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WO2006065590A2 - Compositions antivirales a base de pyridines et de pyrimidines - Google Patents

Compositions antivirales a base de pyridines et de pyrimidines Download PDF

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Publication number
WO2006065590A2
WO2006065590A2 PCT/US2005/044206 US2005044206W WO2006065590A2 WO 2006065590 A2 WO2006065590 A2 WO 2006065590A2 US 2005044206 W US2005044206 W US 2005044206W WO 2006065590 A2 WO2006065590 A2 WO 2006065590A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
group
cycloalkyl
aryl
heteroaryl
Prior art date
Application number
PCT/US2005/044206
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English (en)
Other versions
WO2006065590A3 (fr
Inventor
C. Richard Wobbe
Original Assignee
Xtl Biopharmaceuticals Inc.
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Filing date
Publication date
Application filed by Xtl Biopharmaceuticals Inc. filed Critical Xtl Biopharmaceuticals Inc.
Publication of WO2006065590A2 publication Critical patent/WO2006065590A2/fr
Publication of WO2006065590A3 publication Critical patent/WO2006065590A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Hepatitis C virus is considered to be the major etiological agent of non-A non-B (NANB) hepatitis, chronic liver disease, and hepatocellular carcinoma (HCC) around the world.
  • NANB non-A non-B
  • HCC hepatocellular carcinoma
  • the viral infection accounts for greater than 90% of transfusion-associated hepatitis in U.S. and it is the predominant form of hepatitis in adults over 40 years of age. Almost all of the infections result in chronic hepatitis and nearly 20% develop liver cirrhosis.
  • the virus particle has not been well characterized due to the lack of an efficient in vitro replication system and the extremely low amount of HCV particles in infected liver tissues or blood.
  • molecular cloning of the viral genome has been accomplished by isolating the messenger RNA (mRNA) from the serum of infected chimpanzees then cloned using recombinant methodologies. [Grakoui A. et al. J. Virol. 67: 1385-1395 (1993)].
  • mRNA messenger RNA
  • HCV contains a positive strand RNA genome comprising approximately 9400 nucleotides, whose organization is similar to that of flaviviruses and pestiviruses.
  • the genome of HCV like that of flavi- and pestiviruses, encodes a single large polyprotein of about 3000 amino acids which undergoes proteolysis to form mature viral proteins in infected cells.
  • HCV polyprotein is processed by cellular and viral proteases to produce the putative structural and nonstructural (NS) proteins.
  • At least nine mature viral proteins are produced from the polyprotein by specific proteolysis.
  • the order and nomenclature of the cleavage products are as follows: NH 2 -C-El -E2-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.
  • C capsid
  • El two envelope glycoproteins
  • the host enzyme is also responsible for generating the amino terminus of NS2.
  • the proteolytic processing of the nonstructural proteins are carried out by the viral proteases: NS2-3 and NS3, contained within the viral polyprotein.
  • the NS2-3 protease catalyzes the cleavage between NS2 and NS3. It is a metalloprotease and requires both NS2 and the protease domain of NS3.
  • the NS5B RdRp catalyzes the rest of the cleavages of the substrates in the nonstructural part of the polyprotein.
  • the NS3 protein contains 631 amino acid residues and is comprised of two enzymatic domains: the protease domain contained within amino acid residues 1-181 and a helicase ATPase domain contained within the rest of the protein. It is not known if the 70 kD NS3 protein is cleaved further in infected cells to separate the protease domain from the helicase domain, however, no cleavage has been observed in cell culture expression studies.
  • the NS5B RdRp is a member of the serine proteinase class of enzymes. It contains His, Asp, and Ser as the catalytic triad.
  • HCV NS5B RdRp also requires a cofactor to catalyze some of these cleavage reactions.
  • the NS4A protein is absolutely required for the cleavage of the substrate at the NS3/4A and 4B/5A sites and increases the efficiency of cleavage of the substrate between 5A/5B, and possibly 4A/4B.
  • the HCV NS5B RdRp cleaves the non-structural HCV proteins which are necessary for the HCV replication, the NS5B RdRp can be a target for the development of therapeutic agents against the HCV virus. Thus there is a need for the development of inhibitors of the HCV protease.
  • HCV protease necessary for polypeptide processing and viral replication has been identified, cloned and expressed. See Houghton et al., 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 (El and E2) and several non-structural proteins, including NS 1 , 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 NS5B RdRp 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.
