) -Gly-Phg-MBHA resin). . The ninhydrin assay on small aliquots gave a dark blue resin and solution, indicating a successful reaction. Isobutylchloroformate (0.12 ml, 0.90 mmol) was added to the resin (0.2 g, 0.22 mmol) suspended in 2 ml NMP, followed by addition of diisopropylethylamine (0.31 ml, 1.79 mmol) and the reaction mixture at room temperature. Shake for 18 hours. Qualitative ninhydrin analysis showed colorless beads and solutions, indicating a successful reaction. [819] Step 9: iBoc-G (Chx) -Pro (4t-NHSO 2Synthesis of Bn) -nVal (CO) -Gly-Phg-MBHA Resin: [820] [821] Semicarbazone hydrolysis process D was performed on the compound (iBoc-G (Chx) -Pro (4t-NHSO 2 Bn) -nVal (dpsc) -Gly-Phg-MBHA resin) (200 mg) of the previous step. do. [822] Step 10: iBoc-G (Chx) -Pro (4t-NHSO 2Bn) -nVal (CO) -Gly-Phg-NH 2Synthesis of: [823] [824] Apply the HF cleavage condition (process E) to the previous step (iBoc-G (Chx) -Pro (4t-NHSO 2 Bn) -nVal (CO) -Gly-Phg-MBHA resin) (100 mg) To obtain the desired crude product. This material is purified by HPLC using a 2.2 x 25 cm reversed phase column containing C-18 resin consisting of 10 micron size gel particles with a pore size of 300 microns, eluting with a gradient using 20 to 50% acetonitrile in water. Analytical HPLC results using a 4.6 x 250 mm reversed phase column containing C-18 resin consisting of 5 micron size gel particles with a pore size of 300 microns, eluting with 25-75% acetonitrile (containing 0.1% trifluoroacetic acid) 1 peak at 13.5 minutes. Low resolution mass spectra confirmed the desired mass (MH + = 826.4). [825] IV. Additional compounds prepared by solution phase synthesis: [826] Representative procedures for preparing additional compounds of the invention are set forth below, and the compounds prepared by these procedures are listed in Table 5. [827] Example XXII: Preparation of Compound of Formula XXIII: [828] [829] Step 1: [830] [831] And treated with a 1M solution of anhydrous THF (400ml) in N 2 blankets immigration XXIIIa K- t BuO (220ml, 1.15 eq.) In the stirred solution was cooled to -78 ℃, which was dissolved in THF of (50g, 187.1mmol) under. The reaction mixture is warmed to 0 ° C., stirred for 1 h and then treated with bromomethyl cyclobutane (28 ml, 249 mmol). The reaction mixture is stirred at rt for 48 h and concentrated in vacuo. The residue is dissolved in Et 2 O (300 ml) and treated with aqueous HCl (2M, 300 ml). The resulting solution is stirred at room temperature for 5 hours and extracted with Et 2 O (1 L). The aqueous layer is basified with NaOH (50% aqueous) to pH about 12-14 and extracted with CH 2 Cl 2 (3 × 300 ml). The combined organic layers are dried (MgSO 4 ), filtered and concentrated to give pure amine (XXIIIb, 18 g) as colorless oil. [832] Step 2: [833] [834] A solution of amine XXIIIb (18 g, 105.2 mmol) in CH 2 Cl 2 (350 ml) at 0 ° C. is treated with di-tert-butyldicarbonate (23 g, 105.4 mmol) and stirred at room temperature for 12 hours. After completion of the reaction (TLC), the reaction mixture was concentrated in vacuo, the residue dissolved in THF / H 2 O (200 mL, 1: 1) and treated with LiOH.H 2 O (6.5 g, 158.5 mmol). Then it is stirred for 3 hours at room temperature. The reaction mixture is concentrated and the basic aqueous layer is extracted with Et 2 O. The aqueous layer is acidified with concentrated HCl to pH about 1-2 and extracted with CH 2 Cl 2 . The combined organic layers are dried (MgSO 4 ), filtered and concentrated in vacuo to afford XXIIIc as a colorless viscous oil which is used in the next step without further purification. [835] Step 3: [836] [837] A solution of acid XXIIIc (15.0 g, 62 mmol) in CH 2 Cl 2 (250 ml) was purified by BOP reagent (41.1 g, 93 mmol), N-methyl morpholine (27 ml), N, O-dimethyl hydroxylamine hydrochloride (9.07 g , 93 mmol) and stirred overnight at room temperature. The reaction mixture is diluted with 1N aqueous HCl (250 ml), the layers are separated and the aqueous layer is extracted with CH 2 Cl 2 (3 × 300 ml). The combined organic layers are dried (MgSO 4 ), filtered and concentrated in vacuo and purified by chromatography (SiO 2 , EtOAc / Hex 2: 3) to afford amide XXIIId (15.0 g) as a colorless solid. [838] Step 4: [839] [840] A solution of amide XXIIId (15 g, 52.1 mmol) in anhydrous THF (200 ml) is treated dropwise with a solution of LiAlH 4 (1 M, 93 ml, 93 mmol) at 0 ° C. The reaction mixture is stirred at rt for 1 h, carefully quenched with KHSO 4 (10% aqueous) solution at 0 ° C. and then stirred for 0.5 h. The reaction mixture is diluted with aqueous HCl (1M, 150 ml) and extracted with CH 2 Cl 2 (3 × 200 ml). The combined organic layers are washed with aqueous HCl (1M), saturated NaHCO 3 , brine and dried (MgSO 4 ). The mixture is filtered and concentrated in vacuo to afford XXIIIe as a viscous colorless oil (14 g). [841] Step 5: [842] [843] A solution of aldehyde XXIIIe (14 g, 61.6 mmol) in CH 2 Cl 2 (50 ml) was treated with Et 3 N (10.73 ml, 74.4 mmol) and acetone cyanohydrin (10.86 g, 127.57 mmol) and at room temperature for 24 hours. Stir. The reaction mixture is concentrated in vacuo, diluted with aqueous HCl (1M, 200 ml) and extracted with CH 2 Cl 2 (3 × 200 ml). The combined organic layers were washed with H 2 O, brine, dried (MgSO 4 ), filtered and concentrated in vacuo and purified by chromatography (SiO 2 , EtOAc / Hex 1: 4) to give XXIIIf (10.3 g) colorless. Obtained as a liquid. [844] Step 6: [845] [846] Methanol saturated with HCl (alternative 6M HCl prepared by adding AcCl to anhydrous methanol) may be treated with cyanohydrin XXIIIf, prepared by bubbling HCl gas into CH 3 OH (700 ml) at 0 ° C. Heated to reflux for 24 h. The reaction is concentrated in vacuo to afford XXIIIg, which is used in the next step without purification. [847] Step 7: [848] [849] A solution of amine hydrochloride XXIII g in CH 2 Cl 2 (200 ml) is treated with Et 3 N (45.0 ml, 315 mmol) and Boc 2 O (45.7 g, 209 mmol) at −78 ° C. The reaction mixture is stirred at rt overnight, diluted with HCl (2M, 200 ml) and extracted with CH 2 Cl 2 . The combined organic layers are dried (MgSO 4 ), filtered and concentrated in vacuo and purified by chromatography (EtOAc / Hex 1: 4) to afford hydroxy ester XXIIIh. [850] Step 8: [851] [852] A solution of methyl ester XXIIIh (3 g, 10.5 mmol) in THF / H 2 O (1: 1) is treated with LiOH.H 2 O (645 mg, 15.75 mmol) and stirred at room temperature for 2 hours. The reaction mixture is acidified with aqueous HCl (1M, 15 ml) and concentrated in vacuo. The residue is dried under vacuum. [853] A solution of acid in CH 2 Cl 2 (50 ml) and DMF (25 ml) was added NH 4 Cl (2.94 g, 55.5 mmol), EDCl (3.15 g, 16.5 mmol), HOOBt (2.69 g, 16.5 mmol) and NMM (4.4 g). , 44 mmol). The reaction mixture is stirred for 3 days at room temperature. The solvent is removed in vacuo and the residue is diluted with aqueous HCl (250 ml) and extracted with CH 2 Cl 2 . The combined organic layers are washed with aqueous saturated NaHCO 3 , dried (MgSO 4 ), filtered and concentrated in vacuo to afford XXIIIi, which is used as such in the next step. (On the other hand, by reacting XXIIIf (4.5 g, 17.7 mmol) with aqueous H 2 O 2 (10 ml), LiOH.H 2 O (820 mg, 20.8 mmol) in 50 ml of CH 3 OH at 0 ° C. for 0.5 h, XXIIIi may also be obtained directly). [854] Step 9: [855] [856] The solution of XXIIIi obtained in the previous step is dissolved in 4N HCl in dioxane and stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo to afford XXIIIj as a solid which is used without further purification. [857] Step 10: [858] [859] Except for cleaving Boc groups by reacting Boc-protected amino acids with methanolic HCl, see R. Zhang and J.S. Madalengoitia (J. Org. Chem. 1999, 64, 330)] to prepare amino ester XXIIIl. [860] A solution of commercial amino acids Boc-Chg-OH, XXIIIk (Sennchemicals, 6.64 g, 24.1 mmol) and amine hydrochloride XXIIIl (4.5 g, 22 mmol) in CH 2 Cl 2 (100 ml) at 0 ° C. was treated with BOP reagent and at room temperature Stir for 15 hours. The