US20060205672A1 - Novel peptides as NS3-serine protease inhibitors of hepatitis C virus - Google Patents

Novel peptides as NS3-serine protease inhibitors of hepatitis C virus

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Publication number
US20060205672A1
US20060205672A1 US11/241,656 US24165605A US2006205672A1 US 20060205672 A1 US20060205672 A1 US 20060205672A1 US 24165605 A US24165605 A US 24165605A US 2006205672 A1 US2006205672 A1 US 2006205672A1
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United States
Prior art keywords
compound
conhch
alkyl
mmol
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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US11/241,656
Inventor
Anil Saksena
Viyyoor Girijavallabhan
Raymond Lovey
Edwin Jao
Frank Bennett
Jinping McCormick
Haiyan Wang
Russell Pike
Stephane Bogen
Tin-Yau Chan
Yi-Tsung Liu
Zhaoning Zhu
F. Njoroge
Ashok Arasappan
Tejal Parekh
Ashit Ganguly
Kevin Chen
Srikanth Venkatraman
Henry Vaccaro
Patrick Pinto
Bama Santhanam
Scott Kemp
Odile Levy
Marguerita Lim-Wilby
Susan Tamura
Wanli Wu
Siska Hendrata
Yuhua Huang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Dendreon Pharmaceuticals LLC
Original Assignee
Dendreon Corp
Schering Corp
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Application filed by Dendreon Corp, Schering Corp filed Critical Dendreon Corp
Priority to US11/241,656 priority Critical patent/US20060205672A1/en
Assigned to CORVAS INTERNATIONAL, INC. reassignment CORVAS INTERNATIONAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TAMURA, SUSAN Y., KEMP, SCOTT JEFFREY, LEVY, ODILE ESTHER, LIM-WILBY, MARGUERITA
Assigned to SCHERING CORPORATION reassignment SCHERING CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GANGULY, ASHIT K., SANTHANAM, BAMA, PAREKH, TEJAL, WANG, HAIYAN, ARASAPPAN, ASHOK, BENNETT, FRANK, BOGEN, STEPHANE L., CHAN, TIN-YAU, CHEN, KEVIN X., GIRIJAVALLABHAN, VIYYOOR M., HENDRATA, SISKA, HUANG, YUHUA, JAO, EDWIN, LIU, YI-TSUNG, LOVEY, RAYMOND G., MCCORMICK, JINPING L., NJOROGE, F. GEORGE, PIKE, RUSSELL E., PINTO, PATRICK A., SAKSENA, ANIL, VACCARO, HENRY A., VENKATRAMAN, SRIKANTH, WU, WANLI, ZHU, ZHAONING
Assigned to DENDREON SAN DIEGO LLC reassignment DENDREON SAN DIEGO LLC MERGER (SEE DOCUMENT FOR DETAILS). Assignors: CORVAS INTERNATIONAL, INC.
Assigned to DENDREON CORPORATION reassignment DENDREON CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DENDREON SAN DIEGO LLC
Publication of US20060205672A1 publication Critical patent/US20060205672A1/en
Priority to US12/973,020 priority patent/US20110117057A1/en
Assigned to DRONE ACQUISITION SUB INC. reassignment DRONE ACQUISITION SUB INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DENDREON CORPORATION, AND ITS WHOLLY OWNED SUBSIDIARIES, DENDREON HOLDINGS, LLC, DENDREON DISTRIBUTION, LLC, AND DENDREON MANUFACTORING, LLC
Assigned to DENDREON PHARMACEUTICALS, INC. reassignment DENDREON PHARMACEUTICALS, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: DRONE ACQUISITION SUB INC.
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel hepatitis C virus (“HCV”) protease inhibitors, pharmaceutical compositions containing one or more such inhibitors, methods of preparing such inhibitors and methods of using such inhibitors to treat hepatitis C and related disorders.
  • HCV hepatitis C virus
  • This invention specifically discloses novel peptide compounds as inhibitors of the HCV NS3/NS4a serine protease.
  • Hepatitis C virus is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH)(see, International Patent Application Publication No. WO 89/04669 and European Patent Application Publication No. EP 381 216).
  • NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biliar cirrhosis.
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HDV delta hepatitis virus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • This approximately 3000 amino acid polyprotein contains, from the amino terminus to the carboxy terminus, a nucleocapsid protein (C), envelope proteins (E1 and E2) and several non-structural proteins (NS1, 2, 3, 4a, 5a and 5b).
  • NS3 is an approximately 68 kda protein, encoded by approximately 1893 nucleotides of the HCV genome, and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of the N-terminal amino acids; and (b) an RNA-dependent ATPase domain at the C-terminus of the protein.
  • the NS3 protease is considered a member of the chymotrypsin family because of similarities in protein sequence, overall three-dimensional structure and mechanism of catalysis.
  • Other chymotrypsin-like enzymes are elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA and PSA.
  • the HCV NS3 serine protease is responsible for proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating four viral proteins during viral replication. This has made the HCV NS3 serine protease an attractive target for antiviral chemotherapy.
  • NS4a protein an approximately 6 kda polypeptide
  • NS3/NS4a serine protease activity of NS3 It has been determined that the NS4a protein, an approximately 6 kda polypeptide, is a co-factor for the serine protease activity of NS3.
  • Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine protease occurs intramolecularly (i.e., cis) while the other cleavage sites are processed intermolecularly (i.e., trans).
  • NS3/NS4a junction contains a threonine at P1 and a serine at P1′.
  • the Cys ⁇ Thr substitution at NS3/NS4a is postulated to account for the requirement of cis rather than trans processing at this junction. See, e.g., Pizzi et al. (1994) Proc. Natl. Acad. Sci ( USA ) 91:888-892, Failla et al.
  • the NS3/NS4a cleavage site is also more tolerant of mutagenesis than the other sites. See, e.g., Kollykhalov et al. (1994) J. Virol. 68:7525-7533. It has also been found that acidic residues in the region upstream of the cleavage site are required for efficient cleavage. See, e.g., Komoda et al. (1994) J. Virol. 68:7351-7357.
  • Inhibitors of HCV protease include antioxidants (see, International Patent Application Publication No. WO 98/14181), certain peptides and peptide analogs (see, International Patent Application Publication No. WO 98/17679, Landro et al. (1997) Biochem. 36:9340-9348, Ingallinella et al. (1998) Biochem. 37:8906-8914, Llinàs-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8:1713-1718), inhibitors based on the 70-amino acid polypeptide eglin c (Martin et al. (1998) Biochem.
  • HCV has been implicated in cirrhosis of the liver and in induction of hepatocellular carcinoma.
  • the prognosis for patients suffering from HCV infection is currently poor.
  • HCV infection is more difficult to treat than other forms of hepatitis due to the lack of immunity or remission associated with HCV infection.
  • Current data indicates a less than 50% survival rate at four years post cirrhosis diagnosis.
  • Patients diagnosed with localized resectable hepatocellular carcinoma have a five-year survival rate of 10-30%, whereas those with localized unresectable hepatocellular carcinoma have a five-year survival rate of less than 1%.
  • a still further object of the present invention is to provide methods for modulating the activity of serine proteases, particularly the HCV NS3/NS4a serine protease, using the compounds provided herein.
  • Another object herein is to provide methods of modulating the processing of the HCV polypeptide using the compounds provided herein.
  • the present invention provides a novel class of inhibitors of the HCV protease, pharmaceutical compositions containing one or more of the compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration or one or more of the symptoms of hepatitis C. Also provided are methods of modulating the interaction of an HCV polypeptide with HCV protease. Among the compounds provided herein, compounds that inhibit HCV NS3/NS4a serine protease activity are preferred.
  • the present application discloses a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I: wherein:
  • R 1 is COR 5 with R 5 being H, OH, COOR 8 or CONR 9 R 10 , where R 8 , R 9 and R 10 are defined above.
  • Still preferred moiety for R 1 is COCONR 9 R 10 , where R 9 is H; and 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′), wherein R 14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cyclo
  • R 10 preferred moieties for R 10 are: 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′), wherein R 1′ is H or alkyl, and R 2′ is phenyl, substituted phenyl, hetero atom-substituted
  • R 1′ is H
  • R 11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, ⁇ -methylbenzyl, ⁇ , ⁇ -dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; for
  • Preferred moieties for R 2 are:
  • Preferred moieties for Y are: wherein:
  • Still more preferred moieties for Y are:
  • the unit represents a cyclic ring structure, which may be a five-membered or six-membered ring structure.
  • that cyclic ring represents a five-membered ring
  • that five-membered cyclic ring does not contain a carbonyl group as part of the cyclic ring structure.
  • that five-membered ring is of the structure: wherein R and R′ are defined above.
  • Preferred representations for that five-membered cyclic ring structure is: where R 20 is Selected from the following moieties:
  • R 21 and R 22 may be the same or different and are independently selected from the following moieties:
  • the unit: in Formula I may be represented by the following structures b and 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 ; and Q is CH 2 , CHR, CRR′, NH, NR, O, S, SO 2 , NR, (CH 2 ) p , (CHR) p , and (CRR′) p .
  • alkyl refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single atom having from 1 to 8 carbon atoms, preferably from 1 to 6;
  • tautomers tautomers, rotamers, enantiomers and other optical isomers, as well as prodrugs, of compounds of Formula I, as well as pharmaceutically acceptable salts, solvates and derivatives thereof.
  • a further feature of the invention is pharmaceutical compositions containing as active ingredient a compound of Formula I (or its salt, solvate or isomers) together with a pharmaceutically acceptable carrier or excipient.
  • the invention also provides methods for preparing compounds of Formula I, as well as methods for treating diseases such as, for example, HCV, AIDS (Acquired Immune Deficiency Syndrome), and related disorders.
  • the methods for treating comprise administering to a patient suffering from said disease or diseases a therapeutically effective amount of a compound of Formula I, or pharmaceutical compositions comprising a compound of Formula I.
  • HCV hepatitis C virus
  • HCV protease is the NS3 or NS4a protease.
  • inventive compounds inhibit such protease. They also modulate the processing of hepatitis C virus (HCV) polypeptide.
  • the present invention discloses compounds of Formula I as inhibitors of HCV protease, especially the HCV NS3/NS4a serine protease, or a pharmaceutically acceptable derivative thereof, where the various definitions are given above.
  • the compounds of the invention may form pharmaceutically acceptable salts with organic or inorganic acids, or organic or inorganic bases.
  • suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
  • suitable bases are, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, and the like.
  • this invention provides pharmaceutical compositions comprising the inventive peptides as an active ingredient.
  • the pharmaceutical compositions generally additionally comprise a pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials). Because of their HCV inhibitory activity, such pharmaceutical compositions possess utility in treating hepatitis C and related disorders.
  • the present invention discloses methods for preparing pharmaceutical compositions comprising the inventive compounds as an active ingredient.
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture.
  • Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum and the like.
  • Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • disintegrants namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. HCV inhibitory activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally, intravenously or subcutaneously.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • the quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application.
  • the actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.
  • the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day.
  • the amount and frequency of the administration will be regulated according to the judgment of the attending clinician.
  • a generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1,000 milligrams per day, in single or divided doses.
  • Capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
  • Oral gel refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
  • Powder for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • Diluent refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corm, rice and potato; and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
  • Disintegrant refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • Suitable disintegrants include starches; “cold water soluble” modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
  • Binder refers to substances that bind or “glue” powders together and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
  • the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d′l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
  • Glident material that prevents caking and improve the flow characteristics of granulations, so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Coloring agents that provide coloration to the composition or the dosage form.
  • excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
  • Bioavailability refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
  • Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.
  • Another embodiment of the invention discloses the use of the pharmaceutical compositions disclosed above for treatment of diseases such as, for example, hepatitis C and the like.
  • the method comprises administering a therapeutically effective amount of the inventive pharmaceutical composition to a patient having such a disease or diseases and in need of such a treatment.
  • the compounds of the invention may be used for the treatment of HCV in humans in monotherapy mode or in a combination therapy (e.g., dual combination, triple combination etc.) mode such as, for example, in combination with antiviral and/or immunomodulatory agents.
  • a combination therapy e.g., dual combination, triple combination etc.
  • antiviral and/or immunomodulatory agents examples include Ribavirin (from Schering-Plough Corporation, Madison, N.J.) and LevovirinTM (from ICN Pharmaceuticals, Costa Mesa, Calif.), VP 50406TM (from Viropharma, Incorporated, Exton, Pa.), ISIS 14803TM (from ISIS Pharmaceuticals, Carlsbad, Calif.), Heptazyme (from Ribozyme Pharmaceuticals, Boulder, Colo.), VX 497TM (from Vertex Pharmaceuticals, Cambridge, Mass.), ThymosinTM (from SciClone Pharmaceuticals, San Mateo, Calif.), MaxamineTM (Maxim Pharmaceuticals, San Diego, Calif.), mycophenolate mofetil (from Hoffman-LaRoche, Nutley, N.J.), interferon (such as, for example, interferon-alpha, PEG-interferon alpha conjugates) and the like.
  • Ribavirin from Schering-Plough Corporation, Madison, N.J.
  • PEG-interferon alpha conjugates are interferon alpha molecules covalently attached to a PEG molecule.
  • Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (RoferonTM, from Hoffman La-Roche, Nutley, N.J.) in the form of pegylated interferon alpha-2a (e.g., as sold under the trade name PegasysTM), interferon alpha-2b (IntronTM, from Schering-Plough Corporation) in the form of pegylated interferon alpha-2b (e.g., as sold under the trade name PEG-IntronTM), interferon alpha-2c (Berofor AlphaTM, from Boehringer Ingelheim, Ingelheim, Germany) or consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (InfergenTM, from Amgen, Thousand Oaks, Calif.).
  • the invention includes tautomers, rotamers, enantiomers and other stereoisomers of the inventive compounds also.
  • inventive compounds may exist in suitable isomeric forms. Such variations are contemplated to be within the scope of the invention.
  • Another embodiment of the invention discloses a method of making the compounds disclosed herein.
  • the compounds may be prepared by several techniques known in the art. Representative illustrative procedures are outlined in the following reaction schemes. It is to be understood that while the following illustrative schemes describe the preparation of a few representative inventive compounds, suitable substitution of any of both the natural and unnatural amino acids will result in the formation of the desired compounds based on such substitution. Such variations are contemplated to be within the scope of the invention.
  • Step A (3.0 g) was treated with 4 N HCl/dioxane (36 mL) and stirred at room temperature for 7 min. The mixture was poured into 1.5 L cold (5° C.) hexane and stirred, then allowed to set cold for 0.5 hr.
  • Step B Compound (2.5) was prepared.
  • N-Cbz-hydroxyproline methyl ester available from Bachem Biosciences, Incorporated, King of Prussia, Pa.
  • compound 3.01
  • toluene (30 mL
  • ethyl acetate (30 mL)
  • NaBr/water 1.28 g/5 mL
  • TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical
  • Ethyl acetate 1000 mL was added to the lower acetonitrile layer, and then the layer was washed with 10% aqueous KH 2 PO 4 (2 ⁇ 700 mL), and brine.
  • the filtrate was evaporated under vacuum in a 25° C. water bath, taken up in fresh ethyl acetate (1000 mL), and washed successively with 0.1 N HCl, 0.1 N NaOH, 10% aqueous KH 2 PO 4 , and brine.
  • the organic solution was dried over anhydrous MgSO 4 , filtered, and evaporated under vacuum.
  • Step B Compound (3.7).
  • Step A Compound (4.5) was prepared.
  • Step B Compound (4.6)
  • Step B Compound (4.6) was prepared.
  • Step C Compound (4.7)
  • any open-ended nitrogen atom with unfulfilled valence in the chemical structures in the Examples and Tables refers to NH, or in the case of a terminal nitrogen, —NH 2 .
  • any open-ended oxygen atom with unfulfilled valence in the chemical structures in the Examples and Tables refers to —OH.
  • the synthesis was done in a reaction vessel which was constructed from a polypropylene syringe cartridge fitted with a polypropylene frit at the bottom.
  • the Fmoc-protected amino acids were coupled under standard solid-phase techniques.
  • Each reaction vessel was loaded with 100 mg of the starting Fmoc-Sieber resin (approximately 0.03 mmol).
  • the resin was washed with 2 mL portions of DMF (2 times).
  • the Fmoc protecting group was removed by treatment with 2 mL of a 20% v/v solution of piperidine in DMF for 20 min.
  • the resin was washed with 2 mL portions of DMF (4 times).
  • the coupling was done in DMF (2 mL), using 0.1 mmol of Fmoc-amino acid, 0.1 mmol of HATU [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] and 0.2 mmol of DIPEA (N,N-diisopropylethylamine). After shaking for 2 h, the reaction vessel was drained and the resin was washed with 2 mL portions of DMF (4 times). The coupling cycle was repeated with the next Fmoc-amino acid or capping group.
  • the synthesis was conducted in a reaction vessel which was constructed from a polypropylene syringe cartridge fitted with a polypropylene frit at the bottom.
  • Resin-bound hydroxy compound (approximately 0.03 mmol) was treated with a solution of 0.12 mmol of Dess-Martin periodinane and 0.12 mmol of t-BuOH in 2 mL of DCM for 4 h.
  • the resin was washed with 2 mL portions of a 20% v/v solution of iPrOH in DCM, THF, a 50% v/v solution of THF in water (4 times), THF (4 times) and DCM (4 times).
  • Compound 901B was dissolved in 10% w/w aqueous sodium hydroxide solution (15 mL) and the resulting solution was heated under reflux for 24 h. Concentrated hydrochloric acid was added and the pH was adjusted to neutral (pH 7). The resulting solution containing compound 901C was evaporated under reduced pressure. The residue was dissolved in 5% w/w aqueous sodium bicarbonate solution (150 mL). The solution was cooled to 0° C. in an ice bath and 1,4-dioxane (30 mL) and a solution of 9-fluorenylmethyl succinimidyl carbonate (2.7 g, 8 mmol) in 1,4-dioxane (30 mL) was added at 0° C.
  • N-Fmoc-phenylalanine 801A (5 g, 12.9 mmol) in anhydrous DCM (22 mL) cooled to ⁇ 30° C. in a dry ice-acetone bath was added N-methylpyrrolidine (1.96 mL, 16.1 mmol) and methyl chloroformate (1.2 mL, 15.5 mmol) sequentially.
  • the reaction mixture was stirred at ⁇ 30° C. for 1 h and a solution of N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mol) and N-methylpyrrolidine (1.96 mL, 16.1 mmol) in anhydrous DCM (8 mL) was added.
  • Resin-bound compound 301B, 301C, 301D, 301E, 301F and 301G were prepared according to the general procedure for solid-phase coupling reactions started with 100 mg of Fmoc-Sieber resin (0.03 mmol). Resin-bound compound 301G was oxidized to resin-bound compound 301H according to the general procedure for solid-phase Dess-Martin oxidation. The resin-bound compound 301H was treated with 4 mL of a 2% v/v solution of TFA in DCM for 5 min. The filtrate was added to 1 mL of AcOH and the solution was concentrated by vacuum centrifugation to provide compound 301J (0.0069 g, 29% yield). MS (LCMS-Electrospray) 771.2 MH + .
  • the solution was stirred for 20 minutes at 0° C., then the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran.
  • the aqueous solution was diluted with water (10 mL) and extracted with dichloromethane (3 ⁇ 40 mL). The organic layers were dried (Na 2 SO 4 ), filtered and concentrated. The residue was dissolved in dichloromethane (20 mL) and triethylsilane (310 ⁇ L, 2.0 mmol), then cooled to ⁇ 78° C. and boron trifluoride diethyletherate (270 ⁇ L, 2.13 mmol) was added dropwise.
  • the solution was stirred for 10 minutes at 0° C., then the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran.
  • the aqueous solution was diluted with water (300 mL) and extracted with dichloromethane (3 ⁇ 200 mL). The organic layers were dried (sodium sulfate), filtered and concentrated. The residue was dissolved in dichloromethane (100 mL) and triethylsilane (2.6 mL, mmol), then cooled to ⁇ 78° C. and boron trifluoride diethyletherate (2.2 mL, mmol) was added dropwise.
  • N-Boc-pyroglutamic(4-allyl)-tert-butylester obtained in the Step 1 above (2.68 g, 8.24 mmol) was subjected to a second alkylation with allyl bromide under similar conditions. Flash chromatography in 15:85 ethylacetate:hexanes provided 2.13 g product (71%) as a clear oil.
  • the aqueous layer was then acidified to pH ⁇ 1 with 1N sodium bisulfate solution and extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered and concentrated to a beige foam (1.3 g, 100%).
  • the 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 min.
  • the reaction mixture was stirred at room temperature for 17 h, then concentrated to remove the dioxane and diluted with water (200 mL).
  • the solution was washed with ether (3 ⁇ 100 mL).
  • the pH of the aqueous solution was adjusted to 2 by the addition of citric acid (caution! foaming! and water (100 mL).
  • the mixture was extracted with dichloromethane (400 mL, 100 mL, 100 mL) and the combined organic layers were dried (sodium sulfate), filtered and concentrated to give the title compound.
  • the solution was washed with ether (3 ⁇ 75 mL).
  • the pH of the aqueous solution was adjusted to 2 by the addition of citric acid (approx. 20 g, caution! foaming! and water (100 mL).
  • the mixture was extracted with dichloromethane (4 ⁇ 100 mL), and the combined organic layers were dried (sodium sulfate), filtered and concentrated.
  • the crude product contained a major impurity which necessitated a three step purification.
  • the crude product was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (50 mL) and stirred for 5 h before being concentrated.
  • the residue was purified by preparatory reverse-phase HPLC.
  • the mixture was extracted with ethyl acetate (3 ⁇ 150 mL) and the combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried (sodium sulfate), filtered and concentrated.
  • the crude product was dissolved in saturated aqueous sodium bicarbonate (100 mL) and washed with ether (3 ⁇ 75 mL).
  • the combined organic layers were dried (sodium sulfate), filtered and concentrated to the title compound (1.373 g, 2.94 mmol, 42%).
  • Step I Synthesis of iBoc-G(Chx)-P(4,4-dimethyl)-OMe
  • N-benzyloxycarbonyl-L-phenylglycine 25 g, 88 mmols was dissolved in THF (800 mL) and cooled to ⁇ 10° C.
  • N-methylmorpholine 9.7 mL, 88 mmols
  • isobutylchloroformate (11.4 mL, 88.0 mmols) were added and the mixture allowed to stir for 1 minute.
  • Dimethylamine 100 mL, 2M in THF was added and the reaction was allowed to warm to room temperature. The mixture was filtered and the filtrate concentrated in vacuo to afford N-benzyloxycabonyl-L-phenylglycine dimethylamide (32.5 g) as a yellow oil.
  • N-benzyloxycarbonyl-L-phenylglycine dimethylamide (32.5 g) obtained above was dissolved in methanol (750 ml) and 10% palladium on activated carbon is (3.3 g) was added. This mixture was hydrogenated on a Parr apparatus under 35 psi hydrogen for 2 hours. The reaction mixture was filtered and the solvent removed in vacuo and the residue recrystallized from methanol-hexanes to afford phenylglycine dimethylamide (26 g) as an off white solid. The ee of this material was determined to be >99% by HPLC analysis of the 2,3,4,6-tetra-O-acetylglucopyranosylthioisocyanate derivative.
  • the reaction was diluted with saturated ammonium chloride (50 mL), ethylacetate (100 mL) and hexanes (100 mL). The organic layer was washed with water and brine, dried filtered and concentrated. The residue was stirred with hexanes (70 mL) for 10 min and filtered. The filtrate was concentrated and chromatographed using 25% ethylacetate in hexanes to give the title compound (1.925 g, 12.5 mmol, 65%).
  • the reaction mixture was diluted with dichloromethane (350 ml) and washed twice each with 75 ml portions of 1M hydrochloric acid, saturated sodium bicarbonate and brine. The organic layer was dried, filtered and concentrated. The residue obtained was subjected to flash chromatography in a 2′′ ⁇ 6′′ silica gel column using 10% ethylacetate in hexanes (800 ml) followed by 1:1 ethylacetate in hexanes (800 ml). The fractions corresponding to the product were pooled and concentrated to yield 980 mg (79%) product.
  • the reaction mixture was concentrated and the remaining residue was diluted with ethylacetate and washed successively with two 75 ml portions of 1M hydrochloric acid, saturated sodium bicarbonate and brine. The organic layer was then dried filtered and concentrated.
  • the crude product was subjected to flash chromatography in a 2′′ ⁇ 6′′ silica gel column using 4:1 ethylacetate:hexanes (700 ml) followed by ethylacetate (1000 ml) and 10% methanol in dichloromethane (600 ml). The fractions corresponding to the product were pooled and concentrated to yield 445 mg (80%) white solid.
  • Step 7 Synthesis of iBoc-G(Chx)-Pro(4,4-dimethyl)-Leu-(CO)-Gly-Phg-dimethylamide
  • reactors for the solid-phase synthesis of peptidyl ketoamides are comprised of a reactor vessel with at least one surface permeable to solvent and dissolved reagents, but not permeable to synthesis resin of the selected mesh size.
  • Such reactors include glass solid phase reaction vessels with a sintered glass frit, polypropylene tubes or columns with frits, or reactor KansTM made by Irori Inc., San Diego Calif.
  • the type of reactor chosen depends on volume of solid-phase resin needed, and different reactor types might be used at different stages of a synthesis. The following procedures will be referenced in the subsequent examples:
  • Procedure A Coupling reaction: To the resin suspended in N-methylpyrrolidine (NMP) (10-15 mL/gram resin) was added Fmoc-amino acid (2 eq), HOAt (2 eq), HATU (2 eq) and diisopropylethylamine (4 eq). The mixture was let to react for 4-48 hours. The reactants were drained and the resin was washed successively with dimethylformamide, dichloromethane, methanol, dichloromethane and diethylether (use 10-15 mL solvent/gram resin). The resin was then dried in vacuo.
  • NMP N-methylpyrrolidine
  • Procedure B Fmoc deprotection: The Fmoc-protected resin was treated with 20% piperidine in dimethylformamide (10 mL reagent/g resin) for 30 minutes. The reagents were drained and the resin was washed successively with dimethylformamide, dichloromethane, methanol, dichloromethane and diethyl ether (10 mL solvent/gram resin).
  • Boc deprotection The Boc-protected resin was treated with a 1:1 mixture of dichloromethane and trifluoroacetic acid for 20-60 minutes (10 mL solvent/gram resin). The reagents were drained and the resin was washed successively with dichloromethane, dimethylformamide, 5% diisopropylethylamine in dimethylformamide, dimethylformamide, dichloromethane and dimethylformamide (10 mL solvent/gram resin).
  • Procedure D Semicarbazone hydrolysis: The resin was suspended in the cleavage cocktail (10 mL/g resin) consisting of trifluoroacetic acid: pyruvic acid: dichloromethane: water 9:2:2:1 for 2 hours. The reactants were drained and the procedure was repeated three more times. The resin was washed successively with dichloromethane, water and dichloromethane and dried under vacuum.
  • HF cleavage The dried peptide-nVal(CO)-G-O-PAM resin (50 mg) was placed in an HF vessel containing a small stir bar. Anisole (10% of total volume) was added as a scavenger. In the presence of glutamic acid and cysteine amino acids, thioanisole (10%) and 1,2-ethanedithiol (0.2%) were also added. The HF vessel was then hooked up to the HF apparatus (Immuno Dynamics) and the system was flushed with nitrogen for five minutes. It was then cooled down to ⁇ 70° C. with a dry ice/isopropanol bath. After 20 minutes, HF was distilled to the desired volume (10 mL HF/g resin).
  • the reaction was let to proceed for one and a half hour at 0° C. Work up consisted of removing all the HF using nitrogen. Dichloromethane was then added to the resin and the mixture was stirred for five minutes. This was followed by the addition of 20% acetic acid in water (4 mL). After stirring for 20 minutes, the resin was filtered using a fritted funnel and the dichloromethane was removed under reduced pressure. The remaining residue and the mixture was washed with hexanes (2 ⁇ ) to remove scavengers. Meanwhile, the resin was soaked in 1 mL methanol. The aqueous layer (20% HOAc) was added back to the resin and the mixture was agitated for five minutes and then filtered. The methanol was removed under reduced pressure and the aqueous layer was lyophilized. The peptide was then dissolved in 10-25% methanol (containing 0.1% trifluoroacetic acid) and purified by reverse phase HPLC.
  • Ethyl isocyanoacetate (96.6 ml, 0.88 mol) was added dropwise to a chilled solution of ethanol (1.5 L) and potassium hydroxide (59.52 g, 1.0 mol). The reaction was slowly warmed to room temperature. After two hours the precipitated product was filtered on a glass funnel and washed with several portions of chilled ethanol. The potassium salt of isocyanoacetic acid thus obtained was dried in vacuo to a golden-brown solid (99.92 g, 91.8%).
  • the reaction was quenched with the slow addition of water (100 ml) at 0° C.
  • the methanol was removed under reduced pressure and the remaining aqueous phase was diluted with ethylacetate.
  • the organic layer was washed with water (3 ⁇ 500 ml), saturated sodium bicarbonate (3 ⁇ 500 ml) and brine (500 ml).
  • the organic layer was dried over sodium sulfate, filtered and concentrated to a white solid (21.70 g, 90.5%).
  • Step 1B To a solution of Fmoc-nVal-CHO (Step 1B) (5.47 g, 16.90 mmol) in dichloromethane (170 ml) was added allyl isocyanoacetate (Step 1A) (2.46 ml, 20.28 mmol) and pyridine (5.47 ml, 67.61 mmol). The reaction mixture was cooled to 0° C. and trifluoroacetic acid (3.38 ml, 33.80 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h, and then at room temperature for 48 hours. TLC taken in ethylacetate confirmed the completion of the reaction.
  • Step E To a solution of Fmoc-nVal-(CO)-Gly-Oallyl (Step E) (4.99 g, 10.75 mmol) in ethanol (130 ml) and water (42 ml) was added diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt (Step IC) (7.6 g, 21.5 mmol) and sodium acetate.3H 2 O (1.76 g, 12.9 mmol), successively. The reaction mixture was heated at reflux for 90 minutes. The completion of reaction was confirmed by TLC taken in 1:1 ethylacetate:hexane.
  • dpsc diphenylmethyl semicarbazide trifluoroacetate salt
  • the commercially available MBHA resin (2.6 g, 1.12 mmol/g, 2.91 mmol) was transferred to a 250 mL fritted solid phase reaction vessel equipped with a nitrogen inlet. It was then washed thoroughly with 30 ml portions of dichloromethane, methanol, dimethylformamide and dichloromethane and coupled over 18 hours to the commercially available Fmoc-Phg-OH (2.17 g, 5.82 mmol) according Procedure A with 99.82% efficiency. The resin was then subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a is small aliquot gave dark blue resin and solution, indicating a successful reaction.
  • step II The resin obtained in step II (2.6 g, 0.8 mmol/g, 2.91 mmol) was reacted with Fmoc-nVal-(dpsc)-Gly-Oallyl (Step 1G) (5.82 mmol, 3.77 g) according to Procedure A. After 18 hours, quantitative ninhydrin analysis indicated 99.91% coupling efficiency.
  • the resin was subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a small aliquot gave dark blue resin and solution, indicating a successful reaction.
  • Step 8 Synthesis of iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin
  • the resin obtained in the previous step (Fmoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin) was subjected to Fmoc deprotection according to procedure B.
  • a ninhydrin assay on a small aliquot gave dark blue resin and solution, indicating a successful reaction.
  • To the resin (0.2 g, 0.22 mmol) suspended in 2 ml NMP was added isobutylchloroformate (0.12 ml, 0.90 mmol) followed by diisopropylethylamine (0.31 ml, 1.79 mmol), and the reaction mixture was shaken for 18 hours at room temperature.
  • Qualitative ninhydrin analysis showed colorless beads and solution indicating a successful reaction.
  • Step 9 Synthesis of iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(CO)-Gly-Phg-MBHA resin
  • Step 10 Synthesis of Synthesis of iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(CO)-Gly-Phg-NH
  • the resin of the previous step (iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(CO)-Gly-Phg-MBHA resin) (100 mg) was subjected to HF cleavage condition (Procedure E) to yield the desired crude product.
  • the material was purified by HPLC using a 2.2 ⁇ 25 cm reverse phase column, containing a C-18 resin comprised of 10 micron size gel particles with a 300 angstrom pore size, eluting with a gradient using 20-50% acetonitrile in water.
  • XXIIIi can also be obtained directly by the reaction of XXIIIf (4.5 g, 17.7 mmol) with aq. H 2 O 2 (10 mL), LiOH.H 2 O (820 mg, 20.8 mmol) at 0° C. in 50 mL of CH 3 OH for 0.5 h.)
  • the amino ester XXIIII was prepared following the method of R. Zhang and J. S. Madalengoitia ( J. Org. Chem. 1999, 64, 330), with the exeception that the Boc group was cleved by the reaction of the Boc-protected amino acid with methanolic HCl.
  • the desired product XXIIIi was prepared according to the procedure in Example XXIII, Step 11.
  • the desired product XXVI was prepared according to the procedure in Example XXIII, Step 12.
  • the desired product XXVIIb was prepared according to the procedure in Example XXIV, Step 2.
  • the intermediate XXVIIIb was prepared according to the procedure in Example XXIII, Steps 3-6.
  • the desired acid product was prepared according to the procedure in Example XXIV, Step 3.
  • the desired product XXXIV was prepared according to the procedure in Example XXIX, Steps 4-5.
  • 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 with LiOH.H 2 O (0.86 g). The mixture was stirred for 1 hour at 0° C., then quenched with a solution of Na 2 SO 3 (5.6 g) in water (30 mL), followed by a solution of 0.5 N NaHCO 3 (100 mL). The mixture was concentrated under vacuum to 1 ⁇ 2 volume, diluted with water (to 500 mL), and extracted with CH 2 Cl 2 (4 ⁇ 200 mL).
  • the desired acid product was prepared according to the procedure in Example XXIV, Step 3.
  • the desired acid product was prepared according to the procedure in Example XXIX, Step 4.
  • hydroxy sulfonamide XXXIXd was synthesized similar to the procedure for the synthesis of XXVf except replacing the amine XXVd with XXXIXc. The crude reaction mixture directly used for the next reaction.
  • Spectrophotometric assay for the HCV serine protease was performed on the inventive compounds by following the procedure described by R. Zhang et al, Analytical Biochemistry, 270 (1999) 268-275, the disclosure of which is incorporated herein by reference.
  • the assay based on the proteolysis of chromogenic ester substrates is suitable for the continuous monitoring of HCV NS3 protease activity.
  • chromophoric alcohols 3- or 4-nitrophenol, 7-hydroxy-4-methyl-coumarin, or 4-phenylazophenol.
  • the prewarming block was from USA Scientific (Ocala, Fla.) and the 96-well plate vortexer was from Labline Instruments (Melrose Park, Ill.).
  • a Spectramax Plus microtiter plate reader with monochrometer was obtained from Molecular Devices (Sunnyvale, Calif.).
  • HCV NS3/NS4A protease (strain 1a) was prepared by using the procedures published previously (D. L. Sali et al, Biochemistry, 37 (1998) 3392-3401). Protein concentrations were determined by the Biorad dye method using recombinant HCV protease standards previously quantified by amino acid analysis.
  • the enzyme storage buffer 50 mM sodium phosphate pH 8.0, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside and 10 mM DTT
  • the assay buffer 25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 ⁇ M EDTA and 5 ⁇ M DTT
  • Substrate Synthesis and Purification The synthesis of the substrates was done as reported by R. Zhang et al, (ibid.) and was initiated by anchoring Fmoc-Nva-OH to 2-chlorotrityl chloride resin using a standard protocol (K. Barlos et al, Int J. Pept. Protein Res., 37 (1991), 513-520). The peptides were subsequently assembled, using Fmoc chemistry, either manually or on an automatic ABI model 431 peptide synthesizer.
  • N-acetylated and fully protected peptide fragments were cleaved from the resin either by 10% acetic acid (HOAc) and 10% trifluoroethanol (TFE) in dichloromethane (DCM) for 30 min, or by 2% trifluoroacetic acid (TFA) in DCM for 10 min.
  • HOAc acetic acid
  • TFE trifluoroethanol
  • TFE trifluoroacetic acid
  • ester substrates were assembled using standard acid-alcohol coupling procedures (K. Holmber et al, Acta Chem. Scand., B 33 (1979) 410-412). Peptide fragments were dissolved in anhydrous pyridine (30-60 mg/ml) to which 10 molar equivalents of chromophore and a catalytic amount (0.1 eq.) of para-toluenesulfonic acid (pTSA) were added. Dicyclohexylcarbodiimide (DCC, 3 eq.) was added to initiate the coupling reactions. Product formation was monitored by HPLC and found to be complete following 12-72 hour reaction at room temperature.
  • DCC dicyclohexylcarbodiimide
  • Spectra of Substrates and Products Spectra of substrates and the corresponding chromophore products were obtained in the pH 6.5 assay buffer. Extinction coefficients were determined at the optimal off-peak wavelength in 1-cm cuvettes (340 nm for 3-Np and HMC, 370 nm for PAP and 400 nm for 4-Np) using multiple dilutions. The optimal off-peak wavelength was defined as that wavelength yielding the maximum fractional difference in absorbance between substrate and product (product OD—substrate OD)/substrate OD).
  • HCV protease assays were performed at 30° C. using a 200 ⁇ l reaction mix in a 96-well microtiter plate.
  • Assay buffer conditions 25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 ⁇ M EDTA and 5 ⁇ M DTT
  • Assay buffer conditions 25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 ⁇ M EDTA and 5 ⁇ M DTT
  • 150 ⁇ l mixtures of buffer, substrate and inhibitor were placed in wells (final concentration of DMSO 4% v/v) and allowed to preincubate at 30° C. for approximately 3 minutes.
  • the resulting data were fitted using linear regression and the resulting slope, 1/(Ki*(1+[S] o /K m ), was used to calculate the Ki* value.
  • Ki* values for the various compounds of the present invention are given in the afore-mentioned Tables wherein the compounds have been arranged in the order of ranges of Ki* values. From these test results, it would be apparent to the skilled artisan that the compounds of the invention have excellent utility as NS3-serine protease inhibitors.

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Abstract

The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 60/220,108 filed Jul. 21, 2000, the disclosure of which is hereby incorporated herein by reference. This application is a divisional of U.S. application Ser. No. 09/908,955, filed on Jul. 19, 2001, the disclosure of which is incorporated herein by reference.
    • FIELD OF INVENTION
  • The present invention relates to novel hepatitis C virus (“HCV”) protease inhibitors, pharmaceutical compositions containing one or more such inhibitors, methods of preparing such inhibitors and methods of using such inhibitors to treat hepatitis C and related disorders. This invention specifically discloses novel peptide compounds as inhibitors of the HCV NS3/NS4a serine protease.
    • BACKGROUND OF THE INVENTION
  • Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH)(see, International Patent Application Publication No. WO 89/04669 and European Patent Application Publication No. EP 381 216). NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biliar cirrhosis.
  • Recently, an HCV protease necessary for polypeptide processing and viral replication has been identified, cloned and expressed; (see, e.g., U.S. Pat. No. 5,712,145). This approximately 3000 amino acid polyprotein contains, from the amino terminus to the carboxy terminus, a nucleocapsid protein (C), envelope proteins (E1 and E2) and several non-structural proteins (NS1, 2, 3, 4a, 5a and 5b). NS3 is an approximately 68 kda protein, encoded by approximately 1893 nucleotides of the HCV genome, and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of the N-terminal amino acids; and (b) an RNA-dependent ATPase domain at the C-terminus of the protein. The NS3 protease is considered a member of the chymotrypsin family because of similarities in protein sequence, overall three-dimensional structure and mechanism of catalysis. Other chymotrypsin-like enzymes are elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA and PSA. The HCV NS3 serine protease is responsible for proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating four viral proteins during viral replication. This has made the HCV NS3 serine protease an attractive target for antiviral chemotherapy.
