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HK40006276B - Nucleoside phosphoramidate prodrugs - Google Patents

Nucleoside phosphoramidate prodrugs Download PDF

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HK40006276B
HK40006276B HK19129737.3A HK19129737A HK40006276B HK 40006276 B HK40006276 B HK 40006276B HK 19129737 A HK19129737 A HK 19129737A HK 40006276 B HK40006276 B HK 40006276B
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alkyl
membered ring
joined together
methyl
hydrogen
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HK19129737.3A
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HK40006276A (en
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迈克尔·J·索菲亚
杜锦发
王培源
达纳帕兰·纳加拉特南
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吉利德制药有限责任公司
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Description

Nucleoside phosphoramidate prodrugs
This application is a divisional application of chinese patent application No. 200880018024.2 entitled "nucleoside phosphoramidate prodrugs" filed on 26.3.2008.
The parent application was filed as a PCT international patent application on 26.3.2008, the applicant designated in all countries except the united states is the american company Pharmasset, inc, and the applicant designated in the united states alone is the american national citizen Michael Joseph Sofia, the american national Jinfa Du, the national republic of china Peiyuan Wang, and the american national ghaapalan nagatham; this application claims priority to U.S. provisional application No. 60/909,315, filed on 30/3/2007, U.S. provisional application No. 60/982,309, filed on 24/10/2007, and U.S. non-provisional application No. 12/053,015, filed on 21/3/2008. The contents of each of the above applications are hereby incorporated by reference in their entirety.
Technical Field
The present invention relates to nucleoside phosphoramidates and their use as agents for the treatment of viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, inhibitors of HCV replication, and for treating hepatitis c infection in a mammal. The present invention provides novel compounds, and the use of these compounds, either alone or in combination with other antiviral agents useful in the treatment of HCV infection.
Background
Hepatitis C Virus (HCV) infection is a serious health problem that leads to chronic liver diseases such as cirrhosis and hepatocellular carcinoma in a large number of infected individuals, estimated to be 2-15% of the world population. According to the american centers for disease control, four hundred and fifty thousand people are infected in the united states alone. According to the world health organization, there are over 2 million infected individuals worldwide, with at least 3 to 4 million people infected per year. Once infected, approximately 20% of people clear the virus, but the rest of the people may carry HCV for the rest of their lives. From 10% to 20% of chronically infected individuals eventually develop liver-destructive cirrhosis or cancer. The viral disease is transmitted parenterally through contaminated blood and blood products, contaminated needles; or by sexual propagation; and vertical transmission from infected or carrier mothers to their offspring. Current treatments for HCV infection are limited to recombinant interferon alpha immunotherapy alone or in combination with the nucleoside analog ribavirin, which has limited clinical benefit. Furthermore, there is no complete vaccine against HCV. Thus, there is an urgent need for improved therapeutic agents that are effective in combating chronic HCV infection.
HCV virions are enveloped positive-strand RNA viruses with a single oligonucleotide genomic sequence of about 9600 bases encoding 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 NS 5B. The Nonstructural (NS) protein is thought to provide a catalytic structure for viral replication. The NS3 protease releases NS5B, which is an RNA-dependent RNA polymerase from a polyprotein chain. HCV NS5B polymerase is required for the synthesis of double-stranded RNA from single-stranded viral RNA used as a template in the HCV replication cycle. Thus, NS5B polymerase is considered an essential component in the HCV replication complex (K.Ishi et al, heptology,1999,29, 1227-1235, V.Lohmann et al, virology,1998, 249. Inhibition of HCV NS5B polymerase prevents the formation of double-stranded HCV RNA, and thus constitutes an attractive approach to the development of HCV-specific antiviral therapies.
HCV belongs to a fairly large family of viruses that share many common features.
Flaviviridae (Flaviviridae) viruses
Viruses of the flaviviridae family include at least three distinct genera: pestiviruses (pestiviruses), which cause disease in cattle and pigs; flaviviruses (flavivruses), which are the major causes of diseases such as dengue and yellow fever; and hepaciviruses (hepaciviruses), the only member of which is HCV. The flavivirus genus includes over 68 members, grouped based on serological relationships (Calisher et al, J.Gen.Virol,1993,70, 37-43). Clinical symptoms vary and include fever, encephalitis, and hemorrhagic fever (Fields Virology, eds: fields, b.n., knipe, d.m., and Howley, p.m., lippincott-Raven press, philadelphia, PA,1996, chapter 31, 931-959). Flaviviruses of global interest in relation to human disease include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome virus and japanese encephalitis virus (Halstead, s.b., rev. Infection.dis., 1984,6,251-264, halstead, s.b., science,239, 476-481,1988, month, t.p., new eng.j.med,1988,319, 64-643).
Pestiviruses include Bovine Viral Diarrhea Virus (BVDV), classical swine fever virus (CSFV, also known as hog cholera virus) and sheep Borderline Disease Virus (BDV) (Moennig, V.et al. Adv. Vir. Res.1992,41, 53-98). Pestivirus infection of domestic livestock (cattle, pigs and sheep) causes significant economic losses worldwide. BVDV causes mucosal disease in cattle and is of significant economic importance to animal husbandry (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 characterized as widely as animal pestiviruses. However, serological examination indicates considerable pestivirus exposure in humans.
Pestiviruses and hepaciviruses are closely related groups of viruses within the flaviviridae family. Other closely related viruses in this family include GB virus a, GB virus a-like substances, GB virus B, and GB virus C (also known as hepatitis G virus, HGV). The hepatitis C virus group (hepatitis C virus; HCV) consists of a large 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 similarity between pestiviruses and hepaciviruses and the weak ability of hepaciviruses to grow efficiently in cell culture, bovine Viral Diarrhea Virus (BVDV) is often used as a surrogate for studying HCV virus.
Pestiviruses have a very similar genetic makeup to hepatitis c virus. These positive-stranded RNA viruses have a large Open Reading Frame (ORF) that encodes all the viral proteins required for viral replication. These proteins can be expressed as polyproteins that are co-translated and post-translationally processed by cellular and virally encoded proteases to obtain mature viral proteins. The viral proteins responsible for the replication of the viral genomic RNA are located within the proximity of the carboxy terminus. Two thirds of the ORF is called the Nonstructural (NS) protein. Pestiviruses are very similar in genetic composition and polyprotein processing to the nonstructural protein portion of the ORF of hepatitis c virus. In the case of pestiviruses and hepaciviruses, the mature Nonstructural (NS) protein consists of p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B in sequential order from the amino terminus of the nonstructural protein coding region to the carboxy terminus of the ORF.
The NS proteins of pestiviruses and hepaciviruses share sequence domains that are characterized by specific protein functions. For example, the NS3 proteins of both groups of viruses have amino Acid sequence motifs characterized by serine proteases and 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 motifs characterised by RNA-directed RNA polymerases (Koonin, E.V. and Dolja, V.V., crir. Rev. Biochem. Molec. Biol.1993,28, 375-430).
The actual role and function of the NS proteins of pestiviruses and hepaciviruses in the viral life cycle are completely similar. In both cases, the NS3 serine protease is responsible for all proteolytic processing of its polyprotein precursor downstream of the ORF position (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). In both cases, the NS4A protein serves as a cofactor for the NS3 serine protease (Bartenschlager et al, J.Virol.1994,68,5045-5055, faillea et al, J.Virol.1994,68,3753-3760 Xu et al, J.Virol.,1997, 71. The NS3 proteins of both viruses also function as helicases (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 protein of pestiviruses and hepaciviruses has a predicted RNA-directed RNA polymerase 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 treatment option that has been approved today is the use of recombinant interferon alpha alone or in combination with the nucleoside analog ribavirin as an immunotherapy. This therapy is limited by its clinical efficacy, and only 50% of treated patients respond to the therapy. Thus, there is a significant need for more effective and novel therapies to address the unmet medical need caused by HCV infection.
A number of potential molecular targets for drug development of direct acting antiviral agents as anti-HCV therapeutics have been identified, including but not limited to NS2-NS3 autoprotease (autoprotease), N3 protease, N3 helicase, and NS5B polymerase. RNA-dependent RNA polymerases are absolutely necessary for single-stranded sense RNA genome replication, and this enzyme has attracted significant interest in pharmaceutical chemists.
Inhibitors of HCV NS5B have been reviewed as potential therapies for HCV infection in the following: tan, s. -l., et al, nature rev. Drug discov.,2002,1,867-881; walker, m.p. et al, exp.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 possibility of emergence of resistant HCV strains and the need to identify agents with a broad genotypic range support the need for continued efforts to identify novel and more potent nucleosides as HCV NS5B inhibitors.
Nucleoside inhibitors of NS5B polymerase can be used as unnatural substrates that lead to chain termination or as competitive inhibitors that compete with nucleotides for 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 typically mediated by cellular kinases, which impose additional structural requirements on potential nucleoside polymerase inhibitors. 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 hindered by its poor substrate properties for one or more kinases, which are required to convert the nucleoside to the active triphosphate form. Formation of monophosphate esters by nucleoside kinases is generally considered to be the rate-limiting step of the triphosphorylation event. To avoid the need for an initial phosphorylation step in the metabolism of nucleosides to active triphosphate analogs, stable phosphate prodrug preparations have been reported. Nucleoside phosphoramidate prodrugs have been shown to be precursors to active nucleoside triphosphates and to inhibit viral replication when administered to whole cells infected with viruses (McGuigan, C. Et al, J.Med.Chem.,1996,39,1748-1753, valette, G.et al, J.Med.Chem.,1996,39,1981-1990; US 2006/0241064 and WO 2007/095269.
Also limiting the utility of nucleosides as viable therapeutic agents are their physicochemical and pharmacokinetic properties with time differences. These poor properties can limit the intestinal absorption of the agent and limit uptake into the target tissue or cells. To improve their properties, prodrugs of nucleosides were employed. Nucleoside phosphoramidate preparations have been demonstrated to improve systemic uptake of nucleosides, and further, the phosphoramidate portion of these "prokaryotic nucleotides" is masked by neutral lipophilic groups to obtain appropriate partition coefficients to optimize uptake and transport into cells, thereby significantly increasing the intracellular concentration of nucleoside monophosphate analogs relative to administration of the parent nucleoside alone. Enzyme-mediated hydrolysis of the phosphate moiety produces nucleoside monophosphates in which the rate-limiting initial phosphorylation is not required.
Summary of The Invention
The present invention relates to novel phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which are compounds represented by the following structure, stereoisomers, salts (acid or base addition salts), hydrates, solvates, or crystalline forms thereof:
wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen, C 1-10 Alkyl radical, R 3a Or R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring C (O) CR comprising adjacent N and C atoms 3a R 3b NHR 1 Wherein n is 2 to 4 1 、R 3a And R 3b ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R is 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy, di (lower alkyl) -amino or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
The base is a naturally occurring or modified purine or pyrimidine base, represented by the following structure:
Wherein
Z is N or CR 12 ；
R 7 、R 8 、R 9 、R 10 And R 11 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl such as C.ident.CH, C halogenated (F, cl, br, I) 2 -C 6 Lower alkynyl, C 1 -C 6 C of lower alkoxy, halo (F, cl, br, I) 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R' is optionally substituted alkyl including, but not limited to, optionally substituted C 1-20 Alkyl, optionally substituted C 1-10 Alkyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 2 -C 6 Lower alkenyl, or optionally substituted acyl including, but not limited to, C (O) alkyl, C (O) (C) 1-20 Alkyl), C (O) (C) 1-10 Alkyl) or C (O) (lower alkyl)) Or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
R 12 is H, halogen (including F, cl, br, I), OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl, halo (F, cl, br, I) C 2 -C 6 Lower alkynyl, C 1 -C 6 C of lower alkoxy, halo (F, cl, br, I) 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; with the proviso that when the base consists of R 11 When structure c represents hydrogen, R 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
Definition of
The terms "a" or "an" entity, as used herein, refer to one or more of the entities, e.g., a compound refers to one or more compounds or at least one compound. Likewise, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.
