Patent Grant
11642361
The present invention pertains to nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. The invention provides novel chemical compounds, and the use of these compounds alone or in combination with other antiviral agents for treating HCV infection.
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for Disease Control. According to the World Health Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection.
The HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids. The protein products of the HCV gene consist of the structural proteins C, E1, and E2, and the non-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are believed to provide the catalytic machinery for viral replication. The NS3 protease releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain. HCV NS5B polymerase is required for the synthesis of a double-stranded RNA from a single-stranded viral RNA that serves as a template in the replication cycle of HCV. Therefore, NS5B polymerase is considered to be an essential component in the HCV replication complex (K. Ishi, et al, Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249: 108-118). Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.
HCV belongs to a much larger family of viruses that share many common features.
Flaviviridae Viruses
The Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; flavivruses, which are the primary cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole member is HCV. The flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., 1996, Chapter 31, 931-959). Flaviviruses of global concern that are associated with human disease include the Dengue Hemorrhagic Fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6, 251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., New Eng. J. Med, 1988, 319, 641-643).
The pestivirus genus includes bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called hog cholera virus) and border disease virus (BDV) of sheep (Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to the livestock industry (Meyers, G. and Thiel, H. J., Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Human pestiviruses have not been as extensively characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans.
Pestiviruses and hepaciviruses are closely related virus groups within the Flaviviridae family. Other closely related viruses in this family include the GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV). The hepacivirus group (hepatitis C virus; HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are at least 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus.
The genetic organization of pestiviruses and hepaciviruses is very similar. These positive stranded RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins. The viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed nonstructural (NS) proteins. The genetic organization and polyprotein processing of the nonstructural protein portion of the ORF for pestiviruses and hepaciviruses is very similar. For both the pestiviruses and hepaciviruses, the mature nonstructural (NS) proteins, in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
The NS proteins of pestiviruses and hepaciviruses share sequence domains that are characteristic of specific protein functions. For example, the NS3 proteins of viruses in both groups possess amino acid sequence motifs characteristic of serine proteinases and of helicases (Gorbalenya et al., Nature, 1988, 333, 22; Bazan and Fletterick Virology, 1989, 171, 637-639; Gorbalenya et al., Nucleic Acid Res., 1989, 17, 3889-3897). Similarly, the NS5B proteins of pestiviruses and hepaciviruses have the motifs characteristic of RNA-directed RNA polymerases (Koonin, E. V. and Dolja, V. V., Crir. Rev. Biochem. Molec. Biol. 1993, 28, 375-430).
The actual roles and functions of the NS proteins of pestiviruses and hepaciviruses in the lifecycle of the viruses are directly analogous. In both cases, the NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors downstream of its position in the ORF (Wiskerchen and Collett, Virology, 1991, 184, 341-350; Bartenschlager et al., J. Virol. 1993, 67, 3835-3844; Eckart et al. Biochem. Biophys. Res. Comm. 1993, 192, 399-406; Grakoui et al., J. Virol. 1993, 67, 2832-2843; Grakoui et al., Proc. Natl. Acad Sci. USA 1993, 90, 10583-10587; Hijikata et al., J. Virol. 1993, 67, 4665-4675; Tome et al., J. Virol., 1993, 67, 4017-4026). The NS4A protein, in both cases, acts as a cofactor with the NS3 serine protease (Bartenschlager et al., J. Virol. 1994, 68, 5045-5055; Failla et al., J. Virol. 1994, 68, 3753-3760; Xu et al., J. Virol., 1997, 71:53 12-5322). The NS3 protein of both viruses also functions as a helicase (Kim et al., Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson, Arch. Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, J. Virol. 1995, 69, 1720-1726). Finally, the NS5B proteins of pestiviruses and hepaciviruses have the predicted RNA-directed RNA polymerases activity (Behrens et al., EMBO, 1996, 15, 12-22; Lechmann et al., J. Virol., 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J. Virol., 1998, 72, 9365-9369).
Currently, there are limited treatment options for individuals infected with hepatitis C virus. The current approved therapeutic option is the use of immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin. This therapy is limited in its clinical effectiveness and only 50% of treated patients respond to therapy. Therefore, there is significant need for more effective and novel therapies to address the unmet medical need posed by HCV infection.
A number of potential molecular targets for drug development of direct acting antivirals as anti-HCV therapeutics have now been identified including, but not limited to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase and the NS5B polymerase. The RNA-dependent RNA polymerase is absolutely essential for replication of the single-stranded, positive sense, RNA genome and this enzyme has elicited significant interest among medicinal chemists.
Inhibitors of HCV NS5B as potential therapies for HCV infection have been reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881; Walker, M. P. et al., Ep. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., et al., Current Opinion in Drug Discovery and Development, 2004, 7, 446-459; Beaulieu, P. L., et al., Current Opinion in Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current Drug Targets-Infectious Disorders, 2003, 3, 207-219; Griffith, R. C., et al, Annual Reports in Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., et al., Infectious Disorders-Drug Targets, 2006, 6, 17-29. The potential for the emergence of resistant HCV strains and the need to identify agents with broad genotype coverage supports the need for continuing efforts to identify novel and more effective nucleosides as HCV NS5B inhibitors.
Nucleoside inhibitors of NS5B polymerase can act either as a non-natural substrate that results in chain termination or as a competitive inhibitor which competes with nucleotide binding to the polymerase. To function as a chain terminator the nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site. This conversion to the triphosphate is commonly mediated by cellular kinases which imparts additional structural requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation.
In some cases, the biological activity of a nucleoside is hampered by its poor substrate characteristics for one or more of the kinases needed to convert it to the active triphosphate form. Formation of the monophosphate by a nucleoside kinase is generally viewed as the rate limiting step of the three phosphorylation events. To circumvent the need for the initial phosphorylation step in the metabolism of a nucleoside to the active triphosphate analog, the preparation of stable phosphate prodrugs has been reported. Nucleoside phosphoramidate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (McGuigan, C., et al., J. Med. Chem., 1996, 39, 1748-1753; Valette, G., et al., J. Med Chem., 1996, 39, 1981-1990; Balzarini, J., et al., Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20, 1091-1098; Lee, W. A., et al., Antimicrobial Agents and Chemotherapy, 2005, 49, 1898); US 2006/0241064; and WO 2007/095269.
Also limiting the utility of nucleosides as viable therapeutic agents is their sometimes poor physicochemical and pharmacokinetic properties. These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of nucleosides have been employed. It has been demonstrated that preparation of nucleoside phosphoramidates improves the systemic absorption of a nucleoside and furthermore, the phosphoramidate moiety of these “pronucleotides” is masked with neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake and transport into the cell dramatically enhancing the intracellular concentration of the nucleoside monophosphate analog relative to administering the parent nucleoside alone. Enzyme-mediated hydrolysis of the phosphate ester moiety produces a nucleoside monophosphate wherein the rate limiting initial phosphorylation is unnecessary.
The present invention is directed toward novel phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof, represented by the following structure:
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C2-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen, C1-10 alkyl, R3a or R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, C(O)CR3aR3bNHR1, where n is 2 to 4 and R1, R3a, and R3b;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
the base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
Z is N or CR12;
R7, R8, R9, R10, and R11 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
R12 is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, NO2 lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that when base is represented by the structure c with R11 being hydrogen, R12 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
The phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
The phrase “as defined herein above” refers to the first definition provided in the Summary of the Invention.
The terms “optional” or “optionally” as used herein means that a subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
The term “independently” is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which R appears twice and is defined as “independently carbon or nitrogen”, both R's can be carbon, both R's can be nitrogen, or one R′ can be carbon and the other nitrogen.
The term “alkenyl” refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one olefinic double bond. The term “C2-N alkenyl” refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term “C2-10 alkenyl” refers to an alkenyl comprising 2 to 10 carbon atoms. The term “C2-4 alkenyl” refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl).
The term “halogenated alkenyl” refers to an alkenyl comprising at least one of F, Cl, Br, and I.
The term “alkyl” refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term “C1-M alkyl” refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. The term “C1-4 alkyl” refers to an alkyl containing 1 to 4 carbon atoms. The term “lower alkyl” denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms. “C1-20 alkyl” as used herein refers to an alkyl comprising 1 to 20 carbon atoms. “C1-10 alkyl” as used herein refers to an alkyl comprising 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The term (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group is optionally substituted by an aryl or a heteroaryl group respectively.
The term “cycloalkyl” refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms; more preferably 3 to 6 carbon atoms (i.e., lower cycloalkyls). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term “cycloalkyl alkyl” refers to an additionally unsubstituted or substituted alkyl substituted by a lower cycloalkyl. Examples of cycloalkyl alkyls include, but are not limited to, any one of methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl that is substituted with cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term “cycloheteroalkyl” refers to an unsubstituted or substituted heterocycle, in which the heterocycle contains 2 to 9 carbon atoms; preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms. Examples of cycloheteroalkyls include, but are not limited to, aziridin-2-yl, N—C1-3-alkyl-aziridin-2-yl, azetidinyl, N—C1-3-alkyl-azetidin-m′-yl, pyrrolidin-m′-yl, N—C1-3-alkyl-pyrrolidin-m′-yl, piperidin-m′-yl, and N—C1-3-alkyl-piperidin-m′-yl, where m′ is 2, 3, or 4 depending on the cycloheteroalkyl. Specific examples of N—C1-3-alkyl-cycloheteroalkyls include, but are not limited to, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, and N-methyl-piperidin-4-yl. In the instance of R4, the point of attachment between the cycloheteroalkyl ring carbon and the oxygen occurs at any one of m′
The term “heterocycle” refers to an unsubstituted or substituted heterocycle containing carbon, hydrogen, and at least one of N, O, and S, where the C and N can be trivalent or tetravalent, i.e., sp2- or sp3-hybridized. Examples of heterocycles include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, imidazole, oxazole, piperazine, etc. In the instance of piperazine, as related to R10 for NR′2, the corresponding opposite nitrogen atom of the piperazinyl is substituted by a lower alkyl represented by the following structure:
Preferably, the opposite nitrogen of the piperazinyl is substituted by a methyl group.
The term “halogenated alkyl” (or “haloalkyl”) refers to an unbranched or branched chain alkyl comprising at least one of F, Cl, Br, and I. The term “C1-M haloalkyl” refers to an alkyl comprising 1 to M carbon atoms that comprises at least one of F, Cl, Br, and I, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. “C1-3 haloalkyl” refers to a haloalkyl comprising 1 to 3 carbons and at least one of F, Cl, Br, and I. The term “halogenated lower alkyl” (or “lower haloalkyl”) refers to a haloalkyl comprising 1 to 6 carbon atoms and at least one of F, Cl, Br, and I. Examples include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromomethyl, 2-2-diiodomethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl.
The term “alkynyl” refers to an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one triple bond. The term “C2-N alkynyl” refers to an alkynyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term “C C2-4 alkynyl” refers to an alkynyl comprising 2 to 4 carbon atoms. The term “C2-10 alkynyl” refers to an alkynyl comprising 2 to 10 carbons. Examples include, but are limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.
The term “halogenated alkynyl” refers to an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one triple bond and at least one of F, Cl, Br, and I.
The term “cycloalkyl” refers to a saturated carbocyclic ring comprising 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The term “C3-7 cycloalkyl” as used herein refers to a cycloalkyl comprising 3 to 7 carbons in the carbocyclic ring.
The term “alkoxy” refers to an —O-alkyl group or an —O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above. Examples of —O-alkyl groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy. “Lower alkoxy” as used herein denotes an alkoxy group with a “lower alkyl” group as previously defined. “C1-10 alkoxy” refers to an —O-alkyl wherein alkyl is C1-10. Examples of —O-cycloalkyl groups include, but are not limited to, —O-c-propyl, —O-c-butyl, —O-c-pentyl, and —O-c-hexyl.
The term “halogenated alkoxy” refers to an —O-alkyl group in which the alkyl group comprises at least one of F, Cl, Br, and I.
The term “halogenated lower alkoxy” refers to an —O-(lower alkyl) group in which the lower alkyl group comprises at least one of F, Cl, Br, and I.
The term “amino acid” includes naturally occurring and synthetic α, β γ or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, ρ-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of α, β γ or δ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the D and L-configurations.
The term “aminoacyl” includes N,N-unsubstituted, N,N-monosubstituted, and N,N-disubstituted derivatives of naturally occurring and synthetic α, β γ or δ amino acyls, where the amino acyls are derived from amino acids. The amino-nitrogen can be substituted or unsubstituted. When the amino-nitrogen is substituted, the nitrogen is either mono- or di-substituted, where the substituent bound to the amino-nitrogen is a lower alkyl or an alkaryl. In the instance of its use for Y, the expression “O(aminoacyl)” is used. It is understood that the C3′ carbon of the ribose is bound to the oxygen “O”, which is then bound to the carbonyl carbon of the aminoacyl.
The terms “alkylamino” or “arylamino” refer to an amino group that has one or two alkyl or aryl substituents, respectively.
The term “protected,” as used herein and unless otherwise defined, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, CH2-alkyl, CH2-alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
The term “aryl,” as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl refers to substituted or unsubstituted phenyl. The aryl group can be substituted with one or more moieties selected from among hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3rd ed., John Wiley & Sons, 1999.
The terms “alkaryl” or “alkylaryl” refer to an alkyl group with an aryl substituent, such as benzyl. The terms “aralkyl” or “arylalkyl” refer to an aryl group with an alkyl substituent.
The term “di(lower alkyl)amino-lower alkyl” refers to a lower alkyl substituted by an amino group that is itself substituted by two lower alkyl groups. Examples include, but are not limited to, (CH3)2NCH2, (CH3)2NCH2CH2, (CH3)2NCH2CH2CH2, etc. The examples above show lower alkyls substituted at the terminus carbon atom with an N,N-dimethyl-amino substituent. These are intended as examples only and are not intended to limit the meaning of the term “di(lower alkyl)amino-lower alkyl” so as to require the same. It is contemplated that the lower alkyl chain can be substituted with an N,N-di(lower alkyl)-amino at any point along the chain, e.g., CH3CH(N-(lower alkyl)2)CH2CH2.
The term “halo,” as used herein, includes chloro, bromo, iodo and fluoro.
The term “acyl” refers to a substituent containing a carbonyl moiety and a non-carbonyl moiety. The carbonyl moiety contains a double-bond between the carbonyl carbon and a heteroatom, where the heteroatom is selected from among O, N and S. When the heteroatom is N, the N is substituted by a lower alkyl. The non-carbonyl moiety is selected from straight, branched, and cyclic alkyl, which includes, but is not limited to, a straight, branched, or cyclic C1-20 alkyl, C1-10 alkyl, or lower alkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyl optionally substituted with halogen (F, Cl, Br, I), hydroxyl, C1 to C4 alkyl, or C1 to C4 alkoxy, sulfonate esters, such as alkyl or aralkyl sulphonyl, including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least one aryl group is present in the non-carbonyl moiety, it is preferred that the aryl group comprises a phenyl group.
The term “lower acyl” refers to an acyl group in which the non-carbonyl moiety is lower alkyl.
The term “purine” or “pyrimidine” base includes, but is not limited to, adenine, N6-alkylpurines, N6-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-allcylaminopurine, N6-thioallcyl purine, N2-alkylpurines, N2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-iodopyrimidine, C6-lodo-pyrimidine, C5—Br-vinyl pyrimidine, C6—Br-vinyl pyrimidine, C5-nitropyrimidine, C5-amino-pyrimidine, N2-alkylpurines, N2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
The term “tautomerism” and “tautomers” have their accepted plain meanings.
The term “P*” means that the phosphorous atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of “R” or “S” which have their accepted plain meanings. It is contemplated that compounds of the formula I are racemic because the chirality at phosphorous. Applicants contemplate use of the racemate and/or the resolved enantiomers. In some instances, an asterisk does not appear next to the phosphoroamidate phosphorous atom. In these instances, it is understood that the phosphorous atom is chiral and that one of ordinary skill understands this to be so unless the substituents bound to the phosphorous exclude the possibility of chirality at phosphorous, such as in P(O)Cl3.
An aspect of the invention is directed to a compound, its salts, hydrates, solvates, crystalline forms, and the like represented by formula I:
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen, C1-10 alkyl, R3a or R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, C(O)CR3aR3bNHR1, where n is 2 to 4 and R1, R3a, and R3b;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CHM)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
the base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:
Z is N or CR12;
R7, R8, R9, R10, and R11 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
R12 is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, NO2 lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that when base is represented by the structure c with R11 being hydrogen, R12 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
As can be appreciated from the structure represented by formula I above, there are myriad ways to express the several embodiments and aspects of each embodiment of the present invention. As seen below, the inventors have disclosed certain embodiments directed to the compound of formula I, each having several aspects, based on the identity of the modified purine or pyrimidine base. This is not intended to be an explicit or implicit admission that the three embodiments are independent or distinct nor should it be interpreted as such. Rather, it is intended to convey information so that the full breadth of the present invention can be understood. Furthermore, the following embodiments, and aspects thereof, are not meant to be limiting on the full breadth of the invention as recited by the structure of formula I.
A first embodiment of the invention is directed to a compound represented by formula I-1:
wherein
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen, C1-10 alkyl, R3a or R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, C(O)CR3aR3bNHR1, where n is 2 to 4 and R1, R3a, and R3b;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3 is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)-amino, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R7, R8, R9 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of C2-C6, CO2, CO2R′, CONH2, CONHR′, CONR′2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl.
A first aspect of the first embodiment is directed to a compound represented by formula I-1
wherein
(a) R1 is hydrogen, n-alkyl or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl;
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are independently (i) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 3 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3 is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), or CH2SH and R3b is H;
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, CN, CH3, vinyl, OCH3, OCH2CH3, CH2OH, CH2(halo), such as CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, vinyl, N3, CN, Cl, Br, F, I, O(C1-6 acyl), O(C1-4 alkyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-4 haloalkyl, O(aminoacyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, or N(C1-4 acyl)2;
(i) R7, R8, R9 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of C2-C6, CO2, CO2R′, CONH2, CONHR′, CONR′2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl.
A second aspect of the first embodiment is directed to a compound represented by formula I-1
wherein
(a) R1 is hydrogen, n-alkyl or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a C1-3 alkyl, a C1-3 alkoxy, F, C1, Br, I, nitro, cyano, and a C1-3 haloalkyl;
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are independently (i) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2) so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 3 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), or CH2SH and R3b is H;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, di(lower alkyl)amino-lower alkyl, or aminoacyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2(halo), such as CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2; and
(j) R9 is selected from among OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)sCH3, and N(C(O)(CH2)sCH3)2, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
A third aspect of the first embodiment is directed to a compound represented by formula I-1
wherein
(a) R1 is hydrogen, n-alkyl or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH3, OCH3, F, Cl, Br, I, nitro, cyano, and a CH3-qXq, where X is F, Cl, Br, or I, and q is 1-3;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl or R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl, di(lower alkyl)amino-lower alkyl, or aminoacyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2(halo), such as CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl′; and
(j) R9 is selected from among OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)sCH3, and N(C(O)(CH2)sCH3)2, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
A fourth aspect of the first embodiment is directed to a compound represented by formula I-2
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH3, OCH3, F, Cl, Br, I, nitro, cyano, and a CH3-qXq, where X is F, Cl, Br, or I, and q is 1-3;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl or R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl; and
(j) R9 is selected from among OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)sCH3, and N(C(O)(CH2)sCH3, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
A fifth aspect of the first embodiment is directed to a compound represented by formula I-2
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl, di(lower alkyl)amino-lower alkyl, or aminoacyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl; and
(j) R9 is selected from among OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)sCH3, and N(C(O)(CH2)sCH3)2, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
A sixth aspect of the first embodiment is directed to a compound represented by formula I-2
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3, is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, OMe, CN, CH2F, F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, or N3, OCH3, OC(O)CH3, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Br, SCH3, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2CH3, CONH2, CONHCH3, or CON(CH3)2; and
(j) R9 is selected from among OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)sCH3, and N(C(O)(CH2)sCH3)2, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
A seventh aspect of the first embodiment is directed to a compound represented by formula I-2
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, or N3;
(h) Y is OH, OCH3, OC(O)CH3, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Br, SCH3, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2CH3, CONH2, CONHCH3, or CON(CH3)2; and
(j) R9 is selected from among OH, OCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)sCH3, and N(C(O)(CH2)sCH3)2, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from among 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
An eighth aspect of the first embodiment is directed to a compound represented by formula I-2
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, or N3;
(h) Y is OH, OCH3, OC(O)CH3, or O(aminoacyl);
(i) R7 and R8 are independently H, F, Br, SCH3, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2CH3, CONH2, CONHCH3, or CON(CH3)2;
(j) R9 is selected from among OH, OCH3, NH2, NHCH3, N(CH3)2, OC(O)(C1-20 alkyl), which include but are not limited to OC(O)(CH2)sCH3, NHC(O)(C1-20 alkyl), which include but are not limited to NHC(O)(CH2)CH3, and N(C(O)(CH2)sCH3)2, which include but is not limited to N(C(O)(CH2)sCH3)2, where s is an integer selected from among 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
A second embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula b above, wherein R1, R2, R3a, R3b, R4, R5, R6, X, Y, R7, and R8 are defined in the Summary of the Invention section above.