  • 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 :35-42.
  • 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 for example
  • 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%.
  • RNA-dependent RNA polymerase RdRp
  • HCV NS5B RNA-dependent RNA polymerase RdRp
  • the present invention provides non-nucleoside compounds having antiviral activity against HCV that are based on the compound's inhibitory activity of the recombinant HCV RNA-dependent RNA polymerase (RdRp), NS5B.
  • the compounds are found to have minimal toxicity and side effects and yet are highly effective against HCV.
  • the present invention also provides a novel class of inhibitors of the HCV RdRp, 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 are compounds that inhibit HCV NS5B RdRp activity. hi another aspect, the present invention further provides for an inhibitor of an HCV NS5B RdRp comprising a non-nucleoside compound or a pharmaceutical composition as disclosed herein.
  • the present invention further provides for an inhibitor of an HCV NS5B RdRp comprising a compound or a pharmaceutical composition as disclosed herein.
  • the present invention further comprises a method for treating an individual infected with the HCV virus comprising administering an inhibitor of an HCV NS5B RdRp to said individual, the inhibitor comprises a compound or a pharmaceutical composition as disclosed herein.
  • a method for treating an individual infected with the HCV virus comprising administering an inhibitor of an HCV NS5B RdRp to the individual, wherein the inhibitor comprises a compound or a pharmaceutical composition as disclosed herein.
  • a pharmaceutical composition for treating an individual infected with hepatitis C virus comprises an inhibitor of an HCV NS5B RdRp.
  • the present invention further provides for a pharmaceutical composition for treating an individual infected with hepatitis C virus, said pharmaceutical composition comprises of an inhibitor of an HCV NS5B RdRp and a pharmaceutical carrier.
  • Alkyl represents both branched and straight chain saturated aliphatic hydrocarbon groups, and may be cyclic or acyclic having the specified number of carbon atoms.
  • Alkoxy represents an alkyl group of indicated number of carbon atoms attached to an oxygen atom.
  • 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.
  • Arylalkyl represents a moiety containing an aryl group bonded to or linked via a lower alkyl.
  • lower alkyl represents alkyl groups having 1 to 6 carbons.
  • Alkylaryl represents a moiety containing a lower alkyl bonded to or linked via an aryl group.
  • Carbonyl group represents a radical group -CO-, which may be further substituted or attached to a variety of different substituents to form different carbonyl groups, including acids, acid halides, aldehydes, esters, carbamates, ketones and the like.
  • Carboxy group represent the radical -CO 2 - wherein the carboxy group may be a carboxylic acid group that may also be derivatized or substituted with other functional groups such as carboxy protecting groups.
  • Cycloalkyl represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms.
  • Heterocyclic represents, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic moiety 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 may be localized or delocalized, 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 or halo represents fluorine, chlorine, bromine and iodine.
  • Heteroaryl represents a cyclic moiety 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.
  • the groups may be unsubstituted or further substituted with 1 , 2, 3 or more substituents as described herein.
  • substituents include, for example, halo, cyano, nitro, -CF 3 , oxo, hydroxy, amino, thio, alkyl, alkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, carbonyl, imino, sulfonyl, sulfinyl and the like.
  • Treating means the treatment of existing disease and prophylactic treatment of those at risk of developing the disease.
  • 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.
  • 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, corn, rice and potato; and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
  • 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 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 refers to a 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 are 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.
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is intended to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • the invention encompasses pharmaceutical compositions for treating HCV or HCV mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formulae I, II or III as described herein.
  • 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 in the art.
  • suitable bases are, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, and the like.
  • the present invention provides pharmaceutical compositions comprising the inventive compounds 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, semisolid 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 1 to about 95 percent the 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-prop ylene 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 active composition of the present invention in a unit dose of preparation may be generally varied or adjusted from about 1.0 mg to about 1,000 mg, preferably from about 1.0 to about 950 mg, more preferably from about 1.0 to about 500 mg, and typically from about 1.0 to about 250 mg, 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 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 mg to about 1 ,000 mg per day, in single or divided doses.
  • 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.
  • Formulations include those suitable for oral, rectal, nasal, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. See, for example, Gilman, et al. (eds.) (1990) Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press, Parrytown, N.Y.; Remington's Pharmaceutical Sciences, 17th ed. (1990), Mack Publishing Co., Easton, Pa.; Avis, et al.