  • It has been determined that the NS4a protein, an approximately 6 kda polypeptide, is a co-factor for the serine protease activity of NS3. Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine protease occurs intramolecularly (i.e., cis) while the other cleavage sites are processed intermolecularly (i.e., trans).
  • Analysis of the natural cleavage sites for HCV protease revealed the presence of cysteine at P1 and serine at P1′ and that these residues are strictly conserved in the NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions. The NS3/NS4a junction contains a threonine at P1 and a serine at P1′. The Cys→Thr substitution at NS3/NS4a is postulated to account for the requirement of cis rather than trans processing at this junction. See, e.g., Pizzi et al. (1994) Proc. Natl. Acad. Sci (USA) 91:888-892, Failla et al. (1996) Folding & Design 1:3542. The NS3/NS4a cleavage site is also more tolerant of mutagenesis than the other sites. See, e.g., Kollykhalov et al. (1994) J. Virol. 68:7525-7533. It has also been found that acidic residues in the region upstream of the cleavage site are required for efficient cleavage. See, e.g., Komoda et al. (1994) J. Virol. 68:7351-7357.
  • Inhibitors of HCV protease that have been reported include antioxidants (see, International Patent Application Publication No. WO 98/14181), certain peptides and peptide analogs (see, International Patent Application Publication No. WO 98/17679, Landro et al. (1997) Biochem. 36:9340-9348, Ingallinella et al. (1998) Biochem. 37:8906-8914, Llinàs-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8:1713-1718), inhibitors based on the 70-amino acid polypeptide eglin c (Martin et al. (1998) Biochem. 37:11459-11468, inhibitors affinity selected from human pancreatic secretory trypsin inhibitor (hPSTI-C3) and minibody repertoires (MBip) (Dimasi et al. (1997) J. Virol. 71:7461-7469), cVHE2 (a “camelized” variable domain antibody fragment) (Martin et al. (1997) Protein Eng. 10:607-614), and α1-antichymotrypsin (ACT) (Elzouki et al.) (1997) J. Hepat. 27:42-28). A ribozyme designed to selectively destroy hepatitis C virus RNA has recently been disclosed (see, BioWorld Today 9(217): 4 (Nov. 10, 1998)).
  • Reference is also made to the PCT Publications, No. WO 98/17679, published Apr. 30, 1998 (Vertex Pharmaceuticals Incorporated); WO 98/22496, published May 28, 1998 (F. Hoffmann-La Roche AG); and WO 99/07734, published Feb. 18, 1999 (Boehringer Ingelheim Canada Ltd.).
  • HCV has been implicated in cirrhosis of the liver and in induction of hepatocellular carcinoma. The prognosis for patients suffering from HCV infection is currently poor. HCV infection is more difficult to treat than other forms of hepatitis due to the lack of immunity or remission associated with HCV infection. Current data indicates a less than 50% survival rate at four years post cirrhosis diagnosis. Patients diagnosed with localized resectable hepatocellular carcinoma have a five-year survival rate of 10-30%, whereas those with localized unresectable hepatocellular carcinoma have a five-year survival rate of less than 1%.
  • Reference is made to A. Marchetti et al, Synlett, S1, 1000-1002 (1999) describing the synthesis of bicylic analogs of an inhibitor of HCV NS3 protease. A compound disclosed therein has the formula:
    Figure US20060205672A1-20060914-C00001
  • Reference is also made to W. Han et al, Bioorganic & Medicinal Chem. Lett, (2000) 10, 711-713, which describes the preparation of certain α-ketoamides, α-ketoesters and α-diketones containing allyl and ethyl functionalities.
  • Reference is also made to WO 00/09558 (Assignee: Boehringer Ingelheim Limited; Published Feb. 24, 2000) which discloses peptide derivatives of the formula:
    Figure US20060205672A1-20060914-C00002
    where the various elements are defined therein. An illustrative compound of that
    Figure US20060205672A1-20060914-C00003
  • Reference is also made to WO 00/09543 (Assignee: Boehringer Ingelheim Limited; Published Feb. 24, 2000) which discloses peptide derivatives of the formula:
    Figure US20060205672A1-20060914-C00004
    where the various elements are defined therein. An illustrative compound of that series is:
    Figure US20060205672A1-20060914-C00005
  • Current therapies for hepatitis C include interferon-α (INFα) and combination therapy with ribavirin and interferon. See, e.g., Beremguer et al. (1998) Proc. Assoc. Am. Physicians 110(2):98-112. These therapies suffer from a low sustained response rate and frequent side effects. See, e.g. Hoofnagle et al. (1997) N. Engl. J. Med. 336:347. Currently, no vaccine is available for HCV infection.
  • Pending and copending U.S. patent application Ser. No. 60/194,607, filed Apr. 5, 2000, and Ser. No. 60/198,204, filed Apr. 19, 2000, Ser. No. 60/220,110, filed Jul. 21, 2000, Ser. No. 60/220,109, filed Jul. 21, 2000, Ser. No. 60/220,107, filed Jul. 21, 2000, Ser. No. 60/254,869, filed Dec. 12, 2000, and Ser. No. 60/220,101, filed Jul. 21, 2000, disclose various types of peptides and/or other compounds as NS-3 serine protease inhibitors of hepatitis C virus.
  • There is a need for new treatments and therapies for HCV infection. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of one or more symptoms of hepatitis C.
  • It is a further object herein to provide methods of treatment or prevention or amelioration of one or more symptoms of hepatitis C.
  • A still further object of the present invention is to provide methods for modulating the activity of serine proteases, particularly the HCV NS3/NS4a serine protease, using the compounds provided herein.
  • Another object herein is to provide methods of modulating the processing of the HCV polypeptide using the compounds provided herein.
    • SUMMARY OF THE INVENTION
  • In its many embodiments, the present invention provides a novel class of inhibitors of the HCV protease, pharmaceutical compositions containing one or more of the compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration or one or more of the symptoms of hepatitis C. Also provided are methods of modulating the interaction of an HCV polypeptide with HCV protease. Among the compounds provided herein, compounds that inhibit HCV NS3/NS4a serine protease activity are preferred. The present application discloses a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I:
    Figure US20060205672A1-20060914-C00006
    wherein:
      • Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y maybe optionally substituted with X11 or X12;
      • X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X11 may be additionally optionally substituted with X12;
      • X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X12;
      • R1 is COR5 or B(OR)2, wherein R5 is H, OH, OR8, NR9R10, CF3, C2F5, C3F7, CF2R6, R6, or COR7 wherein R7 is H, OH, OR8, CHR9R10, or NR9R10, wherein R6, R8, R9 and R10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R1′)]pCOOR11, [CH(R1′)]pCONR12R13, [CH(R1′)]pSO2R11, [CH(R1′)]pCOR11, [CH(R1′)]pCH(OH)R11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′)CONR12R13, CH(R1′)CONHCH(R2′)R′, CH(R1′)CONHCH(R2′)CONHCH(R3′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′)COOR11 and CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′) CONR12R13, wherein R1′, R2′, R3′, R4′, R5′, R11, R12, R13 and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;
      • Z is selected from O, N, CH or CR;
      • W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO2;
      • Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2)p, (CHR)p, (CRR′)p, O, NR, S, or SO2; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L;
      • A is O, CH2, (CHR)p, (CHR—CHR′)p, (CRR′)p, NR, S, SO2 or a bond;
      • E is CH, N, CR, or a double bond towards A, L or G;
      • G may be present or absent, and when G is present, G is (CH2)p, (CHR) p, or (CRR′)p; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to;
      • J maybe present or absent, and when J is present, J is (CH2)p, (CHR) p, or (CRR′)p, SO2, NH, NR or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J;
      • L may be present or absent, and when L is present, L is CH, CR, O, S or NR; and when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;
      • M may be present or absent, and when M is present, M is O, NR, S, SO2, (CH2) p, (CHR)p (CHR—CHR′)p, or (CRR′)p;
      • p is a number from 0 to 6; and
      • R, R′, R2, R3 and R4 are independently selected from the group consisting of H; C1-C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;
      • wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;
      • further wherein said unit N-C-G-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N-C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring.
  • Among the above-stated definitions for the various moieties of Formula I, the preferred groups for the various moieties are as follows:
  • Preferred definition for R1 is COR5 with R5 being H, OH, COOR8 or CONR9R10, where R8, R9 and R10 are defined above. Still preferred moiety for R1 is COCONR9R10, where R9 is H; and R10 is H, R14, [CH(R1′)]pCOOR11, [CH(R1′)]pCONR12R13, [CH(R1′)]pSO2R11, [CH(R1′)]pSO2NR12R13, [CH(R1′)]pCOR11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′) CONR12R13, or CH(R1′)CONHCH(R2′)(R′), wherein R14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl.
  • Among the above for R10, preferred moieties for R10 are: H, R14, CH(R1′)COOR11, CH(R1′)CH(R1′)COOR11, CH(R1′)CONR12R13, CH(R1′)CH(R1′)CONR12R13, CH(R1′)CH(R1′)SO2R11, CH(R1′)CH(R1′)SO2NR12R13, CH(R1′)CH(R1′)COR11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′) CONR12R13, or CH(R1′)CONHCH(R2′)(R′), wherein R1′ is H or alkyl, and R2′ is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl.
  • More preferred moieties are: for R1′ is H, for R11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α,α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl; for
    • R′ is hydroxymethyl or CH2CONR12R13 where
    • NR12R13 is selected from the group consisting of:
      Figure US20060205672A1-20060914-C00007
      wherein U6 is H, OH, or CH2OH;
    • R14 is preferably selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl;
    • and R2 is preferably independently selected from the group consisting of:
      Figure US20060205672A1-20060914-C00008
      • wherein:
      • U1 and U2 maybe same or different and are selected from H, F, CH2COOH, CH2COOMe, CH2CONH2, CH2CONHMe, CH2CONMe2, azido, amino, hydroxyl, substituted amino, substituted hydroxyl;
      • U3 and U4 maybe same or different and are selected from O and S;
      • U5 is selected from the moieties consisting of alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof.
  • Preferred moieties for R2 are:
    Figure US20060205672A1-20060914-C00009
    Figure US20060205672A1-20060914-C00010
  • Preferred moieties for R3 are:
    Figure US20060205672A1-20060914-C00011
    Figure US20060205672A1-20060914-C00012
    wherein R31=OH or O-alkyl;
    • Y19 is selected from the following moieties:
      Figure US20060205672A1-20060914-C00013
    • and Y20 is selected from the following moieties:
      Figure US20060205672A1-20060914-C00014
  • Most preferred moieties for R3 are:
    Figure US20060205672A1-20060914-C00015
  • Some other preferred moieties are: for Z it is N, for R4 it is H, and for W it is C═O. Additionally, the moiety Z-C—R3 in Formula I, with R4 being absent, may be represented by the following structures:
    Figure US20060205672A1-20060914-C00016
  • Preferred moieties for Y are:
    Figure US20060205672A1-20060914-C00017
    Figure US20060205672A1-20060914-C00018
    Figure US20060205672A1-20060914-C00019
    Figure US20060205672A1-20060914-C00020
    Figure US20060205672A1-20060914-C00021
    Figure US20060205672A1-20060914-C00022
    Figure US20060205672A1-20060914-C00023
    Figure US20060205672A1-20060914-C00024
    wherein:
    • Y11 is selected from H, COOH, COOEt, OMe, Ph, OPh, NHMe, NHAc, NHPh, CH(Me)2, 1-trazolyl, 1-imidazolyl, and NHCH2COOH;
    • Y12 is selected from H, COOH, COOMe, OMe, F, Cl, or Br;
    • Y13 is selected from the following moieties:
      Figure US20060205672A1-20060914-C00025
    • Y14 is selected from MeSO2, Ac, Boc, iBoc, Cbz, or Alloc;
    • Y15 and Y16 are independently selected from alkyl, aryl, heteroalkyl, and heteroaryl;
    • Y17 is CF3, NO2, CONH2, OH, COOCH3, OCH3, OC6H5, C6H5, COC6H5, NH2, or COOH; and
    • Y18 is COOCH3, NO2, N(CH3)2, F, OCH3, CH2COOH, COOH, SO2NH2, or NHCOCH3.
    • Y may be more preferably represented by:
      Figure US20060205672A1-20060914-C00026
      Figure US20060205672A1-20060914-C00027
      Figure US20060205672A1-20060914-C00028
      Figure US20060205672A1-20060914-C00029
      • wherein:
      • Y17=CF3, NO2, CONH2, OH, NH2, or COOH
      • Y18=F, COOH,
  • Still more preferred moieties for Y are:
    Figure US20060205672A1-20060914-C00030
    Figure US20060205672A1-20060914-C00031
  • As shown in Formula I, the unit:
    Figure US20060205672A1-20060914-C00032
    represents a cyclic ring structure, which may be a five-membered or six-membered ring structure. When that cyclic ring represents a five-membered ring, it is a requirement of this invention that that five-membered cyclic ring does not contain a carbonyl group as part of the cyclic ring structure. Preferably, that five-membered ring is of the structure:
    Figure US20060205672A1-20060914-C00033
    wherein R and R′ are defined above. Preferred representations for that five-membered cyclic ring structure is:
    Figure US20060205672A1-20060914-C00034
    where R20 is Selected from the following moieties:
    Figure US20060205672A1-20060914-C00035
  • Furthermore, that five-membered ring, along with its adjacent two exocyclic carbonyls, may be represented as follows:
    Figure US20060205672A1-20060914-C00036
    in which case, R21 and R22 may be the same or different and are independently selected from the following moieties:
    Figure US20060205672A1-20060914-C00037
    Figure US20060205672A1-20060914-C00038
  • Some preferred illustrations for the five-membered ring structure:
    Figure US20060205672A1-20060914-C00039
    are as follows:
    Figure US20060205672A1-20060914-C00040
  • Additionally, the unit:
    Figure US20060205672A1-20060914-C00041
    in Formula I may be represented by the following structures b and c:
    Figure US20060205672A1-20060914-C00042
  • Preferred definitions for b are:
    Figure US20060205672A1-20060914-C00043
  • In c, G and J are independently selected from the group consisting of (CH2)p, (CHR)p, (CHR—CHR′)p, and (CRR′)p; A and M are independently selected from the group consisting of O, S, SO2, NR, (CH2) p, (CHR)p, (CHR—CHR′)p, and (CRR′)p; and Q is CH2, CHR, CRR′, NH, NR, O, S, SO2, NR, (CH2)p, (CHR)p, and (CRR′)p.
  • Preferred definitions for c are:
    Figure US20060205672A1-20060914-C00044
    Figure US20060205672A1-20060914-C00045
  • When the cyclic ring structure is depicted as:
    Figure US20060205672A1-20060914-C00046
    its most preferred illustrations are as follows:
    Figure US20060205672A1-20060914-C00047
    Figure US20060205672A1-20060914-C00048
    Figure US20060205672A1-20060914-C00049
    Some of the still preferred moieties for the unit:
    Figure US20060205672A1-20060914-C00050
    shown above, are:
    Figure US20060205672A1-20060914-C00051
    Figure US20060205672A1-20060914-C00052
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. Thus, for example, the term alkyl (including the alkyl portions of alkoxy) refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single atom having from 1 to 8 carbon atoms, preferably from 1 to 6;
      • aryl—represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment. Preferred aryl groups include phenyl, 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl;
      • aralkyl—represents a moiety containing an aryl group linked vial a lower alkyl;
      • alkylaryl—represents a moiety containing a lower alkyl linked via an aryl group;
      • cycloalkyl—represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, optionally substituted.
      • heterocyclic—represents, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one O, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl;
      • halogen—represents fluorine, chlorine, bromine and iodine;
      • heteroaryl—represents a cyclic organic group having at least one O, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclyl group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., 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, etc. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; such heteroaryl groups may also be optionally substituted. Additionally, unless otherwise specifically defined, as stated above, the term “substituted or unsubstituted” or “optionally substituted” refers to the subject moiety being optionally and chemically-suitably substituted with a moiety belonging to R12 or R13. As used herein, “prodrug” means compounds that are drug precursors which, following administration to a patient, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • Also included in the invention are tautomers, rotamers, enantiomers and other optical isomers, as well as prodrugs, of compounds of Formula I, as well as pharmaceutically acceptable salts, solvates and derivatives thereof.
  • A further feature of the invention is pharmaceutical compositions containing as active ingredient a compound of Formula I (or its salt, solvate or isomers) together with a pharmaceutically acceptable carrier or excipient.
  • The invention also provides methods for preparing compounds of Formula I, as well as methods for treating diseases such as, for example, HCV, AIDS (Acquired Immune Deficiency Syndrome), and related disorders. The methods for treating comprise administering to a patient suffering from said disease or diseases a therapeutically effective amount of a compound of Formula I, or pharmaceutical compositions comprising a compound of Formula I.
  • Also disclosed is the use of a compound of Formula I for the manufacture of a medicament for treating HCV, AIDS, and related-disorders.
  • Also disclosed is a method of treatment of a hepatitis C virus associated disorder, comprising administering an effective amount of one or more of the inventive compounds.
  • Also disclosed is a method of modulating the activity of hepatitis C virus (HCV) protease, comprising contacting HCV protease with one or more inventive compounds.
  • Also disclosed is a method of treating, preventing, or ameliorating one or more symptoms of hepatitis C, comprising administering an effective amount of one or more of the inventive compounds. The HCV protease is the NS3 or NS4a protease. The inventive compounds inhibit such protease. They also modulate the processing of hepatitis C virus (HCV) polypeptide.
    • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • In one embodiment, the present invention discloses compounds of Formula I as inhibitors of HCV protease, especially the HCV NS3/NS4a serine protease, or a pharmaceutically acceptable derivative thereof, where the various definitions are given above.
  • Representative compounds of the invention which exhibit excellent HCV protease inhibitory activity are listed below in Tables 1 to 5 along with their activity (ranges of Ki* values in nanomolar, nM). Several compounds as well as addiitonal compounds are additionally disclosed in the claims.
    TABLE 1
    Compounds and HCV protease continuous assay results
    Compound from
    Example No. Ki* Range
    1 C
    2 C
    3 C
    4 C
    5 C
    6 C
    7 C
    8 C
    9 C
    10 C
    11 C
    12 C
    13 C
    14 C
    15 C
    16 C
    17 C
    18 C
    19 C
    20 C
    21 C
    22 C
    23 C
    24 C
    25 C
    26 C
    27 C
    28 C
    29 C
    30 C
    31 C
    32 C
    33 C
    34 C
    35 C
    36 C
    37 C
    38 C
    39 C
    40 C
    41 C
    42 C
    43 C
    44 C
    45 C
    46 C
    47 C
    48 C
    49 C
    50 C
    51 C
    52 C
    53 C
    54 C
    55 C
    56 C
    57 C
    58 C
    59 C
    60 C
    61 C
    62 C
    63 C
    64 C
    65 C
    66 C
    67 C
    68 B
    69 C
    70 C
    71 B
    72 C
    73 B
    74 C
    75 C
    76 A
    77 B
    78 A
    79 C
    80 A
    81 C
    82 A
    83 B
    84 C
    85 C
    86 B
    87 B
    88 A
    89 B
    90 C
    91 C
    92 C
    93 C
    94 C
    95 C
    96 C
    97 C
    98 B
    99 B
    100 A
    101 A
    102 C
    103 C
    104 C
    105 C
    106 C
    107 B
    108 A
    109 A
    110 A
    111 A
    112 A
    113 B
    114 A
    115 B
    116 A
    117 A
    118 A
    119 A
    120 A
    121 B
    122 B
    123 A
    124 B
    125 B
    126 B
    127 A
    128 A
    129 A
    130 B
    131 A
    132 A
    133 A
    134 B
    135 A
    136 A
    137 A
    138 A
    139 A
    140 B
    141 A
    142 A
    143 B
    144 B
    145 C
    146 A
    147 A
    148 B
    149 A
    150 A
    151 A
    152 A
    153 A
    154 A
    155 B
    156 B
    157 B
    158 C
    159 B
    160 A
    161 A
    162 A
    163 C
    164 A
    165 C
    166 B
    167 A
    168 C
    169 B
    170 B
    171 A
    172 A
    173 A
    174 A
    175 A
    176 B
    177 B
    178 A
    179 A
    180 B
    181 A
    182 B
    183 A
    184 A
    185 A
    186 A
    187 A
    188 A
    189 B
    190 B
    191 B
    192 A
    193 A
    194 B
    195 A
    196 B
    197 A
    198 A
    199 A
    200 A
    201 B
    202 A
    203 B
    204 B
    205 B
    206 B
    207 B
    208 A
    209 A
    210 A
    211 A
    212 A
    213 B
    214 B
    215 B
    216 B
    217 C
    218 A
    219 A
    220 A
    221 A
    222 A
    223 B
    224 C
    225 C
    226 A
    227 A
    228 C
    229 A
    230 A
    231 A
    232 C
    233 C
    234 C
    235 C
    236 B
    237 C
    238 A
    239 C
    240 A
    241 C
    242 B
    243 C
    244 B
    245 C
    246 B
    247 A
    248 A
    249 C
    250 C
    251 B
    252 C
    253 C
    254 B
    255 B
    256 A
    257 C
    258 A
    259 A
    260 C
    261 C
    262 A
    263 B
    264 B
    265 C
    266 B
    267 A
    268 C
    269 A
    270 C
    271 A
    272 C
    273 C
    274 C
    275 C
    276 A
    277 B
    278 A
    279 B
    280 A
    281 C
    282 C
    283 C
    284 C
    285 C
    286 C
    287 C
    288 B
    289 B
    290 C
    291 C
    292 C
    293 C
    294 C
    295 C
    296 B
    297 C
    298 C
    299 B
    300 B
    301 C
    302 C
    303 B
    304 C
    305 C
    306 C
    307 B
    308 B
    309 C
    310 C
    311 C
    312 C
    313 B
    314 A
    315 B
    316 B
    317 A
    318 A
    319 A
    320 A
    321 C
    322 C
    323 C
    324 C
    325 A
    326 A
    327 C
    328 B
    329 B
    330 A
    331 A
    332 A
    333 B
    334 B
    335 B
    336 A
    337 A
    338 C
    339 A
    340 C
    341 C
    342 C
    343 A
    344 C
    345 C
    346 C
    347 B
    348 B
    349 C
    350 C
    351 C
    352 C
    353 C
    354 C
    355 C
    356 A
    357 A
    358 C
    359 A
    360 B
    361 B
    362 C

    HCV continuous assay Ki* range:

    Category A = 1-100 nM;

    Category B = 101-1,000 nM;

    Category C > 1000 nM.
  • Some types of the inventive compounds and methods of synthesizing the various types of the inventive compounds of Formula I are listed below, then schematically described, followed by the illustrative Examples.
    Figure US20060205672A1-20060914-C00053
    Figure US20060205672A1-20060914-C00054
    Figure US20060205672A1-20060914-C00055
    Figure US20060205672A1-20060914-C00056
    Figure US20060205672A1-20060914-C00057
    Figure US20060205672A1-20060914-C00058
    Figure US20060205672A1-20060914-C00059
    Figure US20060205672A1-20060914-C00060
    Figure US20060205672A1-20060914-C00061
    Figure US20060205672A1-20060914-C00062
    Figure US20060205672A1-20060914-C00063
    Figure US20060205672A1-20060914-C00064
    Figure US20060205672A1-20060914-C00065
    Figure US20060205672A1-20060914-C00066
    Figure US20060205672A1-20060914-C00067
    Figure US20060205672A1-20060914-C00068
    Figure US20060205672A1-20060914-C00069
    Figure US20060205672A1-20060914-C00070
    Figure US20060205672A1-20060914-C00071
    Figure US20060205672A1-20060914-C00072
    Figure US20060205672A1-20060914-C00073
    Figure US20060205672A1-20060914-C00074
    Figure US20060205672A1-20060914-C00075
    Figure US20060205672A1-20060914-C00076
    Figure US20060205672A1-20060914-C00077
    Figure US20060205672A1-20060914-C00078
    Figure US20060205672A1-20060914-C00079
    Figure US20060205672A1-20060914-C00080
    Figure US20060205672A1-20060914-C00081
    Figure US20060205672A1-20060914-C00082
    Figure US20060205672A1-20060914-C00083
    Figure US20060205672A1-20060914-C00084
    Figure US20060205672A1-20060914-C00085
    Figure US20060205672A1-20060914-C00086
    Figure US20060205672A1-20060914-C00087
    Figure US20060205672A1-20060914-C00088
    Figure US20060205672A1-20060914-C00089
    Figure US20060205672A1-20060914-C00090
    Figure US20060205672A1-20060914-C00091
    Figure US20060205672A1-20060914-C00092
    Figure US20060205672A1-20060914-C00093
    Figure US20060205672A1-20060914-C00094
    Figure US20060205672A1-20060914-C00095
    Figure US20060205672A1-20060914-C00096
    Figure US20060205672A1-20060914-C00097
    Figure US20060205672A1-20060914-C00098
    Figure US20060205672A1-20060914-C00099
    Figure US20060205672A1-20060914-C00100
    Figure US20060205672A1-20060914-C00101
    Figure US20060205672A1-20060914-C00102
    Figure US20060205672A1-20060914-C00103
    Figure US20060205672A1-20060914-C00104
    Figure US20060205672A1-20060914-C00105
    Figure US20060205672A1-20060914-C00106
    Figure US20060205672A1-20060914-C00107
    Figure US20060205672A1-20060914-C00108
    Figure US20060205672A1-20060914-C00109
    Figure US20060205672A1-20060914-C00110
    Figure US20060205672A1-20060914-C00111
    Figure US20060205672A1-20060914-C00112
    Figure US20060205672A1-20060914-C00113
    Figure US20060205672A1-20060914-C00114
  • Depending upon their structure, the compounds of the invention may form pharmaceutically acceptable salts with organic or inorganic acids, or organic or inorganic bases. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. For formation of salts with bases, suitable bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, and the like.
  • In another embodiment, this invention provides pharmaceutical compositions comprising the inventive peptides as an active ingredient. The pharmaceutical compositions generally additionally comprise a pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials). Because of their HCV inhibitory activity, such pharmaceutical compositions possess utility in treating hepatitis C and related disorders.
  • In yet another embodiment, the present invention discloses methods for preparing pharmaceutical compositions comprising the inventive compounds as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like.
  • Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.
  • Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. HCV inhibitory activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
  • For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
  • The compounds of the invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • Preferably the compound is administered orally, intravenously or subcutaneously.
  • Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • The quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application. The actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.
  • Generally, the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of the administration will be regulated according to the judgment of the attending clinician. A generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1,000 milligrams per day, in single or divided doses.
  • Some useful terms are described below:
  • Capsule—refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet—refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
  • Oral gel—refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
  • Powder for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • Diluent—refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corm, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
  • Disintegrant—refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; “cold water soluble” modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
  • Binder—refers to substances that bind or “glue” powders together and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant—refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d′l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
  • Glident—material that prevents caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Coloring agents—excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
  • Bioavailability—refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
  • Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.
  • Another embodiment of the invention discloses the use of the pharmaceutical compositions disclosed above for treatment of diseases such as, for example, hepatitis C and the like. The method comprises administering a therapeutically effective amount of the inventive pharmaceutical composition to a patient having such a disease or diseases and in need of such a treatment.
  • In yet another embodiment, the compounds of the invention may be used for the treatment of HCV in humans in monotherapy mode or in a combination therapy (e.g., dual combination, triple combination etc.) mode such as, for example, in combination with antiviral and/or immunomodulatory agents. Examples of such antiviral and/or immunomodulatory agents include Ribavirin (from Schering-Plough Corporation, Madison, N.J.) and Levovirin™ (from ICN Pharmaceuticals, Costa Mesa, Calif.), VP 50406™ (from Viropharma, Incorporated, Exton, Pa.), ISIS 14803™ (from ISIS Pharmaceuticals, Carlsbad, Calif.), Heptazyme (from Ribozyme Pharmaceuticals, Boulder, Colo.), VX 497™ (from Vertex Pharmaceuticals, Cambridge, Mass.), Thymosin™ (from SciClone Pharmaceuticals, San Mateo, Calif.), Maxamine™ (Maxim Pharmaceuticals, San Diego, Calif.), mycophenolate mofetil (from Hoffman-LaRoche, Nutley, N.J.), interferon (such as, for example, interferon-alpha, PEG-interferon alpha conjugates) and the like. “PEG-interferon alpha conjugates” are interferon alpha molecules covalently attached to a PEG molecule. Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (Roferon™, from Hoffman La-Roche, Nutley, N.J.) in the form of pegylated interferon alpha-2a (e.g., as sold under the trade name Pegasys™), interferon alpha-2b (Intron™, from Schering-Plough Corporation) in the form of pegylated interferon alpha-2b (e.g., as sold under the trade name PEG-Intron™), interferon alpha-2c (Berofor Alpha™, from Boehringer Ingelheim, Ingelheim, Germany) or consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen™, from Amgen, Thousand Oaks, Calif.).
  • As stated earlier, the invention includes tautomers, rotamers, enantiomers and other stereoisomers of the inventive compounds also. Thus, as one skilled in the art appreciates, some of the inventive compounds may exist in suitable isomeric forms. Such variations are contemplated to be within the scope of the invention.
  • Another embodiment of the invention discloses a method of making the compounds disclosed herein. The compounds may be prepared by several techniques known in the art. Representative illustrative procedures are outlined in the following reaction schemes. It is to be understood that while the following illustrative schemes describe the preparation of a few representative inventive compounds, suitable substitution of any of both the natural and unnatural amino acids will result in the formation of the desired compounds based on such substitution. Such variations are contemplated to be within the scope of the invention.
  • Abbreviations which are used in the descriptions of the schemes, preparations and the examples that follow are:
    • THF: Tetrahydrofuran
    • DMF: N,N-Dimethylformamide
    • EtOAc: Ethyl acetate
    • AcOH: Acetic acid
    • HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one
    • EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
    • NMM: N-Methylmorpholine
    • ADDP: 1,1′-(Azodicarbobyl)dipiperidine
    • DEAD: Diethylazodicarboxylate
    • MeOH: Methanol
    • EtOH: Ethanol
    • Et2O: Diethyl ether
    • DMSO: Dimethylsulfoxide
    • HOBt: N-Hydroxybenzotriazole
    • PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
    • DCM: Dichloromethane
    • DCC: 1,3-Dicyclohexylcarbodiimide
    • TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy
    • Phg: Phenylglycine
    • Chg: Cyclohexylglycine
    • Bn: Benzyl
    • Bzl: Benzyl
    • Et: Ethyl
    • Ph: Phenyl
    • iBoc: isobutoxycarbonyl
    • iPr: isopropyl
    • tBu or But: tert-Butyl
    • Boc: tert-Butyloxycarbonyl
    • Cbz: Benzyloxycarbonyl
    • Cp: Cylcopentyldienyl
    • Ts: p-toluenesulfonyl
    • Me: Methyl
    • HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
    • DMAP: 4-N,N-Dimethylaminopyridine
    • Bop: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate
      General Preparative Schemes:
  • The following schemes describe the methods of synthesis of intermediate building blocks:
    Figure US20060205672A1-20060914-C00115
    Figure US20060205672A1-20060914-C00116
    Figure US20060205672A1-20060914-C00117
    Figure US20060205672A1-20060914-C00118
    Figure US20060205672A1-20060914-C00119
    Figure US20060205672A1-20060914-C00120
    Figure US20060205672A1-20060914-C00121
    Figure US20060205672A1-20060914-C00122
    Figure US20060205672A1-20060914-C00123
    Figure US20060205672A1-20060914-C00124
    Figure US20060205672A1-20060914-C00125
    Figure US20060205672A1-20060914-C00126
    Figure US20060205672A1-20060914-C00127
    Figure US20060205672A1-20060914-C00128
    Figure US20060205672A1-20060914-C00129
    Figure US20060205672A1-20060914-C00130
    Figure US20060205672A1-20060914-C00131
    Figure US20060205672A1-20060914-C00132
    Figure US20060205672A1-20060914-C00133
    Figure US20060205672A1-20060914-C00134
    Figure US20060205672A1-20060914-C00135
    Figure US20060205672A1-20060914-C00136
    Figure US20060205672A1-20060914-C00137
    Preparation of Intermediates:
    • PREPARATIVE EXAMPLE 1 Step A: Compound (1.1)
  • Figure US20060205672A1-20060914-C00138
  • To a stirred solution of Compound (1.08)(3.00 g, 12.0 mmol (S. L. Harbeson et al. J. Med. Chem. 37 No. 18 (1994) 2918-2929) in DMF (15 mL) and CH2Cl2 (15 mL) at −20° C. 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, followed by addition of HCl.H2N-Gly-OBn (2.56 g, 13.0 mmol). The resulting solution was stirred at −20° C. for 2 hrs, kept refrigerated overnight and then concentrated to dryness, followed by dilution with EtOAc (150 mL). The EtOAc solution was then washed twice with saturated NaHCO3, H2O, 5% H3PO4, brine, dried over Na2SO4, filtered and concentrated to dryness to give the Compound (1.09) (4.5 g, 94%). LRMS m/z MH+=395.1.
    • Step B: Compound (1.1)
  • Figure US20060205672A1-20060914-C00139
  • A solution of Compound (1.09) (7.00 g, 17.8 mmol) in absolute ethanol (300 mL) was stirred at room temperature under a hydrogen atmosphere in the presence of Pd—C (300 mg, 10%). The reaction progress was monitored by tlc. After 2 h, the mixture was filtered through a celite pad and the resulting solution was concentrated in vacuo to give Compound (1.1) (5.40 g, quantitative). LRMS m/z MH+=305.1.
    • PREPARATIVE EXAMPLE 2
  • Step A Compound (1.3)
    Figure US20060205672A1-20060914-C00140
  • A mixture of Compound (1.1) from Preparative Example 1, Step B above (1 eq.), Compound (1.2) (from Novabiochem, Catalog No. 04-12-5147) (1.03 eq.), HOOBt (1.03 eq.), N-methylmorpholine (2.2 eq.), and dimethylformamide (70 mL/g) was stirred at −20° C. EDCl (1.04 eq.) was added and the reaction stirred for 48 hr. The reaction mixture was poured into 5% aqueous KH2PO4 and extracted with ethyl acetate (2×). The combined organics were washed with cold 5% aqueous K2CO3, then 5% aqueous KH2PO4, then brine, and the organic layer was dried over anhydrous MgSO4. The mixture was filtered, then evaporated and the filtrate dried under vacuum, the residue was triturated with Et2O-hexane, and filtered to leave the title compound (1.3)(86% yield), C25H39N3O7 (493.60), mass spec. (FAB) M+1=494.3.
    Step B Compound (1.4)
    Figure US20060205672A1-20060914-C00141
  • Compound (1.3) from Preparative Example 2, Step A (3.0 g) was treated with 4 N HCl/dioxane (36 mL) and stirred at room temperature for 7 min. The mixture was poured into 1.5 L cold (5° C.) hexane and stirred, then allowed to set cold for 0.5 hr. The mixture was suction-filtered in a dry atmosphere, and the collected solid was further dried to afford the title compound (1.4) (2.3 g, 88% yield), C20H31N3O5HCl, H1 NMR (DMSO-d6/NaOD) δ 7.38 (m, 5H), 5.25 (m, 1H), 4.34.1 (m, 1H), 3.8 (m, 2H), 3.4-3.3 (m, obscured by D20), 1.7-1.1 (m, 4H), 1.35 (s, 9H), 0.83 (m, 3H).
    • PREPARATIVE EXAMPLE 3
  • Compound (1.5)
    Figure US20060205672A1-20060914-C00142
  • Compound (1.3) from Preparative Example 2, Step A, was treated in essentially the same manner as in Preparative Example 7, Step A below to afford Compound (1.5).
    • PREPARATIVE EXAMPLE 4
  • Compound (1.6)
    Figure US20060205672A1-20060914-C00143
  • Compound (1.5) from Preparative Example 3, was treated in essentially the same manner as in Preparative Example 2, Step B, to afford Compound (1.6).
    • PREPARATIVE EXAMPLE 5
  • Step A Compound (2.09)
    Figure US20060205672A1-20060914-C00144
  • To a solution of dimethylamine hydrochloride (1.61 g, 19.7 mmol), N-Boc-phenylglycine, Compound (2.08)(4.50 g, 17.9 mmol, Bachem Co. # A-2225), HOOBt (3.07 g, 18.8 mmol) and EDCl (4.12 g, 21.5 mmol) in anhydrous DMF (200 mL) and CH2Cl2 (150 mL) at −20° C. was added NMM (5.90 mL, 53.7 mmol). After being stirred at this temperature for 30 min, the reaction mixture was kept in a freezer overnight (18 h). It was then allowed to warm to rt, and EtOAc (450 mL), brine (100 mL) and 5% H3PO4 (100 mL) were added. After the layers were separated, the organic layer was washed with 5% H3PO4 (100 mL), saturated aqueous sodium bicarbonate solution (2×150 mL), water (150 mL), and brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to afford Compound (2.09) (4.86 g) as a white solid, which was used without further purification.
    Step B Compound (2.1)
    Figure US20060205672A1-20060914-C00145
  • Compound (2.09) from Preparative Example 5, Step A (4.70 g, crude) was dissolved in 4 N HCl (60 mL, 240 mmol) and the resulting solution was stirred at room temperature. The progress of the reaction was monitored by TLC. After 4 h, the solution was concentrated in vacuo to yield Compound (2.1) as a white solid which was used in the next reaction without further purification. LRMS m/z MH+=179.0.
    • PREPARATIVE EXAMPLE 6
  • Step A Compound (2.2)
    Figure US20060205672A1-20060914-C00146
  • In essentially the same manner as Preparative Example 2, Step A. substituting phenylglycine N,N-dimethylamide hydrochloride in place of phenylglycine t-butyl ester hydrochloride, Compound (2.2) was prepared mass spec. (FAB) M+1=465.3.
    Step B Compound (2.3)
    Figure US20060205672A1-20060914-C00147
  • Compound (2.2) from Step A (1.85 g) was reacted with 4 N HCl/dioxane (50 mL) at room temperature for 1 hr. The mixture was evaporated under vacuum in a 20° C. water bath, triturated under isopropyl ether, filtered, and dried to afford Compound (2.3) (1.57 g, 98% yield), C18H28N4O4.HCl, mass spec. (FAB) M+1=365.3
    • PREPARATIVE EXAMPLE 7
  • Step A Compound (2.4)
    Figure US20060205672A1-20060914-C00148
  • A solution of Compound (2.2) from Preparative Example 5, Step A (2.0 g) in dichloromethane (60 mL) was treated with dimethylsulfoxide (3.0 mL) and 2,2-dichloroacetic acid (0.70 mL). The stirred mixture was cooled to 5° C. and then added 1 M dicyclohexylcarbodiimide/dichloromethane solution (8.5 mL). The cold bath was removed and the mixture stirred for 22 hr. Then added 2-propanol (0.5 mL), and stirred for an additional 1 hr. The mixture was filtered then washed with ice-cold 0.1 N NaOH (50 mL), then ice-cold 0.1 N HCl (50 mL), then 5% aqueous KH2PO4, then saturated brine. The organic solution was dried over anhydrous magnesium sulfate, then filtered. The filtrate was evaporated, and chromatographed on silica gel, eluting with ethyl acetate to afford Compound (2.3) (1.87 g, 94% yield), C23H34N4O6, mass spec. (FAB) M+1=463.3.