A first aspect of the second embodiment is directed to a compound represented by formula I-3
wherein
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)cCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3 is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, or N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, or N(C1-4 acyl)2;
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of C2-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl.
The second aspect of the second embodiment is directed to a compound represented by formula I-3
wherein
(a) R1 is hydrogen, n-alkyl or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl;
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are independently (i) R3a is hydrogen and R3b and R2 together are (CH)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 3 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3)2); (vi) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), or CH2SH and R3b is H;
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, CN, CH3, vinyl, OCH3, OCH2CH3, CH2OH, CH2(halo), such as CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, vinyl, N3, CN, Cl, Br, F, I, O(C1-6 acyl), O(C1-4 alkyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, lower alkenyl of C2-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl.
The third aspect of the second embodiment is directed to a compound represented by formula I-3
wherein
(a) R1 is hydrogen, n-alkyl or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a C1-3 alkyl, a C1-3 alkoxy, F, Cl, Br, I, nitro, cyano, and a C1-3 haloalkyl;
(b) R2 is hydrogen, CH3, R3a or R3b and R2 together are (CH2)3 so as to form a cyclic ring that includes the adjoining N and C atoms, C(O)CR3aR3bNHR1, where n is 2 to 4 and R1, R3a, and R3b are as defined herein;
(c) R3a and R3b are independently (i) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 3 to 5, n is 2 to 4, and where R3 is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CHCH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2(halo), such as CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, halogen, NH2, or N3
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2;
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2.
The fourth aspect of the second embodiment is directed to a compound represented by formula I-3
wherein
(a) R1 is hydrogen, n-alkyl or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH3, OCH3, F, Cl, Br, I, nitro, cyano, and a CH3-qXq where X is F, Cl, Br, or I, and q is 1-3;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl or R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2(halo), such as CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2;
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl.
The fifth aspect of the second embodiment is directed to a compound represented by formula I-4
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH3, OCH3, F, Cl, Br, I, nitro, cyano, and a CH3-qXq, where X is F, Cl, Br, or I, and q is 1-3;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl or R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl:
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2;
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl,
The sixth aspect of the second embodiment is directed to a compound represented by formula I-4
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CHM)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R7 and R8 are independently H, F, Cl, Br, I, OH, OCH3, SH, SCH3, NH2, NHCH3, N(CH3)2, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2H, CO2CH3, CONH2, CONHCH3, or CON(CH3)2, wherein R′ is a C1-20 alkyl; a C1-20 cycloalkyl; a C2-C6 alkenyl, a C2-C6 alkynyl.
The seventh aspect of the second embodiment is directed to a compound represented by formula I-4
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, OMe, CN, CH2F, F, Cl, Br, or I;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3,
(i) R7 and R8 are independently H, F, Br, SCH3, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2CH3, CONH2, CONHCH3, or CON(CH3)2;
The eighth aspect of the second embodiment is directed to a compound represented by formula I-4
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R7 and R8 are independently H, F, Br, SCH3, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2CH3, CONH2, CONHCH3, or CON(CH3)2.
The ninth aspect of the second embodiment is directed to a compound represented by formula I-4
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, or N3;
(h) Y is OH, OCH3, or OC(O)CH3;
(i) R7 and R8 are independently H, F, Br, SCH3, CH3, CH3-qXq, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO2CH3, CONH2, CONHCH3, or CON(CH3)2.
A third embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula c above, wherein R1, R2, R3a, R3b, R4, R5, R6, X, Y, Z, R10, R11, and R12 are defined in the Summary of the Invention section above; with the proviso that R11 is not H.
A first aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3 is —OR′ or —N(R3)2); (vi) R3a is H and R3b is from H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3,
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R10 and R11 are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C2-C6, CO2H, COR′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-2 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, NO2 lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H or CH═CHCO2R′.
A second aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H.
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2. N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A third aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I; with the proviso that X is OH, R6 is CH3 or CH2F, R5 cannot be H:
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A fourth aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A fifth aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3 is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is Nor CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A sixth aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H.
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A seventh aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I; with the proviso that X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
An eighth aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A ninth aspect of the third embodiment is directed to a compound represented by formula I-5
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, or N-methyl-pyrrolidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A tenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
An eleventh aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A twelfth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H:
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is Nor CR1; and
R12 is a H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A thirteenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3, is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R′ is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is Nor CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A fourteenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′, with the proviso that when R10 is OH and R11 is not NH2;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A fifteenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3 is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3,
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
An sixteenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, COR′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A seventeenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
An eighteenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3, is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is NH2 and R11 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A nineteenth aspect of the third embodiment is directed to a compound represented by formula I-6
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is NH2 and R11 are independently H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′;
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A fourth embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula c above, where R11 is H and R2, R3a, R3b, R4, R5, R6, X, and Y are defined in the Summary of the Invention section above.
A first aspect of the fourth embodiment is directed to a compound represented by formula I-7
wherein
(a) R1 is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R10 is H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H or CH═CHCO2R′,
wherein R′ is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH2, NHR′, NR′2, NO2 lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C2-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R1 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A second aspect of the fourth embodiment is directed to a compound represented by formula I-7
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H.
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, halogen, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2. N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R′ is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A third aspect of the third embodiment is directed to a compound represented by formula I-7
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I; with the proviso that X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R1 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A fourth aspect of the fourth embodiment is directed to a compound represented by formula I-7
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 and R11 H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is Nor CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R12 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A fifth aspect of the fourth embodiment is directed to a compound represented by formula I-7
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H,
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′.
A sixth aspect of the fourth embodiment is directed to a compound represented by formula I-8
wherein
(a) R1 is hydrogen, n-alkyl: branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1 is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3 and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)f so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3 is —OR′ or —N(R3)2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3,
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that when base is represented by the structure c with R11 being hydrogen, R12 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A seventh aspect of the fourth embodiment is directed to a compound represented by formula I-8
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R′ cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, halogen, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, N02, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R12 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
An eighth aspect of the fourth embodiment is directed to a compound represented by formula I-8
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, n Pr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, NO2, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R′ is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A ninth aspect of the fourth embodiment is directed to a compound represented by formula I-8
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR12; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, N02, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R12 is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A tenth aspect of the fourth embodiment is directed to a compound represented by formula I-8
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl,
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
(i) R10 is H, F, Br, I, OH, OR′, NH2, NHR′, NR′2, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,
wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) or alternatively, in the instance of NR′2, each R′ comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
(j) Z is N or CR2; and
R12 is an H, halogen (including F, Cl, Br, I), OR′, NH2, NHR′, NR′2, N02, lower alkyl of C1-C6, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′; with the proviso that R′ is not a: (i) —C≡C—H, (ii) —C═CH2, or (iii) —NO2.
A fifth embodiment of the invention is directed to a compound represented by formula I in which the base is a structure represented by formula d above, wherein R, R2, R3a, R3b, R4, R5, R6, X, and Y are defined in the Summary of the Invention section above.
The first aspect of the fifth embodiment is directed to a compound represented by formula I-9
wherein
(a) R′ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl; (R1′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1″ is —OR′ or —N(R1′)2);
(b) R2 is hydrogen or CH3;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2) so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3′ is independently hydrogen or C1-6 alkyl and R3″ is —OR′ or —N(R3′)2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3′ is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3″ is —OR′ or —N(R3′)2);
(d) R4 is hydrogen. C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(lower alkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2.
A second aspect of the fifth embodiment is directed to a compound represented by formula I-9
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H.
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, halogen, NH2, or N3,
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3;
A third aspect of the fifth embodiment is directed to a compound represented by formula I-9
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I; with the proviso that X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 N3, OCH3, or OC(O)CH3;
A fourth aspect of the fifth embodiment is directed to a compound represented by formula I-9
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
A fifth aspect of the fifth embodiment is directed to a compound represented by formula I-9
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3, is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CHM)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R′ is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
A sixth aspect of the fifth embodiment is directed to a compound represented by formula I-10
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH3, OCH3, F, Cl, Br, I, nitro, cyano, and a CH3-qXq, where X is F, Cl, Br, or I, and q is 1-3;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl or R3a is CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl:
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3;
(h) Y is OH, H, CH3, vinyl, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3, NH2, NHCH3, NH(vinyl), NH(acetyl), NH(C(O)CH3), N(CH3)2, N(C(O)CH3)2;
A seventh aspect of the fifth embodiment is directed to a compound represented by formula I-10
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH3, OCH3, CH2OH, CH2F, halogen, including F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OCH3, Cl, Br, I, NH2, or N3; and
(h) Y is OH, H, CH3, vinyl, NH2, N3, CN, Cl, Br, F, I, OC(O)CH3, OCH3.
An eighth aspect of the fifth embodiment is directed to a compound represented by formula I-10
wherein
(a) R1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen or CH3;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CHM)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, CN, CH2F, F, Cl, Br, or I, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, F, OCH3, F, Cl, Br, I, NH2 or N3;
(h) Y is H, OH, CH3, F, Cl, Br, I, NH2 or N3, OCH3, or OC(O)CH3;
A ninth aspect of the fifth embodiment is directed to a compound represented by formula I-10
wherein
(a) R1 is hydrogen, methyl, ethyl, i-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3;
A tenth aspect of the fifth embodiment is directed to a compound represented by formula I-10
wherein
(a) R1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R2 is hydrogen;
(c) R3a is H and R3b is H, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, or lower cycloalkyl;
(d) R4 is hydrogen, CH3, Et, iPr, nPr, nBu, 2-butyl, tBu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl;
(e) R5 is H, with the provisos that when X is OH, R6 is CH3 or CH2F, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, or F;
(g) X is H, OH, OCH3, F, NH2 or N3;
(h) Y is OH, NH2, OCH3, or OC(O)CH3.
The following tables contain numeric identifiers associated with various substituent designators that should be viewed in light of the accompanying structure. These structures are contemplated species of the various aspects of the disclosed embodiments and are not intended to be limiting on full breadth of the contemplated compound represented by the structure of formula I. However, it is contemplated that any one of the exemplified nucleoside bases can be used in combination with any one of contemplated species that specify a particular combination of R1, R2, R3a, R3b, R4, R5, R6, X, and Y. In each of the presented tables, the phosphoramidate substituent containing the substituents R3a and R3 are depicted without reference to stereochemical structure (cf structures I-1, I-3, I-5, I-7, and I-9 above). It is contemplated that the compounds recited below embody compounds in which R3a projects toward the viewer while R3b projects away from the viewer (cf. structures I-2, I-4, I-6, I-8, and I-10). Moreover, it is contemplated that the compounds recited below also embody compounds in which R3a projects away from the viewer while R3b projects towards the viewer. Not meant to be limiting, however, it is contemplated that preferred compounds are those in which R3a projects towards the viewer and R3b projects away from the viewer such that the natural L-amino acid (S)-configuration is presented. Additionally, the inventors recognize that the phosphorus atom of the phosphoramidate moiety is another source of chirality. Although the structures below do not specifically depict chirality at phosphorus, the inventors recognize that stereochemical configurations are possible such that in a staggered (or zig-zag) line structure the oxo-substitutent projects towards the viewer while the OR1 substitutent projects away from the viewer, and vice versa, i.e., where the Cahn-Ingold-Prelog stereochemical designation of phosphorous is either R or S. Therefore, the structures below include all possible stereochemical configurations possible for phosphorus.
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
tBu
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iPr
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o
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iPr
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iPr
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N
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o
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N
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N
o
tBu
tBu
tBu
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tBu
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N
o
N
o
N
o
N
o
N
o
N
o
N
o
iPr
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tBu
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nBu
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iPr
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A sixth embodiment of the present invention is directed to a composition for the treatment of any of the viral agents disclosed herein said composition comprising a pharmaceutically acceptable medium selected from among an excipient, carrier, diluent, and equivalent medium and a compound, that is intended to include its salts (acid or basic addition salts), hydrates, solvates, and crystalline forms can be obtained, represented by formula I.
It is contemplated that the formulation of the sixth embodiment can contain any of the compounds contemplated in any of the aspects of the first, second, third, fourth, and fifth embodiments or those specifically recited in the tables above or exemplified herein, either alone or in combination with another compound of the present invention.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. Compounds of the present invention are efficacious when administered by suppository administration, among other routes of administration. The most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral medication.
A compound or compounds of the present invention, as well as their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration. A typical preparation will contain from about 5% to about 95% active compound or compounds (w/w). The term “preparation” or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
The term “excipient” as used herein refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
A “pharmaceutically acceptable salt” form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase “pharmaceutically acceptable salt” of a compound as used herein means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, K+, Mg2+, Ca2+, and NHgR′″4-g+, in which R′″ is a C1-3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
Solid form preparations include powders, tablets, pills, capsules, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa., which is hereby incorporated by reference. The compounds of the present invention can also be encapsulated in liposomes, such as those disclosed in U.S. Pat. Nos. 6,180,134, 5,192,549, 5,376,380, 6,060,080, 6,132,763, each of which is incorporated by reference. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
The modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (e.g., salt formulation), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
A seventh embodiment of the present invention is directed to a use of the compound represented by formula I in the manufacture of a medicament for the treatment of any condition the result of an infection by any one of the following viral agents: hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus and Japanese encephalitis virus.
The term “medicament” means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage form, and the like, comprising the compound of formula I. It is contemplated that the compound of the use of the compound represented by formula I in the manufacture of a medicament for the treatment of any of the antiviral conditions disclosed herein of the seventh embodiment can be any of the compounds contemplated in any of the aspects of the first, second, third, fourth, fifth embodiments or those specifically recited in the tables above or exemplified herein, either alone or in combination with another compound of the present invention. A medicament includes, but is not limited to, any one of the compositions contemplated by the sixth embodiment of the present invention.
A eighth embodiment of the present invention is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective amount of the compound represented by formula I to the subject.
A first aspect of the eighth embodiment is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective of at least two or more different compounds falling within the scope of the compound represented by formula I to the subject.
A second aspect of the eighth embodiment is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of at least two compounds falling within the scope of the compound represented by formula I to the subject.
It is intended that a subject in need thereof is one that has any condition the result of an infection by any of the viral agents disclosed herein, which includes, but is not limited to, hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, flaviviridae viruses or pestiviruses or hepaciviruses or a viral agent causing symptoms equivalent or comparable to any of the above-listed viruses.
The term “subject” means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, preferably the subject is a human. It is contemplated that in the method of treating a subject thereof of the sixth embodiment can be any of the compounds contemplated in any of the aspects of the first, second, and third embodiments or those specifically recited in the tables above, either alone or in combination with another compound of the present invention.
The term “therapeutically effective amount” as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.1 and about 10 g, including all values in between, such as 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per day should be appropriate in monotherapy and/or in combination therapy. A preferred daily dosage is between about 0.5 and about 7.5 g per day, more preferred 1.5 and about 6.0 g per day. Generally, treatment is initiated with a large initial “loading dose” to rapidly reduce or eliminate the virus following by a decreasing the dose to a level sufficient to prevent resurgence of the infection. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
Therapeutic efficacy can be ascertained from tests of liver function including, but not limited to protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5′-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism. Alternatively the therapeutic effectiveness may be monitored by measuring HCV-RNA. The results of these tests will allow the dose to be optimized.
A third aspect of the eighth embodiment, is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering to the subject a therapeutically effective of a compound represented by formula I and a therapeutically effective amount of another antiviral agent; wherein the administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours. Examples of “another antiviral agents” include, but are not limited to: HCV NS3 protease inhibitors (see WO 2008010921, WO 2008010921, EP 1881001, WO 2007015824, WO 2007014925, WO 2007014926, WO 2007014921, WO 2007014920, WO 2007014922, US 2005267018, WO 2005095403, WO 2005037214, WO 2004094452, US 2003187018, WO 200364456, WO 2005028502, and WO 2003006490); HCV NS5B Inhibitors (see US 2007275947, US20072759300, WO2007095269, WO 2007092000, WO 2007076034, WO 200702602, US 2005-98125, WO 2006093801, US 2006166964, WO 2006065590, WO 2006065335, US 2006040927, US 2006040890, WO 2006020082, WO 2006012078, WO 2005123087, US 2005154056, US 2004229840, WO 2004065367, WO 2004003138, WO 2004002977, WO 2004002944, WO 2004002940, WO 2004000858, WO 2003105770, WO 2003010141, WO 2002057425, WO 2002057287, WO 2005021568, WO 2004041201, US 20060293306, US 20060194749, US 20060241064, U.S. Pat. No. 6,784,166, WO 2007088148, WO 2007039142, WO 2005103045, WO 2007039145, WO 2004096210, and WO 2003037895); HCV NS4 Inhibitors (see WO 2007070556 and WO 2005067900); HCV NS5a Inhibitors (see US 2006276511, WO 2006120252, WO 2006120251, WO 2006100310, WO 2006035061); Toll-like receptor agonists (see WO 2007093901); and other inhibitors (see WO 2004035571, WO 2004014852, WO 2004014313, WO 2004009020, WO 2003101993, WO 2000006529).
A fourth aspect of the eighth embodiment, is directed to a method of treatment in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of a compound represented by formula I and another antiviral agent to the subject. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
A fifth aspect of the eighth embodiment, is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering to the subject a therapeutically effective of at least one compound represented by formula I and a therapeutically effective amount of another antiviral agent; wherein the administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
A sixth aspect of the eighth embodiment, is directed to a method of treatment in a subject in need thereof said method comprises alternatively or concurrently administering a therapeutically effective of at least one compound represented by formula I and another antiviral agent to the subject. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
It is contemplated that the another antiviral agent includes, but is not limited to interferon-α, interferon-β, pegylated interferon-α, ribavirin, levovirin, viramidine, another nucleoside HCV polymerase inhibitor, a HCV non-nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCV helicase inhibitor or a HCV fusion inhibitor. When the active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound. When the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives. “Concurrent administration” as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
It will be understood that references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions. Furthermore, the term “treatment” of a HCV infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.