  • 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 mode such as, for example, in combination with antiviral agents such as, for example, ribavirin and/or interferon such as, for example, ointerferon and the like.
  • antiviral agents such as, for example, ribavirin and/or interferon such as, for example, ointerferon and the like.
  • the present compounds also includes tautomers, rotamers, enantiomers and other stereoisomers of the compounds.
  • some of the compounds may exist in suitable isomeric forms. Such forms and variations are contemplated to be within the scope of the invention.
  • Another aspect of the invention provides 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, other related analogs are also contemplated. Such variations are contemplated to be within the scope of the invention.
  • the present invention provides a method of treating HCV for the prevention and treatment of hepatitis C which comprises administering to a human in need thereof a therapeutically effective amount of a non-nucleoside inhibitor having anti-viral activity against HCV.
  • the invention provides the use of an antiviral compound in the manufacture of a medicament for the treatment of viral infection, including hepatitis C.
  • the preparation of the compounds of the present invention may be performed as shown in the above scheme.
  • a 4,6-dihalo-2-substituted pyrimidine compound such as the 4,6-dichloro-2-substituted pyrimidine compound exemplified above may be treated with an amine of the formula R O R 7 NH to form a mono-halo or monochloro pyrimidine compound as shown above.
  • the compound may be purified or the compound may be used as obtained without further purification.
  • the product may be further treated with a compound of the formula R 3 R 4 NH to form the tri-substituted pyrimidine as shown above.
  • the compound may be further derivatized or treated to form their various derivatives as desired.
  • the various substituents R 3 , R 4 , Re and R 7 the compound may be protected prior to a reaction and may optionally be deprotected as desired.
  • protecting groups are well known in the art, and are described, for example, in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
  • the above reactions may be performed in various organic solvents, including alcohols such as methanol, ethanol, isopropanol, DCM, chloroform, acetonitrile, DMF, acetone, DMSO and the like.
  • the reaction may be performed in stoichiometric catalytic ratio of a base relative to the starting material(s).
  • bases include organic bases or inorganic bases, or mixtures thereof.
  • Organic bases may include triethylamine, N,N- diisopropylamine, N,N-dimethylaniline, and the like.
  • the reaction may be performed at ambient temperatures, at 0 to about 25 0 C, or at elevated temperatures from about 30 to about 160 0 C, as long as necessary to allow the reaction to go to completion. In all cases, the reactions are performed in an inert atmosphere such as in nitrogen or argon.
  • X is CH or N
  • Ri is hydrogen or is selected from the group consisting of halo, PeAaIo(C 1 - 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro, thio, (C 3 . ⁇ )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-io)alkyl, heteroaryl(C
  • R 2 is hydrogen, or is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro, thio, (C 3- i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 -i 2 )bicycloaryl, (C 9 -i 2 )bicycloheteroaryl, aryl, heteroaryl, (Ci- ⁇ )alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group, sulfinyl group and phosphonyl group, each of which is further substituted or unsubstituted
  • R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl,
  • R 5 is selected from the group consisting of halo, perhalo(Cr6)alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, thio, (C 3 _i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl, (Ci-o)alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted; provided that when X is nitrogen, Ri is not amino, R 2 is not hydrogen, and R 5 is not (Ci- 6 )alkylthio; or when X is CH, Ri is not amino, R 2 is not carboxyl, and R 5 is not (Ci-6)alkyl; or the pharmaceutically acceptable salts thereof.