reaction mixture is concentrated in vacuo, then it is diluted with aqueous 1M HCl and extracted with EtOAc (3 × 200 ml). The combined organic layers were washed with saturated NaHCO 3 (200 ml), dried (MgSO 4 ), filtered and concentrated in vacuo and chromatographed (SiO 2 , EtOAc / Hex 3: 7) to give XXIIIm (6.0 g) colorless. Obtained as a solid. [861] Step 11: [862] [863] A solution of methyl ester XXIIIm (4.0 g, 9.79 mmol) in THF / H 2 O (1: 1) is treated with LiOH.H 2 O (401 mg, 9.79 mmol) and stirred at room temperature for 3 hours. The reaction mixture is acidified with aqueous HCl and concentrated in vacuo to give a free acid. [864] A solution of acid (1.5 g, 3.74 mmol) in DMF / CH 2 Cl 2 (1: 1 50 ml) at −10 ° C. was added with amine XXIIIj (772 mg, 3.74 mmol), EDCl (1.07 g, 5.61 mmol), HOOBt (959 mg, 5.61 mmol) and NMM (2.15 ml, 14.96 mmol). The reaction mixture is stirred at 0 ° C. for 48 hours and then concentrated in vacuo. The residue is diluted with aqueous 1M HCl and extracted with CH 2 Cl 2 . The combined organic layers are washed with aqueous NaHCO 3 , aqueous HCl, brine, dried (MgSO 4 ), filtered and concentrated in vacuo to afford XXIIIn (2.08 g) as a brown solid. [865] Step 12: [866] [867] A solution of amide XXIIIn (2.08 g, 3.79 mmol) in toluene and DMSO (1: 1 20 ml) at 0 ° C. was treated with EDCl (7.24 g, 37.9 mmol) and dichloroacetic acid (2.42 g, 19.9 mmol) and 4 at room temperature. Stir for hours. The reaction mixture is diluted with CH 2 Cl 2 and washed with saturated NaHCO 3 and brine. The organic layer is dried (MgSO 4 ), filtered and concentrated in vacuo and chromatographed (SiO 2 , acetone / hexane 3: 7) to afford XXIII as a colorless solid. [868] Example XXIV: Preparation of Compound of Formula XXIV: [869] [870] Step 1: [871] [872] A solution of Boc tert-Leu XXIVa (Fluka, 5.0 g, 21.6 mmol) in anhydrous CH 2 Cl 2 / DMF (50 ml, 1: 1) was cooled to 0 ° C. and amine XXIII l (5.3 g, 25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The reaction is stirred at rt for 24 h, diluted with aqueous HCl (1M) and extracted with CH 2 Cl 2 . The combined organic layers were washed with HCl (aq., 1M), saturated NaHCO 3 , brine, dried (MgSO 4 ), filtered and concentrated in vacuo and chromatographed (SiO 2 , acetone / hexane 1: 5). To give XXIVb as a colorless solid. [873] Step 2: [874] [875] A solution of methyl ester XXIVb (4.0 g, 10.46 mmol) is dissolved in HCl (4M solution, dioxane) and stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo to afford the amine hydrochloride salt, which is used for the next step. [876] A solution of amine hydrochloride salt (397 mg, 1.24 mmol) in CH 2 Cl 2 (10 ml) is cooled to −78 ° C., treated with tert-butyl isocyanate (250 mg, 2.5 mmol) and then stirred at rt overnight. The reaction mixture is concentrated in vacuo and the residue is diluted with aqueous HCl (1M) and extracted with CH 2 Cl 2 . The combined organic layers are washed with aqueous HCl (1M), saturated NaHCO 3 and brine. The organic layer is dried, filtered and concentrated in vacuo, and the residue is purified by chromatography (SiO 2 , acetone / hexane 1: 4) to afford XXIVc as a colorless solid. [877] Step 3: [878] [879] A solution of methyl ester XXIVc (381 mg, 1.0 mmol) in THF / H 2 O (1: 1, 5 ml) is treated with LiOH.H 2 O (62 mg, 1.5 mmol) and stirred at room temperature for 3 hours. The reaction mixture is acidified with aqueous HCl and concentrated in vacuo to give a free acid. [880] A solution of acid (254.9 mg, 0.69 mmol) in DMF / CH 2 Cl 2 (1: 1, 5.0 ml) at −20 ° C. was added with amine XXIIIj (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). The reaction mixture is stirred at −20 ° C. for 48 hours and then concentrated in vacuo. The residue is diluted with aqueous 1M HCl and extracted with EtOAc. The combined organic layers are washed with aqueous NaHCO 3 , aqueous HCl, brine, dried (MgSO 4 ), filtered and concentrated in vacuo to afford XXIVd (470 mg) as a brown solid. [881] Step 4: [882] [883] A solution of amide XXIVd (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 4 h at room temperature. Stir while. The reaction mixture is diluted with CH 2 Cl 2 and washed with saturated NaHCO 3 and brine. The organic layer is dried (MgSO 4 ), filtered and concentrated in vacuo and purified by chromatography (SiO 2 , acetone / hexane 3: 7) to afford XXIV as a colorless solid. [884] Example XXV: Preparation of Compound of Formula XXV: [885] [886] Step 1: [887] [888] A solution of Fmoc-glycine (Bachem, 2.0 g, 6.87 mmol) in CH 2 Cl 2 (20 ml) was added 2-phenyl-2-propanol (Aldrich, 3.36 g, 24.7 mmol), DCC (1M solution CH 2 Cl 2 , 8.24). ml), treated with DMAP (167 mg, 1.37 mmol) and stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo and diluted with Et 2 O (100 ml). The separated solid is filtered off and the filtrate is washed with saturated NaHCO 3 . The organic layer is dried (MgSO 4 ), filtered and concentrated in vacuo and purified by chromatography (SiO 2 , acetone / hexane 1: 5) to afford ester XXVc (1.1 g) as a colorless viscous liquid. [889] Step 2: [890] [891] A solution of XXVc in CH 2 Cl 2 (16.0 ml) is treated with piperidine (4.0 ml) and stirred at room temperature for 0.5 h. The reaction mixture is concentrated in vacuo and purified by chromatography (SiO 2 , acetone / hexane 1:10 to 1: 1) to afford amineXXVd (420 mg) as a colorless liquid. [892] Step 3: [893] [894] A solution of methyl ester XXIVc (381 mg, 1.0 mmol) in THF / H 2 O (1: 1, 5 ml) is treated with LiOH.H 2 O (62 mg, 1.5 mmol) and stirred at room temperature for 3 hours. The reaction mixture is acidified with aqueous HCl and concentrated in vacuo to give a free acid. [895] A solution of acid (2.0 g, 5.5 mmol) in DMF / CH 2 Cl 2 (1: 1, 40.0 ml) at −10 ° C. was added with amine XXIIIg (1.51 g, 6.8 mmol), EDCl (1.57 g, 8.25 mmol), HOOBt (1.41 g, 8.25 mmol) and NMM (2.5 g, 24.7 mmol). The reaction mixture is stirred at 0 ° C. for 48 hours and then concentrated in vacuo. The residue is diluted with aqueous 1M HCl (100 ml) and extracted with CH 2 Cl 2 (3 × 100 ml). The combined organic layers are washed with aqueous NaHCO 3 , aqueous HCl, brine, dried (MgSO 4 ), filtered and concentrated in vacuo to afford XXVe (3.17 g) as a brown solid which is used without further purification. [896] Step 4: [897] [898] A solution of methyl ester XXVe (2.5 g, 4.66 mmol) in THF / H 2 O / CH 3 OH (1: 1: 1, 60 ml) was treated with LiOH.H 2 O (200 mg, 4.87 mmol) and 4 h at room temperature. Stir while. The reaction mixture is acidified with aqueous HCl and concentrated in vacuo to give a free acid. [899] A solution of acid (200.0 mg, 0.38 mmol) in DMF / CH 2 Cl 2 (1: 1, 6.0 ml) at −10 ° C. was added with amine XXVd (78 mg, 0.4 mmol), EDCl (105 mg, 0.55 mmol), HOOBt (95 mg). , 0.55 mmol) and NMM (150 mg, 1.48 mmol). The reaction mixture is stirred at 0 ° C. for 48 hours and then concentrated in vacuo. The residue is diluted with aqueous 1M HCl (30 ml) and extracted with CH 2 Cl 2 (3 × 30 ml). The combined organic layers are washed with aqueous NaHCO 3 (2 × 30 ml), aqueous HCl, brine (30 ml), dried (MgSO 4 ), filtered and concentrated in vacuo to afford XXVf (240 mg) as a brown solid. [900] Step 5: [901] [902] A solution of XXVf (240 mg, 0.28 mmol) in CH 2 Cl 2 (10 ml) is treated with Dess-Martin reagent (Omega, 242 mg, 0.56 mmol) and stirred at room temperature for 2 hours. After completion of the oxidation reaction (TLC, acetone / hexane 1: 4), the reaction mixture is diluted with saturated NaHCO 3 (20 ml) and Na 2 S 2 O 3 (10% aqueous solution, 20 ml). The reaction mixture is stirred for 30 minutes and extracted with CH 2 Cl 2 (3 × 30 ml). The combined organic layers were extracted with saturated NaHCO 3 , brine, dried (MgSO 4 ), filtered and concentrated in vacuo and purified by chromatography (SiO 2 , acetone / hexane 1: 5) to give XXV (122 mg) as colorless. Obtained as a solid. [903] Example XXVI: Preparation of Compounds of Formula XXVI: [904] [905] Step 1: [906] [907] N-Boc-3,4-dehydroproline