Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • 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
  • 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

Definitions

• the invention relates to the field of pharmaceutical chemistry, in particular to compounds, compositions and methods for treating viral infections in mammals mediated, at least in part, by a virus in the Flaviviridae family of viruses.
• Chronic infection with ⁇ CV is a major health problem associated with liver cirrhosis, hepatocellular carcinoma and liver failure.
• An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. ' In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV -related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
• Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.
• Liver cirrhosis can ultimately lead to liver failure.
• Liver failure resulting from chronic HCV infection is now recognized as a leading cause of liver transplantation.
• HCV is a member of the Flaviviridae family of RNA viruses that affect animals and humans.
• the genome is a single ⁇ 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
• the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
• the organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-El-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b.
• HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes. 3 ' 4
• IFN-alpha interferon alpha
• IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.
• IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control.
• Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
• Ribavirin an inhibitor of inosine 5 '-monophosphate dehydrogenase (IMPDH)
• IMPDH inosine 5 '-monophosphate dehydrogenase
• a number of approaches are being pursued to combat the virus. They include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
• the viral targets the NS3/4a protease/helicase and the NS5b RNA- dependent RNA polymerase are considered the most promising viral targets for new drugs. 6"8
• antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication.
• host cell proteins that are necessary for viral replication.
• Watashi et al. show how antiviral activity can be achieved by inhibiting host cell cyclophilins.
• a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans. 10
• the present invention is directed to novel compounds, compositions, and methods for treating of viral infections in mammals mediated, at least in part, by a member of the Flaviviridae family viruses such as HCV.
• compounds of this invention are represented by Formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug, or tautomer thereof:
• Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;
• HET is selected from the group consisting of a 6-membered arylene ring, a 6- membered heteroarylene ring containing 1, 2, or 3 heteroatoms selected from N, O, or S, and a bicyclic ring having the formula
• HET is optionally substituted with (X) t
• X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxy, and nitro
• t is an integer equal to 0, 1 or 2
• W 1 , W 4 , and W 5 are independently N or CH
• W 3 is N, CH, or is a bond provided that no more than one nitrogen in the bicyclic ring is optionally oxidized to form an N-oxide
• each dashed line independently represents a single or double bond between the two adjoining atoms, provided that when one of dashed lines is a single bond, the adjoining atoms are each substituted with 1 or 2 hydrogen atoms to satisfy its valency
• one of D or E is C-R a and the other of D or E is S;
• R a and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
• Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and Z is selected from the group consisting of
• R 2 and R 2 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or, alternatively, R and R as defined are taken together with the carbon atom pendent thereto to form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group, or, still further alternatively, one of R 2 or R 2 is hydrogen, alkyl or substituted alkyl, and the other is joined, together with the carbon atom pendent thereto, with either the R and the oxygen atom pendent thereto or R and the nitrogen atom pendent thereto to form a heterocyclic or substituted heterocyclic group;
• R is selected from hydrogen and alkyl or, when R and R are not taken together to form a ring and when R 2 or R 2 and R 7 or R 8 are not joined to form a heterocyclic or substituted heterocyclic group, then R 3 , together with the nitrogen atom pendent thereto, may be taken together with one of R 2 and
• R 2 to form a heterocyclic or substituted heterocyclic ring group
• R 25 , R 26 and R 27 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, or R and R together with the carbon atom pendent thereto form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and
• alkyl refers to monovalent alkyl groups having from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms and more preferably 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, ⁇ o-propyl, n- butyl, t-butyl, n-pentyl and the like.
• Substituted alkyl refers to an alkyl group having from 1 to 3, and preferably 1 to 2, substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
• Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, ⁇ o-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy and the like.
• Substituted alkoxy refers to the group “substituted alkyl-O-”.
• Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl- C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)- cycloalkyl- C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O), heterocyclic-C(O)-, and substituted heterocyclic-C(O)-.
• Acylamino refers to the group -C(0)NR f R g where R f and R g is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R f and R g are joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring.
• Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl- C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl- C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-.
• Alkenyl refers to alkenyl group having from 2 to 10 carbon atoms, preferably having from 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
• Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that any hydroxyl substitution is not pendent to a vinyl carbon atom.
• Alkynyl refers to alkynyl group having from 2 to 10 carbon atoms, preferably having from 2 to 6 carbon atoms, and more preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
• Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that any hydroxyl substitution is not pendent to an acetylenic carbon atom.
• Amino refers to the group -NH 2 .
• substituted amino refers to the group -NR 11 R 1 where R h and R 1 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R h and R 1 are joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group provided that R h and R 1 are both not hydrogen.
• R h is hydrogen and R 1 is alkyl
• the substituted amino group is sometimes referred to herein as alkylamino.
• R h and R 1 are alkyl
• the substituted amino group is sometimes referred to herein as dialkylamino.
• aminoacyl refers to the groups -NR J C(O)alkyl, -NR J C(O)substituted alkyl, -NR J C(O)-cycloalkyl, -NR J C(O)substituted cycloalkyl, -NR J C(O)alkenyl,
• Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is to an aromatic ring atom.
• Preferred aryls include phenyl and naphthyl.
• “Aralkyl” or “arylalkyl” refers to the group aryl-alkyl- and includes, for example, benzyl.
• Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of hydroxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxy, carboxy esters, cyano, thiol, cycloalkyl, substituted cycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, and substituted heterocyclyloxy.
• Arylene and “substituted arylene” refer to divalent aryl and substituted aryl groups as defined above.
• Phenylene is a 6-membered optionally substituted arylene group and includes, for example, 1 ,2-phenylene, 1,3 -phenylene, and 1,4-phenylene.
• Aryloxy refers to the group aryl-O- that includes, by way of example, phenoxy, naphthoxy, and the like. "Substituted aryloxy” refers to substituted aryl-O- groups.
• Carboxy esters refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic.
• Preferred carboxy esters are -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-aryl, and -C(O)O-substituted aryl.
• Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings optionally comprising 1 to 3 exo carbonyl or thiocarbonyl groups.
• Suitable cycloalkyl groups include, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 3-oxocyclohexyl, and the like.
• one or more of the rings may be other than cycloalkyl (e.g., aryl, heteroaryl or heterocyclic) provided that the point of attachment is to a carbon ring atom of the cycloalkyl group.
• the cycloalkyl group does not comprise 1 to 3 exo carbonyl or thiocarbonyl groups.
• the cycloalkyl group does comprise 1 to 3 exo carbonyl or thiocarbonyl groups. It is understood, that the term "exo" refers to the attachment of a carbonyl or thiocarbonyl to a carbon ring atom of the cycloalkyl group.
• Substituted cycloalkyl refers to a cycloalkyl group, having from 1 to 5 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
• Cycloalkenyl refers to cyclic alkenyl but not aromatic groups of from 5 to 10 carbon atoms having single or multiple cyclic rings optionally comprising 1 to 3 exo carbonyl or thiocarbonyl groups.
• Suitable cycloalkenyl groups include, by way of example, cyclopentyl, cyclohexenyl, cyclooctenyl, 3-oxocyclohexenyl, and the like.
• one or more of the rings may be other than cycloalkenyl (e.g., aryl, heteroaryl or heterocyclic) provided that the point of attachment is to a carbon ring atom of the cycloalkyl group.
• the cycloalkenyl group does not comprise 1 to 3 exo carbonyl or thiocarbonyl groups. In another embodiment, the cycloalkenyl group does comprise 1 to 3 exo carbonyl or thiocarbonyl groups. It is understood, that the term “exo” refers to the attachment of a carbonyl or thiocarbonyl to a carbon ring atom of the cycloalkenyl group.
• Substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that for hydroxyl substituents the point of attachment is not to a vinyl carbon atom.
• Cycloalkoxy refers to -O-cycloalkyl groups.
• Substituted cycloalkoxy refers to -O-substituted cycloalkyl groups.
• Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
• Haloalkyl refers to an alkyl group substituted with 1 to 5 halogen groups.
• An example of haloalkyl is CF 3 .
• Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, within the ring.
• such heteroaryl groups are aromatic groups of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
• Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
• the sulfur atom(s) in the heteroaryl group may optionally be oxidized to sulfoxide and sulfone moieties.
• Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl.
• heteroaryl When a specific heteroaryl is defined as "substituted”, e.g., substituted qunioline, it is understood that such a heteroaryl contains the 1 to 3 substituents as recited above.
• Heteroarylene and “substituted heteroarylene” refer to divalent heteroaryl and substituted heteroaryl groups as defined above.
• Heteroaryloxy refers to the group -O-heteroaryl and “substituted heteroaryloxy” refers to the group -O-substituted heteroaryl.
• Heterocycle or “heterocyclic” or “heterocyclyl” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring which ring may optionally comprise 1 to 3 exo carbonyl or thiocarbonyl groups.
• such heterocyclic groups are saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur, or oxygen within the ring.
• the sulfur atom(s) in the heteroaryl group may optionally be oxidized to sulfoxide and sulfone moieties.
• one or more of the rings may be other than heterocyclic (e.g., aryl, heteroaryl or cycloalkyl) provided that the point of attachment is to a heterocyclic ring atom.
• the heterocyclic group does not comprise 1 to 3 exo carbonyl or thiocarbonyl groups.
• the heterocyclic group does comprise 1 to 3 exo carbonyl or thiocarbonyl groups. It is understood, that the term "exo" refers to the attachment of a carbonyl or thiocarbonyl to a carbon ring atom of the heterocyclic group.
• Substituted heterocyclic refers to heterocycle groups that are substituted with from 1 to 3 of the same substituents as defined for substituted cycloalkyl.
• Preferred substituents for substituted heterocyclic groups include heterocyclic groups having from 1 to 5 having substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxy, carboxy esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
• heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,
• Heterocyclyloxy refers to the group -O-heterocyclic and "substituted heterocyclyloxy” refers to the group -O-substituted heterocyclic.
• thiol refers to the group -SH.
• Isosteres are different compounds that have different molecular formulae but exhibit the same or similar properties.
• tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid.
• carboxylic acid isosteres contemplated by the present invention include -COOH, -SO 3 H, -S0 2 HNR k , -PO 2 (R k ) 2 , -CN, -PO 3 (R k ) 2 , -OR k , -SR k , -NHC0R k , - N(R k ) 2 , -C0N(R k ) 2 , -C0NH(0)R k , -C0NHNHS0 2 R k , -COHNSO 2 R k , and -C0NR k CN, where R k is selected from hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, thio, thioal
• carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH 2 , O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions.
• the following structures are non-limiting examples of preferred isosteres contemplated by this invention:
• the atoms of said ring structure may be optionally substituted at one or more positions with R k .
• the present invention contemplates that when chemical substituents are added to a carboxylic isostere then the inventive compound retains the properties of a carboxylic isostere.
• the present invention contemplates that when a carboxylic isostere is optionally substituted with one or more moieties selected from R k , then the substitution cannot eliminate the carboxylic acid isosteric properties of the inventive compound.
• the present invention contemplates that the placement of one or more R k substituents upon the carboxylic acid isostere shall not be permitted at one or more atom(s) which maintain(s) or is/are integral to the carboxylic acid isosteric properties of the inventive compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the inventive compound.
• Carboxylic acid bioisosteres are compounds that behave as isosteres of carboxylic acids under biological conditions. Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated by the present invention.
• Metal refers to any derivative produced in a subject after administration of a parent compound.
• the metabolite may be produced from the parent compound by various biochemical transformations in the subject such as, for example, oxidation, reduction, hydrolysis, or conjugation.
• Metabolites include, for example, oxides and demethylated derivatives.
• “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
• Prodrug refers to art recognized modifications to one or more functional groups which functional groups are metabolized in vivo to provide a compound of this invention or an active metabolite thereof.
• Such functional groups are well known in the art including acyl groups for hydroxyl and/or amino substitution, esters of mono-, di- and tri-phosphates wherein one or more of the pendent hydroxyl groups have been converted to an alkoxy, a substituted alkoxy, an aryloxy or a substituted aryloxy group, and the like.
• Treating” or “treatment” of a disease in a refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
• Patient refers to mammals and includes humans and non-human mammals.
• arylalkyloxycarbonyl refers to the group (aryl)-(alkyl)-O-C(O)-;
• alkylaryloxy refers to the group alkyl-aryl-O-;
• arylalkyloxy refers to the group aryl-alkyl-O-,
• thioalkyl refers to SH-alkyl-;
• alkylthio refers to alkyl-S- etc.
• substituents may also have alternate but equivalent names.
• 2-oxo-ethyl and the term carbonylmethyl both refer to the -C(O)CH 2 - group.
• impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups or a hydroxy group alpha to ethenylic or acetylenic unsaturation.
• impermissible substitution patterns are well known to the skilled artisan.
• Y is selected from the group consisting of aryl, heteroaryl, substituted aryl, and substituted heteroaryl;
• HET is selected from the group consisting of a 6-membered arylene ring, a 6- membered heteroarylene ring containing 1, 2, or 3 heteroatoms selected from N, O, or S, and a bicyclic ring having the formula
• HET is optionally substituted with (X) t
• X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, halo, hydroxy, and nitro
• t is an integer equal to 0, 1 or 2
• W 1 , W 4 , and W 5 are independently N or CH
• W 3 is N, CH, or is a bond provided that no more than one nitrogen in the bicyclic ring is optionally oxidized to form an N-oxide
• each dashed line independently represents a single or double bond between the two adjoining atoms, provided that when one of dashed lines is a single bond, the adjoining atoms are each substituted with 1 or 2 hydrogen atoms to satisfy its valency
• one of D or E is C-R a and the other of D or E is S;
• R a and R are independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
• Q is selected from the group consisting of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• Z is selected from the group consisting of (a) carboxy and carboxy ester
• R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, alternatively, R 8 and R 9 together with the nitrogen atom pendent thereto, form a heterocyclic, a substituted heterocyclic, a heteroaryl or a substituted heteroaryl ring group;
• R 7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R and R are as defined above;
• R 2 and R 2 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or, alternatively, R and R as defined are taken together with the carbon atom pendent thereto to form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group, or, still further alternatively, one of R or R is hydrogen, alkyl or substituted alkyl, and the other is joined, together with the carbon atom pendent thereto, with either the R 7 and the oxygen atom pendent thereto or R 8 and the nitrogen atom pendent thereto to form a heterocyclic or substituted heterocyclic group;
• R is selected from hydrogen and alkyl or, when R and R are not taken together to form a ring and when R or R and R or R are not joined to form a heterocyclic or substituted heterocyclic group, then R 3 , together with the nitrogen atom pendent thereto, may be taken together with one of R 2 and R 2 to form a heterocyclic or substituted heterocyclic ring group; (e) -C(X 2 )-N(R 3 )CR 25 R 26 R 27 , wherein X 2 and R 3 are defined above, and R 25 , R 26 and R 27 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, or R and R together with the carbon atom pendent thereto form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) a carboxylic acid isostere
• Y is selected from the group consisting of substituted aryl and substituted heteroaryl;
• X is independently selected from the group consisting of amino, nitro, alkyl, haloalkyl, and halo;
• t is an integer equal to 0, 1 or 2;
• Q is selected from the group consisting of cyclohexyl and cyclopentyl;
• R 12 and R 13 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, -(CH 2 )o- 3 R 16 , and -NR 17 R 18 , or R 12 and R 13 and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring provided that both R 12 and R 13 are not both hydrogen; wherein R 16 is aryl, heteroaryl, or heterocyclic; and R 17 and R 18 are independently hydrogen or alkyl or R 17 and R 18 together with the nitrogen atom to which they are attached join to form a heterocyclic ring with 4 to 7 ring atoms; one of A or B is C-R a and the other of A or B is S;
• R a is selected from the group consisting of hydrogen, alkyl, and substituted alkyl
• Z is selected from the group consisting of carboxy, carboxy ester, and a carboxylic acid isostere.