An ninth embodiment of the present invention is directed to a process for preparing the compound of formula I, which comprises reacting a suitably substituted phosphochloridate compound 4 with a nucleoside analog 5
wherein the substituents R1, R2, R3a, R3b, R4, R5, X, Y, R6, and base have their meanings as disclosed in the Detailed Description of the Invention and X′ is a leaving group, such as Cl, Br, I, tosylate, mesylate, trifluoroacetate, trifluorosulfonate, pentafluorophenoxide, p-NO2-phenoxide, or other commonly used leaving groups as disclosed in Advanced Organic Chemistry by March, Fourth Edition. Leaving groups and methods that can be used to effect the formation of a phosphoramidate nucleoside conjugate are found in US 20060142238 and WO 2007095269. Preferably, the leaving group is C1.
This reaction is performed in an anhydrous aprotic solvent such tetrahydrofuran, dioxane, or both tetrahydrofuran and dioxane, or any functional equivalent thereof, with tetrahydrofuran being the preferred solvent. The reaction is typically initiated at a temperature range from −78° C. to 40° C. with the preferred reaction temperature being between 0° C. and room temperature. The nucleoside is first stirred with a base (5 to 12 equivalents) such as N-methylimidazole, collidine, pyridine, 2,6-lutidine, 2, 6-tBu-pyridine, etc. a tertiary amine base, such as triethylamine, diisopropylethylamine, etc., or an alkyl Grignard reagent, such as tBuMgCl, tBuMgBr, MeMgCl, MeMgBr, etc. The phosphorochloridate (3-10 equivalents) is dissolved in the reaction solvent and added to the mixture of the nucleoside and base. The reaction is then allowed to stir over a period of time at a temperature between room temperature and 40° C. for a period of 30 min to 24 hr. with the preferred reaction temperature being room temperature and time being 24 hr. The solvent is removed from the reaction mixture and the product is purified by chromatography on silica gel.
A tenth embodiment of the present invention is directed to a product obtained by a process which comprises reacting a suitably substituted phosphochloridate compound 4 with a nucleoside analog 5
wherein the substituents R1, R2, R3a, R3b, R4, R5, X, Y, R6, X′, and base have their meanings as disclosed in the Detailed Description of the Invention.
This reaction can be performed in an anhydrous aprotic solvent or other suitable solvent, such as tetrahydrofuran, dioxane, or a mixture of tetrahydrofuran and dioxane, with tetrahydrofuran being the preferred solvent. The reaction is typically initiated at a temperature range from −78° C. to 40° C. with the preferred reaction temperature being between 0° C. and room temperature. The nucleoside is first stirred with a base (5 to 12 equivalents) such as N-methylimidazole, a tertiary amine base or tButyl Magnesium Chloride. A phosphorochloridate (3-10 equivalents (or suitable “phosphoro-(leaving group)-date”)) is dissolved in the reaction solvent and added to the mixture of the nucleoside and base. The reaction is then allowed to stir over a period of time at a temperature between room temperature and 40° C. for a period of 30 min to 24 hr. with the preferred reaction temperature being room temperature and time being 24 hr. The solvent is removed from the reaction mixture and the product is purified by chromatography on silica gel.
Phosphoramidate compounds of the present invention can be prepared by condensation of a nucleoside analog 5 with a suitably substituted phosphochloridate compound 4 (Scheme 1). The nucleoside analog is made by conventional procedures disclosed in any one of U.S. Published Application Nos. 2005/0009737, 2006/0199783, 2006/0122146, and 2007/0197463, each of which is incorporated by reference in its entirety.
Disclosed 1H-NMR values were recorded on a Varian AS-400 instrument. Mass spectral data were obtain using either a Micromass-Quattromicro API or a Waters Acquity.
Thus, by way of example only, a suitably substituted phenol can be reacted with phosphorus oxychloride (1) to afford an aryloxy phosphorodichloridate 2 (see Example 1) which is subsequently treated with a acid addition salt of an α-amino acid ester in the presence of TEA to afford an aryloxy phosphorochloridate 4. This arylalkoxy-amino acid phosphoramidate is reacted with the nucleoside analog to provide the product I (for procedure see, e.g., C. McGuigan et al. Antiviral Res. 1992 17:311-321; D. Curley et al. Antiviral Res. 1990 14:345-356; McGuigan et al. Antiviral Chem. Chemother 1990 1(2):107-113).
The preparation of nucleoside phosphoramidates requires reacting an appropriately substituted phosphochloridate with a nucleoside containing a free 5′-hydroxyl moiety. In cases where only one hydroxyl group is present, preparation of the phosphoramidate usually proceeds smoothly when the phosphochloridate is reacted with the desired nucleoside. In cases where the nucleoside contains more than one free hydroxyl group, preparation of the appropriately protected nucleoside might be required. Silyl, acetonide or other alcohol protecting groups known in the art might be warranted for protection of the sugar moiety. For protection of the nucleoside base, protecting a free amino group may require amidine protection strategy.
Condensation of the phosphochloridate can be carried out on the unprotected nucleoside. Since the 5′-OH group of a nucleoside is much less hindered than the 3′-OH group, selective phosphoramidation is possible under carefully controlled conditions. After condensation to form a protected phosphoramidate nucleoside, deprotection to obtain the free phosphoramidate nucleoside can be carried out using standard protocols for nucleic acid chemistry. In many cases, the desired product is readily separated from the starting material using column chromatography on silica gel. The synthetic scheme is summarized in Scheme 1.
A further understanding of the disclosed embodiments will be appreciated by consideration of the following examples, which are only meant to be illustrative, and not limit the disclosed invention.
A solution of the appropriate phenol R1—OH (1 eq) and triethylamine (1 eq.) in anhydrous ether was added dropwise to a stirred solution of phosphoryl trichloride 1 (1 eq) at 0° C. over a period of 3 hours under nitrogen. Then the temperature was warmed to room temperature, and the reaction was stirred overnight. The triethylamine salt was quickly removed with suction filtration and the filtrate concentrated in vacuo to dryness to afford 2 as an oil which was used without further purification.
A solution of triethylamine (2 eq) in anhydrous dichloromethane was added dropwise to a solution of aryloxy-phosphodichloridate 2 (1 eq) and the appropriate amino ester 3 (1 eq) in anhydrous dichloromethane with vigorous stirring at −78° C. over a period of 30 to 120 minutes. Then the reaction temperature was allowed to warm to room temperature and stirred over night. Solvent was removed. The residue was washed with ethyl ether and filtered, the filtrate was dried over reduced pressure to give 4.
A solution of the appropriate phosphorochloridate 4 (6.5 equivalents) in anhydrous tetrahydrofuran (THF) was added to a mixture of nucleoside 5 (1 equivalent) and N-methylimidazole (8 equivalents) in anhydrous THF with vigorous stirring at room temperature and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the crude was purified by column chromatography and/or preparative thin layer chromatography to give I.
2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1.0 g, 1 eq) (Clark, J., et al., J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10 ml of anhydrous pyridine and concentrated to dryness in vacuo. The resulting syrup was dissolved in 20 ml of anhydrous pyridine under nitrogen and cooled to 0° C. with stirring. The brown solution was treated with benzoyl chloride (1.63 g, 3 eq) dropwise over 10 min. The ice bath was removed and stirring continued for 1.5 h whereby thin-layer chromatography (TLC) showed no remaining starting material. The mixture was quenched by addition of water (0.5 ml) and concentrated to dryness. The residue was dissolved in 50 mL of dichloromethane (DCM) and washed with saturated NaHCO3 aqueous solution and H2O. The organic phase was dried over NaSO4 and filtered, concentrated to dryness to give N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, Yield: 91%).
N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After cooling and standing at room temperature (15° C.), most of the product precipitated and then was filtered through a sintered funnel. White precipitate was washed with water and co-evaporated with toluene to give a white solid. The filtrate was concentrated and co-evaporated with toluene to give additional product which was washed with water to give a white solid. Combining the two batches of white solid gave 1.50 g of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (Yield: 91%).
To a solution of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60%).
Phenyl methoxyalaninyl phosphorochloridate (1 g, 6.5 eq) dissolved in 3 mL of THF was added to a mixture of 2′-Deoxy-2′-fluoro-2′-C-methyluridine (0.15 g, 1 eq) and N-methylimidazole (0.3 g, 8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product (50.1 mg, 15.6%). 1H NMR (DMSO-d6) δ 1.20-1.27 (m, 6H), 3.58 (d, J=16.0 Hz, 3H), 3.75-3.92 (m, 2H), 4.015-4.379 (m, 2H), 5.54 (t, J=10.2 Hz, 1H), 5.83-5.91 (m, 1H), 6.00-6.16 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.22 (s, 1H), 7.35 (t, J=4.4 Hz, 2H), 7.55 (s, 1H), 11.52 (s, 1H); MS, m/e 502 (M+1)+.
Phenyl methoxy-valyl phosphorochloridate (0.6 g, 3.6 eq) dissolved in 3 mL of THF was added to a mixture of 2′-Deoxy-2′-fluoro-2′-C-methyluridine (0.15 g, 1 eq) and N-methylimidazole (0.44 g, 9 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product (60 mg, 20%). 1H NMR (DMSO-d6) δ 0.74-0.847 (m, 6H), 1.20-1.28 (m, 3H), 1.89-1.92 (m, 1H), 3.50-3.54 (m, 1H), 3.58 (d, J=10.4 Hz, 3H), 3.72-3.95 (m, 1H), 4.03-4.05 (m, 1H), 4.23-4.43 (m, 2H), 5.56 (t, J=16.0 Hz, 1H), 5.85-5.92 (m, 1H), 6.01-6.07 (m, 1H), 7.16-7.21 (m, 3H), 7.37 (t, J=8 Hz, 2H), 7.55-7.60 (m, 1H), 11.52 (s, 1H); MS, m/e 530 (M+1)+.
4-Bromophenyl methoxy-valyl phosphorochloridate (1 g, 3.4 eq) dissolved in 3 mL of THF was added to a mixture of 2′-deoxy-2′-fluoro-2′-C-methyluridine (0.2 g, 1 eq) and N-methylimidazole (0.35 g, 6 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed reduced pressure to give the desired product (120 mg, 26%). 1H NMR (DMSO-d6) δ 0.72-0.82 (m, 6H), 1.19-1.26 (m, 3H), 1.86-1.92 (m, 1H), 3.48-3.50 (m, 1H), 3.56 (d, J=12.0 Hz, 3H), 3.72-3.89 (m, 1H), 3.96-4.03 (m, 1H), 4.22-4.37 (m, 2H), 5.54-5.60 (m, 1H), 5.85-5.91 (m, 1H), 5.98-6.13 (m, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.49-7.56 (m, 3H), 11.53 (s, 1H); MS, m/e 608 (M+1)+.
4-Bromophenyl methoxy-alanyl phosphorochloridate (0.6 g, 5 eq) dissolved in 3 mL of THF was added to a mixture of 2′-deoxy-2′-fluoro-2′-C-methyluridine (0.15 g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product (40 mg, 12%); 1H NMR (DMSO-d6) δ 1.20-1.26 (m, 6H), 3.57 (d, J=2.8 Hz, 3H), 3.84 (s, 1H), 3.97-4.03 (m, 1H), 4.21-4.25 (m, 1H), 4.33-4.37 (m, 2H), 5.54-5.60 (m, 1H), 5.83-5.89 (m, 1H), 5.98-6.19 (m, 1H), 7.16 (t, J=10.2 Hz, 2H), 7.52-7.57 (m, 3H), 11.52 (s, 1H); MS, m/e 580 (M+1)+.
2′-Deoxy-2′-fluoro-2′-C-methylcytidine (500 mg, 1.9 mmol) was stirred with dimethylformamide dimethyl acetal in DMF (10 mL). The resulting mixture was stirred at room temperature overnight. After solvent removal the crude product was used for next step without further purification.
Phenyl methoxyalaninyl phosphorochloridate (0.6 g, 6 eq) dissolved in 3 mL of THF was added to a mixture of N4—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine (0.15 g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product (62 mg, 20.6%). 1H NMR (DMSO-d6) δ 1.16 (d, J=23.2 Hz, 3H), 1.22 (d, J=7.2 Hz, 3H), 3.56 (S, 3H), 3.69-3.75 (d, J=25.6 Hz, 1H), 3.82-3.86 (m, 1H), 3.96-3.98 (m, 1H), 4.21-4.34 (m, 2H), 5.68 (d, J=7.2 Hz, 1H), 5.75-5.77 (m, 1H), 6.07-6.16 (m, 1H), 7.15-7.19 (m, 3H), 7.2 (d, J=9.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H); MS, m/e 501 (M+1)+.
4-Bromophenyl methoxy-valyl phosphorochloridate (1.0 g, 3.4 eq.) dissolved in 3 mL of THF was added to a mixture of N4—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine (0.2 g, 1 eq.) and N-methylimidazole (0.35 g, 6 eq.) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product as a white solid (59 mg, 13%); 1H NMR (DMSO-d6) δ 0.74-0.83 (m, 6H), 1.12-1.20 (m, 3H), 1.89-1.92 (m, 1H), 3.49-3.51 (m, 1H), 3.55 (s, 3H), 3.59-3.68 (m, 1H), 3.72-0.383 (m, 1H), 4.21-4.39 (m, 2H), 5.70-5.72 (m, 1H), 5.76-5.83 (m, 1H), 6.04-6.16 (m, 1H), 7.15 (d, J 13.0 Hz, 2H), 7.26 (s, 1H), 7.33 (s, 1H), 7.46-7.55 (m, 1H), 7.56 (d, J=4.4 Hz, 2H); MS, m/e 607 (M+1)+.
Phenyl methoxy-valyl phosphorochloridate (0.6 g, 6 eq) dissolved in 3 mL of THF was added to a mixture of N4—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine (0.15 g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product as a white solid (86 mg, 42.9%). 1H NMR (DMSO-d6) δ 0.72-0.80 (m, 6H), 1.09-1.18 (m, 3H), 1.87-1.92 (m, 1H), 3.47-3.51 (m, 1H), 3.58 (s, 3H), 3.71-3.75 (m, 1H), 3.97 (t, J=11.2 Hz, 1H), 4.22-4.37 (m, 2H), 5.70 (d, J=8.0 Hz, 1H), 5.76-5.84 (m, 1H), 6.01-6.15 (m, 1H), 7.13-7.18 (m, 3H), 7.27 (s, 2H), 7.34 (d, J=4.0 Hz, 2H), 7.46-7.50 (m, 1H): MS, m/e 529 (M+1)+.
Example numbers 13-54 and 56-66 are prepared using similar procedures described for examples 5-8. The example number, compound identification, and NMR/MS details are shown below:
1HNMR (400 MHz, DMSO-d6): δ 1.20-1.26 (m, 6H), 3.80-3.93 (m,
1HNMR (400 MHz, DMSO-d6): δ 1.21-1.28 (m, 6H), 3.71-3.88 (m,
1H NMR (DMSO-d6) δ 0.80-0.82 (m, 6H), 1.18-1.40 (m, 8H), 1.50-
1H NMR (DMSO-d6) δ 1.05-1.37 (m, 6H), 3.71-3.82 (m, 1H), 3.87-
1H NMR (DMSO-d6) δ 1.18-1.41 (m, 12H), 1.59-1.67 (m, 4H), 3.74-
1H NMR (DMSO-d6) δ 1.18-1.28 (m, 6H), 3.70-3.83 (m, 1H), 3.87-
1HNMR (400 MHz, DMSO-d6): δ 0.81-0.86 (m, 3H), 1.21-1.31 (m,
1HNMR (400 MHz, DMSO-d6): δ 1.10-1.14 (m, 6H), 1.20-1.27 (m,
1H NMR (DMSO-d6) δ 1.20-1.44 (m, 12H), 1.60-1.71 (m, 4H), 3.75-
1HNMR (400 MHz, DMSO-d6): δ = 1.18-1.46 (m, 12H), 1.61-1.69 (m,
1HNMR (400 MHz, DMSO-d6): δ = 0.75-0.82 (m, 3H), 1.12-1.26 (m,
1HNMR (400 MHz, DMSO-d6): δ 0.75-0.88 (m, 3H), 1.26-1.46 (m,
1H NMR (DMSO-d6) δ 0.75-0.84 (m, 3H), 1.24 (d, J = 22.8 Hz, 3H),
1H NMR (DMSO-d6) δ 1.18-1.25(m, 6H), 3.71-3.89 (m, 2H), 3.92-3.99
1H NMR (DMSO-d6) δ 1.17-1.24 (m, 6H), 3.67-3.81 (m, 1H), 3.89-
1H NMR (DMSO-d6) δ 1.13-1.29 (m, 6H), 3.67-3.81 (m, 1H), 3.94-
1H NMR (DMSO-d6) δ 1.20-1.29 (m, 6H), 3.70-3.90 (m, 1H), 3.91-
1H NMR (DMSO-d6) δ 0.20-0.24(m, 2H), 0.47-0.48(m, 2H), 0.76-
1H NMR (DMSO-d6) δ 0.75-0.83 (m, 3H), 1.20-1.28 (m, 3H), 1.49-
The Purification Procedure by Prep-HPLC:
Crude products were dissolved in methanol. Injection volumes of these solutions were 5 mL.
The preparative HPLC system including 2 sets of Gilson 306 pumps, a Gilson 156 UV/Vis detector, a Gilson 215 injector & fraction collector, with Unipoint control software. A Ymc 25×30×2 mm column was used. The mobile phase was HPLC grade water (A), and HPLC grade acetonitrile (B). Fractions were collected into 100*15 mm glass tubes.
HPLC gradient is shown in Table 1. Once the gradient was selected, acetonitrile solution was injected into HPLC system, and then fractions collected according to UV peaks. After the separation, each glass tubes were run MS test to collect the desired compounds. The fractions with target MS were combined in a well-weighted flask. Most of acetonitrile was removed under reduce pressure and the remaining solution was freeze-dried to give desired compound.
Preparation of Compound (b)
To a solution of compound a (1 g, 2.69 mmol) in anhydrous THF (30 mL) was added dropwise 1 M solution of LiAl(OBu-t)3H in THF (2.69 mL, 2.69 mmol) at −20° C. The reaction mixture was stirred for 2-3 h at the same temperature. EtOAc (100 mL) was added followed by saturated NH4Cl solution (10 mL) and reaction mixture was slowly brought to room temperature. Reaction mixture was extracted with EtOAc and washed with 1N HCl and water. Combined organic phase was evaporated to give 0.8 g of crude compound b as transparent oil, which was used directly for next reaction.
Preparation of Compound (d)
To a solution of compound b (0.8 g, 2.1 mmol), compound c (0.45 g, 2.5 mmol) and Ph3P (0.56 g, 2.1 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere was added DEAD (1.8 mL). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduce pressure. The residue was separated by preparative layer chromatography (hexanes:EtOAc=3:1) to give crude compound d (0.8 g). The crude compound d was used to the next step without further purification.
Preparation of Compound (e)
Compound d (0.8 g, 1.57 mmol) was dissolved in THF (2 mL) and THF saturated with ammonia (5 mL) was then added to this solution. The reaction mixture was heated to 90° C. overnight. After 18 hours, the solution was cooled to room temperature by ice water, then the solvent was removed under reduced pressure and the residue was purified by column to give compound e (0.75 g) for the next step.
Preparation of Compound (f)
Compound e (0.5 g, 1.01 mmol) was dissolved in methanol (2 mL) and methanol was saturated with ammonia (5 mL) was then added to this solution. The reaction mixture was stirred at room temperature overnight. After 18 hours, the solvent was removed under reduced pressure and the residue was purified by column to give crude compound f (0.15 g) for the next step.
Preparation of Compound (i)
A solution of triethylamine (1.07 g, 10.6 mmol) in anhydrous dichloromethane (15 mL) was added dropwise to a solution of compound g (1.16 g, 5.3 mmol) and compound h (1.31 g, 5.3 mmol) in dichloromethane (10 mL) with vigorous stirring at −78° C. over a period of 2 hours. After completion of addition, the reaction temperature was allowed to warm to room temperature gradually and stirred over night. Then the solvent was removed under vacuum and anhydrous ether 20 mL was added and the precipitated salt was filtered and the precipitate was washed with ether. The combined organic phase was concentrated to give the colorless oil of compound i (1.0 g).