XXVIa (5.0 g, 23.5 mmol), di-tert-butyl dicarbonate (7.5 g, 34.4 mmol) and 4-N, N- in acetonitrile (100 ml) at room temperature To a stirred solution of dimethylaminopyridine (0.40 g, 3.33 mmol) is added triethylamine (5.0 ml, 35.6 mmol). The resulting solution is stirred at this temperature for 18 hours and then concentrated in vacuo. The dark brown residue is purified by flash column chromatography eluting with 10-25% EtOAc / hexanes to give the product XXVIb as pale yellow oil (5.29 g, 84%). [908] Step 2: [909] [910] To a stirred solution of dehydroproline XXVIb (10.1 g, 37.4 mmol), benzyltriethylammonium chloride (1.60 g, 7.02 mmol) in chloroform (120 ml) at room temperature is added 50% aqueous sodium hydroxide (120 g). After vigorous stirring at this temperature for 24 hours, the black mixture is diluted with CH 2 Cl 2 (200 ml) and diethyl ether (600 ml). After separating the layers, the aqueous solution is extracted with CH 2 Cl 2 / Et 2 O (1: 2, 3 × 600 ml). The organic layer is dried (MgSO 4 ) and concentrated. The residue is purified by flash column chromatography using 5-20% EtOAc / hexanes to yield 9.34 g (71%) of XXVIc as a gray solid. [911] Step 3: [912] [913] A solution of XXVIc (9.34 g, 26.5 mmol) in CH 2 Cl 2 (25 ml) and CF 3 CO 2 H (50 ml) was stirred at rt for 4.5 h, then concentrated in vacuo to give a brown residue, which was added Use in step 4 without purification. [914] Step 4: [915] [916] Commercial concentrated hydrochloric acid (4.5 ml) is added to the residue solution from step 3 in methanol (70 ml) and the resulting mixture is warmed to 65 ° C. in an oil bath. After 18 hours, the mixture is concentrated in vacuo to give brown oil XXVIe, which is used in step 5 without further purification. [917] Step 5: [918] [919] Proline methyl ester XXVIe from step 4 in DMF (200 ml) at 0 ° C., commercial N-Boc-cyclohexylglycine XXVIf (10.2 g, 40.0 mmol) and [O- (7-azabenzotriazol-1-yl)- To a stirred solution of 1,1,3,3-tetramethyluronium hexafluorophosphate] (HATU) (16.0 g, 42.1 mmol) is added diisopropylethylamine (18.0 ml, 104 mmol). After warming to room temperature overnight with an oil bath (18 hours), the reaction mixture is diluted with EtOAc (600 ml), 5% H 3 PO 4 (150 ml) and brine (150 ml). The organic solution is washed with 5% H 3 PO 4 (150 ml), saturated NaHCO 3 (2 × 200 ml), then it is dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 5-20% EtOAc / hexanes to give 3.84 g (32%, 3 steps) of XXVIg as a gray solid. [920] Step 6: [921] [922] A solution of methyl ester XXVIg (5.87 g, 13.1 mmol) and LiOH (1.65 g, 39.3 mmol) in THF / MeOH / H 2 O (1: 1: 1, 90 ml) is stirred at room temperature for 4 hours. Methanol and THF are removed under reduced pressure. The aqueous solution is acidified to pH about 2 with 1 N HCl aqueous solution (50 ml), saturated with solid sodium chloride and extracted with EtOAc (3 × 150 ml). The organic solutions are combined, dried (MgSO 4 ), filtered and concentrated in vacuo to yield white solid XXVIh (5.8 g, quant.). [923] Step 7: [924] [925] According to the procedure of Example XXIII, step 11, the desired product XXIIIi is prepared. [926] Step 8: [927] [928] According to the procedure of Example XXIII, step 12, the desired product XXVI is prepared. [929] Example XXVII: Preparation of Compound of Formula XXVII: [930] [931] Step 1: [932] [933] According to the procedure of Example XXIII, step 9, the desired product XXVIIa is prepared. [934] Step 2: [935] [936] According to the procedure of Example XXIV, step 2, the desired product XXVIIb is prepared. [937] Step 3: [938] [939] According to the procedure of Example XXIII, step 12, the desired product XXVII is prepared. [940] Example XXVIII: Preparation of Compound of Formula XXVIII: [941] [942] Step 1: [943] [944] According to the procedure of Example XXIII, steps 3 to 6, intermediate XXVIIIb is prepared. [945] Step 2: [946] [947] In the manner previously described in Example IX, Step 2a, the acid (XXVIIIc) from Example XXIV, Step 2 (0.7 g) was added with the product from Step 1 (0.436 g), HATU (0.934 g) and DIPEA (1.64 ml). ) To give 0.66 g of the desired product XXVIIId. [948] Step 3: [949] [950] In the manner previously described in Example XX, Step 7, the product of Step 2 (0.5 g) is reacted with Dess-Martin reagent (1 g). Purification by flash column chromatography (40% EtOAc, hexanes, silica) affords 0.35 g of product XXVIIIe. Mass spectrum (LCMS) 522 (M + H + ). [951] Step 4: [952] [953] The product of step 4 (0.3 g) is added to a 1/1 H 2 O / MeOH solution (20 ml) and NaHCO 3 solid (242 mg, 5 equiv). After stirring for 18 hours at room temperature, the reaction is diluted with EtOAc and the layers are separated. The aqueous layer is acidified to pH 2 with HCl 1.0N and extracted with EtOAc. The EtOAc layer was washed with brine, then dried over MgSO 4 , filtered and concentrated in vacuo to afford the product XXVIIIf as a white powder (0.26 g). Mass spectrum (LCMS) 508 (M + H + ). [954] Step 5: [955] [956] The product of step 5 (0.15 g) is dissolved in CH 2 Cl 2 and reacted with HATU (0.137 g), NH 4 Cl (0.08 g, 5 equiv) and DIPEA (0.53 ml). After 2 h at rt, the reaction is diluted with EtOAc, washed with 10% citric acid solution and then with saturated NaHCO 3 solution. The EtOAc layer is washed with brine then dried over MgSO 4 , filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (30% acetone, hexane, silica) affords the desired product XXVIII (0.096 g). Mass spectrum (LCMS) 507 (M + H + ). [957] Example XXIX: Preparation of Compound of Formula XXIX: [958] [959] Step 1: [960] [961] To a 0 ° C. solution of starting aldehyde (4.0 g) in CH 2 Cl 2 (75 ml) was added acetic acid (2.0 equiv, 2.15 ml) followed by methylisocyanoacetate (1.1 equiv, 1.9 ml). The reaction is then gradually warmed to room temperature. After 18 hours (overnight), the reaction is diluted with EtOAc and washed with saturated NaHCO 3 solution. The EtOAc layer is washed with brine then dried over MgSO 4 , filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (30-40% EtOAc, hexanes, silica) affords product XXIXa (4.5 g). [962] Step 2: [963] [964] To a 0 ° C. solution of XXIXa (4.4 g) in THF (100 ml) add 26 ml (2.2 equiv) of a 1.0 N LiOH solution. The reaction is stirred at this temperature for 2 hours and then allowed to warm to room temperature. After 2 hours, the reaction mixture is acidified to pH 2 with 1.0N HCl solution. EtOAc is added and the layers are separated. The EtOAc layer is washed with brine, then dried over MgSO 4 , filtered and concentrated in vacuo to give the product XXIXb (3.7 g). [965] Step 3: [966] [967] In the manner previously described in Example XXI, step 4, the acid XXIXb is reacted with the amine from Example XV. The resulting intermediate is treated with HCl in the manner previously described in Example XXIII, Step 9 to give product XXIXc. [968] Step 4: [969] [970] Acid XXVIIIc (2.43 g) is dissolved in CH 2 Cl 2 and reacted with amines XXIXc (2.47 g), HATU (2.5 g) and DIPEA (5.8 ml) in the manner described in Example IX, step 2a above. Purification by flash column chromatography (4% MeOH, CH 2 Cl 2 , silica) affords the desired product XXIXd (4.35 g). Mass spectrum (LCMS) 727 (M + H + ). [971] Step 5: [972] [973] In the manner previously described in Example XX, Step 7, the product of Step 4 (4.2 g) is reacted with Dess-Martin reagent (6.4 g). Purification by flash column chromatography (100% EtOAc, silica) affords 3 g of the final product XXIX. Mass spectrum (LCMS) 725 (M + H + ). [974] Example XXX: Preparation of a Compound of Formula XXX: [975] [976] Step 1: [977] [978] Alcohol 2- (trifluoromethyl) propan-2-ol (1.28 g) was added with N, N-dixiximinidyl carbonate (3.84 g) and Et 3 N (4.2 ml) in anhydrous CH 3 CN (50 ml). React for hours. The mixture is diluted with EtOAc (200 ml) and then filtered. The filtrate is washed with NaHCO 3 , brine and then dried over MgSO 4 , filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (50% EtOAc, hexanes, silica) affords