• the present invention provides compounds of Formulae (Ib)-
• each of Formula (I) and (Ia) E is S. In other embodiments, D is CH and E is S.
• R a is hydrogen. In other embodiments, R a is substituted alkyl, substituted amino, or substituted aminoalkyl. In some aspects, R a is selected from the following substituents:
• Q is cycloalkyl or substituted cycloalkyl.
• Q is cycloalkyl.
• Q is cycloalkenyl.
• Q is cyclohexyl.
• Q is cyclohexenyl.
• T is cyclopentyl.
• Z is carboxy or carboxy ester.
• Z is selected from carboxy, methyl carboxylate, and ethyl carboxylate.
• Z is a carboxylic acid isostere.
• the carboxylic acid isostere is a carboxylic acid bioisostere.
• the carboxylic acid isostere is selected from lH-tetrazol-5-yl and 5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl.
• R is substituted alkyl.
• the substituted alkyl comprises 1 to 2 substituents selected from the group consisting of sulfonic acid (SO3H), carboxy, carboxy ester, amino, substituted amino, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
• SO3H sulfonic acid
• the substituted alkyl group is selected from the group consisting of 3,4-dimethoxybenzyl, 3,4-dihydroxybenzyl, 3-methoxy-4- hydroxybenzyl, 4-aminosulfonylbenzyl, 4-methylsulfonylbenzyl, (1 -methyl -piperidin-3- yl)methyl, (1 -methyl -pyrrolidin-3-yl)methyl, fur-2-ylmethyl, 6-methylpyridin-2-ylmethyl, 2-(l -methyl-pyrrolidin-3-yl)ethyl, 1 -phenylethyl, 1 -(3-methoxyphenyl)-ethyl, l-(4-methoxyphenyl)-ethyl, ⁇ f', ⁇ f'-dimethylaminoethyl, and 2-(lH-pyrazol
• Z is selected from N-methyl carboxamide, N,N- dimethylcarboxamido, N-isopropyl-carboxamido, N-allyl-carboxamido, and 5-hydroxy- tryptophan-carbonyl.
• R 9 is substituted heteroaryl.
• the substituted heteroaryl is selected from the group consisting of 4-methyl-2-oxo-2H-chromen- 7-yl, l-phenyl-4-carboxy-l ⁇ -pyrazol-5-yl, 5-carboxypyrid-2-yl, 2-carboxypyrazin-3-yl, and 3-carboxythien-2-yl.
• the heterocyclic group is N-morpholino, tetrahydrofuranyl, and 1,1-dioxidotetrahydrothienyl.
• the heterocyclic and substituted heterocyclic rings comprise 4 to 8 membered rings containing 1 to 3 heteroatoms.
• the 1 to 3 heteroatoms comprises 1 to 2 nitrogen atoms.
• the heterocyclic or substituted heterocyclic ring is selected from the group consisting of piperidine, substituted piperidine, piperazine, substituted piperazine, morpholino, substituted morpholino, thiomorpholino and substituted thiomorpholino wherein the sulfur atom of the thiomorpholino or substituted thiomorpholino ring is optionally oxidized to provide for sulfoxide and sulfone moieties.
• the heterocyclic or substituted heterocyclic ring is selected from the group consisting of 4-hydroxypiperidin-l-yl, l,2,3,4-tetrahydro-3- carboxy-isoquinolin-2-yl, 4-methylpiperizin-l-yl, morpholin-4-yl, thiomorpholin-4-yl , 4- methyl-piperazin-1-yl, and 2-oxo-piperazinyl.
• R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
• R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl.
• R 2 is selected from the group consisting of hydrogen, methyl, 1-methylprop-l-yl, sec -butyl, hydroxymethyl, 1- hydroxyeth-1-yl, 4-amino-n-butyl, 2-carboxyeth-l-yl, carboxymethyl, benzyl, (IH- imidazol-4-yl)methyl, (4-phenyl)benzyl, (4-phenylcarbonyl)benzyl, cyclohexylmethyl, cyclohexyl, 2-methylthioeth-l-yl, ⁇ o-propyl, carbamoylmethyl, 2-carbamoyleth-l-yl, (4-hydroxy)benzyl, and 3-guanidino-n-propyl.
• R 1 is selected from the group consisting of hydroxy, alkoxy, amino(N-morpholino), amino, and substituted amino.
• R 1 is selected from the group consisting of hydroxy, alkoxy, amino(N-morpholino), amino, and substituted amino, and R and R , together with the carbon atom and nitrogen atom bound thereto respectively, are joined to form a heterocyclic or substituted heterocyclic group.
• R 1 is selected from the group consisting of hydroxy, alkoxy, amino(N-morpholino), amino, and substituted amino and R 2 and R 3 , together with the carbon atom and nitrogen atom bound thereto respectively, are joined to form a heterocyclic or substituted heterocyclic group, the heterocyclic and substituted heterocyclic groups are selected from the group consisting of pyrrolidinyl, 2- carboxy-pyrrolidinyl, 2-carboxy-4-hydroxypyrrolidinyl, and 3-carboxy-l,2,3,4- tetrahydroisoquinolin-3-yl.
• Z is selected from 1-carboxamidocyclopent-l- ylaminocarbonyl, 1 -carboxamido- 1 -methyl-eth- 1 -ylaminocarbonyl, 5 -carboxy- 1 ,3 -dioxan- 5 -ylaminocarbonyl, 1 -(N-methylcarboxamido)- 1 -(methyl)-eth- 1 -ylaminocarbonyl, 1 -(N ,N- dimethylcarboxamido)- 1 -(methyl)-eth- 1 -ylaminocarbonyl, 1 -carboxy- 1 -methyl-eth- 1 - ylaminocarbonyl, l-(N-methylcarboxamido)-cyclobutanaminocarbonyl, 1 -carboxamido- cyclobutanaminocarbonyl, l-(N,N-dimethylcarboxamido)-cyclobut
• Z is -C(O)NR 21 S(O) 2 R 4 .
• R 4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
• R 4 is methyl, ethyl, isopropyl, propyl, trifluoromethyl, 2,2,2- trifluoroethyl, phenyl, benzyl, phenethyl, 4-bromophenyl, 4-nitrophenyl or 4-methylphenyl, 4-methoxyphenyl, 2-aminoethyl, 2-(dimethylamino)ethyl, 2-N-benzyloxyaminoethyl, pyridinyl, thienyl, 2-chlorothien-5-yl, 2-methoxycarbonylphenyl, naphthyl, 3-chlorophenyl, 2-bromophenyl, 2-chlorophenyl, 4-trifluoromethoxyphenyl, 2,5-difluorophenyl, A- fluorophenyl, 2-methylphenyl, 6-ethoxybenzo
• Z is selected from hydrogen, halo, alkyl, alkoxy, amino, substituted amino, and cyano.
• Z is -C(X 2 )-N(R 3 )CR 25 R 26 R 27 , wherein X 2 and R 3 are defined above, and R , R and are alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl, or R 25 and R 26 together with the carbon atom pendent thereto form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group.
• Z is selected from l-(6-(3-carboxyprop-2-en-l-yl)-lH- benzofJJimidazol ⁇ -y ⁇ cyclobutanaminocarbonyl, 3-(6-(3-carboxyprop-2-en-l-yl)-l ⁇ - benzo[ ⁇ i]imidazol-2-yl)- 1 -methylpyrrolidin-3-aminocarbonyl, 1 -(I -methyl-6-(3- carboxyprop-2-en- 1 -yl)- lH-benzo[ ⁇ i]imidazol-2-yl)cyclobutanaminocarbonyl, 1 - (benzofuran-2-yl)-5-carboxy-cyclobutanaminocarbonyl, l-(2-methylthiazol-4-yl)- cyclobutanaminocarbonyl, 1 -(2-acetylamino-thiazol-4-yl)-cyclobutanaminocarbon
• Z is carboxy, carboxy ester, carboxylic acid isostere, -C(O)NR 8 R 9 , or -C(O)NHS(O) 2 R 4 , wherein R 8 and R 9 are as defined above and R 4 is alkyl or aryl.