    Step B Compound (2.5)
    Figure US20060205672A1-20060914-C00149
  • In essentially the same manner as Preparative Example 2, Step B, Compound (2.5) was prepared.
    • PREPARATIVE EXAMPLE 8
  • Step A Compound (3.1)
    Figure US20060205672A1-20060914-C00150
  • In a flask were combined N-Cbz-hydroxyproline methyl ester (available from Bachem Biosciences, Incorporated, King of Prussia, Pa.), compound (3.01) (3.0 g), toluene (30 mL), and ethyl acetate (30 mL). The mixture was stirred vigorously, and then a solution of NaBr/water (1.28 g/5 mL) was added. To this was added 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO, 17 mg, from Aldrich Chemicals, Milwaukee, Wis.). The stirred mixture was cooled to 5C and then was added a prepared solution of oxidant [commercially available bleach, Clorox® (18 mL), NaHCO3 (2.75 g) and water to make up 40 mL] dropwise over 0.5 hr. To this was added 2-propanol (0.2 mL). The organic layer was separated, and the aqueous layer extracted with ethyl acetate. The organic extracts were combined, washed with 2% sodium thiosulfate, then saturated brine. The organic solution was dried over anhydrous MgSO4, filtered, and evaporated the filtrate under vacuum to leave a pale yellow gum suitable for subsequent reactions (2.9 g, 97% yield), C14H15NO5 (277.28), mass spec. (FAB) M+1=278.1.
    Step B Compound (3.2).
    Figure US20060205672A1-20060914-C00151
  • Compound (3.1) from Step A above (7.8 g) was dissolved in dichloromethane (100 mL), and cooled to 15° C. To this mixture was first added 1,3-propanedithiol (3.1 mL), followed by freshly distilled boron trifluoride etherate (3.7 mL). The mixture was stirred at room temperature for 18 h. While stirring vigorously, a solution of K2CO3/water (2 g/30 mL) was carefully added, followed by saturated NaHCO3 (10 mL). The organic layer was separated from the aqueous layer (pH˜7.4), washed with water (10 mL), then brine. The organic solution was dried over anhydrous MgSO4, filtered, and evaporated under vacuum. The residue was chromatographed on silica gel, eluting with toluene, then a with a gradient of hexane-Et2O (2:3 to 0:1) to afford a brown oil (7.0 g, 68% yield), C17H21NO4S2 (367.48), mass spec. (FAB) M+1=368.1.
    Step C Compound (3.3)
    Figure US20060205672A1-20060914-C00152
  • A solution of compound (3.2) from Step B above (45 g) in acetonitrile (800 mL) at 20° C. was treated with freshly distilled iodotrimethylsilane (53 mL) at once. The reaction was stirred for 30 min., then poured into a freshly prepared solution of di-t-butyldicarbonate (107 g), ethyl ether (150 mL), and diisopropylethylamine (66.5 mL). The mixture stirred for 30 min. more then was washed with hexane (2×500 mL). Ethyl acetate (1000 mL) was added to the lower acetonitrile layer, and then the layer was washed with 10% aqueous KH2PO4 (2×700 mL), and brine. The filtrate was evaporated under vacuum in a 25° C. water bath, taken up in fresh ethyl acetate (1000 mL), and washed successively with 0.1 N HCl, 0.1 N NaOH, 10% aqueous KH2PO4, and brine. The organic solution was dried over anhydrous MgSO4, filtered, and evaporated under vacuum. The residue (66 g) was chromatographed on silica gel (2 kg), eluting with hexane (2 L), then Et2O/hexane (55:45, 2 L), then Et2O (2 L) to afford an orange gum which slowly crystallized on standing (28 g, 69% yield), C14H23NO4S2 (333.46), mass spec. (FAB) M+1=334.1.
    Step D Compound (3.4)
    Figure US20060205672A1-20060914-C00153
  • A solution of compound (3.3) from Step C above (11 g) in dioxane (150 mL) at 20° C. was treated with 1N aqueous LiOH (47 mL) and stirred for 30 h. The mixture was concentrated under vacuum in a 30° C. water bath to half volume. The remainder was diluted with water (300 mL), extracted with Et2O (2×200 mL). The aqueous layer was acidified to pH˜4 with 12 N HCl (34 mL), extracted with ethyl acetate, and washed with brine. The organic solution was dried over anhydrous MgSO4, filtered, and evaporated under vacuum to leave Compound (3.4) (8.1 g, 78%), C13H21NO4S2 (319.44), mass spec. (FAB) M+1=320.1.
    Step E Compound (3.5).
    Figure US20060205672A1-20060914-C00154
  • To a solution of compound (3.3) from Step C above (1 g) in dioxane (5 mL), was added 4 N HCl-dioxane solution (50 mL). The mixture was stirred vigorously for 1 hr. The mixture was evaporated under vacuum in a 25° C. water bath. The residue was triturated with Et2O, and filtered to leave the title compound (0.76 g, 93% yield), C9H15NO2S2.HCl (269.81), mass spec. (FAB) M+1=234.0.
    • PREPARATIVE EXAMPLE 9
  • Step A Compound (3.6)
    Figure US20060205672A1-20060914-C00155
  • Following essentially the same procedure of Preparative Example 8, Step B, substituting ethane dithiol for propane dithiol, compound (3.6) was obtained.
    Step B Compound (3.7).
    Figure US20060205672A1-20060914-C00156
  • Following essentially the same procedure of Preparative Example 8, Step C, substituting compound (3.6) for compound (3.2), the product compound (3.7) was obtained.
    Step C Compound (3.8)
    Figure US20060205672A1-20060914-C00157
  • Following essentially the same procedure of Preparative Example 8, Step D, substituting compound (3.7) for compound (3.3) the product compound (3.8) was obtained.
    Step D Compound (3.9)<
    Figure US20060205672A1-20060914-C00158
  • Following essentially the same procedure of Preparative Example 8, Step E, substituting compound (3.7) for compound (3.3) the product compound (3.9) was obtained.
    • PREPARATIVE EXAMPLE 10
  • Step A Compound (4.1)
    Figure US20060205672A1-20060914-C00159
  • In essentially the same manner as Preparative Example 2, Step A, Compound (4.1) was prepared C33H48N4O9S2 (708.89).
    Step B Compound (4.2)
    Figure US20060205672A1-20060914-C00160
  • In essentially the same manner as Preparative Example 2, Step B, Compound (4.2) was prepared mass spec. (FAB) M+1=609.3.
    Step C Compound (4.3)
    Figure US20060205672A1-20060914-C00161
  • In essentially the same manner as Preparative Example 2, Step A, Compound (4.3) was prepared, C41H61N5O10S2 (708.89), mass spec. (FAB) M+1=709.3.
    Step D Compound (4.4)
    Figure US20060205672A1-20060914-C00162
  • In essentially the same manner as Preparative Example 7, Step A, Compound (4.4) was prepared.
    • PREPARATIVE EXAMPLE 11
  • Step A Compound (4.5)
    Figure US20060205672A1-20060914-C00163
  • In essentially the same manner as Preparative Example 2, Step A, Compound (4.5) was prepared.
    Step B, Compound (4.6)
    Figure US20060205672A1-20060914-C00164
  • In essentially the same manner as Preparative Example 2, Step B, Compound (4.6) was prepared.
    Step C, Compound (4.7)
    Figure US20060205672A1-20060914-C00165
  • Compound (4.9) from Preparative Example 12, was reacted with Compound (4.6) from Step B above, in essentially the same manner as Preparative Example 2, Step A, to afford Compound (4.7).
    Step D, Compound (4.8)
    Figure US20060205672A1-20060914-C00166
  • In essentially the same manner as Preparative Example 7, Step A, Compound (4.8) was prepared.
    • PREPARATIVE EXAMPLE 12
  • Compound (4.9)
    Figure US20060205672A1-20060914-C00167
  • A solution of L-cyclohexylglycine (4.02) (1.0 eq.), dimethylformamide (20 mL/g), and diisopropylethylamine (1.1 eq.) at 5° C. is treated with isobutyl chloroformate (4.01) (1.1 eq.). The cold bath is removed and it is stirred for 6 hr. The reaction mixture is poured into 5% aqueous KH2PO4 and extracted with ethyl acetate (2×). The combined organics are washed with cold 5% aqueous K2CO3, then 5% aqueous KH2PO4, then brine, and the organics are dried over anhydrous MgSO4. The mixture is filtered, the filtrate evaporated under vacuum, the residue chromatographed if necessary or else the residue triturated with Et2O-hexane, and filtered to leave the title compound (4.9), C13H23NO4 (257.33).
    • PREPARATIVE EXAMPLE 13
  • Compound (13.1)
    Figure US20060205672A1-20060914-C00168
  • In essentially the same manner as Preparative Example 12, substituting L-O-benzylthreonine (13.02) (Wang et al, J. Chem. Soc., Perkin Trans. 1, (1997) No. 5, 621-624.) for L-cyclohexylglycine (4.02) Compound (13.1) is prepared C16H23NO5 (309.36), mass spec. (FAB) M+1=310.2.
    • PREPARATIVE EXAMPLE 14
  • Figure US20060205672A1-20060914-C00169
  • Compound (4.8) from Preparative Example 11, Step D (1.0 g) was reacted with a solution of anhydrous trifluoroacetic acid-dichloromethane (1:1, 50 mL) for 2 hr. The solution was diluted with xylene (100 mL) and evaporated under vacuum. The residue was triturated with Et2O, and filtered to leave the title compound (5.1) (0.9 g), C37H53N5O9S2 (775.98), mass spec. (FAB) M+1=776.5.
    Step B Compound (5.2)
    Figure US20060205672A1-20060914-C00170
  • In essentially the same manner as Preparative Example 2, Step A, Compound (5.1) was reacted with ammonia (0.5 M 1,4-dioxane solution), to obtain the title compound (5.2) C37H54N6O8S2 (774.99), mass spec. (FAB) M+1=775.4.
    • PREPARATIVE EXAMPLE 15
  • Figure US20060205672A1-20060914-C00171
  • A mixture of Compound (5.1) from Preparative Example 14, Step A (0.15 g), N,N-dimethylamine (0.12 mL of 2 M THF solution), dimethylformamide (10 mL), and PyBrOP coupling reagent (0.11 g) was cooled to 5° C., then diisopropylethylamine (DIEA or DIPEA, 0.12 mL) was added. The mixture was stirred cold for 1 min., then stirred at room temperature for 6 hr. The reaction mixture was poured into cold 5% aqueous H3PO4 (50 mL) and extracted with ethyl acetate (2×). The combined organics were washed with cold 5% aqueous K2CO3, then 5% aqueous KH2PO4, then brine. The organic solution was dried over anhydrous MgSO4, filtered, and evaporated under vacuum. The residue was chromatographed on silica gel, eluting with MeOH—CH2Cl2 to afford the title compound (5.3), C39H58N6O8S2 (803.05), mass spec. (FAB) M+1=803.5.
    • PREPARATIVE EXAMPLE 16
  • Step A Compound (6.2)
    Figure US20060205672A1-20060914-C00172
  • In essentially the same manner as Preparative Example 2, Step A, Compound (6.1) hydroxyproline benzyl ester hydrochloride was reacted with Compound (4.9) from Preparative Example 12, to obtain the title compound (6.2), C25H36N2O6° (460.56), mass spec. (FAB) M+1=461.2.
    Step B Compound (6.3)
    Figure US20060205672A1-20060914-C00173
  • In essentially the same manner as Preparative Example 8, Compound (6.3) was prepared, C25H34N2O6 (458.55), mass spec. (FAB) M+1=459.2.
    Step C Compound (6.4)
    Figure US20060205672A1-20060914-C00174
  • A mixture of Compound (6.3) from Step B (1 g), 10% Pd/C (0.05 g), and EtOH (100 mL) was stirred under 1 atm. H2 for 6 hr. The mixture was filtered, and evaporated to dryness under vacuum to leave the title compound (6.4) (0.77 g), C18H28N2O6 (368.42) mass spec. (FAB) M+1=369.2.
    • PREPARATIVE EXAMPLE 17
  • Step A Compound (7.1)
    Figure US20060205672A1-20060914-C00175
  • Compound (6.4) from Preparative Example 16, Step C, was reacted with Compound (2.3) from Preparative Example 6, Step B, in essentially the same manner as Preparative Example 2, Step A, to afford Compound (7.1), C36H54N6O9 (714.85), mass spec. (FAB) M+1=715.9.
    Step B Compound (7.2)
    Figure US20060205672A1-20060914-C00176
  • Compound (7.1) was reacted in essentially the same manner as Preparative Example 7, Step A, to afford Compound (7.2), C36H52N6O9 (712.83), mass spec. (FAB) M+1=713.5.
    Step C Compound (7.3)
    Figure US20060205672A1-20060914-C00177
  • Compound (7.2) from Step B above, was reacted in essentially the same manner as Preparative Example 8, Step B, with 1,4-butanedithiol, to obtain the title compound (7.3), C40H60N6O8S2 (817.07), mass spec. (FAB) M+1=817.5.
  • Using the above-noted procedures, the compounds in the attached Table 2 were prepared. As a general note to all the Tables that are attached hereto as well as to the Examples and Schemes in this specification, any open-ended nitrogen atom with unfulfilled valence in the chemical structures in the Examples and Tables refers to NH, or in the case of a terminal nitrogen, —NH2. Similarly, any open-ended oxygen atom with unfulfilled valence in the chemical structures in the Examples and Tables refers to —OH.
  • Solid Phase Synthesis:
  • General Procedure for Solid-Phase Coupling Reactions.
  • The synthesis was done in a reaction vessel which was constructed from a polypropylene syringe cartridge fitted with a polypropylene frit at the bottom. The Fmoc-protected amino acids were coupled under standard solid-phase techniques. Each reaction vessel was loaded with 100 mg of the starting Fmoc-Sieber resin (approximately 0.03 mmol). The resin was washed with 2 mL portions of DMF (2 times). The Fmoc protecting group was removed by treatment with 2 mL of a 20% v/v solution of piperidine in DMF for 20 min. The resin was washed with 2 mL portions of DMF (4 times). The coupling was done in DMF (2 mL), using 0.1 mmol of Fmoc-amino acid, 0.1 mmol of HATU [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] and 0.2 mmol of DIPEA (N,N-diisopropylethylamine). After shaking for 2 h, the reaction vessel was drained and the resin was washed with 2 mL portions of DMF (4 times). The coupling cycle was repeated with the next Fmoc-amino acid or capping group.
  • General Procedure for Solid-Phase Dess-Martin Oxidation.
  • The synthesis was conducted in a reaction vessel which was constructed from a polypropylene syringe cartridge fitted with a polypropylene frit at the bottom. Resin-bound hydroxy compound (approximately 0.03 mmol) was treated with a solution of 0.12 mmol of Dess-Martin periodinane and 0.12 mmol of t-BuOH in 2 mL of DCM for 4 h. The resin was washed with 2 mL portions of a 20% v/v solution of iPrOH in DCM, THF, a 50% v/v solution of THF in water (4 times), THF (4 times) and DCM (4 times).
    • PREPARATIVE EXAMPLE 18 Preparation of N-Fmoc-2′,3′-dimethoxyphenylglycine Compound (901)
  • Figure US20060205672A1-20060914-C00178
  • 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-dimethoxybenzaldehye 901A (2.5 g, 15 mmol) in ethanol (15 mL). The reaction mixture was heated at 40° C. for 24 h. The volume of the solution was reduced to 10 mL by evaporating under reduced pressure. Concentrated hydrochloric acid (15 mL) was added and compound 901B was obtained as a white precipitate. Compound 901B was isolated by filtration (2.2 g, 9.3 mmol). Compound 901B was dissolved in 10% w/w aqueous sodium hydroxide solution (15 mL) and the resulting solution was heated under reflux for 24 h. Concentrated hydrochloric acid was added and the pH was adjusted to neutral (pH 7). The resulting solution containing compound 901C was evaporated under reduced pressure. The residue was dissolved in 5% w/w aqueous sodium bicarbonate solution (150 mL). The solution was cooled to 0° C. in an ice bath and 1,4-dioxane (30 mL) and a solution of 9-fluorenylmethyl succinimidyl carbonate (2.7 g, 8 mmol) in 1,4-dioxane (30 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 24 h. 1,4-dioxane was evaporated under reduced pressure. The aqueous solution was washed with diethyl ether. Concentrated hydrochloric acid was added and the pH was adjusted to acidic (pH 1). Ethyl acetate was added the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford the desired compound 901 as a white foamy solid (3.44 g, 7.9 mmol). MS (LCMS-Electrospray) 434.1 MH+.
    • PREPARATIVE EXAMPLE 19
  • Compound (801)
    Figure US20060205672A1-20060914-C00179
  • To a solution of N-Fmoc-phenylalanine 801A (5 g, 12.9 mmol) in anhydrous DCM (22 mL) cooled to −30° C. in a dry ice-acetone bath was added N-methylpyrrolidine (1.96 mL, 16.1 mmol) and methyl chloroformate (1.2 mL, 15.5 mmol) sequentially. The reaction mixture was stirred at −30° C. for 1 h and a solution of N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mol) and N-methylpyrrolidine (1.96 mL, 16.1 mmol) in anhydrous DCM (8 mL) was added. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. Toluene was added and the organic layer was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afforded compound 801B (4 g, 9.29 mmol).
  • To a solution of Red-Al (6.28 mL, 21.4 mmol) in anhydrous 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 anhydrous toluene (12 mL). The reaction mixture was stirred at −20° C. for 1.5 h. The organic layer was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product 801C was used in the next reaction without further purification.
  • To a solution of compound 801C (approx. 9.29 mmol) in hexane (15 mL) was added 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) sequentially. The reaction mixture was stirred at room temperature for 24 h. Ethyl acetate was added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford compound 801D (2.4 g, 6.03 mmol).
  • To a solution of compound 801D (2.4 g, 6.03 mmol) in 1,4-dioxane (11 mL) was added concentrated hydrochloric acid (11 mL). The reaction mixture was heated at 80° C. for 3 h. Ethyl acetate (25 mL) and water (25 mL) was added. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford the desired compound 801 as a white foamy solid (2 g, 4.8 mmol). MS (LCMS-Electrospray) 418.1 MH+.
    Figure US20060205672A1-20060914-C00180
    Figure US20060205672A1-20060914-C00181
    • EXAMPLE (301J)
  • Scheme 8 Compound (301J)
    Figure US20060205672A1-20060914-C00182
  • Resin-bound compound 301B, 301C, 301D, 301E, 301F and 301G were prepared according to the general procedure for solid-phase coupling reactions started with 100 mg of Fmoc-Sieber resin (0.03 mmol). Resin-bound compound 301G was oxidized to resin-bound compound 301H according to the general procedure for solid-phase Dess-Martin oxidation. The resin-bound compound 301H was treated with 4 mL of a 2% v/v solution of TFA in DCM for 5 min. The filtrate was added to 1 mL of AcOH and the solution was concentrated by vacuum centrifugation to provide compound 301J (0.0069 g, 29% yield). MS (LCMS-Electrospray) 771.2 MH+.
  • Using the solid phase synthesis techniques detailed above, and the following moieties for the various functionalities in the compound of Formula 1, the compounds in Table 3 were prepared:
    • —W—:
      Figure US20060205672A1-20060914-C00183
    • Y—W—:
      Figure US20060205672A1-20060914-C00184
      Figure US20060205672A1-20060914-C00185
      Figure US20060205672A1-20060914-C00186
      Figure US20060205672A1-20060914-C00187
      Figure US20060205672A1-20060914-C00188
      Figure US20060205672A1-20060914-C00189
      Figure US20060205672A1-20060914-C00190
    • —R4:
      Figure US20060205672A1-20060914-C00191
    • -Z-:
      Figure US20060205672A1-20060914-C00192
    • —R3:
      Figure US20060205672A1-20060914-C00193
      Figure US20060205672A1-20060914-C00194
      Figure US20060205672A1-20060914-C00195
    • —R2:
      Figure US20060205672A1-20060914-C00196
    • —R1:
      Figure US20060205672A1-20060914-C00197
    • —R5:
      Figure US20060205672A1-20060914-C00198
    • —R7:
      Figure US20060205672A1-20060914-C00199
    • —R9:
      Figure US20060205672A1-20060914-C00200
  • —R10:
    Figure US20060205672A1-20060914-C00201
    Figure US20060205672A1-20060914-C00202
    Figure US20060205672A1-20060914-C00203
    Figure US20060205672A1-20060914-C00204
    TABLE 3
    Compounds prepared by Solid Phase Synthesis
    STRUCTURE Ki* CLASS
    Figure US20060205672A1-20060914-C00205
         		C
    Figure US20060205672A1-20060914-C00206
         		C
    Figure US20060205672A1-20060914-C00207
         		C
    Figure US20060205672A1-20060914-C00208
         		C
    Figure US20060205672A1-20060914-C00209
         		C
    Figure US20060205672A1-20060914-C00210
         		C
    Figure US20060205672A1-20060914-C00211
         		C
    Figure US20060205672A1-20060914-C00212
         		C
    Figure US20060205672A1-20060914-C00213
         		C
    Figure US20060205672A1-20060914-C00214
         		B
    Figure US20060205672A1-20060914-C00215
         		B
    Figure US20060205672A1-20060914-C00216
         		C
    Figure US20060205672A1-20060914-C00217
         		B
    Figure US20060205672A1-20060914-C00218
         		C
    Figure US20060205672A1-20060914-C00219
         		B
    Figure US20060205672A1-20060914-C00220
         		B
    Figure US20060205672A1-20060914-C00221
         		C
    Figure US20060205672A1-20060914-C00222
         		C
    Figure US20060205672A1-20060914-C00223
         		C
    Figure US20060205672A1-20060914-C00224
         		C
    Figure US20060205672A1-20060914-C00225
         		C
    Figure US20060205672A1-20060914-C00226
         		C
    Figure US20060205672A1-20060914-C00227
         		C
    Figure US20060205672A1-20060914-C00228
         		C
    Figure US20060205672A1-20060914-C00229
         		C
    Figure US20060205672A1-20060914-C00230
         		C
    Figure US20060205672A1-20060914-C00231
         		C
    Figure US20060205672A1-20060914-C00232
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    Figure US20060205672A1-20060914-C00233
         		C
    Figure US20060205672A1-20060914-C00234
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    Figure US20060205672A1-20060914-C00235
         		C
    Figure US20060205672A1-20060914-C00236
         		C
    Figure US20060205672A1-20060914-C00237
         		C
    Figure US20060205672A1-20060914-C00238
         		C
    Figure US20060205672A1-20060914-C00239
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    Figure US20060205672A1-20060914-C00240
         		C
    Figure US20060205672A1-20060914-C00241
         		C
    Figure US20060205672A1-20060914-C00242
         		C
    Figure US20060205672A1-20060914-C00243
         		C
    Figure US20060205672A1-20060914-C00244
         		C
    Figure US20060205672A1-20060914-C00245
         		C
    Figure US20060205672A1-20060914-C00246
         		B
    Figure US20060205672A1-20060914-C00247
         		C
    Figure US20060205672A1-20060914-C00248
         		B
    Figure US20060205672A1-20060914-C00249
         		C
    Figure US20060205672A1-20060914-C00250
         		C
    Figure US20060205672A1-20060914-C00251
         		C
    Figure US20060205672A1-20060914-C00252
         		C
    Figure US20060205672A1-20060914-C00253
         		C
    Figure US20060205672A1-20060914-C00254
         		C
    Figure US20060205672A1-20060914-C00255
         		C
    Figure US20060205672A1-20060914-C00256
         		C
    Figure US20060205672A1-20060914-C00257
         		C
    Figure US20060205672A1-20060914-C00258
         		C
    Figure US20060205672A1-20060914-C00259
         		C
    Figure US20060205672A1-20060914-C00260
         		C
    Figure US20060205672A1-20060914-C00261
         		C
    Figure US20060205672A1-20060914-C00262
         		C
    Figure US20060205672A1-20060914-C00263
         		C
    Figure US20060205672A1-20060914-C00264
         		C
    Figure US20060205672A1-20060914-C00265
         		C
    Figure US20060205672A1-20060914-C00266
         		C
    Figure US20060205672A1-20060914-C00267
         		C
    Figure US20060205672A1-20060914-C00268
         		B
    Figure US20060205672A1-20060914-C00269
         		B
    Figure US20060205672A1-20060914-C00270
         		B
    Figure US20060205672A1-20060914-C00271
         		C
    Figure US20060205672A1-20060914-C00272
         		C
    Figure US20060205672A1-20060914-C00273
         		C
    Figure US20060205672A1-20060914-C00274
         		C
    Figure US20060205672A1-20060914-C00275
         		C
    Figure US20060205672A1-20060914-C00276
         		C
    Figure US20060205672A1-20060914-C00277
         		C
    Figure US20060205672A1-20060914-C00278
         		C
    Figure US20060205672A1-20060914-C00279
         		C
    Figure US20060205672A1-20060914-C00280
         		B
    Figure US20060205672A1-20060914-C00281
         		C
    Figure US20060205672A1-20060914-C00282
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    Figure US20060205672A1-20060914-C00283
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    Figure US20060205672A1-20060914-C00284
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    Figure US20060205672A1-20060914-C00285
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    Figure US20060205672A1-20060914-C00286
         		C
    Figure US20060205672A1-20060914-C00287
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    Figure US20060205672A1-20060914-C00288
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    Figure US20060205672A1-20060914-C00289
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    Figure US20060205672A1-20060914-C00290
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    Figure US20060205672A1-20060914-C00291
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    Figure US20060205672A1-20060914-C00292
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    Figure US20060205672A1-20060914-C00293
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    Figure US20060205672A1-20060914-C00294
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    Figure US20060205672A1-20060914-C00295
         		C
    Figure US20060205672A1-20060914-C00296
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    Figure US20060205672A1-20060914-C00297
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    Figure US20060205672A1-20060914-C00298
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    Figure US20060205672A1-20060914-C00299
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    Figure US20060205672A1-20060914-C00300
         		C
    Figure US20060205672A1-20060914-C00301
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    Figure US20060205672A1-20060914-C00302
         		B
    Figure US20060205672A1-20060914-C00303
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    Figure US20060205672A1-20060914-C00304
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    Figure US20060205672A1-20060914-C00305
         		B
    Figure US20060205672A1-20060914-C00306
         		B
    Figure US20060205672A1-20060914-C00307
         		C
    Figure US20060205672A1-20060914-C00308
         		C
    Figure US20060205672A1-20060914-C00309
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    Figure US20060205672A1-20060914-C00310
         		B
    Figure US20060205672A1-20060914-C00311
         		B
    Figure US20060205672A1-20060914-C00312
         		B
    Figure US20060205672A1-20060914-C00313
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    Figure US20060205672A1-20060914-C00314
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    Figure US20060205672A1-20060914-C00315
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    Figure US20060205672A1-20060914-C00316
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    Figure US20060205672A1-20060914-C00317
         		C
    Figure US20060205672A1-20060914-C00318
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    Figure US20060205672A1-20060914-C00319
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    Figure US20060205672A1-20060914-C00320
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    Figure US20060205672A1-20060914-C00321
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    Figure US20060205672A1-20060914-C00322
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    Figure US20060205672A1-20060914-C00323
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    Figure US20060205672A1-20060914-C00324
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    Figure US20060205672A1-20060914-C00325
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    Figure US20060205672A1-20060914-C00326
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    Figure US20060205672A1-20060914-C00327
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    Figure US20060205672A1-20060914-C00328
         		C
    Figure US20060205672A1-20060914-C00329
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    Figure US20060205672A1-20060914-C00331
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    Figure US20060205672A1-20060914-C00332
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    Figure US20060205672A1-20060914-C00333
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    Figure US20060205672A1-20060914-C00334
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    Figure US20060205672A1-20060914-C00335
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    Figure US20060205672A1-20060914-C00336
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    Figure US20060205672A1-20060914-C00337
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    Figure US20060205672A1-20060914-C00338
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    Figure US20060205672A1-20060914-C00339
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    Figure US20060205672A1-20060914-C00340
         		A
    Figure US20060205672A1-20060914-C00341
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    Figure US20060205672A1-20060914-C00342
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    Figure US20060205672A1-20060914-C00343
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    Figure US20060205672A1-20060914-C00347
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    Figure US20060205672A1-20060914-C00348
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    Figure US20060205672A1-20060914-C00349
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    Figure US20060205672A1-20060914-C00350
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    Figure US20060205672A1-20060914-C00351
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    Figure US20060205672A1-20060914-C00352
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    Figure US20060205672A1-20060914-C00353
         		C
    Figure US20060205672A1-20060914-C00354
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    Figure US20060205672A1-20060914-C00355
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    Figure US20060205672A1-20060914-C00356
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    Figure US20060205672A1-20060914-C00357
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    Figure US20060205672A1-20060914-C00358
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    Figure US20060205672A1-20060914-C00359
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    Figure US20060205672A1-20060914-C00360
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    Figure US20060205672A1-20060914-C00361
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    Figure US20060205672A1-20060914-C00362
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    Figure US20060205672A1-20060914-C00363
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    Figure US20060205672A1-20060914-C00364
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    Figure US20060205672A1-20060914-C00365
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    Figure US20060205672A1-20060914-C00366
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    Figure US20060205672A1-20060914-C00367
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    Figure US20060205672A1-20060914-C00368
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    Figure US20060205672A1-20060914-C00369
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    Figure US20060205672A1-20060914-C00370
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    Figure US20060205672A1-20060914-C00374
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    Figure US20060205672A1-20060914-C00381
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    Figure US20060205672A1-20060914-C00386
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    Figure US20060205672A1-20060914-C00387
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    Figure US20060205672A1-20060914-C00388
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    Figure US20060205672A1-20060914-C00393
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    Figure US20060205672A1-20060914-C00397
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    Figure US20060205672A1-20060914-C00398
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    Figure US20060205672A1-20060914-C00406
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    Figure US20060205672A1-20060914-C00409
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    Figure US20060205672A1-20060914-C00411
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    Figure US20060205672A1-20060914-C00412
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    Figure US20060205672A1-20060914-C00413
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    Figure US20060205672A1-20060914-C00414
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    Figure US20060205672A1-20060914-C00415
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    Figure US20060205672A1-20060914-C00416
         		C
    Figure US20060205672A1-20060914-C00417
         		C
    Figure US20060205672A1-20060914-C00418
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    Figure US20060205672A1-20060914-C00419
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    Figure US20060205672A1-20060914-C00423
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    Figure US20060205672A1-20060914-C00428
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    Figure US20060205672A1-20060914-C00459
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    Figure US20060205672A1-20060914-C00460
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    Figure US20060205672A1-20060914-C00461
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    Figure US20060205672A1-20060914-C00463
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    Figure US20060205672A1-20060914-C00464
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    Figure US20060205672A1-20060914-C00465
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    Figure US20060205672A1-20060914-C00466
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    Figure US20060205672A1-20060914-C00467
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    Figure US20060205672A1-20060914-C00468
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    Figure US20060205672A1-20060914-C00469
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    Figure US20060205672A1-20060914-C00470
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    Figure US20060205672A1-20060914-C00471
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    Figure US20060205672A1-20060914-C00475
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    Figure US20060205672A1-20060914-C00476
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    Figure US20060205672A1-20060914-C00478
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    Figure US20060205672A1-20060914-C00492
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    Figure US20060205672A1-20060914-C00493
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    Figure US20060205672A1-20060914-C00494
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    Figure US20060205672A1-20060914-C00495
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    Figure US20060205672A1-20060914-C00496
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    Figure US20060205672A1-20060914-C00497
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    Figure US20060205672A1-20060914-C00498
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    Figure US20060205672A1-20060914-C00499
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    Figure US20060205672A1-20060914-C00500
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    Figure US20060205672A1-20060914-C00501
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    Figure US20060205672A1-20060914-C00502
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    Figure US20060205672A1-20060914-C00503
         		C
    Figure US20060205672A1-20060914-C00504
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    Figure US20060205672A1-20060914-C00505
         		C
    Figure US20060205672A1-20060914-C00506
         		C
    Figure US20060205672A1-20060914-C00507
         		C
    Figure US20060205672A1-20060914-C00508
         		C
    Figure US20060205672A1-20060914-C00509
         		B
    Figure US20060205672A1-20060914-C00510
         		B
    Figure US20060205672A1-20060914-C00511
         		C
    Figure US20060205672A1-20060914-C00512
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    Figure US20060205672A1-20060914-C00513
         		C
    Figure US20060205672A1-20060914-C00514
         		C
  • Additional compounds that were prepared and their activity (Ki*) ranges are given in the attached Tables 4 and 5. The procedure used to prepare the compounds in Tables 4 and 5 is outlined below.
  • I) Synthesis of Intermediates for the Compounds in Tables 4 and 5
    • EXAMPLE I Synthesis of 4,4-dimethyl proline methyl ester (H-Pro(4,4-diMe)-OMe)
  • Figure US20060205672A1-20060914-C00515
    • Step 1. Synthesis of tert-Butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (Boc-PyroGlu(4-methyl)-OtBu)
  • Figure US20060205672A1-20060914-C00516
  • To a solution of tert-butyl N-tert-butoxycarbonyl-pyroglutamate (11.5 g, 40 mmol) in THF (200 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in THF (42 mL, 42 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (3.11 mL, 50 mmol) was added. After an additional 2 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed with 1:1 ethylacetate/hexanes to give Boc-PyroGlu(4-methyl)-OtBu (10.6 grams, 35.4 mmol, 88%) as a mixture of isomers (2:1 cis to trans).
    • Step 2. Synthesis of tert-Butyl N-tert-butoxycarbonyl-4,4-dimethyl-L-pyroglutamate (Boc-PyroGlu(4,4-dimethyl)-OtBu)
  • Figure US20060205672A1-20060914-C00517
  • To a solution of tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (1.2 g, 4.0 mmol) in tetrahydrofuran (20 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.4 mL, 4.4 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (0.33 mL, 5.2 mmol) was added. After an additional 3 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (40 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (2×50 mL). The combined organic layers were washed with water (2×25 mL), saturated sodium bicarbonate (2×25 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to give Boc-PyroGlu(4,4-dimethyl)-OtBu (0.673 g, 54%).
    • Step 3. Synthesis of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline (Boc-Pro(4,4-dimethyl)-OtBu)
  • Figure US20060205672A1-20060914-C00518
  • Modification of known procedure: Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; Garcia Ruano, J. L. Tetrahedron Letters 1994, 35(13), 2053-2056).
  • To a solution of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylpyroglutamate (2.0 mmol) in tetrahydrofuran (5 mL) stirring at −78° C., was added a 1M solution of lithium triethylborohydride in tetrahydrofuran (2.4 mL, 2.4 mmol) dropwise over 5 minutes. After 30 minutes, the cooling bath was removed and saturated aqueous sodium bicarbonate (5 mL) was added. The reaction mixture was immersed in an ice/water bath and 30% aqueous hydrogen peroxide (10 drops) was added. The solution was stirred for 20 minutes at 0° C., then the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The aqueous solution was diluted with water (10 mL) and extracted with dichloromethane (3×40 mL). The organic layers were dried (Na2SO4), filtered and concentrated. The residue was dissolved in dichloromethane (20 mL) and triethylsilane (310 μL, 2.0 mmol), then cooled to −78° C. and boron trifluoride diethyletherate (270 μL, 2.13 mmol) was added dropwise. Stirring was continued for 30 minutes, at which time additional triethylsilane (310 μL, 2.0 mmol) and boron trifluoride diethyletherate (270 μL, 2.13 mmol) were added. After stirring at −78° C. for an additional two hours, the cooling bath was removed and saturated aqueous sodium bicarbonate (4 mL) was added. After 5 minutes the mixture was extracted with dichloromethane (3×40 mL). The organic layers were dried (Na2SO4), filtered and concentrated to give Boc-Pro(4,4-dimethyl)-OtBu.
    • Step 4. Synthesis of 4,4-dimethylproline (H-Pro(4,4-dimethyl)-OH)
  • Figure US20060205672A1-20060914-C00519
  • A solution of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline in dichloromethane (5 mL) and trifluoroacetic (5 mL) was stirred at room temperature for five hours. The solution was concentrated, dried under high vacuum and taken to the next step without further purification.
    • Step 5. Synthesis of N-tert-butoxycarbonyl 4,4-dimethylproline (Boc-Pro(4,4-dimethyl)-OH)
  • Figure US20060205672A1-20060914-C00520
  • To a solution of 4,4-dimethylproline trifluoroacetic salt (1.5 mmol) in dioxane (7 mL), acetonitrile (12 mL) and diisopropylethylamine (700 μL, 4 mmol) was added a solution of di-tert-butyl-dicarbonate (475 mg, 2.18 mmol) in acetonitrile (5 mL). After stirring for 12 hours at room temperature the solution was concentrated in vacuo, dissolved in saturated aqueous sodium bicarbonate (50 mL) and washed with diethyl ether (3×40 mL). The aqueous layer was acidified to pH=3 with citric acid, then extracted with dichloromethane (3×40 mL). The combined organic layers were dried over sodium sulfate filtered and concentrated.
    • Step 6. Synthesis of 4,4-dimethylproline methylester hydrochloride salt (HCl.H-Pro(4,4-dimethyl)-OMe)
  • Figure US20060205672A1-20060914-C00521
  • To a solution of Boc-Pro(4,4-diMe)-OH (0.5 g, 2.06 mmol) in anhydrous methanol (8 ml) was added dropwise thionylchloride (448 l, 6.18 mmol) and the reaction was stirred for six hours at room temperature. The reaction mixture was concentrated to an amorphous solid (377 mg, 95%).
    • EXAMPLE II General Procedure for the synthesis of N-tertbutoxycarbonyl-4-alkyl-4-methyl proline
  • Figure US20060205672A1-20060914-C00522
  • Compounds where R group is allyl and benzyl were synthesized following steps 1-4 below:
    • Step 1. Synthesis of tert-Butyl N-tert-butoxycarbonyl-4-alkyl-4-methyl-L-pyroglutamate
  • Figure US20060205672A1-20060914-C00523
  • To a solution of tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (10.2 g, mmol) (see Example I, step 1) in tetrahydrofuran (170 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (37.5 mL, 37.5 mmol) dropwise over 5 minutes. After 40 minutes, alkyl halide (61.4 mmol) was added. After an additional 3 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (2×200 mL). The combined organic layers were diluted with hexanes (150 mL) and washed with saturated sodium bicarbonate (100 mL), water (2×100 mL) and brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed using 20% ethylacetate in hexanes to give the pure tert-Butyl N-tert-butoxycarbonyl-4-alkyl-4-methyl-L-pyroglutamate.
    • Step 2. Synthesis of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methylproline
  • Figure US20060205672A1-20060914-C00524
  • Modification of known procedure: Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; Garcia Ruano, J. L. Tetrahedron Letters (1994) 35(13), 2053-2056).
