TW201141513A - Insulin-siRNA conjugates - Google Patents

Abstract

This invention relates generally to therapeutic compounds and methods useful for treating disease in humans. Specifically, the present invention relates to methods and reagents useful for treating humans suffering from metabolic diseases. Specifically, the present invention relates to covalent conjugates of insulin and analogues with nucleic acid derivatives which are capable of modulating gene expression. Furthermore, this invention relates to the use of such conjugated insulins for the treatment of metabolic diseases, including diabetes mellitus.

Description

201141513 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention generally relates to therapeutic compounds and methods useful for treating human diseases. In particular, the present invention relates to methods and medicaments useful in the treatment of humans suffering from metabolic diseases. In particular, the present invention relates to covalent binders of tensin and analogs with nucleic acid derivatives which modulate gene expression. Furthermore, the present invention relates to the use of this combined insulin for the treatment of metabolic diseases, including diabetes. [Prior Art] Since the introduction of insulin in the 1920s, there has been a marked improvement in the treatment of diabetes. The main advancement in treatment was the result of improved insulin purification and availability. The formulation was then modified to develop a method for producing human insulin, and the invention of an "amyloid analog" containing a modified amino acid sequence. One of the most important factors in successful diabetes treatment is the maintenance of precise sugar content (The Diabetes Control and

Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986). Therefore, the main focus of insulin research is to adjust the pharmacokinetics and pharmacodynamic properties of insulin to provide basal insulin that can stably control blood sugar levels within a few hours, as well as insulin that controls the rapid increase in blood sugar levels after meals. This can be achieved by modification of the insulin amino acid sequence or by, for example, fatty acid binding, by formulation. Insulin regulates the amount of glucose in the blood by inhibiting hepatic glucose production and increasing glucose transport to muscle and adipose tissue. At the cellular level, insulin stimulates glucose uptake by triggering a translocation of glucose transporter 4 (GLUT4), which facilitates the diffusion of glucose into the striated muscle and fat cells. Insulin exerts its biological utility by binding to the insulin receptor, a transmembrane receptor that itself has tyrase activity. Due to the structural changes of insulin and insulin receptors, they can bind to ATP and autophosphorylate. This autophosphorylation increases the kinase activity of the receptor to phosphorylate various intracellular substances' initiation signaling cascade, resulting in activation of multiple downstream effectors and ultimately bioreaction, including grape absorption in muscle and adipose tissue' making GLUT4 The glucose transporter rapidly translocates from the intracellular location to the cell surface. With insulin binding and receptor activation, the insulin-Tengda receptor complex is internalized via the pinocytosis of the receptor media after translocation to clathrin-coated pits. This process is based on the presence of a binding insulin ligand on the insulin receptor. As the clathrin-coated vesicles are decoated and fused to the endosomal compartment, insulin is dissociated from its receptor and directed to the secondary endosomes and finally to the lysosomal compartment where it degrades. The ligand-free insulin receptor is recycled back to the cell membrane. (F〇ti, M. et al., Novartis Foundation Symp〇sium (2004) 262, 125-147; Carpentier, J.-L.,

Diabetol〇gla (i994) sUppl 2, 117-124.) Various insulin binding agents have been synthesized. These binders are typically directed against alternative methods of improving the pharmacokinetic and/or pharmacodynamic properties of insulin or promoting insulin delivery, such as oral or pulmonary delivery 201141513. Examples include, but are not limited to, insulin-polyethylene glycol (PEG) binding agents (Hinds, KD and Kim, SW Advanced Drug Delivery Reviews (2002) 54, 505-530; W02007043059A1; W02007007345A1; Uchio, T. et al. Advanced Drug Delivery Reviews (1999) 35, 289-306.); insulin-branched polymer binding agent (WO2006/079641A2); insulin-vitamin B12 binding agent (W02008109068A2); insulin-spira peptide binding agent (Zhang, Y. -Q. et al., Journal of Controlled Release (2006), 115(3), 307-315.); insulin-transferrin binding agent (Xia, CQ et al, Journal of Pharmacology and Experimental Therapeutics (2000), 295 (2), 594-600.); insulin _Fmoc analog binding agent (Gershonov, E. et al, Journal of Medicinal Chemistry (2000), 43 (13), 2530-2537.); glycosylated insulin (Uchio , T. et al., Advanced Drug Delivery Reviews (1999) 35, 289-306.). Methallin has also been used as a drug carrier, such as 5-fluorouracil, by binding to cytotoxic/cytostatic drugs (Huang, j. et al.

Chinese Chemical Letters (2007), 18(3), 247-250). Insulin has been used as a carrier for alpha-1,4-glucosidase. Insulin and this enzyme' or a combination of enzyme and albumin binding agents have been prepared and tested for their cellular relevance, enzyme activity, and intracellular and in vivo distribution (Poznansky, MJ et al. Science (1984). ) 223 (4642), 1304-6). An insignificant insulin-serum albumin binding agent, which is used to form indirect, non-specific and non-specific with DNA by electrostatic and lipophilic interaction of negatively charged DNA with a positively charged 6 201141513 albumin virus Covalent complex. This was used to transfect DNA encoding the neo gene into HEPG2 cells in vitro (Huckett, B. et al., Biochemical Pharmacology (1990), 40(2), 253-63). Taylor, S. K., et al., Angew. Chem. 2009, 121, 4458-4461 describe the use of insulin in combination with a quinine-sensitive DNA element for controlling insulin release. There is no exemplification of a binding agent for insulin to a biologically active compound, wherein the binding agent maintains the biological activity of the insulin receptor and simultaneously affects other targets associated with the treatment of the disease. Approximately 177 million people worldwide have diabetes. Of course, about 17,00 〇, the deaf person is type I diabetes, and the only treatment option is insulin therapy to replace the lack of endocrine insulin secretion. Most people with diabetes have type I diabetes, and the cause is more complicated than simple insulin reduction. It can be treated with various oral anti-diabetic drugs at an early stage. When the disease worsens, it usually requires additional insulin therapy. The increasing rate of type 11 diabetes has led to the development of drugs for the treatment and prevention of diseases other than insulin. . At present, there is no therapeutically effective treatment that can directly imitate and replace insulin. (10) In addition to the treatment of temsin, there are many other biological markers and = can be used to treat type n diabetes. - Lai is promising for the fault by regulating the insulin receptor downstream target cover, jade by Yuemei t ^ ^ Hanwu pancreatic horse Jing sensitivity. However, the signal transmission level initiated by the combination of its receptors is regulated by Sa, and some of them are signal transduction. Improving insulin signaling by 'except 201141513 or inhibiting these negative mediators is particularly beneficial for the development of new therapeutic agents for the treatment of diabetes. An example of a major negative regulator of insulin signaling is the protein citrate (ΡΤΡ) ΐΒ (also known as PTPN1). PTP1B is a family of protein glycosylphosphatases that are enzymes that catalyze the phosphorylation of protein tyrosine. More than one species of human PTP has been isolated and can be used as a negative or positive regulator in different signal conduction paths. PTP plays an indispensable role in intracellular signal transduction by regulating cell tyrosine phosphorylation to control cell growth and differentiation, metabolism, cell migration, gene transcription, ion channel activity, immune response, apoptosis, and skeletal development. Missing role. Among all PTPs, protein tyrosine phosphatase (PTP) IB plays a breeding role in cell signaling and in many human diseases including cancer, diabetes and obesity. In many in vitro and in vivo data, PTP1B has been established as the major negative regulator of the signaling of the receptor and thus the action of insulin. PTP1B acts as an "antagonist" of insulin via direct acidification and inactivation of the insulin receptor' and possibly also by dephosphorylation of downstream targets. This evidence suggests that PTP-1B negatively regulates insulin signaling as a primary target for insulin sensitivity. In addition, its negative regulation regulates leptin signaling and thus affects appetite and body weight (Kasibhatla, B. et al., Current Opinion in Investigational Drugs (2007), 8(10), 805-813.; Tam, S Saiah, E. Drugs of the Future (2008), 33(2), 175-185.; Elchebly, M. et al., Science (1999), 283 (5407), 1544-1548.; Zhong, ZY. ; Lee, SY. Expert Opinion in 8 201141513

Investigational Drugs (2003), 12(2), 223-233.). Despite active efforts and recent advances, the development of therapeutically useful oral bioavailable small molecule PTP1B inhibitors has not been successful. Other pathways that regulate the action of PTP1B are the use of antisense oligonucleotides to inhibit their expression, and the recent siRNA knockdown with in vitro siRNA expression.

(knock-down) has been proposed (w〇 2004016735 A2; WO 2003099227 A2; US 2006025361 Al; US 2006019913 Al; US 2004077574 Al; US 2004009946 A1). In many organisms, the introduction of double-stranded RNA (dsRNA) triggers potency and specific gene silencing. This well-known sequence-specific post-transcriptional gene silences the underlying cellular machinery (called RNA interference), which occurs in plants, animals, and fungi, and is also involved in, for example, viral defense and transposon silencing. Fire and Mello received the 2006 Nobel Prize in Medicine for their role (Ghildiyal, M. & Zamore, PD Nature Reviews Genetics (2009) 10, 94-108. ; Zamore et al., Cell (2000) 101, 25-33; Fire, A. et al, Nature (1998) 391, 806-811; Hamilton et al, Science (1999) 286, 950-951; Fire, A. (Nobel lecture). Angew. Chem. Int. Ed. Engl. (2007) 46, 6966-6984. Mello, CC (Nobel Lecture). Angew. Chem. Int. Ed. Engl. (2007) 46, 6985-6994).

Although it has not yet been fully elucidated, the mechanism of this RNAi has been studied intensively (Rana, TM Nat. Rev. Mol. Cell. Biol. (2007) 8, 23-36. Ghildiyal, M. & Zamore, PD Nature Reviews Genetics (2009) 10, 94-108.). Finally, gene silencing is produced by the identification and sequence specific degradation of mRNA 9 201141513, in which the mRNA encodes the gene product by a short RNA sequence incorporated into the RNA-induced silent complex (Rise). The specific mRNA sequence to be degraded is identified by hybridization with a complementary short RNA sequence in the RISC complex, and once identified, the activity of the argonaute endonuclease in RISC degrades the mRNA (Liu, J. et al,

Science, (2004) 305, 1437-1441.; Song, J-J. et al., Science, (2004) 305, 1434-1437). This is a catalytic process. This short RNA recognition sequence, often referred to as a guide or antisense strand, is typically from about 19 to about 25 nucleotides in length and is generally transmitted and identified to be incorporated into RISC to become a first RNA strand. The part of the double key for the passer or stock. This double strand 'typically has about 2 short nucleotides of nucleotide acid at the 3' end of each strand, and is called interfering RNA (siRNA). The two strands of the siRNA duplex are typically highly complementary to each other, although the presence of a small amount of mismatch may be tolerable' however, having an adverse effect on the performance of RNA interference. When it is phosphorylated for activation, the 5'-hydroxyl group of the siRNA is essential (Chiu et al., Molecular Cell, 2002, 10, 549-561). Once the lead strand is incorporated into the RISC, the passer strand is typically discarded/degraded (Tomari, Y.; Zamore P. D. Genes & Dev. (2005) 19, 517-529). siRNAs are typically produced by longer endogenous or exogenous precursors, which may consist of a dsRNA' consisting of two isolated RNA strands or a dsRNA portion of a single, partially self-complementary RNA single strand. For example, a stem-loop structure in a micro-rna precursor (pre-microRNA). Treatment of these pre-201141513 excipients to form siRNA is carried out by cytoplasmic dicER endonuclease. The use of the therapeutic potential of this natural process to reduce pathological proteins is known to be very rapid, and the use of exogenously administered synthetic siRNA has been pursued in mammalian cells after verification of protein knockdown (Elbashir, SM et al., Nature) (2001) 411, 494-498.). The high specificity and potency of RNAi and its potential to inhibit any gene, including resistance to conventional therapy, make it a highly attractive therapeutic principle (Yang, M. & Mattes, J. Pharmacology & Therapeutics (2008) 17, 94-104). Potential problems such as immune response activation and de-drying effects have been identified and stated (Aagaard, L.; Rossi, JJ Advanced Drug Delivery Reviews (2007) 59, 75-86·; De Paula, D. et al., RNA (2007) 13,431-456· ; Hornung, V. et al., Nature Medicine (2005) ll(3), 263-270.; Eberle, F. et al., The Journal of Immunology (2008) 180, 3229-3237. Judge, AD Molecular Therapy (2006) 13(3), 494-505. ; Jackson, A丄. et al, RNA (2006) 12, 1-9; Marques, JT et al, Nature Biotechnology (2006) 24 (5) 559-565·). Exogenously administered synthetic double-stranded RNA, which is the siRNA itself or a precursor thereof, has been actively tested for its therapeutic potential. Since this new generation of exogenously administered siRNA is synthetic, it can be prepared without modification in nature. These include chemical modifications, double-stranded variations, and extended length and complementarity, and combinations thereof. These modifications are not only added to understand the mechanism of RNAi, but also to synthesize siRNA with improved properties and thus increase the potential of 201141513 as a therapeutic agent. Although, essentially RNAi is an excellent and effective method for down-regulating protein expression, the selection of nucleotide sequences for siRNA is important for achieving efficient and selective protein knock-down. Factors that should be considered include, for example, the ratio of G:C and A:T base pairs and their location and distribution. Although siRNA sequence design relies mostly on experience, there are still many generally accepted guidelines for siRNA sequence design to achieve efficient and specific protein knockdown, and many of these have been formalized into computer algorithms (Ui-Tei, K. et al. , Journal of Biomedicine and Biotechnology (2006) l-8.; Amarzguioui, Μ.; Prydz, Η. Biochem. Biophys. Res. Commun. (2004) 316, 1050-1058.). Many of these algorithms are free or commercially available. In addition to the nucleotide sequence design of one level of siRNA, much work remains to be done on other structural requirements in order to optimize the stability and cost of the oligomer while maintaining or improving its effectiveness and selectivity. These include the most suitable sequence length, the most suitable 3,-protrusion length, longer sequences such as DICER matrices and other studies (Ui-Tei, K. et al, Journal of Biomedicine and Biotechnology (2006) l-8; Manoharan, M. Current Opinion in Chemical

Biology (2004) 8, 570-579; Bumcrot, D. et al, Nature Chemical Biology (2006) 2 (12), 711-719.; Amarzguioui, M. Nucleic Acids Research (2003) 31 (2) 589-595 Kim, DH et al, Nature Biotechnol. (2005) 23, 222-226.; Siolas, D. et al, Nature Biotechnol. (2005) 23, 227-231). 12 201141513 siRNA is easily degraded by nucleases and appropriate precautions must be taken during synthesis and processing. This instability is also a major cause of poor pharmacokinetic properties of siRNA in vivo. Chemical modifications that have been actively studied are not only addressed to this problem, but also to the mechanism of RNAi; to improve the potency and specificity of protein knockdown; to reduce or eliminate siRNA-related immune responses; and to reduce the cost of siRNA oligomers. These chemical modifications include nuclear modification; sugar modification, including substitution of ribonucleosides with ribonucleosides or 2'-substituted sugars; modification of nucleotide linkages, including phosphorothioate Ss and de-linking linkages End modification and binding; and many others (C〇rey, DAJ Clin. Invest. (2007) 117, 3615-3622.; Manoharan, M. Current Opinion in Chemical Biology (2004) 8, 570-579.; Bumcrot, D. et al, Nature Chemical Biology (2006) 2 (12), 711-719.; Ui-Tei, K. et al, Nucleic Acids Research (2008) 36(7), 2136-2151.; Jackson, AL, etc. Human, RNA (2006) 12, 1-9; Amarzguioui, M. Nucleic Acids Research (2003) 31 (2) 589-595.; Braasch, DA et al, Biochemistry (2003) 42, 7967-7975.; , CR et al, J. Med. Chem. (2005) 48, 901-904.; Soutschek, J. et al, Nature (2004) 432, 173-178.; Rana, TM Nat. Rev. Mol. Cell. Biol. (2007) 8, 23-36.; Allerson, CR et al, J. Med. Chem. (2005) 48, 901-904.; De Paula, D. et al., RNA (2007) 13, 431- 456. ; Kore, AR & Ford, LP Current Bioactive Compounds (2008) 4, 6 -14.). In general, methods for designing efficient and selective siRNA sequences are well known to those skilled in the art and have been well documented in the references cited herein and in the references cited therein. In addition, various chemical modifications that are tolerated in specific portions of the siRNA and that improve the properties of these siRNAs are well documented herein; in the literature; and in the references cited in the literature. When combined with a suitable delivery system, one of ordinary skill in the art should be able to combine these data to construct a siRNA sequence having a modification of an effective and selective gene expression silencer. Synthetic methods for siRNA solid phase synthesis are referenced (Beaucage, S. Current Opinion in Drug Discovery &

Development (2008) ll (2), 203-216). Although there are examples of direct application of siRNA to a living body by various routes of administration, the remaining major obstacles to the use of RNAi as a therapeutic rule are poor absorption of siRNA into cells, and poor pharmacokinetic and pharmacodynamic properties of siRNA in vivo. . The poor pharmacokinetic properties of unmodified siRNA are associated with its low stability in vivo and its rapid elimination by renal filtration (Kawakami, S. & Hashida, M. Drug Metab. Pharmacokinet. (2007) 22(3), 142-151). A number of methods have been used to overcome these obstacles, including encapsulation or complexation of siRNAs with various carriers, such as microlipids and related particles; nanoparticulates; cationic polymers such as polyethyleneimine or cationic peptides; and cationic lipids Compound. Some of these vectors have been modified or designed to be tissue and cell specific (Aigner, A. Journal of Biomedicine and Biotechnology (2006) Article ID 71659, 1-15.; Akhtar, S.; Benter, IFJ Clin. Invest. (2007) l 17, 3623-3632.; 201141513

De Paula, D. et al., RNA (2007) 13, 431-456.; Kawakami, S. & Hashida, M. Drug Metab. Pharmacokinet. (2007) 22(3), 142-151.; Kore, AR & Ford, LP Current Bioactive Compounds (2008) 4, 6-14. ; Kumar, P. et al.

Nature (2007) 448, 39-43.; Oliviera, s. et al., Journal of Biomedicine and Biotechnology (2006), Article ID 63675, 1-9.; Shen, Y. IDrugs (2008) l 1(8), 572-578. Kim, DH & Rossi, JJ Nature Reviews Genetics (2007) 8, 173-184; De Rosa, G. Molecules 2009, 14, 2801-2823.). The use of covalent binding agents for siRNA with lipophilic groups such as cholesterol, cholesterol derivatives and analogs, cholic acid, lipids or tocopherols has been somewhat successful. These lipophilic siRNAs may bind to lipoproteins to varying degrees or may be used in combination with the above vectors (De Paula, D. et al, RNA (2007) 13, 431-456.; Juliano, R. Nucleic Acids

Research (2008) 36(12), 4158-4171. Nishina, K. et al., Molecular Therapy (2008) 16(4); Wolfrum, C. et al., Nature Biotechnology (2007) 25(10), 1149-1157 Soutschek, J. et al., Nature (2004) 432, 173-178.). A binding agent or complex of an siRNA to an antibody or fragment thereof, a cell surface receptor ligand or a peptide has been prepared to aid in cellular uptake, tissue targeting or regulation of the distribution of siRNA within the cell. In general, a peptide complex that can be modified by adding a 1% ionic amino acid while maintaining affinity and specificity for its receptor target is suitable as an electrostatic complex with anionic si RNA. Candidates. The complex of s丨RN A with the antibody or its fragment 15 201141513 is usually achieved by an antibody fusion protein containing a cationic peptide, such as protamine. While antibody binding agents are superficially attractive as delivery agents, their introduction into all tissues involves problems with the development of therapeutic antibiotics, such as species specificity, immune activation, humanization, and the like. The cell penetrating peptide has been bound to the siRNA. These peptides can carry molecules that bind to them across the cell membrane. It typically contains a high density of basic amino acid regions' which aids in its uptake by cells in a non-receptor dependent manner. Examples of cell-penetrating peptides include Tat peptides from HIV Tat protein, Ant peptides from the Dro SSOphila antennapedia homeobox, peneplatin, transportan, HSV-1 protein VP22 and MPG, model amphiphilic peptide (MAP) and polyarginine (Meade, BR & Dowdy, SF Advanced Drug Delivery Reviews (2007) 59, 134-140; Gupta, Β· et al, Adv Drug Deliv. Rev. (2005) 57, 637-651; Zorko, Μ· & Langel, U. Adv. Drug Deliv. Rev. (2005) 57, 529-545. Snyder, EL & Dowdy, SF Pharm Res. (2004) 21, 389-393; Gait, MJ Cell. Mol. Life Sci. (2003) 60, 844-853; Muratovska, A. et al., FEBS Letters (2004) 558, 63-68; US2004147027A1 WO06037126A2; WO07056153A2). Non-covalent complexes of siRNA and cell penetrating peptides (Meade, BR & Dowdy, SF Advanced Drug Delivery Reviews (2007) 59, 134-140.) and peptide ligands of modified cell surface receptors 201141513 Into. For example, streptavidin_human insulin receptor antibody binding agents have been used to form non-covalent complexes with biotinylated siRNAB (Xia, C-F. et al., Mol. Pharmaceutics (2009),

Article ASAP, DOI: 10.102l/mp8〇〇194y). This complex is active in cell culture. The utility and results of long-term treatment with a mixture of most of these non-human proteins in vivo are not clear. The 29 amino acid peptides derived from rabies virus glycoproteins containing multiple linked arginine residues can form non-covalent complexes with siRNA and enable siRNA to be delivered to the brain via blood vessels (Kumar, P. et al., NatUre (2007) 448, 39-43.). In general, a peptide ligand which can be modified by the addition of a plurality of cationic amino acids while maintaining affinity and specificity for its receptor target is suitable as a candidate for forming an electrostatic complex with an anion. The binding of the siRNA to the peptide has been carried out to provide a ligand for the cell surface receptor to aid in the pinocytosis and/or tissue targeting of the receptor-mediated copolymer. For example, the IsiRNA targeting IRS-1' designed to treat breast cancer has been successfully combined with the small circular peptide mimetic of IGF-1. These binding agents are active in cell analysis without the addition of transfection agents and are significantly and exclusively absorbed by the cells via the pinocytosis of the receptor-mediated IGF] receptor (Cesarone, G 笪 / is . . . Human, Bioconjugate

Chem. (2007) 18, 1831-1840). SUMMARY OF THE INVENTION The present invention provides covalent binders of membrane proteins and analogs with nucleic acid derivatives that modulate gene expression 17 201141513. More particularly, the present invention relates to covalent binding agents for insulin and insulin analogs to nucleic acid molecules that modulate the synthesis of RNA interference (RNAi). Such nucleic acid derivatives include short interfering nucleic acids (siNA), short interfering RNA (siRNA), double stranded RNA (dsRNA), DICER matrix dsRNA, micro-RNA (miRNA) and short hairpin RNA (shRNA) molecules or precursors thereof. Still more particularly, the present invention relates to covalent binding agents of insulin and insulin analogs to synthetic nucleotide molecules that modulate RN A interference (RNAi), wherein the binding agent binds to the insulin receptor, activates insulin Receptor or internalization with the insulin receptor. In particular, the present invention relates to a covalent binding agent for an analog of a combination of an oxytetracycline and an oxytetracycline analog with a synthetic nucleotide molecule which reduces the expression of a protein involved in disease pathology by RNA interference (RNAi). In particular, the present invention relates to covalent binding agents of insulin and insulin analogs to synthetic nucleotide molecules which, by RNA interference (RNAi), can reduce the expression of proteins involved in the pathology of metabolic diseases. Furthermore, the present invention relates to the use of this combined insulin for the treatment of metabolic diseases, including but not limited to diabetes. When the term "insulin" is used in connection with a compound of the invention, it encompasses insulin of any species, such as porcine insulin, chymosin and human insulin and salts thereof, such as zinc salts and protamine salts, and Dimers and polymers, such as their hexamers. Furthermore, the term "insulin" in the text also covers the "modification of Tengdaosu", which is commonly used by the technical defender's derivatives. See general textbooks, for example, and there are some islands that do not appear in the substituents of the Tengdao prime molecular. - (4) Membrane Island 201141513 The structure-activity relationship is outlined in Biopolymers (Peptide Science) 2007, 88(5), 687-713 and the references cited therein. Modified insulin is typically treated with a chemical and/or enzymatic insulin or a suitable membrane precursor, such as proinsulin, pro-insulin or a truncated analog thereof. For example, the term "insulin" also encompasses insulin molecules at one or more locations, such as at the human insulin B29 position, the human insulin desB30 position, or the bovine insulin B01 deuterated (Journal of Pharmaceutical Sciences (1997) 86 (11) 1264-1268 ). It also covers insulin of the C-terminal guanamine. In addition, the term "insulin" is used herein to encompass the so-called "insulin analogs". Insulin analogs are insulin molecules which have one or more mutations, substitutions, deletions and/or additions of A and/or B amino acid chains relative to human insulin molecules. More particularly, one or more amino acid residues are exchanged with additional amino acid residues, and/or one or more amino acid residues are deleted, and/or one or more amine groups are added. An acid residue is limited in that the peptide analog has sufficient membrane activity. An overview of the structure-activity relationships of some of the simian analogs, as well as examples of tolerable amino acid exchange/deletion/addition are provided in Biop〇lymers (Peptide Science) 2007, 88(5), 687-713 And references cited therein. The insulin analog is preferably one in which one or more of the naturally occurring amino acid residues are substituted with an additional amino acid residue. More preferred examples of insulin analogs are: C-terminally truncated derivatives such as des(B30) human insulin; B-chain N-terminally truncated insulin analogs such as des PheBl insulin or des B1-4 membrane islands 201141513 wherein the A-bond and/or B_ chain has an N-terminally extended insulin analog, including the so-called "pre-insulin", wherein the B-chain has a (four) extension; and wherein the A-chain and/or B-chain An insulin analog having a c_end extension. For example, one or three Args can be added to the B chain. Yet. A preferred example of additional insulin analogs consists of the above-described substitution, truncation and extension. Examples of insulin analogs are described in the following patents and their respective patents. US 5,618,913, EP 254,516, EP 280, 534, US 5,750, 497 and US 6,011, 〇〇7. A similar overview of the membranes used clinically is provided in Bi〇p〇lymers (peptide Science) 2〇〇7, 88(5), 687-713 and the references cited therein. Insulin analogs or precursors thereof are typically prepared using genetic techniques well known to those skilled in the art, typically bacteria or yeast, if desired followed by enzymatic or synthetic processing. Alternatively, the temsin analog can be prepared by chemistry (Biol. Chem. Hoppe Seyler (1986) 135-140).

Examples of specific specific insulin analogues are insulin aspart (also known as AspB28 human insulin); from insulin lispro (ie LysB28, ProB29 human tamsin); Insulin glulisine) (ie, LysB〇3, GluB29 human insulin); and insulin glargine (also known as GlyA21, ArgB3, ArgB32 human insulin). The term "姨岛素" is also used to cover other precursors or intermediates of the knees, such as pro-Tengyuan protoplasma, pro-insulin or where the C-peptide system is truncated, modified or replaced before Tengdao Suyuan or Qianteng a derivative of the island. Finally, the term "insulin" is also used to encompass compounds which may be considered to modify the Tengdao 201141513 or insulin analogues, such as insulin with amino acid exchange/deletion/addition and further modifications such as deuteration or other chemical modifications. These insulins are also known as "insulin derivatives". An example of such a compound is insulin detemir (i.e., LysB29-tetradecyl, des(B30) human). Further examples may be membrane amino acids in which an amino acid, such as a D-amino acid, is incorporated into a non-natural amino acid or a normally non-coding eukaryotic organism (Hoppe Seylers Z. Physiol. Chem. (1976) 357, 1267-1270; Hoppe Seylers Z. Physiol. Chem. (1975) 356, 1635-1649; Hoppe Seylers Z. Physiol. Chem. (1971) 352, 1595-1598). Yet another example is an insulin analog wherein the C-terminal carboxylic acid of the A chain or the B chain or both are substituted with decylamine. When the term "linker" is used in connection with a compound of the invention, it encompasses a chemical group used to link two biomolecules or modified biomolecules to each other. These linkers are well known to those skilled in the art. A description of many of these linkages, as well as reagents and methods for introducing them, are described in Hermanson, G.T., Bioconjugate Techniques (second edition) Academic Press 2008 pages 215-342. However, the term "linker" is not limited to that described in this reference, which also encompasses analogs, homochromosomes, regioisomers, and combinations thereof. Particularly suitable among the present invention are the heterobifunctional linkers described in Hermanson, GT Bioconjugate Techniques (Second Edition) Academic Press 2008 pages 277-334, and analogs, homochromosomes, regioisomers thereof and Its composition. Linkers which can be cleaved under specific conditions in vivo are also particularly suitable for use in the present invention, since release or isolation of insulin from siRNA may be desirable or necessary after internalization into cells of the compounds of the invention. The in vivo cleavable linker includes such linkers containing appropriately functionalized disulfide bonds, which can be cleaved under intracellular reducing conditions, and such linkers containing appropriately functionalized ester functional groups, Intracellular cleavage can be catalyzed by an enzyme or in a pH-dependent manner (〇ishi, M,

Biomacromolecules 2003, 4, 1426-1432; Oishi, M., J. Am.