• Z is carboxy, methyl carboxylate, ethyl carboxylate, 6-( ⁇ -D-glucuronic acid) ester, lH-tetrazol- 5-yl, 5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl, N-2-cyano-ethylamide, N-2-(l ⁇ -tetrazol-5- yl)ethylamide, methylsulfonylaminocarbonyl, trifluoromethylsulfonylaminocarbonyl, or phenylsulfonylaminocarbonyl.
• Z is carboxy.
• Z 1 is selected from the group consisting of hydrogen, halo, alkyl, and haloalkyl.
• R is CvH 2 V-C(O)-OR where v is 1, 2 or 3; and R is hydrogen, alkyl or substituted alkyl.
• R is C v H 2v -C(O)-OR 23
• v is 1.
• R is C v H 2v -C(O)-OR
• R is carboxymethyl or methylcarboxymethyl.
• R is hydrogen.
• R is C v H 2v -C(O)-NR 12 R 13 where v is 1, 2 or 3;
• R 12 and R 13 are selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl alkoxy, substituted alkoxy and -(CH 2 )o_ 3 R 16 ;
• R 16 is aryl, heteroaryl, heterocyclic, -NR 17 R 18 ; and R 17 and R 18 are independently selected from hydrogen, and alkyl, or alternatively, R 17 and R 18 together with the nitrogen atom to which they are attached join to form a heterocyclic ring with 4 to 7 ring atoms; or, alternatively, R and R 13 and the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring; provided that both R and R are not alkoxy and/or substituted alkoxy.
• v is 1.
• the NR 12 R 13 group is selected from N,N-dimethylamino-carbonylmethyl, [N-(4-hydroxy-l,l- dioxidotetrahydro-3 -thienyl)amino] -carbonylmethyl, (cyclopropylmethylamino)- carbonylmethyl, (prop-2-yn- 1 -ylamino)-carbonylmethyl, (2-(morpholino)eth- 1 -ylamino)- carbonylmethyl, (phenylsulfonylamino)-carbonylmethyl, [N-benzylamino]-carbonylmethyl, (N-(4-methylsulfonyl-benzyl)amino)-carbonylmethyl, (tryptophanyl)-carbonylmethyl, (tyrosine)-carbonylmethyl, (N-(I -car
• R is selected from morpholinocarbonylmethyl, N,N- dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidin- 1 -yl)carbonylmethyl, piperazinylcarbonylmethyl.
• R is an oxide of morpholinocarbonylmethyl, ⁇ /, ⁇ /-dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidin- 1 -yl)carbonylmethyl, piperazinylcarbonylmethyl .
• R is selected from [(N,N-dimethylamino)prop-2-en-l-yl]- carbonylmethyl, (N,N-dimethylpiperidin-4-aminium trifluoroacetate)acetyl, 2-(N 5 N- dimethylpiperidin-4-aminium trifluoroacetate)morpholino acetyl, (2-(diisopropyl)eth-l-yl)- carbonylmethyl, (pyridin-4-ylcarbonylhydrazino)-carbonylmethyl, (N-(4-carboxybenzyl)- amino)carbonylhydrazino)-carbonylmethyl, (acetylhydrazino)-carbonylmethyl, ((N' 5 N'- dimethylaminomethyl-carbonyl)hydrazino)-carbonylmethyl.
• R is substituted alkyl, wherein said substituted alkyl is selected from the group consisting of aminoalkyl, substituted aminoalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -CH 2 COOH, and -CH 2 CONR 12 R 13 , wherein R 12 and R 13 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, -(CH 2 ) 0 - 3 R 16 , and -NR 17 R 18 , or R 12 and R 13 and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring provided that both R 12 and R 13 are not both hydrogen; wherein R 16 is aryl, heteroaryl, or
• R is -CH 2 CONR 12 R 13 and at least one of R 12 or R 13 is alkyl, substituted alkyl, or heteroaryl. In some aspects at least one of R or R is methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholin-4-ylethyl, or tetrazoyl-5-yl. In other aspects R is l-methyl-piperidin-4-yl, l-methyl-piperidin-3-ylmethyl, and thiazol-2-yl carbamoyl methyl.
• R is -CH 2 CONR 12 R 13 and R 12 and R 13 and the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring.
• R and R and the nitrogen atom to which they are attached form a substituted or unsubstituted morpholino, substituted or unsubstituted piperidinyl, or a substituted or unsubstituted pyrrolidinyl ring.
• substituted or unsubstituted morpholino, piperidinyl, or pyrrolidinyl ring is selected from the group consisting of morpholino, 4-pyrrolidin-l-yl-piperidinyl, piperidinyl, 4-hydroxypiperidinyl, 4-carboxypiperidinyl, 4-dimethylaminopiperidinyl, 4-diethylaminopiperidinyl, 2- methylpyrrolidinyl, 4-morpholin-4-yl -piperidinyl, 3,5-dimethyl-morpholin-4-yl, 4- methylpiperidinyl.
• R 12 and R 13 and the nitrogen atom to which they are attached together form a group selected from N,N-dimethylamino, N-(4-hydroxy-l,l- dioxidotetrahydro-3-thienyl)amino, cyclopropylmethylamino, prop-2-yn-l-ylamino, 2- (morpholino)eth-l-ylamino, phenylsulfonylamino, N-benzylamino, N-(4-methylsulfonyl- benzyl)amino, tryptophanyl, tyrosine, N-1-carboxyprop-l-ylamino, N-(2-carboxyeth-l-yl)- amino, N-(4-carboxybenzyl)-amino, N-[3-(N'-(4-(acrylic acid)- phenyl)carboxamido)pyrrolidin-3-yl]amino
• HET is selected from quinolinylene and substituted quinolinylene. In another embodiment HET is selected from quinolinylene, isoquinolinylene, 7-methyl-quinolinylene, 7-trifluoromethyl-quinolinylene, 8-fluoro- quinolinylene and 7-fluoro-quinolinylene.
• HET is 2- [substituted]-quinolin-6-yl, 2-[substituted]-7-methyl-quinolinyl, 2-[substituted]-7-fluoro- quinolinyl, 2- [substituted] -7-trifluoromethyl-quinolinyl, and 2-[substituted]-8-fluoro- quinolinyl.
• W 1 is nitrogen.
• HET is selected from the group consisting of
• HET is 1 ,4-phenylene optionally substituted with (X) t where X and t are previously defined.
• t is 0.
• t is 1 and X is amino, nitro, methyl, or halo.
• HET is selected from the following groups:
• Y is substituted aryl or substituted heteroaryl.
• Y is selected from the group consisting of substituted biphenyl, substituted phenyl, substituted 6-membered heteroaryl ring optionally fused to a phenyl ring and having one, two, or three heteroatoms independently selected from the group consisting of N, O, or S wherein the heteroatoms N or S are optionally oxidized, and substituted 5-membered heteroaryl ring optionally fused to a phenyl ring and having one, two, or three heteroatoms independently selected from the group consisting of N, O, or S wherein the heteroatoms N or S are optionally oxidized.
• Y is substituted 5-membered heteroaryl ring optionally fused to a phenyl ring and having one, two, or three heteroatoms independently selected from the group consisting of N, O, or S wherein the heteroatoms N or S are optionally oxidized.
• -Y is -Ar 1 -(G 1 ) q
• Ar 1 is selected from arylene and heteroarylene
• G 1 is selected from halo, hydroxy, nitro, cyano, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy and carboxy ester
• q is an integer from 1 to 3.