  • To a solution of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methylpyroglutamate (16.6 mmol) in tetrahydrofuran (40 mL) stirring at −78° C., was added a 1M solution of lithium triethylborohydride in tetrahydrofuran (20 mL, 20 mmol) dropwise over 10 minutes. After 120 minutes, the cooling bath was allowed to warm to −25° C. at which point saturated aqueous sodium bicarbonate (40 mL) was added. The reaction mixture was immersed in an ice/water bath and 30% aqueous hydrogen peroxide (4 mL) was added. The solution was stirred for 10 minutes at 0° C., then the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The aqueous solution was diluted with water (300 mL) and extracted with dichloromethane (3×200 mL). The organic layers were dried (sodium sulfate), filtered and concentrated. The residue was dissolved in dichloromethane (100 mL) and triethylsilane (2.6 mL, mmol), then cooled to −78° C. and boron trifluoride diethyletherate (2.2 mL, mmol) was added dropwise. Stirring was continued for 1 hour, at which time additional triethylsilane (2.6 mL, mmol) and boron trifluoride diethyletherate (2.2 mL, mmol) were added. After stirring at −78° C. for an additional 4 hours, the cooling bath was removed and saturated aqueous sodium bicarbonate (30 mL) and water (150 mL) were added. After 5 minutes the mixture was extracted with dichloromethane (3×200 mL). The organic layers were dried (Na2SO4), filtered and concentrated.
    • Step 3. Synthesis 4-alkyl-4-methylproline
  • Figure US20060205672A1-20060914-C00525
  • A solution of tert-butyl N-tert-butoxycarbonyl-4-alkyl-4-methylproline in dichloromethane (5 mL) and trifluoroacetic (5 mL) was stirred at room temperature for 5 hours. Toluene was added and the solution was concentrated and then dried under high vacuum.
    • Step 4. Synthesis of N-tert-butoxycarbonyl 4-alkyl-4-methylproline
  • Figure US20060205672A1-20060914-C00526
  • To a solution of 4-alkyl-4-methylproline trifluoroacetic salt (1.5 mmol) in dioxane (7 mL), acetonitrile (12 mL) and diisopropylethylamine (700 μL, 4 mmol) was added a solution of di-tert-butyl-dicarbonate (475 mg, 2.18 mmol) in acetonitrile (5 mL). After stirring for 12 hours at room temperature the solution was concentrated in vacuo, dissolved in saturated aqueous sodium bicarbonate (50 mL) and washed with diethyl ether (3×40 mL). The aqueous layer was acidified to pH=3 with 1N hydrochloric acid, then extracted with dichloromethane (3×40 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using 1:1 ethylacetate/hexanes with 1% acetic acid.
    • EXAMPLE III Synthesis of N-tert-butoxycarbonyl 4-propyl-4-methylproline
  • Figure US20060205672A1-20060914-C00527
  • A solution of N-tertbutoxycarbonyl-4-allyl-4-methylproline (400 mg, 1.48 mmol) (see Example II Step 4) and 10% Pd on carbon (400 mg) in methanol (20 mL) was hydrogenated at 50 psi for 4 hours. The mixture was filtered and concentrated.
    • EXAMPLE IV Synthesis of Boc-4-cyclohexylproline
  • Figure US20060205672A1-20060914-C00528
  • A solution of the commercially available 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 was filtered and concentrated to give 730 mg of product.
    • EXAMPLE V Preparation of Fluorenylmethoxycarbonyl-Pro(4-spirocyclopentane)-carboxylic acid
  • Figure US20060205672A1-20060914-C00529
    • Step 1. Synthesis of Boc-pyroglutamic(4-allyl)-tert-butylester
  • Figure US20060205672A1-20060914-C00530
  • To a cooled (−78° C.) solution of the commercially available N-Bo c-tert-butyl pyroglutamate (10 g, 35.1 mmol) in THF (175 ml) was added lithium hexamethyldisilazide (36.8 mL, 36.8 mmol) over five minutes. Stirring continued for thirty minutes. A solution of allyl bromide (6.1 ml, 70.2 mmol) in THF (39 mL) 15 was added dropwise to the first solution. After two hours at −78° C., the reaction was quenched by the slow addition of saturated ammonium chloride (50 mL) solution. The reaction mixture was then diluted with ethylacetate and the layers were separated. The organic layer dried over sodium sulfate and concentrated. Flash column chromatography carried out in 2:8 ethylacetate:hexanes afforded the product (6 g, 53%). NMR δ ppm (CDCl3): 5.7 (m, 1H), 5.1 (dd, 2H), 4.4 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 1.8-2.2 (m, 1H), 1.45 (s, 9H), 1.4 (s, 9H).
    • Step 2. Synthesis of N-Boc-pyroglutamic(4,4-diallyl)-tert-butylester
  • Figure US20060205672A1-20060914-C00531
  • N-Boc-pyroglutamic(4-allyl)-tert-butylester obtained in the Step 1 above (2.68 g, 8.24 mmol) was subjected to a second alkylation with allyl bromide under similar conditions. Flash chromatography in 15:85 ethylacetate:hexanes provided 2.13 g product (71%) as a clear oil.
    • Step 3. Synthesis of Boc-Pro(4,4-diallyl)-tert-butylester
  • Figure US20060205672A1-20060914-C00532
  • Part a: To a cooled (−78° C.) solution of Boc-PyroGlu(4,4-diallyl)-tert-butylester (2.13 g, 5.83 mmol) in tetrahydrofuran (14 ml) was added lithium triethylborohydride (1M in tetrahydrofuran, 7.29 ml, 7.29 mmol) over five minutes. After two hours at −78° C., the reaction was warmed-up to 0° C. and quenched by the slow addition of saturated sodium bicarbonate solution (20 ml) and 30% hydrogen peroxide (20 drops). Stirring continued for 20 minutes. The tetrahydrofuran was removed under reduced pressure and the remaining thick white residue was diluted with water (80 ml) and extracted three times with dichloromethane. The organic layer was dried, filtered and concentrated and taken to the next step without further purification.
  • Part b): To the product obtained in part (a) in dichloromethane (14 ml) was added triethylsilane (931 μl, 5.83 mmol) followed by boron trifluoride diethyl etherate (776 μl, 6.12 mmol). After thirty minutes more triethylsilane (931 μl, 5.83 mmol) and boron trifluoride diethyl etherate etherate (776 μl, 6.12 mmol) were added and the reaction was stirred at −78° C. for three hours at which time the reaction was quenched by the slow addition of saturated sodium bicarbonate solution and water. The reaction mixture was extracted with dichloromethane and the organic layer was dried, filtered and concentrated. Flash column chromatography in 15% ethylacetate in hexanes afforded 1.07 colorless oil (57%). NMR δ ppm (CDCl3): 5.7-5.8 (m, 2H), 5.1 (m, 4H), 4.1-4.2 (2 dd's, 1H rotamers), 3.5-3.3 (dd, 1H) and 3.2 (dd, 1H) rotamers, 2.2-2.0 (m, 5H), 1.7(m, 1H), 1.46 (s, 9H), 1.43 (s, 9H).
    • Step 4. Synthesis of Boc-Pro(4-spirocyclopentene)-tert-butylester
  • Figure US20060205672A1-20060914-C00533
  • To Boc-Pro(4,4-diallyl)-tert-butylester (1.07 g, 3.31 mmol) in dichloromethane (66 ml) was added 5% Bis(tricyclohexylphosphin)benzylidene ruthenium IV dichloride (Grubbs catalyst) and the mixture was heated at reflux for 1.5 hours. The reaction mixture was concentrated and the remaining residue was purified by flash column chromatography in 15% ethylacetate in hexanes. A yellow oil was obtained (0.57 g, 53%). NMR δ ppm (CDCl3): 5.56 (bs, 2H), 4.2 and 4.1 (t, 1H, rotamers), 3.2-3.5 (m, 2H), 2.2-2.5 (m, 5H), 1.9 (dd, 1H) 1.47 and 1.46 (2 s's, 9H, rotamers), 1.45 and 1.44 (2 s's, 9H, rotamers).
    • Step 5. Synthesis of Boc-Pro(4-spirocyclopentane)-tert-butylester
  • Figure US20060205672A1-20060914-C00534
  • 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 the Parr shaker and was hydrogenated for three hours at 35 psi in the presence of 10% palladium on carbon (300 mg). The catalyst was filtered off and the filtrate was concentrated to a colorless oil (1.26 g). NMR δ ppm (CDCl3): 4.1 and 4.2 (t, 1H, rotamers, 3.4 (d, 1H), 3.2 (d, 1H), 2.1 (m, 1H), 1.9 (m, 1H), 1.6-1.7 (m, 10H), 1.5 (3 s's, 18H, rotamers).
    • Step 6. Synthesis of Fmoc-Pro(4-spirocyclopentane)-carboxylic acid
  • Figure US20060205672A1-20060914-C00535
  • The Boc-Pro(4-spirocyclopentane)-tert-butylester (1.26, 3.9 mmol) was treated with dichloromethane (10 ml) and trifluoroacetic acid (15 ml) for three hours. The reaction mixture was concentrated and the yellow oil obtained was dissolved in water (6 ml). Fluorenylmethyl succinyl carbonate (1.45 g, 4.3 mmol) dissolved in dioxane (6 ml) was added portionwise followed by the addition of potassium carbonate (2.16 g, 15.6 mmol). The reaction was stirred for 18 hours and concentrated. The remaining residue was diluted with the saturated sodium bicarbonate solution (10 mL) and washed with diethylether (3×10 ml). The aqueous layer was then acidified to pH˜1 with 1N sodium bisulfate solution and extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered and concentrated to a beige foam (1.3 g, 100%).
    • EXAMPLE VI Synthesis of Boc-Pro(4t-NH(Fmoc))-OH
  • Figure US20060205672A1-20060914-C00536
    • Step 1. Synthesis of Nα-tert-butoxycarbonyl-cis-4-chloro-L-proline benzyl ester
  • Figure US20060205672A1-20060914-C00537
  • A mixture of the commercially available 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) was stirred for 18 h. Addition of ethyl acetate (100 mL) was followed by filtration. The white cloudy filtrate was clarified by the addition of 1M HCl (100 mL). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL), dried (sodium sulfate), filtered and concentrated. Toluene was added to the crude benzyl ester, and the solution was filtered and reconcentrated. Dichloromethane (70 mL) and carbon tetrachloride (70 mL) was added, followed by triphenylphosphine (21.11 g, 80 mmol). The reaction mixture was stirred for 10 h, quenched with ethanol (7 mL) and stirred for 5 more h. The solution was concentrated to approx. 100 ml, then dichloromethane (40 mL) was added, followed by the addition of ether (200 mL) while stirring. The solution was cooled for 4 h, filtered and concentrated to give a yellow-brown 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%) as a white solid.
    • Step 2. Synthesis of N-tert-butoxycarbonyl-4-trans-4-azido-L-proline benzyl ester
  • Figure US20060205672A1-20060914-C00538
  • A solution of Nα-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 heated at 75° C. for 2 days. Water (100 mL) was added and the reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (3×50 mL), dried (sodium sulfate), filtered and concentrated. The oil was purified by flash chromatography using ethyl acetate/hexanes 1:1 to give the title compound (8.59 g, 24.8 mmol, 94%).
    • Step 3. Synthesis of Boc-Pro(4t-NH(Fmoc))-OH
  • Figure US20060205672A1-20060914-C00539
  • A mixture of N-α-t-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) was hydrogenated at 50 psi for 14 h using a Parr hydrogenation apparatus. The mixture was filtered, concentrated, dissolved in methanol (60 mL), refiltered and concentrated to give a colorless oil. The 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 min. The reaction mixture was stirred at room temperature for 17 h, then concentrated to remove the dioxane and diluted with water (200 mL). The solution was washed with ether (3×100 mL). The pH of the aqueous solution was adjusted to 2 by the addition of citric acid (caution! foaming!) and water (100 mL). The mixture was extracted with dichloromethane (400 mL, 100 mL, 100 mL) and the combined organic layers were dried (sodium sulfate), filtered and concentrated to give the title compound.
    • EXAMPLE VII Synthesis of N-t-butoxycarbonyl-4-trans-(N-fluorenylmethyloxycarbonyl aminomethyl)-L-proline (Boc-Pro(4t-MeNHFmoc)-OH)
  • Figure US20060205672A1-20060914-C00540
    • Step 1. Synthesis tert-butoxycarbonyl cis-4-hydroxy-L-proline benzyl ester (Boc-Pro(4-cis-OH)-OBn)
  • Figure US20060205672A1-20060914-C00541
  • To a mixture of cis-hydroxy-L-proline (5 g, 38.1 mmol) in benzene (45 mL) and benzyl alcohol (45 mL) was added p-toluenesulfonic acid monohydrate (7.6 g, 40.0 mmol). The reaction mixture was heated at 125° C. for 20 h while water (2 ml) was removed using a Dean-Stark trap. The solution was filtered while still hot, and then ether (150 ml) was added. The solution was allowed to cool for three h at room temperature, then three h at 4° C. The resulting solid was collected, washed with ether (100 mL) and dried in vacuo for 1 h to give 13.5 grams of white solid. The 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 min while using an ice bath to maintain a constant reaction temperature. After 10 h at room temperature the reaction mixture was poured into cold water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (3×100 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated. The crude product was purified by flash chromatography using 40-60% ethyl acetate in hexanes to give the title compound (10.04 g, 31.24 mmol, 82%).
    • Step 2. Synthesis of N-t-butoxycarbonyl cis-4-mesyloxy-L-proline benzyl ester (Boc-Pro(4-cis-OMs)-OBn)
  • Figure US20060205672A1-20060914-C00542
  • To a solution of Boc-Pro(4-cis-OH)-OBn (8.45 g, 26.3 mmol) in pyridine (65 mL) at 0° C., was added methanesulfonyl chloride (3.4 mL, 44 mmol) dropwise over 7 min. The reaction mixture was allowed to warm to room temperature over 2 h, then stirred overnight. A solution of 10% water in pyridine (20 mL) was added over 15 min and the reaction mixture was concentrated. The residue was dissolved in water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×50 mL) saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated. The resulting residue was 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%), then used in the next step without purification.
    • Step 3. N-t-butoxycarbonyl-trans-4R-cyano-L-proline benzylester (Boc-Pro(4-trans-CN)-OBn)
  • Figure US20060205672A1-20060914-C00543
  • 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 heated in an oil bath at 55° C. for 28 h. After cooling, water (150 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (3×100 mL) and saturated aqueous sodium chloride (100 mL), dried (sodium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 ether/hexanes) and then recrystallized from ethyl acetate/hexanes to provide the title compound (2.40 g, 7.26 mmol, 28%).
    • Step 4. N-t-butoxycarbonyl-4-trans-(N-fluorenylmethyloxycarbonyl aminomethyl)-L-proline (Boc-Pro(4t-MeNHFmoc)-OH)
  • Figure US20060205672A1-20060914-C00544
  • A mixture of the compound of Step 3 above (2.31 g, 7 mmol), water (10 mL), methanol (85 mL) and 10% palladium on carbon (700 mg) was hydrogenated at 50 psi for 11 h using a Parr hydrogenation apparatus. The mixture was filtered and concentrated. Water (15 mL) and sodium carbonate (1.5 g, 14.2 mmol) was added to the residue. A solution of fluorenylmethyl succinyl carbonate (2.36 g, 7.0 mmol) in dioxane (17 mL) was added over 5 min and stirring was continued for 28 h at room temperature. The reaction was concentrated in vacuo to a 15 mL volume, and water (100 mL) was added. The solution was washed with ether (3×75 mL). The pH of the aqueous solution was adjusted to 2 by the addition of citric acid (approx. 20 g, caution! foaming!) and water (100 mL). The mixture was extracted with dichloromethane (4×100 mL), and the combined organic layers were dried (sodium sulfate), filtered and concentrated. The crude product contained a major impurity which necessitated a three step purification. The crude product was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (50 mL) and stirred for 5 h before being concentrated. The residue was purified by preparatory reverse-phase HPLC. The pure 4-(N-fluorenylmethyloxycarbonyl aminomethyl)proline trifluoroacetate salt (1.887 g, 3.93 mmol) was dissolved in dioxane (10 mL), acetonitrile (20 mL) and diisopropylethylamine (1.4 mL, 8 mmol). To the reaction mixture was added a solution of di-tert-butyldicarbonate (1.1 g, 5 mmol) in dioxane (5 mL). After stirring for 18 h, the pH of the solution was adjusted to 2 by the addition of citric acid (caution: foaming!) and water (100 mL). The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried (sodium sulfate), filtered and concentrated. The crude product was dissolved in saturated aqueous sodium bicarbonate (100 mL) and washed with ether (3×75 mL). The aqueous layer was adjusted to pH=3 by the addition of citric acid, then extracted with dichloromethane (4×100 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated to the title compound (1.373 g, 2.94 mmol, 42%).
    • EXAMPLE VIII Synthesis of 3,4-isopropylideneprolinol
  • Figure US20060205672A1-20060914-C00545
    • Step 1. Cyclopropanation reaction (Tetrahedron Lett. 1993, 34(16), 2691 and 2695)
  • Figure US20060205672A1-20060914-C00546
  • To a stirring solution of isopropyltriphenyl-phosphonium iodide (4.14 g, 9.58 mmol) in tetrahydrofuran (60 mL) at 0° C., was added n-butyllithium (1.6 M in hexanes, 5.64 mL, 9.02 mmol) over 5 min. After 30 min, a solution of enamide ((5R,7S)-5-phenyl-5,6,7,7a-tetrahydro-4-oxapyrrolizin-3-one) (1.206 grams, 6.0 mmol) (see J. Org. Chem. 1999, 64(2), 547 for the synthesis of the enamide starting material) in tetrahydrofuran (40 mL) was added over 10 min. After an additional 10 min, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The reaction was poured into water (400 mL) and extracted with diethyl ether (400 mL) and ethylacetate (2×400 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated to give the desired crude product. The residue was purified by flash chromatography eluting with 3:5:2 ethylacetate/hexanes/methylene chloride to give pure cyclopropanated product (750 mg, 3.08 mmol, 51%).
    • Step 2. Synthesis of 3,4-isopropylideneprolinol P[3,4-(diMe-cyclopropyl)]-alcohol) (J. Org. Chem. (1999) 64(2), 330)
  • Figure US20060205672A1-20060914-C00547
  • A mixture of the product obtained in step 1 above (1.23 grams, 5.06 mmol) and lithium aluminum hydride (1.0 M in THF, 15 mL, 15 mmol) was heated at reflux for 5 hours. After cooling to 0° C., the remaining aluminum hydride was carefully quenched by the dropwise addition of saturated aqueous sodium sulfate (1.5 mL) over 15 min. The mixture was diluted with ethylacetate (40 mL) and then filtered through celite. The filtrate was dried with sodium sulfate, filtered and concentrated to give crude N-benzyl aminoalcohol (1.25 grams), which was carried on to the next step without further purification. A solution of crude N-benzyl aminoalcohol (1.25 grams, 5.06 mmol) in 1:1 acetic acid/ethylacetate (30 mL) with 10% Pd/C (1 gram) was hydrogenated at 50 psi for 16 hours using a Parr hydrogenation apparatus. The reaction mixture was filtered to remove the carbon-based catalyst and the filtrate was concentrated. The residue was dissolved in water (30 mL) and the pH was adjusted to 13 with 50% NaOH. The mixture was extracted with ether (3×60 mL). The combined extract was dried with sodium sulfate, filtered and concentrated to give crude aminoalcohol (485 mg, 3.43 mmol). This material was taken to the next step without further purification.
    • EXAMPLE IX Synthesis of iBoc-G(Chx)-Pro(3,4-isopropylidene)-carboxylic acid
  • Figure US20060205672A1-20060914-C00548
    • Step 1. Synthesis of isobutyloxycarbonyl-cyclohexylglycine (iBoc-G(Chx)-OH)
  • Figure US20060205672A1-20060914-C00549
  • To a solution of the commercially available cyclohexylglycine hydrochloride (15 g, 77.4 mmol) in acetonitrile (320 ml) and water (320 ml) was added potassium carbonate. Isobutylchloroformate (11.1 ml, 85.1 mmol) was added to the clear solution over 15 minutes and the reaction was stirred for 17 hours. The acetonitrile was removed under reduced pressure and the remaining aqueous layer was extracted twice with ether (100 ml). The aqueous layer was then acidified to pH 1 with 6N hydrochloric acid and extracted with dichloromethane (3×300 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 18.64 g (94%) product as a white solid.
    • Step 2. Synthesis of isobutyloxycarbonyl-cyclohexylglycyl-3,4-isopropylideneproline (iBoc-G(Chx)-P[3,4-(diMe-cyclopropyl)]-OH)
  • Figure US20060205672A1-20060914-C00550
    a) Coupling Step
  • 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 grams) and then diisopropylethylamine (2.5 mL, 14 mmol). After a 2 minutes, 3,4-isopropylideneprolinol (485 mg, 3.43 mmol) was added and the reaction mixture was stirred overnight. Addition of saturated aqueous sodium bicarbonate was followed by extraction with ether and ethylacetate. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography eluting with 1:1 ethylacetate/hexanes to give pure dipeptide alcohol iBoc-G(Chx)-3,4-isopropylideneprolinol (870 mg, 2.3 mmol, 67%)
  • b) Jones Oxidation Step
  • To a solution of dipeptide alcohol iBoc-G(Chx)-3,4-isopropylideneprolinol (100 mg, 0.26 mmol) in acetone (2 mL) stirring at 0° C. was added Jones reagent (300 μL) dropwise over 5 min. [Jones Reagent: Prepared from chromium trioxide (13.4 g) and concentrated sulfuric acid (11.5 mL) diluted with water to a total volume of 50 mL.] After stirring at 0° C. for 3 hours, isopropanol (500 μL) was added and stirring continued for an additional 10 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethylacetate (3×70 mL). The combined organic layers were dried, filtered and concentrated to give the dipeptide iBoc-G(Chx)-3,4-isopropylideneproline (100 mg, 0.25 mmol, 96%).
    • EXAMPLE X Synthesis of N-Cbz-3,4-methanoproline
  • Figure US20060205672A1-20060914-C00551
    • Step 1. Synthesis of N-benzyl-3,4-methanoprolinol
  • Figure US20060205672A1-20060914-C00552
  • A mixture of the benzylidene starting material (J. Org. Chem. 1999, 64(2), 547) (4.6 grams, 21.4 mmol) and lithium aluminum hydride (1.0 M in THF, 64 mL, 64 mmol) was heated at reflux for 5 hours. After cooling to 0° C., the remaining aluminum hydride was carefully quenched by the dropwise addition of saturated aqueous sodium sulfate (5 mL) over 15 min. The mixture was diluted with ethylacetate (200 mL) and then filtered through celite. The filtrate was dried with sodium sulfate, filtered and concentrated to give crude N-benzyl aminoalcohol (3.45 grams), which was carried on to the next step without further purification.
    • Step 2. Synthesis of N-benzyloxycarbonyl-3,4-methanoprolinol (CBz-P(3,4-CH2)-ol)
  • Figure US20060205672A1-20060914-C00553
  • A solution of crude N-benzyl aminoalcohol (3 grams, 14.76 mmol) in methanol (120 mL) and concentrated HCl (1.5 mL) with 10% Pd/C (300 mg) was hydrogenated at 50 psi for 16 hours. The reaction mixture was filtered to remove the carbon-based catalyst and the filtrate was concentrated. The residue was dissolved in water/dioxane (100 mL) and diisopropylethylamine (3.2 mL) was added. Benzyl chloroformate (2.76 mL, 16.2 mmol) was added and the reaction was stirred overnight. The reaction mixture was concentrated, dissolved in 1M HCl (100 mL) and extracted with ethylacetate (3×200 mL). The combined organic layers were dried with magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 1:3 ethylacetate/hexanes to give the N-Cbz-3,4-methanoprolinol (2.4 g)
    • Step 3. Synthesis of N-benzyloxycarbonyl-3,4-methanoproline (CBz-P(3,4-CH2)-OH)
  • Figure US20060205672A1-20060914-C00554
  • To a solution of N-Cbz-3,4-methanoprolinol (2.2 g, 8.90 mmol) in acetone (68 mL) stirring at 0° C., was added Jones reagent (6.6 mL) dropwise over 5 min. [Jones Reagent: Prepared from chromium trioxide (13.4 g) and concentrated sulfuric acid (11.5 mL) diluted with water to a total volume of 50 mL.] After stirring at 0° C. for 3 hours, isopropanol (11 mL) was added and stirring continued for an additional 10 minutes. The reaction mixture was diluted with water (400 mL) and extracted with ethylacetate (3×500 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give N-Cbz-3,4-methanoproline (2.25 g, 96%)
    • EXAMPLE XI Synthesis of Boc-(6S-carboethoxymethano) proline
  • Figure US20060205672A1-20060914-C00555
  • The synthesis of the title compound was carried out according to the published procedure: Marinozzi, M.; Nataini, B.; Ni, M. H.; Costantino, G.; Pellicciari R. IL Farmaco (1995) 50 (5), 327-331.
    • EXAMPLE XII Synthesis of Boc-3-morpholine carboxylic acid
  • Figure US20060205672A1-20060914-C00556
  • The synthesis of the title compound was carried out according to the published procedure: Kogami Y., Okawa, K. Bull. Chem. Soc. Jpn. (1987) 60, 2963-2965.
    • EXAMPLE XIII Synthesis of N-tert-butoxycarbonyl 2-aza-3S-hydroxycarbonyl-[2,2,2]-bicyclooctane
  • Figure US20060205672A1-20060914-C00557
  • A solution of crude 2-aza-2-(1-phenylethyl)-3S-methoxycarbonyl-[2,2,2]-bicyclooct-5-ene (10 mmol) (Tetrahedron (1992) 48(44) 9707-9718) and 10% Pd on carbon (1 g) in methanol (30 mL) was acidified with 12N HCl then hydrogenated at 50 psi for 16 hours using a Parr hydrogenation apparatus. The reaction mixture was filtered to remove the carbon-based catalyst and the filtrate was concentrated. The residue was dissolved in concentrated HCl and stirred overnight. The solution was concentrated and redissolved in acetonitrile (50 mL). Diisopropylethylamine (3.5 mL) and di-tert-butyldicarbonate (1 g) were added. The reaction mixture was stirred for 24 hours and then concentrated. The residue was dissolved in CH2Cl2 and 5% aqueous sulfuric acid. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were concentrated. The residue was dissolved in 10% saturated sodium bicarbonate, washed with diethyl ether (2×) and acidified with 5% aqueous sulfuric acid. The aqueous layer was extracted with ethylacetate (2×). The combined ethylacetate layers were dried filtered and concentrated to give N-tert-butoxycarbonyl 2-aza-3S-hydroxycarbonyl-[2,2,2]-bicyclooctane (650 mg).
    • EXAMPLE XIV Synthesis of isobutyloxycarbonyl-cyclohexylglycyl-4,4-dimethyl proline (iBoc-G(Chx)-P(4,4-dimethyl)-OH)
  • Figure US20060205672A1-20060914-C00558
    • Step I. Synthesis of iBoc-G(Chx)-P(4,4-dimethyl)-OMe
  • Figure US20060205672A1-20060914-C00559
  • To a solution of iBoc-G(Chx)-OH (Example IX, Step 1.)(377 mg, 1.95 mmol) in acetonitrile (7 mL) was added successively 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). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate. The organic layer was washed twice with 10 ml portions of saturated sodium bicarbonate solution, 1N hydrochloric solution, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to a white solid (612 mg, 79%).
    • Step 2. Synthesis of iBoc-G(Chx)-P(4,4-dimethyl)-OH
  • Figure US20060205672A1-20060914-C00560
  • The methyl ester obtained in Step 1 above (612 mg, 1.54 mmol) in methanol (6 ml) was saponified in the presence of 2M lithium hydroxide (1.16 ml) for three hours. The methanol was removed under reduced pressure and the remaining residue was diluted with ethylacetate and acidified to pH=2 with 1N hydrochloric acid. The layers were separated and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated.
    • EXAMPLE XV Synthesis of L-phenylglycine dimethylamide
  • Figure US20060205672A1-20060914-C00561
    • Step 1. Synthesis of N-benzyloxycabonyl-L-phenylglycine dimethylamide (CBz-Phg-NMe2)
  • Figure US20060205672A1-20060914-C00562
  • N-benzyloxycarbonyl-L-phenylglycine (25 g, 88 mmols) was dissolved in THF (800 mL) and cooled to −10° C. N-methylmorpholine (9.7 mL, 88 mmols) and isobutylchloroformate (11.4 mL, 88.0 mmols) were added and the mixture allowed to stir for 1 minute. Dimethylamine (100 mL, 2M in THF) was added and the reaction was allowed to warm to room temperature. The mixture was filtered and the filtrate concentrated in vacuo to afford N-benzyloxycabonyl-L-phenylglycine dimethylamide (32.5 g) as a yellow oil.
    Figure US20060205672A1-20060914-C00563
    • Step 2. Synthesis of L-phenylglycine dimethylamide (H-Phg-NMe2)
  • The N-benzyloxycarbonyl-L-phenylglycine dimethylamide (32.5 g) obtained above was dissolved in methanol (750 ml) and 10% palladium on activated carbon is (3.3 g) was added. This mixture was hydrogenated on a Parr apparatus under 35 psi hydrogen for 2 hours. The reaction mixture was filtered and the solvent removed in vacuo and the residue recrystallized from methanol-hexanes to afford phenylglycine dimethylamide (26 g) as an off white solid. The ee of this material was determined to be >99% by HPLC analysis of the 2,3,4,6-tetra-O-acetylglucopyranosylthioisocyanate derivative.
    • EXAMPLE XVI Synthesis of (1-methylcyclohexyl) glycine
  • Figure US20060205672A1-20060914-C00564
    • Step 1. 1-methyl-1-hydroxymethylcyclohexane
  • Figure US20060205672A1-20060914-C00565
  • To a solution of 1-methyl-1-hydroxycarbonylcyclohexane (10 g, 70 mmol) in tetrahydrofuran (300 mL) at 0° C. was added 1M diborane in tetrahydrofuran (200 mL, 200 mmol) over 90 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for two days. The remaining borane was quenched by the slow addition of saturated sodium bisulfate (10 mL) over 90 min with cooling. Additional saturated sodium bisulfate (200 mL) was added and after 20 min of stirring the aqueous layer was removed. The organic layer was washed with water and saturated sodium chloride, dried, filtered and concentrated. The residue was purified by flash chromatography using 20% diethylether in hexanes to give 1-methyl-1-hydroxymethylcyclohexane (6.17 g, 48 mmol, 69%).
    • Step 2. 1-methylcyclohexlycarboxaldehyde:
  • Figure US20060205672A1-20060914-C00566
  • To 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., was added a solution of pyridine sulfur trioxide complex (22.9 g, 144 mmol) in dimethylsulfoxide (150 mL) over 15 min. The cooling bath was allowed to warm to room temperature over two hours, at which time the reaction mixture was poured into brine with ice (400 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were diluted with hexanes (600 mL) and washed with 1M HCl (2×150 mL), saturated sodium chloride (2×100 mL), dried, filtered and concentrated. The residue was purified by flash chromatography to give 1-methylcyclohexylcarboxaldehyde (1.77 g, 13.8 mmol, 29%).
    • Step 3. Synthesis of N-formyl-N-glycosyl-1-methylcyclohexyl-tert-butylamide
  • Figure US20060205672A1-20060914-C00567
  • The synthesis of the 2,3,4-tri-O-pivaloyl-D-arabinosylamine was carried out according to the published procedure (Kunz. H.; Pfrengle, W.; Ruck, K.; Wilfried, S. Synthesis (1991) 1039-1042).
  • To a solution of 1-methylcyclohexylcarboxaldehyde (1.17 g, 8.34 mmol), 2,3,4-tri-O-pivaloyl-D-arabinosylamine (8.3 g, 20.7 mmol), formic acid (850 μL, 22.2 mmol) and tert-butylisocyanide (2.4 mL, 21.2 mmol) in tetrahydrofuran (170 mL) at −30° C. was added 0.5M zinc chloride in tetrahydrofuran (41 mL, 20.57 mmol). The solution was stirred at −20° C. for 3 days, then concentrated. The residue was diluted with CH2Cl2 (500 mL), washed with saturated sodium bicarbonate (2×500 mL), water (500 mL). The organic layer was dried, filtered and concentrated to give a clear oil. Flash chromatography (20% ethylacetate in hexanes) provided pure product (4.3 g, 6.6 mmol, 33%)
    • Step 4. Synthesis of (1-methylcyclohexyl)glycine
  • Figure US20060205672A1-20060914-C00568
  • A solution of the product obtained in step 3 above (4.3 g, 6.6 mmol) in dichloromethane (30 mL) and saturated anhydrous methanolic HCl (30 mL) was stirred overnight. The solution was concentrated and the residue was dissolved in water (100 mL) and washed with pentane (2×100 mL). The aqueous layer was concentrated and the residue was dissolved in 6N HCl (50 mL) and heated at reflux for 30 hours. The solution was concentrated to give the crude (1-methylcyclohexyl)glycine hydrochloride (790 mg, 3.82 mmol, 58%).
    • EXAMPLE XVII Synthesis of (4,4-dimethylcyclohexylglycine
  • Figure US20060205672A1-20060914-C00569
    • Step 1. Synthesis of 4,4-dimethylcyclohexanone
  • Figure US20060205672A1-20060914-C00570
  • A mixture of 4,4-dimethylcyclohex-2-en-1-one (12 mL, 91.2 mmol) and Degussa type 10% Pd on carbon (2 g) was hydrogenated at 40 psi for 18 hours. The mixture was filtered and concentrated (1H NMR showed a mixture of ketone and alcohol in a 5:3 ratio). The mixture was dissolved in acetone (400 mL) and cooled to 0° C. Jones reagent (40 mL) was added over 30 min and the cooling bath was removed. After 2 days the excess acetone was evaporated and the resulting residue was dissolved in water and diethylether. The ether layer was washed with water until colorless, dried, filtered and concentrated to give 4,4-dimethylcyclohexanone (7.4 g, 58.6 mmol, 64%).
    • Step 2. Synthesis of the methyl enol ether of 4,4-dimethylcyclohexylcarboxaldehyde
  • Figure US20060205672A1-20060914-C00571
  • To a solution of methoxymethyl triphenylphosphonium chloride (8.6 g) in tetrahydrofuran (125 mL) at 0° C. was added n-butyllithium (1.6M in hexanes, 14.3 mL) over 10 min. After 30 min the reaction mixture was cooled to −78° C. and a solution of 4,4-dimethylcyclohexanone (2.45 g, 19.1 mmol) in tetrahydrofuran (50 mL) was added over 20 min. After 1 hour the cooling bath was remove and the reaction was warmed slowly to 0° C. The reaction was diluted with saturated ammonium chloride (50 mL), ethylacetate (100 mL) and hexanes (100 mL). The organic layer was washed with water and brine, dried filtered and concentrated. The residue was stirred with hexanes (70 mL) for 10 min and filtered. The filtrate was concentrated and chromatographed using 25% ethylacetate in hexanes to give the title compound (1.925 g, 12.5 mmol, 65%).
    • Step 3: 4,4-dimethylcyclohexylcarboxaldehyde
  • Figure US20060205672A1-20060914-C00572
  • A solution of the methyl enol ether of 4,4-dimethylcyclohexylcarboxaldehyde (1.925 g, 12.5 mmol) (Step II above), tetrahydrofuran (100 mL) and 6M HCl (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with hexanes, diethylether, brine and water. The organic layer was dried, filtered and concentrated to give 4,4-dimethylcyclohexylcarboxaldehyde (1.0 g, 7.1 mmol, 57%).
    • Step 4. Synthesis of N-formyl-N-glycosyl-4,4-dimethylcyclohexyl-tert-butylamide
  • Figure US20060205672A1-20060914-C00573
  • To a solution of 4,4-dimethylcyclohexylcarboxaldehyde (1.17 g, 8.34 mmol), 2,3,4-tri-O-pivaloyl-α-D-arabinosylamine (3.43 g, 8.55 mmol), formic acid (350 μL, 9.17 mmol) and tert-butylisocyanide (990 μL, 8.76 mmol) in THF (70 mL) at −30° C. was added 0.5M zinc chloride in tetrahydrofuran (17 mL, 8.5 mmol). The solution was stirred at −20° C. for 2 days, then concentrated. The residue was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (2×200 mL), water (200 mL). The organic layer was dried, filtered and concentrated to give a clear oil. Flash chromatography (20% ethylacetate in hexanes) provided pure product (2.1 g, 3.3 mmol, 39%)
    • Step 5. Synthesis of (4,4-dimethylcyclohexyl)glycine
  • Figure US20060205672A1-20060914-C00574
  • A solution of the Ugi product obtained in step 4 above (2.1 g, 3.3 mmol) in dichloromethane (20 mL) and saturated anhydrous methanolic HCl (20 mL) was stirred overnight. The solution was concentrated and the residue was dissolved in water (100 mL) and washed with pentane (2×100 mL). The aqueous layer was concentrated and the residue was dissolved in 6N HCl (40 mL) and heated at reflux for 30 hours. The solution was concentrated to give the crude (1-methylcyclohexyl)glycine hydrochloride (300 mg, 1.36 mmol, 41%).
    • EXAMPLE XVIII Synthesis of Boc-nVal-(CHOH)-Gly-OH
  • Figure US20060205672A1-20060914-C00575
    • Step 1. Preparation of Boc-norvalinol
  • Figure US20060205672A1-20060914-C00576
  • To a solution of Boc-norvaline (25.0 g, 0.115 mol) in tetrahydrofuran (461 mL), cooled to 0° C., was added borane/tetrahydrofuran complex (461 mL of a 1.0M solution in tetrahydrofuran) dropwise. After 1 h at 0° C., the solution was warmed to room temperature over a period of 1.5 h. TLC indicated that the reaction was complete. Methanol was added to quench the reaction. The solution was concentrated to yield the title compound (22.56 g, 96%) as a foamy syrup. TLC of the products indicated satisfactory purity. Rf=0.34 (40% ethyl acetate/hexanes).
    • Step 2. Preparation Boc-norvalinal
  • Figure US20060205672A1-20060914-C00577
  • To Boc-norvalinol (7.77 g, 38 mmol), in anhydrous dimethylsulfoxide (153 mL) and toluene (153 mL) was added EDC (73.32 g, 382 mmol). After the solution was cooled to 0° C., dichloroacetic acid (15.8 mL, 191 mmol) was added dropwise. After addition was complete, the reaction was stirred for 15 min. The solution was allowed to warm to room temperature over a period of 2 h. The reaction mixture was concentrated to remove the toluene, then dissolved in ethyl acetate. The solution was washed successively with 1N sodium bisulfate, saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford crude Boc-norvalinal which was used directly in the next step. TLC Rf=0.84 (40% ethyl acetate/hexanes).
    • Step 3. Synthesis of Boc-nVal-(CHOH)-Gly-OEt
  • Figure US20060205672A1-20060914-C00578
  • To a solution of the crude Boc-norvalinal (4.18 g, 20.77 mmol) in dichloromethane (83 mL) was added ethylisocyanoacetate (2.72 ml, 24.93 mmol) and pyridine (6.72 ml, 83.09 mmol). After the solution was cooled to 0° C., trifluoroacetic acid (4.15 ml, 41.54 mmol) was added dropwise. After stirring for 1 h, the solution was stirred at room temperature for 18 hours while allowing the solvent from the reaction mixture in an uncovered vessel to evaporate under ambient conditions. The reaction mixture was concentrated, then dissolved in ethyl acetate. The solution was washed successively with 1N sodium bisulfate, saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and then concentrated. The residue was purified by flash chromatography eluting with 20% to 40% ethylacetate/hexanes to afford 2.8 g of the title compound as a yellow syrup. Low resolution mass spectroscopy confirmed the presence of the desired product (MH+ 333).
    • Step 4. Synthesis of Boc-nVal-(CHOH)-Gly-OH
  • Figure US20060205672A1-20060914-C00579
  • The product obtained (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 two hours at room temperature. The reaction mixture was acidified to pH 2 with Dowex® 50 WX8 ion exchange resin, stirred for 20 minutes and then filtered. The resin was washed well with ethanol and water and the combined filtrates were concentrated to a white foam (0.48 g, 33%).