Chem.  Soc.  2005, 127, 1624-1625). Furthermore, the term "Moon Island" also covers the appropriate starting materials well known to the applicator of this technique, using Hermanson, G. T.  The chemical group produced by the chemical reaction described in Bioconjugate Techniques (Second edition) Academic Press 2008, pages 169-211. When the term "siRNA" is used in connection with the present invention, it encompasses oligomers comprising or containing ribonucleotides which are capable of regulating gene expression by RNA interference. It may also extend to include a ribonucleotide-containing precursor' which requires intracellular enzyme treatment (e. g., DICER) to modulate gene expression by RNA interference. Such oligomers include short interfering nucleic acids (siNA), short interfering RNA (siRNA), double stranded RNA (dsRNA), DICER matrix dsRNA, micro-RNA (miRNA) and short hairpin RNA (shRNA) molecules. In general, the invention is a compound comprising insulin and siRNA. This chimeric compound can be defined by Formula I: Ins-Lin-siRNA (Formula I), wherein insulin (Ins) is linked to siRNA via a linker (Lin) 22 201141513. In a preferred embodiment of the invention, the linker (Un) is a group having the following structure: (Xl)q-(Ll)p-(D)d-(L2)r-(X2)s- (Y)rz (Formula η) wherein XI is a group selected from the group consisting of: -C(〇)_; -OC(O)-; -C(0)-0-; -C(0 )-N(R1)-; -N(R1)-C(0)-; -C(S)-N(R1)-; -N(R1)-C(S)-; -S〇2-; _C(NH2+)-; -0-P(0)(0H)-; -S-; -N(R1)_; =NN(R1)-;; and heterocyclic group; /LI is selected from the following Group: (CrCi8)_alkyl, (o-(crc8)-alkyl)n, ((crc8)_alkyl), (C3_C6)_cycloalkyl, (0-(C3-C6) )-cycloalkyl)n, ((C3_C6)-cycloalkyl hydrazine 、), alkyl-(Q-C6)-cycloalkyl, (CrC6)-cycloalkyl-(Ci_c8)-alkyl, ( C6-C14)-aryl, (Crc8)-alkyl-(c6-c14)-aryl, (c6-c14)-aryl-(CrC8)-alkyl, (CrQ)-cycloalkyl-(c6_Ci4 )-aryl, (C6-C14)-aryl-(crc6)-cycloalkyl, (.丨_.13)_heteroaryl, (Crc8)_alkyl-(CrC)3)-heteroaryl , (CrC13)-heteroaryl-(Ci_c8)-alkyl, (C3-C6)-cycloalkyl-(CrC13)-heteroaryl, (c)_Ci3)-heteroaryl-(Q-C6)- Cycloalkyl, (cvc 3)-heterocyclyl, (Ci_C8)_ Alkyl-(C^Cn)-heterocyclyl, (C^-C)3)-heterocyclyl-(Ci_c8)-alkyl, (CrQ)-cycloalkyl-(C^-Cn)-heterocyclic And (C2_Ci3)_heterocyclyl-(C3-C6)-cycloalkyl; 23 201141513 D is selected from the group consisting of: -C(O)-, -C(0)0-, -OC (O)-, -N(R1)-C(0)-, -C(0)N(R1)-, -N(R1)C(0)-N(R1)_, -SOm-, -C (NH2+)-, -N(R1)-, -N(R1)-N=, =NN(R1)-, -N(R1)-N(R1)-, -0-, -S-, -SS -, -0-(CH2)-, -(CH2)-0-, (0-(C2-C8)-alkyl)n, ((C2-C8)-院基-0)n, (0-S02 -N(Rl)-(CrC8)-alkyl), (N(Rl)-(CrC8)·alkyl), (ISKRUQOHCi-Cs)-alkyl), (Ν(Ι11)ί:(ΝΗ2+Η( 〇8)-alkyl), (N(Rl)C(0)-N(Rl)-(CrC8)-alkyl), (C(0)-N(R1HC"C8)-alkyl), ( N(Rl)-S02-N(Rl)-(CrC8)_alkyl), (N(Rl)-S02-(CrC8)-alkyl), (S02-N(RlHCrC8)-alkyl), (N (Rl)-S02-0-(CrC8)-alkyl), (SOdCrQ)-alkyl), (O-CCOHCrQ)·alkyl), alkyl), (0-C(0)-0-(Ci -C8)-alkyl), (0-C(0)-N(RlHCVC8)-alkyl), (l^RlH^OKMCVCs)-alkyl), (〇-(C3-C6)-cycloalkyl) n, (o-so2-n(rihc3-c6)- Alkyl), (n(ri)-(c3-c6)-cycloalkyl), (n(ri)c(o)-(c3-c6)-cycloalkyl), (N(Rl)C(NH2+) )-(C3-C6)-cycloalkyl) '(N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl)' (C(0)-N(R1)- (C3-C6)-cycloalkyl) '(N(Rl)-S〇2-N(Rl)-(C3-C6)-cycloalkyl)' (n(ri)-so2-(c3_c6)-环Alkyl), (S〇2·N(R1)-(C3--c6)-cycloalkyl), (N(Rl)-S〇2-0-(C3_C6)-cycloalkyl), (SOm- (C3-C6)-cycloalkyl), (o_c(o)-(c3-c6)-cycloalkyl), (c(o)_o-(c3-c6)-cycloalkane 24 201141513 base), (0 -C(0)-0-(C3-C6)-cycloalkyl hydrazine, (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl), (N(Rl)-C (0)-0-(C3-C6)-cycloalkyl), (0_(Ci_c8)·alkyl-(C3-C6)-cycloalkyl)n, (0-S02-N(Rl)-(CrC8) )-alkyl group_(c3-C6)_ bad base), (N(Rl)-(CrC8)-alkyl-(C; 3-C6)-cycloalkyl), (N(Rl)C(0) )-(CrC8)-alkyl-(C3-C6)-cycloalkyl), (N(Rl)C(0)-N(Rl)-(Cr. C8)-alkyl-(C3-C6)-cycloalkyl), (C(0)-N(Rl)-(CrC8)-alkyl-(C3-C6)-cycloalkyl), (N(Rl) )-S〇2-N(Rl)-(CrC8)-alkyl-(C3-C6)-cycloalkyl), (Ν(Κ_1)-8〇2-(〇ν€8)-alkyl _( c3-C6)-cycloalkyl), (SC^-N^RlXCrCs)-alkyl group_(c3-C6)-cycloalkyl), (N(R1)-S02-0-(Ci-C8)-^ _(C3-C6)- ^. ), (S〇m-(CrC8)-alkyl-(C3-C6)-cycloalkyl), ((^(OXCi-Q)-alkyl-(C3-C6)-cycloalkyl), (C (〇)-〇-(C--C8)-alkyl-(c3-C6)-cycloalkyl), (0-C(0)-0-(CrC8)-alkyl-(C3-C6)- Cycloalkyl), (O-CXCO-IsKRlXCi-Cs)··alkyl-(C3-C6)-cycloalkyl), (N(R1)-C(0)-0-(Ci-C8). Pyridyl-(C3-C6)-cycloalkyl), (〇-(C3-C6)-cycloalkyl-(Ci-Cs)-alkyl)n, (0-S〇2-N(Rl)- (C3-C6)-cycloalkyl-(C^-Cs)-alkyl), (N(R1)-(C3-C6)-cycloalkyl-(CVQ)-alkyl), (N(R1) C(0)-(C3-C6)-cycloalkyl-(crC8)-alkyl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-(CVCs )-alkyl), (C(0)-N(R1)_(C3-C6)-cycloalkyl-(CrC8)-alkyl), (N(R1)-S02-N(R1)-(C3 -C6)-cycloalkyl-(CrC8)-alkyl), 25 201141513 (N(Rl)-S〇2-(C3-C6)-cycloalkyl-(Ci_C8)-alkyl), (S〇2 -N(Rl)-(C3-C6)-cycloalkyl-(Ci-Cs)-alkyl), (N(Rl)-S02-0-(C3-C6)-cycloalkyl-(CrCs)- Anthracene), (scv(c3-c6)-cycloalkyl-(crc8)-alkyl), (oc(o)-(c3-c6)-cycloalkyl-(crc8)-alkyl), (c (o)-o-(c3-c6)-cycloalkyl-(crc8)-alkyl), (0-C(0)-0-(C3-C6)-cycloalkyl-(Ci-Q)- Alkyl), (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl-(crc8)-alkyl), (N(Rl)-C(0)-0-(C3_C6 )-cycloalkyl-(CrQ)-alkyl), (o-(c6-c14)-aryl)n, (〇-S02-N(Rl)-(C6-C14)-aryl), (N (R1)-(C6-CI4)-aryl), (N(Rl)C(〇HC6-C14)-aryl), (N(R1)C(0)-N(R1)-(C6-C14 )- Fang ), (C(0)-N(R1)-(C6-C14)-aryl), (N(R1)-S02-N(R1HC6-C14)-aryl), (N(R1)-S02- (C6-C14)·aryl), (S02-N(R1)-(C6-C14)-aryl), (n(ri)_so2-o-(c6-c14)·aryl), (SOm- (C6-C14)-aryl), (0-c(0)-(c6-c14)-aryl), (c(o)-o-(c6-c14)-aryl), (oc(o) )-o-(c6-c14)-aryl), (0-C(0)-N(Rl)-((VC14)-aryl), (N(Rl)-C(〇KKC6-C14)- Aryl), (CKCVQ)-alkyl-(c6-c14)-aryl)n, (O-SCVNCRIHCVQ)-alkyl-(C6-C14)-aryl), (N(Rl)-(CrC8) -alkyl-(C6-C14)-aryl), (N(Rl)C(0)-(CrC8)-alkyl-(C6-C14)-aryl), (N(Rl)C(0) -N(Rl)-(CrC8)-alkyl-(C6-C14)-aryl), (C(0)-N(Rl)-(CrC8)-alkyl-(C6-C14)-aryl) , (N(Rl)-S02-N(Rl)-(CrC8)-alkyl-(C6-C14)-aryl), 26 201141513 (IS^RiySC^-i^Ci-Cs)-alkyl-( C6_Ci4)-aryl), (SCVNCRIXC^-Cs)-alkyl-(C6-C14)-aryl), (Ν(ΚΛ)-8〇2-〇-((^-(Ζ;8)-烧Base-(C6-Cu)-aryl), (SOm. CCi-Cs)-alkyl group_(C6"C14)·aryl), (O-CXOXC^-Q)-alkyl-(c6-c14)-aryl), ((:(〇κκ(ν(:) 8)-alkyl-(c6-c14)-aryl), (0-C(0)-0-(Ci"C8)-homo-(C6-Ci4)-aryl), (O-CXOyiS^ RlXCi-Cs)--alkyl-(CVCh)-aryl), alkyl-(C6_Ci4)-aryl), (0-(C6-C14)-aryl-(CVC8)·alkyl)n, ( 0-S〇2-N(Rl)-(C6_Ci4)·. Aryl-(Ci-Cs)-alkyl), (N(R1)-(C6-C14)-aryl-(CVCs)-alkyl), (N(R1)C(0)-(C6-C14) )-aryl-(Crc8)-alkyl), (N(R1)C(0)-N(R1)-(C6-C14)-aryl-(crc8)-alkyl), (C(0) -N(R1)-(C6-C14)·aryl-(CVC8)-alkyl), (N(R1)-S02-N(R1)_(C6-C14)-aryl-(crc8)-alkane (N(R1)-S02-(C6-C14)-aryl-(C"c8)-alkyl), (S02-N(R1)-(C6-C14)-aryl-(CrQ) -alkyl), (N(Rl)-S02-0-(C6-C14)-aryl-(CVCs)-alkyl), (SOm-(C6-C]4)-aryl-(Ci-Cg )-(alkyl), (0-C(0)-(C6-Ci4)-aryl-(C)-C8)-alkyl), (C(0)-0-(C6-Ci4)-aryl -(Ci-Cg)-alkyl), (0-(2(0)-0-(^6-^4)-aryl-(Ci-Cg)-hyun), (0-C(0) -N(Rl)-(C6-CI4)-aryl-(Ci-Cs)-alkyl), (N(Rl)-C(0)-0-(C6-Ci4)-aryl-(Ci- Cg)-alkyl), (0-(C3-C6)-cycloalkyl-(C6-C14)-aryl)η, 27 201141513 (0-S02-N(Rl)-(C3-C6)-ring (-(c6-c14)-aryl), (N(R1)-(C3-C6)-cycloalkyl-(c6-c14)-aryl), (N(R1)C(0)-( C3-C6)·cycloalkyl-(c6-c14)-aryl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-(C6_C14)-aryl ), (C(0)-N(R1)-(C3-C6)·ring Base —(c6-c14)-aryl), (N(Rl)-S02-N(Rl)-(CrC6)_cycloalkyl-(C6-C14)-aryl), (N(Rl)-S 〇2-(C3_C6)·bad alkyl-(C6-C14)-aryl), (S〇2-N(Rl)-(C3-C6)-cycloalkyl-(C6-CH)-aryl) , (N(Rl)-S〇2-〇-(C3_C6)-cyclohexyl-(C6-Ci4)_aryl), (SOm-(C3-C6)-cycloalkyl-(C6-C14)- Aryl), (0-C(0)-(c3-C6)-cycloalkyl-(CVCh)-aryl), (C(0)-0-(C3_C6)-cycloalkyl-(C6-C14 )-aryl), (0-C(0)-0-(C3-C6)-cycloalkyl-(C6_C14)-aryl), (0-C(0)-N(Rl)-(C3- C6)-cycloalkyl-(C6-C14)-aryl), (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl-(c6-C14)-aryl), (0-(C6-C14)-aryl-(C3-C6)-cycloalkyl)n, (0-S02-N(Rl)-(C6-C14)-aryl-(C3-C6)-cyclic Alkyl), (N(R1)-(C6-C14)-arylcycloalkyl), (N(R1)C(〇HC6-Ch)-aryl-(crC6)-cycloalkyl), (N (R1)C(0)-N(R1)-(C6-C14)-aryl-(C3,C6)-cycloalkyl), (C(0)-N(R1)-(C6-C14)- Aryl-(C3_C6)-cycloalkyl), (N(R1)-S02-N(R1HC6-C14)-aryl-(crc6)-cycloalkyl), WRIVSOHCVCh)-aryl-(CrC6)-cyclic Alkyl), (S02_N(R1)-(C6-C14)-aryl_(C3_C6)_ ring burn ), (n(ri)-so2-o-(c6-c14)_aryl_(C3_C6)·cycloalkyl), 28 201141513 (SOm-(C6-C14)-aryl-(c3-c6)- Cycloalkyl), (〇-C(0)-(C6-C14)-aryl-(c3-c6)-cyclic), (C(0)-0-(C6-C14)-aryl- (c3-c6)-cycloalkyl), (0_C(0)-0-(C6-C14)-aryl-(CrQ)-cycloalkyl), (0-C(0)-N(Rl)- (C6-C14)-aryl-(C3-C6)-cycloalkyl), (N(Rl)-C(0)-0-(C6-C14)-aryl-(c3-c6)-cyclic burn (), (0-(CrC13)-heteroaryl)n, (0-S02-N(Rl)-(CrC13)-heteroaryl), CNKRIHCrCn)-heteroaryl), (N(Rl)C( 0)-(CrC13)-heteroaryl), (^RUQOH^RlHCVCn)-heteroaryl), (C(0)-N(Rl)-(CrC13)-heteroaryl), (N(R1)- S02-N(R1)-(C1-C13)-heteroaryl), (NCRU-SOr^CrCu)-heteroaryl HSOrNCRIHCrCn)-heteroaryl), (Ν(Κ_1)-8〇2-〇-( 〇ν€ι3)-heteroaryl), (SOn^C^-C^)-heteroaryl), (◦cxoHCi-Cn)-heteroaryl), aryl), (oc(o)-o- (crc13)-heteroaryl), (0_C(0)-N(Rl)-(CrC13)-heteroaryl), (N(Rl)-C(0)-0-(CrC13)-heteroaryl) , (CKCVC8)-alkyl-(crc13)-heteroaryl)n, (0_S02-N(RlHCrC8)-alkyl-(CrCn)- Aryl), (NCRIHCVQ)-alkyl-(Crcl3)-hetero J-based, (N(Rl)C(0)-(CrC8)-alkyl-(CrC13)-heteroaryl), (N(Rl) C(0)-N(Rl)_(CrC8)_alkyl, (CrC13)-heteroaryl), (C(0)-N(Rl)-(CrC8)-alkyl-(CrC13)- Aryl), (N(Rl)-S02-N(Rl)-(CrC8)-alkyl-(CrC13)-heteroaryl), (N(Rl)-S02-(CrC8)_alkyl-(CVC13 )-heteroaryl), (SOyNCRlMCVCs)-alkyl-(CVC13)-heteroaryl), 29 201141513 (N^RU-SCVCMCVCs)-alkyl-(CrC13)-heteroaryl), (SOm-CCrCs) -alkyl-(CrCn)-heteroaryl), (〇_C(〇)-(CrC8)-alkyl-(CrC13)-heteroaryl), (qcO-CKQ-Cs)-alkyl-(CVCn )-heteroaryl), (O-CXOHHCrCs)-alkyl-(crc13)-heteroaryl, (O-CXOhNiRlHCrQ)-alkyl-(Ci-Cn)-heteroaryl), (NCRlH^Oi- CKCrQ)-alkyl-(Cl_Cl3)-heteroaryl), (〇_(Ci-Ci3)-heteroyl-(CVCs)-alkyl)n, (0-S02-N(Rl)-(CrC13) -heteroaryl-(crC8)-alkyl), (N(Rl)-(CrC13)-heteroaryl-(CrC8)-alkyl), (N(Rl)C(0)-(CrC13)- Aryl-(CrQ)-alkyl), (NiRUqCO-NiRlHCi-Cn)·heteroaryl-(CrCJ-alkyl), (C(0)-N(Rl)-(CrC13)-heteroaryl-( C "C8)-alkyl), ( N(Rl)-S02-N(Rl)-(CrC13)-heteroaryl-(QQ)-alkyl), (N(Rl)-S〇2-(Ci-Ci3)-heteroaryl-(C1 -C8)-alkyl group, (S02-N(Rl)-(CrC13)-heteroaryl-(CrC8)_alkyl), (NiRU-SCVCKCrCn)-heteroaryl-(CrC8)-alkyl), (SOm-(CrC13)-heteroaryl-(CrC8)-alkyl), (0-C(0)-(CrC13)·heteroaryl-(CVCs)-alkyl), (C(0)-0 -(CrC13)-heteroaryl-(Ci-Cg)-alkyl), (0-C(0)-0-(CpCi3)-heteroaryl-(Ci-Cs)-alkyl), (O- QCO-NiRlMCrCn)-heteroaryl-(CrC8)-alkyl), (N(Rl)-C(0)-0-(CrC13)-heteroaryl-(CVCs)-alkyl), (0-( C2-C13)-heterocyclyl)n, (0-S02-N(Rl)-(C2-C13)-heterocyclyl), (N(R1)-(C2-C13)-heterocyclyl), n(ri)c(o)-(c2-c13)-heterocyclic group, (N(R1)C(0)-N(R1)-(C2-C]3)-heterocyclic group), 201141513 ( C(0)-N(R1)-(C2-Ci3)-heterocyclyl), (N(R1)-S02-N(R1)-(C2-C13)-heterocyclyl), (N(R1) -S02-(C2-C13)-heterocyclic group, (s〇2-N(R1)-(C2-C13)-heterocyclic group), (N(Rl)-S02-0-(C2-C13) -heterocyclic group), (SOm_(C2-C13)-heterocyclic group), (〇-C(〇HC2-Ci3)-heterocyclic group), (C(0)-0-(C2-C13), ring Base), (〇-C(0)-0-(C2- C13)-heterocyclyl), (0-C(0)-N(Rl)-(C2-C13)-heterocyclyl), 0^(1^1)-(^(0)-0-(02 -(^3)-heterocyclic group, (〇-(Ci-C8)-alkyl-(C2-C13)_heterocyclyl)n, (:0-S02-N(Rl)-(CrC8)- Anthracenyl-(匚2-(^13)_heteroyl), (N(R1)-(Ci_C8)-alkyl-(C2-C13)-heterocyclyl), (NiRDCCOHCVQ)-alkyl-(c2 -c13)-heterocyclic group, (N(Rl)C(0)-N(Rl)-(CrC8)-alkyl-(c2-c13)-heterocyclyl), (C(0)-N( RlHCrC8)-alkyl-(c2-c13)·heterocyclic group, (NCRiySCVWRlXCrQ)-alkyl-(C2-C13)-heterocyclic group, (Ν(Ι11)-8〇2-(ίν€8) -alkyl-(C2-Ci3)-heterocyclic group), (S〇2-N(R1)-(Ci-C8)-Enteryl-yl-(C2-C13)-heterocyclic group), (IS^RiySC ^-CMCVQ)-alkyl-(C2-Q3)-heterocyclic group, (SOni-CCi-Cs)-alkyl-(C2-C13)-heterocyclic group, (0-(1:(0)) -((^-08)-alkyl-(C2-C13)-heterocyclyl), (C(0)-0-(CrC8)-alkyl-(c2_Ci3)·heterocyclyl), (0-0 (0)-0-((^-08)-alkyl-(C2-C13)-heterocyclyl), (0-C(0)-N(Rl)-(CrC8)-alkyl-(C2- C13)-heterocyclyl), (N(R1)-C(0)-0-(Ci-C8)-alkyl-(C2_C13)-heterocyclyl), (0-(C2-C13)-heterocycle -(crc8)-alkyl)n, (0-S〇2-N(Rl)-(C2-C13)- Cyclo-(CrCs)-alkyl), 201141513 (N(R1)-(C2-C13)-heterocyclyl-(Ci_c8)_alkyl), (N(R1)C(0)-(C2-C13 )-heterocyclyl-(Ci_c8)_alkyl), (N(R1)C(0)-N(R1)-(C2-C13)-heterocyclyl-(Ci_c8)_alkyl), (C( 0)-N(R1)-(C2-C13)-heterocyclyl-(crc8)_alkyl), (N(R1)-S02-N(R1)-(C2-C13)-heterocyclyl-( Ci_c8)-alkyl), (N(R1)-S02-(C2-C13)-heterocyclyl-(crc8)_alkyl), (S02-N(R1)-(C2-C13)-heterocyclyl _(Ci_c8)_alkyl), (N(Rl)-S02-0-(C2-C13)-heterocyclyl-(Ci_c8)_alkyl), (SOm-(C2-C13)-heterocyclyl- (crc8)-alkyl group, (〇_c(〇)_(c2-C13)-heterocyclyl-(CrQ)-alkyl), (c(〇)_〇_(c2_Ci3)__ heterocyclic group ( CrC8)_alkyl), (0_C(0)-0_(C2-C13)-heterocyclyl-(CVQ)-alkyl), (0-C(0)-N(Rl)-(C2-C13) -heterocyclyl-(crc8)-alkyl) and (N(Rl)-C(0)-0-(C2-C13)-heterocyclyl-(crc8)-alkyl); L2 is selected from the following Groups included: (Ci_Ci8)_alkyl, (CKCVCs)-alkyl)n, ((CrC8)·alkyl group_0)n, (c3_c6)_cycloalkyl, (0-(C3-C6)- Cycloalkyl)n, ((c3-c6)-cycloalkyl-〇)n, (crc8)-alkyl-(CVC6)-cycloalkyl, (CVC 6)-cycloalkylalkyl, (Q-Cm)-#, aryl, (C6-C14)-aryl-(Ci-C:8)-alkyl, (CVC6)-cycloalkyl-( C6_c14)-aryl, (C6_C14)-aryl-(C3-C6)-cycloalkyl, (crCi3)-heteroaryl, (crc8)-alkyl-(CrCn)-heteroaryl, (CVCn)- Heteroaryl-(crc8)-alkyl, (CrC6)-cyclohexyl-(C"Cn)-heteroaryl, (CrC^)-heteroaryl-(Q-C6)-cycloalkyl, (CVC !3)-heterocyclyl, (QQ)-alkyl 32 201141513 -(CVCn)-heterocyclyl, (C2_C13)-heterocyclyl-(Cl_c8)·alkyl, (CVC6)-ring-based-(CVCn -heterocyclyl and (c2-Cn)-heterocyclyl-(c3-c6)-cycloalkyl; X2 is a group selected from the group consisting of: _c(〇)_; -OC(O )- ; -C(0)-0- ' -N(R1)-C(0)- ; -C(0)-N(R1)-; -N(R1)-C(S)- ; -S 〇2- ; -C(NH2+)- ; -〇-P(〇)(〇H)- ; -S-; -N(R1)-; and -O-; Y is a group selected from the group consisting of The group: -C(0)-; -S-; -N(R1)-; -N(R1)-N=; and =NN(R1)·; z is selected from the group consisting of: a direct bond, (Cl_Ci4)-alkyl, alkyl)n, (((^-Cs)-院-〇)n, (crC14)-alkyl-C(O)-, (C3-C6)- Cycloalkyl-C(0)-, (C6-C14)-aryl-C(0)- (crc14)-alkyl-(c6-c14)-aryl-C(0)-, (c6-c14)-aryl-(Ci-C14)-alkyl-C(o)-, (C3-C6 )-cycloalkyl-(c6-C14)-aryl-C(0)-, (C6-C14)-aryl-(C3-C6)-cycloalkyl-C(0)·, (crC13)- Heteroaryl-c(0)-, (Cl-Cl4)-alkyl-(even)-heteroaryl_c(0)-, (CrC13)-heteroaryl-(CrCl4)-alkyl-C ( 0)·, (C3_C6)_cycloalkyl-(Q-Cn)-heteroaryl_C(0)_, (Cl-C13)-heteroaryl_(c3-C6)_cycloalkyl-C( 0)-, (C2-C13)-heterocyclyl-C(0)-, (Cl_Cl4)_alkyl-(C2-C13)-heterocyclyl_c(0)_, (C2-C13)-hetero Cyclol-(crc14)·alkyl-C(0)-, (C3-C6)-cycloalkyl-(C2-C13)-heterocyclyl-C(〇)-, (C2-C13)- 33 201141513 Heterocyclyl-(C3-C6)-ring-based-C(O)-, (crC14)-alkyl-N=, (C3-Q)-ring-based-N=, (C6-C!4) -aryl-N=, (Q-Ch)-alkyl-(C6-C14)-aryl-N=, (CVCWH^-Ch)-alkyl-N=, (C3_c:6)-cycloalkyl -(cvc) 4)-aryl_N=, (C6_Ci4)_aryl-(C3-C6)-cycloalkyl-N=, (Q-Cn)-heteroaryl_N=, (C^- Ch)-院基_(Ci-C13)-heteroaryl-N=, (CrC^)-heteroaryl. (Q-Cm)-alkyl-N-, (C3-C6)-cycloalkyl-(CpCn)-heteroaryl_n=, (CVCn)-heteroaryl-(C3-C6)-cycloalkyl -N=, (C2-C13)-heterocyclyl-(C2-C13)-heterocyclyl-N=, (C2-C13)-heterocyclyl-(Q-Cm)-homo-N= (C3-C6)-cycloalkyl-(C2-Ci3)-heterocyclyl, (C2-CI3)-heterocyclyl-(CrQ)-cycloalkyl-N=, (CrC14)-alkyl-N (R1)-, (C3-C6)-cycloalkyl-N(R1)-, (C6-C14)-aryl-N(Rl)-, (CrC14)-alkyl-(C6-C14)-aryl -N(R1)-, (C6-C14)-aryl-(C丨-C 丨4)-alkyl-n(ri)-, (c3-c6)-cycloalkyl-(c6-c14) -aryl_N(R1)-, (C6-C14)-aryl-(CVC:6)-cycloalkyl-N(R1)-, (CVCu)-heteroaryl-N(R1)-, ( CrC14)-alkyl-(Q-Cu)-heteroaryl-N(R1)-, (CVCn)-heteroaryl-(Q-Cu)-homo-N(R1)-, (C3-C6) -cycloalkyl-(q-Cn)-heteroaryl-N(R1)-, (CrCu)-heteroaryl-(C3-C6)-cycloalkyl-N(R1)-, (C2-C13) -heterocyclyl-N(R1)-, (CrC14)-alkyl-(C2_C13)-heterocyclic group 111)-, (0:2-(:13)-heterocyclyl-(〇1-(: ]4)-alkyl-^[(1〇)-, ((:3-(:6)-cycloalkyl-(CVC)3-heterocyclyl-N(Rl)-, (C2-C13) -heterocyclyl-(C3-C6)-cycloalkyl-N(R1)-, -〇-ρ(〇χ Η)_, (CrCi4)-alkyl-0-P(0)(0H)-, (0-(CrC8)-alkyl)η-〇·ρ(〇)(〇Η)_, ((CrCs) -alkyl-〇)nP(〇)(〇H)_, (C3_C6)_cycloalkyl 34 201141513 -0-Ρ(0)(0Η)-, (CVC14)-alkyl-(C3_C6)_naphthenic Base-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CrCi4)_alkyl-0-Ρ(0)(0Η)-, ((^-(^士芳)七-以(7)(七)印, (c "Ci3)·heteroaryl-ΟΜΟΧΟΗ)-, (Cl_Ci4> alkyl-(CVCi4)_ aryl-0-P(0)(0H)_, (C6-C14)_ Aryl-(Cl_Cl4)_alkyl_0-Ρ(0)(0Η)-, (C3-C6)-cycloalkyl·((;ν(::14)-aryl-0-P(0) (0H)_, (C6-C14)_ arylcycloalkyl-0-P(0)(0H)-, (CrC14)·alkyl-(Cl_Cl3)-heteroaryl-0-P(0)( 0H)-, (ChI: 13)-heteroaryl_(CrCl4)-alkyl-0-P(0)(0H)_, (C3-C:6)-cycloalkyl-(Cl_Cl3)_ heteroaryl Base-0-P(0)(0H)-, (CrC13)-heteroaryl_(c3-c6)-cycloalkyl-0-oxime(0)(0Η)-, (C2_C13)-heterocyclyl_ 〇_p(〇)(OH)_, (c2-c13)-heterocyclyl-(CrCH)-alkyl group_〇_p(〇)(〇H)-, (C^-Ch)-alkyl group- (C2-C13)-heterocyclic group-0-P(〇)(〇H)-, (C2-C13)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(0)(0H )-, (C rC6)-cycloalkyl-(C2-C13)·heterocyclic group-0-P(0)(0H)-, -〇_P(S)(〇H)·, (CrC14)-alkyl-0- P(S)(0H)-, (CHCVQ)-alkyl^^卩(8)(9)!!)-, "^-^)-alkyl-0)nP(S)(0H)-, (C3-C6)- Cycloalkyl-0-P(S)(0H)-, (Q-Cm)-alkyl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (C3-C6) -cycloalkyl-(CrC14)-alkyl-0-P(S)(0H)-, (C6-C14)-aryl-0-P(S)(0H), (CrC13)··heteroaryl -0-P(S)(0H)·, (CrC14)-alkyl-(c6-c14)-aryl-0-P(S)(0H)-, (C6-C14)-aryl-(C1 -C14)-alkyl--0-P(S)(0H)-, (C3-C6)-bad alkyl _(C6-C)4)-aryl-0-P(S)(0H)-, (C6-C14)-aryl-(C3-C6)-cycloalkyl 35 201141513 -0-P(S)(0H)-, (crc14)-alkyl-(CrC13)-heteroaryl-0-P (S)(0H)-, (CrC13)-heteroaryl-(CkCm)-alkyl-0-P(S)(0H)·, (C3-C6)-cycloalkyl-(crC13)-heteroaryl Base-0-P(S)(0H)-, (CrC13)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(0H)·, (C2-C13)-heterocycle Base_〇_p(s)(OH)·, (C2-C13)-heterocyclyl-(C--C14)-alkyl-〇-p(S)(〇h)_, (CrC14)_ alkane -(C2-C13)-heterocyclyl-indole-P(S)(〇H)-, (C2-C13)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(S) (0H)-, (C3-C6)- Alkyl-(C2-C13)-heterocyclyl-0-P(S)(0H)-,-0-P(S)(SH)-, alkyl 0-P(S)(SH)-, ( CKQ-Q)-alkyl)n-〇-P(S)(SH)_, ((Ci-C8)·alkyl-oxime)nP(S)(SH)-, (C3-C6)-cycloalkane 〇-〇_P(S)(SH)-, (CVCh)·alkyl-(C3_C6)-cycloalkyl-〇-P(S)(SH)-, (C3-C6)-cycloalkyl-( (:"(:")-Alkyl-〇-P(S)(SH)-, (C6-C14)-aryl-0-P(S)(SH), (CrC13)_heteroaryl- 〇-P(S)(SH)-, (CVCh)-alkyl-(C6_C14)-aryl-0-P(S)(SH)-, (C6-C14)-aryl-(CrC14)·alkane 〇-〇-P(S)(SH)-, (C3-C6)-cycloalkyl-(C6-C14)-aryl-0-P(S)(SH)-, (C6-C14)-aryl -(C3-C6)-cycloalkyl-0-P(S)(SH)-, (Ci-Ci4)-alkyl-(Ci-Cn)-heteroaryl-0-P(S)(SH )-,(Ci-C]3)-heteroaryl-(Ci_Ci4)-alkyl-indole-P(S)(SH)-, (C3-C6)-cycloalkyl-(CVCn)-heteroaryl -〇-P(S)(SH)·, (CrC13)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(SH)-, (C2-C13)-heterocyclyl -0-P(S)(SH)-, (C2-C13)·Heterocyclyl-(CrC14)-alkyl-0-P(S)(SH)-, (CrC14)-alkyl-(C2- C 13)-heterocyclic group-0-P(S)(SH)-, (C2-C 13)-heterocyclyl-(C3-C6)- 36 201141513 cycloalkyl-fluorene-P(S)(SH )-, (c3-c6 )-cycloalkyl-(C2-C13)-heterocyclyl-0-P(S)(SH)-,-0-P(0)((CrC8)·alkyl)-, (CVQ4)-alkyl -0-P(0)((Ci-C8)-alkyl)-, (O-(Ci-Cs)-alkyl)n-〇-P(〇)((Ci-C8)-alkyl)_ , ((CrC8)-alkyl-oxime) nP(〇)((Ci-C8)-alkyl)-, (C3-C6)_cycloalkyl-〇_p(〇)((Ci-c8)- , (c^-Ch)-alkyl-(C3-C6)-cycloalkyl-O-P(0)((CrC8)-alkyl)-, (c3-c6)-cycloalkyl -((VCh)-alkyl-0-P(0)((CrC8)-alkyl), (c6-c14)-aryl-0-P(0)((CrC8)-alkyl), (C "C13)-heteroaryl-0-P(0)((CrC8)-alkyl)-, (CrCH)-alkyl-(C6-C14)-aryl-0-. Ρ(0)((〇ν(^8)-alkyl)-, (C6-C14)-aryl-(Ci-C")-alkyl--0-P(0)((Ci-C8)- , (C3-C6)-cycloalkyl-(C6-C14)-aryl-04(0)(((^-(^)-alkyl), (C6-C14)-aryl- (C3-C6)-cycloalkyl-〇-P(〇)((CrC8)-alkyl)-, (CVCm)-alkyl-(crc13)-heteroaryl-0-p(())(( Crc8)-alkyl)-, (crc13)-heteroaryl-(Ci-Ch)·alkyl--04(0)(((^-(^)-alkyl)-, (C3-C6)-ring Pyridyl-(CVCn)-heteroaryl-04(0)(((:,-(:8)-alkyl)-, (CrC13)-heteroaryl-(c3-c6)-cycloalkyl-0 -P(0)((CrC8)-alkyl)-, (c2-c13)-heterocyclyl-0-P(0)((CrC8)-alkyl)-, (c2-c13)-heterocyclyl -(crc14)-alkyl-〇-P(〇)((CrC8)-alkyl)-, (crc14)-alkyl-(C2_C13)-heterocyclyl-0-P(0)((CrC8> Base)-, ((: 2-(:13)_heterocyclyl-(C3-C6)-cycloalkyl-fluorene-P(〇)((CrC8)-alkyl)-, (c3-c6)· Cycloalkyl-(C2-C13)-heterocyclyl-04(0)(((^-(^)-alkyl)-, -0-P(0)(N(R2R3))-, (CrC14) -alkyl-0-P(0)(N(R2R3))-, (0-(CrC8)-alkyl)n_0-P(0)(N(R2R3))-, ((CrC8)-alkyl 37 201141513 -0)nP(0)(N(R2R3))-, (C3-C6)-cycloalkyl-0-P(0)(N(R2R3))-, (CrC14)-alkane -(C3-C6)-cycloalkyl-0-P(0)(N(R2R3))-, (C3-C6)-cycloalkyl-(Q-Cu)-alkyl-0-P(0 (N(R2R3))-, (C6-C14)-aryl-0-P(0)(N(R2R3))·, (CrC13)-heteroaryl-0_P(0)(N(R2R3)) ·, (CrCu)-alkyl-(C6-C14)-aryl-0-P(0)(N(R2R3))-, (C6-C14)-aryl-(CrC14)-alkyl-0- P(0)(N(R2R3))-, (C3-C6)-cycloalkyl-(C6-C14)-aryl-0-P(0)(N(R2R3))-, (C6-C14) -aryl-(C3-C6)-cycloalkyl--0-P(0)(N(R2R3))-, (CVCm)-homo-(QC);)-heteroaryl-0-P(0 (N(R2R3))-, (CrC)3)-heteroaryl-(CVCm)-alkyl--0-P(0)(N(R2R3))-, (C3-C6)-cycloalkyl- (Q-Cu)-heteroaryl-0-P(0)(N(R2R3))-, (CVCn)-heteroaryl-(C3-C6)-cycloalkyl-0-P(0)(N (R2R3))-, (C2-C13)-heterocyclic group-0_P(0)(N(R2R3))-, (C2-C13)-heterocyclyl-(CrC14)-alkyl-0-P(0 (N(R2R3))-, (Ci-Ch)-alkyl-(C2-C13)-heterocyclyl-0-P(0)(N(R2R3))-, (C2-C13)-heterocyclic --(C3-C6)·cycloalkyl-0-P(0)(N(R2R3))-, (C3-C6)-cycloalkyl-((VC13)-heterocyclyl-0-P(0 )(N(R2R3))-, -N(Rl)-P(〇)(〇H)·, (CrC14)-alkyl•N(R1)-P(0)(0H)-, (0-( CrC8)-alkyl)nN(Rl)-P(〇)(〇H)- , , (C3- C6)-cycloalkyl-N(R1)-P(0)(0H)-, (CrC14)-alkyl-(C3-C6)-cycloalkyl-N(R1)-P(0)(0H) -, (C3-C6)-cycloalkyl-(CrC14)-alkyl-N(R1)-P(0)(0H)-, (C6-C14)-aryl-N(Rl)-P(〇 (〇H), (CrC13)-heteroaryl-N(R1)-P(0)(0H)-, (CrC14)-alkyl 38 201141513 -(C6-C14)-aryl-N(Rl) -P(〇)(〇H)-, (c6-c14)-aryl-(Cj-Cm)-alkyl-N(R1)-P(0)(0H)-, (c3-c6)-ring Alkyl-(c6-c14)-aryl-N(R1)-P(0)(0H)-, (C6-C14)-aryl-(c3-c6)-cycloalkyl-N(R1)- P(0)(0H)-, (CrC14)-alkyl-(Ci-Cn)-heteroaryl·Ν(ϊα)-Ρ(〇)(〇Η)-, (CVCu)-heteroaryl-( Q-Cm)-alkyl-N(Ri)-p(〇)(〇H)_, (C3_C6)-cycloalkyl-(Cl_Cl3;)_heteroaryl-N(R1)-P(〇)( 〇h)-, (Q-Cn)-heteroaryl-(C3-C6)-cycloalkyl-N(R1)-P(0)(0H)_, (C2_Cl3)_heterocyclyl_N(R1 )_P(0)(0H)_, (c2-c13)-heterocyclyl·(CrCH)-alkyl-N(R1)-P(0)(0H)-, (C!-Ci4)-alkyl -(c2-Ci3)-heterocyclyl-N(Rl)-P(〇)(〇H)-, (C2-C13)-heterocyclyl-(C3_C6)-cycloalkyl·N(R1>p( 〇)(〇H) and (C3-C6)·cycloalkyl-(c2-c13)-heterocyclyl-N(Rl)-P(〇)(〇H)-; d is from 〇 to i〇 Integer integer; n An integer between 1 and 11; πι is 〇, ι or 2; the acoustic q, P, r, s, t are independently of each other 〇, t or 2; R1 is Η, (CVC6)-alkyl; And R3 are independently H, (Ci_C6)-Hyun, wherein the phantom and R3 are "the nitrogen atoms bonded to them form a healthy - to-cyclic heterocyclyl group. Bottom: In a more preferred embodiment of the invention, the groups are defined as X1 is a group selected from the group consisting of: _c(〇)_; 39 201141513 -OC(O)- ; C(〇)-〇- ; -C(0)-N(R1)- ; -N(R1)-C(0)-; -C(S)-N(R1)- ; -N(R1)- C(S)- ; -S02- ; -C(NH2>;-0-P(0)(0H)-;-S-;-N(R1)-;=NN(R1)-;-O-; And a heterocyclic group, LI is selected from the group consisting of: (CrCl())-alkyl, (0-(C2-C3)-alkyl)n, ((c2_C3)_alkyl-〇)n , (C3-C6)-cycloalkyl, (o-(c3-c6)-cycloalkyl)n, ((c3-C6)-cycloalkyl-indole), (crc6)-alkyl-(CVC :6)-cycloalkyl, (c3_c6)-cycloalkyl-(Ci-Q)-alkyl, (c6-c10)-aryl, (Cl_C6)-alkyl-(C6-Ci〇)-aryl , (c6_Cl〇)_^yl-(C)-C6)-alkyl, (c3-C6)-cycloalkyl-(C^-Cio)-aryl, (C6-C1())-aryl- (C3-C6)-cycloalkyl, (crc9)-heteroaryl, (CVC6)-alkyl-(CrC9)-heteroaryl, (qQ)-heteroaryl-(Crc6)-alkyl, (C3 -C6)-% alkyl-(C^-Cp)-heteroaryl, (C1-C9)-heteroaryl-(C3-C6)-cycloalkyl, (c2-C9)-heterocyclyl, Crc6)-alkyl-(c2-c9)-heterocyclyl, (C2_C9)-heterocyclyl-(cr C6)-alkyl, (c3-c6)-cycloalkyl-(CVC9)-heterocyclyl and (c2-C9)-heterocyclyl-(C3-C6)-cycloalkyl; D is independently selected from The following groups are included: _c(〇)---c(0)0-, -OC(O)-, -N(R1)-C(0)-, -C(0)N(R1)- -N(R1)C(0)-N(R1)-, -S0m-, -C(NH2+)-, -N(R1)-, -N(R1)-N=, =NN(R1)· , -N(R1)-N(R1)-, -0-, -S-, -SS-, -0-(CH2)-, -(CH2)-0., (0-(C2-C3)- Burning base) n, ((C2_C3)_alkyl-hydrazine) n, (0-S02-N(RlHCrC6)-alkyl), (l^RlHCVC^)- 201141513 alkyl), (N(R. l) C(0)-(CrC6)-alkyl), (N(Rl)C(NH2+)-(CrC6)-alkyl), (N(Rl)C(0)-N(Rl)-(CrC6 )·(), (CXCO-l^RlHCrQ)-alkyl), (ISKRU-SCVNiRlHCKCy·alkyl), (I^RU-SOHCVC^)·alkyl), (SCVNCRIHCrQ)-alkyl), (NiRiySOz -O-CCrCO-alkyl), (SOm-(CrC6)-alkyl), (0-C(〇HC"C6)_alkyl), (c(o)-o-(crc6)-alkyl) , (o-ccoycHCVQ)-alkyl), (O-qCO-NtRlHCVC^)-alkyl), (l^RlKXOHHCrQ)-alkyl), (o-(c3-c6)-cycloalkyl)η, ( (C3-C6)-cycloalkyl-0)n, (0-S02-N(Rl)-(C3-C6)-cycloalkyl), (N(R1)-(C3-C6)-cycloalkyl ), (N(R1)C(0)-(C3-C6)-cycloalkyl), (N(R1)C(NH2+), (C3-C6)-cycloalkyl) (N(R1)C( 0)-N(R1)-(C3-C6)- ring-base (C(0)-N(R1)-(C3-C6)-cyclo))(N(R1)-S02-N(R1) -(C3-C6)-cycloalkyl) (N(R1)-S02-(C3-C6)-cycloalkyl), (S02-N(R1)-(C3-C6)-cycloalkyl), ( N(Rl)-S02-0-(C3_C6)-cycloalkyl), (SOm-(C3-C6)-cycloalkyl), (oc(o)-(c3-c6).cycloalkyl), c(o)-o_(crc6)-cycloalkyl), (oc(o)-o-(c3-c6).cycloalkyl), (oc (o)-n(ri)-(c3-c6), ·cycloalkyl), (n(ri)-c(o)-o-(c3-c6)_·cycloalkyl), (o-( Crc6)-alkyl-(C3-C6)-cycloalkyl)n, (〇-S〇2-N(R1)-(Ci_C6)-alkyl-(C3_C6)_cycloalkyl), (NiRlHCVQ)- Alkyl-(C3-C6)-cycloalkyl), (l^RUqOHCrQ)-alkyl-(C3-C6)-cycloalkyl), 201141513 (N(Rl)C(0)-N(Rl)- (CrC6)-alkyl-(C3-C6)-cycloalkyl), (C(0)-N(Rl)-(CrC6)-alkyl-(C3_c6)_cycloalkyl), (N(Rl) -S02-N(RlHCrC6)_alkyl-(C3-C6)-cycloalkyl), (NCRU-SOHCrC^)-alkyl-(c3-C6)-cycloalkyl), (S02-N(RlHCrC6) -alkyl-(c3-C6)-cycloalkyl), (N(Rl)-S02-0-(CrC6)-alkyl-(C3-C6)-cycloalkyl), (SOm-(CrC6)- Pyridyl-(C3-C6)-cycloalkyl), (0-C(0)-(CrC6)-alkyl-(C3-C6)-cycloalkyl), (qoyCKCrQ)-hospital-(c3- C6)-cycloalkyl), (0-(:(0)-0-((ν(:6)-alkyl-(C3-C6)-cycloalkyl), (O-CXCO-NfRIXCrCe)-burning -(C3-C6)-cycloalkyl), (N(R1)_C(0)-0-(Ci_C6)-alkyl-(C3-C6)-cycloalkyl), (0-(C3-C6) )-cycloalkyl-(Crc6)-alkyl)n, (0-S02-N(Rl)-(C3-C6)-cycloalkyl-(CrC6)-alkyl), (N(R1)-( C;j-C6)-bad burnt base -(Ci-Cg)-alkyl), (N(R1)C(0)-(C3_C6)-cycloalkyl-(CrCe)-alkyl), (N(R1)C(0)_N(R1) -(C3-C6)-cycloalkyl-(CrC6)-alkyl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-(CrC6)-alkyl), (N (R1)-S02-N(R1)-(C3-C6)-cycloalkyl-(Ci-C6)-alkyl), (N(R1)-S02-(C3-C6)-cycloalkyl-( CVC6)-alkyl), (S02-N(R1HC3-C6)-cycloalkyl-(cvc6)-alkyl), (N(Rl)-S02-0-(C3-C6)-cycloalkyl-( CrQ)-alkyl), (SOm-(C3-C6)-cycloalkyl-(CVC6)-alkyl), (oc(o)-(crc6)-cycloalkyl-(c"c6)-alkyl , (c(o)-o-(crc6)-cycloalkyl-(CVC6)-alkyl), (oc(o)-o-(c3-c6)-cycloalkyl-(CVC6)-alkyl ), 42 201141513 (0-C(0)-N(Rl)-(C3_C6)-cycloalkyl-(crc6)-alkyl), (n(ri)-c(o)-o-(c3-c6 )-cycloalkyl-(C"c6)-alkyl), (o-(c6-c1())-aryl)n, (〇-SO2-N(Rl)-(C6-C10)-aryl ), (N(R1)-(C6-C10)-aryl), (n(ri)c(o)_(c6_c10)_ aryl), (N(Rl)C(O)-N(Rl) -(C6-C10)-aryl), (C(O)-N(Rl)-(C6-C10)-aryl), (N(Rl)-SO2-N(Rl)-(C6-C10) -aryl), (n(ri)-so2-(c6_c10)-aryl), (SO2-N(Rl)-(C6-C10)-aryl), ( N(Rl)-S〇2-O-(C6-C10)-. Aryl), (SOm-(C6-C10)-aryl), (OC(〇HC6-C10)-aryl), (c(o)-o-(c6-c10)-aryl), (oc (o)-o-(c6-c10)-aryl), (oc(o)-n(rihc6-c10)-aryl), (N(R1)-C(0)-0-(C6-Ci 〇)-aryl), (0-(Ci-C6)-homo-(C6-C10)-^l:)n ^ (O-SO2-N(RlHCrC6)-^^-(C6-C10)- Square), (N(R1)-(Ci_C6)-alkyl-(CVCio)·aryl), (N(R1)C(0)-(Ci_C6)·alkyl-(Cg-C^o)- Aryl), (N(R1)C(0)-N(R1)-(Ci_C6)-alkyl-(Cg-Cio)-aryl), (CXOJ-NXRIXCi-Cs)-:院基-(CVCio )-aryl), (N(Rl)-S02-N(Rl)-(CrC6)-alkyl-(C6-C10)-aryl), (N(R1)-S〇2_(Ci-C6) -alkyl-(C6-Ci〇)-aryl), alkyl-(C6-C10)-aryl), (N(R1)-S〇2-0-(Ci_C6)-alkyl-(C6- Ci〇)-aryl), (som-(crc6)·homo-(c6-c10)-aryl), (oc(o)-(crc6)-alkyl-(CVQo)-aryl), C(0)-0-(CrC6)-alkyl-(C6-C10)-aryl), (0-C(0)-0-(CrC6)-alkyl-(C6-Ch))·aryl ), 43 201141513 (0-C(0)-N(Rl)-(CrC6)-alkyl-(c6-C10)-aryl), (NCRU-QCO-CKCrQ)-alkyl-(c6-C10) -aryl), (〇-(C6-Ci〇)-aryl-(CrC6)-croplex n , (O-SO2-N(RlHC6-C10)-aryl-(crC6)-alkyl), (N(R1)-(C6-C1())-aryl-(c"c6)_alkyl ), (n(ri)c(o)-(c6-c10)-aryl-(Cl_c6)_alkyl), (N(Rl)C(O)-N(Rl)-(C6-C10)- Aryl-(crc6)-alkyl), (C(O)-N(RIMCVCh))-arylalkyl), (N(Rl)-SO2-N(Rl)-(C6-C10)-aryl -(CrC6)-alkyl), (N(R1)_S〇2_(C6-Ci〇)-arylalkyl), (S〇2-N(R1)-(C6-C10)-aryl-( C^-Ce)-alkyl), (N(R1)-S〇2-0-(C6-C)〇)-arylalkyl), (SOm-(C6-C1())·aryl- (C丨-C6)_alkyl), (〇-C(0)-(C6-C!〇)-aryl-(crc6)-alkyl), (C(O)-〇-(C6-C10) )-aryl-(crc6)-alkyl), (OC(O)-O-(C6-C10)-aryl-(CVQ)·alkyl), (0-C(0)-N(R1) -(C6-Ci〇)-aryl-(QQ)-hospital), (N(Rl)-C(0)-0-(C6-C1())-aryl-(Ci-C^)- (0-(C3-C6)_cycloalkyl-(c6-c1())-aryl)n, (0-S02-N(Rl)-(C3-C6)-ring-based- (C6-C10)-aryl), (N(R1)-(C3-C6)-cycloalkyl-(C6-C1())-aryl), (N(R1)C(0)-(C3_C6) )-cycloalkyl-(C6-C10)-aryl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-(C6-Cl0)_aryl) , (C(0)-N(R1)-(C3 -C6)-cycloalkyl-(C6-C1())-aryl> (N(R1)-S02-N(R1)-(C3_C6)-cycloalkyl-(C6-Cl0)-aryl 1 201141513 (N(R1)-S02-(C3-C6)-cycloalkyl-(c6_Ci〇)·aryl), (S〇2_N(RlHC:rC6)-cycloalkyl-(C6_Ci〇)·aryl) , (N(Rl)-S〇2_0-(CrC6)-cycloalkyl-(C6_Ci〇)_ aryl), (SOm-(C3-C6)-cycloalkyl-(C6-C10)-aryl) , (〇_c(〇)-(c3-C6)-cycloalkyl-(CVChO-aryl), (c(〇)_〇_(C3_C6)_ cycloalkyl (C6-C1())-aryl (), (〇-c(〇kkc3_C6)_cycloalkyl group_(C6_Ci〇)_aryl), (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl-(C6 -C10)-aryl), (N(Rl)-C(0)-0-(C3-C6)··cycloalkyl)_(c6_ci〇)_aryl), (O-(C6-C10)- Aryl-(CrQ)-cycloalkyl)n, (O-SO2-N(Rl)-(C6-C10)-aryl-(c3-C6)-cycloalkyl), (N(R1HC6-C10) -aryl-(c3-c6)-cycloalkyl), (N(Rl)C(O)-(C6-C10)-aryl-(C:3-C6)-cycloalkyl), (N() Rl)C(O)_N(Rl)-(C6-C10)-aryl-(C3-C6)-cycloalkyl), (C(O)-N(Rl)-(C6-C10)-aryl -(C3-C6)-cycloalkyl), (N(R1)-S〇2-N(R1)-(C6-C10)-aryl-(C3-C6)-cycloalkyl), (N() R1)-S〇2-(C6-Ci〇)-square-(C3-C6)-ring (S〇2-N(R1)-(C6-Ci〇)-square-(C3-C6)-cycloalkyl), (N(Rl)-S〇2-O-(C6- C10)-aryl-(C3-C6)-cycloalkyl), (SOm-(C6-Ci〇)-aryl-(C3-C6)-cycloalkyl), (〇-C(0)-( C6-Ci〇)-aryl-(C3-C6)-cycloalkyl), (CCCO-O-CCVCn))-aryl-(C3-C6)-cycloalkyl), (0-C(0) -0-(C6-Ci〇)-aryl-(C3-C6)-cycloalkyl), (oc(o)-n(rihc6-c10)-aryl-(C3-C6)-cycloalkyl) , (NO^O-QOj-CKC^-Qo). · Aryl-(CVC; 6)-cycloalkyl), (0-(CrC9)-heteroaryl)n, (〇-S〇2_N(Rl)-(CrC9)-heteroaryl), 45 201141513 ( N(Rl)-(CrC9)-heteroaryl), (N(Rl)C(〇HCrC9)-heteroaryl), (N(Rl)C(0)-N(Rl)-(CrC9)- Aryl) (C(0)-N(R1)-(C,-C9)-heteroaryl) (N(Rl)-S02-N(Rl)-(CrC9)-heteroaryl) (ISKRlVSOHCrQ)· Heteroaryl), (SCVNCRIMCrCp)-heteroaryl), (N(Rl)-S02-0-(C"C9)-heteroaryl), (SOn^CrCy-heteroaryl), (0-(: (0)-((^-(:9)-heteroaryl), ((:(0)-0-((^-(^)-heteroaryl)), (0-0(0)-0-) ((^-(:9)-heteroaryl), (0-0(0)^1)-(0^09)-heteroaryl), (N(Rl)-C(0)-0-( CrC9)-heteroaryl), (0-(CrC6)-alkyl-(C"C9)-heteroaryl)n, (0-S02-N(Rl)-(CrC6)-alkyl-(CrC9) _ heteroaryl), (N(Rl)-(CrC6)-alkyl-(CVC9)-heteroaryl), (N(Rl)C(〇HCrC6)-alkyl-(CrC9)-heteroaryl) , (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(CVC9)-heteroaryl), (CCCO-NiRlHCVC^)-alkyl-(C"C9)-heteroaryl (N(Rl)-S02-N(Rl)-(CrC6)_alkyl-(CrC9)-heteroaryl), (N(Rl)-S02-(CrC6)-alkyl-(CrC9) -heteroaryl), (S02-N(Rl)-(CrC6)-alkyl-(CVCp)-heteroaryl), (N(Rl)-S02-0-(CrC6)-alkyl-(CrC9)-heteroaryl), (SOn^CVQ)-alkyl-(CrC9)-heteroaryl), (o-cxohcvq)·alkyl-(CVC9)-heteroaryl), (c(o)-o-(crc6)-alkyl -(crc9)-heteroaryl), (0-C(0)-0-(CrC6)-alkyl-(CVC9)-heteroaryl), (0-C(0)-N(RlHCrC6)-alkane -(crc9)-heteroaryl), (:^(111)-(:(0)-0-((^-(:6)-alkyl-(CrC9)-heteroaryl), 46 201141513 ( ··%%)-heteroaryl_(crc6)-alkyl)n, (O-SC^-NiRlHCVCs»)-heteroaryl-(Q-C6)-alkyl), (NCRlHCi-CJ-hetero -(QQ)-alkyl), (N(Rl)C(0)-(CrC9)-heteroaryl-(CrC6)_alkyl), (N(Rl)C(0)-N(RlHCrC9) _ Heteroaryl-(CrC6)_alkyl), (c(〇)_N(R1)-(Ci-c9)-heteroaryl-(Ci-cy-alkyl), (^[(RU-SCVNiRlXCrCp) -heteroarylalkyl), (N(Rl)-S02-(CrC9)-heteroaryl-(Q-C6)·alkyl), (S〇2-N(Rl)-(CrC9)-heteroaryl -(CrC6)-alkyl), (NCRU-SOrCHCi-Cy-heteroaryl-(QQ)-alkyl), (SOm-CCrCg)-heteroaryl-(CrC6)-alkyl), (〇_ c(〇)-(Crc9), heteroaryl-(CrC6)-alkyl), (¢(0)-0-((^-(:9)-heteroaryl-(c Rc6) alkyl), (o-cxoKKCrCd-heteroaryl-(crc6)-alkyl), (0-C(0)-N(Rl)-(CrC9)-heteroaryl-(QQ)·alkyl ), (ISKRIVCCOKKCVC^)-heteroaryl_(Cl_c6)_alkyl), (0-(C2-C9)-heterocyclyl)n, (〇-S〇2_N(Rl)-(C2-C9)- Heterocyclyl), (N(R1HC2-C9)-heterocyclyl), (N(R1)C(0)-(C2-C9)-heterocyclyl), (N(R1)C(0)-N (R1)-(C2-C9). Heterocyclyl)A, (C(0)-N(R1)-(C2-C9)-heterocyclyl) (N(Rl)-S〇2-N(Rl)-(C2-C9)-heterocyclic (N(R1)_S02-(C2-C9)-heterocyclic group), (s〇2_N(R1)_(C2_C9)·(), (N(Rl)-S02-0-(C2- C9)-heterocyclic group, (machine_((: 2_from heterodiyl), (0-C(0)_(C2_C9)-heterocyclic), (C(0)_0_(C2_C9)) Two bases), (〇-C(〇)-0. -(C2-C9)-heterocyclic group) 201141513 (〇-C(0)-N(Rl)-(C2-C9)-heterocyclyl), (N(Rl)_C(0)-0-( C2_C9)·heterocyclic group), (o-(crc6)-alkyl-(C2-C9)-heterocyclyl)n, (〇-S02-N(Rl)-(CrC6)-alkyl-(C2_C9) _ heterocyclyl), (NiRlHCVCy-alkyl-(C2-C9)-heterocyclyl), (N^UQOHCrQ)-alkyl-(C2-C9)-heterocyclyl), (N^UQOyN^lHCrQ) -alkyl-(C2-C9)-heterocyclyl), (C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (NCRU-SCVi^RlHCrQ) )-alkyl-(C2-C9)-heterocyclic group, (1^(111)-802-((^-(^)-alkyl-(C2-C9)-heterocyclyl), (S〇 2-N(R1)-(Ci-C6)-alkyl-(C2-C9)-heterocyclyl), (N(R1)-S〇2_〇-(Ci-C6)-alkyl-(C2 -C9)-heterocyclic group, (SOmJC^-CG)·alkyl-(C2-C9)-heterocyclic group, (0-0(0)-((^-06)-alkyl-(c2) -c9)-heterocyclyl), (C(0)-0-(CrC6)-alkyl-(c2-c9)-heterocyclyl), (0-0(0)-0-(0^-( ^)-homo-(C2-C9)-heterocyclic group, (OC^CO-NiRlHCrQ)-alkyl-(C2-C9)-heterocyclic group, (N(Rl)-C(0)- 0-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (0-(C2-C9)-heterocyclyl-(Cj-Ce)-alkyl)n, (0-S02-N (Rl)-(C2-C9)-heterocyclyl-(Q-C6)-alkyl), (N(R1)-( C2-C9)-heterocyclyl-(CVC6)-alkyl), (N(Rl)C(〇HC;rC9)-heterocyclyl-(Cl_C6)_alkyl), (N(R1)C(0) )-N(R1)-(C2-C9)-heterocyclyl-(Crc6)·alkyl), (C(0)-N(R1)-(C2_C9)-heterocyclyl-(Cl_c6)_alkyl ), (N(Rl)-S〇2-N(Rl)-(C2-C9)-heterocyclyl-(Cj-Cs)-alkyl), (N(R1)-S02-(C2-C9) -heterocyclyl-(Cl_c6)_alkyl), 48 201141513 (S02-N(R1)-(C2-C9)-heterocyclyl-(crc6)-alkyl), (N(Rl)-S〇2 -0-(C2-C9)-heterocyclyl-(crc6)_alkyl), (SOm-(C2-C9)-heterocyclyl-(CrC6)-hospital), (〇_c(〇)_ (c2-C9)-heterocyclyl-(CrC6)-alkyl), (C(〇)-〇-(c2-C9)-heterocyclyl-(crC6)-alkyl), (0-C(0) -0-(C2-C9)-heterocyclyl-(crc6)-alkyl), (0-C(0)-N(Rl)-(C2-C9)-heterocyclyl-(crc6)_ alkane And (N(Rl)-C(0)-0-(C2_C9)-heterocyclyl-(crc6)-alkyl); L2 is selected from the group consisting of: (Ci_Cw)-alkyl, (0_(C2-C3)·alkyl)n, ((C2-C3)-alkyl group 〇), (C3_C6) _ cycloalkyl, (0-(C3-C6)-cycloalkyl)n, ((c3-c6)-cycloalkyl_0)n, (crc6)-alkyl-(CrQ)-cycloalkyl, (CrC6)-cycloalkyl-(Ci_c6)-alkyl, (C6-C10) -Aryl (crc6)-alkyl-(c6_Cl士aryl, (c6_Ci〇)_aryl-(CrC6)-alkyl, (CVC6)-cycloalkyl-(c6_Ci〇)-aryl, (c6-c10)- Aryl-(c3-c6)-cycloalkyl, (crc9)-heteroaryl, (CVC6)-alkyl-(CrC9)-heteroaryl, (Cl_c9)-heteroaryl-(Ci_c6)alkyl, ((VQ)-cycloalkyl-(Q-C9)-heteroaryl, (crc9)-heteroaryl-(c3-c6)-cycloalkyl, (C2_C9)-heterocyclyl, (crc6)-alkane -(C2-C9)-heteroalkyl, (CVC9)-heterocyclyl-(CrC6)-alkyl, (C3_C6)-cycloalkyl-(C2-C9)-heterocyclyl and (c2-c9) -heterocyclyl-(crc6)-cycloalkyl; X2 is a group selected from the group consisting of: _c(〇)_; -OC(O)-, -C(0)-0-,. . N(R1)_C(0)- ; _C(0)-N(R1)-; -N(R1)-C(S)- , -S〇2- ; -C(NH2+)- ; -0-P (0)(0H)- ; -S-; 49 201141513 and -N(Rl)- ; -Ο-; Υ is a group selected from the group consisting of: -c(o)- ; -s- ; -N(R1)-; -N(R1)-N=; and =NN(R1)-; Z is selected from the group consisting of: a direct bond, (CrC1())-alkyl, ( 0_(C2_C3)_alkyl)n, ((C2-C3)-alkyl·0)η, (CVC).)-Alkyl-C(O)-, (C3-C6)-cycloalkyl-C (O)-, (C6-C10)-aryl-C(O)-, (CVQ)-alkyl-(C6-Cu))-aryl-C(O)-, (C6-C10)-aryl -(C"c6)-alkyl-c(0)-, (c3-c6)-cycloalkyl-(c6-c1())-aryl-c(o)-, (c6-c10)- Aryl-(c3-c6)-cycloalkyl-c(o)-, (crc9)-heteroaryl-C(O)-, (CrC6)-alkyl-(Q-C9)-heteroaryl- c(0)-, (CVC9)·heteroaryl-(crc6)-alkyl-c(0)-, (C3-C6)-cycloalkyl-(CVC9)-heteroaryl-c(0)- ,(crc9)-heteroaryl-(c3-c6)-cycloalkyl-c(0)-, (C2-C9)-heterocyclyl-c(0)-, (Ci-Q)-alkyl- (C2-C9)-heterocyclyl-C(O)-, (c2-c9)-heterocyclyl-(Q-C6)-alkyl-c(0)-, (c3-c6)-cycloalkyl -(C2-C9)-heterocyclyl-(:(0)_, (C2_C9)_heterocyclyl-(C3-C6)-cycloalkyl-c(0 )-, (crC1Q)-alkyl-N=, (crc6)-cycloalkyl-N=, (C6-C10)-aryl-N=, (crc6)-alkyl-(c6-c10)-aryl -N-, (C6-C10)-aryl-(crc6)-alkyl-N=, (c3-c6)-cycloalkyl-(C6-C10)-aryl·Ν= ' (C6-C 】--aryl-(c3-c6)-cycloalkyl·Ν=, (CrC9)-heteroaryl, (CrC6)-alkyl-heteroaryl·n=, (CrC9)- Aryl-(Cioalkyl_N=, (CVC6)_cycloalkyl-(CrC9)-heteroaryl_N=, (CrC9)_heteroaryl_(c3_C6)_cycloalkyl 50 201141513 -N= ,(C2-C9)-heterocyclyl-N=, (CrC6)-alkyl-(C2-C9)-heterocyclyl-N=, (C2-C9)-heterocyclyl-(CrC6)-alkyl -N=, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-N=, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-N=, (CrQ. )-alkyl-N(R1)-, (C3-C6)-cycloalkyl-N(R1)-, (C6-C10)-aryl-N(R1)-, (CrC6)-alkyl-( C6-C10)-aryl-N(R1)_, (C6-C10)-aryl-(CVQ)-alkyl-N(R1)-, (C3-C6)-cycloalkyl-(C6-C10 )-aryl-N(R1)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-N(R1)-, (CrC9)-heteroaryl-N(R1)-, (CVQ)-Alkyl-(CrQ)-heteroaryl-N(R1)-, (CrC9)-heteroaryl-(CrC6)-alkyl-N(R1)-, (C3-C6)-cycloalkane -(CrC9)-heteroaryl-N(R1)-, (CVCy-heteroaryl-(C3-C6)-cycloalkyl-N(R1)-, (C2-C9)-heterocyclyl-N (R1)-, (C "C6)-alkyl-(C2-C9)-heterocyclyl-N(R1)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-N (R1 )-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-N(R1)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-N (R1)-, -Ο-Ρ(ΟΧΟΗ)-. , (CrC1())-alkyl--0-P(0)(0H)-, (0-(C2-C3)-alkyl)η-0-Ρ(0)(0Η)-, ((C2- C3)-Alkyl-0)nP(0)(0H)-, (C3-C6)-cycloalkyl-0-P(0)(0H)-, (CrC6)_alkyl-(C3-C6) -cycloalkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CrC6)-alkyl-0-P(0)(0H)-, (C6-C10)- Aryl-0-P(0)(0H), (CrC9)-heteroaryl-0-oxime(0)(0Η)-, (CrC6)-alkyl-(C6-C10)-aryl-0- P(0)(0H)-, (C6-C10)-aryl-(CrC6)-alkyl-0·Ρ(0)(0Η)-, (C3-C6)-cycloalkyl-(C6-C10 )-aryl-0-P(0)(0H)-, (C6-C1())-aryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (CrC :6)-Alkyl-(CrC9)-heteroaryl 51 201141513 -0-Ρ(0)(0Η)-, (CrC9)-heteroaryl-(CVQ)-alkyl-0-Ρ(0)( 0Η)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0-P(0)(0H)-, (CrCO-heteroaryl-(C3-C6)-cycloalkyl- 0-P(0)(0H)_, (C2-C9)-heterocyclyl-0-P(0)(0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0 -P(0)(0H)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0-oxime(0)(0Η)-, (C2-C9)-heterocyclyl-(C3 -C6)-cycloalkyl-indole-P(〇)(〇H)-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-P(0)(0H)- , -0-P(S)(0H)-, (QC). )-alkyl-0-P(S)(0H)-, (0-(C2-C3)-alkyl)n-0-P(S)(0H)-, ((C2-C3)-alkyl -0) nP(S)(0H)-, (C3-C6)-cycloalkyl-0-P(S)(0H)-, (CrC6)-alkyl-(C3-C6)-cycloalkyl- 0-P(S)(0H)-, (C3-C6)-cycloalkyl-(CrC6)-alkyl-0-P(S)(0H)-, (C6-C10)-aryl-0- P(S)(0H),(CrC9)-heteroaryl-0_P(S)(0H)-, (CrC6)-alkyl-(C6-C10)-aryl-0-P(S)(0H) -, (C6-C10)-aryl-(CrC6)-alkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0- P(S)(0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (CrC6)-alkyl-(Q-C9 )-heteroaryl-0-P(S)(0H)-, (CrC9)-heteroaryl-(CrC6)-alkyl-0-P(S)(0H)-, (C3-C6)-ring Alkyl-(C-C9)-heteroaryl-0-P(S)(0H)-, (CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S) ( 0H)-, (C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(S)(0H )-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl -0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl 52 201141513 -0-P(S)(0H)-, -〇-P( S)(SH)-, (CVQo)-alkyl-0-P(S)(SH)-, (〇-(c2- C3)-Alkyl) „-〇-?(8)(8«〇-,((:2-(:3)-alkyl-OV^SXSH)-, (C3-C6)-cycloalkyl- 0-P(S)(SH)-, (CrC6)-alkyl-(C3-C6)-cycloalkyl-indole_p(S)(SH)-, (C3-C6)-cycloalkyl-( QQ)-Alkyl-〇_p(8)(SH)_, (C6-C10)-aryl-0-P(S)(SH), (CrC9)-heteroaryl-〇_p(s)(SH) -, (CrC6)-alkyl-(C6-Ci〇)-aryl-〇-P(S)(SH)-, (C6-C10)-aryl-(CrC6)-alkyl-0-P ( S) (SH)-, (C3-C6)-cycloalkyl-(C6-C1())-aryl-0-P(S)(SH)-, (C6-C10)-aryl-(C3 -C6)-cycloalkyl-0-P(S)(SH)-, (CVQ)-alkyl-(Ci-Q)-heteroaryl-0-P(S)(SH)-, (CVQ) -heteroaryl-(qQ)-alkyl-0-P(S)(SH)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0-P(S)(SH) -, (CVQ))-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(SH)-, (C2-C9)-heterocyclyl-indole_p(s)(SH )-, (C2-C9)-heterocyclyl-(CrC6)-alkyl--0-P(S)(SH)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0- P(S)(SH)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(S)(SH)-, (C3-C6)-cycloalkyl _ (c2-C9)-heterocyclyl•0-P(S)(SH)-,-0-P(0)((CrC8)-alkyl)-, (CrC1G)-alkyl-O-PCOXiCrQ)- Burning base)-, (〇-(c2-C3)-burning Base) n-〇-P(〇)((CrC8)-alkyl)-, ((C2-C3)-alkyl-O)nP(0)((CrC8)-alkyl)-, (C3-C6 )-cycloalkyl-0-P(0)((CrC8)-alkyl)-, (CVQ)-alkyl-(C3-C6)-cycloalkyl--0(P)((CrC8)- Alkyl)-, (CVC: 6)-cycloalkyl-(crc6)-alkyl-04(0)(((^-(^)-alkyl)-, (C6-C1())-aryl -〇-P(〇)((crc8)- 53 201141513 alkyl), (CrC9)-heteroaryl-04(0)(((^-(:8)-alkyl)-, (Cl_c6)_ alkane -(C6-C10)-aryl-0-P(0)((CrC8)-alkyl)-, (C6-C10)-aryl-(CrC6)-alkyl-04(0)((04 )-alkyl)-, (C3-C6)-cycloalkyl-(c6-c10)-aryl-O-PWXO^-Cs)-alkyl)-, (Q-Cw)-aryl-(C3 -C6)-cycloalkyl-4-(0)(((^-0^)-alkyl)-, (cvc6)-alkyl-(CrQ)-heteroaryl-O-PCCOUCi-Cs)-alkyl )-, (Q-C9)-heteroaryl-(crc6)-alkyl-0-P(0)((CrC8)·alkyl)-, (C3-C6)-cycloalkyl-(crc9)- Heteroaryl-0-p(0)((cvc8)-alkyl)-, (CrC9)-heteroaryl-(CrC6)-cycloalkyl-0-P(0)((CrC8)-alkyl) -, (CrC9)-heterocyclic group-0-P(0)((CrC8)-alkyl)-, (C2-C9)-heterocyclyl-(CVCi. -alkyl-0-P(0)((CrC8>alkyl)-, (CrC1Q)-alkyl-(CVC9)-heterocyclyl-0-P(0)((Ci_C8)-alkyl)- ,(C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl--0-P(0)((CrC8)-alkyl)-, (C3-C6)-cycloalkyl-(C2- C9)-heterocyclic group-04(0)(((^-(^)-alkyl)-,-0-P(0)(N(R2R3))-, (CVC10)-alkyl-0-P (0)(N(R2R3))-, (0-(C2-C3)-alkyl)n-0-P(0)(N(R2R3))-, ((C2-C3)-alkyl-0 nP(0)(N(R2R3))-, (C3-C6)-cycloalkyl-0-P(0)(N(R2R3))-, (CrC6)-alkyl-(C3-C6)- Cycloalkyl-0-P(0)(N(R2R3))-, (C3-C6)-cycloalkyl-(C"C6)-alkyl-0-P(0)(N(R2R3))- , (C6-C10)-aryl-0-P(0)(N(R2R3))-, ((VC9)-heteroaryl-0-P(0)(N(R2R3))-, (Ci- Ce)·alkyl-(C6-C10)-aryl-0-P(0)(N(R2R3))-, (C6-C10)-aryl-(CVC6)-alkyl--0-P(0 (N(R2R3))-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(0)(N(R2R3))_, (C6-C10)-aryl 54 201141513 -(C3-C6)-cycloalkyl-0-P(0)(N(R2R3))-, (CrC6)-alkyl-(CrC9)-heteroaryl-0-P(0)(N (R2R3))-, (CrC9)·heteroaryl-(CVCy-alkyl--0-P(0)(N(R2R3))-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl Base-0-P(0)(N(R2R3))_, (CrC9) _ Heteroaryl (C3-C6)-cycloalkyl-0-P(0)(N(R2R3))-, (C2-C9)-heterocyclyl-0-P(0)(N(R2R3)) -, (C2-C9)-heterocyclyl-(Ci-C6)-alkyl 0-P(0)(N(R2R3))-, (Ci_C6)_---(C2-C9)-heterocyclyl -0-P(0)(N(R2R3))-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(0)(N(R2R3))-, ( C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-P(0)(N(R2R3))-, -N(Rl)-P(〇)(〇H)-, ( QC!. )-alkyl-N(R1)-P(0)(0H)-, (0-(C2-C3)_alkyl)nN(Rl)-P(0)(0H)-, (C3-C6) -cycloalkyl-N(R1)-P(0)(0H)- '(QQ)-alkyl-(C3-C6)·cycloalkyl-N(R1)-P(0)(0H)-, (C3-C6)-cycloalkyl-(CVC6)-alkyl-N(R1)-P(0)(0H)_, (C6-C10)-aryl-N(R1)-P(0)( 0H), (CrC9)-heteroaryl-N(R1)-P(〇)(〇h)_, (crc6)-alkyl-(C6-C!.)-aryl*_N(R1)-P( 0) (0H)-, (C6-C10)-aryl-(6)-Germanyl-N(R1)-P(0)(0H)_, (C3-C6)-cycloalkyl-(C6- C1())-aryl-N(R1)-P(0)(0H)-, (C6-C1())-aryl-(crC6)_cycloalkyl-N(R1)-P(0) (0H)-, (CVQ)-alkyl-(crC9)-heteroaryl-N(R1)-P(0)(0H)-, (CVC9)-heteroaryl-(CVQ)-alkyl-N (R1)-P(0)(0H)-, (CVC6)-cycloalkyl-(;Crc9)-heteroaryl-N(R1)-P(0)(0H)-, (CrC9)-heteroaryl Base —(c3-C6)-cycloalkyl-N(R1)-P(0)(0H)-, (Cr. C9)_heterocyclyl-n(R1)-P(〇)(〇H)-, 55^U4l5l3 Heterocyclyl '(CrC6)-alkyl-N(R1)_P(0)(0H)-, ( CVC6)-(c, 2 <9)-heterocyclyl-N(R1)-P(0)(0H)-, (C2-C9)-heterocyclyl 3 <6)-cycloalkyl-N(R1)-P(0)(0H)- and (C3-C6)-cycloalkyl 2 <9)_heterocyclyl·Ν(ΙΠ)-Ρ(0)(0Η)-; is an integer between 0 and 10; η 4 is an integer between 1 and 11; m is 0, 1 or 2 ; qp, r, s, t are independent of each other, 1, 1 or 2;