  • Ri is hydrogen or is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, thio, (C 3 -i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 -i 2 )bicycloaryl, (C 9-12 )bicycloheteroaryl, aryl, heteroaryl, (Ci- 6 )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted; R 2 is hydrogen, or is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C
  • X is CH or N;
  • Ri is hydrogen or is selected from the group consisting of amino, thio, (Ci- 6 )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted;
  • R 2 is hydrogen, or is selected from the group consisting of cyano, carbonyl group, imino group, sulfonyl group, sulfinyl group and phosphonyl group, each of which is further substituted or unsubstituted;
  • R3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of (C 9 .i 2 )bicycloaryl, (C 9 .i 2 )bicycloheteroaryl, aryl and heteroaryl; or wherein R 3 and R 4 are taken together to form a 5, 6 or 7 membered saturated or unsaturated carbocyclic or heterocyclic ring, each of which is further substituted or unsubstituted; and R 5 is
  • R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of perhalo(Ci- 6 )alkyl, (C ⁇ - 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - ⁇ )alkynyl, (C 3 -i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 .] 2 )bicycloaryl, (C 9 -i 2 )bicycloheteroaryl, aryl, heteroaryl, (Ci- 6 )alkoxy, aryloxy and heteroaryloxy; or wherein R 3 and R 4 are taken together to form a 5, 6 or 7 membered saturated or unsaturated carbocyclic or heterocyclic ring, each of which is further substituted or unsubstituted; R 5 is selected
  • R 3 and R 4 are each independently selected from the group consisting of perhalo(C]- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl,
  • R 3 and R 4 are taken together to form a 5, 6 or 7 membered saturated or unsaturated heterocyclic ring, each of which is unsusbtituted or further substituted with 1 , 2 or 3 substituents selected from the group consisting of perhalo(C ⁇ - 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro, thio, (C 3- i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 .i 2 )bicycloaryl, (C 9 .i 2 )bicycloheteroaryl, aryl, heteroaryl, (Ci- 6 )alkoxy, aryloxy, heteroaryl
  • the heterocyclic ring is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, 2,2-dimethyl-l,3-dioxolane, N-methylpiperidin-3-yl, N-methylpyrrolidin-3-yl, pyrrolidinyl, thiomo ⁇ holinyl, thiomo ⁇ holino-1 -oxide, thiomo ⁇ holino- 1,1 -dioxide, 4- ethyloxycarbonylpiperazinyl, 3-oxopiperazinyl, 2-imidazolidonyl, 2-pyrrolidinonyl, 2- oxohomopiperazinyl and tetrahydropyrimidin-2-one, each of which is unsubstituted or substituted with 1, 2 or 3 substituents
  • Ri 0 is selected from the group consisting of (C 9 _i 2 )bicycloheteroaryl, aryl and heteroaryl, each of which is unsubstituted or substituted with 1 , 2 or 3 substituents selected from the group consisting of perhalo(Ci- 6 )alkyl, (C]- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • Rio is a heteroaryl selected from the group consisting of pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, and carbazole, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • Rio is a heteroaryl selected from the group consisting of pyridine, pyrimidine and quinoline, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - ⁇ )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • R 6 and R 7 are each independently hydrogen or are each independently selected from the group consisting of (C 3- ] 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 . 12 )bicycloheteroaryl, aryl and heteroaryl, each of which is further substituted or unsubstituted.
  • R 6 is hydrogen and R 7 is selected from the group consisting of (C 3 .] 2 )cycloalkyl, aryl(Ci-io)alkyl, (C 9 -i 2 )bicycloaryl, and aryl each of which is further substituted or unsubstituted with 1, 2 or 3 substituents selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - ⁇ )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • R 7 is phenyl or naphthyl, each unsubstituted or further substituted with NRuRi 2 , wherein each Rn and R ]2 are each independently hydrogen, or are independently selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, (C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci-3)alkyl, (C 9 -i 2 )bicycloaryl, aryl, heteroaryl, (Ci- ⁇ )alkoxy, aryloxy and heteroaryloxy; or wherein Ru and Ri 2 are taken together to form a 5, 6 or 7 membered saturated or unsaturated heterocyclic ring, each of which is further
  • R 7 is phenyl or naphthyl, each unsubstituted or further substituted with NR 11 Ri 2 , wherein Ri i and Ri 2 are taken together to form a 5, 6 or 7 membered saturated or unsaturated heterocyclic ring, each of which is further substituted or unsubstituted.
  • R] i and Ri 2 are taken together to form a heterocyclic ring, wherein the heterocyclic ring is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, 2,2-dimethyl-l,3-dioxolane, N-methylpiperidin-3-yl, N-methylpyrrolidin-3-yl, pyrrolidinyl, thiomorpholinyl, thiomorpho lino- 1 -oxide, thiomorpholino- 1,1 -dioxide, 4- ethyloxycarbonylpiperazinyl, 3-oxopiperazinyl, 2-imidazolidonyl, 2-pyrrolidinonyl, 2- oxohomopiperazinyl and tetrahydropyrimidin-2-one, each of which is unsubstitute
  • Rn and Rn are taken together to form a heterocyclic ring, wherein the heterocyclic ring is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl and dihydropyridinyl, each unsubstituted or substituted with a substituent selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 -6)alkynyl, amino, cyano, hydroxy, nitro and thio.