The term "as defined above" refers to the initial definition provided in the summary of the invention.
The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.
The term "independently" as used herein means that the variables can apply in either case without regard to the presence or absence of variables having the same or different definitions within the same compound. Thus, in a compound where R occurs twice and is defined as "independently carbon or nitrogen," two R's can be carbon, two R's can be nitrogen, or one R is carbon and the other is nitrogen.
The term "alkenyl" refers to an unsubstituted hydrocarbon chain radical having 2 to 10 carbon atoms with one or two olefinic double bonds, preferably with one olefinic double bond. The term "C 2-N Alkenyl "refers to alkenyl groups comprising 2 to N carbon atoms, where N is an integer having the following value: 3. 4, 5, 6, 7, 8, 9 or 10. The term "C 2-10 Alkenyl "means an alkenyl group comprising 2 to 10 carbon atoms. The term "C 2-4 Alkenyl "means an alkenyl group comprising 2 to 4 carbon atoms. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), or 2-butenyl (crotyl).
The term "halogenated alkenyl" refers to an alkenyl group that includes at least one of F, cl, br, and I.
The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term "C 1-M Alkyl "refers to an alkyl group comprising 1 to M carbon atoms, wherein M is an integer having the following value: 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 "C 1-4 Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms. The term "lower alkyl" refers to a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms. "C" as used herein 1-20 Alkyl "refers to an alkyl group comprising 1 to 20 carbon atoms. "C" as used herein 1-10 Alkyl "refers to an alkyl group including 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The terms (ar) alkyl or (heteroaryl) alkyl refer to alkyl optionally substituted with aryl or heteroaryl, respectively.
The term "cycloalkyl" refers to an unsubstituted or substituted carbocyclic ring, wherein the carbocyclic ring contains 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms (i.e., lower cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "cycloalkylalkyl" refers to an otherwise unsubstituted alkyl group or a substituted alkyl group substituted with a lower cycloalkyl group. Examples of cycloalkylalkyl groups include, but are not limited to, any of the following: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl substituted by cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloheteroalkyl" refers to an unsubstituted or substituted heterocyclic ring, wherein the heterocyclic ring contains from 2 to 9 carbon atoms, preferably from 2 to 7 carbon atoms, more preferably from 2 to 5 carbon atoms. Examples of cycloheteroalkyl groups include, but are not limited to, aziridin-2-yl, N-C 1-3 -alkyl-aziridin-2-yl, azetidinyl, N-C 1-3 -alkyl-azetidin-m '-yl, pyrrolidin-m' -yl, N-C 1-3 -alkyl-pyrrolidin-m '-yl, piperidin-m' -yl and N-C 1-3 -alkyl-piperidin-m '-yl, wherein m' is 2, 3 or 4 depending on the cycloheteroalkyl. N-C 1-3 Specific examples of-alkyl-cycloheteroalkyl groups include, but are not limited to, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, and N-methyl-piperidin-4-yl. At R 4 In the case of (a), the point of attachment between a cycloheteroalkyl ring carbon and oxygen occurs at either m'.
The term "heterocycle" refers to an unsubstituted or substituted heterocycle containing carbon, hydrogen, and at least one of N, O, and S, wherein C and N may be trivalent or tetravalent, i.e., sp 2 -or sp 3 -hybridization. Examples of heterocycles include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, imidazole, oxazole, piperazine, and the like. In the case of piperazine, such as with NR' 2 R of (A) to (B) 10 Related, the corresponding para-nitrogen atom on the piperazinyl group is substituted with a lower alkyl group represented by the following structure:
preferably, the nitrogen para to the piperazinyl group is substituted with a methyl group.
The term "halogenated alkyl" (or "haloalkyl") refers to a straight or branched chain alkyl group that includes at least one of F, cl, br, and I. The term "C 1-M Haloalkyl "refers to an alkyl group comprising 1 to M carbon atoms, the alkyl group comprising at least one of F, cl, br, and I, wherein M is an integer having the following value: 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."C 1-3 Haloalkyl "refers to haloalkyl groups 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 group comprising 1 to 6 carbon atoms and at least one of F, cl, br, and I. Examples thereof 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 a straight or branched hydrocarbon chain radical having 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, and having one triple bond. The term "C 2-N Alkynyl "refers to an alkynyl group including 2 to N carbon atoms, where N is an integer having the following value: 3. 4, 5, 6, 7, 8, 9 or 10. The term "C 2-4 Alkynyl "refers to alkynyl groups comprising 2 to 4 carbon atoms. The term "C 2-10 Alkynyl "refers to alkynyl groups including 2 to 10 carbons. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.
The term "halogenated alkynyl" refers to a straight or branched hydrocarbon chain radical having from 2 to 10 carbon atoms, preferably from 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 "C" as used herein 3-7 Cycloalkyl "refers to cycloalkyl groups including 3 to 7 carbons in the carbocyclic ring.
The term "alkoxy" refers to an-O-alkyl 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-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy. "lower alkoxy" as used herein refers to an alkoxy group having a "lower alkyl" group as previously defined. "C 1-10 Alkoxy "means an-O-alkyl group wherein alkyl is C 1-10 . Examples of-O-cycloalkyl include, but are not limited to, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and-O-cyclohexyl.
The term "halogenated alkoxy" refers to an-O-alkyl group, wherein the alkyl group includes at least one of F, cl, br, and I.
The term "halogenated lower alkoxy" refers to the group-O- (lower alkyl) wherein lower alkyl includes at least one of F, cl, br and I.
The term "amino acid" includes naturally occurring and synthetic alpha, beta, gamma or delta amino acids, and includes, but is not limited to, the amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L configuration. Alternatively, the amino acid may be a derivative of: alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartyl, glutamyl, lysyl, arginyl, histidinyl, beta-alanyl, beta-valyl, beta-leucyl, beta-isoleucyl, beta-prolyl, beta-phenylalanyl, beta-tryptophanyl, beta-methionyl, beta-glycyl, beta-seryl, beta-threonyl, beta-cysteinyl, beta-tyrosyl, beta-asparaginyl, beta-glutaminyl, beta-aspartyl, beta-glutaminyl, beta-glutamyl, beta-lysyl, beta-arginyl, or beta-histidinyl. When the term amino acid is used, it is believed that various esters of the following amino acids in the D and L configurations are specifically and independently disclosed: alpha, beta, gamma or delta glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine.
The term "aminoacyl" includes the N, N-unsubstituted, N-monosubstituted, and N, N-disubstituted derivatives of naturally occurring and synthetic alpha, beta, gamma, or delta aminoacyl groups, wherein the aminoacyl group is derived from an amino acid. The amino-nitrogen may be substituted or unsubstituted. When the amino-nitrogen is substituted, the nitrogen is mono-or di-substituted, wherein the substituent bonded to the amino-nitrogen is lower alkyl or alkaryl. In the case where it is used for Y, the expression "O (aminoacyl)" is used. It is understood that the C3' carbon of ribose is bonded to the oxygen "O" and then to the carbonyl carbon of the aminoacyl group.
The term "alkylamino" or "arylamino" refers to an amino group having one or two alkyl or aryl substituents, respectively.
The term "protected" as used herein, unless otherwise specified, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent further reaction thereof or for other purposes. Various 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, CH 3 、CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph、CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 Alkyl, SO 2 Aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and 1,3- (1, 3-tetraisopropyldisiloxanylidene) groups.
The term "aryl" as used herein, unless otherwise specified, refers to a substituted or unsubstituted phenyl (Ph), diphenyl or naphthyl, the term aryl preferably referring to a substituted or unsubstituted phenyl. The aryl group may be substituted with one or more moieties selected from: hydroxyl, F, cl, br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate and phosphonate; it may be unprotected or protected as needed, as known to those skilled in the art, for example, as taught by t.w.greene and p.g.m.wuts, "Protective Groups in Organic Synthesis," 3 rd edition, john Wiley & Sons, 1999.
The term "alkaryl" or "alkylaryl" refers to an alkyl group with an aryl substituent such as benzyl. The term "aralkyl" or "arylalkyl" refers to an aryl group with an alkyl substituent.
The term "di (lower alkyl) amino-lower alkyl" refers to a lower alkyl group substituted with an amino group which is itself substituted with two lower alkyl groups. Examples include, but are not limited to (CH) 3 ) 2 NCH 2 、(CH 3 ) 2 NCH 2 CH 2 、(CH 3 ) 2 NCH 2 CH 2 CH 2 And so on. The above examples show lower alkyl groups substituted at the terminal 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" such that the meaning of the term is the same as the examples. It is contemplated that the lower alkyl chain may be substituted with N, N-di (lower alkyl) -amino at any point along the chain, such as CH 3 CH (N- (lower alkyl) 2 )CH 2 CH 2 。
The term "halogen" as used herein includes chlorine, bromine, iodine and fluorine.
The term "acyl" refers to a compound containing a carbonyl groupSubstituents of moieties and non-carbonyl moieties. The carbonyl moiety contains a double bond between the carbonyl carbon and a heteroatom, wherein the heteroatom is selected from the group consisting of O, N, and S. When the heteroatom is N, the N is substituted with a lower alkyl group. The non-carbonyl moiety is selected from: straight, branched, and cyclic alkyl groups, including but not limited to straight, branched, or cyclic C 1-20 Alkyl radical, C 1-10 Alkyl or lower alkyl; alkoxyalkyl groups including methoxymethyl; aralkyl groups including benzyl; aryloxyalkyl such as phenoxymethyl; or aryl, including phenyl optionally substituted with: halogen (F, cl, br, I), hydroxy, C 1 To C 4 Alkyl or C 1 To C 4 Alkoxy, sulfonate esters such as alkyl or aralkyl sulfonyl including methanesulfonyl, mono, di or triphosphate, 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, the aryl group preferably comprises a phenyl group.
The term "lower acyl" refers to acyl groups wherein the non-carbonyl moiety is lower alkyl.
The term "purine" or "pyrimidine" base includes, but is not limited to, adenine, N 6 -alkylpurine, N 6 Acylpurines (in which the acyl group is C (O) (alkyl, aryl, alkylaryl or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinyl purine, N 6 -acetylenic purines, N 6 -acylpurine, N 6 Hydroxyalkyl purine, N 6 Alkyl aminopurine (allcylaminopurine), N 6 Thioalkylpurines (thioallcyl purines), N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidines including 6-azacytosine, 2-and/or 4-mercaptopyrimidine (mercaptopyrmidine), uracil, 5-halouracils including 5-fluorouracil, C 5 Alkyl pyrimidines, C 5 -benzylpyrimidine, C 5 Halogen pyrimidine, C 5 -vinyl pyrimidine, C 5 Acetylenic pyrimidines, C 5 Acyl pyrimidine, C 5 Hydroxy alkanesAlkylpurine, C 5 Acylamidopyrimidines, C 5 -cyanopyrimidine, C 5 Iodopyrimidine, C 6 -iodo (lodo) -pyrimidine, C 5 -Br-vinyl pyrimidine, C 6 -Br-vinyl pyrimidine C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytosine riboside, 5-azauracil, triazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2, 6-diaminopurine, and 6-chloropurine. The functional oxy and nitrogen groups on the base may be protected as needed 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, and acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl.
The terms "tautomerism" and "tautomer" have their accepted clear meanings.