Preparation of Compound 66
To a solution of compound j (0.1 g, 0.35 mmol) dissolved in 10 mL of anhydrous THF, stirred and added 0.4 g NMI till the solution became clear, added compound i (0.8 g, 2.89 mmol) in 10 mL THF dropwise, stirred at r.t. overnight. Compound purity and identification was confirmed by LCMS. The solvent was evaporated and purified by Prep-HPLC to afford 66. (25 mg, Yield: 13.6%). 1H NMR (DMSO-d6) δ 1.08 (d, J=22.8 Hz, 3H), 1.17-1.24 (m, 3H), 3.50-3.52 (m, 3H), 3.78-3.83 (m, 1H), 4.10-4.13 (m, 1H), 4.24-4.44 (m, 2H), 5.85-5.92 (m, 1H), 6.01-6.11 (m, 1H), 6.2-6.27 (m, 1H), 7.08-7.19 (m, 4H), 7.31-7.38 (m, 3H), 8.15 (s, 1H), 8.26 (s, 1H); MS, m/e 525 (M+1)+.
Example numbers 67-74, identified below, were prepared using similar procedures disclosed for Example 66, above.
1H NMR(DMSO-d6) δ 1.06-1.13 (m, 3H), 1.20-1.24 (m, 3H),
1H NMR (DMSO-d6) δ 1.07 (d, J = 22.8 Hz, 3H), 1.19 (d,
1H NMR (DMSO-d6) δ 1.05 (d, J = 22.8 Hz, 3H), 1.09-1.19
1H NMR (DMSO-d6) δ 1.07 (d, J = 22.4 Hz, 3H), 2.35-2.38 (m, 2H), 3.54 (d, J = 9.2 Hz, 3H), 3.59-3.62 (m, 2H), 3.65 (s, 1H), 3.75-3.82 (m, 1H), 4.01-4.13 (m, 2H), 4.22-4.40 (m, 6H), 5.75-5.85 (m, 1H), 6.00-6.07 (m, 4H), 7.15-7.21 (m,
1H NMR (DMSO-d6) δ 1.06-1.28 (m, 12H), 3.55 (d, J = 4.8
1H NMR (DMSO-d6) δ 0.84 (t, J = 7.2 Hz, 3H), 1.01-1.01 (m,
1H NMR (DMSO-d6) δ 1.02-1.08 (m, 3H), 1.18 (d, J = 4.8 Hz,
1H NMR (DMSO-d6) δ 0.97-1.20 (m, 6H), 2.18 (s, 3H), 2.19 (s, 4H), 3.43-3.47 (m, 3H), 3.75 (s, 1H), 4.01-4.06 (m, 4 H), 4.22-4.35 (m, 3H), 5.69-5.75 (m, 1H), 5.98-6.05 (m, 3H), 7.09-7.15 (m, 3H), 7.25-7.29 (m, 2H), 7.77 (d,
Example numbers 75-80 are prepared using similar procedures disclosed for Example 66, above.
Certain exemplified compounds were obtained as mixture of diastereomers because of the chirality at phosphorous. The diastereomers were separated on a Chiralpak-AS-H (2×25 cm) column under Supercritical Fluid Chromatography (SFC) conditions using 20% methanol in carbon dioxide as solvent. The absolute stereochemistry of the P-chiral center of the diastereomers were not determined. However, chromatographic resolution of these two diastereomers provides for isomers that are characterized as fast eluting and slow eluting isomers. Some examples are shown below.
HCV replicon assay. HCV replicon RNA-containing Huh7 cells (clone A cells; Apath, LLC, St. Louis, Mo.) were kept at exponential growth in Dulbecco's modified Eagle's medium (high glucose) containing 10% fetal bovine serum, 4 mM L-glutamine and 1 mM sodium pyruvate, 1×nonessential amino acids, and G418 (1,000 μg/ml). Antiviral assays were performed in the same medium without G418. Cells were seeded in a 96-well plate at 1,500 cells per well, and test compounds were added immediately after seeding. Incubation time 4 days. At the end of the incubation step, total cellular RNA was isolated (RNeasy 96 kit; Qiagen). Replicon RNA and an internal control (TaqMan rRNA control reagents; Applied Biosystems) were amplified in a single-step multiplex RT-PCR protocol as recommended by the manufacturer. The HCV primers and probe were designed with Primer Express software (Applied Biosystems) and covered highly conserved 5′-untranslated region (UTR) sequences (sense, 5′-AGCCATGGCGTTAGTA(T)GAGTGT-3′, and antisense, 5′-TTCCGCAGACCACTATGG-3′; probe, 5′-FAM-CCTCCAGGACCCCCCCTCCC-TAMRA-3′).
To express the antiviral effectiveness of a compound, the threshold RT-PCR cycle of the test compound was subtracted from the average threshold RT-PCR cycle of the no-drug control (ΔCtHCV). A ΔCt of 3.3 equals a 1-log 10 reduction (equal to the 90% effective concentration [EC90]) in replicon RNA levels. The cytotoxicity of the test compound could also be expressed by calculating the ΔCtrRNA values. The ΔΔCt specificity parameter could then be introduced (ΔCtHCV-ΔCtrRNA), in which the levels of HCV RNA are normalized for the rRNA levels and calibrated against the no-drug control.
1(4-BrPh): 4-bromo—phenyl.
The entire contents of U.S. Provisional Application Nos. 60/909,315, filed Mar. 30, 2007, and 60/982,309, filed Oct. 24, 2007, are hereby incorporated by reference in the present application so far as needed to supplement the present disclosure and/or rectify any errors. Moreover, the patent and non-patent references disclosed herein are incorporated by reference. In the event that the incorporated patent and non-patent reference contains a term that conflicts with a term disclosed in either one of the two Provisional Applications or the present application text, the meaning of the term contained in the present application text and the two Provisional Applications controls provided that the overall meaning of the incorporated subject matter is not lost.
This application is a continuation of U.S. patent application Ser. No. 14/817,318, filed Mar. 12, 2020, now abandoned, which is a continuation of U.S. patent application Ser. No. 16/516,192, filed Jul. 18, 2019, now abandoned, which is a continuation of U.S. patent application Ser. No. 16/169,878, filed Oct. 24, 2018, now abandoned, which is a continuation of U.S. patent application Ser. No. 15/411,506, filed Jan. 20, 2017, now U.S. Pat. No. 10,183,037, which is a continuation of U.S. patent application Ser. No. 14/656,546, filed Mar. 12, 2015, now U.S. Pat. No. 9,585,906, which is a continuation of U.S. patent application Ser. No. 14/013,237, filed Aug. 29, 2013, now U.S. Pat. No. 9,085,573, which is a continuation of U.S. patent application Ser. No. 13/609,614, filed Sep. 11, 2012, now U.S. Pat. No. 8,580,765, which is a continuation of U.S. patent application Ser. No. 13/099,671, filed May 3, 2011, now U.S. Pat. No. 8,334,270, which is a continuation of U.S. patent application Ser. No. 12/053,015, filed Mar. 21, 2008, now U.S. Pat. No. 7,964,580, which claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Nos. 60/909,315, filed Mar. 30, 2007, and 60/982,309, filed Oct. 24, 2007, all of which are hereby incorporated by reference in their entireties. The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3798209 | Witkowski et al. | Mar 1974 | A |
| 3852267 | Meyer, Jr. et al. | Dec 1974 | A |
| RE29835 | Witkowski et al. | Nov 1978 | E |
| 4814477 | Wijnberg et al. | Mar 1989 | A |
| 4957924 | Beauchamp | Sep 1990 | A |
| 5026687 | Yarchoan et al. | Jun 1991 | A |
| 5118820 | Hertel | Jun 1992 | A |
| 5149794 | Yatvin et al. | Sep 1992 | A |
| 5157027 | Biller et al. | Oct 1992 | A |
| 5192549 | Barenolz et al. | Mar 1993 | A |
| 5194654 | Hostetler et al. | Mar 1993 | A |
| 5223263 | Hostetler et al. | Jun 1993 | A |
| 5256641 | Yatvin et al. | Oct 1993 | A |
| 5256798 | Chou et al. | Oct 1993 | A |
| 5372808 | Blatt et al. | Dec 1994 | A |
| 5376380 | Kikuchi et al. | Dec 1994 | A |
| 5405598 | Schinazi et al. | Apr 1995 | A |
| 5411947 | Hostetler et al. | May 1995 | A |
| 5420266 | Britton et al. | May 1995 | A |
| 5426183 | Kjell | Jun 1995 | A |
| 5453499 | Chou et al. | Sep 1995 | A |
| 5462724 | Schinazi et al. | Oct 1995 | A |
| 5463092 | Hostetler et al. | Oct 1995 | A |
| 5496546 | Wang et al. | Mar 1996 | A |
| 5538865 | Reyes et al. | Jul 1996 | A |
| 5543389 | Yatvin et al. | Aug 1996 | A |
| 5543390 | Yatvin et al. | Aug 1996 | A |
| 5543391 | Yatvin et al. | Aug 1996 | A |
| 5554728 | Basava et al. | Sep 1996 | A |
| 5610054 | Draper | Mar 1997 | A |
| 5633358 | Gruetzke et al. | May 1997 | A |
| 5633388 | Diana et al. | May 1997 | A |
| 5676942 | Testa et al. | Oct 1997 | A |
| 5703058 | Schinazi et al. | Dec 1997 | A |
| 5711944 | Gilbert et al. | Jan 1998 | A |
| 5725859 | Omer | Mar 1998 | A |
| 5738845 | Imakawa | Apr 1998 | A |
| 5738846 | Greenwald et al. | Apr 1998 | A |
| 5747646 | Hakimi et al. | May 1998 | A |
| 5767097 | Tam | Jun 1998 | A |
| 5792834 | Hakimi et al. | Aug 1998 | A |
| 5830455 | Valtuena et al. | Nov 1998 | A |
| 5830905 | Diana et al. | Nov 1998 | A |
| 5834594 | Hakimi et al. | Nov 1998 | A |
| 5837257 | Tsai et al. | Nov 1998 | A |
| 5846964 | Ozeki | Dec 1998 | A |
| 5849696 | Chretien et al. | Dec 1998 | A |
| 5869253 | Draper | Feb 1999 | A |
| 5891874 | Colacino et al. | Apr 1999 | A |
| 5905070 | Schinazi et al. | May 1999 | A |
| 5908621 | Glue et al. | Jun 1999 | A |
| 5922757 | Chojkier | Jul 1999 | A |
| 5928636 | Alber et al. | Jul 1999 | A |
| 5942223 | Bazer et al. | Aug 1999 | A |
| 5980884 | Blatt et al. | Nov 1999 | A |
| 5990276 | Zhang et al. | Nov 1999 | A |
| 6004933 | Spruce et al. | Dec 1999 | A |
| 6034134 | Gold et al. | Mar 2000 | A |
| 6043077 | Barber et al. | Mar 2000 | A |
| 6056961 | Lavie et al. | May 2000 | A |
| 6060080 | Kikuchi et al. | May 2000 | A |
| 6090932 | McGee et al. | Jul 2000 | A |
| 6130326 | Ramasamy et al. | Oct 2000 | A |
| 6132763 | Fisher | Oct 2000 | A |
| 6156501 | McGall et al. | Dec 2000 | A |
| 6180134 | Zalipsky et al. | Jan 2001 | B1 |
| 6232300 | Schinazi et al. | May 2001 | B1 |
| 6239159 | Brown et al. | May 2001 | B1 |
| 6348587 | Schinazi et al. | Feb 2002 | B1 |
| 6372883 | Attwood et al. | Apr 2002 | B1 |
| 6391859 | Schinazi et al. | May 2002 | B1 |
| 6410531 | Llinas-Brunet et al. | Jun 2002 | B1 |
| 6420380 | Llinas-Brunet et al. | Jul 2002 | B2 |
| 6455513 | McGuigan et al. | Sep 2002 | B1 |
| 6455690 | Tam et al. | Sep 2002 | B1 |
| 6475985 | Wagner et al. | Nov 2002 | B1 |
| 6479463 | Wang et al. | Nov 2002 | B1 |
| 6495677 | Ramasamy et al. | Dec 2002 | B1 |
| 6509320 | Wang et al. | Jan 2003 | B1 |
| 6534523 | Llinas-Brunet et al. | Mar 2003 | B1 |
| 6552183 | Ramasamy et al. | Apr 2003 | B1 |
| 6555677 | Petrillo et al. | Apr 2003 | B2 |
| 6573248 | Ramasamy et al. | Jun 2003 | B2 |
| 6589941 | Fahrig et al. | Jul 2003 | B1 |
| 6642206 | Ramasamy et al. | Nov 2003 | B2 |
| 6660721 | Devos et al. | Dec 2003 | B2 |
| 6677314 | Klecker et al. | Jan 2004 | B2 |
| 6677315 | Klecker et al. | Jan 2004 | B2 |
| 6680303 | Schinazi et al. | Jan 2004 | B2 |
| 6682715 | Klecker et al. | Jan 2004 | B2 |
| 6683045 | Klecker et al. | Jan 2004 | B2 |
| 6703374 | Klecker et al. | Mar 2004 | B1 |
| 6753309 | Klecker et al. | Jun 2004 | B2 |
| 6777395 | Bhat et al. | Aug 2004 | B2 |
| 6784166 | Devos et al. | Aug 2004 | B2 |
| 6787305 | Li et al. | Sep 2004 | B1 |
| 6787526 | Bryant et al. | Sep 2004 | B1 |
| 6812219 | LaColla et al. | Nov 2004 | B2 |
| 6815542 | Hong et al. | Nov 2004 | B2 |
| 6846810 | Martin et al. | Jan 2005 | B2 |
| 6897201 | Boyer et al. | May 2005 | B2 |
| 6908924 | Watanabe et al. | Jun 2005 | B2 |
| 6911424 | Schinazi et al. | Jun 2005 | B2 |
| 6914054 | Sommadossi et al. | Jul 2005 | B2 |
| 6962991 | Dempcy et al. | Nov 2005 | B2 |
| 7018985 | Boyer et al. | Mar 2006 | B1 |
| 7018989 | McGuigan et al. | Mar 2006 | B2 |
| 7081449 | Pietrzkowski et al. | Jul 2006 | B2 |
| 7105493 | Sommadossi et al. | Sep 2006 | B2 |
| 7105499 | Carroll et al. | Sep 2006 | B2 |
| 7125855 | Bhat et al. | Oct 2006 | B2 |
| 7148206 | Sommadossi et al. | Dec 2006 | B2 |
| 7163929 | Sommadossi et al. | Jan 2007 | B2 |
| 7202224 | Eldrup et al. | Apr 2007 | B2 |
| 7217523 | Wagner | May 2007 | B2 |
| 7268119 | Cook et al. | Sep 2007 | B2 |
| 7307065 | Schinazi et al. | Dec 2007 | B2 |
| 7323453 | Olsen et al. | Jan 2008 | B2 |
| 7365057 | LaColla et al. | Apr 2008 | B2 |
| 7390791 | Becker et al. | Jun 2008 | B2 |
| 7429572 | Clark | Sep 2008 | B2 |
| 7601820 | Wang et al. | Oct 2009 | B2 |
| 7608597 | Sommadossi et al. | Oct 2009 | B2 |
| 7608600 | Storer et al. | Oct 2009 | B2 |
| 7635689 | LaColla et al. | Dec 2009 | B2 |
| 7754699 | Chun et al. | Jul 2010 | B2 |
| 7879815 | MacCoss et al. | Feb 2011 | B2 |
| 7964580 | Sofia et al. | Jun 2011 | B2 |
| 8148349 | Meppen et al. | Apr 2012 | B2 |
| 8173621 | Du et al. | May 2012 | B2 |
| 8334270 | Sofia et al. | Dec 2012 | B2 |
| 8415322 | Clark | Apr 2013 | B2 |
| 8551973 | Bao et al. | Oct 2013 | B2 |
| 8580765 | Sofia et al. | Nov 2013 | B2 |
| 8735372 | Du et al. | May 2014 | B2 |
| 8906880 | Du et al. | Dec 2014 | B2 |
| 8957046 | Du et al. | Feb 2015 | B2 |
| 9085573 | Du et al. | Jul 2015 | B2 |
| 9585906 | Du et al. | Mar 2017 | B2 |
| 20010034440 | Shepard et al. | Oct 2001 | A1 |
| 20020058635 | Averett | May 2002 | A1 |
| 20020198173 | Schinazi et al. | Dec 2002 | A1 |
| 20030050229 | Sommadossi et al. | Mar 2003 | A1 |
| 20030060400 | LaColla et al. | Mar 2003 | A1 |
| 20030109697 | Shepard et al. | Jun 2003 | A1 |
| 20030120071 | McGuigan et al. | Jun 2003 | A1 |
| 20030144502 | Pietrzkowski et al. | Jul 2003 | A1 |
| 20030153744 | Mekouar et al. | Aug 2003 | A1 |
| 20030187018 | Llinas-Brunet et al. | Oct 2003 | A1 |
| 20040006007 | Gosselin et al. | Jan 2004 | A1 |
| 20040014108 | Eldrup et al. | Jan 2004 | A1 |
| 20040023240 | Marliere et al. | Feb 2004 | A1 |
| 20040023901 | Cook et al. | Feb 2004 | A1 |
| 20040059104 | Cook et al. | Mar 2004 | A1 |
| 20040063622 | Sommadossi et al. | Apr 2004 | A1 |
| 20040067901 | Bhat et al. | Apr 2004 | A1 |
| 20040072788 | Bhat et al. | Apr 2004 | A1 |
| 20040097461 | Sommadossi et al. | May 2004 | A1 |
| 20040097462 | Sommadossi et al. | May 2004 | A1 |
| 20040101535 | Sommadossi et al. | May 2004 | A1 |
| 20040102414 | Sommadossi et al. | May 2004 | A1 |
| 20040110717 | Carroll et al. | Jun 2004 | A1 |
| 20040167140 | Schinazi et al. | Aug 2004 | A1 |
| 20040191824 | Dempcy et al. | Sep 2004 | A1 |
| 20040214844 | Otto et al. | Oct 2004 | A1 |
| 20040229839 | Babu et al. | Nov 2004 | A1 |
| 20040229840 | Bhat et al. | Nov 2004 | A1 |
| 20040248892 | Wang | Dec 2004 | A1 |
| 20040254141 | Schinazi et al. | Dec 2004 | A1 |
| 20040259934 | Olsen et al. | Dec 2004 | A1 |
| 20040265969 | Li et al. | Dec 2004 | A1 |
| 20040266996 | Rabi | Dec 2004 | A1 |
| 20050009737 | Clark | Jan 2005 | A1 |
| 20050020825 | Storer et al. | Jan 2005 | A1 |
| 20050026853 | Mekouar et al. | Feb 2005 | A1 |
| 20050031588 | Sommadossi et al. | Feb 2005 | A1 |
| 20050059632 | Storer et al. | Mar 2005 | A1 |
| 20050075309 | Storer et al. | Apr 2005 | A1 |
| 20050080034 | Standring et al. | Apr 2005 | A1 |
| 20050090660 | Watanabe et al. | Apr 2005 | A1 |
| 20050124532 | Sommadossi et al. | Jun 2005 | A1 |
| 20050130931 | Boyer et al. | Jun 2005 | A1 |
| 20050137161 | Sommadossi et al. | Jun 2005 | A1 |
| 20050148534 | Castellino et al. | Jul 2005 | A1 |
| 20050154056 | Yang et al. | Jul 2005 | A1 |
| 20050164960 | Olsen et al. | Jul 2005 | A1 |
| 20050215513 | Boojamra et al. | Sep 2005 | A1 |
| 20050227947 | Chen et al. | Oct 2005 | A1 |
| 20050261237 | Boojamra et al. | Nov 2005 | A1 |
| 20050267018 | Blatt et al. | Dec 2005 | A1 |
| 20060003951 | Mekouar et al. | Jan 2006 | A1 |
| 20060014943 | Dempcy et al. | Jan 2006 | A1 |
| 20060035866 | Cannizzaro et al. | Feb 2006 | A1 |
| 20060040890 | Martin et al. | Feb 2006 | A1 |
| 20060040927 | Blake et al. | Feb 2006 | A1 |
| 20060040944 | Gosselin et al. | Feb 2006 | A1 |
| 20060079478 | Boojamra et al. | Apr 2006 | A1 |
| 20060110727 | McGall et al. | May 2006 | A9 |
| 20060116557 | Moore et al. | Jun 2006 | A1 |
| 20060122146 | Chun et al. | Jun 2006 | A1 |
| 20060122154 | Olsen et al. | Jun 2006 | A1 |
| 20060142238 | McGuigan | Jun 2006 | A1 |
| 20060166964 | Hudyma et al. | Jul 2006 | A1 |
| 20060194749 | Keicher et al. | Aug 2006 | A1 |
| 20060199783 | Wang et al. | Sep 2006 | A1 |
| 20060241064 | Roberts et al. | Oct 2006 | A1 |
| 20060276511 | Serrano-Wu et al. | Dec 2006 | A1 |
| 20060293306 | Beaulieu et al. | Dec 2006 | A1 |
| 20070015905 | LaColla et al. | Jan 2007 | A1 |
| 20070037735 | Gosselin et al. | Feb 2007 | A1 |