• -Y is -Ar 1 - (G 1 X 1 )
• Ar 1 is selected from phenyl, thiazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, and pyrrolidinyl.
• G 1 is selected from bromo, chloro, methyl, hydroxy, methoxy, ethoxy, acetyl, acetamido, carboxy, and amino.
• Y is selected from 2,4- dimethylthiazol-5-yl, 3-bromo-4-aminophenyl, 3-amido-4-hydroxy-phenyl, 2-hydroxy-6- methoxy-phenyl, 4-(acetylamino)-phenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxy-6- hydroxyphenyl, and 7-hydroxybenzofuranyl.
• Y is -Ar 1 -Ar 2 - where the -Ar ⁇ Ar 2 - group is selected from the group consisting of-aryl-aryl, -aryl-substituted aryl, -substituted aryl-aryl, -substituted aryl-substituted aryl, -aryl-heteroaryl, -aryl-substituted heteroaryl, -substituted aryl-heteroaryl, -substituted aryl-substituted heteroaryl, heteroaryl-aryl, heteroaryl-substituted aryl, substituted heteroaryl-aryl, substituted heteroaryl-substituted aryl, -aryl-cycloalkyl, -aryl-substituted cycloalkyl, -substituted aryl-cycloalkyl, -substituted aryl,
• the -Ar -Ar - group is selected from the group consisting of 4'-chloro-4-methoxybiphen-2-yl, biphen-2-yl, biphen-4-yl, 4-amino- 4'-chlorobiphen-2-yl, 4'-aminomethyl-4-methoxybiphen-2-yl, 4-carbamoyl-4'- methoxybiphen-2-yl, 4-carbamoyl-4'-fluorobiphen-2-yl, 4-carbamoyl-4'-methoxybiphen-2- yl, 4-carbamoyl-4'-nitrobiphen-2-yl, 4-(carbamoylmethyl-carbamoyl)biphen-2-yl, 4- (carbamoylmethylcarbamoyl)-4'-chlorobiphen-2-yl, 4-carboxy-4'-chlorobiphen-2-yl,
• the -Ar ! -Ar 2 group is selected from the group consisting of 4-(lH-imidazol-l-yl)phenyl, 2-furan-2-yl-5-methoxyphenyl, 5- methoxy-2-thiophen-2-ylphenyl, 2-(2,4-dimethoxypyrimidin-5-yl)-4-methoxyphenyl, 2- (pyrid-4-yl)phenyl, 3 -amino-5 -phenylthiophen-2-yl, 5 -(4-chlorophenyl)-2-methylfuran-2-yl, 3-(4-chlorophenyl)-5-methylisoxazol-4-yl, 2-(4-chlorophenyl)-4-methylthiazol-5-yl, 3-(3,4- dichloro-phenyl)isoxazol-5-yl, 3,5-dimethyl-l-phenyl-
• the -Ar -Ar - group is selected from the group consisting of 2-cyclohexyl- ⁇ /, ⁇ /-dimethylamino-carbonylmethyl-5- methoxyphenyl, and 4-morpholinophenyl.
• Y is is selected from the group consisting of substituted quinolyl, substituted benzofuryl, substituted thiazolyl, substituted furyl, substituted thienyl, substituted pyridinyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrrolidinyl, substituted pyrazolyl, substituted isothiazolyl, substituted 1,2,3-oxadiazolyl, substituted 1,2,3-triazolyl, substituted 1,3,4-thiadiazolyl, substituted pyrimidinyl, substituted 1,3,5-triazinyl, substituted indolizinyl, substituted indolyl, substituted isoindolyl, substituted indazolyl, substituted benzothienyl, substituted benzthiazolyl, substituted purinyl, substituted quinolizin
• Y is substituted with one to three subsitutents independently selected from the group consisting of alkyl, haloalkyl, halo, hydroxy, nitro, cyano, alkoxy, substituted alkoxy, acyl, acylamino, aminoacyl, amino, substituted amino, carboxy, and carboxy ester.
• Y is 2,4- dimethylthiazol-5-yl.
• Y is selected from the corresponding Y groups in Table 1. In some embodiments, - ⁇ et-Y is:
• Preferred compounds of this invention or the pharmaceutically acceptable salts, partial salts, or tautomers thereof include those set forth in Table I below:
• the present invention further provides metabolites of any of compounds of Formula (I), (Ia)-(Is), or of the compounds in Table 1.
• the metabolite is an oxide.
• compositions comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of one of the compounds described herein or mixtures of one or more of such compounds.
• This invention is further directed to methods for treating a viral infection mediated at least in part by a virus in the Flaviviridae family of viruses, such as HCV, in mammals which methods comprise administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of one of the compounds described herein or mixtures of one or more of such compounds.
• present invention provides for use of the compounds of the invention for the preparation of a medicament for treating or preventing said infections.
• the mammal is a human.
• agents active against HCV include ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha, alone or in combination with ribavirin or viramidine.
• the additional agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or viramidine.
• the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
• protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
• Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
• stereoisomers i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
• the compounds of Formula (I) are prepared via a transition metal catalyzed cross-coupling reaction as shown above in Scheme 1 where L and L' are suitable cross-coupling substituents, P' is hydrogen, a nitrogen protecting group, or R, and Z, D, E, R, Q, HET, and Y are as previously defined.
• L or L' is a Sn, B, Zr, or Zn based metal (e.g. -BOH 2 , Sn(CHs) 3 , etc.) and the other of L or L' is a leaving group such as halogen or sulfonate.
• Suitable halogens and sulfonates include Cl, Br, I, -OSO 2 CF 3 , and -OSO 2 CH 3 .
• Suitable transition metal catalysts include Pd and Ni based catalysts (e.g. Pd(PPh 3 ) 2 Cl 2 , Pd[P(Ph 3 )] 4 , etc.).
• one of 1.1 or 1.2 has L is -B(OH) 2 and is prepared by treating a compound of 1.1 or 1.2 where L or L' is halogen with an excess of bis(neopentylglycolato)diboron in the presence of a catalytic amount of triphenylphosphine palladium(II) dichloride.
• the resulting boronic acid is the coupled with the other of 1.1 or 1.2 where L is halogen or a sulfonate under Suzuki coupling conditions to form a compound of Formula (I) or an intermediate 1.3.
• Suitable coupling conditions include reaction of 1.1 and 1.2 in refluxing methanol containing Pd[P(Ph) 3 J 4 and NaHCO 3 for 10 to 20 hours.
• P' is H or a protecting group
• removal of the protecting group followed by functionalization of the resulting NH group yields compound (I).
• An specific example of this transformation is shown in Scheme 5.
• compound 1.1 can be synthesized as shown in Scheme 2 where for illustrative purposes D is CH, E is S, Z is COOP, Q is cyclohexyl, P is a hydroxy protecting group such as alkyl, P' is a nitrogen protecting group, and L is halogen.
• Thiophene 2.1 is treated with a mixture of nitric and sulfuric acid to form nitro compound 2.2. Reduction of the nitro group followed by protection of the resulting amine with a protecting group P' such as t-butyloxycarbonyl affords compound 2.3.
• Thiophene 2.3 can be treated with a halogenating agent such as N-bromosuccinimide (NBS) to form bromide 2.4.
• NBS N-bromosuccinimide
• the L'-HET-Y group 1.2 described in Scheme 1 can be prepared by conventional procedures well known in the art.
• Scheme 3 illustrates one generic method for preparing suitable HET-Y groups for use in such convergent synthesis.
• Scheme 3 employs a bromo and hydroxyl substituted aryl or heteroaryl compound 3.1, which is optionally further substituted with one or more X groups (not shown). If necessary, the hydroxyl group can be protected by conventional protecting groups, Pg, which are well known in the art.