  • the heterocyclic ring is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl and dihydropyridinyl, each unsubstituted or substituted with a substituent selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C
  • Ri is hydrogen or is selected from the group consisting of halo, perhalo(C ⁇ - 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro, thio, (C 3 -i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-]o)alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 .i 2 )bicycloaryl, (C 9 -i 2 )bicycloheteroaryl, aryl, heteroaryl, (Ci- ⁇ )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted;
  • R 2 is hydrogen, or is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (Ci-6)alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro, thio, (C 3 -i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 -i 2 )bicycloaryl, (C 9 -i 2 )bicycloheteroaryl, aryl, heteroaryl, (Ci- 6 )alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group, sulfinyl group and phosphonyl group, each of which is further substituted or unsubstituted
  • R 5 is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, thio, (C 3 .i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci- 3 )alkyl, (Ci- ⁇ )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted; provided that when Ri is hydrogen, R 2 is carboxyl, R 3 is hydrogen and R 4 is 4-N- morpholinophenyl, then R 5 is not methyl; or the pharmaceutically acceptable salts thereof.
  • R 1 is hydrogen or is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - ⁇ )alkynyl, amino, thio, (C 3 -i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-i O )alkyl, heteroaryl(Ci- 3 )alkyl, (C 9 -i 2 )bicycloaryl, (C ⁇ bicycloheteroaryl, aryl, heteroaryl, (Ci- 6 )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted; R 2 is hydrogen, or is selected from the group consisting of halo, perhalo(Ci-6)alkyl, (Ci- ⁇ )alky
  • Ri is hydrogen or is selected from the group consisting of amino, thio, (Ci- 6 )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted;
  • R 2 is hydrogen, or is selected from the group consisting of cyano, carbonyl group, imino group, sulfonyl group, sulfinyl group and phosphonyl group, each of which is further substituted or unsubstituted;
  • R 3 and R 4 are each independently hydrogen or are each independently selected from the group consisting of (Cg.i 2 )bicycloaryl, (C 9 -i 2 )bicycloheteroaryl, aryl and heteroaryl; or wherein R 3 and R 4 are taken together to form a 5, 6 or 7 membered saturated or unsaturated carbocyclic or heterocyclic ring, each of which is further substituted or unsubstituted; and
  • R 5 is selected from the group consisting of (C
  • R 2 is selected from the group consisting of cyano, carbonyl group, imino group, sulfonyl group, sulfinyl group and phosphonyl group, each of which is further substituted or unsubstituted.
  • R 2 is selected from the group consisting of -COOH, -SO3H and -PO 3 H, or the pharmaceutically acceptable salts thereof.
  • Ri is -NR] 3 Ri 4 wherein Ri 3 and R H are each independently hydrogen or are each independently selected from the group consisting of (C 3 -i 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-io)alkyl, heteroaryl(Ci-3)alkyl, (C 9 -i 2 )bicycloaryl, aryl and heteroaryl, each of which is further substituted or unsubstituted.
  • R 13 is hydrogen and R ]4 is selected from the group consisting of (C 3- i 2 )cycloalkyl, aryl(Ci-io)alkyl, and aryl each of which is further substituted or unsubstituted with 1 , 2 or 3 substituents selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • R 14 is phenyl or naphthyl, each unsubstituted or further substituted with NRi 5 R 16 , wherein each R 1 5 and Ri 6 are each independently hydrogen, or are independently selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, (C 3- i 2 )cycloalkyl, hetero(C3-i 2 )cycloalkyl, aryl(Ci-6)alkyl, heteroaryl(Ci-3)alkyl, (C 9 -i 2 )bicycloheteroaryl, aryl, heteroaryl, (Ci- ⁇ )alkoxy, aryloxy and heteroaryloxy; or wherein Ri 1 and Ri 2 are taken together to form a 5, 6 or 7 membered saturated or unsaturated heterocyclic ring, each of which is further substitute
  • Ri 4 is phenyl or naphthyl, each unsubstituted or further substituted with NR 15 R 16 , wherein R 15 and Ri 6 are taken together to form a 5, 6 or 7 membered saturated or unsaturated heterocyclic ring, each of which is further substituted or unsubstituted.