    • EXAMPLE XVIV Synthesis of (2R,3S,4S,5S)-tert-Butyl N-CBz-3-amino-2-hydroxy-4,5 methylene-hexanoate
  • Figure US20060205672A1-20060914-C00580
    • Step 1
  • Figure US20060205672A1-20060914-C00581
  • To a solution of tert-Butyl diethylphosphonoacetate (4.7 mL, 20 mmol) dissolved in THF (50 mL) at −78° C. was added 1.6M n-butyl lithium in hexanes (12.4 mL). After 30 minutes (1S,2S)-2-methylcyclopropylcarboxaldehyde (1 g, 12 mmol) (Barrett, A. G. M.; Doubleday, W. W.; kasdorf, K.; Tustin, G. J., J. Org. Chem. (1996) 61, 3280) in diethyl ether (100 mL) was added over 10 min. The reaction was warmed to 0° C. for 2 hours and to 6° C. for 12 hours. The reaction was quenched with saturated ammonium chloride (20 mL) and the organic layer was separated, washed with 50 mL brine and dried over sodium sulfate, filtered and concentrated to afford 3.5 g of a clear oil. Flash chromatography (20% ethylacetate in hexanes) afforded pure unsaturated tert-butylester (1.4 g).
    • Step 2
  • Figure US20060205672A1-20060914-C00582
  • To a solution of benzyl carbamate (3.55 g, 23.5 mmols) 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). After 15 minutes the reaction was cooled to 0° C. and (DHQ)2PHAL (350 mg, 0.45 mmol) was added in n-propanol (24 mL), followed by unsaturated tert-butyl ester (1.4 g) from above in n-propanol (48 mL). Finally potassium osmate (110 mg, 0.30 mmol) in water (2 mL) was added and the solution very rapidly developed a dark green color which persisted for 4 hours. After 6 hours saturated sodium sulfate (50 mL) was added and the mixture extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. Flash chromatography with 20% ethylacetate in hexanes afforded the desired cBz protected amino tert-butylester as a white solid (316 mg).
    • Step 3
  • Figure US20060205672A1-20060914-C00583
  • A mixture of CBz protected amino tert-butylester (316 mg, 0.9 mmol) and 32 mg 10% palladium on carbon in 9 mL methanol was hydrogenated for 8 hours. The mixture was filtered and concentrated to afford the free amine as a clear oil (195 mg).
    • EXAMPLE XX Synthesis of 1R,2-dimethylpropyl chloroformate
  • Figure US20060205672A1-20060914-C00584
  • To the commercially available 2R-hydroxy-3-methylbutane (410 mg, 4.65 mmol) was added a solution of 20% phosgene in toluene (1 mL, 2 mmol). The solution was stirred for 6 hours to generate the chloroformate (2 mmol) which was reacted directly and immediately with the desired amine. The S-isomer was synthesized by the same procedure.
  • II) Representative Solution Phase Synthesis of HCV Inhibitors
    • EXAMPLE XXI Solution phase synthesis of iBoc-G(Chx)-Pro(4,4-dimethyl)-Leu-(CO)-Gly-Phg-dimethylamide
  • Figure US20060205672A1-20060914-C00585
    • Step 1. Synthesis of tert-butyloxycarbonyl-leucinal (Boc-Leu-CHO)
  • Figure US20060205672A1-20060914-C00586
  • To a solution of the commercially available (Advanced Chem Tech) Boc-L-leucinol (0.78 g, 3.6 mmol) in anhydrous dichloromethane (17.5 ml) was added triethyl amine (2 ml, 14.36 mmol) and the mixture was cooled to 0° C. Dimethyl sulfoxide (17.5 ml) was added followed by sulfur trioxide pyridine complex (2.3 g, 14.36 mmol) and the reaction was stirred for two hours. TLC in 1:1 ethylacetate:hexanes confirmed the completion of the reaction. The reaction mixture was concentrated and the remaining residue diluted with ethylacetate. The ethylacetate layer was washed with 1M hydrochloric acid (2×75 ml) followed by saturated sodium bicarbonate solution (2×75 ml) and brine (75 ml). The organic layer was dried (sodium sulfate), filtered and concentrated to yield 775 mg of product.
    • Step 2. Synthesis of Boc-2-hydroxy-3-amino-5-methyl hexanoyl-glycine ethyl ester (Boc-Leu-(CHOH)-Gly-OEt)
  • Figure US20060205672A1-20060914-C00587
  • 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 was cooled to 0° C. and trifluoroacetic acid (0.55 ml, 7/18 mmol) was added over two minutes. The reaction mixture was capped and stirred at 4° C. for four days, and at room temperature for one day. The reaction mixture was diluted with dichloromethane (350 ml) and washed twice each with 75 ml portions of 1M hydrochloric acid, saturated sodium bicarbonate and brine. The organic layer was dried, filtered and concentrated. The residue obtained was subjected to flash chromatography in a 2″×6″ silica gel column using 10% ethylacetate in hexanes (800 ml) followed by 1:1 ethylacetate in hexanes (800 ml). The fractions corresponding to the product were pooled and concentrated to yield 980 mg (79%) product.
    • Step 3. Synthesis of Boc-Leu-(CHOH)-Gly-OH
  • Figure US20060205672A1-20060914-C00588
  • To a solution of Boc-Leu-(CHOH)-Gly-Oet (0.98 g, 2.83 mmol) in ethanol (11.3 ml) was added 2M lithium hydroxide (4.25 ml) and the reaction was stirred for five hours at room temperature. The ethanol was removed under reduced pressure and the aqueous layer was diluted with ethylacetate. The organic layer was washed with 1M hydrochloric acid followed by brine, dried, filtered and concentrated to yield 775 mg (86%) product as a white solid.
    • Step 4. Synthesis of Boc-Leu-(CHOH)-Gly-Phg-dimethylamide
  • Figure US20060205672A1-20060914-C00589
  • To a solution of Boc-Leu-(CHOH)-Gly-OH (0.37 g, 1.18 mmol) in acetonitrile (23 ml) was added successively phenylglycine dimethylamide (obtained in Example XV, Step 2), EDC (0.34 g, 1.76 mmol), N-hydroxybenzotriazole (HOBt)(0.18 g, 1.18 mmol) and diisopropylethylamine (DIEA) (0.82 ml, 4.7 mmol) and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated and the remaining residue was diluted with ethylacetate and washed successively with two 75 ml portions of 1M hydrochloric acid, saturated sodium bicarbonate and brine. The organic layer was then dried filtered and concentrated. The crude product was subjected to flash chromatography in a 2″×6″ silica gel column using 4:1 ethylacetate:hexanes (700 ml) followed by ethylacetate (1000 ml) and 10% methanol in dichloromethane (600 ml). The fractions corresponding to the product were pooled and concentrated to yield 445 mg (80%) white solid.
    • Step 5. Synthesis of H-Leu-(CHOH)-Gly-Phg-dimethylamide trifluoroacetate salt
  • Figure US20060205672A1-20060914-C00590
  • To a solution Boc-Leu-(CHOH)-Gly-Phg-dimethylamide (70 mg, 0.146 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and taken to the next step without further purification.
    • Step 6. Synthesis of iBoc-G(Chx)-Pro(4,4-dimethyl)-Leu-(CHOH)-Gly-Phg-dimethylamide
  • Figure US20060205672A1-20060914-C00591
  • To a solution of iBoc-G(Chx)-P(4,4-diMe)-OH (Example XIV, step 2)(53 mg, 0.148 mmol) in acetonitrile (3 ml) was added successively TFA.2HN-Leu(CHOH)-Gly-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). The reaction was stirred at room temperature for 18 hours and concentrated. The remaining residue was dissolved in ethylacetate and washed with 1M hydrochloric acid (2×5 ml), saturated sodium bicarbonate solution (2×5 ml), and brine (2×5 ml). The organic layer was dried, filtered and concentrated. The product (100 mg) was taken to the next step without further purification.
    • Step 7. Synthesis of iBoc-G(Chx)-Pro(4,4-dimethyl)-Leu-(CO)-Gly-Phg-dimethylamide
  • Figure US20060205672A1-20060914-C00592
  • To a solution of iBoc-G(Chx)-Pro(4,4-dimethyl)-Leu-(CHOH)-Gly-Phg-dimethylamide (30 mg, 0.04 mmol) in dichloromethane (1 ml) was added the commercially available Dess-Martin reagent (Omega Chemical Company Inc.)(67.8 mg, 0.16 mmol) and the reaction was stirred at room temperature for 90 minutes. The reaction mixture was concentrated and the remaining residue was stirred in 5% sodium thiosulfate. It was then diluted with dichloromethane and the is layers were separated. The organic layer was washed with sodium thiosulfate (4×3 ml), followed by water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in hexanes and isopropyl alcohol and was subjected to HPLC purification using a normal phase Kromasil 5 silica column (Phenomenex, 250×21.20 mm, 100 angstrom pore size, 5 μm gel particles) eluting with a 30 minutes gradient consisting of 0 to 25% isopropyl alcohol in hexanes (25 ml/minutes). The fractions corresponding to the product were pooled and concentrated. Lyophilization from water yielded 6.7 mg white powder. Low resolution mass spectra confirmed the desired mass (MH+=741.4).
  • III) Solid Phase Synthesis:
  • Solid-phase synthesis is useful for the production of small amounts of certain compounds of the present invention. As with the conventional solid-phase synthesis of peptides, reactors for the solid-phase synthesis of peptidyl ketoamides are comprised of a reactor vessel with at least one surface permeable to solvent and dissolved reagents, but not permeable to synthesis resin of the selected mesh size. Such reactors include glass solid phase reaction vessels with a sintered glass frit, polypropylene tubes or columns with frits, or reactor Kans™ made by Irori Inc., San Diego Calif. The type of reactor chosen depends on volume of solid-phase resin needed, and different reactor types might be used at different stages of a synthesis. The following procedures will be referenced in the subsequent examples:
  • Procedure A: Coupling reaction: To the resin suspended in N-methylpyrrolidine (NMP) (10-15 mL/gram resin) was added Fmoc-amino acid (2 eq), HOAt (2 eq), HATU (2 eq) and diisopropylethylamine (4 eq). The mixture was let to react for 4-48 hours. The reactants were drained and the resin was washed successively with dimethylformamide, dichloromethane, methanol, dichloromethane and diethylether (use 10-15 mL solvent/gram resin). The resin was then dried in vacuo.
  • Procedure B: Fmoc deprotection: The Fmoc-protected resin was treated with 20% piperidine in dimethylformamide (10 mL reagent/g resin) for 30 minutes. The reagents were drained and the resin was washed successively with dimethylformamide, dichloromethane, methanol, dichloromethane and diethyl ether (10 mL solvent/gram resin).
  • Procedure C: Boc deprotection: The Boc-protected resin was treated with a 1:1 mixture of dichloromethane and trifluoroacetic acid for 20-60 minutes (10 mL solvent/gram resin). The reagents were drained and the resin was washed successively with dichloromethane, dimethylformamide, 5% diisopropylethylamine in dimethylformamide, dimethylformamide, dichloromethane and dimethylformamide (10 mL solvent/gram resin).
  • Procedure D: Semicarbazone hydrolysis: The resin was suspended in the cleavage cocktail (10 mL/g resin) consisting of trifluoroacetic acid: pyruvic acid: dichloromethane: water 9:2:2:1 for 2 hours. The reactants were drained and the procedure was repeated three more times. The resin was washed successively with dichloromethane, water and dichloromethane and dried under vacuum.
  • Procedure E: HF cleavage: The dried peptide-nVal(CO)-G-O-PAM resin (50 mg) was placed in an HF vessel containing a small stir bar. Anisole (10% of total volume) was added as a scavenger. In the presence of glutamic acid and cysteine amino acids, thioanisole (10%) and 1,2-ethanedithiol (0.2%) were also added. The HF vessel was then hooked up to the HF apparatus (Immuno Dynamics) and the system was flushed with nitrogen for five minutes. It was then cooled down to −70° C. with a dry ice/isopropanol bath. After 20 minutes, HF was distilled to the desired volume (10 mL HF/g resin). The reaction was let to proceed for one and a half hour at 0° C. Work up consisted of removing all the HF using nitrogen. Dichloromethane was then added to the resin and the mixture was stirred for five minutes. This was followed by the addition of 20% acetic acid in water (4 mL). After stirring for 20 minutes, the resin was filtered using a fritted funnel and the dichloromethane was removed under reduced pressure. The remaining residue and the mixture was washed with hexanes (2×) to remove scavengers. Meanwhile, the resin was soaked in 1 mL methanol. The aqueous layer (20% HOAc) was added back to the resin and the mixture was agitated for five minutes and then filtered. The methanol was removed under reduced pressure and the aqueous layer was lyophilized. The peptide was then dissolved in 10-25% methanol (containing 0.1% trifluoroacetic acid) and purified by reverse phase HPLC.
    • EXAMPLE XXII Representative Solid Phase Synthesis of Hep C Inhibitors: (iBoc-G(Chx)-P(4t-NHSO2Ph)-nV-(CO)-G-G(Ph)-NH2)
  • Figure US20060205672A1-20060914-C00593
    • Step 1. Synthesis of Fmoc-nV-(dpsc)-Gly-OH A) Synthesis of allyl isocyanoacetate (steps a-b below) a) Synthesis of isocyanoacetic acid potassium salt
  • Figure US20060205672A1-20060914-C00594
  • Ethyl isocyanoacetate (96.6 ml, 0.88 mol) was added dropwise to a chilled solution of ethanol (1.5 L) and potassium hydroxide (59.52 g, 1.0 mol). The reaction was slowly warmed to room temperature. After two hours the precipitated product was filtered on a glass funnel and washed with several portions of chilled ethanol. The potassium salt of isocyanoacetic acid thus obtained was dried in vacuo to a golden-brown solid (99.92 g, 91.8%).
    • b) Synthesis of allyl isocyanoacetate
  • Figure US20060205672A1-20060914-C00595
  • To the product of part a (99.92 g, 0.81 mol) dissolved in acetonitrile (810 ml) was added allyl bromide (92 ml, 1.05 mol). After heating at reflux for four hours a dark brown solution was obtained. The reaction mixture was concentrated and the remaining residue was dissolved in ether (1.5 L) and washed three times with water (500 ml). The organic layer was dried, filtered and concentrated to a dark brown syrup. The crude was purified by vacuum distillation at 7 mm Hg (98 C) to a clear oil (78.92 g, 78%). NMR δ ppm (CDCl3): 5.9 (m, 1 H), 5.3 (m, 2H), 4.7 (d, 2H), 4.25 (s, 2H).
    • B) Synthesis of 9-fluorenylmethoxycarbonyl-norvalinal (steps a-c below) a) Synthesis of 9-fluorenylmethoxycarbonyl-L-norvaline methyl ester (Fmoc-nVal-OMe)
  • Figure US20060205672A1-20060914-C00596
  • To a chilled solution of the commercially available Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml) was added thionyl chloride (53.76 ml, 737.5 mmol) over one hour. TLC in ethylacetate taken an hour later confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate. The organic layer was washed with several 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried, filtered and concentrated to afford Fmoc-norVal-OMe) as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m, 1H), 1.4 (m, 2H), 0.95 (t, 3H).
    • b) Synthesis of 9-fluorenylmethoxycarbonyl-norvalinol (Fmoc-nValinol)
  • Figure US20060205672A1-20060914-C00597
  • To Fmoc-nVal-OMe (26.03 g, 73.75 mmol) in tetrahydrofuran (123 ml) and methanol (246 ml) was added calcium chloride (16.37 g, 147.49 mmol). The reaction mixture was cooled to 0° C. and sodium borohydride (11.16 g, 294.98 mmol) was added in several batches. To the thick paste obtained, methanol (500 ml) was added and the reaction was let to stir at room temperature for 90 minutes. TLC in 2:3 ethylacetate:hexanes confirmed the completion of the reaction (Rf=0.25). The reaction was quenched with the slow addition of water (100 ml) at 0° C. The methanol was removed under reduced pressure and the remaining aqueous phase was diluted with ethylacetate. The organic layer was washed with water (3×500 ml), saturated sodium bicarbonate (3×500 ml) and brine (500 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to a white solid (21.70 g, 90.5%). NMR δ ppm (CD3OD): 7.8 (m, 2H), 7.7 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3-4.5 (m, 2H), 4.2 (m, 1H), 3.6 (s, 1H), 3.5 (s, 2H), 1.5 (m, 1H), 1.3-1.4 (m, 3H), 0.99 (m, 3H).
    • c) Synthesis of 9-fluorenylmethoxycarbonyl-norvalinal (Fmoc-nVal-CHO)
  • Figure US20060205672A1-20060914-C00598
  • 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) was added to the chilled solution. After one hour, TLC in 2:3 ethylacetate:hexanes confirmed the completion of the reaction. The dichloromethane was removed under reduced pressure and the remaining residue was dissolved in ethylacetate and washed with water (2×50 ml), 1N saturated sodium bisulfate (2×50 ml), saturated sodium bicarbonate (2×50 ml) and brine (50 ml). The organic layer was concentrated to yield a white solid. Theoretical yield (21.57 g) was assumed and the reaction was taken to the next step without further purification.
    • C) Synthesis of diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt (steps a-b below) a) Synthesis of Boc-semicarbazid-4-yl diphenylmethane
  • Figure US20060205672A1-20060914-C00599
  • To a solution of carbonyldiimidazole (16.2 g, 0.10 mole) in dimethylformamide (225 ml) was added a solution of t-butyl carbazate (13.2 g, 0.100 mol) in dimethylformamide (225 ml) dropwise over 30 minutes. Diphenylmethylamine (18.3 g, 0.10 mol) was added next over 30 minutes. The reaction was allowed to stir at room temperature for one hour. Water (10 mL) was added and the mixture was concentrated to about 150 mL under reduced pressure. This solution was poured into water (500 mL) and extracted with ethyl acetate (400 mL). The ethylacetate phase was washed two times each with 75 mL 1N HCl, water, saturated sodium bicarbonate solution and sodium chloride, and dried with magnesium sulfate. The mixture was filtered and the solution was concentrated to give 29.5 g (85% yield) of a white foam. This material could be purified by recrystallization from ethyl acetate/hexane, but was pure enough to use directly in the next step: mp 142-143° C. 1H NMR (CDCl3) d 1.45 (s, 9H), 6.10 (dd, 2H), 6.42 (s, 1H), 6.67 (bs, 1H), 7.21-7.31 (m, 10H). Anal calculated for C19H23N3O3: C, 66.84; H, 6.79; N, 12.31. Found: C, 66.46; H, 6.75; N, 12.90.
    • b) Synthesis of diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt
  • Figure US20060205672A1-20060914-C00600
  • A solution of Boc-semicarbazid-4-yl diphenylmethane (3.43 g, 10 mmol) in dichloromethane (12.5 mL) was treated with 12.5 mL of trifluoroacetic acid at room temperature and stirred for 30 min. The solution was added dropwise to 75 mL of ether and the resulting solid (2.7 g, 80%) was collected by filtration. mp 182-184° C. 1H NMR (CD3OD) d 6.05 (s, 1H), 7.21-7.35 (m, 10H). 13C NMR (CD3OD) d 57.6, 118.3 (q, CF3), 126.7, 127.9, 141.6, 156.9, 160.9 (q, CF3CO2H).
    • D) Synthesis of Fmoc-nVal-(CHOH)-Gly-Oallyl
  • Figure US20060205672A1-20060914-C00601
  • To a solution of Fmoc-nVal-CHO (Step 1B) (5.47 g, 16.90 mmol) in dichloromethane (170 ml) was added allyl isocyanoacetate (Step 1A) (2.46 ml, 20.28 mmol) and pyridine (5.47 ml, 67.61 mmol). The reaction mixture was cooled to 0° C. and trifluoroacetic acid (3.38 ml, 33.80 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h, and then at room temperature for 48 hours. TLC taken in ethylacetate confirmed the completion of the reaction. The reaction mixture was concentrated and subjected to flash chromatography using 20% to 70% ethylacetate in hexanes. Fractions containing the desired product were pooled and concentrated to a white foam (6.88 g, 87.3%). TLC in 50:50 ethylacetate shows one spot (Rf=0.37). NMR δ ppm (CD3OD): 7.8 (m, 2H), 7.65 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 5.9 (m, 1H), 5.1-5.4 (m, 2H), 4.55-4.65 (m, 2H), 4.34.4 (m, 2H), 4.15-4.25 (m, 1H), 4.01 (s, 1H), 3.9-4.0 (m, 3H), 1.5-1.6 (m, 2H), 1.35-1.45 (m, 3H), 0.9 (m, 3H).
    • E) Synthesis of Fmoc-nVal-(CO)-Gly-Oallyl
  • Figure US20060205672A1-20060914-C00602
      • 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) was added EDC (20.6 g, 107.7 mmol). The reaction mixture was cooled to 0° C. and dichloroacetic acid (4.44 ml, 53.83 mmol) was added dropwise. The reaction was stirred for 15 minutes at 0° C. and 1 h at room temperature. After cooling back to 0 C, water (70 ml) was added and the toluene was removed under reduced pressure. The remaining residue was diluted with ethylacetate and washed several times with a saturated sodium bicarbonate solution followed by 1N sodium bisulfate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The theoretical yield of 4.99 g was assumed and the reaction was taken to the next step without further purification. TLC in 50:50 ethylacetate shows one spot (Rf=0.73).
    F) Synthesis of Fmoc-nVal-(dpsc)-Gly-Oallyl
  • Figure US20060205672A1-20060914-C00603
  • To a solution of Fmoc-nVal-(CO)-Gly-Oallyl (Step E) (4.99 g, 10.75 mmol) in ethanol (130 ml) and water (42 ml) was added diphenylmethyl semicarbazide (dpsc) trifluoroacetate salt (Step IC) (7.6 g, 21.5 mmol) and sodium acetate.3H2O (1.76 g, 12.9 mmol), successively. The reaction mixture was heated at reflux for 90 minutes. The completion of reaction was confirmed by TLC taken in 1:1 ethylacetate:hexane. Ethanol was removed under reduced pressure and the remaining residue was dissolved in ethylacetate and washed with 1N sodium bisulfate (2×10 ml), saturated sodium bicarbonate (2×10 ml), followed by brine (10 ml). The organic layer was dried, filtered and concentrated. The resulting residue was purified by flash chromatography in 20% to 50% ethylacetate in hexanes to give a white solid (5.76 g, 78%). TLC in 50:50 ethylacetate:hexanes showed two spots (cis and trans isomers) with Rf=0.42 and 0.5.
    • G) Synthesis of Fmoc-nVal-(dpsc)-Gly-OH
  • Figure US20060205672A1-20060914-C00604
  • To a solution of Fmoc-nVal-(dpsc)-Gly-Oallyl (Step 1G) (4.53 g, 6.59 mmol) in tetrahydrofuran (300 ml) was added dimedone (4.62 g, 32.97 mmol) followed by tetrakis(triphenylphosphine) palladium(0) catalyst (0.76 g, 0.66 mmol). The completion of the reaction was confirmed by TLC after 90 minutes using 9:1 dichloromethane: methanol. The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate and washed three times with 50 ml portions of 0.1M potassium biphosphate. The organic layer was then treated with 50 ml sodium bisulfite and the two phase system was stirred for 15 minutes. The phases were separated and the procedure was repeated twice more. The organic layer was dried and concentrated and subjected to flash chromatography with 20% to 100% ethylacetate in hexanes. This was followed with 9:1 dichloromethane: methanol solution. The fractions corresponding to the pure product were pooled and concentrated to obtain a white solid (3.99 g, 94%). TLC in 9:1 dichloromethane: methanol showed two spots (cis and trans isomers). NMR δ ppm (CD3OD): 7.75 (m, 2H), 7.6 (m, 3H), 7.2-7.4 (m, 14H), 6.1-6.2 (m, 1H), 4.25-4.4 (m, 2H), 4.14.2 (m, 2H), 3.85 (s, 2H), 1.6-1.8 (m, 2H), 1.3-1.5 (m, 2H), 0.95 (t, 3H).
    • Step 2. Synthesis H-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00605
  • The commercially available MBHA resin (2.6 g, 1.12 mmol/g, 2.91 mmol) was transferred to a 250 mL fritted solid phase reaction vessel equipped with a nitrogen inlet. It was then washed thoroughly with 30 ml portions of dichloromethane, methanol, dimethylformamide and dichloromethane and coupled over 18 hours to the commercially available Fmoc-Phg-OH (2.17 g, 5.82 mmol) according Procedure A with 99.82% efficiency. The resin was then subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a is small aliquot gave dark blue resin and solution, indicating a successful reaction.
    • Step 3. Synthesis of H-nVal(dpsc)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00606
  • The resin obtained in step II (2.6 g, 0.8 mmol/g, 2.91 mmol) was reacted with Fmoc-nVal-(dpsc)-Gly-Oallyl (Step 1G) (5.82 mmol, 3.77 g) according to Procedure A. After 18 hours, quantitative ninhydrin analysis indicated 99.91% coupling efficiency. The resin was subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a small aliquot gave dark blue resin and solution, indicating a successful reaction.
    • Step 4. Synthesis of Boc-Pro(4t-NHFmoc)-nVal(dpsc)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00607
  • The compound H-nVal(dpsc)-Gly-Phg-MBHA resin (Step 3 above) (600 mg, 0.8 mmol/g, 0.67 mmol) was transferred to a fritted polypropylene tube and was coupled to Boc-Pro(4t-NHFmoc)-OH (Example VI, Step 3) (610 mg, 1.34 mmol) according to procedure A. After 18 hours, quantitative ninhydrin analysis indicated 99.96% coupling efficiency.
    • Step 5. Synthesis of Boc-Pro(4t-NH2)-nVal(dpsc)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00608
  • The resin from the previous step (Boc-Pro(4t-NHFmoc)-nVal(dpsc)-Gly-Phg-MBHA resin) was subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a small aliquot gave dark blue resin and solution, indicating a successful reaction.
    • Step 6. Synthesis of Boc-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00609
  • To the resin obtained from the previous step (Boc-Pro(4t-NH2)-nVal(dpsc)-Gly-Phg-MBHA resin) (0.2 g, 0.22 mmol) suspended in NMP (2 ml) was added 2,4,6-collidine (0.24 ml, 1.79 mmol) and benzenesulfonyl chloride and the reaction was shaken for 18 hours. The solvent was drained and the resin was washed thoroughly with 2 ml portions of dichloromethane, methanol, dimethylformamide and dichloromethane. Qualitative ninhydrin analysis showed colorless beads and solution indicating a successful reaction.
    • Step 7. Synthesis of Fmoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00610
  • The resin obtained in the previous step (Boc-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin) was subjected to the Boc deprotection procedure according to Procedure C. Fmoc-G(Chx) (0.17 g, 0.45 mmol) was then coupled according to procedure A. After 18 hours qualitative ninhydrin analysis showed colorless beads and the quantitative ninhydrin analysis indicated 99.79% coupling efficiency.
    • Step 8. Synthesis of iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00611
  • The resin obtained in the previous step (Fmoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin) was subjected to Fmoc deprotection according to procedure B. A ninhydrin assay on a small aliquot gave dark blue resin and solution, indicating a successful reaction. To the resin (0.2 g, 0.22 mmol) suspended in 2 ml NMP was added isobutylchloroformate (0.12 ml, 0.90 mmol) followed by diisopropylethylamine (0.31 ml, 1.79 mmol), and the reaction mixture was shaken for 18 hours at room temperature. Qualitative ninhydrin analysis showed colorless beads and solution indicating a successful reaction.
    • Step 9. Synthesis of iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(CO)-Gly-Phg-MBHA resin
  • Figure US20060205672A1-20060914-C00612
  • The compound of the previous step (iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(dpsc)-Gly-Phg-MBHA resin) (200 mg) was subjected to semicarbazone hydrolysis Procedure D.
    • Step 10. Synthesis of Synthesis of iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(CO)-Gly-Phg-NH
  • Figure US20060205672A1-20060914-C00613
  • The resin of the previous step (iBoc-G(Chx)-Pro(4t-NHSO2Bn)-nVal(CO)-Gly-Phg-MBHA resin) (100 mg) was subjected to HF cleavage condition (Procedure E) to yield the desired crude product. The material was purified by HPLC using a 2.2×25 cm reverse phase column, containing a C-18 resin comprised of 10 micron size gel particles with a 300 angstrom pore size, eluting with a gradient using 20-50% acetonitrile in water. Analytical HPLC using a 4.6×250 mm reverse phase column, containing a C-18 resin comprised of 5 micron size gel particles with a 300 angstrom pore size, eluting with 25-75% acetonitrile (containing 0.1% trifluoroacetic acid) showed one peak at 13.5 minutes. Low resolution mass spectrum confirmed the desired mass (MH+ 826.4).
  • IV. Additional Compounds Prepared by Solution Phase Synthesis:
  • Representative procedures to prepare additional inventive compounds are shown below, and the compounds prepared by such procedures are listed in Table 5.
    • EXAMPLE XXIII Preparation of a Compound of Formula XXIII
  • Figure US20060205672A1-20060914-C00614
    • Step 1
  • Figure US20060205672A1-20060914-C00615
  • A stirred solution of ketimime XXIIIa (50 g, 187.1 mmol) under N2 in dry THF (400 mL) was cooled to −78° C. and treated with 1M solution of K-tBuO (220 mL, 1.15 equiv.) in THF. The reaction mixture was warmed to 0° C. and stirred for 1 h and treated with bromomethyl cyclobutane (28 mL, 249 mmol). The reaction mixture was stirred at room temperature for 48 h and concentrated in vacuo. The residue was dissolved in Et2O (300 mL) and treated with aq. HCl (2 M, 300 mL) The resulting solution was stirred at room temperature for 5 h and extracted with Et2O (1 L). The aqueous layer was made basic to pH˜12-14 with NaOH (50% aq.) and extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give pure amine (XXIIIb, 18 g) as a colorless oil.
    • Step 2
  • Figure US20060205672A1-20060914-C00616
  • A solution of amine XXIIIb (18 g, 105.2 mmol) at 0° C. in CH2Cl2 (350 mL) was treated with di-tert-butyldicarbonate (23 g, 105.4 mmol) and stirred at rt. for 12 h. After the completion of the reaction (TLC), the reaction mixture was concentrated in vacuo and the residue was dissolved in THF/H2O (200 ml, 1:1) and treated with LiOH.H2O (6.5 g, 158.5 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the basic aqueous layer was extracted with Et2O. The aqueous layer was acidified with conc. HCl to pH-1-2 and extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to yield XXIIIc as a colorless viscous oil which was used for next step without any further purification.
    • Step 3
  • Figure US20060205672A1-20060914-C00617
  • A solution of acid XXIIIc (15.0 g, 62 mmol) in CH2Cl2 (250 mL) was treated with BOP reagent (41.1 g, 93 mmol), N-methyl morpholine (27 mL), N,O-dimethyl hydroxylamine hydrochloride (9.07 g, 93 mmol) and stirred overnight at rt. The reaction mixture was diluted with 1N aq. HCl (250 mL), and the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×300 ml). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo and purified by chromatography (SiO2, EtOAc/Hex 2:3) to yield the amide XXIIId (15.0 g) as a colorless solid.
    • Step 4
  • Figure US20060205672A1-20060914-C00618
  • A solution of amide XXIIId (15 g, 52.1 mmol) in dry THF (200 mL) was treated dropwisely with a solution of LiAlH4 (1M, 93 mL, 93 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and carefully quenched at 0° C. with a solution of KHSO4 (10% aq.) and stirred for 0.5 h. The reaction mixture was diluted with aq. HCl (1 M, 150 mL) and extracted with CH2Cl2 (3×200 mL), The combined organic layers were washed with aq. HCl (1 M), saturated NaHCO3, brine, and dried (MgSO4). The mixture was filtered and concentrated in vacuo to yield XXIIIe as a viscous colorless oil (14 g).
    • Step 5
  • Figure US20060205672A1-20060914-C00619
  • A solution of the aldehyde XXIIIe (14 g, 61.6 mmol) in CH2Cl2 (50 mL), was treated with Et3N (10.73 mL, 74.4 mmol), and acetone cyanohydrin (10.86 g, 127.57 mmol) and stirred at room temperature for 24 hrs. The reaction mixture was concentrated in vacuo and diluted with aq. HCl (1 M, 200 mL) and extracted into CH2Cl2 (3×200 mL). The combined organic layer were washed with H2O, brine, dried (MgSO4), filtered, concentrated in vacuo and purified by chromatography (SiO2, EtOAc/Hex 1:4) to yield XXIIIf (10.3 g) as a colorless liquid
    • Step 6
  • Figure US20060205672A1-20060914-C00620
  • Methanol saturated with HCl*, prepared by bubbling HCl gas to CH3OH (700 ml) at 0° C., was treated with cyanohydrin XXIIIf and heated to reflux for 24 h. The reaction was concentrated in vacuo to yield XXIIIg, which was used in the next step without purification.
  • * Alternatively 6M HCl prepared by addition of AcCl to dry methanol can also be used.
    • Step 7
  • Figure US20060205672A1-20060914-C00621
  • A solution of the amine hydrochloride XXIIIg in CH2Cl2 (200 mL) was treated with Et3N (45.0 mL, 315 mmol) and Boc2O (45.7 g, 209 mmol) at −78° C. The reaction mixture was then stirred at room temperature overnight and diluted with HCl (2 M, 200 mL) and extracted into CH2Cl2. The combined organic layer were dried (MgSO4) filtered, concentrated in vacuo and purified by chromatography (EtOAc/Hex 1:4) to yield hydroxy ester XXIIIh.
    • Step 8
  • Figure US20060205672A1-20060914-C00622
  • A solution of methyl ester XXIIIh (3 g, 10.5 mmol) in THF/H2O (1:1) was treated with LiOH.H2O (645 mg, 15.75 mmol) and stirred at rt. for 2 h. The reaction mixture was acidfied with aq HCl (1 M, 15 mL) and concentrated in vacuo. The residue was dried in vacuum.
  • A solution of the acid in CH2Cl2 (50 mL) and DMF (25 mL) was treated with NH4Cl (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 was stirred at room temperature for 3 d. The solvents were removed under vacuo and the residue was diluted with aq. HCl (250 mL) and extracted with CH2Cl2. The combined organic layers were washed with aq. Sat'd. NaHCO3, dried (MgSO4) filtered concentrated in vacuo to obtain XXIIIi, which was used as it is in the following steps. (Alternatively XXIIIi can also be obtained directly by the reaction of XXIIIf (4.5 g, 17.7 mmol) with aq. H2O2 (10 mL), LiOH.H2O (820 mg, 20.8 mmol) at 0° C. in 50 mL of CH3OH for 0.5 h.)
    • Step 9
  • Figure US20060205672A1-20060914-C00623
  • A solution of XXIIIi obtained in the previous step was dissolved in 4 N HCl in dioxane and stirred at rt. for 2 h. The reaction mixture was concentrated in vacuo to give XXIIIj as a solid, which was used without further purification.
    • Step 10
  • Figure US20060205672A1-20060914-C00624
  • The amino ester XXIIII was prepared following the method of R. Zhang and J. S. Madalengoitia (J. Org. Chem. 1999, 64, 330), with the exeception that the Boc group was cleved by the reaction of the Boc-protected amino acid with methanolic HCl.
  • A solution of commercial amino acid Boc-Chg-OH, XXIIIk (Senn chemicals, 6.64 g, 24.1 mmol) and amine hydrochloride XXIIII (4.5 g, 22 mmol) in CH2Cl2 (100 mL) at 0° C. was treated with BOP reagent and stirred at rt. for 15 h. The reaction mixture was concentrated in vacuo, then it was diluted with aq. 1 M HCl and extracted into EtOAc (3×200 mL). The combined organic layers were washed with sat'd. NaHCO3 (200 mL), dried (MgSO4), filtered and concentrated in vacuo, and chromatographed (SiO2, EtOAc/Hex 3:7) to obtain XXIIIm (6.0 g) as a colorless solid.
    • Step 11
  • Figure US20060205672A1-20060914-C00625
  • A solution of methyl ester XXIIIm (4.0 g, 9.79 mmol) in THF/H2O (1:1) was treated with LiOH.H2O (401 mg, 9.79 mmol) and stirred at rt. for 3 h. The reaction mixture was acidified with aq. HCl and concentrated in vacuo to obtain the free acid.
  • A solution of acid (1.5 g, 3.74 mmol) in DMF/CH2Cl2 (1:1 50 mL) was treated 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) at −10° C. The reaction mixture was stirred at 0° C. for 48 h and concentrated in vacuo. The residue was diluted with aq. 1M HCl and extracted with CH2Cl2, The combined organic layers were extracted with aq. NaHCO3, aq. HCl, brine, dried (MgSO4), filtered and concentrated in vacuo to obtain XXIIIn (2.08 g) as a tan colored solid.
    • Step 2
  • Figure US20060205672A1-20060914-C00626
  • A solution of amide XXIIIn (2.08 g, 3.79 mmol) in toluene and DMSO (1:1 mL) at 0° C. was treated with EDCl (7.24 g, 37.9 mmol) and dichloroacetic acid (2.42 g, 19.9 mmol) and stirred at rt. for 4 h. The reaction mixture was diluted with CH2Cl2, washed with sat'd. NaHCO3, and brine. The organic layer were dried (MgSO4) filtered, concentrated, in vacuo and purified by chromatography (SiO2, Acetone/Hexanes 3:7) to yield XXIII as a colorless solid.
    • EXAMPLE XXIV Preparation of a Compound of Formula XXIV
  • Figure US20060205672A1-20060914-C00627
    • Step 1
  • Figure US20060205672A1-20060914-C00628
  • A solution of Boc-tert-Lue XXIVa (Fluka, 5.0 g 21.6 mmol) in dry CH2Cl2/DMF (50 mL, 1:1) was cooled to 0° C. and treated with the amine XXIIII (5.3 g, 25.7 mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The reaction was stirred at rt. for 24 h, diluted with aq. HCl (1 M) and extracted with CH2Cl2. The combined organic layers were washed with HCL (aq, 1 M), sat'd. NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo and purified by chromatography (SiO2, Acetone/Hexane 1:5) to yield XXIVb as a colorless solid.
    • Step 2
  • Figure US20060205672A1-20060914-C00629
  • A solution of methyl ester XXIVb (4.0 g, 10.46 mmol) was dissolved in HCl (4 M soln. dioxane) and stirred at rt. for 3 h. The reaction mixture was concentrated in vacuo to obtain the amine hydrochloride salt used in the next step.
  • A solution of the amine hydrochloride salt (397 mg, 1.24 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. and treated with tert-butyl isocyanate (250 mg, 2.5 mmol) and stirred at rt. overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with aq. HCl (1M) and extracted with CH2Cl2. The combined organic layers were washed with aq. HCl (1M), sat'd. NaHCO3 and brine. The organic layers were dried, filtered and concentrated in vacuo and the residue was purified by chromatography (SiO2, acetone/Hex 1:4) to yield XXIVc as a colorless solid.
    • Step 3
  • Figure US20060205672A1-20060914-C00630
  • A solution of methyl ester XXIVc (381 mg, 1.0 mmol) in THF/H2O (1:1, 5 mL) was treated with LiOH.H2O (62 mg, 1.5 mmol) and stirred at rt. for 3 h. The reaction mixture was acidified with aq. HCl and concentrated in vacuo to obtain the free acid.