The term "P" means that the phosphorus atom is chiral and has the corresponding Cahn-Ingold-Prelog designation "R" or "S" which have their accepted clear meaning. The compound of formula I is expected to be racemic due to the chirality of the phosphorus. Applicants contemplate the use of racemates and/or resolved enantiomers. In some cases, no asterisk is shown near the phosphorus atom of the phosphoramidate. In these cases, it is understood that the phosphorus atom is chiral, and the skilled artisan should so understand this, unless substituents bonded to the phosphorus preclude the possibility that the phosphorus is chiral, such as P (O) Cl 3 。
Detailed Description
One aspect of the present invention pertains to compounds represented by formula I, and salts, hydrates, solvates, crystalline forms and the like thereof:
wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen, C 1-10 Alkyl radical, R 3a Or R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring C (O) CR comprising adjacent N and C atoms 3a R 3b NHR 1 Wherein n is 2 to 4 1 、R 3a And R 3b ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R 3a Is hydrogenAnd R is 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl, including but not limited toC 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy, di (lower alkyl) -amino or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO(C 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of hydrogen 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
The base is a naturally occurring or modified purine or pyrimidine base, represented by the following structure:
wherein
Z is N or CR 12 ；
R 7 、R 8 、R 9 、R 10 And R 11 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl such as C.ident.CH, C halogenated (F, cl, br, I) 2 -C 6 Lower alkynyl, C 1 -C 6 C of lower alkoxy, halo (F, cl, br, I) 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R' is optionally substituted alkyl including, but not limited to, optionally substituted C 1-20 Alkyl, optionally substituted C 1-10 Alkyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, C 2 -C 6 Optionally substituted alkynyl, C 2 -C 6 Optionally substituted lower alkenyl, or optionally substituted acyl including, but not limited to, C (O) alkyl, C (O) (C) 1-20 Alkyl), C (O) (C) 1-10 Alkyl) or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
R 12 is H, halogen (including F, cl, br, I), OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl, halo (F, cl, br, I) C 2 -C 6 Lower alkynyl, C 1 -C 6 Lower alkoxy, halo (F, cl, br, I) C 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; with the proviso that when the base consists of R 11 When structure c represents hydrogen, R 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
As understood from the structure represented by formula I above, there are countless ways to represent several embodiments of the present invention and aspects of each embodiment. As shown below, the inventors disclose certain embodiments relating to compounds of formula I, each having several aspects based on the identity of the purine or pyrimidine base being modified. This is not intended to be an explicit or implicit acknowledgement that the three embodiments are separate or distinct and should not be so interpreted. Rather, it is intended to convey information so that the full scope of the invention can be understood. Furthermore, the following embodiments and aspects thereof are not intended to limit the full scope of the invention as exemplified by the structures of formula I.
A first embodiment of the present invention is directed to compounds represented by formula I-1:
wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen, C 1-10 Alkyl radical, R 3a Or R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring C (O) CR comprising contiguous N and C atoms 3a R 3b NHR 1 Wherein n is 2 to 4 1 、R 3a And R 3b ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy, di (lower alkyl) -amino or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) -amino, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, cl, br, I, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl radical)、S(C 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 7 、R 8 、R 9 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 Lower alkyl, lower alkyl of halo (F, cl, br, I), C 2 -C 6 Lower alkenyl, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A first aspect of the first embodiment relates to compounds represented by formula I-1
Wherein
(a)R 1 Is hydrogen, n-alkyl or aryl, including but not limited to phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 A haloalkyl group;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a And R 3b Independently is (i) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Are combined togetherIs (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4' -OH) -Ph) or CH 2 SH，R 3b Is H;
(d)R 4 is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy, di (lower alkyl) -amino or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as pyridyl, substituted aryls A substituted or unsubstituted heteroaryl group;
(e)R 5 is H, CN, CH 3 Vinyl, OCH 3 、OCH 2 CH 3 、CH 2 OH、CH 2 (halo) such as CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 ；
(f)R 6 Is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, cl, br, I, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl, vinyl, N 3 、CN、Cl、Br、F、I、O(C 1-6 Acyl group), O (C) 1-4 Alkyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-4 Haloalkyl, O (aminoacyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 Or N (C) 1-4 Acyl radical) 2 ；
(i)R 7 、R 8 、R 9 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 Lower alkyl, lower alkyl of halo (F, cl, br, I), C 2 -C 6 Lower alkenyl, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A second aspect of the first embodiment relates to compounds represented by formula I-1
Wherein
(a)R 1 Is hydrogen, n-alkyl or substituted or unsubstituted phenyl, wherein the substituents of the substituted phenyl are at least one of: c 1-3 Alkyl radical, C 1-3 Alkoxy, F, cl, br, I, nitro, cyano, and C 1-3 A haloalkyl group;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a And R 3b Independently is (i) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indoleIndole-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4' -OH) -Ph) or CH 2 SH，R 3b Is H;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, di (lower alkyl) amino-lower alkyl or aminoacyl;
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 (halo) such as CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 ；
(f)R 6 Is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 Or O (aminoacyl);
(i)R 7 and R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 (ii) a And
(j)R 9 selected from the following: OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 OC (O) (C1-20 alkyl), including but not limited to OC (O) (CH) 2 ) s CH 3 (ii) a NHC (O) (C1-20 alkyl), including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 ) 2 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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 relates to a compound represented by formula I-1
Wherein
(a)R 1 Is hydrogen, n-alkyl or substituted or unsubstituted phenyl, wherein the substituents of the substituted phenyl are at least one of: CH (CH) 3 、OCH 3 、F、Cl、BrI, nitro, cyano and CH 3-q X q Wherein X is F, cl, br or I, q is 1-3;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, or R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl, di (lower alkyl) amino-lower alkyl or aminoacyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 (halo) such as CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 ；
(f)R 6 Is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 Or O (aminoacyl);
(i)R 7 and R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl, C 2 -C 6 Alkenyl radical, C 2 -C 6 An alkynyl group; and
(j)R 9 selected from the following: OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 OC (O) (C1-20 alkyl), including but not limited to OC (O) (CH) 2 ) s CH 3 (ii) a NHC (O) (C1-20 alkyl), including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 ) 2 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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 relates to compounds represented by formula I-2
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl or substituted or unsubstituted phenyl, wherein the substituent of the substituted phenyl is at least one of the following: CH (CH) 3 、OCH 3 F, cl, br, I, nitro, cyano and CH 3-q X q Wherein X is F, cl, br or I, and q is 1-3;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, or R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H;
(d)R 4 is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 ；
(f)R 6 Is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 Or O (aminoacyl);
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl; and
(j)R 9 selected from the following: OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 OC (O) (C1-20 alkyl), including but not limited to OC (O) (CH) 2 ) s CH 3 (ii) a NHC (O) (C1-20 alkyl), including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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 relates to compounds represented by formula I-2
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl, di (lower alkyl) amino-lower alkyl or aminoacyl;
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen, including F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 Or O (aminoacyl);
(i)R 7 and R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 An alkynyl group; and
(j)R 9 selected from the following: OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、OC(O)(C 1-20 Alkyl) including but not limited to OC (O) (CH) 2 ) s CH 3 ；NHC(O)(C 1-20 Alkyl) including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 ) 2 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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 relates to a compound represented by formula I-2
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl or substituted heteroaryl;
(e)R 5 Is H, OMe, CN, CH 2 F. F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 F, cl, br, I or N 3 ；
(h) Y is H, OH, CH 3 F, cl, br, I or N 3 、OCH 3 、OC(O)CH 3 Or O (aminoacyl);
(i)R 7 and R 8 Independently H, F, br, SCH 3 、CH 3 、CH 3-q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 (ii) a And
(j)R 9 selected from the following: OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、OC(O)(C 1-20 Alkyl), including but not limited to OC (O) (CH) 2 ) s CH 3 ；NHC(O)(C 1-20 Alkyl) including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 ) 2 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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 relates to a compound represented by formula I-2
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 F orN 3 ；
(h) Y is OH, OCH 3 、OC(O)CH 3 Or O (aminoacyl);
(i)R 7 and R 8 Independently H, F, br, SCH 3 、CH 3 、CH 3-q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 (ii) a And
(j)R 9 selected from the following: OH, OCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、OC(O)(C 1-20 Alkyl), including but not limited to OC (O) (CH) 2 ) s CH 3 ；NHC(O)(C 1-20 Alkyl) including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 ) 2 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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.
An eighth aspect of the first embodiment relates to a compound represented by formula I-2
Wherein
(a)R 1 Hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl)) Amino-lower alkyl;
(e)R 5 is H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 F or N 3 ；
(h) Y is OH, OCH 3 、OC(O)CH 3 Or O (aminoacyl);
(i)R 7 And R 8 Independently H, F, br, SCH 3 、CH 3 、CH 3-q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 ；
(j)R 9 Selected from the following: OH, OCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、OC(O)(C 1-20 Alkyl), including but not limited to OC (O) (CH) 2 ) s CH 3 ；NHC(O)(C 1-20 Alkyl) including but not limited to NHC (O) (CH) 2 ) s CH 3 (ii) a And N (C (O) (CH) 2 ) s CH 3 ) 2 Including but not limited to N (C (O) (CH) 2 ) s CH 3 ) 2 Wherein 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 second embodiment of the invention relates to compounds of formula I wherein the base is of the structure shown above as formula b, wherein R is 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 、X、Y、R 7 And R 8 As defined in the summary of the invention section above.
A first aspect of the second embodiment relates to compounds represented by formula I-3
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R is 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently of one another is hydrogenOr C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkylAminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, cl, br, I, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 Or N (C) 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 Or N (C) 1-4 Acyl radical) 2 ；
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 Lower alkyl, lower alkyl of halo (F, cl, br, I), C 2 -C 6 Lower alkenyl, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A second aspect of the second embodiment relates to compounds represented by formula I-3
Wherein
(a)R 1 Is hydrogen, n-alkyl or aryl, including but not limited to phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 A haloalkyl group;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a And R 3b Independently is (i) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4' -OH) -Ph) or CH 2 SH，R 3b Is H;
(d)R 4 is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl or substituted heteroaryl;
(e)R 5 is H, CN, CH 3 Vinyl, OCH 3 、OCH 2 CH 3 、CH 2 OH、CH 2 (halo) such as CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen, including F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl, vinyl, N 3 、CN、Cl、Br、F、I、O(C 1-6 Acyl group), O (C) 1-4 Alkyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 Lower alkyl, halo (F, cl, br, I) lower alkyl, C 2 -C 6 Lower alkenyl of, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A third aspect of the second embodiment relates to a compound represented by formula I-3
(a)R 1 Is hydrogen, n-alkyl or substituted or unsubstituted phenyl, wherein the substituents of the substituted phenyl are at least one of: c 1-3 Alkyl radical, C 1-3 Alkoxy, F, cl, br, I, nitro, cyano and C 1-3 A haloalkyl group;
(b)R 2 is hydrogen, CH 3 ，R 3a Or R 3b And R 2 Together are (CH) 2 ) 3 So as to form a cyclic ring C (O) CR comprising adjacent N and C atoms 3a R 3b NHR 1 Wherein n is 2 to 4 1 、R 3a And R 3b As defined herein;
(c)R 3a and R 3b Independently is (i) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a structure comprisingA cyclic ring of N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridine-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 (halo) such as CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen, including F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 Halogen, NH 2 Or N 3
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 ；
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 。
A fourth aspect of the second embodiment relates to compounds represented by formula I-3
Wherein
(a)R 1 Is hydrogen, n-alkyl or substituted or unsubstituted phenyl, wherein the substituents of the substituted phenyl are at least one of: CH (CH) 3 、OCH 3 F, cl, br, I, nitro, cyano and CH 3-q X q Wherein X is F, cl, br or I, and q is 1-3;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, or R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 (halo) such as CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen, including F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 ；
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I, q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A fifth aspect of the second embodiment relates to compounds represented by formula I-4
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl or substituted or unsubstituted phenyl, wherein the substituent of the substituted phenyl is at least one of the following: CH (CH) 3 、OCH 3 F, cl, br, I, nitro, cyano and CH 3-q X q Wherein X is F, cl, br orI and q are 1 to 3;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, or R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen, including F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 ；
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A sixth aspect of the second embodiment relates to a compound represented by formula I-4
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen, including F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 7 And R 8 Independently H, F, cl, br, I, OH, OCH 3 、SH、SCH 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 、CH 3 、CH 3- q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 H、CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 Wherein R' is C 1-20 Alkyl radical, C 1-20 Cycloalkyl radicals、C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl.
