WO2006093518A2 - Thienyl compounds for treating virus-related conditions - Google Patents

Thienyl compounds for treating virus-related conditions Download PDF

Info

Publication number
WO2006093518A2
WO2006093518A2 PCT/US2005/022559 US2005022559W WO2006093518A2 WO 2006093518 A2 WO2006093518 A2 WO 2006093518A2 US 2005022559 W US2005022559 W US 2005022559W WO 2006093518 A2 WO2006093518 A2 WO 2006093518A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
heterocyclyl
substituted
oxo
alkyl
Prior art date
Application number
PCT/US2005/022559
Other languages
French (fr)
Other versions
WO2006093518A3 (en
Inventor
Paul D. Olivo
Benjamin A. Buscher
Julie Dyall
Jennifer I. Jockel-Balsarotti
Andrew K. O'guin
Robert M. Roth
Gary W. Franklin
Gale W. Starkey
Original Assignee
Apath, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Apath, Llc filed Critical Apath, Llc
Publication of WO2006093518A2 publication Critical patent/WO2006093518A2/en
Publication of WO2006093518A3 publication Critical patent/WO2006093518A3/en

Links

Classifications

    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention is directed generally to thienyl compounds (including salts thereof), and their use as anti-viral agents. More particularly, this invention is directed to (thien-2-yl)amino compounds, pharmaceutical compositions and kits comprising such compounds, and uses of such compounds for preparing medicaments and treating virus-related conditions in animals.
  • RNA viruses The majority of human viral pathogens are RNA viruses.
  • the FDA has approved only two small-molecule antiviral drags for use against RNA viruses, and only one, ribavirin, exhibits broad-spectrum activity. Consequently, for many RNA viruses, there are only limited, if any, therapeutic options available.
  • HCV Hepatitis C virus
  • HCV 3 is an RNA virus that causes chronic hepatitis afflicting an estimated 170 million individuals worldwide, including approximately 4 million in the United States. The level of sickness and mortality associated with HCV is high. The majority of infected patients remain infected for life, and a significant percentage of HCV-infected patients ultimately progress to cirrhosis, liver failure, or hepatocellular carcinoma. No vaccine has been reported for HCV. It is believed that the best available treatment for HCV is a combination of two broad- spectrum antiviral agents, interferon and ribavirin. This therapy, however, is only effective for about half of all patients, and is associated with serious side effects that cause another 10-15% of otherwise suitable patients to discontinue therapy.
  • RSV Respiratory syncytial virus
  • This virus is contracted by virtually all children by the age of three. It spreads rapidly through contact with respiratory secretions, and is the primary cause of bronchopneumonia in infants and children in the United States. It is estimated that RSV infections result in 100,000 hospitalizations and 4,000 deaths each year in the United States alone. Premature infants, immunodeficient patients, and the institutionalized elderly are at the greatest risk for sickness and mortality from RSV. Current treatments for RSV are limited and suboptimal.
  • inhaled ribavirin is difficult to administer and relatively toxic, and, as a result, infrequently used.
  • a prophylactically-administrated monoclonal antibody (Synagis, Medlmmune) also is available, but used only with high- risk patients.
  • Primary screening programs to identify compounds with antiviral activity involve two general methods - “targeted” screening and “unbiased” screening.
  • Targeted a particular biochemical target is chosen, and then inhibitors of the chosen target are screened.
  • the chosen target is typically an enzyme or a receptor that is known or thought to be essential to viral replication.
  • "unbiased" screening inhibitors of viral replication are sought without a priori concern for the target.
  • Unbiased screening necessarily involves the use of cell culture for virus replication. This is due, in part, to the fact that cellular targets are likely targets of many anti-viral agents. Although cell-based screening has been used successfully throughout the drug-discovery field, it has historically been problematic when screening for antiviral compounds because it required inoculation of an infectious virus onto the cells, and then producing additional infectious progeny virus. Handling such infectious material is not easily compatible with the high throughput process of screening large libraries of compounds.
  • Partial viral replication systems have been developed to circumvent the problems associated with cell-based cultures using whole viral systems.
  • viral genomes lacking one or more genetic elements essential for complete replication are used to accomplish viral genomic replication without producing the infectious virus. This is particularly important for viral agents, such as viral hemorrhagic fever, classified as biohazard level 3 or 4 (BL-3 or BL-4).
  • a screening process that utilizes these incomplete viral genomes can identify inhibitors of any biochemical pathway involved in viral genome replication, transcription, and translation. This allows for screening with respect to multiple possible targets. These targets do not have to be known, thus making the screening process unbiased.
  • the targets are pre- validated, given that inhibition of RNA replication is directly relevant to the viral disease process. Screening with partial viral replication systems additionally is advantageous because complex viral replication pathways can be easily monitored by measuring levels of viral RNA or expression of a reporter gene present in the replicon or defective genome.
  • the utility of using partial viral replication systems can be expanded further by screening for multiple viruses simultaneously. More specifically, by combining cell lines, each of which contain a partially replicating viral genome, one can screen for antiviral activity against each virus during the same screen, thereby saving time, reducing costs, and allowing for more effective use of material libraries. And, in addition to measuring the effect of a compound on genomic replication of several viruses, use of a partial viral replication system can provide information on the specificity of the antiviral effect. This information is helpful in accessing, for example, whether the effect is acting on a specific viral target or on a cellular target, and, thus, exerting its effect on the virus indirectly.
  • defects There are generally two types of partial viral replication systems: defective genomes and replicons.
  • Defective genomes (which often are artificial genomes or minigenomes) typically contain all the cw-acting elements required for viral genomic replication and transcription, but lack one or more of the genetic elements that encode the trans-acting factors required for replication. Such defective genomes, therefore, cannot replicate by themselves, but can replicate if the missing factor (or factors) is supplied in trans.
  • cell cultures containing replicating defective viral genomes represent a useful tool for antiviral drug discovery. For example, they may be used to observe the effect of an antiviral agent in the context of living cells, and therefore allow for the selection of agents that can enter and act within living cells. Such cell lines also may be used to immediately identify antiviral agents with undesirable cytotoxicity using well- established cytotoxicity assays. In addition, such cell lines permit cell-based drug discovery screens to be performed on a broad array of viruses, including, for example, viruses (e.g., HCV and Human Papillomavirus (HPV)) that are difficult to culture or cannot be cultured by conventional means.
  • viruses e.g., HCV and Human Papillomavirus (HPV)
  • cell lines are much safer and thus easier to work with than cell lines that make infectious virus.
  • reporter genes e.g., luciferase, beta-galactosidase, secreted alkaline phosphatase, green fluorescent protein, etc.
  • reporter genes e.g., luciferase, beta-galactosidase, secreted alkaline phosphatase, green fluorescent protein, etc.
  • Replicons are subgenomic nucleic acid molecules that are capable of replicating within cells cultured in vitro, In contrast to defective genomes, replicons typically encode all the cis and trans-acting viral components required for replication and transcription of the viral genome within a cell. Replicons, however, lack one or more elements required to replicate a full virus. For example, replicons often lack sequences related to infectivity. Such replicons are safer and easier to work with than a corresponding infectious virus, and are often ideal for studying treatments directed to viral replication because viral functions related to infectivity typically are not required for replication. Recently, several replicons capable of persistent replication in cells have been reported.
  • VRC viral replicon culture
  • Partial viral replication systems are valuable molecular tools that can be used for a variety of purposes. In general, they can be used as tools to promote basic investigations of viral replication and pathogenesis. Specific uses include, for example: identification and evaluation of antiviral agents (e.g.
  • RNAi small molecules
  • diagnostic assays and reagents development and evaluation of diagnostic assays and reagents
  • development and evaluation of vaccines development of vectors (e.g., gene delivery, protein expression, vaccines, etc.), evaluation of the function of viral genes and proteins, localization of viral proteins, characterization of cellular antiviral pathways (e.g., IFN, PKR, RNAi, etc.), characterization of viral RNA replication (within cells and cell-free systems), identification of cis-acting elements, and identification of host proteins required for viral replication.
  • vectors e.g., gene delivery, protein expression, vaccines, etc.
  • evaluation of the function of viral genes and proteins localization of viral proteins
  • characterization of cellular antiviral pathways e.g., IFN, PKR, RNAi, etc.
  • characterization of viral RNA replication within cells and cell-free systems
  • identification of cis-acting elements identification of host proteins required for viral replication.
  • Screening with partial viral replication systems can be applied to any type of viral pathogen, including viruses with RNA or DNA genomes. Examples include those shown in Table 1 :
  • VHF viral hemorrhagic fever
  • Filoviridae Filoviridae
  • Arenaviridae and Bunyaviridae
  • Many of these viruses cause severe, life-threatening diseases that are easily transmitted from person to person, and are listed by the CDC and NIH as category A pathogens.
  • Category B and C viral pathogens include members of the Togaviridae (VEE, etc.), Flaviviridae (YFV, WNV, etc.) said Bunyaviridae families.
  • RNA viruses There have been significant advances in the development of reverse genetic systems for RNA viruses. Generally, all viruses possess genes that encode for RNA-dependent RNA polymerase to produce mRNA and thereby replicate the virus' genome. Upon infection of cells, the genomic RNA of positive strand RNA viruses replicates through the use of a complementary negative strand intermediate in a three phase mechanism. In the first phase, translated viral proteins and one or more host proteins form a replicase complex that attaches to the 3' of the positive-strand viral RNA. In the second phase, the viral RNA is copied to a complementary, negative- strand RNA. In the final phase, the negative RNA serves as a template for synthesis of progeny positive-strand viral RNA. Notably, positive-strand RNA viruses make structural proteins soon after entering the host cell cytoplasm because the viral genome acts as mRNA.
  • Positive-strand RNA viruses include, for example, members of the Togaviridae, Flaviviridae ⁇ e.g., HCV, WNV, and YFV), and Picornaviridae. These viruses were among the first RNA viruses for which reverse genetics studies were performed. See, e.g., Khromykh, "Replicon-based vectors of positive strand RNA viruses," C ⁇ rr. Opin. MoI. Ther. 2:555-69 (2000). See also, Khromykh et al., “Subgenomic replicons of the flavivirus Kunjin: construction and applications," J. Virol. 71:1497-505 (1997). See also, Racaniello, V.
  • Replicons also have been constructed for the closely related Kunjin flavivirus. See, e.g., Khromykh et al., J. Virol. 71 : 1497-505 (1997).
  • a West Nile virus (WNV) replicon modeled on Kunjin and HCV based on the New York 2000 strain of WNV (3000.0259), also has been constructed. See, e.g., Shi et al., "Construction and characterization of subgenomic replicons of New York strain of West Nile virus," Virology 296:219-33 (2002) (57, 67). See also, Yamshchikov et al., "An infectious clone of the West Nile Flavivirus," Virology 281 :294-304 (2001).
  • HCV The HCV genome, in particular, has been analyzed extensively. See, e.g., Blight et al., "Molecular virology of hepatitis C virus: an update with respect to potential antiviral targets," Antiviral Ther. 3:71-81 (1998). HCV has been classified as a member of the family Flaviviridae, which includes flaviviruses (e.g., yellow fever virus) and pestiviruses (e.g., bovine viral diarrhea virus). A major impediment to understanding HCV virology has been the lack of a reliable and robust cell culture replication system. A second problem is that the only animal model with which to study HCV pathogenesis is the chimpanzee.
  • flaviviruses e.g., yellow fever virus
  • pestiviruses e.g., bovine viral diarrhea virus
  • RNA viruses There are generally six families of negative-stranded RNA viruses that have human pathogenic members. Three are non-segmented (Paramyxoviridae ⁇ e.g., RSV), Rhabdomyxoviridae, and Filoviridae), and three are segmented (Orthomyxoviridae, Bunyaviridae, and Ar enaviridae).
  • the RNA of negative-strand RNA viruses must first be copied into positive-strand mRNA before translation and viral replication can occur.
  • negative-strand RNA is transcribed in the host-cell to produce a positive-strand mRNA.
  • the mRNA creates viral proteins including RNA-dependent RNA polymerase.
  • new progeny negative-strand RNA are created.
  • this invention is directed, in part, to a method for treating a viral infection in an animal.
  • the method comprises administering a therapeutically effective amount of a thienyl compound or a pharmaceutically acceptable salt thereof to the animal.
  • the thienyl compound corresponds in structure to formula (I):
  • each substituent R a , R b , R c , R d , and R e is either an independent substituent or forms part of a ring structure. More specifically:
  • R a is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, or -S(R g ). Any such substituent optionally is substituted.
  • R b is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, alkylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkyl, heterocyclylthioalkyl
  • R c is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akyltliioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkyl, heterocyclylthi
  • any such substituent optionally is substituted.
  • RR aa aanndd RR bb ttooggeetthheerr wwiith the atoms to which they are bonded, form optionally-substituted heterocyclyl.
  • R b and R c together with the atoms to which they are bonded, form optionally-substituted heterocyclyl.
  • R d and R e are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylaUsoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclyl
  • R d and R e together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl.
  • Each R bl is independently hydrogen, hydroxy, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, or heterocyclylheterocyclylthioalkyl. Any such substituent optionally is substituted.
  • Each R g is independently hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaniinoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkylaminoalkylaminoalkyl, heterocyclylalkenylamino, or heterocyclylaminoalkyl. Any such substituent optionally is substituted.
  • Each pair of R A and R B form an independently-selected optionally-substituted heterocyclyl.
  • This invention also is directed, in part, to a pharmaceutical composition.
  • the composition comprises a therapeutically effective amount of an above-described thienyl compound or a pharmaceutically acceptable salt thereof.
  • This invention also is directed, in part, to use of an above-described thienyl compound or a pharmaceutically acceptable salt thereof to prepare a medicament (generally in the form of a pharmaceutical composition).
  • the medicament comprises a therapeutically effective amount of the thienyl compound or a pharmaceutically acceptable salt thereof.
  • This invention also is directed, in part, to a pharmaceutical kit.
  • the kit comprises a first dosage form comprising an above-desribed thienyl compound or pharmacetically acceptable salt thereof.
  • the kit also comprises a second dosage form of a second active ingredient.
  • the first dosage form and the second dosage form together comprise a therapeutically-effective amount of the agents for treating a targeted condition(s).
  • RNA virus activity such as HCV, RSV, WNV, and/or YFV activity
  • R a , R b , R c , R d , and R e are defined as follows:
  • R a , R b , and R c are either an independent substituent or forms part of a ring structure. More specifically:
  • R a is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, or -S(R 8 ).
  • each optional substituent is independently selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, oxo, thioxo, nitro, thiol, amino, imino, aminoalkyl, carbocyclyl, heterocyclyl, and heterocyclylalkyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, oxo, thioxo, amino, imino, thiol, and nitro.
  • R b is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyelylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclyl
  • R c is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkyl, heterocyclylthioalky
  • R° is methoxycarbonyl.
  • R c is ethoxycarbonyl.
  • R c is aminocarbonyl.
  • R a and R b together with the atom to which they are bonded, form optionally-substituted heterocyclyl as described above.
  • the heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, heterocyclyl, heterocyclylthio, and heterocyclylalkenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, nitro, thioxo, carbocyclyl, and oxo. Any member of such group is, in turn, optionally substituted with one or more independently selected alkoxy.
  • R b and R c together with the atoms to which they are bonded, form optionally-substituted heterocyclyl.
  • the heterocyclyl optionally is substituted with one or more independently selected R f substituents.
  • the heterocyclyl also optionally is substituted with two substituents such that the two substituents (together with the atom(s) to which they are bonded) form a carbocyclyl or heterocyclyl. This carbocyclyl or heterocyclyl is, in turn, optionally substituted with one or more independently selected R f substituents.
  • each R bl is independently hydrogen, hydroxy, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, or heterocyclylheterocyclylthioalkyl.
  • each optional substituent is independently hydrogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, or heterocyclylheterocyclylthioalkyl. Any member of such group is, in turn, optionally substituted by one or more substituents independently selected from the group
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, alkyl, alkenyl, alkoxy, amino, imino, cyano, nitro, nitroso, alkoxyalkyl, hydroxyalkyl, oxo, thiol, and thioxo. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, oxo, amino, alkyl, and alkoxy.
  • Each R f is independently either an independent substituent or forms a part of a ring structure.
  • R f is independently halogen, hydroxyl, amino, alkyl, hydroxyalkyl, alkylamino, aminoalkylamino, aminoalkyl, alkenyl, alkoxy, alkoxyalkyl, oxo, carbocyclyl, alkylcarbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylamino, heterocyclylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkenyl, heterocyclylthioalkyl, carbocyclylaminoalkenyl, heterocyclylaminoalkenyl, thioxo, hydrazinyl, hydrazinylalkyl, carbocyclylhydrazinyl, carbocyclylalkenylhydrazinyl, aminoalkenyl, alkenylamino, carb
  • Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, hydroxylalkyl, oxo, amino, imino, aminoalkyl, alkylamino, thioxo, thiol, nitro, cyano, alkoxyalkyl, carbocyclyl, alkoxycarbocyclyl, carbocyclylalkyl, carbocyclyloxy, heterocyclyl, and heterocyclylalkyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, imino, amino, oxo, thioxo, thiol, nitro, heterocyclyl, or hydroxyalkyl.
  • R f substituent forms part of a ring structure
  • the R f substituent is bonded to another R f substituent such that both R f substituents (together with the atom(s) to which they are bonded) form a carbocyclyl or heterocyclyl.
  • the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, amino, carbocyclyl, carbocyclylalkenyl, and heterocyclyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
  • Each R s is independently hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkenylamino, heterocyclylthioalkylammoalkylaminoalkyl, or heterocyclylaminoalkyl. Any member of such group optionally is substituted.
  • each optional substituent is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylaminoalkyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl, amino, aminosulfonyl, alkenyl, alkoxy, oxo, thiol, thioxo, cyano, nitro, aminoalkyl, alkoxyalkyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylthio, carbocyclylalkylthio, carbocylcyloxysulfonyl, heterocyclyl, heterocyclylalkyl, and heterocyclylthioalkyl.
  • substituents independently selected from the group consisting of halogen, hydroxy, alkyl, amino, aminosulfonyl, alkenyl, alkoxy, oxo, thiol, thioxo, cyano, nitro, aminoalkyl, alkoxyalkyl, hydroxyal
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, amino, imino, oxo, alkoxyalkyl, carbocyclyl, thioxo, nitro, cyano, and heterocyclyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, amino, and oxo. [55] Each pair of R ⁇ and R B form an independently selected optionally-substituted heterocyclyl. In some preferrred embodiments, each optional substituent is independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, thioxo, nitro, and cyano.
  • R d and R e either are independent substituents or together form a ring structure. More specifically:
  • R d and R e are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclyl
  • each optional substituent is independently selected from the group consisting of halogen, hydroxyl, cyano, thiol, nitro, nitroso, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, bisalkoxyalkyl, thioalky alkylthioalkyl, alkylthioalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclyloxyalkenyl, carbocyclylalkoxyalkyl, carbocycrylthioalkyl, carbocyclylthioalkenyl, carb
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, thiol, nitro, nitroso, oxo, thioxo, amino, and imino.
  • R d is hydrogen. [59] hi some preferred embodiments, R d is methyl.
  • R d is phenyl. [61] hi some preferred embodiments, R d is chlorophenyl. [62] In some preferred embodiments, R d is fluorophenyl. [63] hi some preferred embodiments, R d is methylphenyl. [64] hi some preferred embodiments, R is (dimethyl)phenyl.
  • R is methoxyphenyl.
  • R d is (dimethoxy)phenyl.
  • R d is nitrophenyl.
  • R is butylphenyl.
  • R is benzylphenyl.
  • R d is furanyl. [71] In some preferred embodiments, R d is methylfuranyl. [72] hi some preferred embodiments, R e is hydrogen. [73] hi some preferred embodiments, R e is methyl. [74] hi some preferred embodiments, R e is ethyl.
  • R e is methylcarbonyl. [76] hi some preferred embodiments, R e is ethylcarbonyl. [77] hi some preferred embodiments, R e is phenyl. [78] hi some preferred embodiments, R d and R e are each methyl. [79] hi other embodiments (i.e., when R d and R e are not independently selected substituents), R d and R e , together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl.
  • the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, thiol, nitro, nitroso, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, bisalkoxyalkyl, thioalky alkylthioalkyl, alkylthioalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclyloxyalkenyl, carbocyclylalkoxyalkyl, carbocyclylthioalkyl, carbocyclylthi
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, thiol, nitro, nitroso, oxo, thioxo, amino, and imino.
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl, cyclohexenyl, or cycloheptenyl.
  • substituents optionally are substituted with one or more (often preferably only one) substituents independently selected from the group consisting of methyl, methoxy, and methoxycarbonyl.
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl.
  • R d and R e together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl.
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl.
  • R d and R e together with the atoms to which they are bonded, form methylcyclohexenyl.
  • R d and R e together with the atoms to which they are bonded, form cycloheptenyl.
  • R a and R b together with the atom to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, heterocyclylmethylenyl, heterocyclylthio, and heterocyclylalkenyl.
  • Any such optional substituent is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, nitro, thioxo, carbocyclyl, and oxo. Any member of such group is, in turn, optionally substituted with one or more independently alkoxy.
  • R a and R b together with the atoms to which they are bonded, form pyrrolidinyl, dihydropyrrolyl, hexahydropyrroloisoxazole, pyrrolyl, or
  • any such substituent is optionally is substituted with one or more substituents selected from the group consisting of methyl, oxo, heterocyclylmethylenyl, heterocyclylthio, and phenyl. Any member of such group is, in turn, optionally substituted with chloro, nitro, oxo, thioxo, ethoxy, and phenyl. Any member of such group is, in turn, optionally substituted with one or more independently selected methoxy.
  • R c is ethoxycarbonyl or methylphenylaminocarbonyl.
  • R d and R e are each methyl.
  • R d and R e together with the atoms to which they are bonded, form cyclohexeneyl.
  • the compound corresponds in structure to Formula (I- A):
  • Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, oxo, heterocyclylthio, and heterocyclylthioalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, oxo, amino, methyl, ethyl, methoxy, and ethoxy.
  • R b is ⁇ [3,5- bis(ethoxycarbonyl)-4-methyl-2-thienyl]amino ⁇ (oxo)acetyl, chloroacetyl, 4-amino-4- oxobut-2-enoyl, [3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-l ,4-benzothiazin-2- yl] acetyl, (3-oxo-3,4-dihydro-2H-l ,4-benzothiazin-2-yl)acetyl, (diethylamino)acetyl, (2-phenylquinolin-4-yl)carbonyl, 3-azepan- 1 -ylpropanoyl, (4-ethylpiperazin- 1 - yl)acetyl, 4-[(carboxymethyl)thio]-3-nitrobenzoyl, 3-(2-furanyl
  • R e is hydrogen, halogen, carboxyl, alkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, heterocyclyl, heterocyclylalkyl, carbocyclyl, carbocyclylalkyl, or carbocyclylaminoalkyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, oxo, amino, hydroxyalkyl, aminoalkyl, and carbocyclyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, oxo, and amino.
  • R c is hydrogen, fluoro, bromo, chloro, methyl, ethyl, carboxyl, methoxymethyl, ethoxymethyl, aminomethyl, (piperidinyl)methyl, or phenylaminomethyl. Any such substituent optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, oxo, amino, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, aminopropyl, and phenyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, oxo, methoxy, and ethoxy.
  • R° is hydrogen, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, carboxyl, (3-diethylamino)propyl(aminocarbonyl), 4-methoxyphenyl(aminocarbonyl), piperidinylcarbonyl, 4-ethoxyphenyl(aminocarbonyl), 4-methylphenyl(aminocarbonyl), diethylaminocarbonyl, 2-aminoethyl(aminocarbonyl), 2-hydroxyethyl(aminocarbonyl), or 3-hydroxypropylaniinocarbonyl.
  • R c is methoxycarbonyl. [101] In some particularly preferred embodiments, R c is ethoxycarbonyl.
  • R c is aminocarbonyl.
  • R d and R e are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, oxo, amino, aminoalkyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
  • R d and R e are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, aminomethyl, hydroxymethyl, phenyl, phenylmethyl, and furanyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, oxo, methoxy, and ethoxy.
  • R d and R e are independently selected from the group consisting of hydrogen, phenyl, 4-chlorophenyl, methyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, (dimethylamino)methyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, benzyl, and 2-furanyl.
  • R d is hydrogen.
  • R d is methyl.
  • R is phenyl.
  • R e is hydrogen. [110] hi some preferred embodiments, R e is methyl. [Ill] hi some preferred embodiments, R e is methylcarbonyl. [112] In some preferred embodiments, R e is phenyl. [113] hi some preferred embodiments, R d and R e are each methyl.
  • R d and R e (together with the atoms to which they are bonded) form carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxycarbonyl, oxo, and amino.
  • R d and R e (together with the atoms to which they are bonded) form cyclopentenyl, cyclohexenyl, or cycloheptenyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, and oxo.
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl.
  • R d and R e together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl.
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl.
  • R d and R e together with the atoms to which they are bonded, form methylcyclohexenyl.
  • R d and R e together with the atoms to which they are bonded, form cycloheptenyl.
  • R bl is hydrogen, hydroxyl, methyl, ethyl, propyl, butyl, propenyl, butenyl, methoxy, ethoxy, propoxy, butoxy, amino, aminomethyl, (tetrahydrobenzothienyl)aminopentyl, thienyl, benzofuranyl, chromenyl, dihydrobenzodioxinyl, methoxymethyl, ethoxymethyl, phenyl, furanyl, hydrazinyl, phenylmethyl, phenylethyl, phenylamino, phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, phenylpropenyl, phenylethenyl, phenylmethylenyl, quinolinyl, isoxazolyl, isoxazolidinyl, benzothienyl, (tetrahydroquinoxal
  • any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of hydroxyl, chloro, fluoro, bromo, methyl, ethyl, methoxy, ethoxy, propyloxy, pentyloxy, propyl, butyl, allyl, propenyl, methoxymethyl, ethoxymethyl, hydroxyethyl, thienyl, oxo, thioxo, amino, aminomethyl, imino, nitro, cyano, thiol, phenyl, benzyl, phenylmethylenyl, phenylethenyl, aminosulfonyl, dihydroisoindolyl, tetrahydrobenzothienyl, azepanylsulfonyl, morpholinylsulfonyl, thienylmethylenyl, thienylethenyl, pyridinylmethylenyl
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, fluoro, chloro, bromo, methyl, ethyl, methoxy, phenyl, amino, imino, cyano, nitro, nitroso, methoxymethyl, ethoxymethyl, hydroxyethyl, oxo, thiol, and thioxo.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, fluoro, chloro, bromo, oxo, and methyl.
  • R A and R B form hexahydropyrimidinyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, methoxy, oxo, thioxo, nitro, and cyano.
  • substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, methoxy, oxo, thioxo, nitro, and cyano.
  • the compound corresponds in structure to Formula (I-B):
  • each dashed line represents an optional bond such that the compound of Formula (I-B) corresponds in structure to one of the following formulas:
  • R is hydrogen or an independently selected R substituent.
  • R 8 is hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, carbocyclyl, carbocyclylalkyl, amino, aminoalkyl, aminoalkenyl, alkenylamino, thiol, thioxo, carbocyclylaminoalkyl, heterocyclylaminoalkyl, carbocyclylaminoalkenyl, heterocyclylaminoalkenyl, carbocyclylalkenylamino, heterocyclylalkenylamino, hydrazinylalkyl, or heterocyclyl.
  • Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, hydroxyl, cyano, alkyl, alkoxy, alkoxyalkyl, carbocyclyl, alkoxycarbocyclyl, oxo, amino, alkylamino, aminoalkyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, and carbocyclyloxy. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
  • the compound corresponds in structure to Formula (I-B-2), and R 7 and R 8 , together with the atoms to which they are bonded, form heterocyclyl optionally substituted with one or more independently selected R f substituents.
  • R 9 is selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkenyl, amino, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and -S(R g ). Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminoalkyl, thioxo, thiol, nitro, and heterocyclylalkyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, imino, amino, oxo, thioxo, thiol, and nitro.
  • R a and R 9 (together with the atoms(s) to which they are bonded) form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, carbocyclylalkenyl, and heterocyclyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
  • the compound corresponds in structure to Formula (I-B-2):
  • R 7 is oxo.
  • the compound corresponds in structure to Formula (I-B-2-a):
  • R 7 is thioxo.
  • the compound corresponds in structure to Formula (I-B-2-b):
  • the compound corresponds in structure to Formula (I-B-3):
  • the compound corresponds in structure to Formula (I-B-4):
  • R d and R e are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, oxo, nitro, carbocyclyl, and carbocyclylalkyl.
  • R and R e are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and furanyl.
  • Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, oxo, nitro, phenyl, and phenylmethyl.
  • R d is hydrogen, methyl, phenyl, chlorophenyl, fluorophenyl, methylphenyl, (dimethyl)phenyl, methoxyphenyl, (dimethoxy) ⁇ henyl, nitrophenyl, butylphenyl, benzylphenyl, furanyl, or methylfuranyl.
  • R e is hydrogen, methyl, ethyl, methylcarbonyl, ethylcarbonyl, or phenyl.
  • R d and R e are each methyl.
  • R d and R e (together with the atoms to which they are bonded) form cyclopentenyl or cyclohexenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and propyl.
  • R d and R e are independently selected from the group consisting of hydrogen, methyl, ethyl, ethoxycarbonyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-isopropylphenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2-furanyl, 5-methylfur-2-yl, 3-nitrophenyl, 4-benzylphenyl, and 4-tert-butylphenyl.
  • R d and R e (together with the atoms to which they are bonded) form carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl.
  • R d and R e (together with the atoms to which they are bonded) form cyclopentenyl or cyclohexenyl.
  • R d and R e (together with the atoms to which they are bonded) form cyclopentenyl, cyclohexenyl, methylcyclohexenyl, or butylcyclohexenyl.
  • R 7 is oxo, amino, thiol, thioxo, hydrazinyl, hydrazinylalkyl, carbocyclyl, carbocyclylhydrazinyl, carbocyclylalkenylhydrazinyl, heterocyclyl, heterocyclyloxy, or -S(R S ).
  • Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, oxo, alkyl, and alkoxy.
  • R 7 is oxo, amino, thiol, thioxo, hydrazinyl, hydrazinylmethyl, cyclohexenylhydrazinyl, carbocyclylalkenylhydrazinyl, piperazinyl, phenylmethenylhydrazinyl, quinolinyloxy, or -S(R S ). Any such substitutent optionally is substituted with one or more substituents independently selected from the group consisting of methyl, phenyl, methoxy, phenylmethyl, morpholinyl, morpholiniumyl, and benzodioxolylethyl.
  • R 7 is oxo, thioxo, quinolin- 8-yloxy, (2-methylquinolin-8-yl)oxy, (2- ⁇ [3-ethoxycarbonyl)-5-(methoxycarbonyl)-4- methyl-2-thienyl]amino ⁇ -2-oxoethyl)thio, (2- ⁇ [3-(aminocarbonyi)-5-phenyl-2- thienyl] amino ⁇ -2-oxoethyl)thio, (2- ⁇ [3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino ⁇ -2-oxoetb.yl)thio,
  • R 8 is hydrogen, methyl, ethyl, methoxyethyl, propyl, butyl, allyl, phenyl, phenylmethyl, phenylethyl, amino, aminoethyl, thiol, thioxo, methyleneamino phenylmethyleneamino, benzodioxolylmethyleneamino, furanylmethyleneamino,
  • any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, nitro, cyano, hydroxyl, methyl, methoxy, methoxyphenyl, oxo, amino, methylamino, dihydroindolylidenyl, phenyl, phenylmethyl, imidazolyl, indolyl, phenyl, furanylmethyl, propoxy, propoxymethyl, isopropoxy, isopropoxymethyl, butoxy, isobutoxymethyl, and cyclohexyloxy.
  • R 8 is hydrogen, phenyl, allyl, methyl, butyl, 2-phenylethyl, 4-methylphenyl, 4-methylbenzyl, 3-methylbenzyl, 4-bromobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, amino, [(2- chlorophenyl)methylene] amino, [l,3-benzodioxol-5-ylmethylene]amino, [(5-nitro-2- furanyl)methylene] amino, (4-hydroxybenzylidene)amino, ⁇ [2- (difluoromethoxy)phenyl]methylene ⁇ amino, [(2-chloroimidazo[l,2-a]pyridin-3
  • R is phenyl.
  • R is allyl.
  • the compound corresponds in structure to Formula (I-B-2), and R 7 and R 8 , together with the atoms to which they are bonded, form triazolyl optionally substituted with one or more independently selected R f substituents.
  • R a is selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkenyl, amino, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and -S(R S ). Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminoalkyl, thioxo, thiol, nitro, and heterocyclylalkyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, imino, amino, oxo, thioxo, thiol, and nitro.
  • R 9 and R a are independently selected from the group consisting of hydrogen, methyl, aminomethyl, phenyl, phenylethenyl, benzoisoquinolinylethyl, and -S-R gl . Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminomethyl, thioxo, thiol, and nitro. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, imino, amino, oxo, thioxo, thiol, and nitro.
  • R 9 and R a are independently selected from the group consisting of hydrogen, (l,3-benzodioxol-5- ylmethyl)thio, (l- ⁇ [(2-furanylmethyl)amino]carbonyl ⁇ -3-hydroxypropyl)thio, (2- ⁇ [2- ( ⁇ [(3-allyl-4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2- yl)thio] acetyl ⁇ amino)hexyl] amino ⁇ -2-oxoethyl)thio, (2- ⁇ [2-(3 ,4- dimethoxyphenyl)ethyl]amino ⁇ -2-oxoethyl)thio, (2- ⁇ [2-(4- methoxyphenyl)ethyl]amino ⁇ -2-oxoethyl)thio, l (2- ⁇ [3-(aminocarbonyl
  • R 9 is hydrogen.
  • R 9 is -S-R sl .
  • R 9 and R a (together with the atoms to which they are bonded) form tetrahydroisoquinolinyl optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, propyl, phenyl, and phenylmethylenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy, and ethoxy.
  • R is heterocyclyl, heterocyclylalkyl, or heterocyclylaminoalkyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, aminoalkyl, carbocyclyl, oxo, thioxo, nitro, and cyano. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, thioxo, nitro, and cyano.
  • R is thienylaminoethyl, (dihydrocyclopentathienyl)aminoethyl, or tetrazolyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxymethyl, ethoxymethyl, aminomethyl, phenyl, oxo, thioxo, nitro, and cyano.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, oxo, thioxo, nitro, and cyano.
  • each R gl is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, aminoethyl, cyclohexylaminoethyl, phenylmethyl, phenylethyl, phenyloxyethyl, phenylpropenyl, phenylaminoethyl, phenylaminopropyl, triazolylmethyl, (dihydrotriazolyl)methyl, benzoisoquinolinylethyl, indolylethyl, (dihydroindolyl)ethyl, isoindolylethyl, (dihydroisoindolyl)ethyl, isoindolylbutyl, (dihydroisoindolyl)butyl, (tetrahydrobenzothienyl)aminoethyl, isobenzothieny
  • any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of oxo, fluoro, chloro, bromo, thioxo, cyano, nitro, methyl, amino, aminomethyl, aminoethyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, propyl, aminosulfonyl, phenylmethylthio, butoxy, tert-butoxy, allyl, phenyl, phenylmethyl, phenylethyl, phenylthio, phenyloxysulfonyl, benzodioxolylmethyl, pyridinylmethyl, and furanylmethyl.
  • substituents independently selected from the group consisting of oxo, fluoro, chloro, bromo, thioxo, cyano, nitro, methyl, amino, aminomethyl, aminoethyl, methoxy, me
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, hydroxyl, methyl, ethyl, propyl, amino, oxo, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and phenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, hydroxyl, methyl, ethyl, amino, imino, oxo, methoxy, and ethoxy.
  • the compound corresponds in structure to Formula (I-C):
  • Each dashed line represents an optional bond. When the bond to R .14 . is absent, R 14 also is absent.
  • R is hydrogen or an independently selected R substituent.
  • R 14 and R 15 are independently selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkoxy, alkenyl, carbocyclyl, alkylcarbocyclyl, amino, oxo, heterocyclyl, heterocyclylamino, heterocyclylalkylamino, heterocyclylaminoalkyl, aminoalkyl, alkylamino, and aminoalkylamino.
  • Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, oxo', amino, heterocyclyl, aminoalkyl, and hydroxyalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, oxo, alkoxy, heterocyclyl, and hydroxyalkyl.
  • R 14 and R 15 (together with the atoms to which they are bonded) form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
  • R and R are each hydrogen.
  • R 16 and R 17 (together with the atoms to which they are bonded) form carbocyclyl or heterocyclyl.
  • the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
  • the compound corresponds in structure to Formula (I-C-l):
  • Such compounds include, for example, those wherein R is oxo such that the compound corresponds in structure to Formula (I-C-l -a):
  • the compound corresponds in structure to Formula (I-C-2):
  • Such compounds include, for example, those wherein R 7 is oxo such that the compound corresponds in structure to Formula (I-C-2-a):
  • the compound corresponds in structure to Formula (I-C-3):
  • Such compounds include, for example, those wherein R 7 is oxo such that the compound corresponds in structure to Formula (I-C-3-a):
  • R d and R e are independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, oxo, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, thioxo, and amino.
  • R d and R e are independently selected from the group consisting of hydrogen, methyl, and phenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, oxo, and amino.
  • R d and R e are independently selected from the group consisting of hydrogen, methyl, phenyl, A- methylphenyl, and 4-chlorophenyl.
  • R d and R e (together with the atoms to which they are bonded) form carbocyclyl or heterocyclyl.
  • the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
  • R d and R e (together with the atoms to which they are bonded) form cyclopentenyl, cyclohexenyl, or cycloheptenyl.
  • R d and R e (together with the atoms to which they are bonded) form cyclohexenyl, cycloheptenyl, or methylcyclohexenyl.
  • R 14 and R 15 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydrazinyl, amino, piperidinyl, piperazinyl, morpholinyl, and triazenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, amino, oxo, methoxy, ethoxy, tetrahydrofuranyl, furanyl, morpholinyl, aminopropyl, and hydroxyethyl.
  • Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, oxo, methoxy, ethoxy, tetrahydrofuranyl, furanyl, morpholinyl, and hydroxyethyl.
  • R 14 and R 15 are independently selected from the group consisting of hydrogen, chloro, hydrazinyl, (tetrahydrofuran-2-ylmethyl)amino, (2-furanyhnethyl)amino, (3-morpholin-4-ylpropyl)amino, piperidin-1-yl, [3-(dimethylamino)propyl]arnino, 4-(2-hydroxyethyl)piperazin- 1 -yl, morpholin-4-yl, (2-hydroxyethyl)amino, (2-morpholin-4-ylethyl)amino, and (tetrahydrofuran-2-ymiethyl)amino.
  • R 14 and R 15 (together with the atoms to which they are bonded) form dihydrotriazolyl or dihydrotetrazolyl.
  • R 16 and R 17 (together with the atoms to which they are bonded) form phenyl.
  • Compounds useful with this invention generally may be prepared by methods known in the art. Commercial sources of such compounds include, for example, Otava, Kyiv 187, 03187, Ukraine.
  • the compounds of this invention can be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • salts When a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
  • Pharmaceutically acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate
  • Pharmaceutically acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts.
  • Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group Ha) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Preferred organic salts can be made from amines, such as tromethamine, diethylamine, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C 1 -C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • C 1 -C 6 halides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates
  • long chain halides e.g., decyl, lauryl
  • the salt comprises a hydrochloric acid (HCl) salt.
  • This invention is directed, in part, to a method for treating a pathological condition caused (directly or indirectly) by viral activity.
  • Animals benefiting from such a method generally include, for example, humans.
  • the method may be used in veterinary contexts as well to treat other mammals, such as other primates ⁇ e.g., monkeys, chimpanzees, etc.), companion animals ⁇ e.g., dogs, cats, horses, etc.), farm animals ⁇ e.g., goats, sheep, pigs, cattle, etc.), laboratory animals ⁇ e.g., mice, rats, etc.), and wild and zoo animals ⁇ e.g., wolves, bears, deer, etc.). It is contemplated that the method may further be used in other veterinary contexts to treat, for example, birds, reptiles, fish, and amphibians.
  • mammals such as other primates ⁇ e.g., monkeys, chimpanzees, etc.), companion animals ⁇ e.g., dogs, cats, horses, etc.), farm animals ⁇ e.g., goats, sheep, pigs, cattle, etc.), laboratory animals ⁇ e.g., mice, rats, etc.), and wild and zo
  • the condition is associated with an RNA virus.
  • the condition is associated with a positive-strand RNA virus.
  • viruses include, for example, viruses falling within a viral family selected from the group consisting of Picornaviridae, Caliciviridae, Astroviridae, Coronaviridae, Togaviridae, and Flaviviridae.
  • RNA viruses include Sindbis virus, rubella virus, hepatitis C virus (HCV), West Nile virus (WNV), yellow fever virus (YFV), tick-borne encephalitis (TBE) virus, Japanese encephalitis virus, coxsackievirus, enterovirus, hepatitis A virus, severe acute respiratory syndrome (SARS) virus, Dengue fever virus (DV), poliovirus, Venezuela encephalitis virus (VEE), Western equine encephalomyelitis (WEE) virus, Eastern equine encephalomyelitis (EEE) virus, O'nyong nyong virus, Ross River virus, Chikungunya virus, Rhinovirus, feline caliciviras, murine calicivirus, Norwalk virus, bovine viral diarrhea virus (BVDV), human coronavirus, Semliki Forest virus, Kunjin virus, Omsk hrmorrhagic fever (Omsk HF) virus, Murray Valley encipha