  • Ri 5 and Ri 6 are taken together to form a heterocyclic ring, wherein the heterocyclic ring is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, 2,2-dimethyl-l,3-dioxolane, N-methylpiperidin-3-yl, N-methylpyrrolidin-3-yl, pyrrolidinyl, thiomorpholinyl, thiomorpholino-1 -oxide, thiomorpholino- 1,1 -dioxide, 4- ethyloxycarbonylpiperazinyl, 3-oxopiperazinyl, 2-imidazolidonyl, 2-pyrrolidinonyl, 2- oxohomopiperazinyl and tetrahydropyrimidin-2-one, each of which is unsubstituted or substitute
  • R 15 and Ri 6 are taken together to form a heterocyclic ring, wherein the heterocyclic ring is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl and dihydropyridinyl, each unsubstituted or substituted with a substituent selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • R 2 is hydrogen.
  • R 5 is selected from the group consisting of halo, perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - ⁇ )alkenyl, (C 2 - 6 )alkynyl, amino, thio, (C 3 -i 2 )cycloalkyl, hetero(C3-i 2 )cycloalkyl, aryl(Ci- 6 )alkyl, heteroaryl(Ci-3)alkyl, (Ci- 6 )alkoxy, aryloxy and heteroaryloxy, each of which is further substituted or unsubstituted.
  • R 5 is selected from the group consisting of perhalo(Ci- 6 )alkyl, (Ci- 6 )alkyl, (C 2 - 6 )alkenyl, (C 2 - 6 )alkynyl, amino and thio, each unsusbtituted or further substituted.
  • R 5 is selected from the group consisting of (Ci- 3 )alkyl in which one carbon atom of the (Ci- 3 )alkyl can be optionally replaced by a -O-, -S-, or -NH- group; each (C]- 3 )alkyl unsubstituted or further substituted with a substituent selected from the group consisting of perhalo(Ci- 3 )alkyl, (Ci-3)alkyl, (C 2 - ⁇ )alkenyl, (C 2 - 6 )alkynyl, amino, cyano, hydroxy, nitro and thio.
  • R 5 is selected from the group consisting of (Ci- 3 )alkyl, (Ci- 3 )alkylthio, or (Ci- 3 )alkoxy.
  • Also provided in the present application are the following non-exclusive compounds: ⁇ 4- [6-(4-Diethylamino-phenylamino)-2-ethylsulfanyl-pyrimidin-4-yl]-piperazin-l-yl ⁇ -phenyl- methanone; ⁇ 4-[6-(4-Diethylamino-phenylamino)-2-ethylsulfanyl-pyrimidin-4-yl]-piperazin-l- yl ⁇ -pyridin-4-yl-methanone; ⁇ 4-[6-(4-Diethylamino-phenylamino)-2-ethylsulfanyl-pyrimidin-4- yl] -piperazin- 1 -yl ⁇ -(2-methyl-pyridin-4-yl)-methanone; ⁇ 4-[6-(4-Diethylamino-phenylamino)-2- ethylsulfanyl
  • a pharmaceutical composition comprising, as an active ingredient, a compound according to any one of the above compounds.
  • the composition is a solid or a liquid adapted for oral administration.
  • a method of inhibiting HCV comprising contacting HVC with any of the above compounds.
  • a method of inhibiting HCV comprising contacting any one of the above compounds in a subject in order to inhibit HCV in vivo.
  • a compound exhibiting HCV protease inhibitory activity wherein the compound is selected from any of the above aompounds.
  • a method of treating liver disease in a patient comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition noted above.
  • HCV RNA Polymerase RNA dependent RNA polymerase, NS 5B
  • the following in vitro experiments are conducted to examine the inhibitory effect of the compounds according to the present invention on the activity of HCV RNA dependent RNA Polymerase.
  • Other assays may be employed as is known in the art, and non-exclusive representative assays for determining the inhibitory effects of the compounds are cited herein.
  • the HCV RNA polymerase is prepared as follows:
  • HCV cDNA is obtained from the blood of HCV-Ib type HCV patient and the NS5B region (1773 bps) is amplified by PCR and cloned into pVLHIS, a baculo virus transfer vector, to prepare a recombinant transfer vector.
  • the prepared transfer vector and the wild-type AcNPV vector are co-transfected into Sf 9 insect cell line to yield a recombinant baculovirus containing the histidine-tagged recombinant vectorpVLHIS-NS5B.
  • Sufficiently cultured insect cells are infected with the resulting recombinant baculovirus and cultured in Grace's medium containing 10% FBS for 3 to 4 days.