A seventh aspect of the second embodiment relates to compounds represented by formula I-4
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, OMe, CN, CH 2 F. F, cl, br or I;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 OCH3 or OC (O) CH 3 ；
(i)R 7 And R 8 Independently H, F, br, SCH 3 、CH 3 、CH 3-q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 ；
An eighth aspect of the second embodiment relates to compounds represented by formula I-4
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 7 And R 8 Independently H, F, br, SCH 3 、CH 3 、CH 3-q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 。
A ninth aspect of the second embodiment relates to a compound represented by formula I-4
Wherein
(a)R 1 Is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 F or N 3 ；
(h) Y is OH, OCH 3 Or OC (O) CH 3 ；
(i)R 7 And R 8 Independently H, F, br, SCH 3 、CH 3 、CH 3-q X q Wherein X is F, cl, br or I and q is 1 to 3, vinyl, CO 2 CH 3 、CONH 2 、CONHCH 3 Or CON (CH) 3 ) 2 。
A third embodiment of the invention relates to compounds of formula I wherein the base is of the structure shown above in formula c, wherein R is 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 、X、Y、Z、R 10 、R 11 And R 12 As defined in the summary section above; provided that R is 11 Is not H.
A first aspect of the third embodiment relates to compounds represented by formula I-5
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxyl, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R is 3a And R 3b Are all C 1-6 An alkyl group; (iii) R is 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising adjacent N and C atoms, wherein C is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2To 5, n is 2 to 4, and wherein R 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b From H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 HaloalkanesBase, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl or substituted heteroaryl;
(e)R 5 Is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of hydrogen 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 10 And R 11 Independently H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl such as C.ident.CH, C halogenated (F, cl, br, I) 2 -C 6 Lower alkynyl, C 1 -C 6 Lower alkoxy, halo (F, cl, br, I) C 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' is provided when R 10 R is OH 11 Is other than NH 2 ；
Wherein R' is optionally substituted alkyl including, but not limited to, optionally substituted C 1-20 Alkyl, optionally substituted C 1-10 Alkyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 2 -C 6 Lower alkenyl, or optionally substituted acyl including, but not limited to, C (O) alkyl, C (O) (C) 1-20 Alkyl), C (O) (C) 1-10 Alkyl) or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl, halo (F, cl, br, I) C 2 -C 6 Lower alkynyl, C 1 -C 6 C of lower alkoxy, halo (F, cl, br, I) 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A second aspect of the third embodiment relates to compounds represented by formula I-5
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2、 N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A third aspect of the third embodiment relates to a compound represented by formula I-5
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 2 F. F, cl, br or I, with the proviso that X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A fourth aspect of the third embodiment relates to compounds represented by formula I-5
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or, alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A fifth aspect of the third embodiment relates to compounds represented by formula I-5
Wherein
(a)R 1 Hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A sixth aspect of the third embodiment relates to a compound represented by formula I-5
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A seventh aspect of the third embodiment relates to a compound represented by formula I-5
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 2 F. F, cl, br or I, with the proviso that X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
An eighth aspect of the third embodiment relates to a compound represented by formula I-5
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-toluenePhenyl, bromo-phenyl, chloro-phenyl, fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A ninth aspect of the third embodiment relates to a compound represented by formula I-5
Wherein
(a)R 1 Hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, 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)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In the case of (1), each R' is included inAt least one C atom linked to form a heterocyclic ring comprising at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A tenth aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 (1H-indol-3-yl) methyl, (1H-imidazole-4)-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R is 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R is 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl, including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 Is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, cl, br, I, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
An eleventh aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A twelfth aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 2 F. F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' stripWhen the component is R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or, alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A thirteenth aspect of the third embodiment relates to compounds represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 Is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A fourteenth aspect of the third embodiment relates to the compounds represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, 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 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R' with the proviso that when R 10 R is OH 11 Is other than NH 2 ；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A fifteenth aspect of the third embodiment is directed to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl radical、C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl, including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxyl, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A sixteenth aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen,Methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A seventeenth aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 2 F. F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
An eighteenth aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is NH 2 And R is 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A nineteenth aspect of the third embodiment relates to a compound represented by formula I-6
Wherein
(a)R 1 Is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is NH 2 And R is 11 Independently H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'；
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I)、OR'、NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A fourth embodiment of the invention relates to compounds of formula I wherein the base is of the structure shown above as formula c, wherein R is 11 Is H, R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 X and Y are defined above in the summary of the invention section.
A first aspect of the fourth embodiment relates to a compound represented by formula I-7
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl, including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R is 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of hydrogen 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 10 Is H, F, cl, br, I, OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl such as C.ident.CH, C halogenated (F, cl, br, I) 2 -C 6 Lower alkynyl, C 1 -C 6 Lower alkoxy, halo (F, cl, br, I) C 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R' is optionally substituted alkyl including, but not limited to, optionally substituted C 1-20 Alkyl, optionally substituted C 1-10 Alkyl, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 2 -C 6 Lower alkenyl, or optionally substituted acyl including, but not limited to, C (O) alkyl, C (O) (C) 1-20 Alkyl), C (O) (C) 1-10 Alkyl) or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OH, OR ', SH, SR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, halo (F, cl, br, I) C 1 -C 6 Lower alkyl, C 2 -C 6 Lower alkenyl, halo (F, cl, br, I) C 2 -C 6 Lower alkenyl, C 2 -C 6 Lower alkynyl, halo (F, cl, br, I) C 2 -C 6 Lower alkynyl, C 1 -C 6 C of lower alkoxy, halo (F, cl, br, I) 1 -C 6 Lower alkoxy, CO 2 H、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; with the proviso that R 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A second aspect of the fourth embodiment relates to a compound represented by formula I-7
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen (including F, cl, br or I) Provided that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 Halogen, NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or, alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; provided that R is 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A third aspect of the third embodiment relates to a compound represented by formula I-7
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, CN, CH 2 F. F, cl, br or I, with the proviso that X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; with the proviso that R 12 Is not:(i)–C≡C–H，(ii)–C＝CH 2 or (iii) -NO 2 。
A fourth aspect of the fourth embodiment relates to compounds represented by formula I-7
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 And R 11 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or, alternatively, at NR' 2 In case of (2), each R'Comprising at least one C atom linked to form a heterocyclic ring comprising at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; provided that R is 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A fifth aspect of the fourth embodiment relates to a compound represented by formula I-7
Wherein
(a)R 1 Is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'。
A sixth aspect of the fourth embodiment relates to the compounds represented by formula I-8
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently isHydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxyl, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R is 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 Is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, a baseThe radicals being cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; with the proviso that when the base consists of R 11 When structure c represents hydrogen, R 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A seventh aspect of the fourth embodiment relates to the compounds represented by formula I-8
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 Halogen, NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; provided that R is 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
An eighth aspect of the fourth embodiment relates to a compound represented by formula I-8
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 2 F. F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; provided that R is 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A ninth aspect of the fourth embodiment relates to a compound represented by formula I-8
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; with the proviso that R 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A tenth aspect of the fourth embodiment relates to the compounds represented by formula I-8
Wherein
(a)R 1 Is hydrogenMethyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 ；
(i)R 10 Is H, F, br, I, OH, OR', NH 2 、NHR'、NR' 2 、CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'，
Wherein R 'is lower alkyl, lower cycloalkyl or C (O) (lower alkyl), or alternatively, at NR' 2 In which case each R' includes at least one C atom that is linked to form a heterocyclic ring including at least two carbon atoms; and
(j) Z is N or CR 12 (ii) a And
R 12 is H, halogen (including F, cl, br, I), OR', NH 2 、NHR'、NR' 2 、NO 2 、C 1 -C 6 Lower alkyl, CO 2 R'、CONH 2 、CONHR'、CONR' 2 、CH＝CHCO 2 H or CH = CHCO 2 R'; provided that R is 12 Is not: (i) -C ≡ C-H, (ii) -C = CH 2 Or (iii) -NO 2 。
A fifth embodiment of the invention relates to compounds of formula I wherein the base is of the structure shown above in formula d, wherein R is 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 X and Y are defined in the summary section above.