the desired product XXXa (0.3 g). [979] Step 2: [980] [981] The product from Example XXIX (0.3 g) is treated with 100 ml of 4.0N HCl in dioxane. After 1 h, 200 ml of Et 2 O are added, and the resulting precipitate is filtered off and dried under vacuum to give the product XXXb (0.27 g) as a white powder. Mass spectrum (LCMS) 625 (M-HCl + H + ). [982] Step 3: [983] [984] To a room temperature solution of XXXb (0.05 g) in CH 2 Cl 2 (5 ml) was added DIPEA (0.040 ml), XXXa (1.5 equiv., 0.030 g) followed by addition of one DMAP crystal. After 30 minutes, the reaction is diluted with EtOAc (20 ml) and washed with HCl 1.5N, NaHCO 3 and brine. The EtOAc layer is dried over MgSO 4 , filtered and concentrated in vacuo to afford a crude mixture. Purification by preparative chromatography (40% acetone, hexane, silica) affords the desired product XXX (0.044 g). Mass spectrum (LCMS) 779 (M + H + ). [985] Example XXXI: Preparation of Compound of Formula XXXI: [986] [987] Step 1: [988] [989] To a room temperature solution of XXXb (0.05 g) in CH 2 Cl 2 (5 ml) is added DIPEA (0.040 ml) and tert-butylisocyanate (1.2 equiv, 0.01 ml). After 18 hours, the reaction is diluted with EtOAc (20 ml) and washed with HCl 1.5N, NaHCO 3 and brine. The EtOAc layer is dried over MgSO 4 , filtered and concentrated in vacuo to afford a crude mixture. Purification by preparative chromatography (100% EtOAc, silica) affords the final product XXXI (0.021 g). Mass spectrum (LCMS) 724 (M + H + ). [990] Example XXXII: Preparation of Compound of Formula XXXII: [991] [992] Step 1: [993] [994] In the manner previously described in Example XXX, Step 2, the product from Example XXVIII is treated to yield product XXXIIa. Mass spectrum (LCMS) 407 (M-HCl + H + ). [995] Step 2: [996] [997] In the manner previously described in Example XXX, step 3, amine XXXIIa is reacted with XXXa to give the desired product XXXII. Mass spectrum (LCMS) 508 (M + H + ). [998] Example XXXIII: Preparation of Compound of Formula XXXIII: [999] [1000] Step 1: [1001] [1002] In the manner previously described in Example XXXI, step 1, amine XXXIIa is reacted with tert-butylisocyanate to afford product XXXIII. Mass spectrum (LCMS) 561 (M + H + ). [1003] Example XXXIV: Preparation of Compound of Formula XXXIV: [1004] [1005] Step 1: [1006] [1007] Pyrrolidine (5.7 ml, 66.36 mmol) is added to a mixture of ester (6.0 g) and molecular sieve (5.2 g) in anhydrous methylene chloride (35 ml). The resulting brown slurry is stirred at room temperature under N 2 for 24 hours, filtered and washed with anhydrous CH 3 CN. The combined stock solutions are concentrated to afford the desired product. [1008] Step 2: [1009] [1010] To a solution of the product from the previous step in CH 3 CN (35 ml) is added anhydrous K 2 CO 3 , metalyl chloride (2.77 g, 30.5 mmol), NaI (1.07 g, 6.7 mmol). The resulting slurry is stirred for 24 hours at ambient temperature under N 2 . 50 ml of ice water is added, then 2N KHSO 4 solution is added until pH 1. EtOAc (100 ml) is added and the mixture is stirred for 0.75 h. The combined organic layers are collected, washed with brine, dried over MgSO 4 and evaporated to afford the desired product. [1011] Step 3: [1012] [1013] The product from the previous step (2.7 g, 8.16 mmol) is dissolved in dioxane (20 ml) and treated with freshly prepared 1N LiOH (9 ml). The reaction mixture is stirred at ambient temperature under N 2 for 20 hours. The reaction mixture is taken up in EtOAc and washed with H 2 O. The combined aqueous phases are cooled to 0 ° C. and acidified to pH 1.65 with 1N HCl. The cloudy mixture is extracted with EtOAc (2 x 100 ml). The combined organic layers are washed with brine, dried over MgSO 4 and concentrated to give the desired acid (3.40 g). [1014] Step 4: [1015] [1016] CH exerts a 2 Cl 2 (55ml) solution of the product from the above step in of NaBH (OAc) 3 in anhydrous CH 2 Cl 2 (20ml) and acetic acid (2ml) to a suspension of (3.93g, 18.5mmol). The slurry is stirred at ambient temperature for 20 hours. Ice water (100 ml) is added to the slurry and stirred for 1/2 hour. The organic layer is separated, filtered, dried and evaporated to afford the desired product. [1017] Step 5: [1018] [1019] The solution from the previous step (1.9 g) in MeOH (40 ml) was treated with excess CH 2 N 2 / Et 2 O solution and stirred overnight. The reaction mixture is concentrated to dryness to afford crude residue. This residue is chromatographed on silica gel, eluting with an EtOAc / hexanes gradient to afford 1.07 g of the pure desired product. [1020] Step 6: [1021] [1022] A solution of the product from the previous step (1.36 g) in anhydrous CH 2 Cl 2 (40 ml) was treated with BF 3 · Me 2 O (0.7 ml). The reaction mixture is stirred at ambient temperature for 20 hours, quenched with saturated NaHCO 3 (30 ml) and stirred for 1/2 hour. The organic layer is separated and the combined organic layers are washed with brine, dried over MgSO 4 and concentrated to give crude residue. This residue is chromatographed on silica gel, eluting with an EtOAc / hexanes gradient to give 0.88 g of the desired product. [1023] Step 7: [1024] [1025] To a solution of the product from the previous step (0.92 g) in MeOH (30 ml) is added 10% Pd / C (0.16 g) at room temperature and hydrogenated at ambient temperature under 1 atmosphere. The reaction mixture is stirred for 4 hours and concentrated to dryness to afford the desired compound. [1026] Step 8: [1027] [1028] Following the procedure of Example XXIII, step 10, the desired product was prepared. [1029] Step 9: [1030] [1031] According to the procedure of Example XXIV, step 3, the desired acid product is prepared. [1032] Step 10: [1033] [1034] Following the procedure of Example XXIX, steps 4-5, the desired product XXXIV was prepared. [1035] Example XXXV: Preparation of Compound of Formula XXXV: [1036] [1037] Step 1: [1038] [1039] A solution of triethyl phosphonate (44.8 g) in THF (30 ml) at 0 ° C. is treated with a 1 M solution (200 ml) of sodium bis (trimethylsilylamide) in THF. The resulting mixture is stirred at RT for 0.5 h and then cooled to 0 ° C. A solution of 1,4-cyclohexanedione ethylene ketal (15.6 g) in THF (50 ml) is added dropwise and the resulting solution is stirred at RT for 18 h. The reaction mixture is then cooled to 0 ° C., treated with cold aqueous citric acid and the mixture is extracted with EtOAc. The extract was washed with saturated aqueous NaHCO 3 and then brine; Dry over anhydrous Na 2 SO 4 , filter, and concentrate the filtrate. The residue is chromatographed on silica gel eluting with a gradient of CH 2 Cl 2 / EtOAc to afford the title compound (21 g) in 92% yield. Mass spectrum (FAB) 227.3 (M + H + ). [1040] Step 2: [1041] [1042] The product from the preceding step (20 g) is dissolved in EtOH (150 ml) and treated with 10% Pd / C for 3 days under 1 hydrogen atmosphere. The mixture is filtered and the filtrate is evaporated to give the title compound (20.3 g) in 100% yield. Mass spectrum (FAB) 229.2 (M + H + ). [1043] Step 3: [1044] [1045] The product from the previous step (20 g) is dissolved in MeOH (150 ml) and treated with a solution of LiOH (3.6 g) in water (50 ml). The mixture is stirred for 18 hours and concentrated in vacuo. The residue is dissolved in cold water (100 ml) and the solution is acidified to pH 2-3 with 5N HCl and the resulting mixture is extracted with EtOAc. The extract is dried over anhydrous Na 2 S0 4 , filtered and the filtrate is evaporated to give the title compound (17.1 g) in 97% yield. Mass spectrum (FAB) 201.2 (M + H + ). [1046] Step 4: [1047] [1048] 1. Dissolve the product from the previous step (3.0 g) in Et 2 O (150 ml), treat with Et 3 N (2.1 ml) and then cool the solution to -78 ° C. Pivaloyl chloride (1.85 ml) was added dropwise and further stirred for 0.25 hours, then the reaction was allowed to warm to 0 ° C. over 0.75 hours and then recooled to −78 ° C. for use in the reaction in Part 2 Anhydrous solution is obtained. [1049] 2. Cool