  • A solution of acid (254.9 mg, 0.69 mmol) in DMF/CH2Cl2 (1:1, 5.0 mL) was treated 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) at −20° C. The reaction mixture was stirred at −20° C. for 48 h and concentrated in vacuo. The residue was diluted with aq. 1M HCl and extracted with EtOAc, The combined organic layers were extracted with aq. NaHCO3, aq. HCl, brine, dried (MgSO4) filtered concentrated in vacuo to obtain XXIVd (470 mg) as a tan colored solid.
    • Step 4
  • Figure US20060205672A1-20060914-C00631
  • 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 stirred at 0° C. for 4 h. The reaction mixture was diluted with CH2Cl2, and washed with satd. NaHCO3, and brine. The organic layer was dried (MgSO4), filtered, concentrated, in vacuo and purified by chromatography (SiO2, Acetone/Hexanes 3:7) to yield XXIV as a colorless solid.
    • EXAMPLE XXV Prepration of a Compound of Formula XXV
  • Figure US20060205672A1-20060914-C00632
    • Step 1
  • Figure US20060205672A1-20060914-C00633
  • A solution of Fmoc-glycine (Bachem, 2.0 g, 6.87 mmol) in CH2Cl2 (20 mL) was treated with 2-phenyl-2-propanol (Aldrich, 3.36 g, 24.7 mmol), DCC (1M soln CH2Cl2, 8.24 mL), DMAP (167 mg, 1.37 mmol) and stirred at rt. for 24 h. The reaction mixture was concentrated in vacuo and diluted with Et2O (100 mL). The solid seperating out was filtered and the filterate was washed with satd. NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated in vacuo, and purified by chromatography (SiO2, EtOAc/Hex 1:5) to yield ester XXVc (1.1 g) as a colorless viscous liquid.
    • Step 2
  • Figure US20060205672A1-20060914-C00634
  • A solution of XXVc in CH2Cl2 (16.0 mL) was treated with piperidine (4.0 mL) and stirred at rt. for 0.5 h. The reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, Acetone/Hexanes 1:10 to 1:1) to yield the amine XXVd (420 mg) as a colorless liquid.
    • Step 3
  • Figure US20060205672A1-20060914-C00635
  • A solution of methyl ester XXIVc (381 mg, 1.0 mmol) in THF/H2O (1:1, 5 mL) was treated with LiOH.H2O (62 mg, 1.5 mmol) and stirred at rt. for 3 h. The reaction mixture was acidified with aq. HCl and concentrated in vacuo to obtain the free acid.
  • A solution of acid (2.0 g, 5.5 mmol) in DMF/CH2Cl2 (1:1, 40.0 mL) at −10° C. was treated 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 was stirred at 0° C. for 48 h and concentrated in vacuo. The residue was diluted with aq. 1M HCl (100 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were extracted with aq. NaHCO3, aq. HCl, brine, dried (MgSO4) filtered, concentrated in vacuo to obtain XXVe (3.17 g) as a tan colored solid used further without any purification.
    • Step 4
  • Figure US20060205672A1-20060914-C00636
  • A solution of methyl ester XXVe (2.5 g, 4.66 mmol) in THF/H2O/CH3OH (1:1:1, 60 mL) was treated with LiOH.H2O (200 mg, 4.87 mmol) and stirred at rt. for 4 h. The reaction mixture was acidified with aq. HCl and concentrated in vacuo to obtain the free acid.
  • A solution of acid (200.0 mg, 0.38 mmol) in DMF/CH2Cl2 (1:1, 6.0 mL) at −10° C. was treated 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 was stirred at 0° C. for 48 h and concentrated in vacuo. The residue was diluted with aq. 1M HCl (30 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were extracted with aq. NaHCO3 (2×30 mL), aq. HCl, brine (30 mL), dried (MgSO4) filtered, concentrated in vacuo to obtain XXVf (240 mg) as a tan colored solid.
    • Step 5
  • Figure US20060205672A1-20060914-C00637
  • A solution of XXVf (240 mg, 0.28 mmol) in CH2Cl2 (10 mL) was treated with Dess-Martin reagent (Omega, 242 mg, 0.56 mmol) and stirred at rt. for 2 h. After the oxidation was complete (TLC, Acetone/Hex 1:4) the reaction mixture was diluted with satd. NaHCO3 (20 mL) and Na2S2O3 (10% aq soln, 20 mL). The reaction mixture was stirred for 30 min and extractred with CH2Cl2 (3×30 mL). The combined organic layers were extracted with satd. NaHCO3, brine, dried (MgSO4) filtered concentrated in vacuo and purified by chromatography (SiO2, acetone/Hexanes 1:5) to yield XXV (122 mg) as a colorless solid.
    • EXAMPLE XXVI Preparation of a Compound of Formula XXVI
  • Figure US20060205672A1-20060914-C00638
    • Step 1
  • Figure US20060205672A1-20060914-C00639
  • To a stirred solution of 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-dimethylaminopyridine (0.40 g, 3.33 mmol) in acetonitrile (100 mL) at room temperature was added triethylamine (5.0 mL, 35.6 mmol). The resulting solution was stirred at this temperature for 18 h before it was concentrated in vacuo. The dark brown residue was purified by flash column chromatography eluting with 10-25% EtOAc/hexane to give the product XXVIb as a pale yellow oil (5.29 g, 84%).
    • Step 2
  • Figure US20060205672A1-20060914-C00640
  • 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 was added 50% aqueous sodium hydroxide (120 g). After vigorously stirred at this temperature for 24 h, the black mixture was diluted with CH2Cl2 (200 mL) and diethyl ether (600 mL). After the layers were separated, the aqueous solution was extracted with CH2Cl2/Et2O (1:2, 3×600 mL). The organic solution was dried (MgSO4) and concentrated. The residue was purified by flash column chromatography using 5-20% EtOAc/hexane to afford 9.34 g (71%) of XXVIc as an off-white solid.
    • Step 3
  • Figure US20060205672A1-20060914-C00641
  • The solution of XXVIc (9.34 g, 26.5 mmol) in CH2Cl2 (25 mL) and CF3CO2H (50 mL) was stirred at room temperature for 4.5 h before it was concentrated in vacuo to give a brown residue which was used in Step 4 without further purification.
    • Step 4
  • Figure US20060205672A1-20060914-C00642
  • Commercial concentrated hydrochloric acid (4.5 mL) was added to a solution of the residue from Step 3 in methanol (70 mL) and the resulting mixture was warmed to 65° C. in an oil bath. After 18 h, the mixture was concentrated in vacuo to give a brown oil XXVIe, which was used in Step 5 without further purification.
    • Step 5
  • Figure US20060205672A1-20060914-C00643
  • To a stirred solution of proline methyl ester XXVIe from Step 4, commercial N-Boc-cyclohexylglycine XXVIf (10.2 g, 40.0 mmol) and [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (HATU) (16.0 g, 42.1 mmol) in DMF (200 mL) at 0° C. was added diisopropylethylamine (18.0 mL, 104 mmol). After allowed to warm to room temperature along with the ice bath over night (18 h), the reaction mixture was diluted with EtOAc (600 mL), 5% H3PO4 (150 mL) and brine (150 mL). The organic solution was washed with 5% H3PO4 (150 mL), saturated NaHCO3 (2×200 mL) before it was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 5-20% EtOAc/hexane to afford 3.84 g (32%, three steps) of XXVIg as an off-white solid.
    • Step 6
  • Figure US20060205672A1-20060914-C00644
  • The solution of methyl ester XXVIg (5.87 g, 13.1 mmol) and LiOH (1.65 g, 39.3 mmol) in THF/MeOH/H2O (1:1:1, 90 mL) was stirred at room temperature for 4 h. Methanol and THF were removed under reduced pressure. The aqueous solution was acidified to PH˜2 using 1 N aqueous HCl solution (50 mL) and saturated with solid sodium chloride before it was extracted with EtOAc (3×1 50 mL). The organic solutions were combined, dried (MgSO4), filtered and concentrated in vacuo to give a white solid XXVIh (5.8 g, quantitative).
    • Step 7
  • Figure US20060205672A1-20060914-C00645
  • The desired product XXIIIi was prepared according to the procedure in Example XXIII, Step 11.
    • Step 8
  • Figure US20060205672A1-20060914-C00646
  • The desired product XXVI was prepared according to the procedure in Example XXIII, Step 12.
    • EXAMPLE XXVII Preparation of compound of formula XXVII
  • Figure US20060205672A1-20060914-C00647
    • Step 1
  • Figure US20060205672A1-20060914-C00648
  • The desired product XXVIIa was prepared according to the procedure in Example XXIII, Step 9.
    • Step 2
  • Figure US20060205672A1-20060914-C00649
  • The desired product XXVIIb was prepared according to the procedure in Example XXIV, Step 2.
    • Step 3
  • Figure US20060205672A1-20060914-C00650
  • The desired product XXVII was prepared according to the procedure in Example XXIII, Step 12.
    • EXAMPLE XXVIII Preparation of a Compound of Formula XXVIII
  • Figure US20060205672A1-20060914-C00651
    • Step 1
  • Figure US20060205672A1-20060914-C00652
  • The intermediate XXVIIIb was prepared according to the procedure in Example XXIII, Steps 3-6.
    • Step 2
  • Figure US20060205672A1-20060914-C00653
  • The acid from Example XXIV, Step 2 (XXVIIIc) (0.7 g) was reacted with product from Step 1 above (0.436 g), HATU (0.934 g) and DIPEA (1.64 mL) in the manner previously described in Example IX, Step 2a to afford 0.66 g of the desired product XXVIIId.
    • Step 3
  • Figure US20060205672A1-20060914-C00654
  • The product of Step 2 (0.5 g) was reacted with Dess-Martin reagent (1 g) in the manner previously described in Example XX, Step 7. Purification by flash column chromatography (40% EtOAc, Hexane, silica) furnished 0.35 g of product XXVIIIe. Mass spectrum (LCMS) 522 (M+H+).
    • Step 4
  • Figure US20060205672A1-20060914-C00655
  • The product of Step 4 (0.3 g) was added a 1/1H2O/MeOH solution (20 mL) and NaHCO3 solid (242 mg, 5 equiv.). After being stirred for 18 hours at room temperature, the reaction was diluted with EtOAc and layers were separated. The aqueous layer was acidified to pH 2 with HCl 1.0 N and extracted with EtOAc. The EtOAc layer was washed with brine then dried over MgSO4, filtered and concentrated in vacuo to afford product XXVIIIf as a white powder (0.26 g). Mass spectrum (LCMS) 508 (M+H+).
    • Step 5
  • Figure US20060205672A1-20060914-C00656
  • The product of Step 5 (0.15 g) was dissolved in CH2Cl2 and reacted with HATU (0.137 g), NH4Cl (0.08 g, 5 equiv.) and DIPEA (0.53 mL). After 2 hours at room temperature, the reaction was diluted with EtOAc, washed with a 10% citric acid solution, then a saturated NaHCO3 solution. The EtOAc layer was washed with brine then dried over MgSO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (30% Acetone, Hexane, silica) furnished the desired product XXVIII (0.096 g). Mass spectrum (LCMS) 507 (M+H+).
    • EXAMPLE XXIX Preparation of a Compound of Formula XXIX
  • Figure US20060205672A1-20060914-C00657
    • Step 1
  • Figure US20060205672A1-20060914-C00658
  • To a 0° C. solution of the starting aldehyde (4.0 g) in CH2Cl2 (75 mL) was added acetic acid (2.0 equiv., 2.15 mL) followed by methylisocyanoacetate (1.1 equiv., 1.9 mL). The reaction was then gradually warmed-up to room temperature. After 18 hours (overnight), the reaction was diluted with EtOAc and washed with a saturated NaHCO3 solution. The EtOAc layer was washed with brine then dried over MgSO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (30 to 40% EtOAc, Hexane, silica) furnished the product XXIXa (4.5 g).
    • Step 2
  • Figure US20060205672A1-20060914-C00659
  • To a 0° C. solution of XXIXa (4.4 g) in THF (100 mL) was added 26 mL (2.2 equiv.) of a 1.0 N LiOH solution. The reaction was stirred at this temperature for 2 hours then warmed-up to room temperature. After 2 hours, reaction mixture was acidified to pH 2 with a 1.0 N HCl solution. EtOAc was added and layers were separated. The EtOAc layer was washed with brine then dried over MgSO4, filtered and concentrated in vacuo to afford product XXIXb (3.7 g).
    • Step 3
  • Figure US20060205672A1-20060914-C00660
  • The acid XXIXb was reacted with the amine from Example XV in the manner previously described in Example XXI, Step 4. The resulting intermediate was then treated with HCl in the manner previously described in Example XXIII, Step 9 to afford product XXIXc.
    • Step 4
  • Figure US20060205672A1-20060914-C00661
  • The acid XXVIIIc (2.43 g) was dissolved in CH2Cl2 and was reacted with amine XXIXc (2.47 g), HATU (2.5 g) and DIPEA (5.8 mL) in the manner previously described in Example IX, Step 2a to afford, after purification by flash column chromatography (4% MeOH, CH2Cl2, silica), the desired product XXIXd (4.35 g). Mass spectrum (LCMS) 727 (M+H+).
    • Step 5
  • Figure US20060205672A1-20060914-C00662
  • The product of Step 4 (4.2 g) was reacted with Dess-Martin reagent (6.4 g) in the manner previously described in preparative Example XX, Step 7. Purification by flash column chromatography (100% EtOAc, silica) furnished 3 g of the final product XXIX. Mass spectrum (LCMS) 725 (M+H+).
    • EXAMPLE XXX Preparation of a Compound of Formula XXX
  • Figure US20060205672A1-20060914-C00663
    • Step 1
  • Figure US20060205672A1-20060914-C00664
  • The alcohol 2-(trifluoromethyl)propan-2-ol (1.28 g) was reacted with N,N-disucciminidyl carbonate (3.84 g) and Et3N (4.2 mL) in dry CH3CN (50 mL) for 18 hours. The mixture was diluted with EtOAc (200 mL) and filtered. The filtrate was washed with NaHCO3, brine then dried over MgSO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (50% EtOAc, Hexane, silica) furnished the desired product XXXa (0.3 g).
    • Step 2
  • Figure US20060205672A1-20060914-C00665
  • The product from Example XXIX (0.3 g) was treated with 100 mL of 4.0 N HCl in dioxane. After 1 h, 200 mL of Et2O were added and the resulting precipitate was filtered off and dried under vacuo to afford the product XXXb (0.27 g) as a white powder. Mass spectrum (LCMS) 625 (M−HCl+H+).
    • Step 3
  • Figure US20060205672A1-20060914-C00666
  • To a room temperature solution of XXXb (0.05 g) in CH2Cl2 (5 mL) was added DIPEA (0.040 mL) XXXa (1.5 equiv., 0.030 g), followed by 1 crystal of MAP. After 30 minutes, reaction was diluted with EtOAc (20 mL) and washed with HCl 1.5 N then NaHCO3 then brine. EtOAc layer was dried over MgSO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by preparative chromatography (40% Acetone, Hexane, silica) furnished the desired product XXX (0.044 g). Mass spectrum (LCMS) 779 (M+H+).
    • EXAMPLE XXXI Preparation of a Compound of Formula XXXI
  • Figure US20060205672A1-20060914-C00667
    • Step 1
  • Figure US20060205672A1-20060914-C00668
  • To a solution of XXXb (0.05 g) in CH2Cl2 (5 mL) at room temperature was added DIPEA (0.040 mL) and tert-butylisocyanate (1.2 equiv., 0.01 mL). After 18 hours, reaction was diluted with EtOAc (20 mL) and washed with HCl 1.5 N, NaHCO3 and brine. EtOAc layer was dried over MgSO4, filtered and concentrated in vacuo to afford a crude mixture. Purification by preparative chromatography (100% EtOAc, silica) furnished the final product XXXI (0.021 g). Mass spectrum (LCMS) 724 (M+H+).
    • EXAMPLE XXXII Preparation of a Compound of Formula XXXII
  • Figure US20060205672A1-20060914-C00669
    • Step 1
  • Figure US20060205672A1-20060914-C00670
  • The product from Example XXVIII was treated in the manner previously described in preparative Example XXX, Step 2 to afford product XXXIIa. Mass spectrum (LCMS) 407 (M−HCl+H+).
    • Step 2
  • Figure US20060205672A1-20060914-C00671
  • The amine XXXIIa was reacted with XXXa in the manner previously described in preparative Example XXX, Step 3 to afford the desired product XXXII. Mass spectrum (LCMS) 508 (M+H+).
    • EXAMPLE XXXIII Preparation of a Compound of Formula XXXIII
  • Figure US20060205672A1-20060914-C00672
    • Step 1
  • Figure US20060205672A1-20060914-C00673
  • The amine XXXIIa was reacted with tert-butylisocyanate in the manner previously described in Example XXXI, Step 1, to afford the product XXX III. Mass spectrum (LCMS) 561 (M+H+).
    • EXAMPLE XXXIV Preparation of a Compound of Formula XXXIV
  • Figure US20060205672A1-20060914-C00674
    • Step 1
  • Figure US20060205672A1-20060914-C00675
  • To the mixture of ester (6.0 g) and molecular sieve (5.2 g) in anhydrous methylene chloride (35 mL) was aded pyrrolidine (5.7 mL, 66.36 mmoL). The resulting brown slurry was stirred at room temperature under N2 for 24 h, filtered and washed with anhydrous CH3CN. The combined filtrate was concentrated to yield the desired product.
    • Step 2
  • Figure US20060205672A1-20060914-C00676
  • To a solution of the product from proceeding step in CH3CN (35 mL) was added anhydrous K2CO3, methallyl chloride (2.77 g, 30.5 mmoL), NaI (1.07 g, 6.7 mmoL). The resulting slurry was stirred at ambient temperature under N2 for 24 h. 50 mL of ice-cold water was added followed by 2N KHSO4 solution until pH was 1. EtOAc (100 mL) was added and the mixture was stirred for 0.75 h. Combined organic layer was collected and washed with brine, dried over MgSO4, and evaporated to yield the desired product.
    • Step 3
  • Figure US20060205672A1-20060914-C00677
  • The product from preceding step (2.7 g, 8.16 mmoL) was dissolved in dioxane (20 mL) and treated with freshly prepared 1N LiOH (9 mL). The reaction mixture was stirred at ambient temperature under N2 for 20 h. The reaction mixture was taken in EtOAc and washed with H2O. The combined aqueous phase was cooled to 0° C. and acidifed to pH 1.65 using 1N HCl. The turbid mixture was extracted with EtOAc (2×100 mL). Combined organic layer was washed with brine, dried over MgSO4, concentrated to give the desired acid (3.40 g).
    • Step 4
  • Figure US20060205672A1-20060914-C00678
  • To a suspension of NaBH(OAc)3 (3.93 g, 18.5 mmoL) in CH2Cl2 (55 mL) was added a solution of product from preceding step in anhydrous CH2Cl2 (20 mL) and acetic acid (2 mL). The slurry was stirred at ambient temperature for 20 h. Ice cold water (100 mL) was added to the slurry and stirred for ½ hr. Organic layer was separated, filtered, dried and evaporated to yield the desired product.
    • Step 5
  • Figure US20060205672A1-20060914-C00679
  • To a solution of the product from preceding step (1.9 g) in MeOH (40 mL) was treated with excess of CH2N2/Et2O solution and stirred for overnight. The reaction mixture was concentrated to dryness to yield a crude residue. The residue was chromatographed on silica gel, eluting with a gradient of EtOAc/hexane to afford 1.07 g of the pure desired product.
    • Step 6
  • Figure US20060205672A1-20060914-C00680
  • To a solution of product from preceding step (1.36 g) in anhydrous CH2Cl2 (40 mL) was treated with BF3. Me2O (0.7 mL). The reaction mixture was stirred at ambient temperature for 20 h and quenched with sat. NaHCO3 (30 mL) ad stirred for ½ hr. Organic layer was separated and combined organic layer was washed with brine, dried over MgSO4, concentrated to give crude residue. The residue was chromotagraphed on silica gel eluting with a gradient of EtOAc/hexane to afford 0.88 g of the desired compound.
    • Step 7
  • Figure US20060205672A1-20060914-C00681
  • To a solution of the product (0.92 g) from preceding step in MeOH (30 mL) was added 10% Pd/C (0.16 g) at room temperature and hydrogenated at ambient temperature under 1 atm. Pressure. The reaction mixture was stirred for 4 h and concentrated to dryness to yeild the desired compound.
    • Step 8
  • Figure US20060205672A1-20060914-C00682
  • The desired product was prepared according to the procedure in Example XXIII, Step 10.
    • Step 9
  • Figure US20060205672A1-20060914-C00683
  • The desired acid product was prepared according to the procedure in Example XXIV, Step 3.
    • Step 10
  • Figure US20060205672A1-20060914-C00684
  • The desired product XXXIV was prepared according to the procedure in Example XXIX, Steps 4-5.
    • EXAMPLE XXXV Preparation of a Compound of Formula XXXV
  • Figure US20060205672A1-20060914-C00685
    • Step 1
  • Figure US20060205672A1-20060914-C00686
  • A solution of triethyl phosphonate (44.8 g) in THF (30 mL) at 0° C. was treated with a 1M solution (200 mL) of sodium bis(trimethylsilylamide) in THF. The resulting mixture was stirred at RT for 0.5 hour, and then cooled to 0° C. A solution of 1,4-cyclohexanedione ethylene ketal (15.6 g) in THF (50 mL) was added dropwise, and the resulting solution was stirred at RT for 18 hours. The reaction mixture was then cooled to 0° C., treated with cold aqueous citric acid, and the mixture was extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3, then brine; then dried over anhydrous Na2SO4, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2/EtOAc to afford the title compound (21 g), 92% yield. Mass spectrum (FAB) 227.3 (M+H+).
    • Step 2
  • Figure US20060205672A1-20060914-C00687
  • The product of the preceding step (20 g) was dissolved in EtOH (150 mL) and treated with 10% Pd/C under 1 atm of hydrogen for 3 days. The mixture was filtered and the filtrate evaporated to afford the title compound (20.3 g), 100% yield. Mass spectrum (FAB) 229.2 (M+H+).
    • Step 3
  • Figure US20060205672A1-20060914-C00688
  • The product of the preceding step (20 g) was dissolved in MeOH (150 mL) and treated with a solution of LiOH (3.6 g) in water (50 mL). The mixture was stirred for 18 hours, and concentrated under vacuum. The residue was dissolved in cold water (100 mL), the solution was acidified to pH 2-3 with 5N HCl, and the resulting mixture was extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered, and the filtrate evaporated to afford the title compound (17.1 g), 97% yield. Mass spectrum (FAB) 201.2 (M+H+).
    • Step 4
  • Figure US20060205672A1-20060914-C00689
    1. The product of the preceding step (3.0 g) was dissolved in Et2O (150 mL), treated with Et3N (2.1 mL), and the solution cooled to −78° C. Pivaloyl chloride (1.85 mL) was added dropwise, and after 0.25 hour additional stirring, the reaction was allowed to warm to 0° C. over 0.75 hour, and then cooled again to −78° C. to afford a solution of mixed anhydride for reaction in part 2.
    2. A solution of (S)-4-benzyl-2-oxazolidinone (2.66 g) in THF (22 mL) was cooled to −78° C., and a 1.6 M solution (9.38 mL) of n-butyllithium in hexane was added dropwise. After an additional 0.33 hour stirring at this temperature, the solution was transferred via canula to the cold solution of part 1. The mixture was stirred at −78° C., then warmed to 0° C., and stirred at this temperature for 0.5 hour. The organic layer was separated, the aqueous layer was extracted with Et2O, the combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with a gradient of hexane/EtOAc (9:1) to afford the title compound (5.0 g), 93% yield. Mass spectrum (FAB) 360.4 (M+H+).
    • Step 5
  • Figure US20060205672A1-20060914-C00690
  • The product of the preceding step (2.7 g) was dissolved in THF (25 mL), cooled to −78° C., transferred by canula to a solution of 0.5 M potassium bis(trimethylsilyl)amide/toluene (16.5 mL) in THF (25 mL) at −78° C., and the resulting solution was stirred at −78° C. for 0.75 hour. To this solution was added via canula a solution of trisyl azide (3.01 g) in THF (25 mL) pre-cooled to −78° C. After 1.5 minutes, the reaction was quenched with acetic acid (1.99 mL), the reaction was warmed to RT, and then stirred for 16 hours. The reaction was diluted with EtOAc (300 mL), and washed with 5% aqueous NaCl. The aqueous phase was extracted with EtOAc, the combined organic phases were washed with saturated aqueous NaHCO3, then brine; then dried over anhydrous Na2SO4, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with EtOAc/hexane (1:3) to afford the title compound (2.65 g), 88% yield.
    • Step 6
  • Figure US20060205672A1-20060914-C00691
  • The product of the preceding step (11.4 g) was dissolved in 95% formic acid (70 mL) and heated at 70° C. for 0.5 hour while stirring. The solution was evaporated under vacuum, and the residue was taken up in EtOAc. The solution was washed with saturated aqueous NaHCO3, then brine; then dried over anhydrous Na2SO4, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel to afford the title compound (8.2 g).
    • Step 7
  • Figure US20060205672A1-20060914-C00692
  • The product of the preceding step (8.2 g) was dissolved in CH2Cl2 (16 mL) and treated with diethylaminosulfur trifluoride (DAST, 7.00 mL) at RT for 3 hours. The reaction was poured over ice/water (200 cc), and extracted with CH2Cl2. The extract was washed with saturated aqueous NaHCO3, then brine; then dried over anhydrous Na2SO4, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with EtOAc/hexane (15:85) to afford the title compound (4.5 g), 52% yield.
    • Step 8
  • Figure US20060205672A1-20060914-C00693
  • 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% H2O2 (3.95 mL), and then with LiOH.H2O (0.86 g). The mixture was stirred for 1 hour at 0° C., then quenched with a solution of Na2SO3 (5.6 g) in water (30 mL), followed by a solution of 0.5 N NaHCO3 (100 mL). The mixture was concentrated under vacuum to ½ volume, diluted with water (to 500 mL), and extracted with CH2Cl2 (4×200 mL). The aqueous phase was acidified to pH 1-2 with 5N HCl, and extracted with EtOAc (4×200 mL). The extract was washed brine; then dried over anhydrous Na2SO4, filtered, and the filtrate evaporated to afford the title compound (1.95 g), 91% yield, which was used directly in the next step.
    • Step 9
  • Figure US20060205672A1-20060914-C00694
  • The product of the preceding example (2.6 g) was dissolved in Et2O (50 mL) and treated dropwise with a solution of CH2N2 in Et2O until the solution remained yellow. The solution was stirred for 18 hours, then evaporated under vacuum to afford the title compound (2.8), which was used directly in the next step.
    • Step 10
  • Figure US20060205672A1-20060914-C00695
  • The product of the preceding step (1.95 g) was dissolved in MeOH (150 mL), treated with formic acid (1.7 mL), then treated with 10% Pd/C (3.3 g, Degussa type E101) under 1 atm of hydrogen for 1.5 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (2.1 g) as the formic acid salt, which was used directly in the next step.
    • Step 11
  • Figure US20060205672A1-20060914-C00696
  • The product of the preceding step (2.1 g) was dissolved in 1,4-dioxane (100 mL) and di-tert-butyl dicarbonate (1.9 g) was added, followed by diisopropylethylamine (2.9 mL). The solution was stirred for 18 hours, and concentrated under vacuum. The residue was treated with aqueous 5% KH2PO4 and the mixture extracted with EtOAc. The extract was washed with brine; then dried over anhydrous MgSO4, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2/Et2O to afford the title compound (2.5 g), 99% yield. Mass spectrum (FAB) 307.9 (M+H+).
    • Step 12
  • Figure US20060205672A1-20060914-C00697
  • The product of the preceding step (2.5 g) was dissolved in 1,4-dioxane (35 mL), treated with aqueous 1M LiOH (17 mL), and stirred for 2 hours. The mixture was quenched with ice/water (125 cc), the mixture was acidified to pH 34 with 3N HCl, and extracted with EtOAc. The extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated to afford the title compound (2.3 g), 96% yield. Mass spectrum (FAB) 294.0 (M+H+).
    • Step 13
  • Figure US20060205672A1-20060914-C00698
  • The desired product was prepared according to the procedure in Example XXIII, Step 10.
    • Step 14
  • Figure US20060205672A1-20060914-C00699
  • The desired acid product was prepared according to the procedure in Example XXIV, Step 3.
    • Step 15
  • Figure US20060205672A1-20060914-C00700
  • The desired acid product was prepared according to the procedure in Example XXIX, Step 4.
    • EXAMPLE XXXVI Preparation of compounds of Formulas XXXVI and XXXVIII
  • Compounds of formulas XXXVI and XXXVIII were prepared according to the scheme below and utilizing preparative Examples 11 through 15 discussed above.
    Figure US20060205672A1-20060914-C00701
    The compound of formula XXXVIb was prepared from a compound of formula XXXVIa as follows by known procedures:
    Figure US20060205672A1-20060914-C00702
  • To a solution of Compound XXXVIa (6.58 g, 22 mmol) in 100 mL of MeOH was added 10% Pd/C (0.8 g) and p-toluene sulfonic acid (4.2 g). The reaction mixture was subjected to hydrogenation at room temperature overnight. The reaction mixture was filtered through celite and washed with excess MeOH. The combined filtrate was concentrated in-vacuo to provide the title compound XXXVIb as a gummy. Conversion of XXXVIb to XXXVI and XXXVII followed the route as shown in the scheme above and according to preparative examples 11-15.
    • EXAMPLE XXXVIII Preparation of a Compound of Formula XXXVIII
  • A compound of the formula XXXVIII was prepared utilizing the following scheme and following preparative Examples 11 through 15 discussed earlier.
    Figure US20060205672A1-20060914-C00703
    Figure US20060205672A1-20060914-C00704
    • EXAMPLE XXXIX Synthesis of the compound of Formula XXXIX
  • Figure US20060205672A1-20060914-C00705
    • Step 1
  • Figure US20060205672A1-20060914-C00706
  • A solution of the sulfonyl chloride XXXIXa prepared by the procedure of H. Mcklwain (J. Chem. Soc 1941, 75) was added dropwise to a mixture of 1.1. equiv of t-butylmethylamine and triethylamine at −78° C. and stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, Hex/Acetone 4:1) to yield sulfonamide XXXIXb as a colorless oil.
    • Step 2
  • Figure US20060205672A1-20060914-C00707
  • A solution of the Cbz-protected amine XXXIXb was dissolved in methanol and treated with 5 mol % of Pd/C (5% w/w) and hydrogenated at 60 psi. The reaction mixture was filtered through a plug of celite and concentrated in vacuo to obtain the free amine XXXIXc which solidfied on standing.
    • Step 3
  • Figure US20060205672A1-20060914-C00708
  • The hydroxy sulfonamide XXXIXd was synthesized similar to the procedure for the synthesis of XXVf except replacing the amine XXVd with XXXIXc. The crude reaction mixture directly used for the next reaction.
    • Step 4
  • Figure US20060205672A1-20060914-C00709
  • The hydroxy amide XXXIXd was oxidized to compound XXXIX using the Dess Martin reagent following the procedure for the synthesis of XXV (step 5). The crude mixture was purified by chromatography (SiO2, Acetone/Hexane 3:7) to obtain XXXIX as a colorless solid.
  • Assay for HCV Protease Inhibitory Activity:
  • Spectrophotometric Assay: Spectrophotometric assay for the HCV serine protease was performed on the inventive compounds by following the procedure described by R. Zhang et al, Analytical Biochemistry, 270 (1999) 268-275, the disclosure of which is incorporated herein by reference. The assay based on the proteolysis of chromogenic ester substrates is suitable for the continuous monitoring of HCV NS3 protease activity. The substrates were derived from the P side of the NS5A-NS5B junction sequence (Ac-DTEDVVX(Nva)1 where X=A or P) whose C-terminal carboxyl groups were esterified with one of four different chromophoric alcohols (3- or 4-nitrophenol, 7-hydroxy-4-methyl-coumarin, or 4-phenylazophenol). Presented below are the synthesis, characterization and application of these novel spectrophotometric ester substrates to high throughput screening and detailed kinetic evaluation of HCV NS3 protease inhibitors.
  • Materials and Methods:
  • Materials: Chemical reagents for assay related buffers were obtained from Sigma Chemical Company (St. Louis, Mo.). Reagents for peptide synthesis were from Aldrich Chemicals, Novabiochem (San Diego, Calif.), Applied Biosystems (Foster City, Calif.) and Perseptive Biosystems (Framingham, Mass.). Peptides were synthesized manually or on an automated ABI model 431A synthesizer (from Applied Biosystems). UV/VIS Spectrometer model LAMBDA 12 was from Perkin Elmer (Norwalk, Conn.) and 96-well UV plates were obtained from Corning (Corning, N.Y.). The prewarming block was from USA Scientific (Ocala, Fla.) and the 96-well plate vortexer was from Labline Instruments (Melrose Park, Ill.). A Spectramax Plus microtiter plate reader with monochrometer was obtained from Molecular Devices (Sunnyvale, Calif.).
  • Enzyme Preparation: Recombinant heterodimeric HCV NS3/NS4A protease (strain 1a) was prepared by using the procedures published previously (D. L. Sali et al, Biochemistry, 37 (1998) 3392-3401). Protein concentrations were determined by the Biorad dye method using recombinant HCV protease standards previously quantified by amino acid analysis. Prior to assay initiation, the enzyme storage buffer (50 mM sodium phosphate pH 8.0, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside and 10 mM DTT) was exchanged for the assay buffer (25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 μM DTT) utilizing a Biorad Bio-Spin P-6 prepacked column.
  • Substrate Synthesis and Purification: The synthesis of the substrates was done as reported by R. Zhang et al, (ibid.) and was initiated by anchoring Fmoc-Nva-OH to 2-chlorotrityl chloride resin using a standard protocol (K. Barlos et al, Int J. Pept. Protein Res., 37 (1991), 513-520). The peptides were subsequently assembled, using Fmoc chemistry, either manually or on an automatic ABI model 431 peptide synthesizer. The N-acetylated and fully protected peptide fragments were cleaved from the resin either by 10% acetic acid (HOAc) and 10% trifluoroethanol (TFE) in dichloromethane (DCM) for 30 min, or by 2% trifluoroacetic acid (TFA) in DCM for 10 min. The combined filtrate and DCM wash was evaporated azeotropically (or repeatedly extracted by aqueous Na2CO3 solution) to remove the acid used in cleavage. The DCM phase was dried over Na2SO4 and evaporated.
  • The ester substrates were assembled using standard acid-alcohol coupling procedures (K. Holmber et al, Acta Chem. Scand., B33 (1979) 410-412). Peptide fragments were dissolved in anhydrous pyridine (30-60 mg/ml) to which 10 molar equivalents of chromophore and a catalytic amount (0.1 eq.) of para-toluenesulfonic acid (pTSA) were added. Dicyclohexylcarbodiimide (DCC, 3 eq.) was added to initiate the coupling reactions. Product formation was monitored by HPLC and found to be complete following 12-72 hour reaction at room temperature. Pyridine solvent was evaporated under vacuum and further removed by azeotropic evaporation with toluene. The peptide ester was deprotected with 95% TFA in DCM for two hours and extracted three times with anhydrous ethyl ether to remove excess chromophore. The deprotected substrate was purified by reversed phase HPLC on a C3 or C8 column with a 30% to 60% acetonitrile gradient (using six column volumes). The overall yield following HPLC purification was approximately 20-30%. The molecular mass was confirmed by electrospray ionization mass spectroscopy. The substrates were stored in dry powder form under desiccation.
  • Spectra of Substrates and Products: Spectra of substrates and the corresponding chromophore products were obtained in the pH 6.5 assay buffer. Extinction coefficients were determined at the optimal off-peak wavelength in 1-cm cuvettes (340 nm for 3-Np and HMC, 370 nm for PAP and 400 nm for 4-Np) using multiple dilutions. The optimal off-peak wavelength was defined as that wavelength yielding the maximum fractional difference in absorbance between substrate and product (product OD—substrate OD)/substrate OD).
  • Protease Assay: HCV protease assays were performed at 30° C. using a 200 μl reaction mix in a 96-well microtiter plate. 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) were optimized for the NS3/NS4A heterodimer (D. L. Sali et al, ibid.)). Typically, 150 μl mixtures of buffer, substrate and inhibitor were placed in wells (final concentration of DMSO 4% v/v) and allowed to preincubate at 30° C. for approximately 3 minutes. Fifty μls of prewarmed protease (12 nM, 30° C.) in assay buffer, was then used to initiate the reaction (final volume 200 μl). The plates were monitored over the length of the assay (60 minutes) for change in absorbance at the appropriate wavelength (340 nm for 3-Np and HMC, 370 nm for PAP, and 400 nm for 4-Np) using a Spectromax Plus microtiter plate reader equipped with a monochrometer (acceptable results can be obtained with plate readers that utilize cutoff filters). Proteolytic cleavage of the ester linkage between the Nva and the chromophore was monitored at the appropriate wavelength against a no enzyme blank as a control for non-enzymatic hydrolysis. The evaluation of substrate kinetic parameters was performed over a 30-fold substrate concentration range (˜6-200 μM). Initial velocities were determined using linear regression and kinetic constants were obtained by fitting the data to the Michaelis-Menten equation using non-linear regression analysis (Mac Curve Fit 1.1, K. Raner). Turnover numbers (kcat) were calculated assuming the enzyme was fully active.
  • Evaluation of Inhibitors and Inactivators: The inhibition constants (Ki*) for the competitive inhibitors Ac-D-(D-Gla)-L-1-(Cha)-C-OH (27), Ac-DTEDVVA(Nva)-OH and Ac-DTEDVVP(Nva)-OH were determined experimentally at fixed concentrations of enzyme and substrate by plotting vo/vi vs. inhibitor concentration ([I]o) according to the rearranged Michaelis-Menten equation for competitive inhibition kinetics: vo/vi=1+[I]o/(Ki*(1+[S]o/Km)), where vo is the uninhibited initial velocity, vi is the initial velocity in the presence of inhibitor at any given inhibitor concentration ([I]o) and [S]o is the substrate concentration used. The resulting data were fitted using linear regression and the resulting slope, 1/(Ki*(1+[S]o/Km), was used to calculate the Ki* value.
  • The obtained Ki* values for the various compounds of the present invention are given in the afore-mentioned Tables wherein the compounds have been arranged in the order of ranges of Ki* values. From these test results, it would be apparent to the skilled artisan that the compounds of the invention have excellent utility as NS3-serine protease inhibitors.
  • While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.