| 20070037773 | Sommadossi et al. | Feb 2007 | A1 |
| 20070042939 | LaColla et al. | Feb 2007 | A1 |
| 20070042988 | Klumpp et al. | Feb 2007 | A1 |
| 20070042990 | Gosselin et al. | Feb 2007 | A1 |
| 20070049754 | Boojamra et al. | Mar 2007 | A1 |
| 20070060498 | Gosselin et al. | Mar 2007 | A1 |
| 20070060541 | Gosselin et al. | Mar 2007 | A1 |
| 20070087960 | Storer et al. | Apr 2007 | A1 |
| 20070197463 | Chun et al. | Aug 2007 | A1 |
| 20070225249 | Shi | Sep 2007 | A1 |
| 20070265222 | MacCoss et al. | Nov 2007 | A1 |
| 20070275912 | Bhat et al. | Nov 2007 | A1 |
| 20070275947 | Bergstrom | Nov 2007 | A1 |
| 20080070861 | Clark | Mar 2008 | A1 |
| 20080253995 | Clark | Oct 2008 | A1 |
| 20090004135 | Clark | Jan 2009 | A1 |
| 20090036666 | Clark | Feb 2009 | A1 |
| 20090137521 | Hamilton et al. | May 2009 | A1 |
| 20090176732 | Beigelman et al. | Jul 2009 | A1 |
| 20090233879 | Reddy et al. | Sep 2009 | A1 |
| 20090280084 | Schinazi et al. | Nov 2009 | A1 |
| 20090306007 | Wagner | Dec 2009 | A1 |
| 20100022468 | Meppen et al. | Jan 2010 | A1 |
| 20100029008 | Stutz et al. | Feb 2010 | A1 |
| 20100035835 | Narjes et al. | Feb 2010 | A1 |
| 20100048917 | Wang et al. | Feb 2010 | A1 |
| 20100081628 | Du et al. | Apr 2010 | A1 |
| 20100137576 | Stec et al. | Jun 2010 | A1 |
| 20100152128 | Attenni et al. | Jun 2010 | A1 |
| 20100173863 | Schinazi et al. | Jul 2010 | A1 |
| 20100227801 | Hopkins | Sep 2010 | A1 |
| 20100279973 | Chun et al. | Nov 2010 | A1 |
| 20100286083 | Bao et al. | Nov 2010 | A1 |
| 20100298257 | Ross et al. | Nov 2010 | A1 |
| 20100316594 | Sommadossi et al. | Dec 2010 | A1 |
| 20110015146 | Sofia et al. | Jan 2011 | A1 |
| 20110124592 | McGuigan et al. | May 2011 | A1 |
| 20110245484 | Ross et al. | Oct 2011 | A1 |
| 20110251152 | Ross et al. | Oct 2011 | A1 |
| 20110257122 | Sofia et al. | Oct 2011 | A1 |
| 20120107278 | Berrey et al. | May 2012 | A1 |
| 20120245335 | Clark | Sep 2012 | A1 |
| 20130029929 | Sofia et al. | Jan 2013 | A1 |
| 20130109647 | Berrey et al. | May 2013 | A1 |
| 20130136776 | Cleary et al. | May 2013 | A1 |
| 20130137654 | Ross et al. | May 2013 | A1 |
| 20130165401 | Ross et al. | Jun 2013 | A1 |
| 20130165644 | Ross et al. | Jun 2013 | A1 |
| 20130288997 | Ross et al. | Oct 2013 | A1 |
| 20130310551 | Ross et al. | Nov 2013 | A1 |
| 20180000855 | Du et al. | Jan 2018 | A1 |
| Number | Date | Country |
|---|---|---|
| 101108870 | Jan 2008 | CN |
| 19914474 | Oct 1999 | DE |
| 0180276 | May 1986 | EP |
| 0350287 | Jan 1990 | EP |
| 1828217 | Sep 2007 | EP |
| 1881001 | Jan 2008 | EP |
| 2097430 | Sep 2009 | EP |
| 2124555 | Dec 2009 | EP |
| 2207786 | Jul 2010 | EP |
| 2007505742 | Mar 2007 | JP |
| 5238939 | Jul 2013 | JP |
| WO-8902733 | Apr 1989 | WO |
| WO-9000555 | Jan 1990 | WO |
| WO-9116920 | Nov 1991 | WO |
| WO-9118914 | Dec 1991 | WO |
| WO-9119721 | Dec 1991 | WO |
| WO-9300910 | Jan 1993 | WO |
| WO-9426273 | Nov 1994 | WO |
| WO-9513090 | May 1995 | WO |
| WO-9524185 | Sep 1995 | WO |
| WO-9615132 | May 1996 | WO |
| WO-9629336 | Sep 1996 | WO |
| WO-9632403 | Oct 1996 | WO |
| WO-9712033 | Apr 1997 | WO |
| WO-9736554 | Oct 1997 | WO |
| WO-9816184 | Apr 1998 | WO |
| WO-9817679 | Apr 1998 | WO |
| WO-9822496 | May 1998 | WO |
| WO-9907734 | Feb 1999 | WO |
| WO-9915194 | Apr 1999 | WO |
| WO-9932139 | Jul 1999 | WO |
| WO-9932140 | Jul 1999 | WO |
| WO-9937753 | Jul 1999 | WO |
| WO-9943691 | Sep 1999 | WO |
| WO-9959621 | Nov 1999 | WO |
| WO-9964016 | Dec 1999 | WO |
| WO-0006529 | Feb 2000 | WO |
| WO-0009531 | Feb 2000 | WO |
| WO-0037110 | Jun 2000 | WO |
| WO-0107454 | Feb 2001 | WO |
| WO-0132153 | May 2001 | WO |
| WO-0160315 | Aug 2001 | WO |
| WO-0179246 | Oct 2001 | WO |
| WO-0181359 | Nov 2001 | WO |
| WO-0190121 | Nov 2001 | WO |
| WO-0191737 | Dec 2001 | WO |
| WO-0192282 | Dec 2001 | WO |
| WO-0196353 | Dec 2001 | WO |
| WO-0208187 | Jan 2002 | WO |
| WO-0208198 | Jan 2002 | WO |
| WO-0208241 | Jan 2002 | WO |
| WO-0208251 | Jan 2002 | WO |
| WO-0208256 | Jan 2002 | WO |
| WO-0218404 | Mar 2002 | WO |
| WO-0232414 | Apr 2002 | WO |
| WO-0232920 | Apr 2002 | WO |
| WO-0248116 | Jun 2002 | WO |
| WO-0248157 | Jun 2002 | WO |
| WO-0248165 | Jun 2002 | WO |
| WO-0248172 | Jun 2002 | WO |
| WO-02057287 | Jul 2002 | WO |
| WO-02057425 | Jul 2002 | WO |
| WO-02060926 | Aug 2002 | WO |
| WO-02100415 | Dec 2002 | WO |
| WO-03000713 | Jan 2003 | WO |
| WO-03006490 | Jan 2003 | WO |
| WO-03010141 | Feb 2003 | WO |
| WO-03024461 | Mar 2003 | WO |
| WO-03026589 | Apr 2003 | WO |
| WO-03037895 | May 2003 | WO |
| WO-03051899 | Jun 2003 | WO |
| WO-03053989 | Jul 2003 | WO |
| WO-03061576 | Jul 2003 | WO |
| WO-03062256 | Jul 2003 | WO |
| WO-03064456 | Aug 2003 | WO |
| WO-03068244 | Aug 2003 | WO |
| WO-031 04250 | Dec 2003 | WO |
| WO-031 05770 | Dec 2003 | WO |
| WO-031 06477 | Dec 2003 | WO |
| WO-03101993 | Dec 2003 | WO |
| WO-2004000858 | Dec 2003 | WO |
| WO-2004002422 | Jan 2004 | WO |
| WO-2004002940 | Jan 2004 | WO |
| WO-2004002944 | Jan 2004 | WO |
| WO-2004002977 | Jan 2004 | WO |
| WO-2004002999 | Jan 2004 | WO |
| WO-2004003000 | Jan 2004 | WO |
| WO-2004003138 | Jan 2004 | WO |
| WO-2004007512 | Jan 2004 | WO |
| WO-2004009020 | Jan 2004 | WO |
| WO-2004009610 | Jan 2004 | WO |
| WO-2004011478 | Feb 2004 | WO |
| WO-2004014313 | Feb 2004 | WO |
| WO-2004014852 | Feb 2004 | WO |
| WO-2004035571 | Apr 2004 | WO |
| WO-2004041201 | May 2004 | WO |
| WO-2004046331 | Jun 2004 | WO |
| WO-2004065367 | Aug 2004 | WO |
| WO-2004080466 | Sep 2004 | WO |
| WO-2004094452 | Nov 2004 | WO |
| WO-2004096210 | Nov 2004 | WO |
| WO-2004096234 | Nov 2004 | WO |
| WO-2004096235 | Nov 2004 | WO |
| WO-2004096286 | Nov 2004 | WO |
| WO-2004106356 | Dec 2004 | WO |
| WO-2004113360 | Dec 2004 | WO |
| WO-2005002626 | Jan 2005 | WO |
| WO-2005003147 | Jan 2005 | WO |
| WO-2005003147 | Jan 2005 | WO |
| WO-2005007810 | Jan 2005 | WO |
| WO-2005009418 | Feb 2005 | WO |
| WO-2005012327 | Feb 2005 | WO |
| WO-2005020884 | Mar 2005 | WO |
| WO-2005021568 | Mar 2005 | WO |
| WO-2005028502 | Mar 2005 | WO |
| WO-2005030891 | Apr 2005 | WO |
| WO-2005037214 | Apr 2005 | WO |
| WO-2005067900 | Jul 2005 | WO |
| WO-2005072361 | Aug 2005 | WO |
| WO-2005082144 | Sep 2005 | WO |
| WO-2005087788 | Sep 2005 | WO |
| WO-2005095403 | Oct 2005 | WO |
| WO-2005103045 | Nov 2005 | WO |
| WO-2005123087 | Dec 2005 | WO |
| WO-2006000922 | Jan 2006 | WO |
| WO-2006012078 | Feb 2006 | WO |
| WO-2006012440 | Feb 2006 | WO |
| WO-2006020082 | Feb 2006 | WO |
| WO-2006029081 | Mar 2006 | WO |
| WO-2006031725 | Mar 2006 | WO |
| WO-2006035061 | Apr 2006 | WO |
| WO-2006037028 | Apr 2006 | WO |
| WO-2006050161 | May 2006 | WO |
| WO-2006063149 | Jun 2006 | WO |
| WO-2006063717 | Jun 2006 | WO |
| WO-2006065335 | Jun 2006 | WO |
| WO-2006065590 | Jun 2006 | WO |
| WO-2006067606 | Jun 2006 | WO |
| WO-2006093801 | Sep 2006 | WO |
| WO-2006100310 | Sep 2006 | WO |
| WO-2006116557 | Nov 2006 | WO |
| WO-2006120251 | Nov 2006 | WO |
| WO-2006120252 | Nov 2006 | WO |
| WO-2006121820 | Nov 2006 | WO |
| WO-2007002602 | Jan 2007 | WO |
| WO-2007014920 | Feb 2007 | WO |
| WO-2007014921 | Feb 2007 | WO |
| WO-2007014922 | Feb 2007 | WO |
| WO-2007014925 | Feb 2007 | WO |
| WO-2007014926 | Feb 2007 | WO |
| WO-2007015824 | Feb 2007 | WO |
| WO-2007020193 | Feb 2007 | WO |
| WO-2007027248 | Mar 2007 | WO |
| WO-2007039142 | Apr 2007 | WO |
| WO-2007039145 | Apr 2007 | WO |
| WO-2007065829 | Jun 2007 | WO |
| WO-2007070556 | Jun 2007 | WO |
| WO-2007076034 | Jul 2007 | WO |
| WO-2007088148 | Aug 2007 | WO |
| WO-2007092000 | Aug 2007 | WO |
| WO-2007093901 | Aug 2007 | WO |
| WO-2007095269 | Aug 2007 | WO |
| WO-2008010921 | Jan 2008 | WO |
| WO-2008045419 | Apr 2008 | WO |
| WO-2008048128 | Apr 2008 | WO |
| WO-2008062206 | May 2008 | WO |
| WO-2008079206 | Jul 2008 | WO |
| WO-2008082601 | Jul 2008 | WO |
| WO-2008085508 | Jul 2008 | WO |
| WO-2008104408 | Sep 2008 | WO |
| WO-2008121634 | Oct 2008 | WO |
| WO-2008142055 | Nov 2008 | WO |
| WO-2009052287 | Apr 2009 | WO |
| WO-2009115893 | Sep 2009 | WO |
| WO-2009120878 | Oct 2009 | WO |
| WO-2009129120 | Oct 2009 | WO |
| WO-2009152095 | Dec 2009 | WO |
| WO-2010009121 | Jan 2010 | WO |
| WO-2010042834 | Apr 2010 | WO |
| WO-2010075554 | Jul 2010 | WO |
| WO-2010080878 | Jul 2010 | WO |
| WO-2011123645 | Oct 2011 | WO |
| Entry |
|---|
| Perrone et al. J. Med. Chem. (2007), vol. 50, pp. 1840-1849. |
| U.S. Appl. No. 60/392,350, filed Jun. 28, 2002, Storer. |
| U.S. Appl. No. 60/392,351, filed Jun. 28, 2002, Gosselin. |
| U.S. Appl. No. 60/909,315, filed Mar. 30, 2007, Sofia et al.. |
| U.S. Appl. No. 60/982,309, filed Oct. 24, 2007, Sofia et al.. |
| Abraham et al., “Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-fluoro-2′deoxyuridine and 1-beta-Arabinofuranosylcytosine: Evidence of Phosphoramidase Activity,” J. Med. Chem., vol. 39, No. 23, pp. 4569-4575, (1996). |
| Abraham et al., “Synthesis, Biological Activity and Decomposition Studies of Amino Acid Phosphomonoester Amidates of Acyclovir,” Nucleosides, Nucleotides and Nucleic Acids, vol. 16, No. 10, pp. 2079-2092 (1997). |
| Abstract, 100, presented at the 19th International Conference of Antiviral Research, May 7-11, 2006. |
| Aquaro et al., “Activities of Masked 2′,3′-Dideoxynucleoside Monophosphate Derivaties Against Human Immunodeficiency Virus in Resting Macrophages,” Antimicrobial Agents and Chemotherapy, vol. 44, No. 1, pp. 173-177 (2000). |
| Arnold, et al. Sensitivity of mitochondrial transcription and resistance of RNA polymerase II dependent nuclear transcription to antiviral ribonucleosides. PLoS Pathog. 2012; 8(11): e1003030. doi: 10.1371/journal.ppat.1003030. Epub Nov. 15, 2012. |
| Asif et al., “Pharmacokinetics of the Antiviral Agent B-D-2′-Deoxy-2′-Fluoro-2′-C-Methylcytidine in Rhesus Monkeys,” Antimicrobial Agents and Chemotherapy, vol. 51, No. 8, pp. 2877-2882 (2007). |
| Balzarini et al., Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives, Proc. Natl. Acad. Sci., vol. 93, pp. 7295-7299 (1996). |
| Banker et al., “Prodrugs,” Modern Pharmaceutics, Third Edition, Revised and Expanded, pp. 451 and 596 (1996). |
| Bartenschlager et al., “Kinetic and Structural Analyses of Hepatitis C Virus Polyprotein Processing,” J. Virol., vol. 68, No. 8, pp. 5045-5055 (1994). |
| Bartenschlager et al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., vol. 67, No. 7, pp. 3835-3844 (1993). |
| Baschang et al., “Neue Derivate von Thymidin-3′,5′-cyclophosphat,” Angew. Chem., vol. 85, No. 1, pp. 44-45 (1973). |
| Battaglia et al., “Combination Therapy with Interferon and Ribavirin in the Treatment of Chronic Hepatitis C Infection,” The Annals of Pharmacotherapy, vol. 34, No. 4, pp. 487-494 (2000). |
| Bazan et al., “Detection of a Trypsin-like Serine Protease Domain in Flaviviruses and Pestiviruses,” Virology, vol. 171, pp. 637-639 (1989). |
| Beaulieu et al., “Inhibitors of the HCV NS5B polymerase: New hope for the treatment of hepatitis C infections,” Current Opinion in Investigational Drugs, vol. 5, No. 8, pp. 838-850 (2004). |
| Behrens et al., “Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus,” The EMBO Journal, vol. 15, No. 1, pp. 12-22 (1996). |
| Berenguer, M., “Hepatitis C virus in the transplant setting,” Antiviral Therapy, vol. 3, Supplement 3, pp. 125-136 (1998). |
| Bhat et al., “Synthesis and Pharmacokinetic Properties of Nucleoside Analogues as Possible Inhibitors of HCV RNA Replication,” (Oral Session V: Hepatitis C Virus, Flaviviruses), 16th International Conference on Antiviral Research, Abstract No. 120, p. A75 (Apr. 27-May 1, 2003). |
| Board Opinion dated Jan. 12, 2017 for Chinese Application No. 200880018024.2. |
| Broeders et al., “A 400-and 600-Mhz 'H NMR Confromational Study on Nucleoside Cyclic 3′, 5′PV-TBP Systems. Conformational Transmission Induces Diequatorial Orientation of the 3′, 5′-Dioxaphosphorinane Ring in a Nonchair Confirmation,” J. Am. Chem. Soc., vol. 112, No. 21, pp. 7475-7482 (1990). |
| Cahard, Dominique, et al., Aryloxy Phosphoramidate Triesters as Pro-Tides, Mini-Reviews in Medicinal Chemistry (2004), 4, 371-381. |
| Calisher et al., “Antigenic Relationships between Flaviviruses as Determined by Cross-neutralization Tests with Polyclonal Antisera,” J. Gen. Virol., vol. 70, pp. 37-43 (1989). |
| Carroll et al., “Nucleoside Analog Inhibitors of Hepatitis C Virus Replication,” Infectious Disorders—Drug Targets, vol. 6, No. 1, pp. 17-29 (2006). |
| Chang et al., “Amino Acid Phosphoramidate Monoesters of 3′-Azido-3′-deoxythymidine: Relationship between Antiviral Potency and Intracellular Metabolism,” J. Med. Chem., vol. 44, No. 2, pp. 223-231 (2001). |
| Chang et al., “Deoxyctidine-resistant Stereoisomer Is the Active Form of (±)-2′,3'-Dideoxy-3′-thiacytidine in the Inhibition of Hepatitis B Virus Replication,” J. Bio. Chem, (1992), 267(20):13938-13942. |
| Chapman et al., “Practical Synthesis, Separation, and Stereochemical Assignment of the PMPA Pro-Drug GS-7340,” Nucleosides, Nucleotides & Nucleic Acids, vol. 20, No. 4-7, pp. 621-628 (2001). |
| Chapman et al., “Purification of PMPA Amidate Prodrugs by SMB Chromatography and X-Ray Crystallography of the Diastereomerically Pure GS-7340,” Nucleosides, Nucleotides & Nucleic Acids, vol. 20, No. 4-7, pp. 1085-1090 (2001). |
| Chen et al., “In Vivo Pharmacokinetics and Metabolism of Anti-Human Immunodeficiency Virus Agent D4t-5′-[P-Bromophenyl Methoxyalaninyl Phosphate] (Sampidine) in Mice,” Drug Metabolism and Disposition, vol. 29, No. 7, pp. 1035-1041 (2001). |
| Chen et al., “Metabolism of Stavudine-5′-[P-Bromophenyl Methoxyalaninyl Phosphate], Stampidine, in Mice, Dogs, and Cats,” Drug Metabolism and Disposition, vol. 30, No. 12, pp. 1523-1531 (2002). |
| Chou et al., “Evidence that Human Histidine Triad Nucleotide Binding Protein 3 (Hint3) is a Distinct Branch of the Histidine Triad (HIT) Superfamily,” J. Mol. Biol., vol. 373, pp. 978-989 (2007). |
| Chou et al., “Phosphoramidate Pronucleotides: A Comparison of the Phosphoramidase Substrate Specificity of Human and Escherichia coli Histidine Triad Nucleotide Binding Proteins,” Molecular Pharmaceutics, vol. 4, No. 2, pp. 208-217 (2006). |
| Chu et al., “Isolation and Structure of SCH 351633: A Novel Hepatitis C Virus (HCV) NS3 Protease Inhibitor from the Fungus Penicillium griseofulvum,” Bioorg. & Med. Chem. Lett., vol. 9, pp. 1949-1952 (1999). |
| Chu et al., “Structure of Sch 68631: A New Hepatitis C Virus Proteinase Inhibitor from Streptomyces sp.” Tet. Lett., vol. 37, No. 40, pp. 7229-7232 (1996). |
| Cihlar et al. “Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131,” Antimicrobial Agents and Chemotherapy, vol. 52, No. 2, pp. 655-665 (2008). |
| Clark et al., “Design, Synthesis, and Antiviral Activity of 2′-Deoxy-2′-fluoro-2′-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication,” J. Med. Chem., vol. 48, No. 17, pp. 5504-5508 (2005). XP002415215. |
| Clark et al., “Synthesis and antiviral activity of 2′-deoxy-2′-fluro-2′-C-methyl purine nucleosides as inhibitors of hepatitis C virus RNA replication”, Bioorganic & Medicinal Chemistry Letters, Pergamon, Amsterdam, NL, vol. 16, No. 6, Mar. 15, 2006 (Mar. 15, 2006), pp. 1712-1715, XP027966449, ISSN: 0960-894X. |
| Clayden et al., Organic Chemistry, OUP, 2005, cover page and pp. 48-49. |