A first aspect of the fifth embodiment relates to compounds represented by formula I-9
Wherein
(a)R 1 Is hydrogen, n-alkyl, branched alkyl, cycloalkyl, or aryl, including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with at least one of: c 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, F, cl, br, I, nitro, cyano, C 1-6 Haloalkyl, -N (R) 1' ) 2 、C 1-6 Amido, -NHSO 2 C 1-6 Alkyl, -SO 2 N(R 1' ) 2 、COR 1" and-SO 2 C 1-6 An alkyl group; (R) 1' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 1" is-OR' OR-N (R) 1' ) 2 )；
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a And R 3b (i) Independently selected from hydrogen, C 1-10 Alkyl, cycloalkyl, - (CH) 2 ) c (NR 3' ) 2 、C 1-6 Hydroxyalkyl, -CH 2 SH、-(CH 2 ) 2 S(O) d Me、-(CH 2 ) 3 NHC(＝NH)NH 2 - (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, - (CH) 2 ) e COR 3" Aryl and aryl C 1-3 Alkyl, said aryl being optionally selected from hydroxy, C 1-10 Alkyl radical, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 3a And R 3b Are all C 1-6 An alkyl group; (iii) R is 3a And R 3b Together are (CH) 2 ) f So as to form a spiro ring; (iv) R is 3a Is hydrogen, and R 3b And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms; (v) R is 3b Is hydrogen, and R 3a And R 2 Together are (CH) 2 ) n So as to form a cyclic ring comprising contiguous N and C atoms, wherein 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 wherein R is 3' Independently is hydrogen or C 1-6 Alkyl radical, and R 3" is-OR' OR-N (R) 3' ) 2 )；(vi)R 3a Is H and R 3b Is H, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or (viii) R 3a Is CH 3 、-CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H, wherein R 3' Independently hydrogen or alkyl including but not limited to C 1-20 Alkyl radical, C 1-10 Alkyl or C 1-6 Alkyl radical, R 3" is-OR' OR-N (R) 3' ) 2 )；
(d)R 4 Is hydrogen, C 1-10 Alkyl, C optionally substituted by lower alkyl, alkoxy or halogen 1-10 Alkyl radical, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, di (lower alkyl) amino-lower alkyl, aryl such as phenyl, heteroaryl such as pyridyl, substituted aryl, or substituted heteroaryl;
(e)R 5 is H, lower alkyl, CN, vinyl, O- (lower alkyl), hydroxy lower alkyl, i.e. - (CH) 2 ) p OH, wherein p is 1-6, including hydroxymethyl (CH) 2 OH)、CH 2 F、N 3 、CH 2 CN、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Alkyne (optionally substituted) or halogen, including F, cl, br or I, with the proviso that when X is OH, the base is cytosine and R 6 Is H, R 5 Is not N 3 And when X is OH, R 6 Is CH 3 Or CH 2 F and B are purine bases, R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OMe, halogen, NH 2 Or N 3 ；
(h) Y is OH, H, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, vinyl, N 3 、CN、Cl、Br、F、I、NO 2 、OC(O)O(C 1-4 Alkyl), OC (O) O (C) 1-4 Alkyl), OC (O) O (C) 2-4 Alkynyl), OC (O) O (C) 2-4 Alkenyl), OC 1-10 Haloalkyl, O (aminoacyl), O (C) 1-10 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl group), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-18 Acyl radical) 2 Wherein alkyl, alkynyl, alkenyl, and vinyl are optionally substituted with: n is a radical of 3 CN, 1-3 halogens (Cl, br, F, I), NO 2 、C(O)O(C 1-4 Alkyl), C (O) O (C) 1-4 Alkyl), C (O) O (C) 2-4 Alkynyl), C (O) O (C) 2-4 Alkenyl), O (C) 1-4 Acyl group), O (C) 1-4 Alkyl), O (C) 2-4 Alkenyl), S (C) 1-4 Acyl group), S (C) 1-4 Alkyl), S (C) 2-4 Alkynyl), S (C) 2-4 Alkenyl), SO (C) 1-4 Acyl group), SO (C) 1-4 Alkyl), SO (C) 2-4 Alkynyl), SO (C) 2-4 Alkenyl), SO 2 (C 1-4 Acyl), SO 2 (C 1-4 Alkyl), SO 2 (C 2-4 Alkynyl), SO 2 (C 2-4 Alkenyl), OS (O) 2 (C 1-4 Acyl), OS (O) 2 (C 1-4 Alkyl), OS (O) 2 (C 2-4 Alkenyl), NH 2 、NH(C 1-4 Alkyl), NH (C) 2-4 Alkenyl), NH (C) 2-4 Alkynyl), NH (C) 1-4 Acyl group), N (C) 1-4 Alkyl radical) 2 、N(C 1-4 Acyl radical) 2 。
A second aspect of the fifth embodiment relates to compounds represented by formula I-9
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen, including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 Halogen, NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 。
A third aspect of the fifth embodiment relates to a compound represented by formula I-9
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 2 F. F, cl, br or I, with the proviso that X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 、N 3 、OCH 3 Or OC (O) CH 3 。
A fourth aspect of the fifth embodiment relates to compounds represented by formula I-9
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 Is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 。
A fifth aspect of the fifth embodiment relates to compounds represented by formula I-9
Wherein
(a)R 1 Is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 。
A sixth aspect of the fifth embodiment relates to compounds represented by formula I-10
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl or substituted or unsubstituted phenyl, wherein the substituent of the substituted phenyl is at least one of the following: CH (CH) 3 、OCH 3 F, cl, br, I, nitro, cyano and CH 3-q X q Wherein X is F, cl, br or I, and q is 1-3;
(b)R 2 Is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl; or R 3a Is CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl, R 3b Is H;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F、N 3 、CH 2 CN、CH 2 N 3 、CH 2 NH 2 、CH 2 NHCH 3 、CH 2 N(CH 3 ) 2 Halogen including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is OH, H, CH 3 Vinyl group, N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 、NH 2 、NHCH 3 NH (vinyl), NH (acetyl), NH (C (O) CH 3 )、N(CH 3 ) 2 、N(C(O)CH 3 ) 2 。
A seventh aspect of the fifth embodiment relates to a compound represented by formula I-10
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph、CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 、CH 2 CO 2 H、CH 2 C(O)NH 2 、CH 2 CH 2 COOH、CH 2 CH 2 C(O)NH 2 、CH 2 CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHC(NH)NH 2 、CH 2 -imidazol-4-yl, CH 2 OH、CH(OH)CH 3 、CH 2 ((4'-OH)-Ph)、CH 2 SH or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl ；
(e)R 5 Is H, CN, CH 3 、OCH 3 、CH 2 OH、CH 2 F. Halogen, including F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 F or CN;
(g) X is H, OH, F, OCH 3 、Cl、Br、I、NH 2 Or N 3 (ii) a And
(h) Y is OH, H, CH 3 Vinyl group, NH 2 、N 3 、CN、Cl、Br、F、I、OC(O)CH 3 、OCH 3 。
An eighth aspect of the fifth embodiment relates to a compound represented by formula I-10
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen or CH 3 ；
(c)R 3a Is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, CN, CH 2 F. F, cl, br or I, with the proviso that when X is OH, R 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, F, OCH 3 、F、Cl、Br、I、NH 2 Or N 3 ；
(h) Y is H, OH, CH 3 、F、Cl、Br、I、NH 2 Or N 3 、OCH 3 Or OC (O) CH 3 。
A ninth aspect of the fifth embodiment relates to a compound represented by formula I-10
Wherein
(a)R 1 Is hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 Is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 。
A tenth aspect of the fifth embodiment relates to compounds represented by formula I-10
Wherein
(a)R 1 Is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b)R 2 is hydrogen;
(c)R 3a is H and R 3b Is H, CH 3 、CH(CH 3 ) 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、CH 2 Ph or lower cycloalkyl;
(d)R 4 is hydrogen, CH 3 、Et、 i Pr、 n Pr、 n Bu, 2-butyl, t Bu, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl or di (lower alkyl) amino-lower alkyl;
(e)R 5 is H, with the proviso that R is when X is OH 6 Is CH 3 Or CH 2 F，R 5 Is not H;
(f)R 6 is H, CH 3 、CH 2 F、CHF 2 、CF 3 Or F;
(g) X is H, OH, OCH 3 、F、NH 2 Or N 3 ；
(h) Y is OH, NH 2 、OCH 3 Or OC (O) CH 3 。
The following table includes numerical identifiers associated with various substituent identifiers that should be viewed in light of the attached structure. These structures are contemplated for different aspects of the disclosed embodiments and are not intended to limit the full scope encompassed by the compounds represented by the structures of formula I. However, it is also contemplated that any of the exemplary nucleobases can be associated with a designated R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 Any of the contemplated substances in the specific combinations of X and Y is used in combination. In each given table, the inclusion of substituent R is depicted 3a And R 3b Phosphoramidate substituents of (2), not mentionedStereochemistry (see: structures I-1, I-3, I-5, I-7 and I-9 above). Compounds enumerated below are contemplated to include R 3a Convex toward the viewer and R 3b Compounds that protrude away from the viewer (see structures I-2, I-4, I-6, I-8, and I-10). In addition, it is contemplated that the compounds listed below also include R 3a Convex away from the viewer and R 3b Compounds that are convex towards the viewer. However, without intending to be limiting, it is contemplated that the preferred compound is R 3a Convex toward the viewer and R 3b Those that project away from the viewer so as to assume the (S) configuration of the natural L amino acid. Furthermore, the inventors have recognized that the phosphorus atom of the phosphoramidate moiety is another source of chirality. Although the following structure does not specifically depict the chirality of the phosphorus, the inventors have recognized that stereochemical configurations are possible such that in a staggered (OR zigzag) linear structure, the oxygen-substituents protrude towards the viewer and the OR 1 The substituents project away from the viewer and vice versa, i.e., the Cahn-Ingold-Prelog stereochemistry of phosphorus is R or S. Thus, the following structure includes all possible stereochemical configurations that are reasonable for phosphorus.
Table II-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table II-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II to 17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-31.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-32.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-34.
*R 2 And R 3b By (CH) 2 ) 3 Connection ofTogether to form a five-membered ring.
Tables II-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II to 36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table II-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table II-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables II-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-48.
*R 2 And R 3b By (a)CH 2 ) 3 Are linked together to form a five-membered ring.
Tables II-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables II-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table III-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table III-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table III-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table III-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table III-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table III-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table III-7.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table III-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-39.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formForming a five-membered ring.
Tables III-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-45.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables III-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables III-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IV-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IV-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IV-7.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IV-8.
*R 2 And R 3b By (a) toCH 2 ) 3 Joined together to form a five-membered ring.
Table IV-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IV-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IV-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IV-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables IV-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables IV-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-7.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-8.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-15.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-21.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-31.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-32.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-34.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to form fiveA membered ring.
Table V-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-37.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-39.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formA five-membered ring.
Table V-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table V-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table V-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-2.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-3.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-14.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VI to 15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VI to 17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-31.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VI to 35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VI-41.
*R 2 And R 3b By (a)CH 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 45.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VI-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI to 48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VI-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VII-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VII-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 13.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 15.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 17.
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*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 19.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 21.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII-37.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 39.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formForming a five-membered ring.
Tables VII to 40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII to 47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VII to 49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VII-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE VIII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-3.
*R 2 And R 3b By passing(CH 2 ) 3 Joined together to form a five-membered ring.
TABLE VIII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-8.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE VIII-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-15.
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*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE VIII-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VIII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE VIII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-21.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE VIII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VIII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VIII-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-41.
*R 2 And R 3b By (CH) 2 ) 3 Is connected toTo form a five-membered ring.
Tables VIII-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VIII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table VIII-45.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table VIII-46.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables VIII-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VIII-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VIII-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables VIII-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-39.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table IX-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table IX-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-14.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-21.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-31.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-32.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE X-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-39.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table X-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table X-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-3.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XI-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-15.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-17.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-19.
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*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-21.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XI-23.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-25.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-27.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XI-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XI-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XI-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XI-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XI-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XI-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-7.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XII-8.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XII-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XII-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-15.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-16.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XII-17.
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*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formForming a five-membered ring.
Tables XII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-19.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-21.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-23.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-25.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XII-27.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-29.
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*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-31.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-33.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-35.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XII-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XII-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XII-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-15.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-24.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-27.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XIII-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XIII-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIII-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-3.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-9.
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*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-12.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-13.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-46.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIV-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIV-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIV-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-3.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formForming a five-membered ring.
Table XV-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-7.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-13.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-14.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-40.
*R 2 And R 3b By (C)H 2 ) 3 Joined together to form a five-membered ring.
Table XV-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-46.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XV-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XV-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVI-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVI-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-13.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVI-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVI-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVI-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-39.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVI-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVI-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVI-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVI-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVI-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVI-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVI-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVII-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVII-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVII-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVII-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVII-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVII-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVII-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-2.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XVIII-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-8.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formA five-membered ring.
TABLE XVIII-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-17.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XVIII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVIII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XVIII-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XVIII-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XVIII-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XVIII-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-4.
*R 2 And R 3b By passing(CH 2 ) 3 Joined together to form a five-membered ring.
Table XIX-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-8.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-19.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-31.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-37.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XIX-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XIX-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XIX-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XIX-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-7.
*R 2 And R 3b By (CH) 2 ) 3 Is connected toTo form a five-membered ring.
Table XX-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XX-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XX-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-19.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-21.
*R 2 And R 3b By (C)H 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XX-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XX-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-3.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-7.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-13.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-15.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-24.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-27.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-37.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-45.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXI-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXI-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-14.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-25.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formA five-membered ring.
Table XXII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-45.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXII-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXII-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-14.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-17.
*R 2 And R 3b By (CH) 2 ) 3 Is connected toTo form a five-membered ring.
Table XXIII-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-20.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-24.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-46.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XXIII-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIII-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIII-50.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to form fiveA membered ring.
Table XXIV-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-3.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-31.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-46.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIV-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIV-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-3.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-12.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-15.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-17.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXV-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-32.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXV-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXV-37.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXV-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXV-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-42.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXV-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXV-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-2.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-12.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-15.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVI to 17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVI to 19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVI to 21.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-39.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVI to 45.
*R 2 And R 3b By (CH) 2 ) 3 Are connected togetherTo form a five-membered ring.
Table XXVI-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVI to 47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVI-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVI to 49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVI-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-4.
*R 2 And R 3b By passing(CH 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-6.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-8.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-12.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-13.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-15.
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*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Tables XXVII-19.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-32.
*R 2 And R 3b By (CH) 2 ) 3 Is connected toTo form a five-membered ring.
Table XXVII-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-37.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVII-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVII-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVII-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVII-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-10.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-12.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-15.
*R 2 And R 3b By (CH) 2 ) 3 Are connected together to formA five-membered ring.
Table XXVIII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-17.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-27.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-36.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-38.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-39.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-45.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXVIII-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXVIII-48.
*R 2 And R 3b By (CH) 2 ) 3 Is connected toTogether to form a five-membered ring.
Table XXVIII-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXVIII-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-5.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIX-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIX-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-22.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIX-24.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-29.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIX-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring。
Table XXIX-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIX-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXIX-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXIX-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-1.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-12.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXX-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXX-24.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXX-27.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-28.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXX-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXX-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-41.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXX-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ringAnd (4) a ring.