  • HCV severe
  • the condition is associated with hepatitis C virus. [192] hi some embodiments, the condition is associated with West Nile virus. [193] hi some embodiments, the condition is associated with yellow fever virus.
  • the condition is associated with a negative-strand RNA virus.
  • viruses include, for example, viruses falling within a viral family selected from the group consisting of Paramyxoviridae, Rhabdoviridae, Filoviridae, Orthomyxoviridae, Bunyaviridae, Bornaviridae, and Arenaviridae.
  • RNA viruses include respiratory syncytial virus (RSV), Ebola virus, rabies virus, Lassa fever virus, La Crosse virus, Rift Valley fever virus, Hantaan virus, California encephalitis virus, influenza virus A, influenza virus B, measles virus, mumps virus, Marburg virus, Venezuelan hemorrhagic fever (Bolivian HF) virus, human parainfluenza virus (HPIV), human metapneumovirus (hMPV), Nipah virus, Hendra virus (equine morbillivirus), vesicular stomatitis virus (VSV), lymphocytic choriomeningitis (LCM) virus, Junin virus (Argentine hemorrhagic fever virus or Argentine HF virus), Bunyamwera virus, Uukuniemi virus, and Crimean-Congo hemorrhagic fever (CCHF) virus.
  • RSV respiratory syncytial virus
  • Ebola virus Ebola virus
  • condition is associated with respiratory syncytial virus.
  • condition is associated with a double-strand
  • RNA virus In some such embodiments, the virus is from the Reoviridae virus family. Examples of double-strand RNA viruses include Colorado tick fever.
  • the condition is associated with a DNA virus.
  • the condition is associated with a partial-complex DNA virus.
  • the virus is from the Hepadanviridae virus family. Examples of partial-complex DNA viruses include Hepatitis B virus.
  • the condition is associated with a single-strand DNA virus.
  • the virus is from the Paravavoviridae virus family. Examples of single-strand DNA viruses include human parvovirus.
  • the condition is associated with a double-strand
  • DNA virus Such viruses include, for example, viruses falling within a viral family selected from the group consisting of Papillomaviridae, Polyomaviridae, and Herpesviridae.
  • viruses include, for example, viruses falling within a viral family selected from the group consisting of Papillomaviridae, Polyomaviridae, and Herpesviridae.
  • Specific examples of double-strand DNA viruses include human papillomavirus, JC virus, BK virus, herpes simplex virus 1, herpes simplex virus 2, herpes simplex virus 6, herpes simplex virus 7, herpes simplex virus 8, Eptstein Barr virus, and human cytomegalovirus.
  • the condition is associated with a respiratory virus.
  • viruses include, for example, parainfluenza viruses, human metapneumovirus, rhinoviruses, and hantaviruses.
  • the condition is associated with an enteric virus.
  • Such viruses include, for example, enteroviruses, rotavirus, and caliciviruses.
  • the condition is associated with an encephalitis- causing virus.
  • viruses include, for example, West Nile virus and tick-borne encephalitis virus.
  • the condition is associated with a hemorrhagic fever virus.
  • viruses include, for example, Ebola virus, Marburg virus, and Lassa fever virus.
  • a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in a therapeutically-effective amount to a patient suffering from (or prediposed to) a viral infection.
  • therapeutically-effective amount means an amount that is effective to inhibit activity of the target virus(es) or effective to treat the targeted condition in a reasonable amount of time.
  • the term “inhibit” means reducing or eliminating the targeted viral activity.
  • the term “treat” means ameliorating, suppressing, eradicating, preventing, reducing the risk of, or delaying the onset of the targeted condition.
  • Factors affecting the preferred dosage regimen include, for example, the type, age, weight, sex, diet, and condition of the patient; the type of pathological condition and its severity; the nature of the desired effect; whether the purpose of administration is prophylactic or to treat an existing viral infection; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular anti- viral agent used; the route of administration and whether a drug delivery system is utilized; and whether the anti-viral agent is administered as part of a combination therapy (e.g., whether the agent is administered in combination with one or more other active agents, radiation, etc.).
  • a combination therapy e.g., whether the agent is administered in combination with one or more other active agents, radiation, etc.
  • compositions for oral administration are, for example, preferably prepared in a manner such that a single dose in one or more oral preparations contains at least about 20 mg of the anti- viral compound per square meter of patient body surface area, or at least about 50, 100, 150, 200, 300, 400, or 500 mg of the anti-viral compound per square meter of patient body surface area (the average body surface area for a human is, for example, 1.8 square meters).
  • a single dose of a composition for oral administration contains from about 20 to about 600 mg (more preferably from about 20 to about 400 mg, even more preferably from about 20 to about 300 mg, and still even more preferably from about 20 to about 200 mg) of the anti- viral compound per square meter of patient body surface area.
  • compositions for parenteral administration are, for example, prepared in a manner such that a single dose contains at least about 20 mg of the anti-viral compound per square meter of patient body surface area, or at least about 40, 50, 100, 150, 200, 300, 400, or 500 mg of the anti- viral compound per square meter of patient body surface area.
  • a single dose in one or more parenteral preparations contains from about 20 to about 500 mg (more preferably from about 20 to about 400, even more preferably from about 20 to about 400 mg, and still even more preferably from about 20 to about 350 mg) of the anti- viral compound per square meter of patient body surface area.
  • the thienyl compounds and salts of this invention may be used as part of a combination therapy.
  • combination therapy means the administration of two or more therapeutic treatments directed to the pathological condition.
  • the pathological condition generally comprises a condition associated (directly or indirectly) with viral activity.
  • the therapeutic treatments of the combination generally may be co-administered in a substantially simultaneous manner.
  • Two active agents could be co-administered as, for example: (a) a single formulation (e.g., a single capsule) having a fixed ratio of active ingredients; or (b) multiple, separate formulations (e.g., multiple capsules) for each agent.
  • a combination therapy may comprise administering a thienyl compound or salt of this invention with, for example, one or more additional thienyl compounds or salts of this invention, cytokines (including interferon, and particularly interferon alpha), ribavirin, nucleoside/tide reverse transcriptase inhibitors ("NRTIs", these include abacavir (Ziagen), lamivudine, 3TC (Epivir), tenofovir (Viread), abacavir/lamivudine/zidovudine (Trizivir), lamivudine/zidovudine (Combivir), stavudine, d4T (Zerit), didanosine, ddl (Videx, Videx EC), zalcitabine, ddC (HIVIVI), abacavir (Ziagen), lamivudine, 3TC (Epivir), tenofovir (Viread), a
  • the thienyl compounds and salts of this invention can be used in the form of a kit that is suitable for use in performing the treatment methods described above.
  • the kit comprises a first dosage form comprising a thienyl compound or salt of this invention and a second dosage form comprising another active ingredent in quantities sufficient to carry out the methods of the present invention.
  • the first dosage form and the second dosage form together comprise a therapeutically-effective amount of the agents for treating the targeted condition(s).
  • compositions Containing the Compounds and Salts of this Invention
  • This invention also is directed, in part, to pharmaceutical compositions (or medicaments) comprising a therapeutically-effective amount of a compound or salt of this invention, as well as processes for making such compositions.
  • Such compositions generally comprise one or more pharmaceutically-acceptable carriers ⁇ e.g., excipients, vehicles, auxiliaries, adjuvants, diluents, etc.) and/or other active ingredients.
  • Formulation of these compositions may be achieved by various methods known in the art. A general discussion of these methods may be found in, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975). See also, Liberman, H.A. & Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N. Y., 1980).
  • the preferred composition depends on the route of administration. Any route of administration may be used as long as the target of the compound or salt is available via that route. Often suitable routes of administration include, for example, oral, parenteral, inhalation, rectal, nasal, topical (e.g., transdermal and intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual, and intestinal administration.
  • Pharmaceutically acceptable carriers that may be used in the compositions of this invention are well known to those of ordinary skill in the art.
  • Carriers are selected based on a number of factors including, for example, the particular anti-viral compound(s) or salt(s) used; the compound's concentration, stability, and intended bioavailability; the condition being treated; the subject's age, size, and general condition; the route of administration; etc.
  • a general discussion related to carriers may be found in, for example, J. G. Nairn, Remington's Pharmaceutical Science, pp. 1492- 1517 (A. Gennaro, ed., Mack Publishing Co., Easton, Pa. (1985)).
  • Solid dosage forms for oral administration include, for example, capsules, tablets, gelcaps, pills, dragees, troches, powders, granules, and lozenges.
  • the compounds or salts are ordinarily combined with one or more adjuvants.
  • the compounds or salts can be mixed with lactose, sucrose, starch powder, corn starch, potato starch, magnesium carbonate, microcrystalline cellulose, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, sodium carbonate, agar, mannitol, sorbitol, sodium saccharin, gelatin, acacia gum, alginic acid, sodium alginate, tragacanth, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the compound or salt in hydroxypropylmethyl cellulose.
  • the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can, for example, include a coating ⁇ e.g., an enteric coating) to delay disintegration and absorption.
  • the concentration of the anti- viral agent in a solid oral dosage form is preferably from about 5 and about 50% (more preferably from about 8 to about 40 %, and even more preferably from about 10 to about 30%) by weight based on the total weight of the composition.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art ⁇ e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the concentration of the anti- viral agent preferably is from about 0.01 to about 10 mg (more preferably from about 0.01 to about 5 mg, even more preferably from about 0.01 to about 1 mg, and still even more preferably from about 0.01 to about 0.5 mg) per ml of the composition. Relatively low concentrations are generally preferred because the anti-viral agents tend to be most soluble at low concentrations.
  • tablets or powders for oral administration are prepared by dissolving the anti- viral agent in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution and then evaporating when the solution is dried under vacuum.
  • An additional ca ⁇ ier(s) also may be added to the solution before drying.
  • the resulting solution is dried under vacuum to form a glass.
  • the glass is then mixed with a binder to form a powder.
  • This powder may be mixed with fillers or other conventional tableting agents, and then processed to form a tablet.
  • the powder may be added to a liquid carrier to form a solution, emulsion, suspension, or the like.
  • solutions for oral administration are prepared by dissolving the anti- viral agent in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution.
  • An appropriate volume of a carrier is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration.
  • Parenteral administration includes subcutaneous injections, intravenous injections, intraarterial injections, intraorbital injections, intracapsular injections, intraspinal injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion.
  • Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, and any other dosage form that can be administered parenterally.
  • injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting, and/or suspending agents can be formulated according to the known art using suitable dispersing, wetting, and/or suspending agents.
  • Acceptable vehicles for parenteral use include both aqueous and nonaqueous pharmaceutically-acceptable solvents.
  • Suitable pharmaceutically-acceptable aqueous solvents include, for example, water, saline solutions, dextrose solutions (e.g., such as DW5), electrolyte solutions, etc.
  • Suitable pharmaceutically-acceptable nonaqueous solvents include, for example, the following (as well as mixtures thereof): alcohols (these include, for example, ⁇ -glycerol formal, ⁇ -glycerol formal, 1, 3-butyleneglycol, aliphatic or aromatic alcohols having from 2 to about 30 carbons (e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuranyl alcohol, lauryl alcohol, cetyl alcohol, and stearyl alcohol), fatty acid esters of fatty alcohols (e.g., polyalkylene glycols, such as polypropylene glycol and polyethylene glycol), sorbitan, sucrose, and cholesterol); amides (
  • Examples include diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether), and glycofurol (tetrahydrofurfuranyl alcohol polyethylene glycol ether); ketones (these typically have from about 3 to about 30 carbons. Examples include acetone, methyl ethyl ketone, methyl isobutyl ketone); hydrocarbons (these are typically aliphatic, cycloaliphatic, and aromatic hydrocarbons having from about 4 to about 30 carbons.
  • oils examples include benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n- decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), and tetramethylenesulfoxide); oils (these include oils of mineral, vegetable, animal, essential, or synthetic origin.
  • mineral oils such as aliphatic and wax- based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil
  • vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic, and peanut oil
  • glycerides such as mono-, di-, and triglycerides
  • animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil
  • oleic oils and polyoxyethylated castor oil
  • alkyl, alkenyl, or aryl halides these include alkyl or aryl halides having from 1 to about 30 carbons and one or more halogen substituent.
  • Examples include methylene chloride); monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (SOLUTOL HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; and sorbitan monooleate.
  • Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art.
  • Preferred solvents include those known to stabilize the anti-viral compound(s) or salt(s) of interest. These typically include, for example, oils rich in triglycerides, such as safflower oil, soybean oil, and mixtures thereof; and alkyleneoxy- modified fatty acid esters, such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., CREMOPHOR EL solution or CREMOPHOR RH 40 solution).
  • oils rich in triglycerides such as safflower oil, soybean oil, and mixtures thereof
  • alkyleneoxy- modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., CREMOPHOR EL solution or CREMOPHOR RH 40 solution).
  • triglycerides include INTRALIPID emulsified soybean oil (Kabi-Pharmacia Inc., Sweden), NUTRALIPID emulsion (McGaw, Irvine, California), LIPOSYN II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, IL), LIPOSYN III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, IL), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels of from about 25 to about 100% (by weight based on the total fatty acid content) (DHASCO from Martek Biosciences Corp., Columbia,
  • compositions of this invention for various purposes generally known in the pharmaceutical industry. These components tend to impart properties that, for example, enhance retention of the antiviral compound or salt at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the anti- viral compound or salt into pharmaceutical formulations, and the like.
  • cryoprotective agents include cryoprotective agents; agents for preventing reprecipitation of the anti-viral compound or salt surface; active, wetting, or emulsifying agents (e.g., lecithin, polysorbate-80, TWEEN 80, pluronic 60, and polyoxyethylene stearate); preservatives (e.g., ethyl-p-hydroxybenzoate); microbial preservatives (e.g., benzyl alcohol, phenol, 7/z-cresol, chlorobutanol, sorbic acid, thimerosal, and paraben); agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate, etc.); agents for adjusting osmolality (e.g., glycerin); thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose,
  • Formulations for parenteral administration may, for example, be prepared from one or more sterile powders and/or granules having a compound or salt of this invention and one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the powder or granule typically is added to an appropriate volume of a solvent (typically while agitating (e.g., stirring) the solvent) that is capable of dissolving the powder or granule.
  • a solvent typically include, for example, water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Emulsions for parenteral administration can be prepared by, for example, dissolving a compound or salt of this invention in any pharmaceutically acceptable solvent capable of dissolving the compound to form a solution; and adding an appropriate volume of a carrier, which is an emulsion, to the solution while stirring to form the emulsion.
  • Solutions for parenteral administration can be prepared by, for example, dissolving a compound or salt of this invention in any pharmaceutically acceptable solvent capable of dissolving the compound to form a solution; and adding an appropriate volume of a carrier to the solution while stirring to form the solution.
  • Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols.
  • Topical administration includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
  • the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials, or other conventional containers in concentrated form, and then diluted with a pharmaceutically acceptable liquid (e.g., saline) to form an acceptable anti- viral concentration before use.
  • a pharmaceutically acceptable liquid e.g., saline
  • Other adjuvants and modes of administration well-known in the pharmaceutical art may also be used.
  • alkyl (alone or in combination with another term(s)) means a straight- or branched-chain saturated hydrocarbyl substituent typically containing from
  • substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 1 to about 20 carbon atoms, more typically from about
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms.
  • substituents include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
  • Carbocyclyl (alone or in combination with another term(s)) means a saturated cyclic (i.e., “cycloalkyl”), partially saturated cyclic (i.e.,
  • cycloalkenyl or completely unsaturated (i.e., "aryl”) hydrocarbyl substituent typically containing from 3 to 14 carbon ring atoms
  • ring atoms are the atoms bound together to form the ring or rings of a cyclic substituent.
  • a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl alternatively may be multiple (typically 2 or 3) rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”), fluoreneyl, decalinyl, and norpinanyl.
  • cycloalkyl (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent typically containing from 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl (or “cyclopropanyl”), cyclobutyl (or “cyclobutanyl”), cyclopentyl (or “cyclopentyl”), and cyclohexyl (or “cyclohexyl”).
  • a cycloalkyl alternatively may be multiple (typically 2 or 3) carbon rings fused together, such as decalinyl or norpinanyl.
  • aryl (alone or in combination with another term(s)) means an aromatic carbocyclyl typically containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix
  • C x -C y - wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • Q-Q-alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C 3 -C 6 -cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • nitro (alone or in combination with another term(s)) means -NO 2 .
  • cyano (alone or in combination with another term(s)) means -CN, which also may be depicted:
  • amino (alone or in combination with another term(s)) means -NH 2 .
  • monosubstituted amino (alone or in combination with another term(s)) means an amino substituent wherein a non-hydrogen substituent is in the place of one of the hydrogens.
  • disubstituted amino (alone or in combination with another term(s)) means an amino substituent wherein non-hydrogen substituents (which may be identical or different) are in the place of both of the hydrogens.
  • halogen (alone or in combination with another term(s)) means a fluorine radical ("fluoro", which may be depicted as -F), chlorine radical ("chloro”, which may be depicted as -Cl), bromine radical ("bromo”, which may be depicted as -Br), or iodine radical ("iodo", which may be depicted as -I).
  • fluoro or chloro is preferred, with fluoro often being particularly preferred.
  • a substituent is "substitutable” if it comprises at least one carbon, nitrogen, oxygen, or sulfur atom that is bonded to one or more hydrogen atoms.
  • hydrogen, halogen, and cyano do not fall within this definition.
  • a non-hydrogen substituent is in the place of a hydrogen on a carbon, nitrogen, oxygen, or sulfur of the substituent.
  • a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro
  • difluoroalkyl is alkyl substituted with two fluoros. It should be recognized that if there are more than one substitutions on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).
  • substituent is either (1) substituted, or (2) not substituted.
  • any atom capable of substitution in each member of such group may be (1) substituted, or (2) not substituted.
  • Atoms capable of substitution include, for example, carbon bonded to at least one hydrogen, oxygen bonded to at least one hydrogen, sulfur bonded to at least one hydrogen, or nitrogen bonded to at least one hydrogen.
  • hydrogen alone, halogen, oxo, and cyano do not fall within the definition of being capable of substitution.
  • haloalkyl means an alkyl substituent having a halogen in the place of a hydrogen, or multiple halogens in the place of the same number of hydrogens.
  • haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluorornethyl, 1,1,1-trifluoroethyl, and the like.
  • haloalkoxy means an alkoxy substituent wherein a halogen is in the place of a hydrogen, or multiple halogens are in the place of the same number of hydrogens.
  • haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyloxy”), 1,1,1 ,-trifluoroethoxy, and the like. It should be recognized that if a substituent is substituted by more than one halogen, those halogens may be identical or different (unless otherwise stated).
  • the prefix "perhalo" indicates that a halogen is in the place of each hydrogen on the substituent to which the prefix is attached. If all the halogens are identical, the prefix typically will identify the halogen. Thus, for example, the term “perfluoro” means that a fluoro is in the place of each hydrogen on the substituent to which the prefix is attached. To illustrate, the term “perfluoroalkyl” means an alkyl substituent wherein a fluoro is in the place of each hydrogen.
  • perfluoroalkyl substituents examples include trifluoromethyl (-CF 3 ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like.
  • perfluoroalkoxy means an alkoxy substituent wherein a fluoro is in the place of each hydrogen.
  • perfluoroalkoxy substituents include trifluoromethoxy (-0-CF 3 ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.
  • carbonyl (alone or in combination with another term(s)) means -C(O)-, which also may be depicted as:
  • This term also is intended to encompass a hydrated carbonyl substituent, i.e., -C(OH) 2 -.
  • aminocarbonyl (alone or in combination with another term(s)) means -C(O)-NH 2 , which also may be depicted as:
  • oxy (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -O-.
  • alkoxy (alone or in combination with another term(s)) means ari alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-0-CH 3 ), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkylcarbonyl (alone or in combination with another term(s)) means -C(O)-alkyl.
  • ethylcarbonyl may be depicted as:
  • aminoalkylcarbonyl (alone or in combination with another term(s)) means -C(O)-alkyl-NH 2 .
  • aminomethylcarbonyl may be depicted as:
  • alkoxycarbonyl (alone or in combination with another term(s)) means -C(O)-O-alkyl.
  • ethoxycarbonyl may be depicted as:
  • thio or "thia” (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl” means alkyl-S-alkyl.
  • thiol or “mercapto” (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
  • (thiocarbonyl) (alone or in combination with another term(s)) means a carbonyl wherein a sulfur is in the place of the oxygen.
  • Such a substituent may be depicted as -C(S)-, and also may be depicted as:
  • alkyl-sulfonyl-alkyl means alkyl-S(O) 2 -alkyl.
  • aminosulfonyl (alone or in combination with another term(s)) means -S(O) 2 -NH 2 , which also may be depicted as:
  • alkyl-sulfoxido-alkyl means alkyl-S(O)-alkyl.
  • heterocyclyl (alone or in combination with another term(s)) means a saturated (i.e., “heterocycloalkyl"), non-aromatic partially-saturated (i.e., “heterocycloalkenyl”), or heterocyclic aromatic (i.e., "heteroaryl") ring structure typically containing a total of from 3 to 20 (more typically from 3 to 14) ring atoms. At least one of the ring atoms is a heteroatom (typically oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group typically consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heterocyclyl may be a single ring, which typically contains from 3 to
  • heterocyclyls include furanyl, thienyl (also known as “thiophenyl” and “thiofuranyl”), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as "azoximyl”), 1,2,5-oxadiazolyl (also known as "furazanyl”), and 1,3,4-oxadiazolyl), pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazo
  • a lieterocyclyl alternatively may be from 2 to 5 (more typically from 2 or 3) rings fused together, such as, for example, indolizinyl, pyranopyrrolyl, purinyl, imidazopyrazinyl, imidazolopyridazyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, pyrido[4,3-b]-pyridinyl, and naphthyridinyl), pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, pyrindinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazyl, or 4H-quinolizinyl.
  • the preferred multi-ring heterocyclyls are indolizinyl, pyranopyrrolyl, purinyl, pyridopyridinyl, pyrindinyl, and 4H-quinolizinyl.
  • fused-ring heterocyclyls include benzo-fused heterocyclyls, such as, for example, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzoxazolyl, benzoisoxazolyl (also known as “indoxazinyl"), anthranilyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl”, and “benzothiofuranyl"), isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl”, and “isobenzothiofuranyl"), benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, isoindazolyl (also known as
  • benzpyrazolyl benzoimidazolyl, benzotriazolyl, benzazinyl (including quinolinyl (also known as “1 -benzazinyl”) and isoquinolinyl (also known as “2 -benzazinyl”)), phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) and quinazolinyl (also known as “1,3-benzodiazinyl”)), benzoimidazothiazolyl, carbazolyl, acridinyl, isoindolyl, indoleninyl (also known as "pseudoindolyl”), benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, chromenyl, isochromenyl, thiochromenyl, isothiothi
  • the preferred benzo-fused heterocyclyls are benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzotliienyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, benzazinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, carbazolyl, acridinyl, isoindolyl, indoleninyl, benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, benzodioxanyl, tetrahydroisoquinolinyl, benzoxazinyl, benzoisoxazinyl, and
  • heterocyclyl (alone or in combination with another term(s)) means a saturated, non-aromatic partially-saturated, or heteroaryl containing two fused rings.
  • heterocyclyls include, for example, benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, imidazopyrazinyl, imidazolopyridazyl, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinox
  • preferred 2-fused-ring heterocyclyls include benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyrindinyl, isoindolyl, indoleninyl, benzodioxolyl, benzodioxanyl, tetrahydroisoquinolinyl, 4H-
  • heteroaryl (alone or in combination with another term(s)) means an aromatic heterocyclyl typically containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or multiple (typically 2 or 3) fused rings.
  • Such moieties include, for example, 5-membered rings such as furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, and oxatriazolyl; 6-membered rings such as pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and oxathiazinyl; 7-membered rings such as oxepinyl and thiepinyl; 6/5-membered fused-ring systems such as benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenz
  • the preferred 5-membered rings include furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, and imidazolyl;
  • the preferred 6-membered rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl;
  • the preferred 6/5-membered fused-ring systems include benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, and purinyl; and the preferred 6/6-membered fused-ring systems include quinolinyl, isoquinolinyl, and benzodiazinyl.
  • a carbocyclyl or heterocyclyl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as "alkanoyl"), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl.
  • substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as "alkanoyl”), aryl, arylalkyl, arylalkoxy, arylalk
  • a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, -OH, -C(O)-OH, keto, Q-C ⁇ -alkyl, C] .
  • alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with, for example, one or more halogen.
  • the aryl and cycloalkyl portions of such optional substituents are typically single-rings containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.
  • An aryl or heteroaryl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO 2 , -SH, -C(O)-OH, amino, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylalkyl, carbocyclylcarbonylamino, carbocyclylalkyl
  • an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO 2 , -SH, -C(O)-OH, amino, amino-d-Ce-alkyl, Q-Ce-alkyl, Q-Ce-alkylthio, carboxy-CrC ⁇ -alkylthio, d-C ⁇ -alkylcarbonyloxy, Q-Q-alkoxy, Q-C ⁇ -alkoxy-Ci-C ⁇ -alkyl, d-C ⁇ -alkoxycarbonyl-d-Ce-alkoxy, d-Ce-alkoxy-d-Ce-alkylthio, CrCe-alkoxycarbonyl-CrCe-alkylthio, carboxy-CrC ⁇ -alkoxy, d-C ⁇ -alkoxycarbonyl--CH
  • any hydrogens bound to a carbon in any such substituent may, for example, optionally be replaced with halogen.
  • any cycloalkyl, aryl, and heteroaryl portions of such optional substituents are typically single-rings containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.
  • alkylcycloalkyl contains two components: alkyl and cycloalkyl.
  • the C 1 -C 6 - prefix on d-Q-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C 1 -C 6 - prefix does not describe the cycloalkyl component.
  • the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogens.
  • halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkoxyhaloalkyl.”
  • benzene substituted with cyclohexylthiobutoxy has the following structure:
  • CC50 refers to a standard of measure indicating the concentration of a compound that causes 50 percent of maximum cytotoxicity.
  • "Defective genome” refers to a DNA or RNA molecule that contains all the genetic elements (e.g., cis-acting elements) required for viral genomic replication and transcription, but lacks one or more of the genetic elements that encode the borrowed factors or enzymes (e.g., trans-acting factors) required for replication. Defective genomes require the addition of a missing factor in order to replicate.
  • EC50 refers to a standard measure of effective concentration (EC) which is the concentration of a compound required to achieve a 50 percent inhibition of replication of the virus, e.g., a reduction of 50 percent of the replication achieved in the absence of the compound. Sometimes used interchangeably with IC50.
  • IC50 refers to a standard of measure of inhibitory concentration (IC) which is the concentration of a compound required to achieve a 50 percent inhibition of viral replication. IC50 is often used as interchangeable with EC50.
  • SI Selectivity Index
  • CC cytotoxic concentration
  • EC effective concentration
  • SI CC50/EC50
  • Therapeutic Index Another name for the Selectivity Index (SI) which is a ratio of cell cytotoxic concentration (CC) over the effective concentration (EC).
  • RSV antiviral activity was measured against a RSV minigenome-dependent ⁇ -galactosidase expression assay (RSV ⁇ -Gal). Czs-acting elements are required for the replication and transcription of a number of negative-strand virus genomes. This requirement can be utilized to develop methods for identifying antiviral compounds. Applicants have applied such methods to, for example, RSV to develop a prototype assay for detecting and quantifying negative-strand RNA viruses.
  • RNA transcribed from minigenome cDNA contains the czs-acting elements necessary for replication and transcription in RSV-infected cells, and contains a reporter gene(s) in place of viral genes.
  • One of the challenges has been the need to constitutively express high levels of the viral minigenome RNA in the cytoplasm of the cell.
  • Applicants have developed an infection-independent minigenome expression system for screening anti-RSV drugs.
  • Minigenome replication systems are not true replicons because the cis- and tra/w-acting elements are not contained on the same RNA molecule. They are, however, functionally equivalent and useful for identifying antiviral compounds.
  • Transfected cells were plated in 96 well tissue culture treated rnicroplates and allowed to settle for 4 hours at 37° C and 5% CO 2 (v/v). Test compounds were added to appropriate final concentration with DMSO concentration being held constant at 1% in all wells. No-compound controls consisted of cells with media plus DMSO at 1%. Background control wells were non-transfected cells in media plus DMSO at 1%. Cells were incubated in the presence of compound for 24 hours at 37° C and 5% CO 2 (v/v).
  • Beta-galactosidase activity was detected using Galacto-StarTM ⁇ - Galactosidase Assay Kit (Applied Biosystems of Foster City, California, USA). Media and compound were removed from cells. Cell Lysates were prepared by adding lysis solution from the Galacto-StarTM kit and incubating at room temperature for 30 minutes. Galacto-StarTM detection reagent was added and samples were put on an orbital shaker for 1 hour. Beta-galactosidase dependent luminescence was detected with a FLUOstar reader (BMG Labtechnology, Durham, North Carolina, USA). The results were evaluated to determine the concentration at which 50% RSV efficacy (i.e. EC 50 ) was achieved.
  • HCV antiviral activity was measured in a HCV Neo screening assay by determining HCV replicon reduction effects of compounds through NPTII ELISA quantitation of Neomycin Phosphotransferase levels.
  • ELISA assay kit (Agdia, Inc. of Elkhart, Indiana, USA). Media and compound were removed from cells. Cell lysates were prepared by addition of IX extraction buffer and shaking vigorously for 15 min. Lysates were then transferred to NPTII capture plate and shaken vigorously for 2 hours. Capture plates were washed with PBST 8 times. Plates were filled with conjugated antibody and shaken vigorously for 2 hours. The wash step was repeated. ELISA was developed by addition of TMB substrate. The reaction was incubated at room temperature for 15 minutes and stopped by addition of Red Stop reagent (Neogen Corporation). The results were evaluated to determine the concentration at which 50% HCV efficacy (i.e. EC 50 ) was achieved.
  • test compounds were added to appropriate final concentration with the DMSO concentration being held constant at 1% in all wells.
  • No-compound controls consisted of cells with media plus DMSO at 1%.
  • Background-control wells consisted of non-transfected cells in media plus DMSO at 1%. Cells were incubated in the presence of the test compound for 24 hr at 37 0 C under 5% CO 2 (v/v).
  • Renilla luciferase activity was detected using the Promega Renilla Luciferase Assay Kit (Promega, Madison, WI). The media and compound were removed from the cells. Cell lysates were prepared by adding lysis solution from the Renilla Luciferase Assay kit, and then shaking at room temperature for 15 min. Renilla Luciferase Assay Reagent was added to each well by injection immediately before detection of luminescence. Renilla Luciferase dependent luminescence was detected with a FLUOstar reader (BMG Labtechnology, Durham, NC). The results were evaluated to determine the concentration at which 50% WNV efficacy ⁇ i.e., EC 50 ) was achieved.
  • YF-hRuPac cells were plated in 96- well tissue culture treated microplates and allowed to settle for 4 hr at 37 0 C under 5% CO 2 (v/v). Test compounds were added to appropriate final concentration with the DMSO concentration being held constant at 1% in all wells. No-compound controls consisted of cells with media plus DMSO at 1%. Background-control wells were non- transfected cells in media plus DMSO at 1%. The cells were incubated in the presence of the compound for 24 hr at 37 0 C under 5% CO 2 (v/v).
  • Renilla luciferase activity was detected using the Promega Renilla Luciferase Assay Kit (Promega, Madison, WI). The media and compound were removed from the cells. Cell lysates were prepared by adding lysis solution from the Renilla Luciferase Assay kit and shaking at room temperature for 15 min. Renilla Luciferase Assay Reagent was added to each well by injection immediately before detection of luminescence. Renilla Luciferase dependent luminescence was detected with a FLUOstar reader (BMG Labtechnology, Durham, NC). The results were evaluated to determine the concentration at which 50% YFV efficacy ⁇ i.e., EC 50 ) was achieved.
  • a therapeutic index for each antiviral compound was calculated as the ratio of the CC 50 concentration to the EC 50 concentration, or CC 50 /EC 50 .
  • the antiviral compounds were placed into one of three activity classes as follows:
  • Category B ⁇ 25 ⁇ M efficacy and ⁇ 4 TI
  • Category C > 25 ⁇ M efficacy, and n/a indicates that the antiviral activity was not analyzed.
  • Example 1 A compound corresponding to formula (I) wherein R a and R b together form ⁇ 2-[(6-ethoxy-l,3-benzothiazol-2-yl)thio]-l,4-dioxobutane-l,4- diyljdiyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 2 A compound corresponding to formula (I) wherein R a and R b together form [l,4-dioxobut-2-ene-l,4-diyl]diyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 3 A compound corresponding to formula (I) wherein R a and R b together form [2-(l,3-benzothiazol-2-ylthio)-l,4-dioxobutane-l,4-diyl]diyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • R b form [[2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)isoxazolidine-4,5- diyl]di(carbonyl)]diyl;
  • R c is ethoxycarbonyl; and
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl:
  • R b form [[3-(3-nitr :oophenyl)-2-phenylisoxazolidine-4,5-diyl]di(carbonyl)]diyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 6 A compound corresponding to formula (I) wherein R a and R b form [[2-(2-methylphenyl)-3-phenylisoxazolidine-4,5-diyl]di(carbonyl)]diyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • R b is 4-yl-2- ⁇ [l-(4-methoxyphenyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene]methyl ⁇ -l-methylpenta-l,3-dien-l-yl;
  • R c is [(4-methylphenyl)amino]carbonyl; and
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 8 A compound corresponding to formula (I-A) wherein R is ⁇ [3 ,5 -bis(ethoxycarbonyl)-4-methyl-2-thienyl] amino ⁇ (oxo)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 9 A compound corresponding to formula (I-A) wherein R b is chloroacetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 10 A compound corresponding to formula (I-A) wherein R is 4-amino-4-oxobut-2-enoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 12 A compound corresponding to formula (I-A) wherein R is (3-oxo-3,4-dihydro-2H-l,4-benzothiazin-2-yl)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl: is (diethylamino)acetyl; R c is ethoxycarbonyl; R d is phenyl; and R e is (dimethylamino)methyl :
  • Example 14 A compound corresponding to formula (I-A) wherein R is (2-phenylquinolin-4-yl)carbonyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 15 A compound corresponding to formula (I-A) wherein R is (3-azepan-l-yl)propanoyl; R° is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 16 A compound corresponding to formula (I- A) wherein R is (4-et :hhyyllppiippeerraazziinn--ll--yyll))aacceettyyll;; RR cc iiss eetthhooxxyyccaarrbboonnyyll; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 17 A compound corresponding to formula (I- A) wherein R is (3-oxo-3,4-dihydro-2H-l,4-benzothiazin-2-yl)acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 18 A compound corresponding to formula (I- A) wherein R is 4-[(carboxymethyl)thio]-3-nitrobenzoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 19 A compound corresponding to formula (I- A) wherein R b is (3-(2-furanyl)prop-2-enoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 20 A compound corresponding to formula (I- A) wherein R is 2-cyano-3-(2-furanyl)prop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 21 A compound corresponding to formula (I- A) wherein R is 2-cyano-3-(3-nitrophenyl)prop-2-enoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 22 A compound corresponding to formula (I- A) wherein R b is 3-chloropropanoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 23 A compound corresponding to formula (I- A) wherein BJ is (3-oxo-l,2,3,4-tetrahydroquinoxalm-2-yl)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • R c is ethoxycarbonyl
  • R d is methyl
  • R e is methyl
  • R c is ethoxycarbonyl
  • R d is methyl
  • R e is ethoxycarbonyl
  • Example 29 A compound corresponding to formula (I- A) wherein R is 3-[4-oxo-5-(2-thienylmethylene)-2-thioxo-l,3-thiazolidin-3-yl]propanoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 31 A compound corresponding to formula (I- A) wherein R is [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 32 A compound corresponding to formula (I- A) wherein R b is 3-(4-ethylpiperazin-l-yl)propanoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 33 A compound corresponding to formula (I- A) wherein R ⁇ is [5-(methoxycarbonyl)-3-oxothiomo ⁇ holin-2-yl]acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 35 A compound corresponding to formula (I- A) wherein R ⁇ is [(4-oxo-3,6-diphenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • R c is aminocarbonyl
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 38 A compound corresponding to formula (I- A) wherein R is (4,6-dioxo-2-thioxotetrahydropyrimidm-5(2H)-ylidene)amino; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 39 A compound corresponding to formula (I- A) wherein R is 3-[4-(acetylamino)phenyl]-2-cyanoprop-2-enoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 40 A compound corresponding to formula (I- A) wherein R is [(l-p )hheennyyll--llHH--tteetrazol-5-yl)thio]acetyl, R c is ethoxycarbonyl, R d is methyl, and R e is methoxycarbonyl:
  • Example 41 A compound corresponding to formula (I-A) wherein R b is ( [[1l,,22,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 42 A compound corresponding to formula (I-A) wherein R is (5,6,7,8-tetrahydro[l]benzothieno[2,3-d]pyrimidin-4-ylthio)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 43 A compound corresponding to formula (I-A) wherein R ⁇ is [3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-l,4-benzothiazin-2-yl]acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 44 A compound corresponding to formula (I-A) wherein R ⁇ is (3-oxo-l,2,3,4-tetrahydroquinoxalin-2-yl)acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methyl: is 6- ⁇ [3-(aminocarbonyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]ammo ⁇ -6-oxohexanoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 46 A compound corresponding to formula (I- A) wherein R is (biphenyl-4-yl)carbonyl; R c is aminocarbonyl; R d is methyl; and R e is benzyl:
  • Example 47 A compound corresponding to formula (I- A) wherein R is 4-[5-(4-ethylbenzylidene)-4-oxo-2-thioxo-l,3-thiazolidin-3-yl]butanoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 48 A compound corresponding to formula (I- A) wherein R b is (2-imino-4-oxo-l,3-thiazolidin-5-yl)acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 49 A compound corresponding to formula (I- A) wherein R ⁇ is 4-ethoxy-4-oxobut-2-enoyl; R c is aminocarbonyl; R d is methyl; and R e is benzyl:
  • Example 51 A compound corresponding to formula (I-A) wherein R is 4-(di Lfflluuoorroommeetthhooxxyy))bbeennzzooyyll;; RR cc iiss ccaarrbbooxxyyll;; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 52 A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; R d is phenyl; and R e is hydrogen:
  • Example 54 A compound corresponding to formula (I- A) wherein R is 3-(4-ethylpiperazin-l-yl)propanoyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl: enylacetyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 56 A compound corresponding to formula (I- A) wherein R eridin-l-yl)acetyl; R c is aminocarbonyl; R is hydrogen; and R e is phenyl:
  • Example 58 A compound corresponding to formula (I-A) wherein R is [(4-methylphenyl)thio] acetyl; R c is aminocarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 59 A compound corresponding to formula (I-A) wherein R is 3-(4-methylpiperazin-l-yl)propanoyl; R° is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 60 A compound corresponding to formula (I-A) wherein R ⁇ is [(3-allyl-4-oxo-3,5,6,7-tetraliydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; R d is 4-methoxyphenyl; and R e is hydrogen:
  • Example 61 A compound corresponding to formula (I-A) wherein R is 2-cyano-3-(4-hydroxyphenyl)prop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 62 A compound corresponding to formula (I-A) wherein R ⁇ is [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which
  • Example 63 A compound corresponding to formula (I-A) wherein R is [(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)thio]acetyl; R c is aminocarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 64 A compound corresponding to formula (I- A) wherein R b is [(3-allyl-4-oxo-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyri ⁇ iidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 66 A compound corresponding to formula (I- A) wherein R is [(5-methyl[l,2,4Jtriazolo[4,3-a]quinolin-l-yl)thio]acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 68 A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 69 A compound corresponding to formula (I- A) wherein R is [(3-allyl-5,6-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 70 A compound corresponding to formula (I- A) wherein R is [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; R d is 3,4-dimethoxyphenyl; and R e is hydrogen:
  • Example 71 A compound corresponding to formula (I- A) wherein R b is 3-(4-ethylpiperazin-l-yl)propanoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 73 A compound corresponding to formula (I- A) wherein R is (3-azepan-l-yl)propanoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 74 A compound corresponding to formula (I- A) wherein R b is [(2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)thio]acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 75 A compound corresponding to formula (I- A) wherein Rr is 4-(4-m tneetthhyyllppiippeerriiddiinn--ll--yyll))bbuuttaannooyyll;; RR cc iiss eetthhooxxyyccaarrbboonnyyll;; ⁇ and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 78 A compound corresponding to formula (I- A) wherein R is [(4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 80 A compound corresponding to formula (I- A) wherein R b is 3-(4-methylpiperidin-l-yl)propanoyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 82 A compound corresponding to formula (I- A) wherein R is 4-[(dimethylamino)sulfonyl]benzoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 83 A compound corresponding to formula (I- A) wherein R ⁇ is 3-(2,6-dimethylmorpholin-4-yl)propanoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 84 A compound corresponding to formula (I- A) wherein R is (4-me 3tthhyyllppiippeerriiddiinn--ll--yyll))aacceettyyll;; RR cc iiss eetthhooxxyyccaarrbboonnyyll;; aaind R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 85 A compound corresponding to formula (I- A) wherein R is 4-cyanobenzoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 86 A compound corresponding to formula (I- A) wherein R ⁇ is 3-(4-ethylpiperazin-l-yl)propanoyl; R c is methoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 88 A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-6-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; R c is ethoxycarbonyl; R d is phenyl; and R e is hydrogen:
  • Example 89 A compound corresponding to formula (I- A) wherein R is [(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)thio]acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 90 A compound corresponding to formula (I- A) wherein Ie is [(2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidm-4-yl)thio]acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 91 A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 92 A compound corresponding to formula (I- A) wherein R b is 3-morpholin-4-yl-propanoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 93 A compound corresponding to formula (I- A) wherein R is (azepan-l-yl)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 94 A compound corresponding to formula (I- A) wherein 1 Rr is (3-piperidin-l-yl)propanoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 96 A compound corresponding to formula (I- A) wherein R is[(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 97 A compound corresponding to formula (I- A) wherein R is 3-methylbenzoyl; R c is methoxycarbonyl; R is methyl; and R e is benzyl:
  • Example 98 A compound corresponding to formula (I- A) wherein R is 3-[5-(4-chloro-3-nitrophenyl)-2-furanyl]-2-cyanoprop-2-enoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 99 A compound corresponding to formula (I- A) wherein R is 3-[5-(4-chloro-3-nitrophenyl)-2-furanyl]-2-cyanoprop-2-enoyl; R c is methoxycarbonyl; and R and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 100 A compound corresponding to formula (I- A) wherein R is (3,4-dimethoxyphenyl)acetyl; R c is ethoxycarbonyl; R is hydrogen; and R e is phenyl:
  • Example 102 A compound corresponding to formula (I- A) wherein R is (6,7-dimethyl-3-oxo-l,2,3,4-tetrahydroquinoxalin-2-yl)acetyl; R c is methoxycarbonyl; R is methyl; and R L is methyl:
  • Example 103 A compound corresponding to formula (I- A) wherein R is (2,6-dimethylmorpholin-4-yl)acetyl; R c is aminocarbonyl, R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 105 A compound corresponding to formula (I- A) wherein R b is [(4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 106 A compound corresponding to formula (I- A) wherein R ⁇ is 3-(4-b brroommoo--22--tthhiieennyyll))pprroopp--22--eennooyyll;; RR cc iiss a ammiinnooccaarrbboonnyyll;; aaind R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 107 A compound corresponding to formula (I-A) wherein R is [(3-allyl-4-oxo-6-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 108 A compound corresponding to formula (I-A) wherein R b is 3-morpholin-4-ylpropanoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 109 A compound corresponding to formula (I- A) wherein R is [(6-phenylthieno [2,3 -d] ⁇ yrimidin-4-yl)thio] acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 110 A compound corresponding to formula (I-A) wherein R is l,l-dioxido-l,2-benzisothiazol-3-yl; R c is ethoxycarbonyl; R d is 4-methylphenyl; and R e is hydrogen:
  • R c is 4-tert-butylbenzoyl
  • R c is aminocarbonyl
  • R d is hydrogen
  • R e is phenyl
  • Example 112 A compound corresponding to formula (I- A) wherein R is 3-carboxyprop-2-enoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 113 A compound corresponding to formula (I-A) wherein R is 3-carboxyprop-2-enoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 114 A compound corresponding to formula (I-A) wherein R is 3-(4-methylpiperazin-l-yl)propanoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 115 A compound corresponding to formula (I-A) wherein R ⁇ s 4-chlorobenzoyl; R c is aminocarbonyl; R d is methyl; and R e is benzyl:
  • R c is (4-methylphenyloxy)acetyl; R c is aminocarbonyl; R d is methyl; and R e is methyl:
  • Example 117 A compound corresponding to formula (I-A) wherein R is (2-methoxyphenyloxy)acetyl; R c is aminocarbonyl; R d is methyl; and R e is benzyl:
  • Example 118 A compound corresponding to formula (I- A) wherein R b is 3-(4-methylpiperidin-l-yl)propanoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cycloheptenyl:
  • R c is (4-methylpiperidin-l-yl)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cycloheptenyl:
  • Example 120 A compound corresponding to formula (I- A) wherein R is benzoyl; R c is ⁇ [3-(diethylamino)propyl]amino ⁇ carbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 121 A compound corresponding to formula (I- A) wherein R ⁇ is [4-(2-hydroxyethyl)piperazin-l-yl] acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 122 A compound corresponding to formula (I- A) wherein R is [(4-chlorophenyl)thio]acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 123 A compound corresponding to formula (I- A) wherein R is 3-piperidin-l-yl-propanoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 124 A compound corresponding to formula (I- A) wherein R ⁇ is 4-(difluoromethoxy)benzoyl; R c is aminocarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 125 A compound corresponding to formula (I- A) wherein R b is 3-piperidin-l-ylpropanoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cycloheptenyl:
  • Example 126 A compound corresponding to formula (I- A) wherein R is [(4-m leetthhyyllqquuiinnoo!lin-2-yl)thio]acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • R c is [(4-methylquinolin-2-yl)thio] acetyl; R c is ethoxycarbonyl; R d is 2-furanyl; and R e is hydrogen: is phenyl(phenylthio)acetyl; R c is methoxycarbonyl; R d is methyl; and R e is methoxycarbonyl:
  • Example 129 A compound corresponding to formula (I- A) wherein R is (acetyloxy)(phenyl)acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 130 A compound corresponding to formula (I- A) wherein R b is morpholin-4-ylacetyl; R c is ethoxycarbonyl; R d is 4-chlorophenyl; and R e is methyl: is 2-furoyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 132 A compound corresponding to formula (I- A) wherein R is [2-(2-chlorobenzylidene)hydrazinyl]carbonyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 133 A compound corresponding to formula (I- A) wherein R is 4-chloro-3-nitrobenzoyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 134 A compound corresponding to formula (I- A) wherein Ic is [(4-chlorophenyl)amino]carbonyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 135. A compound corresponding to formula (I- A) wherein R ⁇ is 2-chloro-4-nitrobenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 136 A compound corresponding to formula (I-A) wherein R b is 3-phenylprop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 137 A compound corresponding to formula (I-A) wherein R is 6-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)hexanoyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 138 A compound corresponding to formula (I-A) wherein R is (2-isopropyl-5-methylphenyloxy)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 139 A compound corresponding to formula (I-A) wherein R b is (4-methoxyphenyloxy) acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 140 A compound corresponding to formula (I- A) wherein R is 4-methoxybenzoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 141 A compound corresponding to formula (I-A) wherein R is (2,4-dibromophenyloxy)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • R c is ethoxycarbonyl
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 143 A compound corresponding to formula (I- A) wherein R is butoxycarbonyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 144 A compound corresponding to formula (I- A) wherein R is anilinocarbonyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • R c is chloroacetyl
  • R c is ethoxycarbonyl
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl: is 3-phenyloxypropanoyl
  • R c is ethoxycarbonyl
  • R d is methyl
  • R e is acetyl:
  • Example 147 A compound corresponding to formula (I-A) wherein R is 3-phenyloxypropanoyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 148 A compound corresponding to formula (I-A) wherein R b is 3-phenyloxypropanoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 149 A compound corresponding to formula (I- A) wherein R b is 4-chloro-3-nitrobenzoyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • Example 150 A compound corresponding to formula (I-A) wherein R ⁇ is [2-(2- -hhyyddrrooxxyy--33 --mmeetthhooxx ⁇ ybenzylidene)hydrazinyl]carbonyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • R c is (4-chlorophenyloxy)acetyl
  • R c is aminocarbonyl
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 153 A compound corresponding to formula (I-A) wherein RJ is (2-tert-butyl-4-methylphenyloxy)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 154 A compound corresponding to formula (I-A) wherein R is 4-chlorobenzoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 155 A compound corresponding to formula (I- A) wherein R b is 3-(3,4-dimethoxyphenyl)prop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • R c is ethoxycarbonyl
  • R d is methyl
  • R e is ethoxycarbonyl
  • Example 157 A compound corresponding to formula (I- A) wherein R ⁇ is butyryl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 158 A compound corresponding to formula (I- A) wherein R ⁇ is (2-methoxyphenyloxy) acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 159 A compound corresponding to formula (I-A) wherein R ⁇ is (2-chlorophenyloxy)acetyl; R° is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 160 A compound corresponding to formula (I-A) wherein R is 4-fluorobenzoyl; R c is aminocarbonyl; and R and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 161 A compound corresponding to formula (I-A) wherein R ⁇ is (2-nitrophenyloxy)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 162 A compound corresponding to formula (I- A) wherein R is 2,6-dimethoxybenzoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 163 A compound corresponding to formula (I- A) wherein R b is [3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 164 A compound corresponding to formula (I- A) wherein Ie is (2,6-dimethylphenyloxy)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 165 A compound corresponding to formula (I- A) wherein R is dichloroacetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 166 A compound corresponding to formula (I-A) wherein R is (4-tert-butylphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 167 A compound corresponding to formula (I-A) wherein R is (4-bromo-3-methylphenyloxy)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 168 A compound corresponding to formula (I- A) wherein R b is tiifluoroacetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 169 A compound corresponding to formula (I- A) wherein R ⁇ is 3-phenylprop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 170 A compound corresponding to formula (I-A) wherein R is chloroacetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 171 A compound corresponding to formula (I-A) wherein R is dichloroacetyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 172 A compound corresponding to formula (I- A) wherein R b is (4-chlorophenyloxy)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 173 A compound corresponding to formula (I- A) wherein R is dichloroacetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • R c is aminocarbonyl
  • R and R e together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 175. A compound corresponding to formula (I- A) wherein R is [2-(pyridin-2-yhnethylene)hydrazinyl]carbonyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl: is (4-nitrophenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 178 A compound corresponding to formula (I-A) wherein R ⁇ is (6-bromo-2-oxo-2H-chromen-3-yl)carbonyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl: is 2,3-dihydro-l,4-benzodioxinyl; R c is methoxycarbonyl; and R and R e , together with the atoms to which they are bonded, form methoxycarbonylpentenyl:
  • Example 180 A compound corresponding to formula (I-A) wherein R is (2-methylphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 181 A compound corresponding to formula (I-A) wherein Br is phenyloxyacetyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 182 A compound corresponding to formula (I- A) wherein R b is (4-methoxyphenyloxy) acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 183 A compound corresponding to formula (I-A) wherein R is phenylacetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 184 A compound corresponding to formula (I-A) wherein R is (3-bromophenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 185 A compound corresponding to formula (I-A) wherein R ⁇ is 3-(3-nitrophenyl)prop-2-enoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 186 A compound corresponding to fonnula (I- A) wherein R is l-benzofuran-2-yl-carbonyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • R c is ethoxycarbonyl
  • R d is methyl
  • R e is methyl
  • Example 188 A compound corresponding to formula (I-A) wherein R ⁇ is 3,4,5-trimethoxybenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 189 A compound corresponding to formula (I-A) wherein R is 6-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)hexanoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 190 A compound corresponding to formula (I- A) wherein R is 3-methoxybenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 192 A compound corresponding to formula (I- A) wherein R is 3-phe ;nnyyllpprroopp--22--eennooyyll;; RR cc iiss aammiinnooccaarrbboonnyyll;; aanndd RR cd and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 193 A compound corresponding to formula (I- A) wherein R b is 2-cyano-3-(4-methoxyphenyl)prop-2-enoyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 194 A compound corresponding to formula (I- A) wherein R b is (2,3-dimethylphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 195 A compound corresponding to formula (I- A) wherein R is 3-(3-methoxy-4-propoxyphenyl)prop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • R c is 2-cyano-3-(4-methoxyphenyl)prop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl: is 2-methoxybenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 198 A compound corresponding to formula (I- A) wherein R is (bi ⁇ henyl-4-yloxy)acetyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • Example 199 A compound corresponding to formula (I- A) wherein R is 2-(4-methoxyphenyloxy)propanoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 200 A compound corresponding to formula (I- A) wherein R b is (2-tert-butylphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 201 A compound corresponding to formula (I- A) wherein R is (2-methoxyphenyloxy)acetyl; R c is aminocarbonyl; and R and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 202 A compound corresponding to formula (I- A) wherein R is (2-methylphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • R c is aminocarbonyl
  • R d and R e together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 204 A compound corresponding to formula (I- A) wherein R is (4-nitrophenyloxy)acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 205 A compound corresponding to formula (I- A) wherein R is 2-bromo-3,4,5-trimethoxybenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • R c is 4-chloro-3-nitrobenzoyl
  • R c is methoxycarbonyl
  • R d and R e together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 207 A compound corresponding to formula (I-A) wherein R is (4-bromophenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 208 A compound corresponding to formula (I-A) wherein R is 3,4-dimethoxybenzoyl; R c is ethoxycarbonyl; R is hydrogen; and R e is phenyl:
  • R c is (3-bromophenyloxy)acetyl
  • R c is methoxycarbonyl
  • R d and R e together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 210 A compound corresponding to formula (I-A) wherein R 5" is 2,4-dichlorobenzoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 211 A compound corresponding to formula (I- A) wherein R is 2-chloro-4-nitrobenzoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • R c is (2-nitrophenyloxy)acetyl
  • R c is ethoxycarbonyl
  • R d is hydrogen
  • R e is phenyl
  • Example 21 A compound corresponding to formula (I-A) wherein R is (2,4-dibromophenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 214 A compound corresponding to formula (I-A) wherein R b is [4-(l -methyl- l-phenylethyl)phenyloxy] acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 215. A compound corresponding to formula (I-A) wherein R ⁇ is (4-methoxyphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 216 A compound corresponding to formula (I-A) wherein R is 2-chloro-5-nitrobenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 217 A compound corresponding to formula (I-A) wherein R is 3-(3-nitrophenyl)prop-2-enoyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl: is [2-(2-furanylmethylene)hydrazinyl]carbonyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 219. A compound corresponding to formula (I- A) wherein R is 3-phenylpropanoyl; R° is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 220 A compound corresponding to formula (I- A) wherein R ⁇ is (4-chloro-2-methylphenyloxy)acetyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl: is 2,4-dichlorobenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 223. A compound corresponding to formula (I- A) wherein Iv is 3-(4-ethoxyphenyl)prop-2-enoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 224 A compound corresponding to formula (I- A) wherein R b s 3,4,5-trimethoxybenzoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 225 A compound corresponding to formula (I- A) wherein R is 2-furoyl; R c is aminocarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 226 A compound corresponding to formula (I- A) wherein R is 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)benzoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 227 A compound corresponding to formula (I-A) wherein R b is (2,3,6-trimethylphenyloxy)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 228 A compound corresponding to formula (I- A) wherein R is 3,5-dimethoxybenzoyl; R c is methoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
  • Example 229. A compound corresponding to formula (I- A) wherein R is ⁇ [3-(aminocarbonyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]amino ⁇ (oxo)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 230 A compound corresponding to formula (I- A) wherein R is (2,3,6-trimethylphenyloxy)acetyl; R c is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 23 A compound corresponding to formula (I- A) wherein R is 2-bromo-3-phenylprop-2-enoyl; R c is ethoxycarbonyl; R d is hydrogen; and R e is phenyl:
  • Example 232 A compound corresponding to formula (I- A) wherein R , is 2-bromo-3-phenylprop-2-enoyl; R c is ethoxycarbonyl; R d is methyl; and R e is acetyl:
  • R c is aminocarbonyl
  • R d and R e together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 234 A compound corresponding to formula (I- A) wherein R is 2-bromo-3,4,5-trimethoxybenzoyl; R c is ethoxycarbonyl; R d is methyl; and R e is methyl:
  • Example 235 A compound corresponding to formula (I- A) wherein Ie is 3-[3-methoxy-4-(pentyloxy)phenyl]prop-2-enoyl; R° is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • R c is benzoyl; R c is,3-hydroxypropylaminocarbonyl; R d is methyl; and R e is methyl:
  • Example 237 A compound corresponding to formula (I- A) wherein R ⁇ is 3-methoxybenzoyl; R c is [(4-methoxyphenyl)amino]carbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl: is 2-thienylcarbonyl; R c is piperidin-lylcarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 239. A compound corresponding to formula (I- A) wherein R is 2-furo oyyll;; RR cc iiss [[((44--eetthhooxxyypphheennyyll))aammminoo]]ccaarrbboonnyyll;; a and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 240 A compound corresponding to formula (I- A) wherein R is 2-furoyl; R c is [(4-methylphenyl)amino]carbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 241 A compound corresponding to formula (I-A) wherein R is benzoyl; R c is [(4-methoxyphenyl)amino]carbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 242 A compound corresponding to formula (I-A) wherein R is 2-thie snnyyllccaarrbboonnyyll;; RR cc iiss ((ddiieetthhyyllaammiinnoo))ccaarrbboonnyyll;; a ani d R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 243 A compound corresponding to formula (I-A) wherein R is benzoyl; R c is [(4-methoxyphenyl)amino]carbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 244 A compound corresponding to formula (I- A) wherein R b is benzoyl; R c is [(2-ammoethyl)amino]carbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 245. A compound corresponding to formula (I- A) wherein R is [(4-methoxyphenyl)amino] acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 246 A compound corresponding to formula (I- A) wherein R is benzoyl; R c is [(2-hydroxyethyl)amino]carbonyl; R d is phenyl; and R e is hydrogen:
  • Example 247 A compound corresponding to formula (I- A) wherein R is (7-methyl-4-oxo-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)- acetyl; R c is ethoxycarbonyl; and R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl:
  • Example 250 A compound corresponding to formula (I- A) wherein R is 5-nitro-2-furoyl; R c is ethoxycarbonyl; R d is methyl; and R e is ethoxycarbonyl:
  • R c is ethoxycarbonyl
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl:
  • Example 252 A compound corresponding to formula (I- A) wherein R b is [(4-tert-butylbenzoyl)amino]carbonothioyl; R° is aminocarbonyl; and R d and R e , together with the atoms to which they are bonded, form cyclopentenyl:
  • Example 253 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is hydrogen; and R 9 is 2-phenylvinyl:
  • Example 254 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is [2-(cyclohexylamino)-2-oxoethyl]thio: R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is difluoromethanesulfenyl:
  • Example 256 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is (3- ⁇ [4- (aminosulfonyl)phenyl] amino ⁇ -3 -oxopropyl)thio :
  • R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4- (aminosulfonyl)phenyl]amino ⁇ -2-oxoethyl)thio:
  • Example 258 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is methyl; and R 9 is [4- ' (methoxycarbonyl)benzyl]thio:
  • Example 259. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is [(2-chlorophenyl)methylene]amino; and R 9 is hydrogen:
  • Example 260 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is hydrogen; and R 9 is [(4-phenyl-5-thioxo ' -4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]thio:
  • Example 26 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [2-(3,4-dimethoxyphenyl)ethyl]amino ⁇ -2- oxoethyl)thio:
  • Example 262 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is hydrogen; and R 9 is [2-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)- yl)ethyl]thio:
  • Example 263 A compound corresponding to formula (I-B-2) wherein R e is ethoxycarbonyl; R d is methyl; R 7 is oxo; R 8 is [l,3-benzodioxol-5- ylmethylene] amino; and R 9 is methyl:
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl;
  • R 7 is oxo;
  • R 8 is hydrogen;
  • R 9 is 2-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)-yl)ethyl:
  • Example 265. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(phenyloxysulfonyl)ethyl]thio:
  • Example 266 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [4-(aminosulfonyl)phenyl]amino ⁇ -2-oxoethyl)thio:
  • Example 267 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [4-chloro-3-(trifluoromethyl)phenyl]amino ⁇ -2- oxoethyl)thio:
  • Example 268 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is [2-(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)ethyl]thio:
  • Example 269. A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4- (aminosulfonyl)phenyl]amino ⁇ -2-oxoethyl)thio:
  • Example 270 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3-cyano-6-methyl- 4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)amino] -2-oxoethyl ⁇ thio :
  • Example 271 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is 2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethanesulfenyl: R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(3,4- dimethoxyphenyl)-2-oxoethyl]thio:
  • Example 273 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(l,3- benzodioxol-5-ylamino)-2-oxoethyl]thio:
  • Example 274 A compound corresponding to formula (I-B-2) wherein R e is ethoxycarbonyl; R d is methyl; R 7 is oxo; R 8 is lH-pyrrol-1-yl; and R 9 is hydrogen:
  • Example 275 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2-fluorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 276 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is [(3,5-dimethylisoxazol-4-yl)methyl]thio:
  • Example 277 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-methylphenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2,6- dichlorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 278 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2- (cyclohexylamino)-2-oxoethyl]thio:
  • Example 279. A compound corresponding to formula (I-B-2) wherein R e is ethoxycarbonyl; R d is methyl; R 7 is oxo; R 8 is [(5-nitro-2- furanyl)methylene] amino; and R 9 is hydrogen:
  • Example 280 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(l-adamantylamino)-2-oxoethyl]thio:
  • Example 281 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [2-( ⁇ [(3-allyl-4-oxo-5- phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl ⁇ amino)hexyl]amino ⁇ -2- oxoethyl)thio:
  • Example 282 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino ⁇ -2-oxoethyl)thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4- (acetylamino)phenyl]amino ⁇ -2-oxoethyl)thio: R e is hydrogen; R d is 3,4-dimethoxyphenyl; R 7 is oxo; R 8 is allyl; and R 9 is difluoromethanesulfenyl:
  • Example 285. A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2- [(aminocarbonyl)amino]-2-oxoethyl ⁇ thio:
  • Example 286 A compound corresponding to formula (I-B-2) wherein R e is ethoxycarbonyl; R d is methyl; R 7 is oxo; R 8 is (4-hydroxybenzylidene)amino; and R 9 is hydrogen:
  • Example 287 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is phenyl; and R 9 is [2-(2-naphthyl)-2- oxoethyl]thio:
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl;
  • R 7 is oxo;
  • R is allyl; and
  • R is ⁇ 3-[(4-fluorophenyl)amino]-3-oxopropyl ⁇ thio:
  • R e is phenyl
  • R d is hydrogen
  • R 7 is oxo
  • R 8 is phenyl
  • R 9 is (2- ⁇ [3- (ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2-thienyl]amino ⁇ -2-oxoethyl)thio:
  • Example 290 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is ⁇ [2-(difluoromethoxy)phenyl]methylene ⁇ amino; and R 9 is hydrogen:
  • Example 291 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is [(5,7- dimethylimidazo[l,2-a]pyrimidin-2-yl)methyl]thio:
  • Example 293 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is hydrogen; and R 9 is [(5- ⁇ [4- (methoxycarbonyl)benzyl]thio ⁇ -4-phenyl-4H-l,2,4-triazol-3-yl)methyl]thio:
  • Example 294 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-methylphenyl; R 7 is thioxo; R 8 is hydrogen; and R 9 is hydrogen:
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is (2-mo ⁇ holin-4-yl-2-oxoethyl)thio:
  • Example 296 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is hydrogen; and R 9 is [(5-anilino-l,3,4-thiadiazol-2-yl)methyl]thio:
  • Example 297 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is [ (2-chloroimidazo[l,2-a]pyridin-3- yl)methylene] amino; and R 9 is hydrogen: R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is (cyanomethyl)thio:
  • Example 299. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (3- ⁇ [4-(aminosulfonyl)phenyl]amino ⁇ -3-oxopropyl)thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[4-(ethoxycarbonyl)- 3 ,5 -dimethyl- 1 H-pyrrol-2-yl] -2-oxoethyl ⁇ thio :
  • R is hydrogen; R is 4-methoxyphenyl; R is oxo; R is 2,5-dimethyl-lH-pyrrol-l-yl; and R 9 is hydrogen:
  • Example 302. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-oxo-2- ⁇ [3-(trifluoromethyl)phenyl]amino ⁇ ethyl)thio:
  • Example 303 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl; R is oxo; R is allyl; and R is [(3,5-dimethylisoxazol-4- yl)methyl]thio:
  • Example 304 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(2-furanyl)-2- oxoethyl]thio:
  • Example 305 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3-cyano-2- thienyl)amino] -2-oxoethyl ⁇ thio :
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is [2-(2-methyl-lH-indol-3-yl)-2-oxoethyl]thio:
  • Example 307 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-4-phenyl-2-thienyl]amino ⁇ -2- oxoethyl)thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[(5-methylisoxazol- 3-yl)amino]-2-oxoethyl ⁇ thio:
  • Example 309 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is allyl; and R is (2-oxo-2- ⁇ [3-(trifluoromethyl)phenyl]amino ⁇ ethyl)thio:
  • Example 310 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-chlorophenyl; R 7 is oxo; R 8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R 9 is methyl:
  • Example 311 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4-(aminosulfonyl)phenyl]amino ⁇ -2-oxoethyl)thio:
  • Example 312 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-benzylphenyl; R 7 is oxo; R 8 is amino; and R 9 is hydrogen:
  • Example 31 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(4-ethoxyphenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 31 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is difluoromethanesulfenyl:
  • Example 315 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[(2-methoxyethyl)amino]-2-oxoethyl ⁇ thio:
  • Example 316 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is hydrogen; and R 9 is phenyl:
  • Example 317 A compound corresponding to formula (I-B-2) wherein R and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2,4-dimethylphenyl)amino]-2-oxoethyl ⁇ thio: R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(l,3-benzodioxol-5-ylmethyl)amino]-2-oxoethyl ⁇ thio:
  • Example 319 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is methyl; and R 9 is ⁇ 2-oxo-2-[(pyridin-2-ylmethyl)amino]ethyl ⁇ thio:
  • Example 320 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(4- methylphenyl)amino] -2-oxoethyl ⁇ thio :
  • Example 32 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is thioxo; R 8 is hydrogen; and R 9 is methyl:
  • Example 322 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-anilino-2-oxoethyl)thio:
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is ⁇ 2-[(4-methylphenyl)amino]-2-oxoethyl ⁇ thio:
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is [2-(4-fluorophenyl)-2-oxoethyl]thio:
  • Example 325 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 3,4-dimethylphenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[4- (ethoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl ⁇ thio:
  • Example 326 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2- furanylmethyl)amino]-2-oxoethyl ⁇ thio:
  • Example 327 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(4-ethoxyphenyl)amino]- 2-oxoethyl ⁇ thio: R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2,5-dimethoxyphenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 329 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluoro ⁇ henyl; R 7 is oxo; R 8 is allyl; and R 9 is [(3,5- dimethylisoxazol-4-yl)methyl]thio:
  • Example 330 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3,5- bis(methoxycarbonyl)phenyl] amino ⁇ -2-oxoethyl)thio :
  • Example 331 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-oxo-2-[(2- phenylethyl) amino] ethyl ⁇ thio :
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is (2- ⁇ [3-(ethoxycarbonyl)-4-(4-methoxyphenyl)-2- thienyl] amino ⁇ -2-oxoethyl)thio :
  • Example 333 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-[4-(ethoxycarbonyl)- 3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl ⁇ thio: R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R is ⁇ 2-[(3,4-dimethylphenyl)amino]-2-oxoethyl ⁇ thio:
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R is phenyl; and
  • R is (2-fluorobenzyl)thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[(3-cyano-5,6,7,8- tetrahydro-4H-cyclohepta[b]thien-2-yl)amino]-2-oxoethyl ⁇ thio:
  • Example 337 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[(2,6- dichlorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 338 A compound corresponding to formula (I-B-2) wherein R el is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-oxo-2- ⁇ [2- (trifluoromethyl)phenyl] amino ⁇ ethyl)thio :
  • Example 339 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-5,6,7,8-tetrahydro-4H- cyclohepta[b]thien-2-yl]amino ⁇ -2-oxoethyl)thio: R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3-cyano-6-methyl-4,5,6,7-tetrahydro-l-benzothien-2- yl)amino] -2-oxoethyl ⁇ thio :
  • Example 341 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-oxo-2-[(2- phenylethyl)amino] ethyl ⁇ thio :
  • Example 342 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2,6-dichlorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 343 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(l,3-benzodioxol-5- ylamino)-2-oxoethyl]thio :
  • Example 344 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-oxo-2- ⁇ [2- (trifluoromethyl)phenyl] amino ⁇ ethyl)thio :
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is ⁇ 2-[4-(methoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2- oxoethyljthio:
  • Example 346 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-l- benzothien-2-yl]amino ⁇ -2-oxoethyl)thio:
  • Example 347 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4-chloro-3-(trifluoromethyl)phenyl]amino ⁇ -2- oxoethyl)thio:
  • Example 348 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclop entenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3-cyano-5,6-dihydro-4H-cyclopenta[b]thien-2- yl)amino]-2-oxoethyl ⁇ thio:
  • Example 349 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2-oxopropyl)thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is 2-[(2,6- dimethylphenyl)amino]-2-oxoethanesulfenyl:
  • Example 35 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(4- fluorophenyl)amino] -2-oxoethyl ⁇ thio :
  • Example 352 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-5-phenyl-2-thienyl]amino ⁇ -2- oxoethyl)thio:
  • Example 35 A compound corresponding to formula (I-B-2) wherein
  • Example 354 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is [2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]thio:
  • Example 355. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is [4-(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)butyl]thio :
  • Example 356 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [2-(3,4- dimethoxyphenyl) ethyl] amino ⁇ -2-oxoethyl)thio :
  • Example 357 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (l,3-benzodioxol-5- ylmethyl)thio:
  • Example 358 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-oxo-2-[(2- phenylethyl)amino] ethyl ⁇ thio : R d and R e , together with the atoms to which they are bonded, form cyclop entenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[4-(ethoxycarbonyl)-3 J 5-dimethyl-lH-pyrrol-2-yl]-2- oxoethyl ⁇ tliio:
  • Example 360 A compound corresponding to formula (I-B-2) wherein
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is allyl; and
  • R 9 is [2-(l,3-benzodioxol-5-ylamino)-2-oxoethyl]thio:
  • Example 361 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is allyl; and R is (2- ⁇ [3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopenta[b]thien- 2-yl]amino ⁇ -2-oxoethyl)thio:
  • Example 362 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(l,3-benzodioxol-5- ylmethyl)amino] -2-oxoethyl ⁇ thio :
  • Example 363 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-5- (methoxycarbonyl)-4-methyl-2-thienyl] amino ⁇ -2-oxoethyl)thio :
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is 2-(l,3-benzodioxol-5- yl)-2-oxoethanesulfenyl:
  • Example 365 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclop entenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3-cyano-4,5,6,7-tetrahydro-l-benzothien-2-yl)amino]-2- oxoethyljthio:
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is phenyl; and
  • R 9 is (2-oxo-2- ⁇ [2-(trifluoromethyl)phenyl] amino ⁇ ethyl)thio:
  • R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3- methylphenyl)amino]-2-oxoethyl ⁇ thio: R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [4-(3,4-dimethoxyphenyl)-3-(ethoxycarbonyl)-2- thienyl] amino ⁇ -2-oxoethyl)thio :
  • Example 369 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is allyl; and R is (2-fluorobenzyl)thio:
  • Example 370 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2- yl)amino]-2-oxoethyl ⁇ thio:
  • Example 37 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form methylcyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[(2-fluorophenyl)amino]-2- oxoethyl ⁇ thio:
  • R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is [2-(l,3-dioxo-l,3-dihydro- 2H-isoindol-2-yl)ethyl]thio :
  • Example 373 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is phenyl; and R is [2-(4-methoxyphenyl)-2-oxoethyl]thio:
  • Example 374 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is phenyl; and R is ⁇ 2-[(3-cyano-4,5,6,7-tetrahydro-l-benzothien-2-yl)amino]- 2-oxoethyl ⁇ thio:
  • Example 375 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2,6- dichlorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 376 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-methoxyphenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[4- (ethoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl ⁇ thio:
  • Example 377 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is [2-(2-fluorophenyl)-2-oxoethyl]thio:
  • Example 378 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4-(methoxycarbonyl)phenyl]amino ⁇ -2-oxoethyl)thio:
  • Example 379 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2-oxopropyl)thio:
  • Example 380 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is 2-[(2,6-dimethylphenyl)amino]-2-oxoethanesulfenyl:
  • Example 381 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-methoxyphenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-oxo-2-[(2- phenylethyl)amino]ethyl ⁇ thio :
  • Example 382 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-oxopropyl)thio:
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is phenyl; and
  • R 9 is ⁇ 2-[(2-fluorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 384 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is phenyl; and R 9 is 2-[(2,6- dimethylphenyl)amino]-2-oxoethanesulfenyl:
  • R d and R e together with the atoms to which they are bonded, form cyclohexenyl;
  • R 7 is oxo;
  • R 8 is phenyl; and
  • R 9 is 2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethanesulfenyl:
  • Example 386 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is 2-[(2,6-dimethylphenyl)amino]-2-oxoethanesulfenyl:
  • Example 387 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 3,4-dimethoxyphenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[4- (ethoxycarbonyl)-3 ,5-dimethyl- lH-pyrrol-2-yl] -2-oxoethyl ⁇ thio :
  • Example 388 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is phenyl; and R 9 is [2-(3,4-dimethoxyphenyl)-2-oxoethyl]thio:
  • R and R e together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R is phenyl; and R is ⁇ 2-[(3-cyano-5,6-dihydro-4H-cyclopenta[b]thien-2- yl)amino] -2-oxoethyl ⁇ thio :
  • Example 390 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-oxo-2-[(2-phenylethyl)amino]ethyl ⁇ thio:
  • Example 39 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R is phenyl; and R is [(3,5-dimethylisoxazol-4-yl)methyl]thio:
  • Example 392 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-5,6,7,8-tetrahydro-4H- cyclohepta[b] thien-2-yl] amino ⁇ -2-oxoethyl)thio :
  • Example 393 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(2,6-dichlorophenyl)amino]-2-oxoethyl ⁇ thio:
  • Example 394 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(methoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino ⁇ -2-oxoethyl)thio:
  • Example 395 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R is phenyl; and R is (2- ⁇ [3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino ⁇ -2-oxoethyl)thio:
  • Example 396 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[2,5-dimethyl-l-(4- methylphenyl)-lH-pyrrol-3-yl]-2-oxoethyl ⁇ thio:
  • Example 397 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2-oxo-2- ⁇ [3- (trifluoromethyl)phenyl] amino ⁇ ethyl)thio :
  • Example 398 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2- thienyl] amino ⁇ -2-oxoethyl)thio :
  • Example 399 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo;R 8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R 9 is hydrogen:
  • Example 400 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R 9 is hydrogen:
  • Example 401 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R is allyl; and R is [2-(5-methyl-2-nitrophenyloxy)ethyl]thio:
  • Example 402. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is hydrogen; and R is (4- ⁇ [(2-hydroxyethyl)amino]carbonyl ⁇ benzyl)thio:
  • Example 403 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-tert-butylphenyl; R 7 is oxo; R 8 is amino; and R 9 is methyl:
  • Example 404 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is hydrogen; and R is methyl:
  • Example 405. A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclopentenyl; R 7 is oxo; R is hydrogen; and R is (4- ⁇ [(3-hydroxypropyl)amino]carbonyl ⁇ benzyl)thio:
  • Example 407 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)- 5 -(methoxycarbonyl)-4-methyl-2-thienyl] amino ⁇ -2-oxoethyl)thio :
  • Example 408 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-methylphenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(4- fluorophenyl)amino]-2-oxoethyl ⁇ thio: R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2- [(aminocarbonyl)amino] -2-oxoethyl ⁇ thio :
  • R d and R e together with the atoms to which they are bonded, form cyclopentenyl;
  • R 7 is oxo;
  • R 8 is phenyl; and
  • R 9 is (2-tert-butoxy-2-oxoethyl)thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is 2-(2,3-dihydro-l,4- benzodioxin-6-yl)-2-oxoethanesulfenyl:
  • Example 412 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is allyl; and R 9 is ⁇ 2-[(4- ethoxyphenyl)amino]-2-oxqethyl ⁇ thio:
  • Example 413 A compound corresponding to formula (I-B-2) wherein R d and R e , together with the atoms to which they are bonded, form cyclohexenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ 2,5-dimethyl-l-[3-(trifluoromethyl)phenyl]-lH-pyrrol-3- yl ⁇ -2-oxoethyl)thio :
  • Example 414 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is [2-(l-naphthyl)-2- oxoethyl]thio:
  • Example 415 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is ⁇ 2-[(2- furanylmethyl)amino]-2-oxoethyl ⁇ thio:
  • R e is hydrogen; R d is phenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (2- ⁇ [3,5- bis(methoxycarbonyl)phenyl]amino ⁇ -2-oxoethyl)thio:
  • R e is hydrogen; R d is 4-methoxyphenyl; R 7 is oxo; R 8 is phenyl; and R 9 is (3,4- dichlorobenzyl)thio :
  • Example 418 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [4-chloro-3- (trifiuoromethyl)phenyl] amino ⁇ -2-oxoethyl)thio :
  • Example 419 A compound corresponding to formula (I-B-2) wherein R e is hydrogen; R d is 4-fluorophenyl; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3- (methoxycarbonyl)-5-phenyl-2-thienyl]amino ⁇ -2-oxoethyl)thio:
  • Example 420 A compound corresponding to formula (I-B-2) wherein R e is phenyl; R d is hydrogen; R 7 is oxo; R 8 is allyl; and R 9 is (2- ⁇ [3-(ethoxycarbonyl)- 4-phenyl-2-thienyl] amino ⁇ -2-oxoethyl)thio :
  • Example 421 A compound corresponding to formula (I-B-2) wherein R e is methyl; R d is methyl; R 7 is oxo; R 8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R 9 is hydrogen:

Abstract

This invention is directed to thienyl compounds (particularly (thien-2-yl)amino compounds), pharmaceutical compositions and kits comprising such compounds, and uses of such compounds for preparing medicaments and treating virus-related conditions in animals.

Description

THIENYL COMPOUNDS FOR TREATING VIRUS-RELATED CONDITIONS
PRIORITY CLAIM TO RELATED PATENT APPLICATIONS [1] This patent claims priority to U.S. Provisional Patent Application
Serial No. 60/582,996 (filed June 25, 2004); and U.S. Non-Provisional Patent
Application Serial No. (filed June 24, 2005). The entire text of both patent applications is incorporated by reference into this patent.
FIELD OF THE INVENTION
[2] This invention is directed generally to thienyl compounds (including salts thereof), and their use as anti-viral agents. More particularly, this invention is directed to (thien-2-yl)amino compounds, pharmaceutical compositions and kits comprising such compounds, and uses of such compounds for preparing medicaments and treating virus-related conditions in animals.
BACKGROUND OF THE INVENTION
[3] Significant progress has been made in the development of antiviral drugs. Just thirty years ago, there were no FDA-approved antiviral drugs. Today, there are over forty. Still, the applicability of these drags continues to be limited. More than half the FDA-approved antiviral drugs, for example, are for use in treating infections caused by human immunodeficiency virus (HIV), and most the remaining drags are for use in treating herpes virus infections.
[4] The majority of human viral pathogens are RNA viruses. The FDA has approved only two small-molecule antiviral drags for use against RNA viruses, and only one, ribavirin, exhibits broad-spectrum activity. Consequently, for many RNA viruses, there are only limited, if any, therapeutic options available.
[5] Hepatitis C virus (HCV)3 for example, is an RNA virus that causes chronic hepatitis afflicting an estimated 170 million individuals worldwide, including approximately 4 million in the United States. The level of sickness and mortality associated with HCV is high. The majority of infected patients remain infected for life, and a significant percentage of HCV-infected patients ultimately progress to cirrhosis, liver failure, or hepatocellular carcinoma. No vaccine has been reported for HCV. It is believed that the best available treatment for HCV is a combination of two broad- spectrum antiviral agents, interferon and ribavirin. This therapy, however, is only effective for about half of all patients, and is associated with serious side effects that cause another 10-15% of otherwise suitable patients to discontinue therapy. HCV also tends to develop resistance to antiviral drugs during therapy. It is expected, therefore, that multi-drug "cocktail" therapies, used in different combinations at varying stages of disease progression, will be necessary to effectively manage chronic HCV infection. [6] Respiratory syncytial virus (RSV) is another RNA virus. This virus is contracted by virtually all children by the age of three. It spreads rapidly through contact with respiratory secretions, and is the primary cause of bronchopneumonia in infants and children in the United States. It is estimated that RSV infections result in 100,000 hospitalizations and 4,000 deaths each year in the United States alone. Premature infants, immunodeficient patients, and the institutionalized elderly are at the greatest risk for sickness and mortality from RSV. Current treatments for RSV are limited and suboptimal. For example, inhaled ribavirin is difficult to administer and relatively toxic, and, as a result, infrequently used. A prophylactically-administrated monoclonal antibody (Synagis, Medlmmune) also is available, but used only with high- risk patients. [7] Primary screening programs to identify compounds with antiviral activity involve two general methods - "targeted" screening and "unbiased" screening. In the "targeted" approach, a particular biochemical target is chosen, and then inhibitors of the chosen target are screened. The chosen target is typically an enzyme or a receptor that is known or thought to be essential to viral replication. In the alternative approach, "unbiased" screening, inhibitors of viral replication are sought without a priori concern for the target. Unbiased screening necessarily involves the use of cell culture for virus replication. This is due, in part, to the fact that cellular targets are likely targets of many anti-viral agents. Although cell-based screening has been used successfully throughout the drug-discovery field, it has historically been problematic when screening for antiviral compounds because it required inoculation of an infectious virus onto the cells, and then producing additional infectious progeny virus. Handling such infectious material is not easily compatible with the high throughput process of screening large libraries of compounds.
[8] Partial viral replication systems have been developed to circumvent the problems associated with cell-based cultures using whole viral systems. In the partial viral systems, viral genomes lacking one or more genetic elements essential for complete replication are used to accomplish viral genomic replication without producing the infectious virus. This is particularly important for viral agents, such as viral hemorrhagic fever, classified as biohazard level 3 or 4 (BL-3 or BL-4). A screening process that utilizes these incomplete viral genomes can identify inhibitors of any biochemical pathway involved in viral genome replication, transcription, and translation. This allows for screening with respect to multiple possible targets. These targets do not have to be known, thus making the screening process unbiased. In addition, the targets are pre- validated, given that inhibition of RNA replication is directly relevant to the viral disease process. Screening with partial viral replication systems additionally is advantageous because complex viral replication pathways can be easily monitored by measuring levels of viral RNA or expression of a reporter gene present in the replicon or defective genome.
[9] The utility of using partial viral replication systems can be expanded further by screening for multiple viruses simultaneously. More specifically, by combining cell lines, each of which contain a partially replicating viral genome, one can screen for antiviral activity against each virus during the same screen, thereby saving time, reducing costs, and allowing for more effective use of material libraries. And, in addition to measuring the effect of a compound on genomic replication of several viruses, use of a partial viral replication system can provide information on the specificity of the antiviral effect. This information is helpful in accessing, for example, whether the effect is acting on a specific viral target or on a cellular target, and, thus, exerting its effect on the virus indirectly. This also may be helpful for identifying compounds that exhibit broad antiviral activity (i.e., activity against more than one, and typically several, viruses). [10] There are generally two types of partial viral replication systems: defective genomes and replicons. [11] Defective genomes (which often are artificial genomes or minigenomes) typically contain all the cw-acting elements required for viral genomic replication and transcription, but lack one or more of the genetic elements that encode the trans-acting factors required for replication. Such defective genomes, therefore, cannot replicate by themselves, but can replicate if the missing factor (or factors) is supplied in trans.
When a cell contains both the defective genome and the necessary trans-acting factors, partial viral replication occurs within the cell without infectious virus being produced. Cell cultures containing replicating defective viral genomes represent a useful tool for antiviral drug discovery. For example, they may be used to observe the effect of an antiviral agent in the context of living cells, and therefore allow for the selection of agents that can enter and act within living cells. Such cell lines also may be used to immediately identify antiviral agents with undesirable cytotoxicity using well- established cytotoxicity assays. In addition, such cell lines permit cell-based drug discovery screens to be performed on a broad array of viruses, including, for example, viruses (e.g., HCV and Human Papillomavirus (HPV)) that are difficult to culture or cannot be cultured by conventional means. Further, such cell lines are much safer and thus easier to work with than cell lines that make infectious virus. A still further advantage of such cell lines is that reporter genes (e.g., luciferase, beta-galactosidase, secreted alkaline phosphatase, green fluorescent protein, etc.) that facilitate high throughput automated analysis of viral genome copy number can be incorporated into the defective genome.
[12] Replicons are subgenomic nucleic acid molecules that are capable of replicating within cells cultured in vitro, In contrast to defective genomes, replicons typically encode all the cis and trans-acting viral components required for replication and transcription of the viral genome within a cell. Replicons, however, lack one or more elements required to replicate a full virus. For example, replicons often lack sequences related to infectivity. Such replicons are safer and easier to work with than a corresponding infectious virus, and are often ideal for studying treatments directed to viral replication because viral functions related to infectivity typically are not required for replication. Recently, several replicons capable of persistent replication in cells have been reported. See, e.g., Bartenschlager et al., "Novel cell culture systems for the hepatitis C virus," Antiviral Res. 52:1-17 (2001). See also, Frolov et al., "Selection of RNA replicons capable of persistent noncytopathic replication in mammalian cells," J. Virol. 73:3854-65 (1999). See also, Rice et al., "Transcription of infectious yellow fever RNA from full-length cDNA templates produced by in vitro ligation," New Biol. 1 :285-96 (1989). A viral replicon culture (VRC) is a cell line containing a persistently replicating non-cytopathic viral replicon. VRCs provide benefits similar to those described above with respect to the defective genome cell lines.
[13] Partial viral replication systems are valuable molecular tools that can be used for a variety of purposes. In general, they can be used as tools to promote basic investigations of viral replication and pathogenesis. Specific uses include, for example: identification and evaluation of antiviral agents (e.g. , small molecules, RNAi, antisense, ribozymes, etc.), | development and evaluation of diagnostic assays and reagents, development and evaluation of vaccines, development of vectors (e.g., gene delivery, protein expression, vaccines, etc.), evaluation of the function of viral genes and proteins, localization of viral proteins, characterization of cellular antiviral pathways (e.g., IFN, PKR, RNAi, etc.), characterization of viral RNA replication (within cells and cell-free systems), identification of cis-acting elements, and identification of host proteins required for viral replication.
[14] Screening with partial viral replication systems can be applied to any type of viral pathogen, including viruses with RNA or DNA genomes. Examples include those shown in Table 1 :
Table 1. Viral Replicons for Antiviral Screening
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
[15] Many viruses in Table 1 are priority pathogens of concern for biodefense. One of these, viral hemorrhagic fever (VHF), refers to a group of illnesses that are caused by members of four families of viruses (Flaviviridae, Filoviridae, Arenaviridae, and Bunyaviridae). Many of these viruses cause severe, life-threatening diseases that are easily transmitted from person to person, and are listed by the CDC and NIH as category A pathogens. Category B and C viral pathogens include members of the Togaviridae (VEE, etc.), Flaviviridae (YFV, WNV, etc.) said Bunyaviridae families.
[16] There have been significant advances in the development of reverse genetic systems for RNA viruses. Generally, all viruses possess genes that encode for RNA-dependent RNA polymerase to produce mRNA and thereby replicate the virus' genome. Upon infection of cells, the genomic RNA of positive strand RNA viruses replicates through the use of a complementary negative strand intermediate in a three phase mechanism. In the first phase, translated viral proteins and one or more host proteins form a replicase complex that attaches to the 3' of the positive-strand viral RNA. In the second phase, the viral RNA is copied to a complementary, negative- strand RNA. In the final phase, the negative RNA serves as a template for synthesis of progeny positive-strand viral RNA. Notably, positive-strand RNA viruses make structural proteins soon after entering the host cell cytoplasm because the viral genome acts as mRNA.
[17] Positive-strand RNA viruses include, for example, members of the Togaviridae, Flaviviridae {e.g., HCV, WNV, and YFV), and Picornaviridae. These viruses were among the first RNA viruses for which reverse genetics studies were performed. See, e.g., Khromykh, "Replicon-based vectors of positive strand RNA viruses," Cμrr. Opin. MoI. Ther. 2:555-69 (2000). See also, Khromykh et al., "Subgenomic replicons of the flavivirus Kunjin: construction and applications," J. Virol. 71:1497-505 (1997). See also, Racaniello, V. R., "Studying poliovirus with infectious cloned cDNA," Rev. Infect. Dis. 6 Suppl 2:S514-5 (1984). See also, Rice et al., "Transcription of infectious yellow fever RNA from full-length cDNA templates produced by in vitro ligation," New Biol. 1 :285-96 (1989). There is, therefore, significant experience in genetically manipulating these viruses and constructing genetic tools such as cDNA clones (including infectious cDNA clones), subgenomic replicons, and defective genomes. See, e.g., Lai et al., "Infectious RNA transcribed from stably cloned full-length cDNA dengue type 4 virus," Proc. Natl. Acad. ScL USA 88:5139-43 (1991). See also, Perri et al., "Replicon vectors derived from Sindbis virus and Semliki forest virus that establish persistent replication in host cells," J. Virol. 74:9802-7 (2000). See also, Sumiyoshi et al., "Infectious Japanese encephalitis virus RNA can be synthesized from in vitro-ligated cDNA templates," J. Virol. 66:5425-31 (1992). In fact, the construction of infectious clones has become the standard practice for developing models to study these viruses. An infectious cDNA for yellow fever virus strain 17D, for example, was successfully constructed, and has been used in reverse genetics experiments to help elucidate the role of various viral genes in replication and pathogenesis. See, e.g., Rice et al., "Transcription of infectious yellow fever RNA from full-length cDNA templates produced by in vitro ligation," New Biol. 1 :285-96 (1989). This cDNA clone also has promoted efforts to identify the transacting and genomic czs-acting elements involved in viral replication. See Lindenbach, et al., "trarø-Complementation of yellow fever virus NSl reveals a role in early RNA replication," J. Virol. 71:9608-17 (1997). Full-length cDNA also have enabled investigators to construct replicons. See, e.g., Lindenbach, et al.
[18] Replicons and defective genomes can be used in cultures that lack cell toxicity, thus enabling long-term propagation and reporter or resistance gene expression. See Lindenbach, et al. Flavivirus replicons, for example, have been constructed by many groups, and these efforts have formed the foundation of the recent success in constructing subgenomic replicons of the hepatitis C virus. See, e.g., Blight et al., "Efficient initiation of HCV RNA replication in cell culture," Science 290:1972- 74 (2000). See also, Lohmann et al., "Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line," Science 285: 110-3 (1999). Replicons also have been constructed for the closely related Kunjin flavivirus. See, e.g., Khromykh et al., J. Virol. 71 : 1497-505 (1997). A West Nile virus (WNV) replicon, modeled on Kunjin and HCV based on the New York 2000 strain of WNV (3000.0259), also has been constructed. See, e.g., Shi et al., "Construction and characterization of subgenomic replicons of New York strain of West Nile virus," Virology 296:219-33 (2002) (57, 67). See also, Yamshchikov et al., "An infectious clone of the West Nile Flavivirus," Virology 281 :294-304 (2001).
[19] The HCV genome, in particular, has been analyzed extensively. See, e.g., Blight et al., "Molecular virology of hepatitis C virus: an update with respect to potential antiviral targets," Antiviral Ther. 3:71-81 (1998). HCV has been classified as a member of the family Flaviviridae, which includes flaviviruses (e.g., yellow fever virus) and pestiviruses (e.g., bovine viral diarrhea virus). A major impediment to understanding HCV virology has been the lack of a reliable and robust cell culture replication system. A second problem is that the only animal model with which to study HCV pathogenesis is the chimpanzee. A full-length cDNA clone of the HCV genome has been constructed (consensus Ia). See Kolykhalov et al., "Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA," Science 277:570-4
(1997). In vitro transcripts made from this cDNA were shown to cause HCV hepatitis following intrahepatic injection into chimpanzees. Unfortunately, a robust cell culture system for propagating virus and making stocks of mutant viruses from an infectious cDNA clone is not yet available. Cell lines stably transformed with a subgenomic HCV RNA replicon derived from HCV RNA of genotype Ib have been isolated. See Frese et. al., "Interferon-alpha inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway," J. Gen. Virol. 82:723-33 (2001). See also, Lohmann et al., "Mutations in hepatitis C virus RNAs conferring cell culture adaptation," J. Virol. 75:1437-49 (2001). Frese and Lohmann have reported evidence of HCV RNA replication occurring in the cytoplasm of these cells. Although not capable of generating hepatitis C virus, this system furthered efforts to demonstrate that bonafide HCV RNA replication can occur in a cell culture system. Recently cell lines containing an HCV replicon have reportedly been isolated. See Blight et al., Science 290: 1972-'/ '4 (2000). These cells have been analyzed extensively and shown to contain an HCV replicon that exhibits autonomous HCV RNA replication. Over twenty cell lines that contained a constitutively replicating HCV replicon derived from genotype Ib were isolated. The entire replicon from five cell lines was sequenced, as were the NS 5 a open reading frame in an additional 17 clones. cDNA clones were derived from ten of the clones, which, in turn, were shown to contain adaptive mutations that conferred an increased efficiency of transfection (increased number of G418-resistant colonies following transfection). All these stable Huh7 replicon-containing cell lines, as well as the cDNA plasmids, can be used to generate new cell lines.
[20] There are generally six families of negative-stranded RNA viruses that have human pathogenic members. Three are non-segmented (Paramyxoviridae {e.g., RSV), Rhabdomyxoviridae, and Filoviridae), and three are segmented (Orthomyxoviridae, Bunyaviridae, and Ar enaviridae). In contrast to positive-strand RNA viruses, the RNA of negative-strand RNA viruses must first be copied into positive-strand mRNA before translation and viral replication can occur. In the first phase of a three phase mechanism, negative-strand RNA is transcribed in the host-cell to produce a positive-strand mRNA. In a second phase, the mRNA creates viral proteins including RNA-dependent RNA polymerase. In the last phase, new progeny negative-strand RNA are created.
[21] Although replicons and defective genomes per se have not yet been described for negative-strand viruses, there have been significant advances in the genetic manipulation of various members of these virus families. See, e.g., Roberts et al., "Recovery of negative-stranded RNA viruses from plasmid DNAs: a positive approach revitalizes a negative field," Virology 247:1-6 (1998). Recovery of infectious rabies virus, Sendai virus, vesicular stomatitis virus, measles virus, and RSV, for example, has been accomplished using T7 RNA polymerase to generate full-length antigenomic transcripts from cDNA, together with the viral proteins necessary for nucleocapsid assembly and RNA replication and transcription. See, e.g., Garciii et al., "A highly recombinogenic system for the recovery of infectious Sendai paramyxovirus from cDNA: generation of a novel copy-back nondefective interfering virus," Embo. J. 14:6087-94 (1995). See also, Radecke et al., "Rescue of measles viruses from cloned DNA," Embo. J. 14:5773-84 (1995). See also, Schnell et al., "Infectious rabies viruses from cloned cDNA," Embo. J. 13:4195-203 (1994). See also, Whelan et al., "Efficient recovery of infectious vesicular stomatitis virus entirely from cDNA clones," Proc. Natl. Acad. Sci. USA 92:8388-92 (1995). An infectious cDNA clone for Ebola virus also has been developed. See, e.g., Neumann et al., "Reverse genetics demonstrates that proteolytic processing of Ebola virus glycoprotein is not essential for replication in cell culture," J Virol. 76:406-10 (2002).
[22] Despite the foregoing advances, there are still very few small molecule broad-spectrum antiviral drugs. Consequently, there continues to be a critical medical need for effective therapies against viral pathogens, hi addition, a need continues to exist for broad-spectrum antiviral therapies that are effective against both positive- strand and negative-strand RNA viruses.
SUMMARY OF THE INVENTION [23] Briefly, this invention is directed, in part, to a method for treating a viral infection in an animal. The method comprises administering a therapeutically effective amount of a thienyl compound or a pharmaceutically acceptable salt thereof to the animal. The thienyl compound corresponds in structure to formula (I):
Figure imgf000013_0001
Here, each substituent Ra, Rb, Rc, Rd, and Re is either an independent substituent or forms part of a ring structure. More specifically:
[24] In some embodiments, Ra is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, or -S(Rg). Any such substituent optionally is substituted.
[25] In some embodiments, Rb is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, alkylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, or -N=C(RA)(RB). Any such substituent optionally is substituted.
[26] hi some embodiment, Rc is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akyltliioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, or -N=C(RA)(RB). Any such substituent optionally is substituted. [27] In some embodiments (i.e., when Ra and Rb are not independent substitu teennttss)),, RRaa aanndd RRbb,, ttooggeetthheerr wwiith the atoms to which they are bonded, form optionally-substituted heterocyclyl.
[28] hi some embodiments (i. e. , when Rb and Rc are not independent substituents), Rb and Rc, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl.
[29] hi some embodiments, Rd and Re are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylaUsoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclylalkylthioalkyl. Any member of such group optionally is substituted.
[30] hi some embodiments (i.e., when Rd and Re are not independent substituents), Rd and Re, together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl.
[31] Each Rbl is independently hydrogen, hydroxy, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, or heterocyclylheterocyclylthioalkyl. Any such substituent optionally is substituted.
[32] Each Rg is independently hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaniinoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkylaminoalkylaminoalkyl, heterocyclylalkenylamino, or heterocyclylaminoalkyl. Any such substituent optionally is substituted. [33] Each pair of RA and RB form an independently-selected optionally-substituted heterocyclyl. [34] This invention also is directed, in part, to a pharmaceutical composition. The composition comprises a therapeutically effective amount of an above-described thienyl compound or a pharmaceutically acceptable salt thereof.
[35] This invention also is directed, in part, to use of an above-described thienyl compound or a pharmaceutically acceptable salt thereof to prepare a medicament (generally in the form of a pharmaceutical composition). The medicament comprises a therapeutically effective amount of the thienyl compound or a pharmaceutically acceptable salt thereof.
[36] This invention also is directed, in part, to a pharmaceutical kit. The kit comprises a first dosage form comprising an above-desribed thienyl compound or pharmacetically acceptable salt thereof. The kit also comprises a second dosage form of a second active ingredient. The first dosage form and the second dosage form together comprise a therapeutically-effective amount of the agents for treating a targeted condition(s). [37] Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this patent.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [38] This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating preferred embodiments of this invention, are intended for purposes of illustration only. The present invention, therefore, is not limited to the preferred embodiments described in this patent, and may be variously modified.
A. Compounds of This Invention
[39] In accordance with this invention, Applicants have discovered that compounds comprising a thienyl group (particularly compounds comprising a thienylamino group, and even more particularly compounds comprising a (thien-2-yl)amino group) tend to be effective for inhibiting viral activity (particularly RNA virus activity, such as HCV, RSV, WNV, and/or YFV activity).
[40] As noted above, the compounds used in the present invention generally correspond in structure to Formula I:
Figure imgf000016_0001
In this formula, Ra, Rb, Rc, Rd, and Re are defined as follows:
General Description of Preferred Ra, R , and Rc Substituents [41] Each of Ra, Rb, and Rc is either an independent substituent or forms part of a ring structure. More specifically:
[42] In some embodiments, Ra is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, or -S(R8). Any member of such group optionally is substituted, hi some preferred embodiments, each optional substituent is independently selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, oxo, thioxo, nitro, thiol, amino, imino, aminoalkyl, carbocyclyl, heterocyclyl, and heterocyclylalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, oxo, thioxo, amino, imino, thiol, and nitro.
[43] - In some embodiments, Rb is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyelylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, or -N=C(RA)(RB). Any member of such group optionally is substituted. In some preferred embodiments, each optional substituent is an independently selected Rf substituent.
[44] In some embodiments, Rc is hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-RbI, -C(S)-Rbl, or -N=C(RA)(RB). Any member of such group optionally is substituted. In some preferred embodiments, each optional substituent is an independently selected Rf substituent.
[45] hi some preferred embodiments, R° is methoxycarbonyl. [46] In some preferred embodiments, Rc is ethoxycarbonyl. [47] In some preferred embodiments, Rc is aminocarbonyl. [48] In some embodiments {i.e., when Ra and Rb are not independent substituents), Ra and Rb, together with the atom to which they are bonded, form optionally-substituted heterocyclyl as described above. In some preferred embodiments, the heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, heterocyclyl, heterocyclylthio, and heterocyclylalkenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, nitro, thioxo, carbocyclyl, and oxo. Any member of such group is, in turn, optionally substituted with one or more independently selected alkoxy.
[49] In some embodiments {i.e., when Rb and Rc are not independent substituents), Rb and Rc, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl. In some preferred embodiments, the heterocyclyl optionally is substituted with one or more independently selected Rf substituents. The heterocyclyl also optionally is substituted with two substituents such that the two substituents (together with the atom(s) to which they are bonded) form a carbocyclyl or heterocyclyl. This carbocyclyl or heterocyclyl is, in turn, optionally substituted with one or more independently selected Rf substituents. [50] hi the above definitions, each Rbl is independently hydrogen, hydroxy, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, or heterocyclylheterocyclylthioalkyl. Any member of such group optionally is substituted, hi some preferred embodiments, each optional substituent is independently hydrogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, or heterocyclylheterocyclylthioalkyl. Any member of such group is, in turn, optionally substituted by one or more substituents independently selected from the group
* ( consisting of hydroxyl, halogen, alkyl, alkoxy, alkylthio, alkenyl, alkoxyalkyl, hydroxyalkyl, amino, aminoalkyl, oxo, thioxo, thiol, imino, nitro, cyano, carbocyclyl, carbocyclylalkyl, carbocyclylalkoxy, carbocyclylalkenyl, carbocyclylthio, aminosulfonyl, aminothio, heterocyclyl, heterocyclylsulfonyl, heterocyclylthio, heterocyclylalkyl, and heterocyclylalkenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, alkyl, alkenyl, alkoxy, amino, imino, cyano, nitro, nitroso, alkoxyalkyl, hydroxyalkyl, oxo, thiol, and thioxo. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, oxo, amino, alkyl, and alkoxy.
[51] Each Rf is independently either an independent substituent or forms a part of a ring structure.
[52] When an Rf is an independent substituent, the Rf is independently halogen, hydroxyl, amino, alkyl, hydroxyalkyl, alkylamino, aminoalkylamino, aminoalkyl, alkenyl, alkoxy, alkoxyalkyl, oxo, carbocyclyl, alkylcarbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylamino, heterocyclylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkenyl, heterocyclylthioalkyl, carbocyclylaminoalkenyl, heterocyclylaminoalkenyl, thioxo, hydrazinyl, hydrazinylalkyl, carbocyclylhydrazinyl, carbocyclylalkenylhydrazinyl, aminoalkenyl, alkenylamino, carbocyclylaminoalkyl, heterocyclylaminoalkyl, carbocyclylalkenylamino, heterocyclylalkenylamino, or -S(Rg). Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, hydroxylalkyl, oxo, amino, imino, aminoalkyl, alkylamino, thioxo, thiol, nitro, cyano, alkoxyalkyl, carbocyclyl, alkoxycarbocyclyl, carbocyclylalkyl, carbocyclyloxy, heterocyclyl, and heterocyclylalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, imino, amino, oxo, thioxo, thiol, nitro, heterocyclyl, or hydroxyalkyl.
[53] When an Rf substituent forms part of a ring structure, the Rf substituent is bonded to another Rf substituent such that both Rf substituents (together with the atom(s) to which they are bonded) form a carbocyclyl or heterocyclyl. The carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, amino, carbocyclyl, carbocyclylalkenyl, and heterocyclyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
[54] Each Rs is independently hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkenylamino, heterocyclylthioalkylammoalkylaminoalkyl, or heterocyclylaminoalkyl. Any member of such group optionally is substituted. In some preferred embodiments, each optional substituent is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylaminoalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl, amino, aminosulfonyl, alkenyl, alkoxy, oxo, thiol, thioxo, cyano, nitro, aminoalkyl, alkoxyalkyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylthio, carbocyclylalkylthio, carbocylcyloxysulfonyl, heterocyclyl, heterocyclylalkyl, and heterocyclylthioalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, amino, imino, oxo, alkoxyalkyl, carbocyclyl, thioxo, nitro, cyano, and heterocyclyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, amino, and oxo. [55] Each pair of RΛ and RB form an independently selected optionally-substituted heterocyclyl. In some preferrred embodiments, each optional substituent is independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, thioxo, nitro, and cyano.
General Description of Preferred R and Re Substituents
[56] Rd and Re either are independent substituents or together form a ring structure. More specifically:
[57] In some embodiments, Rd and Re are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclylalkylthioalkyl. Any member of such group optionally is substituted. In some preferred embodiments, each optional substituent is independently selected from the group consisting of halogen, hydroxyl, cyano, thiol, nitro, nitroso, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, bisalkoxyalkyl, thioalky alkylthioalkyl, alkylthioalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclyloxyalkenyl, carbocyclylalkoxyalkyl, carbocycrylthioalkyl, carbocyclylthioalkenyl, carbocyclylsulfonyl, carbocyclylsulfonylalkyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, heterocyclyloxyalkenyl, lieterocyclylalkoxyalkyl, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylsulfonyl, heterocyclylsulfonylalkyl, heterocyclylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, and aminoalkylsulfonyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, thiol, nitro, nitroso, oxo, thioxo, amino, and imino.
[58] hi some preferred embodiments, Rd is hydrogen. [59] hi some preferred embodiments, Rd is methyl.
[60] hi some preferred embodiments, Rd is phenyl. [61] hi some preferred embodiments, Rd is chlorophenyl. [62] In some preferred embodiments, Rd is fluorophenyl. [63] hi some preferred embodiments, Rd is methylphenyl. [64] hi some preferred embodiments, R is (dimethyl)phenyl.
[65] hi some preferred embodiments, R is methoxyphenyl. [66] hi some preferred embodiments, Rd is (dimethoxy)phenyl. [67] hi some preferred embodiments, Rd is nitrophenyl. [68] hi some preferred embodiments, R is butylphenyl. [69] hi some preferred embodiments, R is benzylphenyl.
[70] hi some preferred embodiments, Rd is furanyl. [71] In some preferred embodiments, Rd is methylfuranyl. [72] hi some preferred embodiments, Re is hydrogen. [73] hi some preferred embodiments, Re is methyl. [74] hi some preferred embodiments, Re is ethyl.
[75] hi some preferred embodiments, Re is methylcarbonyl. [76] hi some preferred embodiments, Re is ethylcarbonyl. [77] hi some preferred embodiments, Re is phenyl. [78] hi some preferred embodiments, Rd and Re are each methyl. [79] hi other embodiments (i.e., when Rd and Re are not independently selected substituents), Rd and Re, together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl. hi some preferred embodiments, the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, thiol, nitro, nitroso, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, bisalkoxyalkyl, thioalky alkylthioalkyl, alkylthioalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclyloxyalkenyl, carbocyclylalkoxyalkyl, carbocyclylthioalkyl, carbocyclylthioalkenyl, carbocyclylsulfonyl, carbocyclylsulfonylalkyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, heterocyclyloxyalkenyl, heterocyclylalkoxyalkyl, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylsulfonyl, heterocyclylsulfonylalkyl, heterocyclylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, and aminoalkylsulfonyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, thiol, nitro, nitroso, oxo, thioxo, amino, and imino.
[80] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl, cyclohexenyl, or cycloheptenyl. These substituents optionally are substituted with one or more (often preferably only one) substituents independently selected from the group consisting of methyl, methoxy, and methoxycarbonyl.
[81] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl.
[82] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl. [83] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl.
[84] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl.
[85] Li some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form butylcyclohexenyl.
[86] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl. Detailed Description of Various Preferred Embodiments [87] The above discussion describes the compounds and salts of this invention in general terms. The following discussion, in turn, describes in detail various preferred embodiments.
Preferred Embodiment No. 1
[88] In some preferred embodiments, Ra and Rb, together with the atom to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, heterocyclylmethylenyl, heterocyclylthio, and heterocyclylalkenyl. Any such optional substituent is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, nitro, thioxo, carbocyclyl, and oxo. Any member of such group is, in turn, optionally substituted with one or more independently alkoxy.
Particularly Preferred Embodiments of Embodiment No. 1 [89] hi some particularly preferred embodiments, Ra and Rb, together with the atoms to which they are bonded, form pyrrolidinyl, dihydropyrrolyl, hexahydropyrroloisoxazole, pyrrolyl, or
(dihydrooxaazacyclopentaphenanthreno)pyrrolidinyl. Any such substituent is optionally is substituted with one or more substituents selected from the group consisting of methyl, oxo, heterocyclylmethylenyl, heterocyclylthio, and phenyl. Any member of such group is, in turn, optionally substituted with chloro, nitro, oxo, thioxo, ethoxy, and phenyl. Any member of such group is, in turn, optionally substituted with one or more independently selected methoxy.
[90] hi some particularly preferred embodiments, Rc is ethoxycarbonyl or methylphenylaminocarbonyl.
[91] hi some particularly preferred embodiments, Rd and Re are each methyl. [92] hi some particularly preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cyclohexeneyl. Preferred Embodiment No. 2
[93] In some preferred embodiments, the compound corresponds in structure to Formula (I- A):
Figure imgf000024_0001
Particularly Preferred Embodiments of Embodiment No. 2 [94] In some particularly preferred embodiments, Rb is hydrogen, amino, alkenyl, aminoalkyl, heterocyclyl, heterocylcylthio, carbocyclylalkyl, heterocylcylthioalkenyl, -C(O)-Rbl, -C(S)-Rbl, or -N=C(RA)(RB). Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, oxo, heterocyclylthio, and heterocyclylthioalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino. [95] In some particularly preferred embodiments, Rb is hydrogen, amino, aminornethyl, butenyl, benzisothiazolyl, phenylmethyl, -C(O)-Rbl, -C(S)-Rbl, or -N=C(RA)(RB). Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, tert-butyl, oxo, (benzothiazolyl)thio, and butenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, oxo, amino, methyl, ethyl, methoxy, and ethoxy.
[96] In some particularly preferred embodiments, Rb is {[3,5- bis(ethoxycarbonyl)-4-methyl-2-thienyl]amino}(oxo)acetyl, chloroacetyl, 4-amino-4- oxobut-2-enoyl, [3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-l ,4-benzothiazin-2- yl] acetyl, (3-oxo-3,4-dihydro-2H-l ,4-benzothiazin-2-yl)acetyl, (diethylamino)acetyl, (2-phenylquinolin-4-yl)carbonyl, 3-azepan- 1 -ylpropanoyl, (4-ethylpiperazin- 1 - yl)acetyl, 4-[(carboxymethyl)thio]-3-nitrobenzoyl, 3-(2-furanyl)prop-2-enoyl, 2-cyano- 3-(2-furanyl)prop-2-enoyl, 2-cyano-3-(3-nitrophenyl)prop-2-enoyl, 3-chloropropanoyl, (3-oxo-l ,2,3,4-tetrahydroquinoxalin-2-yl)acetyl, 3-[5-benzylidene-4-oxo-2-thioxo-l ,3- thiazolidin-3-yl]propanoyl, 1-naphthylacetyl, pyrrolidin-1-ylacetyl, 4-(azepan-l- ylsulfonyl)benzoyl, 3-[4-oxo-5-(2-thienylmethylene)-2-thioxo-l,3-thiazolidin-3- yl]propanoyl, (phenylthio)acetyl, [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-2-yl)thio]acetyl, 3-(4-ethylpiperazin-l- yl)propanoyl, [5-(methoxycarbonyl)-3-oxothiomoφholin-2-yl]acetyl, ([l,2,4]triazolo[3,4-b][l,3]benzothiazol-3-ylthio)acetyl, [(4-oxo-3,6-diρhenyl-3,4- dihydrothieno [2,3 -d]pyrimidin-2-yl)thio] acetyl, 3 - [4-oxo-2-thioxo-5 -(3 ,4,5- trimethoxybenzylidene)- 1 ,3-thiazolidin-3-yl]propanoyl, 4-(morpholin-4- ylsulfonyl)benzoyl, (4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)amino, 3- [4-(acetylamino)plienyl] -2-cyanoprop-2-enoyl, [(I -phenyl- 1 H-tetrazol-5 -yl)thio] acetyl, ([l,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl, (5,6,7,8-tetrahydro[l]benzothieno[2,3- d]pyrimidin-4-yltliio)acetyl, 6-{[3-(aminocarbonyl)-4,5,6,7-tetrahydro-l-benzothien-2- yl]amino}-6-oxohexanoyl, biphenyl-4-ylcarbonyl, 4-[5-(4-ethylbenzylidene)-4-oxo-2- thioxo-l,3-thiazolidin-3-yl]butanoyl, (2-immo-4-oxo-l,3-thiazolidin-5-yl)acetyl, 4- ethoxy-4-oxobut-2-enoyl, [(5-methyl[l,2,4]triazolo[4,3-a]quinolin-l-yl)thio]acetyl, 4- (difluoromethoxy)benzoyl, [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-2-yl)thio]acetyl, diphenylacetyl, piperidin-1- ylacetyl, (acetyloxy)(phenyl)acetyl, [(4-methylphenyl)thio] acetyl, 3-(4- methylpiperazin-l-yl)propanoyl, 2-cyano-3-(4-hydroxyphenyl)prop-2-enoyl, [(5,6- dimethylthieno[2,3-d]pyrimidin-4-yl)thio]acetyl, [(3-allyl-4-oxo-3,4,5,6,7,8- hexahydro[ 1 ]benzothieno [2,3 -d]pyrimidin-2-yl)thio] acetyl, [(3 -allyl-5 ,6-dimethyl-4- oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl, [(2-methyl-6,7-dihydro-5H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)thio]acetyl, 4-(4-methylpiperidin-l- yl)butanoyl, [(3-allyl-4-oxo-3,4,5,6,7,8-b.exahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl, [(4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin- 2-yl)thio] acetyl, 3-(4-methylpiperidin-l-yl)propanoyl, [(3-allyl-4-oxo-5-phenyl-3,4- dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl, [(3-allyl-4-oxo-6-phenyl-3,4- dihydrothieno[2,3-d]pyriniidin-2-yl)thio]acetyl, 4-[(dimethylamino)sulfonyl]benzoyl, 3-(2,6-dimethylmorpholin-4-yl)propanoyl, (4-methylρiperidin-l-yl)acetyl, 4- cyanobenzoyl, {[3-allyl-5-(4-fluoropb.enyl)-4-oxo-3,4-dihydrotbieno[2,3-d]pyrimidin- 2-yl]thio} acetyl, [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cycloρenta[4,5]thieno[2,3- d]pyrimidin-2-yl)thio]acetyl, 3-morpholin-4-ylpropanoyl, azepan-1-ylacetyl, 3- (piperidin- 1 -yl)propanoyl, 3-methylbenzoyl, 3-[5-(4-chloro-3-nitrophenyl)-2-furanyl]- 2-cyanoprop-2-enoyl, (3,4-dimethoxyphenyl)acetyl, 3-[5-(2-chloro-4-nitrophenyl)-2- furanyl] -2-cyanoprop-2-enoyl, (6,7-dimethyl-3 -oxo- 1 ,2,3 ,4-tetrahydroquinoxalin-2- yl)acetyl, (2,6-dimethylmorpholin-4-yl)acetyl, 3-[4-(benzoyloxy)phenyl]-2-cyanoprop- 2-enoyl, [(4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)tliio] acetyl, 3-(4-bromo-2-thienyl)prop-2-enoyl, [(3-allyl-4-oxo-6-phenyl-3,4- dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl, [(6-phenylthieno[2,3-d]pyriniidin-4- yl)thio] acetyl, l,l-dioxido-l,2-benzisothiazol-3-yl, 4-tert-butylbenzoyl, 3-carboxyprop- 2-enoyl, 3-(4-methylpiperazin-l-yl)propanoyl, 4-chlorobenzoyl, (4- methylphenyloxy)acetyl, (2-methoxyphenyloxy)acetyl, benzoyl, [4-(2- hydroxyethyl)piperazin- 1 -yl] acetyl, [(4-chlorophenyl)thio] acetyl, A- (difluoromethoxy)benzoyl, i(4-methylquinolm-2-yl)thio] acetyl, phenyl(phenylthio)acetyl, morpholin-4-ylacetyl, 2-furoyl, [2-(2- chlorobenzylidene)hydrazinyl]carbonyl, 4-chloro-3-nitrobenzoyl, [(4- chlorophenyl)amino]carbonyl, 2-chloro-4-nitrobenzoyl, 3-phenylprop-2-enoyl, 6-(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)hexanoyl, (2-isopropyl-5-methylphenyloxy)acetyl, (4-methoxyphenyloxy)acetyl, 4-methoxybeiizoyl, (2,4-dibromophenyloxy)acetyl, (4- nitrophenyloxy) acetyl, butoxycarbonyl, anilinocarbonyl, 3-phenyloxypropanoyl, [2-(2- hydroxy-3-methoxybenzylidene)hydrazinyl]carbonyl, (2-nitrophenyloxy)acetyl, (4- chlorophenyloxy)acetyl, (2-tert-butyl-4-methylphenyloxy)acetyl, 3 -(3 ,A- dimethoxyphenyl)prop-2-enoyl, butyryl, (2-chlorophenyloxy) acetyl, 4-fhiorobenzoyl, 2,6-dimethoxybenzoyl, [3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl, (2,6- dimethylphenyloxy)acetyl, dichloroacetyl, (4-tert-butylphenyloxy)acetyl, (4-bromo-3- methylphenyloxy)acetyl, trifluoroacetyl, [2-(pyridin-2- ylmethylene)hydrazinyl]carbonyl, phenyloxyacetyl, phenylacetyl, 3-(3- nitrophenyl)prop-2-enoyl, l-benzojEuran-2-ylcarbonyl, 3,4,5-trimethoxybenzoyl, 3- methoxybenzoyl, 2-cyano-3-(4-methoxyphenyl)prop-2-enoyl, (2,3- dimethylphenyloxy)acetyl, 3-(3-niethoxy-4-propoxyphenyl)prop-2-enoyl, 2- methoxybenzoyl, (biρhenyl-4-yloxy)acetyl, 2-(4-methoxyphenyloxy)propanoyl, (2-tert- butylphenyloxy)acetyl, (2-methylphenyloxy) acetyl, 2-bromo-3,4,5-trimethoxybenzoyl, (4-bromophenyloxy)acetyl, 3,4-dimethoxybenzoyl, (3-bromophenyloxy)acetyl, 2,4- dichlorobenzoyl, [4-(l -methyl- l-phenylethyl)phenyloxy] acetyl, 2-chloro-5- nitrobenzoyl, [2-(2-furanylmethylene)hydrazinyl]carbonyl, 3-phenylpropanoyl, (4- chloro-2-methylphenyloxy)acetyl, 2-thienylcarbonyl, 3-(4-ethoxyphenyl)prop-2-enoyl, 4-(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)benzoyl5 (2,3,6-trimethylphenyloxy)acetyl, 3,5-dimethoxybenzoyl, {[3-(aminocarbonyl)-4,5,6,7-tetrahydro-l-benzothien-2- yljamino} (oxo)acetyl, 4-(4-chlorophenyloxy)butanoyl, 2-bromo-3,4,5- trimethoxybenzoyl, 3-[3-methoxy-4-(pentyloxy)plienyl]prop-2-enoyl, [(4- methoxyphenyl)amino] acetyl, 2,2,2-trichloro-l-[(fluoroacetyl)amino]ethyl, 5-nitro-2- furoyl, [(4-tert-butylbenzoyl)amino]carbonothioyl, (6-bromo-2-oxo-2H-chromen-3- yl)carbonyl, 2,3-dihydro-l,4-benzodioxinyl, 2-bromo-3-phenyl]prop-2-enoyl, or 7- methyl-4-oxo-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-acetyl. [97] In some particularly preferred embodiments, Re is hydrogen, halogen, carboxyl, alkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, heterocyclyl, heterocyclylalkyl, carbocyclyl, carbocyclylalkyl, or carbocyclylaminoalkyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, oxo, amino, hydroxyalkyl, aminoalkyl, and carbocyclyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, oxo, and amino.
[98] In some particularly preferred embodimetns, Rc is hydrogen, fluoro, bromo, chloro, methyl, ethyl, carboxyl, methoxymethyl, ethoxymethyl, aminomethyl, (piperidinyl)methyl, or phenylaminomethyl. Any such substituent optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, oxo, amino, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminoethyl, aminopropyl, and phenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, oxo, methoxy, and ethoxy. [99] In some particularly preferred embodiments, R° is hydrogen, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, carboxyl, (3-diethylamino)propyl(aminocarbonyl), 4-methoxyphenyl(aminocarbonyl), piperidinylcarbonyl, 4-ethoxyphenyl(aminocarbonyl), 4-methylphenyl(aminocarbonyl), diethylaminocarbonyl, 2-aminoethyl(aminocarbonyl), 2-hydroxyethyl(aminocarbonyl), or 3-hydroxypropylaniinocarbonyl.
[100] In some particularly preferred embodiments, Rc is methoxycarbonyl. [101] In some particularly preferred embodiments, Rc is ethoxycarbonyl.
[102] In some particularly preferred embodiments, Rc is aminocarbonyl. [103] In some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, oxo, amino, aminoalkyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
[104] hi some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, aminomethyl, hydroxymethyl, phenyl, phenylmethyl, and furanyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, oxo, methoxy, and ethoxy.
[105] hi some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, phenyl, 4-chlorophenyl, methyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, (dimethylamino)methyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, benzyl, and 2-furanyl. [106] hi some preferred embodiments, Rd is hydrogen. [107] hi some preferred embodiments, Rd is methyl. [108] hi some preferred embodiments, R is phenyl.
[109] hi some preferred embodiments, Re is hydrogen. [110] hi some preferred embodiments, Re is methyl. [Ill] hi some preferred embodiments, Re is methylcarbonyl. [112] In some preferred embodiments, Re is phenyl. [113] hi some preferred embodiments, Rd and Re are each methyl.
[114] hi some particuarly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxycarbonyl, oxo, and amino.
[115] In some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form cyclopentenyl, cyclohexenyl, or cycloheptenyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, and oxo.
[116] In some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl. [117] In some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl.
[118] In some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl.
[119] hi some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl.
[120] In some preferred embodiments, Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl.
[121] In some particularly preferred embodiments, Rbl is hydrogen, hydroxyl, methyl, ethyl, propyl, butyl, propenyl, butenyl, methoxy, ethoxy, propoxy, butoxy, amino, aminomethyl, (tetrahydrobenzothienyl)aminopentyl, thienyl, benzofuranyl, chromenyl, dihydrobenzodioxinyl, methoxymethyl, ethoxymethyl, phenyl, furanyl, hydrazinyl, phenylmethyl, phenylethyl, phenylamino, phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, phenylpropenyl, phenylethenyl, phenylmethylenyl, quinolinyl, isoxazolyl, isoxazolidinyl, benzothienyl, (tetrahydroquinoxalinyl)methyl, (dihydrobenzothiazinyl)methyl, azepanylmethyl, azepanylpropyl, azepanylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, piperazinylmethyl, piperazinylethyl, piperazinylpropyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl, furanylmethyl, furanylethyl, furanylmethylenyl, furanylethenyl, furanylpropenyl, thiazolidinylmethyl, thiazolidinylethyl, thiazolidinylpropyl, quinoxalinylmethyl, quinoxalinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, isoindolylmethyl, isoindolylethyl, (dihydroisoindolyl)pentyl, naphthyl, phenylthiomethyl, thienopyrimidinylthiomethyl, (dihydrothienopyrimidinyl)thiomethyl, morpholinylmethyl, morpholinylethyl, thienylmethyl, thienylethyl, thienylethenyl, (cyclopentathienopyrimidinytytMomethyl, (hexahydrobenzothienopyrimidinyl)thiomethyl, (tetrahydrobenzothienopyrimidinyl)thiomethyl, thiomorpholinylmethyl, (benzothiazolotriazolyl)thiomethyl, quinolinylthiomethyl,
(triazoloquinolinyl)thiomethyl, thiazolidinylthiomethyl, tetrazolylthiomethyl, (triazolopyridinyl)thiomethyl, (hexahydrobenzothienopyrimidinyl)metliyl, and (hexahydrobenzothienopyrimidmyl)thiomethyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of hydroxyl, chloro, fluoro, bromo, methyl, ethyl, methoxy, ethoxy, propyloxy, pentyloxy, propyl, butyl, allyl, propenyl, methoxymethyl, ethoxymethyl, hydroxyethyl, thienyl, oxo, thioxo, amino, aminomethyl, imino, nitro, cyano, thiol, phenyl, benzyl, phenylmethylenyl, phenylethenyl, aminosulfonyl, dihydroisoindolyl, tetrahydrobenzothienyl, azepanylsulfonyl, morpholinylsulfonyl, thienylmethylenyl, thienylethenyl, pyridinylmethylenyl, pyridinylethenyl, furanylmethylenyl, and furanylethenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, fluoro, chloro, bromo, methyl, ethyl, methoxy, phenyl, amino, imino, cyano, nitro, nitroso, methoxymethyl, ethoxymethyl, hydroxyethyl, oxo, thiol, and thioxo. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, fluoro, chloro, bromo, oxo, and methyl.
[122] m some particularly preferred embodiments, RA and RB form hexahydropyrimidinyl optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, methoxy, oxo, thioxo, nitro, and cyano. Preferred Embodiment No. 3
[123] In some preferred embodiments, the compound corresponds in structure to Formula (I-B):
Figure imgf000031_0001
Here, each dashed line represents an optional bond such that the compound of Formula (I-B) corresponds in structure to one of the following formulas:
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000032_0002
Here:
[124] In some embodiments, R is hydrogen or an independently selected R substituent.
[125] In some embodiments, R8 is hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, carbocyclyl, carbocyclylalkyl, amino, aminoalkyl, aminoalkenyl, alkenylamino, thiol, thioxo, carbocyclylaminoalkyl, heterocyclylaminoalkyl, carbocyclylaminoalkenyl, heterocyclylaminoalkenyl, carbocyclylalkenylamino, heterocyclylalkenylamino, hydrazinylalkyl, or heterocyclyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, hydroxyl, cyano, alkyl, alkoxy, alkoxyalkyl, carbocyclyl, alkoxycarbocyclyl, oxo, amino, alkylamino, aminoalkyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, and carbocyclyloxy. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
[126] In some embodiments, the compound corresponds in structure to Formula (I-B-2), and R7 and R8, together with the atoms to which they are bonded, form heterocyclyl optionally substituted with one or more independently selected Rf substituents.
[127] R9 is selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkenyl, amino, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and -S(Rg). Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminoalkyl, thioxo, thiol, nitro, and heterocyclylalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, imino, amino, oxo, thioxo, thiol, and nitro.
[128] In some alternative embodiments, Ra and R9 (together with the atoms(s) to which they are bonded) form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, carbocyclylalkenyl, and heterocyclyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
Particularly Preferred Embodiments of Embodiment No. 3 [129] In some particularly preferred embodiments, the compound corresponds in structure to Formula (I-B-2):
Figure imgf000033_0001
In some such embodiments, for example, R7 is oxo. In such embodiments, the compound corresponds in structure to Formula (I-B-2-a):
Figure imgf000034_0001
In other such embodiments, for example, R7 is thioxo. In such embodiments, the compound corresponds in structure to Formula (I-B-2-b):
Figure imgf000034_0002
[130] In some particularly preferred embodiments, the compound corresponds in structure to Formula (I-B-3):
Figure imgf000034_0003
[131] In some particularly preferred embodiments, the compound corresponds in structure to Formula (I-B-4):
(I-B-4).
Figure imgf000034_0004
[132] In some particularly preferred embodiments, the compound corresponds in structure to Formula (I-B-4):
Figure imgf000035_0001
[133] In some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, oxo, nitro, carbocyclyl, and carbocyclylalkyl. [134] In some particularly preferred embodiments, R and Re are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and furanyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, oxo, nitro, phenyl, and phenylmethyl.
[135] hi some particularly preferred embodiments, Rd is hydrogen, methyl, phenyl, chlorophenyl, fluorophenyl, methylphenyl, (dimethyl)phenyl, methoxyphenyl, (dimethoxy)ρhenyl, nitrophenyl, butylphenyl, benzylphenyl, furanyl, or methylfuranyl. [136] In some particularly preferred embodiments, Re is hydrogen, methyl, ethyl, methylcarbonyl, ethylcarbonyl, or phenyl.
[137] hi some preferred embodiments, Rd and Re are each methyl. [138] hi some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form cyclopentenyl or cyclohexenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and propyl. [139] In some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, methyl, ethyl, ethoxycarbonyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-isopropylphenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2-furanyl, 5-methylfur-2-yl, 3-nitrophenyl, 4-benzylphenyl, and 4-tert-butylphenyl.
[140] In some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl. [141] hi some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form cyclopentenyl or cyclohexenyl.