• Compound 3.3 is formed by reacting 3.1 under conventional Suzuki conditions with the boronic acid 3.2, which can be prepared in the manner described in Scheme 1 above from the corresponding Y-Br compound. When Pg is not hydrogen, the protecting group can be removed by conventional procedures. The resulting hydroxyl group of compound 3.3 can next be converted under conventional conditions to compound 1.2 for use in the coupling step of Scheme 1.
• 4.2 can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and/or isolation.
• Suitable examples of compound 4.1 include commercially available variants such as 2-nitro-3-methylaniline, 4-methyl-3-nitroaniline (both commercially available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA) as well as 3 -methyl -4-nitroaniline (commercially available from Lancaster Synthesis Inc.).
• Compound 4.2 is next converted to (E)-2-(bromo-2-nitrophenyl)vinyl dimethylamine, compound 4.4, by reaction with an excess of N,N-dimethylformamide dimethylacetal, compound 4.3.
• the reaction is typically conducted in a suitable solvent such as DMF under an inert atmosphere.
• the reaction is conducted at an elevated temperature of from about 100 0 C to about 160 0 C.
• the reaction is continued until it is substantially complete which typically occurs within about 1 to 6 hours.
• the resulting product can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and/or isolation.
• This reaction is typically conducted in an inert diluent such as an aqueous mixture of tetrahydrofuran, dioxane, and the like.
• the reaction is conducted at an ambient conditions and is continued until it is substantially complete which typically occurs within about 0.5 to 6 hours.
• bromo 2-nitrobenzaldehyde compound 4.5
• conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and/or isolation.
• Conventional reduction of compound 4.5 provides for the corresponding bromo 2- aminobenzaldehyde, compound 4.10.
• bromo-5-methoxybenzoyl chloride is converted to the corresponding bromo-3-acetyl-methoxybenzene, compound 4.8, by reaction with dimethyl zinc.
• the reaction is typically conducted in a suitable inert diluent such as benzene, toluene, xylene and the like.
• the dimethyl zinc is present in the solvent prior to addition of compound 4.7 as dimethyl zinc is pyroforic.
• the reaction is initially conducted at a temperature of from about -10 to about 10 0 C and then allowed to slowly proceed to room temperature. The reaction is continued until it is substantially complete which typically occurs within about 0.2 to 2 hours.
• bromo-3-acetyl-methoxy-benzene (compound 4.8) can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and/or isolation.
• bromo-5-methoxybenzoyl chloride compound 4.7
• bromo-5-methoxybenzoyl chloride compound 4.7
• the acid halide can be prepared by contacting the carboxylic acid with an inorganic acid halide, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, or preferably, with oxalyl chloride under conventional conditions.
• this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at temperature in the range of about 0 0 C to about 80 0 C for about 1 to about 48 hours.
• a catalyst such as DMF, may also be used in this reaction.
• Commercially available chlorophenyl boronic acid, compound 4.9 is coupled with compound 4.8 via conventional Suzuki conditions to provide for chlorophenyl substituted 3- acetyl methoxybenzene, compound 4.6. 2-, 3- And 4-chlorophenyl boronic acids are commercially available from Aldrich Chemical Company, supra.
• Compound 4.6 is then coupled with compound 4.10 under condensation conditions to provide for 2-biaryl-6-bromoquinoline, compound 4.11.
• This reaction is preferably conducted by combining approximately stoichiometric amounts of both compounds 4.6 and 4.10 in a suitable inert diluent such as ethanol, isopropanol and the like in the presence of a suitable base such as potassium hydroxide under an inert atmosphere.
• a suitable inert diluent such as ethanol, isopropanol and the like
• a suitable base such as potassium hydroxide under an inert atmosphere.
• the reaction is conducted at a temperature of from about 70 0 C to about 100 0 C and proceeds until it is substantially complete which typically occurs within about 2 to 16 hours.
• the resulting product, compound 4.11 can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or, alternatively, used in the next step without purification and/or isolation.
• Scheme 5 shows one such method where for illustrative puroposes Z is COOH, D is CH, E is S, Q is cyclohexyl, and the R a , and HET-Y groups are as depicted in compound 5.14.
• Compound 5.1 is condensed with the commercially available (Aldrich) 5.2 using the Friedlander conditions to form quinoline 5.3. An example of such conditions is given in Example 2 below.
• Compound 5.3 can be converted to the corresponding alcohol 5.4 using known methods such as with lithium aluminum hydride followed by re -oxidation to aldehyde 5.5 using Dess-Martin reagent.
• thiophene 5.6 is converted to 5.7 by treatment with nitric acid / sulfuric acid.
• Compounds 5.7 and 5.5 are then refluxed together in MeOH in the presence of catalytic amount of pyrrolidine to form the nitro-olefm 5.8.
• Compound 5.8 is next refluxed with triethyl phosphite to afford thieno-pyrrole derivative 5.9.
• the cyclohexyl ring is introduced as in Scheme 2 by heating 5.9 with cyclohexanone in the precense of acetic acid, acetic anhydride, and phosphoric acid to give 5.10.
• Reduction of compound 5.10 with triethylsilane gives 5.11.
• the acetamido moiety is introduced by reacting 5.11 with the commercially available 5.12 in DMF using standard alkylating conditions to form 5.13 which is saponified with aqueous LiOH to give the desired product 5.14.
• compounds of Formula (I) are synthesized as shown in Scheme 6 where for illustrative purposes D is S, E is CH, Z is COOP, Q is cyclohexyl, P is a hydroxy protecting group such as alkyl, P' is a nitrogen protecting group, L' is a leaving group such as halogen, and HET and Y are previously defined.
• Compound 6.1 is reacted with methyl cyanoacetate in the presence of a base such as diisopropylethyl amine to form alkylated product 6.2.
• Scheme 7 illustrates the synthesis of intermediate 7.8 formed from coupling nitro compound 7.3 with aldehyde 7.6.
• Nitration of thiophene 7.1 under suitable nitration conditions such as by addition to a solution of acetic anhydride and nitric acid forms acid 7.2 that is then esterified to give intermediate ester 7.3.
• Coupling partner 7.6 is prepared starting from 2-chloro-6-methylquinoline 7.4 that is halogenated upon treatment with a suitable halogenating reagent such as NBS (N-bromosuccinimide) to give a mixture of mono and dibromides 7.5. The mixture is then refluxed in an aqueous solvent such as 50% aq.
• NBS N-bromosuccinimide
• Scheme 8 illustrates the use of intermediate 7.8 to prepare compounds 8.2-8.6 following the methods described in Scheme 5.
• Scheme 8 illustrates the preparation of compounds such as 9.3 following the methods described in the Schemes above.
• An example of the synthesis of compound 9.3 wherein R' and R" together form a cyclic group is given in Examples 9 and 10.
• the present invention provides novel compounds possessing antiviral activity, including Flaviviridae family viruses such as hepatitis C virus.
• Flaviviridae family viruses such as hepatitis C virus.
• the compounds of this invention inhibit viral replication by inhibiting the enzymes involved in replication, including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of Flaviviridae viruses.
• the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
• the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
• the drug can be administered more than once a day, preferably once or twice a day.
• Therapeutically effective amounts of compounds of the present invention may range from approximately 0.01 to 50 mg per kilogram body weight of the recipient per day; preferably about 0.01-25 mg/kg/day, more preferably from about 0.1 to 10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 7-70 mg per day.
• compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• parenteral e.g., intramuscular, intravenous or subcutaneous
• the preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.
• Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
• Another preferred manner for administering compounds of this invention is inhalation.
• the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
• the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
• suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI).
• MDI metered dose inhalers
• DPI dry powder inhalers
• Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
• MDFs typically are formulation packaged with a compressed gas.
• the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
• DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
• the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
• a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
• compositions are comprised of in general, a compound of the present invention in combination with at least one pharmaceutically acceptable excipient.
• Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
• excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
• Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
• Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
• Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
• Compressed gases may be used to disperse a compound of this invention in aerosol form.
• Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
• Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
• the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
• the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of a compound of the present invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
• the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described in the Formulation Examples section below.
• the present invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of another active agent against RNA- dependent RNA virus and, in particular, against HCV.
• Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of HCV NS3 serine protease, or an inhibitor of inosine monophosphate dehydrognease, interferon- ⁇ , pegylated interferon- ⁇ (peginterferon- ⁇ ), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
• Interferon- ⁇ includes, but is not limited to, recombinant interferon- ⁇ 2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), interferon- ⁇ 2b (such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA), a consensus interferon, and a purified interferon- ⁇ product.
• interferon- ⁇ 2a such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ
• interferon- ⁇ 2b such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA
• a consensus interferon such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA
• the agents active against hepatitis C virus also include agents that inhibit HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and inosine 5 '-monophosphate dehydrogenase.
• Other agents include nucleoside analogs for the treatment of an HCV infection.
• Still other compounds include those disclosed in WO 2004/014313 and WO 2004/014852 and in the references cited therein.
• the patent applications WO 2004/014313 and WO 2004/014852 are hereby incorporated by references in their entirety.
• Specific antiviral agents include Omega IFN (BioMedicines Inc.), BILN-2061
• compositions and methods of the present invention contain a compound of the invention and interferon.
• the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
• compositions and methods of the present invention contain a compound of the invention and a compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
• a compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
• the compound having anti-HCV activity is Ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, or pegylated interferon-alpha alone or in combination with Ribavirin or viramidine.
• the compound having anti-HCV activity is said agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with Ribavirin or viramidine.
• DMEM Dulbeco's Modified Eagle's Medium
• EDTA ethylenediaminetetraacetic acid
• HCV hepatitus C virus
• IPTG isopropyl- ⁇ -D-thiogalactopyranoside
• NTA nitrilotriacetic acid
• NTP nucleoside triphosphate
• Tris Tris(hydroxymenthyl)aminomethane
• reaction mixture was evaporated to dryness; the residue was dissolved in a mixture of 500 mL water and 750 mL ethyl acetate.
• the organic phase was separated, washed with water (2x), saturated NaCl (2x) and was dried (Na 2 SO 4 ). It was then evaporated to dryness to give the crude product as a yellow solid which was purified by filtering through 400 mL silica gel pad using toluene elution;
• Example 2 Example 2
• 4-Amino-3-fluoro-5-iodo-boronic acid 4-Amino-3-fluoro-boronic acid is treated with N-iodosuccinimide in acetic acid. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate), and concentrated to give 4-amino-3-fluoro-5-iodo-boronic acid.
• Step 3 4-Amino-3-fluoro-5-fromyl-boronic acid 4-Amino-3-fluoro-5-iodo-boronic acid is dissolved in THF while CO is bubbled through the reaction vessel. Tetrakis(triphenylphosphino)palladium is added and the reaction heated to 50 0 C. Tributyltin hydride is added. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (sodium sulfate), concentrated, and purified to give 4-amino-3-fluoro-5-formyl-boronic acid . Step 4. 2-(2,4-Dimethyl-thiazol-5-yl)-8-fluoro-quinoline-6-boronic acid
• Step 1 5-Methyl-4-nitro-thiophene-2-carboxylic acid (7.2) Acetic anhydride (17 mL, 176 mmol, 5 equiv ) was cooled to -78 0 C in a dry ice/acetone bath and slowly was added fuming nitric acid ( 6 mL, 113 mmol, 3.2 equiv), and the mixture was warmed to -20 0 C.
• 5-Methyl-thiophene-2-carboxylic acid 7.1 (5 g, 35.2 mmol, 1 equiv) was slowly added in small portions (RAPID EXHOTHERM). The temperature fluctuated between -20 0 C and +10 0 C then stabilized to -20 0 C.
• a microwave reaction vessel was charged with 387 mg (1.13 mmol) compound 7.8 (Example 4), 237 mg (1.69 mmol, 1.5 eq) 2-fluorophenyl boronic acid and 65 mg (0.057 mmol, 0.05 eq) Pd(PPtLs) 4 .
• 12 niL dioxane and 4 niL IM aqueous KsPO 4 was added to this.
• the reaction vessel was sealed, and subsequently degassed and purged with Ar (2x).
• the reaction mixture was then heated by microwave to 120 0 C for 10 min.
• ⁇ PLC analysis confirmed complete consumption of compound 7.8.
• the reaction mixture was allowed to cool to room temperature, during which time a precipitate formed.
• a microwave reaction vessel was charged with 245 mg (0.61 mmol) compound 8.2a, 947 ⁇ L (9.15 mmol, 15 eq) cyclohexanone, 500 ⁇ L acetic anhydride, 500 ⁇ L 85% HsPO 4 and 4 niL acetic acid.
• the reaction vessel was sealed and heated by microwave to 180 0 C for 75 min. HPLC analysis confirmed complete consumption of compound 8.2a.
• the reaction mixture was poured into 50 niL NH 4 OH (cone, aq.) at 0 0 C.
• the aqueous mixture was further diluted with H 2 O and extracted with ethyl acetate (3x).
• reaction vessel was charged with 75 mg (0.16 mmol) compound 8.3a and dissolved with 8 rnL DMF. 11 mg (0.31 mmol, 2 eq) NaH (67% in mineral oil) was then added and the reaction mixture was allowed to stir at room temperature. After 15 min 36 ⁇ L (0.31 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone was added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. After 3 h, HPLC and LC-MS analysis confirmed complete consumption of compound 8.3a. The reaction mixture was quenched by adding 0.1 mL H 2 O, poured into a 50 mL flask and concentrated.
• a microwave reaction vessel was charged with 500 mg (1.46 mmol) compound 7.8 (Example 4), 436 mg (1.82 mmol, 1.25 eq) 2,4-dimethyl-thiazole-5-boronic acid pinacol ester and 84 mg (0.073 mmol, 0.05 eq) Pd(PPh 3 ) 4 .
• the reaction vessel was sealed, and subsequently degassed and purged with Ar (2x).
• the reaction mixture was then heated by microwave to 120 0 C for 10 min. HPLC analysis confirmed complete consumption of compound 7.8.
• the reaction mixture was allowed to cool to room temperature, during which time a precipitate formed.
• reaction vessel was charged with 56 mg (0.11 mmol) compound 8.3b and dissolved with 4 mL DMF. 9 mg (0.22 mmol, 2 eq) NaH (60% in mineral oil) was then added and the reaction mixture was allowed to stir at room temperature. After 15 min 26 ⁇ L (0.22 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone was added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. After 6 h, HPLC and LC-MS analysis confirmed complete consumption of compound 8.3b. The reaction mixture was quenched by adding 0.1 mL H 2 O, poured into a 50 mL flask and concentrated.
• a microwave reaction vessel was charged with 235 mg (0.49 mmol) compound 8.3a (Example 5, Step 2), 116 ⁇ L (0.73 mmol, 1.5 eq) triethylsilane and 5 mL TFA.
• the reaction vessel was sealed and heated by microwave to 70 0 C for 5 min.
• LC-MS analysis confirmed complete consumption of compound 8.3a.
• the reaction mixture was poured into a 50 mL and concentrated to afford 6-cyclohexyl-5-[2-(2-fluoro-phenyl)-quinolin-6-yl]-4H- thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester 8.4a as a red powder.
• the crude residue was dried on vacuum and used without further purification.
• reaction vessel was charged with 307 mg (0.63 mmol) compound 8.4a and dissolved with 20 mL DMF. 50 mg (1.26 mmol, 2 eq) NaH (60% in mineral oil) was then added and the reaction mixture was allowed to stir at room temperature. After 15 min 146 ⁇ L (1.26 mmol, 2 eq) of 2-chloro-l-morpholin-4-yl-ethanone was added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. After 75 min, HPLC and LC-MS analysis confirmed complete consumption of compound 8.4a. The reaction mixture was quenched by adding 0.5 mL H 2 O, poured into a 50 mL flask and concentrated.
• the methyl ester was then transferred to a reaction vial and dissolved with 6 mL THF, 2 mL MeOH and 2 mL LiOH (IM, aq.). The reaction mixture was then heated to 50 0 C and carefully monitored by HPLC and LC-MS analysis. Upon complete conversion, the reaction mixture was neutralized with 1 mL HCl (2M, aq.) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA.
• reaction vessel was charged with 191 mg (0.38 mmol) compound 8.4b (Example 8, Step 1) and dissolved with 15 mL DMF. 30 mg (0.76 mmol, 2 eq) NaH (60% in mineral oil) was then added and the reaction mixture was allowed to stir at room temperature. After 15 min 112 ⁇ L (0.76 mmol, 2 eq) of 2-tert-butylbromoacetate was added in 1 portion and the reaction mixture was allowed to continue stirring at room temperature. The reaction was monitored by HPLC and LC-MS analysis. Upon complete conversion of compound 8.4b, the reaction mixture was quenched by adding 0.5 rnL H 2 O, poured into a 50 rnL flask and concentrated.
• reaction vessel was charged with 107 mg (0.19 mmol) compound 9.2 and dissolved with 3 mL DMF. 86 mg (0.23 mmol, 1.2 eq) ⁇ BTU and 73 ⁇ L (0.42 mmol, 2.2 eq) DIEA was then added and the reaction mixture was allowed to stir at room temperature. After 15 min 24 ⁇ L (0.24 mmol, 1.25 eq) of thiomorpholine was added in 1 portion and the reaction mixture was allowed to continue stirring at 35 0 C. After ⁇ PLC and LC-MS analysis confirmed complete consumption of compound 9.2, the reaction mixture was concentration by speed-vacuum. Cold H 2 O was then added to the crude residue to precipitate the methyl ester.
• the solids were collected by centrifuge and washed once more with H 2 O.
• the methyl ester was then transferred to a reaction vial and dissolved with 3 mL THF, 1 mL MeOH and 1 mL LiOH (IM, aq.).
• the reaction mixture was then heated to 50 0 C and carefully monitored by HPLC and LC-MS analysis. Upon complete conversion, the reaction mixture was neutralized with 0.5 mL HCl (2M, aq.) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA.
• reaction vessel was charged with 107 mg (0.19 mmol) compound 9.2 (Example 9, Step 2) and dissolved with 3 mL DMF. 86 mg (0.23 mmol, 1.2 eq) ⁇ BTU and 73 ⁇ L (0.42 mmol, 2.2 eq) DIEA was then added and the reaction mixture was allowed to stir at room temperature. After 15 min 24 ⁇ L (0.24 mmol, 1.25 eq) of piperidine was added in 1 portion and the reaction mixture was allowed to continue stirring at 35 0 C. After ⁇ PLC and LC- MS analysis confirmed complete consumption of compound 9.2, the reaction mixture was concentration by speed-vacuum. Cold H 2 O was then added to the crude residue to precipitate the methyl ester.
• the solids were collected by centrifuge and washed once more with H 2 O.
• the methyl ester was then transferred to a reaction vial and dissolved with 3 mL THF, 1 mL MeOH and 1 mL LiOH (IM, aq.).
• the reaction mixture was then heated to 50 0 C and carefully monitored by HPLC and LC-MS analysis. Upon complete conversion, the reaction mixture was neutralized with 0.5 mL HCl (2M, aq.) and concentrated. The crude residue was then dissolved with DMF and acidified with TFA.
• Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes needed in the replication cycle, or by other pathways.
• a number of assays have been published to assess these activities.
• a general method that assesses the gross increase of HCV virus in culture was disclosed in U.S. Patent No. 5,738,985 to Miles et al
• In vitro assays have been reported in Ferrari et al. JnI ofVir., 73:1649-1654, 1999; Ishii et al, Hepatology, 29:1227-1235, 1999; Lohmann et al, JnI of Bio. Chem., 274:10807- 10815, 1999; and Yamashita et al, JnI of Bio. Chem., 273:15479-15486, 1998.
• WO 97/12033 filed on September 27, 1996, by Emory University, listing C.
• Hagedorn and A. Reinoldus as inventors which claims priority to United States Provisional Patent Application. Serial No. 60/004,383, filed on September 1995, described an HCV polymerase assay that can be used to evaluate the activity of the of the compounds described herein.
• Another HCV polymerase assay has been reported by Bartholomeusz, et al, Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996:l(Supp 4) 18-24.
• a cell line, ET (Huh-lucubineo-ET) was used for screening of compounds for inhibiting HCV RNA dependent RNA polymerase.
• the ET cell line was stably transfected with RNA transcripts harboring a l 38 c>luc-ubi-neo/NS3-37ET; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I; Kl 846T) (Krieger at al, 2001 and unpublished).
• the ET cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM Glutamine, Penicillin (100
• Luciferase activity was measured 48-72 hours later by adding a lysis buffer and the substrate (Catalog number Glo-lysis buffer E2661 and Bright-Glo luciferase system E2620 Promega, Madison, WI). Cells should not be too confluent during the assay. Percent inhibition of replication data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds were determined using cell proliferation reagent, WST-I (Roche, Germany). The compounds showing antiviral activities, but no significant cytotoxicities were chosen to determine EC 50 and TC 50 , the effective concentration and toxic concentration at which 50% of the maximum inhibition is observed. For these determinations, a 10 point, 2-fold serial dilution for each compound was used, which spans a concentration range of 1000 fold. EC 50 and similarly the TC 50 values were calculated by fitting %inhibition at each concentration to the following equation:
• % inhibition 100%/[(EC 50 /[I]) b + 1] where b is Hill's coefficient.
• the compounds of Formula (I) will have an EC 50 of equal to or less than 50 ⁇ M when tested according to the assay of Example 2. In other aspects the EC50 is equal to or less than 10 ⁇ M. In still other aspects the EC50 is equal to or less than 5 ⁇ M.
• NS5b protein was cloned by PCR from pFKl38c>luc/NS3- 3'/ET as described by Lohmann, V., et al. (1999) Science 285, 110-113 using the primers shown on page 266 of WO 2005/012288.
• the cloned fragment is missing the C terminus 21 amino acid residues.
• the cloned fragment was inserted into an IPTG-inducible expression plasmid that provides an epitope tag (His)6 at the carboxy terminus of the protein.
• the recombinant enzyme was expressed in XL-I cells and after induction of expression, the protein was purified using affinity chromatography on a nickel-NTA column. Storage condition is 10 mM Tris-HCl pH 7.5, 50 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 20% glycerol at -20 0 C.
• the assay mixture (50 ⁇ L) contains 10 mM Tris- HCl (pH 7.5), 5 mM MgCl 2 , 0.2 mM EDTA, 10 mM KCl, 1 unit/ ⁇ L RNAsin, 1 mM DTT, 10 ⁇ M each of NTP, including [ H]-UTP, and 10 ng/ ⁇ L heteropolymeric template.
• Test compounds were initially dissolved in 100% DMSO and further diluted in aqueous buffer containing 5% DMSO. Typically, compounds were tested at concentrations between 1 nM and 100 ⁇ M.
• Reactions were started with addition of enzyme and allowed to continue at 37 0 C for 2 hours. Reactions were quenched with 8 ⁇ L of 100 mM EDTA and reaction mixtures (30 ⁇ L) were transferred to streptavidin-coated scintillation proximity micro titer plates (FlashPlates) and incubated at 4 0 C overnight. Incorporation of radioactivity was determined by scintillation counting.
• the following ingredients are mixed to form a suspension for oral administration.
• Veegum K (Vanderbilt Co .) LO g flavoring 0.035 mL colorings 0.5 mg distilled water q.s. to 100 mL
• a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

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