    TABLE 2
    molecular
    Ex. # STRUCTURE weight
    1
    Figure US20060205672A1-20060914-C00710
         		691.7853
    2
    Figure US20060205672A1-20060914-C00711
         		627.7441
    3
    Figure US20060205672A1-20060914-C00712
         		754.8883
    4
    Figure US20060205672A1-20060914-C00713
         		527.6259
    5
    Figure US20060205672A1-20060914-C00714
         		698.7799
    6
    Figure US20060205672A1-20060914-C00715
         		631.7352
    7
    Figure US20060205672A1-20060914-C00716
         		381.476
    8
    Figure US20060205672A1-20060914-C00717
         		540.6626
    9
    Figure US20060205672A1-20060914-C00718
         		498.5813
    10
    Figure US20060205672A1-20060914-C00719
         		633.7482
    11
    Figure US20060205672A1-20060914-C00720
         		641.7249
    12
    Figure US20060205672A1-20060914-C00721
         		641.7249
    13
    Figure US20060205672A1-20060914-C00722
         		683.8061
    14
    Figure US20060205672A1-20060914-C00723
         		637.7802
    15
    Figure US20060205672A1-20060914-C00724
         		637.7802
    16
    Figure US20060205672A1-20060914-C00725
         		637.7802
    17
    Figure US20060205672A1-20060914-C00726
         		625.769
    18
    Figure US20060205672A1-20060914-C00727
         		613.6707
    19
    Figure US20060205672A1-20060914-C00728
         		613.6707
    20
    Figure US20060205672A1-20060914-C00729
         		627.6978
    21
    Figure US20060205672A1-20060914-C00730
         		609.726
    22
    Figure US20060205672A1-20060914-C00731
         		609.726
    23
    Figure US20060205672A1-20060914-C00732
         		609.726
    24
    Figure US20060205672A1-20060914-C00733
         		611.742
    25
    Figure US20060205672A1-20060914-C00734
         		600.7183
    26
    Figure US20060205672A1-20060914-C00735
         		554.7361
    27
    Figure US20060205672A1-20060914-C00736
         		478.5937
    28
    Figure US20060205672A1-20060914-C00737
         		546.7132
    29
    Figure US20060205672A1-20060914-C00738
         		562.7562
    30
    Figure US20060205672A1-20060914-C00739
         		699.8519
    31
    Figure US20060205672A1-20060914-C00740
         		643.7435
    32
    Figure US20060205672A1-20060914-C00741
         		509.6077
    33
    Figure US20060205672A1-20060914-C00742
         		637.7802
    34
    Figure US20060205672A1-20060914-C00743
         		637.7802
    35
    Figure US20060205672A1-20060914-C00744
         		579.6995
    36
    Figure US20060205672A1-20060914-C00745
         		537.6619
    37
    Figure US20060205672A1-20060914-C00746
         		539.6342
    38
    Figure US20060205672A1-20060914-C00747
         		597.7149
    39
    Figure US20060205672A1-20060914-C00748
         		493.6055
    40
    Figure US20060205672A1-20060914-C00749
         		632.8044
    41
    Figure US20060205672A1-20060914-C00750
         		747.8965
    42
    Figure US20060205672A1-20060914-C00751
         		523.6348
    43
    Figure US20060205672A1-20060914-C00752
         		598.7024
    44
    Figure US20060205672A1-20060914-C00753
         		578.712
    45
    Figure US20060205672A1-20060914-C00754
         		495.6214
    46
    Figure US20060205672A1-20060914-C00755
         		627.7878
    47
    Figure US20060205672A1-20060914-C00756
         		541.6501
    48
    Figure US20060205672A1-20060914-C00757
         		543.666
    49
    Figure US20060205672A1-20060914-C00758
         		501.5847
    50
    Figure US20060205672A1-20060914-C00759
         		656.7394
    51
    Figure US20060205672A1-20060914-C00760
         		578.712
    52
    Figure US20060205672A1-20060914-C00761
         		725.8901
    53
    Figure US20060205672A1-20060914-C00762
         		584.6782
    54
    Figure US20060205672A1-20060914-C00763
         		538.6467
    55
    Figure US20060205672A1-20060914-C00764
         		685.8248
    56
    Figure US20060205672A1-20060914-C00765
         		527.6695
    57
    Figure US20060205672A1-20060914-C00766
         		810.9557
    58
    Figure US20060205672A1-20060914-C00767
         		552.6737
    59
    Figure US20060205672A1-20060914-C00768
         		592.7391
    60
    Figure US20060205672A1-20060914-C00769
         		534.702
    61
    Figure US20060205672A1-20060914-C00770
         		653.8232
    62
    Figure US20060205672A1-20060914-C00771
         		696.892
    63
    Figure US20060205672A1-20060914-C00772
         		606.7662
    64
    Figure US20060205672A1-20060914-C00773
         		643.7435
    65
    Figure US20060205672A1-20060914-C00774
         		742.8771
    66
    Figure US20060205672A1-20060914-C00775
         		747.8965
    67
    Figure US20060205672A1-20060914-C00776
         		747.8965
    68
    Figure US20060205672A1-20060914-C00777
         		761.9236
    69
    Figure US20060205672A1-20060914-C00778
         		747.8965
    70
    Figure US20060205672A1-20060914-C00779
         		733.913
    71
    Figure US20060205672A1-20060914-C00780
         		746.9118
    72
    Figure US20060205672A1-20060914-C00781
         		646.7935
    73
    Figure US20060205672A1-20060914-C00782
         		746.9118
    74
    Figure US20060205672A1-20060914-C00783
         		668.8782
    75
    Figure US20060205672A1-20060914-C00784
         		628.8129
    76
    Figure US20060205672A1-20060914-C00785
         		760.9792
    77
    Figure US20060205672A1-20060914-C00786
         		818.0723
    78
    Figure US20060205672A1-20060914-C00787
         		761.964
    79
    Figure US20060205672A1-20060914-C00788
         		844.0702
    80
    Figure US20060205672A1-20060914-C00789
         		753.9443
    81
    Figure US20060205672A1-20060914-C00790
         		844.0702
    82
    Figure US20060205672A1-20060914-C00791
         		753.9443
    83
    Figure US20060205672A1-20060914-C00792
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         		731.9783
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         		820.9918
    337
    Figure US20060205672A1-20060914-C01046
         		710.8784
    338
    Figure US20060205672A1-20060914-C01047
         		746.9089
    339
    Figure US20060205672A1-20060914-C01048
         		710.8784
    340
    Figure US20060205672A1-20060914-C01049
         		590.6823
    341
    Figure US20060205672A1-20060914-C01050
         		716.9261
    342
    Figure US20060205672A1-20060914-C01051
         		539.675
    343
    Figure US20060205672A1-20060914-C01052
         		772.9473
    344
    Figure US20060205672A1-20060914-C01053
         		731.938
    345
    Figure US20060205672A1-20060914-C01054
         		731.938
    346
    Figure US20060205672A1-20060914-C01055
         		731.938
    347
    Figure US20060205672A1-20060914-C01056
         		546.7132
    348
    Figure US20060205672A1-20060914-C01057
         		606.7662
    349
    Figure US20060205672A1-20060914-C01058
         		578.712
    350
    Figure US20060205672A1-20060914-C01059
         		564.7722
    351
    Figure US20060205672A1-20060914-C01060
         		548.7291
    352
    Figure US20060205672A1-20060914-C01061
         		562.7562
    353
    Figure US20060205672A1-20060914-C01062
         		642.8432
    354
    Figure US20060205672A1-20060914-C01063
         		536.718
    355
    Figure US20060205672A1-20060914-C01064
         		574.7673
    356
    Figure US20060205672A1-20060914-C01065
         		726.9214
    357
    Figure US20060205672A1-20060914-C01066
         		726.9214
    358
    Figure US20060205672A1-20060914-C01067
         		580.7279
    359
    Figure US20060205672A1-20060914-C01068
         		639.799
    360
    Figure US20060205672A1-20060914-C01069
         		538.6902
    361
    Figure US20060205672A1-20060914-C01070
         		562.7562
    362
    Figure US20060205672A1-20060914-C01071
         		566.7444
  • TABLE 4
    Ki*
    STRUCTURE NAME Range
    Figure US20060205672A1-20060914-C01072
         		iBoc-G(Chx)-P(4t- NHiBoc)-nV-(CO)- G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01073
         		(2-CO2)PhCO- G(Chx)-P(4t- MeNHCOPh(3- OPh)-nV-(CO)-G- G(Ph)-Am A
    Figure US20060205672A1-20060914-C01074
         		iBoc-G(Chx)-P(4t- NHSO2Ph)-nV- (CO)-G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01075
         		iBoc-G(Chx)-P(4t- UreaPh)-nV-(CO)- G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01076
         		iBoc-G(Chx)-P(4t- MeNHCOPh)-nV- (CO)-G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01077
         		iBoc-G(Chx)-P(4t- MeNHSO2Ph)-nV- (CO)-G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01078
         		iBoc-G(Chx)-P(4t- MeNHCOPh(3- OPh))-nV-(CO)-G- G(Ph)-Am B
    Figure US20060205672A1-20060914-C01079
         		(2-CO2)PhCO- G(chx)-P(4t- UreaPh)-nV-(CO)- G-G(ph)-Am C
    Figure US20060205672A1-20060914-C01080
         		iBoc-G(Chx)-P(4t- NHSO2-(4Me)Ph)- nV(CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01081
         		iBoc-G(Chx)-P(4t- NHSO2-(3Cl)Ph)- nV-(CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01082
         		iBoc-G(Chx)-P(4t- NHSO2-(4- NHAc)Ph)-nV- (CO)-G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01083
         		iBoc-G(Chx)-P(4t- NHSO2-(3,4- diCl)Ph)-nV-(CO)- G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01084
         		iBoc-G(Chx)-P(4t- Urea-1-Np)-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01085
         		iBoc-G(Chx)-P(4t- NHSO2-2-Np)-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01086
         		iBoc-G(Chx)-P(4t- NHSO2-(4Cl)Ph)- nV-(CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01087
         		iBoc-G(Chx)-P(4t- NHSO2-5(2,3- dihydrobenzofuran))- nV-(CO)-G- G(Ph)-Am B
    Figure US20060205672A1-20060914-C01088
         		iBoc-G(Chx)-P(4t- NHSO2-6(4- OMe)Courmarin)- nV-(CO)-G-G(Ph)- Am B
    Figure US20060205672A1-20060914-C01089
         		iBoc-G(Chx)-P(4t- Urea-Ph(4-OMe))- nV-(CO)-G-G(Ph)- Am A
    Figure US20060205672A1-20060914-C01090
         		iBoc-G(Chx)-P(4t- Urea-Ph(4-Cl))-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01091
         		iBoc-G(Chx)-P(4t- Urea-Ph(4-Cl))-nV- (CO)-G-G(Ph)-Am C
    Figure US20060205672A1-20060914-C01092
         		iBoc-G(Chx)-P(4t- Urea-Ph(4-Ac))- nV-(CO)-G-G(Ph)- Am B
    Figure US20060205672A1-20060914-C01093
         		iBoc-G(Chx)-P(4t- Urea-Ph(4-Ac))- nV-(CO)-G-G(Ph)- Am B
    Figure US20060205672A1-20060914-C01094
         		iBoc-G(Chx)-P(4t- NHSO2-Ph(4- OMe))-nV-(CO)-G- G(Ph)-Am B
    Figure US20060205672A1-20060914-C01095
         		iBoc-V-P(4t- NHSO2-Ph)-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01096
         		iBoc-G(Chx)-P(4t- NHSO2-1Np)-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01097
         		iBoc-G(Chx)-P(4t- NHSO2-8- Quinoline)-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01098
         		(2,5-diF-6- CO2)PhCO- G(Chx)-P(4t-NH- iBoc)-nV-(CO)-G- G(Ph)-Am A
    Figure US20060205672A1-20060914-C01099
         		(2,5-diF-6- CO2)PhCO- G(Chx)-P(4t- NHSO2-Ph)-nV- (CO)-G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01100
         		(3,4-diCl-6- CO2)PhCO- G(Chx)-P(4t-NH- iBoc)-nV-(CO)-G- G(Ph)-Am A
    Figure US20060205672A1-20060914-C01101
         		(3,4-diCl-6- CO2)PhCO- G(Chx)-P(4t- UreaPh)-nV(CO)- G-G(Ph-Am A
    Figure US20060205672A1-20060914-C01102
         		iBoc-G(Chx)-P(4t- Urea-(3-Cl)Ph)-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01103
         		(3,4-diCl-6- CO2)PhCO- G(Chx)-P(4t- NHSO2-Ph)-nV- (CO)-G-G(Ph)-Am A
    Figure US20060205672A1-20060914-C01104
         		iBoc-G(Chx)-P(3,4- iPr)-nV-(CO)-G- G(Ph)-OH A
    Figure US20060205672A1-20060914-C01105
         		iBoc-G(Chx)-P(4t- Chx)-nV-(CO)-G- G(Ph)-Am B
    Figure US20060205672A1-20060914-C01106
         		iBoc-G(Chx)-P(4- diMe)-nV-(CO)-G- G(Ph)-Am A
    Figure US20060205672A1-20060914-C01107
         		iBoc-G(Chx)-P(4- Bn,4-Me)-nV-(CO)- G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01108
         		iBoc-G(Chx)-P(4- spirocyclopentane)- nV-(CO)-G- G(Ph)-OH A
    Figure US20060205672A1-20060914-C01109
         		iBoc-G(Chx)-2- Azabicyclo[2.2.2]octane-3-CO-nV- (CO)-G-G(Ph)-Am B
    Figure US20060205672A1-20060914-C01110
         		iPrOCO-G(Chx)- P(4-OtBu)-nV- (CO)-G-G(Ph)-OH A
    Figure US20060205672A1-20060914-C01111
         		Neopentaxy(CO)- G(Chx)-P(4-OtBu)- nV-(CO)-G-G(Ph)-OH B
    Figure US20060205672A1-20060914-C01112
         		Neopentoxy(CO)- G(Chx)-P(OH)-nV- (CO)-G-G(Ph)-OH B
    Figure US20060205672A1-20060914-C01113
         		Ethoxy(CO)- G(Chx)-P(OH)-nV- (CO)-G-G(Ph)-OH B
    Figure US20060205672A1-20060914-C01114
         		iBoc-G(Chx)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01115
         		iBoc-G(Chx)-P(3,4- iPr)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01116
         		iBoc-G(Chx)-P(4- spirocyclopentane)- nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01117
         		iBoc-G(Chx)-P(4c- Me,4t-Pr)-nV- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01118
         		iBoc-G(Chx)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-OMe A
    Figure US20060205672A1-20060914-C01119
         		iBoc-G(Chx)-P(4- spirocyclopentane)- nV-(CO)-G- G(Ph)-OMe A
    Figure US20060205672A1-20060914-C01120
         		iBoc-G(Chx)-P(3t- Me)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01121
         		iBoc-G(Chx)-P(4,4- diMe)-nV-(CO)- S(Me)-G(Ph)-OH A
    Figure US20060205672A1-20060914-C01122
         		iBoc-G(Chx)-P(4,4- diMe)-nV-(CO)-S- G(Ph)-OH B
    Figure US20060205672A1-20060914-C01123
         		iBoc-G(Chx)-P(4,4- diMe)-nV-(CO)- G(Ac)-G(Ph)-OH C
    Figure US20060205672A1-20060914-C01124
         		N-Me-G(Chx)- P(4,4-diMe)-nV- (CO)-G-G(Ph)- CO2H C
    Figure US20060205672A1-20060914-C01125
         		iBoc-G(tBu)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01126
         		iBoc-G(Chx)-P(3,4- (diMe- cyclopropyl))- G((S,S)-Me- cyclopropyl)-(CO)- G-G(Ph)-N(Me) A
    Figure US20060205672A1-20060914-C01127
         		iBoc-G(Chx)-P(6S- CEM)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01128
         		iPoc-G(tBu)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01129
         		iBoc-G(Chx)-P(6R- CEM)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01130
         		iBoc-G(tBu)-P(4,4- diMe)-L-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01131
         		((R)-1-Me-iBoc)- G(Chx)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01132
         		iBoc-G(Chx)-P(5- c/t-Me)-nV-(CO)- G-G(Ph)-CO2H A
    Figure US20060205672A1-20060914-C01133
         		iBoc-G(Chx)-P(5- cis-Ph)-nV-(CO)- G-G(Ph)-CO2H B
    Figure US20060205672A1-20060914-C01134
         		iBoc-G(4,4- diMeChx)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01135
         		iBoc-G(1-MeChx)- P(4,4-diMe)-nV- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01136
         		iBoc-G(Chx)-P(3,4- CH2)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01137
         		iBoc-Chg-Pip-nV- (CO)-G-G(Ph)- N(Me)2 C
    Figure US20060205672A1-20060914-C01138
         		iBoc-G(Chx)-P(4,4- diMe)-L-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01139
         		iPoc-G(tBu)-P(4,4- diMe)-L-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01140
         		iPoc-G(tBu)-P(5- c/t-Me)-nV-(CO)- G-G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01141
         		((R)-1-Me-iBoc)- G(tBu)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01142
         		(S)-1-MeiBoc- G(Chx)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01143
         		iBoc-G(tBu)-P(4- cis-Me)-nV-(CO)- G-G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01144
         		iBoc-G(Chx)-P(4- cis-Me)-nV-(CO)- G-G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01145
         		iBoc-G(tBu)-P(5- cis-Me)-nV-(CO)- G-G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01146
         		iBoc-G(Chx)-P(5- cis-Me)-nV-(CO)- G-G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01147
         		iBoc-G(Chx)-P(t- 3Ph)-nV-(CO)-G- G(Ph)-N(Me)2 B
    Figure US20060205672A1-20060914-C01148
         		iBoc-allo(IIe)-P(4,4- diMe)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01149
         		iBoc-G(Chx)-Pip(4- morpholino)-nV- (CO)-G-G(Ph)- N(Me)2 B
    Figure US20060205672A1-20060914-C01150
         		iBoc-G(1-MeChx)- P[3,4-(diMe- cyclopropyl)]-nV- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01151
         		iBoc-G(1-MeChx)- P[3,4-(diMe- cyclopropyl)]-L- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01152
         		iBoc-G(tBu)-P[3,4- (diMe- cyclopropyl)]-L- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01153
         		iBoc-erythro-D,L- F(beta-Me)-P(4,4- diMe)- nV-(CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01154
         		((R)-1-Me)iBoc- G(1-MeChx)-P[3,4- (diMe- cyclorpropyl)]-nV- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01155
         		iPoc-G(tBu)-P[3,4- (diMe- cyclopropyl)]-nV- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01156
         		iPoc-G(tBu)-P[3,4- (diMe- cyclopropyl)]-L- (CO)-G-G(Ph)- N(Me)2 A
    Figure US20060205672A1-20060914-C01157
         		iBoc-G(tBu)-P(3,4- CH2)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01158
         		iBoc-G(Chx)-P(3,4- CH2)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01159
         		iPoc-G(tBu)-P(3,4- CH2)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01160
         		((R)-1-Me)iBoc- G(tBu)-P(3,4- CH2)-nV-(CO)-G- G(Ph)-N(Me)2 A
    Figure US20060205672A1-20060914-C01161
         		((R)-1-Me)iBoc- G(1-MeChx)-P(3,4- CH2)-nV-(CO)-G- G(Ph)-N(Me)2 A
  • TABLE 5
    Structure MW Ki* range
    Figure US20060205672A1-20060914-C01162
         		507 B
    Figure US20060205672A1-20060914-C01163
         		481 B
    Figure US20060205672A1-20060914-C01164
         		473 C
    Figure US20060205672A1-20060914-C01165
         		586 B
    Figure US20060205672A1-20060914-C01166
         		497 C
    Figure US20060205672A1-20060914-C01167
         		483 C
    Figure US20060205672A1-20060914-C01168
         		481 C
    Figure US20060205672A1-20060914-C01169
         		479 B
    Figure US20060205672A1-20060914-C01170
         		507 A
    Figure US20060205672A1-20060914-C01171
         		521 A
    Figure US20060205672A1-20060914-C01172
         		612 A
    Figure US20060205672A1-20060914-C01173
         		533 A
    Figure US20060205672A1-20060914-C01174
         		569 A
    Figure US20060205672A1-20060914-C01175
         		557 B
    Figure US20060205672A1-20060914-C01176
         		521 C
    Figure US20060205672A1-20060914-C01177
         		555 A
    Figure US20060205672A1-20060914-C01178
         		497 C
    Figure US20060205672A1-20060914-C01179
         		569 B
    Figure US20060205672A1-20060914-C01180
         		533 B
    Figure US20060205672A1-20060914-C01181
         		519 C
    Figure US20060205672A1-20060914-C01182
         		621 B
    Figure US20060205672A1-20060914-C01183
         		392 C
    Figure US20060205672A1-20060914-C01184
         		418 C
    Figure US20060205672A1-20060914-C01185
         		509 B
    Figure US20060205672A1-20060914-C01186
         		493 C
    Figure US20060205672A1-20060914-C01187
         		507 B
    Figure US20060205672A1-20060914-C01188
         		567 A
    Figure US20060205672A1-20060914-C01189
         		519 A
    Figure US20060205672A1-20060914-C01190
         		519 B
    Figure US20060205672A1-20060914-C01191
         		535 B
    Figure US20060205672A1-20060914-C01192
         		523 C
    Figure US20060205672A1-20060914-C01193
         		493 B
    Figure US20060205672A1-20060914-C01194
         		547 B
    Figure US20060205672A1-20060914-C01195
         		519 A
    Figure US20060205672A1-20060914-C01196
         		505 C
    Figure US20060205672A1-20060914-C01197
         		494 B
    Figure US20060205672A1-20060914-C01198
         		480 B
    Figure US20060205672A1-20060914-C01199
         		466 C
    Figure US20060205672A1-20060914-C01200
         		493 B
    Figure US20060205672A1-20060914-C01201
         		505 B
    Figure US20060205672A1-20060914-C01202
         		491 B
    Figure US20060205672A1-20060914-C01203
         		541 B
    Figure US20060205672A1-20060914-C01204
         		478 C
    Figure US20060205672A1-20060914-C01205
         		555 B
    Figure US20060205672A1-20060914-C01206
         		554 B
    Figure US20060205672A1-20060914-C01207
         		465 C
    Figure US20060205672A1-20060914-C01208
         		520 A
    Figure US20060205672A1-20060914-C01209
         		558 A
    Figure US20060205672A1-20060914-C01210
         		532 A
    Figure US20060205672A1-20060914-C01211
         		547 B
    Figure US20060205672A1-20060914-C01212
         		547 B
    Figure US20060205672A1-20060914-C01213
         		553 A
    Figure US20060205672A1-20060914-C01214
         		520 B
    Figure US20060205672A1-20060914-C01215
         		521 A
    Figure US20060205672A1-20060914-C01216
         		543 C
    Figure US20060205672A1-20060914-C01217
         		569 B
    Figure US20060205672A1-20060914-C01218
         		507 B
    Figure US20060205672A1-20060914-C01219
         		522 B
    Figure US20060205672A1-20060914-C01220
         		606 C
    Figure US20060205672A1-20060914-C01221
         		493 B
    Figure US20060205672A1-20060914-C01222
         		467 C
    Figure US20060205672A1-20060914-C01223
         		507 B
    Figure US20060205672A1-20060914-C01224
         		572 A
    Figure US20060205672A1-20060914-C01225
         		718 C
    Figure US20060205672A1-20060914-C01226
         		547 A
    Figure US20060205672A1-20060914-C01227
         		666 B
    Figure US20060205672A1-20060914-C01228
         		540 C
    Figure US20060205672A1-20060914-C01229
         		554 B
    Figure US20060205672A1-20060914-C01230
         		540 B
    Figure US20060205672A1-20060914-C01231
         		632 B
    Figure US20060205672A1-20060914-C01232
         		580 B
    Figure US20060205672A1-20060914-C01233
         		552 A
    Figure US20060205672A1-20060914-C01234
         		592 A
    Figure US20060205672A1-20060914-C01235
         		518 A
    Figure US20060205672A1-20060914-C01236
         		506 A
    Figure US20060205672A1-20060914-C01237
         		532 A
    Figure US20060205672A1-20060914-C01238
         		581 B
    Figure US20060205672A1-20060914-C01239
         		566 C
    Figure US20060205672A1-20060914-C01240
         		599 B
    Figure US20060205672A1-20060914-C01241
         		553 B
    Figure US20060205672A1-20060914-C01242
         		568 B
    Figure US20060205672A1-20060914-C01243
         		566 A
    Figure US20060205672A1-20060914-C01244
         		566 A
    Figure US20060205672A1-20060914-C01245
         		644 A
    Figure US20060205672A1-20060914-C01246
         		543 C
    Figure US20060205672A1-20060914-C01247
         		574 A
    Figure US20060205672A1-20060914-C01248
         		534 C
    Figure US20060205672A1-20060914-C01249
         		549 B
    Figure US20060205672A1-20060914-C01250
         		562 A
    Figure US20060205672A1-20060914-C01251
         		662 A
    Figure US20060205672A1-20060914-C01252
         		563 B
    Figure US20060205672A1-20060914-C01253
         		518 B
    Figure US20060205672A1-20060914-C01254
         		492 B
    Figure US20060205672A1-20060914-C01255
         		533 A
    Figure US20060205672A1-20060914-C01256
         		510 C
    Figure US20060205672A1-20060914-C01257
         		504 A
    Figure US20060205672A1-20060914-C01258
         		530 B
    Figure US20060205672A1-20060914-C01259
         		516 B
    Figure US20060205672A1-20060914-C01260
         		574 B
    Figure US20060205672A1-20060914-C01261
         		561 B
    Figure US20060205672A1-20060914-C01262
         		533 B
    Figure US20060205672A1-20060914-C01263
         		493 C
    Figure US20060205672A1-20060914-C01264
         		546 A
    Figure US20060205672A1-20060914-C01265
         		561 A
    Figure US20060205672A1-20060914-C01266
         		505 B
    Figure US20060205672A1-20060914-C01267
         		490 B
    Figure US20060205672A1-20060914-C01268
         		539 C
    Figure US20060205672A1-20060914-C01269
         		532 A
    Figure US20060205672A1-20060914-C01270
         		561 A
    Figure US20060205672A1-20060914-C01271
         		573 A
    Figure US20060205672A1-20060914-C01272
         		567 A
    Figure US20060205672A1-20060914-C01273
         		581 A
    Figure US20060205672A1-20060914-C01274
         		608 A
    Figure US20060205672A1-20060914-C01275
         		587 B
    Figure US20060205672A1-20060914-C01276
         		561 B
    Figure US20060205672A1-20060914-C01277
         		581 A
    Figure US20060205672A1-20060914-C01278
         		573 A
    Figure US20060205672A1-20060914-C01279
         		624 A
    Figure US20060205672A1-20060914-C01280
         		547 A
    Figure US20060205672A1-20060914-C01281
         		583 A
    Figure US20060205672A1-20060914-C01282
         		545 B
    Figure US20060205672A1-20060914-C01283
         		609 C
    Figure US20060205672A1-20060914-C01284
         		549 C
    Figure US20060205672A1-20060914-C01285
         		575 C
    Figure US20060205672A1-20060914-C01286
         		613 A
    Figure US20060205672A1-20060914-C01287
         		573 A
    Figure US20060205672A1-20060914-C01288
         		561 A
    Figure US20060205672A1-20060914-C01289
         		625 A
    Figure US20060205672A1-20060914-C01290
         		666 C
    Figure US20060205672A1-20060914-C01291
         		588 A
    Figure US20060205672A1-20060914-C01292
         		599 A
    Figure US20060205672A1-20060914-C01293
         		573 A
    Figure US20060205672A1-20060914-C01294
         		587 A
    Figure US20060205672A1-20060914-C01295
         		615 A
    Figure US20060205672A1-20060914-C01296
         		535 B
    Figure US20060205672A1-20060914-C01297
         		561 A
    Figure US20060205672A1-20060914-C01298
         		531 A
    Figure US20060205672A1-20060914-C01299
         		651 A
    Figure US20060205672A1-20060914-C01300
         		506 A
    Figure US20060205672A1-20060914-C01301
         		520 A
    Figure US20060205672A1-20060914-C01302
         		546 A
    Figure US20060205672A1-20060914-C01303
         		602 A
    Figure US20060205672A1-20060914-C01304
         		549 B
    Figure US20060205672A1-20060914-C01305
         		587 A
    Figure US20060205672A1-20060914-C01306
         		561 A
    Figure US20060205672A1-20060914-C01307
         		517 B
    Figure US20060205672A1-20060914-C01308
         		491 B
    Figure US20060205672A1-20060914-C01309
         		533 B
    Figure US20060205672A1-20060914-C01310
         		507 A
    Figure US20060205672A1-20060914-C01311
         		598 A
    Figure US20060205672A1-20060914-C01312
         		535 A
    Figure US20060205672A1-20060914-C01313
         		561 A
    Figure US20060205672A1-20060914-C01314
         		633 A
    Figure US20060205672A1-20060914-C01315
         		497 C
    Figure US20060205672A1-20060914-C01316
         		607 A
    Figure US20060205672A1-20060914-C01317
         		574 B
    Figure US20060205672A1-20060914-C01318
         		518 B
    Figure US20060205672A1-20060914-C01319
         		580 C
    Figure US20060205672A1-20060914-C01320
         		544 B
    Figure US20060205672A1-20060914-C01321
         		562 A
    Figure US20060205672A1-20060914-C01322
         		561 A
    Figure US20060205672A1-20060914-C01323
         		587 A
    Figure US20060205672A1-20060914-C01324
         		533 A
    Figure US20060205672A1-20060914-C01325
         		559 A
    Figure US20060205672A1-20060914-C01326
         		557 C
    Figure US20060205672A1-20060914-C01327
         		535 A
    Figure US20060205672A1-20060914-C01328
         		535 B
    Figure US20060205672A1-20060914-C01329
         		547 A
    Figure US20060205672A1-20060914-C01330
         		546 A
    Figure US20060205672A1-20060914-C01331
         		546 B
    Figure US20060205672A1-20060914-C01332
         		523 B
    Figure US20060205672A1-20060914-C01333
         		663 C
    Figure US20060205672A1-20060914-C01334
         		637 C
    Figure US20060205672A1-20060914-C01335
         		521 B
    Figure US20060205672A1-20060914-C01336
         		573 B
    Figure US20060205672A1-20060914-C01337
         		559 A
    Figure US20060205672A1-20060914-C01338
         		533 A
    Figure US20060205672A1-20060914-C01339
         		573 B
    Figure US20060205672A1-20060914-C01340
         		595 B
    Figure US20060205672A1-20060914-C01341
         		575 A
    Figure US20060205672A1-20060914-C01342
         		560 B
    Figure US20060205672A1-20060914-C01343
         		534 C
    Figure US20060205672A1-20060914-C01344
         		727 A
    Figure US20060205672A1-20060914-C01345
         		727 A
    Figure US20060205672A1-20060914-C01346
         		753 C
    Figure US20060205672A1-20060914-C01347
         		753 B
    Figure US20060205672A1-20060914-C01348
         		745 A
    Figure US20060205672A1-20060914-C01349
         		745 A
    Figure US20060205672A1-20060914-C01350
         		759 C
    Figure US20060205672A1-20060914-C01351
         		759 B
    Figure US20060205672A1-20060914-C01352
         		669 B
    Figure US20060205672A1-20060914-C01353
         		669 A
    Figure US20060205672A1-20060914-C01354
         		554 C
    Figure US20060205672A1-20060914-C01355
         		610 B
    Figure US20060205672A1-20060914-C01356
         		711 A
    Figure US20060205672A1-20060914-C01357
         		713 A
    Figure US20060205672A1-20060914-C01358
         		713 A
    Figure US20060205672A1-20060914-C01359
         		732 A
    Figure US20060205672A1-20060914-C01360
         		733 A
    Figure US20060205672A1-20060914-C01361
         		733 A
    Figure US20060205672A1-20060914-C01362
         		737 A
    Figure US20060205672A1-20060914-C01363
         		667 A
    Figure US20060205672A1-20060914-C01364
         		612 C
    Figure US20060205672A1-20060914-C01365
         		745 C
    Figure US20060205672A1-20060914-C01366
         		745 C
    Figure US20060205672A1-20060914-C01367
         		745 C
    Figure US20060205672A1-20060914-C01368
         		759 C
    Figure US20060205672A1-20060914-C01369
         		759 C
    Figure US20060205672A1-20060914-C01370
         		759 C
    Figure US20060205672A1-20060914-C01371
         		668 C
    Figure US20060205672A1-20060914-C01372
         		636 B
    Figure US20060205672A1-20060914-C01373
         		733 A
    Figure US20060205672A1-20060914-C01374
         		767 B
    Figure US20060205672A1-20060914-C01375
         		626 B
    Figure US20060205672A1-20060914-C01376
         		715 C
    Figure US20060205672A1-20060914-C01377
         		715 A
    Figure US20060205672A1-20060914-C01378
         		699 B
    Figure US20060205672A1-20060914-C01379
         		725 A
    Figure US20060205672A1-20060914-C01380
         		781 B
    Figure US20060205672A1-20060914-C01381
         		743 B
    Figure US20060205672A1-20060914-C01382
         		743 C
    Figure US20060205672A1-20060914-C01383
         		743 A
    Figure US20060205672A1-20060914-C01384
         		757 B
    Figure US20060205672A1-20060914-C01385
         		757 C
    Figure US20060205672A1-20060914-C01386
         		757 B
    Figure US20060205672A1-20060914-C01387
         		715 A
    Figure US20060205672A1-20060914-C01388
         		715 A
    Figure US20060205672A1-20060914-C01389
         		701 C
    Figure US20060205672A1-20060914-C01390
         		701 A
    Figure US20060205672A1-20060914-C01391
         		713 A
    Figure US20060205672A1-20060914-C01392
         		739 A
    Figure US20060205672A1-20060914-C01393
         		741 C
    Figure US20060205672A1-20060914-C01394
         		715 C
    Figure US20060205672A1-20060914-C01395
         		837 B
    Figure US20060205672A1-20060914-C01396
         		751 A
    Figure US20060205672A1-20060914-C01397
         		725 C
    Figure US20060205672A1-20060914-C01398
         		711 C
    Figure US20060205672A1-20060914-C01399
         		737 A
    Figure US20060205672A1-20060914-C01400
         		775 A
    Figure US20060205672A1-20060914-C01401
         		729 A
    Figure US20060205672A1-20060914-C01402
         		729 A
    Figure US20060205672A1-20060914-C01403
         		715 A
    Figure US20060205672A1-20060914-C01404
         		775 A
    Figure US20060205672A1-20060914-C01405
         		739 A
    Figure US20060205672A1-20060914-C01406
         		713 A
    Figure US20060205672A1-20060914-C01407
         		719 A
    Figure US20060205672A1-20060914-C01408
         		719 A
    Figure US20060205672A1-20060914-C01409
         		719 A
    Figure US20060205672A1-20060914-C01410
         		773 A
    Figure US20060205672A1-20060914-C01411
         		727 A
    Figure US20060205672A1-20060914-C01412
         		727 A
    Figure US20060205672A1-20060914-C01413
         		727 A
    Figure US20060205672A1-20060914-C01414
         		787 A
    Figure US20060205672A1-20060914-C01415
         		809 C
    Figure US20060205672A1-20060914-C01416
         		709 A
    Figure US20060205672A1-20060914-C01417
         		769 B
    Figure US20060205672A1-20060914-C01418
         		723 C
    Figure US20060205672A1-20060914-C01419
         		713 A
    Figure US20060205672A1-20060914-C01420
         		723 A
    Figure US20060205672A1-20060914-C01421
         		723 B
    Figure US20060205672A1-20060914-C01422
         		771 C
    Figure US20060205672A1-20060914-C01423
         		741 A
    Figure US20060205672A1-20060914-C01424
         		725 A
    Figure US20060205672A1-20060914-C01425
         		745 A
    Figure US20060205672A1-20060914-C01426
         		716 A
    Figure US20060205672A1-20060914-C01427
         		733 A
    Figure US20060205672A1-20060914-C01428
         		713 A
    Figure US20060205672A1-20060914-C01429
         		753 A
    Figure US20060205672A1-20060914-C01430
         		726 A
    Figure US20060205672A1-20060914-C01431
         		712 A
    Figure US20060205672A1-20060914-C01432
         		771 B
    Figure US20060205672A1-20060914-C01433
         		804 A
    Figure US20060205672A1-20060914-C01434
         		726 A
    Figure US20060205672A1-20060914-C01435
         		746 A
    Figure US20060205672A1-20060914-C01436
         		752 A
    Figure US20060205672A1-20060914-C01437
         		741 A
    Figure US20060205672A1-20060914-C01438
         		727 A
    Figure US20060205672A1-20060914-C01439
         		699 A
    Figure US20060205672A1-20060914-C01440
         		739 A
    Figure US20060205672A1-20060914-C01441
         		712 A
    Figure US20060205672A1-20060914-C01442
         		698 A
    Figure US20060205672A1-20060914-C01443
         		757 B
    Figure US20060205672A1-20060914-C01444
         		790 A
    Figure US20060205672A1-20060914-C01445
         		712 A
    Figure US20060205672A1-20060914-C01446
         		732 A
    Figure US20060205672A1-20060914-C01447
         		738 A
    Figure US20060205672A1-20060914-C01448
         		869 A
    Figure US20060205672A1-20060914-C01449
         		785 A
    Figure US20060205672A1-20060914-C01450
         		785 A
    Figure US20060205672A1-20060914-C01451
         		785 A
    Figure US20060205672A1-20060914-C01452
         		785 A
    Figure US20060205672A1-20060914-C01453
         		781 A
    Figure US20060205672A1-20060914-C01454
         		780 A
    Figure US20060205672A1-20060914-C01455
         		697 C
    Figure US20060205672A1-20060914-C01456
         		671 C
    Figure US20060205672A1-20060914-C01457
         		780 A
    Figure US20060205672A1-20060914-C01458
         		884 A
    Figure US20060205672A1-20060914-C01459
         		855 A
    Figure US20060205672A1-20060914-C01460
         		757 B
    Figure US20060205672A1-20060914-C01461
         		741 B
    Figure US20060205672A1-20060914-C01462
         		779 B
    Figure US20060205672A1-20060914-C01463
         		725 A
    Figure US20060205672A1-20060914-C01464
         		787 A
    Figure US20060205672A1-20060914-C01465
         		785 A
    Figure US20060205672A1-20060914-C01466
         		737 A
    Figure US20060205672A1-20060914-C01467
         		737 A
    Figure US20060205672A1-20060914-C01468
         		739 A
    Figure US20060205672A1-20060914-C01469
         		855 A
    Figure US20060205672A1-20060914-C01470
         		826 A
    Figure US20060205672A1-20060914-C01471
         		857 A
    Figure US20060205672A1-20060914-C01472
         		826 A
    Figure US20060205672A1-20060914-C01473
         		765 A
    Figure US20060205672A1-20060914-C01474
         		792 A
    Figure US20060205672A1-20060914-C01475
         		799 A
    Figure US20060205672A1-20060914-C01476
         		784 A
    Figure US20060205672A1-20060914-C01477
         		750 A
    Figure US20060205672A1-20060914-C01478
         		771 A
    Figure US20060205672A1-20060914-C01479
         		771 A
    Figure US20060205672A1-20060914-C01480
         		536 C
    Figure US20060205672A1-20060914-C01481
         		508 B
    Figure US20060205672A1-20060914-C01482
         		601 C
    Figure US20060205672A1-20060914-C01483
         		587 B
    Figure US20060205672A1-20060914-C01484
         		494 C
    Figure US20060205672A1-20060914-C01485
         		512 C
    Figure US20060205672A1-20060914-C01486
         		538 C
    Figure US20060205672A1-20060914-C01487
         		538 C
    Figure US20060205672A1-20060914-C01488
         		522 C
    Figure US20060205672A1-20060914-C01489
         		496 C
    Figure US20060205672A1-20060914-C01490
         		522 C
    Figure US20060205672A1-20060914-C01491
         		540 C
    Figure US20060205672A1-20060914-C01492
         		598 C
    Figure US20060205672A1-20060914-C01493
         		480 C
    Figure US20060205672A1-20060914-C01494
         		508 B
    Figure US20060205672A1-20060914-C01495
         		548 C
    Figure US20060205672A1-20060914-C01496
         		534 B
    Figure US20060205672A1-20060914-C01497
         		584 C
    Figure US20060205672A1-20060914-C01498
         		570 B
    Figure US20060205672A1-20060914-C01499
         		558 C
    Figure US20060205672A1-20060914-C01500
         		433 C
    Figure US20060205672A1-20060914-C01501
         		407 C
    Figure US20060205672A1-20060914-C01502
         		393 C
    Figure US20060205672A1-20060914-C01503
         		433 C
    Figure US20060205672A1-20060914-C01504
         		419 C
    Figure US20060205672A1-20060914-C01505
         		534 C
    Figure US20060205672A1-20060914-C01506
         		520 B
    Figure US20060205672A1-20060914-C01507
         		534 C
    Figure US20060205672A1-20060914-C01508
         		520 B
    Figure US20060205672A1-20060914-C01509
         		550 C
    Figure US20060205672A1-20060914-C01510
         		536 C
    Figure US20060205672A1-20060914-C01511
         		538 C
    Figure US20060205672A1-20060914-C01512
         		568 B