  • the culture broth is centrifuged to obtain only the infected cells.
  • the cells are washed three times with PBS and resuspended in binding buffer [50 mM Na-phosphate (pH 8.0), 30 mM NaCl, 10 mM imidazole, 1 mM DTT, 10 % glycerol, 1 % NP-40], sonicated and the clearized lysate is obtained.
  • Recombinant NS5B is purified by affinity column chromatography using a Ni-NTA His bind resin (Novagen) to produce pure NS5B protein.
  • the (His) 6 -tagged NS5B is bound to Ni-NTA resin and washed the binding buffer containing 50 mM imidazole.
  • the bound NS5B is eluted with the binding buffer containing imidazole in a step- gradient manner (100-300 mM).
  • the NS5B protein fractions are dialyzed against buffer [50 mM Tris-HCl, 50 mM NaCl, 1 mM DTT, 5 mg MgCl 2 , 10 % glycerol], followed by at -70 0 C in a small aliquot.
  • the RNA template containing HCV 3' end (3'-UTR) is prepared as follows:
  • the 3'-UTR cDNA (220 bp) of HCV is obtained from Ib HCV RNA of the blood of a hepatitis C patient by PCR and cloned into pcDNA3 vector.
  • Linearized DNA fragment containing the 3'-UTR is prepared using the restriction enzyme Eco RI and used as a template for in vitro transcription using T7 RNA polymerase to prepare RNA fragment containing 3 '- UTR.
  • Measurement of inhibitory activity of compounds of the present invention on recombinant HCV RNA polymerase in vitro. In vitro inhibitory activity of the compounds of the present invention on recombinant HCV RNA polymerase is measured as follows:
  • a streptavidin-coated well plate is prepared suitable for the sample to be examined.
  • 25 ⁇ of 2X assay buffer [50 mM Tris-Cl (pH 7.5), 100 mM NaCl, 10 mM MgCl 2 , 20 mM KCl, 1 mM EDTA, 1 mM DTT] and 10 ⁇ l of purified HCV RNA polymerase 200 ng and 3'-UTR template RNA are added to each well.
  • 5 ⁇ l of the sample to be examined is added to have final concentrations of 10, 1, 0.1 and 0.01 ⁇ g/mL.
  • RNA template of HCV 3'-UTR RNA 10 ⁇ l of a reactant solution containing DIG- (digoxigenin)-UTP, biotin-UTP, ATP, CTP, GTP, and UTP as a nucleotide for the polymerase reaction with the RNA template of HCV 3'-UTR RNA is added to each well.
  • the reaction mixture is incubated at 22 0 C for 60 minutes.
  • HCV polymerase newly generated RNAs including UTP conjugated with biotin and DIG are copied and these new RNAs could bind to streptavidin coated on the well by biotin-conjugated UTP.
  • the plate is washed three times with 200 ⁇ l of a washing buffer (pH 7.0, Roche) to remove unreacted substances and impurities.
  • a washing buffer pH 7.0, Roche
  • the compounds of the present invention shows inhibitory activity of HCV RNA polymerase at about 93 to 99% at 10 ⁇ g/mL; about 60 to 80 % at 1 ⁇ g/mL; about 30 to 55 % at 0.1 ⁇ g/mL; about 15 to 30 % at 0.01 ⁇ g/mL.
  • the results obtained demonstrates that the compounds of the present invention show excellent inhibitory effects on activity of HCV RNA polymerase which plays an important role in reproduction of HCV, thereby inhibiting replication of HCV by this property.
  • the compounds according to the present invention can be advantageously used as a therapeutic or prophylactic agent of C type hepatitis. Cytotoxicity assay
  • cytotoxicity of the compounds of formula I, II and III is examined by the MTT assay, a well established in vitro toxicology assay methods, using Hep G2 cells. All the compounds used in the experiment are found to have CC 50 of greater than 100 ⁇ g/mL, indicating that the compounds have extremely low cytotoxicity.
  • MTT assay a well established in vitro toxicology assay methods, using Hep G2 cells. All the compounds used in the experiment are found to have CC 50 of greater than 100 ⁇ g/mL, indicating that the compounds have extremely low cytotoxicity.
  • the assays of compounds comprising carboxyl groups may also be performed as described below:
  • Spectrophotometric assay for the HCV serine protease is performed on the compounds of the present invention 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.