| Codington, et al., “NucleosiDE-s. XVIII. Synthesis of 2′-Fluorothymidine, 2′-FluoroDE-oxyuridine, and Other 2′-Halogeno-2′-DE-oxy NucleosiDE-s 1′2”, The Division of Nucleoprotein Chemistry, Sloan-Kettering Institute for Cancer Research, Sloan-Kettering Division of Cornell University Medical Colleg, New York 21, New York, vol. 29, pp. 558-564, (1963). |
| Cole et al., R-7128: RNA-directed RNA polymerase (NS5B) inhibitor treatment of hepatitis C virus infection, Drugs of the Future 2009, 34(4):282-290. |
| Communication pursuant to Rules 70(2) and 70a(2) EPC and reference to Rule 39(1) EPC for European Application No. 14179593.0 dated Jan. 19, 2015. |
| Congiatu et al. “Molecular Modeling Studies on the Binding of Some Protides to the Putative Human Phosphoramidase Hint1,” Nucleosides, Nucleotides and Nucleic Acids, vol. 26, pp. 1121-1124 (2007). |
| Congiatu et al., “Naphthyl Phosphoramidate Derivatives of BVdU as Potential Anticancer Agents: Design, Synthesis and Biological Evaluation,” Nucleosides, Nucleotides, and Nucleic Acids, vol. 24, No. 5-7, pp. 485-489 (2005). |
| Congiatu et al., Novel potential anticancer naphthyl phosphoramidates of BVdU: separation of diastereoisomers and assignment of the absolute configuration of the phosphorus center. Journal of Medicinal Chemistry 2006, 49(2):452-455. |
| Curley et al., “Synthesis and anti-HIV evaluation of some phosphoramidate derivatives of AZT: studies on the effect of chain elongation on biological activity,” Antiviral Research, vol. 14, pp. 345-356 (1990). |
| D'Cruz et al., “Stampidine: a selective oculo-genital microbicide,” Journal of Antimicrobial Chemotherapy, vol. 56, pp. 10-19 (2005). |
| Davis, G. L., “Current Therapy for Chronic Hepatitis C,” Gastroenterology, vol. 118, No. 2, pp. S104-S114 (2000). |
| De Francesco et al., Challenges and successes in developing new therapies for hepatitis C. Nature 2005; 436(7053):953-960. |
| De Lombaert et al., “N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (Nep, EC 3.4.24.11) Inhibitors,” J. Med. Chem., vol. 37, No. 4, pp. 498-511 (1994). |
| Drontle et al., “Designing a Pronucleotide Stratagem: Lessons from Amino Acid Phosphoramidates of Anticancer and Antiviral Pyrimidines,” MiniReviews in Medicinal Chemistry, vol. 4, No. 4, pp. 409-419 (2004). |
| Dumez, Darin, et al., “Large-Scale Synthesis and Formulation of GMP-Grade Stampidine, a New Anti-HIV Agent,” Arzneim.-Forsch./Drug Res. (2006); 56(2a):136-151. |
| Dykens et al., Strategies to reduce late-stage drug attrition due to mitochondrial toxicity. Expert Rev Mol Diagn. 2007; 7(2):161-175. |
| Eckart et al., “The Hepatitis C Virus Encodes a Serine Protease Involved in Processing of the Putative Nonstructural Proteins from the Viral Polyprotein Precursor,” Biochemical and Biophysical Research Communications, vol. 192, No. 2, pp. 399-406 (1993). |
| Edmundson et al., “Cyclic Organophosphorus Compounds. Part 23. Configurational Assignments in the 4-Phenyl-1,3,2-dioxaphosphorinane Series. X-Ray Molecular Structure of cis-2-Benzylamino-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide,” J. Chem. Research (S), pp. 122-123 (1989). |
| Egron et al., “S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs” J. Med. Chem., vol. 46, No. 21, pp. 4564-4571 (2003). |
| Eisenberg et al., “Metabolism of GS-7340, a Novel Phenyl Monophosphoramidate Intracellular Prodrug of PMPA, in Blood,” Nucleosides, Nucleotides & Nucleic Acids, vol. 20, No. 4-7, pp. 1091-1098 (2001). |
| Eldrup et al., “Oral Session V: Hepatitis C Virus, Flaviviruses,” Program and Abstracts, The Sixteenth International Conference on Antiviral Research, p. A75, Abstract 119 (Apr. 27 to May 1, 2003). |
| Eldrup et al., “Structure-Activity Relationship of Purine Ribonucleosides for Inhibition of Hepatitis C Virus RNA-Dependent RNA Polymerase,” J. Med. Chem., vol. 47, No. 9, pp. 2283-2295 (2004). |
| EMA Press Release. European Medicines Agency recommends approval of sofosbuvir for the treatment of chronic hepatitis C dated Nov. 22, 2013. |
| Engels et al., “Ctclophosphate, III. Synthese and Eignschaften von Uridin-3′,5′-cyclophosphat-estern,” Chemische Berichte, vol. 110, No. 6, pp. 2019-2027 (1977). |
| English Translation of Office Action for Israeli Application No. 222810 dated Jan. 4, 2015. |
| English Translation of Office Action for Korean Application No. 10-2009-7022652 dated Dec. 19, 2013. |
| English Translation of Office Action in Mexican Application No. MX/A/2012/000289 dated Jan. 22, 2015. |
| English Translation of Office Action in Mexican Application No. MX/A/2012/000289 dated Oct. 30, 2014. |
| Examination Report for Australian Patent Application No. 2019203002 dated Apr. 20, 2020. 5 pages. |
| Extended European Search Report for European Patent Application No. 14169060.2 dated Oct. 10, 2014. 9 pages. |
| Extended European Search Report for European Patent Application No. 14179593.0 dated Dec. 17, 2014. 7 pages. |
| Extended Search Report for European Application No. 14151876.1 dated Sep. 18, 2014. |
| Failla et al., “Both NS3 and NS4A are Required for Proteolytic Processing of Hepatitis C Virus Nonstructural Proteins,” J. Virol., vol. 68, No. 6, pp. 3753-3760 (1994). |
| Farquhar et al., “Synthesis and Biological Evaluation of Neutral Derivatives of 5-Fluoro-2′-deoxyuridine 5′-Phosphate,” J. Med. Chem., vol. 26, No. 8, pp. 1153-1158 (1983). |
| Farquhar et al., “Synthesis of Biological Evaluation of 9[5′-(2-Oxo-1,3,2-oxazaphosphorinan-2-yl)-beta-D-arabinosyl] adenine and 9[5′-(2-Oxo-1,3,2-dioxaphosphorinan-2-yl)-beta-D-arabinosyl]adenine: Potential Neutral Precursors of 9-[beta-D-Arabinofuranosyl]adenine 5′-Monophosphate,” J. Med. Chem., vol. 28, No. 9, pp. 1358-1361 (1985). |
| FDA Consumer Health Information leaflet, “Faster Easier Cures for Hepatitis C”, Jul. 2014. |
| FDA Guidance for Industry Antiviral Product Development—Conducting and Submitting Virology Studies to the Agency, Jun. 2006. |
| Feng et al., Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus. Antimicrob Agents Chemother. Accepted: Nov. 23, 2015; Printed Feb. 2016; 60(2): pp. 806-817. |
| Final Rejection for Brazilian Patent Application No. PI0809654-6 dated Dec. 28, 2020. 2 pages. |
| Freed et al., “Evidence for acyloxymethyl esters of pyrimidine 5′-deoxyribonucleotides as extracellular sources of active 5′-deoxyribonucleotides in cultured cells,” Biochemical Pharmacology, vol. 38, No. 19, pp. 3193-3198 (1989). |
| Furman et al., PSI-7851: A Novel Liver-Targeting Nucleotide Prodrug for the Treatment of Hepatitis C. Poster Presented at 59th Annual Meeting of the American Association for the Study of Liver Diseases, Oct. 31 to Nov. 4, 2008. |
| Furman et al., “The Anti-Hepatitis B Virus Activities, Cytoxicities, and Anabolic Profiles of the (−) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymenthyl)-1,3-Ozathiolan-5-yl]Cytosine,” Antimicrobial Agents and Chemotherapy, (1992), 36(2):2686-2692. |
| Furman et al., Discovery and Development of PSI-6130/RG7128, Antiviral Drugs: From Basic Discovery through Clinical Trials, Edited by Wieslaw M. Kazmierski. Published 2011; pp. 305-315. |
| Ghany et al., Diagnosis, management, and treatment of hepatitis C: An update. Hepatology, Apr. 2009, 49(4), pp. 1335-1374. doi/10.1002/hep.22759. |
| Gillespie, S., et al., “Stereoselective Inhibition of Cholesterol Esterase by Enantiomeric Phosphonates,” Phosphorous, Sulfur and Silicon, 1997, 122: 205-208. |
| Goekjian et al., “Synthesis of Fluorinated Marcocyclic Bis(indolyl)maleimides as Potential 19F NMR Probes for Protein Kinase C,” J. Org. Chem. vol. 64., No. 12, pp. 4238-4246 (1999). |
| Gorbalenya et al., “A conserved NTP-motif in putative helicases,” Nature, vol. 333, p. 22 (1988). |
| Gorbalenya et al., “N-terminal domains of putative helicases of flavi-and pestiviruses may be serine proteases,” Nucleic Acids Research, vol. 17, No. 10, pp. 3889-3897 (1989). |
| Grakoui et al., “A second hepatitis C virus-encoded proteinase,” Proc. Natl. Acad. Sci., vol. 90, pp. 10583-10587 (1993). |
| Grakoui et al., “Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Clevage Sites,” J. Virol., vol. 67, No. 5, pp. 2832-2843 (1993). |
| Griffith et al., “HCV Anti-viral Agents,” Annual Reports in Medicinal Chemistry, vol. 39, pp. 223-237 (2004). |
| Gromova et al., “Optical Rotatory Dispersion and Circular Dichroism of Mono- and Oligonucleotide-Amino Acids (Amidates),”Biochim. Biophys. Acta., vol. 240, No. 1, pp. 1-11 (1971). |
| Gudmundsson et al., Phosphoramidate protides of 2′,3′-dideoxy-3′-fluoroadenosine and related nucleosides with potent activity against HIV and HBV. Nucleosides Nucleotides Nucleic Acids. 2003, 22(10):1953-1961. |
| Gudmundsson, Kristjan S., et al., “Phosphoramidate Protides of Carbocyclic 2′,3′-Dideoxy-2′,3′-Didehydro-7-Deazaadenosine with Potent Activity Against HIV and HBV,” Nucleosides, Nucleotides & Nucleic Acids (2004), 23(12): 1929-1937. |
| Guinic et al.,“Cyclic monophosphate prodrugs of base=modified 2′-C-methyl ribonucleosides as potent inhibitors of hepatitis C virus RNA replicaion,” Bioorg Med Chem Lett., (2007), 17(9):2456-2458. |
| Gunic et al., “6-Hydrazinopurine 2′-methyl ribonucleosides and their 5′-monophosphate prodrugs as potent hepatitis C virus inhibitors,” Bioorg. & Med. Chem. Lett., vol. 17, pp. 2456-2458 (2007). |
| Halstead, S. B., “Pathogenesis of Dengue: Challenges to Molecular Biology,” Science, vol. 239, pp. 476-481 (1988). |
| Halstead, S. B., “Selective Primary Health Care: Strategies for Control of Disease in the Developing World. XI. Dengue,” Review of Infectious Diseases, vol. 6, No. 2, pp. 251-263 (1984). |
| Harris et al., “Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2′-deoxyuridine,” Antiviral Chemistry & Chemotherapy, vol. 12, No. 5, pp. 293-300 (2001). |
| Hernandez et al., “Synthesis of Highly Functionalized Chiral Nitriles by Radical Fragmentation of beta-Hydroxy Azides. Convenient Transformation of Aldononitriles into 1,4- and 1,5-Iminoalditols,” J. Org. Chem., vol. 69, No. 24, pp. 8437-8444 (2004). |
| Hertel et al., “Synthesis of 2-Deoxy-2,2-difluoro-D-ribose and 2-Deoxy-2,2-difluoro-D-ribofuranosyl Nucleosides,” J. Org. Chem., vol. 53, No. 11, pp. 2406-2409 (1988). |
| Hijikata et al., “Two Distinct Proteinase Activities required for the Processing of a Putative Nonstructural Precursor Protein of Hepatitis C Virus,” J. Virol., vol. 67, No. 8, pp. 4665-4675 (1993). |
| Hostetler et al., “Greatly Enhanced Inhibition of Human Immunodeficiency Virus Type 1 Replication in CEM and HT4-6C Cells by 3′-Deoxythymidine Diphosphate Dimyristoylglycerol, a Lipid Prodrug of 3′-Deoxythymidine,” Antimicrobial Agents and Chemotherapy, vol. 36, No. 9, pp. 2025-2029 (1992). |
| Hostetler et al., “Synthesis and Antiretroviral Activity of Phospholipid Analogs of Azidothymidine and Other Antiviral Nucleosides,” J. Biol. Chem., vol. 265, No. 11, pp. 6112-6117 (1990). |
| Howes et al., “The Regiospecific One-Pot Phosphorylation of Either the 5′-or 2′-Hydroxyl in 3′-Deoxycytidines Without Protection: Critical Role of the Base,” Nucleosides, Nucleotides, and Nucleic Acids, vol. 22, No. 5-8, pp. 687-689 (2003). |
| Hrebabecky et al. ,“1-(3,5-0-alkyliDE-ne-2-DE-oxy-4-C-hydroxymethyl-alpha-L-threo-pentofuranosyl) uracils,” Collect. Czhech. Chem. Commun., vol. 62, pp. 957-970, (1997). |
| Hrebabecky, et al., “Synthesis of 1-(3-azido-2,3-dideoxy-4-C-hydroxymethyl-alpha-L-threopentofuranosyl)thymine, 1-(2,3-dideoxy-4-C-hydroxy-methyl-alpha-L-glycero-pentofuranosyl)thymine and 1-(2,3-dideoxy-4-C-hydroxymethyl-alpha-L-glycero-pent-2-enofuranosyl)thymine,” Collect Czech. Chem. Commun., vol. 58, pp. 409-420, (1992). |
| Hrebabecky, et al., “Synthesis of 1-(3-azido-2,3-dideoxy-β-D-allofuranosyl)thymine, 1-(2,3-dideoxy-β-D-allofuranosyl)thymine, and 1-(2,3-dideoxy-β-D-erythro-hex-2-enofuranosyl)thymine,” Carbohydrate Research, 1991, vol. 216, pp. 179-186. |
| Hrebabecky et al., Synthesis of 1-(3-Azido-2,3-dideoxy-β-D-ribo-hexofuranosyl)-, 1-(2,3-Dideoxy-β-D-erythro-hexofuranosyl)- and 1-(2,3-Dideoxy-β-D-erythro-hex-2-enofuranosyl)pyrimidine Nucleosides. Collect. Czech. Chem. Commun. 1994, vol. 59, pp. 412-420. |
| Huheey et al., Inorganic Chemistry: Principles of Structure and Reactivity. Fourth Edition. HarperCollins College Publishers 1993, cover page and pp. 233-234. |
| Hunston et al., “Synthesis and Biological Properties of Some Cyclic Phosphotriesters Derived from 2′-Deoxy-5-fluorouridine,” J. Med. Chem., vol. 27, No. 4, pp. 440-444 (1984). |
| International Preliminary Report on Patentability and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2008/058183 dated Apr. 7, 2010. (17 pages). |
| International Search Report and Written Opinion of the International Searching Authority issued in International Application No. PCT/US2008/058183 dated Mar. 31, 2010. |
| Iyer et al., “Synthesis, in Vitro Anti-Breast Cancer Activity, and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3′-Azido-3′-deoxythymidine (AZT),” J. Med. Chem., vol. 43, No. 11, pp. 2266-2274 (2000). |
| Jin et al., “Expression, Isolation, and characterization of the Hepatitis C Virus ATPase/RNA Helicase,” Archives of Biochemistry and Biophysics, vol. 323, No. 1, pp. 47-53 (1995). |
| Jones et al., “Minireview: Nucleotide Prodrugs,” Antiviral Research, vol. 27, No. 1-2, pp. 1-17 (1995). |
| Juodka et al., “Oligonucleotides and Nucleotide-Peptides. XXXIV. Synthesis and Some Properties of Complex Nucleotidyl (Oligonucleotidyl)-P-N)-Amino Acids (Peptides) and Their Ethyl Esters,” J. Carbohydrates Nucleosides Nucleotides, vol. 6, No. 4, pp. 333-357 (1979). |
| Juodka et al., “Oligonucleotides and Nucleotide-Peptides. XXXV. Some Properties of Nucleotidyl-(5′-N)-Amino Acid Esters Differing in Amino Acid and Nucleotide Components,” J. Carbohydrates Nucleosides Nucleotides, vol. 8, No. 1, pp. 19-39 (1981). |
| Juodka et al., “Oligonucleotides and Nucleotide-Peptides. XXXVII. On the Mechanism of Hydrolysis of Uridylyl-(5′-N)-Amino Acids. IntramolecuLar Catalysis by the alpha-Carboxyl Group of Amino Acids,” J. Carbohydrates Nucleosides Nucleotides, vol. 8, No. 6, pp. 519-535 (1981). |
| Kaplan. Propagation of hepatitis C virus infection: Elucidating targets for therapeutic intervention. Drug Discovery Today: Disease Mechanisms 2006, 3(4), pp. 471-477. |
| Karen Weinstock at the FDA Communication. Dated Jul. 15, 2015. |
| Khamnei et al., “Neighboring Group Catalysis in the Design of Nucleotide Prodrugs,” J. Med. Chem., vol. 39, No. 20, pp. 4109-4115 (1996). |
| Kim et al., “C-Terminal Domain of the Hepatitis C Virus NS3 Protein Contains an RNA Helicase Activity,” Biochemical and Biophysical Research Communications, vol. 215, No. 1, pp. 160-166 (1995). |
| Kim et al., “Direct Measurement of Nucleoside Monophosphate Delivery from a Phosphoramidate Pronucleotide by Stable Isotope Labeling and LC-ESI—MS/MS,” Molecular Pharmaceutics, 2004, 1(2), pp. 102-111. |
| Kim et al., “Monitoring the Intracellular Metabolism of Nucleoside Phosphoramidate Pronucleotides by 31P NMR,” Nucleosides, Nucleotides and Nucleic Acid, vol. 23, No. 1 & 2, pp. 483-493 (2004). |
| Klebl et al., Host Cell Targets in HCV Therapy: Novel Strategy or Proven Practice?, Antiviral Chemistry and Chemotherapy 2005, 16, pp. 69-90. |
| Klumpp, et al., “The Novel Nucleoside Analog R1479(4′-Azidocytidine) Is a Potent Inhibitor of NS5B-dependent RCA Synthesis and Hepatitis C Virus Replication in Cell Culture,” J. Bio. Chem., (2006), 281:3793-3799. |