R1 is H, (Ci-C6)-alkyl; and R3 is independently hydrazine, (Q-C6)-alkyl, wherein R2 and R3 are bonded to each other to form a saturated 5- to 6-membered monocyclic heterocyclyl group. In a more preferred embodiment of the invention, the groups are defined as follows: XI is a group selected from the group consisting of: _C(〇)-; -OC(O)-; -C(0 )-0- ; -C(0)-N(R1)- ; -N(R1)-C(0)-; -C(S)-N(R1)- ; -N(R1)-C(S )_; -S02- ; -C(NH2>; _0_P(0)(0H)-, -S-, -N(Rl)-, =NN(R1)-,-0-, and heterocyclic; LI It is selected from the group consisting of (CrC1())-alkyl, (〇-(C2_C3)-leuco) η, ((C2-C3)-alkyl-)), (C3-C6) - ring-based, (〇-(C3-C6)_cycloalkyl)n, ((C3-C6)-cycloalkyl-oxime)n, (CrC6)-fired 56 201141513 base-(C3_C6)-ring burning , (C3_C6)-cycloalkyl-(crc6)-alkyl, (匸6 匸10)-square, (c^-Ce)·alkyl-(C^-C).)-aryl, c6-C10)_Aryl-(CrC6)-alkyl, (QQ)-cycloalkyl-(C6-Cl〇)-aryl, (C6-CI())-aryl-(C3-C6)- Cycloalkyl, (CVQ)-heteroaryl, (Cl_C6)-alkyl-(CVC9)-heteroaryl, (crc9)-heteroaryl-(cvcy-alkyl, (C3_Q)-cycloalkyl-( crC9)-heteroaryl, (crc9)-heteroaryl-(C3-C6).cycloalkyl, (C2-C9)-heterocyclyl, (crc6)-alkyl-(c2-c9)-heterocyclic Base, (CVC9)-heterocyclyl-(cr C6)-alkyl, (c3-c6)-cycloalkyl-(CVC9)-heterocyclyl and (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl; D is independently selected from The following groups are included: _c(0)---c(0)0-, -OC(O)-, -N(R1)-C(0)_, -C(0)N(R1)- -N(R1)C(0)-N(R1)-, -SOm-, -N(R1)-, -N(R1)-N=, =NN(R1)-, -N(R1)- N(R1)-, -〇-, -S-, -SS-, -0-(CH2)-, -(CH2)-0-, (〇-(C2-C3)~ Hyun")), ( (C2-C3)-alkyl-oxime)n, (N(Rl)-(CrC6)-alkyl), (N(Rl)C(〇HCrC6)·alkyl), (Ν(Ι11)(:( 0)-Ν(ΐαΗ(:Η::6)-alkyl), (C^CO-NiRlHCrC^)-alkyl), (iSKRU-SOr^RlHCVQ)-alkyl), (N(Rl)-S02 -(CrC6)-alkyl), (SCVisKRIHCrQ)·alkyl), (s〇m-(crc6)·alkyl), (oc(o)_(crc6)-alkyl), (C(0)- 0-(CrC6)-alkyl), (O-CXCO-NCRIHCVQ)-alkyl), (N(Rl)-C(0)-0_(CrC6)-alkyl), (0_(C3-C6)· Cycloalkyl)n, ((C3-C6)-cycloalkyl-oxime)n, (N(R1)-(C3-C6)-cycloalkyl), (N(R1)C(0)-(C3 -C6)-cycloalkyl), 57 (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl(C(0)-N(R1)-(C3-C6) - Cycloalkyl (N(R1)-S02-N(R1)-(C3-C 6)-cycloalkyl 201141513 (N(R1)-S02-(C3-C6)-cycloalkyl), (S02-N(R1)-(C3-C6)-cycloalkyl), (SOm-(C3) -C6)-cycloalkyl), (〇-C(0)-(C3-C6)-cycloalkyl), (c(o)-o-(c3-c6)-cycloalkyl), (0- C(0)-N(Rl)-(C3-C6)-cycloalkyl), (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl), (CHQ-Q) -alkyl-(C3-C6)-cycloalkyl)n, (ISKRIHCrQ)-alkyl-(c3-c6)-cycloalkyl), (N(R1)C(0)-(Ci_C6)-alkyl -(C3-C6)-cycloalkyl), (ISKRUCXCO-NiRlHCi-Cy-alkyl-(C3-C6)-cycloalkyl), (C(0)-N(R1)-(C-C6) ·alkyl-(C3-C6)-cycloalkyl), (N(Rl)-S02-N(Rl)-(CrC6)- ^ ^ -(C3-C6)- if ^ , (N(R1)- S02-(Ci-C6)-alkyl-(c3-c6)-cycloalkyl), (SCVNiRlHCVC^)-alkyl-(C3-C6)-cycloalkyl), (SOn^CrQ)-alkyl- (C3-C6)-cycloalkyl), (〇-C(0)-(CVC6)-alkyl-(c3-c6)-cycloalkyl), (C(0)-0-(CrC6)-alkane -(C3-C6)-cycloalkyl), (〇-C(0)-N(Rl)-(CrC6)·alkyl-(C3-C6)-cycloalkyl), alkyl-(c3- C6)-cycloalkyl), (0-(C3-C6)-cycloalkyl-(CVC6)-alkyl)η, (N(R1)-(C3-C6)-cyclomorphyl-(CrC6)- (N(R1)C(0)-(C3_C6)-cycloalkyl -(crc6)·alkyl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-(CVC6)-alkyl), (C(0)-N( R1)-(C3-C6)-cycloalkyl-(crc6)-alkyl), (N(R1)-S02-N(R1)-(C3-C6)-cycloalkyl-(CVC6)-alkyl ), (N(R1)-S02-(C3-C6)·cycloalkyl-(Ci-Q)-alkyl), 58 201141513 (S02-N(R1)-(C3-C6)-cycloalkyl- (CrQ)-alkyl), (SOm-(C3-C6)-cycloalkyl-(CrQ)-alkyl), (oc(o)-(c3-c6)-cycloalkyl-(crc6)-alkane ()(c(o)-o-(c3-c6)-cycloalkyl-(Crc6)-alkyl), (0-C(0)-N(Rl)-(C3-C6)-cycloalkane -(CVC6)-alkyl), (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl-(crc6)-alkyl), (O-(C6-C10)- Aryl)n, (N(R1)-(C6-C10)-aryl), (N(R1)C(0)-(C6~Ci〇)-aryl), (N(Rl)C(O )-N(Rl)-(C6-C10)-aryl), (C(O)-N(Rl)-(C6-C10)-aryl), (N(Rl)-SO2-N(Rl) -(C6-C10)-aryl), (N(Rl)-SO2-(C6-C10)-aryl), (S02-N(R1)-(C6-Ch>)-aryl), (SOm -(C6-C10)-aryl), (OC(〇HC6-C10)-aryl), (c(o)-o-(c6-c10)-aryl), (O_C(O)_N(Rl )_(C6-C10)-aryl), (N(Rl)-C(O)-O-(C6-C10)-aryl), (CKCVC^)-alkyl aryl (n)(N(Rl)-(CrC6)-alkyl-(C6-C10)-aryl HISURUCCOHCVQ)-alkyl-(c6-c10)-aryl), (N(Rl)C(0) -N(Rl)-(CrC6)-alkyl-(C6-C10)-aryl), (C(0)-N(Rl)-(CrC6)-alkyl-(C6-C10)-aryl) , (N(Rl)-S02-N(Rl)_(CrC6)-alkyl-(C6-C10)-aryl), (IS^RlVSOHCrQ)-alkylaryl), (SO2-N(R1) -(Ci-C6)-^^-(c6-C10)-^: A)' (SOm-(C,-C6)> Alkyl-(C6-C1())-aryl), (0- 0(0)-((^-(:6)-alkyl-(C6-C1())-aryl), (c(0)-0_(crc6)-alkyl-(c6-c10)-aryl (), (O-CXOK^RIHCVQ)-alkyl-(CVCU))-aryl), (N(Rl)_C(0)-0-(CrC6)-alkyl-(C6-C1())_ Aryl), 59 201141513 (O-(C6-C10)-aryl-(CVC6)-alkyl)n, (N(R1HC6-C10)_aryl-(Crc6)-alkyl), (N(Rl) C(O)-(C6-C10)-aryl-(Ci-C6)-alkyl), (N(Rl)C(O)-N(RlHC6-C10)-aryl-(CVC6)-alkane (C(O)-N(Rl)-(C6-C10)-aryl-(CVC6)-alkyl), (N(R1)-S〇2-N(R1)-(C6-Ci 〇)-aryl-(Ci_C6)-alkyl), (n(ri)-s〇2-(C6-c10)-aryl-(Ci-cy-alkyl), (SO2-N(Rl)- (C6-C10)-aryl-(CVC6)-alkyl), (SOm-(C6-C10)·aryl-(CVC6)-alkyl), (0-C(0) )-(C6_Ci〇)-aryl-(C1-C6)-alkyl), (C(0)-0-(C6-C1(); l·aryl-(CrC6)-alkyl), (O_C) (O)-N(RlHC6-C10)-aryl-(crc6)-alkyl), (N(R1)-C(0)-0-(C6-Ch))-aryl-(CrC6)-burning ()-(o-(c3-c6)-cycloalkyl-(C6-C10)-aryl)n, (N(R1)-(C3-C6)-cycloalkyl-(C6-C1()) -aryl), (N(R1)C(0)-(C3-C6)·cycloalkyl-(c6-c10)-aryl), (N(R1)C(0)-N(R1HC3-C6 )-cycloalkyl-(c6_c10)-aryl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-(C6-C10)-aryl), (N(R1) -S02_N(R1HC3-C6)_cycloalkyl-(c6-c10)-aryl), (N(R1)-S02-(C3-C6)-cycloalkyl-(C6-C1())·aryl ), (S02_N(R1)-(C3-C6)-cycloalkyl-(c6-c10)-aryl), (S0m-(C3-C6)4 alkyl-(c6-c10)-aryl), (oc(o)_(c3_c6)·cycloalkyl-(C6-C10)-aryl), (c(o)-o-(c3-c6)-cycloalkyl-(CVCh))-aryl) ,(〇-C(〇)-N(Rl)-(C3-C6)-cycloalkyl-(c6-c10)-aryl), (N(Rl)-C(0)-0-(C3- C6)-cycloalkyl-(c6-c10)-aryl), (〇-(c6-c10)-aryl-(C3-C6)-cyclic) n, (N(R1HC6-Ch))- Aryl-(C3-C6)-cycloalkyl), 201141513 (N(R1)C(0)-(C6-C1())-aryl_(C3_C6)_ Alkyl), (N(Rl)C(O)-N(Rl)-(C6_-C10)-aryl-(c3_c6)-cycloalkyl), (C(O)-N(RlHC6-C10)- Aryl-(C3_C6)·cyclohexyl), (N(R1)-S〇2-N(R1)-(C6-C10)·aryl_(c3-C6)-cycloalkyl), (N() Rl)-SO2-(C6-C10)-aryl-(c3_c-cycloalkyl), (SO2-N(Rl)-(C6-C10)·aryl-(c3_c6)_cycloalkyl), (SOm -(C6_C1())-aryl-(C3_C6)-cycloalkyl), (〇_c(〇)_(c6_ci0)_aryl-(C3-C6)-cycloalkyl), (C(〇) -〇_(C6-C10)-aryl-(c3_c6)_cycloalkyl), (oc(o)-n(ri)-(c6_Ci())_aryl_(C3_C6)_cycloalkyl), (N(Rl)-C(O)-O-(CVC10)-aryl-(C3-C6)-cycloalkyl), (ckq-ca heteroaryl)n, (N(R1)_(Ci_C9) _ Heteroaryl), (N^CXOHCrQ)-heteroaryl) (N(Rl)C(0)-N(Rl)-(CrC9)-heteroaryl) (cxoh^rihcvq)-heteroaryl) N(Rl)-S02-N(Rl)-(CrC9)-heteroaryl) (N(Rl)-S02-(CrC9)-heteroaryl), (s〇2-N(Rl)-(CrC9) -heteroaryl), (SOm-(CrC9)-heteroaryl), (0-^:(0)-(0^-(:9)-heteroaryl), (C(0)-0-( CrC9)-heteroaryl), (0_C(0)_N(R1)_(CrC9)_heteroaryl), (N(Rl)-C(0)-0-(CrC9)-heteroaryl) (0-(crc6)-alkyl-(Q-C9)-heteroaryl)n, (N(R1HCl_c6)_alkyl-(Ci_c9)_heteroaryl), (N(Rl)C(〇HCrC6) -alkyl-(CrC9)-heteroaryl), WRUCCCO-NiRlHCVQ)-alkyl-(c--c9)-heteroaryl), (C(0)-N(Rl)-(CrC6)-alkyl _(crc9)_heteroaryl), (N(Rl)-S02-N(Rl)-(CrC6)·alkyl-(CrC9)_heteroaryl), 61 201141513 (N(R1)-S02-( C "C6)-alkyl-(crc9)-heteroaryl), (SCVNCRlHCj-Q)-alkyl-(CVC9)-heteroaryl), (som-(crc6)-alkyl-(CVC9)- Aryl), (o-QOHCi-Q)-alkyl-(CrC9)-heteroaryl), ((:(0)-0-((^-(:6)-alkyl-(crc9)-hetero) Aryl), (0-C(0)-N(Rl)-(CrC6)-alkyl-(CVC9)-heteroaryl), (N(Rl)-C(0)-0_(CrC6)-alkane -(CVC9)-heteroaryl), (CKCrCy-heteroaryl-(CrC6)-alkyl)n, (N(Rl)-(CrC9)-heteroaryl-(CrC6)-alkyl), ( I^RUCXOHCkQ)-heteroaryl-(crc6)-alkyl), (ISKRUCCCO-i^RlHCrQ)-heteroaryl-(crc6)-alkyl), (CXCO-NCRlHCrCd-heteroaryl-(CVC6)- Alkyl), (N(Rl)-S02-N(Rl)-(CrC9)-heteroaryl-(CrQ)-alkyl), (n(ri)-so2-(c)-c9)-heteroaryl -(CrC6)-alkyl), (scvncrihcvq)-hetero -(CrC6)-alkyl), (SOnHCVQ)-heteroaryl-(CrC6)-alkyl), (O-CCOHCrC^)-heteroaryl-(Q-C6)-alkyl), ((:( 0)-0-((^-(:9)-heteroaryl-(crc6)-alkyl), (0-C(0)-N(RlHCrC9)-heteroaryl-(QQ)-alkyl) , (ncru-cxco-chcvc^)-heteroaryl-(CVQ)-alkyl), (o-(c2-c9)-heterocyclyl)n, (N(R1)-(C2-C9)- Cyclo), (N(R1)C(0)-(C2-C9)-heterocyclyl) (N(R1)C(0)-N(R1)-(C2-C9)-heterocyclyl) C(0)-N(R1)-(C2-C9)-heterocyclyl) (N(R1)-S02-N(R1)-(C2-C9)-heterocyclyl) (N(R1)-S02 -(C2-C9)-heterocyclic group), (S02_N(R1)-(C2-C9)-heterocyclic group), (som-(c2-c9)-heterocyclic group), (oc(o)-( C2-c9)-heterocyclyl), 62 201141513 (c(o)-o-(c2-c9)-heterocyclyl), (0-C(0)-N(RlHC2-C9)-heterocyclyl) , (n(ri)-c(o)-o-(c2-c9)-heterocyclyl), (o-(crc6)-alkyl-(C2-C9)-heterocyclyl)n, (NiRlHCrQ) -alkyl-(C2-C9)-heterocyclyl), (N(Rl)C(0)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (N(Rl)C( 0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (CXCO-NCR1HCrQ)-alkyl-(C2-C9)-heterocyclyl), (N(R1) )-S02-N(R1)-(C1-C6)- ^ ^ -(C2-C9)- ϋ ^ ) '(N(Rl)-S02-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (SCVNCRlHCrQ)-alkyl-(C2-C9)-heterocyclyl), (SOm -(Ci_C6)-alkyl-(C2-C9)-hetero), (0-C(0)-(Ci_C6)-alkyl-(C2-C9)-heterocyclic), (C(0) -0-(Ci-C <5)-alkyl-(C2-C9)-heterocyclic group, (O-CCCO-ISKRIHCVC^)-alkyl-(c2-c9)-heterocyclic group, (N(Rl)-C() 0)-0-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (0-(C2-C9)-heterocyclyl-(CrQ)-alkyl)n, (N(R1) -(C2-C9)-heterocyclyl-(CrC6)-alkyl), (N(R1)C(0)-(C2-C9)-heterocyclyl-(crc6)-alkyl), (N() R1)C(0)-N(R1HC2-C9)-heterocyclyl-(crc6)-alkyl), (C(0)_N(R1)-(C2"C9)-heterocyclyl-(CVC6)- Alkyl), (N(R1)-S02-N(R1)-(C2-C9)-heterocyclyl-(QQ)-alkyl), (N(R1)-S02-(C2-C9)- Cyclo-(crc6)-alkyl), (S02-N(R1)-(C2-C9)-heterocyclyl-(CVC6)-alkyl), (SOm_(C2-C9)-heterocyclyl-( (VC6)-alkyl), (oc(o)-(c2-c9)-heterocyclyl-(CVC6)-alkyl), (C(0)-0-(C2-C9)-heterocyclyl- (crc6)-alkyl), (0-C(0)-N(Rl)-(C2-C9)-heterocyclyl-(CVC6)-alkyl) and (N(Rl)-C(0)- 0-(C2-C9)-heterocyclyl-(crc6)-alkyl); 63 201141513 L2 is selected from the group consisting of: (crCl0)-alkyl, (〇-(c2-c3)- Burning base) n, ((c2_C3) 戈基_〇)n, (C3_C6) cycloalkyl, (〇-(C3-C6)_% 炫) n, ((c3_c6)·环院基·〇)η , (c "c6) burning _(c3-c6)-cycloalkyl, (C3_c6)-cycloalkyl-(Ci C-alkyl, (^vc10)-aryl, (Crc6)-alkyl ((VCi〇)·aryl, (c6-c1〇)_aryl-(CrQ)-alkyl, (c3-c6)-cycloalkyl·(CyCj aryl, (c6-c1())-aryl-(c3-c6)-cyclic Alkyl, (Ci_C9)_heteroaryl, (Ci_C6)_homo-(Q-Cy-heteroaryl, heteroaryl-(Ci_c)alkyl, (CVC6)-cycloalkyl-(Cl_C9)- Aryl, (Ci C9)heteroaryl-(C3-C6)-%alkyl, (c2-c9)-heterocyclyl, (Ci_Q)-alkyl group (C2_C9)_heteroyl, (CVC9)- Heterocyclyl-(Ci-Q)-alkyl, (c3-c6)-cycloalkyl-(C2-C9)-heterocyclyl and (c2-c9)-heterocyclyl-(c3_c6)-cycloalkyl X2 is a group selected from the group consisting of: _c(〇)_; -OC(O)-; -C(0)-〇- >-N(R1)-C(0)-;-C(0)-N(R1)-;-N(R1)-C(S)-;-S02-;-C(NH2+)-; -0-P(〇)(〇H)- i -S -; -N(R1)-; and _〇·; y is a group selected from the group consisting of: -c(o)-; -S-; -N(R1)-; -N(R1 ) -N=; and =NN(R1)-; z is selected from the group consisting of: a long bond, (c "Ciq)_alkyl, (o-(c2-c3)-alkyl)n, ((c2_C3)_burning base_0)n, (Ci_Ci. )·alkyl 64 201141513 -C(O)-, (c3-c6)-cycloalkyl_C(0)_, (c6_Cl())_aryl_c(0)_, (CrQ)-hospital -(c6_Cl〇)_ aryl_c(〇)_, (CVCi〇)_ aryl-(CrQ)-alkyl-c(0)_, (C3_C6)_ cycloalkyl_(C6_Ci〇)_芳-C(0)_, (C6-C10)-aryl-(C3_C6)_cycloalkyl-C(0)_, (Ci_c9)_heteroaryl-c(o)·, (Crc6)-alkane Base_(Ci_C9)_heteroaryl_c(〇)_, (Q-C9)-heteroaryl·(CrQ)-alkyl_c(0)_, (C3_C6)_cycloalkyl-(CrC9) -heteroaryl_C(0)_, (CrC9)_heteroaryl_(C3_c6)cycloalkyl-c(o)-, (c2-c9)_heterocyclyl_c(0)_, (Cl_C6 )-alkyl-(C2_C9)_heterocyclyl-C(O)-, (C2-C9)-heterocyclyl-(CVQ)-alkyl-c(0)-, (C3-C6)-cycloalkane Base —(C2_C9)_heterocyclyl_c(0)_, (C2_C9)·heterocyclyl-(c3-c6)-cycloalkyl-c(0)_, (CrCiG)_alkyl group_N=, (C3_C6)_cycloalkyl-N=, (C6-C10)-aryl-N=, (QQ)-alkyl-(c6-c10)-aryl-N-, (C6-C1())- Aryl-(crC6)HN=, (C3-C6)-cycloalkyl-(C6-C1G)-aryl-N=, (C6_ClG)-aryl-(C3_C6)_ ring-based Ν=, ( Qq)-heteroaryl_N=, (Cl_c6)-alkyl group(Ci-C9)_heteroaryl_N=, (q-C9)-heteroaryl_(Cl_C6)_ Base_N=, (C3_C6)_cycloalkyl-(CrC:9)•heteroaryl call=, (Cl_C9)_heteroaryl_(C3_q)_cycloalkyl-N=, (C2-C9)- Heterocyclic group_n=, (CrC6)-alkyl-(C2-C9)-heterocyclyl-N-, (C2-C9)-heterocyclyl-(qQ)-alkyl group_n=, (C3_C6) -cyclohexyl-(CVC9)-heterocyclic group, (Q-C9)-heterocyclylcycloalkyl, ((^--alkyl group, (c3_C6)_cycloalkyl group_N (called, (Qc士aryl-N(R1)_, (Ci_C6)_alkyl-(CVCi〇)_aryl-N(R1>, (C6-C1())-aryl-(crc6)-alkyl-N (R1)_, (C3_C6)_cycloalkyl-(c6-c10)_aryl_N(R1)_, (c6-c10)-aryl_(C3_C6)_m 65 201141513 Alkyl-N(Rl) -, (CrC9)-heteroaryl-N(Rl)-, (CVQ)-alkyl-(CrC9)-heteroaryl-N(R1)-, (CrC9)-heteroaryl-(CrC6)-alkane --N(R1)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-N(R1)-, (C-C9)-heteroaryl-(C3-C6)-ring Alkyl-N(R1)-, (C2-C9)-heterocyclyl-N(R1)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-N(R1)-, (C2 -C9)-heterocyclyl-(CVC6)-alkyl-N(R1)-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-N(R1)-, (C2- C9)-heterocyclyl-(C3-C6)-cycloalkyl-N(R1)_,-0-P(0)(0H)-, (CrCio)-alkyl- 0-P(0)(0H)-, (0-(C2-C3)-alkyl)η-0-Ρ(0)(0Η)-, ((C2-C3)-alkyl-0)nP( 0) (0H)-, (C3-C6)-cycloalkyl-0-P(0)(0H)_, (CrC6)-alkyl-(C3-C6)-cycloalkyl-0-P(0 (0H)-, (C3-C6)-cycloalkyl-(CVQ)-alkyl-0-Ρ(0)(0Η)-, (C6-C10)-aryl-0_P(0)(0H) , (QQ)-heteroaryl-0-P(0)(0H)-, (CrC6)-alkyl-(C6-C10)-aryl-0-P(0)(0H)·, (C6- C10)-aryl-(CrQ)-alkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(0)( 0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (CrC6)-alkyl-(CVC9)-heteroaryl-0 -Ρ(0)(0Η)-, (CrC9)-heteroaryl-(CrC6)-alkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(QQ)- Heteroaryl-0-P(0)(0H)-, (CrCO-heteroaryl-(C3-C6)-cycloalkyl_0-Ρ(0)(0Η)-, (C2-C9)-hetero Ring group-0·Ρ(0)(0Η)-, (C2_C9)_heterocyclyl-(CrQ)-alkyl-0-P(0)(0H)-, (CrC6)-alkyl-(C2- C9)-heterocyclic group-0-oxime (0)(0Η)·, (C2-C9)_heterocyclyl-(C3-C6)-cycloalkyl-〇-P(〇)(〇H)-, (crc6)-cycloalkyl-(c2-c9)-heterocyclyl 66 201141513 _0-Ρ(0)(0Η)-, -0-P(S)(0H)-, (CVC!. )-alkyl-0-P(S)(0H)-, (0-(C2-C3)-alkyl)n-0-P(S)(0H)_, ((C2-C3)-alkyl -0) nP(S)(0H)-, (C3-C6)-cycloalkyl-0-P(S)(0H)-, (crc6)-alkyl-(c3-c6)-cycloalkyl- Op(s)(oh)-, (c3-c6)-cycloalkyl-(CVC6)-alkyl-0-P(S)(0H)-, (C6-C10)-aryl-0-P ( S) (0H), (CrC9)-heteroaryl-0-P(S)(0H)-, (CrC6)-alkyl-(c6-c10)-aryl-0-P(S)(0H) -, (C6-C10)-aryl-(CrC6)-alkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0- P(S)(0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (CVQ)-alkyl-(CVCg)- Heteroaryl-0-P(S)(0H)-, (CVCg)-heteroaryl-(CrC6)-alkyl-0-P(S)(0H)-, (C3-C6)_cycloalkyl -(CVQ)-heteroaryl-0-P(S)(0H)-, (CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, ( C2-C9)-heterocyclic group-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(S)(0H)-, (CrC6 )-alkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P ( S) (0H)- and (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-; d is an integer between 0 and 10; η Is an integer between 1 and 11; m is 0, 1 or 2 q, p, r, s, t are independently 0, 1 or 2; R1 is Η, (CVQ)-alkyl; 67 201141513 R2 and R3 are independently η, (Cl-C6)-alkyl Wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated 5- to 6-membered monocyclic heterocyclyl group. In a more preferred embodiment of the invention, the groups are defined as follows: XI is a group selected from the group consisting of: -OC(O)-; -C(〇)-〇-; -C(0)-N(R1)- ; -N(Rl)-C(〇).; -C(S)-N(R1). ; -N(R1)-C(S)- ; -S02 -; -C(NH2+)-; -0-P(0)(0H)-; -S-; -N(R1)-; =NN(R1)-; -0-; and a heterocyclic group; < LI is selected from the group consisting of: (Ci_c) 〇) _ alkyl, (Ο (C2-C3)-alkyl) n, ((c2_c3)_alkyl 〇), (c3- C6)-cycloalkyl, (0-(C3-C6)-cycloalkyl)n, ((C3_C6)_cycloalkyl·〇)η, (Ci_C6)alkyl-((:3_(:6)_ Cycloalkyl, cycloalkyl-(Ci_c6)-alkyl, (Q-c10)-aryl, (Crc6)_院基_(C6_Ci〇)_aryl, (c6_Ci〇)_aryl-(CVC6) -alkyl, (C3_C6)-cycloalkyl-(c6_Ci〇)aryl, (C6-C10)-aryl·((ν(:6)_cycloalkyl, (Ci_c9)heteroaryl, (Ci_C6) _ calcinyl-(CrC9)-heteroaryl, (C1-C9)-heteroaryl-(crc6)-alkyl, (CrC6)-cycloalkyl-(Ci-C:9)-heteroaryl, Crc9)_heteroaryl-(C^-C6)-cycloalkyl, (C2_C9)_heterocyclyl, (Ci_c6)_ cyclyl-(C2_C9)_heterocyclyl, (C2_C9)-heterocyclyl-( CrC6)-alkyl, (c3_c6)-cycloalkyl-(CVC9)-heterocyclyl and (C2_C9)-heterocyclyl·((:3{6)cycloalkyl; 68 201141513 D is independently selected from the following Groups included: -C(O)-, -C(0)0-, -OC(O)-, -N(R1)-C(0)-, -C(0)N(R1)- -N(R1)C(0)_N(R1)-, -SOm-, -N(R1)-, -N(R1)-N=, =NN(R1)-, -N(R1)-N (R1)_, -O- , -S-, -SS-, -0-(CH2)-, , (CH2)-0_, (0-(C2_C3)-alkyl)n, ((C2-C3)-alkyl group_0)n, (N(RlHCrC6)-alkyl), (N(Rl)C(〇HCrC6)-alkyl), (N(Rl)C(0)-N(Rl)-(Cr.C6)-alkyl), (C(0)-N(Rl)-(CrC6)-alkyl), (NiRU-SCVNCRlMQ-Q)-alkyl), (N(Rl)-S02_(CrC6)-alkyl), (S02-N (Rl)-(CrC6)-alkyl), (SOm-(CrC6)-alkyl), (O-CXOHCVQ)-alkyl), ((^CO-CHCrQ)-alkyl), (0-C() 0)-N(Rl)-(CrC6)-alkyl), (N(Rl)-C(0)-0-(CrC6)··alkyl), (〇-(C3-C6)-cycloalkyl n, ((C3-C6)-cycloalkyl-0)n, (N(R1)-(C3-C6)-cycloalkyl), (N(R1)C(0)-(C3-C6) - cycloalkyl) (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl) (C(0)-N(R1)-(C3-C6)-cycloalkyl (N(Rl)-S〇2-N(Rl)-(C3-C6)-cycloalkyl) (N(R1)-S02-(C3-C6)-cycloalkyl), (S02-N( R1)-(C3-C6)-cycloalkyl), (som-(c3-c6)-cycloalkyl), (o_c(o)-(c3_c6)-cycloalkyl), (c(o)-o -(c3-c6)_cycloalkyl), (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl), (N(Rl)-C(0)-0-( CrC6)-cycloalkyl), (0-(CrC6)-alkyl-(c3-c6)-cycloalkyl)n, (N iRlHQ-Cd-alkyl-(c3-c6)-cycloalkyl), (N(Rl)C(0)-(CrC6)-alkyl-(C3-C6)-cycloalkyl), (N(Rl) C(0)-N(Rl)-(CrC6)_alkyl-(C3-C6)-cycloalkyl), 69 201141513 (CCCO-N^lHCrQ)-alkyl-(C3-C6)-cycloalkane (N(Rl)-S02-N(Rl)-(CrC6)_alkyl-(C3-C6)-cycloalkyl), (NCRU-SOHCrQ)-alkyl-(C3-C6)-cyclic Alkyl), (S02-N(Rl)-(CrC6)-alkyl-(C3-C6)-cycloalkyl), (SOm-AQ)·alkyl-(CrC6)-cycloalkyl), (0 -C(〇HCrC6)-alkyl-(C3-C6)-cycloalkyl), (c(0)_0-(crc6)-alkyl-((:3-(:6)-cycloalkyl), (0-C(0)-N(Rl)-(C"C6)-alkyl-(c3-c6)-cycloalkyl), (N(R1)-C(0)-0-(Ci_C6)- Anthracenyl-(C3-C6)-cycloalkyl), (0-(C3_C6)-cycloalkyl-(crc6)-alkyl)n, (N(R1)-(C3-C6)-cycloalkyl- (CrQ)·alkyl), (N(Rl)C(〇HC3-C6)-cycloalkyl-(crc6)-alkyl), (N(R1)C(0)-N(R1)-(C3 -C6)-cycloalkyl-(crc6)-alkyl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-(CVC6)-alkyl), (N(Rl) -S〇2-N(Rl)-(C3-C6)-cycloalkyl-(Ci-C^)-alkyl), (N(Rl)-S〇2-(C3-C6)-cycloalkyl -(crC6)-alkyl), (S〇2-N(Rl)-(C3-C6)-cycloalkyl-(QQ) -alkyl), (SOm-(C3-C6)-cycloalkyl-(crc6)-alkyl), (〇-C(0)-(C3-C6)-cycloalkyl-(CVC6)-alkyl ), (C(0)-0-(C3-C6)-cycloalkyl-(Ci-Q)-alkyl), (0-C(0), N(Rl)-(C3-C6)-ring Alkyl-(crc6)-alkyl), (N(Rl)-C(0)-0-(C3_C6)-cycloalkyl-(crc6)-alkyl), (O-(C6-C10)-aryl (n), (N(R1)-(C6-C10)-aryl), (N(Rl)C(O)-(C6-C10)-aryl), (N(Rl)C(O)- N(Rl)-(C6-C10)-aryl}, (C(O)-N(Rl)-(C6-C10)-aryl), (N(R1)-S〇2-N(R1) -(C6-C]0)-aryl), (n(ri)_s〇2-(C6_C1())- 201141513 aryl), (so2-n(ri)-((vc10)-aryl), (som-(c6-c10)-aryl), (0-C(〇HC6_C1())~aryl), (C(O)-O-(C6-C10)-aryl), (0-C (0)-N(R1HC6-C1g)-aryl), (N(Rl)-C(O)-O-(C6-C10)-aryl), (〇-(CrC6)-alkyl-(C6 -C10)_aryl)n, (N(Rl)-(CrC6)-alkyl-(C6-C1())-aryl), (N(Rl)C(0)-(CrC6)-alkyl -(C6-C10> aryl), (N(Rl)C(0)-N(Rl)-(CrC6)_alkyl-(C6-C10)-aryl), (C(0)-N( R1)-(C:i-C6)-alkyl-(C6-Ci〇)-aryl), (N(Rl)-S02-N(Rl)-(CrC6)-alkyl-(C6-C10) ·Aryl) (N(R1)-S〇2-(Ci_C6)-alkyl-(C6_Ci〇)·aryl), (S02-N(Rl)-(CrC6)-alkyl-(C6-C10)-aryl) , (SOm-(CrC6)-alkyl-(C6-C10)-aryl), (〇-C(〇HCrC6)-alkyl-(c6-c10)-aryl), (C(0)-0 -(Ci_C6)_alkyl-(cvc^o)-aryl), (〇_C(〇)-N(R1)-(Ci-C6)"alkyl-(C6-Ci〇)-aryl ), (N(R1)-C(0)-0-(Ci-C6)·, alkyl-(C6-Ci〇)-aryl), (O-(C6-C10)-aryl-(CrC6) )-alkyl)n, (N(R1HC6-C10)-aryl-(CVC6)-alkyl), (N(Rl)C(O)-(C6-C10)-aryl-(crc6)·alkane (N(Rl)C(O)-N(RlHC6-C10)-aryl-(crc6)·alkyl), (C(O)-N(Rl)-(C6-C10)-aryl -(CrC6)-alkyl), (N(R1)-S〇2-N(R1)-(C6-Ci〇)-aryl-(Ci-C6)-alkyl), (N(R1)- S〇2-(C6-Ci〇)-aryl-(Ci-C6)-alkyl), (SOrN(Rl)-(CVC10)-aryl-(CrC6)-alkyl), (SOm-(C6) -C10)-aryl-(CrC6)-alkyl), (OC(O)-(C6-C10)-aryl-(Ci-CJ-alkyl), (c(o)_o-(c6-c1) ())-Aryl-(CVC6)•Alkyl), (OC(O)-N(Rl)-(C6-C10).Aryl-(CrC6)-alkyl), 71 201141513 (N(Rl) -C(O)-〇-(C6-C10)_ aryl-(CVC6)-alkyl), (0-(C3- C6)-cycloalkyl-((VC1G)-aryl)n, (N(R1)-(C3-C6)-cycloalkyl-(C6-C1())-aryl), (N(R1) C(0)-(C3-C6)-cycloalkyl-(c6-c10)_aryl), (N(R1)C(0)-N(R1)-(C3-C6)-cyclodecyl- (c6-c) 0)-aryl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-(C6-C10)-aryl), (N(R1)-S02 -N(R1HC3-C6)-cycloalkyl-(C6-C10)_aryl), (N(R1)-S02-(C3-C6)-cycloalkyl-(c6-c10)-aryl), (S02-N(R1)-(C3-C6)-cycloalkyl-(C6-C10)-aryl), (SOm-(C3-C6)-cycloalkyl-(C6-C10)-aryl) , (0-C(0)-(C3-C6)-cycloalkyl-(c6-c1())-aryl), (c(o)-o-(c3-c6)-cycloalkyl-( c6-c1C))-aryl), (〇-C(0)-N(Rl)-(C3-C6)-cycloalkyl-(C6-C1())-aryl), (N(Rl) -C(0)-0-(C3-C6)-cycloalkyl-(C6-C10)-aryl), (O-(C6_C10)-aryl-(C3-C6)-cycloalkyl)n, (N(R1)-(C6-C10)-aryl-(C3-C6)-cycloalkyl), (N(R1)C(0)-(C6_Ci〇)-aryl-(Q-C6)- Cycloalkyl), (N(Rl)C(O)_N(Rl)-(C6-C10)-aryl-(C3-C6)_cycloalkyl), (C(O)-N(Rl)- (C6-C10)-aryl-(C3-C6)-cycloalkyl), (N(R1)-S〇2-N(R1)-(C6-C10)-aryl-(C3-C6)- Cycloalkyl), (N(R1)-S〇2-(C6-C10)-fang -(C3-C6)-cycloalkyl), (S〇2-N(R1)-(C6-Ci〇)-aryl-(C3-C6)-cycloalkyl), (S〇m-( C6-C1())-aryl-(C3-C6)-cycloalkyl), (〇-C(O)-(C6-C10)-aryl-(c3-c6)-cycloalkyl), ( C(0)-0-(C6-C1Q)·aryl-(c3-c6)-cycloalkyl), (〇-C(O)-N(Rl)-(C6-C10)-aryl-( C3-c6)_cycloalkyl), (N(Rl)-C(O)-O-(C6-C10)-aryl-(C3-C6)-cycloalkyl), 72 201141513 (0-(CrC9 )-heteroaryl)n, (N(Rl)-(CrC9)-heteroaryl), (N(Rl)C(0)-(CrC9)-heteroaryl) (N(Rl)C(0) -N(Rl)-(Cr-C9)-heteroaryl) (C(0)-N(Rl)-(CrC9)-heteroaryl) (N(Rl)-S02-N(Rl)-(Cr -C9)-hetero) (N(Rl)-S02-(CrC9)-heteroaryl), heteroaryl), (sOm-A-Cp)·heteroaryl), (oc(〇HCrc9)- Aryl), (C(0)-0-(CrC9)_heteroaryl), (O-CCCO-NCRIHCVCy-heteroaryl), (N(Rl)-C(0)-0-(CrC9)- Heteroaryl), (〇-(CrC6)-alkyl-(C1-C9)-heteroaryl)n, (N(R1)-(Ci_C6)-homo-(C1-C9)-heteroaryl) , (N(Rl)C(0)-(CrC6)-alkyl-(Crc9)-heteroaryl), (N(Rl)C(0)-N(RlHCrC6)-alkyl-(CrC9)- Aryl), (C(0)-N(Rl)-(CrC6)-alkane -(CrC9)-heteroaryl), (NXRlpSC^-NXRlXC^-Cs)·alkyl-(C1-C9)·heteroaryl), (N(R1)-S〇2-(Ci_C6)-院-(CpCg)-heteroaryl), (S〇2_N(R1)-(Ci_C6)-alkyl-(C1-C9)-heteroaryl), (S〇m-(Ci_C6)-alkyl-( CrCg)-heteroaryl), (0-C(0)-(Ci_C6)-alkyl-(CrC9)-heteroaryl), (C(0)-0-(CrC6)-alkyl-(crc9) -heteroaryl), (〇-C(0)-N(RlHCrC6)-alkyl-(CrC9)-heteroaryl), (N(R1)-C(0)-0-(Ci-C6)- Anthracenyl-(CpCg)-heteroaryl), (0-(Ci_C9)_heteroaryl-(Ci_C6)-alkyl)n, (N(R1)-(Ci_C9)-heteroaryl-(CrC6)- Alkyl), (N(Rl)C(0)-(CrC9)-heteroaryl-(CrC6)-alkyl), (N(Rl)C(0)-N(Rl)-(CrC9)-hetero Aryl-(CrC6)_alkyl), (C(0)-N(Rl)-(CrC9)-heteroaryl-(CrC6)·alkyl), 73 201141513 (NCRiySOrl^RlHCVQ)-heteroaryl_ (CrC6)_alkyl), (N(Rl)-S02-(CrC9)-heteroaryl-(Q-C6)-alkyl), (S02-N(Rl)-(CrC9)-heteroaryl- (CrC6)-alkyl), (SOm-(CrC9)-heteroaryl-(CVC6)-alkyl), (O-CCOHCVCp)-heteroaryl-(crc6)-alkyl), (c(o) -o-(crc9)-heteroaryl-(crc6)-alkyl), (O-CXCO-NiRlHQ-C^)-heteroaryl-(Cr C6)-alkyl), (l^RlVCXCO-CKCVCy-heteroaryl-(crc6)-alkyl), (o-(c2-c9)-heterocyclyl)n, (N(R1)-(C2- C9)-heterocyclyl), (N(R1)C(0)-(C2-C9)-heterocyclyl) (N(R1)C(0)-N(R1)-(C2-C9)- (C(0)-N(R1)-(C2-C9)-heterocyclyl) (N(Rl)-S〇2-N(Rl)-(C2-C9)-heterocyclyl) ( N(R1)-S02-(C2-C9)-heterocyclic group, (S02-N(R1)-(C2-C9)-heterocyclic group), (som-(c2-c9)-heterocyclic group) , (oc(o)-(c2-c9)-heterocyclyl), (c(o)-o-(c2-c9)-heterocyclyl), (0-C(0)-N(Rl)- (C2-C9)-heterocyclyl), (N(Rl)-C(0)-0-(C2-C9)-heterocyclyl), (o-(crc6)-alkyl-(C2-C9) -heterocyclyl)n, (I^RIHCVQ)-alkyl-(c2-c9)-heterocyclyl), (N(Rl)C(0)-(CrC6)-alkyl-(C2-C9)- Heterocyclyl), (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (C(0)-N(RlHCrC6)-alkane -(C2-C9)-heterocyclyl), (N^U-SOrNiRlHCrCd-alkyl-(C2-C9)-heterocyclyl), (N(Rl)-S02-(CrC6)-alkyl-( C2-C9)-heterocyclyl), (S02-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (SOm_(Ci_C6)-alkyl-(〇2 <9)_Heterocyclyl), (0_C(0)_(C]-C6)-74 201141513 Alkyl-(C2-C9)-heterocyclyl), (C^OKKCrQ)-alkyl-(C2_C9 )_ heterocyclyl), (0-C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (N(Rl)-C(0)-0 -(CrC6)-alkyl-(C2-C9)-heterocyclyl), (0-(C2-C9)-heterocyclyl-(CrC6)-homo)n, (N(R1)-(C2- C9)-heterocyclyl-(CrC6)-alkyl), (N(R1)C(0)-(C2-C9)-heterocyclyl-(crc6)-alkyl), (N(R1)C( 0)-N(R1HC2-C9)-heterocyclyl-(Crc6)), (C(0)-N(R1)-(C2-C9)-heterocyclyl-(crc6)-alkyl), (N(R1)-S02-N(R1)-(C2-C9)-heterocyclyl-(QQ)-alkyl), (N(R1)-S02-(C2-C9)-heterocyclyl) ), (S02-N(R1)-(C2-C9)-heterocyclyl-(QQ)-alkyl), (SOm-(C2-C9)-heterocyclyl-(CrC6)-alkyl), 〇_c(〇)_(c2-C9)_heterocyclyl-(Crc6)-alkyl), (C(0)-0-(c2-C9)-heterocyclyl-(crc6)-alkyl) , (0-C(0)-N(Rl)"(C2-C9)-heterocyclyl-(crc6)-alkyl) and (N(Rl)-C(0)-0-(C2-C9 ···Heterocyclyl-(Ci-Q)-alkyl); L2 is selected from the group consisting of: (CrCi〇)-alkyl, (0-(C2-C3)-alkyl)n, ((C2-C3)-burning base_〇)n, (c3_c6)· An alkyl group, (0-(C3-C6)-cycloalkyl)n, ((c3-c6)-cycloalkyl_0)n, (Crc6)-alkyl-(CVC6)-cycloalkyl, (( VC6)-cycloalkyl-(Ci_c6)-alkyl, (C6-Ch))-aryl, (c)-c6)-alkyl (C6_Ci〇)-aryl, (c6_Ci〇)_aryl- (CrC6)-alkyl, ((VQ)-cycloalkyl-(c6_ci〇)-aryl, (c6-c1())-aryl-(C3-C6)-cycloalkyl, (Crc9)^ , (Ci_C6)_alkyl-(CrC9)-heteroaryl, (crc:heteroaryl-(Ci_c6)-alkyl, (crc6)-cycloalkyl-(CVC9)-heteroaryl, (CrC9> Heteroaryl 75 201141513 -(c3-c6)-cycloalkyl, (c2-c9)-heterocyclyl, (crc6)-alkyl-(c2-c9)-heterocyclyl, (c2-c9)-hetero Cyclo-(crc6)-alkyl, (c3-c6)-cycloalkyl-(C2-C9)-heterocyclyl and (C2-C9)-hetero-(-3-〇6)-bad burn The group X2 is a group selected from the group consisting of: -C(O)-; -OC(O)-; -C(0)-0- '-N(R1)-C(0)- ; -C(0)-N(R1)-; -N(R1)-C(S)- ; -SO2- ; -C(NH2+)- ; -0-P(0)(0H)- ; -S -; -N(R1)-; and -O-; Y is a group selected from the group consisting of: -C(0)-; -S-; -N(R1)-; -N(R1 )-N=; and =NN(R1)-; Z is selected from the group included in the following: -0-P(0)(0H)-, (Ci-Cio)·alkyl-0-P(0)(0H)-, (〇-(C2-C3)-alkyl)η-0-Ρ( 0) (0Η)-, ((C2-C3)-alkyl-0) η-Ρ(0)(0Η)-, (C3-C6)-cycloalkyl-0-Ρ(0)(0Η)- , (CVC6)-alkyl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CVQ)-alkyl-0-P ( 0) (0H)-, (C6-C10)-aryl-0-P(0)(0H), (CVC9)-heteroaryl-0-oxime (0)(0Η)-, (CrC6)-alkane -(C6-C10)-aryl-0-oxime(0)(0Η)-, (C6-C10)-aryl-(Q-C6)-alkyl-0-P(0)(0H)- ,(C3-C6)-cycloalkyl-(C6-C10)-aryl-0-oxime(0)(0Η)-, (C6-C1())-aryl-(C3-C6)·cycloalkane Base-0-Ρ(0)(0Η)-, (CVC6)-alkyl-(CrC9)-heteroaryl-0-oxime(0)(0Η)-, (CVQ)-heteroaryl-(QQ) -alkyl 76 201141513 -0-Ρ(0)(0Η)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0-oxime (0)(0Η)-, (CrC9)- Heteroaryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C2-C9)_heterocyclyl-0-P(0)(0H)-, (C2-C9 )-heterocyclyl-(Crc6)-alkyl-0-P(0)(0H)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(〇)(0H) -, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(C2-C9)-hetero Ring group-0-P(0)(0H)-, -0-P(S) (0H)-, (CrC!. )-alkyl-0-P(S)(0H)-, (0-(C2-C3)-alkyl)n-0-P(S)(0H)-, ((C2-C3)-alkyl -0) nP(S)(0H)-, (C3-C6)-cycloalkyl-0-P(S)(0H)-, (CVC6)-alkyl-(C3-C6)-cycloalkyl- 0-P(S)(0H)-, (C3-C6)-cycloalkyl-(CrC6)-alkyl-0-P(S)(0H)-, (C6-C10)-aryl-0- P(S)(0H), (CrC9)-heteroaryl-0-P(S)(0H)-, (QQ)-alkyl-(C6-C10)-aryl-0-P(S)( 0H)-, (C6-C10)-aryl pneumatic-indole)-alkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl -0-P(S)(0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (CrC6)-alkyl-( CrC9)-heteroaryl-0-P(S)(0H)-, (CrC9)-heteroaryl-(CrC6)-alkyl-0-P(S)(0H)-, (C3-C6)- Cycloalkyl-(CrC9)-heteroaryl-0-P(S)(0H)-, (CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(0H) -, (C2_C9)_heterocyclic group_0_P(S)(0H)_, (C2-C9)-heterocyclyl-(qQ)-alkyl-0-P(S)(0H)-, (CVQ) -alkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(S (0H)-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-, wherein the phosphorus atom of Z is 3'- or siRNA 5'- 77 201141513 Oxygen atomic connection d is an integer between 〇 and 10; 11 is an integer between 1 and 11; m is 0, 1 or 2; q ' P ' r, s, t are independent of each other, 丨, 丨 or R1 Η, (Cl-C6)_alkyl; 〆' illusion and R3 are independently η, the base, where r2 and their - and their bonded nitrogen atoms together form a saturated 5_ to 6_ a cycloheterocyclyl group. In a more preferred embodiment of the invention, the groups are defined as follows: XI is a group selected from the group consisting of: _c(〇)·; -c(0)_0-; _C(0 )_N(R1)·; _s-; _N(R1)_ ; ; and heterocyclic group; L1 is selected from the group consisting of: (Ci_Ciq)_alkyl, (0-(C2-C3)· Base, n, ((c2-c3)-homo-based), (c3-c6)-cycloalkyl, (0-(C3-C6)-cycloalkyl)n, ((CrC6)-cycloalkane Base-0)n, (Q-C6)-alkylalkyl, (C3-C6)·cycloalkyl-(Ci-Ce)-alkyl, (C6-Ci〇)-square, (Ci_C6)_ --(C6_Ci〇)-aryl, (Cs-CiO)-aryl-(C"C6)-alkyl, (c3-c6)·cycloalkyl-(C6-C10)-aryl, (C6 -C10)-aryl-(C3-C6)-cycloalkyl, (CVC9)-heteroaryl, (crc6)-alkyl-(Ci-C9)-heteroaryl, (C)-C9)-hetero Aryl-(CVQ)-leuco, 78 201141513 (CrC6)-cycloalkyl-(crc9)_heteroaryl, (crc9)-heteroaryl-(Q-C6)-cycloalkyl, (c2_c9)- Heterocyclyl, (crC6)-alkyl-(c2-c9)-heteroyl, (C2-C9)-heterocyclyl-(C1-C6)-alkyl, (C3-C6)-cycloalkyl- (c2-c9)-heterocyclic group and (c2_c9)-heterocyclyl-(C3-C6)-cycloalkyl; D is independently selected from the following Group: -C(O)-, -C(0)0-, -OC(O)-, -N(R1)-C(0)-, -C(0)-N(R1)-, -N (R1)C(0)-N(R1)-, -N(R1)-, -O-, -S-, -S_S-, -0-(CH2)-, -(CH2)-0-, ( 0-(C2-C3)-alkyl)n, ((C2-C3)-alkyl-oxime)n, (N(Rl)-(CrC6)-alkyl), (N(Rl)C(0) -(CrC6)-alkyl), alkyl), (C^CO-l^RlHC^Q)-alkyl), (l^RO-SOHCVQ)-alkyl), (SC^-NiRlHCrCO-alkyl) , (SOm-(CrC6)-alkyl), (O-CCOHCrQ)-alkyl), (CCCO-O-CCi-Q)-alkyl), (OC^OH^RlHCrQ)·alkyl), (NiRlKXOKHCVQ )-alkyl), (0-(C3-C6)-cycloalkyl)n, ((C3-C6)-cycloalkyl-0)n, (N(R1)-(C3-C6)-cycloalkane (N(R1)C(0)-(C3-C6)-cycloalkyl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl), (C(0)-N(R1)-(C3-C6)-cycloalkyl), (N(R1)-S02-(C3-C6)-cycloalkyl), (S02-N(R1)-( C3-C6)-cycloalkyl), (SOm-(C3-C6)-cycloalkyl), (oc(o)-(c3_c6)-cycloalkyl), (c(o)-o_(c3-c6) )-cycloalkyl), (oc(o)-n(ri)-(c3-c6)-cycloalkyl), (N(Rl)-C(0)-0-(C3-C6)-cycloalkane (), (o-(crc6)-alkyl-(C3-C6)-cycloalkyl)n, (N(Rl)-(CrC6) -alkyl-(C3-C6)-cycloalkane 79 201141513 base), (N(Rl)C(0)-(CrC6)-alkyl-(C3-C6; M裒alkyl), (ISKRlMC^-NiRlHCVQ )-alkyl-(CrC6)-cycloalkyl), (C(0)_N(Rl)-(CrC6)-alkyl-(C3-C6)-cycloalkyl), (NCRU-SOHCrCe)-alkyl -(C3-C6)-cycloalkyl), (SOr^RlHCrQ)-alkyl-(C3-C6)-cycloalkyl), (SOm-(CrC6)-alkyl-(CrC6)-cycloalkyl) , (OC^OHCrQ)-alkyl-(CVC6)-cycloalkyl), (C(0)-0-(C"C6)-alkyl-(C3-C6)-cycloalkyl), (0- C(0)-N(RlHCrC6)-alkyl-(C3-C6)-cycloalkyl), (N(Rl)-C(〇HHCrC6)-alkyl-(c3-c6)-cycloalkyl), (0-(C3-C6)-cycloalkyl-(CVC6)·alkyl)n, (N(R1)-(C3-C6)-cycloalkyl-(CrC6)-alkyl), (N(R1) C(0)_(C3-C6)-cycloalkyl-(CrC6)-alkyl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-( CrC6)-alkyl), (c(o)-n(ri)-(c3-c6)-cycloalkyl-(Q-cy-alkyl), (N(Rl)-S〇2-(C3- C6)-cycloalkyl-((^)-alkyl), (S〇2-N(Rl)-(C3-C6)-cycloalkyl-(crc6)_alkyl), (SOm-(C3) -C6)-cycloalkyl-(crc6)-alkyl), (〇-C(0)-(C3-C6)-cycloalkyl-(CrQ)-alkyl), (C(〇)-〇- (C3-C6)-cycloalkyl-(C rC6)-alkyl), (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl-(Crc6)-alkyl), (N(Rl)-C(0)-0 -(C3-C6)-cycloalkyl-(C)-C6)-alkyl), (O-(C6-C10)-aryl)n, (N(R1)-(C6-C10)-aryl ), (N(Rl)C(O)-(C6-C10)-aryl), (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl), (C( O)_N(Rl)-(C6-C10)-aryl), (N(R1)_s〇2-(c6_c10)-aryl), (SO2-N(RlHC6-C10)-aryl), (s 〇m_(c6_c10)-aryl), 201141513 (OC(O)-(C6-C10)-aryl), (C(O)-〇-(C6-C10)aryl), (oc(o)- n(ri)_(c6-c10)-aryl), (N(R1)-C(0)-0-(C6-C1〇V aryl), (〇-(CrC6)·alkyl-(c6) -c10)-aryl)n, (N(Rl)-(CrC6)-alkyl-(c6-c10)-aryl), (ncrimomcvc^)-alkyl-(c6-c10)-aryl), (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(c6-c10)-aryl), (C(0)-N(Rl)-(CrC6)-alkyl- (C6-C10)-aryl), (NCRiySCViCi-Q)-alkyl-(C6_C10)-aryl), (SCVNiRlXCVQ)-alkyl-(C6-C10)-aryl), (SOj^CrQ)- Alkyl-(C6_C10)-aryl), (OC^OHQ-Q)-alkyl-(CVC^)-aryl), (0(0)-0-((1^-06)-alkyl- (C6_Ci〇)-aryl), alkyl-(C6-C10 )-aryl), (^$1)-0(0)-0-((^-06)-alkyl-(C6-Ci〇)-aryl), (0-(C6_Ci). )-aryl-(CrQ)-alkyl)n, (N(R1)-(C6-C10)-aryl-(CrC6)-alkyl), (N(Rl)C(O)-(C6- C10)-aryl-(C^-C^)-alkyl), (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl-(CrC6)-alkyl), (C(0)-N(R1)-(C6-CI())-aryl-(CrC6)-alkyl), (IS^RU-SC^-i^-Cio)-arylalkyl), (S〇2-N(R1)-(C6-C10)-aryl-(Ci-C^)-alkyl), (SOm-(C6-C10)-aryl-(CrC6)-alkyl), (OC(O)-(C6-C10)-aryl-(QQ)-alkyl), (C(O)-O-(C6-C10)-aryl-(CVQ)-alkyl), (OC (O)-N(Rl)-(C6-C10)-aryl-(crc6)-alkyl), (N(Rl)-C(O)-O-(C6-C10)_aryl_(crc6 )-院(), (0_(C3_C6)-cycloalkyl-(C6_Ci.)-aryl)n, (N(R1)-(C3-C6)-cycloalkyl-(Q-Ci.)·芳(N(R1)C(0)-(C3_C6)-cycloalkyl group_(C6-C1())- 201141513 aryl), (N(Rl)C(0)-N(Rl)-( CrC6)-cycloalkyl-(C6-C10)-aryl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-(C6-C10)-aryl), (N (Rl)-S〇2-(C3_C6)-cycloalkyl-(Cg-Cio)-aryl), (S〇2-N(Rl)-(C3_C6)-cyclic 焼"--(C6-Ci〇) )-aryl), (SOm-(C3-C6)_cycloalkyl-(c6_c10)-aryl), (0-C(〇HC3-C6)·cycloalkyl-(c6-c10)- Aryl), (c(o)-o-(c3-c6)-cycloalkyl-(c6-c10)-aryl), (0-C(0)-N(Rl)-(C3_C6)-cyclic Alkyl-(c6-c10)-aryl), (n(ri)-c(o)-o-(c3-c6)-cycloalkyl-(C6_C1())-aryl), (O-( C6-C10)-aryl-(C3-C6)-cycloalkyl)n, (N(R1)-(C6-C10)-aryl-(C3-C6)-cycloalkyl), (N(R1) C(0)-(C6-Ch))-aryl-(C3-C6)-cycloalkyl), (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl -(C3-C6)-cycloalkyl), (C(O)-N(Rl)-(C6_C10)-aryl-(C3-C6)-cycloalkyl), (N(R1)-S〇2 -(C6-C10)-aryl-(C3-C6)-cycloalkyl), (S〇2-N(R1)-(C6-C10)-aryl-(C3-C6)-cycloalkyl) (SOm-(C6-C10)-aryl-(C3-C6)-cycloalkyl), (0-c(0)-(C6-C1{))-aryl-(C3_C6)-cycloalkyl ), ((:(0)-0-((:6-(:1())-aryl)((:3_(:6)·cycloalkyl), (OC(O)-N(Rl) -(C6-C10)-aryl-(C3-C6)-cycloalkyl), (n(ri)-c(〇kkc6-c10)-aryl-(C3-C6)·cycloalkyl), ( CKCi-Cy-heteroaryl)n, (N(Rl)-(CrC9)-heteroaryl), (N(Rl)C(0)-(CrC9)-heteroaryl}, (N(Rl)C (0)-N(Rl)-(CrC9)-heteroaryl), (C^CO-NiRlHCrCy-heteroaryl), (N(Rl)-S〇2-(Crc9)_heteroaryl ), (S02-N(Rl)-(CrC9)·heteroaryl), (S〇m_(Cl_c9)_heteroaryl 82 201141513), (oc(o)-(crc9)-heteroaryl), ( c(o)-o-(crc9)-heteroaryl), (0-C(0)-N(Rl)_(CrC9)-heteroaryl), (1^(111)/(0)-0 -((^(9)-heteroaryl), (0-(crc6)-alkyl-(CrC9)-heteroaryl)n, (N(Rl)-(CrC6)-alkyl-(crc9)- Heteroaryl), (N(Rl)C(〇HCrC6)-alkyl-(CVC9)-heteroaryl), (N(Rl)C(0)-N(RlHCrC6)-alkyl-(CrC9)- Heteroaryl), (CXCO-NCRIHQ-Cy-alkyl-(Ci-Cg)-heteroaryl), (N(Rl)-S02-(CrC6)-alkyl-(CVCy-heteroaryl), ( SCVNCRIHCrQ)-alkyl-(QQ)-heteroaryl), (SOdQ-Q)-alkyl-(Q-C9)-heteroaryl), (〇-C(〇)-(CrC6)-alkyl- (CrC9)-heteroaryl), (C(0)-0-(CrC6)-alkyl-(CrC9)_heteroaryl), (0-C(0)-N(Rl)-(CrC6)- Alkyl-(Ci-C9)-heteroaryl), (N(Rl)-C(〇KKCrC6)-alkyl-(CrC9)-heteroaryl), (0-(CrC9)-heteroaryl-( CrQ)-alkyl)n, (^RlHCi-CAheteroaryl-(CrQ)·alkyl), (N(Rl)C(0)-(CrC9)-heteroaryl-(Cl_c6)_ Hyun ), (l^RlMOhNCRlHQ-Q)-heteroaryl-(Cl_C6)-alkyl), (C(0)-N(Rl)-(CrC9) )-heteroaryl-(CrC6)-alkyl), (N(Rl)_S02-(CrC9)-heteroaryl-(CVC6)-alkyl), (S〇2-N(Rl)-(CrC9) -heteroaryl-(CVQ)-alkyl), (S0m-(CrC9)-heteroaryl-(CrC6)-homo), (0-C(0)-(C)-C9)-heteroaryl -(CrC6)-alkyl), (C(0)-0-(CrC9)-heteroaryl-(crc6)_alkyl), (0-C(0)-N(RlHCrC9)-heteroaryl- (crc6)-alkyl), (N(Rl)-C(0)_0_(Cl_c9)_heteroaryl_(C1_C6)_alkyl), (〇-(C2-C9)-heterocyclyl)n, (N(Ri)-(c2-c9)-heterocyclyl), 83 201141513 (N(R1)C(0)-(C2-C9)-heterocyclyl), (N(R1)C(0)- N(R1)-(C2-C9)-heterocyclyl), (C(0)-N(R1)-(C2-C9)-heterocyclyl), (N(R1)-S02-(C2-C9) )-heterocyclic group, (S02-N(R1)-(C2-C9)-heterocyclic group), (SOm-(C2-C9)-heterocyclic group), (oc(o)-(c2-c9) )-heterocyclic group, (c(o)-o-(c2-c9)-heterocyclic group), (0-C(0)-N(RlHC2-C9)-heterocyclic group), (N(Rl) )-C(0)-0-(C2-C9)-heterocyclic group, (CKCrQ)-alkyl-(C2-C9)-heterocyclyl)n, (N(Rl)-(CrC6)-alkane -(C2-C9)-heterocyclyl), (I^RUCXOMCVQ)-alkyl-(c2-c9)-heterocyclyl), (N(Rl)C(0)-N(Rl)-(CrC6 )-alkyl-(C2-C9)-heterocyclic group), (C (0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (NXRU-SOHCVCe)-alkyl-(C2-C9)-heterocyclyl), (SCVNCRlHCrC^ )-alkyl-(C2-C9)-heterocyclyl), (SOdCrQ)-alkyl-(C2-C9)-heterocyclyl), (0-C(〇HCrC6)-alkyl-(C2-C9) )-heterocyclic group, (C(0)-0-(CrC6)-alkyl-(C2-C9)-heterocyclic group), (〇-C(0)-N(RlHCrC6)-alkyl-( C2-C9)-heterocyclyl), (N^IKXOKHCVQ)-alkyl-(C2-C9)-heterocyclyl), (o-(c2-c9)-heterocyclyl-(CrC6)-alkyl) n, (N(R1)-(C2-C9)-heterocyclyl-(CrC6)-alkyl), (N(R1)C(0)-(C2-C9)-heterocyclyl-(crc6)- Alkyl), (N(R1)C(0)-N(R1)-(C2-C9)-heterocyclyl-(CrQ)-alkyl), (C(0)-N(R1)-(C2 -C9)-heterocyclyl-(crc6)-alkyl), (N(R1)-S02-(C2-C9)-heterocyclyl-(CrQ)-alkyl), (S02-N(R1)- (C2-C9)-heterocyclyl-(crc6)-alkyl), (som-(c2-c9)-heterocyclyl-(crc6)-alkyl), (oc(o)-(c2-c9) - 84 201141513 Heterocyclyl-(CrC6)-alkyl), ((:(0)-0-((^+heterocyclyl)), (oc(o)-n(riHc2-c9)-heterocycle Base - (CrC6 > alkyl) and (N(R1)-C(0)-0_(C2-C9)-heterocyclyl (qQ)-alkyl); L2 is selected from the group consisting of: ( Ci_Ci-alkyl, (0-(C2-C3)-alkyl)n, ((C2-C3)-alkyl 〇), (C3_C6) 炫, (0-(C3-C6)-ring An alkyl group, n, ((C3-C6)-cycloalkyl group 〇), (Ci_Q)-alkyl-(cvc:6)-cycloalkyl, (C3_C6)-cycloalkyl-(Ci_c6)-alkane , (Q-C10)-aryl, (Cl-C6)·alkyl-(c6_Cl0)-aryl, (c6_c)〇)_aryl-(CkC:6)-alkyl, (crC6)-ring Alkyl-(c6_ci〇)-aryl, (C6-C10)-aryl-(C3_C6)_cycloalkyl, (Crc9)·heteroaryl, (Ci_C6)_alkyl-(crC9)-heteroaryl , (Cl_C9)·heteroaryl·((ν(:6)_alkyl, (QQ)-cycloalkyl)(C“C9)-heteroaryl, (Ci_c9)_heteroaryl-(Q-C6 )-cycloalkyl, (Qc:9)-heterocyclyl, (Ci_c-alkyl-(C2_C9)-heterocyclyl, (C2-C9)-heterocyclyl-(CrC6)-alkyl, ((VC6) )-cycloalkyl-(c2-c9)·heterocyclic group and (C2_C:9>heterocyclyl-((Vc)-ring group; X2 is a group selected from the group consisting of: τ(〇 )_ ; -OC(O)- ; -C(0)-0- >-N(R1)-C(0)-; -C(0). N(R1). . S-; -N(R1)-; and ·〇_; Y is a group selected from the group consisting of: _c _s_ ; -N(R1)-; and -N(R1)-N=; 201141513 Z series is selected from the group consisting of: constant key, -0-Ρ(0)(0Η)-, (Q-Ciq)-alkyl-0-P(0)(0H)-, (〇- (C2-C3)-alkyl)η-0-Ρ(0)(0Η)-, ((C2_C3)_alkyl-0)η-Ρ(0)(0Η)-, (C3-C6)-ring Alkyl-0-oxime (0)(0Η)-, (CrC6)-alkyl-(C3-C6)-cycloalkyl-0-oxime (0)(0Η)-, (C3-C6)-cycloalkane -(CrC6)-alkyl-0-oxime (0)(0Η)-, (C6-C]0)-aryl-0-P(0)(0H), (Q-C9)-heteroaryl -0-P(0)(0H)-, (CrC6)-alkyl-(C6-C10)-aryl-0-P(0)(0H)-, (C6-C10)-aryl-(C "C6)-Alkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(0)(0H)-, (C6 -C10)-aryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (CrC6)-alkyl-(CrC9)-heteroaryl-0-P(0)( 0H)-, (CVC9)-heteroaryl-(CVQ)-alkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0- P(0)(0H)-, (CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C2-C9)-heterocyclyl-0- P(0)(0H)-, (C2-C9)-heterocyclyl-(QQ)-alkyl-0-P(0)(0H)-, (CrC6)-alkyl-(C2-C9 )-heterocyclic group-0-P(0)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-indole-P(〇)(〇H)-, ( C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0_P(0)(0H)-,-0-P(S)(0H)-, (CVC!.)-alkyl-0 -P(S)(0H)-, (0_(C2-C3)-alkyl)n-0-P(S)(0H)-, ((C2-C3)-alkyl-0)nP(S) (0H)-, (C3-C6)-cycloalkyl-0-P(S)(0H)·, (crc6)-alkyl-(c3-c6)-cycloalkyl-op(s)(oh) -, (c3-c6)-cycloalkyl-(CrC6)-alkyl-0-P(S)(0H)-, (C6-C10)-aryl-0-P(S)(0H), miscellaneous Aryl-0-P(S)(0H)-, (CrC6)-alkane 86 201141513 base-(c6-c10)-aryl-0-P(S)(0H)-, (c6-c10)-aryl -(crc6)-alkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(S)(0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (CrC6)-alkyl-(CVC9)-heteroaryl-0-P(S )(0H)-, (CVCy-heteroaryl-(CVQ)-alkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0 -P(S)(0H)-, (CVCg)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl_0_P (S)(0H)-, (C2-C9)-heterocyclyl-(CrQ)-alkyl-0-P(S)(0H)-, (CrQ)-alkyl-(C2-C9)-hetero Cyclic group-0-P(S)(0H)-, (C2-C9)-heterocyclic ring -(C3-C6)-cycloalkyl-0-P(S)(0H)- and (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-P(S)( 0H)-, wherein the phosphorus atom of Z is linked to the 3'- or 5'-oxygen atom of the siRNA; d is an integer between 0 and 10; η is an integer between 1 and 11; m is 0 , 1 or 2; q is 1, p, r, s, t are independently 0, 1 or 2; R1 is Η, (CrC6)-alkyl; R2 and R3 are independently Η, (CrC6)- An alkyl group wherein R2 and R3 are bonded together with the nitrogen atom to which they are bonded to form a saturated 5- to 6-membered monocyclic heterocyclyl hydrazine. In a more preferred embodiment of the invention, the groups are defined as 87 201141513: χι is a group selected from the group consisting of -c(o)-; _qQ) Q_ ; -C(0)-N (R1)-; - direct bond; L1 is selected from the group consisting of: (C丨-(: ♦ burnt base, (〇-(C2-C3)-alkyl) n, ((C2-C3) -alkyl-))n, (C3-C6)-cycloalkyl, (C1-C4)-alkyl-(C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl (CrCA) -alkyl, (CVCio)-aryl, (CrC4)-homo-(C6_C10)-aryl, (Cg-Cio)-aryl-(C1-C4)-alkyl, (Ci-C9)- Aryl, alkyl-(CVC9)-heteroaryl, (CrC9)-heteroaryl-(crc4)-alkyl, (C2_C9)-heterocyclyl, (C1-C4)-alkyl-(C2-C9 -heterocyclyl and (c2_c9)_heterocyclyl-(Ci_C4)-alkyl; D is independently selected from the group consisting of: -c(0)-, -c(0)0-, - OC(O)-, -N(R1)-C(0)-, -C(0)-N(R1)-, -N(R1)C(0)-N(R1)-, -N(R1 )-, -O-, -S-, -SS-, -o-(ch2)-, -(ch2)-o-, (o-(c2-c3)-alkyl)n, ((c2-c3 )-alkyl-))n, (N(Rl)-(CrC6)-alkyl), (N(Rl)C(〇HCrC6)-alkyl), (N(Rl)C(0)-N( Rl)-(CrC6)-alkyl), (C(0)-N(Rl)-(CrC6)-alkyl , (OC^OHCVC^)-alkyl), (C(0)-0-(CrC6)-alkyl), (0-C(0)-N(RlHCrC6)·alkyl), (NiRlKXOKKCVCy-alkyl ), (N(R1)_(C3-C6)-cycloalkyl), (N(R1)C(0)-(C3-C6)-cycloalkyl), (N(R1)C(0)- N(R1)-(C3-C6)-cycloalkyl), 88 201141513 (C(0)-N(R1)-(C3-C6)_cycloalkyl), (oc(o)-(c3-c6) )-cycloalkyl), (c(o)-o-(c3-c6)-cyclodendyl), (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl), (n(ri)-c(o)-o-(c3-c6)-cycloalkyl), alkyl-(c3-c6)-cycloalkyl)n, (N(Rl)-(CrC6)-alkane (-(C3-C6)-cycloalkyl), (N(Rl)C(0)-(CrC6)-alkyl-(CrC6)-cycloalkyl), (N(Rl)C(0)-N (Rl)-(CrC6)-alkyl-(C3-C6)-cycloalkyl), (C(0)-N(Rl)-(CrC6)-alkyl-(C3-C6)-cycloalkyl) , (0-C(0)_(CrC6)-alkyl-(C3_C6)-cycloalkyl), (C(0)-0-(Ci-C6)-homo-(C3-C6)-cyclic burn (), (0-C(0)-N(Rl)-(C"C6)-alkyl-(c3-c6)-cycloalkyl), (N(Rl)-C(0)-0-( CrC6)-alkyl-(c3-c6)-cycloalkyl), (o-(c3-c6)-cycloalkyl-(cvc6)-alkyl)n, (N(R1)-(C3-C6) -cycloalkyl-(CrC6)-alkyl), (N(R1)C(0)-(C3-C6)-cycloalkyl-(CVC6)-alkyl), (n( Ri)c(0)-n(ri)-(c3-c6)-cycloalkyl-(crc6)-alkyl), (C(0)-N(R1MC3-C6)-cycloalkyl-(CVC6) -alkyl), (oc(o)-(c3_c6)-cycloalkyl-(crc6)_alkyl), (c(o)-o-(c3-c6)-cycloalkyl-(crc6)-alkane ()-(0-C(0)-N(Rl)-(C3-C6)-cycloalkyl-(crc6)-alkyl), (N(Rl)-C(0)-0-(CrC6) -cycloalkyl-(CrC6)-alkyl), (O-(C6-C10)-aryl)n, (N(R1)-(C6-C10)-aryl), (N(Rl)C( O)-(C6-C10)-aryl), (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl), (c(o)-n(ri)-( C6-c10)-aryl), (oc(o)-(c6-c10)-aryl), (C(O)-O-(C6-C10)-aryl), (〇-C(O) -N(Rl)-(C6-C10)-aryl 89 201141513 base), (N(Rl)-C(O)-O_(C6-C10)-aryl), (0-(CrC6)-alkyl- (c6-c1())-aryl)n, (N(Rl)-(CrC6)-alkyl-(C6-C1Q)-aryl), (N(Rl)C(0)-(CrC6)- Alkyl-(C6-C10)-aryl), alkyl-(C6-C10)-aryl), (0(0)-1^(^)-((^-06)-alkyl-(C6 -Ci〇)-aryl), (0-C(0)-(Ci-C6)-alkyl-(C6-Ci〇)-aryl), (0(0)-0-((1^-) 06)-alkyl-(C6-C10)_aryl), (0-C(0)-N(Rl)-(CrC6)-alkyl-(C6-C1())-aryl), (N (Rl)-C(0)-0-(CrC6)- -(C6-C10)_aryl), (〇-(c6-c10)-aryl-(Crc6)-alkyl)n, (N(R1HC6-C10)-aryl-(crc6)-alkyl ), (N(Rl)C(O)-(C6-C10)-aryl-(Crc6)-alkyl), (N(Rl)C(O)-N(Rl)-(C6-C10)- Aryl-(CVC6)-alkyl), aryl-(Ci-Cg)-alkyl), (OC(O)-(C6-C10)-aryl-(CrC6)-alkyl), (C( O)-O-(C6-C10)_aryl-(Ci-Q)-alkyl), (〇-C(O)-N(Rl)-(C6-C10)-aryl-(Ci-C6) )-(alkyl), (N(R1)-C(0)-0-(C6_Ci〇)-aryl-(CrQ)-alkyl), (〇-(C3_C6)-cycloalkyl-(C6-Ci) 〇)-aryl)n, (N(R1)-(C3-C6)-cycloalkyl-(c6-c10)-aryl), (N(R1)C(0)_(C3-C6)- Cycloalkyl-(Ce-C^o)-aryl), (N(R1)C(0)-N(R1)-(C3-C6)·cycloalkyl-(C6-C10)-aryl) , (C(0)-N(R1)-(C3_C6)-cyclohexyl)-(C6-Ci〇)-aryl), (0-C(0)-(C3_C6)-cycloalkyl-(C6 -Ci〇)-aryl), (C(0)-0-(C3_C6)-cycloalkyl-(C6_Ci〇)-aryl), (0-C(0)-N(Rl)-(C3- C6)-cycloxanyl 1 -(C6-C)indole-aryl), 201141513 (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl-(C6-C10)· Aryl), (0-(C6-C1())-aryl-(C3-C6)-cycloalkyl)n, (N(R1)-(C6-C10)-aryl-(c3-c6) - Alkyl), (N(R1)C(〇HC6-C10)·aryl-(C3-C6)-cycloalkyl), (N(Rl)C(O)-N(Rl)-(C6-C10 )-aryl-(C3-C6)-cycloalkyl), (C(O)-N(Rl)-(C6-C10)-aryl-(C3-C6)-cycloalkyl), (0- C. (〇HC6-C1())-aryl-(c3-c6)-cycloalkyl), (C(O)-O-(C6-C10)-aryl-(c3-c6)-cycloalkyl) , (0-C(0)-N(Rl)-(C6-C1())-aryl-(C3-C6)·* cycloalkyl), (N(Rl)_C(O)-O_(C6 -C10)-aryl-(C;}-C6)-cycloalkyl), (CHQ-Q)-heteroaryl)n, (N(Rl)-(CrC9)-heteroaryl), (N() R1)C(0)-(Ci_C9)·heteroaryl), (N(Rl)C(0)-N(Rl)-(Cr. C9)-heteroaryl), (QOH^RlHCrCy-heteroaryl), (〇-C(〇HCrc9)-heteroaryl), (CXOhCHCVCp)-heteroaryl), (0-C(0)-N (Rl)-(CrC9)-heteroaryl), (N(Rl)-C(0). -0-(CrC9)-heteroaryl), (〇-(CrC6)-alkyl-(Ci-cy-heteroaryl)n, (NCRIMQ-C^)-alkyl-(CVC9)-heteroaryl), (N(R1)C(0)_(Ci_C6)·alkyl-(C1-C9)-heteroaryl),  (N(Rl)C(0)-N(RlHCrC6)_alkyl-(CVC9)-heteroaryl),  (C^CO-NCRIHCVQ)-alkyl-(crc9)-heteroaryl),  (o-c(o)-(crc6)-alkyl-(CrC9)-heteroaryl),  (c(〇HHCrc6)-alkyl-(c]-c9)-heteroaryl),  (O-CXC^-NiRlXCi-Ce)-alkyl-(CrCp)·heteroaryl),  (N(Rl)-C(0)-0-(CrC6)-based-(CrCp)-heteroaryl),  (o-(crc9)·heteroaryl-(CVQ)-alkyl)n, (NCRIHCVcy-heterofang 201141513 base-(CrC6)-alkyl), (N(Rl)C(0)-(CrC9)-heteroaryl-(C]-C6)-alkyl), (Ν(ιιι)(: (ο)-Ν(ΓαΗ(^-(: 9)-heteroaryl-(crc6)-alkyl), (C(0)-N(Rl)-(CrC9)-heteroaryl-(CrC6)-alkyl),  (o-cxomcvCp)-heteroaryl-(Q-cd-alkyl),  (c(o)-o-(crc9)-heteroaryl-(crc6)-alkyl),  (O-C^CO-NCRlHCi-Cg)-heteroaryl-(crc6)-alkyl),  (N(Rl)-C(0)-0-(CrC9)-heteroaryl-(CrC6)-alkyl),  (o-(c2-c9)-heterocyclyl)n, (N(R1)-(C2-C9)-heterocyclic group),  (N(R1)C(0)-(C2-C9)-heterocyclic group),  (N(R1)C(0)-N(R1)-(C2-C9)-heterocyclic group),  (C(0)-N(R1HC2-C9)-heterocyclic group), (o-c(o)-(c2-c9)-heterocyclic group), (c(o)-o-(c2-c9)_heterocyclyl), (o-c(o)-n(ri)-(c2-c9)-heterocyclic group), (n(ri)-c(o)-o-(c2-c9)-heterocyclic group), (o-(crc6)-alkyl-(C2-C9)-heterocyclyl)n, (l^RlHCrC^)-alkyl-(C2-C9)-heterocyclyl), (NiRUCCOHCrQ)-alkyl-(C2-C9)_heterocyclic group),  (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl),  (CCCO-IsKRlHCrQ)-alkyl-(C2-C9)-heterocyclyl),  (o-c(o)-(crc6)-alkyl-(c2-c9)-heterocyclyl),  (CXCO-CHCrQ)-alkyl-(C2-C9)-heterocyclyl),  (O-CXCO-NiRlHQ-Q)-alkyl-(C2-C9)-heterocyclic group),  (1^(111)-(: (0)-0-((^-(: 6)-alkyl-(c2-c9)-heterocyclic group),  (0-(C2-C9)-heterocyclyl-(CrQ)-alkyl)n, (N(R1)-(C2-C9)-heterocyclyl-(CrC6)-alkyl), (N(R1)C(0)-(C2-C9)-heterocyclyl-(crc6)-alkyl), (N(R1)C(0)-N(R1)-(C2-C9)-heterocyclyl-(crc6)-alkane 92 201141513 base), (C(0)-N(R1)-(C2-C9)-heterocyclyl _(Cl_c6)_alkyl),  (0-C(0)-(C2-C9)-heterocyclyl _(Ci_C6)_alkyl),  (C(0)-0-(C2-C9)-heterocyclyl _(Ci_C6)_alkyl),  (0-C(0)-N(Rl)-(C2_C9)-heterocyclyl-(Ci_c6)_alkyl) and (N(R1)-C(0)-0_(C2-C9)-heterocyclyl _(Ci_c6)-burning base);  The L2 is selected from the group consisting of: alkyl,  (o_(c2_c3)-院基) n, ((c2-c3)-burning base _0)n, (c3_C6; Mf base,  (o-(c3-c6)-cycloalkyl)n, ((C3_C6)_cycloalkyl-〇)), (Ci_c6)alkyl-(q-C6)-cycloalkyl, (C3_C6)_cycloalkyl-(Ci_c6)_alkyl,  (^VC10)-aryl, (crc6)-burning base·((ν(: 10) _ aryl, (C6_Ci〇)_ aryl-(q-C6)-alkyl, Cycloalkyl·(CrCM aryl,  (C6-C10)-aryl-(c3-c6)-cycloalkyl, (crc9)-heteroaryl, (Ci_c6)_alkyl-(q-C9)-heteroaryl, (Cl_C9)_heteroaryl_(Ci_c6)_alkyl,  (CrC6)-cycloalkyl-(crc: 9)-heteroaryl, (Ci-c9)_heteroaryl-(C3-C6)-cycloalkyl, (C2_c9)_heterocyclyl, Burning base_(C2 core)_ heterocyclic group, (c2-c9)·Heterocyclyl·((: 1(6)_ silk, (CVC6)_cycloalkyl-(C2-C9)-heterocyclic group and (CrC^heterocyclyl-(CrC^cycloalkyl);  The group containing the group -O-C(o)·;  -C(0)-0-, _N(R1)-C(0) small c(〇) _ _ -N(R1)-; And ;  'γ is a group selected from the group consisting of: ;  _s 93 201141513 -N(Rl)-; And -N(R1)-N=;  The Z series is selected from the group consisting of: Always key, -0-Ρ(0)(0Η)-,  (CVCh))-Alkyl-0-P(0)(0H)- ,  (0-(C2-C3)-alkyl)η-0-Ρ(0)(0Η)-, ((C2-C3)-alkyl-0)η-Ρ(0)(0Η)-,  (C3-C6)-cycloalkyl-0-Ρ(0)(0Η)-, (CrC6)-alkyl-(C3-C6)-cycloalkyl-0-oxime (0)(0Η)-, (C3-C6)-cycloalkyl-(CrC: 6)-Alkyl -0-P(0)(0H)_, (C6-C10)-aryl-0-P(0)(0H), (CrC9)-heteroaryl-0-Ρ(0)(0Η)-, (CrC6)-alkyl-(C6-C10)-aryl-O-Ρ(0)(0Η)-,  (C6-C10)-aryl _((ν(: 6)-Alkyl -0-P(0)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-O-P(0)(0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-Ρ(0)(0Η)-, (CVQ)-alkyl-(CrC9)-heteroaryl-0-Ρ(0)(0Η)-, (OC9)-heteroaryl-(CrC6)-alkyl -0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CrCp)-heteroaryl-0-P(0)(0H)-, (CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-Ρ(0)(0Η)-, (C2-C9)-heterocyclic group-0-Ρ(0)(0Η)-, (C2-C9)-heterocyclyl-(Q-Q)-alkyl-0-P(0)(0H)-, (Q-Q)-alkyl-(C2-C9)-heterocyclyl-0-oxime (0)(0Η)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-Ρ(0)(0Η)-, -0-P(S)(0H)- , (CVC! . )-alkyl -0-P(S)(0H)-, (0-(C2-C3)-alkyl)n-0-P(S)(0H)-, ((C2_C3)_ alkyl-0)n-P(S)(0H)-, (C3-C6)-cycloalkyl-0-P(S)(0H)-,  (CVC6)-alkyl-(c3-c6)-cycloalkyl-o-p(s)(oh)-, (c3-c6)-cycloalkane 94 201141513 --(Crc6)-alkyl-0-P(S)(0H)·, (C6-C10)-aryl-0-P(S)(0H), (CrC9)-heteroaryl-0-P(S)(0H)-, (CrC6)-alkyl-(C^-Cio)-aryl-0-P(S)(0H)-, (C6-Ci〇)-aryl-(Ci_C6)-alkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-O-P(S)(0H)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(S)(0H)- , (CrC6)-alkyl-(CVC9)-heteroaryl-0-P(S)(0H)- , (CrC9)-heteroaryl-(CrC6)-alkyl -0-P(S)(0H)-, (C3-C6)-cycloalkyl-(CVC9)-heteroaryl-0-P(S)(0H)-, (CHS)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (C2_C9)_heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(S)(0H)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-;  Wherein the phosphorus atom of Z is linked to the 3'- or 5'-oxygen atom of the siRNA;  d is an integer between 0 and 5;  η is an integer between 1 and 11;  q is 1;  p, r, s, The t system is 0 independently of each other. 1 or 2;  R1 is Η, (CrC6)-alkyl;  R2 and R3 are independently Η, (CrC6)-alkyl, Wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated 5- to 6-membered monocyclic heterocyclyl group.  95 201141513 In a more preferred embodiment of the invention, These groups are defined as follows:  XI is a group selected from the group consisting of: -C(o)- ;  -C(0)-0- and -C(0)-N(R1)-;  L1 is selected from the group included below: ((VQq)-alkyl,  (0-(C2-C3)-alkyl)n, ((c2_c3)_alkyl-〇)n, (C3-C6)-cycloalkyl,  (CrC4)-alkyl-(c3-c6)-cycloalkyl, (C3-C6)-cycloalkyl-(CVC4)-alkyl, (C6-CiQ)_ square base, (Ci-C4)_alkyl-(C6-Ci〇)-aryl,  (C6-C10)-aryl-(CVC4)-alkyl, (CVC9)-heteroaryl, (CVC4)-alkyl-(C1-C9)-heteroaryl, (C1-C9)-heteroaryl-(CVC4)-alkyl,  (c2-c9)-heterocyclic group, (crc4)-alkyl-(c2-c9)-heterocyclyl and (c2-c9)-hetero-(Ci-C4)-alkyl;  The D series are independently selected from the group included below: -C(O)-, -c(0)0-,  -O-C(O)- ,  -N(R1)-C(0)- ,  -C(0)-N(R1)-,  -N(R1)C(0)-N(R1)-, -N(R1)-, -〇-, -S-, -S-S-,  -0-(CH2)-, -(CH2)-0-, (〇-(C2_C3)-alkyl) n, ((C2-C3)-院基-0)n, (NiRlHCrC: alkyl), (N(Rl)C(〇MCrC6)-alkyl), (N(Rl)C(0)_N(Rl)_(CrC6)-alkyl),  (C(0)-N(Rl)-(CrC6)_alkyl), (0-C(0)-(CrC6)-alkyl),  (C(0)-0-(CrC6)-alkyl), (o-qoknkrihcvq)-alkyl),  (N(Rl)-C(0)-0-(CrC6)-alkyl), (N(R1)-(C3-C6)-cycloalkyl), (N(R1)C(0)-(C3-C6)-cycloalkyl),  96 201141513 (N(R1)C(0)-N(R1)-(C: 3-C6)-cycloalkyl),  (C(0)-N(R1)-(C3-C6)-cycloalkyl), (0-C(0)-(C3-C6)-ring hospital base), (C(0)-0-(CrC6)-cycloalkyl), (0-C(0)-N(RlHC3-C6)-cycloalkyl), (n(ri)-c(0)-0-(c3-c6)-cycloalkyl), (〇_(crc6)_alkyl-(C3-C6)-cycloalkyl)„, (N(Rl)-(CrC6)-alkyl-(C3-C6)-cycloalkyl), Pyridyl-(C3-C6)-cycloalkyl),  (N(R1)C(0)-N(R1)-(C"C6)-alkyl-(C3-C6)-cycloalkyl),  (CXCO-NCRIMCVQ)-alkyl-(C3-C6)-cycloalkyl),  (0-(^(0)-((^-06)-alkyl-(C3-C6)-cyclodyl),  (¢(0)-0-((^-(^6)-alkyl-(C3-C6)_ cycloalkyl),  (O-CXCO-^RlHCrQ)-alkyl-(C3-C6)-cycloalkyl),  (N(Rl)-C(0)-0-(CrC6)-alkyl-(C3-C6)-cycloalkyl),  (〇_(C3-C6)-i^alkyl-(C〗~C6)-Hyun) η, (N(R1)-(C3_C6)-cycloalkyl-(Ci-C6)-alkyl), (N(R1)C(0)-(C3-C6)-cyclodeptyl-(CrC^)-homo), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-(CrC^)-alkyl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-(C^-Cs)-alkyl),  (0-C(0)-(C3_C6)-cycloalkyl-(CVC6)-alkyl),  (C(0)-0-(C3-C6)-cycloalkyl-(C^-Cs)-alkyl),  (〇_C(0)-N(Rl)-(C3-C6)" Cycloalkyl-(Ci-Cg)-alkyl),  (N(Rl)-C(0)-0-(C3-C6)-·cycloalkyl-(cvc^)-alkyl),  (O-(C6-C10)-aryl)n, (Ν(ΪΠ)-((: 6-(: 1())-aryl),  (N(Rl)C(O)-(C6-C10)-aryl),  (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl),  (C(O)-N(Rl)-(C6-C10)-aryl), (o-c(o)-(c6-c10)-aryl),  97 201141513 (C(O)-O-(C6-C10)-aryl), (O-C(O)-N(Rl)_(C6-C10)-aryl), (N(Rl)-C(O)-O-(C6-C10)-aryl), (0-(CrC6)-alkyl-(CVCi. )-aryl)n, (N(R1)-(Ci_C6)-院基-(C6_Ci. )-Aryl),  (NiRUCXOMCrCy-alkyl _(C6-C10)-aryl),  (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(C6-C10)·aryl),  (C(0)-N(Rl)-(CrC6)-alkyl-(C6-C10)-aryl),  (0-C(0)-(Ci-C6)-alkyl-(C6-C1())-aryl), (€(〇)-〇-(0^-0^6)_ 烧基-(C6-Ci〇)-aryl), (0-C(0)-N(Rl)-(CrC6)-homo-(C6-C10)-aryl), (NiRU-CXCO-O-CCi-C^)-alkyl-(〇6-〇10)-aryl), (〇-(C6-C10)-aryl-(Q-Q)-alkyl)n,  (N(R1)-(C6-C10)-aryl-(q-Q)-alkyl),  (N(Rl)C(O)-(C6-C10)-aryl-(Crc6)-alkyl),  (N(R1)C(0)-N(R1)-(C6-C1())-aryl-(CrQ)-alkyl),  (C(O)-N(Rl)-(C6-C10)-aryl-(CVQ)-alkyl),  (0-C(〇HC6-C1())·aryl-(CrQ)-alkyl), (C(O)-〇-(C6-C10)-aryl-(CVQ)-alkyl), (〇_C(0)_N(R1)_(C6_Ci〇)_ aryl-(crc6)-alkyl), (N(Rl)-C(O)-〇-(C6-C10)-aryl-(CrC6)-alkyl), (o-(c3-c6)-cycloalkyl _(c6-c10)-aryl)n,  (N(R1)-(C3-C6)-cycloalkyl-(c6-C10)-aryl),  (N(R1)C(0)-(C3-C6)-cycloalkyl _(c6-C10)-aryl),  (N(Rl)C(0)-N(Rl)-(CrC6)_cycloalkyl-(C6-C10)-aryl),  (C(0)-N(R1HC3-C6)-cycloalkyl _(c6_Cl〇)-aryl),  (0-C(0)-(CrC6)-cycloalkyl _(c6_Cl〇)-aryl),  (C(0)-0-(C3-C6)-cycloalkyl _(C6_Cl〇)_ aryl),  98 201141513 (0-C(0)-N(Rl)-(C3-C6)-cycloalkyl-(c6-C10)-aryl),  (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl-(c6_Cl〇)_ aryl),  (0-(C6_Ci. ) aryl-(C3TMC6)-cycloalkyl)n, (N(R1)-(C6-C10)-aryl-(C3-C6)-cyclodendyl", (N(Rl)C(O)-(C6-C10)-aryl-(C3-C6)_cycloalkyl), (n(ri)c(o)-n(rihc6-c10)-aryl-(c3-c6)_cycloalkyl), (C(O)-N(RIH(VCh))•aryl-(c3-c6)-cycloalkyl),  (O-C(O)-(C6_C10)-aryl-(CrC6)-cycloalkyl),  (C(O)-O-(C6-C10)-aryl-(C3-C6)-cycloalkyl),  (O-C(O)-N(Rl)-(C6-C10)-aryl-(c3-c6)·cycloalkyl),  (N(Rl)-C(O)-O-(C6-C10)-aryl-(C3-C6)-cycloalkyl),  (〇-(Ci-C9)-heteroaryl)„, (lS^RlXC^-Cg)-heteroaryl),  (N(Rl)C(0)-(CrC9)-heteroaryl),  (N(R1)C(0)-N(R1)-(C, -C9)-heteroaryl),  (CXC^-NXRlXCi-Cg)-heteroaryl), ((Χ(0)_((ν〇9)-heteroaryl), ((3(0)-0-((1^-(119)-heteroaryl)), (〇-C(0)-N(Rl)-(crC9)_heteroaryl), (N(Rl)-C(0)-0-(CrC9)_heteroaryl), (〇_(Cl_c士 alkyl-(CrC9)-heteroaryl)n, (N(Rl)-(CrC6)-alkyl-(crc9)-heteroaryl), (N(Rl)C(0)-(CrC6)-homo-(CrC9)-heteroaryl),  (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(CrC9)-heteroaryl),  (CCOj-^RlHCi-Q)-alkyl-(crc9)_heteroaryl),  (O-C^OXCrQ)-alkyl-(Ci-Cp)-heteroaryl),  (0(0)-0-(0^-06)-alkyl-(C^-Cg)-heteroaryl),  (0-C(0)-N(Rl)-(CrC6)-alkyl-(CrC9)-heteroaryl),  (N(Rl)-C(0)-0·%·^)-alkyl-(CpC^)-heteroaryl),  99 201141513 (CHCrCy-heteroaryl-(CrC6)-alkyl)n, (N(Rl)-(CrC9)-heteroaryl-(Q-C6)-alkyl), (N(Rl)C(〇HCrC9)-heteroaryl-(crc6)-alkyl), (N(Rl)C(0)-N(Rl)-(CrC9)-heteroaryl-(CrC6)-alkyl), (C(0)-N(R1)-(Ci-C9)-heteroaryl-(C^-C^)-alkyl),  (o-c(o)-(crc9)-heteroaryl-(crc6)-alkyl),  (C(0)-0-(Ci_C9)·heteroaryl-(Ci_C6)-alkyl),  (0-C(0)-N(RlHC "C9)-heteroaryl-(C"C6)-alkyl),  (N(Rl)-C(0)-0-(CrC9)-heteroaryl-(CrC6)-alkyl),  (o-(c2-c9)-heterocyclyl)n, (N(R1)-(C2-C9)-heterocyclic group),  (N(R1)C(0)-(C2-C9)-heterocyclic group),  (N(R1)C(0)-N(R1)-(C2-C9)_ heterocyclic),  (C(0)-N(R1)_(C2_C9)-heterocyclic group), (o-c(o)-(c2-c9)-heterocyclic group), (c(o)-o-(c2-c9)·heterocyclic group), (o-c(o)-n(ri)-(c2-c9)-heterocyclic group), (n(ri)-c(o)-o_(c2-c9)-heterocyclic group), (o-(crc6)-alkyl-(C2-C9)-heterocyclyl)n, (N(RlHCrC6)-alkyl-(C2-C9)-heterocyclyl), (N(R1)C(0)-(C"C6)-alkyl-(c2-c9)-heterocyclyl),  (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl),  (C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl),  (o_c(o)-(crc6)-alkyl-(c2-c9)-heterocyclic group),  (c(o)-o-(crc6)-alkyl-(c2-c9)-heterocyclyl),  (0-C(0)-N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl),  (N(Rl)-C(0)-0-(CrC6)-alkyl-(C2-C9)-heterocyclyl),  (0-(C2-C9)-heterocyclyl-(CVC6)-alkyl)n, (n(ri)-(c2-c9)-heterocyclic-(crc6)-alkyl), (N(R1)C(0)-(C2-C9)-heterocyclyl-(crc6)- 100 201141513 alkyl) (νοιιαοη^ιηο^α heterocyclyl-(CrC6)alkyl), (C(0)-N(R1)-(C2_C9)-heterocyclyl _(Ci_c6)_alkyl),  (0-C(0)-(C2-C9)-heterocyclic group _(Crc6)·alkyl),  (C(0)-0-(C2-C9)-heterocyclic group _(Ci_c6)_ alkyl),  (0-C(0)-N(Rl)-(C2-C9)-heterocyclyl-(Ci_c6)_alkyl) and (N(Rl)-C(0)-0-(C2-C9)- Heterocyclyl-(crc6)-alkyl);  The L2 is selected from the group consisting of: (Ci_Ci〇)_alkyl,  (0-(C2_C3)·burning base)n, ((Q-C3)-burning base_〇)n, (c3_c6)_cyclic base,  (0-(C3-C6)-cycloalkyl)n, ((C3-C6)-cycloalkyl-〇)), (Crc6)-alkyl-(Cs-C6)-cycloalkyl, (CVC6)-cycloalkyl-Ci_c6)-alkyl,  (C6-C10)·aryl, (CVC6)-alkyl-(C6-C10)-aryl, (c6_c10)-aryl-(CrC6)-alkyl, (CrC6)·cycloalkyl-(c6-Ci〇)_aryl,  (C6-C1())-aryl-(C3-C6)-cycloalkyl, (crc9)-heteroaryl, (q-Q)-alkyl-(Ci-C9)-heteroaryl, (crC9)-heteroaryl_(Cl_c6)_alkyl,  (C3_C6)-cycloalkyl-(CrC9)-heteroaryl, (crc9)-heteroaryl-(C3-C6)-cycloalkyl, (c2-c9)-heterocyclic group, (CVC6)-alkyl-(C2-C9)-heterocyclyl, (CVC9)-heterocyclyl-(crC6)-alkyl, (c3-C6)-cycloalkyl-(C2_C9)-heterocyclyl and (C2_C9)-heterocyclyl-(C3-C6)-cyclodendyl;  X2 is a group selected from the group consisting of: _c(〇)_ ;  -O-C(O)- ;  -C(0)-0- ^ -N(R1)-C(0)- ;  -C(0)-N(R1)- ;  -S-;  -N(R1)·, And -Ο-;  101 201141513 Y is a group selected from the group consisting of: -c(o)-;  -s-;  -N(R1)-; And -N(R1)_N=;  The Z series is selected from the group consisting of: Direct key, -0-Ρ(0)(0Η)-,  (CVC). )-alkyl-0-P(0)(0H)- ,  (0-(C2-C3)-alkyl)n-0-P(0)(0H)-, ((C2-C3)-alkyl-0)η-Ρ(0)(0Η)-,  (C3-C6)-cycloalkyl-0-Ρ(0)(0Η)-, (Q-Q)-alkyl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CVC6)-alkyl -0-P(0)(0H)-, (C6-C10)-aryl-0-P(0)(0H), (CrCg)-heteroaryl-0-P(0)(0H)-, (CrC6)-alkyl-(C6-C10)-aryl-O-Ρ(0)(0Η)-, (C6-C10)-aryl-(CrC6)-alkyl -0-Ρ(0)(0Η)-, (C3-C6)-cycloalkyl-(C6-C10)-aryl-O-Ρ(0)(0Η)-, (C6-C10)-aryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (CrC6)-alkyl-(CrC9)-heteroaryl -0-P(0)(0H)- , (CVC9)-heteroaryl-(CVC6)-alkyl -0-P(0)(0H)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0-Ρ(0)(0Η)-, (CrC9)_heteroaryl-(C3-C6)-cycloalkyl-0-P(0)(0H)-, (C2_C9)_Heterocyclyl _0-Ρ(0)(0Η)-, (C2-C9)-heterocyclyl-(Q-Q)-alkyl-0-P(0)(0H)-, (C "C6)-alkyl-(C2-C9)-heterocyclyl-0-P(0)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-indole-P(〇)(〇H)-, (c3-c6)-cycloalkyl-(c2-c9)-heterocyclyl-0-P(0)(0H)- , -0-P(S)(0H)- , (CrCu))-alkyl -0-P(S)(0H)_, (0-(C2-C3)-alkyl)n-0-P(S)(0H)-, ((C2-C3)-Alkyl-0)n-P(S)(0H)-, (C3-C6)-cycloalkyl _0-P(S)(0H)-,  102 201141513 (CVC6)-Alkyl-(C3-C6)-cycloalkyl-o-p(s)(oh)-, (c3-c6)-cycloalkyl-(CVC6)-alkyl-0-P(S)(0H)-, (C6-C10)-aryl -0_P(S)(0H), (CVC9)-heteroaryl-0-P(S)(0H)-, (CrC6)-alkyl-(C6-C10)-aryl-0-P(S)(0H)-, (c6-c10)-aryl-(crc6)-alkyl-0-P(S)(0H)-, (C3-C6)_cycloalkyl-(C6-C1())-aryl-O-P(S)(0H)-, (C6-'Ci〇)-aryl-(C3-C6)-Children's base -0-P(S)(0H)- , (C "C6)-alkyl-(CrC9)-heteroaryl -0-P(S)(0H)- , (q-Q)-heteroaryl-(CrC6)-alkyl -0-P(S)(0H)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0-P(S)(0H)-, (CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(S)(0H)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(S)(0H)-, (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl-0-P(S)(0H)- and (C3-C6)-cycloalkyl-(C2-C9)-heterocyclyl -OP(S)(OH)-,  Wherein the phosphorus atom of Z is linked to the 3'- or 5'-oxygen atom of the siRNA;  d is an integer between 0 and 5;  η is an integer between 1 and 11;  q is 1;  p, r, s, The t system is 0 independently of each other. 1 or 2;  R1 is Η, (CrQ)-alkyl;  R2 and R3 are independently Η, (CrC6)-alkyl, Wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated 5- to 6-membered 103 201141513 cyclic heterocyclyl group.  In a more preferred embodiment of the invention, These groups are defined as follows:  X1 is a group selected from the group consisting of: -c(o)- and -C(0)-N(R1)-;  L1 is selected from the group included below: (CVCio)-alkyl, ((c2-c3)-burning base-0)n, ((^-(: Cycloalkyl, (Ci_c4)_alkyl_(C3_C6)_cycloalkyl, (CrC6)·cycloalkyl-(CrQ)-alkyl, (C6-C10)-aryl,  (crc4)_烧基-(c6_c]〇> ^基, (C6_Ci〇)_aryl_(Ci_C4)_^ base, (Cl_C9)_heteroaryl, (CrC4)-alkyl-(CrC^)-heteroaryl, · (crc9)-heteroaryl-(Cl_C4)_alkyl, (C2_C9)_heterocyclyl, (CrC4)_homo-(C2-C9)-heterocyclyl and (C2-C9)-heterocyclyl-(CrC4)-alkyl;  The D series are independently selected from the group included below: -C(O)-, -C(0)0-,  -O-C(O)- ,  -N(R1)-C(0)- ,  -C(0)-N(R1)-,  -N(R1)C(0)-N(R1)-, -N(R1)-, -〇-, -S-, -S-S-,  -0-(CH2)-, -(CH2)-0-, (〇-(C2-C3)-alkyl)n, ((c2-c3)-alkyl-))n, (N(Rl)-(CrC6)-alkyl), (N(Rl)C(0)-(CrC6)-alkyl), (NiRUCCC^-NCRlHCrC^)-burning base),  (C(0)-N(Rl)-(CrC6)-alkyl), (O-QOMQ-Q)-alkyl),  (C(0)-0-(CrC6)-alkyl), (O-QCO-NCRIHCVCy-alkyl),  (N(Rl)-C(0)-0-(CrC6)-alkyl), (N(R1)-(C3-C6)-cycloalkyl), (N(Rl)C(0)-(CrC6)-cycloalkyl),  104 201141513 (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl),  (C(0)-N(R1)-(C3-C6)-cycloalkyl), (〇-C(〇HC3_C6)-cycloalkyl), (c(〇)-o-(c3-c6)-cycloalkyl), (0-C(0)-N(RlHC3-C6)-cycloalkyl), (n(ri)_c(o)-o-(c3-c6)-cycloalkyl), (o-(crc6)-alkyl-(C3-C6)-cycloalkyl)n, (N(R1)-(Ci_C6)-alkyl-(C3-C6)-cycloalkyl), (NCRUCXOHCrQ)-alkyl-(C3-C6)-cycloalkyl),  (N(Rl)C(0)-N(Rl)-(CrC6)_alkyl-(C3-C6)-cycloalkyl),  (C(0)-N(Rl)-(CrC6)-alkyl-(C3-C6)-cycloalkyl),  (o-cxoHCrQ)·alkyl-(c3-c6)-cycloalkyl),  (CCCO-CKCrC^)-alkyl-(C3-C6)-cycloalkyl),  (O-CXC^-NiRlHCrC^)-alkyl-(c3-c6)-cycloalkyl),  (IsKRU-CCOi-CKQ-Cy-alkyl-(c3-c6)_cycloalkyl),  (0-(C3-C6)-cycloalkyl-(CrQ)-alkyl)n, (N(R1)-(C3-C6)-cycloalkyl-(crc6)-alkyl), (N(R1)C(0)-(C3-C6)-cycloalkyl-(Q-C6)-alkyl), (N(R1)C(0)-N(R1)-(C3-C6)-cycloalkyl-(crc6)-alkyl), (C(0)-N(R1)-(C3-C6)-cycloalkyl-((VC6)-alkyl),  (o-c(o)-(c3-c6)-cycloalkyl-(crc6)-alkyl),  (c(o)-o-(c3-c6)·cycloalkyl-(crc6)-alkyl),  (0-C(0)-N(Rl)-(C3-C6)_cycloalkyl-(crc6)-alkyl),  (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl-(Ci-Q)-alkyl),  (O-(C6-C10)-aryl)n, (N(R1MC6-C10)-aryl),  (N(Rl)C(O)-(C6-C10)-aryl),  (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl),  (C(O)-N(Rl)-(C6-C10)-aryl), (O-C(O)-(C6-C10)-aryl),  105 201141513 (C(O)-O-(C6-C10)-aryl), (O-C(O)_N(Rl)-((VC10)-aryl), (N(Rl)-C(O)_〇-(C6-C10)-aryl), (CKCrQ)-alkyl-(C6-C1())-aryl)n, (N(Rl)-(CrC6)-alkyl-(C6-C1G)-aryl),  Pyridyl-(C6-C10)-aryl),  (N(Rl)C(0)-N(Rl)-(CrC6)-alkyl _(C6-C10)-aryl),  (CXC^-ISIXRIXCVQ)-alkyl-(C6-C10)-aryl),  (0-0(0)-((^-(^)-alkyl-(C6-C10)-aryl), (匚(0)-0-((^-(1: 6)-alkyl-(C6-C10)-aryl), (〇-C(0)-N(Rl)-(CrC6)-alkyl-(C6-C1())-aryl), (N(Rl)-C(0)-0-(CrC6)-alkyl-(C6-C10)-aryl), (〇-(C6-C10)-aryl-(CrQ)-alkyl)n,  (N(R1)-(C6-Ci〇)-aryl-(CVQ)-alkyl),  (N(Rl)C(O)-(C6-C10)-aryl-(CrCe)-based),  (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl-(CrC^)-alkyl),  (C(O)-N(Rl)-(C6-C10)-aryl _(crc6)-alkyl),  (O_C(O)-(C6-C10)-aryl-(Crc6)-; J^A), (C(O)-〇-(C6-C10)-aryl-(c"c6)-alkyl), (〇-C(O)-N(Rl)-(C6-C10)-aryl-(CrQ)·alkyl), (N(Rl)-C(O)-O_(C6-C10)-aryl-(crC6)-alkyl), (0-(C3-C6)-cycloalkyl-(C6-Ci〇)-aryl)n,  (N(R1)-(C3_C6)-cycloalkyl-(C6-C1())-aryl),  (N(R1)C(0)-(C3-C6)-cycloalkyl-(C6-C10)-aryl),  (N(R1)C(0)-N(R1)-(C3-C6)-cyclodecyl-(C6-Ci〇)-aryl),  (C(0)-N(R1)-(C3-C6)-cycloalkyl-(C6-C10)_aryl),  (0-C(0)-(C3_C6)-cyclic ring base-(C6-C10)-aryl),  (C(0)-0-(C3-C6)-cycloalkylaryl),  106 201141513 (◦-C(0)-N(R1)-(C3-C6)·cycloalkyl-(C6-C10)-aryl),  (N(Rl)-C(0)-0-(C3-C6)-cycloalkyl-(C6-C10)-aryl),  (0_(C6-Ci. )-aryl-(C3-C6)-cycloalkyl)n, (N(R1)-(C6-C10)-aryl-(c3-c6)-cycloalkyl), (n(ri)c(〇hc6_c10)-aryl-(c3-c6)-cycloalkyl), (N(Rl)C(O)-N(Rl)-(C6-C10)-aryl-(C3_C6)_cycloalkyl), (C(O)-N(Rl)-(C6-C10)-aryl-(C3-C6)-cycloalkyl),  (O-C(O)-(C6-C10)-aryl-(c3-c6)-cycloalkyl),  (C(〇)-O-(C6-C10)-aryl-(C3-C6)-cycloalkyl),  (O-C(O)-N(Rl)-(C6-C10)-aryl-(c3-c6)-cycloalkyl),  (N(Rl)-C(O)-O_(C6-C10)-aryl-(C3-C6)-cycloalkyl),  (0-(CrC9)-heteroaryl)n, (N(Rl)-(CrC9)-heteroaryl),  (N(R1)C(0)-(C]-C9)-heteroaryl),  (N(Rl)C(0)-N(Rl)-(CrC9)-heteroaryl),  (CXC^-N^RlXCrC^)-heteroaryl), (O-CCOXCVCg)-heteroaryl), (c(o)-〇-(crc9)-heteroaryl),  Heteroaryl), (ISKRU-CXCO-CKCi-Cg)-heteroaryl), (〇-(crc6)-alkyl-(CVC9)-heteroaryl)n, (N(Rl)-(CrC6)-alkyl-((VC9)-heteroaryl), (N(Rl)C(〇HCrC6)-alkyl-(Crc9)-heteroaryl),  (N(Rl)C(0)-N(RlHCrC6)-alkyl-(crc9)-heteroaryl),  (C(0)-N(Rl)-(CrC6)-alkyl-(crc9)-heteroaryl),  (0-0(0)-((^-06)-alkyl-(cvc9)-heteroaryl),  (^(0)-0-(0^6)-alkyl-(crc9)-heteroaryl),  (O-CCCO-NiRlHCrQ)-alkyl-(CVC9)·heteroaryl),  0^(^)-(^(0)-0-((1^-06)-院基_(C〗-C9)-heteroaryl),  107 201141513 (0-(CrC9)-heteroaryl-(CrC6)-alkyl)η, (N(Rl)-(CrC9)-heteroaryl-(Q-C6)-alkyl), (N(Rl)C(〇MC“C9)-heteroaryl-(crc6)-alkyl), (N(Rl)C(0)-N(Rl)-(CrC9)-heteroaryl-(Ci-Q)-alkyl), (CXCO-NCRIHCrCy-heteroaryl-(CVQ)-alkyl),  (o-c(〇HCrc9)-heteroaryl-(CVC6)-alkyl),  ((: (0)-0-((^-(: 9)-heteroaryl-(Ci-CA alkyl),  (0-C(0)-N(RlHCrC9)-heteroaryl-(crc6)-alkyl),  (1^(111)-(: (0)-0-((^-(: 9)-heteroaryl-(CVC6)-alkyl),  (o-(c2-c9)-heterocyclyl)n, (N(R1)-(C2-C9)-heterocyclic group),  (N(R1)C(0)-(C2-C9)-heterocyclic group),  (N(R1)C(0)-N(R1)-(C2-C9)-heterocyclic group),  (C(0)-N(R1HC2-C9)-heterocyclic group), (〇-c(o)-(c2-c9)-heterocyclic group), (c(o)-o-(c2-c9)-heterocyclic group), (〇-c(o)-n(ri)-(c2-c9)_ heterocyclic group), (n(ri)-c(o)-o-(c2-c9)-heterocyclic group), (o-(crc6)-alkyl-(C2-C9)-heterocyclyl)n, (N(Rl)-(CrC6)-alkyl-(C2-C9)-heterocyclyl), (NCRliCXOHCVC^)-alkyl-(c2-c9)-heterocyclyl),  (NiRUCCC^-NiRlHCrQ)-alkyl-(C2-C9)-heterocyclic group),  (C(0)-N(R1)-(C"C6)-alkyl-(c2-c9)-heterocyclyl),  (O-C^OHCi-Q)-alkyl-(c2-c9)-heterocyclyl),  (c(o)-o-(crc6)-alkyl-(c2-c9)-heterocyclyl),  (0-C(0)-N(RlHC "C6)-alkyl-(c2-c9)-heterocyclic group),  (N(Rl)-C(0)-0-(CrC6)-alkyl-(c2-c9)-heterocyclyl),  (0-(C2-C9)-heterocyclyl-(CrQ)-alkyl)η, (n(ri)-(c2-c9)-heterocyclic group-(CVC6)·alkyl group), (N(R1)C(0)-(C2-C9)-heterocyclyl-(crc6)- 108 201141513 alkyl), (N(R1)C(0)-N(R1)_(C2-C9)-heterocyclyl-(crc6)·alkyl), (C(0)-N(R1)-(C2-C9)-heterocyclylalkyl),  (0-C(0)-(C2-C9)-heterocyclyl _(crc6)_ alkyl),  (C(0)-0-(C2-C9)-heterocyclyl _(crc6)-alkyl),  (0-C(0)-N(RlHC2-C9)-heterocyclyl-(crc6)-alkyl) and (N(Rl)-C(0)-0-(C2-C9)-heterocyclyl- (qQ)-burning base);  The L2 is selected from the group consisting of: (Ci_Ci〇)_alkyl,  (〇-(c2-c3)_ burning base) n, ((C2-C3)-alkyl--0)n, (c3-c6)-cycloalkyl,  (0-(C3_C6)-cycloalkyl)n, ((CrQ)-cycloalkyl _〇)n,  Base - (Cs-C: 6)-cycloalkyl, (CrC6)-cycloalkyl-(crc6)-alkyl,  (C6_c10)-aryl, (crc6)-alkyl-(C6-C10)-aryl, (C6-C10)-aryl-(CrC6)-alkyl, (CrC6)-cycloalkyl-(c6_c10)-aryl,  (c6-c1())-aryl-(c3-c6)-cycloalkyl, (crc9)-heteroaryl, (CrCJ-alkyl-(CrC9)-heteroaryl, (CrC9)-heteroaryl_(crc6)-alkyl,  (C3_Q)-cycloalkyl-(CrC9)-heteroaryl, (crc9)_heteroaryl-(c3-c6)-cycloalkyl, (c2-C9)·Heterocyclyl, (crc6)-alkyl-(c2_c9)_ heterocyclyl, (CVC9)-heterocyclyl-(q-C6)-alkyl, (C; H: 6) _cycloalkyl-(C2-C9)-heterocyclyl and (C2-C9)-heterocyclyl-(C3-C6)-cycloalkyl;  X2 is a group selected from the group consisting of: -C(〇)·;  -C(0)-0-, _C(0)-N(R1)-; And -S-;  Y is a group selected from the group consisting of: _S_&_N(R1)_;  109 201141513 Z series are selected from the following groups: Always key, -0-P(G)(0H)-,  (CrC). )-alkyl-0-P(G)(0H)- ,  (0-(C2-C3)-alkyl)n-0-P(G)(0H)-, ((C2-C3)-alkyl-0)n-P(G)(0H)_,  (C3-C6)-cycloalkyl-0-P(G)(0H)-, (CrC6)-alkyl-(C3-C6)-cycloalkyl-0-P(G)(0H)-, (C3-C6)-cycloalkyl-(CrC6)-alkyl -0-P(G)(0H)-, (C6-C10)-aryl-0-P(G)(0H), (CrC6)-alkyl-(C6-C10)-aryl-0-P(G)(0H)-, (C6-C10)-aryl-(CVQ)-alkyl-0-P(G)(0H)-, (C3-C6)-cycloalkyl-(C6-C1())-aryl-O-P(G)(0H)-, (C2-C9)-heterocyclyl-0-P(G)(0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(G)(0H)-, (CVQ)-alkyl-(C2-C9)-heterocyclyl-0-P(G)(0H)-,  Wherein the phosphorus atom of Z is attached to the 3'- or 5'-oxygen atom of the siRNA strand and G is oxygen or sulfur;  d is an integer between 0 and 3;  η is an integer between 1 and 11;  q is 1;  p, r, s, The t series are independently 0 or 1;  R1 is Η, (CVC3)-alkyl;  R2 and R3 are independently Η, (CVC6)-alkyl, Wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated 5- to 6-membered monocyclic heterocyclyl group.  In general, Any of the 110 201141513 groups that may occur more than once in the compound of formula I, Residues, Hetero atom, Numbers, etc. (4), And this group that appears in any other place, Residues, Hetero atom, The meaning of numbers and the like is irrelevant.  Any group that can occur more than once in a compound of formula I, Residues, Hetero atom, Numbers, etc. may be the same or different.  The term alkyl as used herein is understood in its broadest sense. Means linear, That is, a linear or branched hydrocarbon residue. Furthermore, The term alkyl as used herein, includes saturated groups as well as unsaturated groups. Wherein the unsaturated group may contain one or more, For example, Two or three double and/or 叁 keys, However, the limitation is that the double bond cannot be located in the j smoldering base in the form of a square scent. All of these expressions can also be used when an alkyl group is present as a substituent or as an additional residue. For example, an alkoxy residue, In an alkoxycarbonyl residue or an aralkyl residue. Containing work,  2, 3, 4, 5'6, Examples of alkyl residues of 7 or 8 carbon atoms are sulfhydryl groups, Ethyl, Propyl, Butyl, Amyl, Hexie, Heptyl or octyl,  The n-isomer of all these residues, Isopropyl, Isobutyl, ^曱基丁基, Isoamyl, Neopentyl, 2, 2-dimercaptobutyl, 2-decylpentyl,  3. Methyl amyl, Alien group, Second butyl, Third butyl (tBu), Third pentyl, Second butyl, Third butyl or third pentyl.  Unsaturated alkyl residue, For example, an alkenyl residue such as a vinyl group, 1_ propyl base, 2-propanyl (=dilyl), 2-butadiene, 3-butyl base, 2-mercapto-2-butenyl, 3-mercapto-2-butenyl, 5-hexyl or 1, 3-pentadienyl, Or an alkynyl residue, such as an ethynyl group, 1-propynyl, 2-propyl block (= fast propyl), 2-butynyl, 5-hexynyl. The alkyl group residue may also be unsaturated when it is substituted. Unsaturated residues must contain at least two carbon atoms 111 201141513. therefore, Such as (crcs)-alkyl groups should be understood to include, Including, Saturated acyclic (CrC8)-alkyl, And an unsaturated (C2_C8)-alkyl group such as (CVC8)-alkenyl or (c^8)-alkynyl. Similarly, a group such as (CrC4)_alkyl, It should be understood that the department includes, Including, Saturated acyclic (CrC4)-alkyl, And an unsaturated (CVC4)-alkyl group such as (CVC4)-alkenyl or (C2_C4)-alkynyl.  Unless otherwise stated by S, Otherwise the term alkyl is preferably a non-cyclic saturated hydrocarbon residue having from one to ten carbon atoms and which may be straight or branched. The group of a particular saturated acyclic alkyl residue is formed by a (Crc6)-alkyl residue. Such as methyl, Ethyl, N-propyl, Isopropyl, N-butyl, Isobutyl, Second butyl and tert-butyl, N-pentyl, Isoamyl,  Is the base.  The term cycloalkyl as used herein, It is understood in its broadest sense to mean a cyclic or polycyclic hydrocarbon residue containing at least three carbon atoms. Again, As used herein, the term cycloalkyl includes both saturated groups and unsaturated groups. Wherein the unsaturated group may contain one or more, For example, Two or three double and/or 叁 keys, However, it is limited that the double bond cannot be located in the cycloalkyl group in a manner to form an aromatic system. In addition, As used herein, the 5 Å alkyl group includes polycyclic hydrocarbon residues having complex geometries, For example, adamantyl, A sulfhydryl group and a naphthenic link.  Examples of cycloalkyl residues include 3. 4, 5\^ Residues of the solid ring carbon atom such as cyclopropyl, Cyclobutyl, Cyclopentyl or cyclohexyl, It can also be substituted or unsaturated. Subtracting the (iv) cyclic group or the ring and the alkyl group such as, For example, cyclopentene or cyclohexene, It can be bonded via any carbon atom 112 201141513.  h = otherwise stated' otherwise it is in the definition of the compound of formula I: Any specific substituent bonded to a ruthenium or a cycloalkyl group, The dialkyl group and the alkyl group may generally be unsubstituted or one or more, For example, Linggan or a substituent of the same or different is substituted. Exist in substituted, , yuan: Or any of the oxime substituents of the % silk residue t may be present at the position of any of the slaves, with the proviso that the substitution does not form an unstable / knife. One or more of the real money that was replaced by Wei Chengji. 1 to 2 or 3 hydrogen atoms are bonded to a halogen atom 'specifically a fluorine atom' or a cycloalkyl residue. There are one or more of the substituted alkyl or cyclic alkyl residue. 2 or 3 hydrogen atoms 2 = work this base (·〇Η), An alkyl or cycloalkyl residue substituted with a carboxylic acid functional group (-(7)(tetra) or amidino group such as W-NHC(0)Me.  Means that at least one of the carbon rings has a total light π electron =, , , The + or polycyclic hydrocarbon residue is added thereto. Preferred aromatic residues are (C6-CI4)-aryl residues in which up to 14 ring carbon atoms are present.  (C6_C14) • Examples of aryl residues are phenyl, Naphthyl, Biphenyl, Foundation  Huiji, Tetrahydronaphthyl, •• or p, Hydronaphthalene shouting, Dihydrogenation group, Second ceremony Γ two: Base human r-hydrogen-2-keto group. Unless otherwise indicated; In the formula 1 & Mosquito Moss #巾是财指纽纽 Specific substituent 'aryl residue, Such as phenyl, Cai Ji or Li = as unsubstituted or one or more, For example, two, three,  Substituted with the same or different substituents. The aryl wire can be bonded via any position = phase. Any substituent present in the residue of the silk may be present. 113 201141513 The condition is that the substitution does not form instability, Otherwise, whether in the formula of the compound of formula 1, "has any substituent with an aryl group - rC 'c t on the substituted aryl group, E.g : Especially (Cl_C4) - yard base, Called alkoxy,  ^Do not lick...from the oxy group, (Cl_C technology based thiol, halogen, Shi Xiao = amine base, —((CrC4)·alkyl) alkylamino group such as an ethylamine group, Trifluorotide, Trifluoromethoxy, Base, Side oxy, _p(0)_ph2 Hydroxy • (CrC4)-alkyl group, such as hydroxymethyl or μethyl or lanyl,  : : Dioxy, Ethylenedioxy, 曱醯基, Ethyl group, Cyano group, Amine Methyl feldspar, After several bases, Amine group, (Cl_C4)_^ ethoxylated thiol group, Substituted phenyl, if necessary a substituted phenoxy group, If necessary, in the phenyl-based JU substituted group, A oxy group or the like which is substituted with a phenyl group as needed. These substituents may be present in any desired position' with the proviso that they are required to form a stable molecule. a substituted (tetra) aryl group at a specific position of the compound of formula 1 may be present, Independent of the other groups, it may be substituted with a substituent selected from the substituent subgroups listed above and/or listed in the definition of the group. E.g, The substituted aryl group may be substituted by - or a plurality of substituents selected from the group consisting of: (CrC4)-alkyl, Hydroxy, (Ci_c4)_alkyloxy' F,  C1 Br, I, Cyano group, Nitro, Trifluoromethyl, Amine, Stupid, Benzyl, Phenoxy and benzyloxy.  The term heteroaryl refers to one or more of the ring carbon atoms being, for example, nitrogen, An aryl residue in which a hetero atom of oxygen or sulfur is substituted. E.g, The term heteroaryl Π4 201141513 base core (C5_CM)-aryl, Of the 5 to M ring carbon atoms - or more, The child is, for example, nitrogen, The hetero atom of oxygen or sulfur is replaced. Examples are azaindene, azocinyl, Benzimidazolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzocarbazolyl, Benzothiazolyl, Benzotriazole, Benzotetrazolyl, Benzoisoxazolyl,  This is different, Benzopyrene Sitting on the ground, Leaf sputum,  π Kalinji, 咣基, Terpene, Porphyrin group, Dehydroquinolinyl,  2611-11, 5, 2-dithiaphthyl, Dihydrofuran [2, 3_15]_tetrahydrofuran,  Furanyl, Furfuryl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1Η_ carbazolyl, Porphyrin group, 吲耕基, 吲哚基' 3Η_吲哚基, Isobenzofuranyl, Heteroquinone Isoxazolyl, Isoindolyl, Heteroquinone group, Isoquinolinyl (benzimidazolyl), Isothiazolyl, Isoxazolyl, 喑 pyridine, Octahydroisoquinolinyl, Oxadiazolyl, u, 3_oxadiazolyl, i, 2, 4_ oxadiazolyl, 1, 2, 5-oxadiazolyl, ^, Table oxadiazolidine, Oxazolidine,  Sputum Acridine, Pyrimidinyl, Phenyridinyl, Morpholinyl, Morphin,  Succinyl Phenyl thiol, Brown cultivating base, 呔耕基, Piper, Piperidinyl, Acridine, 嘌呤基, Piperidyl, Pyrolysis base, Pyrazolyl group,  °°°坐琳基, Yan Junji, Flu morphine, 2H-CT荅σ well-3-keto-based, He bites and drinks azole, Pyridoimidazolyl, Pyridothiazolyl, Pyridyl group, Pyridyl group,  Pyrimidinyl, ° specific porphyrin group, 2Η-吼基基, Pyrrolyl group, Quinazolin,  Quinolinyl, 4 quinolinyl, Quinoxalinyl, Acridine, Tetrahydroisoquinolinyl, Tetrahydropyrene Four tillage, 1, 2, 3_three tillage, 丨#-三耕基,  1, 3, 5-3 11 well base, 6H-l, 2, 5. . n stopper base, sputum, i, 2,3_β stopper diazolyl, 1,2,4-. Sesazolyl, 1,2,5-oxadiazolyl, U4. Oxadiazolyl, 115 201141513 1,2,3-triazolyl, 1,2,4-triazolyl and anthracenyl. Preferred are: pyridyl; for example, 2-° ratio, 3 β ratio π-group or 4-° ratio; D ratio σ groups; for example, 2-° ratio group and 3-σ ratio group a thiol group; for example, a 2-mercapto group and a 3-fluorolanyl group; a thienyl group; for example, a 2-thienyl group and a 3-thienyl group; an imidazolyl group, a pyrazolyl group, an uf α-based group, an iso-β-based group, <7 syllidyl, iso-salt base, tetra-sigma base.荅13 well base, 11 ratio σ well base, σ dense bite base, sulfhydryl group, isoindole D, benzofuranyl, benzothiazolyl, 1,3-benzodioxole Alkenyl, carbazolyl, benzo-flavored a-sodium, benzo-salt, benzo. Seyuki, 啥琳基, 喧琳基基, bite base, different bite base, η幸. Lin Ji, swearing. Lin Ke, Yan. Linji, blown σ well base, ° ratio ° and σ m β seat base, 11 bite and bit. It is more than a bite base, a ratio of σ, a pyridine group, a fluorenyl group, an acridinyl group, a 1,2,3-triazolyl group, and a 1,2,4-triazolyl group. The heteroaryl residue can be bonded via any ring carbon atom and, in the case of a nitrogen heterocycle, via any suitable ring nitrogen atom. Thus, for example, the σ ratio ρ base residue may be 1-. Biromyl, 2-. The pyrrolyl or 3-pyrrolyl group; the acridinyl residue may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl. The furyl group may be a 2-furyl group or a 3-11-folyl group; the σ-s-enyl group may be a 2-11-thenyl group or a 3-17-thenyl group; -2-base, microphone. Sodium-4-yl or 11 m sal-5-yl; 1,3-oxazolyl can be 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-quinone Zyridin-5-yl; 1,3-thiazolyl can be 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl; triazolyl can be 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazole-1- 1,1,2,4-triazin-3-yl, 1,2,4-tri-[sodium]-5-yl; ° dense bite base can be ° dense 11--2- base, '3 dense bite-4 - base (=6-mouth bite base) or 5-mouth. Set the foundation. It is called 朵 基 基 116 116 朵 朵 -1- base, 116 201141513 base or 吲哚-7-based. Likewise, benzimidazolyl, benzoxazolyl and benzothiazolyl residues can be bonded via a 2-position and via any of the 4, 5' and 7 positions. The quinolinyl group may be quinoline-2-yl, quinolyl, oxalin-4-yl " 奎琳-5-yl, 喧琳_6_基, 噎琳_7_基 or 噎琳_8_ The isoquinolinyl group can be isoquinolin-1-yl, isoquinoline-3-yl, isoquinoline_4_^, isoquinolin-5-yl, isoquinolin-6-yl, isoquinoline _7_yl or isoquinoline _8_^. In addition to the position of the phase through the quinolinyl and isoquinolinyl groups, the 1,2,3,4-tetrahydroindenyl group and the 12,3,4-tetrahydroisoquinolyl group can also be respectively The gas atoms are bonded via a 1-position and a 2-position. Unless otherwise stated, whether or not any particular substituent bonded to the heteroaryl group or any other heteroaryl group is indicated in the definition of the compound of formula I, the heteroaryl group may be unsubstituted Or one or more of the ring carbon atoms, for example one, two, three, four or five identical or different substituents such as (crC8)-alkyl, especially (Cl_C4)-alkyl, (CrQ)- Phenyloxy' in particular (CrQ)-alkyloxy, (Ci_C4)-alkylthio, halogen, nitro, amine, ((CrC4)-alkyl)carbonylamino such as ethylamino , trifluoromethyl, trifluoromethoxy, hydroxy, thio-(C1-C4)-alkyl group such as hydroxymethyl or 1-ethyl or 2-ethyl, methylenedioxy, sub Ethylenedioxy, fluorenyl, ethanethio, cyano, aminosulfonyl, decylsulfonyl, hydroxycarbonyl, amine carbonyl, (CrC4)-alkyloxycarbonyl, optionally substituted benzene The base is optionally substituted with a phenyloxy group, a benzyl group which is substituted at the phenyl group, a benzyloxy group which is substituted at the stupid group, and the like, if necessary. These substituents may be present at any desired position, with the proviso that a stable molecule needs to be formed. Substituents 117 201141513 are linked to form a cyclic structure which may or may not be a heterocyclic aryl group. Each of the suitable ring nitrogen atoms may independently be unsubstituted: also, with a hydrogen atom, or Substituted, that is, a substituent having a substituent such as (Cii p alkyl group such as (QQ)-alkyl group such as fluorenyl or ethyl group, phenyl group to be substituted by 8 phenyl group, phenyl-(CVC4)-alkyl group , for example, a benzyl group, optionally substituted on a stupid group, a hydroxy-(6)/saltyl group such as 2-hydroxyethyl, a fluorenyl or an additional fluorenyl group, a methylsulfonyl group or another a sulfonyl group, an amine carbonyl group, a (Ci-C:4)-alkyloxycarbonyl group, etc., and a nitrogen heterocycle in the compound of the formula I may also be present in the N-oxidized or quaternary class. The substituted heteroaryl having a specific position of the compound of Formula 1 may, independently of other groups, be selected from the substituents of any of the desired substituent subgroups listed above and/or listed in the definition of 2^ Substituting (azidne), tetrahydronitride, pyrrole, pyrrolidine, imidazole pyrazole, m triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyridin, iota, 2,3·' Three tillage, 1,2,4- Plough, i, 3, 5 - three tillage, four tillage, tetrazole, nitrogen call, biguanide = diazirine, guanidine, 2-diazepine, 1,3-diazepine, M_diazepine , 塔口井,派. 定"底0井" 嘻 纲 “ " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " Monocyclic or polycyclic, saturated or partially saturated residue. The term heterocyclyl includes saturated or partially saturated residues which are taken from the above heteroaryl residues or a partially or fully hydrogenated analog thereof and, if appropriate, It is more highly unsaturated similarly. In addition, it includes monocyclic or polycyclic, saturated or partially saturated filaments containing carbon and heteroatoms such as nitrogen, oxygen or sulfur, which do not have aromatic heteroaryl analogs, including For example, nitrogen and zinc ziddine).丫丙因 118 201141513 Dioxolyl, carbazole, isoxazole, 2-isoxazoline, iso. Equivalent to Ma Fulin, Ethylene Ethylene, Oxaziridine, 1,3_: Oxeene, 1,2-Ploughing, alfalfa, 呤 呤, 丨, 4_呤耕, Oxygen and Nitrogen Yuan thiophene, thiopyran, thiophene, thiazole, isothiazole, isothiazoline, iso-sodium. 1,1,2-oxothiolane, oxime, 〗 2, 2_α, 3, thiazole, ifr, arsenic, sulphide , benzofuran, benzothiofuran, stupid thiophene, benzoxazole, benzo. Sesa, benzotriene, benzoparidal, benzopyrene, benzopyrene, alpha card saliva, 4aH "card saliva", "kalin, 0 grams, butyl, roaring, dechlorination 61^1,5,2-one sigh, dihydrogen. Furan[2,3_|?]_tetrahydroethylene, furan, furazan, imidazolium, imidazoline, imidazole, 1H_carbazole, anthracene Porphyrin "bow, well, ten, 3H, flower, isobenzopyrene, different bite base, different π lead saliva, different ah, different, heterogeneous (benzoic, hollyline, = hydrogen The difference between the two wow side two 嗤, 5-sal, l, 3'4_g two saliva, $ money, - set, ten sit bite, bite, morphine, well, brown, brown ^ ^ "ah, Blowing d well, 喋口疋, 嗓呤 "Thank the bite base, 吼嗤琳, 2Η_σ荅〇井_3_网... than the pyridine and ten sit, (four) and ^, material and shoot the heart f tetrahydro (four) 'four (4) Four two =, 3-two _, 1, 2, 4» three. Well, well, 6H], 2, 5 orders. Well, azole, 1,2,3-thiadiazole, u, 'thio Diazoles, oxadiazoles, stilbene, 1f3, tris, 1,2,4, sorrel, and the name of the heterocyclic ring listed in some kneads are unsaturated or aromatic chemical names. This fact is not meant to be miscellaneous The ring group can only be derived from the unsaturated ring system of individual 119 201141513. These names are used only to describe the ring size and the number of heterocycles associated with the ring system and their relative positions. An aryl residue analog from which the following groups can be derived, examples of which may be mentioned: pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine, anthracene , dioxolane, 2·imidazole, imidazolium, 4,5-dihydro-u-thiazole, 1,3- 口. Sit, full hydrogen brigade 4, all hydrogen-1,4-10 wells ( = 5琳)王虱14-°塞。 Well (=. 塞福福琳), all hydrogen and nitrogen, 吲口朵"^丨木琳, 1,2,3,4_tetrahydroquinoline, ^ 3,4-tetrahydroquinoline, etc., the b, w ^ group can be bonded via any ring carbon atom, and the aziridine 2: through which ring nitrogen atom is suitable for bonding. The pyrrole=residue may be a small base of the bite (4) (4), and the residue of the scale may be a base of the base (^4 ° (well base = material base) or material-2-based. Preferred embodiments include a filature base, a soil and a concrete喃基,吗尹说其,基十3-^.- Better, base, tetrahydro-iso-tine. Unless otherwise stated, otherwise m ^ 唆 · · 2,5 · Is there any indication of any Miscellaneous: in the definition of 11 compounds, the specific substitution of the bond of the group, the two or two other heterocyclic ring carbon atoms through - or more;, : = circle: is not taken: Or a different substituent to replace four or five phases (one base, (C'-c fluorenyl) specifically ^ 120 201141513 base, (crC4)-alkylthio, halogen, nitro, amine, (Ci_C4 — —alkyl”carbonylamino group such as etidylamino, trifluoromethyl, trifluoromethoxy, pendant oxy, hydroxy, hydroxy-(CrC4)-alkyl, such as hydroxy hydrazino or _ hydroxyl Or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, decyl, ethenyl, cyano, aminosulfonyl, decylsulfonyl, hydroxycarbonyl, amine (CrC4)-alkyloxycarbonyl, optionally substituted, phenoxy optionally substituted, optionally substituted in the phenyl group, optionally substituted at the phenyl group Benzyloxy and the like. These substituents may be present at any desired position, with the proviso that a stable molecule is formed. Each of the suitable ring nitrogen atoms in the heterocyclyl group may each independently be unsubstituted, that is, carry a hydrogen atom, or may be substituted, that is, have a substituent such as (CrC8)-alkyl, for example ((^ (^^ alkyl, for example, fluorenyl or ethyl, optionally substituted phenyl, phenyl-(C1_C4)-alkyl, such as benzyl, optionally substituted on phenyl group, hydroxy-(C2_C4) -alkyl such as 2-hydroxyethyl, ethyl hydrazino or another fluorenyl group, fluorenyl sulfonyl or another sulfonyl group, amine carbonyl, (CrC4)-alkyloxycarbonyl, etc. The nitrogen heterocycle in the compound of formula I may also be present as an N.oxide or a quaternary salt. The ring sulfur atom may be oxidized to a sulfoxide or a sulfone. Thus, the tetrahydroanthracene residue may be hydrogen-porphinyl. Existence, or sale of a morpholino residue such as thiafipoline _4_ group may be present in the oxime-oxo-thiafolinol group or the U-dioxy-thiafolfolium _4- group. The (tetra)heterocyclyl group at a particular position, independently of its silk, may be substituted with a substituent selected from any of the desired substituent subgroups listed above and/or listed in the definition of the group. The term "siRNA" as used herein, when used in connection with the present invention, encompasses oligomers comprising or containing ribonucleotides which are capable of regulating gene expression by RNA interference. They may also extend to precursors containing ribonucleotides.    钿 钿 钿 钿 需 需 需 需 需 需 需 需 需 需 需 需 需 § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § dsRNA), DICER-based dsRNA, iT--RNA (miRNA) and short hairpin RNA (shRNA) molecules. Furthermore, it covers that these oligomer types are partially or wholly, well known to those skilled in the art. The method is modified to improve its properties, such as stability, affinity, gene expression regulation, cellular uptake, selectivity, etc., with the proviso that these modifications do not significantly interfere with the oligomer's performance of down-regulating specific target proteins by the RNAi mechanism. , or the ability of a non-activated oligomer to act as an enzyme matrix, wherein the non-activated oligomer forms an oligomer that can be activated by down-regulating the expression of a specific purine protein by the octopus mechanism . The type and extent of the desired effect of the specific properties are well known in the art. For example, a decanted 2 sugar nucleotide can be incorporated into a specific position. An example is a modification of the internucleotide phosphate bond. By, for example, phosphorothioate, dithiophosphoric acid ester, phosphoniumamine, alkyl- and aryl-phosphonate, borane phosphonate base ring, and various defilling linkages, for example (not Limited to) carbonic acid, slow, beautiful, amino acid ester, amine phthalate, thioether, sulfonate, sulfonamide, hydrazine, arylene imine, methylene methyl imine ( MMI), fluorenylene dimethyl hydrazide I (MDH), fluorenyl methoxy thioimine, urea, sulfhydryl, ribose hexadiene 122 201141513 acid and decylamine. Another example of a modification that can be incorporated into an oligomer is the modification of a sugar group of a nucleoside unit. These include 2,-〇-4,-C-anthracene ribose, unlocked nucleic acid (UNA), 2,-deoxy-2,_fluoro-β-d-arabinose, 2,-0-alkyl- Ribose, 2'-0-diluted 6-ribose, 2,_〇_(2_deoxyethyl)-ribose, 2'-0-(2-hydroxyethyl)-ribose, 2,-〇-( 2-Aminoethyl)-ribose, 2,-deoxy-2'-amino-ribose, 2'-deoxy-2,-fluoro-ribose, 4,-thioribose, 5·-deoxy-5 '-Amino-ribose, 2',5,-dideoxyamino-ribose, 5,-deoxy-5'-sulfo-ribose, 2',5,_dideoxy-5,-mercapto Ribose, 5, carboxy-ribose, 5'-drum-2'-deoxyribose and others. Introduction of a suitably modified sugar, such as a terminal nucleotide containing a 5,-modified ribose derivative, can be introduced into a functional group, such as an amine group, a thiol, an acid, a ketone or a carboxylic acid group, which can be used to oligomerize It is linked to other groups such as linkers, labels and other functional groups with improved properties. Yet another example of a modification that can be incorporated into an oligomer is the modification of a nucleobase of a nucleoside unit. In addition to common naturally occurring bases such as adenine, guanine, cytosine, thymine, uracil, etc., any other assay includes microRNA-based or non-naturally occurring examples such as phenyl, naphthyl , difluorobenzhydryl, 3_nitropyrrole, $ 啊 啊, 嗓吟, * 定 _, ♦ 定 _2, sham ♦ ♦ nuclear bitter, 5: C block urinary (four), 2 _ Sulphur urinary tract, 2 • sulfur thymus (4), 4 thiouracil, 4-thiothymidine, 8_(2_amino-ethoxylated sarcasm (8) oxygen #9·triazinone (6) clip ^- brewing Diterpenoid, 2-aminopurine, 2,6-diamine σ 吟, 3· deazapine, 123 201141513 deaza-adenine, 8-nitro-7-deaza-adenine, 8-Nitro-7-deaza-guanine, 8-amino-guanine, 8-amino-adenine, 8-bromo-guanine, N2-alkylaminoguanine, 8-bromo-adenine , 6_thiouranium, 5-methylcytosine, 5-propynylcytosine, 5-bromocytosine, 5-iodocytosine, 5_gastric urinary 5-indomethacin, 5-ang Urine alpha, N4-carbo-cello, Ν4_aryl-cytosine, Ν4_alkyl-aryl-cytosine, 3_deaza-5_nitrogen-cytosine, 6-alkyl-adenine, Ν6_aryl-adenine, Ν6-alkyl-aryl-adenine, xanthine, 7-deazatrim, etc., which may be complementary or non-complementary to the target RNA' In place of the oligomer. Chemically modified derivatives of naturally occurring nucleic acid bases, such as 5-substituted pyrimidines, 8-substituted anthracene and cyclic exocyclic substituted purines and pyrimidines, examples given above , can also be incorporated into the appropriate position of the oligomer. Introduction of a suitable chemically modified nucleic acid base into the oligomer can be introduced into a functional group, such as an amine group, a thiol, an aldehyde, a ketone or a carboxylic acid group, which can be used Attaching oligomers to other groups. These functional groups can be introduced into the terminal or in the oligomer