[142] In some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form cyclopentenyl, cyclohexenyl, methylcyclohexenyl, or butylcyclohexenyl. [143] In some particularly preferred embodiments, R7 is oxo, amino, thiol, thioxo, hydrazinyl, hydrazinylalkyl, carbocyclyl, carbocyclylhydrazinyl, carbocyclylalkenylhydrazinyl, heterocyclyl, heterocyclyloxy, or -S(RS). Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, oxo, alkyl, and alkoxy.
[144] hi some particularly preferred embodiments, R7 is oxo, amino, thiol, thioxo, hydrazinyl, hydrazinylmethyl, cyclohexenylhydrazinyl, carbocyclylalkenylhydrazinyl, piperazinyl, phenylmethenylhydrazinyl, quinolinyloxy, or -S(RS). Any such substitutent optionally is substituted with one or more substituents independently selected from the group consisting of methyl, phenyl, methoxy, phenylmethyl, morpholinyl, morpholiniumyl, and benzodioxolylethyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and methoxy. [145] In some particularly preferred embodiments, R7 is oxo, thioxo, quinolin- 8-yloxy, (2-methylquinolin-8-yl)oxy, (2- {[3-ethoxycarbonyl)-5-(methoxycarbonyl)-4- methyl-2-thienyl]amino}-2-oxoethyl)thio, (2-{[3-(aminocarbonyi)-5-phenyl-2- thienyl] amino }-2-oxoethyl)thio, (2-{[3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino}-2-oxoetb.yl)thio, (2- {[3-(aminocarbonyl)-5,6-dihydro- 4H-cyclopenta[b]thien-2-yl]amino}-2-oxoethyl)thio, 4-benzoylpiperazin-l-yl, 2-(5,5- dimethyl-3 -morpholin-4-iumcyclohex- 1 -en- 1 -yl)hydrazinyl, [2-( 1 ,3 -benzodioxol-5 - yl)ethyl] amino, 2-[2-(difluoromethoxy)benzylidene]hydrazine, or 1-phenyl-lH- tetrazole-5-sulfenyl. [146] In some particularly preferred embodiments, R7 is oxo. In such embodiments, the compound corresponds in structure to the following formula:
[147] In some particularly preferred embodiments, R8 is hydrogen, methyl, ethyl, methoxyethyl, propyl, butyl, allyl, phenyl, phenylmethyl, phenylethyl, amino, aminoethyl, thiol, thioxo, methyleneamino phenylmethyleneamino, benzodioxolylmethyleneamino, furanylmethyleneamino,
(tetrahydrobenzothienyl)aminoethyl, pyridinylmethyleneamino, hydrazinylmethyl, hydrazinylethyl, or pyrrolyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, nitro, cyano, hydroxyl, methyl, methoxy, methoxyphenyl, oxo, amino, methylamino, dihydroindolylidenyl, phenyl, phenylmethyl, imidazolyl, indolyl, phenyl, furanylmethyl, propoxy, propoxymethyl, isopropoxy, isopropoxymethyl, butoxy, isobutoxymethyl, and cyclohexyloxy. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, methoxy, ethoxy, and oxo. [148] In some particularly preferred embodiments, R8 is hydrogen, phenyl, allyl, methyl, butyl, 2-phenylethyl, 4-methylphenyl, 4-methylbenzyl, 3-methylbenzyl, 4-bromobenzyl, 2,4-dichlorobenzyl, 2,6-dichlorobenzyl, amino, [(2- chlorophenyl)methylene] amino, [l,3-benzodioxol-5-ylmethylene]amino, [(5-nitro-2- furanyl)methylene] amino, (4-hydroxybenzylidene)amino, {[2- (difluoromethoxy)phenyl]methylene} amino, [(2-chloroimidazo[l,2-a]pyridin-3- yl)methylene] amino, [2-furanylmethylene] amino, [pyridin-2-ylmethylene] amino, [(dimethylamino)methylene]amino, [(3,4,5-trimethoxyphenyl)methylene]amino, {[4- . (difluoromethoxy)phenyl]methylene} amino, [(3,4-dimethoxyphenyl)metliylene]amino, 2-(benzyloxy)-l-methyl-2-oxoetliyl, 2-(berizylamino)-2-oxoethyl, 2-[(2- furanylmethyl)ammo] -2-oxoethyl, 2-isopropoxy-2-oxoethyl, 2-methoxy- 1 -methyl-2- oxoethyl, 2-(cyclohexyloxy)-2-oxoethyl, 2-methoxy-2-oxoethyl, 2-butoxy-l-methyl-2- oxoethyl, 2-{[3-(ethoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-l-beiizothien-2- yl]amino}-2-oxoethyl, 2-(cyclohexyloxy)-l-methyl-2-oxoethyl, lH-pyrrol-1-yl, 2,5- dimethyl- 1 H-pyrrol- 1 -yl, 2-[2-(l -methyl-2-oxo- 1 ,2-dihydro-3H-indol-3- ylidene)hydrazinyl]-2-oxoethyl, l-(isobutoxycarbonyl)propyl, 1- (isopropoxycarbonyl)propyl, cyanomethyl, 2-[(2-chlorobenzyl)oxy]-l-methyl-2- oxoethyl, or 2-oxo-2-[2-(s-oxo-l,2-dihydro-3H-indol-3-ylidenyl)hydrazinyl]ethyl. [149] In some particularly preferred embodiments, R8 is hydrogen.
[150] In some particularly preferred embodiments, R is phenyl. [151] In some particularly preferred embodiments, R is allyl. [152] hi some particularly preferred embodiments, the compound corresponds in structure to Formula (I-B-2), and R7 and R8, together with the atoms to which they are bonded, form triazolyl optionally substituted with one or more independently selected Rf substituents.
[153] hi some particularly preferred embodiments, Ra is selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkenyl, amino, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and -S(RS). Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminoalkyl, thioxo, thiol, nitro, and heterocyclylalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, imino, amino, oxo, thioxo, thiol, and nitro.
[154] In some particularly preferred embodiments, R9 and Ra are independently selected from the group consisting of hydrogen, methyl, aminomethyl, phenyl, phenylethenyl, benzoisoquinolinylethyl, and -S-Rgl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminomethyl, thioxo, thiol, and nitro. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, imino, amino, oxo, thioxo, thiol, and nitro.
[155] In some particularly preferred embodiments, R9 and Ra are independently selected from the group consisting of hydrogen, (l,3-benzodioxol-5- ylmethyl)thio, (l-{[(2-furanylmethyl)amino]carbonyl}-3-hydroxypropyl)thio, (2-{[2- ({[(3-allyl-4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2- yl)thio] acetyl} amino)hexyl] amino} -2-oxoethyl)thio, (2- { [2-(3 ,4- dimethoxyphenyl)ethyl]amino}-2-oxoethyl)thio, (2-{[2-(4- methoxyphenyl)ethyl]amino}-2-oxoethyl)thio,l (2-{[3-(aminocarbonyl)-5,6-dihydro- 4H-cyclopenta[b]thien-2-yl]amino} -2-oxoethyl)thio, (2- {[3-(ethoxycarbonyl)-4-(4- methoxyphenyl)-2-thienyl]amino}-2-oxoethyl)thio, (2-{[3-(ethoxycarbonyl)-4-phenyl- 2-thienyl]amino}-2-oxoethyl)thio, (2-{[3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4- methyl-2-thienyl]amino}-2-oxoethyl)thio, (2-{[3-(ethoxycarbonyl)-5,6,7,8-tetrahydro- 4H-cyclohepta[b]thien-2-yl]amino}-2-oxoethyl)thio, (2-{[3-(ethoxycarbonyl)-5,6- dihydro-4H-cyclopenta[b]thien-2-yl] amino} -2-oxoethyl)thio, (2- { [3 -(ethoxycarbonyl)- 5 -phenyl-2-thienyl] amino} -2-oxoethyl)thio, (2- { [3 -(ethoxycarbonyl)-6-methyl-4,5 ,6,7- tetrahydro-l-benzothien-2-yl]amino}-2-oxoethyl)thio, (2-{[3-(methoxycarbonyl)-4,5- dimethyl-2-thienyl]amino}-2-oxoethyl)thio, (2-{[3-(methoxycarbonyl)-5,6-dihydro- 4H-cyclopenta[b]thien-2-yl] amino} -2-oxoethyl)thio, (2-{[3-(methoxycarbonyl)-5- phenyl-2-thienyl]amino}-2-oxoethyl)thio, (2- {[3,5- bis(methoxycarbonyl)phenyl] amino }-2-oxoethyl)thio, (2-{[4-(3,4-dimethoxyphenyl)-3- (ethoxycarbonyl)-2-thienyl]amino} -2-oxoethyl)thio, (2- {[4-
(acetylamino)phenyl] amino} -2-oxoethyl)thio, (2- { [4-(aminosulfonyl)phenyl] amino} -2- oxoethyl)thio, (2-{[4-(ethoxycarbonyl)phenyl]amino}-2-oxoethyl)thio, (2-{[4- (methoxycarbonyl)phenyl]amino}-2-oxoethyl)thio, (2-{[4-chloro-3- (trifluoromethyl)phenyl] amino} -2-oxoethyl)thio, (2-{2,5-dimethyl-l-[3-
(trifluoromethyl)phenyl]-lH-pyrrol-3-yl}-2-oxoethyl)thio, (2-anilino-2-oxoethyl)thio, (2-fluorobenzyl)thio, (2-morpholin-4-yl-2-oxoethyl)thio, (2-oxo-2- {[2- (trifluoromethyl)phenyl] amino} ethyl)thio, (2-oxo-2-phenylethyl)thio, (2- oxopropyl)thio, (2-tert-butoxy-2-oxoethyl)thio, (3,4-dichlorobenzyl)thio, (3-{[4- (aminosulfonyl)phenyl]amino}-3-oxopropyl)thio, (4-{[(2- hydroxyethyl)amino]carbonyl}benzyl)thio, (4- {[(3- hydroxypropyl)amino]carbonyl}benzyl)thio, (cyanomethyl)thio, [3-phenylprop-2-en- 1 - yljthio, [(3,5-dimethylisoxazol-4-yl)methyl]thio, [(4-phenyl-5-thioxo-4,5-dihydro-lH- l,2,4-triazol-3-yl)methyl]thio, [(5,7-dimethylimidazo[l,2-a]pyrimidin-2-yl)methyl]thio, [(5-{[4-(methoxycarbonyl)benzyl]thio}-4-phenyl-4H-l,2,4-triazol-3-yl)methyl]thio, [(5-anilino-l,3,4-thiadiazol-2-yl)methyl]thio, [2-(l,3-benzodioxol-5-ylamino)-2- oxoethyl]thio, [2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]thio, [2-(l,3-dioxo- lH-benzo[de]isoquinolin-2(3H)-yl)ethyl]thio, [2-(l-adamantylamino)-2-oxoethyl]thio, [2-(l -naphthyl)-2-oxoethyl]thio, [2-(2-fluoroρhenyl)-2-oxoethyl]thio, [2-(2-furaiiyl)-2- oxoethyl]thio, [2-(2-methyl-lH-indol-3-yl)-2-oxoethyl]thio, [2-(2-naphthyl)-2- oxoethyl]thio, [2-(3,4-dimethoxyphenyl)-2-oxoethyl]thio, [2-(4-fluorophenyl)-2- oxoethyljtbio, [2-(4-methoxyplienyl)-2-oxoethyl]thio, [2-(4-methylpiperidin- 1 -yl)-2- oxoethyljthio, [2-(5-methyl-2-nitrophenyloxy)ethyl]thio, [2-(benzylamino)-2- oxoethyljthio, [2-(cyclohexylamino)-2-oxoethyl]thio, [2-(phenyloxysulfonyl)ethyl]thio, [4-( 1 ,3-dioxo- 1 ,3 -dihydro-2H-isoindol-2-yl)butyl]thio, [4- (methoxycarbonyl)benzyl]thio, {[aniino(imino)methyl] amino} methyl, {2-[(l,3- benzodioxol-5-ylmethyl)amino]-2-oxoethyl}thio, {2-[(2,4-dimethylphenyl)amino]-2- oxoethyl}thio, {2-[(2,5-dimethoxyphenyl)amino]-2-oxoethyl}thio, {2-[(2,6- dichlorophenyl)aniino]-2-oxoethyl}thio, {2-[(2-fluorophenyl)aniino]-2-oxoethyl}thio, {2-[(2-meth.oxyethyl)amino]-2-oxoethyl}thio, {2-[(3,4-dimethylphenyl)amino]-2- oxoethyl}thio, {2-[(3-cyano-2-thienyl)amino]-2-oxoethyl}thio, {2-[(3-cyano-4,5,6,7- tetrahydro-l-benzothien-2-yl)amino]-2-oxoethyl}thio, {2-[(3-cyano-5,6,7,8-tetrahydro- 4H-cycloh.epta[b]thien-2-yl)amino]-2-oxoethyl}thio, {2-[(3-cyano-5,6-dihydro-4H- cyclopenta[b]thien-2-yl)amino]-2-oxoethyl}thio, {2-[(3-cyano-6-methyl-4,5,6,7- tetrahydro- 1 -benzothien-2-yl)amino]-2-oxoethyl}thio, {2-[(3-methoxyphenyl)amino]- 2-oxoethyl}thio, {2-[(3-methylphenyl)amino]-2-oxoethyl}thio, {2-[(4- ethoxyplienyl)amino]-2-oxoethyl}thio, {2-[(5-benzyl-3-cyano-4-methyl-2- thienyl)amino]-2-oxoethyl}thio, {2-[(5-methylisoxazol-3-yl)aniino]-2-oxoethyl}thio, {2-[(aminocarbonyl)amino]-2-oxoethyl}tiiio, {2-[l-(2-methoxyethyl)-2,5-dimethyl-lH- ρyrrol-3-yl]-2-oxoethyl}thio, {2-[2,5-dimethyl- 1 -(4-methylphenyl)- lH-ρyiτol-3-yl]-2- oxoethyl}thio, {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}thio, {2-[4- (ethoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl}thio;, {2-[4- (methoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl}thio, {2-oxo-2-[(2- phenylethyl)amino]ethyl}thio, {2-oxo-2-[(pyridin-2-ylmethyl)amino] ethyl }thio, {3-[(4- fluorophenyl)amino]-3-oxopropyl}thio, 2-(l,3-benzodioxol-5-yl)-2-oxoethanesulfenyl, 2-(l ,3-dioxo- lH-benzo[de]isoquinolin-2(3H)-yl)ethyl, 2-(2,3-dihydro- 1 ,4-benzodioxin- 6-yl)-2-oxoethanesulfenyl, 2-[(2,6-dimethylphenyl)amino]-2-oxoethanesulfenyl, 2- phenylvinyl, difluoromethanesulfenyl, imidazo[l,2-a]pyridin-2-ylmethanesulfenyl, methyl, phenyl, {2-[(4-methylphenyl)amino]-2-oxoethyl}thio, {2-[(2- furanylmethyl)amino]-2-oxoethyl}thio, {2-[(4-fluorophenyl)amino]-2-oxoethyl}thio, {2-[(2,6-difluorophenyl)amino]-2-oxoethyl}thio5 and allyl.
[156] In some particularly preferred embodiments, R9 is hydrogen. [157] In some particularly preferred embodiments, R9 is -S-Rsl .
[158] In some particularly preferred embodiments, R9 and Ra (together with the atoms to which they are bonded) form tetrahydroisoquinolinyl optionally substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, propyl, phenyl, and phenylmethylenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy, and ethoxy.
[159] R is heterocyclyl, heterocyclylalkyl, or heterocyclylaminoalkyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, aminoalkyl, carbocyclyl, oxo, thioxo, nitro, and cyano. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, thioxo, nitro, and cyano.
[160] In some particularly preferred embodiments, R is thienylaminoethyl, (dihydrocyclopentathienyl)aminoethyl, or tetrazolyl. Any such substituent optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxymethyl, ethoxymethyl, aminomethyl, phenyl, oxo, thioxo, nitro, and cyano. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, oxo, thioxo, nitro, and cyano. [161] In some particularly preferred embodiments, each Rgl is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, aminoethyl, cyclohexylaminoethyl, phenylmethyl, phenylethyl, phenyloxyethyl, phenylpropenyl, phenylaminoethyl, phenylaminopropyl, triazolylmethyl, (dihydrotriazolyl)methyl, benzoisoquinolinylethyl, indolylethyl, (dihydroindolyl)ethyl, isoindolylethyl, (dihydroisoindolyl)ethyl, isoindolylbutyl, (dihydroisoindolyl)butyl, (tetrahydrobenzothienyl)aminoethyl, isobenzothienylaminoethyl, (tetrahydroisobenzothienyl)aminoethyl, (tetrahydrobenzothienyl)aminoethyl, benzodioxanylmethyl, benzodioxanylethyl, benzodioxanylaminoethyl, benzodioxolylmethyl, benzodioxolylethyl, benzodioxolylaminoethyl, isoxazolylmethyl, isoxazolylaminoethyl, adamantylaminoethyl, imidazopyridinylmethyleneamino, imidazopyridinylmethyl, imidazopyrimidinyhnethyl, thienylaminoethyl, (dihydrocyclopentathienyl)aminoethyl, cyclohexathienylaminoethyl, (tetrahydrocycloheptathienyl)aminoethyl, naphthylethyl, morpholinylethyl, thiadiazolylmethyl, pyrrolylethyl, pyrrolylaminoethyl, (piperidinyl)methyl, (piperidinyl)ethyl, furanylmethyl, furanylethyl, and
(dihydrothienopyrimidinyl)thioethylaminohexylaminoethyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of oxo, fluoro, chloro, bromo, thioxo, cyano, nitro, methyl, amino, aminomethyl, aminoethyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, propyl, aminosulfonyl, phenylmethylthio, butoxy, tert-butoxy, allyl, phenyl, phenylmethyl, phenylethyl, phenylthio, phenyloxysulfonyl, benzodioxolylmethyl, pyridinylmethyl, and furanylmethyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, hydroxyl, methyl, ethyl, propyl, amino, oxo, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and phenyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, hydroxyl, methyl, ethyl, amino, imino, oxo, methoxy, and ethoxy. Preferred Embodiment No. 4
[162] In some preferred embodiments, the compound corresponds in structure to Formula (I-C):
Figure imgf000043_0001
Here:
[163] Each dashed line represents an optional bond. When the bond to R .14 . is absent, R14 also is absent.
[164] R is hydrogen or an independently selected R substituent. [165] In some embodiments, R14 and R15 are independently selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkoxy, alkenyl, carbocyclyl, alkylcarbocyclyl, amino, oxo, heterocyclyl, heterocyclylamino, heterocyclylalkylamino, heterocyclylaminoalkyl, aminoalkyl, alkylamino, and aminoalkylamino. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, oxo', amino, heterocyclyl, aminoalkyl, and hydroxyalkyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of alkyl, oxo, alkoxy, heterocyclyl, and hydroxyalkyl.
[166] In some embodiments, R14 and R15 (together with the atoms to which they are bonded) form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
[167] In some embodiments, R and R are each hydrogen. [168] In some embodiments, R16 and R17 (together with the atoms to which they are bonded) form carbocyclyl or heterocyclyl. The carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
Particularly Preferred Embodiments of Embodiment No. 4 [169] In some particularly preferred embodiments, the compound corresponds in structure to Formula (I-C-l):
Figure imgf000044_0001
Such compounds include, for example, those wherein R is oxo such that the compound corresponds in structure to Formula (I-C-l -a):
Figure imgf000044_0002
[170] hi some particularly preferred embodiments, the compound corresponds in structure to Formula (I-C-2):
Figure imgf000044_0003
Such compounds include, for example, those wherein R7 is oxo such that the compound corresponds in structure to Formula (I-C-2-a):
Figure imgf000045_0001
[171] In some particularly preferred embodiments, the compound corresponds in structure to Formula (I-C-3):
Figure imgf000045_0002
Such compounds include, for example, those wherein R7 is oxo such that the compound corresponds in structure to Formula (I-C-3-a):
Figure imgf000045_0003
[172] In some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, oxo, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, thioxo, and amino.
[173] In some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, methyl, and phenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, oxo, and amino.
[174] In some particularly preferred embodiments, Rd and Re are independently selected from the group consisting of hydrogen, methyl, phenyl, A- methylphenyl, and 4-chlorophenyl.
[175] In some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form carbocyclyl or heterocyclyl. The carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino. [176] In some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form cyclopentenyl, cyclohexenyl, or cycloheptenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of fluoro, bromo, chloro, methyl, ethyl, methoxy, ethoxy, amino, and oxo. [177] hi some particularly preferred embodiments, Rd and Re (together with the atoms to which they are bonded) form cyclohexenyl, cycloheptenyl, or methylcyclohexenyl.
[178] hi some particularly preferred embodiments, R14 and R15 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydrazinyl, amino, piperidinyl, piperazinyl, morpholinyl, and triazenyl. Any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, amino, oxo, methoxy, ethoxy, tetrahydrofuranyl, furanyl, morpholinyl, aminopropyl, and hydroxyethyl. Any member of such group is, in turn, optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, oxo, methoxy, ethoxy, tetrahydrofuranyl, furanyl, morpholinyl, and hydroxyethyl.
[179] hi some particularly preferred embodiments, R14 and R15 are independently selected from the group consisting of hydrogen, chloro, hydrazinyl, (tetrahydrofuran-2-ylmethyl)amino, (2-furanyhnethyl)amino, (3-morpholin-4-ylpropyl)amino, piperidin-1-yl, [3-(dimethylamino)propyl]arnino, 4-(2-hydroxyethyl)piperazin- 1 -yl, morpholin-4-yl, (2-hydroxyethyl)amino, (2-morpholin-4-ylethyl)amino, and (tetrahydrofuran-2-ymiethyl)amino. [180] In some particularly preferred embodiments, R14 and R15 (together with the atoms to which they are bonded) form dihydrotriazolyl or dihydrotetrazolyl.
[181] In some particularly preferred embodiments, R16 and R17 (together with the atoms to which they are bonded) form phenyl.
B. Preparation and Sources of Compounds Useful With This Invention [182] Compounds useful with this invention generally may be prepared by methods known in the art. Commercial sources of such compounds include, for example, Otava, Kyiv 187, 03187, Ukraine.
C. Salts of the Compounds of this Invention
[183] The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
[184] When a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
[185] Pharmaceutically acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
[186] Pharmaceutically acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group Ha) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from amines, such as tromethamine, diethylamine, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
[187] In some particularly preferred embodiments, the salt comprises a hydrochloric acid (HCl) salt.
D. Treating Conditions Using the Compounds and Salts of this Invention [188] This invention is directed, in part, to a method for treating a pathological condition caused (directly or indirectly) by viral activity. Animals benefiting from such a method generally include, for example, humans. The method, however, may be used in veterinary contexts as well to treat other mammals, such as other primates {e.g., monkeys, chimpanzees, etc.), companion animals {e.g., dogs, cats, horses, etc.), farm animals {e.g., goats, sheep, pigs, cattle, etc.), laboratory animals {e.g., mice, rats, etc.), and wild and zoo animals {e.g., wolves, bears, deer, etc.). It is contemplated that the method may further be used in other veterinary contexts to treat, for example, birds, reptiles, fish, and amphibians.
[189] In some embodiments, the condition is associated with an RNA virus. [190] In some embodiments, the condition is associated with a positive-strand RNA virus. Such viruses include, for example, viruses falling within a viral family selected from the group consisting of Picornaviridae, Caliciviridae, Astroviridae, Coronaviridae, Togaviridae, and Flaviviridae. Specific examples of positive-strand RNA viruses include Sindbis virus, rubella virus, hepatitis C virus (HCV), West Nile virus (WNV), yellow fever virus (YFV), tick-borne encephalitis (TBE) virus, Japanese encephalitis virus, coxsackievirus, enterovirus, hepatitis A virus, severe acute respiratory syndrome (SARS) virus, Dengue fever virus (DV), poliovirus, Venezuela encephalitis virus (VEE), Western equine encephalomyelitis (WEE) virus, Eastern equine encephalomyelitis (EEE) virus, O'nyong nyong virus, Ross River virus, Chikungunya virus, Rhinovirus, feline caliciviras, murine calicivirus, Norwalk virus, bovine viral diarrhea virus (BVDV), human coronavirus, Semliki Forest virus, Kunjin virus, Omsk hrmorrhagic fever (Omsk HF) virus, Murray Valley enciphalitis virus, Kyasanur Forest disease virus, Rocio virus, and astro virus.
[191] In some embodiments, the condition is associated with hepatitis C virus. [192] hi some embodiments, the condition is associated with West Nile virus. [193] hi some embodiments, the condition is associated with yellow fever virus.
[194] In some embodiments, the condition is associated with a negative-strand RNA virus. Such viruses include, for example, viruses falling within a viral family selected from the group consisting of Paramyxoviridae, Rhabdoviridae, Filoviridae, Orthomyxoviridae, Bunyaviridae, Bornaviridae, and Arenaviridae. Specific examples of negative-strand RNA viruses include respiratory syncytial virus (RSV), Ebola virus, rabies virus, Lassa fever virus, La Crosse virus, Rift Valley fever virus, Hantaan virus, California encephalitis virus, influenza virus A, influenza virus B, measles virus, mumps virus, Marburg virus, Bolivian hemorrhagic fever (Bolivian HF) virus, human parainfluenza virus (HPIV), human metapneumovirus (hMPV), Nipah virus, Hendra virus (equine morbillivirus), vesicular stomatitis virus (VSV), lymphocytic choriomeningitis (LCM) virus, Junin virus (Argentine hemorrhagic fever virus or Argentine HF virus), Bunyamwera virus, Uukuniemi virus, and Crimean-Congo hemorrhagic fever (CCHF) virus.
[195] In some embodiments, the condition is associated with respiratory syncytial virus. [196] In some embodiments, the condition is associated with a double-strand
RNA virus. In some such embodiments, the virus is from the Reoviridae virus family. Examples of double-strand RNA viruses include Colorado tick fever.
[197] In some emboments, the condition is associated with a DNA virus. [198] In some embodiments, the condition is associated with a partial-complex DNA virus. In some such embodiments, the virus is from the Hepadanviridae virus family. Examples of partial-complex DNA viruses include Hepatitis B virus.
[199] In some embodiments, the condition is associated with a single-strand DNA virus. In some such embodiments, the virus is from the Paravavoviridae virus family. Examples of single-strand DNA viruses include human parvovirus. [200] hi some embodiments, the condition is associated with a double-strand
DNA virus. Such viruses include, for example, viruses falling within a viral family selected from the group consisting of Papillomaviridae, Polyomaviridae, and Herpesviridae. Specific examples of double-strand DNA viruses include human papillomavirus, JC virus, BK virus, herpes simplex virus 1, herpes simplex virus 2, herpes simplex virus 6, herpes simplex virus 7, herpes simplex virus 8, Eptstein Barr virus, and human cytomegalovirus.
[201] In some embodiments, the condition is associated with a respiratory virus. Such viruses include, for example, parainfluenza viruses, human metapneumovirus, rhinoviruses, and hantaviruses. [202] In some embodiments, the condition is associated with an enteric virus.
Such viruses include, for example, enteroviruses, rotavirus, and caliciviruses.
[203] In some embodiments, the condition is associated with an encephalitis- causing virus. Such viruses include, for example, West Nile virus and tick-borne encephalitis virus. [204] In some embodiments, the condition is associated with a hemorrhagic fever virus. Such viruses include, for example, Ebola virus, Marburg virus, and Lassa fever virus. [205] Typically, a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in a therapeutically-effective amount to a patient suffering from (or prediposed to) a viral infection. Generally, the term "therapeutically-effective amount" means an amount that is effective to inhibit activity of the target virus(es) or effective to treat the targeted condition in a reasonable amount of time. Here, the term "inhibit" means reducing or eliminating the targeted viral activity. And the term "treat" means ameliorating, suppressing, eradicating, preventing, reducing the risk of, or delaying the onset of the targeted condition.
[206] One skilled in the art generally can determine an appropriate dosage. Factors affecting the preferred dosage regimen (including the amount of anti-viral agent delivered, frequency of administration, and whether administration is continuous or intermittent) include, for example, the type, age, weight, sex, diet, and condition of the patient; the type of pathological condition and its severity; the nature of the desired effect; whether the purpose of administration is prophylactic or to treat an existing viral infection; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular anti- viral agent used; the route of administration and whether a drug delivery system is utilized; and whether the anti-viral agent is administered as part of a combination therapy (e.g., whether the agent is administered in combination with one or more other active agents, radiation, etc.). [207] Compositions for oral administration are, for example, preferably prepared in a manner such that a single dose in one or more oral preparations contains at least about 20 mg of the anti- viral compound per square meter of patient body surface area, or at least about 50, 100, 150, 200, 300, 400, or 500 mg of the anti-viral compound per square meter of patient body surface area (the average body surface area for a human is, for example, 1.8 square meters). Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg (more preferably from about 20 to about 400 mg, even more preferably from about 20 to about 300 mg, and still even more preferably from about 20 to about 200 mg) of the anti- viral compound per square meter of patient body surface area. Compositions for parenteral administration are, for example, prepared in a manner such that a single dose contains at least about 20 mg of the anti-viral compound per square meter of patient body surface area, or at least about 40, 50, 100, 150, 200, 300, 400, or 500 mg of the anti- viral compound per square meter of patient body surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg (more preferably from about 20 to about 400, even more preferably from about 20 to about 400 mg, and still even more preferably from about 20 to about 350 mg) of the anti- viral compound per square meter of patient body surface area. It should be recognized that these oral and parenteral dosage ranges simply represent generally preferred dosage ranges, and are not intended to limit the invention. The dosage regimen actually employed can vary widely, and, therefore, can deviate from the normal preferred dosage regimen. It is contemplated that one skilled in the art will tailor these ranges to the individual patient.
[208] As indicated above, it is contemplated that the thienyl compounds and salts of this invention may be used as part of a combination therapy. The term "combination therapy" means the administration of two or more therapeutic treatments directed to the pathological condition. In this specification, the pathological condition generally comprises a condition associated (directly or indirectly) with viral activity. The therapeutic treatments of the combination generally may be co-administered in a substantially simultaneous manner. Two active agents could be co-administered as, for example: (a) a single formulation (e.g., a single capsule) having a fixed ratio of active ingredients; or (b) multiple, separate formulations (e.g., multiple capsules) for each agent. The therapeutic treatments of the combination may alternatively (or additionally) be administered at different times. In either case, the chosen treatment regimen preferably provides beneficial effects of the drug combination in treating the condition. Such a combination therapy may comprise administering a thienyl compound or salt of this invention with, for example, one or more additional thienyl compounds or salts of this invention, cytokines (including interferon, and particularly interferon alpha), ribavirin, nucleoside/tide reverse transcriptase inhibitors ("NRTIs", these include abacavir (Ziagen), lamivudine, 3TC (Epivir), tenofovir (Viread), abacavir/lamivudine/zidovudine (Trizivir), lamivudine/zidovudine (Combivir), stavudine, d4T (Zerit), didanosine, ddl (Videx, Videx EC), zalcitabine, ddC (HIVID), and zidovudine, and AZT (Retrovir)), protease inhibitors ("PIs", these include amprenavir (Agenerase), nelfmavir (Viracept), saquinavir (Fortavase), indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase), and lopinavir/ritonavir (Kaletra)), non-nucleoside reverse transcriptase inhibitors ("NnRTIs", these include delavirdine (Rescriptor), efavirenz (Sustiva), and nevirapine (Viramune)), or a combination thereof.
[209] It is further contemplated that the thienyl compounds and salts of this invention can be used in the form of a kit that is suitable for use in performing the treatment methods described above. In one embodiment, the kit comprises a first dosage form comprising a thienyl compound or salt of this invention and a second dosage form comprising another active ingredent in quantities sufficient to carry out the methods of the present invention. Preferably, the first dosage form and the second dosage form together comprise a therapeutically-effective amount of the agents for treating the targeted condition(s).
E. Pharmaceutical Compositions Containing the Compounds and Salts of this Invention [210] This invention also is directed, in part, to pharmaceutical compositions (or medicaments) comprising a therapeutically-effective amount of a compound or salt of this invention, as well as processes for making such compositions. Such compositions generally comprise one or more pharmaceutically-acceptable carriers {e.g., excipients, vehicles, auxiliaries, adjuvants, diluents, etc.) and/or other active ingredients. Formulation of these compositions may be achieved by various methods known in the art. A general discussion of these methods may be found in, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975). See also, Liberman, H.A. & Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N. Y., 1980).
[211] The preferred composition depends on the route of administration. Any route of administration may be used as long as the target of the compound or salt is available via that route. Often suitable routes of administration include, for example, oral, parenteral, inhalation, rectal, nasal, topical (e.g., transdermal and intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual, and intestinal administration. [212] Pharmaceutically acceptable carriers that may be used in the compositions of this invention are well known to those of ordinary skill in the art. Carriers are selected based on a number of factors including, for example, the particular anti-viral compound(s) or salt(s) used; the compound's concentration, stability, and intended bioavailability; the condition being treated; the subject's age, size, and general condition; the route of administration; etc. A general discussion related to carriers may be found in, for example, J. G. Nairn, Remington's Pharmaceutical Science, pp. 1492- 1517 (A. Gennaro, ed., Mack Publishing Co., Easton, Pa. (1985)).
[213] Solid dosage forms for oral administration include, for example, capsules, tablets, gelcaps, pills, dragees, troches, powders, granules, and lozenges. In such solid dosage forms, the compounds or salts are ordinarily combined with one or more adjuvants. If administered per os, the compounds or salts can be mixed with lactose, sucrose, starch powder, corn starch, potato starch, magnesium carbonate, microcrystalline cellulose, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, sodium carbonate, agar, mannitol, sorbitol, sodium saccharin, gelatin, acacia gum, alginic acid, sodium alginate, tragacanth, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the compound or salt in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can, for example, include a coating {e.g., an enteric coating) to delay disintegration and absorption. The concentration of the anti- viral agent in a solid oral dosage form is preferably from about 5 and about 50% (more preferably from about 8 to about 40 %, and even more preferably from about 10 to about 30%) by weight based on the total weight of the composition.
[214] Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art {e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents. The concentration of the anti- viral agent preferably is from about 0.01 to about 10 mg (more preferably from about 0.01 to about 5 mg, even more preferably from about 0.01 to about 1 mg, and still even more preferably from about 0.01 to about 0.5 mg) per ml of the composition. Relatively low concentrations are generally preferred because the anti-viral agents tend to be most soluble at low concentrations.
[215] Techniques for making oral dosage forms useful in the present invention are generally described in, for example, Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors (1979)). See also, Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981). See also, Ansel, Introduction to Pharmaceutical Dosage Forms (2nd Edition (1976)).
[216] hi some embodiments, for example, tablets or powders for oral administration are prepared by dissolving the anti- viral agent in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution and then evaporating when the solution is dried under vacuum. An additional caπier(s) also may be added to the solution before drying. The resulting solution is dried under vacuum to form a glass. The glass is then mixed with a binder to form a powder. This powder may be mixed with fillers or other conventional tableting agents, and then processed to form a tablet. Alternatively, the powder may be added to a liquid carrier to form a solution, emulsion, suspension, or the like.
[217] hi some embodiments, solutions for oral administration are prepared by dissolving the anti- viral agent in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution. An appropriate volume of a carrier is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration.
[218] "Parenteral administration" includes subcutaneous injections, intravenous injections, intraarterial injections, intraorbital injections, intracapsular injections, intraspinal injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, and any other dosage form that can be administered parenterally. [219] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting, and/or suspending agents. Acceptable vehicles for parenteral use include both aqueous and nonaqueous pharmaceutically-acceptable solvents. [220] Suitable pharmaceutically-acceptable aqueous solvents include, for example, water, saline solutions, dextrose solutions (e.g., such as DW5), electrolyte solutions, etc.
[221] Suitable pharmaceutically-acceptable nonaqueous solvents include, for example, the following (as well as mixtures thereof): alcohols (these include, for example, α-glycerol formal, β-glycerol formal, 1, 3-butyleneglycol, aliphatic or aromatic alcohols having from 2 to about 30 carbons (e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuranyl alcohol, lauryl alcohol, cetyl alcohol, and stearyl alcohol), fatty acid esters of fatty alcohols (e.g., polyalkylene glycols, such as polypropylene glycol and polyethylene glycol), sorbitan, sucrose, and cholesterol); amides (these include, for example, dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide-amides, 2-pyrrolidinone, l-methyl-2-pyrrolidinone, and polyvinylpyrrolidone); esters (these include, for example, acetate esters (e.g., monoacetin, diacetin, and triacetin), aliphatic and aromatic esters (e.g., ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, or benzyl acetate), dimethylsulfoxide (DMSO), esters of glycerin (e.g., mono, di, and tri-glyceryl citrates and tartrates), ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, glyceryl monostearate, glyceride esters (e.g., mono, di, or tri-glycerides), fatty acid esters (e.g., isopropyl myristrate), fatty acid derived PEG esters (e.g., PEG- hydroxyoleate and PEG-hydroxystearate), N-methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters (e.g., poly(ethoxylated)30-6o sorbitol poly(oleate)2-4;poly(oxyethylene)15-2o monooleate, poly(oxyethylene)15-20 mono 12- hydroxystearate, and poly(oxyethylene)15-2o mono ricinoleate), polyoxyethylene sorbitan esters (e.g. , polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and POLYSORBATE 20, 40, 60, and 80 (from ICI Americas, Wilmington, DE)), polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters (e.g., polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils, such as CREMOPHOR EL solution or CREMOPHOR RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses, such as, ribose, ribulose, arabinose, xylose, lyxose, and xylulose; hexoses, such as glucose, fructose, galactose, mannose, and sorbose; trioses; tetroses; heptoses; and octoses), disaccharide (e.g., sucrose, maltose, lactose, and trehalose), oligosaccharide, or a mixture thereof with one or more C4-C22 fatty acids (e.g., saturated fatty acids, such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid; and unsaturated fatty acids, such as palmitoleic acid, oleic acid, elaidic acid, erucic acid, and linoleic acid), and steroidal esters); ethers (these are typically alkyl, aryl, and cyclic ethers having from 2 to about 30 carbons. Examples include diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether), and glycofurol (tetrahydrofurfuranyl alcohol polyethylene glycol ether); ketones (these typically have from about 3 to about 30 carbons. Examples include acetone, methyl ethyl ketone, methyl isobutyl ketone); hydrocarbons (these are typically aliphatic, cycloaliphatic, and aromatic hydrocarbons having from about 4 to about 30 carbons. Examples include benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n- decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), and tetramethylenesulfoxide); oils (these include oils of mineral, vegetable, animal, essential, or synthetic origin. These include mineral oils, such as aliphatic and wax- based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil; vegetable oils, such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic, and peanut oil; glycerides, such as mono-, di-, and triglycerides; animal oils, such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil; oleic oils; and polyoxyethylated castor oil); alkyl, alkenyl, or aryl halides (these include alkyl or aryl halides having from 1 to about 30 carbons and one or more halogen substituent. Examples include methylene chloride); monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (SOLUTOL HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; and sorbitan monooleate. Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art. General discussion relating to such solvents may be found in, for example, The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D. C, and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics 3d ed., (G. Banker et al., eds., Marcel Dekker, Inc., New York, New York (1995)), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds., Marcel Dekker, Inc., New York, New York (1980)), Remington 's Pharmaceutical Sciences, 19th ed., (A. Gennaro, ed., Mack Publishing, Easton, PA, (1995)), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA (2000)), Spiegel, A. J., et al., "Use of Nonaqueous
Solvents in Parenteral Products," J. Pharma. Sciences, Vol. 52, No. 10, pp. 917-927 (1963).
[222] Preferred solvents include those known to stabilize the anti-viral compound(s) or salt(s) of interest. These typically include, for example, oils rich in triglycerides, such as safflower oil, soybean oil, and mixtures thereof; and alkyleneoxy- modified fatty acid esters, such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., CREMOPHOR EL solution or CREMOPHOR RH 40 solution). Commercially available triglycerides include INTRALIPID emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), NUTRALIPID emulsion (McGaw, Irvine, California), LIPOSYN II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, IL), LIPOSYN III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, IL), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels of from about 25 to about 100% (by weight based on the total fatty acid content) (DHASCO from Martek Biosciences Corp., Columbia, MD; DHA MAGURO from Daito Enterprises, Los Angeles, CA; SOYACAL; and TRAVEMULSION. Ethanol is an often preferred solvent for dissolving the anti- viral compound or salt to form solutions, emulsions, and the like.
[223] Additional components can be included in the compositions of this invention for various purposes generally known in the pharmaceutical industry. These components tend to impart properties that, for example, enhance retention of the antiviral compound or salt at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the anti- viral compound or salt into pharmaceutical formulations, and the like. Specific examples of such components include cryoprotective agents; agents for preventing reprecipitation of the anti-viral compound or salt surface; active, wetting, or emulsifying agents (e.g., lecithin, polysorbate-80, TWEEN 80, pluronic 60, and polyoxyethylene stearate); preservatives (e.g., ethyl-p-hydroxybenzoate); microbial preservatives (e.g., benzyl alcohol, phenol, 7/z-cresol, chlorobutanol, sorbic acid, thimerosal, and paraben); agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate, etc.); agents for adjusting osmolality (e.g., glycerin); thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearm, cetyl wax esters, polyethylene glycol, etc.); colorants; dyes; flow aids; non- volatile silicones (e.g., cyclomethicone); clays (e.g., bentonites); adhesives; bulking agents; flavorings; sweeteners; adsorbents; fillers (e.g., sugars such as lactose, sucrose, mannitol, sorbitol, cellulose, calcium phosphate, etc.); diluents (e.g., water, saline, electrolyte solutions, etc.); binders (e.g., gelatin; gum tragacanth; methyl cellulose; hydroxypropyl methylcellulose; sodium carboxymethyl cellulose; polyvinylpyrrolidone; sugars; polymers; acacia; starches, such as maize starch, wheat starch, rice starch, and potato starch; etc.); disintegrating agents (e.g., starches, such as maize starch, wheat starch, rice starch, potato starch, and carboxymethyl starch; cross-linked polyvinyl pyrrolidone; agar; alginic acid or a salt thereof, such as sodium alginate; croscarmellose sodium; crospovidone; etc); lubricants (e.g., silica; talc; stearic acid and salts thereof, such as magnesium stearate; polyethylene glycol; etc.); coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, etc.); and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, thiophenols, etc.).
[224] Techniques and compositions for making parenteral dosage forms are generally known in the art. Formulations for parenteral administration may, for example, be prepared from one or more sterile powders and/or granules having a compound or salt of this invention and one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The powder or granule typically is added to an appropriate volume of a solvent (typically while agitating (e.g., stirring) the solvent) that is capable of dissolving the powder or granule. Preferred solvents include, for example, water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
[225] Emulsions for parenteral administration can be prepared by, for example, dissolving a compound or salt of this invention in any pharmaceutically acceptable solvent capable of dissolving the compound to form a solution; and adding an appropriate volume of a carrier, which is an emulsion, to the solution while stirring to form the emulsion. Solutions for parenteral administration can be prepared by, for example, dissolving a compound or salt of this invention in any pharmaceutically acceptable solvent capable of dissolving the compound to form a solution; and adding an appropriate volume of a carrier to the solution while stirring to form the solution.
[226] Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols.
[227] "Topical administration" includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
[228] If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials, or other conventional containers in concentrated form, and then diluted with a pharmaceutically acceptable liquid (e.g., saline) to form an acceptable anti- viral concentration before use. [229] Other adjuvants and modes of administration well-known in the pharmaceutical art may also be used.
F. Definitions [230] The term "alkyl" (alone or in combination with another term(s)) means a straight- or branched-chain saturated hydrocarbyl substituent typically containing from
1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.
[231] The term "alkenyl" (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 1 to about 20 carbon atoms, more typically from about
2 to about 20 carbon atoms, even more typically from about 2 to about 8 carbon atoms, and still even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ^=CH2, ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like.
[232] The term "alkynyl" (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
[233] The term "carbocyclyl" (alone or in combination with another term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e.,
"cycloalkenyl"), or completely unsaturated (i.e., "aryl") hydrocarbyl substituent typically containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be multiple (typically 2 or 3) rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"), fluoreneyl, decalinyl, and norpinanyl.
[234] The term "cycloalkyl" (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent typically containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl (or "cyclopropanyl"), cyclobutyl (or "cyclobutanyl"), cyclopentyl (or "cyclopentyl"), and cyclohexyl (or "cyclohexyl"). A cycloalkyl alternatively may be multiple (typically 2 or 3) carbon rings fused together, such as decalinyl or norpinanyl.
[235] The term "aryl" (alone or in combination with another term(s)) means an aromatic carbocyclyl typically containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
[236] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix
"Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Q-Q-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms. [237] The term "hydrogen" (alone or in combination with another term(s)) means a hydrogen radical (or "hydrido"), and may be depicted as -H.
[238] The term "hydroxy" (alone or in combination with another term(s)) means -OH.
[239] The term "nitro" (alone or in combination with another term(s)) means -NO2.
[240] The term "cyano" (alone or in combination with another term(s)) means -CN, which also may be depicted:
Figure imgf000062_0001
[241] The term "keto" or "oxo" (alone or in combination with another term(s)) means an oxo radical, and may be depicted as =0.
[242] The term "amino" (alone or in combination with another term(s)) means -NH2. The term "monosubstituted amino" (alone or in combination with another term(s)) means an amino substituent wherein a non-hydrogen substituent is in the place of one of the hydrogens. The term "disubstituted amino" (alone or in combination with another term(s)) means an amino substituent wherein non-hydrogen substituents (which may be identical or different) are in the place of both of the hydrogens.
[243] The term "halogen" (alone or in combination with another term(s)) means a fluorine radical ("fluoro", which may be depicted as -F), chlorine radical ("chloro", which may be depicted as -Cl), bromine radical ("bromo", which may be depicted as -Br), or iodine radical ("iodo", which may be depicted as -I). Typically, fluoro or chloro is preferred, with fluoro often being particularly preferred.
[244] A substituent is "substitutable" if it comprises at least one carbon, nitrogen, oxygen, or sulfur atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.
[245] If a substituent is described as being "substituted", a non-hydrogen substituent is in the place of a hydrogen on a carbon, nitrogen, oxygen, or sulfur of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro, and difluoroalkyl is alkyl substituted with two fluoros. It should be recognized that if there are more than one substitutions on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated). [246] If a substituent is described as being "optionally substituted", the substituent is either (1) substituted, or (2) not substituted. When the members of a group of substituents are described generally as being optionally substituted, any atom capable of substitution in each member of such group may be (1) substituted, or (2) not substituted. Such a characterization contemplates that some members of the group are not substitutable. Atoms capable of substitution include, for example, carbon bonded to at least one hydrogen, oxygen bonded to at least one hydrogen, sulfur bonded to at least one hydrogen, or nitrogen bonded to at least one hydrogen. On the other hand, hydrogen alone, halogen, oxo, and cyano do not fall within the definition of being capable of substitution.
[247] This specification uses the terms "substituent" and "radical" interchangeably.1 [248] The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogens. For example, haloalkyl means an alkyl substituent having a halogen in the place of a hydrogen, or multiple halogens in the place of the same number of hydrogens. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluorornethyl, 1,1,1-trifluoroethyl, and the like. Illustrating further, "haloalkoxy" means an alkoxy substituent wherein a halogen is in the place of a hydrogen, or multiple halogens are in the place of the same number of hydrogens. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), 1,1,1 ,-trifluoroethoxy, and the like. It should be recognized that if a substituent is substituted by more than one halogen, those halogens may be identical or different (unless otherwise stated).
[249] The prefix "perhalo" indicates that a halogen is in the place of each hydrogen on the substituent to which the prefix is attached. If all the halogens are identical, the prefix typically will identify the halogen. Thus, for example, the term "perfluoro" means that a fluoro is in the place of each hydrogen on the substituent to which the prefix is attached. To illustrate, the term "perfluoroalkyl" means an alkyl substituent wherein a fluoro is in the place of each hydrogen. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like. To illustrate further, the term "perfluoroalkoxy" means an alkoxy substituent wherein a fluoro is in the place of each hydrogen. Examples of perfluoroalkoxy substituents include trifluoromethoxy (-0-CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like. [250] The term "carbonyl" (alone or in combination with another term(s)) means -C(O)-, which also may be depicted as:
Figure imgf000065_0001
This term also is intended to encompass a hydrated carbonyl substituent, i.e., -C(OH)2-.
[251] The term "aminocarbonyl" (alone or in combination with another term(s)) means -C(O)-NH2, which also may be depicted as:
Figure imgf000065_0002
[252] The term "oxy" (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -O-.
[253] The term "alkoxy" (alone or in combination with another term(s)) means ari alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-0-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
[254] The term "alkylcarbonyl" (alone or in combination with another term(s)) means -C(O)-alkyl. For example, "ethylcarbonyl" may be depicted as:
Figure imgf000065_0003
[255] The term "aminoalkylcarbonyl" (alone or in combination with another term(s)) means -C(O)-alkyl-NH2. For example, "aminomethylcarbonyl" may be depicted as:
Figure imgf000065_0004
[256] The term "alkoxycarbonyl" (alone or in combination with another term(s)) means -C(O)-O-alkyl. For example, "ethoxycarbonyl" may be depicted as:
Figure imgf000066_0001
[257] The term "thio" or "thia" (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl" means alkyl-S-alkyl.
[258] The term "thiol" or "mercapto" (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
[259] The term "(thiocarbonyl)" (alone or in combination with another term(s)) means a carbonyl wherein a sulfur is in the place of the oxygen. Such a substituent may be depicted as -C(S)-, and also may be depicted as:
Figure imgf000066_0002
[260] The term "sulfonyl" ( or in combination with another term(s)) means -S(O)2-, which also may be depicted as:
Figure imgf000066_0003
Thus, for example, "alkyl-sulfonyl-alkyl" means alkyl-S(O)2-alkyl.
[261] The term "aminosulfonyl" (alone or in combination with another term(s)) means -S(O)2-NH2, which also may be depicted as:
Figure imgf000066_0004
[262] The term "sulfoxido" (alone or in combination with another term(s)) means -S(O)-, which also may be depicted as:
Figure imgf000067_0001
Thus, for example, "alkyl-sulfoxido-alkyl" means alkyl-S(O)-alkyl.
[263] The term "heterocyclyl" (alone or in combination with another term(s)) means a saturated (i.e., "heterocycloalkyl"), non-aromatic partially-saturated (i.e., "heterocycloalkenyl"), or heterocyclic aromatic (i.e., "heteroaryl") ring structure typically containing a total of from 3 to 20 (more typically from 3 to 14) ring atoms. At least one of the ring atoms is a heteroatom (typically oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group typically consisting of carbon, oxygen, nitrogen, and sulfur. [264] A heterocyclyl may be a single ring, which typically contains from 3 to
7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, thienyl (also known as "thiophenyl" and "thiofuranyl"), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as "azoximyl"), 1,2,5-oxadiazolyl (also known as "furazanyl"), and 1,3,4-oxadiazolyl), pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), pyridinyl, diazinyl (including pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3 -diazinyl"), and pyrazinyl (also known as "1,4-diazinyl")), triazinyl (including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazmyl")), oxathiazinyl (including 1,2,5-oxathiazinyl and 1,2,6-oxathiazinyl), oxepinyl, thiepinyl, dihydrofuranyl, tefrahydrofuranyl, dihydrothienyl (also known as "dihydrothiophenyl"), tetrahydrothienyl (also known as "tetraliydrothiophenyl"), isopyrrolyl, pyrrolinyl, pyrrolidinyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, dithiolyl, oxathiolyl, oxathiolanyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, and 1,3,4-dioxazolyl), pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, tetrahydropyranyl, piperidinyl, piperazinyl, oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, and diazepinyl. [265] A lieterocyclyl alternatively may be from 2 to 5 (more typically from 2 or 3) rings fused together, such as, for example, indolizinyl, pyranopyrrolyl, purinyl, imidazopyrazinyl, imidazolopyridazyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, pyrido[4,3-b]-pyridinyl, and naphthyridinyl), pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, pyrindinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazyl, or 4H-quinolizinyl. In some embodiments, the preferred multi-ring heterocyclyls are indolizinyl, pyranopyrrolyl, purinyl, pyridopyridinyl, pyrindinyl, and 4H-quinolizinyl.