| Koonin et al., “Evolution and Taxonomy of Positive-Strand RNA Viruses: Implications of Comparatives Analysis of Amino Acid Sequences,” Critical Reviews in Biochemistry and Molecular Biology, vol. 28, No. 5, pp. 375-430 (1993). |
| Kotra et al., “Structure-Activity Relationships of 2′-Deoxy-2′,2′-difluoro-L-erythro-pentofuranosyl Nucleosides,” J. Med. Chem., vol. 40, No. 22, pp. 3635-3644 (1997). |
| Kowdley et al., Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. Jun. 15, 2013;381 (9883):2100-2107. |
| Kryuchkov et al., “Influence of Solvent on the Strength of Cyclic Oxygen-Containing Phosphorus Acids,” Bulletin of the Academy of Sciences of the USSR. Division of Chemical Science, vol. 36, No. 6, Part 1, pp. 1145-1148 (1987) Translated from Russian. |
| Kucera et al., “Novel Membrane-Interactive Ether Lipid Analogs That Inhibit Infectious HIV-1 Production and Induce Defective Virus Formation,” Aids Research and Human Retroviruses, vol. 6, No. 4, pp. 491-501 (1990). |
| Lackey et al., “Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase,” Biochemical Pharmacology, vol. 61, No. 2, pp. 179-189 (2001). |
| Lalezari et al., Once Daily PSI-7977 Plus PEGIFN/RBV in a Phase 2B Trial: Rapid Virologic Suppression in Treatment-Naive Patients With HCV GT2/GT3. Journal of Hepatology 2011, vol. 54, S25-S44. Abstract 61. |
| Lam et al., Sofosbuvir (Sovaldi) for the treatment of hepatitis C. Expert Review of Clinical Pharmacology 2014, 7(5), pp. 555-566. |
| Landowski et al., “Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxurdine amino acid ester prodrugs,” MCT, (2005), 4(4):659-667. |
| Lawitz et al., Pharmacokinetics, Pharmacodynamics, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor, following Multiple Ascending Doses in Patients with Chronic Hepatitis C Infection. Antimicrobial Agents and Chemotherapy 2013, 57(3), pp. 1209-1217; doi: 10.1128/AAC.01263-12. Epub Dec. 21, 2012. |
| Lawitz et al., Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med 2013; 368(20), pp. 1878-1887. doi: 10.1056/NEJMoa1214853. Epub Apr. 23, 2013. |
| Lee et al., “Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue,” Antimicrobial Agents and Chemotherapy, vol. 49, No. 5, pp. 1898-1906 (2005). |
| Lehsten et al., “An Improved Procedure for the Synthesis of Nucleoside Phosphoramidates,” Organic Process Research and Development, vol. 6, pp. 819-822 (2002). |
| Letter from British Library dated Jun. 8, 2015 confirming publication date of Dykens, et al. Strategies to reduce late-stage drug attrition due to mitochondrial toxicity. Expert Rev Mol Diagn. Mar. 2007;7(2): 161-175. |
| Li et al., Synthesis of the Phosphoramidite Derivative of 2′-Deoxy-2′-C-beta-methylcytidine. J. Org. Chem. 2003, vol. 68, No. 17, pp. 6799-6802. |
| Lima et al., Bioisosterism: a useful strategy for molecular modification and drug design. Current Medicinal Chemistry 2005, vol. 12, pp. 23-49. |
| Lin et al., A stereospecific synthesis of 2′,3′-dideoxy-β-L-cytidine (β-L-ddC), a potent inhibitor against human hep-atitis B virus (HBV) and human immunodeficiency virus (HIV). Tetrahedron Letters 1994, vol. 35, No. 21, pp. 3477-3480. |
| Lohmann et al., “Biochemical Properties of Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase and Identification of Amino Acid Sequence Motifs Essential for Enzymatic Activity,” J. Virol., vol. 71, No. 11, pp. 8416-8428 (1997). |
| Lopez Aparicio et al., “Synthesis of Saccharinic Acid Derivatives,” Carbohydrate Research, vol. 129, pp. 99-109 (1984). |
| Ma et al., “Characterization of the Intracellular Metabolism of β-2′-Deoxy-2′-Fluoro-2′-C-Methyl-Cytidine and the Inhibition of HCV Polymerase NS5B by its 5′-Triphosphate Species,” Antiviral Research, (2007), 74(3): A36; Abstract 23. |
| Ma et al., “Characterization of the Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor B-D-2′-Deoxy-2-Fluoro-2′-C-Methylcytidine (PSI-6130) and Identification of a Novel Active 5′-Triphosphate Species,” J. Biol. Chem., vol. 282, No. 41, pp. 29812-29820 (2007). |
| McGuigan et al.,“Sub Micromolar Inhibitors of HCV Generated from Inactive Nucleosides by Application of ProTide Technology,” Antiviral Research, (2007), 74(3): A36; Abstract 24. |
| McGuigan et al., “Application of Phosphoramidate Pronucleotides Technology to Abacavir Leads to a Significant Enhancement of Antiviral Potency,” J. Med. Chem., vol. 48, No. 10, pp. 3504-3515 (2005). |
| McGuigan et al., “Application of Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of Carbocyclic Adenosine Derivatives,” J. Med. Chem., vol. 49, No. 24, pp. 7215-7226 (2006). |
| McGuigan et al., “Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT,” Antiviral Research, vol. 17, pp. 311-321 (1992). |
| McGuigan et al., “Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite,” J. Med. Chem., vol. 39, No. 8, pp. 1748-1753 (1996). |
| McGuigan et al., “Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency,” Antiviral Chemistry and Chemotherapy, vol. 9, pp. 109-115 (1998). |
| McGuigan et al., “Synthesis and evaluation of some novel phosphoramidate derivatives of 3′-azido-3′-deoxythymidine (AZT) as anti-HIV compounds,” Antiviral Chemistry and Chemotherapy, vol. 1, No. 2, pp. 107-113 (1990). |
| McGuigan et al., Certain Phosphoramidate Derivatives of Dideoxy Uridine (ddU) Are Active Against HIV and Successfully By-pass Thymidine Kinase, FEBS Letters (1994), 351, 11-14. |
| McGuigan et al., Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T). Antiviral Chemistry & Chemotherapy 1998, vol. 9, pp. 473-479. |
| McGuigan, “Phosphoramidate derivatives of stavudine as inhibitors of HIV: unnatural amino acids may substitute for alanine,” Antiviral Chemistry & Chemotherapy, (2000), 11:111-116. |
| McIntee et al., “Amino Acid Phosphoramidate Nucleosides: Potential ADEPT/GDEPT Substrates,” Bioorganic & Medicinal Chemistry Letters, vol. 11, No. 21, pp. 2803-2805 (2001). |
| McIntee et al., “Probing the Mechanism of Action and Decomposition of Amino Acid Phosphomonoester Amidates of Antiviral Nucleoside Prodrugs,” J. Med. Chem., vol. 40, No. 21, pp. 3323-3331 (1997). |
| Meier et al., “Cyclic Saligenyl Phosphotriesters of 2′,3′-Dideoxy-2′,3′-didehydrothymidine (d4T)—A New Pro-Nucleotide Approach,” Bioorg. & Med. Chem. Lett., vol. 7, No. 2, pp. 99-104, (1997). |
| Meyers et al., “Molecular Characterization of Pestiviruses,” Advance in Virus Research, vol. 47, pp. 53-119 (1996). |
| Mitchell et al., “Bioreversible Protection for the Phospho Group: Bioactivation of the Di(4-acyloxybenzyl) and Mono(4-acyloxybenzyl) Phosphoesters of Methylphosphonate and Phosphonoacetate,” J. Chem. Soc. Perkin. Trans. 1, pp. 2345-2353 (1992). |
| Moennig et al., “The Pestiviruses,” Advances in Virus Research, vol. 41, pp. 53-99 (1992). |
| Monath, T. P., M.D., “Japanese Encephalitis—A Plague of the Orient,” N. Engl. J. Med., vol. 319, No. 10, pp. 641-643 (Sep. 8, 1988). |
| Mourier, et al., “Enantioselective synthesis and biological evaluation of 5-o-carboranyl-pyrimidine-nucleosides,” Bioorganic & Medicinal Chemistry, vol. 7, pp. 2759-2766, (1999). |
| Murakami et al., “Mechanism of Activation of beta-D-2′-Deoxy-2′-Fluoro-2′-C-Methylcytidine and Inhibition of hepatitis C Virus NS5B RNA Polymerase,” Antimicrobial Agents and Chemotherapy, vol. 51, No. 2, pp. 503-509 (Feb. 2007). |
| Murakami et al., “The Mechanism of Action of beta-D-2′-Deoxy-2′-Fluoro-2′-C-Methylcytidine Involves a Second Metabolic Pathway Leading to beta-D-2′-Deoxy-2′-Fluoro-2′-C-Methyluridine 5′-Triphosphate, a Potent Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase,” Antimicrobial Agents and Chemotherapy, vol. 52, No. 2, pp. 458-464 (2008). |
| Murakami et al., Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. Nov. 5, 2010;285(45):34337-34347. doi: 10.1074/jbc.M110.161802. Epub Aug. 26, 2010. |
| Murakami, E., et al., “The Mechanism of Action of beta-D-2′-Deoxy-2′-fluoro-2′-C-methylcytidine Involves a Second Metabolic Pathway Leading to beta-D-2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-Triphosphate, a Potent Inhibitor of the HCV RNA-Dependent RNA Polymerase,” 14th International Symposium on Hepatitis C Virus and Related Viruses, Glasgow, Scotland (Sep. 2007). |
| Nakayama, Kensaku, et al., “A Highly Enantioselective Synthesis of Phosphate Triesters,” J. Am. Chem. Soc. (1990) 112:6936-6942. |
| Neidlein et al., “Mild Preparation of 1-Benzyloxyiminoalkylphosphonic Dichlorides: Application to the Synthesis of Cyclic Phosphonic Diesters and Cyclic Monoester Amides,” Heterocycles, vol. 35, No. 2, pp. 1185-1203 (1993). |
| Nelson et al., “The Question of Chair-twist Equilibria for the Phosphate Rings of Nucleoside Cyclic 3′,5′Monophosphates. 1H NMR and X-ray Crystallographic Study of Diastereomers of Thymidine Phenyl Cyclic 3′,5′-Monophosphate,” J. Am. Chem. Soc., vol. 109, No. 13, pp. 4058-4064 (1987). |
| Nelson et al., Once Daily PSI-7977 Plus PEG-IFN/RBV in HCV GT1: 98% Rapid Virologic Response, Complete Early Virologic Response: The Proton Study, Journal of Hepatology 2011, vol. 54, S535-S546. Abstract 1372. |
| Ni et al., “Progress and development of small molecule HCV antivirals,” Current Opinion in Drug Discovery & Development, vol. 7, No. 4, pp. 446-459 (2004). |
| Nifantyev et al., “Synthesis and Structure of Some Stable Phospholane-Phospholanes,” Phosphorus, Sulfur, and Silicon, vol. 113, pp. 1-13 (1996). |
| North et al., Hepatitis C treatment and SVR: the gap between clinical trials and real-world treatment aspirations. Gen Hosp Psychiatry. Mar.-Apr. 2013;35(2): 122-128. doi: 10.1016/j.genhosppsych.2012.11.002. Epub Dec. 6, 2012. |
| Notice of Reasons for Rejection for Japanese Patent Application No. 2018-138161 dated Jul. 9, 2019. 4 pages. |
| Novak, J. J. K., “Chiroptical Properties of 2-Methyl-1,4-Lactones; Revised Absolute Configuration of 2-Deoxy-2-C-Methyl-erythro-D-Pentono-1,4-Lactones,” Collection Czechoslov. Chem. Commun., vol. 39, pp. 869-882 (1974). |
| Novak, J. J. K., “Nucleic Acid Components and Their Analogues CXLIII. Nucleosides Derived from 2-Deoxy-2(R)-C-Methyl-erythro-D-Pentose,” Collection Czechoslov. Chem. Commun., vol. 36, pp. 3670-3677 (1971). |
| Office Action and Search Report for Chinese Patent Application No. 201811280064.6 dated Sep. 9, 2019. 21 pages. |
| Office Action and Search Report for Chinese Patent Application No. 201811348434.5 dated Oct. 8, 2019. 29 pages. |
| Office Action dated May 29, 2015 for Argentina Appl. No. 120100340. |
| Office Action dated Jun. 15, 2015 for Australian Appl. No. 2014215983. |
| Office Action dated Feb. 24, 2016 for European Appl. No. 14179358.8. |
| Office Action dated Mar. 2, 2016 for Argentina Appl. No. 20080101286. |
| Office Action dated Mar. 4, 2016 for Chinese Appl. No. 201410569402.3. |
| Office Action dated Apr. 6, 2016 for Taiwan Appl. No. 097111505. |
| Office Action dated Jul. 5, 2016 for Japanese Appl. No. 2015-139458. |
| Office Action dated Oct. 4, 2016 for Argentina Appl. No. 120100340. |
| Office Action dated Nov. 15, 2016 for Australian Appl. No. 2016213882. |
| Office Action dated Jan. 30, 2017 for Russian Appl. No. 2012152811. |
| Office Action dated Mar.. 17, 2017 for Chinese Appl. No. 201410569402.3. |
| Office Action dated Mar. 21, 2017 for Japanese Appl. No. 2015-139458. |
| Office Action dated Mar. 22, 2017 for Brazilian Appl. No. PI0809654-6. |
| Office Action dated Mar. 22, 2017 for Brazilian Appl. No. PI0823519-8. |
| Office Action dated Jun. 15, 2017 for Malaysian Appl. No. PI2013700240. |
| Office Action dated Jun. 26, 2017 for European Appl. No. 14169060.2. |
| Office Action dated Jun. 28, 2017 for European Appl. No. 14151876.1. |
| Office Action dated Jun. 28, 2017 for European Appl. No. 14179358.8. |
| Office Action dated Jun. 28, 2017 for European Appl. No. 14179593.0. |
| Office Action dated Aug. 15, 2017 for Japanese Appl. No. 2017-000051. |
| Office Action dated Oct. 25, 2017 for Brazilian Appl. No. PI0809654-6. |
| Office Action dated Oct. 25, 2017 for Brazilian Appl. No. PI0823519-8. |
| Office Action dated Oct. 31, 2017 for Argentina Appl. No. 20080101286. |
| Office Action dated Nov. 28, 2017 for Australian Appl. No. 2016231535. |
| Office Action dated Dec. 21, 2017 for Argentina Appl. No. 120100340. |
| Office Action dated Mar. 26, 2018 for Argentina Appl. No. 20080101286. |
| Office Action dated Apr. 17, 2018 for Brazilian Appl. No. PI0823519-8. |
| Office Action dated May 2, 2018 for Brazilian Appl. No. PI0809654-6. |
| Office Action dated May 4, 2018 for Australian Appl. No. 2017261454. |
| Office Action for Australian Application No. 2012241173 dated Apr. 8, 2014. |
| Office Action for Brazilian Patent Application No. PI0809654-6 dated Aug. 6, 2020. 12 pages. |
| Office Action for Brazilian Patent Application No. PI0809654-6 dated Dec. 18, 2019. 13 pages. |
| Office Action and Search Report for Chinese Patent Application No. 201811432281.2 dated Jan. 22, 2020. 17 pages. |
| Office Action for Colombian Application No. 09-120.744A dated Jun. 25, 2014. |
| Office Action for European Patent Application No. 14151876.1 dated Dec. 20, 2018. 4 pages. |
| Office Action for European Patent Application No. 14169060.2 dated Dec. 20, 2018. 5 pages. |
| Office Action for European Patent Application No. 14169060.2 dated Nov. 11, 2019. 4 pages. |
| Office Action for European Patent Application No. 14179593.0 dated Dec. 20, 2018. 6 pages. |
| Office Action for Korean Application No. 10-2012-7004146 dated Oct. 29, 2014. |
| Office Action in Chinese Application No. 200880018024.2 dated Oct. 31, 2014. |
| Office Action in Japanese Application No. 2014-093905 dated Jan. 13, 2015. |
| Official Action for Argentina Patent Application No. 120100340 dated Oct. 29, 2019. 7 pages. |
| Oishi et al., “Asymmetric Dihydroxylation of Chiral Olefins. High Control of Diastereofacial Selection,” Tet. Lett., vol. 34, No. 22, pp. 3573-3576 (1993). |
| Olsen et al., “2′-Modified Nucleoside Analogs as Inhibitors of Hepatitis C RNA Replication,” Program and Abstracts, 16th International Conference on Antiviral Research, Abstract No. 121, p. A76 (Apr. 27-May 1, 2003). |
| Opposition by Actavis Group PTC ehf to European Application No. 08732818.3 dated Feb. 23, 2015. |
| Opposition by Ellis IP Ltd. to European Application No. 08732818.3 dated Feb. 10, 2015. |
| Opposition by Generics [UK] Ltd (trading as Mylan) to European Application No. 08732818.3 dated Feb. 19, 2015. |
| Opposition by Indian Pharmaceutical Alliance to Indian Application No. 3658/KOLNP/2009 dated Feb. 17, 2015. |
| Opposition by IPS to European Application No. 08732818.3 dated Feb. 23, 2015. |
| Opposition by Medecins Du Monde to European Application No. 08732818.3 dated Feb. 10, 2015. |
| Opposition by Mr. Holm Herbert Fleisher to European Application No. 08732818.3 dated Feb. 19, 2015. |
| Opposition by NATCO Pharma Limited to Indian Application No. 3658/KOLNP/2009 dated Mar. 3, 2014. |
| Opposition by Pharmaceutical Works Polpharma S.A. to European Application No. 08732818.3 dated Feb. 19, 2015. |
| Opposition by SANKLAP Rehabilitation Trust to Indian Application No. 3658/KOLNP/2009 dated Sep. 10, 2014. |
| Opposition by Stada Arzneimittel AG to European Application No. 08732818.3 dated Feb. 19, 2015. |
| Opposition by Teva Pharmaceutical Industries to European Application No. 08732818.3 dated Feb. 10, 2015. |
| Opposition by the Initiative for Medicines, Access & Knowledge (I-Mak) to Indian Application No. 3658/KOLNP/2009 dated Nov. 16, 2013. |
| Opposition by ZBM Patents= Zea, Barlocci & Markvardsen to European Application No. 08732818.3 dated Feb. 23, 2015. |