The appropriate position between the limits is that it does not interfere with the RNA interference activity of the oligomer or its treatment. For example, the incorporation of 5-(amino-alkyl)-, 5-(amino-alkenyl)- or 5-(amino-alkynyl)-pyrimidine into siRNA oligomers allows for linkers, labels and other improved properties. The functional group is linked to the siRNA oligomer. It is also the same for urinary effusion and (4) σ 之 5 5 5 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Further, an example of the effect of the achievable oligomer is the modification of the oligomer 5'· and/or the 3,-end. These modifications are due to a number of factors including increasing the stability of the oligomer 124 201141513; reducing the off-target effects caused by the incorporation of the RNAi sense strand into the RISC; and improving other properties of the oligomer such as cell absorption or target or these The combination of reasons is carried out. Such modifications may include, for example, a trans-functional group of a burned or phosphorylated end; a non-nucleophilic group or a non-naturally modified sugar-modified nucleoside. In particular, it is generally desirable to block the 5'-end of the sense strand to prevent its phosphorylation and its incorporation into the RISC complex. This can be carried out by incorporating a 5·-fluorenyl-alkyl group and a glycine derivative, such as 5'-0-fluorenyl and glycine, at the 5'-end of the stock. This can also be achieved by forming a phosphate at the 5'-hydroxyl group, such as an alkyl phosphodiester, an aryl phosphodiester, an aminoalkyl phosphodiester or other groups such as cholesterol or a tocopherol derivative. get on. A bisphosphonate derivative of pyrene or tridecyl stilbene may also be attached to the 5'-end of the sense strand. Further, the acidification of the 5'-end of the antisense strand may also be desirable for improving the activity. Functional groups such as amine, thiol, aldehyde, ketone or carboxylic acid groups can be introduced by introducing appropriate modifications at the 5'- and/or 3'-end of the oligomer by methods well known in the art. 'It can be used to link oligomers to other groups such as linkers, labels and other functional groups with improved properties. Methods and components for introducing many of the modifications discussed above are described in Glen Research Catalog (Glen Research, Sterling, VA, USA). Any of the above modifications may each be combined in a siRNA polymer, with the proviso that the resulting siRNA oligomers are still capable of mediating RNA interference' or still functioning in vivo to produce an RNA interference mediated oligomer. The location of the native and terminal modifications is in some cases limited by the design and topology of the siRNA 2011 tfp〇l〇gy. In general, the 5'-end nucleotide of the siRNA antisense strand must be a hydroxyl functional group that can be phosphorylated in vivo, or an acid-filling functional group capable of mediating RNA interference. For the siRNA oligomers of the invention designed to be incorporated directly into the RISC complex, this restriction means that the 5'-end of the antisense strand must first satisfy these needs. For siRNA oligomers of the invention designed to act in vivo (e.g., by DICER), terminal modifications can be incorporated without this limitation, but the restriction is that the product of action is a siRNA oligomer that meets these requirements. . Fortunately, the type of modification includes the specific incorporation of T-0-ribose modified nucleotides, thiophosphoric acid and terminal modifications. The oligomers covered by these terms "siRNA" of the invention may consist of two individual strands which are mostly, but not necessarily, completely complementary to one another. Furthermore, these oligomers may consist of more than two isolated strands which can be combined into an RNA interference construct via Watson-Crick, Hoogsteen or anti-Hoogsteen. The term "siRNA" in the present invention is further used to encompass a precursor of an oligomer capable of regulating gene expression by RNA interference, including a long double-stranded oligomer and a single-stranded oligomer of self-complementary sequence, for example Stem ring structure. Treatment of these precursors into siRNAs is carried out in cells by, for example, DICER endonuclease. Preferred embodiments of siRNA oligomer length and topology in the present invention are those in which one strand is completely or largely complementary to each other, and each of the strands may have a length of between 11 and 35 nucleotides in length. structure. The optimal length of the oligomer of the invention is 21, 22 or 23 nucleotides in length - a preferred embodiment wherein the two strands are complementary to each other within a length of 19, 20 or 21 nucleotides 126 201141513, A single-stranded protrusion of 2, 3 or 4 nucleotides at the 3'-end of each strand. In general, the design of efficient and selective siRNA sequences is well known in the art and is well documented in the literature cited herein and in the references cited therein (Volkov, AA Oligonucleotides (2009) 19 (2) 191- 202; Czauderna, F. Nucleic Acids Research (2003), 31 (11), 2705-2716). This includes methods for selecting the optimal length, sequence and layout (i.e., single stem, double strand, multiple strands, etc.) of the siRNA oligomer. In addition, chemical modifications of specific portions of various siRNA oligomers that can tolerate and improve siRNA properties are well documented in the literature cited herein and the references cited therein. When combined with a suitable delivery system, one of ordinary skill in the art should be able to combine these data to construct a siRNA sequence with modifications of the effective and selective gene expression silencer. A synthetic method for siRNA solid phase synthesis is referred to (Beaucage, S. Current Opinion in Drug Discovery & Development (2008) 11 (2), 203-216) ° In a preferred embodiment of the invention 'siRNA system The definition is as follows: siRNA is a nucleic acid derivative comprising or containing ribonucleotide units, which can directly or after activation in a cell, can modulate gene expression related to the pathophysiology of the disease by an RNA interference mechanism. The siRNA nucleic acid derivative may consist entirely of natural ribonucleotide units, or it may contain deoxyribonucleotides as, or in addition to, substitutes for certain ribonucleotide units. Furthermore, siRNA nucleic acid derivatives may contain rare, non-natural or chemically repaired saponin derivatives or mixtures thereof, or 127 201141513 plus 'substituents for certain ribonucleotide units. Certain acid diester linkages in siRNA nucleic acid derivatives can be chemically modified. Nucleic acids can be modified by ligation of non-nucleic acid units. The siRNA nucleic acid may consist of two or more individual strands, of which only one of the strands is covalently linked to the unit (Ins)-(Lin), and the other strands are covalently covalently interacted with by this non-covalent interaction. The individual and the (Ins)-(Lin)-connected individual strands are connected. Most of these individual stocks (but not necessarily) are completely complementary to each other. Nucleic acids can also be self-bonded by intracellular nucleic acid base pairing to form a double-stranded body. Structure, such as stem rings. In a more preferred embodiment of the invention, the siRNA is defined as follows: The siRNA is a nucleic acid derivative comprising or containing a ribonucleoside 酉 一 一 疋 直接 直接 直接 直接 直接 直接 直接 直接 直接 直接 直接 直接Regulate gene expression related to the pathophysiology of disease. The siRNA nucleus may consist entirely of natural ribonucleotide units, or it may be composed of two individual strands, such as deoxyribonucleotides, or The ribonucleotide is a substitute for an acid unit. Furthermore, siRNA nucleic acid derivatives may contain rare. Non-natural or chemically modified nucleotide derivatives or mixtures thereof are used or added for the substitution of certain ribonucleotide units. Some decorations. The phosphodiester linkage in the RNA derivative of SlRNA can be chemically repaired: the nucleic acid can be linked by a non-nucleic acid unit at the end or at the position between the other and the other is: Wind, and the first, the middle-strand covalentity is connected to the unit (Ins)-(Lin), and the sister= is connected by nucleic acid base pairing and covalent linkage (InS)_(Lin) It. The siRNA nucleic acid is a double-stranded structure in which the nucleic acid base pairing is combined together 128 201141513 'where the two strands are completely or largely complementary to each other, and each strand may have a length of 11 to 35 nucleotides. In a more preferred embodiment of the invention, the siRNA is defined as follows: The siRNA is a nucleic acid derivative comprising or containing a ribonucleotide unit, which can be modulated and mediated by an RNA interference mechanism, either directly or after activation in a cell. Gene expression related to pathophysiology. The siRNA nucleic acid derivative may consist entirely of natural ribonucleotide units, or it may contain deoxyribonucleotides as, or in addition to, substitutes for certain ribonucleotide units. Furthermore, siRNA nucleic acid derivatives may contain rare, non-natural or chemically modified nucleotide derivatives or mixtures thereof as, or in addition to, substituents for certain ribonucleotide units. Certain in siRNA nucleic acid derivatives The acid diester linkage can be chemically modified. Nucleic acids can be modified by ligating non-nucleic acid units at the ends or at positions. The siRNA nucleic acid can be composed of two individual strands, of which only one of the strands is covalently linked to the unit (Ins)_(Lin), and the second strand is linked by a nucleic acid base pairing and covalent linkage (Ins ) _ (Lin) shares combined. The siRNA nucleic acid is a double-stranded structure in which the nucleic acid base pairing is combined, wherein the two strands are completely or largely complementary to each other, and each of the strands may have a length of from 19 to 27 cores. In a more preferred embodiment of the invention, the siRNA is defined as follows: siRNA is a nucleic acid derivative which comprises or contains ribonucleotide units which, upon activation in cells or in a cell, are capable of regulating and disease by RNA interference mechanisms Gene expression related to pathophysiology. The siRNA nucleic acid derivative may consist entirely of natural ribonucleotide units, or its 129 201141513 may contain deoxyribonucleotides as, or in addition to, substituents for certain ribonucleotide units. Furthermore, siRNA nucleic acid derivatives may contain rare, non-natural or chemically modified nucleotide derivatives or mixtures thereof as, or in addition to, substituents for certain ribonucleotide units. Certain phosphodiester linkages in siRNA nucleic acid derivatives can be chemically modified. Nucleic acids can be modified by ligating non-nucleic acid units at the ends or at positions. The siRNA nucleic acid consists of two individual stocks, whereby only one of the covalents is linked to the unit (Ins)-(Lin), and the second strand is linked by covalent linkages. (Ins)_(Lin) shares combined. The siRNA nucleic acid is a double-stranded structure joined together by nucleic acid base pairing, wherein the two strands are completely or largely complementary to each other, and wherein each strand is 21, 22 or 23 nucleotides in length. In a more preferred embodiment of the invention, the siRNA is defined as follows: siRNA is a nucleic acid derivative comprising or containing ribonucleotide units, which can be printed by RNA interference mechanism, either directly or after activation in a cell. Gene expression related to the pathophysiology of the disease. The siRNA nucleic acid derivative may consist entirely of natural ribonucleotide units, or it may contain deoxyribonucleotides as, or in addition to, substitutes for certain ribonucleotide units. Furthermore, siRNA nucleic acid derivatives may contain rare, non-naturally or chemically modified nucleotide derivatives or mixtures thereof as ' or in addition, for the substitution of certain ribonucleotide units. Certain acid diester linkages in siRNA nucleic acid derivatives can be chemically modified. Nucleic acids can be modified by ligating non-nucleic acid units at the ends or at positions. 130 201141513 ^ °Hai SiRNA core® is a bimonthly structure that combines together by nucleic acid test, and each of the strands is 21, 22 or 23 nucleotides long, and this strand is at 19, 2G or 21 _ (d) are complementary to each other in length, and the 3,-end of each strand has 2, 3 or 4 single-strand protrusions of nuclear phytic acid. Only = one of the covalents is linked to the unit (Ins)_(Lin), and the second is bound by the base of the covalent linkage (Ins)_(Lin) by nucleic acid base pairing. (Ins)-(Lin) may not necessarily be connected to the 5,_ end of the antisense strand. The 5-钿 modification of the antisense strand is limited to acid and nucleotides that can be acidified in the cell by 5,_. In a more preferred embodiment of the invention, the siRNA system is defined as follows: Acid "S_iRNA is a nucleic acid derivative comprising or containing a ribonucleoside, which can be mediated by an RNA interference machine directly or after activation in a cell Gene expression related to the pathophysiology of the disease. This siRNA nucleus y consists entirely of the native ribonucleotide (tetra) unit, or it has a deoxyribonucleotide as an ' or addition, for the replacement of certain ribonucleotides. Furthermore, the siRNA nucleic acid derivative may contain a rare (U) Ub modified nuclear (tetra) derivative or a mixture thereof as a substitute for a purely difficult unit of 'additional'. These, non-natural or chemically modified core (10) derivatives may contain modifications on the nucleotide group. In addition to the common naturally occurring test = 呤 'bird' ^ 呤, cytoplasm, thymus shot and urine feeding. Suitable positions for any other detectable, aryl, fluorenyl group, white chelating oligomer, which is either heterozygous or non-complementary. Nucleotide derivatives which are rare, non-natural or chemically modified may also be modified on a sugar group containing a nucleotide unit. Certain phosphodiester linkages in siRNA nucleic acid derivatives can also be chemically modified. Any or all of the modifications described may be introduced separately, or may be combined with each other in a single nucleotide, with the proviso that the nucleotides produced need to be chemically stable; or the individual nucleotides in the siRNA oligomer Combination. Nucleic acids can be modified at the ends or positions by attachment to non-nucleotide units. The modification of the 5, _ end of the antisense strand is limited to phosphoric acid. The siRNA nucleic acid is a double-stranded structure that is joined together by nucleic acid base pairing and wherein each strand is 21, 22 or 23 nucleotides in length, wherein the two strands are within 19, 20 or 21 nucleotides in length Complementary to each other, with a single strand of 2, 3 or 4 nucleotides at the 3'-end of each strand. Only one of the covalents is linked to the unit (Ins)-(Lin), and the second strand is combined with the covalently linked (Ins)-(Lin) strand by nucleic acid base pairing. (Ins)-(Lin) may not necessarily be connected to the 5'-end of the antisense strand. In a more preferred embodiment of the invention, the siRNA is defined as follows: siRNA is a nucleic acid derivative comprising or comprising a ribonucleotide unit that is capable of modulating and disease by an RNA interference mechanism, either directly or after activation in a cell Gene expression related to pathophysiology. The siRNA nucleic acid derivative may consist entirely of natural ribonucleotide units, or it may contain deoxyribonucleotides as, or in addition to, certain ribonucleotide substitutions. Furthermore, siRNA nucleic acid derivatives may contain rare, non-natural or chemically modified nucleotide derivatives or mixtures thereof as, or in addition to, substituents for certain ribonucleotide units. These rare, non-natural or chemically modified nucleotide derivatives may contain modifications on the 132 201141513 assay group. In addition to the common natural raw urine (four) cockroaches, birds, cytoskeleton, thymus t and two: any other complementary or non-complementary to the target RNA can be suitable for the position of the human body.未基, 蔡基, 二气甲甲甲甲, 3-nitro, 54 base, ketone, fine, pseudourine, 5: propynyl urinary, 2_ thiourea Bite, 2•thiothymidine, 4_thiouracil, 4-thiothymidine, 8_(2-amino-ethoxy)_3_mercapto 3H, 9H 10-oxo^9-diazepine_2 _ 酉 ( (G_夹), 甲醯基. 引 °: 2_amine-based °, order, 2,6-diamine. Tickets, 3-nitrogen orders, 7_ deazepine , 8-nitro-7-deaza-adenine, 8-nitro-7-azepine-guanine, 8-amino-guanine, 8-amino-adenine, 8-bromo-guanine, & Adenine, 6-thioguanine, 5-mercaptocytosine, 5-propylpropionate, cytosine, 5-bromocytosine, 5-iodocytosine, 5-fluorouracil, 5-bromouracil, 5- Iodouracil, 5-propenylamine uracil derivative, 5-propenylaminocytosine derivative, 5-(amino-alkyl)-pyrimidine derivative, 5-(amino-alkenyl)- Pyridine derivative or 5-(amino-alkynyl)-pyrimidine derivative, Ν4_alkyl-cytosine, Ν4-aryl-cytosine, Ν4-alkyl-aryl-cell cleavage, 3-deaza -5-aza-cytosine, Ν6-alkyl-adenine, ν6_aryl-adenine, Ν6-alkyl-aryl-adenine' Ν2-alkylamino guanine, jaundice, 7- Denitrium. These rare, non-natural or chemically modified nucleotide derivatives may also contain sugar group modifications of the nucleotide unit, including 2,-〇_4,-C-methylene ribose, unlocked nucleic acid (UNA), 2,-Deoxy-2,-Fluorine_Arabian 133 201141513 Sugar, 2'-0-alkyl-ribose, 2'-0-allyl-ribose, 2'-0-(2-alkoxy-B Ribosyl, 2'-0-(2-ethyl)-ribose, 2'-0-(2-aminoethyl)-ribose, 2'-deoxy-2'-amino-ribose, 2 '-Deoxy-2'-say-ribose, 4'-thioribose, 5'-deoxy-5'-amino-ribose, 2',5'-dideoxy-5'-amino-ribose 5'-deoxy-5'-mercapto-ribose, 2',5'-dideoxy-5^1 ribose, 5'-carboxy-ribose and 5'-carboxy-2'-deoxyribose. Certain of the acid-filled S-links in siRNA nucleic acid derivatives can be chemically modified. The phosphodiester linkage between the modified nucleotides is phosphorothioate, dithiophosphate, phosphoniumamine, alkyl- and aryl-phosphonate, borane phosphonate, and various Dephosphorization linkages such as, but not limited to, carbonates, carboxylidenes, acetazinates, amine phthalates, thioethers, sulfonates, sulfonamides, hydrazines, mercaptoimides, fluorenylene Imiimine (MMI), fluorenylene dimercaptoalkylene (MDH), fluorenyl methoxyimide, urea, sulfhydryl, ribose acetal and decylamine. Any or all of the described modifications may be introduced separately, or may be combined with each other within a single nucleotide, with the proviso that the nucleotides produced need to be chemically stable; or individual nucleosides within the siRNA oligomer Combination in acid. Nucleic acids can be modified at the ends or positions by attachment to non-nucleotide units. The modification of the 5'-end of the antisense strand is limited to phosphoric acid. The non-nucleotide modification is selected from the group consisting of: (CrC10)-alkyl, 11-(〇-(〇2-〇3)-alkyl) 11, ((〇2-〇3)-alkyl -〇)11,((^)-(1!10)-alkyl-c(o)-, (c3-c6)-cycloalkyl-c(o)-, (c6-c10)-aryl- c(o)-, (crc6)-alkyl-(c6-c10)-aryl-c(o)-, (c6-c10)-aryl-(crc6)-alkyl-c(o)-, (c3-c6)-cycloalkyl-(c6-c10)-aryl 134 201141513 -C(O)-, (C6-Ci〇)-^f'yl-(C3-C6)-cycloalkyl-C (O)-, (Ci-Cp)-heteroaryl-c(0)-, (crc6)-alkyl-(crc9)-heteroaryl-C(O)-, (Ci-C9)-heteroaryl -(CVQ)-alkyl-C(O)-, (C3-C6)-cycloalkyl-(Ci-C9)-heteroaryl-C(O)-, (C)·^)-heteroaryl -(C3-C6)-cycloalkyl-C(O)-, (c2-c9)-heterocyclyl-C(O)-, (Crc6)-alkyl-(C2-C9)-heterocyclyl -c(0)-, (c2-c9)-heterocyclyl-(Crc6)-alkyl-c(0)-, (c3-c6)-cycloalkyl-(c2-c9)-heterocyclyl- C(o)-, (c2-c9)-heterocyclyl-(C3-C6)-cycloalkyl-c(0)-, R4-(CrC1())-alkyl, R4-((C2-C3) )-alkyl-〇)n, R4-(CrC1())-alkyl-c(0)-, R4-(C3-C6)-cycloalkyl-C(O)-, R4-(CrC6)- Alkyl-(C6-C10)-aryl-C(O)-, R4-(C3-C6)-cycloalkyl-(c6..C10)-aryl -C(O)-, R4-(CrC9)·heteroaryl-C(O)-, R4-(crC6)-alkyl-(CrC9)-heteroaryl-C(O)-, R4_(Cl_C9) _heteroaryl-(CrC6)·alkyl-C(O)-, R4-(C3-C6)-cycloalkyl-(qc:heteroaryl_c(0)_, R4_(CrC9)_heteroaryl Base —(C3_c6)_cycloalkyl-C(0)-, R4-(C2-C9)-heterocyclyl-C(O)-, R4-(CrC6)-alkyl-(C2-C9)·环 〇; 0)-, R4-(C2-C9)-heterocyclyl-(CrC6)-alkyl-c(0)-, R4-(c3-c6)-cycloalkyl-(C2-C9) -heterocyclic group_C(〇)_, R4-(C2_C9)-heterocyclic group_(C3_c6)_cycloalkyl-c(〇)·, ho-p(g)(oh)_, (CrC2G)_ Alkyl-0_P(G)(0H)_, H-(o-(c2_c3)-pyring i)n_〇_P(6)(0H)_, ((C2_c3)alkyl 0)nP(G)(0H) -, (c3-C6)_cycloalkyl group _〇_P(6)(〇Η)·, (Ci_C6)_alkyl-(cvc:6)-cycloalkyl·0_Ρ((3)(0Η)_, (c3_C6 )_cycloalkyl-(CrC6)-alkyl_〇_P(G)(〇H)_, (C6-C]〇)_ aryl-0-P(G)(0H), (CrC6)- Alkyl-(C6-C10)-aryl 135 201141513 -0-P(G)(0H)-, (C6-C10)-aryl-(CVQ)-alkyl-0-P(G)(0H) -, (C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(G)(0H)-, (QQ)-alkyl-(CrC9)-heteroaryl-0-P (G)(0H)-, (CVC9)-heteroaryl-(CrQ)-alkyl-0-P (G)(0H)-, (C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0-P(G)(0H)-, (CrC9)-heteroaryl-(C3-C6) -cycloalkyl-0-P(G)(0H)-, (C2-C9)-heterocyclyl-0-P(G)(0H)-, (C2-C9)-heterocyclyl-(CrC6) -alkyl-0-P(G)(0H)-, (CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(G)(0H)-, lUKCrCzo)-alkyl-0 -P(G)(0H)-, R4-((C2-C3)-alkyl-0)nP(G)(0H)-, R4-(C3-C6)-cycloalkyl--0-P(G (0H)-, alkyl-(C3-C6)-cycloalkyl-0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl-(CrQ)-alkyl-0 -P(G)(0H)-, R4-(CrC6)-alkyl-(C6-C10)-aryl-0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl -(C6-C10)-aryl-0-P(G)(0H)-, R4-(CrC6)-alkyl-(CrC9)-heteroaryl-0-P(G)(0H)-, R4 -(CrC9)-heteroaryl-(CrC^)-alkyl-0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0- P(G)(0H)-, 114-((:,-(:9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(G)(0H)-, R4-(C2 -C9)-heterocyclic group-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-(C1-C6)-alkyl--0-P(G)(0H)- And RMCVQ)-alkyl-(C2-C9)-heterocyclyl-0-P(G)(0H)-, wherein n is an integer from 1 to 11, G is Ο or S, and R1 is Η, ( C1-C3)-Alkyl, 136 201141513 R4 is selected from the following Group: Li (Rl), SH, C (0) R1, c (o) oiu, cholesterol base _c (〇) N (R1), fertility _, fertility secret - C (O) 〇 siRNA nucleic acid a double-stranded structure joined together by nucleic acid base pairing, and wherein each strand is 21, 22 or 23 nucleotides in length, wherein the two strands are complementary to each other within a length of 19, 20 or 21 nucleotides, There is a single strand of 2, 3 or 4 nucleotides at the 3'-end of each strand. Only one of the covalents is linked to the unit (Ins)_(Lin), and the second strand is combined with the covalently linked (Ins)_(Lin) strand by nucleic acid base pairing. (Ins)-(Lin) may not necessarily be connected to the 5 ι end of the antisense strand. In the present invention - a more preferred embodiment, the siRNA system is defined as follows: a. An siRNA is a nucleic acid derivative which comprises or contains a ribonucleotide unit', which is activated directly or in a cell, and which modulates the gene expression associated with the pathophysiology of the disease by an RNA interference mechanism. This 3-deleted eight-nuclear 酉夂 bamboo creature consists of a natural ribonucleotide unit, which contains f-deoxyribose nucleus as a substitute, or a substitute for certain ribonucleotide saponins. . Furthermore, siRNA nucleic acid derivatives may contain rare or non-natural or chemically modified nuclear Wei derivatives or mixtures thereof as or in addition to the substitution of certain ribonucleotide units. Some rare, non-natural, or chemically modified (4) nuclear pure derivatives can be modified on the nuclear group of the nuclear phytic acid unit. In addition to the common natural test sites, such as adenine, guanine, cytoplasm, thymus pain, any other test, square or hybrid system that can be complementary or non-complementary to the target leg can be combined with human oligomers. The right location. 137 201141513 These groups are selected from the following group consisting of: 5_- propyl group, 5-methylcytosine, 5-propynyl unity, domain urinary money, 5_ guanamine urinary ejaculation , M-silk (four) derivative, 5-(amino-based)-mouth bite derivative, 5-(amino group-fuchididine derivative and 5-(amino-alkynyl)-pyrimidine derivative. The non-natural or chemically modified nucleotide acid derivative may contain a modification on the sugar group of the nucleic acid unit, including 2,_〇_4, cardiac methylene ribose 2-anthracene-alkyl-ribose, 2, Hexa-allyl-ribose, 2,_〇-(2_ oxyethyl)-ribose, 2, (2·(tetra)yl) ribose, 2, (H2-aminoethyl) ribose, 2'_ go Oxygen 2,-amino-ribose, 2,_deoxy-2,1 ribose, 50-alkyl-ribose, 5,_〇_alkyl 2, deoxyribose, $, deoxygenated_5 ,-Amino ribose,,^,5'·dideoxy-5'-amino-ribose, 5,·deoxy-5, _ thiol _, sugar 2,5-deoxy- 5, only Ribose, 5, _ ribyl-ribose and 5, _carboxy-2'-deoxynucleotide. jdh jl. · ^ The phosphodiester linkage in the RNA derivative of the RNA can be linked via the phosphodiamine side of the phosphoric acid nucleus Sulfur及 ^ 铁 铁 铁 德 德 德 德 德 德 德 德 德 德 德 德 德 德 德 德 德 德 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦 膦The nucleotides need to be a group of people. The second nucleotides may be ligated in the individual nucleotides of the coffee A oligo and/or the 5' end may be linked to the non-nucleic acid unit. The modification of the 5,-end of the antisense strand is limited to phosphoric acid. The modification of the long-term is selected from the group included below. 138 201141513 (CkChO-alkyl, HO-P(G)(OH)-, (CrC2. )-alkyl-0-P(G)(0H)_, H-(0-(C2_C3)-alkyl)n-0_P(G)(0H)-, ((C2-C3)-alkyl-0 nP(G)(0H)-, (C6-C10)-aryl-0-P(G)(0H), (CrC6)-alkyl-(C6-C10)-aryl-0-P(G) )(0H)-, (C6-C10)-aryl-(CrC6)_alkyl-0-P(G)(0H)-, (C2-C9)_heterocyclyl-0-P(G)( 0H)-, (C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(G)(0H)-, (CVC6)-alkyl-(C2-C9)-heterocyclyl-0 -P(G)(0H)-, {^-(CrQo)-alkyl-0-P(G)(0H)-, R4-((C2-C3)-alkyl-0)nP(G)( 0H)-, R4-(C3-C6)-cycloalkyl-0-P(G)(0H)-, R^HCVQ)-alkyl-(C3-C6)-ring-yard-0-P(G )(0H)-, R4-(C 3-C6)-cycloalkyl-(CrC6)-alkyl-0-P(G)(0H)-, R4-(CrC6)-alkyl-(C6-C10)-aryl-0-P(G (0H)-, R4-(C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(G)(0H)-, R4-(CrC6)-alkyl-(CrCp) -heteroaryl-0-P(G)(0H)-, R4-CCVC9)-heteroaryl-(CrQ)-alkyl-0-P(G)(0H)-, R4-(C3-C6) -cycloalkyl-(Q-C9)-heteroaryl-0-P(G)(0H)-, R4-(C"C9)-heteroaryl-(C3-C6)-cycloalkyl-0- P(G)(0H)-, R4-(C2-C9)-heterocyclyl-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-(CVC6)-alkyl -0-P(G)(0H)- and R4-(CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(G)(0H)-, wherein n is from 1 to 11 An integer between, G is 0 or S, R1 is selected from the group consisting of Η, (ChC3)-alkyl, and R4 is selected from the group consisting of NH(R1), SH, C(0) R1, 139 201141513 C(0)0 IU, cholesteryl-C(0)N(R1), tocopheryl- and tocopheryl-C(O). A siRNA nucleic acid is a double-stranded structure joined together by nucleic acid base pairing, and wherein each strand is 21, 22 or 23 nucleotides in length, wherein the two strands are each other within a length of 19, 20 or 21 nucleotides Complementary, with a single strand of 2, 3 or 4 nucleotides at the 3'-end of each strand. Only one of the covalents is linked to the unit (Ins)_(Lin), and the second strand is combined with the covalently linked (Ins)_(Lin) strand by nucleic acid base pairing. (Ins)-(Lin) is attached to the 5,- or 3,-end of the sense strand or to the 3'-end of the countersense strand. In a more preferred embodiment of the present invention, the siRNA system is defined as follows: siRNA is a nucleic acid derivative containing a ribonucleotide unit, which can be directly or after activation in a cell, and can regulate the pathophysiology of the disease by an RNA interference mechanism. Gene expression. The siRNA nucleic acid derivative contains natural ribonucleotide units, as well as other types of natural, rare, non-natural or chemically modified nucleotide derivatives or mixtures thereof, or in addition to 'for certain ribonucleotide units As a substitute, a deoxyribonucleotide can be introduced as, or in addition to, a substituent for certain ribonucleotide units. These rare, non-natural or chemically modified nucleotide derivatives may contain modifications on the nucleobase group of the nucleotide unit. In addition to common naturally occurring bases such as adenine, guanine, cytosine, thymine, and urinary tracts, these groups are selected from the group consisting of: 5 propyl-based uridine, 5 -methylcytosine and 5-propynylcytosine. 140 201141513 Nuclear (4) street organisms containing non-natural or chemical modifications may also be modified by 2,7 1 (saccharide groups), including _acid, 2 ·alkyl ribose, 2,-0-allyl-ribose 2 ethyl), 2' Yang _ hydroxy acetylene, ^ he-amino-ribose, ^ sugar, 4 Ϊ · burning base _ ribose, 5, - 〇 _ (Ci-C3), 々 二气-5 - Amino-ribose, 2,5,-dideoxy-5, face complexion: Glycerol di-t-tose in the VIII nucleic acid derivative. The chemical solution is thiophene/or amine. ^联可经-核;:!, can be introduced separately, or can be stable with each other. Q, the restriction condition is that the produced nuclear acid needs to be a chemical tanker, or can be siRNA The individual nucleotides in the polymer are conjugated at the 3'-end and/or the 5'-end via a poly-nucleotide unit. The modification at the 5'-end of the antisense strand is limited to phosphoric acid. The non-nucleotide end modification is selected from the group consisting of: 1 ClQ)·alkyl, HO-P(G)(OH)-, (CrC2〇)-alkyl: (G) (called, h_(〇) _(C2_C3)alkyl)n 〇p(G)(〇H)-, 2_(:3)·alkyl·〇)η-Ρ(Θ)(ΟΗ)-, R4-(C“C2g)-alkane Base-〇-p(G)(OH)-,alkyl〇)n_p(G)(0H)-, 尺4-^3·0^)-cycloalkyl-0-P(G)(0H)· , R4-(Crc-alkyl (C3_C6)-cycloalkyl-0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl<Ci-C6)-^^.〇- p(G)(〇H)_ n R4.(crc6)-^^-(C6_Clo)-square-〇-P(G)(〇h)_, r4-(C3-C6)-cycloalkyl_ ((VC1())-aryl_〇-P(G)(OH)_, R4-(Ci-C6)-alkyl-(Cl_C9)-heteroaryl 141 201141513 -0-P(G)(0H )-, I^KCrCp)-heteroaryl-(CVCy-alkyl-0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl-(CrC9)-heteroaryl-0 -P(G)(0H)-, R4-(CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(G)(0H)-, R4-(C2-C9)- Cyclol-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-(CVC6)-alkyl--0-P(G)(0H)- and IM-CCrQ)-alkane -(C2-C9)-heterocyclyl-0-P(G)(0H)-, wherein n is an integer between 1 and 11, G is Ο or S, R1 is Η, (C1-C3) -alkyl, R4 is selected from the group consisting of: NH(R1), SH C(0)R1 and C(0)0 IU. The siRNA nucleic acid is a double-stranded structure joined together by nucleic acid base pairing, and each of the strands is 21, 22 or 23 nucleotides long, wherein the two strands are at 19 20, 21 or more nucleotides in length, complementary to each other, with 2, 3 or 4 nucleotides of single-strand protrusion at the 3'-end of each strand. Only one of the strands is covalent and unit (Ins ) - (Lin) is linked, and the second strand is linked to the covalently linked (Ins)-(Lin) strand by nucleic acid base pairing. (InsHLin) is associated with the 5'-end or 3' of the stock. - terminally linked, or linked to the 3'-end of the antisense strand. In a more preferred embodiment of the invention, the siRNA is defined as follows: siRNA is a nucleic acid derivative containing a ribonucleotide unit, either directly or in After activation in the cell, the gene expression related to the pathophysiology of the disease can be modulated by the RNA interference mechanism. This siRNA nucleic acid derivative contains natural ribonucleotide units, as well as other kinds of natural, rare, 142 201141513 non-natural or chemical modification. A nucleotide derivative or a mixture thereof is used as, or in addition to, a substituent for certain ribonucleotide units. The deoxyribonucleotide can be used as, or in addition to, a substitute for certain ribonucleotide units, that is, in the anti-sense stock or the stock of the stock or the second-to-one of the two strands And the last nucleotide. In addition, siRNA nucleic acid derivatives may contain rare, non-ethi chemistry, or mixtures thereof, or, in addition, for the substitution of certain ribonucleoside acid units. These rare, non-natural or chemically modified nucleotide derivatives may contain modifications on the nucleobase group of the nucleotide unit. Uracil and thymine can be replaced by 5-propynyl uracil at any position, and cytosine can be replaced by 5-methylcytosine and 5-propynylcytosine at any position. These rare, non-natural or chemically modified nucleotide derivatives may also contain modifications on the sugar group of the nucleotide unit, i.e., 2,-〇-methyl-ribose. A pyrimidine ribonucleotide in the siRNA sequence when an alternative pattern of (2,-〇H)/(2,-〇Me)- or (2,-OMe)/(2f_OH)·哺 nucleoside 驮 is required Replacement with 2'-〇-methyl-pyrimidine nucleotides, except when more than one consecutive pyrimidine nucleotide is present in the sequence. Another option that can be applied