[266] Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls, such as, for example, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzoxazolyl, benzoisoxazolyl (also known as "indoxazinyl"), anthranilyl, benzothienyl (also known as "benzothiophenyl", "thionaphthenyl", and "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl", "isothionaphthenyl", and "isobenzothiofuranyl"), benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, isoindazolyl (also known as
"benzpyrazolyl"), benzoimidazolyl, benzotriazolyl, benzazinyl (including quinolinyl (also known as "1 -benzazinyl") and isoquinolinyl (also known as "2 -benzazinyl")), phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as "1,2-benzodiazinyl") and quinazolinyl (also known as "1,3-benzodiazinyl")), benzoimidazothiazolyl, carbazolyl, acridinyl, isoindolyl, indoleninyl (also known as "pseudoindolyl"), benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, chromenyl, isochromenyl, thiochromenyl, isothiochromenyl, benzodioxanyl, tetrahydroisoquinolinyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1 -benzoxazinyl, and 3,1,4-benzoxazinyl), benzoisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl), benzoxadiazinyl, and xanthenyl. In some embodiments, the preferred benzo-fused heterocyclyls are benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzotliienyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, benzazinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, carbazolyl, acridinyl, isoindolyl, indoleninyl, benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, benzodioxanyl, tetrahydroisoquinolinyl, benzoxazinyl, benzoisoxazinyl, and xanthenyl.
[267] The term "2-fused-ring" heterocyclyl (alone or in combination with another term(s)) means a saturated, non-aromatic partially-saturated, or heteroaryl containing two fused rings. Such heterocyclyls include, for example, benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, imidazopyrazinyl, imidazolopyridazyl, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, pyrindinyl, isoindolyl, indoleninyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazyl, benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, isothiochromanyl, chromenyl, isochromenyl, thiochromenyl, isothiochromenyl, benzodioxanyl, tetrahydroisoquinolinyl, 4H-quinolizinyl, benzoxazinyl, and benzoisoxazinyl. In some embodiments, preferred 2-fused-ring heterocyclyls include benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyrindinyl, isoindolyl, indoleninyl, benzodioxolyl, benzodioxanyl, tetrahydroisoquinolinyl, 4H-quinolizinyl, benzoxazinyl, and benzoisoxazinyl.
[268] The term "heteroaryl" (alone or in combination with another term(s)) means an aromatic heterocyclyl typically containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or multiple (typically 2 or 3) fused rings. Such moieties include, for example, 5-membered rings such as furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, and oxatriazolyl; 6-membered rings such as pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and oxathiazinyl; 7-membered rings such as oxepinyl and thiepinyl; 6/5-membered fused-ring systems such as benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, imidazopyrazinyl, and imidazolopyridazyl; and 6/6-membered fused-ring systems such as quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, benzoimidazothiazolyl, carbazolyl, and acridinyl. In some embodiments, the preferred 5-membered rings include furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, and imidazolyl; the preferred 6-membered rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; the preferred 6/5-membered fused-ring systems include benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, and purinyl; and the preferred 6/6-membered fused-ring systems include quinolinyl, isoquinolinyl, and benzodiazinyl. [269] A carbocyclyl or heterocyclyl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as "alkanoyl"), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl. More typically, a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, -OH, -C(O)-OH, keto, Q-Cβ-alkyl, C].-C6-alkoxy, CrCe-alkoxy-d-Cβ-alkyl, CrCδ-alkylcarbonyl, aryl, aryl-Q-Co-alkyl, aryl-d-Cό-alkoxy, aryl-d-Cδ-alkoxy-CrCβ-alkyl, aryl-d-Ce-alkoxycarbonyl, cycloalkyl, cycloalkyl-d-Cό-alkyl, cycloalkyl-d-C6-alkoxy, cycloalkyl-d-Cβ-alkoxy-d-Cό-alkyl, and cycloalkyl-d-Cό-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with, for example, one or more halogen. The aryl and cycloalkyl portions of such optional substituents are typically single-rings containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms. [270] An aryl or heteroaryl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -SH, -C(O)-OH, amino, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylalkyl, carbocyclylcarbonyloxy, carbocyclyloxyalkoxycarbocyclyl, carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl, carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino, heterocyclylcarbonyloxy, heterocyclyloxyalkoxyheterocyclyl, heterocyclylthioalkylthioheterocyclyl, heterocyclylthioalkoxyheterocyclyl, and heterocyclyloxyalkylthioheterocyclyl. More typically, an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, -NO2, -SH, -C(O)-OH, amino, amino-d-Ce-alkyl, Q-Ce-alkyl, Q-Ce-alkylthio, carboxy-CrCδ-alkylthio, d-Cβ-alkylcarbonyloxy, Q-Q-alkoxy, Q-Cδ-alkoxy-Ci-Cθ-alkyl, d-Cδ-alkoxycarbonyl-d-Ce-alkoxy, d-Ce-alkoxy-d-Ce-alkylthio, CrCe-alkoxycarbonyl-CrCe-alkylthio, carboxy-CrCβ-alkoxy, d-Cδ-alkoxycarbonyl-d-Cδ-alkoxy, aryl, aryl-d-C6-alkyl, aryloxy, arylthio, aryl-d-C6-alkylthio, arylamino, aryl-Ci-Cβ-alkylamino, arylcarbonylamino, arylcarbonyloxy, aryloxy-d-C6-alkoxyaryl, arylthio-d-C6- alkylthioaryl, arylthio-d-Cό-alkoxyaryl, aryloxy-d-C6-alkylthioaryl, cycloalkyl, cycloalkyl-d-C6-alkyl, cycloalkyloxy, cycloalkylthio, cycloalkyl-Ci-Co-alkylthio, cycloalkylamino, cycloalkyl-CrCβ-alkylamino, cycloalkylcarbonylamino, cycloalkylcarbonyloxy, heteroaryl, heteroaryl-Q-Cδ-alkyl, heteroaryloxy, heteroarylthio, heteroaryl-CrCe-alkylthio, heteroarylamino, heteroaryl-Q-Ce-alkylamino, heteroarylcarbonylamino, and heteroarylcarbonyloxy. Here, one or more hydrogens bound to a carbon in any such substituent may, for example, optionally be replaced with halogen. In addition, any cycloalkyl, aryl, and heteroaryl portions of such optional substituents are typically single-rings containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.
[271] A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Thus, the C1-C6- prefix on d-Q-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6- prefix does not describe the cycloalkyl component. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogens. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkoxyalkyl" rather than "haloalkoxyalkyl." And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkoxyhaloalkyl."
[272] If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other selected substituent(s).
[273] When words are used to describe a substituent, the rightmost-described component of the substituent is the component that has the free valence. To illustrate, benzene substituted with methoxyethyl has the following structure:
Figure imgf000072_0001
As can be seen, the ethyl is bound to the benzene, and the methoxy is the component of the substituent that is the component furthest from the benzene. As further illustration, benzene substituted with cyclohexylthiobutoxy has the following structure:
Figure imgf000072_0002
[274] When words are used to describe a linking element between two other elements of a depicted chemical structure, the rightmost-described component of the substituent is the component that is bound to the left element in the depicted structure. To illustrate, if the chemical structure is X-L-Y and L is described as methylcyclohexylethyl, then the chemical would be X-ethyl-cyclohexyl-methyl-Y.
[275] When a chemical formula is used to describe a mono-valent substituent, the dash on the left side of the formula indicates the portion of the substituent that has the free valence. To illustrate, benzene substituted with -C(O)-OH has the following structure:
Figure imgf000073_0001
[276] When a chemical formula is used to describe a di-valent (or "linking") element between two other elements of a depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if the depicted chemical structure is X-L-Y and L is described as
-C(O)-N(H)-, then the chemical would be:
Figure imgf000073_0002
H
[277] The term "pharmaceutically acceptable" is used adjectivally in this patent to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product. Generally, something is pharmaceutically acceptable if it does not cause an unacceptable adverse or allergic reaction when administered to the patient.
[278] With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent.
[279] "CC50" refers to a standard of measure indicating the concentration of a compound that causes 50 percent of maximum cytotoxicity. [280] "Defective genome" refers to a DNA or RNA molecule that contains all the genetic elements (e.g., cis-acting elements) required for viral genomic replication and transcription, but lacks one or more of the genetic elements that encode the borrowed factors or enzymes (e.g., trans-acting factors) required for replication. Defective genomes require the addition of a missing factor in order to replicate.
[281] "EC50" refers to a standard measure of effective concentration (EC) which is the concentration of a compound required to achieve a 50 percent inhibition of replication of the virus, e.g., a reduction of 50 percent of the replication achieved in the absence of the compound. Sometimes used interchangeably with IC50. [282] "IC50" refers to a standard of measure of inhibitory concentration (IC) which is the concentration of a compound required to achieve a 50 percent inhibition of viral replication. IC50 is often used as interchangeable with EC50.
[283] Selectivity Index (SI): A ratio of cytotoxic concentration (CC) over the effective concentration (EC). For example, SI=CC50/EC50. [284] Therapeutic Index (TI): Another name for the Selectivity Index (SI) which is a ratio of cell cytotoxic concentration (CC) over the effective concentration (EC).
[285] With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent, including the claims below.
EXAMPLES
[286] The following examples are merely illustrative, and not limiting to the remainder of this disclosure in any way.
[287] Examples 1-567. Examples of compounds and their anti-viral activity.
[288] In the following examples, compounds of the present invention were evaluated for anti- viral activity against RSV, HCV, WNV and/or YFV. [289] In conducting the experiments, stock solutions of the antiviral compounds were prepared at a concentration of 1OmM in DMSO. Dilutions were made to screening concentrations in cellular growth media. Compounds were initially tested at 25 μM final concentration, and subsequently tested at a range of from 75 μM to 0.75 μM final concentration. The compounds were added to cells and incubated for 24 hours at 37° C and 5% CO2 (v/v).
Measurement of RSV Antiviral Activity [290] RSV antiviral activity was measured against a RSV minigenome- dependent β-galactosidase expression assay (RSV β -Gal). Czs-acting elements are required for the replication and transcription of a number of negative-strand virus genomes. This requirement can be utilized to develop methods for identifying antiviral compounds. Applicants have applied such methods to, for example, RSV to develop a prototype assay for detecting and quantifying negative-strand RNA viruses. See Olivo et al., "Detection and quantitation of human respiratory syncytial virus (RSV) using minigenome cDNA and a Sindbis virus replicon: a prototype assay for negative-stranded RNA viruses," Virology 251 : 198-205 (1998). In addition, synthetic analogs of genomic RNA have been developed. See Collins et al., "Rescue of synthetic analogs of respiratory syncytial virus genomic RNA and effect of truncations and mutations on the expression of a foreign reporter gene," Proc. Natl. Acad. Sd. USA 88:9663-7 (1991). These analogues of genomic RNA are referred to as "minigenome RNA". RNA transcribed from minigenome cDNA contains the czs-acting elements necessary for replication and transcription in RSV-infected cells, and contains a reporter gene(s) in place of viral genes. One of the challenges has been the need to constitutively express high levels of the viral minigenome RNA in the cytoplasm of the cell. To address this challenge, Applicants have developed an infection-independent minigenome expression system for screening anti-RSV drugs. Minigenome replication systems are not true replicons because the cis- and tra/w-acting elements are not contained on the same RNA molecule. They are, however, functionally equivalent and useful for identifying antiviral compounds. This methodology can be applied to any negative-strand RNA virus by combining knowledge of the specific details of the life cycle of the virus with empiricism. [291] Transfected cells were plated in 96 well tissue culture treated rnicroplates and allowed to settle for 4 hours at 37° C and 5% CO2 (v/v). Test compounds were added to appropriate final concentration with DMSO concentration being held constant at 1% in all wells. No-compound controls consisted of cells with media plus DMSO at 1%. Background control wells were non-transfected cells in media plus DMSO at 1%. Cells were incubated in the presence of compound for 24 hours at 37° C and 5% CO2 (v/v).
[292] Beta-galactosidase activity was detected using Galacto-Star™ β - Galactosidase Assay Kit (Applied Biosystems of Foster City, California, USA). Media and compound were removed from cells. Cell Lysates were prepared by adding lysis solution from the Galacto-Star™ kit and incubating at room temperature for 30 minutes. Galacto-Star™ detection reagent was added and samples were put on an orbital shaker for 1 hour. Beta-galactosidase dependent luminescence was detected with a FLUOstar reader (BMG Labtechnology, Durham, North Carolina, USA). The results were evaluated to determine the concentration at which 50% RSV efficacy (i.e. EC50) was achieved.
Measurement of HCV Antiviral Activity
[293] HCV antiviral activity was measured in a HCV Neo screening assay by determining HCV replicon reduction effects of compounds through NPTII ELISA quantitation of Neomycin Phosphotransferase levels.
[294] Clone A cells, a clone of a human hepatoma-derived cell line (Huh7) which carries constitutively replicating subgenomic hepatits C virus RNA, were plated in 96 well tissue culture treated microplates and allowed to settle for 4 hours at 37° C and 5% CO2 (v/v). Test compounds were added to appropriate final concentration with DMSO concentration being held constant at 1% in all wells. No compound controls consisted of cells with media plus DMSO at 1%. Background control wells were cells treated with 150U Interferon alpha in media plus DMSO at 1%. Cells were incubated in the presence of compound for 24 hours at 37° C and 5% CO2 (v/v). [295] Neomycin Phosphotransferase II protein was quantified using NPTII
ELISA assay kit (Agdia, Inc. of Elkhart, Indiana, USA). Media and compound were removed from cells. Cell lysates were prepared by addition of IX extraction buffer and shaking vigorously for 15 min. Lysates were then transferred to NPTII capture plate and shaken vigorously for 2 hours. Capture plates were washed with PBST 8 times. Plates were filled with conjugated antibody and shaken vigorously for 2 hours. The wash step was repeated. ELISA was developed by addition of TMB substrate. The reaction was incubated at room temperature for 15 minutes and stopped by addition of Red Stop reagent (Neogen Corporation). The results were evaluated to determine the concentration at which 50% HCV efficacy (i.e. EC50) was achieved.
Measurement of WNV Antiviral Activity [296] To measure WNV antiviral activity, WN-hRuPac cells were plated in
96-well tissue culture treated microplates and allowed to settle for 4 hr at 370C under 5% CO2 (v/v). Test compounds were added to appropriate final concentration with the DMSO concentration being held constant at 1% in all wells. No-compound controls consisted of cells with media plus DMSO at 1%. Background-control wells consisted of non-transfected cells in media plus DMSO at 1%. Cells were incubated in the presence of the test compound for 24 hr at 370C under 5% CO2 (v/v).
[297] Renilla luciferase activity was detected using the Promega Renilla Luciferase Assay Kit (Promega, Madison, WI). The media and compound were removed from the cells. Cell lysates were prepared by adding lysis solution from the Renilla Luciferase Assay kit, and then shaking at room temperature for 15 min. Renilla Luciferase Assay Reagent was added to each well by injection immediately before detection of luminescence. Renilla Luciferase dependent luminescence was detected with a FLUOstar reader (BMG Labtechnology, Durham, NC). The results were evaluated to determine the concentration at which 50% WNV efficacy {i.e., EC50) was achieved.
Measurement of YFV Antiviral Activity
[298] To measure YFV antiviral activity, YF-hRuPac cells were plated in 96- well tissue culture treated microplates and allowed to settle for 4 hr at 370C under 5% CO2 (v/v). Test compounds were added to appropriate final concentration with the DMSO concentration being held constant at 1% in all wells. No-compound controls consisted of cells with media plus DMSO at 1%. Background-control wells were non- transfected cells in media plus DMSO at 1%. The cells were incubated in the presence of the compound for 24 hr at 370C under 5% CO2 (v/v).
[299] Renilla luciferase activity was detected using the Promega Renilla Luciferase Assay Kit (Promega, Madison, WI). The media and compound were removed from the cells. Cell lysates were prepared by adding lysis solution from the Renilla Luciferase Assay kit and shaking at room temperature for 15 min. Renilla Luciferase Assay Reagent was added to each well by injection immediately before detection of luminescence. Renilla Luciferase dependent luminescence was detected with a FLUOstar reader (BMG Labtechnology, Durham, NC). The results were evaluated to determine the concentration at which 50% YFV efficacy {i.e., EC50) was achieved.
Measurement of Cell Toxicity [300] In addition to antiviral activity, the animal cell toxicity of each candidate compound was evaluated. Cellular toxicity of the antiviral compounds was measured in an ATP assay wherein the number of viable cells in a culture was determined by the quantitation of intracellular ATP which denotes the presence of metabolically active cells.
[301] Cells were plated in 96 well microplates treated with tissue culture and allowed to settle for 4 hours at 37° C and 5% CO2 (v/v). Test compounds were added to appropriate final concentration with DMSO concentration being held constant at 1% in all wells. No-compound controls consisted of cells with media plus DMSO at 1%. Background control wells were blank wells. The cells were incubated in the presence of compound for 24 hours at 37° C and 5% CO2 (v/v). [302] ATP content of intact cells was measured using the CellTiter-Glo®
Assay Kit (Promega Corporation, Madison, Wisconsin, USA). Media and compound were removed from cells. Fresh media and assay reagent were added in equal volumes. The cells were lysed by shaking. The signal was allowed to stabilize and luminescence was read in a FLUOstar reader (BMG Labtechnology). The results were evaluated to determine the concentration at which 50% cell death occurred {i.e., CCs0). [303] As a measure of cellular toxicity to antiviral activity, a therapeutic index ("TI") for each antiviral compound was calculated as the ratio of the CC50 concentration to the EC50 concentration, or CC50/EC50.
[304] Based on EC50 concentrations and TI index, the antiviral compounds were placed into one of three activity classes as follows:
Category A: < 25 μM efficacy and > 4 TI,
Category B: < 25μM efficacy and < 4 TI,
Category C: > 25μM efficacy, and n/a indicates that the antiviral activity was not analyzed.
[305] Example 1. A compound corresponding to formula (I) wherein Ra and Rb together form {2-[(6-ethoxy-l,3-benzothiazol-2-yl)thio]-l,4-dioxobutane-l,4- diyljdiyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000079_0001
[306] Example 2. A compound corresponding to formula (I) wherein Ra and Rb together form [l,4-dioxobut-2-ene-l,4-diyl]diyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000079_0002
[307] Example 3. A compound corresponding to formula (I) wherein Ra and Rb together form [2-(l,3-benzothiazol-2-ylthio)-l,4-dioxobutane-l,4-diyl]diyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000080_0001
Rb form [[2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)isoxazolidine-4,5- diyl]di(carbonyl)]diyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000080_0002
[309] Example 5. A compound corresponding to formula (I) wherein Ra and
Rb form [[3-(3-nitr :oophenyl)-2-phenylisoxazolidine-4,5-diyl]di(carbonyl)]diyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000080_0003
[310] Example 6. A compound corresponding to formula (I) wherein Ra and Rb form [[2-(2-methylphenyl)-3-phenylisoxazolidine-4,5-diyl]di(carbonyl)]diyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000081_0003
Rb is 4-yl-2-{[l-(4-methoxyphenyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene]methyl}-l-methylpenta-l,3-dien-l-yl; Rc is [(4-methylphenyl)amino]carbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000081_0001
[312] Example 8. A compound corresponding to formula (I-A) wherein R is { [3 ,5 -bis(ethoxycarbonyl)-4-methyl-2-thienyl] amino } (oxo)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000081_0002
[313] Example 9. A compound corresponding to formula (I-A) wherein Rb is chloroacetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000082_0001
[314] Example 10. A compound corresponding to formula (I-A) wherein R is 4-amino-4-oxobut-2-enoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000082_0002
is (3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-l,4-benzothiazin-2-yl)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000082_0003
[316] Example 12. A compound corresponding to formula (I-A) wherein R is (3-oxo-3,4-dihydro-2H-l,4-benzothiazin-2-yl)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000083_0001
is (diethylamino)acetyl; Rc is ethoxycarbonyl; Rd is phenyl; and Re is (dimethylamino)methyl :
Figure imgf000083_0002
[318] Example 14. A compound corresponding to formula (I-A) wherein R is (2-phenylquinolin-4-yl)carbonyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000083_0003
[319] Example 15. A compound corresponding to formula (I-A) wherein R is (3-azepan-l-yl)propanoyl; R° is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000084_0001
[320] Example 16. A compound corresponding to formula (I- A) wherein R is (4-et :hhyyllppiippeerraazziinn--ll--yyll))aacceettyyll;; RRcc iiss eetthhooxxyyccaarrbboonnyyll; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000084_0002
[321] Example 17. A compound corresponding to formula (I- A) wherein R is (3-oxo-3,4-dihydro-2H-l,4-benzothiazin-2-yl)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000084_0003
[322] Example 18. A compound corresponding to formula (I- A) wherein R is 4-[(carboxymethyl)thio]-3-nitrobenzoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000085_0001
[323] Example 19. A compound corresponding to formula (I- A) wherein Rb is (3-(2-furanyl)prop-2-enoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000085_0002
[324] Example 20. A compound corresponding to formula (I- A) wherein R is 2-cyano-3-(2-furanyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000085_0003
[325] Example 21. A compound corresponding to formula (I- A) wherein R is 2-cyano-3-(3-nitrophenyl)prop-2-enoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000085_0004
[326] Example 22. A compound corresponding to formula (I- A) wherein Rb is 3-chloropropanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000086_0001
[327] Example 23. A compound corresponding to formula (I- A) wherein BJ is (3-oxo-l,2,3,4-tetrahydroquinoxalm-2-yl)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000086_0004
Figure imgf000086_0002
is 3-[5-benzylidene-4-oxo-2-thioxo-l,3-thiazolidin-3-yl]propanoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
is 1-naphthylacetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000087_0003
is (pyrrolidin-l-yl)acetyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000087_0001
is 4-[(azepan-l-yl)sulfonyl]benzoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000087_0002
is (4-ethylpiperazin-l-yl)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl :
Figure imgf000088_0004
[333] Example 29. A compound corresponding to formula (I- A) wherein R is 3-[4-oxo-5-(2-thienylmethylene)-2-thioxo-l,3-thiazolidin-3-yl]propanoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000088_0001
is (phenylthio)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000088_0002
[335] Example 31. A compound corresponding to formula (I- A) wherein R is [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000088_0003
[336] Example 32. A compound corresponding to formula (I- A) wherein Rb is 3-(4-ethylpiperazin-l-yl)propanoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000089_0001
[337] Example 33. A compound corresponding to formula (I- A) wherein R^ is [5-(methoxycarbonyl)-3-oxothiomoφholin-2-yl]acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000089_0002
is {([l,2,4]triazolo[3,4-b][l,3]benzothiazol-3-yl)thio}acetyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000089_0003
[339] Example 35. A compound corresponding to formula (I- A) wherein R^ is [(4-oxo-3,6-diphenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000090_0003
is 3-[4-oxo-2-thioxo-5-(3,4,5-trimethoxybenzylidene)-l,3-thiazolidin-3-yl]propanoyl; Rc is aminocarbonyl; and R and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000090_0001
is 4-(morpholin-4-ylsulfonyl)benzoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000090_0002
[342] Example 38. A compound corresponding to formula (I- A) wherein R is (4,6-dioxo-2-thioxotetrahydropyrimidm-5(2H)-ylidene)amino; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000091_0001
[343] Example 39. A compound corresponding to formula (I- A) wherein R is 3-[4-(acetylamino)phenyl]-2-cyanoprop-2-enoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000091_0003
[344] Example 40. A compound corresponding to formula (I- A) wherein R is [(l-p )hheennyyll--llHH--tteetrazol-5-yl)thio]acetyl, Rc is ethoxycarbonyl, Rd is methyl, and Re is methoxycarbonyl:
Figure imgf000091_0002
[345] Example 41. A compound corresponding to formula (I-A) wherein Rb is ( [[1l,,22,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000092_0003
[346] Example 42. A compound corresponding to formula (I-A) wherein R is (5,6,7,8-tetrahydro[l]benzothieno[2,3-d]pyrimidin-4-ylthio)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000092_0001
[347] Example 43. A compound corresponding to formula (I-A) wherein R^ is [3-oxo-6-(trifluoromethyl)-3,4-dihydro-2H-l,4-benzothiazin-2-yl]acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000092_0002
[348] Example 44. A compound corresponding to formula (I-A) wherein R^ is (3-oxo-l,2,3,4-tetrahydroquinoxalin-2-yl)acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000093_0004
Figure imgf000093_0001
is 6-{[3-(aminocarbonyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]ammo}-6-oxohexanoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000093_0002
[350] Example 46. A compound corresponding to formula (I- A) wherein R is (biphenyl-4-yl)carbonyl; Rc is aminocarbonyl; Rd is methyl; and Re is benzyl:
Figure imgf000093_0003
[351] Example 47. A compound corresponding to formula (I- A) wherein R is 4-[5-(4-ethylbenzylidene)-4-oxo-2-thioxo-l,3-thiazolidin-3-yl]butanoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000093_0005
[352] Example 48. A compound corresponding to formula (I- A) wherein Rb is (2-imino-4-oxo-l,3-thiazolidin-5-yl)acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000094_0001
[353] Example 49. A compound corresponding to formula (I- A) wherein R^ is 4-ethoxy-4-oxobut-2-enoyl; Rc is aminocarbonyl; Rd is methyl; and Re is benzyl:
Figure imgf000094_0002
is [(5-methyl[l,2,4]triazolo[4,3-a]quinolin-l-yl)thio]acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000094_0003
[355] Example 51. A compound corresponding to formula (I-A) wherein R is 4-(di Lfflluuoorroommeetthhooxxyy))bbeennzzooyyll;; RRcc iiss ccaarrbbooxxyyll;; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000095_0002
[356] Example 52. A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; Rd is phenyl; and Re is hydrogen:
Figure imgf000095_0001
is [(5-methyl[l,2,4]triazolo[4,3-a]quinolin-l-yl)thio]acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000095_0003
[358] Example 54. A compound corresponding to formula (I- A) wherein R is 3-(4-ethylpiperazin-l-yl)propanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000096_0001
enylacetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000096_0003
[360] Example 56. A compound corresponding to formula (I- A) wherein R eridin-l-yl)acetyl; Rc is aminocarbonyl; R is hydrogen; and Re is phenyl:
Figure imgf000096_0002
tyloxy)(phenyl)acetyl; Rc is methoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000097_0003
[362] Example 58. A compound corresponding to formula (I-A) wherein R is [(4-methylphenyl)thio] acetyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000097_0001
[363] Example 59. A compound corresponding to formula (I-A) wherein R is 3-(4-methylpiperazin-l-yl)propanoyl; R° is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000097_0002
[364] Example 60. A compound corresponding to formula (I-A) wherein R^ is [(3-allyl-4-oxo-3,5,6,7-tetraliydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; Rd is 4-methoxyphenyl; and Re is hydrogen:
Figure imgf000098_0003
[365] Example 61. A compound corresponding to formula (I-A) wherein R is 2-cyano-3-(4-hydroxyphenyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000098_0001
[366] Example 62. A compound corresponding to formula (I-A) wherein R^ is [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which
Figure imgf000098_0004
Figure imgf000098_0002
[367] Example 63. A compound corresponding to formula (I-A) wherein R is [(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)thio]acetyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000098_0005
[368] Example 64. A compound corresponding to formula (I- A) wherein Rb is [(3-allyl-4-oxo-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyriπiidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000099_0004
Figure imgf000099_0001
is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000099_0002
[370] Example 66. A compound corresponding to formula (I- A) wherein R is [(5-methyl[l,2,4Jtriazolo[4,3-a]quinolin-l-yl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000099_0005
Figure imgf000099_0003
is [(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)thio]acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000100_0001
[372] Example 68. A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000100_0004
[373] Example 69. A compound corresponding to formula (I- A) wherein R is [(3-allyl-5,6-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000100_0002
[374] Example 70. A compound corresponding to formula (I- A) wherein R is [(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; Rd is 3,4-dimethoxyphenyl; and Re is hydrogen:
Figure imgf000100_0003
[375] Example 71. A compound corresponding to formula (I- A) wherein Rb is 3-(4-ethylpiperazin-l-yl)propanoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000101_0004
Figure imgf000101_0001
is [(2-methyl-6,7-dihydro-5H-cyclopenta[4,5]tliieno[2,3-d]pyrimidin-4-yl)thio]acetyl; Re is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000101_0002
[377] Example 73. A compound corresponding to formula (I- A) wherein R is (3-azepan-l-yl)propanoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000101_0003
[378] Example 74. A compound corresponding to formula (I- A) wherein Rb is [(2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)thio]acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000102_0003
[379] Example 75. A compound corresponding to formula (I- A) wherein Rr is 4-(4-m tneetthhyyllppiippeerriiddiinn--ll--yyll))bbuuttaannooyyll;; RRcc iiss eetthhooxxyyccaarrbboonnyyll;; ε and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000102_0004
Figure imgf000102_0001
is [(3-allyl-4-oxo-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000102_0002
is [(4-oxo-3-phenyl-3,4,5,657,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000103_0001
[382] Example 78. A compound corresponding to formula (I- A) wherein R is [(4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000103_0003
is 3-(4-methylpiperidin-l-yl)propanoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000103_0002
[384] Example 80. A compound corresponding to formula (I- A) wherein Rb is 3-(4-methylpiperidin-l-yl)propanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000104_0001
is [(3-allyl-4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000104_0002
[386] Example 82. A compound corresponding to formula (I- A) wherein R is 4-[(dimethylamino)sulfonyl]benzoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000104_0003
[387] Example 83. A compound corresponding to formula (I- A) wherein R^ is 3-(2,6-dimethylmorpholin-4-yl)propanoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000105_0001
[388] Example 84. A compound corresponding to formula (I- A) wherein R is (4-me 3tthhyyllppiippeerriiddiinn--ll--yyll))aacceettyyll;; RRcc iiss eetthhooxxyyccaarrbboonnyyll;; aaind Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000105_0003
[389] Example 85. A compound corresponding to formula (I- A) wherein R is 4-cyanobenzoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000105_0002
[390] Example 86. A compound corresponding to formula (I- A) wherein R^ is 3-(4-ethylpiperazin-l-yl)propanoyl; Rc is methoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000106_0001
[391] - ECxample 87. A compound corresponding to formula (I- A) wherein R is {[3-allyl-5-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2- yljthio} acetyl; Rc is methoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000106_0002
[392] Example 88. A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-6-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; Rc is ethoxycarbonyl; Rd is phenyl; and Re is hydrogen:
Figure imgf000106_0003
[393] Example 89. A compound corresponding to formula (I- A) wherein R is [(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000107_0003
[394] Example 90. A compound corresponding to formula (I- A) wherein Ie is [(2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidm-4-yl)thio]acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000107_0001
[395] Example 91. A compound corresponding to formula (I- A) wherein R is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000107_0002
[396] Example 92. A compound corresponding to formula (I- A) wherein Rb is 3-morpholin-4-yl-propanoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000108_0002
[397] Example 93. A compound corresponding to formula (I- A) wherein R is (azepan-l-yl)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000108_0003
[398] Example 94. A compound corresponding to formula (I- A) wherein 1Rr is (3-piperidin-l-yl)propanoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000108_0001
[399] Exa imple 95. A compound corresponding to formula (I- A) wherein R^ is [(3-allyl-4-oxo-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000109_0001
[400] Example 96. A compound corresponding to formula (I- A) wherein R is[(4-oxo-3-phenyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000109_0003
[401] Example 97. A compound corresponding to formula (I- A) wherein R is 3-methylbenzoyl; Rc is methoxycarbonyl; R is methyl; and Re is benzyl:
Figure imgf000109_0002
[402] Example 98. A compound corresponding to formula (I- A) wherein R is 3-[5-(4-chloro-3-nitrophenyl)-2-furanyl]-2-cyanoprop-2-enoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000110_0001
[403] Example 99. A compound corresponding to formula (I- A) wherein R is 3-[5-(4-chloro-3-nitrophenyl)-2-furanyl]-2-cyanoprop-2-enoyl; Rc is methoxycarbonyl; and R and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000110_0002
[404] Example 100. A compound corresponding to formula (I- A) wherein R is (3,4-dimethoxyphenyl)acetyl; Rc is ethoxycarbonyl; R is hydrogen; and Re is phenyl:
Figure imgf000110_0003
is 3-[5-(2-chloro-4-nitrophenyl)-2-furanyl]-2-cyanoprop-2-enoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000111_0004
[406] Example 102. A compound corresponding to formula (I- A) wherein R is (6,7-dimethyl-3-oxo-l,2,3,4-tetrahydroquinoxalin-2-yl)acetyl; Rc is methoxycarbonyl; R is methyl; and RL is methyl:
Figure imgf000111_0001
[407] Example 103. A compound corresponding to formula (I- A) wherein R is (2,6-dimethylmorpholin-4-yl)acetyl; Rc is aminocarbonyl, Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000111_0002
is 3-[4-(benzoyloxy)phenyl]-2-cyanoprop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000111_0003
[409] Example 105. A compound corresponding to formula (I- A) wherein Rb is [(4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro[l]benzothieno[2,3-d]pyrimidin-2- yl)thio] acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000112_0001
[410] Example 106. A compound corresponding to formula (I- A) wherein R^ is 3-(4-b brroommoo--22--tthhiieennyyll))pprroopp--22--eennooyyll;; RRcc iiss a ammiinnooccaarrbboonnyyll;; aaind Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000112_0002
[411] Example 107. A compound corresponding to formula (I-A) wherein R is [(3-allyl-4-oxo-6-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000112_0003
[412] Example 108. A compound corresponding to formula (I-A) wherein Rb is 3-morpholin-4-ylpropanoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000113_0002
[413] Example 109. A compound corresponding to formula (I- A) wherein R is [(6-phenylthieno [2,3 -d]ρyrimidin-4-yl)thio] acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000113_0003
[414] Example 110. A compound corresponding to formula (I-A) wherein R is l,l-dioxido-l,2-benzisothiazol-3-yl; Rc is ethoxycarbonyl; Rd is 4-methylphenyl; and Re is hydrogen:
Figure imgf000113_0001
is 4-tert-butylbenzoyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000114_0001
[416] Example 112. A compound corresponding to formula (I- A) wherein R is 3-carboxyprop-2-enoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000114_0002
[417] Example 113. A compound corresponding to formula (I-A) wherein R is 3-carboxyprop-2-enoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000114_0003
[418] Example 114. A compound corresponding to formula (I-A) wherein R is 3-(4-methylpiperazin-l-yl)propanoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000115_0001
[419] Example 115. A compound corresponding to formula (I-A) wherein R^ s 4-chlorobenzoyl; Rc is aminocarbonyl; Rd is methyl; and Re is benzyl:
Figure imgf000115_0002
is (4-methylphenyloxy)acetyl; Rc is aminocarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000115_0003
[421] Example 117. A compound corresponding to formula (I-A) wherein R is (2-methoxyphenyloxy)acetyl; Rc is aminocarbonyl; Rd is methyl; and Re is benzyl:
Figure imgf000115_0004
[422] Example 118. A compound corresponding to formula (I- A) wherein Rb is 3-(4-methylpiperidin-l-yl)propanoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl:
Figure imgf000116_0001
is (4-methylpiperidin-l-yl)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl:
Figure imgf000116_0002
[424] Example 120. A compound corresponding to formula (I- A) wherein R is benzoyl; Rc is {[3-(diethylamino)propyl]amino}carbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000116_0003
[425] Example 121. A compound corresponding to formula (I- A) wherein R^ is [4-(2-hydroxyethyl)piperazin-l-yl] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000117_0001
[426] Example 122. A compound corresponding to formula (I- A) wherein R is [(4-chlorophenyl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000117_0003
[427] Example 123. A compound corresponding to formula (I- A) wherein R is 3-piperidin-l-yl-propanoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000117_0002
[428] Example 124. A compound corresponding to formula (I- A) wherein R^ is 4-(difluoromethoxy)benzoyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000118_0001
[429] Example 125. A compound corresponding to formula (I- A) wherein Rb is 3-piperidin-l-ylpropanoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl:
Figure imgf000118_0003
[430] Example 126. A compound corresponding to formula (I- A) wherein R is [(4-m leetthhyyllqquuiinnoo!lin-2-yl)thio]acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000118_0002
is [(4-methylquinolin-2-yl)thio] acetyl; Rc is ethoxycarbonyl; Rd is 2-furanyl; and Re is hydrogen:
Figure imgf000119_0001
is phenyl(phenylthio)acetyl; Rc is methoxycarbonyl; Rd is methyl; and Re is methoxycarbonyl:
Figure imgf000119_0002
[433] Example 129. A compound corresponding to formula (I- A) wherein R is (acetyloxy)(phenyl)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000119_0003
[434] Example 130. A compound corresponding to formula (I- A) wherein Rb is morpholin-4-ylacetyl; Rc is ethoxycarbonyl; Rd is 4-chlorophenyl; and Re is methyl:
Figure imgf000120_0001
is 2-furoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000120_0002
[436] Example 132. A compound corresponding to formula (I- A) wherein R is [2-(2-chlorobenzylidene)hydrazinyl]carbonyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000120_0003
[437] Example 133. A compound corresponding to formula (I- A) wherein R is 4-chloro-3-nitrobenzoyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000121_0001
[438] Example 134. A compound corresponding to formula (I- A) wherein Ic is [(4-chlorophenyl)amino]carbonyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000121_0002
[439] Example 135. A compound corresponding to formula (I- A) wherein R^ is 2-chloro-4-nitrobenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000121_0003
[440] Example 136. A compound corresponding to formula (I-A) wherein Rb is 3-phenylprop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000122_0003
[441] Example 137. A compound corresponding to formula (I-A) wherein R is 6-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)hexanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000122_0001
[442] Example 138. A compound corresponding to formula (I-A) wherein R is (2-isopropyl-5-methylphenyloxy)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000122_0002
[443] Example 139. A compound corresponding to formula (I-A) wherein Rb is (4-methoxyphenyloxy) acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000123_0003
[444] Example 140. A compound corresponding to formula (I- A) wherein R is 4-methoxybenzoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000123_0001
[445] Example 141. A compound corresponding to formula (I-A) wherein R is (2,4-dibromophenyloxy)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000123_0002
is (4-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000124_0001
[447] Example 143. A compound corresponding to formula (I- A) wherein R is butoxycarbonyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000124_0002
[448] Example 144. A compound corresponding to formula (I- A) wherein R is anilinocarbonyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000124_0003
is chloroacetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000125_0001
is 3-phenyloxypropanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000125_0002
[451] Example 147. A compound corresponding to formula (I-A) wherein R is 3-phenyloxypropanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000125_0003
[452] Example 148. A compound corresponding to formula (I-A) wherein Rb is 3-phenyloxypropanoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000126_0001
[453] Example 149. A compound corresponding to formula (I- A) wherein Rb is 4-chloro-3-nitrobenzoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000126_0002
[454] Example 150. A compound corresponding to formula (I-A) wherein R^ is [2-(2- -hhyyddrrooxxyy--33 --mmeetthhooxx^ybenzylidene)hydrazinyl]carbonyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000126_0003
is (2-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000127_0003
is (4-chlorophenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000127_0001
[4571 Example 153. A compound corresponding to formula (I-A) wherein RJ is (2-tert-butyl-4-methylphenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000127_0004
[458] Example 154. A compound corresponding to formula (I-A) wherein R is 4-chlorobenzoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000127_0002
[459] Example 155. A compound corresponding to formula (I- A) wherein Rb is 3-(3,4-dimethoxyphenyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000128_0001
is (2-methoxyphenyloxy) acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000128_0002
[461] Example 157. A compound corresponding to formula (I- A) wherein R^ is butyryl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000128_0003
[462] Example 158. A compound corresponding to formula (I- A) wherein R^ is (2-methoxyphenyloxy) acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000129_0001
[463] Example 159. A compound corresponding to formula (I-A) wherein R^ is (2-chlorophenyloxy)acetyl; R° is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000129_0003
[464] Example 160. A compound corresponding to formula (I-A) wherein R is 4-fluorobenzoyl; Rc is aminocarbonyl; and R and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000129_0002
[465] Example 161. A compound corresponding to formula (I-A) wherein R^ is (2-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000130_0003
[466] Example 162. A compound corresponding to formula (I- A) wherein R is 2,6-dimethoxybenzoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000130_0001
[467] Example 163. A compound corresponding to formula (I- A) wherein Rb is [3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000130_0002
[468] Example 164. A compound corresponding to formula (I- A) wherein Ie is (2,6-dimethylphenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000131_0003
[469] Example 165. A compound corresponding to formula (I- A) wherein R is dichloroacetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000131_0001
[470] Example 166. A compound corresponding to formula (I-A) wherein R is (4-tert-butylphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000131_0004
[471] Example 167. A compound corresponding to formula (I-A) wherein R is (4-bromo-3-methylphenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000131_0002
[472] Example 168. A compound corresponding to formula (I- A) wherein Rb is tiifluoroacetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000132_0001
[473] Example 169. A compound corresponding to formula (I- A) wherein R^ is 3-phenylprop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000132_0002
[474] Example 170. A compound corresponding to formula (I-A) wherein R is chloroacetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000132_0003
[475] Example 171. A compound corresponding to formula (I-A) wherein R is dichloroacetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000132_0004
[476] Example 172. A compound corresponding to formula (I- A) wherein Rb is (4-chlorophenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000133_0001
[477] Example 173. A compound corresponding to formula (I- A) wherein R is dichloroacetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000133_0002
is 4-tert-butylbenzoyl; Rc is aminocarbonyl; and R and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000133_0003
[479] Example 175. A compound corresponding to formula (I- A) wherein R is [2-(pyridin-2-yhnethylene)hydrazinyl]carbonyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000134_0001
is (4-nitrophenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000134_0003
is (2-chlorophenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000134_0002
[482] Example 178. A compound corresponding to formula (I-A) wherein R^ is (6-bromo-2-oxo-2H-chromen-3-yl)carbonyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000135_0001
is 2,3-dihydro-l,4-benzodioxinyl; Rc is methoxycarbonyl; and R and Re, together with the atoms to which they are bonded, form methoxycarbonylpentenyl:
Figure imgf000135_0002
[484] Example 180. A compound corresponding to formula (I-A) wherein R is (2-methylphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000135_0003
[485] Example 181. A compound corresponding to formula (I-A) wherein Br is phenyloxyacetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000135_0004
[486] Example 182. A compound corresponding to formula (I- A) wherein Rb is (4-methoxyphenyloxy) acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000136_0001
[487] Example 183. A compound corresponding to formula (I-A) wherein R is phenylacetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000136_0003
[488] Example 184. A compound corresponding to formula (I-A) wherein R is (3-bromophenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000136_0002
[489] Example 185. A compound corresponding to formula (I-A) wherein R^ is 3-(3-nitrophenyl)prop-2-enoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000137_0001
[490] Example 186. A compound corresponding to fonnula (I- A) wherein R is l-benzofuran-2-yl-carbonyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000137_0002
is (4-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000137_0003
[492] Example 188. A compound corresponding to formula (I-A) wherein R^ is 3,4,5-trimethoxybenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000137_0004
[493] Example 189. A compound corresponding to formula (I-A) wherein R is 6-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)hexanoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000138_0003
[494] Example 190. A compound corresponding to formula (I- A) wherein R is 3-methoxybenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000138_0004
Figure imgf000138_0001
is (2-cyano-3-(4-methoxyphenyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000138_0005
[496] Example 192. A compound corresponding to formula (I- A) wherein R is 3-phe ;nnyyllpprroopp--22--eennooyyll;; RRcc iiss aammiinnooccaarrbboonnyyll;; aanndd RRcd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000138_0002
[497] Example 193. A compound corresponding to formula (I- A) wherein Rb is 2-cyano-3-(4-methoxyphenyl)prop-2-enoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000139_0001
[498] Example 194. A compound corresponding to formula (I- A) wherein Rb is (2,3-dimethylphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000139_0002
[499] Example 195. A compound corresponding to formula (I- A) wherein R is 3-(3-methoxy-4-propoxyphenyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000139_0004
Figure imgf000139_0003
is 2-cyano-3-(4-methoxyphenyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000140_0003
is 2-methoxybenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000140_0002
[502] Example 198. A compound corresponding to formula (I- A) wherein R is (biρhenyl-4-yloxy)acetyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000140_0004
[503] Example 199. A compound corresponding to formula (I- A) wherein R is 2-(4-methoxyphenyloxy)propanoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000140_0005
[504] Example 200. A compound corresponding to formula (I- A) wherein Rb is (2-tert-butylphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000141_0001
[505] Example 201. A compound corresponding to formula (I- A) wherein R is (2-methoxyphenyloxy)acetyl; Rc is aminocarbonyl; and R and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000141_0003
[506] Example 202. A compound corresponding to formula (I- A) wherein R is (2-methylphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000141_0004
Figure imgf000141_0002
is 3,4,5-trimethoxybenzoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000142_0003
[508] Example 204. A compound corresponding to formula (I- A) wherein R is (4-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000142_0001
[509] Example 205. A compound corresponding to formula (I- A) wherein R is 2-bromo-3,4,5-trimethoxybenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000142_0002
is 4-chloro-3-nitrobenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000143_0001
[511] Example 207. A compound corresponding to formula (I-A) wherein R is (4-bromophenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000143_0002
[512] Example 208. A compound corresponding to formula (I-A) wherein R is 3,4-dimethoxybenzoyl; Rc is ethoxycarbonyl; R is hydrogen; and Re is phenyl:
Figure imgf000143_0005
Figure imgf000143_0003
is (3-bromophenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000143_0004
[514] Example 210. A compound corresponding to formula (I-A) wherein R5" is 2,4-dichlorobenzoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000144_0003
[515] Example 211. A compound corresponding to formula (I- A) wherein R is 2-chloro-4-nitrobenzoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000144_0001
is (2-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000144_0004
[517] Example 213. A compound corresponding to formula (I-A) wherein R is (2,4-dibromophenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000144_0002
[518] Example 214. A compound corresponding to formula (I-A) wherein Rb is [4-(l -methyl- l-phenylethyl)phenyloxy] acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000145_0001
[519] Example 215. A compound corresponding to formula (I-A) wherein R^ is (4-methoxyphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000145_0002
Example 216. A compound corresponding to formula (I-A) wherein R is 2-chloro-5-nitrobenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000145_0003
[521] Example 217. A compound corresponding to formula (I-A) wherein R is 3-(3-nitrophenyl)prop-2-enoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000146_0001
is [2-(2-furanylmethylene)hydrazinyl]carbonyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000146_0003
[523] Example 219. A compound corresponding to formula (I- A) wherein R is 3-phenylpropanoyl; R° is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000146_0002
[524] Example 220. A compound corresponding to formula (I- A) wherein R^ is (4-chloro-2-methylphenyloxy)acetyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000147_0001
is 2,4-dichlorobenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000147_0004
Figure imgf000147_0002
is 2-thienylcarbonyl; Rc is aminocarbonyl; R is hydrogen; and Re is phenyl:
Figure imgf000147_0003
[527] Example 223. A compound corresponding to formula (I- A) wherein Iv is 3-(4-ethoxyphenyl)prop-2-enoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000147_0005
[528] Example 224. A compound corresponding to formula (I- A) wherein Rb s 3,4,5-trimethoxybenzoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000148_0003
[529] Example 225. A compound corresponding to formula (I- A) wherein R is 2-furoyl; Rc is aminocarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000148_0001