    Figure US20060205672A1-20060914-C01513
         		582 C
    Figure US20060205672A1-20060914-C01514
         		570 C
  • TABLE 5
    Figure US20060205672A1-20060914-C01515
         		584 C
    Figure US20060205672A1-20060914-C01516
         		418 C
    Figure US20060205672A1-20060914-C01517
         		554 C
    Figure US20060205672A1-20060914-C01518
         		508 C
    Figure US20060205672A1-20060914-C01519
         		494 B
    Figure US20060205672A1-20060914-C01520
         		562 C
    Figure US20060205672A1-20060914-C01521
         		548 A
    Figure US20060205672A1-20060914-C01522
         		520 C
    Figure US20060205672A1-20060914-C01523
         		506 C
    Figure US20060205672A1-20060914-C01524
         		540 C
    Figure US20060205672A1-20060914-C01525
         		562 C
    Figure US20060205672A1-20060914-C01526
         		548 B
    Figure US20060205672A1-20060914-C01527
         		480 C
    Figure US20060205672A1-20060914-C01528
         		466 C
    Figure US20060205672A1-20060914-C01529
         		568 C
    Figure US20060205672A1-20060914-C01530
         		554 B
    Figure US20060205672A1-20060914-C01531
         		508 B
    Figure US20060205672A1-20060914-C01532
         		482 C
    Figure US20060205672A1-20060914-C01533
         		496 C
    Figure US20060205672A1-20060914-C01534
         		522 C
    Figure US20060205672A1-20060914-C01535
         		535 C
    Figure US20060205672A1-20060914-C01536
         		539 B
    Figure US20060205672A1-20060914-C01537
         		563 B
    Figure US20060205672A1-20060914-C01538
         		567 C
    Figure US20060205672A1-20060914-C01539
         		561 C
    Figure US20060205672A1-20060914-C01540
         		567 C
    Figure US20060205672A1-20060914-C01541
         		581 C
    Figure US20060205672A1-20060914-C01542
         		495 C
    Figure US20060205672A1-20060914-C01543
         		654 B
    Figure US20060205672A1-20060914-C01544
         		549 C
    Figure US20060205672A1-20060914-C01545
         		567 C
    Figure US20060205672A1-20060914-C01546
         		581 C
    Figure US20060205672A1-20060914-C01547
         		654 C
    Figure US20060205672A1-20060914-C01548
         		626 B
    Figure US20060205672A1-20060914-C01549
         		654 A
    Figure US20060205672A1-20060914-C01550
         		535 C
    Figure US20060205672A1-20060914-C01551
         		535 B
    Figure US20060205672A1-20060914-C01552
         		523 C
    Figure US20060205672A1-20060914-C01553
         		523 C
    Figure US20060205672A1-20060914-C01554
         		561 B
    Figure US20060205672A1-20060914-C01555
         		511 C
    Figure US20060205672A1-20060914-C01556
         		537 C
    Figure US20060205672A1-20060914-C01557
         		654 B
    Figure US20060205672A1-20060914-C01558
         		654 A
    Figure US20060205672A1-20060914-C01559
         		626 B
    Figure US20060205672A1-20060914-C01560
         		652 B
    Figure US20060205672A1-20060914-C01561
         		525 C
    Figure US20060205672A1-20060914-C01562
         		539 C
    Figure US20060205672A1-20060914-C01563
         		549 C
    Figure US20060205672A1-20060914-C01564
         		641 B
    Figure US20060205672A1-20060914-C01565
         		630 C
    Figure US20060205672A1-20060914-C01566
         		653 B
    Figure US20060205672A1-20060914-C01567
         		653 B
    Figure US20060205672A1-20060914-C01568
         		553 C
    Figure US20060205672A1-20060914-C01569
         		655 C
    Figure US20060205672A1-20060914-C01570
         		629 C
    Figure US20060205672A1-20060914-C01571
         		539 C
    Figure US20060205672A1-20060914-C01572
         		521 C
    Figure US20060205672A1-20060914-C01573
         		521 C
    Figure US20060205672A1-20060914-C01574
         		547 C
    Figure US20060205672A1-20060914-C01575
         		547 C
    Figure US20060205672A1-20060914-C01576
         		590 B
    Figure US20060205672A1-20060914-C01577
         		590 B
    Figure US20060205672A1-20060914-C01578
         		641 B
    Figure US20060205672A1-20060914-C01579
         		565 C
    Figure US20060205672A1-20060914-C01580
         		579 C
    Figure US20060205672A1-20060914-C01581
         		644 C
    Figure US20060205672A1-20060914-C01582
         		587 C
    Figure US20060205672A1-20060914-C01583
         		654 B
    Figure US20060205672A1-20060914-C01584
         		716 B
    Figure US20060205672A1-20060914-C01585
         		668 B
    Figure US20060205672A1-20060914-C01586
         		670 A
    Figure US20060205672A1-20060914-C01587
         		666 C
    Figure US20060205672A1-20060914-C01588
         		666 C
    Figure US20060205672A1-20060914-C01589
         		630 B
    Figure US20060205672A1-20060914-C01590
         		531 C
    Figure US20060205672A1-20060914-C01591
         		563 C
    Figure US20060205672A1-20060914-C01592
         		537 C
    Figure US20060205672A1-20060914-C01593
         		575 B
    Figure US20060205672A1-20060914-C01594
         		591 B
    Figure US20060205672A1-20060914-C01595
         		586 C
    Figure US20060205672A1-20060914-C01596
         		586 C
    Figure US20060205672A1-20060914-C01597
         		585 B
    Figure US20060205672A1-20060914-C01598
         		563 B
    Figure US20060205672A1-20060914-C01599
         		547 B
    Figure US20060205672A1-20060914-C01600
         		519 C
    Figure US20060205672A1-20060914-C01601
         		640 B
    Figure US20060205672A1-20060914-C01602
         		546 B
    Figure US20060205672A1-20060914-C01603
         		646 B
    Figure US20060205672A1-20060914-C01604
         		594 C
    Figure US20060205672A1-20060914-C01605
         		592 B
    Figure US20060205672A1-20060914-C01606
         		533 C
    Figure US20060205672A1-20060914-C01607
         		545 C
    Figure US20060205672A1-20060914-C01608
         		659 B
    Figure US20060205672A1-20060914-C01609
         		609 A
    Figure US20060205672A1-20060914-C01610
         		635 B
    Figure US20060205672A1-20060914-C01611
         		685 B
    Figure US20060205672A1-20060914-C01612
         		519 C
    Figure US20060205672A1-20060914-C01613
         		621 B
    Figure US20060205672A1-20060914-C01614
         		521 B
    Figure US20060205672A1-20060914-C01615
         		547 B
    Figure US20060205672A1-20060914-C01616
         		573 B
    Figure US20060205672A1-20060914-C01617
         		609 B
    Figure US20060205672A1-20060914-C01618
         		547 B
    Figure US20060205672A1-20060914-C01619
         		719 B
    Figure US20060205672A1-20060914-C01620
         		719 C
    Figure US20060205672A1-20060914-C01621
         		653 B
    Figure US20060205672A1-20060914-C01622
         		597 B
    Figure US20060205672A1-20060914-C01623
         		697 A
    Figure US20060205672A1-20060914-C01624
         		619 B
    Figure US20060205672A1-20060914-C01625
         		651 C
    Figure US20060205672A1-20060914-C01626
         		592 B
    Figure US20060205672A1-20060914-C01627
         		587 C
    Figure US20060205672A1-20060914-C01628
         		563 B
    Figure US20060205672A1-20060914-C01629
         		589 C
    Figure US20060205672A1-20060914-C01630
         		621 C
    Figure US20060205672A1-20060914-C01631
         		519 C
    Figure US20060205672A1-20060914-C01632
         		597 B
    Figure US20060205672A1-20060914-C01633
         		549 C
    Figure US20060205672A1-20060914-C01634
         		535 B
    Figure US20060205672A1-20060914-C01635
         		521 B
    Figure US20060205672A1-20060914-C01636
         		519 C
    Figure US20060205672A1-20060914-C01637
         		689 C
    Figure US20060205672A1-20060914-C01638
         		611 C
    Figure US20060205672A1-20060914-C01639
         		600 C
    Figure US20060205672A1-20060914-C01640
         		595 B
    Figure US20060205672A1-20060914-C01641
         		541 C
    Figure US20060205672A1-20060914-C01642
         		549 B
    Figure US20060205672A1-20060914-C01643
         		593 C
    Figure US20060205672A1-20060914-C01644
         		680 B
    Figure US20060205672A1-20060914-C01645
         		559 C
    Figure US20060205672A1-20060914-C01646
         		559 C
    Figure US20060205672A1-20060914-C01647
         		573 B
    Figure US20060205672A1-20060914-C01648
         		644 C
    Figure US20060205672A1-20060914-C01649
         		537 C
    Figure US20060205672A1-20060914-C01650
         		627 C
    Figure US20060205672A1-20060914-C01651
         		609 B
    Figure US20060205672A1-20060914-C01652
         		664 B
    Figure US20060205672A1-20060914-C01653
         		650 C
    Figure US20060205672A1-20060914-C01654
         		661 B
    Figure US20060205672A1-20060914-C01655
         		571 C
    Figure US20060205672A1-20060914-C01656
         		661 B
    Figure US20060205672A1-20060914-C01657
         		607 B
    Figure US20060205672A1-20060914-C01658
         		625 C
    Figure US20060205672A1-20060914-C01659
         		575 B
    Figure US20060205672A1-20060914-C01660
         		575 B
    Figure US20060205672A1-20060914-C01661
         		575 B
    Figure US20060205672A1-20060914-C01662
         		575 B
    Figure US20060205672A1-20060914-C01663
         		559 B
    Figure US20060205672A1-20060914-C01664
         		573 B
    Figure US20060205672A1-20060914-C01665
         		637 B
    Figure US20060205672A1-20060914-C01666
         		473 C
    Figure US20060205672A1-20060914-C01667
         		559 B
    Figure US20060205672A1-20060914-C01668
         		549 C
    Figure US20060205672A1-20060914-C01669
         		587 C
    Figure US20060205672A1-20060914-C01670
         		547 C
    Figure US20060205672A1-20060914-C01671
         		547 B
    Figure US20060205672A1-20060914-C01672
         		573 C
    Figure US20060205672A1-20060914-C01673
         		573 C
    Figure US20060205672A1-20060914-C01674
         		607 C
    Figure US20060205672A1-20060914-C01675
         		595 B
    Figure US20060205672A1-20060914-C01676
         		581 B
    Figure US20060205672A1-20060914-C01677
         		609 B
    Figure US20060205672A1-20060914-C01678
         		629 C
    Figure US20060205672A1-20060914-C01679
         		694 C
    Figure US20060205672A1-20060914-C01680
         		605 C
    Figure US20060205672A1-20060914-C01681
         		579 C
    Figure US20060205672A1-20060914-C01682
         		627 C
    Figure US20060205672A1-20060914-C01683
         		563 C
    Figure US20060205672A1-20060914-C01684
         		571 C
    Figure US20060205672A1-20060914-C01685
         		572 B
    Figure US20060205672A1-20060914-C01686
         		551 C
    Figure US20060205672A1-20060914-C01687
         		609 C
    Figure US20060205672A1-20060914-C01688
         		593 B
    Figure US20060205672A1-20060914-C01689
         		593 C
    Figure US20060205672A1-20060914-C01690
         		613 C
    Figure US20060205672A1-20060914-C01691
         		595 B
    Figure US20060205672A1-20060914-C01692
         		581 C
    Figure US20060205672A1-20060914-C01693
         		571 B
    Figure US20060205672A1-20060914-C01694
         		577 C
    Figure US20060205672A1-20060914-C01695
         		615 C
    Figure US20060205672A1-20060914-C01696
         		571 C
    Figure US20060205672A1-20060914-C01697
         		571 C
    Figure US20060205672A1-20060914-C01698
         		545 C
    Figure US20060205672A1-20060914-C01699
         		633 C
    Figure US20060205672A1-20060914-C01700
         		585 B
    Figure US20060205672A1-20060914-C01701
         		587 B
    Figure US20060205672A1-20060914-C01702
         		647 B
    Figure US20060205672A1-20060914-C01703
         		512 C
    Figure US20060205672A1-20060914-C01704
         		575 C
    Figure US20060205672A1-20060914-C01705
         		685 C
    Figure US20060205672A1-20060914-C01706
         		621 C
    Figure US20060205672A1-20060914-C01707
         		565 C
    Figure US20060205672A1-20060914-C01708
         		572 A
    Figure US20060205672A1-20060914-C01709
         		587 A
    Figure US20060205672A1-20060914-C01710
         		587 B
    Figure US20060205672A1-20060914-C01711
         		509 C
    Figure US20060205672A1-20060914-C01712
         		533 C
    Figure US20060205672A1-20060914-C01713
         		587 B
    Figure US20060205672A1-20060914-C01714
         		644 C
    Figure US20060205672A1-20060914-C01715
         		594 B
    Figure US20060205672A1-20060914-C01716
         		695 B
    Figure US20060205672A1-20060914-C01717
         		650 B
    Figure US20060205672A1-20060914-C01718
         		600 B
    Figure US20060205672A1-20060914-C01719
         		628 A
    Figure US20060205672A1-20060914-C01720
         		556 B
    Figure US20060205672A1-20060914-C01721
         		674 B
    Figure US20060205672A1-20060914-C01722
         		579 C
    Figure US20060205672A1-20060914-C01723
         		637 C
    Figure US20060205672A1-20060914-C01724
         		671 C
    Figure US20060205672A1-20060914-C01725
         		583 C
    Figure US20060205672A1-20060914-C01726
         		587 B
    Figure US20060205672A1-20060914-C01727
         		601 B
    Figure US20060205672A1-20060914-C01728
         		623 B
    Figure US20060205672A1-20060914-C01729
         		621 A
    Figure US20060205672A1-20060914-C01730
         		645 C
    Figure US20060205672A1-20060914-C01731
         		664 B
    Figure US20060205672A1-20060914-C01732
         		573 C
    Figure US20060205672A1-20060914-C01733
         		559 C
    Figure US20060205672A1-20060914-C01734
         		847 B
    Figure US20060205672A1-20060914-C01735
         		651 B
    Figure US20060205672A1-20060914-C01736
         		547 C
    Figure US20060205672A1-20060914-C01737
         		561 B
    Figure US20060205672A1-20060914-C01738
         		561 B
    Figure US20060205672A1-20060914-C01739
         		546 C
    Figure US20060205672A1-20060914-C01740
         		545 C
    Figure US20060205672A1-20060914-C01741
         		633 B
    Figure US20060205672A1-20060914-C01742
         		681 C
    Figure US20060205672A1-20060914-C01743
         		561 C
    Figure US20060205672A1-20060914-C01744
         		598 B
    Figure US20060205672A1-20060914-C01745
         		583 C
    Figure US20060205672A1-20060914-C01746
         		567 C
    Figure US20060205672A1-20060914-C01747
         		539 C
    Figure US20060205672A1-20060914-C01748
         		519 C
    Figure US20060205672A1-20060914-C01749
         		708 B
    Figure US20060205672A1-20060914-C01750
         		649 C
    Figure US20060205672A1-20060914-C01751
         		561 B
    Figure US20060205672A1-20060914-C01752
         		461 C
    Figure US20060205672A1-20060914-C01753
         		531 C
    Figure US20060205672A1-20060914-C01754
         		606 A
    Figure US20060205672A1-20060914-C01755
         		606 A
    Figure US20060205672A1-20060914-C01756
         		592 A
    Figure US20060205672A1-20060914-C01757
         		666 C
    Figure US20060205672A1-20060914-C01758
         		626 B
    Figure US20060205672A1-20060914-C01759
         		640 B
    Figure US20060205672A1-20060914-C01760
         		654 B
    Figure US20060205672A1-20060914-C01761
         		698 B
    Figure US20060205672A1-20060914-C01762
         		654 B
    Figure US20060205672A1-20060914-C01763
         		758 C
    Figure US20060205672A1-20060914-C01764
         		638 A
    Figure US20060205672A1-20060914-C01765
         		683 B
    Figure US20060205672A1-20060914-C01766
         		593 A
    Figure US20060205672A1-20060914-C01767
         		621 A
    Figure US20060205672A1-20060914-C01768
         		607 B
    Figure US20060205672A1-20060914-C01769
         		627 B
    Figure US20060205672A1-20060914-C01770
         		586 A
    Figure US20060205672A1-20060914-C01771
         		534 B
    Figure US20060205672A1-20060914-C01772
         		560 C
    Figure US20060205672A1-20060914-C01773
         		621 A
    Figure US20060205672A1-20060914-C01774
         		616 B
    Figure US20060205672A1-20060914-C01775
         		572 A
    Figure US20060205672A1-20060914-C01776
         		547 C
    Figure US20060205672A1-20060914-C01777
         		561 C
    Figure US20060205672A1-20060914-C01778
         		521 C
    Figure US20060205672A1-20060914-C01779
         		620 B
    Figure US20060205672A1-20060914-C01780
         		578 B
    Figure US20060205672A1-20060914-C01781
         		560 A
    Figure US20060205672A1-20060914-C01782
         		620 A
    Figure US20060205672A1-20060914-C01783
         		618 B
    Figure US20060205672A1-20060914-C01784
         		632 B
    Figure US20060205672A1-20060914-C01785
         		662 B
    Figure US20060205672A1-20060914-C01786
         		592 B
    Figure US20060205672A1-20060914-C01787
         		590 B
    Figure US20060205672A1-20060914-C01788
         		690 B
    Figure US20060205672A1-20060914-C01789
         		609 B
    Figure US20060205672A1-20060914-C01790
         		749 B
    Figure US20060205672A1-20060914-C01791
         		648 A
    Figure US20060205672A1-20060914-C01792
         		783 B
    Figure US20060205672A1-20060914-C01793
         		783 B
    Figure US20060205672A1-20060914-C01794
         		634 C
    Figure US20060205672A1-20060914-C01795
         		648 C
    Figure US20060205672A1-20060914-C01796
         		634 C
    Figure US20060205672A1-20060914-C01797
         		649 C
    Figure US20060205672A1-20060914-C01798
         		629 C
    Figure US20060205672A1-20060914-C01799
         		657 C
    Figure US20060205672A1-20060914-C01800
         		614 A
    Figure US20060205672A1-20060914-C01801
         		702 B
    Figure US20060205672A1-20060914-C01802
         		702 A
    Figure US20060205672A1-20060914-C01803
         		675 B
    Figure US20060205672A1-20060914-C01804
         		647 B
    Figure US20060205672A1-20060914-C01805
         		568 C
    Figure US20060205672A1-20060914-C01806
         		619 C
    Figure US20060205672A1-20060914-C01807
         		482 C
    Figure US20060205672A1-20060914-C01808
         		576 C
    Figure US20060205672A1-20060914-C01809
         		617 B
    Figure US20060205672A1-20060914-C01810
         		651 C
    Figure US20060205672A1-20060914-C01811
         		637 C
    Figure US20060205672A1-20060914-C01812
         		684 B
    Figure US20060205672A1-20060914-C01813
         		685 B
    Figure US20060205672A1-20060914-C01814
         		698 B
    Figure US20060205672A1-20060914-C01815
         		605 B
    Figure US20060205672A1-20060914-C01816
         		620 B
    Figure US20060205672A1-20060914-C01817
         		672 C
    Figure US20060205672A1-20060914-C01818
         		620 B
    Figure US20060205672A1-20060914-C01819
         		594 B
    Figure US20060205672A1-20060914-C01820
         		606 B
    Figure US20060205672A1-20060914-C01821
         		580 C
    Figure US20060205672A1-20060914-C01822
         		532 B
    Figure US20060205672A1-20060914-C01823
         		572 B
    Figure US20060205672A1-20060914-C01824
         		738 A
    Figure US20060205672A1-20060914-C01825
         		718 B
    Figure US20060205672A1-20060914-C01826
         		664 B
    Figure US20060205672A1-20060914-C01827
         		614 B
    Figure US20060205672A1-20060914-C01828
         		624 B
    Figure US20060205672A1-20060914-C01829
         		558 B
    Figure US20060205672A1-20060914-C01830
         		633 B
    Figure US20060205672A1-20060914-C01831
         		770 C
    Figure US20060205672A1-20060914-C01832
         		535 C
    Figure US20060205672A1-20060914-C01833
         		533 C
    Figure US20060205672A1-20060914-C01834
         		677 C
    Figure US20060205672A1-20060914-C01835
         		563 B
    Figure US20060205672A1-20060914-C01836
         		651 A
    Figure US20060205672A1-20060914-C01837
         		634 A
    Figure US20060205672A1-20060914-C01838
         		706 C
    Figure US20060205672A1-20060914-C01839
         		757 A
    Figure US20060205672A1-20060914-C01840
         		662 A
    Figure US20060205672A1-20060914-C01841
         		660 A
    Figure US20060205672A1-20060914-C01842
         		648 A
    Figure US20060205672A1-20060914-C01843
         		648 C
    Figure US20060205672A1-20060914-C01844
         		668 B
    Figure US20060205672A1-20060914-C01845
         		618 A
    Figure US20060205672A1-20060914-C01846
         		660 B
    Figure US20060205672A1-20060914-C01847
         		601 B
    Figure US20060205672A1-20060914-C01848
         		673 B
    Figure US20060205672A1-20060914-C01849
         		662 A
    Figure US20060205672A1-20060914-C01850
         		602 A
    Figure US20060205672A1-20060914-C01851
         		681 A
    Figure US20060205672A1-20060914-C01852
         		681 C
    Figure US20060205672A1-20060914-C01853
         		655 C
    Figure US20060205672A1-20060914-C01854
         		689 B
    Figure US20060205672A1-20060914-C01855
         		660 A
    Figure US20060205672A1-20060914-C01856
         		538 C
    Figure US20060205672A1-20060914-C01857
         		764 A
    Figure US20060205672A1-20060914-C01858
         		816 C
    Figure US20060205672A1-20060914-C01859
         		780 B
    Figure US20060205672A1-20060914-C01860
         		560 C
    Figure US20060205672A1-20060914-C01861
         		602 C
    Figure US20060205672A1-20060914-C01862
         		625 B
    Figure US20060205672A1-20060914-C01863
         		685 B
    Figure US20060205672A1-20060914-C01864
         		587 A
    Figure US20060205672A1-20060914-C01865
         		587 A
    Figure US20060205672A1-20060914-C01866
         		601 A
    Figure US20060205672A1-20060914-C01867
         		625 B
    Figure US20060205672A1-20060914-C01868
         		601 A
    Figure US20060205672A1-20060914-C01869
         		627 B
    Figure US20060205672A1-20060914-C01870
         		679 A
    Figure US20060205672A1-20060914-C01871
         		628 A
  • TABLE 5
    Figure US20060205672A1-20060914-C01872
         		587 A
    Figure US20060205672A1-20060914-C01873
         		641 A
    Figure US20060205672A1-20060914-C01874
         		659 A
    Figure US20060205672A1-20060914-C01875
         		674 A
    Figure US20060205672A1-20060914-C01876
         		615 B
    Figure US20060205672A1-20060914-C01877
         		641 B
    Figure US20060205672A1-20060914-C01878
         		641 B
    Figure US20060205672A1-20060914-C01879
         		627 A
    Figure US20060205672A1-20060914-C01880
         		665 A
    Figure US20060205672A1-20060914-C01881
         		614 A
    Figure US20060205672A1-20060914-C01882
         		737 B
    Figure US20060205672A1-20060914-C01883
         		666 A
    Figure US20060205672A1-20060914-C01884
         		660 A
    Figure US20060205672A1-20060914-C01885
         		591 C
    Figure US20060205672A1-20060914-C01886
         		615 C
    Figure US20060205672A1-20060914-C01887
         		754 B
    Figure US20060205672A1-20060914-C01888
         		577 C
    Figure US20060205672A1-20060914-C01889
         		694 A
    Figure US20060205672A1-20060914-C01890
         		702 A
    Figure US20060205672A1-20060914-C01891
         		701 A
    Figure US20060205672A1-20060914-C01892
         		546 B
    Figure US20060205672A1-20060914-C01893
         		520 B
    Figure US20060205672A1-20060914-C01894
         		546 B
    Figure US20060205672A1-20060914-C01895
         		723 B
    Figure US20060205672A1-20060914-C01896
         		675 A
    Figure US20060205672A1-20060914-C01897
         		771 B
    Figure US20060205672A1-20060914-C01898
         		847 C
    Figure US20060205672A1-20060914-C01899
         		641 A
    Figure US20060205672A1-20060914-C01900
         		613 A
    Figure US20060205672A1-20060914-C01901
         		651 C
    Figure US20060205672A1-20060914-C01902
         		700 A
    Figure US20060205672A1-20060914-C01903
         		569 A
    Figure US20060205672A1-20060914-C01904
         		756 B
    Figure US20060205672A1-20060914-C01905
         		786 A
    Figure US20060205672A1-20060914-C01906
         		669 B
    Figure US20060205672A1-20060914-C01907
         		601 A
    Figure US20060205672A1-20060914-C01908
         		601 B
    Figure US20060205672A1-20060914-C01909
         		683 A
    Figure US20060205672A1-20060914-C01910
         		673 A
    Figure US20060205672A1-20060914-C01911
         		680 A
    Figure US20060205672A1-20060914-C01912
         		602 A
    Figure US20060205672A1-20060914-C01913
         		735 A
    Figure US20060205672A1-20060914-C01914
         		743 A
    Figure US20060205672A1-20060914-C01915
         		655 B
    Figure US20060205672A1-20060914-C01916
         		692 A
    Figure US20060205672A1-20060914-C01917
         		639 A
    Figure US20060205672A1-20060914-C01918
         		639 A
    Figure US20060205672A1-20060914-C01919
         		675 A
    Figure US20060205672A1-20060914-C01920
         		621 A
    Figure US20060205672A1-20060914-C01921
         		668 A
    Figure US20060205672A1-20060914-C01922
         		642 A
    Figure US20060205672A1-20060914-C01923
         		654 A
    Figure US20060205672A1-20060914-C01924
         		601 C
    Figure US20060205672A1-20060914-C01925
         		663 B
    Figure US20060205672A1-20060914-C01926
         		641 A
    Figure US20060205672A1-20060914-C01927
         		702 A
    Figure US20060205672A1-20060914-C01928
         		701 A
    Figure US20060205672A1-20060914-C01929
         		588 B
    Figure US20060205672A1-20060914-C01930
         		638 A
    Figure US20060205672A1-20060914-C01931
         		630 A
    Figure US20060205672A1-20060914-C01932
         		697 A
    Figure US20060205672A1-20060914-C01933
         		621 A
    Figure US20060205672A1-20060914-C01934
         		608 B
    Figure US20060205672A1-20060914-C01935
         		682 A
    Figure US20060205672A1-20060914-C01936
         		667 B
    Figure US20060205672A1-20060914-C01937
         		520 B
    Figure US20060205672A1-20060914-C01938
         		645 B
    Figure US20060205672A1-20060914-C01939
         		669 C
    Figure US20060205672A1-20060914-C01940
         		575 A
    Figure US20060205672A1-20060914-C01941
         		709 B
    Figure US20060205672A1-20060914-C01942
         		652 B
    Figure US20060205672A1-20060914-C01943
         		714 A
    Figure US20060205672A1-20060914-C01944
         		561 B
    Figure US20060205672A1-20060914-C01945
         		561 B
    Figure US20060205672A1-20060914-C01946
         		685 B
    Structure MW Ki* Range
    Figure US20060205672A1-20060914-C01947
         		580 A
    Figure US20060205672A1-20060914-C01948
         		606 A
    Figure US20060205672A1-20060914-C01949
         		653 A
    Figure US20060205672A1-20060914-C01950
         		667 A

Claims (34)

1. A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I:
Figure US20060205672A1-20060914-C01951
wherein:
Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y maybe optionally substituted with X11 or X12;
X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X11 may be additionally optionally substituted with X12;
X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X12;
R1 is COR5, wherein R5 is COOR8, CONR9R10CF3, C2F5, C3F7, CF2R6, R6, wherein R6, R8, R9 and R10 are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R1′)]pCOOR11, [CH(R1′)]pCONR12R13, [CH(R1′)]pSO2R11, [CH(R1′)]pCOR11, [CH(R1′)]pCH(OH)R11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′)CONR12R13, CH(R1′)CONHCH(R2′)R′, CH(R1′)CONHCH(R2′)CONHCH(R3′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′)COOR11 and CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′) CONR12R13, wherein R1′, R2′, R3′, R4′, R5′, R11, R12, R13, and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl;
Z is selected from O, N, CH or CR;
W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO2;
Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2)p, (CHR)p, (CRR′)p, O, NR, S, or SO2; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L;
A is O, CH2, (CHR) p, (CHR—CHR′) p, (CRR′) p, NR, S, or SO2;
E is CH, N, CR, or a double bond towards A, L or G;
G may be present or absent, and when G is present, G is (CH2)p, (CHR) p, or (CRR′)p; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to;
J may be present or absent, and when J is present, J is (CH2)p, (CHR) p, or (CRR′)p, SO2, NH, NR or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J;
L may be present or absent, and when L is present, L is CH, CR, O, S or NR; and when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E;
M may be present or absent, and when M is present, M is O, NR, S, SO2, (CH2) p, (CHR) p (CHR—CHR′)p, or (CRR′) p;
p is a number from 0 to 6; and
R, R′, R2, R3 and R4 are independently selected from the group consisting of H; C1-C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino other than for R2, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;
further wherein said unit N-C-G-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N-C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring;
provided that in Formula I when W is C═O and the moiety:
Figure US20060205672A1-20060914-C01952
represents the structure:
Figure US20060205672A1-20060914-C01953
where R30 and R31 are independently H, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaryalkyl, with R30 and R31 being optionally substituted with 1-3 R33 substituents selected from alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocycylalkyl, keto, hydroxy, amino, alkylamino, alkanoylamino, aroylalmino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl, acetyl, sulfonyl, or sulfonamido, wherein said R33 substituents can be optionally substituted with alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, amino, alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, fomryl, sulfonyl or sulfonamido;
α is a bond, —C(H)(R34)—, —O—, —S—, or —N(R35)—, where R34 is H, alkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl and is optionally substituted with 1-3 R33 substituents, and R35 is H, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkanoyl, —C(O)R36, —SO2R36, or carboxamido and is optionally substituted with 1-3 R33 substituents, or R35 and y together with the atoms to which they are bound, form a nitrogen containing mono- or bicyclic ring system optionally substituted with 1-3 R33 substituents, and R36 is alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl;
β is a bond, —CH2-, —C(O)—, —C(O)C(O)—, —S(O)—, —S(O)2—, OR—S(O)R34;
γ is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —OR37 or —N(R37)2, wherein any carbon atom is optionally substituted with R33, wherein R37 is independently H, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl, wherein any carbon of R37 is optionally substituted with R33;
then R10 is H and R8 and R9 are independently selected from the group consisting of CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′)CONR12R13, CH(R1′)CONHCH(R2′)R′, CH(R1′)CONHCH(R2′)CONHCH(R3′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)COOR11, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONR12R13, CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′)COOR11 and CH(R1′)CONHCH(R2′)CONHCH(R3′)CONHCH(R4′)CONHCH(R5′)CONR12R13; and
provided that the proline at the P2 position is modified, wherein the P2 position is the position corresponding to the second amino acid from the keto amide group.
2. The compound of claim 1, wherein R1 is COCONR9R10, and R9 is H, R10 is H, R4, CH(R1′)COOR11, CH(R1′)CH(R1′)COOR11, CH(R1′)CONR12R13, CH(R1′)CH(R1′)CONR12R13, CH(R1′)CH(R1′)SO2R11, CH(R1′)CH(R1′)SO2NR12R13, CH(R1′)CH(R1′)COR11, CH(R1′)CONHCH(R2′)COOR11, CH(R1′)CONHCH(R2′) CONR12R13, or CH(R1′)CONHCH(R2′)(R1′), wherein R14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl; wherein R1 is H or alkyl, and R2′ is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl; and
wherein R11 is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α,α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl;
R′ is hydroxymethyl or CH2CONR12R13;
R2′ is independently selected from the group consisting of:
Figure US20060205672A1-20060914-C01954
wherein:
U1 and U2 maybe same or different and are selected from H, F, CH2COOH, CH2COOMe, CH2CONH2, CH2CONHMe, CH2CONMe2, azido, amino, hydroxyl, substituted amino, substituted hydroxyl;
U3 and U4 maybe same or different and are selected from O and S;
U5 is selected from the moieties consisting of alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof;
and NR12R13 is selected from the group consisting of:
Figure US20060205672A1-20060914-C01955
wherein U6 is H, OH, or CH2OH, and
R14 is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl.
3. The compound of claim 2, wherein R2 is selected from the group consisting of the following moieties:
Figure US20060205672A1-20060914-C01956
Figure US20060205672A1-20060914-C01957
4. The compound of claim 3, wherein R3 is selected from the group consisting of:
Figure US20060205672A1-20060914-C01958
Figure US20060205672A1-20060914-C01959
wherein R31=OH or O-alkyl;
Y19 is selected from the following moieties:
Figure US20060205672A1-20060914-C01960
and Y20 is selected from the following moieties:
Figure US20060205672A1-20060914-C01961
5. The compound of claim 4, wherein R3 is selected from the group consisting of the following moieties:
Figure US20060205672A1-20060914-C01962
6. The compound of claim 5, wherein Z is N and R4 is H.
7. The compound of claim 6, wherein W is C═O.
8. The compound of claim 7, wherein Y is selected from the following moieties:
Figure US20060205672A1-20060914-C01963
Figure US20060205672A1-20060914-C01964
Figure US20060205672A1-20060914-C01965
Figure US20060205672A1-20060914-C01966
Figure US20060205672A1-20060914-C01967
Figure US20060205672A1-20060914-C01968
Figure US20060205672A1-20060914-C01969
Figure US20060205672A1-20060914-C01970
wherein:
Y11 is selected from H, COOH, COOEt, OMe, Ph, OPh; NHMe, NHAc, NHPh, CH(Me)2, 1-triazolyl, 1-imidazolyl, and NHCH2COOH;
Y12 is selected from H, COOH, COOMe, OMe, F, Cl, or Br;
Y13 is selected from the following moieties:
Figure US20060205672A1-20060914-C01971
Y14 is selected from MeSO2, Ac, Boc, iBoc, Cbz, or Alloc;
Y15 and Y16 are independently selected from alkyl, aryl, heteroalkyl, and heteroaryl;
Y17 is CF3, NO2, CONH2, OH, COOCH3, OCH3, OC6H5, C6H5, COC6H5, NH2, or COOH; and
Y18 is COOCH3, NO2, N(CH3)2, F, OCH3, CH2COOH, COOH, SO2NH2, or NHCOCH3.
9. The compound of claim 8, wherein Y is selected from the group consisting of:
Figure US20060205672A1-20060914-C01972
Figure US20060205672A1-20060914-C01973
Figure US20060205672A1-20060914-C01974
wherein:
Y17=CF3, NO2, CONH2, OH, NH2, or COOH;
Y18=F, COOH,
10. The compound of claim 9, wherein Y is selected from the group consisting of:
Figure US20060205672A1-20060914-C01975
Figure US20060205672A1-20060914-C01976
11. The compound of claim 10, wherein L and M are absent, and J is directly linked to E.
12. The compound of claim 10, wherein L, J and M are absent and E is directly linked to N.
13. The compound of claim 10, wherein G and M are absent.
14. The compound of claim 10, wherein the moiety:
Figure US20060205672A1-20060914-C01977
15. The compound of claim 14, wherein structure a is selected from the following structures:
Figure US20060205672A1-20060914-C01978
16. The compound of claim 14, wherein structure a is:
Figure US20060205672A1-20060914-C01979
wherein R20 is selected from the following structures:
Figure US20060205672A1-20060914-C01980
17. The compound of claim 14, wherein structure a is:
Figure US20060205672A1-20060914-C01981
wherein R21 and R22 may be the same or different and are independently selected from the following structures:
Figure US20060205672A1-20060914-C01982
Figure US20060205672A1-20060914-C01983
18. The compound of claim 14, wherein structure a is selected from the following structures:
Figure US20060205672A1-20060914-C01984
Figure US20060205672A1-20060914-C01985
19. The compound of claim 10, wherein:
Figure US20060205672A1-20060914-C01986
wherein Q may be present or absent, and if Q is absent, M is directly linked to A.
20. The compound of claim 19, wherein structure b is selected from the following structures:
Figure US20060205672A1-20060914-C01987
21. The compound of claim 10, wherein:
Figure US20060205672A1-20060914-C01988
wherein G and J are independently selected from the group consisting of (CH2)p, (CHR)p, (CHR—CHR′)p, and (CRR′)p; A and M are independently selected from the group consisting of O, S, SO2, NR, (CH2) p, (CHR)p, (CHR—CHR′)p, and (CRR′)p; and Q is CH2, CHR, CRR′, NH, NR, O, S, SO2, NR, (CH2) p, (CHR)p, and (CRR′)p.
22. The compound of claim 21, wherein structure c is selected from the following structures:
Figure US20060205672A1-20060914-C01989
Figure US20060205672A1-20060914-C01990
23. The compound of claim 10, wherein:
Figure US20060205672A1-20060914-C01991
is selected from the following structures:
Figure US20060205672A1-20060914-C01992
Figure US20060205672A1-20060914-C01993
Figure US20060205672A1-20060914-C01994
24. The compound of claim 23, wherein:
Figure US20060205672A1-20060914-C01995
is selected from the following structures:
Figure US20060205672A1-20060914-C01996
Figure US20060205672A1-20060914-C01997
25. A pharmaceutical composition comprising as an active ingredient a compound of claim 1.
26. The pharmaceutical composition of claim 25 for use in treating disorders associated with HCV.
27. The pharmaceutical composition of claim 25 additionally comprising a pharmaceutically acceptable carrier.
28. The pharmaceutical composition of claim 27, additionally containing an antiviral agent.
29. The pharmaceutical composition of claim 28, still additionally containing an interferon.
30. The pharmaceutical composition of claim 29, wherein said antiviral agent is ribavirin and said interferon is α-interferon or pegylated interferon.
31. A method of treating disorders associated with the HCV, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of a compound of claim 1.
32. The method of claim 31, wherein said administration is oral or subcutaneous.
33. The use of a compound of claim 1 for the manufacture of a medicament to treat disorders associated with the HCV.
34. A method of preparing a pharmaceutical composition for treating the disorders associated with the HCV, said method comprising bringing into intimate contact a compound of claim 1 and a pharmaceutically acceptable carrier.
US11/241,656 2000-07-21 2005-09-30 Novel peptides as NS3-serine protease inhibitors of hepatitis C virus Abandoned US20060205672A1 (en)

Priority Applications (2)

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US11/241,656 US20060205672A1 (en) 2000-07-21 2005-09-30 Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
US12/973,020 US20110117057A1 (en) 2000-07-21 2010-12-20 Novel peptides as ns3-serine protease inhibitors of hepatitis c virus

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