a solution of (S) -4-benzyl-2-oxazolidinone (2.66 g) in THF (22 ml) to −78 ° C. and add 1.6 M solution of n-butyllithium (9.38 ml) in hexanes dropwise. do. After a further 0.33 hours of stirring at this temperature, the solution is transferred via cannula to the cold solution of Part 1. The mixture is stirred at −78 ° C., then warmed to 0 ° C. and stirred at this temperature for 0.5 h. The organic layer is separated, the aqueous layer is extracted with Et 2 O, the combined organics are washed with brine, dried over anhydrous Na 2 SO 4 , filtered and the filtrate is evaporated. The residue is chromatographed on silica gel, eluting with a hexane / EtOAc (9: 1) gradient to afford the title compound (5.0 g) in 93% yield. Mass spectrum (FAB) 360.4 (M + H + ). [1050] Step 5: [1051] [1052] The product from the previous step (2.7 g) was dissolved in THF (25 ml), cooled to -78 ° C, and 0.5 M potassium bis (trimethylsilyl) amide / toluene (16.5) in THF (25 ml) at -78 ° C through cannula. ml) solution, and the resulting solution is stirred at −78 ° C. for 0.75 hours. To this solution is added a solution of trisyl azide (3.01 g) in THF (25 ml) precooled to -78 ° C via cannula. After 1.5 minutes, the reaction is quenched with acetic acid (1.99 ml) and the reaction is allowed to warm to RT and then stirred for 16 h. The reaction is diluted with EtOAc (300 ml) and washed with 5% aqueous NaCl. The aqueous phase is extracted with EtOAc and the combined organic phases are washed with saturated aqueous NaHCO 3 and then brine, dried over anhydrous Na 2 SO 4 , filtered and the filtrate is concentrated. The residue is chromatographed on silica gel eluting with EtOAc / hexanes (1: 3) to afford the title compound (2.65 g) in 88% yield. [1053] Step 6: [1054] [1055] The product of the preceding step (11.4 g) is dissolved in 95% formic acid (70 ml) and heated at 70 ° C. for 0.5 h with stirring. This solution is evaporated in vacuo and the residue is taken up in EtOAc. The solution is washed with saturated aqueous NaHCO 3 and then brine, dried over anhydrous Na 2 SO 4 , filtered and the filtrate is evaporated. The residue is chromatographed on silica gel to give the title compound (8.2 g). [1056] Step 7: [1057] [1058] The product of the preceding step (8.2 g) is dissolved in CH 2 Cl 2 (16 ml) and treated with diethylaminosulfur trifluoride (DAST, 7.00 ml) for 3 h at RT. The reaction is poured into ice water (200 cc) and extracted with CH 2 Cl 2 . The extract is washed with saturated aqueous NaHCO 3 and then brine, dried over anhydrous Na 2 SO 4 , filtered and the filtrate is evaporated. The residue is chromatographed on silica gel eluting with EtOAc / hexanes (15:85) to afford the title compound (4.5 g) in 52% yield. [1059] Step 8: [1060] [1061] The product of the preceding step (3.7 g) was dissolved in a mixture of THF (150 ml) and water (48 ml), cooled to 0 ° C., treated with 30% H 2 O 2 (3.95 ml) and then LiOH.H 2 O ( 0.86 g). The mixture is stirred at 0 ° C. for 1 hour and then quenched with a solution of Na 2 SO 3 (5.6 g) in water (30 ml) followed by a 0.5 N NaHCO 3 (100 ml) solution. The mixture is concentrated in vacuo to a half volume, diluted with water (to 500 ml) and extracted with CH 2 Cl 2 (4 × 200 ml). The aqueous phase is acidified to pH 1-2 with 5N HCl and extracted with EtOAc (4 × 200 ml). The extract is washed with brine, then dried over anhydrous Na 2 SO 4 , filtered and the filtrate is evaporated to yield the title compound (1.95 g) in 91% yield, which is used directly in the next step. [1062] Step 9: [1063] [1064] The product of the previous example (2.6 g) was dissolved in Et 2 O (50 ml) and treated dropwise with a solution of CH 2 N 2 in Et 2 O until the solution remained yellow. The solution is stirred for 18 h and evaporated in vacuo to give the title compound (2.8 g), which is used directly in the next step. [1065] Step 10: [1066] [1067] The product of the previous step (1.95 g) is dissolved in MeOH (150 ml), treated with formic acid (1.7 ml) and then treated with 10% Pd / C (3.3 g, Degussa type E101) for 1.5 hours under hydrogen pressure. . The mixture is filtered and the filtrate is evaporated to give the title compound (2.1 g) as formic acid salt, which is used directly in the next step. [1068] Step 11: [1069] [1070] The product of the previous step (2.1 g) is dissolved in 1,4-dioxane (100 ml), di-tert-butyl dicarbonate (1.9 g) is added, followed by diisopropylethylamine (2.9 ml). . The solution is stirred for 18 hours and concentrated in vacuo. The residue is treated with aqueous 5% KH 2 PO 4 and the mixture is extracted with EtOAc. The extract is washed with brine, then dried over anhydrous MgSO 4 , filtered and the filtrate is evaporated. The residue is chromatographed on silica gel eluting with a gradient of CH 2 Cl 2 / Et 2 O to afford the title compound (2.5 g) in 99% yield. Mass spectrum (FAB) 307.9 (M + H + ). [1071] Step 12: [1072] [1073] The product of the preceding step (2.5 g) is dissolved in 1,4-dioxane (35 ml), washed with aqueous 1M LiOH (17 ml) and stirred for 2 hours. The mixture is quenched with ice water (125 cc), the mixture is acidified to pH 3-4 with 3N HCl and extracted with EtOAc. The extract is dried over anhydrous MgSO 4 , filtered and the filtrate is evaporated to give the title compound (2.3 g) in 96% yield. Mass spectrum (FAB) 294.0 (M + H + ). [1074] Step 13: [1075] [1076] Following the procedure of Example XXIII, step 10, the desired product was prepared. [1077] Step 14: [1078] [1079] According to the procedure of Example XXIV, step 3, the desired acid product is prepared. [1080] Step 15: [1081] [1082] Following the procedure of Example XXIX, step 4, the desired acid product is prepared. [1083] Example XXXVI: Preparation of Compounds of Formulas XXXVI and XXXVIII: [1084] According to the following schemes, compounds of formula XXXVI and XXXVIII are prepared using Preparation Examples 11-15 discussed above: [1085] [1086] Compounds of formula XXXVIb are prepared from compounds of formula XXXVIa by known procedures: [1087] [1088] To a solution of compound XXXVIa (6.58 g, 22 mmol) in 100 ml of MeOH is added 10% Pd / C (0.8 g) and p-toluene sulfonic acid (4.2 g). The reaction mixture is hydrogenated overnight at room temperature. The reaction mixture is filtered through celite and washed with excess MeOH. The combined filtrates are concentrated in vacuo to afford the title compound XXXVIb as a gum material. The route as shown in the above scheme is carried out and XXXVIb is converted to XXXVI and XXXVII according to Preparation Examples 11-15. [1089] Example XXXVIII: Preparation of Compound of Formula XXXVIII: [1090] Using the following schemes and according to Preparation Examples 11-15 discussed above, the compounds of formula XXXVIII are prepared: [1091] [1092] Example XXXIX Synthesis of Compound of Formula XXXIX [1093] [1094] Step 1: [1095] [1096] A solution of sulfonyl chloride XXXIXa prepared by the process of H. Mcklwain (J. Chem. Soc 1941, 75) was added to a mixture of 1.1 equivalents of t-butylmethylamine and triethylamine at −78 ° C. Add dropwise and stir at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and purified by chromatography (SiO 2 , Hex / acetone 4: 1) to give sulfonamide XXXIXb as a colorless oil. [1097] Step 2: [1098] [1099] A solution of Cbz-protected amine XXXIXb is dissolved in methanol, treated with 5 mol% Pd / C (5% w / w) and then hydrogenated at 60 psi. The reaction mixture is filtered through a plug of celite and concentrated in vacuo to give the free amine XXXIXc, which solidifies upon standing. [1100] Step 3: [1101] [1102] Similar to the procedure for the synthesis of XXVf, hydroxy sulfonamide XXXIXd is synthesized, except that the amine XXVd is replaced with XXXIXc. This crude reaction mixture is used directly for the next reaction. [1103] Step 4: [1104] [1105] The hydroxy amine XXXIXd is oxidized to compound XXXIX using the Dess-Martin reagent while performing the synthesis process of XXV (step 5). This