Table XXX-43.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXX-44.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXX-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Tables XXX-49.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXX-50.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-1.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-4.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-9.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-11.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-14.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-18.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXI-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-23.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-24.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-25.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-26.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXI-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-30.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-32.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-33.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-34.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-35.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-40.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXI-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXI-44.
*R 2 And R 3b By (CH) 2 ) 3 Connection ofTogether to form a five-membered ring.
Table XXXI-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-46.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-47.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-48.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXI-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXI-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-1.
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*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-2.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-3.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-4.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-5.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-6.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-7.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-8.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-9.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-10.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-11.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXII-12.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-13.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-14.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-15.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-16.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-17.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-18.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-19.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-20.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-21.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-22.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-23.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-24.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-25.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-26.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-27.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-28.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-29.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-30.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-31.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-32.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-33.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-34.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXII-35.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-36.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-37.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-38.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-39.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-40.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-41.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-42.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-43.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
TABLE XXXII-44.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-45.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-46.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-47.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Table XXXII-48.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
Table XXXII-49.
*R 2 And R 3b By (CH) 2 ) 3 Are linked together to form a five-membered ring.
TABLE XXXII-50.
*R 2 And R 3b By (CH) 2 ) 3 Joined together to form a five-membered ring.
Dosage, administration and use
A sixth embodiment of the invention relates to a composition for use in the treatment of any of the viral agents disclosed herein, the composition comprising a pharmaceutically acceptable medium selected from excipients, carriers, diluents and equivalent media, and a compound represented by formula I, which is intended to include salts (acid or base addition salts), hydrates, solvates and crystalline forms thereof, which may be obtained.
It is contemplated that the formulation (formulation) of the sixth embodiment may comprise a compound comprised in any of the first, second, third, fourth and fifth embodiments or any of those specifically recited in the above table or exemplified herein, alone or in combination with another compound of the invention.
The compounds of the present invention may be formulated with carriers into a variety of oral dosage forms. Oral administration may be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are effective when administered by suppository administration as well as other routes of administration. The most convenient mode of administration is usually oral, using a convenient daily dosage regimen, which may be adjusted according to the severity of the disease and the patient's response to the antiviral drug.
The compounds of the present invention and their pharmaceutically acceptable salts may be incorporated in the form of pharmaceutical compositions and unit dosages, together with one or more conventional excipients, carriers or diluents. The pharmaceutical compositions and unit dosage forms can comprise conventional ingredients in conventional proportions, with or without other active compounds, and the unit dosage form can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical composition may be in the form of a solid such as a tablet or a filled capsule, a semi-solid, a powder, a sustained release formulation or a liquid such as a suspension, an emulsion or a filled capsule for oral use; or in the form of suppositories for rectal or vaginal administration. Typical formulations contain from about 5% to about 95% active compound (w/w). The term "formulation" or "dosage form" is intended to include both solid and liquid formulations of the active compound, and it will be understood by those skilled in the art that the active ingredient may be present in different formulations depending on the desired dosage and pharmacokinetic parameters.
The term "excipient" as used herein refers to a compound used to prepare a pharmaceutical composition, which is generally safe, non-toxic, biologically or otherwise desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. The compounds of the invention may 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.
The "pharmaceutically acceptable salt" form of the active ingredient may also initially impart desirable pharmacokinetic properties not present in the non-salt form of the active ingredient, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in vivo. The phrase "pharmaceutically acceptable salt" of a compound, as used herein, refers to 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 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, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like; or (2) a base addition salt formed with a conjugate base of any of the inorganic acids listed above, wherein the conjugate base comprises a base selected from Na + 、K + 、Mg 2+ 、Ca 2+ And NH g R”' 4-g + Wherein R' "is C 1-3 Alkyl, g is a number selected from 0, 1, 2, 3 or 4. It is to be understood that all references to pharmaceutically acceptable are intended to be interpreted as being acceptableSalts include solvent addition forms (solvates) or crystalline 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 is usually a finely divided solid which is in admixture with the finely divided active component. In tablets, the active component is usually 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, sucrose, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Formulations in solid form may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
Liquid formulations also suitable for oral administration include liquid formulations including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. Emulsions may be prepared in solution, for example in aqueous propylene glycol solution, or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions may 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 then dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and solidify.
The compounds of the 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 are described in Remington, the Science and Practice of Pharmacy 1995, e.w. martin, mack Publishing Company, 19 th edition, easton, pennsylvania, along with pharmaceutical carriers, diluents and excipients, which are hereby incorporated by reference. The compounds of the invention may 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. Experienced formulators within the teachings of this specification can vary the formulation to provide a wide variety of formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
For example, modification of the compounds of the present invention to render them more soluble in water or other carriers can be readily accomplished by minor modifications (e.g., salt formulations), which are well within the ordinary skill in the art. It is well within the ordinary skill in the art to vary the route of administration and dosage regimen of a particular compound to take advantage of the pharmacokinetics of the compounds of the present invention to produce the greatest beneficial effect in a patient.
A seventh embodiment of the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of any condition caused by infection with any one of the following viral agents: hepatitis c virus, west nile virus, yellow fever virus, dengue fever virus, rhinovirus, poliovirus, hepatitis a virus, bovine viral diarrhea virus, and japanese encephalitis virus.
The term "drug" refers to a substance used in a method of treating and/or preventing a subject in need thereof, wherein the substance includes, but is not limited to, compositions, formulations, dosage forms, and the like, comprising a compound of formula I. It is contemplated that the compound of the seventh embodiment for use of the compound represented by formula I in the manufacture of a medicament for treating any of the antiviral conditions disclosed herein may be a compound encompassed by any of the first, second, third, fourth, fifth embodiments, or any of those specifically recited in the above table or exemplified herein, alone or in combination with another compound of the invention. Medicaments include, but are not limited to, any of the compositions contemplated by the sixth embodiment of the present invention.
An eighth embodiment of the invention is directed to a method of treating and/or preventing a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I.
A first aspect of an eighth embodiment relates to a method of treating and/or preventing a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least two or more different compounds falling within the scope of the compound of formula I.
A second aspect of the eighth embodiment relates to a method of treatment and/or prophylaxis of a subject in need thereof, which method comprises administering to the subject alternately or simultaneously at least two therapeutically effective compounds falling within the scope of the compounds of formula I.
A subject in need thereof means a subject having any of the signs caused by infection with any of the viral agents disclosed herein, including, but not limited to, 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, flavivirus or pestivirus or hepatitis c virus, or a viral agent causing symptoms equivalent or equivalent to those caused by any of the viruses listed above.
The term "subject" refers to a mammal, including but not limited to cattle, pigs, sheep, chickens, turkeys, buffalos, camels (llama), ostriches, dogs, cats, and humans, preferably the subject is a human. It is envisaged that the method of treatment of a subject in accordance with the sixth embodiment may be a compound encompassed by any of the first, second and third embodiments, or any of those compounds specifically recited in the above table, alone or in combination with another compound of the invention.
The term "therapeutically effective amount" as used herein refers to the amount required to reduce the symptoms of a disease in an individual. In each particular case, the dosage should be adjusted to the individual requirements. The dosage may vary within wide limits depending upon a number of factors, such as the severity of the disease to be treated, the age and general health of the patient, the other drugs being treated for the patient, the route and form of administration, and the preferences and experience of the practitioner involved. For oral administration, suitable daily dosages in monotherapy and/or in combination therapy per day are between about 0.1g and about 10g, including all values such as between 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, etc. Preferred daily dosages are between about 0.5 g/day to about 7.5 g/day, more preferably 1.5 g/day to about 6.0 g/day. Generally, treatment is initiated with a large initial "loading dose" to rapidly reduce or eliminate the virus, and then the dose is reduced to a level sufficient to prevent recurrence of the infection. One of ordinary skill in the treatment of the diseases described herein will be able to determine, without undue experimentation and depending on the individual's knowledge, experience, and disclosure of the application, a therapeutically effective amount of a compound of the present invention for a given disease and patient.
The efficacy of treatment can be determined according to the following assay: liver function, including but not limited to protein levels such as serum proteins (e.g., albumin, coagulation factors, alkaline phosphatase, aminotransferases (e.g., alanine aminotransferase, aspartate aminotransferase), 5' -nucleosidase, gamma-glutamyltranspeptidase, etc.), the synthesis of bilirubin, cholesterol, and bile acid; hepatic metabolic functions, including but not limited to carbohydrate metabolism, amino acid and ammonia metabolism. Alternatively, the effect of treatment can be monitored by measuring HCV-RNA. The results of these assays allow optimization of the dose.
A third aspect of the eighth embodiment relates to a method of treating and/or preventing a subject in need thereof, the method comprising administering to the subject a therapeutically effective compound of formula I and a therapeutically effective amount of another antiviral agent, wherein the administrations are simultaneous or alternating. It is understood that the time between alternate administrations can range between 1-24 hours, including any subrange between 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 agent" include, but are not limited to: HCV NS3 protease inhibitors (see 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 2003010147425, WO 2002057287, WO 2005021568, WO 2004140201, US 20060293306, US 200601949, US 20031041064, US 414141066, WO 20070200703978397851048, WO 200200703940510200304145 and WO 2006088160); 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 relates to a method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective compound of formula I and another antiviral agent, alternately or simultaneously. It is to be understood that the time between alternating administrations can range between 1-24 hours, including any subrange between 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 relates to a method of treating and/or preventing a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound represented by formula I and a therapeutically effective amount of another antiviral agent, wherein the administration is simultaneous or alternating. It is to be understood that the time between alternating administrations can range between 1-24 hours, including any subrange between 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 relates to a method of treating a subject in need thereof, comprising administering to the subject alternately or simultaneously therapeutically effective at least one compound represented by formula I and another antiviral agent. It is to be understood that the time between alternating administrations can range between 1-24 hours, including any subrange between 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 another antiviral agent includes, but is not limited to, interferon alpha, interferon beta, pegylated interferon alpha, ribavirin, levovirin, viramidine, another nucleoside HCV polymerase inhibitor, an HCV non-nucleoside polymerase inhibitor, an HCV protease inhibitor, an HCV helicase inhibitor, or an HCV fusion inhibitor. The activity of the active compounds, or derivatives or salts thereof, may be increased over the parent compound when administered in combination with another antiviral agent. When the treatment is a combination treatment, such administration may be simultaneous or sequential with respect to the administration of the nucleoside derivative. Thus, "simultaneously administering" as used herein includes administering the agents simultaneously or at different times. The simultaneous administration of two or more agents may be achieved by a single formulation containing two or more active ingredients, or by the substantially simultaneous administration of two or more dosage forms with one active agent.
It will be understood that references herein to treatment extend to both prevention and treatment of the conditions present. Furthermore, the term "treatment" of HCV infection as used herein also includes the treatment or prevention of a disease or condition associated with or mediated by HCV infection or clinical symptoms thereof.
Preparation method
A ninth embodiment of the present invention relates to a process for the preparation of a compound of formula I, which comprises reacting a suitably substituted phosphorochloridate compound 4 with a nucleoside analogue 5.
Wherein the substituent R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、X、Y、R 6 And the base has the meaning as disclosed in the detailed description of the invention, X' is a leaving group, such as Cl, br, I, tosylate, mesylate, trifluoroacetate, triflate, pentafluorobenzene oxide, p-NO 2 Phenoxy compounds, or other customary leaving groups as disclosed in the fourth edition of march of Advanced Organic Chemistry. Leaving groups and methods that can be used to influence the formation of phosphoramidate nucleoside conjugates are found in US 20060142238 and WO 2007095269. Preferably, the leaving group is Cl.