  • Presented below are the synthesis, characterization and application of these novel spectrophotometric compounds, including ester substrates to high throughput screening and detailed kinetic evaluation of HCV NS 3 protease inhibitors. Materials and Methods:
  • Recombinant heterodimeric HCV NS3/NS4A protease (strain Ia) is prepared by using the procedures published previously (D. L. SaIi et al, Biochemistry, 37 (1998) 3392-3401). Protein concentrations are determined by the Biorad dye method using recombinant HCV protease standards previously quantified by amino acid analysis.
  • 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
  • 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
  • Spectra of substrates and the corresponding chromophore products are obtained in the pH 6.5 assay buffer. Extinction coefficients are 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 is 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 are performed at 30 0 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 are optimized for the NS3/NS4A heterodimer (D. L. SaIi et al., ibid.)).
  • 150 ⁇ l mixtures of buffer, substrate and inhibitor are placed in wells (final concentration of DMSO 4% v/v) and allowed to preincubate at 30 0 C for approximately 3 minutes.
  • Fifty ⁇ l of prewarmed protease (12 nM, 30 0 C) in assay buffer, is then used to initiate the reaction (final volume 200 ⁇ l).
  • the plates are 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 is monitored at the appropriate wavelength against a no enzyme blank as a control for non-enzymatic hydrolysis.
  • the evaluation of substrate kinetic parameters is performed over a 30-fold substrate concentration range (about 6-200 ⁇ M).
  • the resulting data are fitted using linear regression and the resulting slope, 1/(Kj (1+[S] 0 /K n ,), is used to calculate the Ki value.

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Abstract

La présente invention se rapporte à des dérivés pyridines et pyrimidines représentés par la formule (I), dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans le descriptif de l'invention, et à des compositions pharmaceutiques les contenant, utiles comme composés antiviraux. L'invention a également trait à des procédés de préparation desdits composés et à des procédés d'utilisation de ces derniers comme agents antiviraux dans le cadre d'un traitement.
PCT/US2005/044206 2004-12-16 2005-12-05 Compositions antivirales a base de pyridines et de pyrimidines WO2006065590A2 (fr)

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WO2008121634A2 (fr) 2007-03-30 2008-10-09 Pharmasset, Inc. Promédicaments de phosphoramidate de nucléoside
WO2010022128A1 (fr) * 2008-08-20 2010-02-25 Schering Corporation Dérivés de pyridine et de pyrimidine substitués par éthényle et leur utilisation dans le traitement d'infections virales
WO2010075554A1 (fr) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthèse de nucléosides de type purine
WO2010075517A2 (fr) 2008-12-23 2010-07-01 Pharmasset, Inc. Analogues de nucléoside
WO2010075549A2 (fr) 2008-12-23 2010-07-01 Pharmasset, Inc. Phosphoramidates de nucléosides
WO2010135569A1 (fr) 2009-05-20 2010-11-25 Pharmasset, Inc. Ester de n-[(2 ' r) -2' -désoxy-2' -fluoro-2' -méthyl-p-phényl-5' -uridylyl]-l-alanine 1-méthyléthyle et son procédé de production
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WO2011123668A2 (fr) 2010-03-31 2011-10-06 Pharmasset, Inc. Synthèse stéréosélective d'agents actifs contenant du phosphore
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WO2012075140A1 (fr) 2010-11-30 2012-06-07 Pharmasset, Inc. Composés
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8470834B2 (en) 2008-08-20 2013-06-25 Merck Sharp & Dohme Corp. AZO-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8541434B2 (en) 2008-08-20 2013-09-24 Merck Sharp & Dohme Corp. Ethynyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
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EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
JP2012500281A (ja) * 2008-08-20 2012-01-05 シェーリング コーポレイション エテニル置換ピリジンおよびピリミジン誘導体およびウイルス感染の治療におけるそれらの使用
WO2010022128A1 (fr) * 2008-08-20 2010-02-25 Schering Corporation Dérivés de pyridine et de pyrimidine substitués par éthényle et leur utilisation dans le traitement d'infections virales
US8470834B2 (en) 2008-08-20 2013-06-25 Merck Sharp & Dohme Corp. AZO-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8541434B2 (en) 2008-08-20 2013-09-24 Merck Sharp & Dohme Corp. Ethynyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
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US8697694B2 (en) 2008-08-20 2014-04-15 Merck Sharp & Dohme Corp. Substituted pyridine and pyrimidine derivatives and their use in treating viral infections
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