crude mixture is purified by chromatography (SiO 2 , acetone / hexane 3: 7) to afford XXXIX as a colorless solid. [1106] Assays for HCV protease inhibitory activity: [1107] Spectrometric Assay: [1108] For the compounds of the present invention, see R. Zhang et al., Analytical Biochemistry, 270 (1999) 268-275; Spectrometric assays for HCV serine protease are performed by the procedure described in its entirety herein. The assay based on proteolytic degradation of the pigmented ester substrate is suitable for continuously monitoring HCV NS3 protease activity. The substrate is derived from the P side of the NS5A-NS5B linking sequence (Ac-DTEDVVX (Nva), wherein X is A or P), whose C-terminal carboxyl group is comprised of four different chromogenic alcohols (3- or 4). Nitrophenol, 7-hydroxy-4-methyl-coumarin or 4-phenylazophenol). In the following, the synthesis, characterization and application of these novel spectrometric ester substrates to high power screening and detailed epidemiological evaluation of HCV NS3 protease inhibitors are presented. [1109] Material and method: [1110] Material: Chemical reagents for assay related buffers are obtained from Sigma Chemical Company (St. Louis, Missouri). Reagents for peptide synthesis are obtained from sources [Aldrich Chemicals, Novabiochem (San Diego, California), Applied Biosystems (Foster City, California) and Perseptive Biosystems (Framingham, Massachusetts). Peptides are synthesized manually or on an automated ABI model 431A synthesizer (Applied Biosystems). UV / VIS spectrometer model LAMBDA 12 is purchased from Perkin Elmer (Norwalk, Connecticut) and 96-well UV plates are obtained from Corning (Corning, New York). Prewarming blocks are obtained from the supplier [USA Scientific (Ocala, Florida)] and 96-well plate vibrators are obtained from the supplier (Labline Instruments (Melrose Park, Illinois)). Spectramax Plus microtiter plate readers equipped with monochrometers are obtained from Molecular Devices (Sunnyvale, California). [1111] Enzyme Manufacturing: [1112] See, D.L. Recombinant heterodimeric HCV NS3 / NS4A protease (strain 1a) is prepared using the procedure disclosed in Sali et al., Biochemistry, 37 (1998) 3392-3401. Protein concentrations are determined by the Biorad dye method using recombinant HCV protease standards previously quantified by amino acid analysis. Prior to initiating the assay, enzyme storage buffer (50 mM sodium phosphate pH 8.0, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside and 10 mM DTT) utilizing a Biorad Bio-Spin P-6 prepacked column Is exchanged for assay buffer (25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 μM DTT). [1113] Substrate Synthesis and Purification: [1114] Substrate synthesis is performed as reported in R. Zhang et al. (Ibid) and standard protocols are described in K. Barlos et al., Int. J. Pept. Protein Res., 37 (1991), 513-520, discloses this synthesis by directing Fmoc-Nva-OH towards 2-chlorotrityl chloride resin. Subsequently, the peptides are assembled manually or on an automated ABI Model 431 peptide synthesizer using Fmoc chemistry. The N-acetylated and fully protected peptide fragments are subjected to 10% acetic acid (HOAc in dichloromethane (DCM) for 30 minutes. ) And 10% trifluoroethanol (TFE) or 2% trifluoroacetic acid (TFA) in DCM for 10 minutes. The combined filtrate and DCM washes are azeotropically evaporated (or repeatedly extracted with aqueous Na 2 CO 3 ) to remove the acid used for cleavage. The DCM phase is dried over Na 2 SO 4 and then evaporated. [1115] The ester substrate was subjected to a standard acid-alcohol coupling procedure [K. Holmber et al., Acta Chem. Scand., B33 (1979) 410-412]. The peptide fragment is dissolved in anhydrous pyridine (30-60 mg / ml), to which 10 molar equivalents of chromophore and catalytic amount (0.1 equivalents) of para-toluenesulfonic acid (pTSA) are added. Dicyclohexylcarbodiimide (DCC, 3 equiv) is added to initiate the coupling reaction. Product formation was monitored by HPLC and found to be complete within 12-72 hours at room temperature. The pyridine solvent is evaporated in vacuo and further removed by azeotropic evaporation with toluene. The peptide ester is deprotected with 95% TFA in DCM for 2 hours and extracted three times with anhydrous ethyl ether to remove excess chromophore. This deprotected substrate is purified by reverse phase HPLC on a C3 or C8 column using a 30% to 60% acetonitrile gradient (using six column volumes). The overall yield after HPLC purification is approximately 20-30%. The molecular weight was confirmed by electrospray ionization mass spectroscopy. The substrate is stored in dry powder form under drying action. [1116] Spectrum of Substrate and Product: [1117] Spectra of the substrate and the corresponding chromophore products are obtained in buffer for pH 6.5 assay. Optimal off-peak wavelength at 1 cm cuvette using multiple dilutions (340 nm for 3-Np and HMC, 370 nm for PAP, 400 nm for 4-Np) Determine the extinction coefficient at. The optimal off-peak wavelength is defined as the wavelength that gives the maximum absorbance fraction between the substrate and the product [(Product OD-Substrate OD) / Substrate OD]. [1118] Protease Assay: [1119] The HCV protease assay is performed at 30 ° C. using 200 μl reaction mixture in 96-well microtiter plates. Assay buffer conditions (25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 μM DTT) are optimized for NS3 / NS4A heterodimer. See DLSali et al., Ibid. ]. Typically, 150 μl mixture of buffer, substrate and inhibitor are placed in the wells (final concentration of DMSO 4% v / v) and preincubated at 30 ° C. for approximately 3 minutes. The reaction is then initiated using 50 μl of pre-warmed protease (12 nM, 30 ° C.) in assay buffer (final volume 200 μl). The plates were subjected to a constant calibration period (60 minutes) using a Spectromax Plus microtiter plate reader equipped with a monochromator at a suitable wavelength (340 nm for 3-Np and HMC, 370 nm for PAP). , And 400 nm in the case of 4-Np) and monitor the change in absorbance (a plate reader utilizing a cutoff filter can be used to obtain acceptable levels of results). Proteolytic cleavage of the ester linkage between Nva and the chromophore is monitored at a suitable wavelength for the blank without enzyme as a control for non-enzymatic hydrolysis. Over a 30-fold substrate concentration range (about 6-200 μM), substrate dynamics parameters are evaluated. Determine the initial velocity using linear regression and obtain the kinetics constant by fixing the data to the Michaelis-Menten equation using non-linear regression analysis (Mac Curve Fit 1.1, K. Raner) . The turnover number (k cat ) is calculated assuming that the enzyme is fully active. [1120] Evaluation of Inhibitors and Inactivators: [1121] Rearranged Michaelis-Menten equation for competitive inhibition kinetics: v o / v i = 1 + [I] o / (K i * (1 + [S] o / K m )) [where v o is the suppression that the initial velocity is not, v i is the initial speed of the presence of the inhibitor and of a given inhibitor concentration ([I] o), [ S] o is the is the substrate concentration used; the thus v o / v i vs. inhibitor concentration ( [I] o ) by plotting competitive inhibitors Ac-D- (D-Gla) -LI- (Cha) -C-OH (27), Ac-DTEDVVA (Nva) -OH and Ac-DTEDVVP (Nva) Inhibition constant (K i *) for -OH is determined experimentally at fixed concentrations of enzyme and substrate. The data thus generated is fixed using linear regression and the K i * value is calculated using the production slope 1 / (K i * (1 + [S] o / K m )). [1122] The K i * values obtained for the various compounds of the invention are shown in the table above, where the compounds are arranged in the order of the K i * value range. From these test results, one skilled in the art will clearly see that the compounds of the present invention have excellent efficacy as NS3-serine protease inhibitors. [1123] Although the invention has been described in connection with the specific embodiments set forth above, many alternatives, modifications and other variations of the invention will be apparent to those skilled in the art. Such alternatives, modifications and variations are also within the spirit and scope of the invention. [1124] TABLE 2 [1125] [1126] [1127] [1128] [1129] [1130] [1131] [1132] [1133] [1134] [1135] [1136] [1137] [1138] [1139] [1140] [1141] [1142] [1143] [1144] [1145] [1146] [1147] [1148] [1149] [1150] [1151] [1152] [1153] [1154] [1155] [1156] [1157] [1158] [1159] [1160] [1161] [1162] [1163] [1164] [1165] [1166] [1167] [1168] [1169] [1170] [1171] [1172] [1173] [1174] [1175] [1176] [1177] TABLE 4 [1178] [1179] [1180] [1181] [1182] [1183] [1184] [1185] [1186] [1187] [1188] [1189] [1190] [1191] TABLE 5 [1192] [1193] [1194] [1195] [1196] [1197] [1198] [1199] [1200] [1201] [1202] [1203] [1204] [1205] [1206] [1207] [1208] [1209] [1210] [1211] [1212] [1213] [1214] [1215] [1216] [1217] [1218] [1219] [1220] [1221] [1222] [1223] [1224] [1225] [1226] [1227] [1228] [1229] [1230] [1231] [1232] [1233] [1234] [1235] [1236] [1237] [1238] [1239] [1240] [1241] [1242] [1243] [1244] [1245] [1246] [1247] [1248] [1249] [1250] [1251] [1252] [1253] [1254] [1255] [1256] [1257] [1258] [1259] [1260] [1261] [1262] [1263] [1264] [1265] [1266] [1267] [1268] [1269] [1270] [1271] [1272] [1273] [1274] [1275] [1276] [1277] [1278] [1279] [1280] [1281] [1282] [1283] [1284] [1285] [1286] [1287] [1288] [1289] [1290] [1291] [1292] ] [1293] [1294] [1295] [1296] [1297] [1298] [1299] [1300] [1301] [1302] [1303] [1304] [1305]
权利要求:
Claims (49) [1" claim-type="Currently amended] A compound of formula (I) and an enantiomer, stereoisomer, rotamer, tautomer, racemate and prodrug, and a pharmaceutically acceptable salt or solvent of said compound or prodrug freight: Formula I In the above formula, Y is 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, provided that Y is optionally substituted by X 11 or X 12 ; X 11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl or heteroarylalkyl, provided that 11 may be optionally further substituted by X 12 ; X 12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carboalkoxy, Carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano or nitro, provided that alkyl, alkoxy and aryl are optionally added by residues independently selected from X 12 Optionally substituted; R 1 is COR 5 or B (OR) 2 , and R 5 is H, OH, OR 8 , NR 9 R 10 , CF 3 , C 2 F 5 , C 3 F 7 , CF 2 R 6 , R 6 , or COR 7 , R 7 is H, OH, OR 8 , CHR 9 R 10 or NR 9 R 10 , and R 6 , R 8 , R 9 and R 10 are H, alkyl, aryl, heteroalkyl, heteroaryl, cyclo Alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH (R 1 ′ )] p COOR 11 , [CH (R 1 ′ )] p CONR 12 R 13 , [CH (R 1 ′ )] p SO 2 R 11 , [CH (R 1 ′ )] p COR 11 , [CH (R 1 ′ )] p CH (OH) R 11 , CH (R 1 ′ ) CONHCH (R 2 ′ ) COOR 11 , CH (R 1 ′ CONHCH (R 2 ' ) CONR 12 R 13 , CH (R 1' ) CONHCH (R 2 ' ) R', CH (R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) COOR 11 , CH ( R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) CONR 12 R 13 , CH (R 1' ) CONHCH (R 2 ' ) CONHCH (R 3' ) CONHCH (R 4 ' ) COOR 11 , CH ( R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) CONHCH (R 4' ) CONR 12 R 13 , CH (R 1 ' ) CONHCH (R 2' ) CONHCH (R 3 ' ) CONHCH (R 4' ) CONHCH (R 5 ′ ) COOR 11 , and CH (R 1 ′ ) CONHCH (R 2 ′ ) CONHCH (R 3 ′ ) CONHCH (R 4 ′ ) CONHCH (R 5 ′ ) CONR 12 R 13 Select R 1 ' , R 2' , R 3 ' , R 4' , R 5 ' , R 11 , R 12 , R 13 and R' are H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl Independently selected from the group consisting of aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W may be present or absent, and when W is present, W is selected from C═O, C═S, C (═N—CN) or SO 2 ; Q can be present or absent, and when Q is present, Q is CH, N, P, (CH 2 ) p , (CHR) p , (CRR ') p , O, NR, S or SO 2 , When Q is absent, M can also be present or absent; When Q and M are absent, A is directly linked to L; A is O, CH 2 , (CHR) p , (CHR-CHR ') p , (CRR') p , NR, S, SO 2 or a bond; E is CH, N or CR, or a double bond to A, L or G; G may be present or absent, and when G is present, G is (CH 2 ) p , (CHR) p , or (CRR ′) p , and when G is absent, J is present and E is present in G Directly linked to a carbon atom in formula (I) as linked; J may be present or absent, and when J is present, J is (CH 2 ) p , (CHR) p , (CRR ′) p , SO 2 , 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; L can be present or absent, if L is present, L is CH, CR, O, S or NR, and if L is absent, M can be present or absent and L is present and M is present When M is directly and independently linked to E, J is directly and independently linked to E; M may be present or absent, and when M is present, M may be O, NR, S, SO 2 , (CH 2 ) p , (CHR) p , (CHR-CHR ') p , or (CRR') p ; p is a number from 0 to 6; R, R ', R 2 , R 3 and R 4 are H; C 1 -C 10 alkyl; C 2 -C 10 alkenyl; C 3 -C 8 cycloalkyl; C 3 -C 8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (Cycloalkyl) alkyl and (heterocycloalkyl) alkyl, wherein the cycloalkyl is made from 3 to 8 carbon atoms, 0 to 6 oxygen, nitrogen, sulfur or phosphorus atoms, the alkyl having 1 to 6 carbon atoms ; Aryl; Heteroaryl; Alkyl-aryl; And alkyl-heteroaryl, independently selected from the group consisting of The alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally chemically substituted, and the term "substituted" is alkyl, alkenyl, alkynyl , Aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, sia O, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide and hydroxamate, optionally chemically substituted by one or more residues selected from the group consisting of; Further, the unit NCGELJN represents a five or six membered cyclic ring structure, provided that the unit NCGELJN represents a five membered cyclic ring structure, or N, C, G, E, L, J, N, A When the bicyclic ring structure in formula (I) comprising Q, M represents a 5-membered cyclic ring structure, such 5-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring. [2" claim-type="Currently amended] The compound of claim 1, wherein R 1 is COR 5 and R 5 is H, OH, COOR 8 or CONR 9 R 10 . [3" claim-type="Currently amended] The compound of claim 2, wherein R 1 is COCONR 9 R 10 , R 9 is H, R 10 is H, R 14 , [CH (R 1 ′ )] p COOR 11 , [CH (R 1 ′ )] p. CONR 12 R 13 , [CH (R 1 ′ )] p SO 2 R 11 , [CH (R 1 ′ )] p SO 2 NR 12 R 13 , [CH (R 1 ′ )] p COR 11 , CH (R 1 ′ ) CONHCH (R 2 ′ ) COOR 11 , CH (R 1 ′ ) CONHCH (R 2 ′ ) CONR 12 R 13 or CH (R 1 ′ ) CONHCH (R 2 ′ ) (R ′), with R 14 H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, aryl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl. [4" claim-type="Currently amended] The compound of claim 3, wherein R 10 is H, R 14 , CH (R 1 ′ ) COOR 11 , CH (R 1 ′ ) CH (R 1 ′ ) COOR 11 , CH (R 1 ′ ) CONR 12 R 13 , CH (R 1 ′ ) CH (R 1 ′ ) CONR 12 R 13 , CH (R 1 ′ ) CH (R 1 ′ ) SO 2 R 11 , CH (R 1 ′ ) CH (R 1 ′ ) SO 2 NR 12 R 13 , CH (R 1 ′ ) CH (R 1 ′ ) COR 11 , CH (R 1 ′ ) CONHCH (R 2 ′ ) COOR 11 , CH (R 1 ′ ) CONHCH (R 2 ′ ) CONR 12 R 13 or CH (R 1 ′ ) CONHCH (R 2 ′ ) (R ′), R 1 ′ is H or alkyl, R 2 ′ is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, p Compounds that are ferridyl or pyridyl. [5" claim-type="Currently amended] The compound of claim 4, wherein R 1 ′ is H. 6. [6" claim-type="Currently amended] The compound of claim 5, wherein R 11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α, α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; R 'is hydroxymethyl or CH 2 CONR 12 R 13 , R 2 ' Independently selected from the group consisting of; U 1 and U 2 may be the same or different and H, F, CH 2 COOH, CH 2 COOMe, CH 2 CONH 2 , CH 2 CONHMe, CH 2 CONMe 2 , azido, amino, hydroxyl, substituted amino , Substituted hydroxyl; U 3 and U 4 may be the same or different and are selected from O and S; U 5 is alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryl Oxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or combinations thereof; NR 12 R 13 2 It is selected from the group consisting of; U 6 is H, OH or CH 2 OH; R 14 is H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl , OMe, cyclopropylmethyl compound selected from the group consisting of. [7" claim-type="Currently amended] The compound of claim 2, wherein R 2 is selected from the group consisting of: [8" claim-type="Currently amended] 8. A compound according to claim 7, wherein R 3 is selected from the group consisting of: In the above formula, R 31 is = OH or O-alkyl; Y 19 is Is selected from; Y 20 is selected from the following residues: [9" claim-type="Currently amended] The compound of claim 8, wherein R 3 is selected from the group consisting of: [10" claim-type="Currently amended] The compound of claim 9, wherein Z is N; R 4 is H. [11" claim-type="Currently amended] The compound of claim 10, wherein W is C═O. [12" claim-type="Currently amended] The compound of claim 11, wherein Y is selected from the following residues: In the above formula, Y 11 is selected from H, COOH, COOEt, OMe, Ph, OPh, NHMe, NHAc, NHPh, CH (Me) 2 , 1-triazolyl, 1-imidazolyl and NHCH 2 COOH; Y 12 is selected from H, COOH, COOMe, OMe, F, Cl or Br; Y 13 is the residue Is selected from; Y 14 is selected from MeSO 2 , Ac, Boc, iBoc, Cbz or Alloc; Y 15 and Y 16 are independently selected from alkyl, aryl, heteroalkyl and heteroaryl; Y 17 is CF 3 , NO 2 , CONH 2 , OH, COOCH 3 , OCH 3 , OC 6 H 5 , C 6 H 5 , COC 6 H 5 , NH 2 or COOH; Y 18 is COOCH 3 , NO 2 , N (CH 3 ) 2 , F, OCH 3 , CH 2 COOH, COOH, SO 2 NH 2 or NHCOCH 3 . [13" claim-type="Currently amended] The compound of claim 12, wherein Y is selected from the group consisting of: In the above formula, Y 17 is CF 3 , NO 2 , CONH 2 , OH, NH 2 or COOH; Y 18 is F, COOH. [14" claim-type="Currently amended] The compound of claim 13, wherein Y is selected from the group consisting of: [15" claim-type="Currently amended] 15. The compound of claim 14, wherein L and M are absent and J is directly linked to E. [16" claim-type="Currently amended] The compound of claim 14, wherein L, J and M are absent and E is directly linked to N. 16. [17" claim-type="Currently amended] The compound of claim 14, wherein G and M are absent. [18" claim-type="Currently amended] 15. The moiety according to claim 14, wherein end Phosphorus compounds. [19" claim-type="Currently amended] The compound of claim 18, wherein structure a is selected from the following structures: [20" claim-type="Currently amended] The compound of claim 18, wherein structure a is the following structure: Wherein R 20 is selected from the following structures: [21" claim-type="Currently amended] The compound of claim 18, wherein structure a is the following structure: Wherein R 21 and R 22 may be the same or different and are independently selected from the following structures: [22" claim-type="Currently amended] The compound of claim 18, wherein structure a is selected from the following structures: [23" claim-type="Currently amended] 15. The residue of claim 14, wherein the residue end Phosphorus Compound: In the above formula, Q may be present or absent, and when Q is absent, M is directly linked to A. [24" claim-type="Currently amended] The compound of claim 23, wherein structure b is selected from the following structures: [25" claim-type="Currently amended] 15. The residue of claim 14, wherein the residue end Phosphorus Compound: In the above formula, G and J are independently selected from the group consisting of (CH 2 ) p , (CHR) p , (CHR—CHR ′) p and (CRR ′) p ; A and M are independently selected from the group consisting of O, S, SO 2 , NR, (CH 2 ) p , (CHR) p , (CHR—CHR ′) p and (CRR ′) p ; Q is CH 2 , CHR, CRR ', NH, NR, O, S, SO 2 , NR, (CH 2 ) p , (CHR) p and (CRR') p . [26" claim-type="Currently amended] The compound of claim 25, wherein structure c is selected from the following structures: [27" claim-type="Currently amended] The method of claim 14, Is selected from the following structures: [28" claim-type="Currently amended] The method of claim 27, Is selected from the following structures: [29" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1 as an active ingredient. [30" claim-type="Currently amended] The pharmaceutical composition of claim 29 for use in treating a disease associated with HCV. [31" claim-type="Currently amended] The pharmaceutical composition of claim 29, further comprising a pharmaceutically acceptable carrier. [32" claim-type="Currently amended] 32. The pharmaceutical composition of claim 31, further comprising an antiviral agent. [33" claim-type="Currently amended] 33. The pharmaceutical composition of claim 32, further containing interferon. [34" claim-type="Currently amended] The pharmaceutical composition of claim 33, wherein the antiviral agent is ribavirin and the interferon is α-interferon or pegylated interferon. [35" claim-type="Currently amended] A method of treating a disease associated with HCV, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 to a patient in need thereof. [36" claim-type="Currently amended] 36. The method of claim 35, wherein said administration is oral or subcutaneous administration. [37" claim-type="Currently amended] Use of a compound of claim 1 for the manufacture of a medicament for treating a disease associated with HCV. [38" claim-type="Currently amended] A method of preparing a pharmaceutical composition for treating a disease associated with HCV, comprising intimate contact of a compound of claim 1 with a pharmaceutically acceptable carrier. [39" claim-type="Currently amended] Compounds exhibiting HCV protease inhibitory activity, selected from compounds of the structures listed below, and enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrugs thereof, and pharmaceutically acceptable compounds or prodrugs thereof Salts or Solvates [40" claim-type="Currently amended] A pharmaceutical composition for treating a disease associated with HCV, comprising a therapeutically effective amount of one or more compounds of claim 39 and a pharmaceutically acceptable carrier. [41" claim-type="Currently amended] 41. The pharmaceutical composition of claim 40, further comprising an antiviral agent. [42" claim-type="Currently amended] 42. The pharmaceutical composition of claim 41 additionally containing an interferon or PEG-interferon alpha conjugate. [43" claim-type="Currently amended] The pharmaceutical composition of claim 42, wherein the antiviral agent is ribavirin and the interferon is α-interferon. [44" claim-type="Currently amended] A method of treating a disease associated with hepatitis C virus, comprising administering an effective amount of one or more compounds of claim 39. [45" claim-type="Currently amended] A method of modulating the activity of hepatitis C virus (HCV) protease, including contacting an HCV protease with one or more compounds of claim 39. [46" claim-type="Currently amended] A method of treating, preventing or alleviating one or more symptoms of hepatitis C, comprising administering an effective amount of one or more compounds of claim 39. [47" claim-type="Currently amended] 46. The method of claim 45, wherein the HCV protease is an NS3 / NS4a protease. [48" claim-type="Currently amended] 48. The method of claim 47, wherein said compound (s) inhibit HCV NS3 / NS4a protease. [49" claim-type="Currently amended] A method of modulating processing of an HCV polypeptide, comprising contacting a composition containing a hepatitis C virus (HCV) polypeptide with one or more compounds of claim 39 under conditions under which the polypeptide is processed.
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引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2000-07-21|Priority to US22010800P 2000-07-21|Priority to US60/220,108 2001-07-19|Application filed by 쉐링 코포레이션, 코르바스 인터내셔날, 인코포레이티드 2001-07-19|Priority to PCT/US2001/022678 2003-03-28|Publication of KR20030025277A 2009-06-25|Application granted 2009-06-25|Publication of KR100904788B1
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