The reaction is carried out in an anhydrous aprotic solvent such as tetrahydrofuran, dioxane, or both tetrahydrofuran and dioxane, or any functional equivalent thereof, with tetrahydrofuran being the preferred solvent. The reaction is generally initiated at a temperature in the range of-78 ℃ to 40 ℃, with a preferred reaction temperature being between 0 ℃ 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- t Bu-pyridine, etc.; tertiary amine bases such as triethylamine, diisopropylethylamine, and the like; or alkyl grignard reagents such as tbugcg, tbuggbr, memcg, meMgBr, and the like. Phosphorus oxychloride (3-10 equivalents) was dissolved in the reaction solvent and added to the mixture of nucleoside and base. The reaction is then allowed to stir at a temperature between room temperature and 40 ℃ for a period of time ranging from 30min to 24hr, preferably at room temperature and for a period of 24hr. From the reactionThe mixture was freed of solvent and the product was purified by chromatography on silica gel.
A tenth embodiment of the invention relates to the product obtained by a process comprising reacting an appropriately substituted phosphorus chloride compound 4 with a nucleoside analogue 5
Wherein the substituent R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、X、Y、R 6 X', and base have their meanings disclosed in the detailed description of the invention.
The reaction is carried out in an anhydrous aprotic solvent such as tetrahydrofuran, dioxane, or a mixture of tetrahydrofuran and dioxane, with tetrahydrofuran being a preferred solvent, or other suitable solvent. The reaction is generally initiated at a temperature in the range of-78 ℃ to 40 ℃, with a preferred reaction temperature between 0 ℃ and room temperature. The nucleoside is first stirred with a base (5 to 12 equivalents) such as N-methylimidazole, tertiary amine base, or tert-butyl magnesium chloride. Phosphorus oxychloride (3-10 equivalents (or a suitable "phosphorus- (leaving group) -compound")) is dissolved in the reaction solvent and added to the mixture of nucleoside and base. The reaction is then allowed to stir at a temperature between room temperature and 40 ℃ for a period of time ranging from 30min to 24hr, preferably at room temperature and for a period of 24hr. The solvent was removed from the reaction mixture and the product was purified by silica gel chromatography.
Compounds and formulations
The phosphoramidate compounds of the present invention can be prepared by condensing nucleoside analogs 5 with appropriately substituted phosphorus chloride compounds 4 (scheme 1). Nucleoside analogs are prepared by conventional procedures disclosed in any of U.S. published applications Nos. 2005/0009737, 2006/0199783, 2006/0122146, and 2007/0197463, each of which is incorporated by reference in its entirety.
The 1H-NMR values disclosed are recorded on a Varian AS-400 instrument. Mass spectral data were acquired using either a Micromass-Quattromic API or a Waters Acity.
Thus, by way of example only, a suitably substituted phenol can be reacted with phosphorus oxychloride (1) to give aryloxyphosphoryl dichloride 2 (see example 1), which is then treated with an acid addition salt of an alpha-amino acid ester in the presence of TEA to give aryloxyphosphoryl chloride 4. This aryl alkoxy-amino acid phosphoramidate is reacted with a nucleoside analogue to give product I (for steps 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).
Scheme 1
The preparation of nucleoside phosphoramidates requires the reaction of an appropriately substituted phosphorus chloride with a nucleoside containing a free 5' -hydroxyl moiety. In the case where only one hydroxyl group is present, the preparation of phosphoramidates generally proceeds smoothly when the phosphorus chloride is reacted with the desired nucleoside. In the case of nucleosides containing more than one free hydroxyl group, it may be necessary to prepare appropriately protected nucleosides. Silyl, acetonide or other alcohol protecting groups known in the art may ensure protection of the sugar moiety. For protection of nucleoside bases, protection of the free amino group requires an amidine protection strategy.
The condensation of phosphorus chloride can be performed on an unprotected nucleoside. Since the 5'-OH group of nucleosides is much less hindered than the 3' -OH group, selective phosphorylation of amino groups is possible under carefully controlled conditions. Following condensation to form the protected phosphoramidate nucleoside, deprotection to obtain the free phosphoramidate nucleoside can be performed using standard protocols of nucleic acid chemistry. In most cases, the desired product can be easily isolated from the starting material using silica gel column chromatography. A schematic of the synthesis is summarized in scheme 1.
A further understanding of the disclosed embodiments will be obtained by consideration of the following examples, which are intended to be illustrative only and do not limit the disclosed invention.
Example 1
General procedure for the preparation of Phosphoryldichloride
The appropriate phenol R is reacted with 1 A solution of-OH (1 eq) and triethylamine (1 eq) in anhydrous ether was added dropwise to a stirred solution of phosphoryl trichloride 1 (1 eq) under nitrogen at 0 ℃ over a period of 3 hours. The temperature was then raised to room temperature and the reaction was stirred overnight. The triethylamine salt was quickly removed using suction filtration and the filtrate was concentrated in vacuo to dryness to give 2 as an oil which was used without further purification.
Example 2
General procedure for the preparation of phosphorus oxychloride
A solution of triethylamine (2 equivalents) in dry dichloromethane was added dropwise over a period of 30 to 120 minutes to a solution of aryloxy-phosphorus dichloride 2 (1 equivalent) and the appropriate amino ester 3 (1 equivalent) in dry dichloromethane at-78 ℃ with vigorous stirring. The reaction temperature was then allowed to rise to room temperature and stirred overnight. The solvent was removed. The residue was washed with diethyl ether and filtered, and the filtrate was dried under reduced pressure to give 4.
Example 3
General procedure for nucleoside phosphoramidate derivatives
A solution of the appropriate phosphorus oxychloride 4 (6.5 equiv.) in anhydrous Tetrahydrofuran (THF) was added to a mixture of nucleoside 5 (1 equiv.) and N-methylimidazole (8 equiv.) in anhydrous THF at room temperature with vigorous stirring and the reaction mixture was stirred overnight. The solvent is removed in vacuo and the crude product is purified by column chromatography and/or preparative thin layer chromatography to give I.
Example 4
Preparation of 2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine
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 10ml of anhydrous pyridine and concentrated to dryness in vacuo. The resulting slurry was dissolved in 20ml of anhydrous pyridine under nitrogen and cooled to 0 ℃ with stirring. The brown solution was treated dropwise over 10min using benzoyl chloride (1.63g, 3 equivalents). The ice bath was removed and stirring was continued for 1.5h, whereby Thin Layer Chromatography (TLC) showed no starting material remaining. The mixture was quenched by addition of water (0.5 ml) and concentrated to dryness. The residue was dissolved in 50mL Dichloromethane (DCM) and saturated NaHCO 3 Aqueous solution and H 2 And O washing. The organic phase is passed through NaSO 4 Drying, filtering, concentrating to dryness to obtain N 4 3',5' -Tribenzoyl-2 ' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (2.0 g, yield: 91%).
N is to be 4 3',5' -Tribenzoyl-2 ' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (2.0 g,1 eq.) was refluxed overnight in 80% aqueous AcOH. After cooling and standing at room temperature (15 ℃), most of the product precipitated and was then filtered through a sintered funnel. The 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 the other product, which was washed with water to give a white solid. The two white solids were combined to give 1.50g of 3',5' -dibenzoyl-2 ' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (yield: 91%).
A saturated solution of ammonia in MeOH (20 mL) was added to a solution of 3',5' -dibenzoyl-2 ' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (1.5g, 1 eq) in MeOH (10 mL). The reaction mixture was stirred at 0 ℃ for 30min and then slowly warmed to room temperature. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give a residue, which was purified by column chromatography to obtain pure compound 2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (500 mg, yield: 60%).
Example 5
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methyluridine 5' - (phenyl methoxy-alanyl phosphate)
Phenylmethoxyisopropylpropionyloxy (alaninyl) phosphoryl chloride (1g, 6.5 equivalents) dissolved in 3mL of THF was added to a mixture of 2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (0.15g, 1 equivalent) and N-methylimidazole (0.3g, 8 equivalents) in 3mL of THF at room temperature with vigorous stirring, and the reaction was stirred overnight. The solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol and purified by eluting the mobile phase using a water/acetonitrile gradient on a preparative YMC 25X30X2mm column. Removal of acetonitrile and water under reduced pressure gave the desired product (50.1mg, 15.6%). 1 H NMR(DMSO-d 6 )δ1.20-1.27(m,6H),3.58(d,J＝16.0Hz,3H),3.75-3.92(m,2H),4.015-4.379(m,2H),5.54(t,J＝10.2Hz,1H),5.83-5.91(m,1H),6.00-6.16(m,1H),7.18(d,J＝8.0Hz,2H),7.22(s,1H),7.35(t,J＝4.4Hz,2H),7.55(s,1H),11.52(s,1H)；MS,m/e 502(M+1) + 。
Example 6
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methyluridine 5' - (phenylmethoxy-valyl phosphate)
Phenylmethoxy-valylphosphoryl chloride (0.6 g,3.6 equivalents) dissolved in 3mL THF was added to a mixture of 2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (0.15g, 1 equivalent) and N-methylimidazole (0.44g, 9 equivalents) in 3mL THF at room temperature with vigorous stirring, and the reaction was stirred overnight. The solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol and purified by eluting the mobile phase with a water/acetonitrile gradient on a preparative HPLC YMC 25X30X2mm column. Removal of acetonitrile and water under reduced pressure gave the desired product (60mg, 20%). 1 H NMR(DMSO-d 6 )δ0.74-0.847(m,6H),1.20-1.28(m,3H),1.89-1.92(m,1H),3.50-3.54(m,1H),3.58(d,J＝10.4Hz,3H),3.72-3.95(m,1H),4.03-4.05(m,1H),4.23-4.43(m,2H),5.56(t,J＝16.0Hz,1H),5.85-5.92(m,1H),6.01-6.07(m,1H),7.16-7.21(m,3H),7.37(t,J＝8Hz,2H),7.55-7.60(m,1H),11.52(s,1H)；MS,m/e 530(M+1) + 。
Example 7
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methyluridine 5' - (4-bromophenyl methoxy-valyl phosphate)
4-bromophenylmethoxy-valylphosphoryl chloride (1g, 3.4 equivalents) dissolved in 3mL of THF was added to a mixture of 2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (0.2g, 1 equivalent) and N-methylimidazole (0.35g, 6 equivalents) in 3mL of THF at room temperature with vigorous stirring, and the reaction was stirred overnight. The solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol and purified by eluting the mobile phase with a water/acetonitrile gradient on a preparative HPLC YMC 25X30X2mm column. Acetonitrile and water were removed under reduced pressure to give the desired product (120mg, 26%). 1 H NMR(DMSO-d 6 )δ0.72-0.82(m,6H),1.19-1.26(m,3H),1.86-1.92(m,1H),3.48-3.50(m,1H),3.56(d,J＝12.0Hz,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＝8.0Hz,2H),7.49-7.56(m,3H),11.53(s,1H)；MS,m/e 608(M+1) + 。
Example 8
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methyluridine 5' - (4-bromophenyl-methoxy-alanyl phosphate)
4-bromophenyl methoxy-alanyl phosphoryl chloride (0.6 g,5 equivalents) dissolved in 3mL of THF was added to a mixture of 2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (0.15g, 1 equivalent) and N-methylimidazole (0.3g, 7.8 equivalents) in 3mL of THF at room temperature with vigorous stirring, and the reaction was stirred overnight. The solvent was removed by reduced pressure.The resulting crude product was dissolved in methanol and purified by eluting the mobile phase with a water/acetonitrile gradient on a preparative HPLC YMC 25X30X2mm column. Removal of acetonitrile and water under reduced pressure gave the desired product (40mg, 12%); 1 H NMR(DMSO-d 6 )δ1.20-1.26(m,6H),3.57(d,J＝2.8Hz,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＝10.2Hz,2H),7.52-7.57(m,3H),11.52(s,1H)；MS,m/e 580(M+1) + 。
Example 9
N 4 Preparation of (N, N-dimethylcarbamimidoyl) -2' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine
2' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (500mg, 1.9mmol) was stirred with a solution of dimethylformamide dimethyl acetal in DMF (10 mL). The resulting mixture was stirred at room temperature overnight. After removal of the solvent, the crude product was used in the next step without further purification.
Example 10
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methylcytidine 5' - (phenyl methoxy-alanyl phosphate)
Phenylmethoxyisopropanoylphosphoryl chloride (0.6 g,6 equivalents) dissolved in 3mL of THF is added to N at room temperature with vigorous stirring 4 A mixture of- (N, N-dimethylaminoamido) -2' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (0.15g, 1 eq) and N-methylimidazole (0.3g, 7.8 eq) in 3mL THF was stirred for the reaction overnight. The solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol and purified by eluting the mobile phase using a water/acetonitrile gradient on a preparative YMC 25X30X2mm column. Removal of acetonitrile and water under reduced pressure gave the desired product (62mg, 20.6%). 1 H NMR(DMSO-d 6 )δ1.16(d,J＝23.2Hz,3H),1.22(d,J＝7.2Hz,3H),3.56(S,3H),3.69-3.75(d,J＝25.6Hz,1H),3.82-3.86(m,1H),3.96-3.98(m,1H),4.21-4.34(m,2H),5.68(d,J＝7.2Hz,1H),5.75-5.77(m,1H),6.07-6.16(m,1H),7.15-7.19(m,3H),7.2(d,J＝9.2Hz,2H),7.39(t,J＝7.8Hz,2H),7.48(d,J＝9.2Hz,1H)；MS,m/e 501(M+1) + 。
Example 11
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methylcytidine 5' - (4-bromophenyl methoxy-valyl phosphate)
4-bromophenylmethoxy-valylphosphoryl chloride (1.0 g,3.4 equivalents) dissolved in 3mL of THF was added to N at room temperature with vigorous stirring 4 A mixture of- (N, N-dimethylcarbamimidoyl) -2' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (0.2g, 1 eq) and N-methylimidazole (0.35g, 6 eq) in 3mL THF was stirred overnight. The solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol and purified by eluting the mobile phase using a water/acetonitrile gradient on a preparative YMC 25X30X2mm column. Removal of acetonitrile and water under reduced pressure gave the desired product as a white solid (59mg, 13%); 1 H NMR(DMSO-d 6 )δ0.74-0.83(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-.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＝13.0Hz,2H),7.26(s,1H),7.33(s,1H),7.46-7.55(m,1H),7.56(d,J＝4.4Hz,2H)；MS,m/e 607(M+1) + 。
example 12
Preparation of 2 '-deoxy-2' -fluoro-2 '-C-methylcytidine 5' - (phenyl methoxy-valyl phosphate)
Phenylmethoxy-valyl phosphoryl chloride (0.6 g,6 equivalents) dissolved in 3mL THF is added to N at room temperature with vigorous stirring 4 - (N, N-dimethyl)A mixture of carbamimidoyl) -2' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (0.15g, 1 equivalent) and N-methylimidazole (0.3g, 7.8 equivalents) in 3mL THF was then stirred the reaction overnight. The solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol and purified by eluting the mobile phase using a water/acetonitrile gradient on a preparative YMC 25X30X2mm column. Removal of acetonitrile and water under reduced pressure gave the desired product as a white solid (86mg, 42.9%). 1 H NMR(DMSO-d 6 )δ0.72-0.80(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＝11.2Hz,1H),4.22-4.37(m,2H),5.70(d,J＝8.0Hz,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＝4.0Hz,2H),7.46-7.50(m,1H)；MS,m/e 529(M+1) + 。
Examples
Examples Nos. 13-54 and 56-66 were prepared using procedures similar to those described for examples 5-8. Example number, compound identification and NMR/MS details are shown below:
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*R 2 And R 3b Together being- (CH) derived from L-proline 2 ) 3 –
Purification step by preparative HPLC:
the crude product was dissolved in methanol. The injection volume of these solutions was 5mL.
The preparative HPLC system included 2 sets of Gilson 306 pumps, gilson 156 UV/Vis detector, gilson 215 injector & fraction collector, and Unipoint control software. Ymc 25X 30X 2mm columns were used. The mobile phases were HPLC grade water (a) and HPLC grade acetonitrile (B). Fractions were collected into 100 x 15mm glass tubes.
HPLC gradients are shown in table 1. After selection of the gradient, the acetonitrile solution was injected into the HPLC system and fractions were collected according to the UV peak. After separation, each glass tube was subjected to MS test to collect the desired compound. Fractions with target MS were combined in an accurately weighed flask. Most of the acetonitrile was removed under reduced pressure and the remaining solution was freeze-dried to give the desired compound.
Table 1:
preparation of example 66
Illustration of the drawings
Preparation of Compound (b)
Mixing LiAl (OBu-t) 3 A1M solution of H in THF (2.69mL, 2.69mmol) was added dropwise to a solution of compound a (1g, 2.69mmol) in dry THF (30 mL) at-20 ℃. The reaction mixture was stirred at the same temperature for 2-3h. EtOAc (100 mL) was added followed by saturated NH 4 Cl solution (10 mL) and the reaction mixture was slowly warmed to room temperature. The reaction mixture was extracted with EtOAc and washed with 1N HCl and water. The combined organic phases were evaporated to give 0.8g of crude compound b as a clear oil, which was used directly in the next reaction.
Preparation of Compound (d)
DEAD (1.8 mL) was added to compound b (0.8g, 2.1mmol), compound c (0.45g, 2.5mmol) and Ph under a nitrogen atmosphere 3 P (0.56g, 2.1 mmol) in dry THF (20 mL). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was separated by preparative chromatography (hexane: etOAc = 3. The crude compound d was used in the next step without further purification.
Preparation of Compound (e)
Compound d (0.8g, 1.57mmol) was dissolved in THF (2 mL) and ammonia-saturated THF (5 mL) was added to the solution. The reaction mixture was heated to 90 ℃ 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) which was used in the next step.
Preparation of Compound (f)
Compound e (0.5g, 1.01mmol) was dissolved in methanol (2 mL), and then ammonia-saturated methanol (5 mL) was added to the solution. The reaction mixture was stirred at room temperature overnight. After 18 h, 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 (1.07g, 10.6 mmol) in dry dichloromethane (15 mL) was added dropwise over a period of 2 hours to a solution of compound g (1.16g, 5.3mmol) and compound h (1.31g, 5.3mmol) in dichloromethane (10 mL) at-78 deg.C with vigorous stirring. After the addition was complete, the reaction temperature was allowed to gradually rise to room temperature and stirred overnight. The solvent was then removed under vacuum, 20mL of anhydrous ether was added, the precipitated salt was filtered and the precipitate was washed with ether. The combined organic phases were concentrated to give compound i as a colourless oil (1.0 g).
Preparation of Compound 66
0.4g of NMI was added to a stirred solution of compound j (0.1g, 0.35mmol) in 10mL of anhydrous THF until the solution became clear, and a solution of compound i (0.8g, 2.89mmol) in 10mL of THF was added dropwise and stirred at room temperature overnight. The purity of the compound was confirmed by LCMS and identified. The solvent was evaporated and purified by preparative HPLC to give 66 (25mg, yield. 1 H NMR(DMSO-d 6 )δ1.08(d,J＝22.8Hz,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) + 。
The following identified examples, nos. 67-74, were prepared using procedures similar to those disclosed above for example 66.
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Examples No. 75-80 were prepared using procedures analogous to those disclosed above for example 66.
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Example 81
Due to the chirality of phosphorus, certain exemplified compounds are obtained as mixtures of diastereomers. The diastereomers were separated under Supercritical Fluid Chromatography (SFC) conditions on a Chiralpak-AS-H (2X 25 cm) column using 20% methanol in carbon dioxide AS solvent. The absolute stereochemistry of the diastereomer P-chiral center is not determined. However, chromatographic resolution of these two diastereomers provides an isomer characterized by a fast eluting isomer and a slow eluting isomer. Some examples are shown below.
Example 82
Huh7 cells (clone A cells; apath, LLC, st. Louis, mo.) containing HCV replicon RNA were maintained in exponential growth in Darber modified eagle medium (high glucose) containing 10% fetal bovine serum, 4mM L-glutamine and 1mM sodium pyruvate, 1 × non-essential amino acids and G418 (1,000 μ G/ml). The antiviral assay was performed in the same medium without G418. Cells were seeded in 96-well plates at 1,500 cells/well and test compounds were added immediately after seeding. The incubation time was 4 days. At the end of the incubation step, total cellular RNA was isolated (RNeasy 96 kit; qiagen). Replicon RNA and internal control controls (TaqMan rRNA control reagents; applied Biosystems) were amplified in a one-step multiplex RT-PCR protocol recommended by the manufacturer. HCV primers and probes were designed using primer expression software (Applied Biosystems) and cover the highly conserved 5' -untranslated region (UTR) sequence (sense 5' -AGCCATGGCGTTAGTA (T) GAGTGT-3' and antisense 5- > TTCCGCAGACCACTATGG-.
To show the antiviral effect of the compounds, the mean RT-PCR cycle threshold for the no drug control was subtracted by the RT-PCR cycle threshold (Δ Ct) for the test compound HCV ). Delta Ct 3.3 corresponds to a 1-log 10 reduction in replicon RNA levels (equivalent to an effective concentration of 90% [ EC ] 90 ]). Cytotoxicity of test compounds can also be determined by calculating the Δ Ct rRNA A value. Then substituting the specific parameter of delta Ct into (delta Ct) HCV -ΔCt rRNA ) Wherein HCV RNA levels are normalized to rRNA levels and corrected relative to no drug controls.
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1 (4-BrPh): 4-bromo-phenyl.
The entire contents of 60/909,315 as filed 3/30/2007, 60/982,309 as filed 10/24/2007, and 12/053,015 as filed 21/3/2008 are hereby incorporated by reference into this application to supplement the present disclosure and/or correct any errors as needed. Further, the patent documents and non-patent documents disclosed herein are incorporated by reference. In the event that the incorporated patent and non-patent documents contain a term that conflicts with the term disclosed in either provisional application or the present application text, the meaning of the term contained in the present application text and in both provisional applications shall govern, provided that the overall meaning of the incorporated subject matter is not lost.

Claims (6)

1. A compound selected from:
methyl 2- (((S) - ((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) acetate;
Methyl 2- (((R) - ((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) acetate;
(S) -isopropyl 2- (((S) - (4-chlorophenoxy) (((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionate;
(S) -isopropyl 2- (((R) - (4-chlorophenoxy) (((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) phosphoryl) amino) propionate;
(S) -cyclohexyl 2- (((S) - (((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate; and
cyclohexyl (S) -2- (((R) - (((2r, 3r,4r, 5r) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate.
2. A pharmaceutical composition comprising a compound of claim 1.
3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable vehicle.
4. A pharmaceutical composition according to claim 3 comprising an effective amount of a compound according to claim 1 for the treatment of hepatitis c infection.
5. Use of a compound of claim 1 in the manufacture of a medicament for treating a subject infected with a virus that is hepatitis c virus.
6. The use of claim 5, further comprising administering to the subject an effective amount of another antiviral agent.
HK19129737.3A 2007-03-30 2011-05-25 Nucleoside phosphoramidate prodrugs HK40006276B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US60/909,315 2007-03-30
US60/982,309 2007-10-24
US12/053,015 2008-03-21

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
HK11105202.0A Addition HK1150450B (en) 2007-03-30 2008-03-26 Nucleoside phosphoramidate prodrugs

Related Child Applications (1)

Application Number Title Priority Date Filing Date
HK11105202.0A Division HK1150450B (en) 2007-03-30 2008-03-26 Nucleoside phosphoramidate prodrugs

Publications (2)

Publication Number Publication Date
HK40006276A HK40006276A (en) 2020-05-22
HK40006276B true HK40006276B (en) 2023-07-28

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