| Otto, M., “Evaluation of Nucleoside Analogs in the Hepatitis C Virus Replicon System,” Framing the Knowledge of Therapeutics for Viral Hepatitis, IHL Press, First Edition, pp. 247-261 (2006). |
| Perrone et al. “Application of the Phosphoramidate ProTide Approach to 4′-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside,” J. Med. Chem., vol. 50, No. 8, 1840-1849 (2007). |
| Perrone et al., “First Example of Phosphoramidate Approach Applied to a 4′-Substituted Purine Nucleoside (4′-Azidoadenosine): Conversion of an Inactive Nucleoside to a Submicromolar Compound versus Hepatitis C Virus,” J. Med. Chem., vol. 50, No. 22, pp. 5463-5470 (2007). |
| Perrone, Thesis entitled Design, synthesis and biological evaluation of novel nucleotide prodrugs as potential anti hepatitis C virus agents. Cardiff University (2007). |
| Pharmasset, Inc., Pharmasset Announces 91% SVR12 From the PROTON Trial in Subjects With Hepatitis C Genotype 1. Press Release dated Sep. 6, 2011. |
| Pharmasset, Inc., Press Release dated Jul. 31, 2009. |
| Piantadosi et al., “Synthesis and Evaluation of Novel Ether Lipid Nucleoside Conjugates for Anti-HIV-1 Activity,” J. Med. Chem., vol. 34, No. 4, pp. 1408-1414 (1991). |
| Pierra et al., “Synthesis and Pharmacokinetics of Valopicitabine (NM283), an Efficient Prodrug of the Potent Anti-HCV Agent 2′-C-Methylcytidine,” J. Med. Chem., vol. 49, No. 22, pp. 6614-6620 (2006). |
| Pockros et al., JUMP-C: A randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype ¼ patients. Hepatology 2013, pp. 514-523. doi.org/10.1002/hep.26275|. Epub Jun. 24, 2013. |
| Pogam et al., “No Evidence of R7128 Drug Resistance After Up to 4 Weeks Treatment of GT1, 2 and 3 Hepatitis C Virus Infected Individuals”, 44th Annual Meeting of European Association for the Study of the Liver (EASL), Copenhagen, Denmark (Apr. 22-26, 2009). |
| Protide. Retrieved on Apr. 16, 2021 from internet: en.wikipedia.org/wiki/Protide. |
| Ray et al., “Intracellular Metabolism of the Nucleotide Prodrugs GS-9131, a Potent Anti-Human Immunodeficiency Virus Agent,” Antimicrobial Agents and Chemotherapy, vol. 52, No. 2, pp. 648-654 (2008). |
| Rejection Decision dated apr. 18, 2018 for Chinese Appl. No. 201410569402.3. |
| Rejection decision for Brazilian Patent Application No. PI0823519-8 dated Aug. 21, 2018. 20 pages. |
| Rejection Decision for Chinese Patent Application No. 201811432281.2 dated Feb. 2, 2021. 18 pages. |
| Remy et al., “Studies on Flourinated Pyrimidines. XIV. The Synthesis of Derivatives of 5-Fluoro-2′-deoxyuridine 5′-Phosphate and Related Compounds,” J. Org. Chem., vol. 27, No. 7, pp. 2491-2500 (1962). |
| Rice, C. M., “Flaviviridae: The Viruses and Their Replication,” Fields Virology, 3rd Edition, vol. 1, pp. 931-959 (1996). |
| Roberts et al., Interim results of a multiple ascending dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV patients. Journal of Hepatology 2006, 44(S2):S269. |
| Robins et al., Nucleic Acid Related Compounds. 91. Biomimetic Reactions Are in Harmony with Loss of 2′-Substituents as Free Radicals (Not Anions) during Mechanism-Based Inactivation of Ribonucleotide Reductases. Differential Interactions of Azide, Halogen, and Alkylthio Groups with Tributylstannane and Triphenylsilane. Journal of the American Chemical Society 1996, vol. 118, No. 46, pp. 11341-11348. |
| Robinson. Organic Stereochemistry. OUP, 2005, cover page and Sections 1.4-1.8. |
| Saboulard et al., “Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine,” Mol. Pharmacol., vol. 56, pp. 693-704 (1999). |
| Saneyoshi, “Facile synthesis of 2′-O-cyanoethyluridine by ring-opening reaction of 2,2′-anhydrouridine with cyanoethyl trimethylsilyl ether in the presence of BF3 Et2O,” Tetrahedron Letters, vol. 48, pp. 8554-8557, (2007). |
| Schultz, C., “Prodrugs of Biologically Active Phosphate Esters” Bioorg. and Med. Chem., vol. 11, pp. 885-898 (2003). |
| Second Examination Report for Malaysian Patent Application No. PI2013700238 dated Jul. 28, 2020. 2 pages. |
| Second Examination Report for Malaysian Patent Application No. PI2013700240 dated Jul. 28, 2020. 3 pages. |
| Second Office Action for Chinese Patent Application No. 201811432281.2 dated Jul. 29, 2020. 17 pages. |
| Shih et al., “Preparation and Structures of 2-Dimethylamino-4-phenyl-1,3,2-dioxaphosphorinane-2-oxides,” Bull. Inst. Chem., Acad. Sin., vol. 41, pp. 9-16, (Mar. 1994). |
| Siccardi et al., “Stereoselective and Concentration-Dependent Polarized Epithelial Permeability of a Series of Phosphoramidate Triester Prodrugs of d4T: An in Vitro Study in Caco-2 and Madin-Darby Canine Kidney Cell Monolayers,” J. Pharmacol, and Exp. Ther., vol. 307, No. 3, pp. 1112-1119 (2003). |
| Siccardi et al., “Stereospecific chemical and enzymatic stability of phosphoramidate triester prodrugs of d4T in vitro,” European Journal of Pharmaceutical Sciences, vol. 22, pp. 25-31 (2004). |
| Siddiqui et al., “Design and Synthesis of Lipophilic Phosphoramidate d4T-MP Prodrugs Expressing High Potency Against HIV in Cell Culture: Structural Determinants for in Vitro Activity and QSAR,” J. Med. Chem., vol. 42, No. 20, pp. 4122-4128 (1999). |
| Siddiqui et al., “Enhancing the Aqueous Solubility of d4T-based Phosphoramidate Prodrugs,” Bioorg. and Med. Chem. Lett., vol. 10, pp. 381-384 (2000). |
| Siddiqui, Adam Q., et al., “The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivatives of d4T Enhances Anti-HIV Efficacy in Cell Culture: A Structure-Activity Relationship,” J. Med. Chem. (1999) 42:393-399. |
| Smirrnov et al., “A Fluorescent Study of Tryptophan Derivatives of Oligonucleotides and Their Helical Complexes with Polyuridylic,” FEBS Letters, vol. 51. No. 1, pp. 211-214 (1975). |
| Sofia et al., “beta-D-2′-Deoxy-2′-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication”, Poster #P-259, 14th International Symposium on Hepatitis C Virus and Related Viruses, Glasgow, Scotland, UK (Sep. 9 to 13, 2007). |
| Sofia et al., “beta-D-2′-Deoxy-2′-fluoro-2′-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication”, 2nd International Workshop on HCV, Poster #7 (Oct. 31, 2007). |
| Sofia et al., Discovery of a beta-D-2′-Deoxy-2′-alpha-fluoro-2′-beta-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus. J. Med. Chem. 2010, 53, 19, 7202-7218. |
| Sofia, M.J., “beta-D-2′-Deoxy-2′-fluoro-2′-C-methyluridine Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication”, 2nd International Workshop on HCV-Resistance and New Compounds (Oct. 31, 2007). |
| Sofia, M.J., “R7128, A Potent and Selective Nucleoside Inhibitor of HCV NS5B Polymerase: An Overview of Clinical Efficacy and Progress Toward Second Generation Inhibitors”, HCV Drug Discovery 2008, Chicago, IL (Apr. 28, 2008). |
| Song et al., “Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats,” Antimicrobial Agents and Chemotherapy, vol. 46, No. 5, pp. 1357-1363 (2002). |
| Soriano et al., Hepatitis C therapy with HCV NS5B polymerase inhibitors. Expert Opin Pharmacother. 2013, 14(9):1161-1170.doi: 10.1517/14656566.2013.795543. Epub Apr. 27, 2013. |
| Starrett, Jr. et al., “Synthesis, Oral Bioavailability Determination, and in Vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA),” J. Med. Chem., vol. 37, No. 12, pp. 1857-1864 (1994). |
| Stella, V. J., “Prodrugs as Therapeutics,” Expert opinion on therapeutic patents, vol. 14, No. 3, pp. 277-280 (Mar. 2004). |
| Strader et al., Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004; 39(4):1147-1171. |
| Stuyver et al., “Dynamics of Subgenomic Hepatitis C Virus Replicon RNA Levels in Huh-7 Cells after Exposure to Nucleoside Antimetabolites,” J. Virol., vol. 77, No. 19, p. 10689-10694 (2003). |
| Stuyver et al., “Inhibition of hepatitis C replicon RNA synthesis by B-D-2'-deoxy-2'-fluoro-2'-C-methlcytidine: a specific inhibitor of hepatitis C virus replication,” Antiviral Chemistry & Chemotherapy, vol. 17, No. 2, pp. 79-87 (2006). |
| Stuyver et al., “Inhibition of the Subgenomic Hepatitis C Virus Replicon in Huh-7 Cells by 2′-Deoxy-2′-Fluorocytidine,” Antimicrobial Agents and Chemotherapy, vol. 48, No. 2, pp. 651-654 (2004). |
| Stuyver et al., “Ribonucleoside Analogue that Blocks Replication of Bovine Viral Diarrhea and Hepatitis C Viruses in Culture,” Antimicrobial Agents and Chemotherapy, vol. 47, No. 1, pp. 244-254 (2003). |
| Subsequent Substantive Examination Report for Philippines Application No. Jan. 2009/501847 dated Nov. 10, 2014. |
| Substantive Examination Report for Malaysian Patent Application No. PI2013700238 dated Mar. 6, 2020. 3 pages. |
| Substantive Examination Report for Malaysian Patent Application No. PI2013700240 dated Aug. 15, 2019. 3 pages. |
| Substantive Examination Report for Philippines Patent Application No. 1-2014-502771 dated Nov. 28, 2019. 5 pages. |
| Tan et al., “Hepatitis C Therapeutics: current Status and Emerging Strategies,” Nature Reviews, vol. 1, pp. 867-881 (2002). |
| Third Party Observations dated 2018-02-14 for Brazilian Appl. No. PI0823519-8. |
| Tomei et al., “NS3 Is a Serine Protease Required for Processing of Hepatitis C Virus Polyprotein,” J. Virol., vol. 67, No. 7, pp. 4017-4026 (1993). |
| Trousdale, et al..“Activity of 1-(2′-Fluoro-2′-Deoxy-β-D-Arabinofuranosyl)Thymine Against Herpes Simplex Virus in Cell Cultures and Rabbit Eyes,” Antimicrobial Agents and Chemotherapy, (1983), 23(6):808-813. |
| Uchiyama, Mamoru, et al., “O-Selective Phosphorylation of Nucleosides without N-Protection,” J. Org. Chem. (1993) 58:373-379. |
| Uckun et al., “In Vivo Pharmacokinetics and Toxicity Profile of the Anti-HIV Agent Stampidine in Dogs and Feline Immunodeficiency Virus-infected Cats,” Arzneim.-Forsch./Drug Res., vol. 56, No. 2a, pp. 176-192 (2006). |
| Valette et al., “Decomposition Pathways and in Vitro HIV Inhibitory Effects of IsoddA Pronucleotides: Toward a Rational Approach for Intracellular Delivery of Nucleoside 5′-Monophosphates,” J. Med. Chem., vol. 39, No. 10, pp. 1981-1990 (1996). |
| Van Rompaey, et al., “Mycobacterium tuberculosis thymidine monophosphate kinase inhibitors; biological evaluation and conformational analysis of 2′-and 3′-modified thymidine analogues,” Eur. J. Org. Chem., pp. 2911-2918, (2003). |
| Vanheusden et al., “Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase,” J. Med. Chem., vol. 47, pp. 6187-6194, (2004). |
| Vanheusden et al., Synthesis and evaluation of thymidine-5′-O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase. Bioorganic & Medicinal Chemistry Letters, vol. 12, pp. 2695-2698 (2002). |
| Venkatachalam et al., “Rational Drug Design of Multifunctional Phosphoramidate Substituted Nucleoside Analogs,” Current Pharmaceutical Design, vol. 10, No. 15, pp. 1713-1726 (2004). |
| Venkatachalam et al., “Synthesis and metabolism of naphthyl substituted phosphoramidate derivatives of stavudine,” Bioorg. and Med. Chem., vol. 14, pp. 5161-5177 (2006). |
| Wagner et al., “Antiviral Nucleoside Drug Delivery via Amino Acid Phosphoramidates,” Nucleosides, Nucleotides and Nucleic Acids, vol. 18, Nos. 4 & 5, pp. 913-919 (1999). |
| Wagner et al., Pronucleotides: Toward the in vivo delivery of antiviral and anticancer nucleotides. Medicinal Research Reviews 2000, 20(6), pp. 417-451. |
| Walker et al., Promising candidates for the treatment of chronic hepatitis C. Expert Opinion on Investigational Drugs, vol. 12, No. 8, pp. 1269-1280 (2003). |
| Warrener et al., “Pestivirus NS3 (p80) Protein Possesses RNA Helicase Activity,” J. Virol., vol. 69, No. 3, pp. 1720-1726 (1995). |
| Wedemeyer et al., PROPEL: a randomized trial of mericitabine plus peginterferon alpha-2a/ribavirin therapy in treatment-naïve HCV genotype ¼ patients. Hepatology 2013, 58(2):524-537. doi: 10.1002/hep.26274. Epub Jun. 26, 2013. |
| Wiskerchen et al., Pestivirus Gene Expression: Protein p80 of Bovine Viral Diarrhea Virus Is a Proteinase Involved in Polyprotein Processing, Virology, vol. 184, pp. 341-350 (1991). |
| Wolff, M.E., “Burger's Medicinal Chemistry and Drug Discovery,” Fifth Edition, vol. 1, pp. 975-977 (1995). |
| World Health Organisation—Model List of Essential Medicines, Aug. 2015. |
| Wozniak, Lucyna A., et al., “The stereospecific synthesis of P-chiral biophosphates and their analogues by the Stec reaction,” Chem. Soc. Rev. (2003) 32:158-169. |
| Wu et al., “Synthesis and Biological Activity of a Gemcitabine Phosphoramidate Prodrug,” J. Med. Chem., vol. 50, No. 15, pp. 3743-3746 (2007). |
| Wu et al., Targeting NS5B RNA-dependent RNA polymerase for anti-HCV chemotherapy. Current Drug Targets Infectious Disorders 2003, vol. 3, No. 3, pp. 207-219. |
| Xiao-Ling et al., “Study on the Chirality of Sulfur in Ethyl (2S, 3R, 4R)-4,5-0-Isopropylidene-2,3-sulfinyl-2,3,4,5-tetrahydroxy-pentanoate”, Acta Chimica Sinica, vol. 55, pp. 600-604 (1997). |
| Xiao-Ling et al., “The Synthesis of (2S,3R)-Sphingosine from D-Mannitol”, Acta Chimica Sinica, vol. 54, pp. 826-832 (1996). |
| Xu et al., “Bovine Viral Diarrhea Virus NS3 Serine Proteinase: Polyprotein Cleavage Sites, Cofactor Requirements, and Molecular Model of an Enzyme Essential for Pestivirus Replication,” J. Viral., vol. 71, No. 7, pp. 5312-5322 (1997). |
| Yuan et al., “Expression, Purification, and Partial Characterization of HCV RNA Polymerase,” Biochemical and Biophysical Research Communications, vol. 232, No. 1, pp. 231-235 (1997). |
| Yuodka et al., “Oligonucleotides and Polynucleotides. XXVI. Synthesis of Esters of Nucleotidyl-and Oligonucleotidyl-(5′-N)-(Amino Acid)S and -Peptides,” Soviet Journal of Bioorganic Chemistry, vol. 2, No. 11, pp. 1089-1094 (1976) Translated from Russian. |
| Yuodka et al., Bioorganicheskaya Khimiya, 2(11), 1513-1519 (1976) (translated from Russian). |
| Zemlicka, Lipophilic phosporamidates as antiviral pornucleotides, Biochem Biophys Acta, (2002), 276-286. |
| Zhong et al., “Identification and characterization of an RNA-Dependent RNA Polymerase Activity within the Nonstructural Protein 5B Region of Bovine Viral Diarrhea Virus,” J. Virol., vol. 72, No. 11, pp. 9365-9369 (1998). |
| Zon, G., “4 Cyclophosphoamide Analogues,” Progress in Medicinal Chemistry, vol. 19, pp. 205-246 (1982). |
| Blanver's Third-party Opinion Brief in Brazilian Patent Application No. PI0809654-6 dated Dec. 18, 2020. 26 pages. |
| Erti et al. A comparative study of the in vitro and in vivo antiviral activities of acyclovir and penciclovir. Antiviral Chemistry & Chemotherapy. 1995, 6(2), 89-97, p. 89, left column, “Summary”, pp. 89-93, section “Results”, pp. 93,94, section “Discussion”. |
| Office Action and Search Report for Chinese Patent Application No. 201811280509.0 dated Mar. 3, 2022. 22 pages. |
| Office Action for Chinese Patent Application No. 201811280064.6 dated Apr. 2, 2022. 13 pages. |
| Office Action for Chinese Patent Application No. 201811348434.5 dated Apr. 2, 2022. 12 pages. |
| Official Action for Argentinian Patent Application No. 20170103608 dated Jan. 26, 2022. 6 pages. |
| Official Action for Russian Patent Application No. 2018103329 dated May 24, 2021. 26 pages. |
| Opposition by Mr. Yellajyosula Lakshmi Narasimha Murthy dated Oct. 28, 2021. 17 pages. |
| Rejection Resolution for Argentinean Patent Application No. 20120100340 dated May 31, 2022. 16 pages. |
| Examination Report for Australian Application No. 2021202327 dated Aug. 18, 2022. 9 pages. |
| Office Action for Chinese Application No. 201811280509.0 dated Oct. 13, 2022. 13 pages. |
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