Alternative pattern of (2''OH)/(2'-OMe)- or (2'-OMe)/(2'-OH)-syntaxin in SlRNA. The specific phosphodiester linkage in the SlRNA nucleic acid derivative can be slightly replaced by the melon generation, ie, either the antisense or the stock, or the 3,-ya of the second strand. , t % or the 5th end or the second end of the last and the last phosphodiester linkage. Any or all of the described modifications may be introduced separately or may be combined with each other in 143 201141513 siRNA oligomers. This nucleic acid can be modified at the 3'-end and/or 5'-end by attachment to a non-nucleotide unit, wherein the modification of the 5'-end of the antisense strand is limited to phosphoric acid. The non-nucleotide end modification is selected from the group consisting of: (CrC3)-alkyl, HO-P(G)(OH)-, alkyl-0-P(G)(0H)-, H-( 0-(C2-C3)-alkyl)n-0-P(G)(0H)-, ((C2-C3)-alkyl--0)nP(G)(0H)-, R4-(CrC2. -alkyl-O-(())(,) -0-P(G)(0H)-, R^KCrCd-alkyl-(C3-C6)-cycloalkyl--0-P(G)(0H)-, R4-(C3-C6)-cyclic -(CrC6)-alkyl-0-P(G)(0H)-, R4-(CrC6)-alkyl-(C6-C10)-aryl-0-P(G)(0H)-, R4 -(C3-C6)-cycloalkyl-(C6-C1())-aryl-0-P(G)(0H)-, R4-(CrC6)-alkyl-(CrC9)-heteroaryl- 0-P(G)(0H)-, I^KCrQ)-heteroaryl-(CrC6)-alkyl-0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl- (CVQ)-heteroaryl-0-P(G)(0H)-, R4-(CrC9)-heteroaryl-(C3-C6)-cycloalkyl-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-(CVQ)-alkyl-0-P(G)(0H )- and R4-(CrC6)-alkyl-(C2-C9)-heterocyclyl-0-P(G)(0H)-, wherein n is an integer between 1 and 11, and G is Ο or S R1 is selected from the group consisting of Η, (C1-C3)-alkyl, and R4 is selected from the group consisting of NH(R1), SH, C(0)R1 and C(0)0R1. 144 201141513 The siRNA nucleus is a double-stranded structure that binds together by nucleic acid test, and each of the strands is 21, 22 or 23 nucleotides long, wherein the two strands are at 19, 20 or 21 nucleotides. Complementary to each other within length, with a single strand of 2, 3 or 4 nucleotides at the 3'-end of each strand. Only one of the covalents is linked to the unit (Ins)_(Lin), and the second strand is combined with the covalently linked (InsHUn) strand by nucleic acid base pairing. (InsHLin) is connected to the 5, _ or 3, _ end of the stock, and the 3' end of the stock is connected. In a more preferred embodiment of the present invention, the siRNA system is defined as follows: siRNA is a nucleic acid derivative containing a ribonucleotide unit, which can be directly or after activation in a cell, and can be related to disease and physiology by a leg interference mechanism (4) Gene expression. This siRNA nucleic acid derivative lacks a ribonucleotide pure single-it, as well as other natural or chemically modified nucleotide derivatives or mixtures thereof, and is used as a substitute for certain ribonucleotide units. ‘·, , = sugar nucleotides act as, or add, 'for a certain dissociation of the deoxynucleotide, that is, the second and last nucleotides of any unit 14 of the antisense I. Further, the siRNA nucleic acid derivative may contain a modified nucleotide derivative or a mixture thereof to naturally or chemically substitute a certain ribonucleotide unit. siRNA, sputum or extra, used for nucleobases with uracil, cell blasting, and nucleotides in birds. siRNA, in the nucleotide acid of the bitter acid, thymus or 2,-0-mercapto-ribose, wherein a sugar, deoxyribose introduced into the deoxyribonucleic acid*, 145 201141513 early substitution, also That is, the penultimate and last of the anti-sense

A nuclear sweet potato. When (2i-OMe)/(2,-OH)-pyrimidine nucleotides are required

Or, in addition, for any of the ribonucleotide or the stock of any of the strands, or two strands of one nucleotide. When it is necessary to change 'but there are more than one continuous shot nucleus in the sequence. Alternatively, an alternative model for siRNA (2, _ 〇 2, _ 〇 _ or (2 -OMe) / (2 - OH) - nucleus nucleus can be applied. The specific phosphodiester linkage can be linked by a phosphorothioate linkage, 'that is, any strand of the antisense strand or the stock strand or the third, last or last of the 3, _ or 5H end of the two strands 1. Any or all of the described modifications may be introduced separately or in combination with each other within the siRNA conjugate. This nucleic acid may be linked to the non-nucleotide unit at the 3'-end and/or 5'-end. Modifications] wherein the modification of the 5, _ terminal of the antisense strand is limited to squaric acid. The modification of the nucleoside SiL end is selected from the group consisting of: (Cl-C3)-alkyl, H0-P(G) ( 0H)_, (CVQoV alkyl °-p(G)(〇H)- . H-(〇-(c2-C3)- ^ S )n-0-P(G)(〇H)- ' (( 2 C3) Horizon base-0) nP(G)(0H)-, R4-(Ci-C2〇)-alkyl group=(G)(〇H)j R4if _c+alkyl group._p(G)(〇 H)_, where n is an integer between 1 and 11, G is 0 or s, and τα is selected from the group consisting of jj, (Ci c3)_alkyl groups. 146 201141513 R4 is NH(R1). siRNA nucleic acids are combined by nucleic acid test pairing a strand structure in which each strand is 21, 22 or 23 nucleotides in length, wherein the strands are complementary to each other within a length of 19, 20 or 21 nucleotides, and have 2, 3 at the 31-end of each strand Or a single nucleotide of 4 nucleotides. Only one of the covalents is linked to the unit (Ins)-(Lin), and the second strand is linked by a nucleic acid to the covalent linkage (Ins - (Lin) shares are combined. (Ins)-(Lin) is linked to the 5'-end or 3'-end of the sense strand or to the 3'-end of the antisense strand. In a more preferred embodiment, the siRNA system is defined as follows: siRNA is a nucleic acid derivative containing a ribonucleotide unit, which, when activated directly or in a cell, can modulate the gene expression associated with the pathophysiology of the disease by an RNA interference mechanism. siRNA nucleic acid derivatives contain natural ribonucleotide units, as well as other types of natural, rare, non-natural or chemically modified nucleotide derivatives or mixtures thereof, for use in certain ribonucleotide units. a substitute. The enucleated deuteron nucleus can be introduced as a 'or additional' for the substitute of certain ribonucleotide units. That is, any one of the antisense or stocks or the second and last of the two strands _ is called a solid nucleotide. In addition, siRNA nucleic acid derivatives may contain rare, non-natural or modified nuclear-derived derivatives. Or a mixture thereof, or in addition, is used as a substitute for some ribonucleotide (4) units. The siRNA sequence nucleoside acid has a urine _, a cell + a fixed, a bird ° ticket, a gland # 呤, a thymus mouth The saccharide group in the nucleobase of the siRNA sequence is ribose, deoxyribose 147 201141513 or 2-mercapto-ribose, which can be introduced as deoxyribonucleotide or, in addition, for certain ribonucleotide units. A substitute, that is, any one of the antisense or stock shares or the second and last nucleotides of the 3'-end of the two strands. A pyrimidine ribonucleoside in the siRNA sequence when an alternative pattern of (2'-〇H)/(2,-OMe)- or (2'-OMe)/(2'-OH)-nipidine nucleotide is required The acid is replaced by 2'-0-mercapto-denonucleotide, except when more than one contiguous pyrimidine nucleotide is present in the sequence. Alternatively, a '(2'-0H)/(2'-0Me)- or (2'-OMe)/(2'-OH)-pyrimidine nucleotide substitution pattern in the siRNA sequence can be applied. The specific phosphodiester bond in the siRNA nucleic acid derivative is replaced by a phosphorothioate linkage, that is, the antisense strand or the second strand of the stock strand has a 3'-end or a 5,_-end or a two-end reciprocal The second sum, or acid diester linkage. Transferring a Phosphore Any or all of the modifications described may be introduced separately or in combination with siRNA oligomers. The nucleic acid can be modified at the 3'-end and attached to the acid-cutting unit, wherein the antisense strand is limited to phosphoric acid. The modification of the non-nucleotide end is selected from the following packages (c--alkyl, H0_P(G)(0H)... and: (6) Tao...called (four)). Burning) η·〇ρ((ς ^基(=))(:Λ0)η,0Η)_, R4-(c々alkyl-〇-P(G)(〇H)- and R4-((C2-C3)-alkyl-_0) n_P(G)(〇H), soil wherein η is an integer between 1 and 11, 148 201141513 G is 0 or S, and R1 is selected from the group consisting of Η, (C1-C3)-alkyl, R4 is NH(R1). The siRNA nucleic acid is a double-stranded structure combined by nucleic acid test, and each strand is 21, 22 or 23 nucleotides long, and the two strands are at 19, 20 or 21 Within each nucleotide length, they are complementary to each other with a single strand of 2, 3 or 4 nucleotides at the end of each strand. Only one of the strands is covalently linked to the unit (Ins)_(Lin). The second strand is linked to the covalently linked (Ins)-(Lin) strand by nucleic acid base pairing. The (Ins)-(Lin) line is linked to the 5'-end or 3'-end of the sense strand. Or in conjunction with the 3'-end of the antisense strand. In a more preferred embodiment of the invention, the siRNA is defined as follows: siRNA is a nucleic acid derivative containing a ribonucleotide unit, either directly or in After activation in cells, 'the expression of the ρτρ-lB gene can be regulated by an RNA interference mechanism. This siRNA nucleic acid derivative contains a natural ribonucleotide unit' and other kinds of natural, rare, non-natural or chemically modified nucleotides. a derivative or a mixture thereof as, or in addition to, a substitute for certain ribonucleotide units. Deoxyribonucleotides may be introduced as, or in addition to, a substitute for certain ribonucleotide units, That is, in either the antisense or the stock, or the second and last nucleotides of the 3'-end of the two strands. In addition, the siRNA nucleic acid derivative may contain rare, non-natural or chemically modified nucleotide derivatives. Or a mixture thereof, or in addition, for the substitution of certain ribonucleotide units. The nucleotides of the siRNA sequence 149 201141513 have nucleobases such as uracil, cytosine, guanine, adenine, thymine. The sugar group in the nucleotide of the siRNA sequence is ribose, deoxyribose or 2-0-methyl-ribose, wherein deoxyribonucleotides can be introduced as, or in addition, for certain ribonucleotides. Unit take Substitute, that is, any one of the antisense or stock shares or the second and last nucleotides of the 3,-end of the two strands. When (2l_OH)/(2,_〇Me)_ or (2) is required In the alternative mode of '-0Me)/(2'-0H)-pyridinidine, the pyrimidine ribonucleotide in the siRNA sequence is replaced by 2,-〇-mercapto-pyrimidine nucleotide, but when Except when more than one contiguous pyrimidine nucleotide is present in the sequence. Another option may be to use (2'-OH)/(2'-OMe)· or (2'-OMe)/(2' in the siRNA sequence. -OH)-Acetidine nucleoside replacement mode. The specific phosphodiester linkage in the siRNA nucleic acid derivative can be replaced by a phosphorothioate linkage, that is, any strand of the antisense strand or the stock or the 3'-end or 5'-end or the second of the strand The second and last phosphodiester linkages are linked. Any or all of the described modifications may be introduced separately or may be combined with each other in a siRNA oligomer. This nucleic acid can be modified at the 3'-end and/or 5'-end by attachment to a non-nucleotide unit, wherein the modification of the 5,-end of the antisense strand is limited to phosphoric acid. The non-nucleotide end modification is selected from the group consisting of: (Ci-C3)_院, HO-P(G)(OH)-, (C1-C2G)-alkyl-〇-P(G) (OH)-, H-(0-(C2-C3)-alkyl)n-〇-p(G)(OH)-, ((C2-C3)-alkyl-oxime)nP(G)(〇 H)-, RWCi-Czo)-alkyl hydrazine-P(G)(OH)- and R4-((C2-C3)-alkyl group-0)nP(G)(0H)-, 150 201141513 where n is An integer between 1 and 11, wherein G is Ο or S' R1 is selected from the group consisting of Η, (ChC3)-alkyl, and R4 is NH(R1). The siRNA nucleic acid is a double-stranded structure in which the nucleic acid is paired together, and wherein each strand is 21, 22 or 23 nucleotides in length, wherein the two strands are each other within a length of 19, 20 or 21 nucleotides Complementary, with a single strand of 2, 3 or 4 nuclear acid at the 3'-end of each strand. Only one of the covalents is linked to the unit (Ins)-(Lin), and the second strand is bound by the base of the covalent linkage (Ins)_(Lin) by nucleic acid base pairing. The (Ins)-(Lin) system is linked to the 5'-end or the 3'-end of the sense strand or to the 3'-end of the countersense strand. Thus, an embodiment of the invention is a conjugated compound comprising temsin and siRNA. The (Lin) is linked to the siRNA. Another embodiment of the invention is a chimeric compound as defined by formula (1): Ins-Lm-siRNA (Formula I), wherein insulin (Ins) is a chimeric compound as described above, wherein insulin is linked via another embodiment of the invention It is selected from the group consisting of: human, membrane analogs and insulin derivatives. Another embodiment of the invention is: human insulin, animal islets

The following groups are included: 151 201141513

Gly (A21), Arg (B31), Arg (B32) human insulin, Lys (B3), Glu (B29) human insulin, Asp (B28) human insulin, Lys (B28) Pro (B29) human insulin and Des (B30 Human insulin, Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32)-NH2 human insulin, Arg (AO), His ( A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32)-NH2 human insulin, Arg (AO), His (A8), Glu (A15), Asp (A18 , Gly(A21), Arg(B31), Arg(B32)-NH2 human insulin; and insulin derivatives are selected from the group consisting of B29-N-carnitine-des (B30) human Insulin, B29-N-palm-des (B30) human insulin, B29-N-carnitine-based human insulin, B29-N-palm-based human insulin, B28-N-carnitine LysB28ProB29 human insulin, B28-N-palmitoyl-LysB28ProB29 human insulin, B30-N-myristyl-ThrB29LysB30 human insulin, B30-N-palostyl ThrB29LysB30 human insulin, B29-N-(N-brown Mercapto-Y-glutamic acid sulfhydryl)-des(B39) human insulin, B29-N-(N-stone choline-Y-glutamine sulfhydryl) -des (B30) human insulin, Β29-Ν-(ω-carboxyheptadecanyl)-des(B30) human insulin and Β29-Ν-(ω-carboxyheptadecanyl) human insulin. Another embodiment of the present invention is the chimeric compound as described above, wherein the linker (Lin) is a group having the following structure: (X1)q-(L 1 )p-(D)d-(L2)r-( X2) s-(Y)tZ (Formula II) wherein 152 201141513 XI is a group selected from the group consisting of: _c(〇)_; -OC(O)-; -C(0)-〇- ; -C(0)-N(R1)- ; -N(R1)-C(0)-; -C(S)-N(R1)- ; -N(R1)-C(S)- ; S02-; -C(NH2+)- » •0-P(0)(0H)-; -S-; -N(R1)·; =NN(R1)-; ;heterocyclic group; LI system is independently selected From the group included below: alkyl, (〇-alkyl). , (alkyl-0) η, cycloalkyl, (〇-cycloalkyl) η, (cycloalkyl-hydrazine, alkyl-% alkyl, cycloalkyl-alkyl, aryl, alkyl_ Aryl, aryl-alkyl, cycloalkyl-aryl, aryl-cycloalkyl, heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl, cycloalkyl-heteroaryl, hetero Aryl-cycloalkyl, heterocyclic, alkyl-heterocyclyl, heterocyclyl-alkyl, cycloalkyl-heterocyclyl, heterocyclyl-cycloalkyl; D is independently selected from the following Group, c(〇)·, _c(〇)〇_, -OC(O)-, -N(R1)-C(0)-, -C(0)N(R1)-, -N( R1)C(0)-N(R1)-, _C(s)N(Rj)_, _s〇m_, _c(丽2+)-, -P(0)(0H)0-, -N(R1 )_, -N(Rl)_N=, =N_N(R1)·, -N(R1)-N(R1)-, ·〇-, -S-, -SS-, _〇_(ch2)_, -(CH2)-0-, (0-alkyl)n, (alkyl-0)n, (s-alkyl), (〇_S〇2_N(R1)·alkyl), (N(R1) -alkyl), (N(Rl)C(O)-alkyl), (N(R1)c(NH2+){yl), (N(R1)C(0)-N(R1)-alkyl) , (c(〇)-N(R1)_alkyl), (n(ri)-so2_n(ri)_alkyl), (N(R1)_s〇2_alkyl), (s〇2-n( Ri)-burning base, (N(R1)_S(v〇•alkyl), S〇m_alkyl), (0-C(0)-alkyl), (c(0>0-alkyl), (0_c(0)_0_alkyl), 153 201141513 (OC(O)- N(Rl)-alkyl), (N(Rl)-C(0)-0-alkyl), (0-cycloalkyl)n, (cycloalkyl-fluorene) n, (S-cycloalkyl ), (0-S02-N(Rl)-cycloalkyl), (N(R1)-cycloalkyl), (N(Rl)C(O)-cycloalkyl), (N(R1)C( NH2+)-cycloalkyl), (N(R1)C(0)-N(R1)-cycloalkyl), (C(O)-N(Rl)-cycloalkyl), (N(R1)- S02-N(R1)-cycloalkyl), (N(R1)-S02-cycloalkyl), (S〇2-N(Rl)-cycloalkyl), (N(Rl)-S02-0- Cycloalkyl), (SOm-cycloalkyl), (oc(o)-cycloalkyl), (c(o)-o-cycloalkyl), (OC(O)-O-cycloalkyl), (OC(O)-N(Rl)-cycloalkyl), (N(Rl)-C(0)-0-cycloalkyl), (0-alkyl-cycloalkyl)n, (S-alkane) -cycloalkyl), (〇-S〇2-N(Rl)-alkyl-cycloalkyl), (N(R1)-alkyl-cycloalkyl), (N(Rl)C(O) -alkyl-cycloalkyl), (N(R1)C(0)-N(R1)-alkyl-cycloalkyl), (C(O)-N(Rl)-alkyl-cycloalkyl) , (N(R1)-S02-N(R1)-alkyl-cycloalkyl), (N(R1)-S02-alkyl-cycloalkyl), (S〇2-N ( Rl)-alkylcycloalkyl), (N(Rl)-S02-0-alkyl-cycloalkyl), (som-alkyl-cycloalkyl), (oc(o)-alkyl-cycle Alkyl), (c(o)-o-alkyl-cycloalkyl), (oc(o)-o-alkyl-cycloalkyl), (OC(O)-N(Rl)-alkyl- Cycloalkyl), (N(Rl)-C(0)-0-alkyl-cycloalkyl), (〇-cycloalkyl-alkyl)n, (S-cycloalkyl-alkyl), ( 0-S02-N(Rl)-cycloalkyl-alkyl), (N(R1)-cycloalkyl-alkyl), (N(R1)C(0)-cycloalkyl-alkyl), ( N(R1)C(0)-N(R1)-cycloalkyl-alkyl), (C(O)-N(Rl)-cycloalkyl-alkyl), (N(R1)-S02-N (R1)-cycloalkyl-alkyl), (N(R1)-S02-cycloalkyl-alkyl), (S02-N(R1)-cycloalkyl-alkyl), (n(ri)- So2-o-cycloalkyl-alkyl), (som-cycloalkyl-alkyl), (oc(o)-cycloalkyl-alkyl), (c(o)-o-cycloalkyl-alkane 154 201141513 base), (OC(O)-O-cycloalkyl-alkyl), (OC(o)-N(RI)-cycloalkyl-alkyl), (N(Rl)-C(0) -0-cycloalkyl-alkyl), (〇-aryl)n, (s-aryl), (0-S02-N(Rl)-aryl), (N(R1)-aryl), (N(Rl)C(O)-aryl), (N(R1)C(0)-N(R1)-aryl) , (C(0)-N(R1)_aryl), (N(R1)-S02-N(R1)-aryl), (N(R1)-S02-aryl), (S02-N() R1)-aryl), (N(Rl)-S02-0-aryl), (SCV aryl), (OC(O)-aryl), (C(O)-O-aryl), ( Oc(o)-o-aryl), (OC(O)-N(Rl)-aryl), (N(Rl)-C(0)-0-aryl), (0-alkyl-aryl) η, (S-alkyl-aryl), (〇-S〇2-N(Rl)-alkyl-aryl), (N(R1)-alkyl-aryl), (N(Rl) C(O)-alkyl-aryl), (N(R1)C(0)-N(R1)-alkyl-aryl), (C(O)-N(Rl)-alkyl-aryl (N(R1)-S02-N(R1)-alkyl-aryl), (N(R1)-S02-alkyl-aryl), (S02-N(R1)-alkylaryl ), (N(Rl)-S02-0-alkyl-aryl), (SOm-alkyl-aryl), (OC(O)-alkyl-aryl), (C(O)-O- Alkylaryl), (OC(O)-O-alkyl-aryl), (OC(O)-N(Rl).alkyl-aryl), (N(Rl)-C(0)- 0-alkyl-aryl), (Ο-aryl-alkyl) n, (S-aryl-alkyl), (0-S02-N(Rl)-aryl-alkyl), (N() R1)-aryl-alkyl), (N(Rl)C(O)-aryl-alkyl), (N(R1)C(0)-N(R1)-aryl-alkyl), ( C(O)-N (Rl)-aryl-alkyl), (n(ri)-so2-n(ri)-aryl-alkyl), (N(R1)-S02-aryl-alkyl), (S02-N) (R1)-aryl-alkyl), (n(ri)-so2-o-aryl-alkyl), (som-aryl-alkyl), (oc(o)-aryl-alkyl) , (C(O)-O-aryl-alkyl), (OC(O)-O-aryl-alkyl), (OC(O)-N(Rl)-aryl-alkyl)' ( N(Rl)-C(0)-0-aryl-alkyl), (〇-cycloalkyl-aryl 155 201141513 base) η, (S-cycloalkyl-aryl), (〇_s〇2 -N(R1)-cycloalkyl-aryl), (N(R1)-cycloalkyl-aryl), (N(R1)c(〇)_cycloalkyl-aryl), (N(R1) C(0)-N(R1)-cycloalkyl-aryl), (c(〇)-N(R1)-cycloalkyl-aryl), (N(R1)_S02-N(R1)- Cycloalkyl-aryl), (N(R1)-S02-cycloalkyl-aryl), (so2-n(ri)-cycloalkyl-aryl), (N(Rl)-S〇2_0- Cycloalkyl-aryl), (s〇m_cycloalkyl-aryl), (OC(O)-cycloalkyl-aryl), (C(0)_0_cycloalkyl-aryl), (OC(O)-O-cycloalkyl-aryl), (OC(O)-N(Rl)-cycloalkyl-aryl), (N(Rl)-C(0)-0-cycloalkane (-aryl), (0-aryl-cycloalkylindole, (S-aryl-ring) (), (0-S02-N(Rl)-aryl-cycloalkyl), (N(R1> aryl-cycloalkyl), (N(Rl)C(O)-aryl-cycloalkyl) ), (N(R1)C(0)-N(R1)-aryl-cycloalkyl), (C(O)-N(Rl)-aryl-cycloalkyl), (N(R1)- S02-N(R1)-aryl-cycloalkyl), (N(R1)-S02-aryl-cycloalkyl), (S〇2_N(Rl)-aryl-cycloalkyl), (N() Rl)-S〇2-0-aryl-cycloalkyl), (SOm-aryl-cycloalkyl), (oc(o)-aryl-cycloalkyl), (c(o)-o- Aryl-cycloalkyl), (OC(O)-O-aryl- lysole), (OC(O)-N(Rl)-aryl-cycloalkyl), (N(Rl)- C(0)-0-aryl-cycloalkyl), (〇-heteroaryl)n, (S_heteroaryl), (〇-S02-N(Rl)-heteroaryl), (N(R1) )-heteroaryl), (N(Rl)C(O)-heteroaryl), (N(R1)C(0)-N(R1)-heteroaryl), (C(O)-N() Rl)-heteroaryl), (N(R1)-S02-N(R1)-heteroaryl), (N(R1)-S02-heteroaryl), (S02-N(R1)-heteroaryl) ), (N(Rl)-S02-0-heteroaryl), (S0m-heteroaryl), (OC(O)-heteroaryl), (c(o)-o-heteroaryl), ( Oc(o)-o-heteroaryl), 156 201141513 (OC(O)-N(Rl)-heteroaryl), N(Rl)-C(0)-0-heteroaryl), (Ο-alkyl-heteroaryl)η, (S-alkyl·heteroaryl), (〇-S02-N(Rl)- Alkyl-heteroaryl), (N(R1)-alkyl-heteroaryl), (N(Rl)C(O)-alkyl-heteroaryl), (N(R1)C(0)- N(R1)-alkyl·heteroaryl), (C(O)-N(Rl)-alkyl-heteroaryl), (N(R1)-S02-N(R1)-alkyl-heteroaryl ()(n(ri)-so2-alkyl-heteroaryl), (so2-n(ri)-alkyl-heteroaryl), (N(Rl)_S02-0-alkyl-heteroaryl ), (som-alkyl-heteroaryl), (OC(O)-alkyl-heteroaryl), (C(o)-o-alkyl-heteroaryl), (OC(O)-O -alkyl-heteroaryl), (OC(O)-N(Rl)-alkyl-heteroaryl), (N(Rl)-C(0)-0-alkyl-heteroaryl), 〇-heteroaryl-alkyl)n, (S-heteroaryl-alkyl), (0-S02-N(Rl)-heteroaryl-alkyl), (N(R1)-heteroaryl- Alkyl), (N(Rl)C(O)-heteroaryl-alkyl), (N(R1)C(0>N(R1)-heteroaryl-alkyl), (C(O)- N(Rl)-heteroaryl-alkyl), (N(R1)-S02-N(R1)-heteroaryl-alkyl), (N(R1)-S02-heteroaryl-alkyl), (S02-N(R1)-heteroaryl-alkyl), (N(Rl)-S02-0-heteroaryl-alkyl), (S0m-heteroaryl-alkyl), (OC(O)-heteroaryl-alkyl), (C(o)-o-heteroaryl-alkyl), (OC(O)-O- Aryl-alkyl), (OC(O)-N(Rl)-heteroaryl-alkyl), (N(Rl)-C(0)-0-heteroarylalkyl), (〇-ring) Alkyl-heteroaryl)n, (0-S02-N(Rl)-cycloalkyl-heteroaryl), (N(R1)-cycloalkyl-heteroaryl), (N(Rl)C( O)-cycloalkyl-heteroaryl), (N(R1)C(0)-N(R1)-cycloalkyl-heteroaryl), (c(O)-N(Rl)-cycloalkyl -heteroaryl), (N(R1)-S02-N(R1)-cycloalkyl-heteroaryl), (N(R1)-S02-cycloalkyl-heteroaryl), (S02-N() R1)-cycloalkyl-heteroaryl 157 201141513 base), (N(Rl)-S02-0-cycloalkyl-heteroaryl), (som-cycloalkyl-heteroaryl), (oc(o) -cycloalkyl-heteroaryl), (c(o)-o-cycloalkyl-heteroaryl), (OC(O)-O-cycloalkylheteroaryl), (OC(O)-N (Rl)-cycloalkyl-heteroaryl), (N(Rl)-C(0)-0-cycloalkyl-heteroaryl), (〇-heteroaryl-cycloalkyl)η, (S -heteroaryl-cycloalkyl), (〇-S02-N(Rl)-heteroaryl-cycloalkyl), (N(R1)-heteroaryl-cycloalkyl), (N(Rl)C (O)-heteroaryl-cycloalkyl , (N(R1)C(0)-N(R1)-heteroaryl-cycloalkyl), (C(O)-N(Rl)-heteroaryl-cycloalkyl), (n(R1) -S02-N(R1)-heteroaryl-cycloalkyl), (N(R1)-S02-heteroaryl-cycloalkyl), (S02-N(R1)_heteroaryl-cycloalkyl) , (N(Rl)-S02-0-heteroarylcycloalkyl), (S0m_heteroaryl-cycloalkyl), (OC(O)-heteroaryl-cycloalkyl), (C(O) )-O-heteroaryl-cycloalkyl), (OC(O)-O-heteroaryl-cycloalkyl), (OC(O)-N(Rl)-heteroaryl-cycloalkyl), (n(ri)_c(〇)-〇-heteroaryl-cycloalkyl), (0-heterocyclyl)n, (S-heterocyclyl), (〇_s〇2-N(R1)- Heterocyclic group), (N(R1)-heterocyclic group), (n(ri)c(〇)-heterocyclic group), (N(R1)C(0)-N(R1)-heterocyclic group) , (c(〇)_n(R1)-heterocyclic group), (n(ri)-so2-n(ri)_heterocyclic group), (N(R1)_s〇2_heterocyclic group), (so2 -n(ri)-heterocyclic group), (N(R1)_s〇r〇_heterocyclic group), (s〇m heterocyclic group), (0-C(0)-heterocyclic group), (c (〇)_〇_heterocyclic group, (〇_c(〇)_〇_heterocyclic group), (OC(O)-N(Rl)-heterocyclic group), (N(R1)_c(〇) )_〇_heterocyclic group, (〇-alkyl-heterocyclic group) n, S_alkyl-heterocyclic group, (〇_s〇2_N(R1)_alkyl-heterocyclic group), (N(R1)-alkyl·heterocyclic group), (wind illusion to (7)-alkane (hetero-heterocyclic group), (N(R1)C(0)_N(R1)-alkyl-heterocyclic group), (C(O)-N(Rl).alkyl-heterocyclic group), (N (Rl) s〇2_N(R1)_alkyl-hetero 158 201141513 cyclyl), (N(R1)-S02-alkyl-heterocyclyl), (S02-N(R1)-alkyl-heterocyclyl) , (N(Rl)-S02-0-alkyl-heterocyclyl), (SCV alkyl-heterocyclyl), (oc(o)-alkyl-heterocyclyl), (C(o)- O-alkyl-heterocyclyl), (〇-C(0)_0-alkyl-heterocyclyl), (OC(O)-N(Rl).alkyl-heterocyclyl), (N(Rl) )-C(0)-0-leuko-heterocyclyl), (0-heterocyclyl-hospital) η, (S-heterocyclyl-alkyl), (o-so2-n(ri)_ Heterocyclyl-alkyl), (N(R1)-heterocyclyl-alkyl), (N(Rl)C(O)-heterocyclyl-alkyl), (N(R1)C(0)- N(R1)-heterocyclyl-alkyl), (C(O)-N(Rl)-heterocyclylalkyl), (N(R1)-S02-N(R1)-heterocyclyl-alkane ()(n(R1)-S02-heterocyclyl-alkyl), (SCVN(Rl)-heterocyclyl-alkyl), (N(Rl)-S〇2_0.heterocyclyl-alkyl) (S〇m-heterocyclyl-alkyl) , (OC(o)-heterocyclyl-alkyl), (C(〇)-〇-heterocyclyl-alkyl), (OC(O)-O-heterocyclyl-alkyl), (〇) _c(〇)-N(Rl)-heterocyclyl-alkyl), (N(Rl)-C(0)-0.heterocyclyl-alkyl), (〇_ ring-formyl-heterocyclyl) n, (OS02-N(R1)·cycloalkyl·heterocyclyl), (N(R1)·cycloalkyl·heterocyclyl), (N(Rl)C(O)-cycloalkyl-hetero Cyclo), (N(R1)C(0)_N(R1)_cycloalkyl-heterocyclyl), (c(〇)-N(R1)-cycloalkyl-heterocyclyl), (N() R1)-S02-N(R1)_cycloalkyl-heterocyclyl), (N(R1)_S〇2-cycloalkyl-heterocyclyl), (S〇2_N(R1)_cycloalkyl-hetero Cyclo), (n(ri)-so2_〇-cycloalkylheterocyclyl), (s〇m_cycloalkyl.heterocyclyl), (〇-C(0)-cycloalkyl-heterocycle (), (c(〇)_〇_cycloalkyl-heterocyclyl), (〇-C(〇)-〇-cycloalkyl-heterocyclyl), (〇_c(〇)_N(R1) _cycloalkyl-heterocyclyl), (N(Rl)-C(0)-0-cycloalkyl-heterocyclyl), (〇-heterocyclyl-cycloalkyl)n, (〇-S〇 2-N(Rl)-heterocyclyl-cycloalkyl), (N(R1)_ 159 201141513 heterocyclyl-cycloalkyl), (N(R1)C(0)_heterocyclyl-cycloalkyl ), (N(R1) C(0)-N(R1)-heterocyclyl-cycloalkyl), (c(〇)_N(R1)heterocyclyl-cycloalkyl), (N(Ri)_S〇2_N(R1)_ Heterocyclylcycloalkyl)(n(ri)-s(vheterocyclyl-cycloalkyl), (s〇2_N(R1)_heterocyclyl-environmentyl), (N(Rl)-SCVO -heterocyclyl-cycloalkyl), (s〇m_heterocyclyl-cycloalkyl), (OC(O)-heterocyclyl-cycloalkyl), (c(〇)_〇_heterocyclyl) _Environmental group), (oc(o)-o-heterocyclyl-cycloalkyl), (0_C(0)_N(R1)_heterocyclyl-cycloalkyl), (N(Rl)_c(0) -0-heterocyclyl-cycloalkyl); L2 is selected from the group consisting of alkyl, (〇-alkyl)n, (alkyl-hydrazine) n, cycloalkyl, alkyl-ring Alkyl, cycloalkyl-alkyl, aryl, alkyl-aryl, aryl-alkyl, cycloalkyl-aryl, aryl-cycloalkyl, heteroaryl, alkyl-heteroaryl, Heteroaryl-alkyl, cycloalkyl-heteroaryl, heteroaryl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, heterocyclyl-alkyl, cycloalkyl-heterocyclyl, hetero Cyclo-cycloalkyl; X2 is a group selected from the group consisting of: <(〇)_;-OC(O)-; -C(0)-〇- > -N(R1) -C(0)- ; -C(0)-N(R1)-; -N (R1)-C(S)- ; -S02- ; -C(NH2+)- ; -0-P(0)(0H)- ; -S-; -N(R1)- ; -〇-; Y is a group selected from the group consisting of: _C(0)_; -S-; -N(R1)-; -N(R1)-N= ; =NN(R1)-; 160 201141513 From the group included below: always bond, alkyl, (〇-alkyl)n, (alkyl-〇)n, alkyl-C(O)-, cycloalkyl-(:(〇)_, Aryl-C(〇)...alkyl-aryl-C(〇)-, aryl-alkyl-C(〇)_, cycloalkyl-aryl-c(0)-, aryl-naphthenic Base „c(0)_,heteroaryl_c(〇)...alkyl-heteroaryl-c(〇)-,heteroaryl-alkyl-c(0)-,cycloalkyl-heteroaryl _c(0)_, heteroaryl-cycloalkyl-c(0)_, heterocyclyl-c(0)-, alkyl-heterocyclyl-c(o)-, heterocyclyl-alkyl _c(0)_, cycloalkyl-heterocyclyl-c(〇)_, heterocyclyl-cycloalkyl group 〇(〇)_, alkyl group _n=, cycloalkyl group _^=, aryl group _]^=, alkyl-aryl-N=, aryl-alkyl group_N=, cycloalkyl-aryl·N=, aryl-cycloalkyl-N=, heteroaryl_N=, Alkyl-heteroaryl-N=,heteroaryl-alkyl-N-,heteroaryl-heteroaryl_N==,heteroaryl-cycloalkyl,heterocyclyl-N=,alkyl- Heterocyclic group_N=, heterocyclic group-alkyl group_N=, naphthenic -heterocyclyl-N=,heterocyclyl-cycloalkyl-N=,alkyl-N(R1)...cycloalkyl-N(R1)·, aryl-N(R1)_, alkyl-aryl ·N(R1)_, arylalkyl-N(R1)-, cycloalkyl-aryl-n(ri)_, aryl-cycloalkyl-N(R1)_, heteroaryl-N (R1)-, alkyl-heteroaryl_N(R1)_, heteroaryl-alkyl-N(R1)-, cycloalkyl-heteroaryl_N(R1)_, heteroaryl-ring Alkyl-N(R1)-, heterocyclyl-N(R1)_, alkyl-heterocyclyl-N(R1)-, heterocyclyl-alkyl-N(R1)-, poorly burnt-mixed Base _^(尺1)_, heterocyclic group_cycloalkyl-N(R1)-, -〇-P(〇)(〇H)-, alkyl_〇_p(〇)(〇H)... (〇 基) η-0-Ρ(0)(0Η)-, (alkyl-〇)n_p(〇)(〇H)_, cycloalkyl-0-Ρ(0)(0Η)-, alkane --cycloalkyl·〇_ρ(〇)(〇Η)_, cyclization-based alkyl group_0-Ρ(0)(0Η)-, aryl _〇_ρ(〇)(〇Η), miscellaneous Aryl-0-oxime (0)(0Η)-, alkyl-aryl _〇_Ρ(〇)(〇Η)_, arylalkyl 161 201141513 -0-Ρ(0)(0Η)·, Cycloalkyl-aryl_〇_p(〇)(〇H)_, arylcycloalkyl-0-Ρ(0)(0Η)-, alkyl-heteroaryl_0_P(0)(0H) _,heteroaryl_alkyl-0-Ρ(0)(0Η)-, cycloalkyl-heteroaryl_〇_P(〇)(〇H)_,heteroaryl- Alkyl-0-oxime (0)(0Η)-, heterocyclic group_0_P(〇)(〇H)_,heterocyclyl-alkyl-0-P(0)(0H)-,alkyl-hetero Ring group _〇_p(〇)(〇H)_, heterocyclic group·cycloalkyl group-0-Ρ(0)(0Η)-, cycloalkyl-heterocyclic group-0-P(0)(0H )-,-0-P(S)(0H)-, alkyl-〇-P(s)(〇H)·, (〇-alkyl)n-〇-P(S)(OH)-, ( Burning group_0)n_P(8)(0Η)·, cycloalkyl-0-P(S)(0H)-, alkyl-cycloalkyl_〇_P(s)(〇H)_, cycloalkyl·alkane -OP(S)(OH)-, aryl-〇-P(s)(〇h), heteroaryl_〇_p(s)(〇h)-, alkyl aryl-〇-P ( S) (OH)-, aryl-alkyl-O-P(S)(0H)-, cycloalkyl-aryl-0-P(S)(0H)-, arylcycloalkyl-〇_P (s)(〇H)_, alkyl-heteroaryl-0-P(S)(0H)-,heteroaryl-alkyl-〇_P(s)(:〇H)_, cycloalkyl -heteroaryl-0-P(S)(0H)-,heteroaryl-cycloalkyl-〇_P(s)(〇H)_, heterocyclyl--0-P(S)(0H)- , heterocyclyl-alkyl_〇_P(s)(〇H)_, alkyl_heterocyclyl-0-P(S)(0H)-, heterocyclyl-cycloalkyl·〇_Ρ( 8) (〇Η)-Cycloalkyl-heterocyclyl-〇-P(S)(〇H)_, _〇_p(S)(SH)_, alkyl-0-P(S)(SH) -, (〇_ alkyl)η·〇_ρ(8)(SH)_, (alkyl-0)nP(S)(SH)·, cycloalkyl_ _p(8)(SH)_, alkyl-cycloalkyl-0-P(S)(SH)-, cycloalkyl-alkyl-〇_p(8)(SH)_, aryl-0-P(S)(SH ),heteroaryl_〇_p(8)(SH)·,alkyl-aryl-0-P(S)(SH)-, aryl-alkyl 〇_p(8)(SH)_, cycloalkyl-aryl -0-P(S)(SH)-, aryl-cycloalkyl-〇_p(s)(SH)_, alkyl-heteroaryl_0_P(S)(SH)_, heteroaryl -alkyl-0-P(S)(SH)-, cycloalkyl-heteroaryl 162 201141513 base-0-P(S)(SH)-,heteroaryl-cycloalkyl-〇_p(s) (SH)-,heterocyclyl-0-P(S)(SH)-,heterocyclyl-alkyl-oxime-P(S)(SH)-,alkyl-heterocyclyl-0-P(S (SH)-,heterocyclyl-cyclohexyl-fluorene-P(s)(SH)-, cycloalkyl-heterocyclyl- 0-P(S)(SH)-,-0-P(0 )(alkyl)-, alkyl-Ο-Ρ(Ο)(alkyl), (0-alkyl)η-0-Ρ(0)(alkyl)-, (alkyl-〇)η-Ρ (〇)(alkyl)_, cycloalkyl-0-oxime (0) (alkyl)-, alkyl-cycloalkyl-〇-Ρ(〇)(alkyl)-, cycloalkyl-alkyl -0-Ρ(0)(alkyl)-, aryl-〇-Ρ(〇)(alkyl),heteroaryl-0-oxime(0)(hospital)-,alkyl-aryl-0 - Ρ(0)(alkyl)-, aryl-alkyl-hydrazine-hydrazine (hydrazine) (alkyl)-, cycloalkyl-aryl-fluorene-fluorene (fluorene) (alkyl)-, aryl -cycloalkyl-0-oxime (0) (alkyl)-, alkane -heteroaryl-〇-Ρ(〇)(alkyl)-,heteroaryl-alkyl-0-oxime(0)(alkyl)-,cycloalkyl-heteroaryl-〇-Ρ(〇) (alkyl)-,heteroaryl-cycloalkyl-0-oxime(0)(alkyl)-,heterocyclyl-0-oxime(0)(alkyl)-,heterocyclyl-alkyl-0 - Ρ(0)(alkyl)-, alkyl-heterocyclyl-0-oxime (0) (alkyl)-, heterocyclyl-cycloalkyl-0-oxime (0) (alkyl)-, Cycloalkyl-heterocyclyl-0-oxime (0)(alkyl)-,-0-P(0)(N(R2R3))·, alkyl-0-P(0)(N(R2R3)) -, (0-alkyl) n-〇-P(〇)(N(R2R3))_, (alkyl-O)nP(0)(N(R2R3))-, cycloalkyl-〇-P ( 〇)(N(R2R3))-, alkyl-cycloalkyl-0-P(0)(N(R2R3))-, cycloalkyl-alkyl-0-P(0)(N(R2R3)) -, aryl-〇-P(〇)(N(R2R3))_, heteroaryl-0_P(0)(N(R2R3))-, alkyl-aryl-〇-P(〇)(N(( R2R3))-, aryl-alkyl-0-P(0)(N(R2R3))-, cycloalkyl-aryl-0-P(0)(N(R2R3))-, aryl-ring alkyl-〇-P(〇)(N(R2R3))-, alkyl·heteroaryl-0-P(0)(N(R2R3))-,heteroarylalkyl-0-P(0) (N(R2R3))-, cycloalkyl-heteroaryl 163 201141513 -0-P(0)(N(R2R3))-,heteroaryl-cyclodecyl-0-P(0)(N(R2R3) ))-,heterocyclyl-〇-P(〇)(N(R2R3))-,heterocyclyl-alkyl-0-P (0) (N(R2R3))-, alkyl-heterocyclyl-0-P(0)(N(R2R3))-, heterocyclyl-cycloalkyl--0-P(0) (N(R2R3) ))-, cycloalkyl-heterocyclic group-0-P(0)(N(R2R3))-, -N(R1)-P(0)(0H)-, alkyl-N(R1)_P( 0) (0H)-, (decyl) nN(Rl)-P(0)(0H)-, cycloalkyl-N(R1)-P(0)(0H)-, alkyl-cycloalkyl -N(Rl)-P(〇)(〇H)-, cycloalkyl-alkyl-N(R1)-P(0)(0H)-, aryl-N(R1)-P(0)( 0H),heteroaryl-N(R1)-P(0)(0H)-,alkyl-aryl-N(R1)-P(0)(0H)-, aryl-alkyl-N(Rl )-P(〇)(〇H)-, cycloalkyl-aryl-N(Rl)-P(〇)(〇H)-, aryl-cycloalkyl-N(R1)-P(0) (0H)-,alkyl-heteroaryl-N(Rl)-P(〇)(〇H)-,heteroaryl-alkyl-N(Rl)-P(〇)(〇H)-, ring Alkyl-heteroaryl-N(R1)-P(0)(0H)-,heteroaryl-cycloalkyl-N(Rl)-P(〇)(〇H)-, heterocyclyl-N( R1)-P(0)(0H)-,heterocyclyl-alkyl-N(R1)-P(0)(0H)_,alkyl-heterocyclyl-N(Rl)-P(〇)( 〇H)-,heterocyclyl-cycloalkyl-N(R1)-P(0)(0H)-, cycloalkyl-heterocyclyl-N(R1)-P(0)(0H)-; d Is an integer between 0 and 10; η is an integer between 1 and 11; m is 0, 1 or 2; q, p, r, s, t are mutually independent, 1, 1 or 2; R1 Why , calcining base, 164 201141513 wherein the R2 and R3 moieties 5- to 6-membered R2 and R3 are independently η, (CrC6)-alkyl, which together with the nitrogen atom bonded thereto form a saturated ring heterocycle Base group. Invented another siRMA π _ back chimeric compound, potted 兮

SlRNA is composed of two individual stocks, according to which only y valence is linked to the unit (Ins) _ (Lin), and the second ": conjugate co-pairing and covalent linkage (Ins) _ (Lin The dimer of the dimer may have a length of between 11 and 35 nucleotides. Another embodiment of the invention is a chimeric compound as described above, wherein each strand of the siRNA moiety is 21, 22 or 23 The nucleotides are long; this one is complementary to each other within a length of 19, 20 or 21 nucleotides, and has a single-stranded protrusion of 2, 3 or 4 nucleotides at the 3'-end of each strand. Another embodiment of the present invention is the chimeric compound as described above, wherein the nucleotide group of the siRNA is independently selected from the group consisting of adenine, guanine, cytosine, thymidine, uracil, 5_ Propionate-based uracil bite, 5-mercaptocell bleed, 5-propynyl spur bite, 5-fluorourine π-bite, 5- acrylamide-based urinary π-bite derivative, 5-acetonitrile An aminocytosine derivative, a 5-(amino-alkyl)-pyrimidine derivative, a 5-(amino-alkenyl)-pyrimidine derivative, and a 5-(amino-alkynyl)-pyrimidine derivative. Another embodiment of the invention is as described above Wherein the glycosyl group of the siRNA is independently selected from the group consisting of ribose, 2'-deoxyribose, 2,-0-4, -C-decylene ribose, 2'-fluorenyl-alkyl -ribose, 2'-non-allyl ribose, 2,-0-(2-alkoxyethyl)-ribose, 2'-0-(2-hydroxyethyl)-ribose, 2'-〇- (2. Aminoethyl)-ribose, 2'-deoxygenated 165 201141513 -2,-amine-based, 2,-silk_2,|minus, 5,. 2,:)------- - thiol ribose, 5, carboxyl-ribose and 5, deoxyribose. Brute-2- - another embodiment of the invention is a chimeric compound as described above wherein the internucleotide linkages of the siRNA are independently selected from the group consisting of Groups of groups: phosphodiesters, phosphorothioates, dithiophosphates, phosphorus, alkyl and aryl-phosphonates, and borane phosphonates. Another embodiment of the invention is as The chimeric compound described above, wherein the =RNA nucleic acid can be modified at the 3, the end and/or the 5' end via a non-nucleic acid; = wherein the modification of the antisense strand 5, the end is limited to phosphoric acid and The N-denosine end-modification system is independently selected from the following (=...resistant (G-chest...di-p-P(G)(〇H)·, H-(〇-(C2-C3)-alkyl)n_ 〇_p (G)(〇H), ((c2-c3> 烧基_〇)n_p(6)(0H)... _,_), (Cl-C6)_ 烧基〇-P(G)(〇H)-,( C6-c10)-aryl-(Crc6)_alkyl〇P(G)(〇H)-, (C2-C9)-heterocyclyl_〇-p(6)(〇H)-, (c2_c9)· heterocycle Base-(CrC6)-alkyl-〇-P(G)(〇H)_, (Crc6)_alkyl-(c2-c9> Heterocyclyl-0_P(G)(0H)_, R4 (C) C2. )alkyl-〇-P(G)(〇h)-, R4-((CVC3)-alkyl-oxime)np(G)(〇H)_, R4-(C3-C6)·cycloalkyl_ 〇_P(G)(〇H)_, R4(Ci_C6)alkyl-(C3_C6)-ring-based 〇_p(g)(〇h)-, R4-(C3-C6)-cycloalkyl -(c]-c6)-alkyl group_0_P(G)(0H)_, R4_(CrC6)_alkyl·(^^ι〇)_ 166 201141513 aryl-0-P(G)(0H)_ , R4-(C3-C6)-cycloalkyl-(C6-C10)-aryl-0-P(G)(0H)-, R4-(CrC6)-alkyl-(C"C9)-heteroaryl Base-0-P(G)(0H)-, R4-(CrC9)-heteroaryl-(CrC6)-alkyl-0-P(G)(0H)-, R4-(C3-C6)-cyclic Alkylheteroaryl-0-P(G)(0H)-, rU-d-CA heteroaryl-(C3-C6)-cycloalkyl-0-P(G)(0H)-, R4-( C2-C9)-heterocyclic group-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-(CrC6)-alkyl-0-P(G)(0H)-, R4-( QQ)-alkyl-(C2-C9)-heterocyclyl-0_P(G)(0H)-, wherein n is an integer between 1 and 11; G is Ο or S; R1 is Η, (C1-C3)-Hyun; R4 is NH(R1), SH, C(0)R1, C(0)0R1, Cholesterol-C(0)N(R1), Tocopheryl-, Tocopheryl _C(0). Another embodiment of the invention is a pharmaceutical formulation comprising a chimeric compound as described above. Another embodiment of the invention is a pharmaceutical formulation as described above and as described above A compound for use in the treatment of diabetes. Another embodiment of the present invention is a method for producing a chimeric compound as described above, (a) recombinantly producing the desired insulin (b) covalently linking the linker to insulin And subsequently (c) covalently linked to the siRNA, or (4) linking the pre-linked siRNA complex to the transcript 167 201141513, replacing the steps (b) and (c), and purifying the resulting chimeric compound. The present invention is described by the following examples, but is not intended to limit the scope of the invention. Description of the synthetic methods: The compounds of the present invention can be synthesized by various methods depending on the linkage used. In general, insulin is modified to introduce a chemically reactive group. This insulin derivative is then reacted with an appropriately chemically reactive guanidine-modified siRNA. Examples of typical reaction modes include ( But not limited to): thiol/thiopyranyl; thiol/thionitropyridinyl; thiol/methyleneimine; thiol acetyl group; thiol/acrylic acid; Amine Nitride; aldehyde (or ketone) / hydrazine; aldehyde (or ketone) / hydrazine and many others (Hermanson, G τ, Bioconjugate Techniques (Second Edition) Academic press fiber). The connection of several anti-ship linker bases with this can also be considered as a condition for controlling the nature of the linker. Depending on the nature of the linker selected and the modification of the type and performance of the siRNA, the modified S_A can be used as "insulin in the form of a straight intact double strand. Alternative selection", where appropriate, the compounds of the invention may be The modified single-stranded RNA is reacted with the modified insulin and then bonded to the second modified RNA strand to construct the reactive group. The method of introducing the reactive group into the island is the sequence modification, which will be 168 201141513, for example, free caspase Amine acid is incorporated into the insulin sequence with the restriction that it is imperceptible to interfere with insulin activity. Another method is direct reaction with a heterobifunctional linker containing an amine group and insulin reaction. ^Functional base. In most of the insulin, and by selecting the appropriate solvent and the pH of the reaction solution, this allows the linker to preferentially link to the N- and B-chain N (Canadian Journal

Biochemistr 〆丨 979) 57 (6) 489-496). The preferential linkage of the N-terminus of the B-chain can be achieved by optimizing the reaction conditions. A mixture of geometrically different shopping and insulin in which more than one linker is linked can be isolated by, for example, HPLC purification. The nature of the geometric isomers formed can be determined by NMR analysis or LC-MS analysis of the natural linker-insulin binding agent and post-disulfide reduction and/or enzyme digestion. The N-terminus of insulin may be specifically protected by a suitable protecting group such as b〇c or Msc. The remaining amine functional groups, e.g., from the amine acid side chain, can be subsequently reacted with a linker in a molecule other than the insulin, wherein the linker contains a functional group that reacts with the amine functional group. Removal of the protecting group results in a linker-insulin binding agent in which the linker is not linked to the N-terminal phase of the insulin. Alternatively, insulins with different protection modes, such as A01/B29 protected insulin, can be produced using optimal pH control, solvent and appropriate protecting group reagents, which can then be used for 'for example B-chain N-terminus The introduction of a linker (Kurtzhals, P. et al., Biochem. J. (1995) 312, 725-731; Hoppe Seylers Z. Physiol. 169 201141513

Chem. (1971) 352, 1487-1490.; J. Pharmaceutical

Sciences (1997) 86 (ll), 1264-1268.; Chem. Ber. (1975) l〇8, 2758-2763). The resulting linker-insulin binding agent can then be reacted with a suitably functionalized siRNA. These siRNAs have functional groups that specifically react with the heterobifunctional linker on the insulin. Alternatively, the chemically reactive linker group can be introduced into an exotoxin precursor such as proinsulin or pro-proinsulin. The additional amino acid is present as a reaction to prevent either or both of the N-termini of the insulin from the linker reagent. After the action of an enzyme with a chemically modified insulin precursor, this provides a convenient route for the modification of the tampondin in an alternative position such as LysB29. Many of the components used to introduce appropriate reactive functional groups into siRNA have been described or are commercially available (eg, Glen Research).

Catalog, Glen Research, Sterling, VA, USA). These include the introduction of amine functional groups, thiol functional groups, aldehydes/ketones, activated carboxy functions, alkynes and many other phosphonium amides and functionalized solid supports. The siRNA modified with these groups can be used to directly react with chemically modified insulin or with other linker molecules, for example, to modify the final linker length or chemical reactivity. DETAILED DESCRIPTION OF THE INVENTION - A preferred embodiment is an insulin which has been linked to a heterobifunctional linker 3, the (iv) hetero-based di-weit linker consisting of an amine reactive group reactive group. The resulting linker membrane complex has a single thiol reactive linker to the filamentous group in the islet. (d) reacting it with siRNA, wherein 170 201141513 siRNA is functionalized with a thiol group to give an siRNA-insulin conjugate of the type desired in the present invention. Thiol-functionalized siRNAs may carry a thiol functional group to protect against disulfide bond formation. Removal of the thiol protecting group and/or cleavage of the disulfide-linked homologous dimer is typically carried out with a mild reducing agent such as dithiothreitol or TCEP. In the case of insulin in which all of the amine functional groups are blocked by a linker and additionally protected by a protecting group, a homobifunctional linker can be used in place of the heterobifunctional linker. For example, a linker containing two amine reactive f-radical groups is reacted with a protected mono-free amine functional group on the insulin. The resulting protected insulin containing a single amine-reactive linker can then be specifically reacted with an amine-modified siRNA, such that subsequent removal of the protecting group is not impaired or degraded: knot: In some cases, the band is used There are some or all 2, · protecting groups may be organic, the restriction is that no damage or drop =: ##下' can be obtained from the siRNA•Tengdaosu binding agent. τ &lt;one abbreviation: SPDP: 3 octyl dithiol)-propyl aryl H3 · ((4) yueji county gt. _[1_(pyridin-2-yldithio)·B 4-(2,5-di-oxo-2,5-dihydromethylcyclohexyl 7.1 201141513 PBS: phosphate buffered saline NAP: nucleic acid purified desalting column TFA : Trifluoroacetic acid DMSO: Dimercaptosulfoxide FCS: Fetal bovine serum DMEM: Dulbecco's modified Eagle's medium TCEP: (bis-carboxyindenyl-phosphoryl)-dotted line in the structure of acetic acid: Examples of Cys-Cys disulfide-bonded insulin-linker binding agents: Example 1 B01-SPDP-human insulin. The structure of the compounds described in this example is shown in Table 4. Dissolving human insulin (1 g) 5 mM HCl (100 ml), and added 100 mM borax buffer pH 8.5 (4 ml). 3-(pyridin-2-yldithio)-propionic acid 2,5-di-oxo-pyrrolidin-1-yl The ester [SPDP ligating reagent] (162 mg) was dissolved in DMSO (3 ml) and the insulin solution was added. The reaction was gently shaken at room temperature for 16 hours. The turbid solution was centrifuged at 5000 rpm for 4 hours. The supernatant was separated. and Prepare HPLC (gradient 20-51% acetonitrile / water + 0.1% TFA, 21 min, 50 mL / min) on Agilent 300SB-C18 column (30 X 250 mm) to purify the product at RT. The yield was 229 mg. LC-MS: m/z 6004. NMR analysis confirmed properties and geometry 172 201141513 isomers. Example 2 A01-SPDP-human insulin. The structure of the compounds described in this example is shown in the table. 4. The human insulin (200 mg) was dissolved in 12.5 mM borax buffer pH 8.5 (20 ml). The 3-(π ratio α-di-2-dithio)-propionic acid 2,5-two side Oxy-pyrrolidin-1-yl ester [SPDP ligating reagent] (16.2 mg) was dissolved in DMSO (300 μM) and added to the insulin solution. The reaction was allowed to stand at room temperature for 16 hours. Then the pH was lowered to 3.6 by the addition of 1 MHCl aqueous solution. The product was purified on a Agilent 300SB-C18 column (9.4 x 250 mm) at room temperature by preparative HPLC (gradient 15-60% acetonitrile / water + &lt;RTI ID=0.0&gt; The fractions were combined and the yield was 20 mg. LC-MS: m/z 6000.. Example 3 BOl-(LC-SPDP)-human insulin. The structure of the compounds described in this example is shown in Table 4. Human insulin (200 mg) was dissolved in 5 mM HCl (20 mL) and 12.5 mM borax buffer pH 8.5 (20 mL) was added. 6-[3-(Pyridin-2-yldithio)-propionylamino]-hexanoic acid 2,5-di-oxo-pyrrolidinyl 1-yl S [LC-SPDP ligation reagent] (22 Mg) was dissolved in DMSO (300 μl) and added to the insulin solution. The reaction was allowed to relax at room temperature for 5 173, 2011,415,113 hours, then the pH was lowered to 3.6 by the addition of 1 mM aqueous solution. The product was purified by preparative HPLC (gradient 15-60% EtOAc/water: &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& The product fractions were combined and lyophilized. The yield was 59.2 mg. LC-MS: m/z 6113. The properties and geometric isomers were confirmed by NMR analysis. Example 4 B01-SMPT-human insulin. The compound structures described in this example are shown in Table 4. Human insulin (200 mg) was dissolved in 12.5 mM borax buffer pH 8.5 (25 mL). 4-[1-(Pyridin-2-yldithio)-ethyl]-benzoic acid 5-dioxaxo-pyrrolidin-1-yl ester [SMPT ligation reagent] (13.4 mg) dissolved in DMSO (300 μl) and add the insulin solution. The reaction was allowed to stand at room temperature for 16 hours. The product was purified on a Agilent 300SB-C18 column (9.4 x 250 mm) eluting with EtOAc (EtOAc: EtOAc (EtOAc) The product fractions were combined and lyophilized. Yield U. 6 mg. LC-MS: m/z 6081. The properties and geometric isomers were confirmed by NMR analysis. Example 5 A01-SMPT-human insulin. The compound structures described in this example are shown in Table 4. This compound was isolated by the same reaction as described in Example 4, 174 201141513. The yield was 20.6 mg. LC-MS: m/z 6081. The properties and geometric isomers were confirmed by NMR analysis. Example 6 A01-SMCC-human insulin. The compound structures described in this example are shown in Table 4. Human insulin (20 mg) was dissolved in 12.5 mM borax buffer pH 8.5 (2.5 mL). 4-(2,5-di-oxo-2,5-dipyrrolidinomethyl)-cyclohexanecarboxylic acid 2,5-dioxo-3-sulfonyl-pyrrolidin-1-yl ester Acid-SMCC linker] (2.25 mg) was dissolved in water (200 μL) and added to the insulin solution. The reaction was shaken for 1 hour at room temperature. The product was purified by preparative HPLC (gradient 15-60% acetonitrile/water + 0.1% TFA, 17.5 min, 10 mL/min) on an Agilent 300SB-C18 column (9.4 x 250 mm). The product fractions were combined and lyophilized. The output is 2 mg. LC-MS: m/z 6021. The properties and geometric isomers were confirmed by NMR analysis. Example 7 BO 1-SPDP-Insulin Glargine. The structure of the compounds described in this example is shown in Table 4. Insulin glargine (100 mg) was dissolved in 5 niM HCl (10 ml), and 12.5 mM borax buffer pH 8.5 (10 ml) was added, whereby insulin glargine was precipitated. Add 1 M HCl (about 100 microliters) until the glargine insulin is redissolved. 3-(Pyridin-2-yldithio)-propionic acid 2,5-di-oxo-. More than 175 201141513 Roridin-1-yl ester [SPDP Linker] (7.7 mg) was dissolved in DMSO (150 μL) and added to the solution. The reaction was allowed to relax at room temperature for 16 hours. The product was purified by preparative HPLC (gradient 15-60% acetonitrile/water + 0.1% TFA, 17.5 min, 10 mL/min) on an Agilent 300SB-C18 column (9.4 x 250 mm) at room temperature. The product fractions were combined and lyophilized. The yield is 19 mg. LC-MS: m/z 6256. The properties and geometric isomers were confirmed by NMR analysis. Example 8 BOl-(LC-SPDP)-glargine. The structure of the compounds described in this example is shown in Table 4. Insulin glargine (100 mg) was dissolved in 5 mM HCl (10 ml), and 12.5 mM borax buffer pH 8.5 (10 ml) was added, whereby insulin glargine was precipitated. Add 1 M HCl (about 100 microliters) until the glycogen is dissolved. 6-[3-(π ratio β-den-2-yldithio)-propyl-arylamino]-hexanoic acid 2,5-di-oxo-. Bilpyridin-1-yl ester [1^(:-8?0? linking reagent] (1〇.5 mg) was dissolved in DMSO (150 pl) and the solution of the peptide was added. The reaction was allowed to relax at room temperature. The product was purified by preparative HPLC (gradient 15-60% acetonitrile / water + &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&& The product fractions were combined and dried to give a yield of 33 mg. LC-MS: m/z 6369. Characters and geometric isomers were confirmed by NMR analysis. Example 9 176 201141513 BO 1-SPDP·insulin Glulisine The structure of the compounds described in this example is shown in Table 4. Glucine insulin (100 mg) was dissolved in 5 mM HCl (10 ml) and 12.5 mM borax buffer pH 8.5 (10 ml) was added. 3-(pyridin-2-yldithio)-propionic acid 2,5-di-oxo-pyrrolidin-1-yl ester [SPDP ligating reagent] (8 mg) dissolved in DMSO (150 μL) and added to the solution The reaction was gently shaken for 16 hours at room temperature. The product was prepared by preparative HPLC (gradient 15-60% acetonitrile/water + 〇.i 〇/oTFA, 17 5 min, 1 〇 ml/min) at Agilent 300SB- C18 on the column (9.4x250mm) The product was combined and lyophilized to give a yield of 17 mg. LC-MS: m/z 6015. </ RTI> NMR analysis confirmed the identity and the geometric isomers. Example 10 B03-SPDP-Grusin Insulin. The structure of the compound described in the above is shown in Table 4. ^ This compound was isolated by the same reaction as described in Example 9. 6.5 g of the product. LC-MS: m/z 6015. Geometric isomers. Example 11 BO 1 -(LC-SPDP)-Glucintam. The structure of the compounds described in this example is shown in Table 4. Glucinin insulin (100 mg) was dissolved in 5 mM. Hcl (1 〇 177 201141513 liters)' and added 12.5 mM borax buffer pH 8.5 (10 ml). 6-[3-(°-pyridin-2-yldithio)-propionylamino]- Caproic acid 2,5-dioxaxo-pyrrolidin-1-yl ester [LC-SPDP ligating reagent] (1 mg) was dissolved in DMSO (150 μL) and added to the solution. The reaction was gently shaken at room temperature for 16 hours. The product was purified by preparative HPLC (gradient acetonitrile / water + 0.1% TFA, 1 .5 min, 10 mL / min) on Agilent 30086- (: 18 column (9.4\25 〇 111111) at room temperature. The product fractions were combined and dried up to 20 mg. LC-MS: m/z ό 128. Characters and geometric isomers were confirmed by NMR analysis. Example 12 B03-(LC-SPDP)-Grucinten The structure of the compound described in this example is shown in Table 4. Glucine insulin (100 mg) was dissolved in 5 mM HCl (10 ml) and 12.5 mM borax buffer pH 8.5 (10 ml) was added. -[3 decapyridin-2-yldithio)-propionylamino]-hexanoic acid 2,5-di-oxo-oxazolidin-1-yl ester [LC-SPDP ligation reagent] (η mg ) Dissolved in DMSO (150 μl) and added to the solution. The reaction was allowed to relax at room temperature for 16 hours. The product was purified by preparative HPLC (gradient 15-60% acetonitrile / water &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&& The product fractions are combined and lyophilized. The yield is 14 mg. LC-MS: m/z 6128. The properties and geometric isomers were confirmed by NMR analysis. Examples of insulin-siRNA linkers: 178 201141513 Example 13 The chimeric compound structures described in this example are shown in Table 4. Sequence name used: 5 's488_3'sThio double-stranded RNA, purchased from Qiagen Company: SEQ. ID NO: 82

HO^^S

I

S

5?r(GAAUUUGGCACCUUCGAUC)d(AC)-3D 〇-P-d(TT)r(CUUAAACCGUGGAAGCUAG) 5*

OH 3' I

HO-P- SEQ. ID NO: 81 0

410 μl of 40 mM TCEP in PBS was added to 410 μl of lOOpMRNA double stranded sequence 5 's488_3'sThio in PBS. The reaction was allowed to relax at room temperature for 1 hour. The solution was applied to a NAP-10 column and dissolved in PBS. The resulting solution was then used in a NAP-25 column 'dissolved in PBS. A solution of BOl-(LC-SPDP)-human insulin [Example 3] (1 mg) in 5 mM HC1 (500 μl) was added to this solution. The reaction was allowed to relax at room temperature for 16 hours. The product was prepared as a solution of the formula HpLC (gradient 15-60% lOOmM NH4Oac in water: acetonitrile (1:1) solution / 100 mM NH4Oac in water, 45 min, 1 〇 ml / min) on Agilent 300SB-C18 column 179 201141513 The upper (9.4 x 25 〇mm) was purified at room temperature. The product fractions were combined and acetonitrile was removed by vacuum centrifugation. The product was desalted on a NAP-10 column and dried. Yield 0_2 mg. LC-MS: m/z 20150. Example 14 The chimeric compound structure described in this example is shown in Table 4. Sequence name: 3‘as488_3‘s Thio double-stranded RNA, purchased from Qiagen:

SEQ. ID NO: 82

3. PH 〇 5?r(GAAUUUGGCACCUUCGAUC)d(AC)—P-o

O-p-d(TT)r(CUUAAACCGUGGAAGCUAG)-5' 0 oh 3. , 0H

SEQ. ID NO: 81 2 ml of 40 mM TCEP in PBS was added to 2 ml of ΙΟΟμΜ RNA double-stranded sequence 5's488_3's Thio in PBS. The reaction was allowed to relax at room temperature for 1 hour. The solution was applied to a NAP-25 column 'dissolved in PBS. The resulting solution was then applied to three NAP-25 columns and dissolved in PBS. A solution of BOl-(LC-SPDP)-human insulin [Example 3] (45 mg) in 5 mM HCl (5 ml) was added to this solution. The reaction was allowed to relax at room temperature for 16 hours. The product was prepared by preparative HPLC (gradient 15-60% 100 mM NH4Oac in water: acetonitrile (1:1) solution / l mM mM] S [H4 〇 ac aqueous solution, 45 minutes 180 201141513 minutes, 10 ml / min) Purify in human layer at 11 〖30083-(1:18 column (9.4\250 mm) at RT. Combine the product fractions and remove acetonitrile by vacuum centrifugation. The product is desalted on a NAP-25 column and Lyophilization. Yield 1.34 mg. LC-MS: m/z 20184. Example 15 The structure of the chimeric compound described in this example is shown in Table 4. Sequence name: Dl-ds__3'-Thio double-stranded RNA, purchased from Qiagen Company: SEQ. ID NO: 82 Η0-Ρ-0-/ HO^A^O, —〇~ 5?r(GAAUUUGGCACCUUCGAUC)d(AC) 3. 〇-?-d(TT)r(CUUAAACCGUGGAAGCUAG)- 5, OH 3' SEQ. ID NO: 81 2 ml of 40 mM TCEP in PBS was added to 2 ml of ΙΟΟμΜ RNA double-stranded sequence Dl-ds_3'-Thio in PBS. The reaction was moderated at room temperature for 2 hours. The solution was applied to two NAP-25 columns and dissolved in PBS. The resulting solution was then applied to three NAP-25 columns and dissolved in PBS. B01-SPDP-human insulin was added to this solution [Example 1] ] (12 mg) at 5 Solution in mM HC1 (9 ml). The reaction was shaken at room temperature for 3 days. The product was prepared by preparative HPLC (gradient 15-60% lOOmM NH4Oac in water: acetonitrile (1:1) solution / 100 mM NH4Oac The solution in water, 45 minutes, 181 201141513 10 ml / min) was purified at 笆丨 161 ^ 30088 - (318 column (9.4 乂 250 mm) at room temperature. The product was combined and the acetonitrile was removed by vacuum centrifugation. The product was desalted on a NAP-25 column and lyophilized to yield 1.47 mg. LC-MS: m/z 6601, 12785, 19389. Example 16 The chimeric compound structure described in this example is shown in Table 4. Sequence name: #9-ds_3'-Thio double-stranded RNA, purchased from Qiagen Company: SEQ. ID NO: 18 9 pQ HO 卞OJ \--0 5?r(UUCUGCUCCCACACCAUCU)d(CC) 3, 〇-pd (TT)r(AAGACGAGGGUGUGGUAGA)-5' OH 3' SEQ. ID NO: 17 This compound was synthesized similarly to Example 15 using the sequence #9-ds_3 '-Thio. Yield 1.81 mg. LC-MS: m/z 6433, 12943, 19378. Example 17 The chimeric compound structure described in this example is shown in Table 4. Sequence name: Dl-ds__5 '-Thio double-stranded RNA, purchased from Qiagen Company: 182 201141513 SEQ. ID NO: 82 5?r(GAAUUUGGCACCUUCGAUC)d(AC) 3' 3' d(TT)r(CUUAAACCGUGGAAGCUAG) 5'

OH SEQ. ID NO: 81 This compound was similar to Example 15 using the sequence D1 -ds_5 ‘-Thio. Yield 0.64 mg. LC-MS: m/z 6601, 12784, 19386. Example 18 The chimeric compound structure described in this example is shown in Table 4. Sequence name: Dl-ds_3 '-Thio double-stranded RNA, purchased from Qiagen Company: SEQ. ID NO: 82

3' 5?r(GAAUUUGGCACCUUCGAUC)d(AC) Ο 〇-ii_cl(TT)r(CUUAAACCGUGGAAGCUAG)-5' OH 3, SEQ. ID NO: 81 This compound is similar to Example 15 but using A01-SPDP-human insulin ( Example 2) synthesized. The yield was 0.82 mg. C-MS: m/z 6601, 12784. Example 19 183 201141513 The structure of the compound to be described in this example is shown in Table 4. Sequence name: Dl-ds-3'-Thio double-stranded RNA 'purchased from Qiagen Company: SEQ. ID NO: 82

5?r(GAAUUUGGCACCUUCGAUC)d(AC) 3 〇.?-.d(TT)r(CUUAAACCGUGGAAGCUAG)-5, OH 3' SEQ. ID NO: 81 This compound is similar to Example 15 but using B〇1-SMPT- Human insulin (Example 4) was synthesized. Yield 0.46 mg. LC-MS: m/z 6601, 12860. Example 20 The structure of the host compound described in this example is shown in Table 4. Sequence name: Dl_mod_ll〇fll_2 double-stranded RNA, purchased from Qiagen:

HO

5' ΗΟ-Ρ*〇 SEQ. ID NO: 82 3, r(GAAuUuGGcAcCullcGAuC)d(*A*C) 〇-P-d(T*T*)r(cUuAAAcCGuGGAAGcUAG)-5' SEQ. ID NO: 81

OH wherein * represents a phosphorothioate linkage and lowercase letters represent a 2'-0-methyl nucleotide. This compound was synthesized similarly to Example 15 using the modified RNA sequence Dl_mod_llofll_2. The yield is 1.55 mg. LC-MS: 184 201141513 m/z 6811, 12887, 19698. Example 21 The structure of the chimeric compound described in this example is shown in Table 4. Sequence name: Dl_mod_llofll_l double-stranded RNA, purchased from Qiagen Company: 5_ ?H Η0-Ρ=0 SEQ. ID NO: 82

HO

3'

II 0-P- I OH r(GAAuUuGGcAcCuUcGAuC)d(*A*C)-Alexa647 d(T*T*)r(cUuAAAcCGuGGAAGcUAG)-5' 3, SEQ. ID NO: 81 where * represents a phosphorothioate bond The lower and lower case letters represent 2'-0-mercaptonucleotide. This compound was synthesized similarly to Example 15 using the modified RNA sequence Dl_mod_llofll_l. Yield 2.70 mg. LC-MS: m/z 7864, 12886, 20751. Example 22 The chimeric compound structure described in this example is shown in Table 4. Sequence name: D1 mod llofll 2 double-stranded RNA, purchased from Qiagen Company: 〇 0-JLd(T*T*)r(cUuAAAcCGuGGAAGcUAG)-5, OH 3' SEQ. ID NO: 81

5'

OH SEQ. ID NO: 82 H〇'f° 3. r(GAAuUuGGcAcCuUcGAuC)d(*A*C) 185 201141513 wherein * represents a phosphorothioate linkage and lowercase letters represent a 2'-0-methyl nucleoside acid. This compound was synthesized similarly to Example 15 but using B01-SPDP-glucine insulin (Example 9) and using the modified RNA sequence Dl__mod_llofll_2. Yield 0.79 mg. LC-MS: m/z 6811, 13014, 19826. Examples of related bioassays: Example 23 Signal transduction activity of insulin and insulin binding agents in intact cells: Insulin receptor (IR) phosphorylation analysis The following methods are described for measurement of overexpression of insulin receptor (CHO-hIR) In-cell western procedure for insulin receptor phosphorylation status in CHO cells, the volume shown is the volume per well. For the determination of IR phosphorylation, CHO-hIR cells were seeded into 96-well plates (Corning, 20,000·30,000 cells/well) and grown for 48 hours. After washing with lxPBS and starving for 3-4 hours in serum-free (180 μl/well) F-12 (HAM) medium, add 20 μl of insulin-containing or insulin-binding in each well in a dose-dependent manner. A solution of the agent (final concentration 0-400 nM) was stimulated for 20 minutes. After removing the medium, the cells were fixed with 200 μl of 3.7% freshly prepared trimeric formaldehyde (diluted with Sigma, lx PBS) for 2 minutes. The supernatant was discarded and 200 μl of ixPBS + 〇 1 % Trit〇n_x_1〇〇 m 201141513 solution was added to permeabilize the cells for 20 minutes. The osmotic solution was removed and a blocking buffer (Odyssey Blocking Buffer, Lic〇r) was added for development. After 4 hours (: 12 hours later, 50 μl of anti-phosphorylated insulin receptor (anti-pIR (pY 1162/63), 1.600 in blocking buffer, Bi〇source) one-stage antibody or general phosphate cheese The amine-specific antibody (4 (} 10, i: 1000, Upstate) was added to the fixed cell layer and incubated for 2 hours at room temperature. The cells were treated with 200 μl of solution containing lxPBS + 〇·ι % Tween 2〇. Wash five times with 50 μl of secondary anti-rabbit IgG_8〇〇_cw antibody (1:1, hydrazine in blocking buffer, Rockland) or anti-mouse-IgG-800-CW Antibody (1.1,000 in blocking buffer, sputum (^1&amp;11(1) and 1^ human dye T0-PR03 (1.5,000 in blocking buffer, Molecular Probes) culture (protected from light) The system was used for cell number correction. After 1 hour, the cell layer was washed five times with 200 μl of a solution containing lx PBS + 0.1% Tween 20, and the cells at 700 and 800 nm were measured using an Odyssey infrared imaging system (Licor Biosciences). Optical signal. The relative EC50 concentration of human recombinant insulin and insulin binding agent was determined in each experiment using the relative fluorescent signal (RU) of the antibody, and then the number of experiments will be performed. According to the average. Example 24 Lipolytic analysis of human visceral or subcutaneous preadipocytes (Lonza, Verviers, model #PT-5005, donor 5F0246, or model #PT5001, donor 2F0963) in endothelial cell growth medium MV" low serum Mit added amplification in Mix (PromoCell, Heidelberg). Pre-adipocytes were plated in 187 201141513 96-well plates (2, 8x104 cells/well) for differentiation. After attachment, pre-adipocytes were described as Viceenati et al. Differentiated into mature adipocytes with the following modifications: Into the differentiation, the first three days were added 1〇nM L-Thyroxine (Sigma, Karlsruhe); during the whole differentiation period, the medium was supplemented with 15 mM Hepes pH 7, 4 (Sigma , Karlsruhe), PPAR7 accelerator (100 nM) and antibiotic-antimycotic (Invitrogen, Karlsruhe, ΙΟΟχ, diluted 1:160). Two weeks after the start of differentiation (usually on days 14, 15 or 16), fat cells The medium was changed to an adipocyte medium without insulin and PPARr promoter for 16 hours. The fat cells were then PBS (Invitrogen, Karlsruhe) +1 ° /. The fatty acid-free BSA (MP Biomedicals, Heidelberg) was washed twice; then, medium 199 (Pan-Biotech, Aidenbach) + was added to each well to supplement the 1% fatty acid-free BSA of the test compound at the appropriate concentration. After incubating for 4 hours at 5% C02 atmosphere and 37 ° C, the supernatant was carefully removed. Glycerol and unesterified fatty acid content was measured using a glycerol reagent (WAK Chemie, Steinbach/Taunus) or Nefa-HR2 kit (Wako Chemicals, Neuss) according to the manufacturer's instructions. • Vicenati et al. (2002), InU Obes 26, 905-911. Example 25 Glucose uptake The visceral or subcutaneous preadipocytes were plated into 96-well Cytostar-T plates (GE Healthcare, Miinchen) and differentiated into mature adipocytes as described in the lipolytic assay above. One week after the start of differentiation (usually at 7 188 201141513 or 8 days), the fat cell medium was changed to a medium without insulin, FCS and dexamethasone for 16 hours. The cells were washed twice with PBS (Invitrogen, Karlsruhe), and then KRB (120 mM NaCl, 25 mM NaHC03, 4, 8 mM KC1, 1, 2 mM MgS04, 1, supplemented with the appropriate concentration of the test compound was added to each well. 2 mM KH2PO4, 1,7 mM CaCl2, adjusted to ~pH 7,4 with carbogen, all chemicals from Merck, Darmstadt). After incubation for 40 minutes at 5% C02 atmosphere and 37 ° C, C14 deoxygen-glucose (GE Healthcare, Miinchen) was added to a final concentration of 6.6 mM and the cells were incubated for an additional 20 minutes at 5% CO 2 atmosphere and 37 ° C. Glucose uptake was stopped by the addition of Cytochalasin B (Sigma, Taufkirchen; final concentration: 20 μM); the radioactivity was calculated using a Micro Beta Trilux instrument (Perkin Elmer, Rodgau). Example 26 Selected examples of insulin activity compilation: Example 13 EC50: 255 nM (IR phosphorylation) EC50: 1.05 nM (monthly solution (visceral) analysis) EC50: 23 nM (glucose absorption (visceral) analysis) Example 14 EC50: 121 nM (IR phosphorylation) 189 201141513 EC50 · · 0·617ηΜ (lipid (visceral) analysis) EC50 : 20nM (glucose absorption (visceral) analysis) Example 15 EC50 : 120nM (IR phosphorylation) EC50 : 0.824nM (month Analysis (visceral) analysis) EC50: 23nM (glucose absorption (visceral) analysis) EC50: 43nM (glucose absorption (subcutaneous) analysis) Example 16 EC50: 138nM (IR phosphorylation) EC50: 1.286nM (monthly solution ( Visceral) analysis) EC50: 42nM (glucose absorption (subcutaneous) analysis) Example 17 EC50: 132nM (IR phosphorylation) EC50: 0.665nM (monthly solution (visceral) analysis) EC50: 16nM (glucose absorption (subcutaneous) analysis) Example 18 EC50: >400 nM (IR phosphorylation) EC50: 2·569ηΜ (monthly solution (visceral) analysis) EC50: 36ηΜ (glucose absorption (visceral) analysis) 190 201141513 Example 19 EC50: 71.5 nM (IR phosphoric acid) EC50: 0.569nM (lipid (visceral) analysis) Example 20 EC50 : 43.8nM ( IR phosphorylation) EC50: 0.713 nM (lipid (visceral) analysis) EC50: 39 nM (glucose absorption (visceral) analysis) Example 21 EC50: 34.4 nM (IR phosphorylation) EC50: 0.650 nM (lipid solution (viscera) Analytical) EC50: 10 nM (glucose uptake (visceral) analysis) Example 22 EC50: 106.8 nM (IR phosphorylation) EC50: 1.709 nM (lipid (visceral) analysis) Example 27 21mer siRNA sequence with human PTP-1B The 21mer siRNA sequence of the standard is applied to Dharmacon's siRNA design tool (http://www.dharmacon.com/DesignCenter/Design CenterPage.aspx), and the GenoQuest's Sanofi-Aventis performs the RNAi functionality of 191 201141513 (http://genomequest. Sanofi-aventis.com) or by re-synthesis of pre-designed siRNAs from Dharmacon and Qiagen. In addition, 40 siRNAs were individually selected from the characteristics of human, mouse and rat PTP-1B sequences. The sequence of the non-silent siRNA control group was selected based on Sanofi-Aventis internal bioinformatics prediction and validation. All 21 mer siRNA lines that were not chemically modified were synthesized by Qiagen's but the referenced siRNA (#41) was purchased from Dharmacon and included in each experiment. The siRNA sequences are shown in Table 1. Example 28 25/27mer Dicer Matrix siRNA Sequence: Dicer Matrix siRNA (DsiRNAs) Targeting Human PTP-1B, Using Integrated DNA Technologies' (IDT) siRNA Design Tool (http://eu.idtdna.eom/Scitools /Applications/RNAi/RNAi.a spx), designed by converting a functional 21mer to a 25/27mer sequence or pre-designed at Bio-Rad (model 179-0311, 179-0411). This custom DsiRNA and a pre-designed non-silent Dicer matrix siRNA control were purchased from IDT. The DsiRNA sequences are shown in Table 2. Example 29 mRNA knuck-down analysis 192 201141513

PTP-1B mRNA knockdown by free, unbound (D) siRNA or 姨- siRNA-binding agent was determined in human HepG2 cells containing mM sodium pyruvate, lx MEM non-essential amine Growth was carried out in a collagen I cell-coated culture flask of acid, 2 mM L-glutamine and 10% FCS in MEM medium. For the free (D) siRNA transfection experiment, the lxlO4 HepG2 cells per well in a 96-well plate coated with collagen I were reverse-stained using 0.2 μl of Lipofectamine RNAiMAX and 5 or 50 nM (D) siRNA at 100. The total volume of microliters was incubated for 24 hours according to the manufacturer's instructions. The insulin-siRNA binding agent was transfected using the Lipofectamine 2000 method and 0.3 microliter of reagent per well. After the medium was changed and further cultured for 24 hours, the cells were dissociated and the amount of PTP-1B mRNA was quantified using a branch-DNA-technology-based QuantiGene reagent system (Panomics). Cell dissociation was accomplished by removing the cell culture medium and adding 200 microliters of a dissociation mixture containing 0.33 micrograms per microliter of proteinase K, pre-warmed at 37 °C, diluted 1:3. Before or after incubation at 65 ° C for 90 minutes, the cell dissociation solution was pipetted 5-10 times to completely suspend it, followed by a secondary freeze/thaw cycle. PTP-1B was quantified by mixing 20 μl of the probe set with 2 μL of the diluted dissociation mixture and 60 μl of cell dissociation solution, transferring it to a capture tray and incubating at 55 ° C overnight. For the quantification of the normalized RPL37a rnRNAs, a 2 〇 microliter probe set was mixed with 6 〇 microliter of the diluted dissociation mixture and 20 μl of a 1:4 〇 diluted cell dissociation solution. All other conditions are based on the pan〇mics instructions. Sample readings were taken using a Tecan GENi〇S ΡΓ〇 luminescence reader. For the determination of PTP-1B 193 201141513 mRNA knockdown, the background 値, normalized and mean performance was subtracted by the mean performance of the non-silent (D) siRNA RNA control group, all tested = PTP_lB(D) siRNA and The relative residual performance of the island-siRNA binding agent is summarized in Tables 3a-c. Example 30 Fluorescence Microscopy HEK293 cells overexpressing human insulin receptor were placed in a fibronectin-coated μ-dishes dish (Ibidi, Martinsried) and in DMEM/10% FCS at 5% C02 Incubate for 48 hours in the atmosphere at 370C. For the internalization study, cells were washed twice with PBS and then DMEM supplemented with 10 μM of insulin-labeled conjugated insulin-catalyzed Example 21 was added. After incubation for 20 minutes at 5% C 〇 2 atmosphere and 37 ° C, it was again washed twice with PBS and then placed on a conditioned PVCOLeica TCS-SP2 conjugated focus microscope. The internalization was monitored online at 37 ° C ' DMEM for up to 20 minutes. In the control experiment, HEK cells without excessive expression of the insulin receptor were treated as described. Examples are as described in Figure 1+2. 194 201141513

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Co H〇 ττ 201141513 [Simplified Schematic] Figure 1: HEK293 cells overexpressing the insulin receptor were cultured at 37 ° C with the binding agent of Example 21. Figure 2: HEK293 cells that did not overexpress the insulin receptor were cultured at 37 °C with the binding agent of Example 21. 222 201141513 Sequence Listing &lt;110> sanofi-aventis &lt;120&gt; Insulin-siRNA Conjugate&lt;130> DE2010/078 &lt;160&gt; 249 &lt;170> Patentln Version 3.3 &lt;210> 1 &lt;211&gt; 21 &lt;;212>DNA&lt;213>artificial&lt;220>&lt;223&gt;&lt;400> 1 cuuccuaaga acaaaaacct t 21 &lt;210> 2 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400> 2 gguuuuuguu cuuaggaagc t 21 &lt;210> 3 &lt;211> 21 201141513 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; Uuccuaagaa caaaaaccgt t 21 &lt;210> 4 &lt;211> 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400> 4 cgguuuuugu ucuuaggaag c 21 &lt;210> 5 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 5 gaagauaaug acuauaucat t 21 &lt;210> 6 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; 201141513 &lt;220> &lt;223&gt;&lt;400> 6 ugauauaguc auuaucuuct t 21 &lt;210> 7 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt;&lt;220>&lt;223&gt;&lt;400> 7 aagauaauga cuauaucaat t 21 &lt;210> 8 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400 〉 8 uugauauagu cauuaucuuc 21 &lt;210> 9 &lt;211> 21 &lt;212&gt; DNA &lt;213&gt; man-made 3 &lt;220> 201141513 &lt;223&gt;&lt;400> 9 ugggagaugg ugugggagct t 21 &lt;210> 10 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 10 gcucccacac caucucccaa a 21 &lt;210> 11 &lt;211> 21 &lt;212> &lt;213&gt;;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 11 gggagauggu gugggagcat t 21 &lt;210> 12 &lt;211> 21 &lt;212> &lt;213&gt; DNA artificial &lt;220> &lt;223&gt; 4 201141513 &lt;400&gt; 12 ugcucccaca ccaucuccca a 21 &lt;210> 13 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 13 ggagauggug ugggagcagt t 21 &lt ;210> 14 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 14 c Ugcucccac accaucuccc a 21 &lt;210> 15 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 15 gagauggugu gggagcagat t 21 5 201141513 &lt;210&gt; 16 &lt;;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 16 ucugcuccca caccaucucc c 21 &lt;210> 17 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; Artificial &lt;220> &lt;223&gt;&lt;400&gt; 17 agauggugug ggagcagaat t 21 &lt;210> 18 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt;manmade &lt;220&gt;&lt;223&gt;&lt;;400&gt; 18 uucugcuccc acaccaucuc c 21 6 201141513 &lt;210> 19 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 19 uggccugacu uuggagucct t 21 &lt; 210> 20 &lt;211> 21 &lt;212> &lt;213> &lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 20 ggacuccaaa gucaggccat g 21 &lt;210> 21 &lt;211&gt; 21 &lt;212&gt;&lt;213〉&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 21 ggccugacuu uggaguccct t 21 &lt;210> 22 &lt;211 21 7 201141513 &lt;212> DNA &lt;213> &lt;220> &lt;223&gt; artificial &lt;400> 22 gggacuccaa agucaggcca t 21 &lt;210> 23 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;;220>&lt;223&gt; DNA artificial &lt;400> 23 uucaaagucc gagagucagt t 21 &lt;210> 24 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt; 400> 24 cugacucucg gacuuugaaa a 21 &lt;210> 25 &lt;211> 21 &lt;212> &lt;213&gt; DNA artificial 8 201141513 &lt;220> &lt;223&gt;&lt;400&gt; 25 ucaaaguccg agagucaggt t 21 &lt;210&gt 26 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 26 ccugacucuc ggacuuugaa a 21 &lt;210> 27 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400&gt; 27 cugauggaca agaggaaagt t 21 &lt;210&gt; 28 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; man-made 9 &lt;220&gt; 201141513 &lt;223&gt;&lt;400&gt; 28 cuuuccucuu guccaucagc a 21 &lt;210> 29 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;Lt;223&gt; DNA artificial &lt;400> 29 ugauggacaa gaggaaagat t 21 &lt;210> 30 &lt;211&gt; 21 &lt;212&gt;&lt;213>&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 30 Ucuuuccucu uguccaucag c 21 &lt;210> 31 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 10 201141513 &lt;400&gt; 31 gauggacaag aggaaagact t 21 &lt;210> 32 &lt;;211> 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400&gt; 32 gucuuuccuc uuguccauca g 21 &lt;210> 33 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 33 auggacaaga ggaaagacct t 21 &lt;210&gt; 34 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt; 400> 34 ggucuuuccu cuuguccauc a 21 11 201141513 &lt;210> 35 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 35 uggacaagag gaaagaccct t 21 &lt; 210> 36 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 36 gggucuuuc c ucuuguccat c 21 &lt;210> 37 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400&gt; 37 cugcgcuucu ccuaccuggt t 21 12 201141513 &lt;210&gt; 38 &lt;;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 38 ccagguagga gaagcgcagc t 21 &lt;210> 39 &lt;211&gt; 21 &lt;212&gt;&lt;220>&lt;223> DNA artificial &lt;400&gt; 39 ugcgcuucuc cuaccuggct t 21 &lt;210&gt; 40 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt; 400> 40 gccagguagg agaagcgcag c 21 &lt;210> 41 &lt;211&gt; 21 13 201141513 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 41 gcgcuucucc uaccuggcut t 21 &lt; 210> 42 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400> 42 agccagguag gagaagcgca g 21 &lt;210> 43 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400&gt; 43 cgcuucuccu accuggcugt t 21 &lt;210> 44 &lt;211&gt; 21 &lt;212 DNA &lt;213&gt; man-made 14 201141513 &lt;220> &lt;223&gt;&lt;400&gt; 44 cagccaggua ggagaagcgc a 21 &lt;210&gt; 45 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; man-made &lt;220 〉 &lt;223&gt;&lt;400&gt; 45 gcuucuccua ccuggcugut t 21 &lt;210&gt; 46 &lt;211> 21 &lt;212&gt; DNA &lt;213 &gt; 213 &lt;220&gt;&lt;223&gt;&lt;400&gt; 46 acagccaggu aggagaagcg c 21 &lt;210&gt; 47 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; man-made 15 &lt;220&gt; 201141513 &lt;223&gt;&lt;400&gt; 47 gugcaggauc aguggaaggt t 21 &lt;210&gt; 48 &lt;211 〉 21 &lt;212&gt; DNA &lt;213>artificial &lt;220&gt;223&gt;&lt;400>48 ccuuccacug auccugcacg g 21 &lt;210> 49 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt;&lt;220&gt;223&gt;&lt;400&gt; 49 ugcaggauca guggaaggat t 21 &lt;210&gt; 50 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt;manmade &lt;220&gt;&lt;223&gt; 16 201141513 &lt;;400> 50 uccuuccacu gauccugcac g 21 &lt;210> 51 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt;DNA造&lt;400&gt; 51 gcaggaucag uggaaggagt t 21 &lt;210> 52 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 52 cuccuuccac ugauccugca c 21 &lt ;210> 53 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 53 caggaucagu ggaaggagct t 21 17 201141513 &lt;210> 54 &lt;211> 21 &lt;;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400&gt; 54 gcuccuucca cugauccugc a 21 &lt;210&gt; 55 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt; 400> 55 aggaucagug gaaggagcut t 21 &lt;210&gt; 56 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213>artificial &lt;220> &lt;223&gt;&lt;400&gt; 56 agcuccuucc acugauccug c 21

&lt;210&gt; 57 &lt;211&gt; 21 &lt;212> DNA 18 201141513 &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400> 57 cccccaccuc cccggccact t 21 &lt;210> 58 &lt;211&gt;&lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400&gt; 58 guggccgggg aggugggggg a 21 &lt;210> 59 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; artificial &lt;;220&gt;&lt;223&gt;&lt;400&gt; 59 ccccaccucc ccggccacct t 21 &lt;210> 60 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; man-made 19 201141513 &lt;220> &lt;223&gt;&lt;400 〉 60 gguggccggg gagguggggg g 21 &lt;210&gt; 61 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 61 cccaccuccc cggccaccct t 21 &lt;210> 62 &lt ;211> 21 &lt;212> &lt;213> &lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 62 ggguggccgg ggaggugggg g 21 &lt;210> 63 &lt;211> 21 &lt;212> &lt;213&gt; DNA artificial &lt;220> &lt;223&gt; 20 201141513 &lt;400> 63 ccaccucccc ggccacccat t 21 &lt;210> 64 &lt;211> 21 &lt;212&gt; DNA &lt;213&gt;manmade &lt;220&gt;&lt;223&gt;&lt;400&gt; 64 uggguggccg gggagguggg g 21 &lt;210&gt; 65 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; man-made &lt;220&gt;223&gt;&lt;400&gt; 65 caccuccccg gccacccaat t 21 &lt;210&gt; 66 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt;manmade &lt;220&gt;&lt;223&gt;&lt;400&gt;&gt;400 21 201141513 uuggguggcc ggggaggugg g 21 &lt;210> 67 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 67 accuccccgg ccacccaaat t 21 &lt;210> 68 &lt;211> 21 &lt;;212>&lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400> 68 uuuggguggc cggggaggug g 21 &lt;210> 69 &lt;211&gt; 21 &lt;212> .&lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400&gt; 69 ccuccccggc cacccaaact t 21 22 201141513 &lt;210&gt; 70 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 70 guuugggugg ccggggaggt g 21 &lt;210> 71 &lt;211> 21 &lt;212&gt;&lt;213>&lt;220>&lt;223&gt; DNA artificial &l t;400&gt; 71 cuccccggcc acccaaacgt t 21 &lt;210> 72 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 72 cguuugggug gccggggagg t 21 &lt;210&gt 73 23 201141513 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 73 acuggaagcc cuuccuggut t 21 &lt;210&gt; 74 &lt;211&gt; 21 &lt;212&gt ; DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400> 74 accaggaagg gcuuccagua a 21 &lt;210&gt; 75 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; man-made &lt;220&gt;&lt;223&gt;&lt;400〉 75 cuggaagccc uuccugguct t 21

&lt;210> 76 &lt;211> 21 &lt;212> DNA 24 201141513 &lt;213> Artificial &lt;220> &lt;223&gt;&lt;400> 76 gaccaggaag ggcuuccagt a 21 &lt;210> 77 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 77 uggaagcccu uccuggucat t 21 &lt;210> 78 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 78 ugaccaggaa gggcuuccag t 21 &lt;210> 79 &lt;211> 21 &lt;212&gt;&lt;213&gt; DNA artificial 25 201141513 &lt;220&gt;&lt;223&gt;&lt;400 〉 79 ggaagcccuu ccuggucaat t 21 &lt;210〉 80 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 80 uugaccagga agggcuucca g 21 &lt;210> 81 &lt ;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 81 gaucgaaggu gccaaauuct t 21 &lt;210> 82 &lt;211> 21 &lt;212&gt;&lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 26 201141513 &lt;400> 82 gaauuuggca ccuucgauca c 21 &lt;210> 83 &lt;211&gt; 21 &l t; 212> &lt;213> &lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 83 ggauuaaacu acaucaagat t 21 &lt;210> 84 &lt;211&gt; 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400&gt; 84 ucuugaugua guuuaauccg a 21 &lt;210&gt; 85 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 27 201141513 cugaagauau caagucauat t 21 &lt;210> 86 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 86 uaugacuuga uaucuucaga g 21 &lt;210> 87 &lt;;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223> DNA artificial &lt;400> 87 gaccauaguc ggauuaaact t 21 &lt;210&gt; 88 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223> DNA artificial &lt;400> 88 guuuaauccg acuaugguca a 21 28 201141513 &lt;210> 89 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 89 ggagaaaggu ucguuaaaat t 21 &lt;210> 90 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt DNA artificial &lt;400&gt; 90 uuuuaacgaa ccuuucucca t 21 &lt;210> 91 &lt;211&gt; 21 &lt;212> &lt;213&gt; DNA artificial &lt;220> &lt;223&gt;&lt;400&gt; 91 cuaccuggcu gugaucgaat t 21 &lt;210> 92 29 201141513 &lt;211&gt; 21 &lt;212&gt;&lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400> 92 uucgaucaca gccagguagg a 21 &lt;210> 93 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 93 gcccaaagga guuacauuct t 21 &lt;210&gt; 94 &lt;211> 21 &lt;212> &lt;213&gt; 〉 &lt;223&gt; DNA artificial &lt;400> 94 gaauguaacu ccuuugggct t 21

&lt;210&gt; 95 &lt;211&gt; 21 &lt;212> DNA 30 201141513 &lt;213&gt; Artificial &lt;220> &lt;223&gt;&lt;400> 95 gcgacagcua gaauuggaat t 21 &lt;210> 96 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 96 uuccaauucu agcugucgca c 21 &lt;210&gt; 97 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 97 gccucauucu ugaacuuuct t 21 &lt;210&gt; 98 &lt;211> 21 &lt;212&gt;&lt;213> DNA artificial 31 201141513 &lt;220> &lt;223&gt;&lt;400 〉 98 gaaaguucaa gaaugaggct g 21 &lt;210> 99 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400> 99 cguggguauu uaauaagaat t 21 &lt;210> 100 &lt ;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 100 uucuuauuaa auacccacgt g 21 &lt;210> 101 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; Artificial &lt;220> &lt;223&gt; 32 201141513 &lt;400&gt; 101 ggcaugccgc gguagguaat t 21 &lt;210> 102 &lt;211&gt; 21 &lt;2 12> DNA &lt;213>artificial &lt;220&gt;&lt;223&gt;&lt;400> 102 uuaccuaccg cggcaugcct g 21 &lt;210> 103 &lt;211&gt; 21 &lt;212> DNA &lt;213>artificial &lt;220 〉 &lt;223&gt;&lt;400> 103 ggaauaggca uuugccuaat t 21 &lt;210> 104 &lt;211> 21 &lt;212> DNA &lt;213>artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 104 33 201141513 Uuaggcaaau gccuauucct g 21 &lt;210> 105 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 105 uuucaaaguc cgagagucat t 21 &lt;210&gt; 106 &lt;211&gt 21 &lt;212&gt;&lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400> 106 ugacucucgg acuuugaaaa g 21 &lt;210&gt; 107 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt; 220> &lt;223&gt; DNA artificial &lt;400&gt; 107 ccacauggcc ugacuuuggt t 21 34 201141513 &lt;210&gt; 108 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DMA artificial &lt;223&gt;;400> 108 ccaaagucag gccauguggt a 21 &lt;210&gt; 109 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&gt; DNA artificial &lt;400> 109 aagcuuccua agaacaaaat t 21 &lt;210> 110 &lt;211&gt; 21 &lt;212> &lt;213> &lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; no uuuuguucuu aggaagcuug g 21 &lt;210&gt; 111 35 201141513 &lt;211&gt; 21 &lt;212>DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400&gt; 111 ccaagaaacu cgagagauct t 21 &lt;210&gt; 112 &lt;211 〉 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400> 112 gaucucucga guuucuuggg t 21 &lt;210&gt; 113 &lt;211> 21 &lt;212>DNA &lt;213&gt;&lt;220〉&lt;223&gt;&lt;400> 113 gcacaauacu ggccacaaat t 21

&lt;210> 114 &lt;211> 21 &lt;212> DNA 36 201141513 &lt;213> Artificial &lt;220> &lt;223&gt;&lt;400&gt; 114 uuuguggcca guauugugcg c 21 &lt;210> 115 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 115 uuacaauggc cauggaauat t 21 &lt;210> 116 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 116 uauuccaugg ccauuguaaa a 21 &lt;210> 117 &lt;211> 21 &lt;212> &lt;213> DNA artificial 37 201141513 &lt;220> &lt;223&gt;&lt;400&gt; 117 agaaagugcu guuagaaaut t 21 &lt;210> 118 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 118 auuucuaaca gcacuuucut g 21 &lt;210> 119 &lt;;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 119 cugaagaccu ccacauuaat t 21 &lt;210&gt; 120 &lt;211> 21 &lt;212&gt;&lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 38 201141513 &lt;400> 120 uuaaugugga ggucuucagt t 21 &lt;210&gt; 121 &Lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 121 caacagagug auggagaaat t 21 &lt;210> 122 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;;&lt;220>&lt;223&gt; DNA artificial &lt;400> 122 uuucuccauc acucuguuga g 21 &lt;210> 123 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 123 39 201141513 aagaaagugc uguuagaaat t 21 &lt;210&gt; 124 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 124 uuucuaacag cacuuucuug a 21 &lt ; 210> 125 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 125 ccgagaagga cgaggaccat t 21 &lt;210> 126 &lt;211&gt; 21 &lt;212 〉 &lt;213&gt;&lt;220〉&lt;223&gt; DNA artificial &lt;400> 126 ugguccucgu ccuucucggg c 21 40 201141513 &lt;210> 127 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;;223&gt; DNA artificial &lt;400> 127 cgaaauaggu acagagacgt t 21 &lt;210&gt; 128 &lt;211&gt; 21 &lt;212&gt;Lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400> 128 cgucucugua ccuauuucgg t 21 &lt;210> 129 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 129 ggaagaagcc caaaggagut t 21 &lt;210&gt; 130 41 201141513 &lt;211> 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400> 130 acuccuuugg gcuucuucca t 21 &lt;210> 131 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 131 ucaacagagu gauggagaat t 21 &lt;210&gt; 132 &lt;211&gt;&lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 132 uucuccauca cucuguugag c 21

&lt;210> 133 &lt;211> 21 &lt;212&gt; DNA 42 201141513 &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 133 gagaaagguu cguuaaaaut t 21 &lt;210&gt; 134 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 134 auuuuaacga accuuucucc a 21 &lt;210&gt; 135 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 135 auaaugaaca cguggguaut t 21 &lt;210> 136 &lt;211&gt; 21 &lt;212> &lt;213> DNA artificial 43 201141513 &lt;220> &lt;223&gt;&lt;400 〉 136 auacccacgu guucauuaua t 21 &lt;210> 137 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400&gt; 137 uuagugauau uguggguaat t 21 &lt;210> 138 &lt;;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 138 uuacccacaa uaucacuaaa t 21 &lt;210> 139 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 44 201141513 &lt;400&gt; 139 aaauggacgu acugguuuat t 21 &lt;210> 140 &lt;211&gt; 21 &lt;212>DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 140 uaaaccagua cguccauuut g 21 &lt;210&gt; 141 &lt;211&gt; 21 &lt;212> DNA &lt; 213 &gt; artificial &lt;220&gt;223&gt;&lt;400> 141 aggaagagac ccaggaggat t 21 &lt;210> 142 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; man-made &lt;220&gt;&lt;223&gt;&lt;400&gt; 142 45 201141513 aggaagagac ccaggaggat t 21 &lt;210> 143 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 143 aggaagagac ccaggaggat t 21 &lt ;210> 144 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 144 uuugauaaag cccuugaugc a 21 &lt;210&gt; 145 &lt;211> 21 &lt;212 〉 &lt;213&gt;&lt;220〉&lt;223&gt; DNA artificial &lt;400> 145 agaagccagu acagagaaat t 21 46 201141513 &lt;210&gt; 146 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;;223> DNA artificial &lt;400&gt; 146 uuucucugua cuggcuucua c 21 &lt;210> 147 &lt;211> 21 &lt;212〉 &lt;213&g t; &lt;220> &lt;223&gt; DNA artificial &lt;400> 147 ucaagaaagu gcuguuagat t 21 &lt;210> 148 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 148 ucuaacagca cuuucuugat a 21 &lt;210&gt; 149 47 201141513 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 149 gaagagaccc aggaggauat t 21 &lt;210> 150 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400> 150 uauccuccug ggucucuucc t 21 &lt;210> 151 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 151 cuauaugccu uaagccaaut t 21

&lt;210> 152 &lt;211&gt; 21 &lt;212> DNA 48 201141513 &lt;213&gt; Artificial &lt;220> &lt;223&gt;&lt;400> 152 auuggcuuaa ggcauauagc a 21 &lt;210> 153 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 153 gaagaagccc aaaggaguut t 21 &lt;210> 154 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 154 aacuccuuug ggcuucuucc a 21 &lt;210> 155 &lt;211> 21 &lt;212&gt;&lt;213&gt; DNA artificial 49 201141513 &lt;220> &lt;223&gt;&lt;400&gt; 155 caaaggaguu acauucuuat t 21 &lt;210> 156 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 156 uaagaaugua acuccuuugg g 21 &lt;210> 157 &lt;;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 157 aagagaccca ggaggauaat t 21 &lt;210> 158 &lt;211> 21 &lt;212> &lt;213&gt; DNA artificial &lt;220〉 &lt;223> 50 201141513 &lt;400> 158 uuauccuccu gggucucuuc c 21 &lt;210&gt; 159 &lt ;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 159 gguuguaagc aguuguuaut t 21 &lt;210> 160 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; Artificial &lt;220> &lt;223&gt;&lt;400&gt; 160 auaacaacug cuuacaaccg t 21 &lt;210> 161 &lt;211> 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;;400&gt; 161 51 201141513 gcuauaugcc uuaagccaat t 21 &lt;210> 162 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400&gt; 162 uuggcuuaag gcauauagca g 21 &lt;210&gt; 163 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 163 ggagccacac aaugggaaat t 21 &lt;210> 164 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 164 uuucccauug uguggcucca g 21 52 201141513 &lt;210> 165 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 165 gaggagagug aaagagagut t 21 &lt;210> 166 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 166 acucucuuuc acucuccuca a 21 &lt;210> 167 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;;400&gt; 167 ggagagugaa agagaguact t 21 &lt;210&gt; 168 53 201141513 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 168 guacucucuu ucacucucct c 21 &lt;210&gt; 169 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 169 gcaucaaggg cuuuaucaat t 21 &lt;210&gt; 170 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt;manmade &lt;220&gt;&lt;223&gt;&lt;400&gt; 170 uugauaaagc ccuugaugca a 21

&lt;210&gt; 171 &lt;211&gt; 21 &lt;212&gt; DNA 54 201141513 &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 171 uggagaaagg uucguuaaat t 21 &lt;210> 172 &lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 172 uuuaacgaac cuuucuccat c 21 &lt;210> 173 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400&gt; 173 cauauuauac agugcgacat t 21 &lt;210&gt; 174 &lt;211&gt; 21 &lt;212> &lt;213> DNA artificial 55 201141513 &lt;220> &lt;223> &lt;400 〉 ugu ug ug ua ua ua ua ua ;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 176 aguuucuugg guuguaaggt t 21 &lt;210> 177 &lt;211> 21 &lt;212&gt;&lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 56 201141513 &lt;400> 177 gcaucgaaag caugagucat t 21 &lt;210> 178 &lt; 21 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 178 ugacucaugc uuucgaugcc g 21 &lt;210> 179 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213&gt; Artificial &lt;220> &lt;223&gt;&lt;400&gt; 179 aagcaugagu caagacacut t 21 &lt;210> 180 &lt;211> 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 180 57 201141513 agugucuuga cucaugcuut c 21 &lt;210&gt; 181 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 181 gagucaagac acugaaguut t 21 &lt;210&gt ; 182 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 182 aacuucagug ucuugacuca t 21 &lt;210> 183 &lt;211> 21 &lt;212&gt;;213>&lt;220>&lt;223&gt; DNA artificial &lt;400&gt; 183 ggaaggagga cgguuguaat t 21 58 201141513 &lt;210> 184 &lt;211&gt; 21 &lt;212&gt;&lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400〉 184 uuacaaccgu ccuccuuccc a 21 &lt;210> 185 &lt;211> 21 &lt;212〉 &lt;213&g t; &lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 185 gugccaggcu guaagcauut t 21 &lt;210> 186 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 186 aaugcuuaca gccuggcacc t 21 &lt;210&gt; 187 59 201141513 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 187 cguuaaaaug cgcacaauat t 21 &lt;210> 188 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 188 uauugugcgc auuuuaacga a 21 &lt;210> 189 &lt;211&gt; 21 &lt; 212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 189 gccucuugcu gauggacaat t 21

&lt;210&gt; 190 &lt;211> 21 &lt;212> DNA 60 201141513 &lt;213> Artificial &lt;220&gt;&lt;223&gt;&lt;400> 190 uuguccauca gcaagaggca g 21 &lt;210> 191 &lt;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 191 ggaaaugcag ggaguucuut t 21 &lt;210> 192 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 192 aagaacuccc ugcauuuccc a 21 &lt;210> 193 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt; DNA artificial 61 201141513 &lt;220> &lt;223&gt;&lt;400&gt 193 agucaagaca cugaaguuat t 21 &lt;210> 194 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400&gt; 194 uaacuucagu gucuugacuc a 21 &lt;210&gt; 195 &lt;;211> 21 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 195 cgucacugcc cgagaaggat t 21 &lt;210> 196 &lt;211> 21 &lt;212> &lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 62 201141513 &lt;400&gt; 196 uccuucucgg gcagugacgg c 21 &lt;210> 197 &l 21; &lt; 211 &gt; 21 &lt; 213 &lt; 213 &lt; 220 &lt; 223 &gt; DNA artificial &lt;400 &gt; 197 uaauaaaucc ucagguagut t 21 &lt;210> 198 &lt;211&gt; 21 &lt;212&gt;&lt;213 〉 &lt;220〉 &lt;223&gt; DNA artificial &lt;400> 198 acuaccugag gauuuauuat t 21 &lt;210> 199 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 199 63 201141513 guccaaccug ccugugcaut t 21 &lt;210&gt; 200 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223> DNA artificial &lt;400> 200 augcacaggc agguuggact t 21 &lt ; 210> 201 &lt;211&gt; 21 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 201 cgaggaccau gcacugagut t 21 &lt;210&gt; 202 &lt;211> 21 &lt;212 〉 &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 202 acucagugca ugguccucgt c 21 64 201141513 &lt;210&gt; 203 &lt;211> 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;;223&gt; DNA artificial &lt;400> 203 gcaugacacu cuagugacut t 21 &lt;210&gt; 204 &lt;211> 21 &lt;212〉 &l t; 213> &lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 204 agucacuaga gugucaugcc a 21 &lt;210&gt; 205 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400&gt; 205 guagaagcca guacagagat t 21 &lt;210&gt; 206 65 201141513 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 206 ucucuguacu ggcuucuacc a 21 &lt;210> 207 &lt;211> 21 &lt;212&gt;&lt;213>&lt;220>&lt;223> DNA artificial &lt;400> 207 uaagaaacau gaugugagat t 21 &lt;210> 208 &lt;211&gt; 21 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 208 ucucacauca uguuucuuat t 21

&lt;210> 209 &lt;211> 21 &lt;212> DNA 66 201141513 &lt;213&gt; Artificial &lt;220> &lt;223&gt;&lt;400&gt; 209 ccaggauauc cgacaugaat t 21 &lt;210&gt; 210 &lt;211&gt;&lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400&gt; 210 uucaugucgg auauccuggt a 21 &lt;210&gt; 211 &lt;211> 21 &lt;212&gt; DNA &lt;213&gt; 220> &lt;223&gt;&lt;400> 211 accgaaauag guacagagat t 21 &lt;210> 212 &lt;211&gt; 21 &lt;212&gt; DNA &lt;213>artificial 67 201141513 &lt;220&gt;&lt;223&gt;&lt;400 〉 212 ucucuguacc uauuucggut t 21 &lt;210> 213 &lt;211> 21 &lt;212> &lt;213> &lt;220> &lt;223> DNA artificial &lt;400> 213 gccuguugcu gaagucauut t 21 &lt;210> 214 &lt;;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 214 aaugacuuca gcaacaggct t 21 &lt;210> 215 &lt;211> 21 &lt;212> &lt;213&gt; DNA artificial &lt;220&gt;&lt;223&gt; 68 201141513 &lt;400> 215 acacgugggu auuuaauaat t 21 &lt;210> 216 &lt;211> 21 &l t; 212>DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400> 216 uuauuaaaua cccacgugut c 21 &lt;210> 217 &lt;211&gt; 21 &lt;212> DNA &lt;213>artificial &lt;;220&gt;&lt;223&gt;&lt;400> 217 ccauagucgg auuaaacuat t 21 &lt;210&gt; 218 &lt;211&gt; 21 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400> 218 69 201141513 uaguuuaauc cgacuauggt c 21 &lt;210> 219 &lt;211> 21 &lt;212&gt;&lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400> 219 cggauuaaac uacaucaagt t 21 &lt;210> 220 &lt;;211> 21 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400> 220 cuugauguag uuuaauccga c 21 &lt;210> 221 &lt;211> 25 &lt;212> &lt;213&gt;&lt;220>&lt;223&gt; DNA artificial &lt;400> 221 gaucgaaggu gccaaauuca ucatg 25 70 201141513 &lt;210> 222 &lt;211> 27 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 222 caugaugaau uuggcaccuu cgaucac 27 &lt;210> 223 &lt;211&gt; 25 &lt;212&gt;&lt;213&gt;&lt;223&gt; DNA artificial &lt;400&gt; 223 ccaagaaacu cgagagaucu uacat 25 &lt;210> 224 &lt;211> 27 &lt;212&gt;&lt;213>&lt;220>&lt;223&gt; DNA artificial &lt;400> 224 Auguaagauc ucucgaguuu cuugggu 27 &lt;210> 225 71 201141513 &lt;211&gt; 25 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 225 guccaaccug ccugugcaug acctg 25 &lt;210> 226 &lt;;211&gt; 27 &lt;212&gt; DNA &lt;213&gt;manmade &lt;220&gt;&lt;223&gt;&lt;400&gt; 226 caggucaugc acaggcaggu uggacuu 27 &lt;210> 227 &lt;211&gt; 25 &lt;212> DNA &lt;213&gt;;manmade&lt;220&gt;&lt;223&gt;&lt;400&gt; 227 cgaggaccau gcacugaguu acugg 25

&lt;210&gt; 228 &lt;211&gt; 27 &lt;212&gt; DNA 72 201141513 &lt;213&gt; artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 228 ccaguaacuc agugcauggu ccucguc 27 &lt;210> 229 &lt;211&gt;&lt;212&gt; DNA &lt;213>artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 229 gcaugacacu cuagugacuu ccugg 25 &lt;210> 230 &lt;211&gt; 27 &lt;212> DNA &lt;213&gt; 220> &lt;223&gt;&lt;400> 230 ccaggaaguc acuagagugu caugcca 27 &lt;210> 231 &lt;211> 25 &lt;212> DNA &lt;213&gt; man-made 73 201141513 &lt;220> &lt;223&gt;&lt;400 231 guagaagcca guacagagaa auuct 25 &lt;210> 232 &lt;211> 27 &lt;212&gt; DNA &lt;213&gt; artificial &lt;220> &lt;223&gt;&lt;400> 232 agaauuucuc uguacuggcu ucuacca 27 &lt;210> 233 &lt;;211&gt; 25 &lt;212> DNA &lt;213&gt; artificial &lt;220&gt;223&gt;&lt;400&gt; 233 uaagaaacau gaugugagau uactt 25 &lt;210&gt; 234 &lt;211> 27 &lt;212> DNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt; 74 201141513 &lt;400&gt; 234 aaguaaucuc acaucauguu ucuuauu 27 &lt;210&gt; 235 &lt;211&gt; 25 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 235 ccaggauauc cgacaugaag ccagt 25 &lt;210> 236 &lt;211&gt; 27 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 236 acuggcuuca ugucggauau ccuggua 27 &lt;210&gt; 237 &lt;211> 25 &lt;212> &lt;213> &lt;220> &lt;223&gt; DNA artificial &lt;400&gt; 237 7:5 201141513 accgaaauag guacagagac gucag 25 &lt;210&gt; 238 &lt;211> 27 &lt;212> &lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; Cugacgucuc uguaccuauu ucgguuu 27 &lt;210> 239 &lt;211> 25 &lt;212&gt;&lt;213>&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 239 gccuguugcu gaagucauug ucgct 25 &lt;210&gt; 240 &lt;211&gt 27 &lt;212> &lt;213> &lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 240 agcgacaaug acuucagcaa caggcuu 27 76 201141513 &lt;210> 241 &lt;211&gt; 25 &lt;212&gt;&lt;213&gt;&lt;220〉&lt;223&gt; DNA artificial &lt;400> 241 agucaagaca cugaaguuag Aagtc 25 &lt;210&gt; 242 &lt;211&gt; 27 &lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400> 242 gacuucuaac uucagugucu ugacuca 27 &lt;210> 243 &lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; DNA artificial &lt;400&gt; 243 cggauuaaac uacaucaaga agata 25 &lt;210> 244 77 201141513 &lt;211&gt; 27 &lt;212> DNA &lt;213&gt;&lt;220〉&lt;223&gt;&lt;400> 244 27 uaucuucuug auguaguuua auccgac &lt;210> 245 &lt;211> 21 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400> 245

Gly lie Val Glu Gin Cys Cys Thr Ser lie Cys Ser Leu Tyr Gin Leu 15 10 15

Glu Asn Tyr Cys Asn 20 &lt;210> 246 &lt;211> 30 &lt;212> PRT &lt;213&gt; Homo sapiens &lt;400&gt; 246

Phe Val Asn Gin His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr 15 10 15

Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr 78 201141513 20 25 30 &lt;210&gt; 247 &lt;211&gt; 21 &lt;212&gt; PRT &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400&gt; 247

Gly lie Val Glu Gin Cys Cys Thr Ser lie Cys Ser Leu Tyr Gin Leu 15 10 15

Glu Asn Tyr Cys Gly 20 &lt;210> 248 &lt;211&gt; 32 &lt;212> PRT &lt;213&gt;manmade &lt;220&gt;&lt;223&gt;&lt;400&gt;

Phe Val Asn Gin His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr 15 10 15

Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg 20 25 30 79 201141513 &lt;210> 249 &lt;211> 30 &lt;212>PRT &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt;&lt;400〉 249

Phe Val Lys Gin His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr 15 10 15

Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Glu Thr 20 25 30 80

Claims (1)

201141513 VII. Patent application scope: 1. A chimeric compound comprising temsin and siRNA. 2. As embedded in the first paragraph of the patent application (Formula D, the chimeric compound is as defined in Formula 1 wherein insulin (IV) is linked to the siRNA by a linker (10). 3. If the compound is included in the item of the scope of the application, the insulin is selected from the group consisting of human tampondin, animal insulin, insulin analogue and insulin derivative. 4. The chimeric compound according to any one of items 1 to 3, wherein the animal is selected from the group consisting of: Niutengsu and Xuji Island, insulin analogues. Is selected from the group consisting of Gly (A21), Arg (B31), Arg (B32) human insulin, Lys (B3), Glu (B29) human insulin, Asp (B28) human insulin, Lys (B28) Pr〇(B29) human insulin and Des(B30) human insulin, Arg(A〇), ms(A8), Glu(A5), Asp(Al 8), Gly(A21), Arg(B31), Arg(B32 )- NH2 human insulin, Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32)-NH2 human insulin, Arg (AO), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Arg (B32)-NH2 human insulin; and insulin derivatives are selected from the group consisting of: B29- N-Meat Stem-des(B30) Human Membrane, B29-N-palm-based-des(B30) Human Insulin, 201141513 B29-N-Meat Stem-Based Human Insulin, B29-N-Palm醯基人腾腾岛素, B28-N-肉苴蔻醯基 LysB28ProB29 human insulin, B28-N-palm 醯 _LysB28ProB2 9 human insulin, B30-N·meat sulphonyl-ThrB29LysB30 human insulin, B30-N-palmitoyl _ThrB29LysB3G human insulin, B29-N-(N-palmitoyl-Y-glutamyl fluorenyl)-des (B39) Human insulin, B29-N-(N-stone-cholestyl-Y- facetamine)-des(B30) human insulin, Β29-Ν-(ω·carboxyl-17-)-des (B30) Human insulin and Β29-Ν-(ω-carboxy17-decyl) human insulin. 5. The compound according to any one of claims 1 to 4, wherein the linker (Lin) has a group of the formula: (X1)q-(L 1 )P-(D)d -(L2)r-(X2)s-(Y)rZ (Formula II) wherein XI is a group selected from the group consisting of: 〇:(〇)-; -〇-C(0)- ; -C(0)-0- ; -C(0)-N(R1)- ; -N(R1)-C(0)- ; -C(S)-N(R1)-; -N(R1 )-C(S)- ; -S02- ; -C(NH2+)- ; -0-P(0)(0H)- ; -S-; -N(R1)- ; =N_N(R1)_ ; Heterocyclyl; LI is independently selected from the group consisting of alkyl, (〇-alkyl) n, (alkyl-hydrazine) η, cycloalkyl, (〇-cycloalkyl) η, ( Cycloalkyl-hydrazine), alkyl-% alkyl, % alkyl-alkyl, aryl, alkyl-aryl, aryl-alkyl, cycloalkyl-aryl, aryl-cycloalkyl ,heteroaryl,alkyl-heteroaryl,heteroaryl-alkyl, %alkyl-heterocyclyl,heteroaryl-cycloalkyl,heterocyclyl, 2 201141513 alkyl-heterocyclyl, heterocycle a base group, a cycloalkyl group-heterocyclic group, a heterocyclic group-cycloalkyl group; the D system is independently selected from the group consisting of: _c(〇)·, _c(〇)〇_, -OC( O)-, -N(R1)-C(0)-, -C( 0) N(R1)., -N(R1)C(0)_N(R1)-, -C(S)N(R1)-, -SOm-, -C(NH2+)-, -P(0) (0H)0-, -N(R1)-, -N(R1)-N=, =NN(R1)-, -N(R1)-N(R1)-, -〇-, -S-, - SS-, -CKCH2)-, -(CH2)-0-, (O-shallow) n, (alkyl-oxime) n, (S-alkyl), (0-S02-N(Rl)-burning (), (N(R1)-alkyl), (N(R1)C(0)-alkyl), (N(R1)C(NH2+)-alkyl), (N(R1)C(0) -N(R1)-alkyl), (C(O)-N(Rl)-alkyl), (N(R1)-S02-N(R1)-alkyl), (N(R1)-S02- Alkyl), (S02-N(R1)-alkyl), (N(Rl)-S02-0-alkyl), (S0m-alkyl), (oc(o).alkyl), (C( 0)-0-alkyl), (OC(O)-O-alkyl), (OC(O)-N(Rl)-alkyl), (N(Rl)-C(0)-0-alkane (), (0-cycloalkyl)n, (cycloalkyl-fluorene) n, (S-cycloalkyl), (0-S02-N(Rl)-cycloalkyl), (N(R1)- Cycloalkyl), (N(Rl)C(O)-cycloalkyl), (N(R1)C(NH2+)-cycloalkyl), (N(R1)C(0)-N(R1)· Cycloalkyl), (C(O)-N(Rl).cycloalkyl), (N(R1)-S02-N(R1)-cycloalkyl), (N(R1)-S02-cycloalkyl ), (S02-N(R1)-cycloalkyl), (N(Rl)-S02-0-cycloalkyl), (SOm-ring) Alkyl), (OC(o)-cycloalkyl), (c(o)-o-cycloalkyl), (oc(o)-o-cycloalkyl), (OC(O)-N(Rl )-cycloalkyl), (N(Rl)-C(0)-0-cycloalkyl), (0-alkyl-cycloalkyl)n, (s-alkyl-cycloalkyl), (0 -S02-N(Rl)-alkyl 201141513 -cycloalkyl), (N(R1)-alkyl-cycloalkyl), (N(Rl)C(O)-alkyl-cycloalkyl), ( N(R1)C(0)-N(R1)-alkyl-cycloalkyl), (C(O)-N(Rl)-alkyl-cycloalkyl), (N(R1)-S02-N (R1)-alkyl-cycloalkyl), (N(R1)-S02-alkylcycloalkyl), (so2-n(ri)-alkyl-cycloalkyl), (N(Rl)- SOrO-alkyl-cycloalkyl), (SOm_alkyl-cycloalkyl), (oc(o)-alkyl-cycloalkyl), (c(o)-o-alkyl-cycloalkyl) , (OC(O)-O-alkyl.cycloalkyl), (OC(O)-N(Rl)-alkyl-cycloalkyl), (N(Rl)-C(0)-0-alkane -cycloalkyl), (0-cycloalkyl-alkyl)n, (S-cycloalkyl-alkyl), (〇-S02-N(Rl)-cycloalkyl-alkyl), (N (R1)-cycloalkyl-alkyl), (N(Rl)C(O)-cycloalkyl-alkyl), (N(R1)C(0)-N(R1)-cycloalkyl-alkane ()(C(O)-N(Rl)-cycloalkyl-alkyl), (n(ri)-so2-n (ri)-cycloalkyl-alkyl), (n(ri)-so2-cycloalkyl-alkyl), (so2-n(ri)-cycloalkyl-alkyl), (n(ri)- So2-o-cycloalkyl-alkyl), (som-cycloalkyl-alkyl), (oc(o)-cycloalkyl-alkyl), (c(o)-o-cycloalkyl-alkane ()(OC(O)-O-cycloalkyl-alkyl), (OC(O)-N(Rl)-cycloalkyl-alkyl), (N(Rl)-C(0)-0 -cycloalkyl-alkyl), (〇-aryl)n, (S-aryl), (〇-S02-N(Rl)-aryl), (N(R1)-aryl), (N (Rl)C(O)-aryl), (N(R1)C(0)-N(R1)-aryl), (C(O)-N(Rl)-aryl), (N(R1) )-S02-N(R1)-aryl), (N(R1)-S02-aryl), (S02-N(R1)-aryl), (N(Rl)-S02-0-aryl) , (S0m-aryl), (0-C(0)_aryl), (C(0)_0-aryl), (OC(O)-O-aryl), (OC(O)-N (Rl)-aryl), (N(Rl)-C(0)-0-aryl), 4 201141513 (〇-alkyl-aryl)η, (S-alkyl-aryl), (〇 -S〇2-N(Rl)-alkyl-aryl), (N(R1)-alkyl-aryl), (N(Rl)C(O)-alkyl-aryl), (N() R1)C(0)_N(R1)_alkyl-aryl), (c(O)-N(Rl)-alkyl-aryl), (n(ri)-so2- n(ri)-alkylaryl), (N(R1)-S02-alkyl-aryl), (S〇2-N(Rl)-alkyl-aryl), (n(R1)-S02 -0-alkyl-aryl), (som-alkyl-aryl), (oc(o)-alkyl-aryl), (C(O)-O-alkyl-aryl), (OC (O)-O-alkyl-aryl), (OC(O)-N(Rl)-alkyl-aryl), (N(Rl)-C(0)-0-homo-aryl) , (〇-aryl-alkyl) n, (S-aryl-alkyl), (〇-S〇2-N(Rl)-aryl-family), (N(R1)-aryl- Alkyl), (N(Rl)C(O)-aryl-alkyl), (N(R1)C(0)-N(R1)-aryl-alkyl), (c(O)-N (Rl)-aryl-alkyl), (n(ri)-so2-n(ri)-aryl-leuco), (n(R1)-S02.aryl_alkyl), (S02_N(R1) ) _ aryl-alkyl), (n(R1)_S02-0-aryl-hospital), (som-aryl-alkyl), (OC(O)-aryl-alkyl), (c (o)-o-aryl-alkyl), (OC(O)-O-aryl-alkyl), (OC(O)-N(Rl)-aryl-alkyl), (N(Rl) )-C(0)-0-aryl-alkyl), (〇-cycloalkyl-aryl)n, (S-cycloalkyl-aryl), (〇s〇2-N(R1)- Cycloalkyl-aryl), (N(R1)-cycloalkyl-aryl), (n(RI)C(O)-ring (-aryl), (N(R1)C(0)-N(R1).·cycloalkyl-aryl), (c(〇)-N(Rl)-cycloalkyl-aryl), ( N(R1)&quot;S02-N(R1)-cycloalkyl-aryl), (N(R1)-S02-cycloalkyl-aryl), (s〇2-N(R1)-cycloalkyl · aryl), (N(Rl)-S02-0-cycloalkyl-aryl), (s〇m_cycloalkyl-aryl), (OC(O)-cycloalkyl-aryl), (c(O)-O-cycloalkyl-aryl), (OC(O)-O-cycloalkyl-aryl), (OC(O)-N(Rl)-cycloalkyl-aryl 201141513 ), (N(Rl)-C(0)-0-cycloalkyl-aryl), (0-aryl-cycloalkyl)η, (S-aryl-ring-based), (〇-S) 2-N(Rl)-aryl-cycloalkyl), (N(R1)-aryl-cycloalkyl), (N(Rl)C(O)-aryl-cycloalkyl), (N (R1)C(0)-N(R1)-aryl-cycloalkyl), (c(O)-N(Rl)-#-cycloalkyl), (N(R1)-S02-N ( R1)-aryl-cycloalkyl), (N(R1)-S02-aryl-cycloalkyl), (S02-N(R1)-aryl-cycloalkyl), (N(Rl)-S 〇2-0-aryl-ring-based), (som-aryl-cycloalkyl), (OC(O)-aryl-cycloalkyl), (C(O)-O-aryl-ring Alkyl), (OC(O)-O-aryl-cycloalkyl), (OC(o)-N(RI)- Aryl-cycloalkyl), (N(Rl)-C(0)-0-aryl-cycloalkyl), (0-heteroaryl)n, (S-heteroaryl), (〇-S) 2-(Nl(Rl)-heteroaryl), (N(Rl)C(O)-heteroaryl), (N(R1)C(0)-N (R1)-heteroaryl), (C(O)-N(Rl)-heteroaryl), (N(R1)-S02-N(R1)-heteroaryl), (n(ri)-so2 -heteroaryl), (so2-n(ri)-heteroaryl), (N(Rl)-S02-0-heteroaryl), (som-heteroaryl), (OC(O)-heteroaryl ()(c(o)-o-heteroaryl), (oc(o)-o-heteroaryl), (OC(O)-N(Rl)-heteroaryl), (N(Rl) -C(0)-0-heteroaryl), (0-alkyl-heteroaryl)n, (S-alkyl-heteroaryl), (0-S02-N(Rl).alkyl-hetero Aryl), (N(R1)-alkyl-heteroaryl), (N(Rl)C(O)-alkyl-heteroaryl), (N(R1)C(0)-N(R1) -alkyl-heteroaryl), (C(0)-N(R1)-alkyl-heteroaryl), (n(ri)-so2-n(ri)-alkyl-heteroaryl), (n (ri)-so2-alkyl-heteroaryl), (so2-n(ri)-alkyl-heteroaryl), (N(Rl)-S02-0-alkyl-heteroaryl), (som -alkyl-heteroaryl), (oc(o)-alkyl-heteroaryl), (c(o)-o-alkyl-heteroaryl) , 6 201141513 (OC(O)-O-alkyl-heteroaryl), (0_C(0)_n(R1)_alkyl-heteroaryl), (N(Rl)-C(0)-0- Alkylheteroaryl), (〇-heteroaryl-alkyl)n, (S-heteroaryl-alkyl), (〇-S〇2-N(Rl)-heteroaryl-alkyl) , (N(R1)-heteroaryl-based group), (N(Rl)C(O)-heteroaryl-alkyl), (N(R1)C(0)-N(R1)-heteroaryl (C-O)-(C(O)-N(Rl).heteroaryl-alkyl), (N(R1)-S02-N(R1)-heteroaryl-alkyl), (N(R1) )-S02-heteroaryl-alkyl), (S〇2-N(Rl)-heteroaryl-alkyl), (N(Rl)-S02-0-heteroaryl-alkyl), (SOm -heteroaryl-alkyl), (OC(O)-heteroaryl-alkyl), (C(O)-O-heteroaryl-alkyl), (OC(O)-O-heteroaryl) -alkyl), (OC(O)-N(Rl)-heteroaryl-alkyl), (N(Rl)-C(0)-0-heteroarylalkyl), (0-naphthene) (heteroaryl)n, (0-S02-N(Rl)-cycloalkyl-heteroaryl), (N(R1).cycloalkyl-heteroaryl), (N(Rl)C(O) )-cycloalkyl-heteroaryl), (N(R1)C(0)-N(R1)-cycloalkyl-heteroaryl), (C(O)-N(Rl).cycloalkyl- Heteroaryl), (N(R1)-S02-N(R1)-cycloalkyl-heteroaryl), (N(R1) -S02-cycloalkyl-heteroaryl), (SCVN(Rl)-cycloalkylheteroaryl), (N(Rl)-S〇2_0-cycloalkyl-heteroaryl), (S〇m- Cycloalkyl-heteroaryl), (OC(O)-cycloalkyl-heteroaryl), (C(o)-o-cycloalkyl-heteroaryl), (OC(O)-O- ring Alkyl-heteroaryl), (OC(O)-N(Rl)-cycloalkyl-heteroaryl), (N(Rl)-C(0)-0-cycloalkyl-heteroaryl), (〇-heteroaryl-cycloalkyl)n, (S-heteroaryl-cycloalkyl), (〇_s〇2-N(R1)-heteroaryl-cycloalkyl), (N(R1) )-heteroaryl-cycloalkyl), (N(R1)C(0)_heteroaryl-cycloalkyl), (N(R1)C(0)-N(R1)-heteroaryl-ring Alkyl), (C(O)-N(Rl)-heteroaryl-ring-based), (N(R1)-S02-N(R1)-heteroaryl 201141513-cycloalkyl), (N() R1)-S02-heteroaryl-cycloalkyl), (S02-N(R1)-heteroaryl-cycloalkyl), (N(Rl)-S〇2-〇-heteroaryl-cycloalkyl ), (S〇m-heteroaryl-cycloalkyl), (OC(o)-heteroaryl-cycloalkyl), (C(o)-o-heteroaryl-cycloalkyl), (OC (O)-O-heteroaryl-cycloalkyl), (OC(O)-N(Rl)-heteroaryl-cycloalkyl), (N(Rl)-C(OH)-heteroaryl) Cycloalkyl), ( 0-heterocyclic)n, (s-heterocyclic), (〇-S02-N(Rl)-heterocyclic), (N(R1)-heterocyclic), (N(Rl)C(O) )-heterocyclic group, (n(R1)C(0)-N(R1)-heterocyclic group), (C(O)-N(Rl)-heterocyclic group), (n(R1)-S02 -N(R1)-heterocyclic group, (N(R1)-S02-heterocyclic group), (s〇2-N(R1)-heterocyclic group), (N(Rl)-S02-0· Ring group), (S〇m-heterocyclic group), (OC(O)-heterocyclic group), (C(O)-O-heterocyclic group), (0-c(0)_0_heterocyclic group), ( OC(O)-N(Rl)-heterocyclyl), (N(Rl)-C(〇)-〇-heterocyclyl), (0-alkyl-heterocyclyl)n, (S-alkyl) -heterocyclic group), (〇_s〇2-N(R1)-alkyl-heterocyclic group), (N(R1)-alkyl-heterocyclic group), (N(R1)c(〇)_ Alkyl-heterocyclyl), (N(R1)C(0)-N(R1)-alkyl.heterocyclyl), (c(〇)_N(R1)-alkyl-heterocyclyl), N(R1)-S02-N(R1)-alkyl-heterocyclyl), (n(ri)-s〇2_homo-heterocyclyl), (s〇2_N(R1)_alkylidene Cyclo), (n(ri)-so2-o-alkyl-heterocyclyl), (s〇malkyl-heterocyclyl), (oc(o)-alkyl-heterocyclyl), (c (0)_0_Alkyl-heterocyclic group, (OC(O)-O.alkyl-heterocyclic group), (〇_ c(〇)_N(R1)_alkyl-heterocyclyl), (N(Rl)-C(0)-0•alkyl-heterocyclyl), (〇-heterocyclyl-alkyl)n, (S-heterocyclyl-alkyl), (〇_s〇2-N(R1)_heterocyclyl-alkyl), (N(R1)-heterocyclyl-alkyl), (N(R1) c(〇)_heterocyclyl-alkyl), (N(R1)C(0)-N(R1)_heterocyclyl-alkyl), (c(〇)_N(R1)_hetero 201141513 cyclyl -alkyl), (N(R1)-S02-N(R1)-heterocyclyl-alkyl), (N(kl)-S〇2-heterocyclyl-alkyl), (S02-N(R1) )-heterocyclyl-alkyl), (N(Rl)-S02-0-heterocyclyl-alkyl), (SOm-heterocyclyl-alkyl), (OC(O)-heterocyclyl-alkane , (c(o)-o-heterocyclyl-alkyl), (OC(O)-O-heterocyclyl-alkyl), (OC(O)-N(Rl)-heterocyclyl- Alkyl), (N(Rl)-C(0)-0-heterocyclyl-alkyl), (0-cycloalkyl-heterocyclyl)n, (0-S02-N(Rl)-cycloalkane (N-(R1)-cycloalkyl-heterocyclyl), (N(Rl)C(O)-cycloalkyl-heterocyclyl), (N(R1)C(0) -N(R1)-cycloalkyl-heterocyclyl), (c(O)-N(Rl)-cycloalkyl-heterocyclyl), (N(Rl)-S(VN(Rl)-cycloalkane) (heterocyclyl), (n(ri)-so2-cycloalkyl-heterocyclic), (S〇2-N(Rl) )-cycloalkyl-heterocyclic group, (N(Rl)-S02-0-cycloalkyl-heterocyclic group), (s〇m_cycloalkyl-heterocyclic group), (0-C(0) )-cycloalkyl-heterocyclyl), (C(9)-〇-cycloalkyl, cyclo), (oc(o)-o-cycloalkyl..heterocyclyl), (0_C(0)_N(R1) )-cycloalkyl-heterocyclyl), (N(Rl)-C(0)-0-cycloalkyl-heterocyclyl), (0-heterocyclyl-cycloalkyl)n, (〇-S) 2-N(Rl)-heterocyclyl-cycloalkyl), (N(R1)-heterocyclyl-cycloalkyl), (N(R1)c(〇)_heterocyclyl-cycloalkyl) (N(R1)C(0)-N(R1)-heterocyclyl-cycloalkyl), (c(〇)_N(R1)_heterocyclyl-cycloalkyl), (N(R1)- S02~N(R1)-heterocyclyl-cycloalkyl), (N(Rl)-S〇2_heterocyclyl-cycloalkyl), (s〇2_N(R1)_heterocyclyl-cycloalkyl , (N(Rl)-S〇2_0-heterocyclyl-cycloalkyl), (s〇m_heterocyclyl-cycloalkyl), (OC(O)-heterocyclyl-cycloalkyl), (c(〇)_〇_heterocyclyl-cycloalkyl), (OC(O)-O-heterocyclylcycloalkyl), (〇_c(〇)_N(R1)_heterocyclyl- Cycloalkyl), (N(Rl)-C(0)-0-heterocyclyl-cycloalkyl), 201141513 L2 is selected from the group consisting of: alkyl, (〇_烧n, (alkyl-hydrazine) η, cycloalkyl, alkyl cycloalkyl, cycloalkyl-alkyl, aryl, alkyl-aryl, aryl-alkyl, cycloalkyl aryl , aryl-cycloalkyl, heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl, cycloalkyl-heteroaryl, heteroaryl-cycloalkyl, heterocyclyl, alkyl Cyclo, heterocyclyl-alkyl, cycloalkyl-heterocyclyl, heterocyclyl-cycloalkyl; Χ2 is a group selected from the group consisting of: _c(〇)·; -OC(O )-; -C(0)-0- ' -N(R1)-C(0)- ; -C(0)-N(R1)- ; -N(R1)-C(S)-; -S02 -; -C(NH2+)-; -0-P(〇)(〇H)- ; -S_ ; -N(R1)- ; -O-; Y is a group selected from the group consisting of: -C(〇)- ; -S-; -N(R1)- ; -N(R1)-N= ; =NN(R1)-; Z is selected from the group consisting of: a direct bond, an alkane , (0-alkyl)η, (alkyl-0)n, alkyl-C(0)-, cycloalkyl-c(0)-, aryl-c(0)-, alkyl-aryl -C(0)-, aryl-alkyl-C(0)-, cycloalkyl-aryl-c(〇)_, aryl-cycloalkyl-C(0)-, heteroaryl- C(0)-, alkyl-heteroaryl_c(0)_, heteroaryl-alkyl-c(o)-, cycloalkyl-heteroaryl-c(0)-, heteroaryl- Alkyl-C(〇)_, heterocyclyl-C(〇)-, alkyl-heterocyclyl-c(0)-, heterocyclyl-alkyl-C(0)-, cycloalkyl-hetero Cyclo-c(0)-, heterocyclyl-cycloalkyl-C(0)-, 院基·Ν=, ring-based-N=, aryl-N=, alkyl-aryl _n= , aryl- 201141513 alkyl-N=, cycloalkyl-aryl-N=, aryl-cycloalkyl-N=, heteroaryl-N=, alkyl-heteroaryl, heteroaryl-院-N=, cycloalkyl-heteroaryl-N=,heteroaryl·cycloalkyl-N=,heterocyclyl-N=,alkyl-heterocyclyl-N=,heterocyclyl-alkyl -N=:, cycloalkyl-heterocyclyl-n=, heterocyclylcyclohexanyl, alkyl-N(R1)-, cycloalkyl-N(R1)-, aryl-N ( R1)-, alkyl-aryl-N(R1)-, aryl-alkyl·Ν(ΐα)-, cycloalkyl-aryl-n(R1)_, aryl-cycloalkyl-N ( R1)-,heteroaryl-N(R1)-,alkyl-heteroaryl_n(R1)-,heteroaryl-alkyl-N(R1)-, cycloalkyl-heteroaryl,heteroaryl _ cycloalkyl-N(R1)-, heterocyclyl-N(Rl)-, alkyl-heterocyclyl to 丨), heterocyclyl-alkyl-N(R1)-, cycloalkyl _ Heterocyclyl-N(R1)...heterocyclyl-cycloalkyl-N(R1)-, soil, alkyl_0-Ρ(0)(0Η)_, (〇·alkyl)η-0-Ρ (0)(0Η)_, (Alkyl_〇)n_p(〇)(〇H)...cycloalkyl-0-Ρ(0)(0Η)-, yard-ring-fired base (9)(〇Η)·, cycloalkylalkyl group _ 0-Ρ(0)(0Η&gt;, aryl_〇_ρ(〇)(〇Η), heteroaryl•0-Ρ(0)(0Η)_, alkyl-aryl 〇_ρ(〇 )(〇Η)_, aryl alkane, its -0-Ρ(0)(0Η)-, cycloalkyl-aryl _〇_ρ(〇)(〇Η)_, aryl ring burned beauty-0- Ρ(0)(0Η)·, alkyl-heteroaryl ρ(〇)(〇Η)·, heteroaryl _ 烧二-0-Ρ(0)(0Η)·, 环丝_(四)基_ 〇·ρ(9) 宽 _ ^ 烧基-〇·Ρ(〇)(〇Η)-, heterocyclic group VII·ρ(〇)(〇Η)_, hetero^ base·0-_(_, ring-based base, Heterocyclic group 〇) "衣坑_〇_P(sx〇H&gt;, burnt-like (8) (〇H)- 201141513 base) n_〇-P(S)(OH)-, (alkyl_〇) N_p(8)(〇H)_, cycloalkyl-0-P(S)(0H)-, alkyl-cycloalkyl-〇p(s)(〇H)_, cycloalkyl-alkyl-0_P(S )(0H)-, aryl-〇_p(8)(〇H), heteroaryl-〇p(8)(〇H)_, alkyl-aryl-0-P(S)(0H)-, aryl-alkane 〇·〇_ρ(8χ〇Η)_, cycloalkyl-aryl-0-P(S)(0H)-, aryl-cycloalkyl-〇_p(s)(〇H)_, alkane Base _heteroaryl-0-P(S)(0H)-,heteroarylalkyl-〇_p(s)( H)_, cycloalkyl-heteroaryl-0-P(S)(0H)-, heteroaryl-cycloalkyl-〇_p(s)(〇H)_, heterocyclyl--0-P (S)(0H)-, heterocyclic group_alkyl_〇_p(s)(〇H)_, alkyl_heterocyclyl-0-P(S)(0H)-, heterocyclyl ring Alkane *_〇_p(s)(〇H)_, cycloalkyl-heterocyclyl-0-P(S)(0H&gt;, -0-P(S)(SH)-, alkyl group_〇_ p (8)(SH)_ , (〇_ alkyl)n-0-P(S)(SH)-, (alkyl_〇)n_p(s)(SH)_, cycloalkyl-0-P(S ) (SH)-, alkyl-cycloalkyl-〇_p(s)(SH)_, cycloalkyl-alkyl--0-P(S)(SH)_, aryl-〇_p(8)(SH ),heteroaryl_〇_p(8)(SH)_, alkyl-aryl-〇-P(S)(SH)-, aryl-alkyl-〇_p(s)(SH)-, naphthenic aryl-O-P(S)(SH)-, aryl-cycloalkyl_0_P(S)(SH)-, alkyl-heteroaryl-0-P(S)(SH)-, Heteroaryl-alkyl group_0·Ρ(8)(SH)_, cycloalkyl_heteroaryl-0_P(S)(SH)-,heteroaryl·cycloalkyl_〇-p(s)(SH)- , heterocyclic group-0-P(S)(SH)-, heterocyclic group-alkyl group_0_P(S)(SH)_, alkyl group_heterocyclyl-0-P(S)(SH)-, Heterocyclyl-cycloalkyl-〇_p(s)(Sh)-, cycloalkyl·heterocyclyl-0-P(S)(SH)-, -0-P(0)(alkyl)- , alkyl-〇-P(〇)(alkyl)-, (0-alkyl)n-0-P(0)(alkyl ...(alkyl_0)n_P(0)(alkyl)-, cycloalkyl-0-P(0)(alkyl)-, alkyl-cycloalkyl-〇-P(〇)(alkyl) -, cycloalkyl _ 12 201141513 alkyl-0·Ρ(0)(alkyl)-, aryl-0-!&gt;(0)(alkyl),heteroaryl-0-P(0)( Alkyl)-,alkyl-aryl-0-P(0)(alkyl)-, aryl-alkyl-0-P(0)(alkyl)-, cycloalkyl-aryl-0- P(0)(alkyl)-, aryl-cycloalkyl-0-P(0)(alkyl)-, alkyl-heteroaryl-0-P(0)(alkyl)-, heteroaryl -alkyl-0-P(0)(alkyl)-, cycloalkyl-heteroaryl-0-P(0)(alkyl)-,heteroaryl-cycloalkyl-indole-P(〇 )(alkyl)-,heterocyclyl-0-P(0)(alkyl)-,heterocyclyl-alkyl-oxime-P(oxime)(alkyl)-,alkyl-heterocyclyl-0 Ρ(0)(alkyl)-, heterocyclyl-cycloalkyl-0-oxime (0)(alkyl)-, cycloalkyl-heterocyclyl-o.ρ(ο)(alkyl), -0-P(0)(N(R2R3))-, alkyl-〇-P(〇)(N(R2R3))-, (0-alkyl)n-0-P(0)(N(R2R3) ))-, (Alkyl-indole) n_p(〇)(N(R2R3))-, cycloalkyl-0-P(0)(N(R2R3))·, alkyl·cycloalkyl-0-P (0)(N(R2R3))-, cycloalkyl-alkyl-〇-P(〇)(N(R2R3))-, aryl-0-P(0)(N(R2R3))-, miscellaneous aryl-〇-P(〇)(N(R2R3))-, alkyl-aryl-0- P(0)(N(R2R3))-, aryl-alkyl-〇-P(〇)(N(R2R3))-, cycloalkyl-aryl-〇-P(〇)(N(R2R3) )-, aryl-cycloalkyl-0-P(0)(N(R2R3))-, alkyl-heteroaryl-〇-P(〇)(N(R2R3))-, heteroaryl-alkane Base-0-P(0)(N(R2R3))-, cycloalkyl-heteroaryl-0-P(0)(N(R2R3))-, heteroaryl-cycloalkyl-〇-P ( 〇)(N(R2R3))-, heterocyclyl-0-P(0)(N(R2R3))-, heterocyclyl-alkyl-0-P(0)(N(R2R3))-, alkane -heterocyclyl-indole-P(〇)(N(R2R3))-, heterocyclyl-cycloalkyl-0-P(0)(N(R2R3))-, cycloalkyl-heterocyclyl- 0-P(0)(N(R2R3))-, -N(R1)-P(0)(0H)-, alkyl-N(Rl)-P(〇)(〇H)-, (0_alkane 13 201141513 基)nN(Rl)-P(0)(0H)-, cycloalkyl·Ν(Εα)-Ρ(〇)(〇Η)-, alkyl-cycloalkyl-N(R1)-P (0)(0H)-, cycloalkyl-alkyl-N(R1)-P(0)(0H)-, aryl-N(Rl)-P(〇)(〇H),heteroaryl- N(R1)-P(0)(0H)-, alkyl-aryl-N(R1)-P(0)(0H)-, aryl-alkyl-N(R1)-P(0)( 0H)-, cycloalkyl-aryl-N(R1)-P(0)(0H)-, aryl-cycloalkyl-N(Rl)-P(〇)(〇H)-, alkyl- Heteroaryl-N(R1)-P(0)(0H)-,heteroaryl-alkyl-N(R1)-P(0)(0H)-, cycloalkyl-heteroaryl-N(R1 )-P(0)(0H)-, miscellaneous -cycloalkyl-N(R1)-P(0)(0H)-, heterocyclyl-N(R1)-P(0)(0H)-, heterocyclyl-alkyl-N(R1)- P(0)(0H)-, alkyl-heterocyclyl_N(Rl)-P(〇)(〇H)-, heterocyclyl-cycloalkyl-N(R1)-P(〇)(〇 h)-, cycloalkyl-heterocyclyl-N(Rl)-P(〇)(〇H)-; d is an integer between 〇 and 10; η is an integer between 1 and 11; m Is 0, 1 or 2; q, p, r, s, t are each independently 〇, 1 or 2; R1 is Η, (C "C6)-alkyl; R2 and R3 are independently H, (CrC6 And an alkyl group in which R2 and R3 are bonded together with the nitrogen atom to which they are bonded to form a saturated 5- to 6-membered monocyclic heterocyclic group. 6. The chimeric compound according to any one of claims 1 to 5, wherein the siRNA nucleic acid is composed of two individual stocks, wherein only one of the 201141513 strands is covalently linked to the unit (InsHLin) And the second strand is combined with a covalently linked (InsHLin) strand by nucleic acid test pairing, wherein each strand can be between 11 and 35 nucleotides in length. 7. A chimeric compound according to claim 6 wherein each strand is 21, 22 or 23 nucleotides in length, wherein the two strands are complementary to each other within a length of 19, 20 or 21 nucleotides, The 3, _ end of each strand has a single strand of 2, 3 or 4 nucleotides. 8. If you apply for the patent scope! The chimeric compound according to any one of the items 7, wherein the nucleobase group of the siRNA is independently selected from the group consisting of adenine, guanine, cytosine, thymine, uracil, alkyne Uridine, 5-methylcytosine, 5-propynylcytosine, 5-fluorouracil, 5-propenylamine uracil derivative, N2-alkylaminoguanine, 5-propenylamine a pyrimidine derivative, a 5-(amino-alkylpyrimidine derivative, a 5-(amino-alkenyl)-pyrimidine derivative, and a 5-(amino-alkynylpyrimidine quinone. 9) as claimed in claims 1 to 8 The chimeric compound of any one of the items, wherein the sugar group of the si RN A is independently selected from the group consisting of the following, 'sugar, 2,-deoxyribose, 2,-〇-4, heart 曱Riboose, 2, 〇 烧 烧 - - hexose, 2'- 〇-allyl-ribose, 2, - 〇 _ (2 _ oxyethyl) ribose, 2, hexahydroxyethyl) ribose , 2'-0-(2-Aminoethyl)-ribose, 2,-deoxy-,-amine ribose, 2,-deoxy-2,-gas-ribose, 5,·deoxy-5,-amino ·ribose, 2, 15 201141513 dideoxy-5'-amino-ribose, 5'-deoxy-5'-weiki-ribose, 2' 5'-dideoxy-5'-mercapto ribose, 5'-carboxy-ribose and 5'-carboxy-2'-deoxyribose. 10. Embedding according to any one of claims 1 to 9 a compound wherein the bond between the nucleotides is independently selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, phosphoniumamine, alkyl- and aryl-phosphine 11. The chimeric compound of any one of claims 1 to 10, wherein the siRNA nucleic acid is operably linked to the non-nucleotide at the 3'-end and/or the 5'-end. The unit linkage is modified, wherein the modification of the 5'-end of the antisense strand is limited to phosphoric acid, and the modification of the non-nucleotide end is independently selected from the group consisting of: (CrC1())-alkyl, HO-P (G)(OH)-, (CrC2.)-alkyl-0-P(G)(0H)-, H-(0-(C2-C3)-alkyl)n-0-P(G)( 0H)-, ((C2-C3)-alkyl-0) nP(G)(0H)-, (C6-C10)-aryl-0_P(G)(0H), (CrC6)-alkyl-( C6-C10)-aryl-0-P(G)(0H)-, (C6-C10)-aryl (CrQ)-alkyl-0-P(G)(0H)-, (C2-C9) -heterocyclic group-0-P(G)(0H)-, (C2-C9)-heterocyclyl-(CVQ)-alkyl-0-P(G)(0H)-, (Cr C6)-Alkyl-(C2-C9)-heterocyclyl-0-P(G)(0H)-, R4-(Ci-C2〇)- ^ ^ -0-P(G)(0H)- ^ R4-((C2-C3)-alkyl--0)nP(G)(0H)-, R4-(C3-C6)·cycloalkyl-0-P(G)(0H)-, alkyl-( C3-C6)-cycloalkyl-0-P(G)(0H)-, 16 201141513 R4-(C3-C6)-cycloalkyl-(CVQ)-alkyl-0-P(G)(0H) -, R4-(C,-C6)- ^ ^ -(C6-C,〇)- ^ i -0-P(G)(0H)-, R4-(C3-C6)-cycloalkyl-(C6 -C]0)-aryl-0-P(G)(0H)-, R4-(C1-C6)- ^ A -(C,-C9)- m ^ ^ -0-P(G)(0H )-, R4-(CrC9)-heteroaryl-(CrC6)-alkyl-0-P(G)(0H)-, R4_(C3-C6)-cycloalkyl-(CrC9)-heteroaryl- 0-P(G)(0H)-, I^KCrCO-heteroaryl-(C3-C6)-cycloalkyl_0-P(G)(0H)-, R4-(C2-C9)-heterocyclic Base-0-P(G)(0H)-, R4-(C2-C9)-heterocyclyl-(CrC6)-^&amp;-0-P(G)(0H)- &gt; R4-(CrC6) -^^-(C2-C9)-heterocyclyl-0-P(G)(0H)-, wherein n is an integer between 1 and 11; G is Ο or S; R1 is Η, (C1- C3)-alkyl; R4 is NH(R1), SH, C(0)R1, C(0)0R1, cholesteryl-C(0)N(R1), tocopheryl-, tocopheryl-C ( O). 12. A chimeric compound characterized by any one of Formulas 13-22 of Table 4. A pharmaceutical formulation comprising the embedded compound according to any one of claims 1 to 12. 14. Use of a pharmaceutical formulation according to claim 13 of the patent application or a chimeric compound according to any one of claims M2 of the patent application for the treatment of diabetes 21 201141513. A method for producing a chimeric compound according to any one of claims 1 to 12, which comprises the steps of: (a) recombining to produce a desired insulin, (b) co-ligating the linker with insulin Valency linkage, and subsequent (c) covalent attachment to siRNA, or (d) covalent attachment of a preformed linker and siRNA complex to insulin, replacing steps (b) and (c), and the resulting chimera Compound purification.