[530] Example 226. A compound corresponding to formula (I- A) wherein R is 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)benzoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000148_0002
[531] Example 227. A compound corresponding to formula (I-A) wherein Rb is (2,3,6-trimethylphenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000149_0001
[532] Example 228. A compound corresponding to formula (I- A) wherein R is 3,5-dimethoxybenzoyl; Rc is methoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methoxycarbonylcyclopentenyl:
Figure imgf000149_0002
[533] Example 229. A compound corresponding to formula (I- A) wherein R is {[3-(aminocarbonyl)-4,5,6,7-tetrahydro-l-benzothien-2-yl]amino}(oxo)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000149_0003
[534] Example 230. A compound corresponding to formula (I- A) wherein R is (2,3,6-trimethylphenyloxy)acetyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000149_0004
[5351 Example 231. A compound corresponding to formula (I- A) wherein R is 2-bromo-3-phenylprop-2-enoyl; Rc is ethoxycarbonyl; Rd is hydrogen; and Re is phenyl:
Figure imgf000150_0002
[536] Example 232. A compound corresponding to formula (I- A) wherein R , is 2-bromo-3-phenylprop-2-enoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is acetyl:
Figure imgf000150_0003
Figure imgf000150_0001
is 4-(4-chlorophenyloxy)butanoyl; Rc is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000150_0004
[538] Example 234. A compound corresponding to formula (I- A) wherein R is 2-bromo-3,4,5-trimethoxybenzoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000151_0003
[539] Example 235. A compound corresponding to formula (I- A) wherein Ie is 3-[3-methoxy-4-(pentyloxy)phenyl]prop-2-enoyl; R° is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000151_0001
is benzoyl; Rc is,3-hydroxypropylaminocarbonyl; Rd is methyl; and Re is methyl:
Figure imgf000151_0002
[541] Example 237. A compound corresponding to formula (I- A) wherein R^ is 3-methoxybenzoyl; Rc is [(4-methoxyphenyl)amino]carbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000152_0004
Figure imgf000152_0001
is 2-thienylcarbonyl; Rc is piperidin-lylcarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000152_0002
[543] Example 239. A compound corresponding to formula (I- A) wherein R is 2-furo oyyll;; RRcc iiss [[((44--eetthhooxxyypphheennyyll))aammminoo]]ccaarrbboonnyyll;; a and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000152_0003
[544] Example 240. A compound corresponding to formula (I- A) wherein R is 2-furoyl; Rc is [(4-methylphenyl)amino]carbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000153_0001
[545] Example 241. A compound corresponding to formula (I-A) wherein R is benzoyl; Rc is [(4-methoxyphenyl)amino]carbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000153_0002
[546] Example 242. A compound corresponding to formula (I-A) wherein R is 2-thie snnyyllccaarrbboonnyyll;; RRcc iiss ((ddiieetthhyyllaammiinnoo))ccaarrbboonnyyll;; a ani d Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
HCV RSV WNV YFV
C n/a n/a n/a
H3C
^CH3
[547] Example 243. A compound corresponding to formula (I-A) wherein R is benzoyl; Rc is [(4-methoxyphenyl)amino]carbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000154_0001
[548] Example 244. A compound corresponding to formula (I- A) wherein Rb is benzoyl; Rc is [(2-ammoethyl)amino]carbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000154_0002
[549] Example 245. A compound corresponding to formula (I- A) wherein R is [(4-methoxyphenyl)amino] acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000154_0003
[550] Example 246. A compound corresponding to formula (I- A) wherein R is benzoyl; Rc is [(2-hydroxyethyl)amino]carbonyl; Rd is phenyl; and Re is hydrogen:
Figure imgf000155_0001
[551] Example 247. A compound corresponding to formula (I- A) wherein R is (7-methyl-4-oxo-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)- acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000155_0002
is (4-ethylpiperazin-l-yl)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl:
Figure imgf000156_0002
is 2,2,2-triphloro-l-[(fluoroacetyl)amino]ethyl; Rc is ethoxycarbonyl; Rd is phenyl; and Re is hydrogen:
Figure imgf000156_0003
[554] Example 250. A compound corresponding to formula (I- A) wherein R is 5-nitro-2-furoyl; Rc is ethoxycarbonyl; Rd is methyl; and Re is ethoxycarbonyl:
Figure imgf000156_0001
is (4-nitrophenyloxy)acetyl; Rc is ethoxycarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl:
Figure imgf000157_0001
[556] Example 252. A compound corresponding to formula (I- A) wherein Rb is [(4-tert-butylbenzoyl)amino]carbonothioyl; R° is aminocarbonyl; and Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl:
Figure imgf000157_0002
[557] Example 253. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is hydrogen; and R9 is 2-phenylvinyl:
Figure imgf000157_0003
[558] Example 254. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(cyclohexylamino)-2-oxoethyl]thio:
Figure imgf000158_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is difluoromethanesulfenyl:
Figure imgf000158_0003
[560] Example 256. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is (3-{[4- (aminosulfonyl)phenyl] amino } -3 -oxopropyl)thio :
Figure imgf000158_0004
Figure imgf000158_0002
Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4- (aminosulfonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000159_0001
[562] Example 258. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is methyl; and R9 is [4-'(methoxycarbonyl)benzyl]thio:
Figure imgf000159_0002
[563] Example 259. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is [(2-chlorophenyl)methylene]amino; and R9 is hydrogen:
Figure imgf000159_0004
[564] Example 260. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is hydrogen; and R9 is [(4-phenyl-5-thioxo'-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]thio:
Figure imgf000159_0003
[565] Example 261. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2- oxoethyl)thio:
Figure imgf000160_0002
[566] Example 262. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is hydrogen; and R9 is [2-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)- yl)ethyl]thio:
Figure imgf000160_0003
[567] Example 263. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is [l,3-benzodioxol-5- ylmethylene] amino; and R9 is methyl:
Figure imgf000160_0004
Figure imgf000160_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is hydrogen; and R9 is 2-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)-yl)ethyl:
Figure imgf000160_0005
[569] Example 265. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is [2-(phenyloxysulfonyl)ethyl]thio:
Figure imgf000161_0002
[570] Example 266. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[4-(aminosulfonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000161_0003
[571] Example 267. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-2- oxoethyl)thio:
[572] Example 268. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)ethyl]thio:
Figure imgf000162_0001
[573] Example 269. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4- (aminosulfonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000162_0003
[574] Example 270. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(3-cyano-6-methyl- 4,5 ,6,7-tetrahydro- 1 -benzothien-2-yl)amino] -2-oxoethyl} thio :
Figure imgf000162_0002
[575] Example 271. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is 2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethanesulfenyl:
Figure imgf000163_0001
Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is [2-(3,4- dimethoxyphenyl)-2-oxoethyl]thio:
Figure imgf000163_0002
[577] Example 273. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is [2-(l,3- benzodioxol-5-ylamino)-2-oxoethyl]thio:
Figure imgf000163_0003
[578] Example 274. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is lH-pyrrol-1-yl; and R9 is hydrogen:
Figure imgf000164_0001
[579] Example 275. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2-fluorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000164_0002
[580] Example 276. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is [(3,5-dimethylisoxazol-4-yl)methyl]thio:
Figure imgf000164_0003
[581] Example 277. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,6- dichlorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000165_0001
[582] Example 278. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is [2- (cyclohexylamino)-2-oxoethyl]thio:
Figure imgf000165_0002
[583] Example 279. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is [(5-nitro-2- furanyl)methylene] amino; and R9 is hydrogen:
Figure imgf000165_0003
[584] Example 280. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is [2-(l-adamantylamino)-2-oxoethyl]thio:
Figure imgf000166_0001
[585] Example 281. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[2-({[(3-allyl-4-oxo-5- phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio]acetyl}amino)hexyl]amino}-2- oxoethyl)thio:
Figure imgf000166_0003
[586] Example 282. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino}-2-oxoethyl)thio:
Figure imgf000166_0002
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4- (acetylamino)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000167_0002
Figure imgf000167_0001
Re is hydrogen; Rd is 3,4-dimethoxyphenyl; R7 is oxo; R8 is allyl; and R9 is difluoromethanesulfenyl:
Figure imgf000167_0003
[589] Example 285. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is {2- [(aminocarbonyl)amino]-2-oxoethyl}thio:
Figure imgf000167_0004
[590] Example 286. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is (4-hydroxybenzylidene)amino; and R9 is hydrogen:
Figure imgf000167_0005
[591] Example 287. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is phenyl; and R9 is [2-(2-naphthyl)-2- oxoethyl]thio:
Figure imgf000168_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is allyl; and R is {3-[(4-fluorophenyl)amino]-3-oxopropyl}thio:
Figure imgf000168_0002
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is phenyl; and R9 is (2-{[3- (ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2-thienyl]amino}-2-oxoethyl)thio:
Figure imgf000168_0003
[594] Example 290. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is {[2-(difluoromethoxy)phenyl]methylene} amino; and R9 is hydrogen:
Figure imgf000169_0001
[595] Example 291. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is [(5,7- dimethylimidazo[l,2-a]pyrimidin-2-yl)methyl]thio:
Figure imgf000169_0002
[596] O Example 292. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is [(3,5-dimethylisoxazol-4-yl)methyl]thio:
Figure imgf000169_0003
[597] Example 293. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is hydrogen; and R9 is [(5-{[4- (methoxycarbonyl)benzyl]thio}-4-phenyl-4H-l,2,4-triazol-3-yl)methyl]thio:
Figure imgf000170_0001
[598] Example 294. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is thioxo; R8 is hydrogen; and R9 is hydrogen:
Figure imgf000170_0003
Figure imgf000170_0002
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-moφholin-4-yl-2-oxoethyl)thio:
Figure imgf000170_0004
[600] Example 296. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is hydrogen; and R9 is [(5-anilino-l,3,4-thiadiazol-2-yl)methyl]thio:
Figure imgf000170_0005
[601] Example 297. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is [ (2-chloroimidazo[l,2-a]pyridin-3- yl)methylene] amino; and R9 is hydrogen:
Figure imgf000171_0001
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is (cyanomethyl)thio:
Figure imgf000171_0002
[603] Example 299. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (3-{[4-(aminosulfonyl)phenyl]amino}-3-oxopropyl)thio:
Figure imgf000171_0004
Figure imgf000171_0003
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[4-(ethoxycarbonyl)- 3 ,5 -dimethyl- 1 H-pyrrol-2-yl] -2-oxoethyl} thio :
Figure imgf000172_0002
R is hydrogen; R is 4-methoxyphenyl; R is oxo; R is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is hydrogen:
Figure imgf000172_0003
[606] Example 302. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl)thio:
Figure imgf000172_0001
[607] Example 303. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R is oxo; R is allyl; and R is [(3,5-dimethylisoxazol-4- yl)methyl]thio:
Figure imgf000173_0004
[608] Example 304. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is [2-(2-furanyl)-2- oxoethyl]thio:
Figure imgf000173_0001
[609] Example 305. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is {2-[(3-cyano-2- thienyl)amino] -2-oxoethyl} thio :
Figure imgf000173_0005
Figure imgf000173_0002
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is [2-(2-methyl-lH-indol-3-yl)-2-oxoethyl]thio:
Figure imgf000173_0003
[611] Example 307. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-4-phenyl-2-thienyl]amino}-2- oxoethyl)thio:
Figure imgf000174_0002
Figure imgf000174_0001
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(5-methylisoxazol- 3-yl)amino]-2-oxoethyl}thio:
Figure imgf000174_0003
[613] Example 309. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is allyl; and R is (2-oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl)thio:
Figure imgf000174_0004
[614] Example 310. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-chlorophenyl; R7 is oxo; R8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is methyl:
Figure imgf000175_0001
[615] Example 311. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4-(aminosulfonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000175_0002
[616] Example 312. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-benzylphenyl; R7 is oxo; R8 is amino; and R9 is hydrogen:
Figure imgf000175_0003
[617] Example 313. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(4-ethoxyphenyl)amino]-2-oxoethyl}thio:
Figure imgf000175_0004
[618] Example 314. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is difluoromethanesulfenyl:
Figure imgf000176_0001
[619] Example 315. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(2-methoxyethyl)amino]-2-oxoethyl}thio:
Figure imgf000176_0002
[620] Example 316. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is hydrogen; and R9 is phenyl:
Figure imgf000176_0003
[621] Example 317. A compound corresponding to formula (I-B-2) wherein R and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,4-dimethylphenyl)amino]-2-oxoethyl}thio:
Figure imgf000177_0004
Figure imgf000177_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(l,3-benzodioxol-5-ylmethyl)amino]-2-oxoethyl}thio:
Figure imgf000177_0002
[623] Example 319. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is methyl; and R9 is {2-oxo-2-[(pyridin-2-ylmethyl)amino]ethyl}thio:
Figure imgf000177_0003
[624] Example 320. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is {2-[(4- methylphenyl)amino] -2-oxoethyl} thio :
Figure imgf000178_0003
[625] Example 321. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is thioxo; R8 is hydrogen; and R9 is methyl:
Figure imgf000178_0004
[626] Example 322. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-anilino-2-oxoethyl)thio:
Figure imgf000178_0005
Figure imgf000178_0001
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(4-methylphenyl)amino]-2-oxoethyl}thio:
Figure imgf000178_0006
Figure imgf000178_0002
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is [2-(4-fluorophenyl)-2-oxoethyl]thio:
Figure imgf000179_0002
[629] Example 325. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3,4-dimethylphenyl; R7 is oxo; R8 is allyl; and R9 is {2-[4- (ethoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl}thio:
Figure imgf000179_0001
[630] Example 326. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2- furanylmethyl)amino]-2-oxoethyl}thio:
Figure imgf000179_0003
[631] Example 327. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is {2-[(4-ethoxyphenyl)amino]- 2-oxoethyl}thio:
Figure imgf000180_0003
Figure imgf000180_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,5-dimethoxyphenyl)amino]-2-oxoethyl}thio:
Figure imgf000180_0004
[633] Example 329. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluoroρhenyl; R7 is oxo; R8 is allyl; and R9 is [(3,5- dimethylisoxazol-4-yl)methyl]thio:
Figure imgf000180_0002
[634] Example 330. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3,5- bis(methoxycarbonyl)phenyl] amino } -2-oxoethyl)thio :
Figure imgf000181_0002
[635] Example 331. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is {2-oxo-2-[(2- phenylethyl) amino] ethyl } thio :
Figure imgf000181_0001
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-4-(4-methoxyphenyl)-2- thienyl] amino } -2-oxoethyl)thio :
Figure imgf000181_0003
[637] Example 333. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is (2-[4-(ethoxycarbonyl)- 3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl}thio:
Figure imgf000182_0003
Figure imgf000182_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R is {2-[(3,4-dimethylphenyl)amino]-2-oxoethyl}thio:
Figure imgf000182_0004
Figure imgf000182_0002
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is phenyl; and R is (2-fluorobenzyl)thio:
Figure imgf000182_0005
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(3-cyano-5,6,7,8- tetrahydro-4H-cyclohepta[b]thien-2-yl)amino]-2-oxoethyl}thio:
Figure imgf000183_0003
[641] Example 337. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(2,6- dichlorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000183_0001
[642] Example 338. A compound corresponding to formula (I-B-2) wherein Rel is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is (2-oxo-2- {[2- (trifluoromethyl)phenyl] amino } ethyl)thio :
Figure imgf000183_0002
[643] Example 339. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[3-(ethoxycarbonyl)-5,6,7,8-tetrahydro-4H- cyclohepta[b]thien-2-yl]amino}-2-oxoethyl)thio:
Figure imgf000184_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(3-cyano-6-methyl-4,5,6,7-tetrahydro-l-benzothien-2- yl)amino] -2-oxoethyl} thio :
Figure imgf000184_0002
[645] Example 341. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-oxo-2-[(2- phenylethyl)amino] ethyl} thio :
Figure imgf000184_0003
[646] Example 342. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,6-dichlorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000185_0002
[647] Example 343. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is [2-(l,3-benzodioxol-5- ylamino)-2-oxoethyl]thio :
Figure imgf000185_0003
[648] Example 344. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is (2-oxo-2-{[2- (trifluoromethyl)phenyl] amino } ethyl)thio :
Figure imgf000185_0004
Figure imgf000185_0001
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is {2-[4-(methoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2- oxoethyljthio:
Figure imgf000186_0001
' [650] Example 346. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-l- benzothien-2-yl]amino}-2-oxoethyl)thio:
Figure imgf000186_0002
[651] Example 347. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-2- oxoethyl)thio:
Figure imgf000186_0003
[652] Example 348. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclop entenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(3-cyano-5,6-dihydro-4H-cyclopenta[b]thien-2- yl)amino]-2-oxoethyl}thio:
Figure imgf000187_0002
[653] Example 349. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is (2-oxopropyl)thio:
Figure imgf000187_0001
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is 2-[(2,6- dimethylphenyl)amino]-2-oxoethanesulfenyl:
Figure imgf000187_0003
[655] Example 351. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is{2-[(4- fluorophenyl)amino] -2-oxoethyl} thio :
Figure imgf000187_0004
[656] Example 352. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-5-phenyl-2-thienyl]amino}-2- oxoethyl)thio:
Figure imgf000188_0003
[657] Example 353. A compound corresponding to formula (I-B-2) wherein
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2-[4-(ethoxycarbonyl)- 3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl}thio:
Figure imgf000188_0001
[658] Example 354. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]thio:
Figure imgf000188_0002
[659] Example 355. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is allyl; and R9 is [4-(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)butyl]thio :
Figure imgf000189_0001
[660] Example 356. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is (2-{[2-(3,4- dimethoxyphenyl) ethyl] amino } -2-oxoethyl)thio :
Figure imgf000189_0003
[661] Example 357. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is (l,3-benzodioxol-5- ylmethyl)thio:
Figure imgf000189_0002
[662] Example 358. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2-oxo-2-[(2- phenylethyl)amino] ethyl} thio :
Figure imgf000190_0003
Figure imgf000190_0001
Rd and Re, together with the atoms to which they are bonded, form cyclop entenyl; R7 is oxo; R8 is allyl; and R9 is {2-[4-(ethoxycarbonyl)-3J5-dimethyl-lH-pyrrol-2-yl]-2- oxoethyl}tliio:
Figure imgf000190_0002
[664] Example 360. A compound corresponding to formula (I-B-2) wherein
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is [2-(l,3-benzodioxol-5-ylamino)-2-oxoethyl]thio:
Figure imgf000190_0004
[665] Example 361. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is allyl; and R is (2-{[3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopenta[b]thien- 2-yl]amino}-2-oxoethyl)thio:
Figure imgf000191_0002
[666] Example 362. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(l,3-benzodioxol-5- ylmethyl)amino] -2-oxoethyl} thio :
Figure imgf000191_0003
[667] Example 363. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-5- (methoxycarbonyl)-4-methyl-2-thienyl] amino } -2-oxoethyl)thio :
Figure imgf000191_0004
Figure imgf000191_0001
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is 2-(l,3-benzodioxol-5- yl)-2-oxoethanesulfenyl:
Figure imgf000192_0001
[669] Example 365. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclop entenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(3-cyano-4,5,6,7-tetrahydro-l-benzothien-2-yl)amino]-2- oxoethyljthio:
Figure imgf000192_0004
Figure imgf000192_0002
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-oxo-2-{[2-(trifluoromethyl)phenyl] amino }ethyl)thio:
Figure imgf000192_0005
Figure imgf000192_0003
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2-[(3- methylphenyl)amino]-2-oxoethyl}thio:
Figure imgf000193_0004
Figure imgf000193_0001
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[4-(3,4-dimethoxyphenyl)-3-(ethoxycarbonyl)-2- thienyl] amino } -2-oxoethyl)thio :
Figure imgf000193_0002
[673] Example 369. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is allyl; and R is (2-fluorobenzyl)thio:
Figure imgf000193_0003
[674] Example 370. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2- yl)amino]-2-oxoethyl}thio:
Figure imgf000194_0001
[675] Example 371. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(2-fluorophenyl)amino]-2- oxoethyl}thio:
Figure imgf000194_0002
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is [2-(l,3-dioxo-l,3-dihydro- 2H-isoindol-2-yl)ethyl]thio :
Figure imgf000194_0003
[677] Example 373. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is phenyl; and R is [2-(4-methoxyphenyl)-2-oxoethyl]thio:
Figure imgf000195_0001
[678] Example 374. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is phenyl; and R is {2-[(3-cyano-4,5,6,7-tetrahydro-l-benzothien-2-yl)amino]- 2-oxoethyl}thio:
Figure imgf000195_0003
[679] Example 375. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,6- dichlorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000195_0002
[680] Example 376. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methoxyphenyl; R7 is oxo; R8 is allyl; and R9 is {2-[4- (ethoxycarbonyl)-3,5-dimethyl-lH-pyrrol-2-yl]-2-oxoethyl}thio:
Figure imgf000196_0001
[681] Example 377. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is [2-(2-fluorophenyl)-2-oxoethyl]thio:
Figure imgf000196_0002
[682] Example 378. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4-(methoxycarbonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000196_0003
[683] Example 379. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-oxopropyl)thio:
Figure imgf000196_0004
[684] Example 380. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is 2-[(2,6-dimethylphenyl)amino]-2-oxoethanesulfenyl:
Figure imgf000197_0002
[685] Example 381. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methoxyphenyl; R7 is oxo; R8 is phenyl; and R9 is {2-oxo-2-[(2- phenylethyl)amino]ethyl} thio :
Figure imgf000197_0003
[686] Example 382. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is (2-oxopropyl)thio:
Figure imgf000197_0004
Figure imgf000197_0001
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(2-fluorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000198_0003
[688] Example 384. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is phenyl; and R9 is 2-[(2,6- dimethylphenyl)amino]-2-oxoethanesulfenyl:
Figure imgf000198_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is 2-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxoethanesulfenyl:
Figure imgf000198_0002
[690] Example 386. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is 2-[(2,6-dimethylphenyl)amino]-2-oxoethanesulfenyl:
Figure imgf000199_0001
[691] Example 387. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3,4-dimethoxyphenyl; R7 is oxo; R8 is allyl; and R9 is {2-[4- (ethoxycarbonyl)-3 ,5-dimethyl- lH-pyrrol-2-yl] -2-oxoethyl} thio :
Figure imgf000199_0003
[692] Example 388. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(3,4-dimethoxyphenyl)-2-oxoethyl]thio:
Figure imgf000199_0002
R and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is phenyl; and R is {2-[(3-cyano-5,6-dihydro-4H-cyclopenta[b]thien-2- yl)amino] -2-oxoethyl} thio :
Figure imgf000200_0001
[694] Example 390. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-oxo-2-[(2-phenylethyl)amino]ethyl}thio:
Figure imgf000200_0003
[695] Example 391. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is phenyl; and R is [(3,5-dimethylisoxazol-4-yl)methyl]thio:
Figure imgf000200_0002
[696] Example 392. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-5,6,7,8-tetrahydro-4H- cyclohepta[b] thien-2-yl] amino } -2-oxoethyl)thio :
Figure imgf000201_0002
[697] Example 393. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,6-dichlorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000201_0001
[698] Example 394. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(methoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino}-2-oxoethyl)thio:
Figure imgf000201_0003
[699] Example 395. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is phenyl; and R is (2-{[3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino}-2-oxoethyl)thio:
Figure imgf000202_0001
[700 'J] Example 396. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is allyl; and R9 is {2-[2,5-dimethyl-l-(4- methylphenyl)-lH-pyrrol-3-yl]-2-oxoethyl}thio:
Figure imgf000202_0002
[701] Example 397. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is (2-oxo-2-{[3- (trifluoromethyl)phenyl] amino} ethyl)thio :
Figure imgf000202_0003
[702] Example 398. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2- thienyl] amino } -2-oxoethyl)thio :
Figure imgf000203_0002
[703] Example 399. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo;R8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is hydrogen:
Figure imgf000203_0001
[704] Example 400. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is hydrogen:
Figure imgf000203_0003
[705] Example 401. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is allyl; and R is [2-(5-methyl-2-nitrophenyloxy)ethyl]thio:
Figure imgf000204_0001
[706] Example 402. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is hydrogen; and R is (4-{[(2-hydroxyethyl)amino]carbonyl}benzyl)thio:
Figure imgf000204_0002
[707] Example 403. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-tert-butylphenyl; R7 is oxo; R8 is amino; and R9 is methyl:
Figure imgf000204_0003
[708] Example 404. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is hydrogen; and R is methyl:
Figure imgf000204_0004
[709] Example 405. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is hydrogen; and R is (4-{[(3-hydroxypropyl)amino]carbonyl}benzyl)thio:
Figure imgf000205_0004
Figure imgf000205_0001
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is phenyl; and R9 is {2-[2,5-dimethyl-l-(4- methylphenyl)- 1 H-pyrrol-3 -yl] -2-oxoethyl} thio :
Figure imgf000205_0002
[711] Example 407. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)- 5 -(methoxycarbonyl)-4-methyl-2-thienyl] amino } -2-oxoethyl)thio :
Figure imgf000205_0003
[712] Example 408. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(4- fluorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000206_0004
Figure imgf000206_0001
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2- [(aminocarbonyl)amino] -2-oxoethyl} thio :
Figure imgf000206_0005
Figure imgf000206_0002
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is (2-tert-butoxy-2-oxoethyl)thio:
Figure imgf000206_0006
Figure imgf000206_0003
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is 2-(2,3-dihydro-l,4- benzodioxin-6-yl)-2-oxoethanesulfenyl:
Figure imgf000207_0001
[716] Example 412. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(4- ethoxyphenyl)amino]-2-oxqethyl}thio:
Figure imgf000207_0002
[717] Example 413. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{2,5-dimethyl-l-[3-(trifluoromethyl)phenyl]-lH-pyrrol-3- yl} -2-oxoethyl)thio :
Figure imgf000207_0003
[718] Example 414. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is [2-(l-naphthyl)-2- oxoethyl]thio:
Figure imgf000208_0001
[719] Example 415. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(2- furanylmethyl)amino]-2-oxoethyl}thio:
Figure imgf000208_0002
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[3,5- bis(methoxycarbonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000208_0003
Re is hydrogen; Rd is 4-methoxyphenyl; R7 is oxo; R8 is phenyl; and R9 is (3,4- dichlorobenzyl)thio :
Figure imgf000209_0001
[722] Example 418. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is (2-{[4-chloro-3- (trifiuoromethyl)phenyl] amino } -2-oxoethyl)thio :
Figure imgf000209_0002
[723] Example 419. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3- (methoxycarbonyl)-5-phenyl-2-thienyl]amino}-2-oxoethyl)thio:
Figure imgf000209_0003
[724] Example 420. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)- 4-phenyl-2-thienyl] amino } -2-oxoethyl)thio :
Figure imgf000210_0003
[725] Example 421. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is hydrogen:
Figure imgf000210_0001
[726] Example 422. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is oxo; R8 is allyl; and R9 is {2- [(aminocarbonyl)amino]-2-oxoethyl}thio:
Figure imgf000210_0002
[727] Example 423. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is [2-furanylmethylene] amino; and R9 is hydrogen:
Figure imgf000210_0004
[728] Example 424. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is [pyridin-2-ylmethylene] amino; and R9 is hydrogen:
Figure imgf000211_0001
[729] Example 425. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2- thienyl] amino } -2-oxoethyl)thio :
Figure imgf000211_0002
[730] Example 426. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is phenyl; and R9 is {2-[(5-methylisoxazol- 3 -yl)amino] -2-oxoethyl} thio :
Figure imgf000211_0003
[731] Example 427. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(3,4-dimethylphenyl)amino]-2-oxoethyl}thio:
Figure imgf000212_0001
[732] Example 428. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-isopropylphenyl; R7 and R8, together with the atoms to which they are bonded, form triazolyl; and R9 is hydrogen:
Figure imgf000212_0002
[733] Example 429. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is phenyl; and R9 is 2-(2,3-dihydro-l,4- benzodioxin-6-yl)-2-oxoethanesulfenyl:
Figure imgf000212_0003
[734] Example 430. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3,4-dimethylphenyl; R7 is thioxo; R8 is hydrogen; and R9 is hydrogen:
Figure imgf000213_0003
Figure imgf000213_0001
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(aminocarbonyl)-5,6-dihydro-4H-cyclopenta[b]thien- 2-yl] amino } -2-oxoethyl)thio :
Figure imgf000213_0004
[736] Example 432. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(2-fluorophenyl)-2- oxoethyljthio:
Figure imgf000213_0005
Figure imgf000213_0002
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is phenyl; and R is (2-{[3-(aminocarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl] amino } -2-oxoethyl)thio :
Figure imgf000214_0002
[738] Example 434. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is thioxo; R8 is hydrogen; and R9 is methyl:
Figure imgf000214_0003
[739] Example 435. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2-[4-
Figure imgf000214_0001
[740] Example 436. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[4- (aminosulfonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000215_0002
[741] Example 437. A compound corresponding to formula (I-B-2) wherein Rd and Re; together with the atoms to which they are bonded; form cyclopentenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(2,6-dichlorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000215_0003
[742] Example 438. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is (2-{[3-(methoxycarbonyl)-4,5-dimethyl-2-thienyl]amino}- 2-oxoethyl)thio:
Figure imgf000215_0001
[743] Example 439. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is (2-{[3-(aminocarbonyl)- 5,6-dihydro-4H-cyclopenta[b]thien-2-yl]amino}-2-oxoethyl)tliio:
Figure imgf000216_0002
[744] Example 440. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylρhenyl; R7 is oxo; R8 is allyl; and R9 is [(3,5- dimethylisoxazol-4-yl)methyl]thio:
Figure imgf000216_0003
[745] Example 441. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(2- fluorophenyl)-2-oxoethyl]thio:
Figure imgf000216_0001
[746] Example 442. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is [2-(2-methyl-lH-indol-3-yl)-2-oxoethyl]thio:
Figure imgf000217_0001
[747] Example 443. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is phenyl; and R is [2-(benzylamino)-2-oxoethyl]thio:
Figure imgf000217_0003
[748] Example 444. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methoxyphenyl; R7 is oxo; R8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is methyl:
Figure imgf000217_0004
Figure imgf000217_0002
Re is methyl; Rd is methyl; R7 is oxo; R8 is phenyl; and R9 is [2-(benzylamino)-2- oxoethyl]thio:
Figure imgf000218_0001
[750] Example 446. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is [(3,5-dimethylisoxazol-4- yl)methyl]thio:
Figure imgf000218_0002
[751] Example 447. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is phenyl; and R is [2-(benzylammo)-2-oxoethyl]thio:
Figure imgf000218_0003
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R is allyl; and R is (l-{[(2-furanylmethyl)amino]carbonyl}-3- hydroxypropyl)thio :
Figure imgf000219_0001
[753] Example 449. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclop entenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(5-methylisoxazol-3-yl)amino]-2-oxoethyl}thio:
Figure imgf000219_0002
[754] Example 450. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 5-methylfur-2-yl; R7 is oxo; R8 is phenyl; and R9 is {2-oxo-2-[(2- phenylethyl)amino] ethyl} thio :
Figure imgf000219_0003
[755] Example 451. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is 2-(benzyloxy)-l-methyl-2-oxoethyl; and R9 is hydrogen:
Figure imgf000220_0001
[756] Example 452. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(3-cyano-2-thienyi)amino]- 2-oxoethyl}thio:
Figure imgf000220_0002
[757] Example 453. A compound corresponding to formula (I-B-2) wherein
Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is oxo; R8 is hydrogen; and R9 is [3-phenylprop-2-en-l-yl]thio:
Figure imgf000220_0003
[758] Example 454. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is allyl; and R is [2-(4-methylpiperidin-l-yl)-2-oxoethyl]thio:
Figure imgf000221_0001
[759] Example 455. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is methyl; and R9 is {2-[(5-benzyl-3-cyano-4- methyl-2-thienyl) amino] -2-oxoethyl} thio :
Figure imgf000221_0002
[760] Example 456. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is allyl; and R9 is (2-oxo-2- phenylethyl)thio :
Figure imgf000221_0003
[761] Example 457. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form ethyldimethylcyclohexenyl; R7 is oxo; R8 is [(dimethylamino)methylene]amino; and R9 is methyl:
Figure imgf000222_0002
[762] Example 458. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is [(3,4,5- trimethoxyphenyl)methylene] amino; and R9 is hydrogen:
Figure imgf000222_0001
[763] Example 459. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is (2-oxopropyl)thio:
Figure imgf000222_0003
[764] Example 460. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2-[(2- fluorophenyl)amino] -2-oxoethyl} thio :
Figure imgf000222_0004
[765] Example 461. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is [2-(4-methylpiperidm-l- yl)-2-oxoethyl]thio :
Figure imgf000223_0002
[766] Example 462. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is (2-{[4- (acetylamino)phenyl] amino } -2-oxoethyl)thio :
Figure imgf000223_0003
[767] Example 463. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is phenyl; and R9 is [2-(l,3-benzodioxol-5- ylamino)-2-oxoethyl]thio :
Figure imgf000223_0001
[768] Example 464. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is lH-pyrrol-1-yl; and R9 is hydrogen:
Figure imgf000224_0001
[7691 Example 465. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 2-furanyl; R7 is oxo; R8 is phenyl; and R9 is {2-[(4- fluorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000224_0002
[770] Example 466. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 5-methylfur-2-yl; R7 is oxo; R8 is phenyl; and R9 is (2- oxopropyl)thio:
Figure imgf000224_0003
Re is methyl; Rd is phenyl; R7 is oxo; R8 is {[4- (difluoromethoxy)phenyl]methylene} amino; and R9 is hydrogen:
Figure imgf000225_0001
[772] Example 468. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 2-furanyl; R7 is oxo; R8 is allyl; and R9 is [2-(benzylamino)-2- oxoethyl]thio:
Figure imgf000225_0002
[773] Example 469. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 2-furanyl; R7 is oxo; R8 is allyl; and R9 is (2-{[4- (ethoxycarbonyl)phenyl]amino}-2-oxoethyl)thio:
Figure imgf000225_0003
[774] Example 470. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is oxo; R8 is lH-pyrrol-1-yl; and R9 is hydrogen:
Figure imgf000225_0004
[775] Example 471. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[l-(2-methoxyethyl)-2,5-dimethyl-lH-ρyrrol-3-yl]-2- oxoethyl}thio:
Figure imgf000226_0002
[776] Example 472. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is allyl; and R9 is (2-{[2-(4- methoxyphenyl)ethyl]ammo}-2-oxoethyl)thio:
Figure imgf000226_0003
[777] Example 473. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is 2,5-dimethyl-lH-pyrrol-l-yl; and R9 is methyl:
Figure imgf000226_0001
Re is methyl; Rd is phenyl; R7 is oxo; R8 is [(3,4-dimethoxyphenyl)methylene]amino; and R9 is hydrogen:
Figure imgf000227_0001
[779] Example 475. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is allyl; and R9 is {2-[l-(2-methoxyethyl)- 2,5-dimethyl-lH-pyrrol-3-yl]-2-oxoethyl}thio:
Figure imgf000227_0002
[780] Example 476. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 2-furanyl; R7 is oxo; R8 is phenyl; and R9 is [2-(4-fluorophenyl)- 2-oxoethyl]thio:
Figure imgf000227_0003
[781] Example 477. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 5-methylfur-2-yl; R7 is oxo; R8 is lH-pyrrol-1-yl; and R9 is methyl:
Figure imgf000228_0003
Figure imgf000228_0001
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is allyl; and R9 is {2-[(2,6-difluorophenyl)amino]-2-oxoethyl}thio:
Figure imgf000228_0004
[783] Example 479. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is allyl; and R9 is {2-[(3- methoxyphenyl)amino]-2-oxoethyl}thio:
Figure imgf000228_0005
Figure imgf000228_0002
Re is hydrogen; Rd is 5-methylfur-2-yl; R7 is oxo; R8 is allyl; and R9 is (2- oxopropyl)thio:
Figure imgf000228_0006
[785] Example 481. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3-nitrophenyl; R7 is oxo; R8 is 4-methylbenzyl; and R9 is hydrogen:
Figure imgf000229_0002
Figure imgf000229_0001
Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R is oxo; R is 2-oxo-2-[2-(2-oxo-l,2-dihydro-3H-indol-3- ylidenyl)hydrazinyl]ethyl; and R9 is hydrogen:
Figure imgf000229_0003
[787] Example 483. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is thioxo; R8 is hydrogen; and R9 is hydrogen:
Figure imgf000229_0004
[788] Example 484. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is 2-[2-(l-methyl-2-oxo-l,2-dihydro-3H-indol-3-ylidene)hydrazinyl]-2- oxoethyl; and R9 is hydrogen:
Figure imgf000230_0002
[789] Example 485. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]-2-oxoethyl; and R9 is hydrogen:
Figure imgf000230_0003
[790] Example 486. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3-nitrophenyl; R7 is oxo; R8 is hydrogen; and R9 is hydrogen:
Figure imgf000230_0001
[791] Example 487. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is l-(isopropoxycarbonyl)propyl; and R9 is hydrogen:
Figure imgf000230_0004
[792] Example 488. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is l-(isopropoxycarbonyl)propyl; and R9 is hydrogen:
Figure imgf000231_0002
[793] Example 489. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is 2-phenylethyl; and R9 is hydrogen:
Figure imgf000231_0003
Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is butyl; and R9 is hydrogen:
Figure imgf000231_0001
Re is hydrogen; Rd is 4-chlorophenyl; R7 is thioxo; R8 is hydrogen; and R9 is hydrogen:
Figure imgf000231_0004
[796] Example 492. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is 2-(benzylamino)-2-oxoethyl; and R9 is hydrogen:
Figure imgf000232_0001
[797] Example 493. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]-2-oxoethyl; and R9 is hydrogen:
Figure imgf000232_0002
[798] Example 494. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is butyl; and R9 is hydrogen:
Figure imgf000232_0003
[799] Example 495. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]-2-oxoethyl; and R9 is hydrogen:
Figure imgf000233_0001
[800] Example 496. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is oxo; R8 is 2-isopropoxy-2-oxoethyl; and R9 is hydrogen:
Figure imgf000233_0002
[801] Example 497. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R is 2-methoxy-l-methyl-2-oxoethyl; and R is hydrogen:
Figure imgf000233_0003
[802] Example 498. A compound corresponding to formula (I-B-2) wherein Re is methyl; Rd is methyl; R7 is oxo; R8 is 2-[(2-furanyhnethyl)ammo]-2-oxoethyl; and R9 is hydrogen:
Figure imgf000233_0004
[803] Example 499. A compound corresponding to formula (I-B-2) wherein
Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R7 is oxo; R8 is 2-(cyclohexyloxy)-l-methyl-2-oxoethyl; and R9 is hydrogen:
Figure imgf000234_0003
Figure imgf000234_0001
Re is methyl; Rd is methyl; R7 is oxo; R8 is 4-bromobenzyl; and R9 is hydrogen:
Figure imgf000234_0004
[805] Example 501. A compound corresponding to formula (I-B-2) wherein Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is 2-(cyclohexyloxy)-2-oxoethyl; and R9 is hydrogen:
Figure imgf000234_0005
[806] Example 502. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is 2-phenylethyl; and R9 is hydrogen:
Figure imgf000234_0002
[807] Example 503. A compound corresponding to formula (I-B-2) wherein
Re is hydrogen; Rd is 4-chlorophenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]-2- oxoethyl; and R9 is hydrogen:
Figure imgf000235_0001
Re is hydrogen; Rd is phenyl; R7 is oxo; R8 is 2-methoxy-2-oxoethyl; and R9 is hydrogen:
Figure imgf000235_0003
[809] Example 505. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3,4-dimethylphenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]- 2-oxoethyl; and R9 is hydrogen:
Figure imgf000235_0002
[810] Example 506. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is 2-butoxy-l-methyl-2-oxoethyl; and R9 is hydrogen:
Figure imgf000236_0003
Figure imgf000236_0001
Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R and R , together with the atoms to which they are bonded, form methoxyphenyltriazolyl; and R9 is hydrogen:
Figure imgf000236_0004
[812] Example 508. A compound corresponding to formula (I-B-2) wherein
Re is ethoxycarbonyl; Rd is methyl; R7 is oxo; R8 is 2,6-dichlorobenzyl; and R9 is hydrogen:
Figure imgf000236_0002
[813] Example 509. A compound corresponding to formula (I-B-2) wherein R and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is l-(isobutoxycarbonyl)propyl; and R9 is hydrogen:
Figure imgf000236_0005
[814] Example 510. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methoxyphenyl; R7 is oxo; R8 is butyl; and R9 is hydrogen:
Figure imgf000237_0003
[815] Example 511. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form
1 Si methylcyclohexenyl; R is oxo; R is 2-{[3-(ethoxycarbonyl)-6-methyl-4,5,6,7- tetrahydro-l-benzothien-2-yl]amino}-2-oxoethyl; and R9 is hydrogen:
Figure imgf000237_0001
[816] Example 512. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3-nitrophenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]-2- oxoethyl; and R9 is hydrogen:
Figure imgf000237_0002
[817] Example 513. A compound corresponding to formula (I-B-2) wherein
Re is hydrogen; Rd is 3-nitrophenyl; R7 is oxo; R8 is 3-methylbenzyl; and R9 is hydrogen:
Figure imgf000238_0004
[818] Example 514. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 3-nitrophenyl; R7 is oxo; R8 is 2-(benzylamino)-2-oxoethyl; and R9 is hydrogen:
Figure imgf000238_0001
[819] Example 5 315. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is oxo; R8 is 2-[(2-furanylmethyl)amino]-2- oxoethyl; and R9 is hydrogen:
Figure imgf000238_0005
Figure imgf000238_0002
Re is hydrogen; Rd is 3-nitrophenyl; R7 is oxo; R8 is 2,4-dichlorobenzyl; and R9 is hydrogen:
Figure imgf000238_0003
[821] Example 517. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methoxyphenyl; R7 is oxo; R8 is 2,6-dichlorobenzyl; and R9 is hydrogen:
Figure imgf000239_0001
[822] Example 518. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-methoxyρhenyl; R7 is oxo; R8 is 4-bromobenzyl; and R9 is hydrogen:
Figure imgf000239_0003
[823] Example 519. A compound corresponding to formula (I-B-2) wherein Re is hydrogen; Rd is 4-chlorophenyl; R7 is oxo; R8 is CH2CN; and R9 is hydrogen:
Figure imgf000239_0002
[824] Example 520. A compound corresponding to formula (I-B-2) wherein Re is phenyl; Rd is hydrogen; R7 is oxo; R8 is 2-[(2-chlorobenzyl)oxy]-l-methyl-2- oxoethyl; and R9 is hydrogen:
Figure imgf000239_0004
[825] Example 521. A compound corresponding to formula (I-B-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; R8 is 4-methylphenyl; and R9 is {[amino(imino)methyl] amino} methyl:
Figure imgf000240_0001
Re is hydrogen; Rd is phenyl; R7 is oxo; and R9 is imidazo[l,2-a]pyridm-2- ylmethanesulfenyl; and Ra is allyl:
Figure imgf000240_0002
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is oxo; and Ra and R9 together form l-(3,4-dimethoxybenzylidene)-o-xylen-l',2'-diyl:
Figure imgf000240_0003
[828] Example 524. A compound corresponding to formula (I-B-5) wherein
Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is quinolin-8-yloxy; and R9 is hydrogen:
Figure imgf000241_0001
[829] Example 525. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is (2-{[3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2-thienyl]amino}-2- oxoethyl)thio; and R9 is hydrogen:
Figure imgf000241_0003
[830] Example 526. A compound corresponding to formula (I-B-5) wherein Re is methyl; Rd is methyl; R7 is (2-{[3-(aminocarbonyl)-5-phenyl-2-thienyl]amino-2- oxoethyl)thio; and R9 is hydrogen:
Figure imgf000241_0002
[831] Example 527. A compound corresponding to formula (I-B-5) wherein Re is methyl; Rd is methyl; R7 is (2- {[3-(ethoxycarbonyl)-5,6-dihydro-4H- cyclopenta[b]thien-2-yl]amino}-2-oxoethyl)thio; and R9 is hydrogen:
Figure imgf000242_0001
[832] Example 528. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclop entenyl; R7 is (2-{[3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4-methyl-2-thienyl]amino}-2- oxoethyl)thio; and R9 is methyl:
Figure imgf000242_0002
[833] Example 529. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is (2-{[3-(aminocarbonyl)-5,6-dihydro-4H-cyclopenta[b]thien-2-yl]amino}-2- oxoethyl)thio; and R9 is methyl:
Figure imgf000242_0003
[834] Example 530. A compound corresponding to formula (I-B-5) wherein Re is hydrogen; Rd is phenyl; R7 (2-methylquinolin-8-yl)oxy; and R9 is hydrogen:
Figure imgf000243_0002
[835] Example 531. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 (2- methylquinorin-8-yl)oxy; and R is hydrogen:
Figure imgf000243_0003
[836] Example 532. A compound corresponding to formula (I-B-5) wherein Re is methyl; Rd is methyl; R7 is (2-{[3-(ethoxycarbonyl)-5-(methoxycarbonyl)-4- methyl-2-thienyl] amino }-2-oxoethyl)thio; and R9 is hydrogen:
Figure imgf000243_0001
[837] Example 533. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is (2-{[3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopenta[b]thien-2-yl]amino}-2- oxoethyl)thio; and R9 is methyl:
Figure imgf000244_0001
[838] Example 534. A compound corresponding to formula (I-B-5) wherein Re is phenyl; Rd is hydrogen; R7 is(2-{[3-(aminocarbonyl)-5,6-dihydro-4H- cyclopenta[b] thien-2-yl] amino }-2-oxoethyl)thio; and R9 is hydrogen:
Figure imgf000244_0002
Re is ethyl; Rd is hydrogen; R7 is 4-benzoylpiperazin-l-yl; and R9 is hydrogen:
Figure imgf000244_0003
[840] Example 536. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is 2-(5,5-dimethyl-3-morpholin-4-iumcyclohex-l-en-l-yl)hydrazinyl; and R9 is hydrogen:
Figure imgf000245_0001
[841] Example 537. A compound corresponding to formula (I-B-5) wherein Re is hydrogen; Rd is 4-fluorophenyl; R7 is [2-(l,3-benzodioxol-5-yl)ethyl]amino; and R9 is hydrogen:
Figure imgf000245_0002
[842] Example 538. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R7 is 2-[2-(difluoromethoxy)benzylidene]hydrazinyl; and R9 is hydrogen:
Figure imgf000245_0003
[843] Example 539. A compound corresponding to formula (I-B-5) wherein Rd and Re, together with the atoms to which they are bonded, form cyclopentenyl; R7 is 1 -phenyl- lH-tetrazole-5-sulfenyl; and R9 is methyl:
Figure imgf000246_0004
Figure imgf000246_0001
Rd and Re, together with the atoms to which they are bonded, form cyclop entenyl; R7 is l-phenyl-lH-tetrazole-5-sulfenyl; and R9 is hydrogen:
Figure imgf000246_0002
[845] Example 541. A compound corresponding to formula (I-B-5) wherein Re is hydrogen; Rd is 4-methylphenyl; R7 is l-phenyl-lH-tetrazole-5-sulfenyl; and R9 is hydrogen:
Figure imgf000246_0003
[846] Example 542. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl; R15 is chloro; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000247_0001
[847] Example 543. A compound corresponding to formula (I-C-2) wherein Re is hydrogen; Rd is phenyl; R15 is chloro; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000247_0002
[848] Example 544. A compound corresponding to formula (I-C-2) wherein
Re is me etthhyyll;; RRd0 iiss mmeetthhyyll;; RR115D iiss cchhllooro; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000247_0003
[849] Example 545. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R15 is chloro; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000248_0001
[850] Example 546. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R15 is
1 (\ 1 *7 hydrazinyl; R is hydrogen; and R is hydrogen:
Figure imgf000248_0002
[851] Example 547. A compound corresponding to formula (I-C-2) wherein Re is hydrogen; Rd is phenyl; R15 is hydrazinyl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000248_0003
[852] Example 548. A compound corresponding to formula (I-C-2) wherein Re is hydrogen; Rd is phenyl; R15 is (tetraliydrofuran-2-ylmethyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000249_0003
[853] Example 549. A compound corresponding to formula (I-C-2) wherein
R is hy yddrrooggeenn;; RRd iiss pphheennyyll;; RR1 155 ii *ss
Figure imgf000249_0001
a *~n~.dΆ T RJ I D a Λ-n_d J T R> 17 , together with the atoms to which they are bonded, form phenyl:
Figure imgf000249_0004
[854] Example 550. A compound corresponding to formula (I-C-2) wherein Re is hydrogen; Rd is phenyl; R15 is (3-moφholin-4-ylpropyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000249_0005
Figure imgf000249_0002
R is methyl; R is methyl; R , 15 is (2-furanylmethyl)amino; R 16 . is hydrogen; and R , 17 is hydrogen:
Figure imgf000250_0001
Re is hydrogen; Rd is phenyl; R15 is piperidin-1-yl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000250_0003
[857] Example 553. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R15 is (2-furanylmethyl)amino; R16 is hydrogen; and R17 is hydrogen:
Figure imgf000250_0002
[858] Example 554. A compound corresponding to formula (I-C-2) wherein Re is methyl; Rd is methyl; R15 is [3-(dimethylamino)ρropyl]amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000251_0001
[859] Example 555. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R15 is [3-(dimethylamino)propyl]amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000251_0002
[860] Example 556. A compound corresponding to formula (I-C-2) wherein
Re is hy yddrrooggeenn;; RRdd iiss pphheennyyll;; RR1155 iiss 44--((22--hhyyddrrooxxyyeetthhyyll))ppiippeerraazziinn-l-yl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000251_0003
[861] Example 557. A compound corresponding to formula (I-C-2) wherein Re is hydrogen; Rd is 4-chlorophenyl; R15 is 4-(2-hydroxyethyl)piperazin-l-yl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000252_0003
[862] Example 558. A compound corresponding to formula (I-C-2) wherein Re is methyl; Rd is methyl; R15 is 4-(2-hydroxyethyl)piperazin-l-yl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000252_0001
Re is hydrogen; Rd is methylphenyl; R15 is 4-(2-hydroxyethyl)piperazin-l-yl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000252_0002
Re is methyl; Rd is methyl; R15 is (2-furanylmethyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000253_0001
Re is hydrogen; Rd is phenyl; R15 is morpholin-4-yl; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000253_0002
[866] Example 562. A compound corresponding to formula (I-C-2) wherein Re is hydrogen; Rd is phenyl; R15 is (2-hydroxyethyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000253_0003
[867] Example 563. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form cycloheptenyl; R15 is (2-morpholin-4-ylethyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000254_0001
[868] Example 564. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form methylcyclohexenyl; R15 is (2-furanyhnethyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000254_0002
[869] Example 565. A compound corresponding to formula (I-C-2) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R15 is (tetrahydrofuran-2-ylmethyl)amino; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000254_0003
[870] Example 566. A compound corresponding to formula (I-C-3) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R14 and R15, together with the atoms to which they are bonded, form dihydro-lH- [l,2,4]triazole; and R16 and R17, together with the atoms to which they are bonded, form phenyl:
Figure imgf000255_0001
[871] Example 567. A compound corresponding to formula (I-C-3) wherein Rd and Re, together with the atoms to which they are bonded, form cyclohexenyl; R14 and R15, together with the atoms to which they are bonded, form dihydrotetrazole; R16 is hydrogen; and R17 is hydrogen:
Figure imgf000255_0002
A * * * * * * * *
[872] The above detailed description of preferred embodiments is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the above embodiments, and may be variously modified.

Claims

We claim:
1. A method for treating a viral infection in an animal, wherein: the method comprises administering a therapeutically effective amount of a thienyl compound or a pharmaceutically acceptable salt thereof to the animal; and the thienyl compound corresponds in structure to formula (I):
Figure imgf000256_0001
as to Ra:
Ra is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, and -S(R8), wherein any member of such group optionally is substituted, or Ra and Rb, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl; and as to Rb:
Rb and Ra, together with the atom to which they are bonded, form optionally-substituted heterocyclyl, or Rb and Rc, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl, or when Rb does not form a heterocyclyl with Ra or Rc, Rb is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein any member of such group optionally is substituted; and as to Rc:
Rc is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylallcoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclyltliioalkenyl, heterocyclylalkylthioalkyl,
-C(O)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein any member of such group optionally is substituted, or
R° and Rb, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl; and as to Rd and Re:
Rd and Re, together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl, or
R and Re are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclylalkylthioalkyl, wherein any member of such group optionally is substituted; and each Rbl is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, and heterocyclylheterocyclylthioalkyl, wherein any member of such group optionally is substituted; and each Rg is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkenylamino, heterocyclylthioalkylaminoalkylaminoalkyl, and heterocyclylaminoalkyl, wherein: any member of such group optionally is substituted; and each pair of RA and RB form an independently selected optionally-substituted heterocyclyl.
2. A method according to claim 1, wherein: as to Ra:
Ra is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, and -S(RS), wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, oxo, thioxo, nitro, thiol, amino, imino, aminoalkyl, carbocyclyl, heterocyclyl, and heterocyclylalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, oxo, thioxo, amino, imino, thiol, and nitro, or
Ra and Rb, together with the atoms to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently
257
/ selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, heterocyclyl, heterocyclylthio, and heterocyclylalkenyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, nitro, thioxo, carbocyclyl, and oxo, wherein: any member of such group optionally is substituted with one or more independently selected alkoxy; and as to Rb:
Rb and Ra, together with the atom to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, and heterocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo, or
Rb and Rc, together with the atoms to which they are bonded, form heterocyclyl, wherein: the heterocyclyl optionally is substituted with one or more independently selected Rf substituents, and the heterocyclyl optionally is substituted with two substituents such that the two substituents, together with the atom(s) to which they are bonded, form a carbocyclyl or heterocyclyl, wherein: the carbocyclyl or heterocyclyl is, in turn, optionally substituted with one or more independently selected Rf substituents, or when Rb does not form a heterocyclyl with Ra or Rc, R is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(0)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein: any member of such group optionally is substituted with one or more independently selected Rf substituents; and as to Rc:
Rc is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein: any member of such group optionally is substituted with one or more independently selected Rf substituents, or Rc and Rb, together with the atoms to which they are bonded, form heterocyclyl, wherein: the heterocyclyl optionally is substituted with one or more independently selected Rf substituents, and the heterocyclyl optionally is substituted with two substituents such that the two substituents, together with the atom(s) to which they are bonded, form a carbocyclyl or heterocyclyl, wherein: the carbocyclyl or heterocyclyl is, in turn, optionally substituted with one or more independently selected Rf substituents; and as to Rd and Re:
Rd and Re are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkyltliioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclylalkylthioalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, thiol, nitro, nitroso, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, bisalkoxyalkyl, thioalky alkylthioalkyl, alkylthioalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclyloxyalkenyl, carbocyclylalkoxyalkyl, carbocyclylthioalkyl, carbocyclylthioalkenyl, carbocyclylsulfonyl, carbocyclylsulfonylalkyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, heterocyclyloxyalkenyl, heterocyclylalkoxyalkyl, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylsulfonyl, heterocyclylsulfonylalkyl, heterocyclylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, and aminoalkylsulfonyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, cyano, thiol, nitro, nitroso, oxo, thioxo, amino, and imino, or Rd and Re, together with the atoms to which they are bonded, form carbocyclyl or heterocyclyl, wherein: the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, thiol, nitro, nitroso, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, bisalkoxyalkyl, thioalky alkylthioalkyl, alkylthioalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclyloxyalkenyl, carbocyclylalkoxyalkyl, carbocyclylthioalkyl, carbocyclylthioalkenyl, carbocyclylsulfonyl, carbocyclylsulfonylalkyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, lieterocyclylalkenyl, heterocyclyloxyalkyl, heterocyclyloxyalkenyl, heterocyclylalkdxyalkyl, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylsulfonyl, lieterocyclylsulfonylalkyl, heterocyclylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, and aminoalkylsulfonyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, cyano, thiol, nitro, nitroso, oxo, thioxo, amino, and imino; and each Rbl is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, and heterocyclylheterocyclylthioalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, alkylthio, alkenyl, alkoxyalkyl, hydroxyalkyl, amino, aminoalkyl, oxo, thioxo, thiol, imino, nitro, cyano, carbocyclyl, carbocyclylalkyl, carbocyclylalkoxy, carbocyclylalkenyl, carbocyclylthio, aminosulfonyl, aminothio, heterocyclyl, heterocyclylsulfonyl, heterocyclylthio, heterocyclylalkyl, and heterocyclylalkenyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, alkyl, alkenyl, alkoxy, amino, imino, cyano, nitro, nitroso, alkoxyalkyl, hydroxyalkyl, oxo, thiol, and thioxo, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, oxo, amino, alkyl, and alkoxy; and each R is independently: is selected from the group consisting of halogen, hydroxyl, amino, alkyl, hydroxyalkyl, alkylamino, arninoalkylamino, aminoalkyl, alkenyl, alkoxy, alkoxyalkyl, oxo, carbocyclyl, alkylcarbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylamino, heterocyclylalkylamino, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkenyl, heterocyclylthioalkyl, carbocyclylaminoalkenyl, heterocyclylaminoalkenyl, thioxo, hydrazinyl, hydrazinylalkyl, carbocyclylhydrazinyl, carbocyclylalkenylhydrazinyl, aminoalkenyl, alkenylamino, carbocyclylaminoalkyl, heterocyclylaminoalkyl, carbocyclylalkenylamino, heterocyclylalkenylamino, and -S(Rg), wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, hydroxylalkyl, oxo, amino, irnino, aminoalkyl, alkylamino, thioxo, thiol, nitro, cyano, alkoxyalkyl, carbocyclyl, alkoxycarbocyclyl, carbocyclylalkyl, carbocyclyloxy, heterocyclyl, and heterocyclylalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, imino, amino, oxo, thioxo, thiol, nitro, heterocyclyl, or hydroxyalkyl, or bonded to a second R substituent such that both R substituents, together with the atom(s) to which they are bonded, form a carbocyclyl or heterocyclyl, wherein: the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, amino, carbocyclyl, carbocyclylalkenyl, and heterocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo; and each Rg is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkenylamino, heterocyclylthioalkylaminoalkylaminoalkyl, and heterocyclylaminoalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, amino, aminosulfonyl, alkenyl, alkoxy, oxo, thiol, tliioxo, cyano, nitro, aminoalkyl, alkoxyalkyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylthio, carbocyclylalkylthio, carbocylcyloxysulfonyl, heterocyclyl, heterocyclylalkyl, and heterocyclylthioalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, alkoxy, amino, oxo, alkoxyalkyl, carbocyclyl, thioxo, nitro, cyano, and heterocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, amino, imino, and oxo; and each pair of RA and RB form an independently selected heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, thioxo, nitro, and cyano.
3. A method according to claim 2, wherein Ra and Rb, together with the atoms to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, heterocyclyl, heterocyclylthio, and heterocyclylalkenyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, nitro, tliioxo, carbocyclyl, and oxo, wherein: any member of such group optionally is substituted with one or more independently selected alkoxy. 4. A method according to claim 3, wherein the compound is selected from the group consisting of:
Figure imgf000265_0001
Figure imgf000265_0002
Figure imgf000265_0004
Figure imgf000265_0003
Figure imgf000266_0001
5. A method according to claim 2, wherein: the thienyl compound corresponds in structure to formula (I- A):
Figure imgf000266_0002
Rb is selected from the group consisting of hydrogen, amino, alkenyl, aminoalkyl, heterocyclyl, heterocylcylthio, carbocyclylalkyl, heterocylcylthioalkenyl, -C(O)-R131, -C(S)-Rbl, and -N-C(RA)(RB), wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, oxo, heterocyclylthio, and heterocyclylthioalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino; and Rc is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, heterocyclyl, heterocyclylalkyl, carbocyclyl, carbocyclylalkyl, and carbocyclylaminoalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, oxo, amino, hydroxyalkyl, aminoalkyl, and carbocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, oxo, and amino; and as to Rd and Re:
Rd and Re are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, oxo, amino, aminoalkyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino, or Rd and Re, together with the atoms to which they are bonded, form carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxycarbonyl, oxo, and amino.
6. A method according to claim 2, wherein the compound is selected from the group consisting of:
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000268_0002
Figure imgf000268_0003
Figure imgf000268_0004
Figure imgf000268_0005
Figure imgf000269_0002
Figure imgf000269_0001
Figure imgf000269_0003
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000273_0003
Figure imgf000273_0002
Figure imgf000273_0005
Figure imgf000273_0004
Figure imgf000274_0001
Figure imgf000274_0002
Figure imgf000274_0004
Figure imgf000274_0003
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000278_0002
Figure imgf000278_0003
Figure imgf000278_0004
Figure imgf000279_0001
Figure imgf000279_0002
Figure imgf000279_0003
Figure imgf000279_0004
Figure imgf000280_0001
Figure imgf000280_0002
Figure imgf000280_0003
Figure imgf000280_0004
Figure imgf000281_0001
Figure imgf000281_0002
Figure imgf000281_0003
Figure imgf000281_0004
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000284_0002
Figure imgf000284_0003
Figure imgf000284_0004
Figure imgf000285_0001
Figure imgf000285_0003
Figure imgf000285_0002
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000287_0002
Figure imgf000287_0004
Figure imgf000287_0003
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000292_0002
Figure imgf000292_0004
Figure imgf000292_0003
Figure imgf000292_0005
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
7. A method according to claim 2, wherein the thienyl compound corresponds in structure to one of the following formulas:
Figure imgf000296_0001
Figure imgf000296_0002
Figure imgf000296_0003
Figure imgf000297_0001
as to R7 and R8:
R is selected from the group consisting hydrogen and R substituents; and R8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, carbocyclyl, carbocyclylalkyl, amino, aminoalkyl, aminoalkenyl, alkenylamino, thiol, thioxo, carbocyclylaminoalkyl, heterocyclylaminoalkyl, carbocyclylaminoalkenyl, heterocyclylaminoalkenyl, carbocyclylalkenylamino, heterocyclylalkenylamino, hydrazinylalkyl, and heterocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, nitro, hydroxyl, cyano, alkyl, alkoxy, alkoxyalkyl, carbocyclyl, alkoxycarbocyclyl, oxo, amino, alkylamino, aminoalkyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, and carbocyclyloxy, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo, or R7 and R8, together with the atoms to which they are bonded, form heterocyclyl optionally substituted with one or more independently selected Rf substitutents; and as to Ra and R9:
Ra and R9 are independently selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkenyl, amino, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, and -S(R8), wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, amino, imino, aminoalkyl, thioxo, thiol, nitro, and heterocyclylalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkyl, imino, amino, oxo, thioxo, thiol, and nitro, or
Ra and R9, together with the atoms(s) to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, carbocyclyl, carbocyclylalkenyl, and heterocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and oxo.
8. A method according to claim 7, wherein:
R7 is selected from the group consisting of oxo, amino, thiol, thioxo, hydrazinyl, hydrazinylalkyl, carbocyclyl, carbocyclylhydrazinyl, carbocyclylalkenylhydrazinyl, heterocyclyl, heterocyclyloxy, and -S(RS), wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, oxo, alkyl, and alkoxy; and as to Rd and Re:
Rd and Re, together with the atoms to which they are bonded, form carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl, or Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, carbocyclyl, and heterocyclyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, oxo, nitro, carbocyclyl, and carbocyclylalkyl; and R is selected from the group consisting of heterocyclyl, heterocyclylalkyl, and heterocyclylaminoalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, aminoalkyl, carbocyclyl, oxo, thioxo, nitro, and cyano, wherein:, any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, oxo, thioxo, nitro, and cyano.
9. A method according to claim 7, wherein the compound is selected from the group consisting of:
Figure imgf000299_0001
Figure imgf000299_0002
Figure imgf000299_0003
Figure imgf000300_0001
Figure imgf000300_0002
Figure imgf000300_0004
Figure imgf000300_0003
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000303_0002
Figure imgf000303_0003
Figure imgf000303_0004
Figure imgf000304_0001
Figure imgf000304_0002
Figure imgf000304_0003
Figure imgf000304_0004
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000308_0002
Figure imgf000308_0004
Figure imgf000308_0003
Figure imgf000308_0005
Figure imgf000309_0001
Figure imgf000309_0003
Figure imgf000309_0002
Figure imgf000309_0004
Figure imgf000309_0005
Figure imgf000310_0001
Figure imgf000310_0002
Figure imgf000310_0004
Figure imgf000310_0003
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000312_0003
Figure imgf000312_0002
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000314_0002
Figure imgf000314_0003
Figure imgf000314_0004
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000317_0002
Figure imgf000317_0003
Figure imgf000317_0004
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000320_0002
Figure imgf000320_0003
Figure imgf000320_0004
Figure imgf000321_0001
Figure imgf000321_0002
Figure imgf000321_0003
Figure imgf000321_0004
Figure imgf000321_0005
Figure imgf000322_0001
Figure imgf000322_0002
Figure imgf000322_0004
Figure imgf000322_0003
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000324_0002
Figure imgf000324_0003
Figure imgf000324_0004
Figure imgf000324_0005
Figure imgf000325_0001
Figure imgf000325_0002
Figure imgf000325_0003
Figure imgf000326_0001
Figure imgf000326_0003
Figure imgf000326_0002
Figure imgf000326_0004
Figure imgf000327_0002
Figure imgf000327_0003
Figure imgf000327_0004
Figure imgf000327_0001
Figure imgf000327_0005
Figure imgf000328_0001
Figure imgf000328_0002
Figure imgf000328_0004
Figure imgf000328_0005
Figure imgf000328_0003
Figure imgf000328_0006
Figure imgf000329_0001
Figure imgf000329_0002
Figure imgf000329_0003
Figure imgf000329_0005
Figure imgf000329_0004
Figure imgf000329_0006
Figure imgf000330_0001
Figure imgf000330_0003
Figure imgf000330_0002
Figure imgf000331_0001
Figure imgf000331_0003
Figure imgf000331_0002
Figure imgf000331_0004
Figure imgf000332_0001
10. A method according to claim 2, wherein the thienyl compound corresponds in structure to one of the following formulas:
Figure imgf000332_0002
Figure imgf000333_0001
*7 F
R is selected from the group consisting of hydrogen and R substituents; as to R14 and R15:
R14 and R15 are independently selected from the group consisting of hydrogen, halogen, hydrazinyl, alkyl, alkoxy, alkenyl, carbocyclyl, alkylcarbocyclyl, amino, oxo, heterocyclyl, heterocyclylamino, heterocyclylalkylamino, heterocyclylaminoalkyl, aminoalkyl, alkylamino, and aminoalkylamino, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, oxo, amino, heterocyclyl, aminoalkyl, and hydroxyalkyl, wherein: any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of alkyl, oxo, alkoxy, heterocyclyl, and hydroxyalkyl, or
R14 and R15, together with the atoms to which they are bonded, form heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino; and as to R16 and R17:
R16 and R17 are each hydrogen, or
R16 and R17, together with the atoms to which they are bonded, form carbocyclyl or heterocyclyl, wherein: the carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, oxo, and amino.
1 LA method according to claim 10, wherein the compound is selected from the group consisting of:
Figure imgf000334_0002
Figure imgf000334_0001
Figure imgf000334_0003
Figure imgf000335_0001
Figure imgf000335_0002
Figure imgf000335_0003
Figure imgf000335_0004
Figure imgf000336_0001
Figure imgf000336_0003
Figure imgf000336_0002
Figure imgf000337_0001
12. A method according to claim 1, wherein the viral infection is caused by an RNA virus.
13. A method according to claim 12, wherein the viral infection is caused by a positive-strand RNA virus.
14. A method according to claim 12, wherein the infection is caused by a negative-strand RNA virus.
15. A method according to claim 12, wherein the virus is from a virus family selected from the group consisting of Paramyxoviridae, Rhabdoviridae, Filoviridae, Orthomyxoviridae, Bunyaviridae, Bornaviridae, Arenaviridae, Picornaviridae, Caliciviridae, Astroviridae, Coronaviridae, Togaviridae, Flaviviridae, and Reoviridae.
16. A method according to claim 12, wherein the virus is selected from the group consisting of respiratory syncytial virus, Ebola virus, rabies virus, Lassa fever virus, La Crosse virus, Rift Valley fever virus, Hantaan virus, California encephalitis virus, influenza virus A3 influenza virus B, measles virus, mumps virus, Marburg virus, Bolivian hemorrhagic fever virus, human parainfluenza virus, human metapneumovirus, Nipah virus, Hendra virus, vesicular stomatitis virus, lymphocytic choriomeningitis virus, Junin virus, Bunyamwera virus, Uukuniemi virus, Crimean- Congo hemorrhagic fever virus, Sindbis virus, rubella virus, hepatitis C virus, West Nile virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, coxsackievirus, enterovirus, hepatitis A virus, severe acute respiratory syndrome virus, astrovirus virus, Dengue fever virus, poliovirus virus, Venezuela encephalitis virus, Western equine encephalomyelitis virus, Eastern equine encephalomyelitis, O'nyong nyong virus, Ross River virus, Chikungunya virus, Rhinovirus, feline calicivirus, murine calicivirus, Norwalk virus, bovine viral diarrhea virus, human coronavirus, Semliki Forest virus, Kunjin virus, Omsk hrmorrhagic fever virus, Murray Valley enciphalitis virus, Kyasanur Forest disease virus, Rocio virus, Astrovirus, and Colorado tick fever.
17. A method according to claim 1, wherein the viral infection is caused by a DNA virus.
18. A method according to claim 17, wherein the virus is from a virus family selected from the group consisting of Papillomaviridae, Polyomaviridae, Herpesviridae, Paravavoviridae, and Hepadanviridae.
19. A method according to claim 17, wherein the virus is selected from the group consisting of human papillomavirus, JC virus, BK virus, herpes simplex virus 1, herpes simplex virus 2, herpes simplex virus 6, herpes simplex virus 7, herpes simplex virus 8, Eptstein Barr virus, human cytomegalovirus, human parvovirus, and Hepatitis B virus.
20. A method according to claim 1, wherein the virus is a respiratory virus, an enteric virus, an encephalitis-causing virus, or a hemorrhagic virus.
21. A method according to claim 1, wherein the method further comprises adminstering interferon or ribavirin to the animal.
22. A pharmaceutical composition for treating a viral infection in an animal, wherein: the composition comprises a therapeutically effective amount of a thienyl compound or a pharmaceutically acceptable salt thereof; and the thienyl compound corresponds in structure to formula (I):
Figure imgf000339_0001
as to Ra:
Ra is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkylsulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, and -S(Rε), wherein any member of such group optionally is substituted, or
Ra and Rb, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl; and as to Rb:
Rb and Ra, together with the atom to which they are bonded, form optionally-substituted heterocyclyl, or
Rb and Rc, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl, or when Rb does not form a heterocyclyl with Ra or Rc, Rb is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein any member of such group optionally is substituted; and ' as to Rc:
Rc is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein any member of such group optionally is substituted, or
Rc and Rb, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl; and as to Rd and Re: Rd and Re, together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl, or
Rd and Re are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclylalkylthioalkyl, wherein any member of such group optionally is substituted; and each Rbl is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylthioalkyl, and heterocyclylheterocyclylthioalkyl, wherein any member of such group optionally is substituted; and each Rs is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkenylamino, heterocyclylthioalkylaminoalkylaminoalkyl, and heterocyclylaminoalkyl, wherein: any member of such group optionally is substituted; and each pair of RA and RB form an independently selected optionally-substituted heterocyclyl.
23. A use of a thienyl compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a viral infection in an animal, wherein: the medicament comprises a therapeutically effective amount of the thienyl compound or a pharmaceutically acceptable salt thereof; and the thienyl compound corresponds in structure to formula (I):
Figure imgf000341_0001
as to Ra:
Ra is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, aminoalkyl, alkyl'sulfonyl, alkoxyalkyl, alkoxyalkenyl, alkylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclyloxyalkyl, hydrazinyl, and -S(Re), wherein any member of such group optionally is substituted, or
Ra and Rb, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl; and as to Rb: Rb and Ra, together with the atom to which they are bonded, form optionally-substituted heterocyclyl, or
Rb and Rc, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl, or when Rb does not form a heterocyclyl with Ra or Rc, Rb is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, and -N=C(R^(R8), wherein any member of such group optionally is substituted; and as to Rc:
Rc is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, akylthioalkyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthio, heterocyclylthioalkyl, heterocyclylthioalkenyl, heterocyclylalkylthioalkyl, -C(O)-Rbl, -C(S)-Rbl, and -N=C(RA)(RB), wherein any member of such group optionally is substituted, or
R° and Rb, together with the atoms to which they are bonded, form optionally-substituted heterocyclyl; and as to Rd and Re: Rd and Re, together with the atoms to which they are bonded, form optionally-substituted carbocyclyl or optionally-substituted heterocyclyl, or Rd and Re are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkoxy, amino, alkoxyalkyl, aminoalkyl, hydroxyalkyl, akylthioalkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, carbocyclylyalkenyl, carbocyclylalkynyl, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl, carbocyclylalkylthio, carbocyclylthioalkyl, carbocyclylalkylthioalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylalkylthio, heterocyclylthioalkyl, and heterocyclylalkylthioalkyl, wherein any member of such group optionally is substituted; and each Rbl is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkoxy, amino, aminoalkyl, heterocyclylaminoalkyl, alkoxyalkyl, carbocyclyl, heterocyclyl, hydrazinyl, carbocyclylalkyl, carbocyclylamino, carbocyclyloxyalkyl, carbocyclylalkenyl, heterocyclylaUcyl, heterocyclylalkenyl, heterocyclylthioalkyl, and heterocyclylheterocyclylthioalkyl, wherein any member of such group optionally is substituted; and each Rs is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aminoalkyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxyalkyl, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkenylamino, heterocyclylthioalkylaminoalkylaminoalkyl, and heterocyclylaminoalkyl, wherein: any member of such group optionally is substituted; and each pair of RΛ and RB form an independently selected optionally-substituted heterocyclyl.
PCT/US2005/022559 2004-06-25 2005-06-25 Thienyl compounds for treating virus-related conditions WO2006093518A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58299604P 2004-06-25 2004-06-25
US60/582,996 2004-06-25

Publications (2)

Publication Number Publication Date
WO2006093518A2 true WO2006093518A2 (en) 2006-09-08
WO2006093518A3 WO2006093518A3 (en) 2007-03-22

Family

ID=36941577

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/022559 WO2006093518A2 (en) 2004-06-25 2005-06-25 Thienyl compounds for treating virus-related conditions

Country Status (1)

Country Link
WO (1) WO2006093518A2 (en)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007083689A1 (en) * 2006-01-19 2007-07-26 Renascience Co., Ltd. Plasminogen activator inhibitor-1 inhibitor
WO2008155468A1 (en) * 2007-06-20 2008-12-24 Marikki Laiho Activators and therapeutic applications thereof
US7576080B2 (en) * 2004-12-23 2009-08-18 Memory Pharmaceuticals Corporation Certain thienopyrimidine derivatives as phosphodiesterase 10 inhibitors
EP2148678A1 (en) * 2007-05-23 2010-02-03 Siga Technologies, Inc. Antiviral drugs for treatment or prevention of dengue infection
JP2010505953A (en) * 2006-10-10 2010-02-25 プレジデント アンド フェロウズ オブ ハーバード カレッジ Compounds, screening, and therapeutic methods
JP2010509373A (en) * 2006-11-13 2010-03-25 イーライ リリー アンド カンパニー Thienopyrimidinone for the treatment of inflammatory diseases and cancer
US20100158798A1 (en) * 2007-10-22 2010-06-24 Emmanuel Skordalakes FP-Pocket-Binding Effectors and Methods for Using the Same to Modulate Telomerase Activity
WO2010098866A1 (en) * 2009-02-27 2010-09-02 Supergen, Inc. Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors
US7906553B2 (en) * 2008-08-27 2011-03-15 Calcimedica, Inc. Substituted thiophene modulators of intracellular calcium
EP2293671A1 (en) * 2008-06-03 2011-03-16 Siga Technologies, Inc. Small molecule inhibitors for the treatment or prevention of dengue virus infection
JP2011519876A (en) * 2008-05-05 2011-07-14 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Thienopyridone derivatives as protein kinase (AMPK) activators activated by AMP
WO2011136269A1 (en) 2010-04-28 2011-11-03 アステラス製薬株式会社 Tetrahydrobenzothiophene compound
US8158675B2 (en) 2005-05-13 2012-04-17 Vertex Pharmaceuticals (Canada) Incorporated Compounds and methods for the treatment or prevention of Flavivirus infections
US8263641B2 (en) 2007-09-10 2012-09-11 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2013062065A1 (en) 2011-10-27 2013-05-02 アステラス製薬株式会社 Aminoalkyl-substituted n-thienyl benzamide derivative
US20130225610A1 (en) * 2010-04-06 2013-08-29 Marc Hansen Antimetastatic compounds
US8524763B2 (en) 2008-09-22 2013-09-03 Calcimedica, Inc. Inhibitors of store operated calcium release
US8618307B2 (en) 2009-09-16 2013-12-31 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US20150252053A1 (en) * 2007-08-27 2015-09-10 Duquesne University Of The Holy Spirit Tricyclic Compounds Having Antimitotic and/or Antitumor Activity and Methods of Use Thereof
US9234230B2 (en) 2010-02-08 2016-01-12 The Wistar Institute Screening method and compounds for modulating telomerase activity
US9376430B2 (en) 2009-03-20 2016-06-28 University Of Virginia Patent Foundation Broad spectrum benzothiophene-nitrothiazolide and other antimicrobials
US9604994B2 (en) 2011-11-23 2017-03-28 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
JP2017515891A (en) * 2014-04-17 2017-06-15 インスティチュート パストゥール コリア Compounds for the treatment of viral infections
CN106916164A (en) * 2017-03-06 2017-07-04 中国药科大学 Thiazolopyrimidinone class IDO1 inhibitor and its medical usage
WO2018122317A1 (en) * 2016-12-29 2018-07-05 Enyo Pharma Thiophene derivatives as antiviral agents
WO2019154949A1 (en) * 2018-02-08 2019-08-15 Enyo Pharma Fused thiophene derivatives and their uses
CN110437232A (en) * 2018-05-04 2019-11-12 上海长森药业有限公司 Double and ring ureas nucleocapsid inhibitor and its medicinal usage
WO2020102889A1 (en) * 2018-11-19 2020-05-28 Fouda Ahmed 4,5,6,7-tetrahydro-l-benzothiophene modulators of retinoic acid receptor related (rar) orphan nuclear receptors (rors)
CN112851633A (en) * 2021-01-19 2021-05-28 上海应用技术大学 2-aminothiophene neuraminidase inhibitor and preparation method and application thereof
WO2022106646A1 (en) * 2020-11-20 2022-05-27 Université Catholique de Louvain Lactam and lactone derivatives of formula (ia) for use in the treatment of diseases caused by a coronavirus infection and/or a viral respiratory infection

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054192A1 (en) * 1997-05-29 1998-12-03 Smithkline Beecham P.L.C. Thienoxazinone derivatives as antiviral agents
US6239142B1 (en) * 1999-03-09 2001-05-29 Pharmacia & Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5carboxamides as antiviral agents
US20040048802A1 (en) * 2002-05-20 2004-03-11 Amy Ripka Hepatitis C virus inhibitors
WO2004022567A1 (en) * 2002-09-04 2004-03-18 Pharmacia & Upjohn Company Llc Heteroaryl-ethanolamine derivatives as antiviral agents
US20040087577A1 (en) * 2002-11-01 2004-05-06 Pratt John K Anti-infective agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054192A1 (en) * 1997-05-29 1998-12-03 Smithkline Beecham P.L.C. Thienoxazinone derivatives as antiviral agents
US6239142B1 (en) * 1999-03-09 2001-05-29 Pharmacia & Upjohn Company 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5carboxamides as antiviral agents
US20040048802A1 (en) * 2002-05-20 2004-03-11 Amy Ripka Hepatitis C virus inhibitors
WO2004022567A1 (en) * 2002-09-04 2004-03-18 Pharmacia & Upjohn Company Llc Heteroaryl-ethanolamine derivatives as antiviral agents
US20040087577A1 (en) * 2002-11-01 2004-05-06 Pratt John K Anti-infective agents

Cited By (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576080B2 (en) * 2004-12-23 2009-08-18 Memory Pharmaceuticals Corporation Certain thienopyrimidine derivatives as phosphodiesterase 10 inhibitors
US8674118B2 (en) 2005-05-13 2014-03-18 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
US8158675B2 (en) 2005-05-13 2012-04-17 Vertex Pharmaceuticals (Canada) Incorporated Compounds and methods for the treatment or prevention of Flavivirus infections
WO2007083689A1 (en) * 2006-01-19 2007-07-26 Renascience Co., Ltd. Plasminogen activator inhibitor-1 inhibitor
JP2010505953A (en) * 2006-10-10 2010-02-25 プレジデント アンド フェロウズ オブ ハーバード カレッジ Compounds, screening, and therapeutic methods
JP2010509373A (en) * 2006-11-13 2010-03-25 イーライ リリー アンド カンパニー Thienopyrimidinone for the treatment of inflammatory diseases and cancer
EP2148678A4 (en) * 2007-05-23 2010-08-04 Siga Technologies Inc Antiviral drugs for treatment or prevention of dengue infection
EP2148678A1 (en) * 2007-05-23 2010-02-03 Siga Technologies, Inc. Antiviral drugs for treatment or prevention of dengue infection
JP2010528051A (en) * 2007-05-23 2010-08-19 シガ・テクノロジーズ・インコーポレーテッド Antiviral drugs for the treatment or prevention of dengue infections
US8518960B2 (en) 2007-05-23 2013-08-27 Siga Technologies, Inc. Antiviral drugs for treatment or prevention of dengue infection
US9353051B2 (en) 2007-05-23 2016-05-31 Siga Technologies, Inc. Antiviral drugs for treatment or prevention of dengue infection
US8680107B2 (en) 2007-06-20 2014-03-25 The Johns Hopkins University Activators and therapeutic applications thereof
WO2008155468A1 (en) * 2007-06-20 2008-12-24 Marikki Laiho Activators and therapeutic applications thereof
WO2008155441A1 (en) * 2007-06-20 2008-12-24 Marikki Laiho Activators and therapeutic applications thereof
EP2889297A3 (en) * 2007-06-20 2015-09-23 Johns Hopkins University Activators and therapeutic applications thereof
US10414777B2 (en) 2007-08-27 2019-09-17 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and method of use thereof
US9987283B2 (en) 2007-08-27 2018-06-05 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US9458167B2 (en) * 2007-08-27 2016-10-04 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US9556198B2 (en) 2007-08-27 2017-01-31 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US10464944B2 (en) 2007-08-27 2019-11-05 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US11091500B2 (en) 2007-08-27 2021-08-17 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US20150252053A1 (en) * 2007-08-27 2015-09-10 Duquesne University Of The Holy Spirit Tricyclic Compounds Having Antimitotic and/or Antitumor Activity and Methods of Use Thereof
US10676483B2 (en) 2007-08-27 2020-06-09 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US9802955B2 (en) 2007-08-27 2017-10-31 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
US8263641B2 (en) 2007-09-10 2012-09-11 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8524765B2 (en) 2007-09-10 2013-09-03 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8518940B2 (en) * 2007-10-22 2013-08-27 The Wistar Institute FP-pocket-binding effectors and methods for using the same to modulate telomerase activity
US20100158798A1 (en) * 2007-10-22 2010-06-24 Emmanuel Skordalakes FP-Pocket-Binding Effectors and Methods for Using the Same to Modulate Telomerase Activity
JP2011519876A (en) * 2008-05-05 2011-07-14 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Thienopyridone derivatives as protein kinase (AMPK) activators activated by AMP
US9029376B2 (en) 2008-06-03 2015-05-12 Siga Technologies, Inc. Small molecule inhibitors for the treatment or prevention of dengue virus infection
EP2293671A1 (en) * 2008-06-03 2011-03-16 Siga Technologies, Inc. Small molecule inhibitors for the treatment or prevention of dengue virus infection
EP2293671A4 (en) * 2008-06-03 2012-03-21 Siga Technologies Inc Small molecule inhibitors for the treatment or prevention of dengue virus infection
US7906553B2 (en) * 2008-08-27 2011-03-15 Calcimedica, Inc. Substituted thiophene modulators of intracellular calcium
US8383670B2 (en) 2008-08-27 2013-02-26 Calcimedica, Inc. Trisubstituted thiophenes that modulate intracellular calcium
AU2009288245B2 (en) * 2008-08-27 2012-12-20 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8394848B2 (en) 2008-08-27 2013-03-12 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8524763B2 (en) 2008-09-22 2013-09-03 Calcimedica, Inc. Inhibitors of store operated calcium release
WO2010098866A1 (en) * 2009-02-27 2010-09-02 Supergen, Inc. Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors
US9376430B2 (en) 2009-03-20 2016-06-28 University Of Virginia Patent Foundation Broad spectrum benzothiophene-nitrothiazolide and other antimicrobials
US8618307B2 (en) 2009-09-16 2013-12-31 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9234230B2 (en) 2010-02-08 2016-01-12 The Wistar Institute Screening method and compounds for modulating telomerase activity
US20130225610A1 (en) * 2010-04-06 2013-08-29 Marc Hansen Antimetastatic compounds
US9284295B2 (en) 2010-04-28 2016-03-15 Astellas Pharma Inc. Tetrahydrobenzothiophene compound
US8729068B2 (en) 2010-04-28 2014-05-20 Astellas Pharma Inc. Tetrahydrobenzothiophene compound
KR20130073908A (en) 2010-04-28 2013-07-03 아스텔라스세이야쿠 가부시키가이샤 Tetrahydrobenzothiophene compound
WO2011136269A1 (en) 2010-04-28 2011-11-03 アステラス製薬株式会社 Tetrahydrobenzothiophene compound
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9605003B2 (en) 2011-07-19 2017-03-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9062032B2 (en) 2011-10-27 2015-06-23 Astellas Pharma Inc. Aminoalkyl-substituted N-thienylbenzamide derivative
WO2013062065A1 (en) 2011-10-27 2013-05-02 アステラス製薬株式会社 Aminoalkyl-substituted n-thienyl benzamide derivative
KR20140096322A (en) 2011-10-27 2014-08-05 아스텔라스세이야쿠 가부시키가이샤 Aminoalkyl-substituted n-thienyl benzamide derivative
JPWO2013062065A1 (en) * 2011-10-27 2015-04-02 アステラス製薬株式会社 Aminoalkyl-substituted N-thienylbenzamide derivatives
US10183950B2 (en) 2011-11-23 2019-01-22 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
US9604994B2 (en) 2011-11-23 2017-03-28 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
US10954251B2 (en) 2011-11-23 2021-03-23 Cancer Research Technology Limited Thienopyrimidine inhibitors of atypical protein kinase C
JP2017515891A (en) * 2014-04-17 2017-06-15 インスティチュート パストゥール コリア Compounds for the treatment of viral infections
US11279683B2 (en) 2016-12-29 2022-03-22 Enyo Pharma Thiophene derivatives as antiviral agents
WO2018122317A1 (en) * 2016-12-29 2018-07-05 Enyo Pharma Thiophene derivatives as antiviral agents
US11807618B2 (en) 2016-12-29 2023-11-07 Enyo Pharma Thiophene derivatives as antiviral agents
CN110114349A (en) * 2016-12-29 2019-08-09 埃尼奥制药公司 Thiophene derivant as antivirotic
CN106916164A (en) * 2017-03-06 2017-07-04 中国药科大学 Thiazolopyrimidinone class IDO1 inhibitor and its medical usage
WO2019154949A1 (en) * 2018-02-08 2019-08-15 Enyo Pharma Fused thiophene derivatives and their uses
US11603368B2 (en) 2018-02-08 2023-03-14 Enyo Pharma Fused thiophene derivatives and their uses
CN110437232B (en) * 2018-05-04 2022-04-12 上海长森药业有限公司 Bicyclourea nucleocapsid inhibitor and pharmaceutical use thereof
CN110437232A (en) * 2018-05-04 2019-11-12 上海长森药业有限公司 Double and ring ureas nucleocapsid inhibitor and its medicinal usage
WO2020102889A1 (en) * 2018-11-19 2020-05-28 Fouda Ahmed 4,5,6,7-tetrahydro-l-benzothiophene modulators of retinoic acid receptor related (rar) orphan nuclear receptors (rors)
WO2022106646A1 (en) * 2020-11-20 2022-05-27 Université Catholique de Louvain Lactam and lactone derivatives of formula (ia) for use in the treatment of diseases caused by a coronavirus infection and/or a viral respiratory infection
CN112851633B (en) * 2021-01-19 2021-12-07 上海应用技术大学 2-aminothiophene neuraminidase inhibitor and preparation method and application thereof
CN112851633A (en) * 2021-01-19 2021-05-28 上海应用技术大学 2-aminothiophene neuraminidase inhibitor and preparation method and application thereof

Also Published As

Publication number Publication date
WO2006093518A3 (en) 2007-03-22

Similar Documents

Publication Publication Date Title
WO2006093518A2 (en) Thienyl compounds for treating virus-related conditions
US20090221624A1 (en) 4-aminoquinoline compounds for treating virus-related conditions
JP6061437B2 (en) Heterocyclic modulators of lipid synthesis
AU2005230416B2 (en) Composition comprising a JNK inhibitor and cyclosporin
CN109153640A (en) Hepatitis type B virus is eliminated with antivirotic
US8871790B2 (en) Heterocyclic modulators of lipid synthesis
US20050080113A1 (en) Medicinal compositions
JP2002537396A (en) [1,8] Naphthyridine derivative having antiviral activity
ES2683736T3 (en) Procedures to improve pharmacokinetics
BR112019020401A2 (en) 4-pyridone compound or its salt, and pharmaceutical composition and formulation that includes the same
HRP20050199A2 (en) Pyridazinone-derivatives as pde4 inhibitors
CA2408156A1 (en) Heterobicyclic sulfonamides and their use as platelet adp receptor inhibitors
DK2474543T3 (en) Therapeutic agent for affective disorders.
BRPI0608910A2 (en) use of a compound of the formula or a pharmaceutically acceptable salt or hydrate thereof, compound or salt or hydrate thereof, pharmaceutical composition and packaged pharmaceutical composition
JP2008531596A (en) Benzisothiazole useful for treating or preventing HCV infection
US10150742B2 (en) Substituted heterocyclic compounds for treating or preventing viral infections
JP2004518727A (en) Phthaline-on-piperidino-derivatives as PDE4 inhibitors
Das et al. Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors
JP2023113691A (en) P38 kinase inhibitors for reducing dux4 and downstream gene expression for the treatment of fshd
US20160101106A1 (en) Methods for treating hcv infection
JP2023033259A (en) Heterocyclic modulators of lipid synthesis
JP2016501883A (en) Thienopyridine derivatives for the treatment and prevention of dengue virus infection
CN103889963B (en) The similar thing of quinazolinone and the similar thing of quinazolinone are being used for the treatment of or are preventing the application in some virus infection
WO2007005541A2 (en) Small molecule inhibitors against west nile virus replication
CN105683202B (en) A kind of boronic acid compounds

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase