CN1777423A

CN1777423A - Chemokine receptor binding heterocyclic compounds with enhanced efficacy

Info

Publication number: CN1777423A
Application number: CN 200480010845
Authority: CN
Inventors: G·J·布里杰; E·J·麦基切恩; R·斯基勒; D·斯古尔斯; I·贝尔德; A·凯勒; C·哈维格; Y·朱; G·陈; K·斯库平斯卡; M·梅茨
Original assignee: Anormed Inc
Current assignee: Anormed Inc
Priority date: 2003-04-22
Filing date: 2004-04-22
Publication date: 2006-05-24
Also published as: ZA200508518B

Abstract

Compounds that interact with the CXCR4 receptor are described. The compounds are useful in treating for Example, HIV infection and inflammatory conditions such as rheumatoid arthritis, as well as asthma or cancer, and are useful in methods to elevate progenitor and stem cell counts as well as methods to elevate white blood cell counts.

Description

Has the bonded heterocyclic compound of chemokine receptors that promotes effect

The related application of cross-application

The priority text that the application requires is: be filed in 22 days Nos.60/505 of JIUYUE in 2003, No. 230 and be filed in 60/464, No. 858 U.S. Provisional Patent Application on April 22nd, 2003, both all are cited in this application.

Technical field

The present invention relates generally to chemical compound, pharmaceutical composition and their application of novelty.The present invention relates to novel heterocyclic compound more specifically; it combines with the chemokine receptors that comprises CXCR4 and CCR5; and show anti-target cell by the protective effect that human immunodeficiency virus (HIV) infects, can promote equally CFU-GM and/or stem cell quantity growth, stimulate the generation of leukocyte and/or influence the regeneration of heart tissue.

Background technology

Kind of human chemokine surplus scientist has disclosed 40, its function is at least with regard to part, be by regulating a kind of complex, and exosmose in (extravasation) and the tissue infiltration important a series of biological activities of lymphocyte motion, leukocyte are overlapping and realize (seeing when replying stimulant, Ponath for example, P., Exp.Opin.Invest.Drugs (1998) 7:1-18).These chemotactic cytokines or chemotactic factor have been formed gang's protein, and its albumen size is about 8-10kDa.As if the total identical structural motif (motif) of chemotactic factor, this primitive is made up of 4 conservative cysteine of keeping tertiary structure.Chemotactic factor has 2 main subfamilies: " CC " or beta-chemokine and " CXC " or α-chemotactic factorThe receptor of these chemotactic factors is according to the chemotactic factor classification that constitutes the receptor native ligand.The receptor of beta-chemokine is called " CCR ", and the receptor of α-chemotactic factor is called " CXCR ".

Chemotactic factor be considered to the generation of inflammation and continue in primary medium (seeing what Humana Press (1999) published, " chemotactic factor in the disease " that people such as C.Herbert, Murdoch compile, Blood (2000) 95:3032-3043).More specifically, find that chemotactic factor plays an important role in the function of regulating endotheliocyte, these functions comprise propagation, migration and the differentiation (Gupta etc., J.Biolog.Chem. (1998) 7:4282-4287) in angiogenesis and damage back living again of the endothelium process.In learning, human immunodeficiency virus (HIV) pathogenic infection relates to two kinds of concrete chemotactic factors.

Under modal situation, HIV is at first by its gp120 capsid protein and the CD4 receptors bind of target cell.Gp120 seems occurred conformation to be changed, and makes it subsequently to combine (Wyatt etc., Science (1998) 280:1884-1888) with chemokine receptors as CCR5.The HIV-1 separator that increases subsequently in infection combines with the CXCR4 chemokine receptors.Another is relevant, and retrovirus---feline immunodeficiency virus need not elder generation and CD4 receptors bind when combining with chemokine receptors, and from this true angle, having enlightened chemokine receptors may be the retroviral original obligate receptor of immunodeficiency.

After initial combination of HIV and CD4, virus-cell fusion has taken place, this process is by member's mediation of chemokine receptors family, the fusion cofactor (Carroll etc., Science (1997) 276:273-276 that serve as HIV-1 macrophage tropism (M-tropism) and T cell line tropism (T-tropism) separator by different members; Feng etc., Science (1996) 272:872-877; Bleul etc., Nature (1996) 382:829-833; Oberlin etc., Nature (1996) 382:833-835; Cocchi etc., Science (1995) 270:1811-1815; Dragic etc., Nature (1996) 381:667-673; Deng etc., Nature (1996) 381:661-666; Alkhatib etc., Science (1996) 272:1955-1958).In the intravital course of infection of patient, seeming most of HIV granule changes into from M-tropism and has more invasive pathogenic T-tropism virus phenotype (Miedema etc., Immune.Rev. (1994) 140:35; Blaak etc., Proc.Natl.Acad.Sci. (2000) 97:1269-1274; J.Virol. such as Simmonds (1996) 70:8355-8360; Tersmette etc., J.Virol. (1988) 62:2026-2032; Connor, R.I., Ho, D.D., J.Virol. (1994) 68:4400-4408; Schuitemaker etc., J.Virol. (1992) 66:1354-1360).The ability that enters cell after M-tropism virus phenotype and virus and the CCR5 receptors bind is closely related, and T-tropism's virus phenotype is then with virus and CXCR4 receptors bind and to enter cell after the film fusion takes place closely related.The clinical observation prompting, as if the patient who has CCR5 or CXCR4 gene mutation infect HIV and have resistance or less sensitivity (Liu etc., Cell (1996) 86:367-377; Samson etc., Nature (1996) 382:722-725; Michael etc., Nature Med. (1997) 3:338-340; Michael etc., J.Virol. (1998) 72:6040-6047; Obrien etc., Lancet (1997) 349:1219; Zhang etc., AIDS Res.Hum.Retroviruses (1997) 13:1357-1366; Rana etc., J.Virol. (1997) 71:3219-3227; Theodorou etc., Lancet (1997) 349:1219-1220).Although reported the quantity that mediation HIV enters the chemokine receptors of cell, CCR5 goes up relevant coreceptor (Zhang etc., J.Virol. (1998) 72:9307-9312 with the used unique physiology of the seemingly various clinically main HIV-1 strains of CXCR4; Zhang etc., J.Virol. (1999) 73:3443-3448; Simmonds etc., J.Virol. (1988) 72:8453-8457).T-tropism's virus of utilizing CXCR4 to merge and entering cell can be that the natural CXC-chemotactic factor stromal cell source factor-1 suppresses, M-tropism's virus of utilizing CCR5 to merge and entering cell then is natural CC-chemotactic factor, promptly " activate the normal T-cellular expression and the regulation of secretion factor " (Regulated on Activation NormalT-cell Expressed and Secreted) (RANTES) and macrophage inflammatory protein (MIP-1 α and β) suppress.

Yet the combination of chemokine receptors and their native ligands appears to play a part more to evolve and key than the medium that infects as just HIV.The combination of native ligand---pre-B cell growth stimulating factor/stromal cell source factor (PBSF/SDF-1) and CXCR4 chemokine receptors provides important signal transduction mechanism a: CXCR4 or SDF-1 knock-out mice to show that cerebellum, heart and gastrointestinal are unusual, and dead in uterus (Zou etc., Nature (1998) 393:591-594; Tachibana etc., Nature (1998) 393:591-594; Nagasawa etc., Nature (1996) 382:635-638).The CXCR4-deficient mice equally also demonstrates hemopoietic function defective (Nagasawa etc., Nature (1996) 382:635-638); As if leukocyte and hemopoietic progenitor cell that CXCR4 expresses are moved to SDF-1, to keeping B cell lineage and CD34 ⁺Bone marrow location very important (Bleul etc., J.Exp.Med. (1998) 187:753-762 of CFU-GM; Viardot etc., Ann.Hematol. (1998) 77:195-197; Auiti etc., J.Exp.Med. (1997) 185:111-120; Peled etc., Science (1999) 283:845-848; Qing etc., Immunity (1999) 10:463-471; Lataillade etc., Blood (1999) 95:756-768; Ishii etc., J.Immunol. (1999) 163:3612-3620; Maekawa etc., InternalMedicine (2000) 39:90-100; Fedyk etc., J.Leukocyte Biol. (1999) 66:667-673; Peled etc., Blood (2000) 95:3289-3296).

Hemocyte is to keep comprising in people's the health of animal and the existence having vital part.Leukocyte comprises neutrophil cell, macrophage, eosinophilic granulocyte and basophilic granulocyte/mastocyte, comprises B cell and T cell in the immune system too.Leukocyte constantly upgrades by hemopoietic system, by colony stimulating factor (CSF) and different effect of cytokines, specifically is that those act on the stem cell in the hemopoietic tissue and the factor in the CFU-GM.The nucleotide sequence of many factors of encoding in these somatomedin is cloned and is checked order.That be widely known by the people most in these somatomedin may be granulocyte colony-stimulating factor (G-CSF), and oneself be approved for propagation (procedure for peripheral blood stem cells activation method) by stimulating leukocyte and CFU-GM with the antagonism chemotherapy side effect its.About the discussion of this factor pair hemopoietic influence, can in the United States Patent (USP) in the list of references of listing jointly as the present invention 5,582,823, find.

It is reported that other several factors can increase leukocyte and CFU-GM quantity in the experimenter and animal.These actors comprise granulocyte-macrophage colony stimutaing factor (GM-CSF), il-1 (IL-1), interleukin-3 (IL-3), interleukin-8 (IL-8), PIXY-321 (GM-CSF/IL-3 fusion rotein), macrophage inflammatory protein, stem cell factor, the relevant oncogene (Dale with growth of thrombopoietin single or combination, D. etc., Am.J.of Hematol. (1998) 57:7-15; Rosenfeld, C. etc., Bone MarrowTransplantation (1997) 17:179-183; Pruijt, J. etc., Cur.Op.in Hematol. (1999) 6:152-158; Broxmeyer, H. etc., Exp.Hematol. (1995) 23:335-340; Broxmeyer etc., Blood Cells, Molecules and Diseases (1998) 24:14-30; Glaspy, J. etc., CancerChemother.Pharmacol. (1996) 38 (suppl): S53-S57; Vadhan-Raj, S. etc., Ann.Intern.Med. (1997) 126:673-681; King, A. etc., Blood (2001) 97:1534-1542; Glaspy, J. etc., Blood (1997) 90:2939-2951).

Though endogenous somatomedin is effectively on the pharmacology, the shortcoming as drug use protein and polypeptide is as everyone knows, has produced adding the potential demand of micromolecule actor in this somatomedin inventory.From another point of view, when the needs mass production, these micromolecule take advantage than protein and polypeptide.

May in relevant tumor cell proliferation of tumor growth and angiogenesis adjusting, play an important role in conjunction with the signal that produces by SDF-1 and CXCR4 and (to see Humana Press (1999) publication, B.J.Rollins; " chemotactic factor and cancer " J.Leukocyte Biol. (1997) 62:554-562 that Arenburg etc. compile; Moore etc., J.Invest.Med. (1998) 46:113-120; Moore etc., Trends Cardiovasc.Med. (1998) 8:51-58; Seghal etc., J.Surg.Oncol. (1998) 69:99-104); Known angiogenesis factor VEG-F and bFGF can just regulate the CXCR4 level in the endotheliocyte, and SDF-1 then can reduce intravital neovascularization (Salcedo etc., Am.J.Pathol. (1999) 154:1125-1135); Express leukaemia's migration of CXCR4 and be attached to lymph node and marrow stromal cell (Burger etc., Blood (1999) 94:3658-3667 that expresses SDF-1; Arai etc., Eur.J.Haematol. (2000) 64:323-332; Bradstock etc., Leukemia (2000) 14:882-888).

SDF-1 combines equally and arteriosclerosis (Abi-Younes etc. with CXCR4's, Circ.Res. allos renal transplant rejection (Eitner etc. (2000) 86:131-138),, Transplantation (1998) 66:1551-1557), asthma and respiratory tract anaphylaxis inflammation (Yssel etc., Clinical and Experimental Allergy (1998) 28:104-109; J.Immunol. (2000) 164:5935-5943; Gonzalo etc., (2000) 165:499-508) and Alzheimer (Xia etc. J.Immunol., J.Neurovirology (1999) 5:32-41) relevant with the pathogeny of arthritis (Nanki etc., J.Immunol. (2000) 164:5010-5014).

In order to understand the relation between chemotactic factor and receptor thereof better, carried out the test that retardance HIV merges, enters cell and duplicate by the CXCR4 chemokine receptors at present, monoclonal antibody or micromolecule have been adopted in these tests, as if this measure proposed a kind of effective therapeutic strategy (Schols etc., J.Exp.Med. (1997) 186:1383-1388; Schols etc., Antiviral Research (1997) 35:147-156; Bridger etc., J.Med.Chem. (1999) 42:3971-3981; Published by JAI press, E.De Clercq compiles, Bridger etc., " as the Bicyclam derivant of hiv inhibitor ", Advances in Antiviral Drug Design (1999) rolls up 3:161-229).As if micromolecule as bicyclam, combine with CXCR4 but not CCR5 (Donzella etc., Nature Medicine (1998) 4:72-77) specifically.These testing and verifications external interference HIV enter with film and merge into target cell.Recently, bicyclam demonstrates equally to utilizing CXCR4 to enter the fusion of feline immunodeficiency virus (FIV) of cell and the inhibitory action (Egberink etc., J.Virol. (1999) 73:6346-6352) of duplicating.

Other test shows that bicyclam dose dependent ground suppresses the signal conduction (showing as the rise of intracellular calcium ion) that combines and respond SDF-1 of SDF-1 with the CXCR4 of 125I-labelling.Therefore, bicyclam can be used as substrate derivative factor or SDF-1 α, natural chemotactic factor combine the signal conduction that causes with CXCR4 antagonist equally.Bicyclam is suppressed at HIV gp120 (capsid) mediated Apoptosis (Blanco etc., Antimicrobial Agents and Chemother. (2000) 44:51-56) in the cell of non-HIV infection equally.

Full text is classified the United States Patent (USP) 5,583,131,5,698,546,5,817,807,5,021,409 and 6,001,826 of list of references as in the present invention, discloses to have anti-HIV-1 and the active cyclic compound of HIV-2 in vitro tests.Found and in PCT WO 02/34745, further disclose these chemical compounds subsequently by combining, and demonstrated HIV (human immunodeficiency virus)-resistant activity with the chemokine receptors CXCR4 of some cell surface expression in the immune system.By this emulative join protection these target cells, make it exempt from the infection that utilizes the HIV that the CXCR4 receptor enters.In addition, these chemical compound antagonisms the native ligand of CXCR4---combination, the signal of the chemotactic factor stromal cell source factor-1 α (SDF-1) produce and chemotactic influence.We are further disclosed to be that these compounds demonstrate antagonism by combining the protection effect that the target cell HIV that causes infects with the CCR5 receptor external.

In addition, we are at United States Patent (USP) 6,365, disclose the effect that enhancing leukocyte that these cyclic polyamine antiviral agent described in patent/patent application as mentioned have produces and the ntiviral characteristic of demonstration in 583.Therefore, these actors help to control the healing and the burn treatment of the side effect in the chemotherapy, the success rate that improves bone marrow transplantation, promotion wound, and to the bacterial infection in the leukemia.

Recently, we disclose a series of heterocyclic compounds in PCT WO 00/56729, PCT WO 02/22600, PCT WO 02/22599 and PCT WO 02/34745, these chemical compounds by be expressed in immune system in the chemokine receptors CXCR4 of some cell surface and combining of CCR5, demonstrate HIV (human immunodeficiency virus)-resistant activity.By this competitive join protection these target cells, make it exempt from the infection that utilizes the HIV that the CXCR4 receptor enters.In addition, these chemical compound antagonisms combination, the signal of the native ligand of CXCR4---native ligand of the chemotactic factor stromal cell source factor-1 α (SDF-1) and/or CCR5---chemotactic factor RANTES produce and chemotactic influence.

Researcher has been found chemokine receptors---CXCR4 is gastrointestinal tract vascularization (Tachibana etc., Nature (1998) 393:591-594), and hemopoietic and cerebellum development (Zou etc., Nature (1998) 393:591-594) are necessary.Disturb in these critical functions that combine realization that pass through the pre-B cell growth stimulating factor/stromal cell source factor (PBSF/SDF-1) and CXCR4 chemokine receptors each, all can cause the lethal defective in vascular development, hemopoietic and the heart generation.Similarly, the cerebellum development of fetus as if depend among the central nervous system CXCR4 nerve cell migration and the typing in bring into play function effectively.As if the granulocyte of this G albumen coupling chemokine receptors in guaranteeing little brain rudiment play an important role in moving with essential pattern.

In the present invention, we disclose have unique chemistry and by with previous disclosed macrocyclic compound similar mode binding chemotactic factor receptor CXCR4 and CCR5, thereby demonstrate the chemical compound of the protection effect that anti-target cell infected by HIV.These chemical compound antagonisms combination, the signal of the native ligand of CXCR4---native ligand of the chemotactic factor stromal cell source factor-1 α (SDF-1) and/or CCR5---chemotactic factor RANTES produce and chemotactic influence.

Furthermore, chemical compound of the present invention has the effect that increases CFU-GM and/or stem cell.Further, chemical compound of the present invention not only has the effect that increases the leukocyte generation, equally also demonstrates antiviral characteristic.Therefore, these actors help to influence in the leukopenia treatment to the active influence of bone marrow, thereby the healing and the burn treatment of the side effect in control chemotherapy, the radiotherapy, the success rate that improves bone marrow transplantation, promotion wound, and to the bacterial infection in the leukemia.Further, the regeneration of compounds affect heart tissue of the present invention.

Quoting of file above do not meaned admit that above any described all is the technology formerly of keeping to the point.All about the date or about the request of these file contents, all be based on available information, and relevant these file date correctness or content correctness do not constituted any approval from the applicant.In addition, the All Files of quoting in the application's full text is all quoted by integral body in this application as a reference.

Summary of the invention

The invention provides a kind of chemokine receptors that is incorporated into, and native ligand is combined the compounds that plays interference effect with chemokine receptors.Chemical compound of the present invention is that target cell HIV is infected the useful effect thing that shows protective effect, and is same effective to the treatment of rheumatoid arthritis.Specific embodiment of the present invention is the chemical compound as chemokine receptor anagonists or agonist, and it can be effectively as passing through to improve CD4 ⁺Thereby the immune actor of level reconstruct of cell, as immunocyte such as CD8 ⁺The antagonism thing of cell and neuronal cell apoptosis, be cell to migration antagonism thing and other bioactive actor relevant with the bonded ability of chemokine receptors of the substrate source factor 1 with the chemokine inhibiting of these chemical compounds as people's bone marrow B.

In addition, the present invention relates to treat animal subject to increase the method for CFU-GM and/or stem cell population, specifically is the veterinary's class animal subject and the experimenter.Described CFU-GM and/or stem cell can be collects collecting cell and is used for cell transplantation.In one embodiment, activatory myeloid progenitor and/or stem cell are used to myocardial repair.Furthermore, the present invention relates to treat the method for animal subject, be specially leukocyte (WBC) counting defective or after using chemical compound disclosed by the invention, will benefit from sick beast and the patient that the WBC level improves.In addition, the invention still further relates to carrying out the method for the regenerated animal subject effective regeneration of heart tissue heart tissue by chemical compound disclosed by the invention.

On the one hand, the present invention relates to have the chemical compound of following structural formula

In the formula, ring A and B are the optional 5-6 unit bicyclic heteroaryl that replaces independently of one another;

Ring C is the 5-8 unit ring of the optional saturated or fractional saturation that replaces;

Y is H, contain one or more heteroatomic C _1-6Alkyl or annulus, and can choose replacement wantonly separately;

L is (CR ³ ₂) ₁Or NR (CR ³ ₂) ₁, alkyl bond wherein can be substituted by chain ethylene linkage or acetylene bond;

Each R wherein ³Be H or non-interfering (non-interfering) substituent group independently;

L is 1-6;

R ¹And R ²Be H or non-interferential substituent group independently; Wherein, C is piperidyl or 1,2,3 when ring, the 6-tetrahydro pyridyl, and ring A and B be when being pyridine radicals, R ¹And R ²Have at least one not to be H; When ring C is piperidyl and ring A and B when being pyridine radicals, R ¹And R ²Be not naphthyl simultaneously;

If L-Y is CH ₃, then encircle C and be not 4-oxo-piperidines-3,5-dicarboxylic acids; And

If L-Y is a benzyl, then encircles C and be not 4-hydroxyl-1,2,5,6-tetrahydrochysene-pyridine-3-carboxylic acid ester.

In above-mentioned structural formula 1, the substituent group on the optional ring that replaces can be inorganic part, alkyl (C _1-10), alkenyl (C _2-10), alkynyl group (C _2-10), aryl (5-12 unit), aralkyl, arylalkenyl or sweet-smelling alkynyl, each group can be chosen wantonly and contain one or more and be selected from O, S and N hetero atom, and each group can further be replaced.

Substituent group on ring A, B and the C is non-interferential substituent group.Usually, " non-interferential substituent group " refers to that this substituent existence does not destroy and has the ability of compound in structural formula I as chemokine receptor anagonists.Be meant that specifically substituent existence does not destroy the effectiveness of chemical compound.Owing to show that chemical compound of the present invention can suppress HIV and duplicate and specificity ground and CXCR4 acceptor interaction, so chemical compound of the present invention also will be effective to the treatment disease of the activity adjusting that need mediate CXCR4 and CCR5.

The non-interfering substituent group that is fit to comprises alkyl (C _1-10), alkenyl (C _2-10), alkynyl (C _2-10), aryl (" C " _5-12), aralkyl, arylalkenyl or sweet-smelling alkynyl, each group can be chosen wantonly and contain one or more hetero atom that is selected from O, S and N and each group can further be replaced; Or optional what replace is acyl group, aroyl, alkyl-alkenyl, alkynyl or arylsulfonyl form, and their the replacement form that contains heteroatomic alkyl, alkenyl, alkynyl or aryl moiety.Other non-interfering substituent group comprises OR, SR, NR ₂, COOR, CONR ₂, wherein R is as above-mentioned defined H or alkyl, alkenyl, alkynyl or aryl.When substituted atom was C, substituent group also can comprise, the halogen except substituent group listed above (halo), OOCR, NROCR, and wherein R is H or above-mentioned substituent group, or can be=O, or can be NO ₂, SO ₂R, SOR, CN, CF ₃, OCF ₃Or=NOR.

In above-mentioned structural formula 1, R ¹And R ²The non-interfering substituent group that can be H or define as mentioned.Furthermore, the optional replacement part in the structural formula 1 can be by inorganic part, alkyl (C _1-10), alkenyl (C _2-10), alkynyl (C _2-10), aryl (5-12 unit), aralkyl, arylalkenyl or sweet-smelling alkynyl replace, each group can be chosen wantonly and contain one or more hetero atom that is selected from O, S and N and each group can further be replaced.

In above-mentioned structural formula 1, R ³The non-interfering substituent group that can be H or define as mentioned.In specific embodiment, R ³Be H.

In above-mentioned structural formula 1, A, each ring of B can be a pyridine independently, pyrimidine, pyrazine, pyridazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3, the 5-triazine, 1,2,4, the 5-tetrazine, the pyrroles, imidazoles, pyrazoles, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, thiazole oxazole, isothiazole isoxazole, 1,2, the 3-thiadiazoles, 1,3, the 4-thiadiazoles, 1,2, the 3-oxadiazole, 1,3, the 4-oxadiazole, quinoline, isoquinolin 1,4-Benzodiazine, quinazoline, 2 (pthalazine), cinnoline, 1,2, the 3-phentriazine, 1,2, the 4-phentriazine, indole, benzimidazole, 1H-indazole benzoxazole, benzothiazole, benzo [d] isoxazole, benzo [d] isothiazole, or purine.In specific embodiment, each ring of A, B is pyridine, pyrimidine, imidazoles or benzimidazole independently.In certain embodiments, ring A can be identical with B.

In above-mentioned structural formula 1, ring C can be pyrrolidine, piperidines, six hydrogen-1H-azatropylidene, piperazine, morpholine, thiomorpholine, azepan (azepane), Azacyclooctane (azocane), 2,3,4,7-tetrahydrochysene-1H-azatropylidene, 2,3,6,7-tetrahydrochysene-1H-azatropylidene, the 3-pyrrolin, 1,2,3, the 6-tetrahydropyridine, isoindoline, 1,2,3, the 4-tetrahydroisoquinoline, 2,3,4,5-tetrahydrochysene-1H-benzo [d] azatropylidene, 2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene, Tetramethylene., Pentamethylene., cyclohexane extraction, cycloheptane, cyclooctane, cyclopentenes, cyclohexene, cycloheptene, cyclo-octene, Pentamethylene oxide., tetrahydric thiapyran, oxepane (oxepane), thia cycloheptane (thiepane), oxocane (oxocane), or thia cyclooctane (thiocane).In certain embodiments, ring C is pyrrolidine, piperidines, piperazine or six hydrogen-1H-azatropylidene.

In above-mentioned structural formula 1, Y can be aromatics, heteroaromatic or heterocyclic part.In specific embodiment, Y is phenyl, imidazoles, pyridine, thiophene, pyrrolidine, pyrazoles, piperidines, azetidine, benzimidazole, benzo [d] isoxazole or thiazole.In other embodiments, Y is replaced by following group is optional: halogen, cyano group, nitro, hydroxyl, by carbonyl, annulus or alkyl, alkenyl or the optional assorted moieties that contains one or more N, O, S of alkyl or the optional hydroxyl that replaces of haloalkyl, replacement, each randomly is an oxide form.

In above-mentioned structural formula 1, Y can randomly be replaced by the optional annulus that contains one or more N, O or S.This annulus can be the aromatics or the heteroaromatic moiety of the optional 5-12 unit ring that replaces.The example of annulus includes but not limited to pyridine, phenyl, piperidines or 2H-tetrazolium.

In above-mentioned structural formula 1, Y can be phenyl or imidazoles.In other embodiments, Y can be selected from:

-(CR ₂) _mNR ₂、

-(CR ₂) _mNR ₂(CR ₃)、

-(CR ₂) _mNR(CR ₂) _mNR ²、

-(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mOR、

-(CR ₂) _mCO(CR ₂) _mOR、

-(CR ₂) _mCO(CR ₂) _mNR ₂、

-(CR ₂) _mCO(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNRCO(CR ₂) _mNR ₂、

_-(CR ₂) _mNR(CR ₂) _mCO ₂R、

_-(CR ₂) _mNR(CR ₂) _mCOR、

_-(CR ₂) _mNR(CR ₂) _mSO ₂R、

-(CR ₂) _mNRCO(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNRCO(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mOR、

-(CR ₂) _mCR＝NOH、

-(CR ₂) _mCONR(CR ₂) _mOR、

-(CR ₂) _mN[(CR ₂) _mCO ₂R] ₂、

-(CR ₂) _mONRCONR ₂、

-(CR ₂) _m-Z、

-(CR ₂) _mNR-(CO) _mZ、

-(CR ₂) _mNR-(CR ₂) _mZ and

-(CR ₂) _m-CR＝N＝Z；

R in various is H or non-interfering substituent group independently, and each m is for being 0-4 independently, and Z is the optional aromatics or the heteroaromatic moiety that contain 5-12 unit ring that replaces.

In a certain embodiment, Y is (CH ₂) ₁NR ₂, wherein R is H or non-interfering substituent group, and 1 is 1-10.

In above-mentioned structural formula 1, each ring of A, B can contain single substituent group at its connecting key adjacent with ring C.In a certain embodiment, this substituent group on being positioned at ring A and encircling B is identical.

In above-mentioned structural formula 1, R ¹And R ²Can be unsubstituted alkyl independently.In a certain embodiment, R ¹And R ²Be positioned at the adjacent of the key that links to each other with ring C.

In above-mentioned structural formula 1, ring C can be saturated or contains a two key.

Multiple embodiments of the present invention is set forth in an embodiment to some extent.The present invention comprises other chemical compound with structural formula 1, and their substituent group is independently selected from the chemical compound among the embodiment.Therefore, the concrete replacement that the invention is not restricted in the multiple embodiments as described below is basis set.

Say from others, the present invention relates to contain the pharmaceutical composition that has a compound in structural formula I at least, and relate to the method for improvement by the condition of illness of CXCR4 receptor or CCR5 receptor modulators.These condition of illness comprise HIV infection, the disease relevant with inflammation, disease and some tumor of being correlated with the immunity expression.These condition of illness comprise that also those benefit from stem cell and CFU-GM quantity increases and the disease of white blood cell count raising.

Description of drawings

Fig. 1 shows: single patient gives the reaction of AMD3100 (1,1 '-[1,4-phenylene two (methylene)]-two-1,4,8,11-four-azacyclo-tetradecane) to intravenous injection.

Fig. 2 shows: from the raising reaction of the observed WBC counting of the hiv infected patient of accepting continuous 10 days continuous intravenous infusions of AMD3100.

Implement pattern of the present invention

The invention provides the as above described chemical compound of structural formula I, it is for chemotactic factor and thereby become the regulator of chemokine receptors.

More particularly, this chemical compound binding chemotactic factor receptor also disturbs combining of chemokine receptors and its native ligand, exempts from the protection effect that HIV infects thereby demonstrate the protection target cell.This chemical compound also can be used as the antagonist or the agonist of chemokine receptors, thereby and has by improving CD4 ⁺The immune ability of horizontal reconstruct; As the antagonist of immunocyte apoptosis, as CD8 ⁺Cell and neuronal cell; As people's bone marrow B is cell to the originate antagonist of the factor-1 migration of substrate, is used for other biological activity relevant with the bonded function of chemokine receptors with these chemical compound chemokine inhibitings equally.

This chemical compound suppresses the combination and the signal conduction of native ligand-chemotactic factor SDF-1 mediation equally.Though do not wish to be limited by any theory, because this inhibition produces the effect of stem cell and/or CFU-GM growth thereby have compound in structural formula I inhibition SDF-1 with combining of CXCR4.Increase stem cell in the blood and/or CFU-GM and in treatment, help to alleviate in the therapeutic scheme, cause the scheme of leukopenia as those for the harmful effect of bone marrow.These are well-known side effect in the chemotherapy and radiation.Have success rate that compound in structural formula I improves bone marrow transplantation equally, promote the healing and the burn treatment of wound and help to repair impaired histoorgan.These chemical compounds are equally to ubiquitous bacterial infection in the leukemia.Have compound in structural formula I be used in conjunction with or not under the situation in conjunction with other activation factor, by separation property blood transfusion activation with collect CD34 ⁺Cell.The cell that collection obtains needing to be used for the treatment of stem cell transplantation.

Used in the present invention term " CFU-GM " refers to reply some stimulation can form the hematopoietic cell of differentiation or those cells of medullary cell.The existence of CFU-GM can be assessed by the ability that cells in sample forms different types of colony forming unit, comprise for example CFU-GM (colony forming unit, granulocyte-macrophage), CFU-GEMM (colony forming unit, versatility), BFU-E (burst forming unit, erythrocyte sample), HPP-CFC (high proliferation potential colony forming unit cell), maybe can cultivate the differentiated colony of other type that obtains by known rules.

The CFU-GM that cell refers to less differentiation type " done " in used in the present invention term.This class cell typically is generally the CD34 positive.Yet, have some stem cell not contain this labelling.These CD34 ⁺Cell can identify by the cell divide (fluorescence activated cell sorting (FACS)) by fluorescence-activation, thereby and their existence can be with this technology evaluation in sample.

Usually, CD34 ⁺Cell only is present in the blood with low-level, but is present in the bone marrow in a large number.And the cell of other type also can show this labelling as endotheliocyte and mastocyte, and CD34 is considered to a kind of sign that stem cell exists.

Disturb the chemokine antagonists of chemotactic factor and its receptors bind also to can be used for by improving CD4 ⁺The level of cell and reconstruct immune system (Biard-Piechaczyk etc., Immunol.Lett. (1999) 70:1-3); As the antagonist of immunocyte apoptosis, as CD8 ⁺Cell (Herbin etc., Nature (1998) 395:189-193) and as antagonist (Ohagen etc., J.of Virol. (1999) 73:897-906 of neuronal apoptosis; With Hesselgesser etc., Curr.Biol. (1998) 8:595-598).It is cell migration to the originate migration (see as: E.Fedyk etc., J.of LeukocyteBiol. (1999) 66:667-783) of the factor-1 of substrate that chemokine receptor anagonists also suppresses people's bone marrow B.

The present invention includes a kind of pharmaceutical composition with compound in structural formula I and at least a excipient for the treatment of effective dose that contains, and the method for using said composition treatment human body or other animal body.The invention provides a kind ofly by blocking-up or disturb chemokine receptors and the bonded method of its native ligand, it comprises makes contacting as compound in structural formula I of described chemokine receptors and effective dose.The present invention includes a kind of protection and have the method for the target cell of chemokine receptors (pathogen is by causing disease or pathological changes with combining of this receptor), comprise that giving the mammals animal subject contains the pharmaceutical composition with compound in structural formula I for the treatment of effective dose.But the present invention includes and have compound in structural formula I and making blocking-up or disturbing chemokine receptors to combine purposes in the medicine of disease treatment of produce effects with its native ligand.According to treatment effective dose, determine the recipe quantity of this chemical compound in compositions with compound in structural formula I.

Chemical compound of the present invention

Chemical compound of the present invention can " prodrug " form uses, i.e. the protected form of chemical compound, and it discharges chemical compound after to experimenter's administration.For example, this chemical compound can have protecting group, its cracking, thereby release of active compounds, or oxidized or reduction in body fluid by hydrolysis in body fluid (as blood), thus discharge this chemical compound.The discussion of prodrug can be " " Smith and William Si " drug design principle introduction " ( Smith and Williams ' Introduction to the Principles of Drug Design), second edition, H.J.Smith, Wright work, London is found in 1988.

Chemical compound of the present invention is also can be nontoxic to be used with the form of acid organic or inorganic or the salt that alkali became.Alleged avirulence must taking in according to untreated infected patient in advance afterwards now.The salt that forms with inorganic base is exemplified as the hydroxide (as calcium, magnesium etc.) of alkali-metal hydroxide (as sodium hydroxide, potassium hydroxide etc.), alkaline-earth metal and aluminium hydroxide, ammonium hydroxide etc.The salt that forms with organic base comprises and trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N '-dibenzyl ethylene diamine etc.The example of the salt that forms with mineral acid comprises the salt that forms with hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid etc.The salt that forms with organic acid comprises the acid that forms with formic acid, oxalic acid, acetic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc.Comprise the salt that forms with basic amino acid equally, as the salt that forms with arginine, lysine, ornithine etc., and the salt that forms with acidic amino acid, as the salt that forms with aspartic acid, glutamic acid etc.

Chemical compound of the present invention also can comprise other chiral centre except the chiral centre that has shown.Consider the chiral centre that these hydroxide are other, the present invention includes the mixture of the mixture of stereoisomer, single stereoisomer and enantiomeric mixture and multiple stereoisomer.

Chemical compound of the present invention is briefly described with structural formula I, lists this structural formula as follows once more for ease of discussion hereinafter.

In the formula, each is the optional 5-6 unit bicyclic heteroaryl that replaces independently ring A and B;

L is 1-6;

Ring A and B illustrative embodiment comprise pyridine, pyrimidine, pyrazine, pyridazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3, the 5-triazine, 1,2,4, the 5-tetrazine, the pyrroles, imidazoles, pyrazoles, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, thiazole oxazole, isothiazole isoxazole, 1,2, the 3-thiadiazoles, 1,3, the 4-thiadiazoles, 1,2, the 3-oxadiazole, 1,3, the 4-oxadiazole, quinoline, isoquinolin 1,4-Benzodiazine, quinazoline, 2, the 3-benzodiazine, cinnoline, 1,2, the 3-phentriazine, 1,2, the 4-phentriazine, indole, benzimidazole, 1H-indazole benzoxazole, benzothiazole, benzo [d] isoxazole, benzo [d] isothiazole, and/or purine (and orpurine).

In the embodiment, what ring A and B were preferable is pyridine, pyrimidine, imidazoles and/or benzimidazole.Equally preferably encircle A identical with B have a compound in structural formula I.

Ring C illustrative embodiment comprises pyrrolidine, piperidines, six hydrogen-1H-azatropylidene, piperazine, morpholine, thiomorpholine, azepan, Azacyclooctane, 2,3,4,7-tetrahydrochysene-1H-azatropylidene, 2,3,6,7-tetrahydrochysene-1H-azatropylidene, the 3-pyrrolin, 1,2,3, the 6-tetrahydropyridine, isoindoline, 1,2,3, the 4-tetrahydroisoquinoline, 2,3,4,5-tetrahydrochysene-1H-benzo [d] azatropylidene, 2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene, Tetramethylene., Pentamethylene., cyclohexane extraction, cycloheptane, cyclooctane, cyclopentenes, cyclohexene, cycloheptene, cyclo-octene, Pentamethylene oxide., tetrahydric thiapyran, oxepane, the thia cycloheptane, oxocane, with the thia cyclooctane.

The preferable embodiment of ring C is pyrrolidine, piperidines, piperazine and six hydrogen-1H-azatropylidene.

In a certain embodiment, Y is selected from:

-(CR ₂) _mNR ₂、

-(CR ₂) _mNR ₂(CR ₃)、

-(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mOR、

-(CR ₂) _mCO(CR ₂) _mOR、

-(CR ₂) _mCO(CR ₂) _mNR ₂、

-(CR ₂) _mCO(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNRCO(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mCO ₂R、

-(CR ₂) _mNR(CR ₂) _mCOR、

-(CR ₂) _mNR(CR ₂) _mSO ₂R、

-(CR ₂) _mNRCO(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNRCO(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mOR、

-(CR ₂) _mCR＝NOH、

-(CR ₂) _mCONR(CR ₂) _mOR、

-(CR ₂) _mN[(CR ₂) _mCO ₂R] ₂、

-(CR ₂) _mONRCONR ₂、

-(CR ₂) _m-Z、

-(CR ₂) _mNR-(CO) _mZ、

-(CR ₂) _mNR-(CR ₂) _mZ and

-(CR ₂) _m-CR＝N＝Z；

R in various is H or non-interfering substituent group independently, and each m is 0-4 independently, and Z is the optional aromatics or the heteroaromatic moiety that contain 5-12 unit ring that replaces.

In addition, the embodiment of Y comprises, for example inorganic part." inorganic part " used herein refers to not contain the part of carbon.Exemplify and include but not limited to halogen, hydroxyl, SH, NO ₂Or NH ₂.

The preferable embodiment of Z comprises the azo-cycle that contains of fractional saturation.

Concrete preferably A ring of chemical compound of the present invention and B ring contain substituent group at its connecting key adjacent with ring C.Particularly embodiment preferred medium ring A is identical with substituent group on the B.

The concrete preferable embodiment of Y contains (CH ₂) ₁-NR ₂, wherein R is 1-10 as above-mentioned definition and 1.

In the same preferable embodiment on any ring A, B, C or the Y with ring (comprising ring Z) on substituent group condense on the additional ring system.

Optional substituted alkyl group exemplifies and comprises methyl, ethyl, propyl group etc., and comprises cycloalkyl such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc.; Optional kiki alkenyl group exemplifies and comprises pi-allyl, crotyl, pentenyl, 3-hexenyl, 2-cyclopentenyl, 2-cyclohexenyl group, 2-cyclopentenyl methyl, 2-cyclohexenyl group methyl etc.; Preferable is C1-6 alkyl and alkenyl.

Halogen exemplifies and comprises fluorine, chlorine, bromine, iodine etc., is preferable with fluorine and chlorine.

Optional substituted hydroxy and mercaptan exemplify and comprise that alkoxyl or alkyl thio-base are (as C _1-10Alkyl), for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc.; Optional aralkoxy that replaces or aralkyl thiol are (as phenyl-C _1-4Alkyl is as benzyl, phenethyl etc.).When having two adjacent hydroxyls or thiol substituent group, hetero atom can connect as O (CH by alkylidene ₂) _nO and S (CH ₂) _nS (wherein n=1-5).Comprise methylene-dioxy, ethylenedioxy etc. for example.The oxide of sulfide group such as sulfoxide class and sulfone class are also in imagination.

The optional oh group that replaces comprises the optional C that replaces for example equally _2-4Alkanoyl (as, acetyl group, propiono, bytyry, isobutyryl etc.), C _1-4Alkyl sulphonyl (as, mesyl, ethylsulfonyl etc.) and optional aromatics and the heterocycle carbonyl group that replaces comprise benzoyl, pyridine carbonyl etc.

Substituent group on the optional substituted-amino can mutually combine and constitute a cyclic amino (as, 5-to the first cyclic amino of 6-etc., as nafoxidine, piperazine, piperidines, pyrrolidine, morpholine, thiomorpholine, pyrroles, imidazoles etc.).Described cyclic amino can have substituent group, substituent group comprise for example halogen (as, fluorine, chlorine, bromine, iodine etc.), nitro, cyano group, hydroxyl, thiol, amino, carbonyl, optional halo C _1-4Alkyl (as, trifluoromethyl, methyl, ethyl etc.), optional halo C _1-4Alkoxyl (as, methoxyl group, ethyoxyl, trifluoromethoxy, trifluoro ethoxy etc.), C _2-4Alkanoyl (as, acetyl group, propiono etc.), C _1-4The alkane sulfonyl (as, mesyl, ethylsulfonyl etc.), preferable substituent quantity is 1 to 3.

Amino group also can be substituted one to secondary (constituting secondary amine or tertiary amine), and substituent group comprises C as the optional alkyl that replaces _1-10Alkyl (as, methyl, ethyl, propyl group etc.), the optional alkenyl that replaces such as pi-allyl, crotyl, pentenyl, 3-hexenyl etc. or the optional cycloalkyl that replaces such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc.In these examples, with C _1-6Alkyl, alkenyl and cycloalkyl are preferable.Amino group also can be by aromatics or heterocyclic group, aralkyl (as, phenyl C _1-4Alkyl) or assorted alkyl such as phenyl, pyridine, benzyl (benzyl), phenethyl, picolyl, pyridine ethyl etc. group is optional replaces.This heterocyclic group can be and contains 1-4 heteroatomic 5 or 6 yuan of rings.

The C that amino group can be optionally substituted _2-4Alkanoyl is as acetyl group, propiono, bytyry, isobutyryl etc. or C _1-4Aromatic ring or heterocycle that alkane sulfonyl (as mesyl, ethylsulfonyl etc.) or carbonyl or sulfonyl replace replace as groups such as benzenesulfonyl, benzoyl, pyridine sulfonyl, pyridine carbonyl are optional.Heterocycle as hereinbefore defined.

Optional carbonyl group or the sulfonyl group that replaces comprises the optional replacement form that these groups are formed by multiple alkyl for example, as the first mono-cyclic aromatic group of alkyl, alkenyl and 5-6 (as, phenyl, pyridine radicals etc.), as hereinbefore defined.

Use and administration

The present invention relates to regulate the compound in structural formula I that has of chemokine receptor activity.Chemokine receptors includes but not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3 and CXCR4.

In a certain embodiment; the invention provides a kind of binding chemotactic factor receptor specifically that passes through; influence native ligand and combine, thereby present the compound in structural formula I that has of protective effect that the anti-HIV of target cell is infected with CCR5 and/or the CXCR4 of target cell.

In another embodiment, chemical compound of the present invention is as influencing chemokine receptors, actor as CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3, CXCR4, these chemokine receptors are got in touch the important medium for being the immunomodulating disease, also are the important medium of many inflammation.

Other comprises that as the disease of medium blood vessel takes place and the tumor generation with chemotactic factor equally, as the tumor of the cerebral tumor, breast carcinoma and prostate, lung or hemopoietic tissue.Therefore, the chemical compound of regulating these chemokine receptor activities helps treatment or prevents these diseases.

Term herein " regulator " comprises antagonist, agonist, partial antagonist and/or partial agonist, i.e. inhibitor and activator.In a certain embodiment of the present invention, have compound in structural formula I and be by suppressing HIV and chemokine receptor CCR 5 of target cell and/or combining of CXCR4, thereby present the protective effect of the anti-HIV infection of target cell.This adjusting is by comprising that thereby making target cell contact the viral method that combines this step with chemokine receptors of effectively inhibition with the described chemical compound of some realizes.

The chemical compound of chemokine inhibiting receptor active and function can be used for treating the disease relevant with inflammation, include but not limited to inflammatory or hypersensitive disease, as asthma, allergic rhinitis, hypersensitivity pulmonary disease, hypersensitivity pneumonia, eosinophilic pneumonia, delayed hypersensitivity, interstitial lung disease (ILD) (becoming or ILD, systemic lupus erythematosus (sle), ankylosing spondylitis, systemic sclerosis, Sjogren ' s syndrome, polymyositis or the dermatomyositis relevant) with rheumatoid arthritis as the constitutional cystic fibrosis; Systemic anaphylaxis or allergy, drug allergy, sting allergy; Autoimmune disease is as rheumatoid arthritis, psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes; Glomerulonephritis, autoimmune thyroiditis (throiditis), transplant rejection comprise the anti-host disease of allograft rejection or mortifier; Inflammatory bowel disease is as Crohn disease and ulcerative colitis; Spondyloarthropathy; Scleroderma; Psoriasis (comprising the psoriasis that T is cell-mediated) and inflammatory skin are sick as dermatitis, eczema, atopic dermatitis, contact dermatitis, urticaria; Vasculitis (as gangrenosum acne, skin and hypersensitive angiitis); Acidophil myositis (myotis), the eosinophilic fasciitis; And cancer.

Chemical compound of the present invention has the purposes of preparation medicine for treatment equally, for example is used to prepare treatment HIV, chemokine mediated disease, treatment inflammation disease such as rheumatoid arthritis or the medication of treatment tumor disease of treatment.

In addition, activation or promote the chemical compound of chemokine receptor function to be used for the treatment of the disease relevant, to stand the treatment (as the corticosteroid treatment) of chemotherapy, radiotherapy, promotion wound healing and burn treating, autoimmune disease or other drug as individuality with immunosuppressant, or be used for the immunosuppressant conventional medicament that causes that autoimmune disease and allograft/transplant rejection treats and combine; Because the birth defect of function of receptors or the immunosuppressant that other reasons causes; And infectious disease, as parasitic disease, include but not limited to helminthic infection, as nematicide (roundworm); Whipworm, pinworm, ascarid, ancylostome, quasi-colubriformis, trichinella, filaricide, trematodiasis, the internal organs anthelmintic, visceral larva migrans (as the bow ascarid), oxyphil cell's gastroenteritis is (as Anisakid nematode, Mus intestine moistening nematicide (Phocanema spp.)), skin larval migration (ancylostoma braziliense (Ancylostona braziliense)), dog ancylostome (Ancylostoma canium)), the protozoacide Plasmodium vivax (Plasmodium vivax) that causes malaria, human cytomegalic inclusion disease virus, herpesvirus saimiri (Herpesvirus saimiri), with Kaposi sarcoma hepatovirus, be also referred to as the infection of people's hepatovirus 8 and poxvirus MCV (Moluscum contagiosum).

Method of the present invention can be improved or classical symptom that on the other hand can produce effects comprises hematopoietic disorder, the hemopoietic defective (hematopoietic deficits) that causes as aplastic anemia, leukemia, drug induced anemia and chemotherapy or radiotherapy.Method of the present invention is used among the immunosuppressant therapy equally or afterwards, to improve the success rate of transplanting, the treatment that equally also is used for wound healing and bacterial infection is to obtain better effect.Method of the present invention is also effective to treating patient that immunity weakens or immune system injury.Method of the present invention can be improved or classical symptom that on the other hand can produce effects comprises that those are reversed the patient's of viral infection symptom, more particularly the patient who is infected by human immunodeficiency virus (HIV).Therefore, method of the present invention at: but promote patient's CFU-GM and/or stem cell produce effects, but or carry out the wide spectrum disease that CFU-GM and/or stem cell are collected produce effects for follow-up stem cell transplantation.In addition, method of the present invention also at: with the white blood cell count deficiency is feature, but or improves the wide spectrum disease of described WBC counting produce effects.

Chemical compound of the present invention can prodrug forms preparation, i.e. the protected form of chemical compound, it discharges chemical compound after to experimenter's administration.Usually, protecting group is by being hydrolyzed in body fluid (as blood), thus release of active compounds, or oxidized in vivo or reduction, thereby discharge chemical compound.The discussion of prodrug can be " " Smith and William Si " drug design principle introduction " ( Smith and Williams ' Introduction to the Principles of Drug Design), second edition, H.J.Smith, Wright work, London is found in 1988.

Chemical compound of the present invention can be independent delivery of active ingredients, with different form of mixtures administrations with compound in structural formula I, and/or with the additional activity mixture of ingredients form administration with therapeutical effect or nutritive validity, these supplementary elements such as antibiotic, vitamin, herb extracts, anti-inflammatory agent, glucose, antipyretic, analgesic, granulocyte-macrophage colony stimutaing factor (GM-CSF), il-1 (IL-1), interleukin-3 (IL-3), interleukin-8 (IL-8), PIXY-321 (GM-CSF/IL-3 fusion rotein), macrophage inflammatory protein, stem cell factor, thrombopoietin, relevant oncogene of growth or chemotherapeutics, and the like.In addition, chemical compound of the present invention can with the additional activity mixture of ingredients form administration with therapeutical effect or nutritive validity, these supplementary elements such as antibiotic, vitamin, herb extracts, anti-inflammatory agent, glucose, antipyretic, analgesic, and the like.

Chemical compound of the present invention can be with being to suffer from veterinary medicine to prepare for the known preparation technique of those of ordinary skill in this area.Be fit to concrete administration form and have the preparation of the chemical compound of structural formula I representative type, can " Lei Mingdun medicament science " ( Remington ' s Pharmaceutical Sciences), by Mack PublishingCompany, Easton finds in the latest edition that PA publishes.

Preferably, chemical compound more preferably by intravenous injection, can pass through subcutaneous injection or intraperitoneal injection with the injection form administration equally, and the like form administration.Other parenteral administration approach comprises intramuscular injection and intra-articular injection.For intravenous injection or parenteral administration approach, chemical compound of the present invention is made suitable liquid form according to the requirement and the excipient of prescription.Said composition can contain liposome or other carrier that is fit to.For intravenous injection, this solution need use the isosmotic solution preparation through the preparation of standard fabrication method, as Hank solution.

Except that injection, other route of administration also can be used.But the chemical compound preparation is tablet, capsule, syrup, powder or other is suitable for oral form.By using suitable excipient, these chemical compounds equally can be by mucosa with suppository or nasal cavity spray delivery.By using suitable transdermal enhancer and sustained release speed, percutaneous dosing is effective too.

The selection of drug-delivery preparation form and approach will and be decided by the diagnosis amount body that cures mainly the professional usually according to the disease character of individual patients, the required treatment of patient.

Suitable dosage range with compound in structural formula I changes with these considerations.But this chemical compound is with the dosage range administration of about 0.1 μ g/kg-5mg/kg body weight usually; Preferable scope is about 1 μ g/kg-300 μ g/kg body weight; Better is about 10 μ g/kg-100 μ g/kg body weight.Therefore, for the patient that a typical body weight is 70-kg, dosage range is about 0.7 μ g-350mg; That preferable is about 700 μ g-21mg; That better is about 700 μ g-7mg.During oral or percutaneous dosing, the dosage of chemical compound as the i.v. administration want greatly.

This chemical compound can single bolus quantities administration, time dosed administration, i.v. or percutaneous dosing or with compound dosed administration.

, have compound in structural formula I and can be used for preparing cell culture in the external treatment scheme patient's administration except that directly, this cell culture is used to replenish patient's hemocyte subsequently.External treatment can be based on self cell that is collected in peripheral blood or bone marrow, or collects from mating donor's allotransplant.Compound concentrations or single to have the bonded concentration of compound in structural formula I or itself and other actor (as, macrophage inflammatory protein) be the problem of an optimization routine (routine optimization).

When this therapeutic alliance helps regulating chemokine receptor activity, thereby when preventing and treating inflammation and immunomodulating disease, chemical compound of the present invention can further be united use with other any activator or Pharmaceutical composition.

Chemical compound of the present invention can further have the actor that prevents or treat the HIV effect with one or more and unite use.This type of actor comprises for example:

(1) nucleotide reverse transcriptase inhibitors, fumaric acid is for Nuo Fuwei ground rope hydroxypropyl acrylate (tenofovir disoproxilfumarate), lamivudine/zidovudine, Abacavir/lamivudine/zidovudine, emtricitabine, An Dekewei (amdoxovir), alovudine, DPC-817, SPD-756, SPD-754, GS7340, ACH-126,443 (β)-L-F d4C, azidothymidine AZT, zalcitabine, stavudine, A Defuwei (adefovir), A Defuwei two peopentyl esters (adefovir dipivoxil), Fu Xifu finalizes polyester (fozivudine todoxil) etc.;

(2) non-nucleotide reverse transcriptase inhibitors (comprising the medicine that has as the antioxidant activity of Yi Minuo card (imminocal), oltipraz etc.) is as nevirapine, delavirdine, Ai Fuweien, Luo Weilide (loviride), Yi Minuo card, oltipraz, TMC-125, DPC-083, Kai Puweilin (capravarine), MIAOMAO poon lactone A, SJ-3366 series etc.;

(3) protease inhibitor is as Saquinavir, Lopinavir/ritonavir, A Tanawei, Fu Shanawei, tipranavir, TMC-114, DPC-684, indinavir, nelfinavir, amprenavir, palinavir (palinavir), LASINAVIR BMS-234475 Lasinavir [INN (lasinavir) etc.;

(4) entry inhibitor is as T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806 series and 5-spiral (5-Helix);

(5) CCR5 acceptor inhibitor is as Sch-C (or SCH351125), Sch-D and SCH350634, TAK779, UK 427,857 and TAK 449;

(6) integrase inhibitor, as L-870,810, GW-810781 (S-1360); And

(7) inhibitor that sprouts is as PA-344 and PA-457.

The coupling of chemical compound of the present invention and HIV medicament is not limited to (1), (2) and/or (3), also comprises with other any to the coupling of HIV treatment efficacious agents.The coupling of chemical compound of the present invention and other HIV medicament can separately or cooperate administration.A certain medicament is for other medicament can go ahead of the rest administration, administration simultaneously or administration subsequently.

As chemical compound of the present invention---AMD3100 is a kind of antagonist (Gerlach etc., J.Biol.Chem. (2001) 276:14153-14160) of CXCR4 chemokine receptors.CXCR4 on the SDF-1 that these chemical compounds disturb bone marrow substrate cell sources and the stem cell combines, thereby makes hematopoietic stem cell be discharged into (Broxmeyer etc., Blood (2001) 98:811a (summary)) the blood circulation from bone marrow.In the first phase test of Washington State University (Washington State University, Seattle), the AMD3100 of single dose 80 μ g/kg makes the WBC counting reach 17,000/ μ l, and when 6 hours time point, the CD34 in the circulation ⁺The long peak value (Liles etc., Blood (2001) 98:737a (summary)) of 6 multiplications appears in CFU-GM/stem cell.In another nearest test, mice is injected rhG-CSF and the reorganization murine stem cell factor (rrSCF) enters blood circulation to mobilize a large amount of bone marrow stem cells, then it is induced once heart attack.The coupling of RrSCF and rhG-CSF the circulating stem cell maximum amount occurs after 5 injections every day.Perform the operation back 27 days the time, the survival rate of treatment group has improved 68% with respect to matched group.At this moment, substitute dead tissue with regenerated cardiac muscle, the functional parameter of all tests is all than matched group make moderate progress (Orlic etc., PNAS (2001) 98:10344-10349).

Therefore, but the propagation of chemical compound effective stimulus stem cell of the present invention and CFU-GM.

Chemical compound of the present invention can prodrug forms preparation, i.e. the protected form of chemical compound, it discharges chemical compound after to experimenter's administration.Usually, protecting group is by being hydrolyzed in body fluid (as blood), thus release of active compounds, or oxidized in vivo or reduction, thereby discharge this chemical compound.The discussion of prodrug can be " " Smith and William Si " drug design principle introduction " ( Smith and Williams ' Introduction to the Principles of Drug Design) second edition, H.J.Smith, Wright work, London is found in 1988.

Chemical compound of the present invention because it is the polyamines class, can be allowed to make the slaine or the metal composite of its acid-addition salts or this acid-addition salts.The salt that forms with mineral acid that the acid-addition salts that is fit to comprises biocompatibility, comprise the salt that forms with acid such as HCl, HBr, sulphuric acid, phosphoric acid and the like for example, comprise the salt that forms with organic acid salt equally as forming with acetic acid, propanoic acid, butanoic acid and the like acid, and the acid that contains an above carboxyl, the salt that acid forms as oxalic acid, 1,3-propanedicarboxylic acid, adipic acid and the like.Usually, under the physiological pH condition, chemical compound of the present invention exists with the form of acid-addition salts.Concrete preferable is the hydrochloric acid salt.In addition, when making respective pure form, the also crystallizable one-tenth hydrate of this chemical compound.

Chemical compound of the present invention can be independent delivery of active ingredients, with different form of mixtures administrations with compound in structural formula I, and/or with the additional activity mixture of ingredients form administration with therapeutical effect or nutritive validity, these supplementary elements such as antibiotic, vitamin, herb extracts, anti-inflammatory agent, glucose, antipyretic, analgesic, granulocyte-macrophage colony stimutaing factor (GM-CSF), il-1 (IL-1), interleukin-3 (IL-3), interleukin-8 (IL-8), PIXY-321 (GM-CSF/IL-3 fusion rotein), macrophage inflammatory protein, stem cell factor, thrombopoietin, relevant oncogene of growth or chemotherapeutics, and the like.

Chemical compound of the present invention can be with being to suffer from veterinary medicine to prepare for the known preparation technique of those of ordinary skill in this area.The concrete administration form that is fit to and have the preparation of the chemical compound of structural formula I representative type, can " Lei Mingdun medicament science " ( Remington ' s Pharmaceutical Sciences), by Mack PublishingCompany, Easton finds in the latest edition that PA publishes.

The selection of drug-delivery preparation form and approach will and come the amount body to decide according to the diagnosis that cures mainly the professional according to the disease character of individual patients, the required treatment of patient usually.

Suitable dosage range with chemical compound of structural formula (1) changes with these considerations.But this chemical compound is with the dosage range administration of about 0.1 μ g/kg-5mg/kg body weight usually; Preferable scope is about 1 μ g/kg-300 μ g/kg body weight; Better is about 10 μ g/kg-100 μ g/kg body weight.Therefore, for the patient that a typical body weight is 70-kg, dosage range is about 0.7 μ g-350mg; That preferable is about 700 μ g-21mg; That better is about 700 μ g-7mg.During oral or percutaneous dosing, the dosage of chemical compound as the i.v. administration want greatly.

, have compound in structural formula I and can be used for preparing cell culture in the external treatment scheme patient's administration except that directly, this cell culture is used to replenish patient's hemocyte subsequently.The carrying out of external treatment can be based on self cell that is collected in peripheral blood or bone marrow, or collects from mating donor's allotransplant.Compound concentrations or single to have the bonded concentration of compound in structural formula I or itself and other actor (as, macrophage inflammatory protein) be the problem (a matter of routine optimization) of an optimization routine.

Can comprise the individuality of the favourable reaction of method of the present invention and medical science and veterinary's individuality generally include human patient.Other individuality of method produce effects of the present invention is cat, Canis familiaris L., larger animal, poultry such as chicken, and the like.Usually, any individuality of benefiting from CFU-GM and/or stem cell lifting, or the individuality that those need CFU-GM and/or stem cell carries out stem cell transplantation all are suitable for method administration of the present invention.

But by the hemopoietic function can improve or on the other hand the classical symptom of produce effects comprise hematopoietic disorder, the hemopoietic defective (hematopoietic deficits) that causes as aplastic anemia, leukemia, drug induced anemia and chemotherapy or radiotherapy.Chemical compound of the present invention is used among the immunosuppressant therapy or afterwards equally, to improve the success rate of transplanting, equally also be used in the treatment of wound healing and bacterial infection also can being effective to treat patient that immunity weakens or immune system injury to obtain better effect.But by the hemopoietic function can improve or on the other hand the classical symptom of produce effects comprise that those are reversed the patient of viral infection, the patient who is infected by human immunodeficiency virus (HIV) more particularly.Therefore, method of the present invention at: but promote patient's CFU-GM and/or stem cell produce effects, but or carry out the wide spectrum disease that CFU-GM and/or stem cell are collected produce effects for follow-up stem cell transplantation or input.

Chemical compound of the present invention is used for impelling myocardium regenerated administration by Effects of Bone Marrow Stem Cells Mobilization equally.

The administering mode scope of expection is very extensive.Therefore, chemical compound of the present invention can be oral, intramuscular injection, intraperitoneal injection, intravenous injection, intracerebral injection (intracisternal) or transfusion, subcutaneous injection, percutaneous, mucosal or implantation.They also can suck by spraying, from nasal cavity, vagina, rectum, Sublingual or topical routes, and can be in the dosage unit preparations that is fit to separately or co-production, contain the routine that is fit to each route of administration, nontoxic pharmaceutically acceptable carrier, adjuvant and excipient in the said preparation.

Chemical compound of the present invention is used for treatment of animals, comprises mice, rat, horse, cattle, sheep, Canis familiaris L., cat and monkey, and poultry such as chicken, and the like.Chemical compound of the present invention is used for human effectively same.Usually, any individuality of benefiting from CFU-GM and/or stem cell lifting, or the individuality that those need CFU-GM and/or stem cell carries out stem cell transplantation, all be suitable for method administration of the present invention, and/or the insufficient individuality of any WBC or, more specifically, any numeration of leukocyte of benefiting from improves or benefits from the regenerated individuality of heart tissue and all is suitable for method administration of the present invention.

The present invention relates to a kind of pharmaceutical composition equally, and it comprises the compound in structural formula I that has of pharmaceutically acceptable carrier or diluent and effective dose.This chemical compound can be individually dosed or with pharmaceutically acceptable carrier (as, solid dosage forms such as tablet, capsule, granule, powder etc.; Liquid dosage form such as syrup, injection etc.) form administration behind the mixture, can oral or non-oral administration.Non-peroral dosage form comprises for example, injection, drop, suppository, pessary.

Regulate in the control of chemokine receptors at needs, suitable dosage level is generally for about 0.01 to the every kg whose body weight of 500mg every day, but single dose administration or multiple dose administration.Preferably, dosage level was about 0.1 to about 250mg/kg every day.Be understandable that concrete dosage level and dose frequency should vary with each individual to patient, and depend on all multifactor and change activity, this chemical compound metabolic stability and the action length comprise used particular compound, patient's age, body weight, health status, sex, diet, pattern and time, excretion rate, coupling medicine, the order of severity of concrete symptom and the patient who receives treatment of administration.

Test portion

Intermediate N (4-methylol-benzyl)-2-nitro-N-pyridine-2-ylmethyl-benzsulfamide is according to as people such as Bridger, in U.S. Patent No. 6,506, and the prepared described in 770.Intermediate 2-bromomethyl-5-cyano group-essence of Niobe is according to the prepared described in the WO 02/34745, and these two pieces of patents are all listed this paper in as list of references of the present invention.

General step

General step A: six hydrogen-[2,2 '; 6 ' 2 "] the N-alkylation of terpyridyl

Six hydrogen-[2,2 ' that replacing; 6 ' 2 "] DMF or the CH of terpyridyl (1 equivalent) ₃CN solution (concentration is～add alkyl halide (1-1.4 equivalent), KI (0.05-0.16 equivalent) and N in 0.1-0.2M), and N-isopropyl ethamine (DIPEA) (1.5-2 equivalent) spends the night this mixture in 60 ℃ of stirrings.Cool off this reactant mixture, with CH ₂Cl ₂(10mL/mmol amine) dilution, and pour saturated NaHCO into ₃In the aqueous solution (10mL/mmol alcohol).Separate biphase, with CH ₂Cl ₂(3 * 10mL/mmol amine) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Drying, and concentrating under reduced pressure.Crude product obtains required N-alkylate through chromatography purification.

General step B: with the salify of saturated HBr (g) in HOAc

The saturated HOAc solution (2mL) that in the glacial acetic acid solution (2mL) of free alkali, adds HBr (g).Add a large amount of ethers (25mL) then with precipitated solid, allow solid be sunken to drag and supernatant decanted liquid.(washing of 3 * 25mL) decantations, vacuum is removed residual trace solvent to the gained solid with ether.This solid be dissolved in MeOH and with a large amount of ether redeposition to be further purified.With ether decantation washing gained solid, with vacuum (0.1 Torr) drying, make required compound then.

General step C:NaBH (OAc) ₃Or NaBH ₄Direct reduction amination

Under the room temperature, at the CH of the amine (1 equivalent) that stirs ₂Cl ₂Solution (in the concentration～0.2M), adds carbonyl compound (～1-2 equivalent), glacial acetic acid (0-2 equivalent) and NaBH (OAc) ₃(～1.5-3 equivalent), gained solution at room temperature stirs.Pour reactant mixture into saturated NaHCO ₃In aqueous solution or the 1.0MNaOH aqueous solution (10mL/mmol amine).Separate biphase, with CH ₂Cl ₂(3 * 10mL/mmol amine) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Drying, and concentrating under reduced pressure.Crude product is with chromatography purification.

General step D: two-step method Mannich condensation (Mannich Condensation)

Under 0 ℃, (concentration～0.1-1M) adds NH in the MeOH solution of suitable pyridine carboxaldehyde (2 equivalent) ₄OAc (1.1 equivalent), slowly (in about 15min) adds 1 then, 3-acetone dicarboxylic acid (1 equivalent).After treating that violent bubbling is disappeared, make it be warmed to room temperature in the time of with solution stirring 1h.Solvent is removed in decompression, adds CH ₂Cl ₂(10mL/mmol amine) and saturated Na ₂CO ₃Aqueous solution (10mL/mmol amine).Separate biphase, and with CH ₂Cl ₂(2 * 10mL/mmol amine) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Drying, and concentrating under reduced pressure.This crude product is with the silica gel chromatography purification.

General step E:Wolff-Kishner reduction reaction

Following being reflected under the nitrogen current carried out in the three neck round-bottomed flasks of being furnished with reflux condensing tube, and with heating jacket (the Variac controlled heating mantle) heating of the back-up sand of adjustable transformer control.In the tetrahydrochysene-1 ' H-[2 of suitable replacement, 2 '; 6 ', 2 "] diethylene glycol solution of terpyridyl-4 '-ketone (1 equivalent) (adds single hydrazine hydrate (40 equivalent) and potassium hydroxide granule (20 equivalent), is reflected at 80 ℃ of stirring 1-2h down in the concentration～0.1-0.2M).Use the distillation of short-path distillation device to remove excessive hydrazine (bathing temperature is～200 ℃), residual mixture is cooled to room temperature.Reactant is with CH ₂Cl ₂(10mL/mmol amine) and H ₂O (10mL/mmol amine) dilution, and separate each layer.Water is with CH ₂Cl ₂(10mL/mmol amine) extraction, the organic extract of merging is with Na ₂SO ₄Drying, and concentrating under reduced pressure.Crude product obtains required replacement-tetrahydrochysene-1 ' H-[2,2 ' with the silica gel column chromatography purification; 6 ', 2 "] terpyridyl.

General step F: the reaction of alcohol and mesyl chloride

During room temperature (or 0 ℃), the alcohol (1 equivalent) and the Et that are stirring ₃The CH of N (1.5-2 equivalent) ₂Cl ₂(concentration～0.1M) add mesyl chloride (MsCl) (～1.5 equivalent), 0.5-1h is at room temperature stirred in reaction in (or THF) solution.Pour reactant mixture into NaHCO ₃Saturated aqueous solution or saturated NH ₄Cl (10mL/mmol alcohol).Separate biphase, with CH ₂Cl ₂(3 * 10mL/mmol amine) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Drying, and concentrating under reduced pressure.Crude product is with chromatography purification, or is directly used in the N-alkylation step without being further purified.

The coupling of general step G:EDCI

At 1 ° that stirs or 2 ° of amine (0.1-0.3mmol), hydrochloric acid 1-[3-(dimethylamino) propyl group]-CH of 3-ethyl carbon diacyl imines (EDCI) (1.5 equivalent), hydration 1-hydroxyl-benzotriazole (HOBT) (1.5 equivalent) and DIPEA (2.0 equivalent) ₂Cl ₂Or in the solution of DMF (0.05M), add carboxylic acid (1.0-2.0 equivalent).Solution stirs 16h at ambient temperature.Reaction is with saturated NaHCO ₃The solution cancellation, and with CH ₂Cl ₂Extract three times.The organic facies that merges is with Na ₂SO ₄Drying is filtered, and concentrates.The gained crude product is with silicagel column purification (5%MeOH/CH ₂Cl ₂).

Embodiment 1

Chemical compound 1:

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine

Under the Ar atmosphere, at N, N, N ', N '-tetramethylethylenediamine (TMEDA) (4.06mL, in dry THF 26.9mmol) (50mL) cold (78 ℃) solution, the adding n-BuLi (the 2.5M hexane solution, 10.7mL, 26.9mmol).(3.0mL 26.9mmol), is warming up to-55 ℃ of 30min to be added dropwise to 2-bromo-3-picoline.Reactant mixture reddens.Then it is cooled to-78 ℃, and the adding Glutaric Acid Dimethyl ester (1.65mL, 11.2mmol).Reactant mixture stirs 1h down at-78 ℃.Add entry (200mL), with CH ₂Cl ₂The extraction mixture (3 times, 200mL).The organic extract that merges washs with saturated aqueous common salt (200mL), and passes through MgSO ₄Drying is filtered and is concentrated.(1: 1 EtOAc: hexane) go up purification, 1.5g (48%) 1, the 5-that makes white solid is two-(3-methyl-pyridine-2-yl)-penta-1, the 5-diketone at silica gel with flash chromatography for crude product. ¹H NMR(CDCl ₃)δ2.00(p，2H，J＝7.5Hz)，2.44(s，6H)，3.19(t，4H，J＝7.5Hz)，7.18(dd，2H，J＝7.8，4.2Hz)，7.43(d，2H，J＝7.8Hz)，8.33(d，2H，J＝4.2Hz)。

1,5-pair-(3-methyl-pyridine-2-yl)-penta-1, add NaBH in the solution of the MeOH (15mL) of 5-diketone (340mg, 1.20mmol)) ₄(100mg, 2.65mmol), mixture at room temperature stirs 2h.Vacuum is removed MeOH, adds entry (25mL) in residue, and mixture is with CH ₂Cl ₂Extraction (3 25mL).Organic extract is with MgSO ₄Drying concentrates and obtains 365mg (100%) white foam shape 1, and 5-pair-(3-methyl-pyridine-2-yl)-1, the 5-pentanediol. ¹H NMR(CDCl ₃)：δ1.52-1.81(m，6H)，2.33(s，6H)，4.69(dd，2H，J＝7.5，4.5Hz)，4.79-4.86(m，2H)，7.09-7.14(m，2H)，7.43-7.45(m，2H)，8.36-8.39(m，2H)。

1,5-pair-(3-methyl-pyridine-2-yl)-penta-1,5-glycol (527mg, dry CH 1.84mmol) ₂Cl ₂(25mL) in cold (20 ℃) solution, add Et ₃N (0.767mL, 5.52mmol), add then mesyl chloride (0.357mL, 4.61mmol).Mixture stirs 2h down at-20 ℃, is adding saturated NaHCO then ₃Solution (20mL) is preceding to be heated to 0 ℃.Separate biphasely, water is with CH ₂Cl ₂Extraction (3 20mL).The organic extract that merges is with MgSO ₄Drying, filtration also reduces solvent volume to about 5mL under the condition that does not heat.A gains ¹H NMR shows that reactant is converted into disulfonate for a full due.

In the time of 0 ℃, (1.38mL, 18.4mmol), reactant mixture is warmed to room temperature and stirs 17h to add allyl amine in above-mentioned disulfonate solution.Add saturated NaHCO ₃Solution (20mL), mixture is with CH ₂Cl ₂Extraction (3 20mL).The organic extract that merges is with MgSO ₄Drying is filtered and concentrated cis and trans 1: 1 the mixture of two kinds of products of making.(be followed successively by 2: 1 hexanes: EtOAc, EtOAc MeOH), obtains 204mg polarity weak slightly cis-isomer and the stronger transisomer of 194mg polarity to separate two kinds of isomers by flash chromatography with silica gel.The stronger isomer of polarity further through chromatography (with NH ₄The Et that OH is saturated ₂O) make 142mg (25%) 1 '-pi-allyl-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl. ¹H NMR(CDCl ₃)：δ1.48-1.75(br m，3H)，1.77-2.10(m，3H)，2.45(br s，6H)，2.80(d，2H，J＝6.9Hz)，3.98(br d，2H，J＝9.9Hz)，4.28-4.36(br m，1H)，4.72(brs，1H)，5.64(br s，1H)，7.04(dd，2H，J＝7.8，4.8Hz)，7.39(d，2H，J＝7.8Hz)，8.35(br s，2H)；ES-MS m/z 308.3(M ⁺H)。

At 1 '-pi-allyl-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (142mg, CH 0.462mmol) ₂Cl ₂In the solution, add 1, and 3-dimethyl barbituric acid (1,3-dimethylbarbaturic acid) (361mg, 2.31mmol) and Pd (PPh ₃) ₄(53mg 0.046mmol), stirs 20h with reactant mixture.Add NaHCO ₃Saturated solution (10mL), mixture is with CH ₂Cl ₂Extraction (3 20mL).Organic extract is with MgSO ₄Drying is filtered and is concentrated.Crude product by flash chromatography with silica gel (9: 1: 0.2 CH ₂Cl ₂-MeOH-NH ₄OH) purification obtains clarifying oily 105mg (85%) 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl. ¹H NMR(CDCl ₃)δ1.51-1.63(m，2H)，1.76-1.85(m，3H)，2.11-2.15(m，1H)，2.37(s，6H)，3.10-3.30(m，1H)，4.22(d，2H，J＝10.8Hz)，7.02(dd，2H，J＝7.5，4.5Hz)，7.38(d，2H，J＝7.5Hz)，8.45(d，2H，J＝4.5Hz)； ¹³C NMR(CDCl ₃)δ18.68，25.84，32.28，57.60，121.96，129.73，138.04，147.31，160.94；ES-MS m/z 269.1(M ⁺H)。Analytical calculation value (Anal.Calcd.) C ₁₇H ₂₁N ₃0.1CH ₂Cl ₂: C, 74.45; H, 7.75; N, 15.23. measured value (found): C, 74.70; H, 7.80; N, 15.18.

3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (75.4mg is in DMF 0.282mmol) (6mL) solution; add 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (159mg, 0.564mmol), (4mg; 0.03mmol), DIPEA (0.6mL), mixture stirs 17h down at 60 ℃ to KI.Remove volatilizable thing with the condition of high vacuum degree Rotary Evaporators.Add saturated NaHCO ₃Solution (10mL), mixture is with CH ₂Cl ₂Extract 3 times (20mL).Organic extract is with MgSO ₄Drying is filtered and is concentrated.Crude product (is used 1: 1 EtOAc: hexane, EtOAc, 9: 1 EtOAc: MeOH) make 83.6mg (63%) white foam shape 2-[4-(3; 3 by column chromatography successively with silica gel purification "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone. ¹H NMR(CDCl ₃)δ0.75(br s，1H)，0.91-0.97(m，2H)，1.56-1.66(m，3H)，1.94-2.04(m，2H)，2.15-2.29(m，2H)，2.41(s，6H)，2.50-2.72(m，2H)，3.23(dd，2H，J＝6.9，7.2Hz)，4.0(br s，2H)，6.99(dd，2H，J＝7.5，4.5Hz)，7.31(d，2H，J＝7.5Hz)，7.68-7.71(m，2H)，7.75-7.81(m，2H)，8.41(br s，2H)。

2-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, (83mg in EtOH 0.1771mmol) (25mL) solution, adds single hydrazine hydrate (0.3mL) to the 3-diketone, and reactant mixture at room temperature stirs 17h.Concentrated reaction mixture, crude product by radial chromatography with silica gel purification (1mm plate, 9: 1: 0.1 CH ₂Cl ₂-MeOH-NH ₄OH), make the chemical compound 1 of 37mg (62%) colorless oil. ¹H NMR(CDCl ₃)δ0.66-0.80(m，3H)，1.57-1.66(m，3H)，1.97-2.22(br m，7H)，2.52(brs，6H)，2.50-2.54(br s，1H)，4.02(d，2H，J＝10.8Hz)，7.08(dd，2H，J＝4.5，7.2Hz)，7.42(d，2H，J＝7.2Hz)，8.45(br s，2H)； ¹³C NMR(CDCl ₃)δ19.2，23.3，30.6，31.1，41.6，49.8，64.1，71.4，122.2，138.7，139.8，147.0，160.7；ES-MS m/z339.3(M ⁺H)。Analytical calculation value C ₂₂H ₃₁N ₅O0.5H ₂O0.5CH ₂Cl ₂: C, 66.22; H, 8.27; N, 14.37. measured value: C, 65.82; H, 8.24; N, 14.20.

Embodiment 2

Chemical compound 2:

[3-aminomethyl-4-meso-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

Under 0 ℃, (43.27g in MeOH 357mmol) (179mL) solution, adds NH at 3-picoline formaldehyde ₄OAc (151.14g, 197mmol).Then in 15min lentamente with 1, (26.10g 178.6mmol) adds in the reaction 3-acetone dicarboxylic acid.After treating that a large amount of bubbles are eliminated, solution is warmed to room temperature 1h while stirring.Solvent is removed in decompression, adds CH ₂Cl ₂(500mL).Solution is with saturated Na ₂CO ₃Aqueous solution (350mL) washing also separates.Water is with CH ₂Cl ₂(2 * 400mL) extractions, the organic principle of merging is with Na ₂SO ₄Drying, and concentrating under reduced pressure, by flash chromatography with silica gel bolt purification (2: 0.5: 97.5 MeOH/NH ₄OH/CH ₂Cl ₂), make yellow meso-3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone (30.1g, 60%). ¹HNMR(CDCl ₃)δ2.37(s，6H)，2.55(m，2H)，2.82(m，2H)，3.37(m，1H，NH)，4.50(t，2H，J＝9.0Hz)，7.10(m，2H)，7.45(d，2H，J＝7.5Hz)，8.47(d，2H，J＝4.5Hz)。

The above-mentioned ketone of preparation (20.00g, diethylene glycol 71.1mmol) (350mL) solution in the three neck round-bottomed flasks of 1L.Container is with N ₂Air-flow purge, and assembling condensing tube.(138mL, 2.84mol) (79.77g 1.42mol) adds in the solution, is equipped with the overhead type mechanical agitator in the flask with the KOH granule with single hydrazine hydrate.Stirred reaction mixture, and be heated to 80 ℃, 2h with the adjustable transformer control heating jacket that the sand of tinfoil bag is filled.Excessive hydrazine is bathed temperature distillation from reaction system by～200 ℃ and is removed.In case after collecting all hydrazines, allow the slow cool to room temperature of solution.Add CH ₂Cl ₂(500mL) and H ₂O (400mL) separates organic facies.Then with CH ₂Cl ₂(2 * 500mL) aqueous phase extracted, the organic principle of merging is with Na ₂SO ₄Drying, and concentrating under reduced pressure are through column chromatography (NH ₃/ Et ₂The O gradient becomes the NH of 5%MeOH ₃/ Et ₂O solution, the NH of 10%MeOH then ₃/ Et ₂O solution) after, make light yellow solid meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (15.0g, 79%). ¹H NMR(CDCl ₃)δ1.59(dq，2H，J＝12.4，3.6Hz)，1.80(m，2H)，2.13(m，1H)，2.37(s，6H)，3.09(br，1H，NH)，4.20(br d，2H，J＝11.1Hz)，7.03(m，2H)，7.39(d，2H，J＝7.5Hz)，8.46(d，2H，J＝4.5Hz)。

With dense H ₂SO ₄(10mL 188mmol) handles 4-methyl-3-nitro benzoic acid (27.95g, MeOH 154mmol) (550mL) solution, and be heated to backflow 17h.Cooling reaction system, and concentrating under reduced pressure.Add EtOAc (300mL) and saturated aqueous common salt (400mL), and cooling solution to 0 ℃.Slowly add 10N NaOH solution (40mL) and obtain neutralization and solution is alkalescence until acid content.Separate organic facies, (2 * 400mL) aqueous phase extracted, the organic facies of merging is with MgSO with EtOAc then ₄Drying filter, and concentrating under reduced pressure obtains white solid 4-methyl-3-nitro essence of Niobe (29.37g, 98%).

(29.37g 150mmol) joins in the 2L Pa Er hydrogenation flask (Parr hydrogenationflask) ester that the last step was made, and is dissolved in anhydrous MeOH (200mL) and adds EtOAc (25mL).Then with 10%Pd/C (2.25g, 50% wet) Treatment Solution, and insert hydrogenation apparatus.Behind hydrogen purge flask 3 times, mixture jolts 1h with 30psi.Shift out flask then, filter and wash with MeOH through Celite pad.Solvent is removed in decompression, makes white solid 3-amino-4-methyl-essence of Niobe (25.0g, 100%). ¹H NMR(CDCl ₃)δ2.21(s，3H)，3.70(br s，2H，NH ₂)，3.88(s，3H)，7.10(d，1H，J＝7.5Hz)，7.35(s，1H)，7.37(d，1H，J＝8.4Hz)。

(25.00g, 150mmol) suspend in water (140mL) handle with hydrochloric acid (41mL) under 0 ℃ with above-mentioned amine.During dissolving, add the water (33mL) of another part.Then, with this substrate solution with NaNO ₂(11.39g, water 165mmol) (26mL) solution-treated stir 0.5h.With K ₂CO ₃In the (～20g) and acidic moiety after, mixture under 60 ℃, with mixture with sleeve pipe (cannula) add to NaCN (17.64g, 360mmol) and CuCN (16.12g is in aqueous solution 180mmol) (65mL).Then, with mixture heated to the 1h that refluxes.Behind the cool to room temperature, mixture is put saturated NaHCO ₃Aqueous solution (200mL) and CH ₂Cl ₂Distribute (400mL), and separate organic facies.Water is with CH ₂Cl ₂(3 * 300mL) extractions, the organic principle of merging is with Na ₂SO ₄Drying is filtered, and concentrating under reduced pressure, by silica gel column chromatography (5%EtOAc/ hexane), makes pink solid, shaped 3-cyano group-4-methyl-essence of Niobe (15.8g, 60%). ¹H NMR(CDCl ₃)δ2.62(s，3H)，3.94(s，3H)，7.41(d，1H，J＝7.5Hz)，8.13(d，1H，J＝7.5Hz)，8.27(s，1H)。

At above-mentioned nitrile (5.08g, CCl 29.0mmol) ₄(90mL) in the solution, and adding N-bromine butanimide (5.68g, 32.0mmol) with 1,1 '-azo two (cyclohexane extraction formonitrile HCN) (1.06g, 4.3mmol).This solution refluxes and stirs 2h, adds second portion 1 then, and 1 '-azo two (cyclohexane extraction formonitrile HCN) (0.35g, 1.4mmol).Reflux once more behind the stirring 16h, this solution filters (medium glass fritted funnel) through cooling through medium fritted glass filter, and concentrating under reduced pressure.Through silica gel column chromatography (the 5%EtOAc/ hexane carries out the transition to the 20%EtOAc/ hexane), make light orange solid, shaped 4-bromomethyl-3-cyano group-essence of Niobe (3.94g, 53%). ¹H NMR(CDCl ₃)δ3.96(s，3H)，4.65(s，2H)，7.65(d，1H，J＝7.5Hz)，8.23(d，1H，J＝7.5Hz)，8.33(s，1H)。

With meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (1.01g, 3.8mmol), 4-bromomethyl-3-cyano group-essence of Niobe (1.25g; 4.9mmol) and KI (126mg, dry DMF 0.76mmol) (19mL) solution is with DIPEA (1.32mL; 7.6mmol) handle, and stir 16h down at 60 ℃.Be dissolved among the EtOAc (25mL) then with this mixture concentrating under reduced pressure, and with residue.(5 * 20mL) washings are with MgSO with saturated aqueous common salt for this organic solution ₄Drying, and concentrating under reduced pressure.Through silica gel column chromatography purification (2: 0.5: 97.5 MeOH/NH ₄OH/CH ₂Cl ₂), make the light beige solid, shaped 3-cyano group-4-(meso-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (1.52g, 91%). ¹H NMR(CDCl ₃)δ1.70(m，3H)，2.05(m，1H)，2.33(m，2H)，2.49(s，6H)，3.73(s，2H)，3.85(s，3H)，4.15(br d，2H，J＝10.5Hz)，6.85(m，2H)，7.25(d，2H，J＝7.5Hz)，7.67(s，1H)，7.77(d，1H，J＝7.5Hz)，7.85(d，1H，J＝7.5Hz)，8.25(d，2H，J＝4.5Hz)。

The alkylate that the last step was made (1.52g 3.45mmol) is dissolved among THF (30mL) and the MeOH (30mL), is cooled to 0 ℃, and with solid LiBH ₄(0.90g 41.4mmol) handles.After treating that violent bubbling is disappeared, mixture in 1h, is warmed to room temperature while stirring.Excessive LiBH ₄Add saturated aqueous common salt (30mL) cancellation with 1N NaOH solution (10mL).Water is with CH ₂Cl ₂(3 * 60mL) extractions are with Na ₂SO ₄Drying, and through concentrating under reduced pressure, make loose white solid 2-(meso-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methylol-benzonitrile (1.42g, 100%).

The above-mentioned alcohol of preparation in 250mL Pa Er hydrogenation flask (0.69g, MeOH 1.67mmol) (20mL) solution, and adding anhydrous solid Raney nickel (RaneyNickel) (～1g).Then that mixture is saturated with ammonia, and it is transferred on the hydrogenation apparatus.Reaction vessel purifies back (with hydrogen flushing 3 times), and reaction flask is pressurized to 50psiH ₂, and jolt 16h.Then flask is taken off from hydrogenation apparatus, filter (for several times), and the gained filtrate decompression is concentrated, make the light green color solid, can not draw that it is correct with the MeOH flushing through Celite pad ¹H NMR spectrum.Then the gained solid is dissolved in MeOH (5mL) and the water (5mL), (0.33g 6.7mmol) handles 0.5h, to remove nickel impurity under 50 ℃ with NaCN.After the cooling, solution is with CH ₂Cl ₂(3 * 15mL) extractions, dry (Na ₂SO ₄), and concentrating under reduced pressure, through silica gel column chromatography (1: 1: 10 MeOH: NH ₄OH: CH ₂Cl ₂), make white solid chemical compound 2 (0.46g, 65%). ¹H NMR(CDCl ₃)δ1.67(m，3H)，2.04(m，1H)，2.26(m，2H)，2.42(s，6H)，2.58(br，3H)，3.48(br s，2H)，3.59(s，2H)，4.13(br d，2H，J＝11.4Hz)，4.40(s，2H)，6.75(d，1H，J＝7.5Hz)，6.86(m，3H)，7.00(m，1H)，7.18(d，2H，J＝4.8Hz)，8.29(d，2H，J＝4.2Hz)。 ¹³C NMR(CDCl ₃)δ.18.87(2C)，25.26(2C)，28.79，42.51，53.43，64.69(2C)，66.34，121.85(2C)，124.41，125.96，129.24，131.72(2C)，137.47，137.86(2C)，138.71，139.06，146.35(2C)，159.66(2C)。ES-MS m/z 417(M ⁺H)。Analytical calculation value C ₂₆H ₃₂N ₄O0.5CH ₂Cl ₂: C, 69.34; H, 7.25; N, 12.21. measured value: C, 69.63; H, 7.54; N, 12.30.

Embodiment 3

Chemical compound 3:(1-[4-((2 ' S, 6 ' R)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-3-(1H-imidazoles-2-yl)-urea

With 2-aminooimidazole sulfate (0.100g, 0.757mmol), 1,1 '-phosphinylidyne diimidazole (carbonyldiimidazole) (0.129g, 0.796mmol) and DIPEA (0.293g, 2.27mmol) CH of mixture ₂Cl ₂(10mL) solution stirring 5h removes solvent then.Residue dissolves with DMF (6mL), and adding 4-((2 ' S, 6 ' R)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (0.130g, 0.384mmol) and DIPEA (0.293g, 2.27mmol).Mixture is heated 16h down for 75 ℃, be cooled to room temperature then.Add saturated NaHCO ₃Aqueous solution (20mL), and with mixture with CH ₂Cl ₂(3 * 30mL) extractions.Merge extract and with Na ₂SO ₄Dry.After the filtration, vaporising under vacuum is removed solvent, residue through silicagel column with purified by flash chromatography (100: 5: 2 CH ₂Cl ₂/ CH ₃OH/NH ₄OH), with CH2Cl ₂/ hexane precipitation makes light yellow solid (0.115g, 67%) through vacuum evaporation. ¹H NMR(CDCl ₃)δ0.70-0.85(m，4H)，1.46-1.66(m，3H)，1.90-2.00(m，2H)，2.15-2.19(m，2H)，2.41(s，6H)，2.53-2.70(m，1H)，2.75-2.83(m，2H)，3.95-4.00(m，2H)，6.69(s，2H)，6.90-7.02(m，2H)，7.30-7.40(m，2H)，8.34-8.42(m，2H)； ¹³C NMR(CDCl ₃)δ18.96，22.82，25.22，27.67，31.30，39.41，50.56，63.61，122.03，131.12，138.63，144.22，146.85，155.71，160.40.ES-MS m/z 448(M ⁺H)。Analytical calculation value C ₂₅H ₃₃N ₇O0.1CH ₂Cl ₂0.1C ₆H ₁₄: C, 66.43; H, 7.50; N, 21.10. measured value: C, 66.41; H, 7.46; N, 20.87.

Embodiment 4

Chemical compound 4:4-(3,3 "-diisopropyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (HBr salt)

50% hydrogen peroxide (24.89mL) is slowly added 3-isopropyl-2-methyl-pyridine, and (24.5g is 183mmol) in HOAc (280mL) solution of (Ishiguro, etc., Yakugaku Zasshi (1958) 78:220).Mixture is warmed to 70 ℃, and stirs 18h, and cool to room temperature, and vacuum concentration is then removed most of HOAc.Mixture is with saturated NaHCO ₃Solution alkalizes to pH12, and with CH ₂Cl ₂(3 * 150mL) extractions.The organic layer that merges is with Na ₂SO ₄Drying, and vacuum concentration make yellow oily 3-isopropyl-2-methyl-pyridine 1-oxide (26.05g, 94%). ¹H NMR(CDCl ₃)δ1.24(d，6H，J＝7.0Hz)，2.56(s，3H)，3.13(sep，1H，J＝7.0Hz)，7.06-7.17(m，2H)，8.17(d，1H，J＝6.6Hz)。

3-isopropyl-2-methyl-pyridine 1-oxide (26.05g, CH 173mmol) that is stirring ₂Cl ₂(690mL) in the solution, in 30min, be added dropwise to TFAA (51.83mL).Again in N ₂Under stir 3h.Attention: exothermic reaction takes place when adding TFAA.Mixture is to be concentrated in vacuo to a minimum volume.Add saturated aqueous common salt (200mL), with solid K ₂CO ₃Slowly alkalize to pH9, then with aqueous mixture with CH ₂Cl ₂(3 * 100mL) extractions.The organic layer that merges is with Na ₂SO ₄Drying, and vacuum concentration make orange oily (3-isopropyl-pyridine-2-yl)-methanol (26g, 99%). ¹H NMR(CDCl ₃)δ1.24(d，6H，7.0Hz)，2.92(sep，1H，J＝6.6Hz)，4.79(s，2H)，7.02-7.25(m，1H)，7.61(d，1H，J＝7.9Hz)，8.41(d，1H，J＝4.8Hz)。

Under the nitrogen, at (3-isopropyl-pyridine-2-yl)-methanol (26g, CH 170mmol) of vigorous stirring ₂Cl ₂(575mL) in the solution, add MnO ₂(105g, 1.20mol).Mixture stirs 18h, filters through Celite pad then.And vacuum concentration.With silica gel column chromatography purification (EtOAc/ hexane, 1: 3), make orange oily 3-isopropyl-pyridine-2-formaldehyde (15.65g, 61%). ¹H NMR(CDCl ₃)δ1.26(d，6H，J＝7.0Hz)，4.17(sep，1H，J＝6.6Hz)7.45(dd，1H，J＝7.9，4.4Hz)，7.84(d，1H，J＝7.9Hz)，8.56(dd，1H，J＝4.4，1.3Hz)，10.2(s，1H)。

(235mg in MeOH 1.57mmol) (10mL) solution, adds NH at 3-isopropyl-pyridine-2-formaldehyde ₄(67mg, 0.866mmol) with 1, (115mg 0.787mmol), at room temperature stirs 2h with mixture to the 3-acetone dicarboxylic acid to OAc.Mixture adds CH through vacuum concentration ₂Cl ₂Add saturated NaHCO (20mL) again ₃(10mL).Separate biphasely, water is again with CH ₂Cl ₂(2 20mL) extracting twice.Organic extract is with MgSO ₄Drying is filtered and is concentrated.Crude product with flash chromatography on silica gel method purification (10: 1 EtOAc: hexane), make solid, shaped 106mg (40%) 3,3 "-diisopropyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone. ¹H NMR(CDCl ₃)δ1.25(d，6H，J＝9.3Hz)，2.54(d，2H，J＝13.5Hz)，2.88(dd，2H，J＝12.0，12.6Hz)，3.16-3.26(m，2H)，3.46-3.55(m，1H)，4.59-4.63(m，2H)，7.16(dd，2H，J＝7.8，4.5Hz)，7.57(d，2H，J＝7.8Hz)，8.48(d，2H，J＝4.5Hz)。

3,3 "-diisopropyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone (106mg, add in diethylene glycol 0.314mmol) (3mL) solution KOH (352mg, 6.29mmol) and single hydrazine hydrate (0.61mL, 12.6mmol).With extremely～100 ℃ in sand bath reacting by heating mixture, 1h.Behind the 1h, be warming up to 200 ℃, about 45min.In remaining mixture, add CH ₂Cl ₂(50mL), and with water (3 50mL) wash.With MgSO ₄Dry organic layer filters and concentrated 100mg (99%) 3,3 of obtaining "-diisopropyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (containing some DEG). ¹H NMR(CDCl ₃)δ1.25(d，6H，J＝9.3Hz)，1.57-1.65(m，2H)，1.68-1.89(m，3H)，2.10-2.14(m，1H)，3.19-3.30(m，3H)，4.33(br s，1H)，7.10(dd，2H，J＝7.8，4.5Hz)，7.53(d，2H，J＝78Hz)，8.46(d，2H，J＝4.5Hz)。

3,3 "-diisopropyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (100mg is in DMF 0.3141mmol) (3mL) solution; add 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (106mg, 0.376mmol), KI (4mg; 0.03mmol) and DIPEA (0.10mL, 0.62mmol), and with mixture at 60 ℃ of stirring 17h down.Remove volatile matter with condition of high vacuum degree rotary evaporator.Add saturated NaHCO ₃(10mL), with CH ₂Cl ₂(20mL) extraction mixture.Organic extract is with MgSO ₄Drying is filtered and is concentrated.Crude product is through silica gel column chromatography (NH ₄The Et that OH is saturated ₂O), make white foam shape 81.3mg (49%) 2-[4-(3,3 "-diisopropyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone. ¹HNMR shows that this product is the mixture that two kinds of rotamers form with about 2.5: 1 ratio.ES-MS m/z525(M ⁺H)。

2-[4-(3,3 "-diisopropyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, (80mg in EtOH 0.153mmol) (25mL) solution, adds single hydrazine hydrate (0.3mL), and reactant mixture is at room temperature stirred 17h the 3-diketone.Reactant mixture is through concentrating, and with crude product with silica gel radial chromatography purification (1mm plate, 20: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), make colorless oil 56mg (93%) 4-(3,3 "-diisopropyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine. ¹H NMR demonstration obtains mixture of isomers, and (～2: 1), they can and have equal quality (m/z 395 (M through the LCMS separation ⁺H)).

4-(3,3 "-diisopropyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] (53mg in glacial acetic acid 0.134mmol) (1.0mL) solution, adds the saturated HOAc (1.0mL) of HBr to terpyridyl-1 '-yl)-butylamine.Reactant mixture stirs 2min, adds Et then ₂O (100mL).Allow the white depositions sedimentation, and remove solvent with dropper (pipette).The gained solid is with Et ₂O (100mL) is washed twice again.The gained white powder makes 79.4mg (88%) chemical compound 4 through drying under reduced pressure. ¹H NMR(D ₂O)δ1.14-1.23(m，3H)，1.32-1.36(m，7H)，1.54-1.76(m，3H)，1.93-1.96(m，1H)，2.05-2.16(m，2H)，2.25-2.33(m，2H)，2.69-2.75(m，2H)，3.45-3.56(m，2H)，7.95(dd，2H，J＝8.4，5.7Hz)，8.60(d，2H，J＝8.4Hz)，8.67(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ20.2，22.5，22.7，23.5，25.0，27.9，34.0，39.4，52.2，57.6，126.6，140.2，146.0，146.9，153.1；ES-MS m/z 395.4(M ⁺H)。Analytical calculation value C ₂₅H ₃₈N ₄3HBr2.2H ₂O:C, 44.36; H, 6.76; N, 8.28; Br, 35.41. measured value: C, 44.67; H, 6.69; N, 8.50; Br, 35.65.

Embodiment 5

Chemical compound 5:(2 ' R, 6 ' S)-1 '-[3-(1H-imidazol-4 yl)-propyl group]-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (HBr salt)

At 4-(3-hydroxyl-propyl group)-imidazoles-1-carboxylic acid tert-butyl ester (147mg, anhydrous CH 0.648mmol) ₂Cl ₂(5mL) in the solution, add pyridine (0.080mL, 0.98mmol), add then p-toluenesulfonyl chloride (247mg, 1.30mmol) and DMAP (8.0mg, 0.065mmol).The gained mixture stirs under room temperature and spends the night.Mixture is with saturated NaHCO ₃Aqueous solution (25mL) dilution, and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is through Na ₂SO ₄Drying is filtered, and concentrating under reduced pressure.Through flash chromatography on silica gel method (hexane/EtOAc, 60: 40) purification, make colourless oily regional isomer 4-[3-(toluene-4-sulfonyloxy)-propyl group]-imidazoles-1-carboxylic acid tert-butyl ester (99mg, 40%).The main region isomer ¹H NMR (CDCl ₃) δ 1.59 (s, 9H), 1.99 (t, 2H, J=7.2Hz), 2.43 (s, 3H), 2.57 (t, 2H, J=7.4Hz), 4.04 (t, 2H, J=6.3Hz), 7.00 (s, 1H), 7.33 (d, 2H, J=8.3Hz), 7.77 (d, 2H, J=8.4Hz), 7.93 (s, 1H).

At 4-[3-(toluene-4 sulfonyloxy)-propyl group]-imidazoles-1-carboxylic acid tert-butyl ester (99mg, dry CH 0.26mmol) ₃In CN (2.5mL) solution, add (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (104mg, 0.389mmol) and DIPEA (0.14mL, 0.78mmol).Gained solution is heated to 60 ℃ and spends the night, and is cooled to room temperature then.Concentrated reaction mixture, residue is at CH ₂Cl ₂(15mL) with saturated NaHCO ₃Distribute between aqueous solution (25mL).Water phase separated, and with CH ₂Cl ₂(2 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrating under reduced pressure.Through flash chromatography on silica gel method purification (CH ₂Cl ₂/ MeOH/NH ₄OH, 92: 4: 4), the amine that makes expection with (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', the mixture of 2 "] terpyridyl (93mg).This mixture is dissolved in CH ₂Cl ₂(2mL), and handle with TFA (1mL).Gained solution at room temperature stirs 1.5h, concentrates then.Residue is at CH ₂Cl ₂(15mL) with saturated NaHCO ₃Distribute between aqueous solution (40mL).Water phase separated, and with CH ₂Cl ₂(2 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrating under reduced pressure.Through radial chromatography with 1mm silica gel plate (CH ₂Cl ₂/ MeOH/NH ₄OH, 96: 2: 2,92: 4: 4 then) purification, make title compound free alkali (18mg, 13% through two steps).

According to general step B: will go up the free alkali that the step obtains (18mg 0.049mmol) is converted into HBr salt, then with crude product in MeOH/ ether in precipitation, make Off-white solid chemical compound 5 (25mg, 77%). ¹HNMR(D ₂O).1.43-1.83(m，5H)，1.88-2.04(m，1H)，2.07-2.19(m，2H)，2.19-2.29(m，2H)，2.29-2.39(m，2H)，2.52(s，6H)，4.59(d，2H，J＝9.2Hz)，6.90(s，1H)，7.80-7.93(m，2H)，8.38(d，2H，J＝7.6Hz)，8.49(s，1H)，8.67(d，2H，J＝5.0Hz)； ¹³C NMR(D ₂O).17.08，21.36，22.22，22.40，32.42，51.43，58.39，115.99，126.03，132.90，133.38，136.65，140.35，148.95，154.36；ES-MS m/z 376(M H)。Analytical calculation value C ₂₃H ₂₉N ₅3.0HBr2.7H ₂O:C, 41.42; H, 5.65; N, 10.50; Br, 35.94. measured value: C, 41.58; H, 5.71; N, 10.45; Br, 35.82.

Embodiment 6

Chemical compound 6:(2 ' R, 6 ' S)-3,3 " dimethyl-1 '-[2-(1H-pyrazoles-4-yl)-ethyl]-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

With methoxyl methyl-triphenyl-phosphonium chlorides (2.06g, 6.00mmol) suspension in dry THF (20mL) is cooled to-15 ℃ (ethohexadiol/dry ice), slowly add LDA (2.0MTHF solution, 3.1mL, 6.2mmol).After the adding, mixture is stirred down 30min at-15 ℃, and add 2-benzyl-1H-pyrazoles-4-formaldehyde (1.00g, 5.37mmol) THF (15mL) solution of (Werner, A. is etc., Tetrahedron (1995) 51:4779-4800).Reactant mixture at room temperature stirs 16h.Add entry (30mL), and with EtOAc (30mL) and CH ₂Cl ₂(2 * 30mL) extraction mixture.Merge extract, and with Na ₂SO ₄Dry.After the filtration, remove solvent with vacuum evaporation, residue with flash chromatography through silicagel column (CH ₂Cl ₂) purification, make colorless oil.This grease is dissolved among the THF (3mL), and adding HCl aqueous solution (4N, 15mL).After stirring 72h, mixture is with saturated K ₂CO ₃The aqueous solution neutralization, and with CH ₂Cl ₂(3 * 30mL) extractions.Merge extract, and with Na ₂SO ₄Dry.After the filtration, remove solvent through vacuum evaporation, residue with flash chromatography through silicagel column (2: 1 CH ₂Cl ₂/ Et ₂O) purification makes colorless oil (2-benzyl-1H-pyrazoles-4-yl)-acetaldehyde (0.548g, 51%). ¹H NMR(CDCl ₃)δ3.56(d，2H，J＝2.1Hz)，5.29(s，2H)，7.21-7.24(m，2H)，7.28-7.39(m，4H)，7.45(s，1H)，9.70(t，1H，J＝2.1Hz)。

(0.548g 2.74mmol) is dissolved among the dry EtOH (20mL), and is cooled to 0 ℃ with (2-benzyl-1H-pyrazoles-4-yl)-acetaldehyde.Add NaBH ₄(0.104g 2.74mmol), at room temperature stirs 2h with mixture.Add water (10mL), remove MeOH with vacuum evaporation.Contain water surplus with HCl (1N) neutralization, then with CH ₂Cl ₂(3 * 30mL) extractions.Merge extract, and with Na ₂SO ₄Dry.After the filtration, remove solvent, make light yellow oil through vacuum evaporation.

Under 0 ℃, at the CH of last step gained grease ₂Cl ₂(10mL) add in the solution MsCl (0.345g, 3.01mmol) and Et ₃N (0.415g, 4.11mmol).Mixture at room temperature stirs 30min.Add entry (10mL), with CH ₂Cl ₂(3 * 20mL) extraction mixture.Merge extract and with Na ₂SO ₄Dry.After the filtration, remove through vacuum evaporation and to desolvate, with flash chromatography through silicagel column (4: 1 CH ₂Cl ₂/ Et ₂O) purification residue makes light yellow oily methanesulfonic acid 2-(2-benzyl-1H-pyrazoles-4-yl)-ethyl ester (0.734g, 96%). ¹H NMR(CDCl ₃)δ2.84(s，3H)，2.87(t，2H，J＝6.6Hz)，4.27(t，2H，J＝6.6Hz)，5.22(s，2H)，7.17-7.20(m，2H)，7.27-7.35(m，4H)，7.40(s，1H)。

Will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.320g, 1.20mmol), methanesulfonic acid 2-(2-benzyl-1H-pyrazoles-4-yl)-ethyl ester (0.540g, 1.60mmol) and 2,2,6,6-tetramethyl piperidine (0.255g, 1.80mmol) CH of mixture ₃CN (5mL) solution stirs and reflux is spent the night.Remove solvent, add entry (20mL), mixture is with CH ₂Cl ₂(3 * 20mL) extractions.Merge extract and with Na ₂SO ₄Dry.After the filtration, remove through vacuum evaporation and to desolvate, with flash chromatography through silicagel column (500: 15: 1CH ₂Cl ₂/ CH ₃OH/NH ₄OH) purification residue, make light yellow oily (2 ' R, 6 ' S)-1 '-[2-(2-benzyl-1H-pyrazoles-4-yl)-ethyl]-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.420g, 93%).

(2 ' R, 6 ' S)-1 '-[2-(2-benzyl-1H-pyrazoles-4-yl)-ethyl]-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.130g, in dry DMSO (0.70mL) 0.288mmol) and THF (12mL) solution, add the 4 molecular sieves be preheating to 140 ℃ (～1g) and KO ^tBu (0.600g, 5.35mmol).At room temperature solution froths 1h with air (predrying by the NaOH post).Add saturated NH ₄Cl aqueous solution (20mL).Mixture filters through the kieselguhr cake, and thoroughly washs this kieselguhr cake with EtOAc.Collect the organic layer in the filtrate, aqueous layer is with CH ₂Cl ₂(3 * 30mL) extractions.Merge extract and with Na ₂SO ₄Dry.After the filtration, remove through vacuum evaporation and to desolvate, with flash chromatography through silicagel column (200: 10: 1 CH ₂Cl ₂/ CH ₃OH/NH ₄OH) the purification residue is used CH ₂Cl ₂/ hexane is separated out after vacuum evaporation makes light yellow solid (0.067g, 64%). ¹HNMR(CDCl ₃)δ1.60-1.85(4H)，2.00-2.15(m，2H)，2.25-2.62(m，10H)，4.10-4.20(m，2H)，6.73(s，2H)，7.07-7.12(m，2H)，7.43(d，2H，J＝7.2Hz)，8.45(s，br.2H)； ¹³C NMR(CD ₂Cl ₂)δ19.02，21.33，25.61，30.31，50.86，64.12，118.85，122.40，132.22，132.65，138.78，147.03，160.46.ES-MS m/z362(M ⁺H)。Analytical calculation value C ₂₂H ₂₇N ₅0.2H ₂O:C, 72.38; H, 7.56; N, 19.18. measured value: C, 72.31; H, 7.70; N, 18.98.

Embodiment 7

Chemical compound 7:[2-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methylol-benzyl]-urea

Under the room temperature, with trimethylsilyl isocyanate (63 μ L, 0.46mmol) handle [3-aminomethyl-4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (0.138mg, isopropyl alcohol 0.33mmol) (2.2mL) solution.Reaction system stirs 24h and concentrating under reduced pressure.Thus, through silica gel column chromatography (10: 1: 1 CH ₂Cl ₂: MeOH: NH ₄OH) purification makes white crystalline solid shape chemical compound 7 (112mg, 74%). ¹H NMR(CDCl ₃)δ1.64(m，3H)，1.98(m，1H)，2.19(m，2H)，2.45(s，6H)，3.51(s，2H)，3.88(br s，2H)，3.94(br d，2H，J＝10.5Hz)，4.35(s，2H)，5.00(br，3H)，6.65(d，1H，J＝7.5Hz)，6.79(d，1H，J＝7.5Hz)，6.85(m，3H)，7.23(d，2H，J＝7.5Hz)，8.22(d，2H，J＝3.9Hz)。 ¹³C NMR(CDCl ₃)δ.19.24(2C)，25.00，32.01(2C)，41.64，57.50，64.59(2C)，65.85，122.21(2C)，124.59，126.36，129.96，130.96(2C)，135.74，138.31，138.52(2C)，140.25，146.79(2C)，160.41，160.86(2C)。.ES-MS m/z 460(M ⁺H)。Analytical calculation value C ₂₇H ₃₃N ₅O ₂0.6CH ₂Cl ₂: C, 64.93; H, 6.75; N, 13.72. measured value: C, 64.60; H, 6.90; N, 13.74.

Embodiment 8

Chemical compound 8:2-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methylol-Benzoylamide

With 2-(meso-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(100mg 0.24mmol) is dissolved in the solution of 50% hydrogen peroxide (0.07mL), 3NNaOH (0.3mL) and MeOH (0.75mL), and is heated to 60 ℃, 20h 5-methylol-benzonitrile.Add entry (5mL) and CH ₂Cl ₂(10mL), separation is biphase.With CH ₂C1 ₂(2 * 10mL) aqueous phase extracted, the organic principle of merging is with Na ₂SO ₄Drying, and concentrating under reduced pressure.Thus, by silica gel with radial chromatography purification (5: 0.5: 94.5CH ₃OH/NH ₄OH/CH ₂Cl ₂), make light yellow solid shape chemical compound 8 (33mg, 32%). ¹H NMR(CDCl ₃)δ1.66(m，3H)，2.05(m，1H)，2.22(m，2H)，2.44(s，6H)，3.71(s，2H)，4.05(brd，2H，J＝8.4Hz)，4.40(s，2H)，5.74(br，1H，NH)，6.84(m，2H)，6.92(d，1H，J＝7.8Hz)，7.07(d，1H，J＝7.5Hz)，7.18(m，3H)，8.25(d，2H，J＝3.9Hz)，9.49(br，1H，NH)。 ¹³C NMR(CDCl ₃)δ18.87(2C)，24.65，30.37(2C)，53.45，64.08，65.79(2C)，121.87(2C)，126.90，127.37(2C)，130.53，130.73，134.94，135.32，138.02(2C)，139.79，146.48(2C)，159.89，170.53(2C)。.ES-MSm/z 431(M ⁺H)。Analytical calculation value C ₂₆H3 ₀N ₄O ₂0.7CH ₂Cl ₂: C, 65.45; H, 6.46; N, 11.43. measured value: C, 65.30; H, 6.54; N, 11.44.

Embodiment 9A and 9B

Chemical compound 9A chemical compound 9B

Chemical compound 9A:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-Benzoylamide and

Chemical combination 9B:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzoic acid

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (0.260g, 0.98mmol), 2-bromomethyl-5-cyano group-essence of Niobe (0.360g, 1.42mmol), KI (37mg, 0.22mmol) and DIPEA (0.35mL, DMF 2.01mmol) (5mL) solution heating keeps 60 ℃, 17h.Crude product with silica gel through column chromatography purification (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH), make 415mg (96%) brown solid shape 5-cyano group-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe.

5-cyano group-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.409g in cold (0 ℃) solution of THF 0.937mmol) (4.5mL) and MeOH (9mL), adds LiBH to essence of Niobe ₄(229mg 10.52mmol), appoints mixture to be warmed to ambient temperature overnight.Mixture dilutes with 1.0NNaOH (10mL), and with CH ₂Cl ₂(5 * 25mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography purification (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH), make 0.332g (87%) white foam shape 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile. ¹H NMR(CDCl ₃)δ1.61-1.77(m，3H)，2.05-2.14(m，1H)，2.30-2.44(m，2H)，2.51(s，6H)，3.71(s，2H)，4.11(d，2H，J＝10.8Hz)，4.46(s，2H)，4.94(br s，1H)，6.87-6.96(m，4H)，7.22-7.27(m，3H)，8.21(d，2H，J＝4.2Hz)。

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (0.310g, add in MeOH 0.75mmol) (4mL) solution entry (4mL) and solid NaOH (0.315g, 7.88mmol).The gained mixture heated refluxes and spends the night, and is cooled to room temperature then.Mixture with 4N HCl (～2mL) regulate pH to～4, with CH ₂Cl ₂(5 * 20mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying concentrates.Crude product through silica gel with radial chromatography purification (1mm plate, 5: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH then is 5: 1: 1: 1 CH ₂Cl ₂-CH ₃CN-CH ₃OH-NH ₄OH), make 24mg (6%) light yellow solid shape chemical compound 9A and 171mg (45%) white solid chemical compound 9B.

The sign numerical value of light yellow solid shape chemical compound 9A (24mg, 6%). ¹H NMR(CDCl ₃)δ1.60-1.75(m，3H)，1.80-2.15(m，1H)，2.23-2.43(m，2H)，2.51(s，6H)，3.68(s，2H)，4.06(d，2H，J＝10.8Hz)，4.44(s，2H)，5.45(br s，1H)，5.97(br s，1H)，6.83-6.96(m，3H)，7.19-7.32(m，4H)，8.19(d，2H，J＝10.2Hz) ¹³CNMR(CDCl ₃)δ19.43，25.69，29.52，53.39，62.67，67.47，122.38，126.18，127.64，129.20，131.27，131.95，138.53，139.05，143.49，146.83，159.66，169.56；ES-MS m/z 431(M ⁺H)。Analytical calculation value C ₂₆H ₃₀N ₄O ₂1.4CH ₂Cl ₂: C, 59.90; H, 6.02; N, 10.20. measured value: C, 60.22; H, 5.99; N, 10.38.

The sign numerical value of white solid chemical compound 9B (171mg, 45%). ¹H NMR(CDCl ₃)δ1.66-1.77(m，3H)，2.00-2.07(m，1H)，2.24-2.32(m，2H)，2.46(s，6H)，3.71(s，2H)，4.14(d，2H，J＝10.8Hz)，4.39(s，2H)，6.86(dd，2H，J＝4.8，7.5Hz)，6.94(d，1H，J＝7.8Hz)，7.24(d，2H，J＝7.5Hz)，7.46(d，1H，J＝7.8Hz)，7.68(s，1H)，8.24(d，2H，J＝4.8Hz)； ¹³C NMR(CDCl ₃)δ19.17，25.02，30.39，54.42，62.52，66.71，122.66，128.25，129.40，130.22，130.80，131.93，138.97，139.12，142.19，146.66，159.27，170.67；ES-MS m/z 432(M ⁺H)。Analytical calculation value C ₂₆H ₂₉N ₃O ₃0.5H ₂O0.7CH ₂Cl ₂: C, 64.14; H, 6.33; N, 8.40. measured value: C, 63.76; H, 6.24; N, 8.60.

Embodiment 10

Chemical compound 10:N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzyl]-Methanesulfomide

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (0.64g, CH 1.55mmol) ₂Cl ₂(15mL) add 3 in the solution, 4-dihydro-2H-pyrans (0.7mL, 7.67mmol), add then right-toluenesulfonic acid monohydrate (1.21g, 6.35mmol).The gained mixture at room temperature stirs and spends the night, then with CH ₂Cl ₂(50mL) dilution.With 1.0N NaOH (15mL), saturated NaHCO ₃Aqueous solution (15mL) and saturated aqueous common salt (15mL) wash this solution, with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) follow through silica gel with column chromatography (NH ₄The Et that OH is saturated ₂O) purification, make 0.56g (72%) brown cystose 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-(tetrahydrochysene-pyrans-2-yloxymethyl)-benzonitrile.

(0.56g 1.12mmol) is dissolved in NH with this brown foam ₃Among the saturated MeOH (8mL), handle, place 50psi H with Raney nickel (500mg) ₂Down, on the Parr shaker (Parr shaker), vibration 5h.Mixture is through diatomite filtration, with MeOH washing kieselguhr cake.This eluent is through concentrating under reduced pressure, the material of gained through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.405g (72%) orange solids shape 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-(tetrahydrochysene-pyrans-2-yloxymethyl)-benzyl amine.

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-(tetrahydrochysene-pyrans-2-yloxymethyl)-benzyl amine (0.104g, CH 0.21mmol) ₂Cl ₂(2mL) in the solution, add Et ₃N (0.09mL, 0.65mmol), add then MsCl (24 μ L, 0.31mmol).The mixture of gained at room temperature stirs 40min, then with saturated aqueous common salt (5mL) and CH ₂Cl ₂(20mL) dilution.Separate biphase, organic facies with saturated aqueous common salt (3 * 5mL) washing, with Na ₂SO ₄Drying, and concentrate, make the 105mg white solid.This white solid (105mg) is dissolved among the THF (3.5mL), and with 6N HCl (3mL) water (3mL) processing then.Mixture at room temperature stirs 2.5h.Mixture is with solid K ₂CO ₃(～3g) is saturated, and with CH ₂Cl ₂(30mL) and water (10mL) dilution.Separate biphase, with CH ₂Cl ₂(3 * 10mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes white solid chemical compound 10 (59mg, 59%). ¹HNMR(CDCl ₃)δ1.61-1.71(m，3H)，2.01-2.05(m，1H)，2.26-2.36(m，2H)，2.50(s，6H)，2.84(s，3H)，3.64(s，2H)，4.01(m，4H)4.31(t，1H，J＝6.0Hz)，4.37(s，2H)，5.10(br s，1H)，6.65(d，1H，J＝7.5Hz)，6.76(d，1H，J＝7.5Hz)，6.83-6.87(m，3H)，7.23-7.26(m，2H)，8.21(d，2H，J＝3.3Hz)； ¹³CNMR(CDCl ₃)δ19.42，25.59，30.16，41.19，47.03，54.27，62.46，67.31，122.18，126.13，128.44，129.60，131.75，134.83，138.49，139.78，146.80，160.05；ES-MS m/z 495(M ⁺H)。Analytical calculation value C ₂₇H ₃₄N ₄O ₃S0.3H ₂O1.0CH ₂Cl ₂: C, 57.49; H, 6.31; N, 9.58; S, 5.48. measured value: C, 57.45; H, 6.35; N, 9.63; S, 5.53.

Embodiment 11

Chemical compound 11:[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzyl amino]-methyl acetate

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.112g in THF 0.22mmol) (2mL) cold (0 ℃) solution, adds Et to 3-(tetrahydrochysene-pyrans-2-yloxymethyl)-benzyl amine ₃N (0.04mL, 0.28mmol), add then methyl bromoacetate (24 μ L, 0.25mmol).The gained mixture is warmed to ambient temperature overnight.With CH ₂Cl ₂(20mL) diluted mixture thing is with saturated aqueous common salt (5 * 5mL) washings, Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the 43mg yellow oil.This grease (43mg) is dissolved among the THF (2mL), with 6N HCl (2mL) water (2mL) processing then.Mixture at room temperature stirs and spends the night.Mixture is with solid K ₂CO ₃(～1.8g) is saturated, and with CH ₂Cl ₂(25mL) and water (5mL) dilution.Separate biphase, and with CH ₂Cl ₂(3 * 10mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes white solid chemical compound 11 (27mg, 24%). ¹HNMR(CDCl ₃)δ1.60-1.71(m，3H)，1.92-2.06(m，1H)，2.28-2.36(m，2H)，2.50(s，6H)，3.23(s，2H)，3.51(s，2H)，3.64(s，2H)，3.73(s，3H)，4.20(d，2H，J＝10.8Hz)，4.35(s，2H)，6.62(d，1H，J＝7.5Hz)，6.73(d，1H，J＝7.5Hz)，6.83-6.87(m，3H)，7.22-7.26(m，2H)，8.23(d，2H，J＝3.6Hz)； ¹³C NMR(CDCl ₃)δ19.45，25.62，30.20，49.90，52.17，52.92，54.90，62.95，67.49，122.08，126.57，129.38，129.59，131.73，137.52，137.87，138.45，139.28，146.86，160.18，173.18；ES-MS m/z489(M ⁺H)。Analytical calculation value C ₂₉H ₃₆N ₄O ₃1.0H ₂O:C, 68.75; H, 7.56; N, 11.06. measured value: C, 68.89; H, 7.29; N, 10.82.

Embodiment 12

Chemical compound 12:N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzyl]-2,2-dimethyl-propionic acid amide.

With 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (0.412g, NH 1.00mmol) ₃Saturated MeOH (20mL) solution is handled with Raney nickel (500mg), places 50psi H ₂Under Parr shaker in, the vibration 5h.The mixture diatomite filtration washs this kieselguhr cake with MeOH.The eluent concentrating under reduced pressure.Crude product through silica gel with column chromatography (10: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.371g (89%) white solid [5-aminomethyl-2-(and 3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol.

[5-aminomethyl-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (126mg, CH 0.30mmol) ₂Cl ₂In cold (0 ℃) solution, add Et ₃N (0.08mL, 0.58mmol), add then pivalyl chloride (42 μ L, 0.34mmol).Behind the 30min, with reactant mixture with CH ₂Cl ₂(20mL) dilution is with saturated aqueous common salt (3 * 5mL) washings, Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 12 (111mg, 67%) of white solid. ¹H NMR(CDCl ₃)δ1.18(s，9H)，1.60-1.72(m，3H)，1.97-2.05(m，1H)，2.28-2.37(m，2H)，2.50(s，6H)，3.63(s，2H)，4.02(d，2H，J＝10.8Hz)，4.12(d，2H，J＝5.4Hz)，4.36(s，2H)，5.13(br s，1H)，5.58(br s，1H)，6.57(d，1H，J＝7.5Hz)，6.72(d，1H，J＝7.5Hz)，6.81-6.86(m，3H)，7.22-7.26(m，2H)，8.22(d，2H，J＝4.2Hz)； ¹³C NMR(CDCl ₃)δ19.45，25.70，27.96，29.57，38.99，43.53，53.83，63.01，67.68，122.10，126.16，128.78，129.51，131.92，136.47，138.02，138.41，139.29，146.79，160.01，178.33；ES-MS m/z 501(M ⁺H)。Analytical calculation value C ₃₁H ₄₀N ₄O ₂0.6H ₂O0.4CH ₂Cl ₂: C, 69.14; H, 7.76; N, 10.27. measured value: C, 68.85; H, 7.74; N, 10.20.

Embodiment 13

Chemical compound 13:[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzyl]-urea

[5-aminomethyl-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (98mg, in 2-propanol (4mL) solution 0.24mmol), the adding trimethylsilyl isocyanate (30 μ L, 0.22mmol).Gained solution at room temperature stirs and spends the night, and concentrates then.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes white solid chemical compound 13 (62mg, 49%). ¹H NMR(CDCl ₃)δ1.60-1.71(m，3H)，1.99-2.05(m，1H)，2.22-2.31(m，2H)，2.48(s，6H)，3.58(s，2H)，3.97(d，2H，J＝10.8Hz)，4.06(d，2H，J＝5.7Hz)，4.33(s，2H)，4.68(s，2H)，5.28(br s，1H)，6.60(d，1H，J＝7.8Hz)，6.64(d，1H，J＝7.8Hz)，6.82-6.86(m，3H)，7.24(d，2H，J＝7.8Hz)，8.19(d，2H，J＝3.3Hz)； ¹³C NMR(CDCl ₃)δ19.52，25.64，30.82，43.99，55.21，62.78，67.58，122.29，126.06，128.12，129.37，131.60，137.66，138.47，139.16，146.89，159.93；ES-MS m/z 460(M ⁺H)。Analytical calculation value C ₂₇H ₃₃N ₅O ₂0.9CH ₂Cl ₂: C, 62.52; H, 6.54; N, 13.07. measured value: C, 62.81; H, 6.56; N, 13.01.

Embodiment 14

Chemical compound 14:N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-acetamide (HBr salt)

(99mg in water 0.21mmol) (1mL) solution, adds 1.0NNaOH (2mL) at chemical compound 1 (hydrochlorate).Mixture is with CH ₂Cl ₂(4 * 10mL) extractions.The organic extract that merges is with (Na ₂SO ₄Drying concentrates, and makes the free alkali of 71mg (99%) chemical compound 1.At chemical compound 1 free alkali (99mg, CH 0.21mmol) ₂Cl ₂(4mL) in the solution, add Et ₃N (90 μ L, 0.65mmol), add then acetic anhydride (40 μ L, 0.43mmol).Gained solution at room temperature stirs 90min.Mixture is with CH ₂Cl ₂(20mL) dilution is with saturated aqueous common salt (4 * 5mL) washings, Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 25: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of the title compound of 72mg (89%) white foam shape.

According to general step B: the foam (72mg) that will go up the step gained is converted into its HBr salt, then with MeOH/ ether redeposition intermedium solid, makes the chemical compound 14 (107mg, 78%) of white solid. ¹HNMR(D ₂O)δ1.01-1.22(m，4H)，1.45-1.57(m 2H)，1.65-1.73(m，1H)，1.85(s，3H)，1.92-1.98(m，1H)，1.99-2.28(m，4H)，2.60(s，6H)，2.86(t，2H，J＝6.3Hz)，4.58(dd，2H，J＝2.4，11.1Hz)，7.89(dd，2H，J＝5.7，8.1Hz)，8.43(d，2H，J＝8.1Hz)，8.66(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ17.07，20.23，22.21，22.45，26.37，32.57，38.74，53.05，58.19，125.98，136.88，139.69，149.48，154.92，174.08；ES-MS m/z 381(M ⁺H)。Analytical calculation value C ₂₃H ₃₂N ₄O3.0HBr1.8H ₂O1.2CH ₃CO ₂H:C, 41.92; H, 6.01; N, 7.70; Br, 32.94. measured value: C, 42.04; H, 6.12; N, 7.71; Br, 32.86.

Embodiment 15

Chemical compound 15:[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-urea (HBr salt)

Chemical compound 1 free alkali (75mg, add in 2-propanol (2mL) solution 0.22mmol) trimethylsilyl isocyanate (30 μ L, 0.22mmol).Gained solution at room temperature stirs and spends the night, and concentrates then.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of the title compound of 33mg (40%) white foam shape.

According to general step B: white foam shape thing (33mg) is converted into its HBr salt,, makes the chemical compound 15 (42mg, 28%) of white solid then by MeOH/ ether redeposition intermedium solid. ¹HNMR(D ₂O)δ1.04-1.27(m，4H)，1.48-1.60(m，2H)，1.67-1.80(m，2H)，1.94-2.00(m，1H)，2.09-2.27(m，4H)，2.62(s，6H)，2.80(t，2H，J＝6.3Hz)，4.61(dd，2H，J＝2.7，11.1Hz)，7.91(dd，2H，J＝6.0，7.8Hz)，8.44(d，2H，J＝7.8Hz)，8.67(d，2H，J＝6.0Hz)； ¹³C NMR(D ₂O)δ17.06，20.00，22.44，26.92，32.58，39.03，53.14，58.28，125.95，136.89，139.67，149.45，154.92；ES-MS m/z382(M ⁺H)。Analytical calculation value C ₂₂H ₃₁N ₅O3.1HBr2.4H ₂O0.4CH ₃CH ₂OCH ₂CH ₃: C, 40.19; H, 6.13; N, 9.93; Br, 35.12. measured value: C, 40.45; H, 6.05; N, 9.92; Br, 34.78.

Embodiment 16

Chemical compound 16:N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-6-hydroxyl-nicotiamide (HBr salt)

At chemical compound 1 free alkali (149mg, 0.42mmol) dry DMF (4mL) solution in, add 6-hydroxyl-nicotinic acid (80mg, 0.57mmol), add then EDCI (113mg, 0.59mmol), HOBT (80mg, 0.59mmol), DMAP (10mg, 0.09mmol) and DIPEA (0.15mL, 0.86mmol).The gained mixture at room temperature stirs 6h.Mixture is with EtOAc (20mL), saturated aqueous common salt (5mL) and water (5mL) dilution.Separate biphase, organic facies with saturated aqueous common salt (4 * 5mL) washing, with MgSO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (1mm plate, 10: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of the title compound of 69mg (35%) white foam shape.

According to general step B: the free alkali (59mg) of gained is converted into HBr salt, then with MeOH/ ether redeposition intermedium solid, make white solid chemical compound 16 (79mg, 83%). ¹H NMR(D ₂O)δ1.16-1.22(m，4H)，1.45-1.57(m，2H)，1.66-1.79(m，1H)，1.94-1.98(m，1H)，2.0-2.16(m，2H)，2.25-2.31(m，2H)，2.55(s，6H)，3.09-3.13(m，2H)，4.59(dd，2H，J＝11.4，3.0Hz)，6.71(d，1H，J＝9.3Hz)，7.84-8.01(m，4H)，8.34(d，2H，J＝7.5Hz)，8.67(d，2H，J＝5.1Hz) ¹³C NMR(D ₂O)δ17.02，20.19，22.41，26.47，32.55，38.84，53.23，58.29，115.50，119.43，125.91，136.75，137.50，139.72，140.90，149.32，154.94，165.47，166.89；ES-MS m/z460(M ⁺H)。Analytical calculation value C ₂₇H ₃₃N ₅O ₂3.0HBr2.5H ₂O:C, 43.39; H, 5.53; N, 9.37; Br, the 32.07. measured value; C, 43.33; H, 5.54; N, 9.31; Br, 32.11.

Embodiment 17

Chemical compound 17: meso-2 ' β, 6 ' β-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propylamine]

(0.61mL, in DMF 6.0mmol) (8mL) solution, (0.2756g 1.5mmol), stirs 17h down at 90 ℃ to add potassium phthalimide at dibromopropane.Mixture is concentrated, add 1NNaOH (10mL), with CH ₂Cl ₂(2 * 30mL) extractions.(1 * 15mL) washing is with Na with water for the organic extract that merges ₂SO ₄Drying, and concentrate.(purification of 4: 1 hexanes-EtOAc) makes 2-(3-bromo-the propyl group)-iso-indoles-1 of 0.1977g (49%) white solid, 3-diketone to crude product with column chromatography through silica gel. ¹H NMR(CDCl ₃)δ2.21-2.30(m，2H)，3.41(t，2H，J＝6.0Hz)，3.83(t，2H，J＝6.0Hz)，7.69-7.75(m，2H)，7.82-7.86(m，2H)。

According to general step A: with meso-2 ', 6 '-[3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.1796g, 0.67mmol), 2-(3-bromo-propyl group)-iso-indoles-1, the 3-diketone (0.1977g; 0.74mmol), KI (0.0116g; 0.07mmol), DIPEA (0.23mL, 1.34mmol) and the mixed solution of DMF (6.7mL) under 60 ℃, stir 18h.Crude product through silica gel with column chromatography (33: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the orange foamed meso-2 ' of 0.2823g (93%), 6 '-[2-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-yl)-propyl group]-iso-indoles-1, the 3-diketone]. ¹H NMR(CDCl ₃)δ1.55-1.64(m，2H)，1.86-1.95(m，2H)，2.28-2.30(m，2H)，2.46-2.48(m，4H)，2.88-2.95(m，2H)，4.00-4.05(m，2H)，6.87-6.88(m，2H)，7.23-7.25(m，2H)，7.67-7.73(m，4H)，8.29-8.30(m，2H)。

In meso-2 ', 6 '-[2-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-yl)-propyl group]-iso-indoles-1, the 3-diketone] (0.2823g, in EtOH 0.62mmol) (6.2mL) solution, (0.30mL 6.21mmol), stirs 16h under the room temperature to add single hydrazine hydrate.Concentrated reaction mixture, crude product through silica gel with column chromatography (25: 1: 1 12: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes the light yellow sticky oily compound 17 of 0.1606g (80%). ¹H NMR(CDCl ₃)δ0.69(s，1H)，1.53-1.66(m，3H)，2.01-2.02(m，5H)，2.29-2.30(m，2H)，2.52(s，6H)，2.52-2.53(m，1H)，4.04(d，2H，J＝9.9Hz)，7.04-7.08(m，2H)，7.41(d，2H，J＝7.5Hz)，8.43(s，2H)。 ¹³C NMR(CDCl ₃)δ19.03，25.48，29.67，40.13，46.71，64.73，71.53，122.18，131.97，138.63，146.81，160.45.ES-MS m/z 325.4(M ⁺H)。Analytical calculation value C ₂₀H ₂₈N ₄0.7CH ₂Cl ₂: C, 64.76; H, 7.72; N, 14.59. measured value: C, 64.51; H, 7.96; N, 14.65.

Embodiment 18

Chemical compound 18:N-[3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-acetamide (HBr salt)

At chemical compound 17 (0.118g, CH 0.36mmol) ₂Cl ₂(7mL) in the solution, add Et ₃N (0.15mL, 1.08mmol), add then acetic anhydride (0.07mL, 0.75mmol).Gained solution at room temperature stirs and spends the night.Mixture is with CH ₂Cl ₂(30mL) dilution is with saturated aqueous common salt (3 * 10mL) washings, Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of the title compound of 105mg (79%) colorless oil.

According to general step B: gained grease (27mg) is converted into its HBr salt, makes white solid chemical compound 18 (172mg, 93%). ¹H NMR(D ₂O)δ1.23-1.63(m，8H)，1.79-1.84(m，1H)，1.98-2.08(m，4H)，2.45(s，6H)，2.60(t，2H，J＝6.0Hz)，4.43(dd，2H，J＝3.0，11.1Hz)，7.79(dd，2H，J＝6.0，8.1Hz)，8.31(d，2H，J＝8.1Hz)，8.53(d，2H，J＝6.0Hz)； ¹³C NMR(D ₂O)δ17.05，22.03，22.40，23.05，32.49，37.00，50.27，58.04，126.07，136.95，139.92，149.40，154.66，180.52；ES-MS m/z 367(M ⁺H)。Analytical calculation value C ₂₂H ₃₀N ₄O3.0HBr1.8H ₂O:C, 41.18; H, 5.75; N, 8.73; Br, 37.36. measured value: C, 41.22; H, 5.65; N, 8.50; Br, 37.40.

Embodiment 19

Chemical compound 19:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-essence of Niobe

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.107g in MeOH 0.25mmol) (10mL) solution, adds dense H to 3-methylol-benzoic acid ₂SO ₄(0.5mL), and with mixture heated spend the night to refluxing.Mixture is cooled to room temperature, concentrating under reduced pressure.Residue is dissolved in CH ₂Cl ₂(30mL) with saturated Na ₂CO ₃In the aqueous solution (10mL).Separate biphasely, water is with CH ₂Cl ₂(3 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 50: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 19 (86mg, 75%) of white solid. ¹H NMR(CDCl ₃)δ1.60-1.77(m，3H)，2.07-2.11(m，1H)，2.34-2.46(m，2H)，2.51(s，6H)，3.72(s，2H)，3.81(s，3H)，4.10(d，2H，J＝12.0Hz)，4.44(s，2H)，4.90(br s，1H)，6.82-6.87(m，3H)，7.23(d，2H，J＝7.5Hz)，7.34(d，1H，J＝9.0Hz)，7.59(s，1H)，8.21(d，2H，J＝3.9Hz)； ¹³C NMR(CDCl ₃)δ19.38，25.69，29.11，52.20，53.05，62.82，67.35，122.41，127.86，128.01，128.93，130.27，131.99，138.50，138.92，144.87，146.82，159.60，167.35；ES-MS m/z446(M ⁺H)。Analytical calculation value C ₂₇H ₃₁N ₃O ₃0.2CH ₂Cl ₂: C, 70.63; H, 6.84; N, 9.08. measured value: C, 70.61; H, 6.95; N, 8.91.

Embodiment 20

Chemical compound 20:[3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-yl]-methanol

At 3-methyl-2-cyanopyridine (3-methylpicolinonitrile) (700mg, CCl 5.93mmol) ₄(15mL) in the solution, add recrystallization N-bromine butanimide (1.21g, 6.82mmol), add then glacial acetic acid (0.34mL, 1.0 equivalents) and AIBN (97mg, 0.60mmol).Heating gained mixture to 65 ℃ 3h, 80 ℃ of 2h are cooled to room temperature then.Mixture is through filter paper filtering, concentrated filtrate.Crude product makes the 3-bromomethyl-pyridine-2-formonitrile HCN (250mg, 21%) of white solid through flash chromatography (hexane/EtOAc, 90: 10,80: 20 then) purification. ¹H NMR(CDCl ₃)δ4.63(s，2H)，7.55(dd，1H，J＝8.0，4.6Hz)，7.93(dd，1H，J＝7.9，1.2Hz)，8.64(dd，1H，J＝4.8，1.4Hz)。

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (0.104g, 0.39mmol), 3-bromomethyl-pyridine-2-formonitrile HCN (0.115g, 0.58mmol), KI (23mg, 0.14mmol) and DIPEA (0.15mL, DMF 0.86mmol) (4mL) solution heating keeps 60 ℃, 20h.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 133mg (88%) brown solid shape 3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-nitrile.

3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-nitrile (0.127g, add among MeOH 0.33mmol) (3mL) entry (3mL) and solid NaOH (0.120g, 2.99mmol).The gained mixture heated refluxes and spends the night, and is cooled to room temperature then.With 3N HCl (～1mL) regulate mixture pH to～4, with CH ₂Cl ₂(5 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated, make the 0.14g white solid.This white solid (0.14g) is dissolved among the MeOH (10mL), with dense H ₂SO ₄(0.5mL) handle, and reflux is spent the night.Mixture is cooled to room temperature, concentrating under reduced pressure.Residue is dissolved in CH ₂Cl ₂(20mL) with saturated Na ₂CO ₃In the aqueous solution (5mL).Separate biphasely, water is with CH ₂Cl ₂(3 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 72.0mg (52%) white solid 3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-the pyridine-2-carboxylic acids methyl ester.

3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(72mg in THF 0.17mmol) (2mL) and MeOH (2mL) cold (0 ℃) solution, adds LiBH to the pyridine-2-carboxylic acids methyl ester ₄(75mg 3.45mmol), allows mixture be warming up to ambient temperature overnight.With 1.0N NaOH (10mL) diluted mixture thing, and with CH ₂Cl ₂(5 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 20 (50mg, 74%) of white solid. ¹H NMR(CDCl ₃)δ1.65-1.78(m，3H)，2.12-2.14(m，1H)，2.33-2.48(m，8H)，3.49(s，2H)，4.21(d，2H，J＝11.1Hz)，4.29(s，2H)，4.66(brs，1H)，6.74(dd，1H，J＝4.8，7.5Hz)，6.86(dd，2H，J＝4.5，7.5Hz)，7.20(d，2H，J＝7.5Hz)，7.45(d，1H，J＝7.5Hz)，7.96(d，1H，J＝4.5Hz)，8.28(d，2H，J＝4.5Hz)； ¹³C NMR(CDCl ₃)δ19.15，25.70，27.29，46.27，61.30，66.87，121.16，122.46，132.32，133.57，136.63，138.18，144.84，146.78，154.48，159.25；ES-MS m/z 389(M ⁺H)。Analytical calculation value C ₂₄H ₂₈N ₄O0.3H ₂O:C, 73.18; H, 7.32; N, 14.22. measured value: C, 73.17; H, 7.23; N, 14.17.

Embodiment 21

Chemical compound 21:C-[3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-yl]-methylamine (HBr salt)

With 3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-formonitrile HCN (0.161g, NH 0.42mmol) ₃Saturated MeOH (8mL) solution is handled with Raney nickel (80mg), puts on the Parr shaker in 50psi H ₂Following 19h.Mixture is through diatomite filtration, and the kieselguhr cake washs with MeOH.The concentrating under reduced pressure eluent.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of the title compound of 109mg (67%) white solid.

According to general step B: this white solid (101mg) is converted into its HBr salt, makes the chemical compound 21 (194mg, 94%) of white solid. ¹H NMR(D ₂O)δ1.55-1.86(m，3H)，1.99-2.08(m，1H)，2.17-2.22(m，2H)，2.56(s，6H)，3.79(s，2H)，4.07(s，2H)，4.59(d，2H J＝9.0Hz)，7.16(dd，1H，J＝7.5，4.5Hz)，7.60(d，1H，J＝7.5Hz)，7.77(dd，2H，J＝7.8，5.7Hz)，8.19(d，1H，J＝4.5Hz)，8.31(d，2H，J＝7.8Hz)，8.62(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ17.35，22.25，33.09，40.58，57.76，61.98，124.19，126.25，130.22，136.94，139.65，140.10，149.19，149.37，149.67，154.93；ES-MS m/z 388(M ⁺H)。Analytical calculation value C ₂₄H ₂₉N ₅4.2HBr3.3H ₂O:C, 36.64; H, 5.10; N, 8.90; Br, 42.65. measured value: C, 36.68; H, 5.13; N, 8.68; Br, 42.59.

Embodiment 22

Chemical compound 22:3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-carboxylic amide

3N NaOH (0.76mL, 2.28mmol) and 50%H ₂O ₂(0.06mL, in MeOH 1.04mmol) (1mL) solution, add 3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-pyridine-2-formonitrile HCN (0.175g, MeOH 0.46mmol) (4mL) solution.The gained mixture heated keeps 60 ℃, and 6h is cooled to room temperature then.Mixture is with saturated aqueous common salt (10mL) dilution, with CH ₂Cl ₂(4 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 22 (138mg, 75%) of white solid. ¹H NMR(CDCl ₃)δ1.61-1.71(m，3H)，1.97-2.03(m，1H)，2.22-2.34(m，2H)，2.43(s，6H)，4.05-4.10(m，4H)，5.27(br s，1H)，6.80(dd，2H，J＝4.8，7.5Hz)，7.09(dd，1H，J＝4.8，7.5Hz)，7.21(d，2H，J＝7.5Hz)，7.51(br s，1H)，7.95(d，1H，J＝4.8Hz)，8.22(d，2H，J＝3.3Hz)，8.40(d，1H，J＝7.8Hz)； ¹³C NMR(CDCl ₃)δ19.51，25.33，31.27，52.74，53.85，67.03，121.91.124.85，131.56，138.21，139.60，141.42，145.07，147.19，160.26，169.19；ES-MS m/z 402(M ⁺H)。Analytical calculation value C ₂₄H ₂₇N ₅O0.3H ₂O:C, 70.84; H, 6.84; N, 17.21. measured value: C, 70.85; H, 6.74; N, 17.16.

Embodiment 23

Chemical compound 23:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-thiophene-3-carboxylic acid amide

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (0.097g; 0.37mmol), 4-bromomethyl-thiophene-3-formonitrile HCN (0.168g, 0.83mmol) (Terpstra, J.W.; etc.; J.Org.Chem. (1986) 51:230-238), KI (21mg, 0.13mmol) and DIPEA (0.15mL, DMF 0.86mmol) (3mL) solution; be heated to 60 ℃, 21h.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 118mg (84%) brown solid shape 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-thiophene-3-formonitrile HCN.

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-thiophene-3-nitrile (0.118g, in MeOH 0.30mmol) (3mL) solution, add entry (3mL) and solid NaOH (0.109g, 2.72mmol).The gained mixture heated refluxes and spends the night, and is cooled to room temperature then.With 3N HCl (～1mL) regulate mixture pH, and with CH to～4 ₂Cl ₂(5 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate, make the 0.12g brown solid.This brown solid (0.12g) is dissolved among the MeOH (10mL), with dense H ₂SO ₄(0.5mL) handle, and reflux is spent the night.Mixture is cooled to room temperature, concentrating under reduced pressure.Residue is dissolved in CH ₂Cl ₂(20mL) with saturated Na ₂CO ₃In the aqueous solution (5mL).Separate biphasely, water is with CH ₂Cl ₂(3 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 25: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 23 (43mg, 31%) of white solid. ¹H NMR(CDCl ₃)δ1.53-1.64(m，1H)，1.69-1.74(m，2H)，1.91-1.98(m，1H)，2.08-2.22(m，2H)，2.34(s，6H)，3.56(s，2H)，3.82(dd，2H，J＝11.4，3.0Hz)，5.55(br s，1H)，6.84-6.91(m，3H)，7.22(d，2H，J＝7.5Hz)，7.47(d，1H，J＝2.7Hz)，8.36(d，2H，J＝3.6Hz)，9.27(br s，1H)； ¹³C NMR(CDCl ₃)δ19.34，24.65，33.00，56.95，66.39，122.27，125.11，130.22，132.84，136.92，137.16，138.35，147.33，160.54，164.99；ES-MS m/z 407(M ⁺H)。Analytical calculation value C ₂₃H ₂₆N ₄OS0.5CH ₂Cl ₂: C, 62.86; H, 6.06; N, 12.48; S, 7.14. measured value: C, 63.08; H, 6.36; N, 12.31; S, 6.94.

Embodiment 24

Chemical compound 24:C-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-thiene-3-yl-]-methylamine (HBr salt)

At cold (0 ℃) LiAlH ₄(131mg, 3.46mmol) in the mixture in dry THF (3mL), add 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-thiophene-3-formonitrile HCN (129mg, THF 0.33mmol) (6mL) solution.The gained mixture at room temperature stirs 6h, cools off with ice-water bath then.Mixture is handled with saturated sodium tartrate aqueous solutions of potassium (2mL), and diluted with THF (10mL).Mixture is with solid Na ₂SO ₄(2 spoonfuls) are handled, and with filter paper filtering.Concentrate eluant, thus the material of gained through silica gel with radial chromatography (1mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of the title compound of 47mg (35%) white foam shape.

According to general step B: this white foam shape thing (47mg) is converted into its HBr salt, makes the chemical compound 24 (69mg, 84%) of white solid. ¹H NMR(D ₂O)δ1.49-1.61(m，2H)，1.68-1.78(m，1H)，1.95-2.01(m，1H)，2.14-2.19(m，2H)，2.53(s，6H)，3.70(s，4H)，4.52(dd，2H，J＝12.0，3.0Hz)，7.11(d，1H，J＝3.0Hz)，7.36(d，1H，J＝3.0Hz)，7.78(dd，2H，J＝7.8，6.0Hz)，8.32(d，2H，J＝7.8Hz)，8.60(d，2H，J＝6.0Hz)； ¹³CNMR(D ₂O)δ17.23，22.24，32.93，36.10，54.38，61.57，125.91，128.31，128.68，131.57，134.97，136.57，139.45，149.23，155.44；ES-MS m/z393(M ⁺H)。Analytical calculation value C ₂₃H ₂₈N ₄S3.2HBr2.4H ₂O:C, 39.76; H, 5.22; N, 8.06; Br, 36.81; S, 4.61. measured value: C, 39.77; H, 5.12; N, 7.78; Br, 36.81; S, 4.48.

Embodiment 25

Chemical compound 25:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-thiophene-3-carboxylate methyl ester

With 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.120g, MeOH 0.31mmol) (6mL) solution is with dense H for thiophene-3-formonitrile HCN ₂SO ₄(0.5mL) handle with dense HCl (0.5mL), the gained vlil is spent the night.Mixture is cooled to room temperature, and with 1.0N NaOH (～10mL) neutralization.With CH ₂Cl ₂(5 * 20mL) extraction mixture.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 50: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 25 (50mg, 39%) of white solid. ¹H NMR(CDCl ₃)δ1.51-1.70(m，3H)，1.92-1.99(m，1H)，2.12-2.25(m，2H)，2.34(s，6H)，3.66(s，3H)，3.81(s，2H)，4.03(d，2H，J＝9.6Hz)，6.90(dd，2H，J＝4.8，7.2Hz)，7.24-7.27(m，2H)，7.37(br s，1H)，7.52(d，1H，J＝3.3Hz)，8.34(d，2H，J＝4.8Hz)； ¹³CNMR(CDCl ₃)δ19.26，25.57，29.46，47.58，51.60，66.60，122.07，124.99，132.06，132.42，138.21，139.75，142.64，146.85，160.17，163.50；ES-MS m/z422(M ⁺H)。Analytical calculation value C ₂₄H ₂₇N ₃O ₂S0.7H ₂O:C, 66.39; H, 6.59; N, 9.68; S, 7.38. measured value: C, 66.75; H, 6.74; N, 9.47; S, 7.11.

Embodiment 26

Chemical compound 26:(2 ' R, 6 ' S)-3,3 " dimethyl-1 '-(2-thiazole-5-base-ethyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (HBr salt)

With 5-methyl-thiazole (1.00g, 10.1mmol), NBS (2.06g, 11.6mmol) and 2,2 '-azodiisobutyronitrile (0.164, CCl 1.00mmol) ₄(60mL) solution stirring, and reflux 3h.After treating that solution is cooled to room temperature, add NaS ₂O ₃Water (5g) (50mL) solution is collected organic facies.With CH ₂Cl ₂(3 * 60mL) aqueous phase extracted.Merge organic facies, wash, and be concentrated into～150mL with vacuum evaporation with water (50mL).Add DMF (40mL) and NaCN (1.00g, water 20.4mmol) (20mL) solution, and remove lower boiling solvent (CH then with vacuum evaporation ₂Cl ₂And CCl ₄).Then residue is stirred and spend the night.Add entry (40mL), with Et ₂O (5 * 100mL) extraction mixture.Merge extract, with water (50mL) washing, with Na ₂SO ₄Dry.After the filtration, remove through vacuum evaporation and to desolvate, residue through silicagel column with flash chromatography (3: 4 Et ₂O/CH ₂Cl ₂) purification, make light yellow liquid shape thiazole-5-formonitrile HCN (0.550g, 44%). ¹H NMR(CDCl ₃)δ3.97(s，2H)，7.85(s，1H)，8.81(s，1H)。

(0.550g, 4.43mmol) (3N, 20mL) suspension in stirs and is heated to 50 ℃, 2h, cool to room temperature then at the NaOH aqueous solution with thiazole-5-formonitrile HCN.With HCl aqueous solution (4N) regulator solution acidity to pH=～3, and with EtOAc (10 * 50mL) extraction.Merge extract and with Na ₂SO ₄Dry.After the filtration, remove solvent, make the thiazole-5-base-acetic acid of light yellow solid shape with vacuum vapor deposition method.

This solid is dissolved in the dry THF (10mL), and solution is cooled to 0 ℃.Slowly add BH ₃(in the THF solution of 1.0M, 10mL, 10mmol).After the adding, mixture is at room temperature stirred 20h.Add MeOH (10mL) then, with the mixture heated 2h that refluxes.Under the room temperature, with the vacuum evaporation enriched mixture, ((EtOAc) purification makes light yellow liquid shape 2-thiazole-5-base-ethanol (0.154g, 27% liang of step) to residue with flash chromatography through silicagel column.

In the time of 0 ℃, at 2-thiazole-5-base-ethanol (0.154g, CH 1.19mmol) ₂Cl ₂(10mL) in the solution, add MsCl (0.150g, 1.31mmol) and Et ₃N (0.180g, 1.79mmol).Mixture at room temperature stirs 1h.Add entry (20mL), with CH ₂Cl ₂(3 * 30mL) extraction mixture.Merge extract, and with Na ₂SO ₄Dry.After the filtration, except that desolvating, residue with flash chromatography (EtOAc) purification, makes light yellow liquid shape methanesulfonic acid 2-thiazole-5-base-ethyl ester (0.246g, 100%) through silicagel column through vacuum evaporation. ¹H NMR(CDCl ₃)δ2.99(s，3H)，3.33(t，2H，J＝6.3Hz)，4.42(t，2H，J＝6.3Hz)，7.73(s，1H)，8.74(s，1H)。

Will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.140g, 0.523mmol), methanesulfonic acid 2-thiazole-5-base-ethyl ester (0.105g, 0.505mmol) and 2,2,6,6-tetramethyl piperidine (0.107g, CH 0.758mmol) ₃CN (2mL) solution stirring, and reflux is spent the night.Remove solvent, add saturated NaHCO ₃Aqueous solution (10mL) is with CH ₂Cl ₂(3 * 20mL) extraction mixture.Merge extract and with Na ₂SO ₄Dry.After the filtration, remove through vacuum evaporation and to desolvate, residue through silicagel column with flash chromatography (500: 25: 1 CH ₂Cl ₂/ CH ₃OH/NH ₄OH) purification makes colorless oil (0.144g, 75%).

According to general step B: (0.115g 0.303mmol) handles with HBr/MeOH, makes the HBr salt (0.210g, 96%) of yellow solid shape with this grease. ¹H NMR(D ₂O)δ1.52-1.64(2H)，1.72-1.86(m，1H)，1.95-2.00(m，1H)，2.17-2.22(m，2H)，2.59-2.70(m，8H)，3.07-3.13(m，2H)，4.70-4.76(m，2H)，7.78(s，1H)，7.92(dd，2H，J＝5.4，8.1Hz)，8.45(d，2H，J＝8.1Hz)，8.70(d，2H，J＝5.4Hz)，9.65(s，1H)； ¹³CNMR(D ₂O)δ17.41，21.03，22.35，32.60，52.84，57.74，126.34，131.83，137.08，140.23，140.77，149.97，153.75，157.08.ES-MS m/z 379(M ⁺H)。Analytical calculation value C ₂₂H ₂₆N ₄S3.6HBr1.8H ₂O0.3C ₄H ₁₀O:C, 38.46; H, 5.04; N, 7.73; Br, 39.70; S, 4.43. measured value: C, 38.46; H, 5.07; N, 7.66; Br, 39.63; S, 4.37.

Embodiment 27

Chemical compound 27:3,5-two chloro-N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-is suitable-[2,2 ': 6 ', 2 "] terpyridyl-1 '-yl) butyl]-Pyrazinamide

(103mg is 0.22mmol) with 1M NaOH (25mL) neutralization, with CHCl with chemical compound 1 ₃(25mL * 3) extraction of free base.The organic solution that merges is with Na ₂SO ₄Drying is filtered and concentrating under reduced pressure, makes the free alkali (72mg, 100%) of yellow oily.

3, and 5-dichloropyridine-4-carboxylic acid (89mg, 0.46mmol) and the CH of DMF (2) ₂Cl ₂(4mL) in the suspension, and the adding oxalyl chloride (0.12mL, 1.4mmol).Under the room temperature, with the gained suspension at N ₂Under stir 25min, then with the evaporation under reduced pressure removed solvent.With rough acyl chlorides drying under reduced pressure, add THF (4mL) solution of the free alkali of going up the step then, and NEt ₃(0.04mL, 0.3mmol).Under the room temperature, with the gained suspension at N ₂Under stir 50min.With saturated NaHCO ₃Aqueous solution (25mL) diluted mixture thing, and with CH ₂Cl ₂(25mL * 3) extraction.The organic solution that merges is with Na ₂SO ₄Drying is filtered and concentrating under reduced pressure.By silica gel with flash chromatography (CH ₂Cl ₂/ MeOH/NH ₄OH, 19: 1: 0.2) make the amide (77.5mg, 0.15mmol, 68%) of white foam shape. ¹H NMR(MeOH-d ₄)δ0.82-0.97(m，3H)，1.60-1.78(m，3H)，1.95-2.18(m，3H)，2.22-2.34(m，2H)，2.55-2.78(m，6H)，2.83-3.01(m，3H)，3.91-4.21(m，2H)，7.16-7.28(m，2H)，7.62(d，2H，J＝8.4Hz)，8.24-8.38(m，2H)，8.56(s，2H)。ES-MS m/z 512(M ⁺H)，514(M ⁺2 ⁺H)。Analytical calculation value C ₂₇H ₃₁C1 ₂N ₅O0.6CH ₄O:C, 62.35; H, 6.33; N, 13.17; Cl, 13.34. measured value: C, 62.03; H, 6.07; N, 13.42; Cl, 13.61.

Embodiment 28

Chemical compound 28:4-meso [2,7-pair-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene azatropylidene-1-yl] butylamine

Under the room temperature, (2.42g 20mmol) is dissolved in MeOH (100mL, anhydrous) with 3-methyl-2-pyridine carboxaldehyde.Add NH ₄(0.86g 11mmol), stirs the mixture and dissolves up to all solids OAc.With the indium powder (99.99% ,-100 mesh sieves 1.84g) all once drop into, then in 5min, be added dropwise to allyl bromide, bromoallylene (1.9mL, 22mmol).Under the room temperature, with mixture at N ₂Following stirring is spent the night, then with saturated NaHCO ₃(100mL) cancellation.Add kieselguhr (5g), filtering mixt.Filter cake is with MeOH (50mL) and CH ₂Cl ₂(50mL) washing.Filtrate concentrates on Rotary Evaporators, removes most of volatile matter, and residue is with CH ₂Cl ₂Extraction.The extract that merges is with Na ₂SO ₄Drying concentrates on Rotary Evaporators, by 200mL silica gel with by 1: 1 hexane-EtOAc graded column chromatography to the eluent of EtOAc, make the light brown oily pair-[1-(3-methyl-pyridine-2-yl)-Ding-3-thiazolinyl]-amine, 2.06g (67%). ¹H NMR δ(CDCl ₃)：1.86(s，6H)，2.54-2.31(m，4H)，2.69(br，1H)，3.70(t，2H，J＝7.5Hz)，4.97-4.85(m，4H)，5.58(m，2H)，7.00(dd，2H，J＝7.5，4.5Hz)，7.29(dd，2H，J＝5，0.9Hz)，8.47(dd，2H，J＝4.5，0.9Hz)； ¹³C NMR δ(CDCl ₃)：160.52，147.07，137.54，135.15，131.45，121.36，116.89，56.31，40.91，17.99。

Under the room temperature, two-[1-(3-methyl-pyridine-2-yl)-Ding-3-thiazolinyl]-amine (1.40g, 4.55mmol), DIPEA (0.79mL, 9.10mmol) and the CH of the DMAP of catalytic amount ₂Cl ₂(20mL) in the solution, and adding TFAA (0.77mL, 5.46mmol).Be reflected in the 15min and finish.Vacuum is removed volatile matter, residue by silica gel with flash chromatography (4: 1 hexanes: EtOAc ⁺1%NH ₄OH) purification makes 2,2 of 1.01g (55%) Off-white solid shape, 2-three fluoro-N, N-pair-[1-(3-methyl-pyridine-2-yl)-Ding-3-thiazolinyl]-acetamide. ¹HNMR(CDCl ₃)δ2.05(br s，3H)，2.20(br s，3H)，2.39(br s，1H)，2.52(br s，1H)，3.51-3.65(m，2H)，4.96-5.25(m，6H)，5.55(br s，1H)，5.84(br s，1H)，6.75(brs，2H)，6.86-6.93(m，2H)，8.15-8.21(m，2H)；ES-MS m/z 426(M ⁺Na ⁺)，404(M ⁺H ⁺)。

Under the vigorous stirring, with 2,2,2-three fluoro-N, N-pair-(1.00g, toluene 2.48mmol) (70mL) solution purifies with Ar [1-(3-methyl-pyridine-2-yl)-Ding-3-thiazolinyl]-acetamide.This catalyst of adding croup (Grubb ' scatalyst) (two (tricyclohexyl phosphine) ruthenous chlorides of benzylidene) (204mg 10mol%), is heated to 60 ℃ with reactant mixture, 4h.Course of reaction has TLC control.Add another part catalyst (160mg), reactant mixture was stirred 2 days.Vacuum is removed solvent, residue by silica gel with column chromatography (5: 1 hexanes: EtOAc) make 76.1mg (8%) product (also have small amounts of by-products), and 117.2mg contains 30%1-[2,7-pair-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene-azatropylidene-1-yl]-2,2, the original material that the by-product of 2-trifluoro ethyl ketone and 665mg reclaim. ¹H NMR(CDCl ₃)δ2.31(6H，s)，3.01-3.07(m，2H)，3.38(dd，2H，J＝16.2，4.2Hz)，5.56(s，2H)，5.98(br s，2H)，7.07(dd，2H，J＝7.5，4.2Hz)，7.40(d，2H，J＝7.5Hz)，8.35(d，2H，J＝4.2Hz)；ES-MS m/z 376(M ⁺H ⁺)。

With 1-[2,7-pair-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene-azatropylidene-1-yl]-2,2, (73mg 0.194mmol) is dissolved among MeOH (8mL) and the 6N HCl (2mL) 2-trifluoro ethyl ketone, is heated to 65 ℃, 5h.The blackening of mixture color and luster.Vacuum is removed solvent, and residue alkalizes with 10N NaOH solution.With CH ₂Cl ₂(3 * 50mL) extraction mixture.Organic extract is with MgSO ₄Drying is filtered and is concentrated.Residue obtains 30.2mg 2 through radial chromatography (1mm plate, 1: 5 EtOAc: hexane, EtOAc 10: 1 EtOAc/MeOH then then), and 7-is two-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene-1H-azatropylidene. ¹H NMR (CDCl ₃) δ 2.29-2.36 (m 3H), 2.41 (6H, s), 3.04 (dd, 2H, J=16.2,10.2Hz), 5.15 (d, 2H, J=15.6Hz), 5.81-5.90 (m, 2H), 7.04 (dd, 2H, J=7.5,4.2Hz), 7.43 (d, 2H, J=7.5Hz), 8.35 (d, 2H, J=4.2Hz).

With 2,7-pair-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene-1H-azatropylidene (30.2mg, 0.108mmol), 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (33.5mg, 0.119mmol), (～4mg) mixture is heated to 110 ℃ for DMF (3mL), DIPEA (0.3mL) and KI, 4h, and spend the night in 90 ℃.Remove solvent, in residue, add CH ₂Cl ₂(20mL).With saturated NaHCO ₃(10mL) washing.Water is with CH ₂Cl ₂Extracting twice again.Organic facies is with MgSO ₄Drying is filtered and is concentrated.Crude product through silica gel with radial chromatography (1mm plate, 2: 1 hexanes: EtOAc) purification, make the membranaceous 2-{4-[2 of 13.3mg, 7-is two-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene-azatropylidene-1-yl] butyl }-iso-indoles-1, the 3-diketone. ¹H NMR(CDCl ₃)δ0.53-0.59(m，1H)，0.65-1.00(m，3H)，2.36(s，6H)，2.36-2.41(m，1H)，2.47-2.50(m，2H)，3.02-3.24(m，5H)，4.72(dd，2H，J＝9.6，1.8Hz)，5.80-5.83(m，2H)，6.90(dd，2H，J＝7.5，4.2Hz)，7.23(d，2H，J＝7.5Hz)，7.67-7.73(m，2H)，7.76-7.86(m，2H)，8.35(d，2H，J＝4.2Hz)。

At 2-{4-[2,7-pair-(3-methyl-pyridine-2-yl)-2,3,6,7-tetrahydrochysene-azatropylidene-1-yl] butyl }-iso-indoles-1,3-diketone (13mg, 0.027mmol) EtOH (2mL) solution in add excessive n-butylamine (10 equivalent), reaction mixture refluxed stirs 17h.Vacuum is removed solvent, and residue is through radial chromatography (1mm plate, 100: 10: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) by silica gel purification, obtain 3.8mg (40%) oily compound 28. ¹HNMR(CDCl ₃)δ0.51-0.59(m，1H)，0.65-0.87(m，3H)，1.00-1.25(br，3H)，2.14(t，2H，J＝6.9Hz)，2.37-2.46(m，3H)，2.46(s，6H)，2.47-2.53(m，1H)，3.05(dt，1H，J＝13.5，8.1Hz)，4.77(d，2H，J＝9.8Hz)，5.83(s，2H)，7.02(dd，2H，J＝4.8，7.5Hz)，7.36(d，2H，J＝7.5Hz)，8.40(d，2H，J＝4.8Hz)； ¹³CNMR(CDCl ₃)δ19.0，26.5，31.3，31.5，42.1，49.4，62.5，122.1，129.7，132.2，138.3，146.3，161.9；ES-MS m/z 351(M ⁺H)。

Embodiment 29

Chemical compound 29: meso-suitable-2 ', 5 '-[4-(2,5-two-pyridine-2-base-pyrrolidine-1-yl)-butylamine] HBr salt

(4.0mL, EtOH 42.0mmol) (45mL) solution add sodium acetate (1.1388g with the Ar purge with the 2-pyridine carboxaldehyde, 8.4mmol) and 3-benzyl-5-(2-ethoxy)-4-methyl isophthalic acid, 3-thiazole chlorine (1.1323g, 4.2mmol), and when stirring reflux (80 ℃).In 30min, (2.1mL, 21.0mmol) (Tetrahedron (1996) 52,26:8707-8724) to be added dropwise to divinylsulfone in reaction.Reactant mixture stirs 18h in 80 ℃, is cooled to room temperature and concentrated then.With CH ₂Cl ₂(300mL) and water (100mL) dilution, and separate biphase.Water is with CH ₂Cl ₂(3 * 200mL) extractions, the organic extract of merging is with saturated aqueous common salt (1 * 150mL) washing, Na ₂SO ₄Drying, and concentrate.Crude product with column chromatography (4: 1 hexane-EtOAc, MeOH then) purification, makes 1.18g (23%) ecru solid, shaped 1,4-two-pyridine-2-base-butane-1,4-diketone through silica gel. ¹HNMR(CDCl ₃)δ3.70(s，4H)，7.48-7.50(m，2H)，7.83-7.84(m，2H)，8.03-8.06(m，2H)，8.71(d，2H，J＝3.0Hz)。

According to general step C: 1,4-two-pyridine-2-base-butane-1, the 4-diketone (0.2049g, 0.85mmol) and NaBH (OAc) ₃(0.4584g, CH 2.13mmol) ₂Cl ₂(10mL) in the solution, in 2h, drip (4-amine butyl)-t-butyl carbamate (0.1621g, CH 0.85mmol) ₂Cl ₂(5mL) solution, and at room temperature stir 19h.Crude product through silica gel with column chromatography (100: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification, and then through silica gel with radial chromatography (200: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the orange oily meso of 48.6mg (14%)-suitable-2 ', 5 '-[4-(2,5-two-pyridine-2-base-pyrrolidine-1-yl) butyl]-t-butyl carbamate. ¹HNMR(CDCl ₃)δ1.14-1.25(m，3H)，1.39(s，9H)，1.77(s，2H)，1.84-1.88(m，2H)，2.34-2.38(m，2H)，2.56-2.61(m，2H)，2.80(t，2H，J＝6.0Hz)，4.00-4.06(m，2H)，7.15-7.19(m，2H)，7.71-7.78(m，4H)，8.53(d，2H，J＝3.0Hz)。

According to general step B: with meso-suitable-2 ', 5 '-[4-(2,5-two-pyridine-2-base-pyrrolidine-1-yl) butyl]-t-butyl carbamate (0.0486g, 0.12mmol) be converted into its HBr salt, then with MeOH/ ether redeposition intermedium solid, make yellow solid shape chemical compound 29 (72.1mg, 94%). ¹H NMR(D ₂O)δ1.33-1.35(m，2H)，1.43-1.46(m，2H)，2.04-2.05(m，2H)，2.63-2.64(m，2H)，2.75-2.85(m，4H)，3.33(s，1H)，4.68-4.70(m，3H)，7.95(t，2H，J＝6.3Hz)，8.13(d，2H，J＝8.1Hz)，8.50-8.55(m，2H)，8.76(d，2H，J＝5.1Hz)。 ¹³CNMR(D ₂O)δ24.26，25.05，33.18，39.37，53.34，65.99，126.67，141.55，147.80，157.15.ES-MS m/z 297(M ⁺H)。Analytical calculation value C ₁₈H ₂₄N ₄3.12HBr2.88H ₂O:C, 35.99; H, 5.52; N, 9.33; Br, 41.49. measured value: C, 36.07; H, 5.64; N, 9.04; Br, 41.50.

Embodiment 30

Chemical compound 30:(2 ' R, 6 ' S)-1 '-(1H-benzimidazole-4-ylmethyl)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A, use (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.134g, 0.501mmol), 4-bromomethyl-benzimidazole-1-carboxylic acid tert-butyl ester (0.168g, 0.602mmol), DIPEA (0.129g, 1.00mmol) and KI (0.0083g, CH 0.050mmol) ₃CN (5mL) solution reacts.Through silicagel column with flash chromatography (500: 20: 1 CH ₂Cl ₂/ CH ₃OH/NH ₄OH) purification makes white solid.

With the CH of gained white solid with TFA (1mL) ₂Cl ₂(2mL) solution-treated is to remove the group of tertbutyloxycarbonyl protection.Through silicagel column with flash chromatography (20: 1: 1 CH ₂Cl ₂/ CH ₃OH/NH ₄OH) purification makes white solid (0.109g, 53% liang of step). ¹H NMR(CDCl ₃)δ1.62-1.78(m，4H)，1.92-2.20(m，8H)，3.65(s，br.2H)，3.87-3.92(m，2H)，6.05(s，br.1H)，6.51(t，1H，J＝8.1Hz)，6.85(s，br.2H)，7.07(s，br.2H)，7.29(d，1H，J＝8.1Hz)，8.13(s，1H)，8.24(s，br.2H)； ¹³C NMR(CDCl ₃)δ18.78，25.14，32.57(br.)，59.28，117.21，120.40，120.93，122.21，124.38，131.97(br.)，132.88，138.51，140.13，142.48，146.01，160.24.ES-MS m/z 398(M ⁺Na)。Analytical calculation value C ₂₅H ₂₇N ₅0.4CH ₂Cl ₂: C, 70.70; H, 6.49; N, 16.23. measured value: C, 70.79; H, 6.61; N, 15.98.

Embodiment 31

Chemical compound 31: meso-2 ', 6 '-[5-aminomethyl-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

According to general step A: in meso-2 ', 6 '-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.4647g, in DMF 1.7mmol) (17mL) solution, add 2-bromomethyl-5-cyano group-essence of Niobe (0.5035g, 2.0mmol), KI (0.0309g, 0.2mmol) and DIPEA (0.62mL, 3.6mmol).Mixture after stirring 23h under 60 ℃, is concentrated.Add saturated NaHCO ₃(50mL), and with CH ₂Cl ₂(3 * 75mL) extractions.(organic extract that 1 * 50mL) washing merges is with Na with saturated aqueous common salt ₂SO ₄Drying, and concentrate.Crude product through silica gel with column chromatography (33: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.6284g (82%) orange solids shape, 6 '-[5-cyano group-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe]. ¹HNMR(CDCl ₃)δ1.61-1.74(m，3H)，2.06-2.10(m，1H)，2.26-2.38(m，2H)，2.44(s，6H)，3.85(s，3H)，3.98(s，2H)，4.14(d，2H，J＝9.0Hz)，6.83-6.88(m，2H)，7.19(d，2H，J＝9.0Hz)，7.34-7.38(m，1H)，7.56(d，1H，J＝3.0Hz)，7.90-7.93(m，1H)，8.22(d，2H，J＝6.0Hz)。

Under the Ar, in meso-2 ', 6 '-[5-cyano group-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and essence of Niobe] (0.6284g in MeOH 1.42mmol) (14mL) solution, adds LiBH ₄(0.3505g 14.2mmol), and stirs 1h under room temperature.Concentrated reaction mixture adds CH ₂Cl ₂(50mL) with 1N NaOH (15mL), and separate phase, water is with CH ₂Cl ₂(2 * 50mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates, and makes the pulverous meso-2 ' of 0.5703g (97%) ecru, 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-3-methylol benzyl nitrile]. ¹H NMR(CDCl ₃)δ1.62-1.76(m，3H)，2.32-2.43(m，3H)，2.50(s，6H)，3.70(s，2H)，4.12(d，2H，J＝9.0Hz)，4.45(d，2H，J＝6.0Hz)，6.83-6.96(m，4H)，7.17-7.24(m，3H)，8.21(d，2H，J＝3.0Hz)。 ¹³CNMR(CDCl ₃)δ19.26，25.61，28.03，51.97，61.64，66.92，109.29，119.57，122.28，129.19，129.68，131.03，132.28，138.44，139.92，144.92，146.59。

In washed Raney nickel with MeOH, add meso-2 ', 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and 3-methylol benzyl nitrile] (0.5703g, MeOH 1.38mmol) (10mL) solution.In solution, feed NH _{3 (g)}10min places it on hydrogenator then, 40psi, 22h.The gained mixture washes with Ar, filters through plug of celite (plug of celite), with CH ₂Cl ₂Flushing also concentrates.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the white solid chemical compound 31 of 0.2823g (49%). ¹H NMR(CDCl ₃)δ1.61-1.70(m，3H)，2.00-2.01(m，1H)，2.29-2.33(m，2H)，2.48(s，6H)，3.54(s，2H)，3.61(s，2H)，4.00(d，2H，J＝12.0Hz)，4.32(s，2H)，6.59(d，1H，J＝6.0Hz)，6.73(d，1H，J＝6.0Hz)，6.80-6.84(m，3H)，7.22(d，2H，J＝6.0Hz)，8.22(d，2H，J＝3.0Hz)。 ¹³C NMR(CDCl ₃)δ19.32，25.62，29.36，46.27，52.37，62.47，67.08，122.02，125.09，127.30，129.26，131.94，137.32，138.27，139.23，140.84，146.61，159.99.ES-MS m/z 417.3(M ⁺H)。Analytical calculation value C ₂₆H ₃₂N ₄O0.3CH ₂Cl ₂0.5H ₂O:C, 70.03; H, 7.51; N, 12.42. measured value: C, 69.82; H, 7.55; N, 12.12.

Embodiment 32

Chemical compound 32: meso-2 ', 6 '-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-urea

In meso-2 ', 6 '-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group amine] (0.0869g, in 2-propanol (3mL) solution 0.27mmol), (0.15mL, 1.11mmol), mixture at room temperature stirs 18h to add the trimethyl isocyanates.Enriched mixture, crude product through silica gel with column chromatography (25: 2: 1 16: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes the chemical compound 32 of 0.0697g (64%) white solid. ¹H NMR(CDCl ₃)δ1.56-1.68(m，3H)，1.97-2.00(m，1H)，2.12-2.17(m，2H)，2.34-2.47(m，4H)，2.49(s，6H)，3.65(s，1H)，3.95(d，2H，J＝12.0Hz)，4.47(s，1H)，7.09-7.11(m，2H)，7.44(d，2H，J＝6.0Hz)，8.44(s，2H)。 ¹³C NMR(CDCl ₃)δ19.18，25.35，26.91，30.97，39.22，49.73，64.71，122.34，131.68，138.82，146.98，159.44，160.73.ES-MS m/z 368.2(M ⁺H)。Analytical calculation value C ₂₁H ₂₉N ₅O0.4CH ₂Cl ₂: C, 64.02; H, 7.48; N, 17.44. measured value: C, 63.75; H, 7.52; N, 17.16.

Embodiment 33

Chemical compound 33: meso-2 ', 6 '-N-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzyl]-acetamide

In meso-2 ', 6 '-[5-aminomethyl-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (0.1089g, CH 0.35mmol) ₃In CN (4mL) solution, add acetic anhydride (0.03mL, 0.35mmol), Et ₃N (0.07mL, 0.53mmol) and KI (0.0059g 0.04mmol), and at room temperature stirs 18h.Add saturated NaHCO ₃(10mL), with CH ₂Cl ₂(3 * 30mL) extractions, with the organic extract that merges with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with radial chromatography purification (20: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), make the white solid chemical compound 33 of 0.0709g (37%). ¹H NMR(CDCl ₃)δ1.61-1.69(m，3H)，1.96(s，3H)，2.04-2.08(m，1H)，2.30-2.38(m，2H)，2.51(s，6H)，3.65(s，2H)，4.04(d，2H，J＝11.4Hz)，4.12(d，2H，J＝5.4Hz)，4.37(s，2H)，5.45(s，1H)，6.58(d，1H，J＝7.5Hz)，6.72(d，2H，J＝7.5Hz)，6.81-6.86(m，3H)，7.23(d，2H，J＝7.8Hz)，8.21(d，2H，J＝4.5Hz)。

¹³C NMR(CDCl ₃)δ19.42，23.56，25.66，29.73，43.50，53.68，62.79，67.54，122.10，126.19，128.48，129.44，131.88，136.26，138.24，138.42，139.30，146.74，160.00，170.11.ES-MS m/z 459.3(M ⁺H)。Analytical calculation value C ₂₈H ₃₄N ₄O ₂1.1CH ₂Cl ₂: C, 63.32; H, 6.61; N, 10.15. measured value: C, 63.65; H, 6.65; N, 10.19.

Embodiment 34

Chemical compound 34: meso-2 ', 6 '-[3,5-two chloro-N-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzyl]-Pyrazinamide]

In meso-2 ', 6 '-[5-aminomethyl-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 '; 2 " ] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (0.1765g, 0.57mmol) DMF (6mL) solution in, add 3, and 5-two chloro-.gamma.-pyridinecarboxylic acid (0.1201g, 0.63mmol), EDCI (0.1309g, 0.68mmol), HOBT (0.0915g, 0.68mmol) and DIPEA (0.2mL 1.14mmol), and at room temperature stirs 16h.Concentrated reaction mixture adds saturated aqueous common salt (10mL), water (5mL) and EtOAc (30mL) and stirs 10min.Separate biphase, organic facies with saturated aqueous common salt (3 * 20mL) washing, with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the chemical compound 34 of 0.0403g (45%) white solid. ¹H NMR(CDCl ₃)δ1.60-1.64(m，3H)，2.02-2.06(m，1H)，2.29-2.33(m，4H)，2.50(s，6H)，3.62(s，2H)，4.02(d，2H，J＝10.5Hz)，4.33(s，2H)，4.38(d，2H，J＝5.7Hz)，6.02(s，1H)，6.67-6.76(m，2H)，6.80-6.84(m，2H)，6.90(s，1H)，7.23(d，2H，J＝7.5Hz)，8.19(d，2H，J＝4.2Hz)，8.50(s，2H)。 ¹³C NMR(CDCl ₃)δ18.04，24.22，28.52，42.38，52.87，61.33，66.19，120.73，124.83，127.23，127.98，128.22，130.43，133.53，137.09，138.12，141.34，145.36，146.63，158.62.ES-MS m/z 591.2(M ⁺H)。Analytical calculation value C ₃₂H ₃₃N ₅Cl ₂O ₂1.1CH ₂Cl ₂0.6H ₂O:C, 57.22; H, 5.28; N, 10.08; Cl, 21.43. measured value: C, 57.18; H, 5.21; N, 9.95; Cl, 21.36.

Embodiment 35

Chemical compound 35: meso-2 ', 6 '-N-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-6-hydroxyl-nicotiamide

In meso-2 ', 6 '-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propylamine] (0.2190g, CH 0.67mmol) ₂Cl ₂(10mL) in the solution, add the 6-hydroxy niacin (0.1406g, 1.01mmol), EDCI (0.1973g, 1.01mmol), HOBT (0.1397g, 1.01mmol) and DIPEA (0.2mL 1.01mmol), and at room temperature stirs 16h.Add saturated NaHCO ₃Solution (15mL) is with CH ₂Cl ₂(3 * 40mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (20: 1: 1 15: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes the chemical compound 35 of 0.2624g (76%) white solid. ¹H NMR(CDCl ₃)δ1.66-1.70(m，4H)，1.95-2.06(m，3H)，2.32-2.33(m，2H)，2.54(s，6H)，2.68(s，4H)，3.30-3.32(m，1H)，3.94-4.07(m，2H)，6.50(d，1H，J＝9.6Hz)，7.08-7.12(m，2H)，7.49(d，2H，J＝6.9Hz)，7.67-7.91(m，2H)，8.19-8.26(m，2H)。 ¹³C NMR(CDCl ₃)δ19.43，21.96，26.45，32.82，39.28，65.69，72.44，116.02，120.28，123.80，133.80，138.86，140.77，141.44，147.73，161.67，166.03.ES-MS m/z446.4(M ⁺H)。Analytical calculation value C ₂₆H ₃₁N ₅O ₂0.7CH ₂Cl ₂: C, 63.50; H, 6.47; N, 13.87. measured value: C, 63.64; H, 6.70; N, 14.09.

Embodiment 36

Chemical compound 36: meso-2 ', 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-but-2-ene base amine] (HBr salt)

According to general step A: with meso-2 ', 6 '-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.1456g; 0.54mmol), (4-chloro-but-2-ene base)-t-butyl carbamate (Casara; P; etc.; J.Am.Chem.Soc. (1989) 111:9111-9113) (0.1358g, 0.65mmol), KI (0.0090g, 0.05mmol), (0.2mL; 1.08mmol) and DMF (6mL) stirs 18h down in 60 ℃ to DIPEA.Crude product through silica gel with column chromatography (33: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), follow through silica gel with radial chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.0968g (41%) ecru solid, shaped, 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-yl)-but-2-ene base]-t-butyl carbamate. ¹H NMR(CDCl ₃)δ1.37(s，9H)，1.87-1.89(m，6H)，2.46(s，6H)，2.93-2.95(m，2H)，3.12-3.14(m，2H)，4.22(s，1H)，4.50-4.51(m，2H)，5.41-5.43(m，1H)，7.10-7.14(m，2H)，7.46-7.48(m，2H)，8.43-8.44(m，2H)。

According to general step B: with meso-2 ', 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-yl)-but-2-ene base]-(0.0968g 0.22mmol) is converted into its HBr salt to t-butyl carbamate, with MeOH/ ether redeposition intermedium solid, makes white solid chemical compound 36 (0.0879g, 65%) then. ¹H NMR(D ₂O)δ1.51-1.60(m，2H)，1.66-1.74(m，1H)，1.93-1.94(m，1H)，2.15(d，2H，J＝13.2Hz)，2.54(s，6H)，3.03-3.04(s，4H)，4.59(d，2H，J＝10.8Hz)，5.42-5.44(m，1H)，5.76-5.78(m，1H)，7.85-7.89(m，2H)，8.39(d，2H，J＝7.5Hz)，8.66(d，2H，J＝4.2Hz)。 ¹³C NMR(D ₂O)δ17.12，22.37，32.54，35.84，50.96，59.22，124.55，126.17，130.56，137.00，139.88，149.51，154.58.ES-MS m/z 337.4(M ⁺H)。Analytical calculation value C ₂₁H ₂₈N ₄3.0HBr2.0H ₂O:C, 41.00; H, 5.73; N, 9.11; Br, 38.96. measured value: C, 41.17; H, 5.70; N, 8.78; Br, 38.88.

Embodiment 37

Chemical compound 37: meso-2 ', 6 '-[1,4-pair-N-(3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 " methyl-benzene] terpyridyl)]

According to general step A: with meso-2 ', 6 '-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.2324g, 0.87mmol), 1,4-is two-bromomethyl-benzene (0.1148g, 0.43mmol), KI (0.0066g, 0.04mmol), DIPEA (0.22mL, 1.29mmol) and DMF (5mL), at 60 ℃ of stirring 18h down.Crude product through silica gel with column chromatography (33: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.1603g (47%) ecru solid, shaped chemical compound 37. ¹H NMR(CDCl ₃)δ1.65-1.70(m，4H)，1.95-2.03(m，6H)，2.33(s，12H)，3.42(s，4H)，3.91(s，4H)，4.98-5.00(m，2H)，6.21(s，4H)，6.97-7.01(m，4H)，7.30(d，4H，J＝7.5Hz)，8.44(d，4H，J＝2.1Hz)。 ¹³C NMR(CDCl ₃)δ19.18，25.57，29.94，51.43，64.60，122.03，128.19，132.25，136.41，138.60，146.80，160.61.ES-MS m/z 637.8(M ⁺H)。Analytical calculation value C ₄₂H ₄₈N ₆1.8CH ₂Cl ₂: C, 66.61; H, 6.59; N, 10.64. measured value: C, 66.47; H, 6.53; N, 10-73.

Embodiment 38

Chemical compound 38: meso-2 ', 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzyl]-pyridine-2-ylmethyl-amine

0 ℃, under the Ar, at N-(4-methylol-benzyl)-2-nitro-N-pyridine-2-ylmethyl-benzsulfamide that stirs (Bridger, etc., U.S. serial number 09/111,895) (0.2096g, CH 0.51mmol) ₂Cl ₂(5mL) in the solution, add Et ₃N (0.14mL, 1.02mmol) and MsCl (0.05mL, 0.66mmol).Mixture stirs 2h down at 0 ℃, at room temperature stirs 3h then.Add Et again ₃N (0.30mL, 2.16mmol) and MsCl (0.10mL 1.32mmol), and stirs 18h.Add saturated NaHCO ₃(10mL), and with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates, and obtains the methanesulfonic acid 4-{[(2-nitro-benzenesulfonyl of 0.2383g (95%) yellow oily)-pyridine-2-ylmethyl-amino]-methyl }-benzyl ester. ¹HNMR(CDCl ₃)δ3.14(s，3H)，4.51(s，2H)，4.60(s，4H)，7.02-7.24(m，6H)，7.54-7.57(m，2H)，7.66(d，2H，J＝3.0Hz)，7.94(d，1H，J＝9.0Hz)，8.41-8.43(m，1H)。

In meso-2 ', 6 '-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.0997g; 0.37mmol) and methanesulfonic acid 4-{[(2-nitro-benzenesulfonyl)-pyridine-2-ylmethyl-amino]-methyl-benzyl ester (0.2383g; in DMF 0.48mmol) (4mL) solution; add KI (0.0066g; 0.04mmol) and DIPEA (0.13mL, 0.74mmol).Mixture at room temperature stirs 66h, concentrates then.Add saturated NaHCO ₃(10mL), and with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 20mL) washings, Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.2005g (82%) ecru solid, shaped, 6 '-N-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzyl]-2-nitro-N-pyridine-2-ylmethyl-benzsulfamide. ¹H NMR(CDCl ₃)δ1.57-1.70(m，2H)，1.99-2.03(m，1H)，2.12-2.25(m，2H)，2.36(s，6H)，3.43-3.48(m，3H)，4.05(d，2H，J＝9.0Hz)，4.43(d，4H，J＝9.0Hz)，6.42(d，2H，J＝6.0Hz)，6.71(d，2H，J＝6.0Hz)，6.97-7.00(m，2H)，7.09-7.12(m，2H)，7.27-7.28(m，2H)，7.49-7.51(m，2H)，7.61-7.63(m，2H)，7.92(d，1H，J＝6.0Hz)，8.40-8.41(m，3H)。

In meso-2 ', 6 '-N-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzyl]-2-nitro-N-pyridine-2-ylmethyl-benzsulfamide (0.2005g, CH 0.30mmol) ₃In CN (3mL) solution, add K ₂CO ₃(0.2625g, 1.80mmol) and phenylmercaptan. (0.16mL, 1.51mmol).After stirring 16h under the room temperature, enriched mixture, and add CH ₂Cl ₂(50mL), with saturated aqueous common salt (3 * 30mL) washings, Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (25: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the light yellow oily chemical compound 38 of 0.0763g (49%). ¹HNMR(CDCl ₃)δ1.50-1.70(m，4H)，1.96-2.00(m，1H)，2.08-2.20(m，2H)，2.37(s，6H)，3.52(s，2H)，3.66(s，2H)，3.82(s，2H)，4.05(d，2H，J＝10.8Hz)，6.68(d，2H，J＝7.2Hz)，6.91(d，2H，J＝7.5Hz)，6.95-6.99(m，2H)，7.13-7.17(m，1H)，7.27-7.28(m，2H)，7.62-7.63(m，1H)，8.43(d，2H，J＝3.3Hz)，8.54(d，1H，J＝4.5Hz)。 ¹³C NMR(CDCl ₃)δ19.17，25.65，29.56，52.11，53.51，54.64，65.13，122.13，122.26，122.63，127.42，129.03，130.38，132.37，136.74，137.73，138.46，146.85，149.69，160.21，160.53.ES-MS m/z478.3(M ⁺H)。Analytical calculation value C ₃₁H ₃₅N ₅0.5CH ₂Cl ₂: C, 72.74; H, 6.98; N, 13.46. measured value: C, 72.56; H, 6.94; N, 13.35.

Embodiment 39

Chemical compound 39: meso-2 ', 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-phenyl]-methanol

According to general step A: in meso-2 ', 6 '-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.1339g, in DMF 0.50mmol) (5mL) solution, add a 4-bromomethyl-benzene two dimethyl esters (0.1438g, 0.50mmol), KI (0.0083g, 0.05mmol) and DIPEA (0.17mL, 1.00mmol).Mixture concentrates after stirring 16h under 60 ℃.Crude product through silica gel with column chromatography (50: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.2473g (100%) yellow solid shape meso-2 ' β, 6 ' β-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-dimethyl isophthalate]. ¹H NMR(CDCl ₃)δ1.64-1.69(m，2H)，2.31-2.41(m，2H)，2.44(s，6H)，2.75(s，2H)，3.83(s，6H)，3.99(s，2H)，4.15(d，2H，J＝12.0Hz)，6.80-6.84(m，2H)，7.14-7.17(m，2H)，7.74(s，2H)，7.92(s，1H)，8.23(d，2H，J＝3.0Hz)。

0 ℃, under the Ar, in meso-2 ', 6 '-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and dimethyl isophthalate] (0.2273g in THF 0.48mmol) (5mL) solution, adds LiAlH ₄(0.3100g, 4.80mmol).Mixture at room temperature stirs 2h, adds distilled water (0.3mL) then and then adds 15%NaOH (1mL) and distilled water (3mL), stirs 15min.Mixture through diatomite filtration with CH ₂Cl ₂Washing also concentrates.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the chemical compound 39 of 0.1282g (59%) white solid. ¹H NMR(CDCl ₃)δ1.61-1.65(m，3H)，2.01-2.02(m，1H)，2.30-2.34(m，2H)，2.49(s，6H)，3.63(s，2H)，4.02(d，2H，J＝11.1Hz)，4.33(s，2H)，4.38(s，2H)，6.65-6.68(m，1H)，6.74-6.77(m，1H)，6.80-6.85(m，2H)，6.90(s，1H)，7.22(d，2H，J＝7.5Hz)，8.20(d，2H，J＝3.9Hz)。 ¹³C NMR(CDCl ₃)δ19.44，25.67，29.69，53.70，62.82，64.86，67.61，122.15，125.24，127.71，129.23，131.93，138.00，138.45，138.90，139.44，146.72，159.97.ES-MS m/z418.5(M ⁺H)。Analytical calculation value C ₂₆H ₃₁N ₃O ₂0.4CH ₂Cl ₂: C, 70.15; H, 7.09; N, 9.29. measured value: C, 70.17; H, 7.05; N, 9.19.

Embodiment 40

Chemical compound 40: meso-2 ', 6 '-[4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine] (HBr salt)

At (3,5-dimethyl-pyridine-2-yl)-methanol (2.12g, 15.45mmol) CH of (Weidmann, K. is etc., J.Med.Chem. (1992) 35:438-450) ₂Cl ₂(50mL) in the solution, add MnO ₂(9.41g 108.18mmol), and spends the night reaction mixture refluxed.Reaction mixture then is with one deck diatomite filtration.Concentrated filtrate makes palm fibre/yellow oil.By silica gel with flash chromatography with 30%EtOAc/ hexane eluting, make yellow oily 3,5-dimethyl-pyridine-2-formaldehyde (960mg, 31% through three the step). ¹HNMR(CDCl ₃)δ2.39(s，3H)，2.62(s，3H)，7.41(s，1H)，8.47(s，1H)，10.15(s，1H)。

According to general step D: 3,5-dimethyl-pyridine-2-formaldehyde (adds NH among the 0.6551g, MeOH 4.9mmol) (24mL) ₄(0.2172g, 2.6mmol) with 1, (0.3533g 2.4mmol), and at room temperature stirs 4h to the 3-acetone dicarboxylic acid to OAc.Crude product through silica gel with column chromatography (200: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.4526g (61%) yellow solid shape, 6 '-[3,5,3 ", 5 "-tetramethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone]. ¹HNMR(CDCl ₃)δ2.27(s，6H)，2.32(s，6H)，2.46-2.55(m，2H)，2.78-2.86(m，2H)，3.24(t，1H，J＝12.0Hz)，4.40-4.47(m，2H)，7.25(s，2H)，8.28(s，2H)。

According to general step E: use meso-2 ', 6 '-[3,5,3 ", 5 "-tetramethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (0.4526g, 1.5mmol), KOH (1.64g, 29.3mmol), single hydrazine hydrate (2.84mL, 58.5mmol) and diethylene glycol (10mL).Crude product through silica gel with column chromatography (50: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the dark orange buttery meso-2 ' β of 0.3521g (79%), 6 ' β-[3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl]. ¹HNMR(CDCl ₃)δ1.55-1.63(m，2H)，1.79-1.84(m，3H)，2.09-2.13(m，1H)，2.24(s，6H)，2.33(s，6H)，4.16-4.19(m，2H)，7.20(s，2H)，8.27(s，2H)。

According to general step A: with meso-2 ', 6 '-[3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.0939g; 0.32mmol), 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (0.0913g, 0.32mmol), KI (0.0053g; 0.03mmol), DIPEA (0.11mL, 0.64mmol) and DMF (3.2mL) stir 17h down at 60 ℃.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.0951g (60%) white solid, 6 '-[2-[4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone]. ¹H NMR(CDCl ₃)δ0.92-0.94(m，2H)，1.63-1.64(m，2H)，1.94-2.04(m，2H)，2.22(s，6H)，2.23-2.26(m，2H)，2.40(s，6H)，2.49-2.58(m，2H)，2.95-3.03(m，2H)，3.20-3.25(m，2H)，3.99-4.00(m，2H)，7.13(s，2H)，7.68-7.71(m，2H)，7.77-7.82(m，2H)，8.23(s，2H)。

In meso-2 ', 6 '-[2-[4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ' 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.0951g, among EtOH 0.19mmol) (2mL), (0.1mL 1.90mmol), and at room temperature stirs 17h to add single hydrazine hydrate.Concentrated reaction mixture, crude product through silica gel with column chromatography (25: 1: 1 12: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.0474g (68%) colorless oil, 6 '-[4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine]. ¹H NMR(CDCl ₃)δ0.76-0.91(m，2H)，1.58-1.62(m，4H)，1.91-2.04(m，3H)，2.18-2.23(m，4H)，2.26(s，6H)，2.45(s，6H)，2.58-2.59(m，1H)，3.98(d，2H，J＝12.0Hz)，7.22(s，2H)，8.26(s，2H)。

According to general step B: with meso-2 ', 6 '-[4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine] be converted into its HBr salt, with MeOH/ ether redeposition intermedium solid, make white solid chemical compound 40 (0.0621g, 68%) then. ¹H NMR(D ₂O)δ1.14-1.15(m，2H)，1.28-1.29(m，2H)，1.39-1.50(m，2H)，1.59-1.67(m，1H)，1.87-1.91(m，1H)，2.03-2.10(m，2H)，2.17-2.20(m，2H)，2.45(s，6H)，2.51(s，6H)，2.69-2.70(m，2H)，4.51(d，2H，J＝10.2Hz)，8.22(s，2H)，8.46(s，2H)。 ¹³CNMR(D ₂O)δ16.92，17.53，19.99，22.41，25.16，32.63，39.31，52.07，57.49，135.99，137.37，139.18，150.04，151.71.EMS m/z 367.4(M ⁺H)。Analytical calculation value C ₂₃H ₃₄N ₄3.3HBr2.1CH ₄O:C, 43.02; H, 6.57; N, 7.99; Br, 37.62. measured value: C, 42.96; H, 6.44; N, 8.23; Br, 37.49.

Embodiment 41

Chemical compound 41: meso-2 ', 6 '-[5-aminomethyl-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

According to general step D: 3, (0.6551g in MeOH 4.9mmol) (24mL) solution, adds NH to 5-dimethyl-pyridine-2-formaldehyde ₄(0.2172g, 2.6mmol) with 1, (0.3533g 2.4mmol), and at room temperature stirs 4h to the 3-acetone dicarboxylic acid to OAc.Crude product through silica gel with column chromatography (200: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' of 0.4526g (61%) yellow solid shape, 6 '-[3,5,3 ", 5 "-tetramethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone]. ¹H NMR(CDCl ₃)δ2.27(s，6H)，2.32(s，6H)，2.46-2.55(m，2H)，2.78-2.86(m，2H)，3.24(t，1H，J＝12.0Hz)，4.40-4.47(m，2H)，7.25(s，2H)，8.28(s，2H)。

According to general step E: use meso-2 ', 6 '-[3,5,3 ", 5 "-tetramethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (0.4526g, 1.5mmol), KOH (1.64g, 29.3mmol), single hydrazine hydrate (2.84mL, 58.5mmol) and diethylene glycol (10mL).Crude product through silica gel with column chromatography (50: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the dark orange oily meso-2 ' β of 0.3521g (79%), 6 ' β-[3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl]. ¹HNMR(CDCl ₃)δ1.55-1.63(m，2H)，1.79-1.84(m，3H)，2.09-2.13(m，1H)，2.24(s，6H)，2.33(s，6H)，4.16-4.19(m，2H)，7.20(s，2H)，8.27(s，2H)。

According to general step A: with meso-2 ', 6 '-[3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ' 2 "] terpyridyl] (0.1903g; 0.64mmol), 2-bromomethyl-5-cyano group-essence of Niobe (0.1630g; 0.64mmol), KI (0.0100g, 0.06mmol), DIPEA (0.22mL, 1.29mmol) and DMF (6.4mL) stir down 17h at 60 ℃.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the brown oily meso-2 ' of 0.2682g (89%), 6 '-[5-cyano group-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe]. ¹H NMR(CDCl ₃)δ1.63-1.67(m，3H)，2.00-2.05(m，1H)，2.12(s，6H)，2.21-2.31(m，2H)，2.36(s，6H)，3.84(s，3H)，3.90-3.94(m，2H)，4.05-4.08(m，2H)，6.96(s，2H)，7.37(d，1H，J＝9.0Hz)，7.56(d，1H，J＝3.0Hz)，7.90(s，1H)，8.02(s，2H)。

Under 0 ℃, Ar, in meso-2 ', 6 '-[5-cyano group-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-suitable-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and essence of Niobe] (0.2682g in THF 0.57mmol) (6mL) solution, drips 1.0M LiAlH ₄THF solution (5.7mL, 5.72mmol).Mixture at room temperature stirs 2h, adds distilled water (0.3mL) then, then adds 15%NaOH (1mL) and distilled water (3mL), stirs 15min.Mixture through diatomite filtration with CH ₂Cl ₂Washing, and concentrate.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the chemical compound 41 of 0.1435g (54%) white solid. ¹H NMR(CDCl ₃)δ1.58-1.62(m，4H)，2.01-2.07(m，2H)，2.10(s，6H)，2.31-2.35(m，2H)，2.45(s，6H)，3.58(d，4H，J＝10.8Hz)，4.36(s，2H)，6.57-6.67(m，2H)，6.85(s，1H)，7.02(s，2H)，8.01(s，2H)。 ¹³C NMR(CDCl ₃)δ18.08，19.26，25.84，29.08，46.30，52.52，62.98，67.18，125.22，125.72，127.84，129.13，131.23，131.41，138.04，138.94，140.91，146.94，157.02.ES-MS m/z 445.5(M ⁺H)。Analytical calculation value C ₂₈H ₃₆N ₄O0.2CH ₂Cl ₂0.3H ₂O:C, 72.53; H, 7.99; N, 12.00. measured value: C, 72.91; H, 8.07; N, 11.91.

Embodiment 42

Chemical compound 42: meso-2 ' β, 4 ' α, 6 ' β-[1 '-(the amino butyl of 4-)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 '-phenol]

Under the Ar, in meso-2 ', 6 '-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (0.1666g in MeOH 0.59mmol) (6mL) solution, adds NaBH ₄(0.0552g 1.48mmol), and at room temperature stirs 1h.Enriched mixture then, and add saturated NaHCO ₃(10mL), with CH ₂Cl ₂(3 * 40mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.1462g (82%) yellow solid shape meso-2 ' β, 4 ' β, and 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol]. ¹H NMR(CDCl ₃)δ1.43-1.55(m，2H)，1.81-1.97(m，2H)，2.14-2.18(m，2H)，2.36(s，6H)，3.97-4.07(m，1H)，4.19-4.20(m，2H)，7.00-7.07(m，2H)，7.38-7.42(m，2H)，8.44(d，2H)，J＝6.0Hz)。

According to general step A: at meso-2 ' β, 4 ' α, 6 ' β '-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] (0.1462g in DMF 0.49mmol) (5mL) solution, adds 2-(4-brombutyl)-iso-indoles-1; the 3-diketone (0.1466g; 0.49mmol), KI (0.0081g, 0.05mmol) and DIPEA (0.17mL, 0.97mmol).Mixture concentrates then in 60 ℃ of stirring 17h.Crude product through silica gel with column chromatography (33: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' β of 0.1144g (47%) ecru solid, shaped, 4 ' β, and 6 ' β-[2-[4-(4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone]. ¹H NMR(CDCl ₃)δ0.78-0.83(m，2H)，1.50-1.58(m，1H)，1.98-2.04(m，2H)，2.14-2.23(m，4H)，2.30-2.46(m，2H)，2.46(s，6H)，3.11-3.15(m，2H)，3.92(s，1H)，4.08-4.18(m，2H)，6.92-6.96(m，2H)，7.23-7.25(m，2H)，7.73-7.80(m，4H)，8.38(d，2H，J＝3.0Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[2-[4-(4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.1144g, in EtOH 0.23mmol) (3mL) solution, (0.11mL 2.28mmol), at room temperature stirs 18h to add single hydrazine hydrate.Concentrated reaction mixture, crude product through silica gel with column chromatography (13: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.0537g (62%) white solid chemical compound 42. ¹H NMR(CDCl ₃)δ0.52-0.55(m，1H)，0.72(t，2H，J＝6.9Hz)，2.02-2.24(m，10H)，2.48(s，6H)，2.65(s，2H)，3.84-3.89(m，1H)，4.13(d，2H，J＝9.9Hz)，7.06-7.10(m，2H)，7.44(d，2H，J＝7.5Hz)，8.42(d，2H，J＝3.0Hz)。 ¹³C NMR(CDCl ₃)δ19.06，23.81，30.78，38.81，41.42，47.56，62.01，69.75，122.46，132.04，138.76，146.92，159.38.ES-MS m/z355.4(M ⁺H)。Analytical calculation value C ₂₁H ₃₀N ₄O0.1CH ₂Cl ₂0.5CH ₄O:C, 68.45; H, 8.56; N, 14.78. measured value: C, 68.11; H, 8.48; N, 14.61.

Embodiment 43

Chemical compound 43: meso-2 ', 6 '-[4-(3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine]

According to general step D: (0.6151g adds NH in MeOH 4.35mmol) (22mL) solution at 3-chloro-pyridine-2-formaldehyde ₄(0.1841g, 2.39mmol) with 1, (0.3211g 2.17mmol), and at room temperature stirs 2.5h to the 3-acetone dicarboxylic acid to OAc.Crude product through silica gel with column chromatography (3: 2 purification of 1: 1 hexane-EtOAc) then make the meso-2 ' of 0.2018g (29%) white solid, 6 '-[3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone]. ¹H NMR(CDCl ₃)δ2.55-2.63(m，2H)，2.70-2.76(m，2H)，3.42-3.43(m，1H)，4.84(t，2H，J＝9.0Hz)，7.16-7.20(m，2H)，7.66-7.69(m，2H)，8.54-8.56(m，2H)。

According to general step E: use meso-2 ', 6 '-[3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-1 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone] (0.3667g, 1.14mmol), KOH (1.2943g; 22.76mmol), (2.21mL 45.52mmol) and diethylene glycol (6mL), makes the meso-2 ' of 0.4004g (100%) yellow oily; 6 '-[3; 3 to single hydrazine hydrate "-two chloro-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl]. ¹H NMR(CDCl3)δ1.70(s，2H)，1.89-1.98(m，4H)，3.12-3.21(m，1H)，3.61-3.66(m，1H)，3.75-3.78(m，1H)，4.50-4.53(m，2H)，7.09-7.14(m，2H)，7.62-7.68(m，2H)，8.52-8.54(m，2H)。

According to general step A: with meso-2 ', 6 '-[3,3 "-two chloro-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl] (0.4004g, 1.3mmol), 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (0.4815g, 1.7mmol), KI (0.0216g, 0.1mmol), DIPEA (0.45mL, 2.6mmol) and DMF (13mL) stir 22h at 60 ℃.Crude product through silica gel with column chromatography (100: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the orange buttery meso-2 ' of 0.4142g (63%), 6 '-[2-[4-(3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone]. ¹H NMR(CDCl ₃)δ1.06-1.08(m，4H)，1.56-1.62(m，2H)，1.89-2.03(m，3H)，2.12-2.17(m，2H)，3.32-3.36(m，2H)，4.37(d，2H，J＝9.0Hz)，7.06-7.10(m，2H)，7.55-7.58(m，2H)，7.68-7.70(m，2H)，7.77-7.78(m，2H)，8.52-8.54(m，2H)。

In meso-2 ', 6 '-[2-[4-(3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.4142g, among EtOH 0.81mmol) (8mL), (0.4mL 8.13mmol), and at room temperature stirs 16h to add single hydrazine hydrate.Concentrated reaction mixture, crude product through silica gel with column chromatography (100: 1: 1,50: 1: 1 then, 20: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.1399g (44%) white solid chemical compound 43. ¹H NMR(CDCl ₃)δ0.78-0.88(m，2H)，1.05-1.15(m，2H)，1.53-1.62(m，1H)，1.72(d，2H，J＝11.4Hz)，1.92-1.99(m，3H)，2.14(t，2H，J＝8.1Hz)，2.30(t，2H，J＝6.9Hz)，4.39(d，2H，J＝10.5Hz)，7.09-7.13(m，2H)，7.64(d，2H，J＝8.1Hz)，8.57(d，2H，J＝3.6Hz。 ¹³CNMR(CDCl ₃)δ20.83，24.83，31.46，31.78，41.69，50.27，61.97，122.82，130.62，137.29，147.80，159.07.EMS m/z 379.3(M ⁺H)。Analytical calculation value C ₁₉H ₂₄N ₄Cl ₂0.7H ₂O:C, 58.23; H, 6.53; N, 14.29; Cl, 18.09. measured value: C, 58.30; H, 6.33; N, 14.07; Cl, 18.23.

Embodiment 44

Chemical compound 44: meso-2 ' β, 4 ' α, 6 ' β-[1 '-(the amino butyl of 4-)-3,4 ', 3 "-trimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 '-phenol] and meso-2 ' β, 4 ' β, 6 ' β-[1 '-(the amino butyl of 4-)-3,4 ', 3 "-trimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 '-phenol] 1: 1 mixture

In meso-2 ', 6 '-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (2.0601g adds Et in THF 7.32mmol) (50mL) solution ₃N (2.04mL, 14.64mmol) and Boc ₂O (1.6083g, THF 7.32mmol) (20mL) solution.Mixture stirs 18h down at 70 ℃, concentrates then.Add saturated NaHCO ₃(30mL), and with CH ₂Cl ₂(2 * 50mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 30mL) washings, Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (purification of 1: 1 hexane-EtOAc) makes the orange meso-2 ' of 1.9598g (70%), 6 '-[3,3 "-dimethyl-4 '-oxo-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tert-butyl ester]. ¹HNMR(CDCl ₃)δ1.27(s，9H)，2.37(s，6H)，2.50-2.58(m，2H)，3.16-3.24(m，2H)，5.78(t，2H，J＝6.0Hz)，6.93-6.98(m，2H)，7.35(d，2H，J＝9.0Hz)，8.07(d，2H，J＝6.0Hz)。

Under 0 ℃, Ar, in meso-2 ', 6 '-[3,3 "-dimethyl-4 '-oxo-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester] (1.1179g in THF 2.9mmol) (30mL) solution, is added dropwise to the Et of 3.0M MeMgBr ₂O solution (4.88mL, 14.7mmol).Mixture stirs 20h down at 70 ℃, is cooled to 0 ℃ then, and slowly adds distilled water (30mL), stirs 15min.Then, concentrate with removal THF, and with EtOAc (3 * 100mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), then with another post (purification of 1: 1 hexane-EtOAc) makes the meso-2 ' β of 0.1256g (11%) colorless oil, 6 ' β-[4 ' *-hydroxyl-3,4 ', 3 "-trimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tert-butyl ester] and the meso-2 ' β of 0.1606g (19%) ecru solid, shaped, 6 ' β-[3,4 ', 3 "-trimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 ' *-phenol.Be respectively: ¹H NMR (CDCl ₃) δ 1.19 (s, 9H), 1.22-1.40 (m, 2H), 1.47 (s, 3H), 1.86-1.92 (m, 2H), 2.35-2.38 (m, 2H), 2.42 (s, 6H), 5.37-5.39 (m, 2H), 6.97-7.01 (m, 2H), 7.38 (d, 2H, J=6.0Hz), 8.13 (d, 2H, J=3.0Hz) and ¹H NMR (CDCl ₃) δ 1.51 (s, 3H), 1.56-1.64 (m, 2H), 1.82-1.94 (m, 3H), 2.36 (s, 6H), 3.09-3.11 (m, 1H), 4.15-4.21 (m, 2H), 7.00-7.06 (m, 2H), 7.40 (d, 2H, J=6.0Hz), 8.45 (d, 2H, J=3.0Hz).

At meso-2 ' β, 6 ' β-[3,4 ', 3 "-trimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 ' ^*-phenol (0.2499g in DMF 0.84mmol) (9mL) solution, adds 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (0.2605g, 0.92mmol), KI (0.0142g, 0.08mmol) and DIPEA (0.29mL, 1.68mmol), and at 60 ℃ of stirring 24h.Enriched mixture adds saturated NaHCO ₃(30mL), and with CH ₂Cl ₂(3 * 35mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 20mL) washings, Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' β of 0.3144g (75%) white solid, 6 ' β-[2-[4-(4 ' *-hydroxyl-3,4 ', 3 "-trimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 " butyl] terpyridyl-1 ' base)]-iso-indoles-1, the 3-diketone. ¹HNMR(CDCl ₃)δ0.48(s，1H)，0.86(s，2H)，1.42(s，3H)，1.68-1.72(m，2H)，2.18-2.38(m，6H)，2.45(s，6H)，3.15(t，2H，J＝6.0Hz)，4.13(d，2H，J＝12.0Hz)，6.94-7.03(m，2H)，7.25-7.34(m，2H)，7.67-7.70(m，2H)，7.75-7.78(m，2H)，8.32-8.34(m，2H)。

At meso-2 ' β, 6 ' β-[2-[4-(4 ' *-hydroxyl-3,4 ', 3 "-trimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.3144g, in EtOH 0.63mmol) (6mL) solution, (0.31mL 6.31mmol), and stirs 19h, concentrates then to add single hydrazine hydrate.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the chemical compound 44 of 0.1324g (52%) white solid. ¹H NMR(CDCl ₃)δ0.72-0.76(m，4H)，1.42(s，3H)，1.42(d，2H，J＝12.0Hz)，2.19-2.73(m，6H)，2.45(s，6H)，2.46-4.48(m，1H)，4.12(d，2H，J＝11.4Hz)，7.03-7.07(m，2H)，7.41(d，2H，J＝7.2Hz)，8.37-8.38(m，2H)。 ¹³C NMR(CDCl ₃)δ18.98，22.71，25.31，31.15，41.47，44.21，48.20，61.01，69.41，122.29，131.23，138.75，146.95，159.68.ES-MS m/z 369.4(M ⁺H)。Analytical calculation value C ₂₂H ₃₂N ₄O0.2CH ₂Cl ₂0.7CH ₄O:C, 67.43; H, 8.70; N, 13.73. measured value: C, 67.25; H, 8.57; N, 13.66.

Embodiment 45

Chemical compound 45:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-N-hydroxyl-3-methylol-Benzoylamide

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (1.6g, 6.0mmol) with 2-bromomethyl-5-cyano group-essence of Niobe (1.5g, 6.0mmol) reaction, make light yellow solid shape 5-cyano group-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (2.05g, 78%).

(2.05g in MeOH 4.6mmol) (50mL) solution, divides three parts to add LiBH to step gained ester on stirring at room ₄(1.0g, 50mmol).Observe effervescence, and mixture is stirred 3.5h.Enriched mixture also adds 1N NaOH (50mL) in residue.Aqueous mixture is with CH ₂Cl ₂(3 * 50mL) extractions.Merge organic extract, with Na ₂SO ₄Drying, and concentrate.(40g is with 5%NH with column chromatography through silica gel for crude product ₄OH/5%MeOH/CH ₂Cl ₂Eluting) purification, make light yellow solid shape 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (1.63g, 86%).

Nitrile (1.13g, 2.7mmol) the 50%H of backflow with gained of last step ₂SO ₄Stir 16h (50mL).Solution is cooled to room temperature and concentrates, to remove water.Residue is dissolved in MeOH (50mL) and concentrates three times.In the residue of gained, add MeOH, with the solution 2h that refluxes.Concentrated solution is to remove MeOH.Residue alkalizes with 10NNaOH (whole pH=10), and with CH ₂Cl ₂(3 * 100mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying, and concentrate.(30g is with 5%NH through silica gel column chromatography for crude product ₄OH/5%MeOH/CH ₂Cl ₂Eluting) purification, make two kinds of product: 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-essence of Niobe (700mg, 58%), and 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methoxyl methyl-essence of Niobe (210mg, 17%).

(320mg adds NH in anhydrous MeOH (15mL) solution 14mmol) at the sodium that stirs ₂OHH ₂O (550mg, 7.9mmol), add then 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-essence of Niobe (700mg, anhydrous MeOH (7mL) solution 1.6mmol).Mixture stirs 2h, by stopping of TLC Indicator Reaction.With sodium (320mg, 14mmol) and NH ₂OHH ₂(550mg, anhydrous MeOH (8mL) solution 7.9mmol) adds in the reactant mixture O, and continuous stirring 2h.Reactant mixture is with CHCl ₃(100mL) dilution, and pour saturated NaHCO into ₃In the solution (100mL).Water is with CHCl ₃(5 * 100mL) extractions.The organic moiety that concentrates merging is to 100mL, with saturated NaHCO ₃Solution (20mL) washs once, with Na ₂SO ₄Drying concentrates, and is dry under the fine vacuum, makes beige solid shape chemical compound 45 (647mg, 92%). ¹H NMR(DMSO-d ₆)δ1.46(d，2H，J＝12.0Hz)，1.69-1.84(m，1H)，2.01-2.11(m，1H)，2.48(s，6H)，3.59(s，2H)，4.13(d，2H，J＝3.8Hz)，4.40(d，2H，J＝10.8Hz)，4.79-4.85(m，1H)，5.74(s，1H)，6.84-6.91(m，3H)，7.06(d，1H，J＝7.5Hz)，7.18-7.28(m，3H)，8.14(d，2H，J＝3.3Hz)，8.75(s br，1H)，10.82(s br，1H)； ¹³C NMR(D ₂O)δ18.38(2)，24.40，25.32(2)，55.27，60.85(2)，64.75，122.31(2)，123.64，124.88，126.82，132.62，137.64(2)，138.08，143.18，145.86(2)，158.58，164.49；ES-MS m/z 447(M ⁺H)。Analytical calculation value C ₂₆H ₃₀N ₄O ₃1.1H ₂O:C, 66.96; H, 6.96; N, 12.01. measured value: C, 66.95; H, 6.71; N, 11.66.

Embodiment 46

Chemical compound 46:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-N-hydroxyl-3-methoxyl methyl-Benzoylamide

(100mg in anhydrous MeOH (4mL) solution 4.2mmol), adds NH at the sodium that stirs ₂OHH ₂O (260mg, 3.7mmol), add then 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methoxyl methyl-essence of Niobe (170mg, anhydrous MeOH (4mL) solution 0.37mmol).Mixture stirs 16h, with CHCl ₃(50mL) dilute and pour saturated NaHCO into ₃In the solution (50mL).Water is with CHCl ₃(5 * 25mL) extractions.The organic moiety that merges is with Na ₂SO ₄Dry and concentrated.(10g is with 5%NH through silicagel column for the gained crude product ₄OH/10%MeOH/CH ₂Cl ₂Eluting) purification, and dry under fine vacuum, make white solid chemical compound 46 (60mg, 35%). ¹H NMR(CDCl ₃)δ1.57-1.71(m，2H)，1.80-2.14(m，2H)，2.31-2.40(m，2H)，2.44(s，6H)，3.25(s，3H)，3.61(s，2H)，4.12(s，4H)，6.61-6.71(m，1H)，6.74-6.84(m，2H)，6.88-6.97(m，1H)，7.20(s，3H)，8.22(s，2H)，9.85(s br，1H)；ES-MS m/z461(M ⁺H)。

Embodiment 47

Chemical compound 47:6-((2 ' S, 6 ' R)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-2,2 '; 6 ', 2 " terpyridyl-1 '-ylmethyl)-1.2-benzoisoxazole-3-base amine (HBr salt)

N ₂Down, 1-bromo-2-fluoro-4-methyl-benzene (2.59g, 13.7mmol) and Zn (CN) ₂(1.60g, in dry DMF (50mL) suspension 13.7mmol), add 1,1 '-two (diphenylphosphino) ferrocene (DPPF) (0.0753g, 0.136mmol) and Pd ₂(dba) ₃(dba=two (benzylidene) acetone) (0.0623g, 0.0681mmol).Then, with mixture heated to 130 ℃, 2 days, solvent was removed in vacuum evaporation, and adds saturated NaHCO ₃Aqueous solution (40mL).With CH ₂Cl ₂(3 * 40mL) extraction aqueous suspensions, extract is with Na ₂SO ₄Dry.After the filtration, except that desolvating, the remaining solid thing through flash chromatography (1: 20 EtOAc/ hexane) purification, makes the 2-fluoro-4-methyl-benzonitrile (1.21g, 65%) of light yellow solid shape by silica gel through vacuum evaporation. ¹H NMR(CDCl ₃)δ2.43(s，3H)，7.01-7.07(m，2H)，7.48-7.52(m，1H)。

At 2-fluoro-4-methyl-benzonitrile (1.45g, CCl 10.7mmol) ₄(100mL) add 1 in the solution, 1 '-azo two (cyclohexane extraction formonitrile HCNs) (0.240g, 0.982mmol) and NBS (2.19g, 12.3mmol).Stir the mixture, and reflux and spend the night, be cooled to room temperature then.Add Na ₂S ₂O ₃Water (5g) (100mL) solution, and collect organic facies.With CH ₂Cl ₂(3 * 50mL) aqueous phase extracted merge extract and with Na ₂SO ₄Dry.After the filtration, except that desolvating, residue makes the 4-bromomethyl-2-fluoro-benzonitrile (1.49g, 65%) of light yellow oily through silicagel column (1: 10 EtOAc/ hexane) purification through vacuum evaporation. ¹H NMR(CDCl ₃)δ4.45(s，2H)，7.24-7.30(m，2H)，7.60(dd，1H，J＝6.3，8.1Hz)。

Will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.267g, 1.00mmol), 4-bromomethyl-2-fluoro-benzonitrile (0.321g, 1.50mmol), DIPEA (0.259g, 2.00mmol) and KI (0.017g, 0.10mmol) the dry CH of mixture ₃CN (10mL) solution stirs 16h in 60 ℃.Remove CH with vacuum evaporation behind the 16h ₃CN, and add saturated NaHCO ₃Aqueous solution (20mL).With CH ₂Cl ₂(3 * 30mL) extraction aqueous mixtures, extract is with Na ₂SO ₄Dry.After the filtration, remove through vacuum evaporation and to desolvate, residue through silicagel column (1000: 30: 1, CH ₂Cl ₂/ CH ₃OH/NH ₄OH) purification, make white foam shape 4-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-2-fluoro-benzonitrile (0.400g, 100%). ¹H NMR(CDCl ₃)δ1.65-1.80(m，3H)，2.09-2.14(m，1H)，2.20-2.38(m，2H)，2.44(s，6H)，3.58(s，2H)，4.16(s，1H)，4.20(s，1H)，6.37-6.43(m，2H)，6.93-7.03(m，3H)，7.23(d，2H，J＝7.5Hz)，8.35(dd，2H，J＝0.9，4.5Hz)。

(0.140g, (0.0877g 1.20mmol), and stirs 30min with mixture to add acetone oxime in dry DMF (5mL) solution 1.25mmol) at potassium tert-butoxide.Add then 4-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.400g, dry DMF (5mL) solution 1.00mmol) spend the night the mixture stirring to 2-fluoro-benzonitrile.Remove solvent with vacuum evaporation then, and add saturated NaHCO ₃Aqueous solution (10mL).(3 * 30mL) extractions, extract is with Na with EtOAc for mixture ₂SO ₄Dry.After the filtration, except that desolvating, residue is through silicagel column (1000: 25: 1 CH through vacuum evaporation ₂Cl ₂/ CH ₃OH/NH ₄OH) purification, make the light yellow solid shape 4-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-2-isopropylidene aminooxy group-benzonitrile (0.311g, 69%). ¹H NMR(CDCl ₃)δ1.65-1.75(m，3H)，2.06(s，3H)，2.07(s，3H)，2.09-2.14(m，1H)，2.20-2.40(m，2H)，2.45(s，6H)，3.58(s，2H)，4.19(s，1H)，4.23(s，1H)，6.14(d，1H，J＝7.8Hz)，6.68(s，1H)，6.91-6.96(m，3H)，7.22(d，2H，J＝7.2Hz)，8.35(d，2H，J＝3.9Hz)。

4-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-2-isopropylidene aminooxy group-benzonitrile (0.145g, add in EtOH 0.320mmol) (4mL) solution HCl aqueous solution (3N, 4mL), and with mixture under agitation reflux spend the night.Then mixture is cooled to room temperature, removes EtOH, and add saturated NaHCO ₃Aqueous solution (20mL).With CH ₂Cl ₂(4 * 40mL) extraction aqueous mixtures, the extract of merging is with Na ₂SO ₄Dry.After the filtration, except that desolvating, residue is through silicagel column (100: 5: 2 CH through vacuum evaporation ₂Cl ₂/ CH ₃OH/NH ₄OH) purification, make white solid 6-((2 ' S, 6 ' R)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-2,2 '; 6 ', 2 " terpyridyl-1 '-ylmethyl)-1,2-benzoisoxazole-3-base amine (0.082g, 62%).

According to general step B, (0.060g 0.15mmol), makes the HBr salt (0.099g, 96%) of yellow solid shape to handle this white solid with HBr/MeOH. ¹H NMR(CD ₃OD)δ1.83-1.94(m，3H)，2.03-2.16(m，3H)，2.63(s，6H)，3.77(s，2H)，4.57-4.60(m，2H)，6.99(d，1H，J＝8.1Hz)，7.03(s，1H)，7.43(d，1H，J＝8.1Hz)，7.76(dd，2H，J＝5.7，7.8Hz)，8.29(d，2H，J＝7.8Hz)，8.69(d，2H，J＝5.7Hz)。 ¹³C NMR(CD ₃OD/D ₂O)δ16.98，22.07，38.37，61.33，61.83，110.25，114.90，122.14，124.69，125.39，136.38，138.93，139.65，148.66，154.78，157.50，161.07.ES-MS m/z414(M ⁺H)。Analytical calculation value C ₂₅H ₂₇N ₅O3.4HBr1.1H ₂O:C, 42.39; H, 4.64; N, 9.89; Br, 38.35. measured value: C, 42.22; H, 4.55; N, 9.60; Br, 38.54.

Embodiment 48

Chemical compound 48: meso-2 ' β, 4 ' α, 6 ' β-[1 '-(the amino butyl of 4-)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 '-phenol]

Under-78 ℃, Ar, at meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (3.5417g; in THF 12.6mmol) (90mL) solution; (13.8mL 13.8mmol), and stirs 30min (Tetrahedron:Asymmetry (1999) 10:2225-2235) slowly to add 3-sec-butyl lithium borohydride (L-selectride).Add MeOH (35mL), and at room temperature add distilled water (70mL), with CH ₂Cl ₂(3 * 150mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates and obtain the heavy-gravity orange oily meso-2 ' β of 5.37g (100%), 4 ' β, and 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] and meso-2 ' β, 4 ' α, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] 1: 1 mixture. ¹H NMR(CDCl ₃)δ1.43-1.55(m，2H)，1.81-1.97(m，2H)，2.14-2.18(m，2H)，2.36(s，6H)，3.97-4.07(m，1H)，4.19-4.20(m，2H)，7.00-7.07(m，2H)，7.38-7.42(m，2H)，8.44-8.45(m，2H)。

At meso-2 ' β, 4 ' β, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] and meso-2 ' β, 4 ' α, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] in THF (90mL) solution of 1: 1 mixture, add DIPEA (4.36mL, 25.2mmol) and Boc ₂(3.3407g 15.1mmol), and stirs 16h to O under 50 ℃.Enriched mixture adds saturated NaHCO ₃(75mL), and with CH ₂Cl ₂(3 * 100mL) extractions.With saturated aqueous common salt (organic extract that 2 * 75mL) washings merge, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (purification of 1: 1 hexane-EtOAc) makes the meso-2 ' β of 1.2984g (27%) yellow solid shape, 4 ' β, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] meso-2 ' β of terpyridyl-1 '-carboxylic acid tert-butyl ester and 0.8605g (18%) light yellow solid shape, 4 ' α, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl]-1 '-carboxylic acid tert-butyl ester.Be respectively: ¹H NMR (CDCl ₃) δ 1.17 (s, 9H), 2.19 (t, 4H, J=6.6Hz), 2.40 (s, 6H), 4.17-4.20 (m, 1H), 5.38 (t, 2H, J=6.3Hz), 6.05 (d, 1H, J=10.2Hz), 6.94-6.98 (m, 2H), 7.34-7.36 (m, 2H), 8.11 (d, 2H, J=3.9Hz) and ¹H NMR (CDCl ₃) δ 1.50 (s, 9H), 1.67-1.76 (m, 2H), 2.21 (s, 6H), 2.69-2.76 (m, 2H), 5.62-5.67 (m, 1H), 5.80-5.83 (m, 2H), 6.68-6.72 (m, 2H), 6.97-7.05 (m, 2H), 7.99 (d, 2H, J=3Hz).

At meso-2 ' β, 4 ' α, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl]-1 '-carboxylic acid tert-butyl ester (0.2508g, CH 0.66mmol) ₂Cl ₂(5mL) in the solution, add TFA (5mL), and at room temperature stir 3.5h.Enriched mixture adds distilled water (2mL) and 10NNaOH (2mL), and with CH ₂Cl ₂(3 * 50mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Make 0.2182g (100%) ecru solid, shaped meso-2 ' β, 4 ' α, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol]. ¹H NMR(CDCl ₃)δ1.82-1.97(m，4H)，2.39(s，6H)，4.46-4.48(m，1H)，4.90-4.93(m，2H)，7.04-7.08(m，2H)，7.40-7.43(m，2H)，8.44(d，2H，J＝3.0Hz)。

According to general step A: at meso-2 ' β, 4 ' α, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] (0.2182g in DMF 0.77mmol) (5mL) solution, adds 2-(4-brombutyl)-iso-indoles-1; the 3-diketone (0.2389g; 0.85mmol), KI (0.0128g, 0.08mmol) and DIPEA (0.27mL, 1.54mmol).Mixture is stirred 21h down at 60 ℃, concentrate then.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.2356g (61%) meso-2 ' β, 4 ' α, 6 ' β-2-[4-(4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone. ¹H NMR(CDCl ₃)δ0.46-0.47(m，2H)，0.85-0.89(m，2H)，1.72(d，2H，J＝12.0Hz)，2.34-2.40(m，2H)，2.48(s，6H)，2.49-2.50(m，2H)，3.16(t，2H，J＝6.0Hz)，4.44-4.45(m，1H)，4.71(d，2H，J＝6.0Hz)，6.94-6.98(m，2H)，7.27-7.29(m，2H)，7.69-7.72(m，2H)，7.78-7.81(m，2H)，8.38(d，2H，J＝6.0Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-2-[4-(4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, (0.2356g, (0.23mL 4.70mmol), and at room temperature stirs 17h to the 3-diketone to add single hydrazine hydrate in EtOH 0.47mmol) (5mL) solution.Concentrated reaction mixture, crude product through silica gel with column chromatography (15: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.1297g (72%) white solid chemical compound 48. ¹H NMR(CDCl ₃)δ0.40-0.42(m，2H)，0.66-0.71(m，2H)，1.72(d，2H，J＝15.0Hz)，2.13-2.14(m，2H)，2.27-2.32(m，2H)，2.49-2.54(m，2H)，2.55(s，6H)，4.44(s，1H)，4.70(d，2H，J＝9.0Hz)，7.06-7.10(m，2H)，7.43(d，2H，J＝9.0Hz)，8.43(d，2H，J＝3.0Hz)。 ¹³C NMR(CDCl ₃)δ19.02，24.67，28.82，35.26，41.38，46.36，57.34，64.78，122.19，132.69，138.41，146.53，160.21.ES-MS m/z 355.3(M ⁺H)。Analytical calculation value C ₂₁H ₃₀N ₄O0.2CH ₂Cl ₂0.8H ₂O:C, 65.99; H, 8.36; N, 14.52. measured value: C, 66.22; H, 8.28; N, 14.88.

Embodiment 49

Chemical compound 49: meso-2 ' β, 4 ' α, 6 ' β-[4-(4 '-fluoro-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine]

Under 0 ℃, Ar, at meso-2 ' β, 4 ' β, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl]-1 '-carboxylic acid tert-butyl ester (0.5022g, CH 1.31mmol) ₂Cl ₂(13mL) in the solution, (diethylin) sulfur is fluoridized in dropping three, and (0.19mL 1.44mmol), and stirs 20min, at room temperature stirs 40min then.Add saturated NaHCO ₃Solution (20mL), and with CH ₂Cl ₂(3 * 30mL) extractions.With saturated aqueous common salt (organic extract that 1 * 20mL) washing merges, dry (Na ₂SO ₄), filter, and concentrate.Crude product with column chromatography (1: 1 hexane-EtOAc, EtOAc then) purification, makes the meso-2 ' β of the amber oily of 0.1524g (30%), 4 ' α through silica gel, 6 ' β-[4 '-fluoro-3,3 "-dimethyl-3 ', 4 '; 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl]-1 '-carboxylic acid tert-butyl ester. ¹H NMR(CDCl ₃)δ1.43(s，9H)，1.44-1.45(m，1H)，1.88-2.01(m，2H)，2.25(s，6H)，2.78-2.88(m，2H)，5.78(t，2H，J＝5.1Hz)，6.75-6.79(m，2H)，7.11(d，2H，J＝7.7Hz)，8.00(d，2H，J＝4.8Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[4 '-fluoro-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl] CH of-1 '-carboxylic acid tert-butyl ester ₂Cl ₂(5mL) in the solution, add TFA (5mL), and at room temperature stir 18h.Enriched mixture adds distilled water (2mL) and 10N NaOH (2mL), and with CH ₂Cl ₂(3 * 40mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates, and makes the meso-2 ' β of the amber oily of 0.0834g (73%), 4 ' α, and 6 ' β-[4 '-fluoro-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl]. ¹H NMR(CDCl ₃)δ1.81-1.90(m，1H)，1.96-2.18(m，4H)，2.40(s，6H)，2.71-3.00(m，1H)，4.68(d，2H，J＝10.2Hz)，7.03-7.07(m，2H)，7.41(d，2H，J＝7.7Hz)，8.43(d，2H，J＝4.5Hz)。

According to general step A: at meso-2 ' β, 4 ' α, 6 ' β-[4 '-fluoro-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl] (0.0834g in DMF 0.29mmol) (5mL) solution, adds 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (0.0946g, 0.32mmol), KI (0.0048g, 0.03mmol) and DIPEA (0.10mL, 0.58mmol).Mixture is stirred 21h down at 60 ℃, concentrate then.Crude product through silica gel with column chromatography (100: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.0839g (63%) meso-2 ' β, 4 ' α, and 6 ' β-[4-(4 '-fluoro-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-yl)-butylamine]. ¹H NMR(CDCl ₃)δ0.74-0.84(m，2H)，1.87(s，6H)，2.34-2.44(m，3H)，2.48(s，6H)，3.12(t，2H，J＝7.0Hz)，4.67(d，2H，J＝11.4Hz)，6.92-6.96(m，2H)，7.23-7.25(m，2H)，7.71-7.73(m，2H)，7.78-7.82(m，2H)，8.36(d，2H，J＝6.0Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[4-(4 '-fluoro-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-yl)-butylamine] (0.0839g, in EtOH 0.18mmol) (2mL) solution, (0.10mL 1.83mmol), and at room temperature stirs 20h to add single hydrazine hydrate.Concentrated reaction mixture, crude product through silica gel with column chromatography (75: 1: 1 25: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.0482g (73%) white solid chemical compound 49. ¹H NMR(CDCl ₃)δ0.36-0.38(m，2H)，0.61-0.71(m，3H)，1.97(t，2H，J＝12.0Hz)，2.10(t，2H，J＝6.3Hz)，2.30(t，2H，J＝7.8Hz)，2.41-2.61(m，4H)，2.53(s，6H)，4.66(d，2H，J＝11.7Hz)，7.07-7.12(m，2H)，7.44(d，2H，J＝7.5Hz)，8.43(d，2H，J＝4.2Hz)。 ¹³C NMR(CDCl ₃)δ18.94，25.73，31.18，31.64，31.90，41.76，44.59，57.59，122.87，133.03，138.37，146.68，159.05.ES-MS m/z 357.3(M ⁺H)。Analytical calculation value C ₂₁H ₂₉N ₄F0.1CH ₂Cl ₂: C, 69.44; H, 8.06; N, 15.35; F, 5.21. measured value: C, 69.57; H, 8.12; N, 15.04; F, 5.06.

Embodiment 50

Chemical compound 50: meso-2 ' β, 6 ' β-[2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile]

At meso-2 ' β, 6 ' β-[3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.2860g, in DMF 0.97mmol) (10mL) solution, add 5-(2-chloro-ethyl)-1H-imidazoles (0.1896g, 1.45mmol), KI (0.0161g, 0.10mmol) and DIPEA (0.34mL, 1.94mmol).Be reflected at 80 ℃ and stir 18h down, concentrate then.Add saturated NaHCO ₃(25mL), and with CH ₂Cl ₂(3 * 50mL) extractions.With saturated aqueous common salt (organic extract that 3 * 30mL) washings merge, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (100: 1: 1 50: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes 76.7mg (19%) ecru solid, shaped chemical compound 50. ¹H NMR(CDCl ₃)δ1.53-1.67(m，4H)，1.84-2.06(m，4H)，2.21(s，6H)，2.34(s，6H)，2.46-2.57(m，2H)，3.86(d，2H，J＝6.0Hz)，6.14(s，1H)，7.18(s，2H)，7.39(s，1H)，8.17(s，2H)。 ¹³C NMR(CDCl ₃)17.44，18.22，22.51，24.67，31.07，50.85，64.51，119.07，130.19，130.81，133.62，138.86，140.08，146.54，157.06.ES-MS m/z 390.3(M ⁺H)。Analytical calculation value C ₂₄H ₃₁N ₅0.4CH ₂Cl ₂: C, 69.20; H, 7.57; N, 16.54. measured value: C, 69.05; H, 7.75; N, 16.46.

Embodiment 51

Chemical compound 51: meso-2 ' β, 4 ' β, 6 ' β-[4 '-benzyloxy-1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

At meso-2 ' β, 4 ' β, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester] (0.7035g, in DMF 1.8mmol) (18mL) solution, (0.1440g 3.6mmol), and at room temperature stirs 1h to add 60% the NaH in the mineral oil of being scattered in.Add cylite (1.07mL, 9.0mmol) and KI (0.0664g, 0.4mmol), and at 80 ℃ of stirring 20h.Enriched mixture adds saturated NaHCO ₃Solution (30mL), and with CH ₂Cl ₂(3 * 50mL) extractions.With saturated aqueous common salt (organic extract that 3 * 50mL) washings merge, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (100: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the original material meso-2 ' β of the buttery recovery of peony, 4 ' β, and 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester] and product meso-2 ' β, 4 ' β, 6 ' β-[4 '-benzyloxy-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester] 1: 1 mixture.

CH at last step gained mixture ₂Cl ₂(10mL) in the solution, add TFA (10mL), and at room temperature stir 1h.The concentration response thing adds entry (5mL) and CH ₂Cl ₂(40mL).Slowly add 10N NaOH (10mL) until alkalization, separate biphase.With CH ₂Cl ₂(2 * 40mL) aqueous phase extracted, with the organic extract that merges with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), then with another post (100: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the meso-2 ' β of 0.1282g (19%, 2 step) yellow oily, 4 ' β, and 6 ' β-[4 '-benzyloxy-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl. ¹H NMR(CDCl ₃)δ2.19-2.31(m，2H)，2.37(s，3H)，2.42(s，3H)，3.84-3.89(m，1H)，4.20(d，2H，J＝9.0Hz)，4.63(s，2H)，5.39(t，1H，J＝7.5Hz)，7.01-7.07(m，4H)，7.29-7.42(m，5H)，8.45(d，2H，J＝3.0Hz)。

At meso-2 ' β, 4 ' β, 6 ' β-[4 '-benzyloxy-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl (0.1282g, in DMF 0.34mmol) (4mL) solution, add 2-(2-chloro-ethyl)-1H-imidazoles (0.0672g, 0.51mmol), DIPEA (0.12mL, 0.68mmol) and KI (0.0056g, 0.03mmol).To be reflected at 80 ℃ and stir 65h down, concentrate then.Add saturated NaHCO ₃Solution (15mL), and with CH ₂Cl ₂(3 * 20mL) extractions.With saturated aqueous common salt (organic extract that 2 * 30mL) washings merge, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (50: 1: 1,25: 1: 1,10: 1 then: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification, and then through silica gel with radial chromatography (20: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 24.4mg (13%) white solid chemical compound 51. ¹HNMR(CDCl ₃)δ2.09-2.28(m，4H)，2.40(s，6H)，2.53-2.65(m，2H)，2.95-3.04(m，1H)，3.71-3.77，4.02(d，2H，J＝11.7Hz)，4.20(t，1H，J＝6.9Hz)，4.59(s，2H)，6.15(s，1H)，7.05-7.09(m，2H)，7.28-7.33(m，5H)，7.36-7.42(m，3H)，8.38-8.39(m，2H)。 ¹³C NMR(CDCl ₃)19.10，24.07，30.27，32.30，36.52，44.46，47.36，50.02，166.68，122.72，127.85，128.76，131.88，134.38，135.70，137.17，139.09，140.39，146.59，147.05，159.32.ES-MS m/z468.5(M ⁺H)。Analytical calculation value C ₂₉H ₃₃O0.6CH ₂Cl ₂0.6H ₅NO:C, 65.89; H, 6.95; N, 14.54. measured value: C, 66.08; H, 6.79; N, 14.75.

Embodiment 52

Chemical compound 52:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-dimethyl isophthalate

(1.09g 6.22mmol) is suspended in the mixture of water (25mL) and concentrated sulphuric acid (10mL) with 5-cyano group-2-methyl-essence of Niobe.This yellow solution is stirred 4h down at 150 ℃, make light yellow slurry.Reactant mixture is cooled to room temperature, the sucking filtration precipitation separation, (2 * 10mL) washings, vacuum drying makes brown solid shape 4-methyl-isophthalic acid with water.Then this diacid is suspended in MeOH (25mL) and the concentrated sulphuric acid (10mL), the gained mixture stirs 14h down at 90 ℃, obtains jonquilleous solution.MeOH is removed in decompression, and remaining aqueous solution is diluted with saturated aqueous common salt (60mL) and EtOAc (50mL), approaches 10 with 3M NaOH neutralization until the pH of water then.With EtOAc (3 * 100mL) aqueous phase extracted, dry (Na ₂SO ₄), filter, and vacuum concentration, make the pure 4-methyl-dimethyl isophthalate (1.06g, 82%, 2 step) of light orange solid, shaped. ¹HNMR(CDCl ₃)δ2.66(s，3H)，3.92(s，3H)，3.93(s，3H)，7.33(d，1H，J＝9.0Hz)，8.05(dd，1H，J＝9.0，3.0Hz)，8.57(d，1H，J＝3.0Hz)。

With 4-methyl-dimethyl isophthalate (1.06g, 5.10mmol), (1.00g, 5.61mmol) and 1, (0.31g 1.27mmol) is suspended in the carbon tetrachloride (22mL) 1 '-azo two (cyclohexane extraction formonitrile HCN) N-bromine butanimide, and the gained mixture is at N ₂Following backflow 16h.This orange solution of concentrating under reduced pressure, the orange residue of gained through silica gel with column chromatography (hexane: EtOAc, 7: 1, v/v) purification.Separate the 4-bromomethyl-dimethyl isophthalate (1.05g, 72%) that makes the yellow crystal solid, shaped. ¹H NMR(CDCl ₃)δ3.95(s，3H)，3.97(s，3H)，4.96(s，2H)，7.57(d，1H，J＝9.0Hz)，8.13(dd，1H，J＝9.0，3.0Hz)，8.62(d，1H，J＝3.0Hz)。

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.402g, 1.50mmol), 4-bromomethyl-dimethyl isophthalate (0.603g, 2.10mmol), KI (63mg, 0.38mmol) and DIPEA (0.60mL, DMF 3.44mmol) (7.5mL) solution is heated to 60 ℃, 24h.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 710mg (99%) white solid chemical compound 52. ¹H NMR(CDCl ₃)δ1.63-1.77(m，3H)，2.09(br s，1H)，2.34-2.52(m，8H)，3.84(s，6H)，4.02(s，2H)，4.18(d，2H，J＝11.1Hz)，6.82(dd，2H，J＝4.8，7.5Hz)，7.14(d，2H，J＝7.5Hz)，7.72(s，2H)，7.92(s，1H)，8.22(d，2H，J＝4.8Hz)； ¹³C NMR(CDCl ₃)δ19.32，25.66，28.30，50.13，52.23，52.36，67.14，122.20，126.83，128.07，130.49，131.08，131.33，132.14，138.08，146.90，149.71，159.50，166.88，167.23；ES-MS m/z 474(M ⁺H)。Analytical calculation value C ₂₈H ₃₁N ₃O ₄0.3H ₂O:C, 70.21; H, 6.65; N, 8.77. measured value: C, 70.17; H, 6.60; N, 8.72.

Embodiment 53

Chemical compound 53:2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methylol-essence of Niobe

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.710g in cold (0 ℃) solution of THF 1.50mmol) (15mL) and MeOH (15mL), adds LiBH to dimethyl isophthalate ₄(720mg 33.1mmol), and is warmed to ambient temperature overnight with mixture.With 1.0N NaOH (15mL) diluted mixture thing, and with CH ₂Cl ₂(5 * 40mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 31mg (4%) white foam shape 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-4-of dimethyl isophthalate, 155mg (23%) white foam shape (3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-chemical compound 53 of 3-methylol-essence of Niobe and 375mg (56%) white foam shape.The characterization data of chemical compound 53: ¹H NMR (CDCl ₃) δ 1.52-1.74 (m, 3H), 2.05-2.10 (m, 1H), 2.31-2.45 (m, 8H), 2.62 (br s, 1H, OH), 3.80 (s, 3H), 3.96 (s, 2H), 4.14 (d, 2H, J=11.1Hz), 4.46 (d, 2H, J=3Hz), and 6.82-6.87 (dd, 2H, J=4.8,7.5Hz), 7.10-7.17 (m, 3H), 7.25 (s, 1H), 7.62 (d, 1H, J=7.5Hz), 8.24 (d, 2H, J=4.8Hz); ¹³C NMR (CDCl ₃) δ 19.38,25.62,28.97,50.63,52.01,64.91,67.26,122.05,127.58,128.07,129.26,131.61,132.08,137.64,138.09,143.24,146.85,159.86,167.97; ES-MS m/z446 (M ⁺H).Analytical calculation value C ₂₇H ₃₁N ₃O ₃1.3H ₂O:C, 69.15; H, 7.22; N, 8.96. measured value: C, 69.22; H, 6.90; N, 8.87.

Embodiment 54

Chemical compound 542-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methoxyl methyl-essence of Niobe

2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methylol-essence of Niobe (0.290g is in THF 0.65mmol) (3mL) cold (0 ℃) solution; add NaH (95% does 0.105g, THF 4.38mmol) (10mL) pulpous state liquid; add then pure MeI (0.40mL, 6.43mmol).The gained mixture is stirred 3h, with saturated NaHCO ₃Aqueous solution (15mL) and CH ₂Cl ₂(50mL) handle.Separate biphase, with CH ₂Cl ₂(3 * 15mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes white solid chemical compound 54 (239mg, 80%). ¹H NMR(CDCl ₃)δ1.63-1.69(m，3H)，2.04-2.08(m，1H)，2.30-2.48(m，8H)，3.24(s，3H)，3.80(s，3H)，3.95(s，2H)，4.13(d，2H，J＝11.7Hz)，4.23(s，2H)，6.82(dd，2H，J＝4.5，7.5Hz)，7.06-7.22(m，4H)，7.61(d，1H，J＝7.8Hz)，8.25(d，2H，J＝4.5Hz)； ¹³C NMR(CDCl ₃)δ19.31，25.55，28.99，50.64，51.97，58.01，66.99，74.20，122.01，127.92，128.41，130.02，131.46，131.98，134.84，138.05，143.31，146.84，159.84，167.91；ES-MS m/z 460(M ⁺H)。Analytical calculation value C ₂₈H ₃₃N ₃O ₃: C, 73.18; H, 7.24; N, 9.14. measured value: C, 73.07; H, 7.15; N, 9.16.

Embodiment 55

Chemical compound 55:1 '-(2,4-pair-methoxyl methyl-benzyl)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.191g in THF 0.42mmol) (8mL) solution, adds LiBH to 5-methoxyl methyl-essence of Niobe ₄(89mg 4.07mmol), and with the mixture heated 3h that refluxes, is cooled to room temperature then.With 1.0N NaOH (5mL) diluted mixture thing, and with CH ₂Cl ₂(5 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (1mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 153mg (83%) white solid [2-(and 3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methoxyl methyl-phenyl]-methanol. ¹H NMR(CDCl ₃)δ1.61-1.73(m，3H)，2.02-2.14(m，1H)，2.29-2.42(m，2H)，2.50(s，6H)，3.19(s，3H)，3.65(s，2H)，4.03(d，2H，J＝10.8Hz)，4.17(s，2H)，4.35(s，2H)，5.09(br s，1H)，6.63(d，1H，J＝7.5Hz)，6.74(d，1H，J＝7.5Hz)，6.82-6.86(m，3H)，7.23(d，2H，J＝7.2Hz)，8.22(d，2H，J＝3.6Hz)； ¹³C NMR(CDCl ₃)δ19.44，25.66，30.06，54.39，57.89，62.89，67.47，74.45，122.08，126.07，128.95，129.20，131.76，136.26，138.42，139.05，146.82，160.11；ES-MS m/z 432(M ⁺H)。Analytical calculation value C ₂₇H ₃₃N ₃O ₂0.6H ₂O:C, 73.31; H, 7.79; N, 9.50. measured value: C, 73.20; H, 7.60; N, 9.36.

[2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methoxyl methyl-phenyl]-methanol (0.085g is in THF 0.20mmol) (2mL) cold (0 ℃) solution; add NaH (95% does 0.100g, THF 4.17mmol) (2mL) pulpous state liquid; add then pure MeI (0.25mL, 4.02mmol).The gained mixture is stirred 2.5h, with saturated aqueous common salt (5mL) and CH ₂Cl ₂(10mL) handle.Separate biphase, with CH ₂Cl ₂(4 * 10mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (1mm plate, 50: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 55 (60mg, 64%) of colorless oil. ¹H NMR(CDCl ₃)δ1.65-1.73(m，3H)，2.00-2.07(m，1H)，2.20-2.41(m，8H)，3.21(s，6H)，3.56(s，2H)，3.97(m，2H)，4.18(s，2H)，4.22(s，2H)，6.77(s，1H)，6.83-6.89(m，3H)，7.14-7.20(m，3H)，8.31(d，2H，J＝3.6Hz)； ¹³C NMR(CDCl ₃)δ19.22，25.72，28.37，48.62，57.85，58.50，66.60，72.27，74.68，122.14，125.94，126.81，129.51，132.43，135.29，135.36，138.11，138.62，146.56，160.00；ES-MS m/z 446(M ⁺H)。Analytical calculation value C ₂₈H ₃₅N ₃O ₂0.3CH ₂Cl ₂: C, 72.16; H, 7.62; N, 8.92. measured value: C, 71.88; H, 7.61; N, 8.95.

Embodiment 56

Chemical compound 56:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.260g, 0.98mmol), 2-bromomethyl-5-cyano group-essence of Niobe (0.360g, 1.42mmol), KI (37mg, 0.22mmol) and DIPEA (0.35mL, DMF 2.01mmol) (5mL) solution is heated to 60 ℃, 17h.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 415mg (96%) brown solid shape 5-cyano group-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe.5-cyano group-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.409g in cold (0 ℃) solution of THF 0.937mmol) (4.5mL) and MeOH (9mL), adds LiBH to essence of Niobe ₄(229mg 10.52mmol), and is warmed to ambient temperature overnight with mixture.With 1.0NNaOH (10mL) diluted mixture thing, and with CH ₂Cl ₂(5 * 25mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 56 of 0.332g (87%) white foam shape. ¹H NMR(CDCl ₃)δ1.61-1.77(m，3H)，2.05-2.14(m，1H)，2.30-2.44(m，2H)，2.51(s，6H)，3.71(s，2H)，4.11(d，2H，J＝10.8Hz)，4.46(s，2H)，4.94(br s，1H)，6.87-6.96(m，4H)，7.22-7.27(m，3H)，8.21(d，2H，J＝4.2Hz)。 ¹³C NMR(CDCl ₃)δ19.35，25.70，28.19，51.31，62.24，67.36，109.58，119.48，122.56，129.25，130.02，132.00，132.24，138.53，139.79，145.29，146.76，159.25；ES-MS m/z 413(M ⁺H)。Analytical calculation value C ₂₆H ₂₈N ₄O1.0H ₂O ₂: C, 72.53; H, 7.02; N, 13.01. measured value: C, 72.46; H, 6.73; N, 12.91.

Embodiment 57

Chemical compound 57; [2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-(2-methyl-2H-tetrazolium-5-yl)-phenyl]-methanol

(1.069g in 2-methyl cellosolve 6.10mmol) (6mL) solution, adds NaN at 5-cyano group-2-methyl toluate ₃(0.400g, 6.16mmol), add then LiCl (0.421g, 9.94mmol).Gained mixture heated backflow 6h is cooled to room temperature then.Mixture is fallen on ice (～25g), and handle with 37%HCl (2mL).With CH ₂Cl ₂(4 * 25mL) extraction mixture.The organic extract that merges is with Na ₂SO ₄Dry and concentrated, make the 1.43g orange solids.In the DMF of this orange solids (1.43g) (6mL) and 1, in the cold soln of 4-dioxane (6mL) (0 ℃), add K ₂CO ₃(2.52g, 18.23mmol), add then MeI (1.0mL, 16.06mmol).Mixture is warmed to room temperature.Behind the 4h, with water (10mL) and EtOAc (60mL) diluted mixture thing.Separate biphase, and with saturated aqueous common salt (3 * 10mL) washing organic faciess, dry (Na ₂SO ₄) and concentrate.(8: 1: hexane-EtOAc) made 5-(2-methyl-2H-tetrazolium-5-yl)-2-ar-Toluic acid 2-methoxyl group ethyl ester of 0.50g (30%) white solid to crude product with column chromatography through silica gel. ¹H NMR(CDCl ₃)δ2.66(s，3H)，3.44(s，3H)，3.75(t，2H，J＝6.6Hz)，4.41(s，3H)，4.49(t，2H，J＝6.6Hz)，7.37(d，1H，J＝7.5Hz)，8.15(dd，1H，J＝7.5，2.4Hz)。

CCl at 5-(2-methyl-2H-tetrazolium-5-yl)-2-ar-Toluic acid 2-methoxyl group ethyl ester ₄(6mL) in the solution, adding N-bromine butanimide (0.366g 2.06mmol), adds 1 then, and 1 '-azo two (cyclohexane extraction formonitrile HCN) (74mg, 0.30mmol).With gained mixture backflow 6h, be cooled to room temperature then, through filter paper filtering, and concentrate.(4: 1: the purification of hexane-EtOAc) made the 0.35g white solid to crude product with column chromatography through silica gel.According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.140g, 0.52mmol), this white solid (0.35g), KI (16mg, 0.10mmol) and DIPEA (0.18mL, DMF 1.03mmol) (5mL) solution is heated to 60 ℃, 23h.Crude product through silica gel with column chromatography (40: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.28g (99%) brown solid shape 5-(2-methyl-2H-tetrazolium-5-yl) 2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzoic acid 2-methoxyl group ethyl ester.(0.280g in THF 0.52mmol) (10mL) cold soln, adds LiBH at this ester ₄(168mg 7.72mmol), and refluxes mixture and spends the night.Mixture is cooled to room temperature, with 1.0N NaOH (5mL) dilution, and with CH ₂Cl ₂(4 * 20mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 0.215g (85%) white solid chemical compound 57. ¹H NMR(CDCl ₃)δ1.63-1.77(m，3H)，2.06-2.13(m，1H)，2.38-2.47(m，2H)，2.54(s，6H)，3.75(s，2H)，4.12(d，2H，J＝12.0Hz)，4.34(s，3H)，4.48(s，2H)，4.98(br s，1H)，6.82(dd，2H，J＝7.5，4.8Hz)，6.90(d，1H，J＝7.5Hz)，7.23(d，2H，J＝7.5Hz)，7.44(dd，1H，J＝7.5，1.5Hz)，7.66(d，1H，J＝1.5Hz)，8.22(d，2H，J＝4.8Hz)。 ¹³C NMR(CDCl ₃)δ19.42，25.72，28.99，39.75，52.92，63.08，67.58，122.31，124.98，125.19，127.58，129.53，132.08，138.49，139.38，141.98，146.80，159.69，165.44；ES-MS m/z 470(M ⁺H)。Analytical calculation value C ₂₇H ₃₁N ₇O0.8H ₂O:C, 67.00; H, 6.79; N, 20.26. measured value: C, 66.68; H, 6.39; N, 19.93.

Embodiment 58

Chemical compound 58:2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzylamine (HBr salt)

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.602g, 2.25mmol), α-bromo-neighbour-tolunitrile (0.668g, 3.41mmol), KI (100mg, 0.60mmol) and DIPEA (0.80mL, DMF 4.59mmol) (11mL) solution is heated to 60 ℃, 23h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.78g (91%) brown solid shape 2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile. ¹HNMR(CDCl ₃)δ1.63-1.73(m，3H)，2.02-2.07(m，1H)，2.26-2.38(m，2H)，2.48(s，6H)，3.69(s，2H)，4.12(d，2H，J＝10.8Hz)，6.83-6.89(m，3H)，6.99(d，1H，J＝7.2Hz)，7.19-7.26(m，3H)，7.64(d，1H，J＝7.8Hz)，8.27(d，2H，J＝3.9Hz)。 ¹³C NMR(CDCl ₃)δ19.44，25.53，29.42，52.72，67.05，109.86，118.06，122.19，125.90，130.68，131.41，131.54，132.02，138.18，145.77，147.23，159.61；ES-MS m/z 383(M ⁺H)。Analytical calculation value C ₂₅H ₂₆N ₄C, 78.50; H, 6.852; N, 14.65. measured value: C, 78.28; H, 6.93; N, 14.57.

With Raney nickel (60mg) handle 2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.129g, 0.34mmol) with NH ₃The solution of saturated MeOH (5mL), and it is placed 50psi H ₂Under Parr shaker on 3.5h.Mixture is through diatomite filtration, and the kieselguhr cake is washed with MeOH.Eluent is through concentrating under reduced pressure.Crude product through silica gel with column chromatography (10: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the free alkali of 96mg (73%) white solid title compound.According to general step B: this white solid (92mg) is converted into its HBr salt, makes white solid chemical compound 58 (152mg, 96%). ¹HNMR(D ₂O)δ1.49-1.61(m，2H)，1.71-1.84(m，1H)，1.96-2.03(m，1H)，2.14-2.20(m，2H)，2.54(s，6H)，3.82(s，2H)，3.96(s，2H)，4.57(dd，2H J＝11.4，3.0Hz)，6.96(d，1H，J＝7.8Hz)，7.08-7.13(m，1H)，7.18-7.26(m，2H)，7.73(dd，2H，J＝7.8，5.7Hz)，8.26(d，2H，J＝7.8Hz)，8.53(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ17.25，22.25，33.11，39.91，58.88，61.96，125.96，129.91，130.13，130.57，131.21，132.11，134.86，136.53，139.49，149.14，155.32；ES-MS m/z 387(M ⁺H)。Analytical calculation value C ₂₅H ₃₀N ₄3.0HBr2.0H ₂O:C, 45.13; H, 5.61; N, 8.42; Br, 36.03. measured value: C, 45.07; H, 5.71; N, 8.23; Br, 36.20.

Embodiment 59

Chemical compound 59:[3-amino-4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

(5.52g in MeOH 30.5mmol) (100mL) solution, adds 98% sulphuric acid (2mL), the gained mixture is refluxed spend the night, and is cooled to room temperature then at 4-methyl-3-nitro benzoic acid.Enriched mixture, and residue is dissolved in CH ₂Cl ₂(50mL) and in the water (20mL).Add solid Na ₂CO ₃Be alkalescence until water through the litmus paper detection.Separate biphase, and with CH ₂Cl ₂(5 * 20mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Dry and concentrated, make 5.79g (97%) white solid 4-methyl-3-nitro essence of Niobe.At 4-methyl-3-nitro essence of Niobe (5.01g, CCl 25.7mmol) ₄(65mL) add in the solution N-bromine butanimide (5.04g 28.3mmol), adds 1 then, 1 '-azo two (cyclohexane extraction formonitrile HCN) (1.21g, 4.96mmol).With gained mixture backflow 24h, be cooled to room temperature then, through filter paper filtering, and concentrate.(9: 1: the purification of hexane-EtOAc) made the 4-bromomethyl-3-nitrobenzoic acid methyl ester of 4.30g (61%) yellow oily to crude product with column chromatography through silica gel. ¹HNMR(CDCl ₃)δ3.98(s，3H)，4.85(s，2H)，7.67(d，1H，J＝7.8Hz)，8.25(d，1H，J＝7.8，1.5Hz)，8.66(d，1H，J＝1.5Hz)。

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.829g, 3.10mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26g, 4.61mmol), KI (115mg, 0.69mmol) and DIPEA (1.20mL, DMF 6.89mmol) (16mL) solution is heated to 60 ℃, 18h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 1.40g (98%) brown solid shape 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-nitro-essence of Niobe.4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(1.40g in MeOH 3.03mmol) (15mL) and EtOAc (15mL) solution, adds the activated carbon (0.30g) that contains 10 weight % palladiums (50% with water-wet) to 3-nitro-essence of Niobe.The gained mixture is with 30psi hydrogenation 3h on Parr shaker.Mixture is through the kieselguhr vacuum filtration, and filter cake is with MeOH and EtOAc washing.Solvent is removed in decompression from filtrate, then will be thus the grease of gained through silica gel with column chromatography (40: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.90g (69%) 3-amino-4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe.

3-amino-4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.61g in THF 1.42mmol) (14mL) solution, adds LiBH to essence of Niobe ₄(430mg 19.74mmol), and refluxes mixture heated and spends the night.Mixture is cooled to room temperature, with 1.0NNaOH (20mL) dilution, and with CH ₂Cl ₂(5 * 30mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (2mm plate, 20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 0.220g (37%) white solid chemical compound 59. ¹H NMR(CDCl ₃)δ1.23(br s，1H)，1.47-1.72(m，3H)，1.88-1.95(m，1H)，2.04-2.18(m，2H)，2.35(s，6H)，3.32(s，2H)，3.73(dd，2H，J＝11.7，3.0Hz)，4.26(d，2H，J＝3.3Hz)，4.53(br s，2H)，6.03(s，1H)，6.07(d，1H，J＝7.8Hz)，6.48(d，1H，J＝7.2Hz)，6.86(dd，2H，J＝7.8，4.8Hz)，7.15(d，2H，J＝7.5Hz)，8.33(d，2H，J＝3.9Hz)。 ¹³CNMR(CDCl ₃)δ19.44，25.02，32.92，60.69，65.60，68.25，112.98，115.09，122.09，122.80，129.96，131.38，138.18，140.42，146.89，147.51，161.18；ES-MS m/z 403(M ⁺H)。Analytical calculation value C ₂₅H ₃₀N ₄O1.0H ₂O:C, 71.40; H, 7.67; N, 13.32. measured value: C, 71.31; H, 7.55; N, 13.22.

Embodiment 60

Chemical compound 60:2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe

At 2-methyl-essence of Niobe (4.58g, CCl 30.5mmol) ₄(75mL) add in the solution N-bromine butanimide (5.79g 32.5mmol), adds 1 then, 1 '-azo two (cyclohexane extraction formonitrile HCN) (1.42g, 5.80mmol).With gained mixture backflow 6h, be cooled to room temperature then, through filter paper filtering, and concentrate.(20: 1: the purification of hexane-EtOAc) made the 2-bromomethyl-essence of Niobe of 5.44g (78%) colorless oil to crude product with column chromatography through silica gel. ¹H NMR(CDCl ₃)δ3.95(s，3H)，4.96(s，2H)，7.36-7.50(m，3H)，7.97(d，1H，J＝7.8Hz)。

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.901g, 3.37mmol), 2-bromomethyl-essence of Niobe (1.17g, 5.13mmol), KI (121mg, 0.73mmol) and DIPEA (1.50mL, DMF 8.61mmol) (17mL) solution is heated to 60 ℃, 23h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 1.19g (85%) brown solid shape chemical compound 60. ¹HNMR(CDCl ₃)61.58-1.72(m，3H)，2.02-2.06(m，1H)，2.31-2.42(m，8H)，3.80(s，3H)，3.94(s，2H)，4.11(d，2H，J＝10.5Hz)，6.79-6.91(m，3H)，7.09-7.26(m，4H)，7.63(d，1H，J＝7.5Hz)，8.26(d，2H，J＝3.6Hz)。 ¹³C NMR(CDCl ₃)δ19.39，25.69，28.76，50.43，51.98，67.31，122.06，124.90，128.02，129.03，130.54，131.20，132.11，138.04，143.92，146.89，159.83，168.12；ES-MS m/z416(M ⁺H)。Analytical calculation value C ₂₆H ₂₉N ₃O ₂0.2H ₂O:C, 74.51; H, 7.07; N, 10.03. measured value: C, 74.56; H, 7.08; N, 9.99.

Embodiment 61

Chemical compound 61:[2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.204g in THF 0.49mmol) (5mL) solution, adds LiBH to essence of Niobe ₄(133mg 6.13mmol), and refluxes mixture heated and spends the night.Mixture is cooled to room temperature, with 1.0N NaOH (5mL) dilution, and with CH ₂Cl ₂(4 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 61 of 0.139g (70%) white solid. ¹HNMR(CDCl ₃)δ1.60-1.73(m，3H)，2.02-2.40(m，3H)，2.50(s，6H)，3.66(s，2H)，4.04(d，2H，J＝9.0Hz)，4.36(s，2H)，5.14(br s，1H)，6.63-6.93(m，6H)，7.24(d，2H，J＝8.1Hz)，8.22(d，2H，J＝3.9Hz)。 ¹³CNMR(CDCl ₃)δ19.46，25.67，29.68，54.30，63.19，67.73，122.24，126.60，126.81，128.99，129.61，131.87，138.43，138.85，139.13，146.85，159.92；ES-MS m/z 388(M ⁺H)。Analytical calculation value C ₂₅H ₂₉N ₃O0.9H ₂O:C, 74.37; H, 7.69; N, 10.41. measured value: C, 74.43; H, 7.44; N, 10.34.

Embodiment 62

Chemical compound 62:1 '-(2-methyl fluoride-benzyl)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

[2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (0.107g, CH 0.28mmol) ₂Cl ₂(3mL) in the cold soln (0 ℃), add three fluoridize (lignocaine) sulfur (80 μ L, 0.61mmol).Behind the 15min, remove cryostat, reactant mixture is warmed to room temperature.After three hours, with saturated NaHCO ₃Aqueous solution (5mL) reaction mixture, and with CH ₂Cl ₂(4 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (1mm plate, 100: 1: 1CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 0.032g (29%) white solid chemical compound 62. ¹HNMR(CDCl ₃)δ1.60-1.74(m，3H)，2.02-2.10(m，1H)，2.26-2.41(m，8H)，3.56(s，2H)，4.13(d，2H，J＝11.1Hz)，5.06(d，2H，JC-F＝48Hz)，6.81-6.88(m，5H)，7.14-7.16(m，3H)，8.31(d，2H，J＝3.6Hz)。 ¹³C NMR(CDCl ₃)δ19.24，25.64，28.65，50.09，67.20，82.93(d，J _C-F＝648Hz)，122.29，125.94，127.47，127.62，129.79，132.36，133.66(d，J _C-F＝62Hz)，138.14，139.34，146.63，159.99；ES-MS m/z 390(M ⁺H)。Analytical calculation value C ₂₅H ₂₈N ₃F0.1H ₂O:C, 76.73; H, 7.26; N, 10.74. measured value: C, 76.66; H, 7.23; N, 10.70.

Embodiment 63

Chemical compound 63:2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-the benzoic acid sodium salt

2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (0.723g, in MeOH 1.74mmol) (5mL) solution, add entry (5mL) and solid NaOH (0.757g, 18.93mmol).The backflow of gained mixture heated is spent the night, be cooled to room temperature then.With CH ₂Cl ₂(5 * 20mL) extraction mixture.The organic extract that merges is with Na ₂SO ₄Drying also concentrates, and makes the chemical compound 63 of 0.80g (97%) white solid. ¹H NMR(D ₂O)δ1.58-1.73(m，3H)，1.88-2.04(m，3H)，2.36(s，6H)，3.66(s，2H)，4.12(d，2H，J＝10.2Hz)，6.82(t，1H，J＝7.2Hz)，6.92-7.03(m，4H)，7.40-7.47(m，3H)，8.13(d，2H，J＝3.9Hz)。 ¹³C NMR(D ₂O)δ16.66，24.13，32.40，56.97，65.27，122.76，125.65，127.27，128.10，130.45，132.60，136.88，139.70，146.15，159.77，177.12；ES-MS m/z 402(M ⁺H)，424(M ⁺Na)。Analytical calculation value C ₂₅H ₂₆N ₃O ₂Na2.7H ₂O:C, 63.60; H, 6.70; N, 8.90. measured value: C, 63.60; H, 6.78; N, 8.55.

Embodiment 64

Chemical compound 64:3,3 " dimethyl-1 '-(2-nitro-benzyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.431g, 1.61mmol), the 2-nitro benzyl bromide (0.509g, 2.75mmol), KI (60mg, 0.36mmol) and DIPEA (0.6mL, DMF 3.44mmol) (8mL) solution is heated to 60 ℃, 24h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 0.58g (90%) yellow solid shape chemical compound 64. ¹H NMR(CDCl ₃)δ1.63-1.70(m，3H)，2.04-2.08(m，1H)，2.31-2.43(m，8H)，3.85(s，2H)，4.12(d，2H，J＝11.1Hz)，6.83-6.91(m，3H)，7.18-7.29(m，4H)，7.78(d，1H，J＝7.5Hz)，8.24(d，2H，J＝3.9Hz)；ES-MS m/z 403(M ⁺H)。

Embodiment 65

Chemical compound 65:2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-aniline

3,3 " dimethyl-1 '-(2-nitro-benzyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (adds the activated carbon (0.113g) that contains 10 weight % palladiums (50% with water-wet) among the 0.55g, MeOH 1.37mmol) (20mL).The gained mixture under 30psi, is put hydrogenation 3h on the Parr shaker.Mixture is through the kieselguhr vacuum filtration, and filter cake washs with MeOH.Solvent is removed in decompression from filtrate, with the grease of gained thus through silica gel with radial chromatography (2mm plate, 100: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 80mg (16%) white solid chemical compound 65. ¹H NMR(CDCl ₃)δ1.49-1.72(m，3H)，1.88-1.95(m，1H)，2.06-2.20(m，2H)，2.36(s，6H)，3.33(s，2H)，3.75(dd，2H，J＝11.7，3.0Hz)，4.47(br s，2H)，6.07(dd，2H，J＝7.5，6.0Hz)，6.42-6.45(m，1H)，6.54(td，1H，J＝7.5，1.2Hz)，6.87(dd，2H，J＝7.5，4.8Hz)，7.15(d，2H，J＝7.5Hz)，8.33(d，2H，J＝3.9Hz)；ES-MS m/z 373(M ⁺H)。

Embodiment 66

Chemical compound 66:1-[2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-ethyl ketone

2 '-methyl-acetophenone (2.68g, in benzene 20.0mmol) (100mL) solution, add ethylene glycol (2.0mL, 35.9mmol), add then right-toluenesulfonic acid-hydrate (0.39g, 2.10mmol).Place Dean-Rodney Stark water separator (Dean-Stark trap) at the reaction flask top, and the mixture heated backflow is spent the night.Mixture is cooled to room temperature, with Et ₂O (100mL) dilution is with saturated NaHCO ₃Aqueous solution (5 * 20mL) and saturated aqueous common salt (3 * 25mL) washing, with MgSO ₄Drying, and concentrate.(3.6g) is dissolved in CCl with the gained colorless oil ₄(50mL), and in this solution, add N-bromine butanimide (3.76g 21.1mmol), adds 1 then, 1 '-azo two (ring-hexane formonitrile HCN) (0.98g, 3.99mmol).With gained mixture backflow 5h, be cooled to room temperature then, through filter paper filtering, and concentrate.(20: 1: the purification of hexane-EtOAc) made 2-(2-bromomethyl-phenyl)-2-methyl-[1,3] dioxolanes of 4.09g (80%) colorless oil to crude product with column chromatography through silica gel. ¹HNMR(CDCl ₃)δ1.74(s，3H)，3.75-3.81(m，2H)，4.04-4.08(m，2H)，4.89(s，2H)，7.24-7.31(m，2H)，7.44-7.57(m，2H)。

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.547g, 2.04mmol), 2-(2-bromomethyl-phenyl)-2-methyl-[1; 3] dioxolanes (1.03g, 3.99mmol), KI (73mg, 0.42mmol) and DIPEA (0.70mL; DMF 4.02mmol) (10mL) solution is heated to 60 ℃, 24h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.81g (90%) white solid 3,3 " dimethyl-1 '-[2-(2-methyl-[1,3] dioxolanes-2-yl)-benzyl]-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl. ¹H NMR(CDCl ₃)δ1.46(s，3H)，1.60-1.83(m，3H)，2.15-2.20(m，1H)，2.47-2.57(m，8H)，3.26-3.31(m，2H)，3.82-3.87(m，2H)，4.01(s，2H)，4.44(d，2H，J＝10.8Hz)，6.72-6.82(m，4H)，7.05(dd，1H，J＝7.2，1.5Hz)，7.21(d，2H，J＝7.2Hz)，7.46(d，1H，J＝6.9Hz)，8.19(d，2H，J＝4.8Hz)；ES-MS m/z 444(M ⁺H)。

3,3 " dimethyl-1 '-[2-(2-methyl-[1,3] dioxolanes-2-yl)-benzyl]-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.78g, in THF 1.76mmol) (8mL) solution, adding 1.0N HCl (18mL, 18.0mmol), and with the mixture stirred overnight at room temperature.With 10N NaOH (2mL) diluted mixture thing, and with CH ₂Cl ₂(4 * 50mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (30: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 0.64g (91%) white solid chemical compound 66. ¹H NMR(CDCl ₃)δ1.58-1.71(m，3H)，2.02-2.12(m，1H)，2.30-2.37(m，5H)，2.44(s，6H)，3.82(s，2H)，4.09(d，2H，J＝11.1Hz)，6.81-6.85(m，3H)，7.04-7.18(m，4H)，7.76(d，1H，J＝7.8Hz)，8.26(d，2H，J＝3.6Hz)；ES-MSm/z 400(M ⁺H)。

Embodiment 67

Chemical compound 67:2-[2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-propan-2-ol

1-[2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-(0.283g in THF 0.71mmol) (14mL) cold soln (78 ℃), adds the MeLi (Et of 1.32M to ethyl ketone ₂O solution, 1.10mL, 1.45mmol).Behind the 15min, remove cryostat, and reactant mixture is warmed to room temperature.Behind 5h, with saturated aqueous common salt (15mL) and EtOAc (30mL) diluted reaction mixture.Separate biphase, and with saturated aqueous common salt (2 * 10mL) washing organic faciess, dry (Na ₂SO ₄) and concentrate.Crude product through silica gel with radial chromatography (1mm plate, 50: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 67 of 0.111g (38%) light yellow solid shape. ¹H NMR(CDCl ₃)δ1.46(s，6H)，1.57-1.78(m，3H)，2.14-2.20(m，1H)，2.52-2.62(m，8H)，4.14-4.40(m，5H)，6.59-6.84(m，6H)，7.10-7.27(m，2H)，8.14-8.21(m，2H)；ES-MS m/z 416(M ⁺H)。

Embodiment 68

Chemical compound 68:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzylamine

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.502g, 1.83mmol), α-bromo-is right-tolunitrile (0.538g, 2.75mmol), KI (65mg, 0.40mmol) and DIPEA (0.72mL, DMF 4.13mmol) (9mL) solution is heated to 60 ℃, 16h.Crude product through silica gel with column chromatography (40: 1: 1 CH ²Cl ²-CH ₃OH-NH ₄OH) purification, make 0.66g (94%) white solid 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile. ¹H NMR(CDCl ₃)δ1.60-1.73(m，3H)，2.02-2.12(m，1H)，2.18-2.34(m，2H)，2.41(s，6H)，3.56(s，2H)，4.14(d，2H，J＝10.5Hz)，6.64(d，2H，J＝8.1Hz)，6.95(dd，2H，J＝7.5，4.8Hz)，7.10(d，2H，J＝7.8Hz)，7.22(d，2H，J＝7.2Hz)，8.37(d，2H，J＝3.9Hz)；ES-MS m/z 383(M ⁺H)。

With Raney nickel (100mg) handle 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.122g, NH 0.32mmol) ₃Saturated MeOH (3mL) solution, and in 50psi H ₂Put 4h on the Parr shaker down.With diatomite filtration, filter cake washs with MeOH with mixture.The concentrating under reduced pressure eluent.Crude product through silica gel with column chromatography (20: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes the chemical compound 68 of 93mg (76%) white solid. ¹H NMR(CDCl ₃)δ1.44-1.57(m，1H)，1.66-1.72(m，2H)，1.90-2.11(m，3H)，2.34(s，6H)，3.51(s，2H)，3.71(s，2H)，3.98(d，2H J＝10.5Hz)，6.54(d，2H，J＝7.8Hz)，6.93(d，2H，J＝7.8Hz)，7.01(dd，2H，J＝7.5，4.8Hz)，7.34(d，2H，J＝7.5Hz)，8.47(d，2H，J＝3.9Hz)；ES-MS m/z 387(M ⁺H)。

Embodiment 69

Chemical compound 69:3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzylamine

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.414g, 1.55mmol), between α-bromo--tolunitrile (0.466g, 2.38mmol), KI (53mg, 0.32mmol) and DIPEA (0.55mL, DMF 3.16mmol) (8mL) solution is heated to 60 ℃, 18h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.447g (75%) ecru solid, shaped 3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile. ¹HNMR(CDCl ₃)δ1.56-1.72(m，3H)，2.05-2.10(m，1H)，2.18-2.34(m，2H)，2.41(s，6H)，3.53(s，2H)，4.10(d，2H，J＝11.1Hz)，6.71(s，1H)，6.83(d，1H，J＝7.8Hz)，6.93-7.00(m，3H)，7.13(d，1H，J＝7.5Hz)，7.25-7.27(m，2H)，8.39(dd，2H，J＝4.8，1.2Hz)；ES-MS m/z 383(M ⁺H)。

With Raney nickel (100mg) handle 3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.107g, NH 0.28mmol) ₃Saturated MeOH (5mL) solution, and in 50psi H ₂Put on the Parr shaker 4h down.Mixture is through diatomite filtration, and filter cake washs with MeOH.The concentrating under reduced pressure eluent.Crude product through silica gel with column chromatography (10: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 62mg (58%) white solid chemical compound 69. ¹H NMR(CDCl ₃)δ1.49-1.71(m，3H)，1.95-2.23(m，3H)，2.36(s，6H)，3.52(s，2H)，3.61(s，2H)，4.01(d，2H J＝10.2Hz)，6.42-6.48(m，2H)，6.91-7.02(m，4H)，7.24-7.31(m，2H)，8.45(d，2H，J＝3.9Hz)；ES-MS m/z 387(M ⁺H)。

Embodiment 70

Chemical compound 70:3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-Benzoylamide

3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.178g adds entry (2.0mL) in MeOH 0.47mmol) (5.0mL) solution, add then sodium perborate tetrahydrate (0.218g, 1.42mmol).With gained mixture heated to 50 ℃, 5h is cooled to room temperature then.Mixture is diluted with water (10mL), and with CH ₂Cl ₂(5 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (1mm plate, 25: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 52mg (28%) white solid chemical compound 70. ¹H NMR(CDCl ₃)δ1.55-1.75(m，3H)，1.93-2.01(m，1H)，2.06-2.19(m，2H)，2.40(s，6H)，3.37(s，2H)，3.96(dd，2H，J＝11.4，2.7Hz)，5.52(br s，1H)，6.46(d，1H，J＝7.5Hz)，6.74(dd，1H，J＝7.5，7.5Hz)，6.85(dd，2H，J＝4.8，7.5Hz)，7.25-7.28(m，2H)，7.40(d，1H，J＝7.8Hz)，7.85(s，1H)，8.24(d，2H，J＝3.6Hz)，8.57(br s，1H)；ES-MS m/z401(M ⁺H)。

Embodiment 71

Chemical compound 71:3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-N-hydroxyl-benzenecarboximidamide

3-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(0.117g in MeOH 0.31mmol) (3.0mL) solution, adds Et to benzonitrile ₃(0.14mL 1.00mmol), adds NH to N then ₂OHH ₂O (0.070g, 1.01mmol).The gained mixture at room temperature stirred spend the night.With water (5mL) diluted mixture thing, and with CH ₂Cl ₂(5 * 10mL) extractions.The organic extract that merges is through Na ₂SO ₄Dry and concentrated.Crude product through silica gel with column chromatography (10: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification makes 113mg (88%) white solid chemical compound 71. ¹H NMR(CDCl ₃)δ1.50-1.72(m，3H)，1.94-2.19(m，3H)，2.40(s，6H)，3.40(s，2H)，3.97(d，2H，J＝9.3Hz)，5.75(brs，2H)，6.37(d，1H，J＝7.5Hz)，6.71(dd，1H，J＝7.5，7.5Hz)，6.89(dd，2H，J＝7.5，4.8Hz)，7.19(d，1H，J＝8.1Hz)，7.26-7.29(m，2H)，7.42(s，1H)，8.30(d，2H，J＝3.9Hz)；ES-MS m/z 416(M ⁺H)。

Embodiment 72

Chemical compound 72:4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl) N-hydroxyl-Benzoylamide

According to general step A: with 3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.485g, 1.81mmol), 4-bromomethyl-essence of Niobe (0.642g, 2.80mmol), KI (64mg, 0.38mmol) and DIPEA (0.65mL, DMF 3.73mmol) (9mL) solution is heated to 60 ℃, 23h.Crude product through silica gel with column chromatography (40: 1: 1 CH ₂Cl ₂-CH ₃OH-NH ₄OH) purification, make 0.67g (89%) white solid 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe. ¹HNMR(CDCl ₃)δ1.54-1.72(m，3H)，2.02-2.08(m，1H)，2.20-2.34(m，2H)，2.40(s，6H)，3.58(s，2H)，3.83(s，3H)，4.12(d，2H，J＝11.4Hz)，6.57(d，2H，J＝7.8Hz)，6.96(dd，2H，J＝7.5，4.5Hz)，7.23(d，2H，J＝7.5Hz)，7.53(d，2H，J＝7.8Hz)，8.26(d，2H，J＝4.5Hz)；ES-MS m/z 416(M ⁺H)。

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (O.420g, in MeOH 1.01mmol) (5mL) solution, add entry (5mL) and solid NaOH (0.448g, 11.21mmol).The backflow of gained mixture heated is spent the night, be cooled to room temperature then.(～the pH that 2mL) regulates mixture is to～5, and with CH with 6N HCl ₂Cl ₂(5 * 20mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrate, make 0.440g (quantitative yield) white solid 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzoic acid. ¹H NMR(CDCl ₃)δ1.80-2.05(m，6H)，2.42(s，6H)，3.83(br s，2H)，4.55(br s，2H)6.79(d，2H，J＝8.1Hz)，7.02(dd，2H，J＝7.5，5.1Hz)，7.34(d，2H，J＝7.5Hz)，7.65(d，2H，J＝7.8Hz)，8.42(d，2H，J＝3.9Hz)；ES-MS m/z 402(M ⁺H)。

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzoic acid (0.124g, CH 0.31mmol) ₂Cl ₂(3mL) and in DMF (5) cold soln (0 ℃), add oxalyl chloride (0.11mL, 1.26mmol).Behind the 15min, enriched mixture makes the ecru solid.This solid is dissolved among the DMF (3mL), and (0.50mL 2.87mmol) handles, then with NH with DIPEA ₂OHH ₂(72mg 1.04mmol) handles O.The gained mixture at room temperature stirred spend the night.With saturated NH ₄Cl aqueous solution (5mL) diluted mixture thing, and with CH ₂Cl ₂(5 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (1mm plate, 5: 1: 1 CH ₂ClN-CH ₃OH-NH ₄OH) purification makes 21mg (16%) white solid chemical compound 72. ¹H NMR(CDCl ₃)δ1.48-1.67(m，3H)，1.88-2.13(m，3H)，2.31(s，6H)，3.46(s，2H)，3.94(d，2H，J＝10.5Hz)，6.54(d，2H，J＝6.9Hz)，6.93(dd，2H，J＝7.5，4.5Hz)，7.26-7.39(m，4H)，8.28(d，2H，J＝3.3Hz)；ES-MS m/z 417(M ⁺H)

Embodiment 73

Chemical compound 73:(2 ' R, 6 ' S)-3,3 " dimethyl-1 '-pyridine-2-ylmethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (166mg, 0.621mmol), 2-(bromomethyl) pyridine hydrobromide salt (189mg, 0.745mmol), DIPEA (265 μ L, 1.52mmol) and KI (10mg, CH 0.060mmol) ₃CN (6mL) solution is warmed to 50 ℃, and stirs 15.5h.By flash chromatography, utilize CH through silica gel ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting makes orange solids shape chemical compound 73 (127mg, 57%). ¹HNMR(CDCl ₃)δ1.75-1.85(m，3H)，1.93-2.02(m，1H)，2.09-2.21(m，2H)，2.42(s，6H)，3.80(bs，2H)，6.81-6.85(m，2H)，6.96(dd，2H，J＝7.7，3.9Hz)，7.23-7.30(m，3H)，8.18(d，1H，J＝4.8Hz)，8.40(d，2H，J＝4.4Hz)；ES-MS m/z 359(M ⁺H)。

Embodiment 74

Chemical compound 74:(2 ' R, 6 ' S)-3,3 " dimethyl-1 '-the pyridin-4-yl methyl isophthalic acid ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (163mg, 0.609mmol), 4-(bromomethyl) pyridine hydrogen bromide salt (185mg, 0.730mmol), DIPEA (265 μ L, 1.52mmol) and KI (10mg, CH 0.060mmol) ₃CN (6mL) solution is warmed to 50 ℃ and stir 15.5h.By silica gel through flash chromatography with CH ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting makes orange oily solid, shaped chemical compound 74 (110mg, 37%). ¹H NMR(CDCl ₃)δ1.63-1.73(m，3H)，2.08-2.20(m，2H)，2.28-2.42(m，2H)，2.46(s，6H)，3.56(s，2H)，4.22(d，2H，J＝11.8Hz)，6.14(d，2H，J＝5.3Hz)，6.96(dd，2H，J＝7.5，4.8Hz)，7.22(d，2H，J＝7.9Hz)，8.00(d，2H，J＝4.4Hz)，8.37(d，2H，J＝4.4Hz)；ES-MS m/z 359(M ⁺H)。

Embodiment 75

Chemical compound 75:(2 ' R, 6 ' S)-1 '-(2-difluoro-methoxy-benzyl)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (169mg, 0.624mmol), 2-(difluoro-methoxy) cylite (114 μ L, 0.745mmol), DIPEA (160 μ L, 0.936mmol) and KI (10mg, CH 0.060mmol) ₃CN (6mL) solution is warmed to 50 ℃ and stir 15.5h.Through silica gel with flash chromatography, with CH ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting makes white solid chemical compound 75 (238mg, 90%). ¹H NMR(CDCl ₃)δ1.65-1.70(m，3H)，2.05-2.07(m，2H)，2.30-2.45(m，3H)，3.63(s，2H)，4.16(d，2H，J＝10.2Hz)，6.50(s，1H)，6.78-6.83(m，4H)，7.20-7.30(m，3H)，8.30(d，2H，J＝3.1Hz)；ES-MS m/z 424(M ⁺H)。

Embodiment 76

Chemical compound 76:(2 ' R, 6 ' S)-1 '-(2,3-dimethoxy-benzyl)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (164mg, 0.613mmol), 2,3-Dimethoxyphenyl chlorine (136mg, 0.731mmol), DIPEA (160 μ L, 0.936mmol) and KI (10mg, CH 0.060mmol) ₃CN (6mL) solution is warmed to 50 ℃, and stirs 15.5h.Through silica gel with flash chromatography, with CH ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting makes white solid chemical compound 76 (61mg, 24%). ¹H NMR(CDCl ₃)δ1.61-1.76(m，3H)，2.16-2.23(m，3H)，2.45(s，6H)，3.68(s，6H)，4.16(d，2H，J＝9.1Hz)，6.45-6.48(m，1H)，6.62-6.65(m，2H)，6.89-6.73(m，2H)，7.26-7.29(m，2H)，8.38(d，2H，J＝3.1Hz)；ES-MS m/z 418(M ⁺H)。

Embodiment 77

Chemical compound 77:(2 ' R, 6 ' S)-1 '-(2-methoxyl group-benzyl)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (197.6mg, 0.739mmol), 2-methoxy-benzyl chlorine (125 μ L, 0.898mmol), DIPEA (195 μ L, 1.12mmol) and KI (10mg, CH 0.060mmol) ₃CN (6mL) solution is warmed to 50 ℃, and stirs 26h.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting) purification makes white solid chemical compound 77 (78mg, 31%). ¹H NMR(CDCl ₃)δ1.20-1.30(m，3H)，1.65-1.72(m，1H)，2.15-2.25(m，2H)，2.40(s，6H)，3.59(s，3H)，4.05-4.15(m，2H)，6.32(bs，1H)，6.55-6.60(m，1H)，6.81-6.91(m，4H)，7.23-7.25(m，2H)，8.36(bs，2H)；ES-MS m/z 388(M ⁺H)。

Embodiment 78

Chemical compound 78:[4-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-dimethyl-amine HBr salt

With 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (221mg, water 0.476mmol) (10mL) solution alkalizes to pH13 with 1N NaOH (3mL), and with it with CH ₂Cl ₂(3 * 40mL) extractions.With the organic facies that merges with Na ₂SO ₄Drying is vacuum concentration also, makes the free alkali (177mg) of yellow oily.

At this free alkali (177mg, CH 0.511mmol) ₂Cl ₂(5mL) add in the solution paraformaldehyde (133mg, 4.43mmol).Mixture is stirred 10min.Add NaBH (OAc) then ₃(1.30g 6.14mmol), and stirs 16h at ambient temperature with mixture.With saturated NaHCO ₃Solution (10mL) cancellation reaction, and with CH ₂Cl ₂(30mL) dilution separates phase then.Water is with CH ₂Cl ₂(3 * 30mL) extractions.The organic layer that merges is with Na ₂SO ₄Dry also vacuum concentration.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (94.5: 5: 0.5) eluting) purification makes the title compound (188mg, 100%) of yellow oily. ¹H NMR(CDCl ₃)δ0.75-0.80(m，3H)，1.64-1.77(m，5H)，1.95-2.05(m，9H)，2.17-2.23(m，2H)，2.45-2.75(m，9H)，4.07(d，2H，J＝10.5Hz)，7.07(dd，2H，J＝7.5，4.8Hz)，7.42(d，2H，J＝7.5Hz)，8.46(bs，2H)。

According to general step B, [4-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-(188mg in MeOH 0.511mmol) (1mL) solution, adds the saturated MeOH solution (1mL) of HBr to dimethylamine.Collect the chemical compound 78 (199mg, 38%) of white solid. ¹HNMR(D ₂O)δ1.25-1.34(m，4H)，1.45-1.55(m，2H)，1.67-1.78(m，1H)，1.92-2.00(m，1H)，2.15(d，2H，J＝13.6Hz)，2.25-2.31(m，2H)，2.60(s，6H)，2.71(s，6H)，2.99-2.93(m，2H)，4.60(dd，2H，J＝11.3，2.9Hz)，7.90(dd，2H，J＝8.0，5.9Hz)，8.44(d，2H，J＝7.7Hz)，8.68(d，2H，J＝5.5Hz)； ¹³CNMR(D ₂O)δ19.44，22.19，24.71，34.83，45.26，54.39，56.69，60.03，128.34，139.34，142.13，151.92；ES-MS m/z 367(M ⁺H)。Analytical calculation value C ₂₃H ₃₄N ₄4.0 (HBr) 1.0 (H ₂O) 0.5 (C ₄H ₁₀O): C, 40.29; H, 6.09; N, 7.52; Br, 42.89. measured value: C, 40.31; H, 6.36; N, 7.57; Br, 42.81.

Embodiment 79

Chemical compound 79:5-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-the valeryl azanol

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (306mg, 1.12mmol), 5-bromo-ethyl valerate (263mg, 1.12mmol), DIPEA (260 μ L, 1.49mmol) and KI (10mg, CH 0.060mmol) ₃CN (12mL) solution is warmed to 60 ℃, and stirs 23h.Through silica gel with flash chromatography, with CH ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting purification, make yellow oily 5-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethyl valerate (417mg, 90%). ¹H NMR(CDCl ₃)δ0.75-0.94(m，3H)，1.17(t，3H，J＝7.1Hz)，1.55-2.01(m 8H)，2.20-2.35(m，6H)，2.47(s，6H)，3.99(q，2H，J＝7.2Hz)，7.05-7.09(m，2H)，7.43(d，2H，J＝7.6Hz)，8.46(bs，2H)。

(1.36g, the warm solution of MeOH 28.9mmol) (6.0mL) (50 ℃) joins NH with KOH ₂OHH ₂(1.00g is in the warm solution of MeOH 14.3mmol) (10.2mL) (50 ℃) for O.Stir 5min, generate white precipitate during this period rapidly.With the ice bath cooling, and the limpid hydroxylamine free acid solution of decantation.

With MeOH (5.3mL) solution of the azanol of prepared fresh add 5-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethyl valerate (228mg, 0.575mmol) in, and stir 23h at ambient temperature.Mixture is concentrated the removal volatile matter.To be collected in CH ₂Cl ₂Extract (50mL) is with saturated NaHCO ₃(30mL) solution washing is to pH8.Separate and with CH ₂Cl ₂(2 * 50mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry also vacuum concentration.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (89: 10: 1) eluting) purification makes the chemical compound 79 (121.3,55%) of white solid. ¹H NMR(CDCl ₃)δ0.85-0.95(m，4H)，1.55-2.00(m，14H)，2.40(s，6H)，3.85-3.93(bs，2H)，7.03-7.06(m，2H)，7.47(d，2H，J＝Hz)，8.31(bs，2H)； ¹³CNMR(CDCl ₃)δ18.86，22.73，23.59，32.31，32.76，53.44，62.23，122.17，130.73，139.26，146.78，169.62；ES-MS m/z 383(M ⁺H)。Analytical calculation value C ₂₂H ₃₀N ₄O ₂0.5 (CH ₂Cl ₂): C, 63.59; H, 7.35; N, 13.18. measured value: C, 63.69; H, 7.51; N, 13.36.

Embodiment 80

Chemical compound 80:6-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-the hexanoyl azanol

According to general step A, will (2 ' R, 6 ' S)-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (308mg, 1.15mmol), 6-bromo-ethyl hexanoate (283mg, 1.27mmol), DIPEA (260 μ L, 1.49mmol) and KI (10mg, CH 0.060mmol) ₃CN (12mL) solution is warmed to 60 ℃, and stirs 23h.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (94: 5: 1) eluting) purification, make yellow oily 6-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethyl hexanoate (425mg, 90%). ¹H NMR(CDCl ₃)δ0.60-0.68(m，2H)，0.79-0.85(m，1H)，1.13-1.25(m，5H)，1.58-1.70(m，3H)，1.94-1.98(m，4H)，2.08-2.25(m，7H)，2.48(bs，6H)，1.50-2.63(m，2H)，4.03(q，2H，J＝7.1Hz)，7.05-7.08(m，2H)，7.43(d，2H，J＝7.3Hz)，8.47(bs，2H)。

(1.36g, the warm solution of MeOH 28.9mmol) (6.0mL) (50 ℃) joins NH with KOH ₂OHH ₂(1.00g is in the warm solution of MeOH 14.3mmol) (10.2mL) (50 ℃) for O.Stir 5min, during the adularescent precipitation generate rapidly.With the ice bath cooling, and the limpid hydroxylamine free acid solution of decantation.

With MeOH (5.8L) solution of the azanol of prepared fresh add 5-((2 ' R, 6 ' S)-3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethyl valerate (262mg, 0.638mmol) in, under ambient temperature, stir 23h.Enriched mixture is to remove volatile matter.To be collected in CH ₂Cl ₂Extract (50mL) is with saturated NaHCO ₃(30mL) solution washing is to pH8.Separate and with CH ₂Cl ₂(2 * 50mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry also vacuum concentration.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (89: 10: 1) eluting) purification makes the chemical compound 80 (152,60%) of white solid. ¹H NMR(CDCl ₃)δ0.20-0.30(m，2H)，0.70-0.78(m，2H)，1.14-1.19(m，2H)，1.50-1.63(m，2H)，1.85-1.95(m，6H)，2.39(s，6H)，3.86(bs，2H)，7.02-7.06(m，2h)，7.46(d，2H，J＝6.7Hz)，8.48(d，2H，J＝3.0Hz)； ¹³C NMR(CDCl ₃)δ19.03，23.29，24.69，25.93，32.47，33.05，53.44，62.82，121.91，130.74，139.15，146.71，160.24，169.87；ES-MS m/z 383(M ⁺H)。Analytical calculation value C ₂₃H ₃₂N ₄O ₂0.4 (CH ₂Cl ₂): C, 65.29; H, 7.68; N, 13.01. measured value: C, 65.59; H, 7.78; N, 13.21.

Embodiment 81

Chemical compound 81: methyl-[4-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl) butyl]-amine HBr salt

(4-hydroxybutyl)-methyl-t-butyl carbamate (497mg, 2.44mmol) and Et ₃N (850 μ L, CH 6.10mmol) ₂Cl ₂(12mL) (0 ℃) in the cold soln, and adding MsCl (416 μ L, 0.537mmol).Mixture is warmed to ambient temperature, and stirs 1h.Add entry (20mL), and with mixture with CH ₂Cl ₂(3 * 50mL) extractions.With the organic facies that merges with Na ₂SO ₄Drying is vacuum concentration also, makes the methanesulfonates (815mg) of yellow oily.

In this methanesulfonates (815mg) and 2,2,6,6-tetramethyl piperidine (240 μ L, CH 1.42mmol) ₃Add 3,5,3 in CN (10mL) solution ", 5 " tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (328mg, 1.11mmol).According to general step A, mixture is warmed to 60 ℃, and stirs 16h.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (94.3: 5: 0.7) eluting) purification makes the product that contains enriched fraction.Product mixtures is dissolved in the CH that adds TFA (3mL) ₂Cl ₂(12mL), stir 16h.Reactant with 10N NaOH (7mL) alkalization, is added water (15mL) dilution, and with CH ₂Cl ₂(50mL) extraction.With CH ₂Cl ₂(2 * 40mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry also vacuum concentration.Through silica gel with flash chromatography (with CH ₂Cl ₂/ MeOH/NH ₄OH (90: 5: 5) eluting) purification makes free alkali (168mg, 40%). ¹H NMR(CDCl ₃)δ0.79-0.93(m，3H)，1.41-1.64(m，3H)，1.86-2.25(m，16H)，2.42(s，6H)，2.45-2.60(m，1H)，3.97(d，2H，J＝Hz)，7.22(s，2H)，8.18-8.29(m，2H)。

According to general step B, methyl-[4-(and 3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-(168mg in MeOH 0.440mmol) (1mL) solution, adds the saturated MeOH solution (1mL) of HBr to amine, collects the chemical compound 81 (240mg, 82%) of white solid. ¹H NMR(D ₂O)δ1.19-1.31(m，4H)，1.46-1.56(m，2H)，1.65-1.70(m，1H)，1.90-1.95(m，1H)，2.11(d，2H，J＝13.0Hz)，2.22-2.27(m，2H)，2.50(s，6H)，2.55(s，6H)，2.57(s，3H)，2.75-2.81(m，2H)，4.53(d，2H，J＝9.1Hz)，8.26(s，2H)，8.51(s，2H)； ¹³C NMR(D ₂O)δ16.96，17.56，20.05，22.43，23.84，32.65，32.99，48.80，52.14，57.55，136.00，137.42，139.20，150.10，151.69；ES-MS m/z381(M ⁺H)。Analytical calculation value C ₂₄H ₃₆N ₄3.0 (HBr) 2.1 (H ₂O): C, 43.60; H, 6.59; N, 8.47; Br, 36.26. measured value: C, 43.62; H, 6.38; N, 8.15; Br, 36.26.

Embodiment 82

Chemical compound 82:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butyramide (HBr salt)

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-(121mg in TFA 0.363mmol) (2.5mL) solution, adds dense H to butyronitrile ₂SO ₄(5-6 drips), and solution stirring refluxed spend the night.Reaction is cooled to room temperature, adds water (10mL) dilution, alkalize to pH＞10 with 4N NaOH, and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying concentrates, and through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂/ MeOH/NH ₄OH, 25: 1: 1) purification, make the primary amide (94mg, 74%) of white solid.

According to general step B: (94mg 0.27mmol) is converted into its HBr salt, then with MeOH/ ether redeposition crude product, makes the chemical compound 82 (136mg, 79%) of white solid will to go up the free alkali of step gained. ¹HNMR(D ₂O)δ.1.46-1.59(m，4H)，1.66-1.78(m，1H)，1.85(t，2H，J＝6.9Hz)，1.93-1.98(m，1H)，2.11-2.24(m，4H)，2.60(s，6H)，4.60(dd，2H，J＝11.4，2.7Hz)，7.89(dd，2H，J＝8.1，6Hz)，8.42(d，2H，J＝8.1Hz)，8.67(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ17.16，19.26，22.45，32.33，32.57，52.08，58.07，126.04，137.09，139.72，149.56，154.59，178.48；ES-MS m/z 353(M ⁺H)。Analytical calculation value C ₂₁H ₂₈N ₄O2.7HBr2.8H ₂O0.3 C ₄H ₁₀O:C, 41.43; H, 6.15; N, 8.70; Br, 33.52. measured value: C, 41.30; H, 5.86; N, 8.56; Br, 33.77.

Embodiment 83

Chemical compound 83:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butyronitrile (HBr salt)

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (0.293g, 1.10mmol), 4-bromine butyronitrile (0.15mL, 1.51mmol), (0.30mL, DMF 1.73mmol) (3mL) solution is heated to 65 ℃, 17h for KI (10mg) and DIPEA.Crude product through silica gel with column chromatography (CH ₂Cl ₂-CH ₃OH, 96: 4) purification, make 290mg (79%) colorless oil 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butyronitrile.

According to general step B: with the free alkali of gained (60mg 0.18mmol) is converted into HBr salt, then with MeOH/ ether redeposition crude product, make the yellow solid shape chemical compound 83 (86mg, 90%). ¹HNMR(D ₂O)δ.1.50-1.80(m，5H)，1.95-2.00(m，1H)，2.12-2.18(m，4H)，2.30-2.40(m，2H)，2.61(s，6H)，4.63(dd，2H，J＝11.4，3.0Hz)，7.91(dd，2H，J＝8.1，6Hz)，8.44(d，2H，J＝8.1Hz)，8.69(d，2H，J＝5.7Hz)； ¹³CNMR(D ₂O)δ.14.88，17.19，19.02，22.39，32.55，51.34，57.89，120.71，126.16，137.16，139.92，149.716，154.27；ES-MS m/z 335(M ⁺H)。Analytical calculation value C ₂₁H ₂₆N ₄2.1HBr1.4H ₂O:C, 47.63; H, 5.88; N, 10.58; Br, 31.68. measured value: C, 47.64; H, 5.85; N, 10.60; Br, 31.61.

Embodiment 84

Chemical compound 84:[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-pyridine-2-ylmethyl-amine (HBr salt)

According to general step C: 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (84mg, CH 0.249mmol) ₂Cl ₂(5mL) in the solution, (0.019mL 0.20mmol), adds NaBH (OAc) then to add the 2-pyridine carboxaldehyde ₃(73mg, 0.34mmol), 3h is at room temperature stirred in reaction.Crude product through silica gel with radial chromatography (1mm plate, 25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification, make 30mg (35%) colorless oil [4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-pyridine-2-base methylamine.

According to general step B: with the free alkali of gained (30mg 0.070mmol) is converted into HBr salt, then with MeOH/ ether redeposition crude product, make the orange solids shape chemical compound 84 (26mg, 46%). ¹HNMR(D ₂O)δ.1.35-1.57(m，6H)，1.64-1.76(m，1H)，1.92-1.97(m，1H)，2.12-2.16(m，2H)，2.25-2.30(m，2H)，2.60(s，6H)，2.99-3.04(m，2H)，4.50(s，2H)，4.61(d，2H，J＝9.3Hz)，7.82-7.99(m，4H)，8.42(d，2H，J＝7.8Hz)，8.44-8.49(m，1H)，8.68(d，2H，J＝5.7Hz)，8.77(d，1H，J＝5Hz)； ¹³CNMR(D ₂0)δ.17.28，19.99，22.44，23.98，32.55，48.07，48.43，52.11，57.74，126.05，127.67，127.78，136.97，139.85，145.04，146.11，149.67，154.51；ES-MS m/z 430(M ⁺H)。Analytical calculation value C ₂₇H ₃₅N ₅3.9HBr3.3H ₂O:C, 40.30; H, 5.70; N, 8.70; Br, 38.73. measured value: C, 40.53; H, 5.53; N, 8.32; Br, 38.81.

Embodiment 85

Chemical compound 85:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-N-hydroxyl-butyramide

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butyronitrile (348mg, EtOH/H 1.04mmol) ₂(1: 1, (455mg 11.4mmol), and will react to reflux and spend the night O 10mL) to add NaOH in the solution.With the mixture cooling, be acidified to pH3-4 then with 6N HCl, and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated, make the foamed required carboxylic acid of brown (270mg).

Under 0 ℃, at the CH of last step gained crude acid (270mg) ₂Cl ₂(5mL) add DMF (3) in the solution, add then oxalyl chloride (0.10mL, 1.15mmol).Reaction is warmed to room temperature, stirs 1h45min.Vacuum concentration then.CH at the rough residue of gained ₂Cl ₂(5mL) in the solution, add DIPEA (0.35mL, 2.01mmol), NH ₂OHH ₂O (82mg, 1.18mmol), EDC (157mg, 0.82mmol) and HOBt (110mg 0.81mmol), and stirs mixture and spends the night.Reaction is with CH ₂Cl ₂(25mL) with saturated NaHCO ₃Aqueous solution (25mL) dilution is with CH ₂Cl ₂(2 * 10mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Drying concentrates, and through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-MeOH-NH ₄OH, 25: 1: 1 10: 1: 1 then) purification, make colorless oil chemical compound 85 (52mg, 18%, 2 step). ¹H NMR(CDCl ₃)δ.1.22-1.30(br m，2H)，1.46-1.56(m，3H)，1.67-1.71(m，2H)，1.80-1.87(m，5H)，2.05(br s，2H)，2.46(s，6H)，3.92(d，2H，J＝9Hz)，7.01(dd，2H，J＝7.5，4.8Hz)，7.50(d，2H，J＝7.5Hz)，8.10(d，2H，J＝4.8Hz)； ¹³C NMR(CDCl ₃)δ.18.62，19.48，25.76，31.22，33.55，51.21，62.85，122.21，131.26，139.48，146.87，160.16，169.24；ES-MS m/z 369(M ⁺H)。Analytical calculation value C ₂₁H ₂₈N ₄O ₂0.7H ₂O:C, 66.19; H, 7.78; N, 14.70. measured value: C, 66.22; H, 7.64; N, 14.40.

Embodiment 86

Chemical compound 86:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-daminozide

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] (163mg, in EtOH 0.445mmol) (5mL) solution, (0.65mL 13.4mmol), and is heated to 80 ℃, 2.5d with reaction to terpyridyl-1 '-yl)-ethyl n-butyrate. to add single hydrazine hydrate.Enriched mixture then, through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂/ CH ₃OH/NH ₄OH, 50: 1: 1 25: 1: 1 then) purification, obtain white solid chemical compound 86 (145mg, 89%). ¹H NMR(CDCl ₃)δ0.77-0.81(br m，2H)，1.49-1.66(m，5H)，1.92-2.11(m，3H)，2.22-2.29(m，2H)，2.47(s，6H)，3.66(br s，2H)，3.98(dd，2H，J＝11.4，2.4Hz)，4.34(br s，1H)，7.07(dd，2H，J＝7.5，4.8Hz)，7.42(d，2H，J＝7.5Hz)，8.43(br m，2H)； ¹³C NMR(CDCl ₃)δ.19.25，22.19，25.18，32.19，32.46，52.60，63.79，122.22，131.13，138.91，147.09，161.00，173.75；ES-MS m/z368(M ⁺H)。Analytical calculation value C ₂₁H ₂₉N ₅O1.2H ₂O:C, 64.82; H, 8.13; N, 18.00. measured value: C, 64.99; H, 7.97; N, 17.69.

Embodiment 87

Chemical compound 87:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 ' tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-Ding-1-alcohol

Under 0 ℃, 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] (332mg in THF 0.87mmol) (5mL) solution, adds LiAlH to terpyridyl-1 '-yl)-ethyl n-butyrate. ₄(the THF solution of 1.0M, 1.4mL 1.4mmol), will be reflected at interior stirring of 2h and be warmed to room temperature by 0 ℃.Mixture is with water (0.050mL), 15%NaOH aqueous solution (0.050mL) cancellation, and then adds water (0.15mL) and stir 15min.With Na ₂SO ₄Drying composite, and filter, with CH ₂Cl ₂Eluting.Concentrated filtrate, and through silica gel with column chromatography (CH ₂Cl ₂/ CH ₃OH/NH ₄OH, 96: 4: 0 88: 10: 2 then) purification, make the chemical compound 87 (266mg, 90%) of colorless oil. ¹H NMR(CDCl ₃)δ0.88-0.92(m，4H)，1.57-1.63(m，3H)，1.92-2.06(m，3H)，2.22-2.29(m，2H)，2.46(s，6H)，2.63(m，1H)，3.13-3.15(m，2H)，4.15-4.21(m，2H)，7.08(dd，2H，J＝7.5，4.8Hz)，7.43(d，2H，J＝7.5Hz)，8.44(br m，2H)； ¹³C NMR(CDCl ₃)δ.19.04，21.57，25.11，30.51，49.73，62.15，63.65，71.12，122.37，131.86，138.87，147.02，160.10；ES-MS m/z 340(M ⁺H)。Analytical calculation value C ₂₁H ₂₉N ₃O1.4H ₂O:C, 69.16; H, 8.79; N, 11.52. measured value: C, 69.21; H, 8.56; N, 11.50.

Embodiment 88

Chemical compound 88:4-(5,5 "-two chloro-4 '-hydroxyls-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-Benzoylamide

(1.99g adds NH in MeOH 12.81mmol) (30mL) solution at 5-chloro-3-methyl-pyridine-2-formaldehyde ₄(530mg, 6.88mmol) and 1, (913mg 6.25mmol), and at room temperature stirs 29h with mixture to the 3-acetone dicarboxylic acid to OAc.Vacuum concentrated mixture adds saturated NaHCO successively ₃(50mL) and CH ₂Cl ₂(75mL).Separate biphase, with CH ₂Cl ₂(2 * 30mL) aqueous phase extracted.Organic extract is with Na ₂SO ₄Drying is filtered and is concentrated.Crude product with flash chromatography (EtOAc: hexane, 1: 31: 1 then) purification, makes yellow cystose 5,5 by silica gel "-two chloro-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone.

Under 0 ℃, in the MeOH of above-mentioned ketone (1.12g) (20mL) solution, add NaBH ₄(260mg 6.87mmol), and will be reflected at 0 ℃ of stirring 30min down.Then it is warmed to room temperature, and stirs 5h.Mixture is through vacuum concentration, then with CH ₂Cl ₂(40mL) with saturated NaHCO ₃Aqueous solution (30mL) dilution.Water is with CH ₂Cl ₂(2 * 10mL) extractions, the organic extract of merging is with Na ₂SO ₄Dry and concentrated.Rough orange (369mg) through silica gel with column chromatography (CH ₂Cl ₂/ MeOH, 96: 4 92: 8 then) purification, make 5,5 "-two chloro-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl-4 '-alcohol (590mg, 27%, 2 step). ¹H NMR(CDCl ₃)δ1.30(q，2H，J＝11.7Hz)，1.98(d，2H，J＝12Hz)，2.31(s，6H)，2.72-2.82(m，2H)，3.84-3.89(m，1H)，4.05(t，2H，J＝11.1Hz)，7.40(s，2H)，8.35(s，2H)。

According to general step A: with 5,5 "-two chloro-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 '; 2 " ] terpyridyl-4 '-alcohol (590mg, 1.68mmol), 2-bromomethyl-5-cyano group-essence of Niobe (39144-20059.00, U.S. Patent application) (512mg, 2.02mmol), KI (15mg) and DIPEA (0.45mL, 2.59mmol) DMF (4mL) solution be heated to 70 ℃, 17h.Crude product through silica gel with column chromatography (CH ₂Cl ₂-CH ₃OH, 99: 1 96: 4 then) purification, make the brown foamed required alkylation material of 779mg (88%).

(152mg in THF 0.29mmol) (5mL) cold soln (0 ℃), adds LiBH at last step gained methyl ester ₄(51mg 2.34mmol), and is warmed to room temperature with mixture, is heated to 65 ℃ then, 4h15min.With 1NNaOH (10mL) diluted mixture thing, and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Dry and concentrated, gained alcohol is directly used in the next step without being further purified.

MeOH/H at last step gained nitrile ₂O (2: 1,6mL) in the solution, add NaBO ₃-4H ₂(121mg 0.79mmol), and is heated to 55 ℃, 2.5d with reaction to O.Enriched mixture, and through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-CH ₃OH-NH ₄OH, 100: 1: 1 50: 1: 1 then) purification, make white solid chemical compound 88 (25mg, 17%, 2 step). ¹H NMR(DMSO-d ₆)δ1.70-1.75(m，2H)，2.22(q，2H，J＝12Hz)，2.50(s，6H)，3.48(s，2H)，3.84-3.90(m，1H)，4.18(d，2H，J＝4.8Hz)，4.41(br d，2H，J＝11.7Hz)，4.82(d，2H，J＝4.5Hz)，6.79(d，1H，J＝7.8Hz)，7.02(s，1H)，7.25(d，1H，J＝7.8Hz)，7.37(s，1H)，7.43(s，2H)，7.59(s，1H)，8.18(s，2H)； ¹³C NMR(DMSO-d ₆)δ.17.96，33.68，41.65，61.10，61.73，68.61，124.71，125.84，126.51，129.64，130.88，135.14，137.00，138.04，142.85，144.15，156.53，168.02；ES-MS m/z 537(M ⁺Na)。Analytical calculation value C ₂₆H ₂₈N ₄O ₃Cl ₂1.8H ₂O:C, 57.00; H, 5.81; N, 10.23; Cl, 12.94. measured value: C, 56.98; H, 5.79; N, 9.88; Cl, 12.95.

Embodiment 89

Chemical compound 89:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] N-(2-hydroxyl-ethyl)-butyramide of terpyridyl-1 '-yl)

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butyronitrile (430mg, EtOH/H 1.29mmol) ₂(1: 1, (590mg 14.75mmol), and will react stirring and refluxing and spend the night O 4mL) to add NaOH in the solution.Reaction is cooled to room temperature, regulates pH to 3 with 6N HCl, and with CH ₂Cl ₂(3 * 15mL) extractions.With the organic extract that merges with Na ₂SO ₄Dry and concentrated, make the required acid of ecru cystose (0.42g).

At the last CH that goes on foot the crude acid (107mg) that makes ₂Cl ₂(5mL) in the solution, 0 add DIPEA (0.12mL, 0.69mmol), add then HOBt (59mg, 0.44mmol), ethanolamine (0.040mL, 0.66mmol) and EDC (76mg 0.40mmol), and spends the night the mixture stirring.To react with CH ₂Cl ₂(15mL) with saturated NaHCO ₃Aqueous solution (25mL) dilution, water is with CH ₂Cl ₂(2 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying concentrates, and through silica gel with radial chromatography (1mm plate, CH ₂Cl2-MeOH-NH ₄OH, 100: 1: 1 25: 1: 1 then) purification, make the chemical compound 89 (83mg, 70%, 2 step) of colorless oil. ¹HNMR(CDCl ₃)δ.0.69-0.73(m，2H)，1.42(t，2H，J＝6.3Hz)，1.50-1.68(m，3H)，1.91-1.97(m，1H)，2.04-2.17(m，2H)，2.23(t，2H，J＝6.3Hz)，2.42(s，6H)，3.39-3.43(m，2H)，3.57-3.70(m，1H)，3.77-3.81(m，2H)，3.85(d，2H，J＝12Hz)，7.07(dd，2H，J＝7.5，4.8Hz)，7.44(dd，2H，J＝7.5，0.9Hz)，8.12(br s，1H)，8.41(d，2H，J＝3.9Hz)； ¹³C NMR(CDCl ₃)δ.19.54，22.99，25.78，32.67，36.18，43.08，55.05，62.34，65.59，122.52，131.29，138.99，147.16，160.56，174.15；ES-MS m/z 397(M ⁺H)。Analytical calculation value C ₂₃H ₃₂N ₄O ₂2.2H ₂O:C, 63.34; H, 8.41; N, 12.85. measured value: C, 63.31; H, 8.21; N, 12.55.

Embodiment 90

Chemical compound 90:2 ' S, 6 ' R)-1 '-[3-(the 1H-benzimidazolyl-2 radicals-yl)-propyl group]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] (113mg in 3M HCl (3mL) solution 0.32mmol), adds 1 to terpyridyl-1 '-yl)-butanoic acid, and (40mg 0.37mmol), and will react backflow and spend the night the 2-phenylenediamine.Mixture is cooled to room temperature, with solid Na ₂CO ₃Neutralization, and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying concentrates, through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-MeOH-NH ₄OH, 50: 1: 1 25: 1: 1 then) purification, make light yellow oily chemical compound 90 (31mg, 23%). ¹H NMR(CDCl ₃)δ1.16-1.26(m，2H)，1.50-1.66(m，3H)，1.88-2.07(m，3H)，2.21-2.30(m，3H)，2.35(s，6H)，2.46-2.57(m，1H)，3.97(d，2H，J＝12Hz)，5.62(br s，1H)，6.87(dd，2H，J＝7.2，4.8Hz)，7.13-7.20(m，4H)，7.28-7.35(br m，1H)，7.53-7.59(br m，1H)，8.20-8.26(m，2H)； ¹³CNMR(CDCl ₃)δ.19.22，24.78，25.14，27.09，32.66，52.74，63.85，111.25，118.84，121.76，122.17，131.17，138.85，146.79，155.44，160.86；ES-MS m/z426(M ⁺H)。Analytical calculation value C ₂₇H ₃₁N ₅3.0H ₂O:C, 67.62; H, 7.78; N, 14.60. measured value: C, 67.36; H, 7.68; N, 14.97.

Embodiment 91

Chemical compound 91:[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-(1H-imidazoles-2-yl)-amine

Under-78 ℃, the oxalyl chloride (0.2mL, CH 2.29mmol) that are stirring ₂Cl ₂(5mL) in the solution, and adding DMSO (0.40mL, 5.64mmol).Behind the 15min, under-78 ℃, add successively 4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-Ding-1-alcohol (227mg, CH 0.67mmol) ₂Cl ₂(5mL) solution and Et ₃(1.0mL 7.18mmol), is warmed to reaction room temperature and stirs 2h N then.With CH ₂Cl ₂(20mL) with saturated NaHCO ₃Aqueous solution (25mL) diluting reaction, and with water with CH ₂Cl ₂(3 * 10mL) extractions.The organic facies that merges is with Na ₂SO ₄Drying is filtered and concentrating under reduced pressure, makes brown buttery required aldehyde (250mg).

With 2-aminooimidazole sulfate (354mg, 2.68mmol) and NaOH (120mg, MeOH 3.0mmol) (3mL) suspension stir and to spend the night, then with CH ₂Cl ₂(20mL) dilution, and through diatomite filtration, with 10: 1CH ₂Cl ₂/ MeOH washing.Concentrated filtrate makes brown buttery free 2-aminooimidazole (167mg).MeOH (5mL) solution of free amine group imidazoles and last step gained aldehyde (0.67mmol) under 40 ℃, is stirred 3d.Add NaBH then ₄(110mg 2.91mmol), and will react and stir 1h, concentrate, with CH ₂Cl ₂(25mL) with saturated NaHCO ₃Aqueous solution (25mL) dilution.Water is with CH ₂Cl ₂(2 * 10mL) extractions are with Na ₂SO ₄The dry organic facies that merges, concentrating under reduced pressure, through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-MeOH-NH ₄OH, 50: 1: 1 25: 1: 1 then) purification, make ecru foam-like compound 91 (78mg, 29%, 2 step). ¹H NMR(CDCl ₃)δ.0.70-0.75(m，3H)，1.50-1.65(m，3H)，1.89-2.08(m，6H)，2.39(s，6H)，2.69-2.73(m，3H)，3.95(dd，2H，J＝9.6，1.2Hz)，4.17(br s，1H)，6.56(s，2H)，6.96-7.01(m，2H)，7.36(d，2H，J＝7.5Hz)，8.29(d，2H，J＝3Hz)； ¹³CNMR(CDCl ₃)δ.19.16，22.60，25.35，28.06，31.72，43.81，50.61，63.37，117.98，122.22，131.45，138.90，146.93，151.64，160.86；ES-MS m/z405(M ⁺H)。Analytical calculation value C ₂₄H ₃₂N ₆1.4H ₂O:C, 67.07; H, 8.16; N, 19.55. measured value: C, 67.23; H, 7.83; N, 19.17.

Embodiment 92

Chemical compound 92:3,3 "-dimethyl-1 '-(2-pyridin-3-yl-ethyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl

Under 0 ℃ ,-(983mg in THF 5.95mmol) (10mL) solution, adds LiAlH to the pyridylacetic acid ethyl ester ₄(in the 1.0MTHF solution, 9.0mL, 9.0mmol) solution, and will react and stir 15min.Under 0 ℃, successively with water (0.35mL), 15%NaOH aqueous solution (0.35mL), H ₂O (1.0mL) cancellation.Mixture is stirred 10min.Filter then, with Et ₂O and EtOAc washing.Concentrated filtrate, through silica gel with column chromatography (CH ₂Cl ₂/ MeOH, 96: 4) purification, make the required alcohol (0.47g, 64%) of colorless oil.

Under-78 ℃, at last step gained alcohol (366mg, CH 2.98mmol) ₂Cl ₂(10mL) in the solution, add Et ₃N (0.85mL, 6.11mmol) and mesyl chloride (0.35mL 4.52mmol), will be reflected under-78 ℃ then, stir 25min.With mixture with CH ₂Cl ₂(25mL) with saturated NaHCO ₃Aqueous solution (25mL) dilution, water is with CH ₂Cl ₂(2 * 10mL) extractions.The organic facies that merges is through Na ₂SO ₄Dry and concentrated, make methanesulfonic acid 2-pyridin-3-yl-ethyl ester, and it is used for next step reaction without being further purified.

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (0.219g, 0.82mmol), (0.25mL, DMF 1.44mmol) (3mL) solution is heated to 80 ℃, 17h for methanesulfonic acid 2-pyridin-3-yl-ethyl ester (about 3mmol), KI (15mg) and DIPEA.Crude product through silica gel with column chromatography (CH ₂Cl ₂-CH ₃OH-NH ₄OH, 94: 4: 2) purification, and then through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-CH ₃OH-NH ₄OH, 50: 1: 1) purification, make the chemical compound 92 of 193mg (63%) colorless oil. ¹H NMR(CDCl ₃)δ.1.61-1.70(m，4H)，2.00-2.22(m，4H)，2.51(s，6H)，2.51-2.55(m，2H)，4.14-4.18(m，2H)，6.55-6.60(m，1H)，6.85(dd，1H，J＝7.5，4.8Hz)，7.09-7.12(m，2H)，7.42(d，2H，J＝6.9Hz)，7.54-7.60(m，1H)，8.18(dd，1H，J＝4.8，1.5Hz)，8.42-8.46(m，2H)； ¹³C NMR(CDCl ₃)δ.17.59，22.43，24.32，26.23，28.85，30.67，47.26，51.85，63.52，70.06，121.05，121.87，131.24，134.51，137.16，138.57，145.34，145.73，148.78，158.55；ES-MS m/z 373(M ⁺H)。Analytical calculation value C ₂₄H ₂₈N ₄0.3H ₂O:C, 76.28; H, 7.63; N, 14.83. measured value: C, 76.14; H, 7.78; N, 14.82.

Embodiment 93

Chemical compound 93:O-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-azanol

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 '; 2 " ] terpyridyl (253mg, 0.95mmol), 2-(3-bromo-propoxyl group)-iso-indoles-1,3-diketone (Canne, L.E, Deng, (1996) 118:5891-5896 J.Am.Chem.Soc.) (334mg, 1.18mmol), KI (15mg) and DIPEA (0.35mL, DMF 2.01mmol) (3mL) solution, be heated to 70 ℃, 17h.Crude product through silica gel with column chromatography (CH ₂Cl ₂-CH ₃OH-NH ₄OH, 96: 4: 0 94: 4: 2 then), make brown cystose alkylation material (260mg, 58%).

(181mg, in MeOH 0.385mmol) (5mL) solution, (0.10mL 2.06mmol), and at room temperature will react to stir and spend the night to add single hydrazine hydrate at last step gained phthalimide.Filtering mixt, concentrate and through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-CH ₃OH-NH ₄OH, 50: 1: 1 25: 1: 1 then) purification, make the chemical compound 93 (88mg, 67%) of colorless oil. ¹H MR(CDCl ₃)δ.0.91-0.97(m，1H)，1.55-1.66(m，3H)，1.94-2.08(m，3H)，2.29(t，2H，J＝6Hz)，2.50(s，6H)，2.95-3.04(m，2H)，4.04(br d，2H，J＝12Hz)，4.83(br s，3H)，7.05(dd，1H，J＝7.5，4.8Hz)，7.40(d，2H，J＝7.5Hz)，8.41-8.43(m，2H)； ¹³C NMR(CDCl ₃)δ.21.06，26.85，27.52，31.84，47.27，49.48，66.12，73.32，76.51，124.11，140.54，141.82，148.93，162.55；ES-MS m/z 341(M ⁺H)。Analytical calculation value C ₂₀H ₂₈N ₄O0.7H ₂O:C, 68.04; H, 8.39; N, 15.87. measured value: C, 68.04; H, 8.34; N, 15.62.

Embodiment 94

Chemical compound 94:O-(3,3 "-dimethyl-3 ' 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-hydroxyurea

O-[3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-azanol (100mg, CH 0.29mmol) ₂Cl ₂(4.5mL) in the solution, (0.075mL 0.55mmol), and will react and stir 2.5d to add Carbimide. trimethyl first estersil.Enriched mixture, through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-CH ₃OH-NH ₄OH, 25: 1: 1) purification, make the chemical compound 94 (43mg, 39%) of white solid. ¹H NMR(CD ₃OD)δ.1.09-1.16(m，1H)，1.61-1.70(m，4H)，1.98-2.16(m，3H)，2.29-2.34(m，2H)，2.61-2.71(m，6H)，3.09-3.18(m，2H)，3.97-4.10(m，2H)，7.19-7.23(m，2H)，7.61(d，2H，J＝7.5Hz)，8.30-8.35(m，2H)； ¹³CNMR(CD ₃OD)δ.19.38，20.10，25.06，26.55，29.07，31.53，39.72，47.17，66.39，72.15，75.95，76.55，124.05，134.47，141.02，142.25，147.16，147.58，161.33，164.28；ES-MS m/z 384(M ⁺H)。Analytical calculation value C ₂₁H ₂₉N ₅O ₂0.3H ₂O:C, 64.86; H, 7.67; N, 18.01. measured value: C, 64.97; H, 7.63; N, 17.83.

Embodiment 95

Chemical compound 95:[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-the N-hydroxyurea

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (558mg, 2.09mmol), the 4-nitro benzyl bromide (547mg, 2.53mmol), KI (15mg) and DIPEA (0.60mL, CH 3.45mmol) ₃CN (10mL) solution is heated to 65 ℃, 17h.Crude product through silica gel with column chromatography (CH ₂Cl ₂-CH ₃OH, 96: 4 92: 8 then) purification, make yellow foamed N-alkylation material (0.73g, 87%).

3,3 "-dimethyl-1 '-(4-nitro-benzyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (245mg, in THF 0.61mmol) (3mL) solution, add successively rhodium (5% drapes over one's shoulders on carbon, 15mg) and hydrazine hydrate (0.30mL 6.15mmol), and will react and stir 6.5h.With mixture through diatomite filtration, with MeOH and CH ₂Cl ₂Washing, concentrated filtrate.CH at the gained residue ₂Cl ₂(0.13mL 0.96mmol), and will react to stir and spend the night (6mL) to add Carbimide. trimethyl first estersil in the solution.Enriched mixture, through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-CH ₃OH-NH ₄OH, 50: 1: 1 to 10: 1: 1) purification, make yellow foam-like compound 95 (37mg, 14%). ¹H NMR(CDCl ₃/CD ₃OD)δ.1.34-1.42(m，1H)，1.59-1.81(m，5H)，2.24(s，6H)，3.15(s，2H)，3.24-3.46(m，3H)，3.82(br d，2H，J＝9Hz)，6.28(d，2H，J＝7.5Hz)，7.00(dd，2H，J＝7.2，4.8Hz)，7.16(d，2H，J＝8.1Hz)，7.34(d，2H，J＝7.2Hz)，8.29(d，2H，J＝3Hz)； ¹³CNMR(CDCl ₃/CD ₃OD)δ.18.79，24.68，32.36，53.94，62.16，119.82，122.59，129.65，130.42，131.67，138.70，141.42，146.67，158.98，159.94；ES-MS m/z432(M ⁺H)。Analytical calculation value C ₂₅H ₂₉N ₅O ₂1.9H ₂O:C, 64.47; H, 7.10; N, 15.04. measured value: C, 64.43; H, 6.77; N, 15.05.

Embodiment 96

Chemical compound 96:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-N-(1H-imidazoles-2-yl)-butyramide

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-suitable-[2,2 '; 6 '; 2 " ] terpyridyl-1 '-yl)-butanoic acid (192mg, 0.544mmol) DMF (3mL) solution in, add 2-aminooimidazole sulfate (99mg, 0.75mmol), DIPEA (0.30mL, 1.73mmol), HOBt (99mg, 0.73mmol) and EDC (160mg, 0.83mmol), and mixture stirred spend the night.With CH ₂Cl ₂(30mL) with saturated NaHCO ₃Aqueous solution (25mL) diluted mixture thing, and with CH ₂Cl ₂(2 * 15mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Drying concentrates, and through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-MeOH-NH ₄OH, 25: 1: 1) purification, make white solid chemical compound 96 (132mg, 58%). ¹H NMR(CDCl ₃)δ.0.97-1.03(m，1H)，1.58-1.81(m，6H)，1.95-2.15(m，3H)，2.32-2.45(m，3H)，2.46(s，6H)，3.85-3.96(m，1H)，4.04-4.08(m，2H)，6.41(br s，1H)，6.68(br s，1H)，6.96(dd，2H，J＝7.5，4.8Hz)，7.32(d，2H，J＝7.5Hz)，8.35-8.39(m，2H)，10.66(br s，1H)； ¹³C NMR(CDCl ₃)δ.19.14，22.20，25.50，30.58，34.48，49.14，63.77，111.36，122.10，123.75，131.56，138.65，143.42，147.09，160.49，172.87；ES-MS m/z 419(M ⁺H)。Analytical calculation value C ₂₄H ₃₀N ₆O1.0H ₂O:C, 66.03; H, 7.39; N, 19.25. measured value: C, 65.96; H, 7.33; N, 19.09.

Embodiment 97

Chemical compound 97:(3,3 "-dimethyl-1 '-(2-pyridine-2-base-ethyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] the preparation of terpyridyl

Under-78 ℃, at 2-(2-ethoxy) pyridine (602mg, CH 4.89mmol) ₂Cl ₂(10mL) add Et in the solution ₃N (1.0mL, 7.20mmol) and mesyl chloride (0.45mL 5.8mmol), is warmed to reaction room temperature and stirs 15min.With mixture with CH ₂Cl ₂(25mL) with saturated NaHCO ₃Aqueous solution (25mL) dilution, and with CH ₂Cl ₂(2 * 10mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry and concentrated, make required methylsulfonyl ester (1.01g), it is used for next step reaction without being further purified.

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-suitable-[2,2 '; 6 ', 2 "] terpyridyl (252mg, 0.94mmol), methanesulfonic acid 2-pyridine-2-base-ethyl ester (about 4.9mmol) and K ₂CO ₃(1.30g, DMF 9.42mmol) (5mL) suspension is heated in 85 ℃ 2.5d.Crude product through silica gel with column chromatography (CH ₂Cl ₂-CH ₃OH-NH ₄OH, 96: 4: 0 94: 4: 2 then) purification, and then through silica gel with radial chromatography (1mm plate, CH ₂Cl ₂-CH ₃OH-NH ₄OH, 25: 1: 1) purification, make the light yellow oily chemical compound 97 of 152mg (43%). ¹H NMR(CDCl ₃)δ.1.60-1.72(m，3H)，1.96-2.23(m，5H)，2.51(s，6H)，2.61-2.66(m，2H)，4.15(d，2H，J＝12Hz)，6.33-6.38(m，1H)，6.85(dd，1H，J＝7.2，5.1Hz)，7.07(dd，2H，J＝7.5，4.8Hz)，7.27(dt，1H，J＝7.5，1.5Hz)，7.40(d，2H，J＝7.5Hz)，8.19(d，1H，J＝4.8Hz)，8.42-8.47(m，2H)； ¹³CNMR(CDCl ₃)δ.19.18，25.52，30.76，34.77，49.87，63.61，120.80，122.22，122.76，131.72，136.15，138.83，147.10，149.18，160.47，161.42；ES-MS m/z373(M ⁺H)。Analytical calculation value C ₂₄H ₂₈N ₄1.6H ₂O:C, 71.83; H, 7.84; N, 13.96. measured value: C, 71.84; H, 7.53; N, 13.65.

Embodiment 98

Chemical compound 98:4-(3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 ,-ylmethyl)-3-methylol-Benzoylamide

According to general step A: with 3,3 "-two chloro-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (304mg, 0.987mmol), 2-bromomethyl-5-cyano group-essence of Niobe (351mg, 1.38mmol), KI (32.7mg, 0.197mmol), (0.34mL 1.97mmol) and DMF (5mL), stirs 3h down at 60 ℃ to DIPEA.Crude product with silica gel through flash chromatography (CH ₂Cl ₂/ MeOH, 98: 2) purification, make yellow oily 5-cyano group-2-(3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (391mg, 82%). ¹H NMR(CDCl ₃)δ.1.63-1.78(m，3H)，2.01-2.14(m，1H)，2.18-2.38(m，2H)，3.87(s，3H)，3.95(s，2H)，4.52(dd，2H，J＝11.4，1.6Hz)，6.89(dd，2H，J＝8.4，4.9Hz)，7.38-7.48(m，3H)，7.57(d，1H，J＝1.7Hz)，8.22-8.32(m，3H)。

5-cyano group-2-(3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-(391mg in the cold soln (0 ℃) of THF 0.813mmol) (4mL) and MeOH (4mL), adds LiBH to essence of Niobe ₄(88mg 4.1mmol), and is warmed to room temperature with mixture, stirs 3.5h.With 1.0NNaOH (20mL) diluted mixture thing, and with CH ₂Cl ₂(4 * 10mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, through vacuum concentration obtain without any 4-that is further purified (3,3 "-two chloro-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (367mg).In the MeOH of crude product (160mg) (4.5mL) solution, add entry (2.5mL) and NaBO ₃4H ₂O (108mg, 0.707mmol).With gained mixture heated to 50 ℃, 5h, and at room temperature stir and spend the night.Concentrated reaction mixture, residue with silica gel through flash chromatography (CH ₂Cl ₂/ MeOH/NH ₄OH, 90: 5: 5 85: 10: 5 then) purification, make white solid chemical compound 98 (54mg, 32%, 2 step). ¹H NMR(CDCl ₃)δ.1.63-1.79(m，3H)，1.93-2.06(m，1H)，2.11-2.30(m，2H)，2.33-2.47(m，2H)，3.63(s，2H)，4.59(d，2H，J＝9.92Hz)，4.41(s，2H)，4.99(br s，1H)，5.67(br s，1H)，6.15(br s，1H)，6.85-6.96(m，2H)，7.04(d，1H，J＝7.8Hz)，7.24(d，1H，J＝1.8Hz)，7.38(d，1H，J＝1.5Hz)，7.48(dd，2H，J＝7.8，1.5Hz)，8.30(dd，2H，J＝4.5，1.2Hz)； ¹³C NMR(CDCl ₃)δ.24.98，31.59，57.28，62.72，66.56，123.45，126.39，128.11，129.90，131.55，131.70，137.47，140.08，142.64，147.77，158.55，169.17；ES-MS m/z 473(M ⁺1 ⁺H)。Analytical calculation value C ₂₄H ₂₄N ₄Cl ₂O ₂0.5 H ₂O:C, 60.01; H, 5.25; N, 11.66. measured value: C, 60.00; H, 5.15; N, 11.49.

Embodiment 99

Chemical compound 99:1 '-(3-imidazoles-1-base-propyl group)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (HBr salt)

(500mg, 7.35mmol) with 1, (356mg 8.82mmol), and with gained mixture backflow 1h, at room temperature stirs then and spends the night to add 60%NaH in THF (35mL) solution of 3-dibromopropane (2.2mL, 22.0) at the imidazoles that stirs.With mixture with water (25mL) cancellation, and with CH ₂Cl ₂(40mL) dilution.Water phase separated, and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and is concentrated into dried.With silica gel through flash chromatography (CH ₂Cl ₂/ MeOH, 97: 3) purification, make 1-(3-bromo-the propyl group)-1H-imidazoles (410mg, 30%) of colorless oil. ¹H NMR(CDCl ₃)δ2.20-2.34(m，2H)，3.31(t，2H，J＝6.3Hz)，4.16(t，2H，J＝6.2Hz)，6.93(s，1H)，7.08(s，1H)，7.51(s，1H)。

According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (91.3mg, 0.341mmol), 1-(3-bromo-propyl group)-1H-imidazoles (129mg, 0.680mmol), KI (5.6mg, 0.034mmol), (0.18mL 1.02mmol) and DMF (3.4mL), stirs down at 60 ℃ and to spend the night DIPEA.Crude product with silica gel through purified by flash chromatography (CH ₂Cl ₂/ MeOH/NH ₄OH, 90: 5: 5), and then through radial chromatography with 1mmTLC level silica gel plate purification (CH ₂Cl ₂/ MeOH/NH ₄OH, 96: 2: 2), make the free alkali (48mg, 38%) of the title compound of colorless oil.

According to general step B: with the free alkali of gained (48mg 0.13mmol) is converted into HBr salt, then with MeOH/ ether redeposition crude product, make the beige solid shape chemical compound 99 (84mg, 94%). ¹HNMR(D ₂O)δ.1.42-1.61(m，2H)，1.63-2.00(m，4H)，2.07-2.25(m，4H)，2.55(s，6H)，3.93(t，2H，J＝6.3Hz)，4.57(d，2H，J＝11.1Hz)，7.32(d，1H，J＝15.9Hz)，7.91(dd，2H，J＝7.8，6.0Hz)，8.42(d，2H，J＝8.1Hz)，8.53(s，1H)，8.69(d，2H，J＝5.4Hz)； ¹³C NMR(D ₂O)δ17.30，22.39，24.10，32.50，47.16，49.25，57.97，120.62，121.91，126.23，134.97，136.96，140.10，149.71，153.99；ES-MS m/z 376(M ⁺H)。Analytical calculation value C ₂₃H ₂₉N ₅3.3HBr2.8H ₂O:C, 39.87; H, 5.51; N, 10.11; Br, 38.05. measured value: C, 39.82; H, 5.45; N, 9.97; Br, 38.30.

Embodiment 100

Chemical compound 100:1 '-(4-imidazoles-1-base butyl)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (HBr salt)

(500mg, 7.35mmol) with 1, in THF (50mL) solution of 4-dibromobutane (2.6mL, 22.0), (356mg 8.81mmol), and with gained mixture backflow 2h, at room temperature stirs then and spends the night to add 60%NaH at the imidazoles that stirs.With mixture with water (50mL) cancellation, and with CH ₂Cl ₂(75mL) dilution.Water phase separated and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and is concentrated into drying.With silica gel through flash chromatography (CH ₂Cl ₂/ MeOH, 97: 3) purification, make 1-(4-brombutyl)-1H-imidazoles that part is decomposed.This material is further purified direct use without any.According to general step A: with 3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (94.4mg, 0.353mmol), impure 1-(4-brombutyl)-1H-imidazoles (145mg), KI (6.0mg, 0.035mmol), DIPEA (0.18mL, 1.02mmol) and DMF (3.5mL) in 60 ℃, stir 48h.Crude product is through the silica gel plate purification (CH of radial chromatography with the 1mmTLC level ₂Cl ₂/ MeOH/NH ₄OH, 96: 2: 2), make the free alkali (47mg, 34%, 2 step) of the title compound of colorless oil.

According to general step B: with the free alkali of gained (48mg 0.13mmol) is converted into HBr salt, then with MeOH/ ether redeposition crude product, make the beige solid shape chemical compound 100 (85mg, 92%). ¹HNMR(D ₂O)δ.1.01-1.19(m，2H)，1.35-1.56(m，4H)，1.58-1.80(m，1H)，1.82-1.95(m，1H)，1.96-2.15(m，2H)，2.16-2.32(m，2H)，2.51(s，6H)，4.02(t，2H，J＝6.9Hz)，4.52(d，2H，J＝11.1Hz)，7.31(s，1H)，7.41(s，1H)，7.87(dd，2H，J＝7.8，6.0Hz)，8.39(d，2H，J＝7.8Hz)，8.58(s，1H)，8.65(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ17.21，20.16，20.89，22.43，27.26，32.59，49.06，52.95，58.22，120.30，122.01，126.05，134.75，136.82，139.80，149.59，154.67；ES-MS m/z 390(M ⁺H)。Analytical calculation value C ₂₄H ₃₁N ₅3.9HBr2.9H ₂O:C, 38.06; H, 5.42; N, 9.25; Br, 41.15. measured value: C, 37.99; H, 5.14; N, 9.30; Br, 41.29.

Embodiment 101

Chemical compound 101:2 meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-Benzoylamide

With DIPEA (0.14mL 0.80mmol) handles meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (107mg, 0.40mmol), 2-bromomethyl-benzonitrile (102mg, 0.52mmol) and KI (13mg, dry DMF 0.08mmol) (2.0mL) solution, and stir down 16h at 60 ℃.Add EtOAc (10mL), and with saturated aqueous common salt (5 * 5mL) washing organic faciess, dry (MgSO ₄), and concentrating under reduced pressure.Through silica gel column chromatography (50: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) purification, make thus light beige solid, shaped 2-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (143mg, 93%).

(143mg, MeOH 0.37mmol) (3.0mL) solution adds 50%H will to go up step gained nitrile ₂O ₂(0.11mL, 1.9mmol) (0.6mL is 1.9mmol) in the solution with 3N NaOH.Reaction is heated to 80 ℃, and 16h is cooled to ambient temperature then.Add entry (2mL), and with this intermedium with CH ₂Cl ₂(3 * 15mL) extractions.Then with Na ₂SO ₄The dry organic facies that merges, and concentrating under reduced pressure are through radial chromatography purification (33: 1: 0.1 CH on silica gel plate ₂Cl ₂/ MeOH/NH ₄OH), make white solid chemical compound 101 (61mg, 40%). ¹H NMR(CDCl ₃)δ1.64(m，3H)，2.02(m，1H)，2.28(q，2H，J＝13.8Hz)，2.46(s，6H)，3.72(s，2H)，4.07(d，2H，J＝11.1Hz)，5.72(br，1H(NH))，6.79-6.90(m，4H)，7.06(d，1H，J＝7.8Hz)，7.19(d，3H，J＝7.5Hz)，8.24(d，2H，J＝3.9Hz)，9.44(br，1H(NH))。 ¹³C NMR(CDCl ₃)δ18.86(2C)，24.81，29.62(2C)，55.81，65.95(2C)，121.92(2C)，126.60，128.55，128.78(2C)，129.83，130.88，135.19，136.33，137.94(2C)，146.45(2C)，159.77(2C)，170.68.ES-MS m/z 401(M ⁺H)。Analytical calculation value C ₂₅H ₂₈N ₄O0.3CH ₂Cl ₂0.1H ₂O:C, 71.03; H, 6.79; N, 13.10. measured value: C, 70.75; H, 6.81; N, 12.95.

Embodiment 102

Chemical compound 102:1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (HBr salt)

(499mg adds concentrated sulphuric acid (1mL) in MeOH 3.07mmol) (10mL) solution, and mixture heated to 80 ℃ is spent the night at the 4-imidazoleacetic acid hydrochlorate.Then with mixture cooling and concentrated.Residue is dissolved in CH ₂Cl ₂(30mL), with saturated NaHCO ₃(30mL) dilution.Water is saturated with the NaCl solid, and with EtOAc (3 * 30mL) extractions.The organic facies that merges is through MgSO ₄) drying, filter, and concentrate, make (1H-imidazol-4 yl)-methyl acetate (330mg, 66% of yellow oily. ¹H NMR(CDCl ₃)δ3.70(s，2H)，3.72(s，3H)，6.97(s，1H)，7.59(s，1H)。

Last step gained ester (330mg, add in DMF 2.35mmol) (5mL) solution DIPEA (1.2mL, 7.05mmol) and Sem-chloride (0.49mL 2.83mmol), stirs reactant mixture then and spends the night.Mixture through vacuum concentration, and is dissolved in residue among the EtOAc (30mL), with water (25mL) and saturated aqueous common salt (2 * 25mL) washings.With CH ₂Cl ₂(the water that 2 * 30mL) extractions merge.The organic facies that merges is with MgSO ₄Drying is filtered, and concentrates, and makes yellow oil.By silica gel with flash chromatography through 2%CH ₃OH/CH ₂Cl ₂The eluting purification makes [1-(2-TMS-ethoxyl methyl)-1H-the imidazol-4 yl]-methyl acetate (240mg, 73%) of yellow oily. ¹H NMR (CDCl ₃) δ-0.03 and-0.02 (s, 9H altogether), 0.85-0.93 (m, 2H), 3.40-3.50 (m, 2H), 3.71 and 3.72 (s, 3H altogether), 5.22 and 5.29 (s, 2H altogether), 6.98 and 7.00 (s, 2H altogether), 7.52 (s, 1H).

Under 0 ℃, (240mg in THF 0.89mmol) (3mL) solution, adds LiAlH at last step gained ester ₄(1.2mL 1.15mmol), and stirs 1h with reactant mixture.With mixture with H ₂O (0.2mL), 15%NaOH (0.2mL) and H ₂O (0.6mL) cancellation, and with CH ₂Cl ₂(4 * 20mL) extractions.The organic facies that merges is with MgSO ₄) drying, filter, and concentrate, make light yellow oil.By silica gel with flash chromatography through 2%CH ₃OH/CH ₂Cl ₂The eluting purification makes 2-[1-(2-TMS-ethoxyl methyl)-1H-imidazol-4 yl of light yellow oily]-ethanol (154mg, 71%). ¹H NMR (CDCl ₃) δ 0.88 (td, 2H, J=7.5,3.0Hz), 2.78 and 2.87 (t is total to 2H, J=6.0Hz), 3.45 (td, 2H, J=7.5,3.0Hz), 3.80-3.88 (m, 2H), 5.19 and 5.24 (s, 2H altogether), 6.82 and 6.84 (s, 1H), 7.46 and 7.47 (s, 1H).

According to general step F, under-78 ℃, at last step gained alcohol (152mg, CH 0.63mmol) ₂Cl ₂(5mL) add Et in the solution ₃N (0.18mL, 1.26mmol) and MsCl (0.07mL, 0.94mmol).Before entering next step without being further purified.

According to general step A, will go up step gained methylsulfonyl ester (190mg, 0.59mmol), meso-4-(3,3 '-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (132mg, 0.49mmol), N, N ,-diisopropylethylamine (0.13mL, 0.74mmol) and KI (9mg, DMF 0.05mmol) (5mL) solution.Through silica gel with radial chromatography (2mm plate; With CH ₂Cl ₂/ CH ₃OH/NH ₄OH; 50: 1: 1 → 25: 1: 1 eluting), make yellow oil product (50mg, 20%).

(58mg, 6N HCl (4mL) solution 0.12mmol) stir down at 60 ℃ will to go up step gained amine.Behind the 3h, with the reactant mixture cooling and with K ₂CO ₃Solid is quenched to pH=9.With CH ₂Cl ₂(4 * 20mL) extraction mixture.The organic facies that merges is with MgSO ₄Drying is filtered, and concentrates, and makes light yellow oil.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ CH ₃OH/NH ₄OH; 50: 1: 1 → 25: 1: 1 → 10: 1: 1 eluting) purification makes light yellow oily product (38mg, 88%). ¹H NMR(CDCl ₃)δ1.60-1.67(m，2H)，1.93-1.97(m，2H)，2.06-2.14(m，2H)，2.40(s，6H)，2.509t，2H，J＝6.0Hz)，2.86(br s，2H)，3.92(d，2H，J＝6.0Hz)，6.13(s，1H)，7.02(t，2H，J＝6.0Hz)，7.37-7.40(m，3H)，8.37(d，2H，J＝6.0Hz)。

According to general step B, (38mg in HOAc 0.11mmol) (2mL) solution, adds the saturated HOAc (2mL) of HBr at last step gained amine.After vacuum drying spends the night, separate the chemical compound 102 that obtains the yellow solid shape. ¹H NMR(D ₂O)δ1.54-1.58(m，2H)，1.70-1.83(m，1H)，1.93-1.96(m，1H)，2.19(d，2H，J＝13.5Hz)，2.60(s，6H)，2.63-2.65(m，2H)，2.77-2.82(m，2H)，4.73-4.74(m，2H)，6.92(s，1H)，7.91(dd，2H，J＝8.0，6.0Hz)，8.43(d，2H，J＝3.3Hz)，8.46(s，1H)，8.69(d，2H，133＝5.7Hz)。 ¹³C NMR (D ₂O) δ 17.13,18.51,22.32,32.57,50.80,57.70,115.85,126.22,130.71,133.69,137.13,140.04,149.78,154.01.ES-MS m/z 362[M ⁺H] ⁺. analytical calculation value C ₂₂H ₂₇N ₅3.3HBr2.6H ₂O0.3C ₄H ₁₀O:C, 39.95; H, 5.56; N, 10.04; Br, 37.80. measured value: C, 39.95; H, 5.46; N, 9.96; Br, 37.85.

Embodiment 103

Chemical compound 103:[2-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methoxyl group-phenyl]-methanol

With dimethyl sulfate (1.42mL, 15.0mmol) and K ₂CO ₃(2.59g 18.8mmol) handles 4-methyl-3-nitro phenol (1.92g, acetone 12.5mmol) (60mL) solution, 18h.Solvent is removed in decompression, and with solid (50mL) soluble in water.Then with this aqueous with CH ₂Cl ₂(3 * 50mL) extractions, and with Na ₂SO ₄The dry organic facies that merges, concentrating under reduced pressure.(purification of 20: 1 hexanes/EtOAc) makes light yellow liquid shape 4-methoxyl group-1-methyl-2-Nitrobenzol (1.91g, 91%) thus through column chromatography by silica gel.

(1.91g, in MeOH 11.4mmol) (15mL) solution, (50% is wet, 400mg) to add 10%Pd/C at last step chemical compound.Under nitrogen atmosphere (30psi) stirs 1.5h with this reagent.Reactant mixture is through diatomite filtration, and solvent is removed in decompression.Thus, make the 5-methoxyl group-2-methyl-phenyl amine (1.57g, 100%) of brown liquid shape. ¹H NMR(CDCl ₃)δ2.11(s，3H)，3.61(br，2H(NH2))，3.75(s，3H)，6.27(s，1H)，6.29(d，1H，J＝7.8Hz)，6.94(d，1H，J＝7.8Hz)。

(1.57g 11.4mmol) is suspended in H will to go up step gained amine ₂Among O (3mL) and the dense HCl (3mL).And then adding 8mLH ₂O is cooled to 0 ℃.Slowly add NaNO ₂(0.87g, H 12.6mmol) ₂O (2mL) solution, and mixture stirred 0.5h.Then should acid with K ₂CO ₃(1.9g, 3.8mmol) neutralization, and under 60 ℃ of stirrings, mixture poured into Sodium cyanate (NaOCN) (1.35g, 27.5mmol) and copper cyanider (I) (1.23g, H 13.7mmol) ₂In O (7.5mL) solution.Be warming up to 110 ℃, will react and stir 1h.Add CH then ₂Cl ₂(50mL) and saturated aqueous common salt (50mL), separate organic facies then.Then with CH ₂Cl ₂(2 * 50mL) aqueous phase extracted, the organic facies of merging is with Na ₂SO ₄Drying, and concentrating under reduced pressure (behind the purification of 10: 1 hexanes/EtOAc), make brown liquid shape 5-methoxyl group-2-methyl-benzonitrile (0.93g, 55%) through silica gel column chromatography.

Under 160 ℃, (0.93g 6.3mmol) is dissolved in H will to go up step gained chemical compound ₂O (12mL) and dense H ₂SO ₄(18mL).Behind the 4h, cool off this solution and filter, with Et through medium fritted glass filter ₂O washs residue.Then with Et ₂O (3 * 50mL) extraction filtrates, dry (MgSO ₄) and concentrating under reduced pressure, make black solid (0.47g).This material is dissolved in anhydrous MeOH (10mL) and dense H ₂SO ₄(0.5mL), reflux also stirs 16h.This solution is cooled to room temperature, and at Et ₂Distribute in O (15mL) and the saturated aqueous common salt (10mL).After the separation, with saturated aqueous common salt (3 * 10mL) washing organic faciess.Then with MgSO ₄Dry organic facies is filtered, and concentrating under reduced pressure, and (purification of 5: 1 hexanes/EtOAc) makes the 5-hydroxy-2-methyl-essence of Niobe (0.28g, 27%) of light brown solid, shaped through silica gel column chromatography.Notice that methoxyl group loses. ¹H NMR(CDCl ₃)δ2.51(s，3H)，3.89(s，3H)，4.94(s，1H(OH))，6.91(dd，1H，J＝1.5，7.5Hz)，7.12(d，1H，J＝7.8Hz)，7.41(d，1H，J＝1.5Hz)。

With dimethyl sulfate (0.19mL, 2.0mmol) and K ₂CO ₃(0.35g, 2.5mmol) step gained ester (0.28g, acetone 1.7mmol) (9mL) solution 18h gone up in processing.Decompression is removed solvent and solid is dissolved in H ₂Among the O (5mL).Aqueous is with CH ₂Cl ₂(3 * 10mL) extractions, and with Na ₂SO ₄Dry organic facies, concentrating under reduced pressure.(purification of 20: 1 hexanes/EtOAc) makes light yellow liquid shape 5-methoxyl group-2-methyl-essence of Niobe (0.24g, 80%) by silica gel through column chromatography.

At last step gained ester (0.24g, CCl 1.3mmol) ₄(5mL) in the solution, and adding N-bromine butanimide (0.26g, 1.5mmol) with 1,1 '-azo two (cyclohexane extraction formonitrile HCN) (64mg, 0.26mmol).16h is stirred in the solution backflow, be cooled to room temperature then, filter through medium fritted glass filter, and concentrating under reduced pressure.(purification of 100: 1 hexanes/EtOAc) makes colourless liquid shape 2-bromomethyl-5-methoxyl group-essence of Niobe (0.24g, 70%) thus through silica gel column chromatography. ¹H NMR(CDCl ₃)δ3.85(s，3H)，3.95(s，3H)，4.93(s，2H)，7.01(dd，1H，J＝1.5，7.5Hz)，7.37(d，1H，J＝7.5Hz)，7.48(d，1H，J＝1.5Hz)。

With DIPEA (0.24mL 1.4mmol) handles meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (185mg, 0.69mmol), 2-bromomethyl-5-methoxyl group-essence of Niobe (235mg, 0.90mmol) and KI (23mg, dry DMF 0.14mmol) (3.5mL) solution, and stir 16h in 60 ℃.Be dissolved in EtOAc (15mL) then with the mixture concentrating under reduced pressure, and with residue.(5 * 10mL) washings are with MgSO with saturated aqueous common salt for organic solution ₄Drying, and concentrating under reduced pressure.Through silica gel column chromatography (2: 0.5: 97.5MeOH/NH ₄OH/CH ₂Cl ₂) purification, make thus the light beige solid, shaped meso-2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-methoxyl group-essence of Niobe (0.29g, 93%).

(0.29g 0.65mmol) is dissolved among THF (6mL) and the MeOH (6mL), is cooled to 0 ℃, and with solid LiBH will to go up step gained alkylate ₄(0.16g 7.8mmol) handles.After treating that violent bubbling is disappeared, mixture stirred in 1h be warmed to room temperature.Excessive LiBH ₄Add saturated aqueous common salt (15mL) cancellation with 1N NaOH solution (5mL).Then with CH ₂Cl ₂(3 * 20mL) aqueous phase extracted, dry (Na ₂SO ₄), and concentrating under reduced pressure, through radial chromatography with silica gel plate (50: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) purification makes loose white solid chemical compound 103 (77mg, 29%). ¹H NMR(CDCl ₃)δ1.64(br d，3H，J＝10.8Hz)，2.00(br，1H)，2.30(m，2H)，2.49(s，6H)，3.56(s，2H)，3.60(s，3H)，3.95(br d，2H，J＝11.4Hz)，4.30(s，2H)，6.18(d，1H，J＝8.1Hz)，6.50(s，1H)，6.62(d，1H，J＝8.4Hz)，6.86(m，2H)，7.25(d，2H，J＝8.4Hz)，8.25(d，2H，J＝3.9Hz)。 ¹³CNMR(CDCl ₃).19.14(2C)，25.27，30.23(2C)，55.20(2C)，62.76，67.78(2C)，112.24(2C)，114.22，121.67(2C)，130.02，130.72，131.23，138.07(2C)，140.20，146.54(2C)，157.82，160.00(2C)。ES-MS m/z 418(M ⁺H)。Analytical calculation value C ₂₆H ₃₁N ₃O ₂0.1NH ₄OH1.0H ₂O:C, 71.12; H, 7.69; N, 9.89. measured value: C, 71.25; H, 7.41; N, 10.23.

Embodiment 104

Chemical compound 104:N-[3 meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-N '-hydroxyurea

With DIPEA (0.31mL 1.8mmol) handles meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (235mg, 0.88mmol), 2-(3-bromo-propyl group)-iso-indoles-1, the 3-diketone (306mg, 1.14mmol) and KI (29mg, dry DMF 0.18mmol) (4.0mL) solution, and stir 16h down at 60 ℃.Then with the mixture concentrating under reduced pressure, with EtOAc (15mL) dissolving residue.(5 * 10mL) wash this organic solution, dry (MgSO with saturated aqueous common salt ₄), and concentrating under reduced pressure.Through silica gel column chromatography (20: 1: 0.2CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make light yellow solid 2-[3-bromoacetoxylphenylhexan thus, 3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl]-propyl group]-iso-indoles-1,3-diketone (0.40g, 100%). ¹H NMR(CDCl ₃)δ0.95(br，2H)，1.58(m，2H)，1.86(m，1H)，2.07(m，1H)，2.32(br，2H)，2.50(s，8H)，2.90(br，2H)，4.06(d，2H)，6.89(m，2H)，7.26(br，2H)，7.70(m，4H)，8.27(br，2H)。

(0.48mL 8.8mmol) handle to go up step gained chemical compound (400mg, EtOH 0.88mmol) (9mL) solution, and at room temperature stir 16h with single hydrazine hydrate.Add CH ₂Cl ₂(10mL), white mixture is filtered to remove solids.Then filtrate decompression is concentrated and vacuum drying.Through radial chromatography with silica gel (10: 1: 0.1CH ₂Cl ₂/ CH ₃OH/NH ₄OH) behind the purification, make thus light yellow solid 3-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propylamine (233mg, 82%).

(233mg, 0.71mmol) with 1, (115mg, THF 0.71mmol) (7mL) solution at room temperature stirs 30min to the 1-carbonyl dimidazoles will to go up step gained chemical compound.Solvent is removed in decompression then, and residue is dissolved among the DMF (3.5mL).Then with NH ₂OHH ₂O (200mg, 2.8mmol) and DIPEA (0.62mL, 3.5mmol) Treatment Solution, and at room temperature stir 18h.To be reflected at CH then ₂Cl ₂(15mL) and between saturated aqueous common salt (10mL) distribute, and separate.(4 * 10mL) washing several are with Na with saturated aqueous common salt with organic facies then ₂SO ₄Dry organic facies and concentrating under reduced pressure are through silica gel column chromatography (50: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) purification makes white solid chemical compound 104 (81mg, 30%). ¹H NMR(CDCl ₃)δ1.55(m，1H)，1.67(d，2H，J＝11.7Hz)，1.94(m，1H)，2.06(q，2H，J＝10.5Hz)，2.35(br，2H)，2.44(s，6H)，2.60(br d，2H，J＝12.0Hz)，6.94(br，1H)，7.10(m，2H)，7.44(d，2H，J＝7.8Hz)，7.70(br，1H)，8.48(br，2H)，10.14(br，1H)。 ¹³C NMR(CDCl ₃)δ19.01(2C)，25.03，26.34，32.12(2C)，38.23，51.04，64.37(2C)，122.09(2C)，130.95(2C)，138.84(2C)，146.89(2C)，160.05(2C)，161.86.ES-MS m/z384(M ⁺H)。Analytical calculation value C ₂₁H ₂₉N ₅O ₂0.4CH ₂Cl ₂: C, 61.57; H, 7.19; N, 16.78. measured value: C, 61.23; H, 7.35; N, 16.43.

Embodiment 105

Chemical compound 105:[4 meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methoxyl group-phenyl]-methanol

At 3-methoxyl group-4-methyl-essence of Niobe (0.25g, CCl 1.4mmol) ₄(5mL) in the solution, and adding N-bromine butanimide (0.27g, 1.5mmol) with 1,1 '-azo two (cyclohexane extraction formonitrile HCN) (68mg, 0.28mmol).Solution stirring backflow 16h is cooled to room temperature then, and concentrating under reduced pressure.(behind the purification of 60: 1 hexanes/EtOAc), make colourless liquid shape 4-bromomethyl-3-methoxyl group-essence of Niobe and small amount of impurities (～15%) (0.39g, excessive) thus through silica gel column chromatography. ¹H NMR(CDCl ₃)δ3.92(s，3H)，3.95(s，3H)，4.55(s，2H)，7.39(d，1H，J＝7.5Hz)，7.55(s，1H)，7.61(d，1H，J＝7.5Hz)。

With DIPEA (0.32mL 1.9mmol) handles meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.25g, 0.93mmol), on go on foot the gained methyl ester (0.36g, 1.4mmol) and KI (31mg, dry DMF 0.20mmol) (4.7mL) solution, and stir down 16h at 60 ℃.Be dissolved among the EtOAc (15mL) then with the mixture concentrating under reduced pressure, and with residue.(5 * 10mL) washings are with MgSO with saturated aqueous common salt for organic facies ₄Drying, and concentrating under reduced pressure.Through silica gel column chromatography (saturated NH ₃/ Et ₂O) behind the purification, make thus colorless solid 4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methoxyl group-essence of Niobe (0.26g, 63%).

(0.25g 0.56mmol) is dissolved in THF (6mL), and with solid LiBH will to go up step gained alkylate ₄(0.20g 7.8mmol) handles.Then with mixture heated to 75 ℃, 16h.Excessive LiBH ₄Add saturated aqueous common salt (15mL) cancellation with 1N NaOH solution (4mL).Then with water with CH ₂Cl ₂(3 * 20mL) extractions, dry (Na ₂SO ₄), and concentrating under reduced pressure, on silica gel plate through column chromatography (20: 1: 0.1CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make the chemical compound 105 (200mg, 87%) of white solid. ¹HNMR(CDCl ₃)δ1.49(m，1H)，1.66(m，3H)，1.98(m，1H)，2.17(m，2H)，2.39(s，6H)，3.46(s，3H)，3.57(s，2H)，4.08(br d，2H，J＝11.4Hz)，4.46(s，2H)，6.39(s，1H)，6.54(d，1H，J＝7.2Hz)，6.89(m，2H)，6.99(d，1H，J＝7.2Hz)，7.22(d，2H，J＝7.5Hz)，8.34(d，2H，J＝3.9Hz)。 ¹³C NMR(CDCl ₃)δ.18.84(2C)，25.12，30.09(2C)，46.91(2C)，54.53，65.18(2C)，107.56，117.77，121.41(2C)，127.30，131.05，131.59(2C)，137.66(2C)，139.80，146.17(2C)，156.52，160.44(2C)。ES-MS m/z 418(M ⁺H)。Analytical calculation value C ₂₆H ₃₁N ₃O ₂0.4CH ₂Cl ₂: C, 70.23; H, 7.10; N, 9.31. measured value: C, 70.46; H, 7.33; N, 9.34.

Embodiment 106

Chemical compound 106:[2 meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-fluoro-phenyl]-methanol

(0.29g 1.9mmol) is dissolved in anhydrous MeOH (7mL), and adds dense H with 5-fluoro-2-methyl-benzoic acid ₂SO ₄(0.12mL, 2.3mmol), reflux 16h.Solution is cooled to room temperature, and in EtOAc (15mL) and saturated aqueous common salt (10mL), distributes.Separate biphase after, with water with EtOAc (2 * 10mL) extractions, dry (MgSO ₄), filter, and concentrating under reduced pressure, make the liquid 5-fluoro-of light brown 2-methyl-essence of Niobe (0.25g, 78%).

At last step gained ester (0.25g, CCl 1.5mmol) ₄(5mL) add in the solution N-bromine butanimide (0.29g, 1.6mmol) and 1,1 '-azo two (cyclohexane extraction formonitrile HCN) (73mg, 0.30mmol).Solution refluxes and stirs 16h, is cooled to room temperature and concentrating under reduced pressure then.(behind the purification of 50: 1 hexanes/EtOAc), make light yellow liquid shape 2-bromomethyl-5-fluoro-essence of Niobe (0.23g, 62%) by silica gel through column chromatography. ¹H NMR(CDCl ₃)δ3.94(s，3H)，4.93(s，2H)，7.20(dt，1H，J＝7.5，1.5Hz)，7.45(m，1H)，7.67(dd，1H，J＝7.5，1.5Hz)。

With DIPEA (0.24mL 1.4mmol) handles meso-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (190mg, 0.72mmol), on go on foot the gained bromide (235mg, 0.90mmol) and KI (23mg, dry DMF 0.14mmol) (3.5mL) solution, and stir down 16h at 60 ℃.Be dissolved among the EtOAc (15mL) then with the mixture concentrating under reduced pressure, and with residue.(5 * 10mL) washings are with MgSO with saturated aqueous common salt with this organic solution ₄Drying, and concentrating under reduced pressure.Through silica gel column chromatography (50: 1: 0.1CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make white solid 2-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-5-fluoro-essence of Niobe (0.28g, 90%).

(0.28g 0.65mmol) is dissolved among the THF (6mL), and with solid LiBH will to go up step gained alkylate ₄(0.17g 7.7mmol) handles.Then with mixture heated to 75 ℃, 16h.Excessive LiBH ₄Add saturated aqueous common salt (15mL) cancellation with 1NNaOH solution (4mL).Then with water with CH ₂Cl ₂(3 * 20mL) extractions, dry (Na ₂SO ₄), and concentrating under reduced pressure, make white solid chemical compound 106 (239mg, 92%). ¹HNMR(CDCl ₃)δ1.66(m，3H)，2.05(m，1H)，2.31(m，2H)，2.50(s，6H)，3.59(s，2H)，4.00(br d，2H，J＝10.8Hz)，4.34(s，2H)，5.10(br，1H(OH))，6.32(dt，1H，J＝8.4，2.4Hz)，6.63(dd，1H，J＝9.6，2.7Hz)，6.69(t，1H，J＝7.2Hz)，6.88(m，2H)，7.25(d，2H，J＝6.0Hz)，8.25(d，2H，J＝3.9Hz)。 ¹³CNMR(CDCl ₃)δ.19.06(2C)，25.22，29.76(2C)，54.06，62.13，67.44(2C)，112.57(d，1C，J＝83Hz)，115.25(d，1C，J＝84Hz)，121.84(2C)，130.24，131.31(2C)，134.00，138.11(2C)，141.13，146.51(2C)，159.71(2C)，161.08(d，1C，J＝971Hz)。ES-MS m/z 406(M ⁺H)。Analytical calculation value C ₂₅H ₂₈N ₃OF0.2CH ₂Cl ₂: C, 71.64; H, 6.77; N, 9.95. measured value: C, 71.45; H, 6.85; N, 9.95.

Embodiment 107

Chemical compound 107:N-[4 meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-benzsulfamide (HBr salt)

With benzene sulfonyl chloride (44 μ L, 0.34mmol) and Et ₃N (63 μ L, 0.45mmol) processing 4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (90mg, CH 0.27mmol) ₂Cl ₂(2mL) solution 1h.Add saturated aqueous common salt (1mL), and separate phase.Water is with CH ₂Cl ₂(2 * 2mL) extractions, the organic facies of merging is with Na ₂SO ₄Dry and concentrating under reduced pressure was through silica gel column chromatography (50: 1: 0.1CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make white solid the N-[4 meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-benzsulfamide (102mg, 79%).

According to general step B: with the material of above-mentioned gained (100mg 0.21mmol) is converted into HBr salt, make white solid chemical compound 107 (115mg). ¹H NMR(D ₂O)δ.1.04(qt，2H，J＝6.6Hz)，1.25(qt，2H，J＝7.8Hz)，1.50(m，2H)，1.70(q，1H，J＝12.9Hz)，1.95(d，1H，J＝13.2Hz)，2.16(m，4H)，2.55(m，2H)，2.59(s，6H)，4.55(d，2H，J＝9.3Hz)，7.59(m，2H)，7.70(m，3H)，7.88(t，2H，J＝6.8Hz)，8.40(d，2H，J＝8.1Hz)，8.65(d，2H，J＝5.4Hz)。 ¹³C NMR(D ₂O)δ.17.16(2C)，19.32，22.49，26.10，32.57(2C)，41.97，52.22，57.97(2C)，125.97(2C)，126.92(2C)，129.98(2C)，133.96，136.90(2C)，138.43，139.71(2C)，149.59(2C)，154.76(2C)。ES-MS m/z479(M ⁺H)。Analytical calculation value C ₂₇H ₃₄N ₄O ₂S2.5HBr1.8H ₂O0.4C ₄H ₁₀O:C, 46.23; H, 5.98; N, 7.54; Br, 26.89; S, 4.31. measured value: C, 46.37; H, 6.06; N, 7.57; Br, 26.67; S, 4.28.

Embodiment 108

Chemical compound 108:N-[4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-Methanesulfomide (HBr salt)

With MsCl (29 μ L, 0.37mmol) and Et ₃N (68 μ L, 0.49mmol) processing 4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (97mg, CH 0.29mmol) ₂Cl ₂(2mL) solution 1h.Add saturated aqueous common salt (1mL), and separate phase.Water is with CH ₂Cl ₂(2 * 2mL) extractions, the organic facies of merging is with Na ₂SO ₄Dry and concentrating under reduced pressure was through silica gel column chromatography (50: 1: 0.1CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make light brown solid, shaped N-[4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-Methanesulfomide (100mg, 84%).

According to general step B: will go up the step gained material (95mg 0.24mmol) is converted into HBr salt, make white solid chemical compound 108 (121mg). ¹H NMR(D ₂O)δ1.12(qt，2H，J＝6.6Hz)，1.31(qt，2H，J＝7.8Hz)，1.50(m，2H)，1.70(q，1H，J＝12.9Hz)，1.95(d，1H，J＝13.2Hz)，2.12(br，2H)，2.24(br，2H)，2.60(s，6H)，2.77(br，2H)，2.90(s，3H)，4.60(d，2H，J＝9.3Hz)，7.88(t，2H，J＝6.8Hz)，8.40(d，2H，J＝8.1Hz)，8.64(d，2H，J＝5.4Hz)。 ¹³C NMR(D ₂O)δ.17.13(2C)，19.47，22.46，26.67，32.60(2C)，38.74，41.95，52.61，58.11(2C)，125.95(2C)，136.90(2C)，139.66(2C)，149.59(2C)，154.86(2C)。ES-MS m/z 417(M ⁺H)。Analytical calculation value C ₂₂H ₃₂N ₄O ₂S2.6HBr1.8H ₂O:C, 40.07; H, 5.84; N, 8.50; Br, 31.51; S, 4.86. measured value: C, 40.39; H, 6.20; N, 8.14; Br, 31.28; S, 4.60.

Embodiment 109

Chemical compound 109:[4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-urea (HBr salt)

According to general step A, at above-claimed cpd (356mg, 1.2mmol) DMF (6mL) solution in add 2-(4-brombutyl)-iso-indoles-1,3-diketone (442mg, 1.6mmol), KI (40mg, 0.24mmol) and DIPEA (0.42mL 2.4mmol), and down stirs mixture at 60 ℃ and to spend the night.Through post processing and silica gel column chromatography (20: 1: 0.2 CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make the 2-[4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1,3-diketone (515mg, 86%).

(0.50mL 10.4mmol) handle to go up step gained chemical compound (515mg, EtOH 1.04mmol) (10mL) solution, and at room temperature stir 16h with single hydrazine hydrate.Add CH ₂Cl ₂(10mL), and with white mixture filter to remove solids.Then filtrate decompression is concentrated and vacuum drying.Through silica gel column chromatography (20: 1: 0.1CH ₂Cl ₂/ CH ₃OH/NH ₄OH) purification, make sticky white solid 4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (0.25g, 66%). ¹HNMR(CDCl ₃)δ0.80(br，3H)，1.54(m，1H)，1.62(d，2H，J＝12.0Hz)，1.97(m，3H)，2.16(t，2H，J＝7.5Hz)，2.27(s，6H)，2.40(br，1H)，2.47(s，6H)，2.60(br，2H)，3.93(br，2H，J＝9.0Hz)，7.24(s，2H)，8.31(s，2H)。

To go up step gained amine and be dissolved in the isopropyl alcohol (2.3mL), and (64 μ L 0.47mmol) handle 16h under room temperature with Carbimide. trimethyl first estersil.Then solution decompression is concentrated, crude product is through silica gel column chromatography (40: 1THF-Et ₂O/NH ₄OH) purification, make colorless oil [the 4-meso (and 3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-urea (46mg, 33%).

According to general step B: with the material of gained (45mg 0.11mmol) is converted into HBr salt, make white solid chemical compound 109 (44mg). ¹H NMR(D ₂O)δ1.02(qt，2H，J＝6.9Hz)，1.13(qt，2H，J＝6.6Hz)，1.46(m，2H)，1.65(m，1H)，1.90(m，1H)，2.07(d，2H，J＝12.6Hz)，2.16(br，2H)，2.46(s，6H)，2.52(s，6H)，2.74(m，2H)，4.47(d，2H，J＝9.9Hz)，8.23(s，2H)，8.46(s，2H)。 ¹³C NMR(D ₂O)δ.16.91(2C)，17.57(2C)，20.26，22.48，26.85，32.71(2C)，39.11，53.26，58.16(2C)，136.00(2C)，137.38(2C)，138.98(2C)，150.01(2C)，152.09(2C)，162.21.ES-MSm/z 410(M ⁺H)。Analytical calculation value C ₂₄H ₃₅N ₅O3.1HBr5.0H ₂O:C, 38.41; H, 6.46; N, 9.33; Br, 33.01. measured value: C, 38.29; H, 6.30; N, 9.10; Br, 33.17.

Embodiment 110

Chemical compound 110:N-[4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-N '-hydroxyurea

With the 4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] (127mg, 0.35mmol) and 1, (56mg, THF 0.35mmol) (3.5mL) solution stirs 30min to the 1-carbonyl dimidazoles to terpyridyl-1 '-yl)-butylamine under room temperature.Solvent is removed in decompression then, and residue is dissolved in DMF (2mL).Then with solution with NH ₂OHH ₂O (97mg, 1.4mmol) and DIPEA (0.30mL 1.7mmol) handles, and at room temperature stirs 18h.Be reflected at CH ₂Cl ₂(15mL) with between saturated aqueous common salt (10mL) distribute and separate.Organic facies with saturated aqueous common salt (4 * 10mL) washings for several times, and with Na ₂SO ₄Dry organic facies, concentrating under reduced pressure is through silica gel column chromatography (20: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) purification makes white solid chemical compound 110 (92mg, 62%). ¹H NMR(CDCl ₃)δ0.79(br，3H)，1.60(br，3H)，1.95(br，3H)，2.26(s，6H)，2.39(s，6H)，2.72(m，5H)，3.87(br，2H)，5.65(br，1H)，7.25(s，2H)，8.20(br，1H)，8.29(s，2H)。 ¹³C NMR(CDCl ₃)δ.18.25(2C)，19.12(2C)，22.24，25.53，28.15，32.81(2C)，39.28，51.39，62.82(2C)，130.36(2C)，131.63(2C)，139.83(2C)，147.49(2C)，157.64(2C)，162.22.ES-MS m/z 426(M ⁺H)。Analytical calculation value C ₂₄H ₃₅N ₅O ₂1.1H ₂O:C, 64.72; H, 8.42; N, 15.72. measured value: C, 64.80; H, 8.55; N, 15.72.

Embodiment 111

Chemical compound 111:N-[3-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-N '-hydroxyurea

According to general step A, in meso-3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl (172mg adds 2-(3-bromo-propyl group)-iso-indoles-1 in DMF 0.58mmol) (3mL) solution; the 3-diketone (203mg, 0.76mmol), KI (19mg, 0.12mmol) and DIPEA (0.20mL; 1.2mmol), and mixture spent the night in 60 ℃ of stirrings.Through post processing and through silica gel column chromatography (20: 1: 0.2CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make the 2-[3-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propyl group]-iso-indoles-1,3-diketone (259mg, 92%). ¹HNMR(CDCl ₃)δ.1.16(br，1H)，1.60(br，3H)，2.00(m，3H)，2.15(s，6H)，2.24(m，2H)，2.38(s，6H)，2.57(br，1H)，3.03(br，2H)，3.96(br，2H)，7.02(s，2H)，7.70(m，4H)，8.18(s，2H)。

(0.26mL 5.4mmol) handle to go up step gained chemical compound (259mg, EtOH 0.54mmol) (5.4mL) solution, and at room temperature stir 16h with single hydrazine hydrate.Add CH ₂Cl ₂(10mL), white mixture is filtered to remove solids.Then filtrate decompression is concentrated and vacuum drying.Through silica gel column chromatography (20: 1: 0.1CH ₂Cl ₂/ CH ₃OH/NH ₄OH) behind the purification, make thus sticky white solid 3-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propylamine (0.15g, 78%).

(146mg, 0.41mmol) with 1, (67mg, THF 0.41mmol) (4.0mL) solution at room temperature stirs 45min to the 1-carbonyl dimidazoles will to go up step gained amine.Solvent is removed in decompression then, and residue is dissolved among the DMF (2mL).Then with NH ₂OHH ₂O (115mg, 1.6mmol) and DIPEA (0.36mL, 2.1mmol) Treatment Solution, and at room temperature stir 18h.To be reflected at CH then ₂Cl ₂(15mL) and between saturated aqueous common salt (10mL) distribute, and separate.(4 * 10mL) washing several are with Na with saturated aqueous common salt with organic facies then ₂SO ₄Dry organic facies and concentrating under reduced pressure are through silica gel column chromatography (20: 1: 0.1 CH ₂Cl ₂: MeOH/NH ₄OH) purification makes white solid chemical compound 111 (84mg, 49%). ¹H NMR(CDCl ₃)δ44(br，2H)，1.60(br，3H)，1.95(br，3H)，2.27(s，6H)，2.39(s，6H)，2.50(br，2H)，2.60(br，2H)，3.72(br，2H)，6.86(br，1H)，7.26(s，2H)，7.77(br，1H)，8.30(s，2H)，10.41(br，1H)。 ¹³C NMR(CDCl ₃)δ.18.31(2C)，19.31(2C)，25.37，26.80，32.96(2C)，38.86，52.34，64.61(2C)，130.57(2C)，131.90(2C)，139.85(2C)，147.68(2C)，157.58(2C)，162.29.ES-MS m/z 412(M ⁺H)。Analytical calculation value C ₂₃H ₃₃N ₅O ₂0.3H ₂O:C, 66.26; H, 8.12; N, 16.80. measured value: C, 66.30; H, 7.96; N, 16.90.

Embodiment 112

Chemical compound 112:N-[4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-suitable-but-2-ene base]-N '-hydroxyurea

According to general step A, in meso-3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl (150mg, CH 0.51mmol) ₃Add in CN (2.5mL) solution suitable-(4-chloro-but-2-ene base)-t-butyl carbamate (115mg, 0.56mmol), KI (8mg, 0.05mmol) and DIPEA (0.13mL 0.76mmol), and spends the night mixture in 60 ℃ of stirrings.Through post processing and through silica gel column chromatography (50: 1: 0.1CH ₂Cl ₂/ MeOH/NH ₄OH) purification, make [the 4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-suitable-but-2-ene base]-t-butyl carbamate (213mg, 90%).

To go on foot gained chemical compound (0.213g, CH 0.46mmol) in TFA (1.0mL) processing ₂Cl ₂(1.5mL) solution 1h.Slowly add then the 15%NaOH aqueous solution (～3mL), be neutralized until acid moieties, solution be alkalescence (pH=8 to 12).Separate phase then, with CH ₂Cl ₂(2 * 10mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry and concentrating under reduced pressure, make the 4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-suitable-but-2-ene base amine (184mg, excessive), and be used for next step reaction immediately.

To go up step gained amine and 1, (80mg, THF 0.501mmol) (5.0mL) solution at room temperature stirs 45min to the 1-carbonyl dimidazoles.Solvent is removed in decompression then, and residue is dissolved among the DMF (2mL).Then with NH ₂OHH ₂O (137mg, 2.0mmol) and DIPEA (0.43mL, 2.5mmol) Treatment Solution, and at room temperature stir 18h.To be reflected at CH then ₂Cl ₂(15mL) and between saturated aqueous common salt (10mL) distribute, and separate.(4 * 10mL) washing several are with Na with saturated aqueous common salt with organic facies then ₂SO ₄Dry organic facies and concentrating under reduced pressure are through silica gel column chromatography (20: 1: 0.1 CH ₂Cl ₂: MeOH/NH ₄OH), make white solid chemical compound 112 (51mg, 24%). ¹H NMR(CDCl ₃)δ1.54(br，1H)，1.64(br，2H)，1.92(br，3H)，2.23(s，6H)，2.37(s，6H)，2.96(br，2H)，3.03(br，2H)，5.30(br，2H)，5.73(br，1H)，7.26(s，2H)，8.27(br，2H)，10.44(br，1H)。 ¹³C NMR(CDCl ₃)δ.17.85(2C)，18.70(2C)，25.15，32.90(2C)，35.83，46.73，61.43(2C)，126.95，128.48，130.04，130.35(2C)，139.49(3C)，147.18(2C)，157.10(2C)，161.56.ES-MS m/z 424(M ⁺H)。Analytical calculation value C ₂₄H ₃₃N ₅0 ₂0.5CH ₂Cl ₂: C, 63.14; H, 7.35; N, 15.03. measured value: C, 63.42; H, 7.56; N, 15.01.

Embodiment 113

Chemical compound 113:N-[4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-suitable-but-2-ene base]-N '-hydroxyurea

According to general step A, in meso-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl (133mg, CH 0.50mmol) ₃Add in CN (5mL) solution suitable-(4-chloro-but-2-ene base)-t-butyl carbamate (113mg, 0.55mmol), KI (8mg, 0.05mmol) and DIPEA (0.13mL 0.76mmol), and spends the night mixture in 60 ℃ of stirrings.Through through post processing and silica gel column chromatography (20: 1: 0.1CH ₂Cl ₂/ MeOH/NH ₄OH) purification, make [the 4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-suitable-but-2-ene base]-t-butyl carbamate (202mg, 93%). ¹HNMR(CDCl ₃)δ.1.39(s，9H)，1.60(m，1H)，1.73(br，2H)，2.00(br，3H)，2.45(br，5H)，2.57(s，3H)，2.68(br，1H)，2.89(br，2H)，4.02(br，2H)，5.17(br，1H)，5.42(br，1H)，7.08(m，2H)，7.41(m，2H)，8.47(br，2H)。

To go on foot gained chemical compound (0.20g, CH 0.46mmol) in TFA (1.0mL) processing ₂Cl ₂(1.5mL) solution 1h.Slowly add then the 15%NaOH aqueous solution (～3mL), be neutralized until acid moieties, solution be alkalescence (pH=8 to 12).Separate phase then, with CH ₂Cl ₂(2 * 10mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry and concentrating under reduced pressure, make the 4-meso (3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-suitable-but-2-ene base amine (151mg, 98%), and be used for next step reaction immediately.

To go up step gained amine and 1, (148mg, THF 0.44mmol) (4.5mL) solution at room temperature stirs 45min to the 1-carbonyl dimidazoles.Solvent is removed in decompression then, and residue is dissolved among the DMF (2mL).Then with NH ₂OHH ₂O (122mg, 1.8mmol) and DIPEA (0.38mL, 2.2mmol) Treatment Solution, and at room temperature stir 18h.To be reflected at CH then ₂Cl ₂(15mL) and between saturated aqueous common salt (10mL) distribute, and separate.(4 * 10mL) washing several are with Na with saturated aqueous common salt with organic facies then ₂SO ₄Dry organic facies and concentrating under reduced pressure are through silica gel column chromatography (20: 1: 0.1 CH ₂Cl ₂: MeOH/NH ₄OH), make white solid chemical compound 113 (117mg, 67%). ¹H NMR(CDCl ₃)δ.1.53(m，1H)，1.67(m，2H)，1.92(m，3H)，2.40(s，6H)，2.88(br，2H)，2.98(br，2H)，4.02(br，2H)，5.28(br，1H)，5.40(m，1H)，5.62(br，1H)，7.05(m，2H)，7.46(d，2H，J＝7.0Hz)，8.44(d，2H，J＝3.5Hz)。 ¹³C NMR(CDCl ₃)δ.19.24(2C)，25.46，33.15(2C)，36.03，47.26，62.35(2C)，122.41(2C)，127.25，129.05，131.21(2C)，139.36(2C)，147.16(2C)，160.31(2C)，161.98.ES-MS m/z 396(M ⁺H)。Analytical calculation value C ₂₂H ₂₉N ₅O ₂1.5H ₂O0.2C ₃H ₄N ₂: C, 62.24; H, 7.58; N, 17.34. measured value: C, 62.34; H, 7.59; N, 17.31.

Embodiment 114

Chemical compound 114:3-methylol-4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe

With meso-3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.44g, 1.5mmol), 2-bromomethyl-5-cyano group-essence of Niobe (0.49g; 1.9mmol) and KI (49mg; (0.52mL 3.0mmol) handles dry DMF 0.30mmol) (7.5mL) solution, and stirs 16h in 60 ℃ with DIPEA.Be dissolved in EtOAc (20mL) then with the mixture concentrating under reduced pressure, and with residue.Organic solution is with saturated aqueous common salt (5 * 15mL) washings, dry (MgSO ₄), and concentrating under reduced pressure.Through silica gel column chromatography (25: 1CH ₂Cl ₂/ MeOH) purification, make light beige solid, shaped 5-cyano group-2-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (0.60g, 86%). ¹H NMR(CDCl ₃)δ1.64(br，3H)，2.05(br，1H)，2.13(s，6H)，2.30(br，2H)，2.37(s，6H)，3.85(s，3H)，3.91(s，2H)，4.06(d，2H，J＝12.0Hz)，6.97(s，2H)，7.36(d，1H，J＝7.5Hz)，7.56(s，1H)，7.90(d，1H，J＝6.0Hz)，8.03(s，2H)。

(0.60g 1.3mmol) is dissolved among THF (15mL) and the MeOH (15mL), is cooled to 0 ℃, and with solid LiBH will to go up step gained alkylate ₄(0.33g 15.4mmol) handles.After treating that violent bubbling is disappeared, mixture stirred in 1h be warmed to room temperature.Excessive LiBH ₄Add saturated aqueous common salt (25mL) cancellation with 1N NaOH solution (5mL).Then with CH ₂Cl ₂(3 * 30mL) aqueous phase extracted, dry (Na ₂SO ₄), and concentrating under reduced pressure, on silica gel plate through column chromatography (50: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) purification, make loose white solid 3-methylol-4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.45g, 80%).

To go up the step makes chemical compound (0.44g 1.0mmol) is dissolved in MeOH (2.5mL) and the water (2.5mL), and (0.40g is 10mmol) in 100 ℃ of following processing 16h with the NaOH granule.Reaction is cooled to room temperature, and adding 4NHCl (～2mL) until pH value of solution=5.Add saturated aqueous common salt (10mL) and with CH ₂Cl ₂(5 * 15mL) aqueous phase extracted several times.The organic facies that merges is with Na ₂SO ₄Drying, and concentrating under reduced pressure, make required 3-methylol-4-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-and benzoic acid adds～and 15% can't isolating amide by-product (0.37g, 86%).

(0.37g 0.8mmol) is dissolved among the MeOH (9mL), and with dense H will to go up step gained mixture then ₂SO ₄(55 μ L 1.0mmol) handle 16h down in 85 ℃.Cooling react to room temperature and add 15%NaOH solution (～1-2mL) be pH=8-12 until solution basicity.Add saturated aqueous common salt (10mL), and with CH ₂Cl ₂(3 * 15mL) aqueous phase extracted.The organic facies that merges is with Na ₂SO ₄Dry also concentrating under reduced pressure is through silica gel column chromatography (50: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) behind the purification, make white solid chemical compound 114 (0.26g, 69%). ¹H NMR(CDCl ₃)δ.1.64(br，3H)，2.08(s，6H)，2.11(br，1H)，2.38(m，2H)，2.46(s，6H)，3.68(br，2H)，3.81(s，3H)，4.03(d，2H，J＝11.1Hz)，4.46(s，2H)，6.77(d，1H，J＝7.5Hz)，7.03(s，2H)，7.31(d，1H，J＝7.5Hz)，7.59(s，1H)，8.00(s，2H)。 ¹³C NMR(CDCl ₃)δ.17.66(2C)，18.89(2C)，25.42，28.73(2C)，51.80，62.59(2C)，66.69(2C)，127.21，127.46，128.57(2C)，130.13，130.99(2C)，131.42，138.56，138.72(2C)，144.76，146.76(2C)，156.30(2C)，167.06.ES-MS m/z 474(M ⁺H)。Analytical calculation value C ₂₉H ₃₅N ₃O ₃0.2CH ₂Cl ₂: C, 71.49; H, 7.27; N, 8.57. measured value: C, 71.76; H, 7.39; N, 8.52.

Embodiment 115

Chemical compound 115:[5-methylol-2-meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

With 3-methylol-4 meso (3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe (0.20g 0.42mmol) is dissolved among the THF (4mL), and with solid LiBH ₄(0.11g is 5.1mmol) in 75 ℃ of following stir process 16h.Excessive LiBH ₄Add saturated aqueous common salt (15mL) cancellation with 1N NaOH solution (5mL).Then with CH ₂Cl ₂(3 * 20mL) aqueous phase extracted, dry (Na ₂SO ₄) organic layer that merges, and concentrating under reduced pressure, by silica gel through column chromatography (50: 1: 0.1 CH ₂Cl ₂/ MeOH/NH ₄OH) purification makes white solid chemical compound 115 (174mg, 93%). ¹H NMR(CDCl ₃)δ.1.64(br，3H)，2.02(m，1H)，2.11(s，6H)，2.34(m，2H)，2.45(s，6H)，3.62(br，2H)，3.97(d，2H，J＝13.5Hz)，4.38(s，2H)，4.40(s，2H)，6.66(m，2H)，6.91(s，1H)，7.03(s，2H)，8.01(s，2H)。 ¹³C NMR(CDCl ₃)δ.17.69(2C)，18.92(2C)，25.26，30.07(2C)，54.37，62.34(2C)，64.59(2C)，66.60(2C)，124.89(2C)，127.57，128.92，130.67，131.06(2C)，137.65，138.69(2C)，138.84，139.04，146.69(2C)，156.74(2C)。ES-MS m/z 446(M ⁺H)。Analytical calculation value C ₂₈H ₃₅N ₃O ₂0.4CH ₂C1 ₂: C, 71.13; H, 7.52; N, 8.76. measured value: C, 70.97; H, 7.71; N, 8.84.

Embodiment 116

Under-78 ℃ of the chemical compound 116:4-mesos [3,5-is two-(3-methyl-pyridine-2-yl)-morpholine-4-yl]-butylamine (HBr salt), at N, N, N ¹, N ¹(4.1mL, (12.0mL 26.93mmol), and is warmed to-55 ℃ approximately with reactant mixture to-tetramethylethylenediamine to add n-BuLi in the solution of THF 26.93mmol) (50mL).Behind the 30min, mixture heavily is cooled to-78 ℃, is added dropwise to the THF solution (10mL) of methoxycarbonyl group methoxyl group-methyl acetate then.Behind the 2h, with reactant mixture with water (100mL) cancellation, and with CH ₂Cl ₂(3 * 100mL) extractions.The organic facies that merges is with MgSO ₄Drying is filtered, and concentrates, and makes yellow solid.Should rough solid recrystallization from hot EtOAc, the white needle of separating out (1.04g, 31%) makes 1-(3-methyl-pyridine-2-yl)-2-[2-(3-methyl-pyridine-2-yl)-2-oxo-ethyoxyl through vacuum drying]-ethyl ketone. ¹H NMR(CDCl ₃)δ2.65(s，6H)，5.26(s，4H)，7.35(dd，2H，J＝6.0，3.0Hz)，7.60(dd，2H，J＝9.0，3.0Hz)，8.46(d，2H，J＝3.0Hz)。

(750mg adds NaBH in MeOH 2.64mmol) (30mL) suspension at last step gained diketone ₄(220mg, 5.80mmol).Behind the 1h, with water (1mL) cancellation reactant mixture, concentrating under reduced pressure is dissolved in CH with it ₂Cl ₂/ H ₂O (1: 1) (50mL), and with CH ₂Cl ₂(3 * 25mL) extractions.The organic facies that merges is through MgSO ₄Drying is filtered, and concentrates, and makes light yellow oily 2-[2-hydroxyl-2-(3-methyl-pyridine-2-yl)-ethyoxyl]-1-(3-methyl-pyridine-2-yl)-ethanol (646mg).

Under-20 ℃, at last step gained glycol (646mg, CH 2.24mmol) ₂Cl ₂(30mL) add Et in the solution successively ₃N (0.93mL, 6.72mmol) and MsCl (0.43mL, 5.60mmol).Behind the 2h, reactant mixture is warmed to 0 ℃, and with saturated NaHCO ₃(25mL) cancellation.Then with CH ₂Cl ₂(3 * 25mL) extraction mixture.The organic facies that merges is with MgSO ₄) drying, filter, and concentrate, until the about 5mL solvent of residue.

Under 0 ℃, at the CH of last step gained diformazan sulfonyl ester ₂Cl ₂(1.7mL 22.40mmol), and slowly is warmed to room temperature with reactant mixture, stirs then and spends the night (5mL) to add allyl amine in the solution.With mixture with saturated NaHCO ₃(20mL) cancellation, and with CH ₂Cl ₂(3 * 20mL) extractions.The organic extract that merges is with MgSO ₄Drying is filtered, and the concentrated yellow oil that makes.With flash column chromatography,, make light yellow oily 4-pi-allyl-meso-3 by silica gel, 5-pair-(3-methyl-pyridine-2-yl)-morpholine (166mg, 24%) with EtOAc/ hexane (4: 1) eluting. ¹H NMR(CDCl ₃)δ2.52(s，6H)，2.89(d，2H，J＝6.0Hz)，3.82(dd，2H，J＝9.0，3.0Hz)，3.97(t，2H，J＝16.0Hz)，4.28(dd，2H，J＝9.0，3.0Hz)，4.45(d，1H，J＝18.0Hz)，4.81(d，1H，J＝12.0Hz)，5.68-5.77(m，1H)，7.09(dd，2H，J＝7.5，4.5Hz)，7.42(d，2H，J＝6.0Hz)，8.50(d，2H，J＝3.0Hz)。

At last step gained amine (200mg, CH 0.65mmol) ₂Cl ₂(30mL) add 1 in the solution, and the 3-dimethyl barbituric acid (505mg, 3.23mmol) and Pd (PPh ₃) ₄(81mg 0.07mmol), and stirs reactant mixture and spends the night.With saturated NaHCO ₃(20mL) cancellation reactant mixture, and with CH ₂Cl ₂(3 * 20mL) extractions.The organic facies that merges is with MgSO ₄Drying is filtered, and the concentrated orange that makes.Through silica gel with radial chromatography (1mm plate; With MeOH/CH ₂Cl ₂1: 100 eluting) purification makes light yellow oily meso-3,5-pair-(3-methyl-pyridine-2-yl)-morpholine (97mg, 55%).

According to general step A, last step gained amine (97mg, 0.36mmol) and 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (203mg, add in DMF 0.72mmol) (5mL) solution DIPEA (0.16mL, 0.90mmol) and KI (7mg, 0.04mmol).By silica gel with flash column chromatography through MeOH/EtOAc (1: 9) eluting purification, make light yellow cystose 2-{4-meso [3,5-is two-(3-methyl-pyridine-2-yl)-morpholine-4-yl] butyl }-iso-indoles-1,3-diketone (56mg, 34%). ¹H NMR(CDCl ₃)δ0.78(br s，2H)，1.00-1.10(m，2H)，2.31(t，2H，J＝7.5Hz)，2.50(s，6H)，3.23(t，2H，J＝7.5Hz)，3.79(dd，2H，J＝9.0，3.0Hz)，4.08(t，2H，J＝7.5Hz)，4.26(dd，2H，J＝9.0，3.0Hz)，7.01(dd，2H，J＝7.5，4.8Hz)，7.35(d，2H，J＝7.5Hz)，7.68-7.73(m，2H)，7.76-7.80(m，2H)，8.41(d，2H，J＝3.9Hz)。

(56mg, (30 μ L 0.85mmol), and stir reactant mixture and spend the night to add hydrazine in EtOH 0.12mmol) (2mL) solution at last step gained amine.Decompression is removed solvent and is made light yellow solid.Through silica gel with radial chromatography (1mm plate; With NH ₄OH/CH ₃OH/CH ₂Cl ₂1: 1: 25 → 1: 1: 10 eluting) purification makes light yellow oily 4-meso [3,5-pair-(3-methyl-pyridine-2-yl)-morpholine-4-yl]-butylamine (33mg, 81%).

According to general step B, (33mg in HOAc 0.10mmol) (2mL) solution, adds the saturated HOAc (2mL) of HBr at last step gained amine.After vacuum drying spends the night, isolate light yellow solid (58mg). ¹HNMR(D ₂O)δ1.24-1.34(m，4H)，2.41(t，2H，J＝8.0Hz)，2.66(s，6H)，2.76(t，2H，J＝7.8Hz)，3.55(t，2H，J＝11.4Hz)，4.23(dd，2H，J＝12.0，3.9Hz)，4.87(dd，2H，J＝10.5，3.9Hz)，7.97(dd，2H，J＝7.8，6.0Hz)，8.48(d，2H，J＝7.8Hz)，8.75(d，2H，J＝5.7Hz)。 ¹³C NMR (D ₂O) δ 17.27,20.37,25.04,39.30,52.17,56.52,69.57,126.91,138.53,140.66,149.15,149.66.ES-MSm/z 341[M ⁺H] ⁺. analytical calculation value C ₂₀H ₂₈N ₄O3.0HBr2.2H ₂O0.2C ₄H ₁₀O:C, 39.18; H, 5.91; N, 8.79; Br, 37.59. measured value: C, 39.03; H, 5.78; N, 8.68; Br, 37.88.

Embodiment 117

Chemical compound 117: meso-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 ': 6 ', 2 "] terpyridyl-1 ,-Ji-butyl)-carbomethoxy methyl-amino]-methyl acetate

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 ' ,-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (544mg, CH 1.61mmol) ₂Cl ₂(30mL) add in the solution DIPEA (0.28mL, 1.61mmol) and methyl bromoacetate (0.14mL, 1.45mmol).By silica gel with flash column chromatography through MeOH/NH ₄OH/CH ₂Cl ₂(2: 1: 97) eluting purification makes yellow oil product (248mg, 32%). ¹HNMR(CDCl ₃)δ0.59-0.70(m，4H)，1.54-1.63(m，3H)，1.96-2.16(m，7H)，2.50(brs，6H)，3.27(s，4H)，3.61(s，6H)，4.02(br s，2H)，7.03(t，2H，J＝6.0Hz)，7.38(d，2H，J＝6.0Hz)，8.38(br s，2H)。 ¹³C NMR (CDCl ₃) δ 17.46,19.07,23.59,25.67,29.48,30.43,47.85,50.62,51.81,54.47,54.85,60.75,64.19,71.45,122.17,132.08,138.53,139.64,146.88,160.55,171.92.ES-MS m/z 483[M ⁺H] ⁺. analytical calculation value C ₂₇H ₃₈N ₄O ₄0.2CH ₂Cl ₂0.4H ₂O:C, 64.46; H, 7.80; N, 11.05. measured value: C, 64.79; H, 7.81; N, 11.14.

Embodiment 118

Compound 118: meso-2-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] the fourth amino of terpyridyl-2 '-yl)]-ethanol

Meso-[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 ' ,-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the fourth amino of terpyridyl-1 '-yl)]-(63mg adds LiAlH in THF 0.15mmol) (2mL) solution to methyl acetate ₄(29mg, 0.77mmol).Behind the 1h, with reactant mixture with saturated NH ₄Cl (10mL) cancellation, and with 2%MeOH/CH ₂Cl ₂(4 * 20mL) extractions.The organic facies that merges is with Na ₂SO ₄Drying is filtered, and the concentrated yellow oil that makes.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 25: 1: 1 eluting), make yellow oil (23mg, 40%). ¹H NMR(CDCl ³)δ.1.54-1.67(m，4H)，1.94-2.05(m，8H)，2.48(s，6H)，2.88-2.95(m，4H)，3.48-3.54(m，2H)，4.02(d，2H，J＝12.0Hz)，7.05-7.09(m，2H)，7.42(d，2H，J＝6.0Hz)，8.45(brs，2H)。 ¹³C NMR (D ₂O) δ 19.21,23.05,25.45,27.80,31.49,48.97,50.61,51.04,53.82,60.98,63.54,71.27,122.17,131.32,138.75,139.72,147.21,160.88.ES-MS m/z 383[M ⁺H] ⁺. analytical calculation value C ₂₃H ₃₄N ₄O1.5H ₂O:C, 67.45; H, 9.11; N, 13.68. measured value: C, 67.42; H, 8.74; N, 13.89.

Embodiment 119

Chemical compound 119:1 '-(2-imidazoles-1-base-ethyl)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (HBr salt)

Imidazoles (1.33g, add in THF 19.54mmol) (40mL) solution NaH (60%, 0.94g, 23.45mmol) and glycol dibromide (5.1mL 58.61mmol), and stirs reactant mixture and spends the night.Then with mixture with H ₂O (25mL) cancellation, and with CH ₂Cl ₂(2 * 30mL) extractions.The organic facies that merges is with MgSO ₄Drying is filtered, and concentrates and make light yellow oil (1.31g), is used without being further purified promptly.

According to general step A, step gained bromide in the stirring (1.31g, 7.48mmol), meso-4-(3,3 '-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (0.67g, 2.49mmol), DIPEA (0.65mL, 3.74mmol) and KI (41mg, 0.25mmol) DMF of mixture (5mL) solution.By silica gel with flash column chromatography through MeOH/NH ₄OH/CH ₂Cl ₂(2: 1: 97) eluting purification, again through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 25: 1: 1 eluting) purification makes yellow oily 1 '-(2-imidazoles-1-base-ethyl)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (38mg, 1%, 2 step). ¹H NMR(CDCl ₃)δ1.61-1.73(m，2H)，2.22-2.35(m，2H)，2.48(s，6H)，2.69(s，4H，J＝9.0Hz)，2.88(s，2H)，4.19(d，2H，J＝12.0Hz)，5.90(s，1H)，6.52(s，1H)，6.67(s，1H)，7.14(dd，2H，J＝7.5，4.8Hz)，7.47(dd，2H，J＝7.7，0.6Hz)，8.48(d，2H，J＝3.9Hz)。

According to general step B, (38mg adds saturated HOAc (2mL) solution of HBr in HOAc 0.11mmol) (2mL) solution at last step gained amine.After vacuum drying spends the night, isolate sticky orange solids (60mg). ¹HNMR(D ₂O)δ1.52-1.64(m，2H)，1.71-1.84(m，1H)，1.97-2.02(m，1H)，2.20(d，2H，J＝12.0Hz)，2.61(s，6H)，2.89(t，2H，J＝7.5Hz)，4.21(t，2H，J＝7.5Hz)，4.71(s，2H)，7.06(s，1H)，7.34(s，1H)，7.95(dd，2H，J＝7.8，6.0Hz)，8.47(s，1H)，8.50(d，2H，J＝6.9Hz)，8.71(d，2H，J＝5.7Hz)。 ¹³C NMR (D ₂O) δ 17.18,22.15,32.65,44.27,52.06,58.56,120.77,121.79,126.49,135.07,137.21,140.37,150.07,153.40.ES-MS m/z 362[M ⁺H] ⁺. analytical calculation value C ₂₂H ₂₇N ₅3.4HBr3.2H ₂O0.5C ₄H ₁₀O:C, 39.42; H, 5.76; N, 9.58; Br, 37.15. measured value: C, 39.50; H, 5.70; N, 9.66; Br, 37.10.

Embodiment 120

Chemical compound 120:[4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-hydroxyurea

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (105mg adds 1 in THF 0.31mmol) (5mL) solution, 1 '-carbonyl dimidazoles (80mg, 0.49mmol), and behind 40min with the mixture vacuum concentration.Residue is dissolved among the DMF (5mL) again, and with DIPEA (0.43mL, 2.45mmol) and NH ₂OH.H ₂(136mg 1.96mmol) handles O salt, reactant mixture is stirred spend the night.Then with mixture with CH ₂Cl ₂(25mL) dilution, and with saturated aqueous common salt (5 * 15mL) washings.Organic facies is with MgSO ₄Drying is filtered, and the concentrated light yellow oil that makes.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 25: 1: 1 → 10: 1: 1 eluting) purification makes the foamed product that is white in color (54mg, 44%). ¹H NMR(CDCl ₃)δ0.78(br s，4H)，1.53-1.68(m，3H)，1.92-2.07(m，3H)，2.14(br s，2H)，2.44(s，6H)，2.72(br s，3H)，3.96(d，2H，J＝9.0Hz)，5.64(s，1H)，7.08(dd，2H，J＝6.0，3.0Hz)，7.44(d，2H，J＝6.0Hz)，8.46(s，3H)，10.35(s，1H)。 ¹³C NMR (CDCl ₃) δ 19.23,23.18,25.48,27.98,31.87,39.16,51.27,53.81,64.16,71.47,122.42,131.42,139.24,147.06,160.33,162.15.ES-MS m/z 398[M ⁺H] ⁺. analytical calculation value C ₂₂H ₃₁N ₅O ₂0.3CH ₂Cl ₂: C, 63.32; H, 7.53; N, l6.56. measured value: C, 63.13; H, 7.68; N, 16.46.

Embodiment 121

Chemical compound 121:2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethylamine

Under-20 ℃, N-(2-hydroxyl-ethyl)-2-nitro-benzsulfamide (2.0g, 8.12mmol) and Et ₃N (1.35mL, CH 9.74mmol) ₂Cl ₂(20mL) in the solution, in 45min, be added dropwise to MsCl (0.63mL, CH 8.12mol) by syringe ₂Cl ₂(5mL) solution.After the adding, mixture is stirred 20min down in-20 ℃.Then with reactant with saturated NH ₄Cl (2 * 50mL) and saturated aqueous common salt (2 * 50mL) washings, dry (MgSO ₄, filter, and the concentrated yellow oil (2.0g, 86%) that makes. ¹H NMR(CDCl ₃)δ3.03(s，3H)，3.51(q，2H，J＝6.0Hz)，4.30(t，2H，J＝4.5Hz)，5.82(t，1H，J＝6.0Hz)，7.76-7.79(m，2H)，7.90-7.91(m，1H)，8.13-8.16(m，1H)。

(2.03g in benzene 6.95mmol) (20mL) solution, adds KOH (1.95g, H 34.73mmol) rapidly at methanesulfonic acid 2-(2-nitro-benzenesulfonyl the amine)-ethyl ester of last step gained ₂O (8mL) solution.Behind the 2h, add entry (15mL) and separate phase.Organic facies is with MgSO ₄Drying is filtered, and concentrates 1-(2-nitro-benzenesulfonyl)-aziridine (0.88g, 55%) that makes yellow oily. ¹H NMR(CDCl ₃)δ2.63(s，4H)，7.74-7.80(m，3H)，8.20-8.22(m，1H)。

With meso-4-(3,3 '-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (550mg, 2.06mmol), the nosyl aziridine (470mg, 2.06mmol) and DIPEA (0.57mL, THF 3.30mmol) (10mL) solution at room temperature stirs 3d.Be dissolved in CH then with the mixture vacuum concentration, and with residue ₂Cl ₂(20mL), and with saturated NaHCO ₃(3 * 20mL) washings.Organic facies is with MgSO ₄Drying is filtered, and the concentrated yellow solid that makes.(use 5%MeOH/CH by silica gel with flash column chromatography ₂Cl ₂Eluting) purification makes impure yellow solid shape product (650mg, 64%), without being further purified direct use.

At last step gained amine (650mg, CH 1.31mmol) ₃In CN (13mL) solution, add K ₂CO ₃(1.09g, 7.86mmol) and phenylmercaptan. (0.74mL, 7.21mmol).Behind the 2h, with mixture with CH ₂Cl ₂(20mL) and H ₂O (20mL) dilution.Water is with CH ₂Cl ₂(2 * 20mL) extractions.The organic facies that merges is with MgSO ₄Drying is filtered, and the concentrated glassy yellow grease that makes.By silica gel with flash column chromatography through MeOH/CH ₂Cl ₂(2% → 5%), the eluting purification makes yellow cystose product (309mg, 48%, 2 step). ¹H NMR(CDCl ₃)δ1.62(m，2H)，1.70-1.78(m，3H)，1.91-1.93(m，1H)，2.15-2.20(m，2H)，2.39-2.44(m，8H)，4.07(d，2H，J＝9.0Hz)，7.18(dd，2H，J＝6.0，3.0Hz)，7.53(d，2H，J＝6.0Hz)，8.60(d，2H，J＝3.0Hz)，9.36(br s，2H)。 ¹³CNMR (CDCl ₃) d 19.22,25.12,30.06,34.19,35.53,49.86,66.77,123.06,127.53,127.86,129.43,131.37,139.75,140.12,140.48,147.47,160.07.ES-MS m/z 311[M ⁺H] ⁺. analytical calculation value C ₁₉H ₂₆N ₄0.8CH ₂Cl ₂1.3H ₂O:C, 59.19; H, 7.58; N, 13.94. measured value: C, 59.46; H, 7.59; N, 14.10.

Embodiment 122

Chemical compound 122:[2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethyl] hydroxyurea

2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethylamine (84mg adds 1 in THF 0.27mmol) (3mL) suspension, 1 '-carbonyl dimidazoles (44mg, 0.27mmol), and with mixture heated to 60 ℃.Behind the 2h, with the mixture vacuum concentration.Residue is dissolved in DMF (3mL) again, and with DIPEA (O.13mL, 1.35mmol) and NH ₂(75mg 1.08mmol) handles OHHCl, reactant mixture is stirred spend the night.Then with mixture with CH ₂Cl ₂(20mL) dilution, and with saturated aqueous common salt (5 * 15mL) washings.Organic facies is with MgSO ₄Drying is filtered, and the concentrated yellow oil that makes.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄The OH eluting; 25: 1: 1) purification, make white solid product (27mg, 27%). ¹H NMR(CDCl ₃)δ1.53-1.57(m，1H)，1.70(d，2H，J＝15.0Hz)，1.92-2.09(m，5H)，2.43-2.45(m，8H)，3.86(d，2H，J＝9.0Hz)，4.70(br s，1H)，6.43(br s，1H)，7.09(dd，2H，J＝6.0，3.0Hz)，7.46(d，2H，J＝9.0Hz)，8.53(d，2H，J＝3.0Hz)，10.07(br s，1H)。 ¹³C NMR (CDCl ₃) δ 19.33,24.96,33.13,38.80,55.54,66.00,122.70,130.80,139.36,147.73,161.02,162.06.ES-MS m/z 370[M ⁺H] ⁺. analytical calculation value C ₂₀H ₂₇N ₅O ₂0.2CH ₂Cl ₂: C, 62.78; H, 7.15; N, 18.12. measured value: C, 62.86; H, 7.46; N, 17.97.

Embodiment 123

Chemical compound 123:1 '-(1H-imidazol-4 yl methyl)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

4-(methylol) imidazole hydrochloride (526mg, add in DMF 3.91mmol) (5mL) solution DIPEA (2.04mL, 11.73mmol) and Sem-chloride (0.82mL, 4.69mmol).Behind the 3h, with reactant mixture with EtOAc (25mL) dilution, and with water (2 * 20mL) and saturated aqueous common salt (2 * 20mL) wash.Organic facies is with MgSO ₄Drying is filtered, and the concentrated yellow oil that makes.By silica gel with flash chromatography through MeOH/NH ₄OH/CH ₂Cl ₂(3: 1: 96) purification makes yellow oily [3-(2-TMS-ethoxyl methyl)-3H-imidazol-4 yl]-methanol (354mg, 40%). ¹H NMR (CDCl ₃) δ-0.01 (s, 9H), 0.88-0.94 (m, 2H), 2.60-2.62 (br m, 1H), 3.45-3.53 (m, 2H), 4.61 and 4.67 (br s, 2H altogether), 5.23 and 5.36 (s is 2H altogether), 6.99 and 7.04 (s, 1H altogether), 7.55 and 7.56 (s, 1H altogether).

According to general step F, under 0 ℃, at last step gained alcohol (354mg, CH 1.55mmol) ₂Cl ₂Add Et in the solution ₃N (0.43mL, 3.10mmol) and MsCl (0.13mL, 2.33mmol).Without being further purified, make yellow oil (270mg).

According to general step A, will go up step gained methylsulfonyl ester (270mg, 0.88mmol), meso-4-(3,3 '-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (236mg, 0.88mmol), DIPEA (0.23mL, 1.32mmol) and KI (15mg, DMF 0.09mmol) (10mL) suspension stirs jointly.Through flash column chromatography, with MeOH/NH ₄OH/CH ₂Cl ₂(2: 1: 97) eluting purification makes yellow oil product (110mg).

(110mg, 6N HCl (10mL) solution 0.23mmol) stirs down at 60 ℃ will to go up step gained amine.Behind the 3h, reaction mixture and with solid K ₂CO ₃Regulate pH=10-11.Then with CH ₂Cl ₂(4 * 30mL) extractions.The organic facies that merges is with MgSO ₄Drying is filtered, and the concentrated light yellow solid that makes.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 25: 1: 1 eluting) purification makes white solid product (34mg, 43%). ¹H NMR(CDCl ₃)δ1.44-1.57(m，1H)，1.73(d，2H，J＝12.0Hz)，1.89-2.04(m，3H)，2.47(br s，6H)，3.31(s，2H)，3.84(br d，2H，J＝12.0Hz)，6.02(br s，1H)，7.07(br s，2H)，7.41-7.43(m，3H)，8.42(d，2H，J＝3.0Hz)。 ¹³C NMR (CDCl ₃) δ 19.34,25.26,31.80,32.36,46.07,70.19,121.87,122.53,126.77,135.13,137.96,147.04,160.63.ES-MS m/z 348[M ⁺H] ⁺. analytical calculation value C ₂₁H ₂₅N ₅0.8H ₂O:C, 69.70; H, 7.41; N, 19.35. measured value: C, 69.78; H, 7.41; N, 19.01.

Embodiment 124

Chemical compound 124:4-[2-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 ' ,-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-ethyl]-1,3-dimethyl-3H-imidazoles-1-iodide

Under 0 ℃, at 1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (223mg, add in THF 0.62mmol) (6mL) solution NaH (60%, 27mg, 0.68mmol) and MeI (40 μ L, 0.62mmol).Reactant mixture is warmed to room temperature and stirs spend the night.With the mixture vacuum filtration, and concentrated filtrate makes orange foam.Through silica gel with radial chromatography (2mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 5: 1: 1 eluting) purification makes yellow oil product (103mg, 32%). ¹H NMR(CDCl ₃)δ1.55-1.66(m，2H)，1.79-1.81(m，1H)，1.92-2.11(m，3H)，2.44(s，6H)，3.12(m，2H)，3.39(s 2H)，3.78(s，3H)，4.04(d，2H，J＝9.0Hz)，6.42(s，1H)，7.11-7.15(m，2H)，7.49(d，2H，J＝9.0Hz)，8.42(br s，2H)，9.45(s，1H)。 ¹³C NMR (CDCl ₃) δ 19.36,23.41,25.13,30.22,33.43,36.98,50.01,65.09,71.21,120.00,122.95,131.97,134.07,137.02,139.19,140.60,146.69,147.14,160.05.ES-MS m/z 390[M-I] ⁺. analytical calculation value C ₂₄H ₃₃N ₅I0.9H ₂O0.4CH ₂Cl ₂: C, 51.89; H, 6.05; N, 12.30; I, 22.29. measured value: C, 52.03; H, 6.45; N, 12.42; I, 22.14.

Embodiment 125

Chemical compound 125:3,3 " dimethyl-1 '-[2-(1-methyl isophthalic acid H-imidazol-4 yl)-ethyl]-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

At 1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (167mg, add in THF 0.46mmol) (5mL) solution NaH (60%, 7mg, 0.17mmol).Behind 0 ℃ of following 30min, (10mL 0.15mmol), and is warmed to stirred overnight at room temperature with reactant mixture to add MeI.Next day, enriched mixture makes yellow foam.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 10: 1: 1 eluting) purification makes yellow oil product (23mg, 41%). ¹H NMR(CDCl ₃)δ1.57-1.72(m，3H)，1.94-2.16(m，3H)，2.48-2.53(m，8H)，3.41(s，3H)，3.71(s，2H)，4.13(d，2H，J＝9.0Hz)，5.94(br 2，1H)，7.02-7.06(m，3H)，7.40(d，2H，J＝9.0Hz)，8.45(br s，2H)。 ¹³C NMR (CDCl ₃) δ 19.25,23.34,25.40,32.42,33.46,50.08,62.13,115.93,122.07,132.50,136.91,138.83,141.50,147.32,160.82.ES-MS m/z 376[M ⁺H] ⁺. analytical calculation value C ₂₃H ₂₉N ₅1.4H ₂O0.4CH ₂Cl ₂: C, 64.65; H, 7.56; N, 16.11. measured value: C, 65.01; H, 7.67; N, 15.99.

Embodiment 126

Chemical compound 126:1 ' (1H-imidazoles-2-ylmethyl)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

At 2-imidazole formaldehyde (1.01g, CH 10.51mmol) ₂Cl ₂(25mL) add Et in the suspension ₃N (2.9mL, 21.02mmol) and toluene sulfochloride (3.01g 15.77mmol), and spends the night the reactant mixture reflux.Cooling mixture then, and with saturated NH ₄Cl (4 * 30mL) washings.Organic facies is with MgSO ₄Drying is filtered, and the concentrated burgundy grease that makes.By silica gel with flash column chromatography through 2%MeOH/CH ₂Cl ₂Purification makes yellow oily 1-(toluene-4 sulfonyl)-1H-imidazoles-2-formaldehyde (1.53g, 58%). ¹H NMR(CDCl ₃)δ2.45(s，3H)，7.31(s，1H)，7.49(d，2H，J＝6.0Hz)，7.83(s，1H)，8.00(d，2H，J＝7.5hz)，9.78(s，1H)。

Under 0 ℃, at last step gained aldehyde (1.53g, CH 6.11mmol) ₂Cl ₂(50mL) in the solution, add TFA (5mL) (described in J.Med.Chem. (1997) 40:2196).With EtOAc/ hexane (1: 1) eluting purification, make white solid [1-(toluene-4 sulfonyl)-1H-imidazoles-2-yl]-methanol (0.55g, 36%) by flash chromatography. ¹H NMR(CDCl ₃)δ2.45(s，3H)，3.03(br s，1H)，4.84(s，2H)，6.99(d，1H，J＝3.0Hz)，7.35(s，1H)，7.39(d，2H，J＝3.0Hz)，7.83(d，2H，J＝9.0Hz)。

Under 0 ℃, last step gained alcohol (0.55g, 2.17mmol) and CBr ₄(1.08g, CH 3.26mmol) ₂Cl ₂(25mL) add triphenyl phasphine (0.68g, CH 2.60mmol) in the solution ₂Cl ₂(10mL) solution (described in J.Med.Chem. (1997) 40,14:2196).With 25%EtOAc/ hexane eluting purification, make 2-bromomethyl-1-(toluene-4 the sulfonyl)-1H-imidazoles (0.31g, 45%) of yellow oily by flash column chromatography. ¹HNMR(CDCl ₃)δ2.45(s，3H)，4.81(s，2H)，7.04(s，1H)，7.37(d，2H，J＝9.0Hz)，7.42(s，1H)，7.92(d，2H，J＝9.0Hz)。

According to general step A, will go up step gained bromide (310mg, 0.98mmol), meso-4-(3,3 '-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (88mg, 0.33mmol), DIPEA (0.23mL, 1.32mmol) and KI (5mg, 0.03mmol) DMF of mixture (5mL) solution stirs jointly.By silica gel with flash column chromatography through MeOH/CH ₂Cl ₂(2% → 5%) purification makes yellow oil product (76mg, 46%).

(76mg, (82mg 0.61mmol), and stirs reactant mixture and spends the night to add HOBT in MeOH 0.15mmol) (1mL) solution at last step gained tosylate.Enriched mixture makes brown oil then.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 10: 1: 1 eluting), make yellow oil product (32mg, 59%). ¹H NMR(CDCl ₃)δ1.54-1.63(m，1H)，1.73(d，2H，J＝16.0Hz)，1.91-1.21(m，3H)，2.44(s，6H)，3.40(s，2H)，3.96(d，2H，J＝9.0Hz)，6.49(br s，1H)，6.67(br s，1H)，6.94-6.99(m，2H)，7.37(d，2H，J＝9.0Hz)，8.35(d，2H，J＝3.0Hz)。 ¹³C NMR (CDCl ₃) δ 19.42,20.27,33.11,53.77,65.87,122.32,131.49,139.03,147.13,160.37.ES-MSm/z 347[M ⁺H] ⁺. analytical calculation value C ₂₁H ₂₅N ₅1.1H ₂O:C, 68.68; H, 7.46; N, 19.07. measured value: C, 68.49; H, 7.37; N, 19.27.

Embodiment 127

Chemical compound 127:3,3 "-dimethyl-1 '-(4-pyrrolidine-1-base butyl)-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butyraldehyde (155mg, 0.46mmol) and pyrrolidine (50 μ L (stir 30min) in MeOH 0.55mmol) (5mL) solution in advance altogether, add NaBH ₃CN (58mg, 0.92mmol).The reactant mixture stirring is spent the night, then vacuum concentration.Residue is dissolved in CH ₂Cl ₂(20mL), and with saturated NaHCO ₃(3 * 20mL) washings.Organic facies is with MgSO ₄Drying is filtered, and the concentrated yellow oil that makes.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH (50: 1: 1) eluting), make yellow oil product (34mg, 19%). ¹HNMR(CDCl ₃)δ0.81(br s，3H)，1.54-1.67(m，6H)，1.92-2.00(m，5H)，2.16-2.22(m，6H)，2.47(br s，5H)，2.64(br s，1H)，3.77(s，2H)，4.06(d，2H)，J＝12.0Hz)，7.06(dd，2H，J＝6.0，3.0Hz)，7.40(d，2H，J＝6.0Hz)，8.45(br s，2H)。ES-MS m/z 393[M ⁺H] ⁺。

Embodiment 128

Chemical compound 128:4-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene 22 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-piperidines-1-hydroxyurea

At different piperidine ethyl formate (ethyl isonipectotate) (2.0mL, CH 12.99mmol) ₂Cl ₂(20mL) add Et in the solution ₃N (3.6mL, 25.98mmol) and p-toluenesulfonyl chloride (3.71g stirs 19.48mmol) and with reactant mixture and to spend the night.Then with mixture with CH ₂Cl ₂(10mL) dilution, and with saturated NH ₄Cl (3 * 30mL) washings.Organic facies is with MgSO ₄Drying is filtered, and the concentrated yellow solid that makes.By silica gel with flash column chromatography through hexane/EtOAc (3: 1) eluting purification, make white solid 1-(toluene-4 sulfonyl)-piperidines-4-carboxylic acid, ethyl ester (3.45g, 85%).

Under 0 ℃, at last step gained ester (1.29g, CH 4.79mmol) ₂Cl ₂(20mL) in the solution, add LiAlH ₄THF (1.0M, 13.9mL, 13.87mmol) solution, and mixture heated refluxed.Behind the 1h, mixture is cooled to 0 ℃, and with water (0.51mL), 15%NaOH (0.51mL) and H ₂O (1.53mL) cancellation.After stirring 30min, reactant mixture is with MgSO ₄Drying is filtered, and concentrated clarification oily [1-(toluene-4 sulfonyl)-the piperidin-4-yl]-methanol (1.24g, 100%) that makes. ¹H NMR(CDCl ₃)δ1.31-1.43(m，4H)，1.79(d，2H，J＝12.0Hz)，2.24(t，2H，J＝12.0Hz)，2.43(s，3H)，3.47(d，2H，J＝6.0Hz)，3.81(d，2H，J＝12.0Hz)，7.32(d，2H，J＝6.0Hz)，7.64(d，2H，J＝6.0Hz)。

According to general step F, under 0 ℃, at last step gained alcohol (1.24g, CH 4.79mmol) ₂Cl ₂(20mL) in the solution, add Et ₃N (1.3mL, 9.58mmol) and MsCl (0.56mL, 7.18mmol).Without being further purified, make light yellow solid (1.49g, 90%).

According to general step A, will go up step gained methylsulfonyl ester (485mg, 1.40mmol), meso-4-(3,3 '-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine (311mg, 1.16mmol), DIPEA (0.30mL, 1.71mmol) and KI (20mg, DMF 0.12mmol) (5mL) solution stirs jointly.By silica gel with flash column chromatography through MeOH/NH ₄OH/CH ₂Cl ₂(2: 1: 97) eluting purification makes brown cystose 3,3 "-dimethyl-1 '-[1-(toluene-4 sulfonyl)-piperidin-4-yl methyl]-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (385mg, 77%). ¹H NMR(CDCl ₃)δ0.11-0.22(m，2H)，1.00(d，2H，J＝15.0Hz)，1.51-1.69(m，5H)，2.04-2.08(m，1H)，2.25-2.36(m，4H)，2.45(s，3H)，2.50(s，6H)，3.18(d，2H，J＝12.0Hz)，3.64(s，1H)，4.10(d，2H，J＝12.0Hz)，7.01(dd，2H，J＝6.0，3.0Hz)，7.25(d，2H，J＝7.5Hz)，7.35(d，2H，J＝7.5Hz)，7.45(d，2H，J＝6.0Hz)，8.33(d，2H，J＝6.0Hz)。

(348mg, the saturated HOAc of HBr 0.67mmol) (4mL) solution stir down in 70 ℃ and spend the night will to go up step gained tosylate.Reaction mixture and concentrated is dissolved in minimum H with residue then ₂Among the O, and alkalize to pH=11 with 10N NaOH.With CH ₂Cl ₂(5 * 20mL) aqueous phase extracted.The organic facies that merges is with MgSO ₄Drying is filtered, and the concentrated brown oil that makes.By silica gel with flash column chromatography through MeOH/NH ₄OH/CH ₂Cl ₂(2: 1: 97) eluting purification makes yellow oily 3,3 '-dimethyl-1 '-piperidin-4-yl methyl isophthalic acid ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (80mg, 33%).

(71mg, (46mg 0.23mmol), and stirs reactant mixture down in 70 ℃ to add hydroxyurea 4-nitro 1-phenylester in THF 0.19mmol) (5mL) solution at last step gained amine.Behind the 2h, will react concentrating under reduced pressure.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 25: 1: 1 eluting) purification makes white solid product (16mg, 20%). ¹H NMR (CDCl ₃) δ-0.46 (br m, 1H), 0.04 (br m, 1H), 1.07 (d, 2H, J=12.0Hz), and 1.55-1.71 (m, 3H), 2.01-2.35 (m, 12H), 2.50 (s, 6H), 3.45 (d, 2H, J=12.0Hz), 4.12 (d, 2H, J=9.0Hz), 6.47 (s, 1H), 7.09 (d, 2H, J=6.0,3.0Hz), 7.42 (d, 2H, J=6.0Hz), 8.41 (d, 2H, J=6.0Hz) ¹³C NMR (CDCl ₃) δ 0.39,19.06,25.74,26.56,29.73,36.44,43.64,44.44,53.82,65.60,122.55,132.61,138.26,146.65,160.35,160.85.ES-MS m/z 424[M ⁺H] ⁺. analytical calculation value C ₂₄H ₃₃N ₅O ₂1.2CH ₂Cl ₂: C, 57.60; H, 6.79; N, 13.33. measured value: C, 57.90; H, 6.82; N, 13.40.

Embodiment 129

Chemical compound 129:1 '-[2-(1-benzyl-1H-imidazol-4 yl)-ethyl]-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

Under 0 ℃, at 1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (191mg, in THF 0.53mmol) (5mL) solution, add NaH (60%, 8mg, 0.20mmol).0 ℃ down stir 30min after, (21 μ L 0.18mmol), and stir the gained mixture and to spend the night under room temperature to add cylite.In inferior morning,, make brown residue with the mixture concentrating under reduced pressure.Through silica gel with radial chromatography (1mm plate; With CH ₂Cl ₂/ MeOH/NH ₄OH; 50: 1: 1 → 10: 1: 1 eluting) purification makes yellow oil product (39mg, 48%). ¹H NMR(CDCl ₃)δ1.57-1.70(m，3H)，1.93-2.16(m，5H)，2.46(br s，8H)，4.12(d，2H，J＝9.0Hz)，4.36(s，2H，4.83(s，2H)，5.94(s，1H)，6.99(br s，4H)，7.17(s，1H)，7.28(s，3H)，7.36(d，2H，J＝9.0Hz)，8.42(s，2H)。 ¹³C NMR (CDCl ₃) δ 19.23,23.41,25.39,32.47,50.23,50.97,62.04,115.12,122.07,127.64,128.49,129.23,136.52,138.84,147.33,160.82.ES-MS m/z 452[M ⁺H] ⁺. analytical calculation value C ₂₉H ₃₃N ₅0.5CH ₂Cl ₂: C, 71.71; H, 6.94; N, 14.17. measured value: C, 71.78; H, 7.23; N, 14.10.

Embodiment 130

Chemical compound 130:1 '-[2-(1-pi-allyl-1H-imidazol-4 yl)-ethyl]-3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

Under 0 ℃, at 1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (202mg, in THF 0.56mmol) (5mL) solution, add NaH (60%, 8mg, 0.21mmol).Behind 0 ℃ of following 30min, and the adding allyl bromide, bromoallylene (16mL, 0.19mmol).Behind the 4h, concentrated reaction mixture makes orange solids.Through silica gel with radial chromatography (2mm plate; With CH ₂Cl ₂/ CH ₃OH/NH ₄OH; 50: 1: 1 → 10: 1: 1 eluting) purification makes light yellow oily product (25mg, 33%). ¹H NMR(CDCl ₃)δ1.58-1.73(m，3H)，1.95-2.08(m，3H)，2.38-2.48(m，8H)，2.93(s，2H)，4.14(d，2H，J＝9.0Hz)，4.27(d，2H，J＝6.0Hz)，5.02(d，1H，J＝18.0Hz)，5.16(d，1H，J＝9.0Hz)，5.71-5.84(m，1H)，5.96(s，1H)，7.06(dd，2H，J＝6.0，3.0Hz)，7.12(s，1H)，7.40(d，2H，J＝9.0Hz)，8.46(s，2H)。 ¹³C NMR (CDCl ₃) δ 19.21,23.68,25.45,30.08,31.94,49.56,62.43,114.86,118.69,122.07,131.27,133.15,136.13,138.79,141.84,147.25,160.74.ES-MS m/z 402[M ⁺H] ⁺. analytical calculation value C ₂₅H ₃₁N ₅1.5H ₂O:C, 70.06; H, 8.00; N, 16.34. measured value: C, 70.19; H, 7.98; N, 16.05.

Embodiment 131

Chemical compound 131:N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "]-terpyridyls-1 '-ylmethyl)-3-methylol-benzyl]-2-phenyl-butyramide

3,3 " dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (0.500g, CH 1.87mmol) ₃Add in CN (10mL) solution 2-bromomethyl-5-cyano group-essence of Niobe (0.500g, 1.96mmol) and K ₂CO ₃(0.720g, 5.61mmol).With mixture in 80 ℃, N ₂Direct draught stirs 15h.Vacuum concentrated mixture, and with saturated NaCl aqueous solution (25mL) cancellation, and with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and vacuum concentration, makes brown oil, not purified direct use.

The brown oil of gained of last step is dissolved among the MeOH (10mL), slowly adds LiBH then ₄(0.411g, 18.7mmol), to guarantee reactant mixture do not bubble over (bubble over).Mixture is at room temperature stirred 16h.Vacuum concentrated mixture, and it is dissolved in CH again ₂Cl ₂(30mL), with saturated NaHCO ₃Aqueous solution (30mL) cancellation.With the gained mixture with CH ₂Cl ₂(3 * 40mL) extractions, and with the organic extract that merges with Na ₂SO ₄Drying is filtered, and vacuum concentration makes yellow foam.Through silica gel with column chromatography (CH ₂Cl ₂: MeOH: NH ₄OH, 92: 5: 3, v/v/v) purification, make white foam shape 4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (0.610g, 80%, 2 step). ¹H NMR(CDCl ₃)δ1.58-1.69(m，3H)，2.05(m，1H)，2.29-2.41(m，2H)，2.48(s，6H)，3.67(s，2H)，4.11(d，2H，J＝12.0Hz)，4.44(s，2H)，5.13(br s，1H)，6.85(dd，2H，J＝6.0，4.5Hz)，6.92(s，2H)，7.23(s ⁺d，3H)，8.16(d，2H，J＝3.0Hz)。

4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-3-methylol-benzonitrile (0.610g, in MeOH 1.48mmol) (12mL) solution, logical ammonia 10min.With the Raney nickel of prerinse (～1.5g) mixture joins in this nitrile, and mixture is jolted 2.5h with 45psi on hydrogenator.Mixture filters through the sintered glass funnel of a band diatom core, and with the filtrate vacuum concentration, makes green foam shape thing.Through silica gel with column chromatography (CH ₂Cl ₂: MeOH: NH ₄OH, 87: 8: 5, v/v/v) purification, make the white foam shape [5-aminomethyl-2-(and 3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "]-terpyridyls-1 '-ylmethyl)-phenyl]-methanol (0.540g, 88%). ¹H NMR(CDCl3)δ1.25(br s，1H)，1.62-1.72(m，3H)，2.03(m，1H)，2.32(m，2H)，2.49(s，6H)，2.81(br s，1H)，3.55(s，2H)，3.62(s，1H)，4.01(d，2H，J＝9.0Hz)，4.34(s，2H)，5.18(br s，1H)，6.59(d，1H，J＝9.0Hz)，6.72(d，1H，J＝9.0Hz)，6.83(m，3H)，7.23(d，2H，J＝9.0Hz)，8.22(d，2H，J＝3.0Hz)。

Will [5-aminomethyl-2-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (0.121g, 0.29mmol), S-( ⁺)-2-phenylbutyric acid (54 μ L, 0.35mmol), HOBT (0.047g, 0.35mmol), EDCI (0.067g, 0.35mmol) and DIPEA (61 μ L are 0.35mmol) at CH ₂Cl ₂React according to general step G (8mL).Through silica gel with column chromatography (CH ₂Cl ₂: MeOH: NH ₄OH, 94: 5: 1, v/v/v) purification, make white solid N-[4-(3,3 " dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "]-terpyridyls-1 '-ylmethyl)-3-methylol-benzyl]-2-phenyl-butyramide (0.120g, 73%). ¹HNMR(CDCl ₃)δ.0.86(t，3H，J＝7.5Hz)，1.59-1.76(m，3H)，2.04(m，1H)，2.32(m，2H)，2.49(s，6H)，3.62(s，2H)，4.00-4.09(m，4H)，4.32(s，2H)，5.07(br s，1H)，5.35(br s，1H)，6.44(d，1H，J＝7.5Hz)，6.63(d，2H，J＝9.0Hz)，6.75(m，2H)，7.13-7.33(m，7H)，8.22(d，2H，J＝3.0Hz)。HPLC：94％.ES-MS m/z 563[M ⁺H] ⁺，585[M ⁺Na] ⁺。

Embodiment 132

Chemical compound 132:N-[3-methylol-4-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzyl]-2-phenyl-butyramide

3,5,3 ", 5 " and tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "]-terpyridyls (0.130g, CH 0.44mmol) ₃Add in CN (5mL) solution 2-bromomethyl-5-cyano group-essence of Niobe (0.117g, 0.46mmol) and K ₂CO ₃(0.169g, 1.32mmol).With mixture at 80 ℃, N ₂Direct draught stirs 15h.With the mixture vacuum concentration, and with saturated NaCl aqueous solution (25mL) cancellation, with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and vacuum concentration makes yellow oil, not purified direct use.

To go up step gained yellow oil and be dissolved among the MeOH (5mL), slowly add LiBH then ₄(0.097g is 4.41mmol) to guarantee that reactant mixture does not bubble over.Mixture is at room temperature stirred 16h.Vacuum concentrated mixture, and it is dissolved in CH again ₂Cl ₂(30mL), with saturated NaHCO ₃Aqueous solution (30mL) cancellation.With the gained mixture with CH ₂Cl ₂(3 * 40mL) extractions, and with the organic extract that merges with Na ₂SO ₄Drying is filtered, and vacuum concentration makes yellow oil.Through silica gel with column chromatography (CH ₂Cl ₂: MeOH: NH ₄OH, 92: 5: 3, v/v/v) purification, make yellow oily 3-methylol-4-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.060g, 31%, 2 step). ¹H NMR(CDCl ₃)δ1.58-1.69(m，3H)，2.05(m，1H)，2.14(s，6H)，2.26-2.35(m，2H)，2.43(s，6H)，3.63(s，2H)，4.00(d，2H，J＝12.0Hz)，4.44(s，2H)，5.26(br s，1H)，6.82(d，1H，J＝9.0Hz)，6.92(d，1H，J＝9.0Hz)，7.05(s，2H)，7.26(s，1H)，8.01(s，2H)。

3-methylol-4-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile (0.060g, in MeOH 0.14mmol) (7mL) solution, logical ammonia 10min.With the Raney nickel of prerinse (～0.5g) mixture joins in this nitrile, and mixture is jolted 2h with 40psi on hydrogenator.Mixture filters through the sintered glass funnel of a band diatom core, and with the filtrate vacuum concentration, makes green foam shape thing.Through silica gel with column chromatography (CH ₂Cl ₂: MeOH: NH ₄OH, 87: 8: 5, v/v/v) purification, make light yellow cystose [5-aminomethyl-2-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol (0.061g, 99%). ¹H NMR(CDCl3)δ1.52-1.62(m，3H)，1.98(m，1H)，2.10(s，6H)，2.20-2.30(m，2H)，2.37(s，6H)，3.50(s，2H)，3.57(s，1H)，3.88(d，2H，J＝9.0Hz)，4.27(s，2H)，6.59(d，1H，J＝9.0Hz)，6.68(d，1H，J＝9.0Hz)，6.89(s，1H)，7.03(s，2H)，8.03(s，2H)。

Will [5-aminomethyl-2-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "]-terpyridyls-1 '-ylmethyl)-phenyl]-methanol (0.061g, 0.14mmol), S-( ⁺)-2-phenylbutyric acid (22 μ L, 0.16mmol), HOBT (0.022g, 0.16mmol), EDCI (0.032g, 0.16mmol) and DIPEA (29 μ L are 0.16mmol) at CH ₂Cl ₂React according to general step G (8mL).Through silica gel with column chromatography (CH ₂Cl ₂: MeOH: NH ₄OH, 94: 5: 1, v/v/v) purification, make white solid N-[3-methylol-4-(3,5,3 ", 5 " tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-benzyl]-2-phenyl-butyramide (0.045g, 55%). ¹HNMR(CDC13)δ.0.86(t，3H，J＝7.5Hz)，1.66-1.76(m，3H)，2.10(s ⁺m，7H)，2.32(m，2H)，2.42(s，6H)，3.65(br s，2H)，3.92(m，4H)，4.35(s，2H)，5.46(brs，1H)，6.45(d，1H，J＝7.5Hz)，6.60(d，1H，J＝9.0Hz)，6.68(s，1H)，7.00(s，2H)，7.13-7.33(m，7H)，8.00(s，2H)。HPLC：93％.ES-MS m/z 591[M ⁺H] ⁺，613[M ⁺Na] ⁺。

Embodiment 133

Chemical compound 133:N ¹-(3,3 "-dimethyl-3 ', 4 ', 5 ' 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-propane-1,3-diamidogen (HBr salt)

Under the room temperature, 3,3 '-dimethyl-1 ', 2 ', 3 ' 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] (850mg adds NaNO in 1N HCl (20mL) solution 3.18mmol) to terpyridyl ₂(658mg, 9.54mmol), and with mixture heated to 70 ℃, 2h.Then mixture is cooled to room temperature and neutralizes with 10N NaOH.With CH ₂Cl ₂(3 * 50mL) extractions.The organic extract that merges is with MgSO ₄Drying is filtered and is concentrated, and makes yellow solid.

With gained of last step 3,3 "-dimethyl-1 '-nitroso-group-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl is dissolved among the EtOH (5mL), and is cooled to 0 ℃.Add NH ₄OH (5mL), NH ₄OAc (193mg, 2.51mmol) and zinc powder (225mg 5.0mmol), and at room temperature stirs 1h with mixture.Zinc is after filtration and with water (10mL) and CH ₂Cl ₂(20mL) washing.Separate biphase, and with organic facies with MgSO ₄Drying is filtered and is concentrated.Crude product through silica gel with column chromatography (19: 1: 0.2 CH ₂Cl ₂: CH ₃OH: NH ₄OH) purification obtains 3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-Ji amine (430mg, 48%). ¹H NMR(CDCl ₃)δ1.55-1.69(m，1H)，1.75-1.95(m，3H)，2.01-2.14(m，2H)，2.40-2.75(br m，8H)，3.65-3.80(br s，2H)，7.07(dd，2H，J＝4.2，7.5Hz)，7.43(d，2H，J＝7.2Hz)，8.45(br s，2H)。

With 3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-Ji amine (92.6mg, 0.328mmol) and 3-(tert-butoxy carbonyl amino)-1-propionic aldehyde (Bioorg.Med.Chem.Lett. (2000) 10:559-562) (114mg 0.64mmol) stirs 2h in dry EtOH (10mL).Remove solvent, and add dry THF (10mL), mixture is cooled to 0 ℃ then.Add LiAlH ₄(the THF solution of 1.0M/0.48mmol) and with mixture be warmed to stirring at room 30min.Add entry (10mL), and with mixture with CH ₂Cl ₂(2 * 20mL) extractions, the organic extract of merging is with MgSO ₄Dry and concentrated.Crude product through silica gel with radial chromatography (with NH ₄The Et that OH is saturated ₂O) purification, make [3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-Ji amino)-propyl group]-t-butyl carbamate (49mg, 34%).

According to salifiable general step B, with the saturated HOAc of HBr will [3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-Ji amino)-propyl group]-(49mg 0.111mmol) is converted into chemical compound 133 (67mg, 79%) to t-butyl carbamate. ¹H NMR(D ₂O)δ1.20-1.29(m，2H)，1.54-1.74(m，3H)，1.90-1.06(m，1H)，2.17-2.23(m，2H)，2.30-2.46(m，4H)，2.16(s，6H)，7.90(dd，2H，J＝5.7，7.8Hz)，8.44(d，2H，J＝7.8Hz)，8.67(d，2H，J＝5.7Hz)； ¹³C NMR(D ₂O)δ17.0，22.3，26.1，32.6，37.5，41.6，61.4，125.9，136.9，139.5，149.5，154.6；ES-MS m/z 340(M ⁺H)。Analytical calculation value C ₂₀H ₂₉N ₅2.4H ₂O3.8HBr0.3C ₄H ₁₀O:C, 35.74; H, 5.74; N, 9.83; Br, 42.62. measured value: C, 35.83; H, 5.56; N, 9.86; Br, 42.41.

Embodiment 134

Chemical compound 134:3-(3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-azetidine-1-carboxylic acid hydroxamides

(441mg 2.35mmol) is dissolved in CH with 3-(aminomethyl)-1-azetidine carboxylic tert-butyl ester (J.Med.Chem., (2001) 44:94-104) ₂Cl ₂(2mL) and among the TFA (1.5mL), and mixture at room temperature stirred 2h.Volatile matter is removed in decompression, and residue is dissolved among the dry MeOH (5mL).Add solid NaHCO ₃(～500mg) also stirred 17h with mixture.Remove MeOH, add CH ₂Cl ₂(50mL) and with mixture filter by the diatom core.Concentrated filtrate, and residue is dissolved in DMF (15mL).(0.817mL, 4.70mmol) (580mg 2.58mmol), stirs 2h with mixture with the 2-nitrobenzene sulfonyl chloride to add DIPEA.Enriched mixture, and with residue through silica gel with column chromatography (100%EtOAc) purification, obtain [1-(2-nitro-benzenesulfonyl)-azetidin-3-yl]-methanol (167mg, 26%). ¹H NMR(CDCl ₃)δ2.73-2.80(m，1H)，3.76(dd，2H，J＝5.4，5.7Hz)，3.90(dd，2H，J＝5.7，8.1Hz)，4.17(dd，2H，J＝8.1，8.1Hz)。

(165mg adds Et in EtOAc 0.606mmol) (15mL) solution successively at [1-(2-nitro-benzenesulfonyl)-azetidin-3-yl]-methanol of 0 ℃ ₃N (0.101mL, 0.727mmol) and mesyl chloride (0.052mL, 0.666mmol).Reactant mixture is stirred 1h under room temperature.Precipitation is filtered and is washed with EtOAc through the diatom core.Concentrated filtrate, and rough methylsulfonyl ester is dissolved in DMF (5mL).In this solution, add DIPEA (0.211mL, 1.20mmol) and 3,3 '-dimethyl-1 ', 2 ', 3 ' 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (162mg, 0.606mmol), and with mixture heated to 80 ℃, 17h.Add saturated NaHCO ₃(15mL), and with mixture with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with MgSO ₄Drying is filtered and is concentrated.Crude product through silica gel with radial chromatography (NH ₄The Et that OH is saturated ₂O) purification makes 3,3 '-dimethyl-1 '-[1-(2-nitro-benzenesulfonyl)-azetidin-3-ylmethyl]-1 ', 2 ', 3 ' 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (168mg, 53%).

With 3,3 '-dimethyl-1 '-[1-(2-nitro-benzenesulfonyl)-azetidin-3-ylmethyl]-1 ', 2 ', 3 ' 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (168mg, 0.322mmol), thiophenol (0.3mL), K ₂CO ₃(500mg) mixture is at CH ₃Solution among the CN (5mL) at room temperature stirs 17h.Volatile matter is removed in decompression, and adds saturated NaHCO ₃(15mL), and with CH ₂Cl ₂(3 * 30mL) extraction mixture.The organic extract that merges is with MgSO ₄Drying is filtered and is concentrated.Crude product through silica gel with column chromatography (10: 1: 0.1 CH ₂Cl ₂: CH ₃OH: NH ₄OH; 10: 1: 0.5 then) purification, obtain 1 '-azetidin-3-ylmethyl-1 ', 2 ', 3 ' 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (74mg,, LC/MS80% is pure).

Step gained 1 '-azetidin-3-ylmethyl-1 ' on 0 ℃, 2 ', 3 ' 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl (74mg, toluene 0.219mmol) (2.5mL) and DIPEA (0.095mL, 0.5mmol) add in the solution phosgene toluene solution (20 weight %, 0.12mL, 0.26mmol).Reactant mixture is warmed to room temperature, and stirs 1.5h.Volatile matter is removed in decompression, and will remain yellow solid and be dissolved in DMF (5mL).Add DIPEA (0.40mL) and NH ₂OHH ₂(100mg 1.56mmol), and stirs 17h with mixture to O under room temperature.Add saturated NaHCO ₃(15mL), and with mixture with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with MgSO ₄Drying is filtered and is concentrated.Crude product is through radial column chromatography (10: 1: 0.2 CH ₂Cl ₂: CH ₃OH: NH ₄OH), make the membranaceous chemical compound 134 (27mg, 31%) of clarification by silica gel purification. ¹H NMR(CDCl ₃)δ1.16-1.19(m，1H)，1.53-1.65(m，3H)，1.94-2.11(m，3H)，2.42(s，6H)，2.41-2.43(m，2H)，3.01-3.06(m，2H)，3.45(t，2H，J＝8.4Hz)，3.60(br s，1H)，3.88(d，2H，J＝10.2Hz)，7.10(dd，2H，J＝4.2，7.5Hz)，7.45(d，2H，J＝7.5Hz)，8.41(d，2H，J＝4.2Hz)； ¹³C NMR(CDCl ₃)δ19.2，25.2，29.2，30.8，55.0，57.4，65.5，122.7，131.4，139.2，147.2，160.6，163.5；ES-MS m/z396(M ⁺H)。Analytical calculation value C ₂₂H ₂₉N ₅O ₂0.1H ₂O1.2CH ₂Cl ₂: C, 55.82; H, 6.38; N, 14.03. measured value: C, 55.75; H, 6.35; N, 14.08.

Embodiment 135

Chemical compound 135: meso-2 ' β, 6 ' β-[5-aminomethyl-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-phenyl]-methanol

According to general step A, with meso-2 ' β, 6 ' β-[3,5,3 ", 5 "-tetramethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl] (0.1903g; 0.64mmol), 2-bromomethyl-5-cyano group-essence of Niobe (0.1630g; 0.64mmol), KI (0.0100g, 0.06mmol), DIPEA (0.22mL, 1.29mmol) and DMF (6.4mL) stir down 17h at 60 ℃.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the brown oily meso-2 ' of 0.2682g (89%) β, 6 ' β-[5-cyano group-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-essence of Niobe]. ¹H NMR(CDCl ₃)δ1.63-1.67(m，3H)，2.00-2.05(m，1H)，2.12(s，6H)，2.21-2.31(m，2H)，2.36(s，6H)，3.84(s，3H)，3.90-3.94(m，2H)，4.05-4.08(m，2H)，6.96(s，2H)，7.37(d，1H，J＝9.0Hz)，7.56(d，1H，J＝3.0Hz)，7.90(s，1H)，8.02(s，2H)。

Under 0 ℃, Ar, at meso-2 ' β, 6 ' β-[5-cyano group-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and essence of Niobe] (0.2682g is added dropwise to 1.0M LiAlH in THF 0.57mmol) (6mL) solution ₄THF solution (5.7mL, 5.72mmol).Mixture is at room temperature stirred 2h, add distilled water (0.3mL), 15%NaOH (1mL) and distilled water (3mL) then successively, stir 15min.With mixture through diatomite filtration with CH ₂Cl ₂Washing, and concentrate.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.1435g (54%) white solid chemical compound 135. ¹H NMR(CDCl ₃)δ1.58-1.62(m，4H)，2.01-2.07(m，2H)，2.10(s，6H)，2.31-2.35(m，2H)，2.45(s，6H)，3.58(d，4H，J＝10.8Hz)，4.36(s，2H)，6.57-6.67(m，2H)，6.85(s，1H)，7.02(s，2H)，8.01(s，2H)。 ¹³C NMR(CDCl ₃)δ18.08，19.26，25.84，29.08，46.30，52.52，62.98，67.18，125.22，125.72，127.84，129.13，131.23，131.41，138.04，138.94，140.91，146.94，157.02.ES-MS m/z 445.5(M ⁺H)。Analytical calculation value C ₂₈H ₃₆N ₄O0.2CH ₂Cl ₂0.3H ₂O:C, 72.53; H, 7.99; N, 12.00. measured value: C, 72.91; H, 8.07; N, 11.91.

Embodiment 136

Chemical compound 136: meso-2 ' β, 4 ' α, 6 ' β-[1 '-(the amino butyl of 4-)-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl-4 '-formonitrile HCN]

Under the Ar, at meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (1.0760g adds NaBH in MeOH 3.8mmol) (38mL) solution ₄(0.3631g 9.6mmol), and at room temperature stirs 3.5h.Enriched mixture then, and add saturated NaHCO ₃(40mL), and with CH ₂Cl ₂(3 * 60mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates and obtain 1.0466g (92%) yellow solid shape meso-2 ' β, 4 ' β, and 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol]. ¹H NMR(CDCl ₃)δ1.43-1.55(m，2H)，1.81-1.97(m，2H)，2.14-2.18(m，2H)，2.36(s，6H)，3.97-4.07(m，1H)，4.19-4.20(m，2H)，7.00-7.07(m，2H)，7.38-7.42(m，2H)，8.44(d，2H)，J＝6.0Hz)。

At meso-2 ' β, 4 ' β, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] (1.0466g, add in THF 3.48mmol) (20mL) solution DIPEA (1.80mL, 10.44mmol) and Boc ₂O (1.5484g, THF 6.96mmol) (15mL) solution.Mixture is stirred 16h down at 50 ℃, concentrate then.Add saturated NaHCO ₃(40mL) and with CH ₂Cl ₂(3 * 60mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 25mL) washing several, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.8317g (62%) meso-2 ' β, 4 ' β, and 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester]. ¹H NMR(CDCl ₃)δ1.17(s，9H)，2.19(t，4H，J＝6.6Hz)，2.40(s，6H)，4.17-4.20(m，1H)，5.38(t，2H，J＝6.3Hz)，6.05(d，1H，J＝10.2Hz)，6.94-6.98(m，2H)，7.34-7.36(m，2H)，8.11(d，2H，J＝3.9Hz)。

Under 0 ℃, Ar, at meso-2 ' β, 4 ' β, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester] (0.8317g, 2.17mmol) and Et ₃N (0.45mL, CH 3.26mmol) ₂Cl ₂(22mL) add in the solution MsCl (0.20mL, 2.60mmol).Mixture is stirred 30min down at 0 ℃, under room temperature, stir 2h then, and with saturated NaHCO ₃(15mL) cancellation is with CH ₂Cl ₂(3 * 50mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates the meso-2 ' β that obtains 1.0185g (100%) orange solids shape, 4 ' β, and 6 ' β-[4 '-mesyloxy-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester]. ¹H NMR(CDCl ₃)δ1.20(s，9H)，2.37(s，6H)，2.41-2.45(m，2H)，2.88-2.99(m，2H)，3.07(s，3H)，5.07-5.14(m，1H)，5.39-5.44(m，2H)，6.94-6.98(m，2H)，7.33-7.35(m，2H)，8.09(d，2H，J＝6.0Hz)。

At meso-2 ' β, 4 ' β, 6 ' β-[4 '-mesyloxy-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester] (1.0185g, (2.2398g 44.22mmol), and stirs 17h under 80 ℃ to add NaCN in DMSO 2.21mmol) (11mL) solution.Enriched mixture adds saturated NaHCO ₃(40mL), and with CH ₂Cl ₂(3 * 100mL) extractions.The organic extract that merges is with saturated aqueous common salt (3 * 40mL) washings, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (4: 1 hexane-EtOAc, 100: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.4933g (57%) ecru solid meso-2 ' β, 4 ' α, and 6 ' β-[4 '-cyano group-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tertiary butyl ester]. ¹H NMR(CDCl ₃)δ1.56(s，9H)，1.97-2.07(m，2H)，2.15(s，6H)，2.79-2.84(m，2H)，5.13-5.23(m，1H)，5.74(s，2H，J＝6.0Hz)，6.66-6.70(m，2H)，7.00(d，2H，J＝9.0Hz)，7.94(d，2H，J＝6.0Hz)。

At last step gained nitrile (0.3118g, CH 0.79mmol) ₂Cl ₂(5mL) add TFA (5mL) in the solution, and at room temperature stir 3h, concentrate then.Add distilled water (5mL) and 10N NaOH (3mL), and with CH ₂Cl ₂(3 * 50mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (100: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes the orange oily meso-2 ' of 0.1304g (56%) β, 4 ' α, and 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-formonitrile HCN]. ¹H NMR(CDCl ₃)δ1.92-2.02(m，4H)，2.43(s，6H)，2.80-2.88(m，1H)，3.42(s，1H)，4.58-4.61(m，2H)，6.98-7.09(m，2H)，7.42-7.45(m，2H)，8.42(d，2H，J＝6.0Hz)。

According to general step A, with meso-2 ' β, 4 ' α, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-formonitrile HCN] (0.1304g; 0.45mmol), 2-(4-brombutyl)-iso-indoles-1, the 3-diketone (0.1383g, 0.49mmol), KI (0.0075g; 0.05mmol), DIPEA (0.16mL, 0.90mmol) and DMF (5mL) stir 16h down at 60 ℃.Crude product through silica gel with column chromatography (100: 1: 1CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.1064g (48%) white solid meso-2 ' β, 4 ' α, and 6 ' β-[1 '-[4-(1,3-dioxo-1,3-dihydro-iso-indoles-2-yl) butyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-formonitrile HCN]. ¹H NMR(CDCl ₃)δ0.25-0.27(m，2H)，0.77-0.82(m，2H)，1.85(d，2H，J＝14.7Hz)，2.35(t，2H，J＝7.5Hz)，2.50(s，6H)，2.54-2.63(m，2H)，3.11(t，2H，J＝7.2Hz)，3.35-3.36(m，1H)，4.57(d，2H，J＝12.0Hz)，6.94-6.98(m，2H)，7.27-7.29(m，2H)，7.71-7.75(m，2H)，7.79-7.82(m，2H)，8.36(d，2H，J＝3.0Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[1 '-[4-(1,3-dioxo-1,3-dihydro-iso-indoles-2-yl) butyl]-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-formonitrile HCN] (0.1064g, (0.10mL 2.16mmol), and at room temperature stirs 16h, concentrates then to add single hydrazine hydrate in EtOH 0.22mmol) (2.2mL) solution.Crude product through silica gel with column chromatography (50: 1: 1,30: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.0313g (39%) colorless oil chemical compound 136. ¹H NMR(CDCl ₃)δ0.46-0.48(m，2H)，0.63-0.73(m，2H)，1.89(d，2H，J＝13.8Hz)，2.12(t，2H，J＝6.9Hz)，2.26(t，2H，J＝7.8Hz)，2.48-2.52(m，2H)，2.53(s，6H)，2.90-3.10(bs，1H)，3.31-3.33(m，1H)，4.55(d，2H，J＝11.1Hz)，7.09-7.13(m，2H)，7.46(d，2H，J＝7.5Hz)，8.44(d，2H，J＝3.9Hz)。 ¹³C NMR(CDCl ₃)δ18.94，25.19，27.10，29.26，31.27，41.77，45.81，59.61，122.46，122.81，132.75，138.64，146.88，158.33.ES-MS m/z364.4(M ⁺H)。Analytical calculation value C ₂₂H ₂₉N ₅0.3CH ₂Cl ₂: C, 68.86; H, 7.67; N, 18.00. measured value: C, 69.22; H, 7.88; N, 18.15.

Embodiment 137

Chemical compound 137: meso-2 ' β, 4 ' α, 6 ' β-[4-(4 '-methoxyl group-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-yl)-butylamine

Under-78 ℃, Ar, at meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (3.5417g; in THF 12.6mmol) (90mL) solution; (13.8mL 13.8mmol), and stirs 30min (Tetrahedron:Asymmetry (1999) 10:2225-2235) slowly to add three sec-butyl boron lithiums (L-selectride).Add MeOH (35mL), and at room temperature add distilled water (70mL), with CH ₂Cl ₂(3 * 150mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates and obtain the sticky orange oily meso-2 ' β of 5.37g (100%), 4 ' β, and 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] and meso-2 ' β, 4 ' α, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] 1: 1 mixture. ¹H NMR(CDCl ₃)δ1.43-1.55(m，2H)，1.81-1.97(m，2H)，2.14-2.18(m，2H)，2.36(s，6H)，3.97-4.07(m，1H)，4.19-4.20(m，2H)，7.00-7.07(m，2H)，7.38-7.42(m，2H)，8.44-8.45(m，2H)。

At meso-2 ' β, 4 ' α, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl] (0.1427g, (0.0224g 0.56mmol), and at room temperature stirs 1h to-1 '-carboxylic acid tert-butyl ester to add the mineral oil that contains 60%NaH in THF 0.37mmol) (4mL) solution.(0.05mL 0.75mL), and stirs 16h, concentrates to add MeI.Crude product through silica gel with column chromatography (NH ₄The Et that OH is saturated ₂O) purification makes 0.1034g (70%) yellow oily meso-2 ' β, 4 ' α, and 6 ' β-[4 '-methoxyl group-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl]. ¹H NMR(CDCl ₃)δ1.35(s，9H)，1.69-1.78(m，2H)，2.29(s，6H)，2.64-2.72(m，2H)，3.44-3.51(m，3H)，4.79-4.83(m，1H)，5.66(t，2H，J＝4.5Hz)，6.78-6.82(m，2H)，7.15(d，2H，J＝9.0Hz)，8.06(d，2H，J＝3.0Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[4 '-methoxyl group-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl] (0.1236g, CH 0.31mmol) ₂Cl ₂(3mL) add TFA (3mL) in the solution, and at room temperature stir 2.5h.Enriched mixture adds distilled water (2mL) and 10N NaOH (3mL) and with CH ₂Cl ₂(3 * 15mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates and obtain 0.0666g (72%) yellow oily meso-2 ' β, 4 ' α, and 6 ' β-[4 '-methoxyl group-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl]. ¹H NMR(CDCl ₃)δ1.73-1.82(m，4H)，2.03-2.07(m，1H)，2.39(s，6H)，3.49(s，3H)，3.92-3.94(m，1H)，4.61(d，2H，J＝12.0Hz)，7.01-7.05(m，2H)，7.39(d，2H，J＝6.0Hz)，8.44(d，2H，J＝6.0Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[4 '-methoxyl group-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl] (0.0666g adds 2-(4-brombutyl)-iso-indoles-1 in DMF 0.22mmol) (3mL) solution, 3-diketone, KI (0.0033g, 0.02mmol) and DIPEA (0.08mL 0.44mmol), and stirs 24h down at 60 ℃.Concentrated reaction mixture adds saturated NaHCO ₃(5mL) and with CH ₂Cl ₂(3 * 20mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 15mL) washings, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) make the white sticky cystose meso-2 ' β of 0.1006g (92%), 4 ' α, 6 ' β-[2-[4-(4 '-methoxyl group-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone].

At meso-2 ' β, 4 ' α, 6 ' β-[2-[4-(4 '-methoxyl group-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.1006g, (0.1mL 2.02mmol), and at room temperature stirs 16h to add single hydrazine hydrate in EtOH 0.20mmol) (2mL) solution.Concentrated reaction mixture, crude product through silica gel with column chromatography (50: 1: 1 25: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.0471g (60%) colorless oil chemical compound 137. ¹H NMR(CDCl ₃)δ0.40-0.42(m，2H)，0.62-0.71(m，2H)，1.88(d，2H，J＝13.5Hz)，2.09-2.13(m，2H)，2.45-2.40(m，4H)，2.53(s，6H)，3.39(s，3H)，3.82(s，1H)，4.57(d，2H，J＝12.0Hz)，7.04-7.08(m，2H)，7.41(d，2H，J＝7.5Hz)，8.42(d，2H，J＝3.9Hz)。 ¹³CNMR(CDCl ₃)δ19.07，25.21，31.12，31.36，41.82，45.66，56.39，57.65，75.10，122.26，132.79，138.31，146.69，160.04.ES-MS m/z 369.4(M ⁺H)。Analytical calculation value C ₂₂H ₃₂N ₄O0.1CH ₂Cl ₂1.0H ₂O:C, 67.20; H, 8.73; N, 14.18. measured value: C, 67.46; H, 8.80; N, 14.07.

Embodiment 138

Chemical compound 138: meso-2 ' β, 6 ' β-[1 '-(the amino butyl of 4-)-3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone O-ethyl-oxime]

At meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (0.3065g adds O-ethyl hydroxylamine hydrochloride, and at room temperature stirs 24h in MeOH 1.1mmol) (22mL) solution.Add saturated NaHCO ₃, and with CH ₂Cl ₂(3 * 30mL) extractions, the organic extract of merging is with Na ₂SO ₄Drying is filtered, and concentrates, and obtains 0.4528g (100%) yellow oily meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone O-ethyl-oxime]. ¹HNMR(CDCl ₃)δ1.27(t，3H，J＝7.5Hz)，1.71(s，1H)，2.10-2.18(m，1H)，2.39(s，6H)，2.43-2.53(m，2H)，3.30-3.41(m，1H)，3.44-3.49(m，1H)，4.09-4.16(m，2H)，4.28-4.35(m，2H)，7.05-7.09(m，2H)，7.43(d，2H，J＝9.0Hz)，8.46(d，2H，J＝6.0Hz)。

At meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 '; 2 " ] terpyridyl-4 '-ketone O-ethyl-oxime] (0.4528g, 1.40mmol) DMF (14mL) solution in add 2-(4-brombutyl)-iso-indoles-1,3-diketone (0.4329g, 1.54mmol), KI (0.0232g, 0.14mmol) and DIPEA (0.49mL, 2.80mmol), and at 60 ℃ of following 20h that stir.Concentrated reaction mixture, and add saturated NaHCO ₃(15mL), with CH ₂Cl ₂(3 * 40mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (purification of 4: 1 hexanes-EtOAc) makes the yellow cystose meso-2 ' of 0.2813g β, 6 ' β-[2-[4-(4 '-ethoxy imino-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone].

At meso-2 ' β, 6 ' β-[2-[4-(4 '-ethoxy imino-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.2813g, (0.53mL 5.35mmol), concentrates after stirring 16h down at 80 ℃ to add n-butylamine in EtOH 0.54mmol) (5mL) solution.Crude product through silica gel with column chromatography (50: 1: 1 15: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes the light yellow oily chemical compound 138 of 0.1325g (23%, 2 step). ¹H NMR(CDCl ₃)δ0.22-0.25(bs，2H)，0.58-0.63(m，2H)，1.23(t，3H，J＝6.9Hz)，2.04(t，2H，J＝6.6Hz)，2.33-2.44(m，3H)，2.51(s，6H)，2.77-2.87(m，1H)，3.09-3.29(m，2H)，4.04-4.10(m，2H)，4.28-4.38(m，2H)，7.09-7.11(m，2H)，7.43(d，2H，J＝7.2Hz)，8.41-8.42(m，2H)。 ¹³C NMR(CDCl ₃)δ14.88，18.75，26.22，31.04，32.01，41.68，42.60，63.32，64.49，69.00，122.34，122.71，133.11，133.25，137.88，138.25，146.44，146.50，157.83，157.87，159.50.ES-MS m/z396.4(M ⁺H)。Analytical calculation value C ₂₃H ₃₃N ₅O0.7H ₂O:C, 67.68; H, 8.49; N, 17.16. measured value: C, 67.74; H, 8.37; N, 16.98.

Embodiment 139

Chemical compound 139: meso-2 ' β, 6 ' β-[1 '-(the amino butyl of 4-)-3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone O-benzyl-oxime]

At meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (0.2902g, (0.1811g 1.1mmol), and at room temperature stirs 22h to add O-benzyl hydroxylamine hydrochlorate in MeOH 1.0mmol) (20mL) solution.Add saturated NaHCO ₃(15mL), and with CH ₂Cl ₂(3 * 40mL) extractions, the organic extract of merging is with Na ₂SO ₄Drying is filtered, and concentrated 0.4358g (100%) yellow oily meso-2 ' β that obtains, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ', 2 "] terpyridyl-4 '-O oxygen-benzyl-oxime]. ¹H NMR(CDCl ₃)δ2.13-2.21(m，1H)，2.37(s，6H)，2.40-2.59(m，2H)，3.22(bs，1H)，3.49-3.54(m，1H)，4.30(d，2H，J＝22.8Hz)，5.13(s，2H)，7.06-7.09(m，2H)，7.32-7.43(m，7H)，8.45(d，2H，J＝6.0Hz)。

At meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 '; 2 " ] terpyridyl-4 '-ketone O-benzyl-oxime] (0.4358g, 1.13mmol) DMF (11mL) solution in add 2-(4-brombutyl)-iso-indoles-1,3-diketone (0.3498g, 1.24mmol), KI (0.0188g, 0.11mmol) and DIPEA (0.39mL, 2.26mmol), and at 60 ℃ of following 19h that stir.Concentrated reaction mixture, and add saturated NaHCO ₃(15mL), with CH ₂Cl ₂(3 * 40mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates.Crude product through silica gel with column chromatography (purification of 4: 1 hexanes-EtOAc) makes the orange cystose meso-2 ' of 0.4436g β, 6 ' β-[2-[4-(4 '-benzyloxy imino group-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone].

At meso-2 ' β, 6 ' β-[2-[4-(4 '-benzyloxy imino group-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] the butyl of terpyridyl-1 '-yl)]-iso-indoles-1, the 3-diketone] (0.4436g, (0.75mL 7.55mmol), before concentrating, stirs 16h down at 80 ℃ to add n-butylamine in EtOH 0.75mmol) (8mL) solution.Crude product through silica gel with column chromatography (50: 1: 1 20: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification makes the light yellow oily chemical compound 139 of 0.1276g (24%, 2 step). ¹H NMR(CDCl ₃)δ0.19-0.22(bs，2H)，0.56-0.66(m，2H)，2.04(t，2H，J＝6.9Hz)，2.36-2.46(m，3H)，2.51(s，6H)，2.87(t，1H，J＝13.2Hz)，3.16(t，1H，J＝13.8Hz)，3.32(d，1H，J＝14.4Hz)，4.27-4.39(m，2H)，5.08(s，2H)，7.08-7.12(m，2H)，7.28-7.44(m，7H)，8.41(d，2H，J＝4.2Hz)。 ¹³C NMR(CDCl ₃)δ18.83，25.75，27.15，31.14，32.76，41.75，43.58，62.91，64.20，75.69，122.78，127.97，128.44，128.63，130.31，132.91，133.01，138.41，146.66，146.71，157.95，160.30.ES-MS m/z458.4(M ⁺H)。Analytical calculation value C ₂₈H ₃₅N ₅O0.9H ₂O:C, 70.98; H, 7.83; N, 14.78. measured value: C, 70.87; H, 7.62; N, 14.58.

Embodiment 140

Chemical compound 140: meso-2 ' β, 6 ' β-[3-methylol-4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ', 2 "] terpyridyl-1 '-ylmethyl)-Benzoylamide

At meso-2 ' β, 6 ' β-[5-cyano group-2-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and essence of Niobe] (0.4541g in MeOH 0.97mmol) (5mL) and THF (5mL) solution, adds LiBH down in 0 ℃ ₄(0.1053g, 4.84mmol).To react and at room temperature stir 4h, add 1N NaOH (20mL) and CH then ₂Cl ₂(30mL), and stir 10min.Separate biphase, and with CH ₂Cl ₂(3 * 20mL) aqueous phase extracted.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrated 0.4030g (94%) the yellow solid shape meso-2 ' β that obtains, 6 ' β-[3-methylol-4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-benzonitrile]. ¹H NMR(CDCl ₃)δ1.58-1.69(m，2H)，2.13(s，6H)，2.45(s，6H)，2.88-2.91(m，2H)，3.66(s，2H)，4.01-4.05(m，2H)，4.46(s，2H)，5.22(s，1H)，6.82-6.84(m，1H)，6.92-6.94(m，1H)，7.05(s，2H)，7.23(s，1H)，8.00(s，2H)。

At meso-2 ' β, 6 ' β-[3-methylol-4-(3,5,3 ", 5 "-tetramethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-ylmethyl)-and benzonitrile] (0.4030g, (0.2815g 1.83mmol), and stirs 16h under 50 ℃ to add sodium perborate tetrahydrate in the solution of MeOH 0.91mmol) (9mL) and water (6mL).Enriched mixture, crude product through silica gel with column chromatography (100: 1: 1 20: 1: 1 CH then ₂Cl ₂-MeOH-NH ₄OH) purification is then with another column purification (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), make 45.3mg (9%) white solid chemical compound 140. ¹H NMR(CDCl ₃)δ1.59-1.68(m，3H)，2.03-2.08(m，1H)，2.09(s，6H)，2.30-2.37(m，2H)，2.45(s，6H)，3.64(s，2H)，4.99(d，2H，J＝11.1Hz)，4.47(s，2H)，5.68(s，1H)，6.21(s，1H)，6.77(d，1H，J＝7.5Hz)，7.04(s，2H)，7.21(d，1H，J＝7.8Hz)，7.35(s，1H)，8.00(s，2H)。 ¹³C NMR(CDCl ₃)18.07，19.30，25.69，30.26，54.42，62.49，67.02，126.23，127.20，127.64，129.31，131.14，131.83，139.13，139.25，143.24，147.18，156.82，169.70.ES-MS m/z459.5(M ⁺H)。Analytical calculation value C ₂₈H ₃₄N ₄O ₂1.1CH ₂Cl ₂0.2H ₂O:C, 62.91; H, 6.64; N, 10.08. measured value: C, 62.66; H, 6.64; N, 9.95.

Embodiment 141

Chemical compound 141: meso-2 ' β, 4 ' β, 6 ' β-1 '-[2-(3H-imidazol-4 yl)-ethyl]-4 '-methoxyl group-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ', 2 "] terpyridyl

Under the Ar, at meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ' 2 "] terpyridyl-4 '-ketone] (1.0760g adds NaBH in MeOH 3.8mmol) (38mL) solution ₄(0.3631g 9.6mmol), and at room temperature stirs 3.5h.Then mixture is concentrated, and add saturated NaHCO ₃(40mL), with CH ₂Cl ₂(3 * 60mL) extractions.The organic extract that merges is with Na ₂SO ₄Drying is filtered, and concentrates and obtain 1.0466g (92%) yellow solid shape meso-2 ' β, 4 ' β, and 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol]. ¹H NMR(CDCl ₃)δ1.43-1.55(m，2H)，1.81-1.97(m，2H)，2.14-2.18(m，2H)，2.36(s，6H)，3.97-4.07(m，1H)，4.19-4.20(m，2H)，7.00-7.07(m，2H)，7.38-7.42(m，2H)，8.44(d，2H)，J＝6.0Hz)。

At meso-2 ' β, 4 ' β, 6 ' β-[3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl-4 '-phenol] (1.0466g, add in THF 3.48mmol) (20mL) solution DIPEA (1.80mL, 10.44mmol) and Boc ₂O (1.5484g, THF 6.96mmol) (15mL) solution.Mixture is stirred 16h down at 50 ℃, concentrate then.Add saturated NaHCO ₃(40mL), and with CH ₂Cl ₂(3 * 60mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 25mL) washings, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.8317g (62%) meso-2 ' β, 4 ' β, and 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl-1 '-carboxylic acid tert-butyl ester]. ¹H NMR(CDCl ₃)δ1.17(s，9H)，2.19(t，4H，J＝6.6Hz)，2.40(s，6H)，4.17-4.20(m，1H)，5.38(t，2H，J＝6.3Hz)，6.05(d，1H，J＝10.2Hz)，6.94-6.98(m，2H)，7.34-7.36(m，2H)，8.11(d，2H，J＝3.9Hz)。

At meso-2 ' β, 4 ' α, 6 ' β-[4 '-hydroxyl-3,3 "-dimethyl-3 ', 4 ', 5 ', 6 '-tetrahydrochysene-2 ' H-[2,2 '; 6 ' 2 "] terpyridyl] (0.5194g, (0.0816g 2.04mmol), and at room temperature stirs 1h to-1 '-carboxylic acid tert-butyl ester to add the mineral oil that contains 60%NaH in DMF 1.36mmol) (5mL) solution.(0.17mL 2.72mL), and stirs 3.5h, concentrates to add MeI.Crude product through silica gel with column chromatography (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 0.4289g (79%) ecru solid meso-2 ' β, 4 ' β, and 6 ' β-[4 '-methoxyl group-3,3 "-dimethyl-1 ', 2 ', 3 ', 4 ', 5 ', 6 '-six hydrogen-[2,2 '; 6 ' 2 "] terpyridyl].ES-MS m/z 398.3(M ⁺H)。

At last step gained material (0.2435g, 0.82mmol) DMF (8mL) solution in add 5-(2-chloro-ethyl)-1H-imidazoles (0.1606g, 1.23mmol), DIPEA (0.29mL, 1.64mmol) and KI (0.0133g, 0.08mmol), and under 80 ℃, stir 48h.Enriched mixture also adds saturated NaHCO ₃(15mL), with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 30mL) washings, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification is then with another column purification (50: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH), make 39.9mg (11%) light beige solid, shaped chemical compound 141. ¹H NMR(CDCl ₃)δ1.74(s，1H)，2.03-2.05(m，4H)，2.41(s，6H)，2.50-2.52(m，2H)，2.63(s，1H)，3.35(s，3H)，3.49-3.50(m，1H)，4.04-4.05(m，2H)，6.11(s，1H)，7.04-7.06(m，2H)，7.33(s，1H)，7.39(d，2H，J＝6.9Hz)，8.35-8.36(m，2H)。 ¹³C NMR(CDCl ₃)19.08，23.69，36.45，49.86，55.70，62.59，68.86，118.64，122.62，131.69，134.50，139.08，140.32，147.05，159.35.ES-MS m/z 392.2(M ⁺H)。Analytical calculation value C ₂₃H ₂₉N ₅O0.4CH ₂Cl ₂: C, 66.06; H, 7.06; N, 16.46. measured value: C, 66.38; H, 7.31; N, 16.32.

Embodiment 142

Chemical compound 142: meso-2 ' β, 6 ' β-1 '-[2-(3H-imidazol-4 yl)-ethyl]-3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 ', 2 "] terpyridyl-4 '-ketone O-benzyl-oxime }

At meso-2 ' β, 6 ' β-[3,3 "-dimethyl-2 ', 3 ', 5 ', 6 '-tetrahydrochysene-1 ' H-[2,2 '; 6 '; 2 " ] terpyridyl-4 '-ketone O-benzyl-oxime] (0.1449g, 1.11mmol) DMF (7mL) solution in add 5-(2-chloro-ethyl)-1H-imidazoles (0.0966g, 0.74mmol), KI (0.0123g, 0.07mmol) and DIPEA (0.25mL, 1.48mmol), and under 80 ℃, stir 19h.Concentrated reaction mixture, and add saturated NaHCO ₃(15mL), with CH ₂Cl ₂(3 * 30mL) extractions.The organic extract that merges is with saturated aqueous common salt (2 * 25mL) washings, dry (Na ₂SO ₄), filter, and concentrate.Crude product through silica gel with column chromatography (100: 1: 1 10: 1 then: 1CH ²Cl ²-MeOH-NH ₄OH) purification is then with radial chromatography (25: 1: 1 CH ₂Cl ₂-MeOH-NH ₄OH) purification makes 19.6mg (5%) yellow oily chemical compound 142. ¹H NMR(CDCl ₃)δ1.58-1.59(m，1H)，2.39-2.43(m，2H)，2.44(s，6H)，2.68(t，2H，J＝7.5Hz)，2.84(t，1H，J＝12.3Hz)，3.10(t，1H，J＝12.3Hz)，3.30(d，1H，J＝14.7Hz)，4.22-4.33(m，2H)，5.08(s，2H)，6.13(s，1H)，7.09(t，2H，J＝6.3Hz)，7.27-7.34(m，7H)，7.42(d，2H，J＝7.5Hz)，8.40-8.41(m，2H)。 ¹³C NMR(CDCl ₃)δ18.94，25.27，28.56，34.04，46.33，63.05，64.34，75.79，119.70，122.96，128.07，128.46，128.69，132.54，132.68，134.42，138.37，138.83，146.90，158.01，159.27.ES-MS m/z481.5(M ⁺H)。Analytical calculation value C ₂₉H ₃₂N ₆O0.4H ₂O0.3CH ₂Cl ₂: C, 68.56; H, 6.56; N, 16.37. measured value: C, 68.87; H, 6.53; N, 16.65.

Embodiment 143

HIV-1 in the PBMC cell (NL4.3) duplicates inhibition test

According to the description of document formerly, carried out HIV-1NL4.3 among the PBMC (peripheral blood lymphocytes) and duplicated inhibition test (De Clercq is etc., Proc.Natl.Acad.Sci. (1992) 89:5286-5290; De Clercq, etc., Antimicrob.Agents Chemother. (1994) 38:668-674; Schols, D., etc., J.Exp.Med. (1997) 186:1383-1388).In brief, this test is the PBMC that isolates healthy donor by density gradient centrifugation, uses PHA to stimulate 3d with 1 μ g/ml (Sigma Chemical Co., Bornem, Belgium) down at 37 ℃ then.(blast cell that PHA stimulates, PHA-stimulated blasts) washes 3 times with PBS with activatory cell, and (Science 1995,270,1811-1815) by the method for descriptions such as Cocchi it to be carried out viral infection.The blast cell that HIV (mock-infected) PHA that infect or simulated infection is stimulated is cultivated in the presence of the test compounds of the IL-2 of 25U/mL and variable concentrations.Collected supernatant in the 6th day and the 10th day, and with p24 ELISA test kit (DuPont-Merck Pharmaceutical Co, Wilmington, DE) the HIV-1 cAg in the analysis culture supernatant.50% inhibition concentration (IC ₅₀) be defined as and suppress the concentration that 50%p24 antigen produces required test compounds.

When carrying out above-mentioned test, the inhibition IC of compound exhibits of the present invention ₅₀Scope is 0.5nM-5 μ M.

Embodiment 144

The inhibition test of the inductive Ca stream of the SDF-1 α in the cem cell

Inhibition test to the inductive calcium current of SDF-1 is undertaken by the CCRF-CEM cell, and this cell is the T-Lymphoblastoid strain of a kind of CXCR4 of expression.The CCRF-CEM cell (5 * 10 of 1 μ M Fluo-4 fluorescence calcium indicating dye will be mixed in advance ⁶Individual cell/mL is in RPMI 1640 culture medium that contain 2% hyclone), hatch 40min in 37 ℃.The cell of washing through mixing; and it is suspended in the buffer that contains 20mm HEPES pH7.4,1X Hanks balanced salt solution (HBSS), 0.2% bovine serum albumin and 2.5mm4-(dipropyl sulfamoyl) benzoic acid (probenecid), then with 3.5 * 10 ⁵The density kind of individual cells/well is gone in the 96 hole tissue culturing plates.This cell and test compounds or buffering contrasted in 37 ℃ hatch 15min.Calcium current stimulates generation by the 25nM SDF-1 that adds, and measures fluorescent screen reader (FLEXstation fluorescenceplate reader) (Molecular Devices) with FLEX then and measures fluorescence intensity.After adding SDF-1 80sec, add ionomycin to measure total calcium incorporation.The test concentrations scope of chemical compound is 2000-0.128nM.With reference to untreated contrast, standardization is carried out in fluoremetry.50% inhibition concentration (IC ₅₀Value) is defined as: compare with untreated contrast, suppress the concentration of the required test compounds of the inductive calcium current of 50%SDF-1.

Embodiment 145

The lifting test of mice CFU-GM level

C3H/H3 J mice is carried out subcutaneous 1,1 '-[1,4-phenylene two (methylene)]-two-1,4,8, its influence for the quantity of the granular leukocyte macrophage (CFU-GM) in every mL blood, erythroid cells (BFU-E) and multipotency (CFU-GEMM) CFU-GM is measured in 11-four-azacyclo-tetradecane (AMD3100) administration.By mixing culture medium (the pokeweedmitogen mouse spleen cell conditioned medium of 1U/mlrhu Epo, 50ng/ml rhu SLF, the regulation and control of 5%v/v pokeweed mitogen mouse boosting cell, PWMSCM) and the 0.1mm protoferriheme, form the clone in the stimulated in vitro CFU-GM.Hatch back 7d assay plate value.

The time-dependent effect of the activatory CFU-GM quantity of AMD3100 is that its effect sees Table 1 through single s.c. injection 5mg/Kg.

Table 1

	CFU-GM absolute value/ML blood methylcellulose is cultivated
				CFU-GM	BFU-E	CFU-GEMM
Contrast AMD3100:15 " AMD3100:30 " AMD3100:120 "	289.8 791.6 1805.5 828.7	49.4 134.5 209.3 102.3	25.8 90.4 113.5 47.6	CFU-GM	BFU-E	CFU-GEMM

Be to measure dosage and rely on effect, with 1,2.5,5 and the dosage single s.c. injection of 10mg/Kg give AMD3100, and behind administration 1h, measure the CFU-GM number in every mL blood, result of the test sees Table 2.

Table 2

	CFU-GM absolute value/ML blood methylcellulose is cultivated
				CFU-GM	BFU-E	CFU-GEMM
Saline AMD3100:10mg/kg AMD3100:5mg/kg AMD3100:2.5mg/kg AMD3100:1mg/kg	188.1 825.6 608.4 687.6 424	16 120.5 92.8 98.9 62	19 79.8 69.5 70.6 27.1	CFU-GM	BFU-E	CFU-GEMM

With 0 " time relatively multiple proportions change

	The CFU-GM methylcellulose is cultivated
	The CFU-GM methylcellulose is cultivated			Time	CFU-GM	BFU-E	CFU-GEMM
15” 30” 2’	2.73 6.23 2.86	2.72 4.24 2.07	3.51 4.41 1.85	Time	CFU-GM	BFU-E	CFU-GEMM

Maximum mice progenitor cell activation amount sees Table 3 obtaining after about 0.5 to 1h behind the injection 10mg/kgAMD3100.Chemical compound of the present invention and AMD3100 have similar performance.

Embodiment 146

Activation with MIP-1 α and G-CSF combination back mice CFU-GM

Giving in advance or do not giving under the condition of rhu G-CSF, AMD3100 and mice (mu) macrophage inflammatory protein (MIP-1 α) combination back are being tested the activation capacity of CFU-GM.MIP-1 α, (etc., Blood Cells, Molecules, andDiseases (1998) 24 (2): 14-30) for Broxmeyer, H.E. formerly to have shown the CFU-GM that can activate Mus and people.

The mice random packet to accept contrast diluent (saline) or G-CSF, by the s.c. injection, with the dosage of 2.5 μ g/ mices, every day twice, was injected two days.Behind last pump pickle or the G-CSF 11h, mice group is accepted the combination of MIP-1 α administration (I.V., accumulated dose is 5 μ g), AMD3100 administration (s.c., dosage are 5mg/Kg) or isodose MIP-1 α and AMD3100.Behind the 1h, put to death mice, measure CFU-GM quantity/mL blood.These data are summarized in Fig. 1.

When uniting use with mice (mu) macrophage inflammatory protein (MIP)-1 α, AMD3100 is with the collaborative performance progenitor cell activation effect higher than adduction mode, both are all adding rhu G-CSF or contrast diluent (saline) after 11h, and before blood sampling 1h.Chemical compound of the present invention has with AMD3100 and similarly shows.

Embodiment 147

The clinical raising of CFU-GM level

With five initial white cell countings is 4,500-7,500 cells/mm ³The healthy volunteer carry out this research.Each patient's single subcutaneous (s.c.) injection 80 μ g/kgAMD3100 (that is, 1,1 '-[1,4-phenylene two (methylene)]-two-1,4,8,11-four-azacyclo-tetradecane) 0.9% saline solution (deriving from the 10mg/mLAMD3100 saline storing solution under the aseptic condition).Blood sample is gathered before administration through conduit, and gathers until 24h for several times after administration.

Total white blood cell count of assessment blood sample, the positive CFU-GM of CD34 (passing through facs analysis) shared percentage ratio in total leukocyte, and granular leukocyte macrophage (CFU-GM), erythroid cells (BFU-E) and absolute quantity and the periodic state of multipotency (CFU-GEMM) CFU-GM in every mL blood sample.

As shown in Tables 3 and 4, give white blood cell count and the positive CFU-GM number of CD34 that AMD3100 can promote human volunteer, and 6h reaches maximum after administration.

Table 3

AMD3100 induces activation (* 10 to individual volunteer's leukocyte ³ WBC)

Numbering	Screening (Screen)	Baseline	Handle
			Handle							30min	1h	2h	4h	6h	9h	The 2nd day
			P1	7.4	6.41	8.02	14.8	21.4	23.2	30min	1h	2h	4h	6h	9h	The 2nd day	26.2	22.3	7.07
P2	6.04	5.45	P1	7.4	6.41	8.02	14.8	21.4	23.2	6.53	8.93	13.5	18.00	19.2	19.6	8.03	26.2	22.3	7.07
P2	6.04	5.45	P3	4.38	5.8	7.14	9.28	ND	18.10	6.53	8.93	13.5	18.00	19.2	19.6	8.03	17.9	18.4	4.98
P4	5.08	5.31	P3	4.38	5.8	7.14	9.28	ND	18.10	4.37	7.38	12.4	14.6	15.8	13.9	4.98	17.9	18.4	4.98
P4	5.08	5.31	P5	4.53	5.02	6.08	8.43	ND	16.90	4.37	7.38	12.4	14.6	15.8	13.9	4.98	19.3	19.00	4.57

Table 4

The inductive CD34 positive cell activation of AMD3100 is expressed as the percentage ratio that accounts for the total WBC of individual volunteer

Numbering	Baseline	Handle
		Handle					1h	3h	6h	9h	The 2nd day
		P1	.07	.04	.07	.11	1h	3h	6h	9h	The 2nd day	.11	.08
P2	.08	P1	.07	.04	.07	.11	.06	.08	.13	.11	.12	.11	.08
P2	.08	P3	.07	.16	.06	ND	.06	.08	.13	.11	.12	.11	.07
P4	.05	P3	.07	.16	.06	ND	.07	.09	.09	.1	.1	.11	.07
P4	.05	P5	.12	.12	.13	.2	.07	.09	.09	.1	.1	.2	.16

Blood sample also is used to analyze activatory these CFU-GM of AMD3100.

Measured normal donor behind s.c. injection AMD3100, it is unsegregated and low-density in every mL blood that (the Fei Kehai Parker is isolating, Fico-hypaque) absolute quantity of nucleated cell, and the absolute quantity and the periodic state of granular leukocyte macrophage (CFU-GM), erythroid cells (BFU-E) and multipotency (CFU-GEMM) CFU-GM in every mL blood.Assessed before the injection and injection AMD31001,3,6,9 and 24h after above-mentioned parameter.The result of all CFU-GM all is based on the counting to 3 culture plates of each test every bit.

For measuring CFU-GM quantity and periodic state, a large amount of CFU-GM, BFU-E and CFU-GEMM are cultivated in methylcellulose, and stimulate with recombined human (rhu) erythropoietin, 100U/ml Granulocyte Colony-stimulating (GM-CSF), 100U/ml recombination human interleukin-3 (IL-3) and the 50ng/ml recombined human steel factor (SLF=stem cell factor (SCF)) of 1 iu (U)/ml.CFU-GM also cultivates by agar, stimulates with 100U/ml rhu GM-CSF and 50ng/ml rhu SLF and measures.In this two classes test, colony count all carries out after cultivating 14 days under the humidification atmosphere, and this atmosphere is 5%CO ₂With (5%) O that reduces ₂Concentration.The progenitor cells periodic state is to kill and wound technology (high specific activity tritiated thymidine kill technique by the active deuterium-labeled thymidine of foregoing high specificity, Broxmeyer, H.E., etc., Exp.Hematol. (1989) 17:455-459).

The result provides at first that all five donors (=time (T) 0) and injection back 1,3,6,9 and 24h before injection relatively draw, and the average multiple proportions of nucleated cell and CFU-GM absolute quantity changes, and sees Table 5-7.

In following table,

The STD-standard deviation

The STE-standard error

PBL-US-peripheral blood-do not separate

PBL-LD-peripheral blood-low-density (Fei Keer separation)

The significance that P-draws by two tail t checks

Table 5 changes (five donors' meansigma methodss) with the multiple proportions that time=0 relatively draws

Nucleated cell constitutes
Nucleated cell constitutes											PBL-US					PBL-LD
Meansigma methods	STD	STE	％CHG	P	Meansigma methods	STD	STE	％CHG	P		PBL-US					PBL-LD
Meansigma methods	STD	STE	％CHG	P	Meansigma methods	STD	STE	％CHG	P	T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	1.00 1.69 2.80 3.26 3.09 1.07	0.00 0.00 0.51 0.61 0.69 0.65	0.00 0.00 0.23 0.27 0.31 0.29	0.0％ 68.6％ 180.2％ 225.8％ 209.4％ 7.0％	0.017 0.000 0.000 0.000 0.553	1.00 1.86 2.86 3.66 3.64 1.05	0.00 0.00 0.28 0.43 1.18 1.19	0.00 0.00 0.12 0.19 0.53 0.53	0.0％ 86.2％ 185.6％ 266.3％ 264.3％ 4.6％	0.000 0.000 0.001 0.001 0.815

Table 6

Methylcellulose is cultivated
Methylcellulose is cultivated																CFU-GM					BFUE					CRU-GEMM
Meansigma methods	STD	STE	％CHG	P	Meansigma methods	STD	STE	％CHG	P	Meansigma methods	STD	STE	％CHG	P		CFU-GM					BFUE					CRU-GEMM
Meansigma methods	STD	STE	％CHG	P	Meansigma methods	STD	STE	％CHG	P	Meansigma methods	STD	STE	％CHG	P	T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	1.00 4.77 13.66 21.71 10.47 1.58	0.00 0.00 1.56 5.78 5.09 3.01	0.00 0.00 0.70 2.58 2.28 1.34	0.0％ 376.7％ 1266.5％ 2070.6％ 947.3％ 55.5％	0.001 0.001 0.000 0.000 0.005	1.00 1.99 3.21 6.01 4.34 1.26	0.00 0.00 0.50 1.25 2.99 1.02	0.00 0.00 0.22 0.56 1.34 0.45	0.0％ 98.9％ 221.3％ 500.5％ 334.4％ 26.3％	0.002 0.004 0.006 0.000 0.194	1.00 2.32 4.33 10.07 5.25 1.53	0.00 0.00 0.44 0.59 4.54 3.04	0.00 0.00 0.20 0.27 2.03 1.36	0.0％ 131.8％ 332.5％ 907.2％ 425.4％ 53.2％	0.000 0.000 0.002 0.014 0.199

Table 7

	Agar is cultivated CFU-GM
	Agar is cultivated CFU-GM					Meansigma methods	STD	STE	％CHG	P
T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	1.00 2.81 8.54 17.93 10.25 2.08	0.00 0.00 0.75 1.62 4.57 2.06	0.00 0.00 0.34 0.72 2.04 1.03	0.0％ 180.8％ 754.1％ 1692.8％ 924.9％ 108.3％	0.001 0.000 0.000 0.000 0.073	Meansigma methods	STD	STE	％CHG	P

Shown in the result that then each donor changes from the multiple proportions that the T=0 level begins, seen Table 8-10.Changing of each individual patient of table 8 (P) with time=0 multiple proportions relatively

Nucleated cell constitutes
Nucleated cell constitutes											PBL-US					PBL-LD
P1	P2	P3	P4	P5	P1	P2	P3	P4	P5		PBL-US					PBL-LD
P1	P2	P3	P4	P5	P1	P2	P3	P4	P5	T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	1.00 2.54 3.55 3.97 3.27 1.21	1.00 1.38 2.74 2.94 3.30 1.43	1.00 1.38 2.02 2.74 2.69 0.96	1.00 1.36 2.46 2.60 2.24 0.77	1.00 1.76 3.23 4.04 3.96 0.99	1.00 2.07 2.83 4.07 3.65 1.01	1.00 1.99 3.25 3.90 4.43 1.71	1.00 1.48 2.17 2.27 2.47 0.79	1.00 1.66 2.82 2.78 2.48 0.60	1.00 2.10 3.20 5.30 5.17 1.12

Table 9 CFU-GM

Methylcellulose is cultivated
Methylcellulose is cultivated																CFU-GM					BFU-E					CFU-GEMM
P1	P2	P3	P4	P5	P1	P2	P3	P4	P5	P1	P2	P3	P4	P5		CFU-GM					BFU-E					CFU-GEMM
P1	P2	P3	P4	P5	P1	P2	P3	P4	P5	P1	P2	P3	P4	P5	T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	1.00 5.09 7.12 14.66 6.26 1.10	1.00 5.33 17.02 23.96 12.51 1.91	1.00 3.70 15.07 20.99 9.42 1.43	1.00 6.87 20.72 28.54 14.08 1.51	1.00 2.84 8.40 20.39 10.09 1.83	1.00 2.58 5.13 9.14 5.43 1.06	1.00 1.48 1.98 3.67 4.61 1.88	1.00 2.30 2.61 4.54 3.71 1.14	1.00 1.46 2.60 3.34 2.93 0.79	1.00 2.13 3.75 9.35 5.05 1.44	1.00 2.07 4.25 7.47 2.64 1.12	1.00 2.26 3.47 9.35 7.09 2.62	1.00 2.22 4.34 6.52 2.47 0.69	1.00 1.96 5.14 9.10 4.52 0.98	1.00 3.07 4.43 17.92 9.55 2.25

Table 10

	Agar is cultivated CFU-GM
	Agar is cultivated CFU-GM					P1	P2	P3	P4	P5
T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	1.00 3.05 8.88 17.77	1.00 3.74 9.49 24.01 10.28 3.69	1.00 1.67 7.47 14.04 7.72 1.13	1.00 2.71 10.46 13.07 10.22 1.30	1.00 2.87 6.40 20.75 12.78 2.20	P1	P2	P3	P4	P5

Actual nucleated cell in every mL blood and CFU-GM number, and five donors (#P1, P2, P3, P4 and P5) CFU-GM periodic state (=% is in the CFU-GM of synthetic (S) phase of DNA in the cell cycle) separately see Table 11 and 12.

Table 11

	CFU-GM		BFU-E P1		CFU-GEMM		CFU-GM		BFU-E P2		CFU-GEMM
	CFU-GM		BFU-E P1		CFU-GEMM		CFU-GM		BFU-E P2		CFU-GEMM		CFU-GM absolute number/mL	The all bright situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM
T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	247 1259 1760 3624 1547 271	6％ 1％ 1％ 0％ 2％ 0％	261 674 1340 2388 1418 278	0％ 0％ 13％ 0％ 11％ 0％	127 264 540 949 335 142	6％ 0％ 7％ 0％ 0％ 0％	273 1455 4646 6540 3416 512	0％ 0％ 2％ 0％ 0％ 3％	410 608 809 1502 1886 768	2％ 3％ 0％ 0％ 0％ 2％	120 272 418 1126 854 316	0％ 6％ 0％ 0％ 4％ 0％	CFU-GM absolute number/mL	The all bright situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM

	CFU-GM		BFU-E P3		CFU-GEMM		CFU-GM		BFU-E P4		CFU-GEMM
	CFU-GM		BFU-E P3		CFU-GEMM		CFU-GM		BFU-E P4		CFU-GEMM		CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM
T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	281 1040 4223 5895 2647 402	0％ 0％ 1％ 0％ 0％ 0％	351 806 915 1593 1302 402	0％ 0％ 0％ 0％ 0％ 0％	140 312 610 916 347 97	0％ 0％ 0％ 0％ 0％ 0％	138 947 2857 3936 1942 208	0％ 0％ 5％ 0％ 0％ 5％	460 672 1195 1533 1348 362	0％ 0％ 9％ 0％ 0％ 3％	101 199 519 920 457 99	0％ 0％ 0％ 8％ 0％ 0％	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM

	CFU-GM		BFU-E P5		CFU-GEMM
	CFU-GM		BFU-E P5		CFU-GEMM		CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM
T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	169 481 1423 3454 1710 310	0％ 0％ 5％ 0％ 0％ 0％	343 730 1288 3208 1731 495	1％ 0％ 3％ 1％ 0％ 0％	55 169 244 987 526 124	0％ 0％ 0％ 0％ 0％ 0％	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM

Table 12

Agar is cultivated CFU-GM		Agar is cultivated CFU-GM		Agar is cultivated CFU-GM		Agar is cultivated CFU-GM		Agar is cultivated CFU-GM
Agar is cultivated CFU-GM		Agar is cultivated CFU-GM		Agar is cultivated CFU-GM		Agar is cultivated CFU-GM		Agar is cultivated CFU-GM			P1		P2		P3		P4		P5
CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM		P1		P2		P3		P4		P5
CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	CFU-GM absolute number/mL	The cycle situation of CFU-GM	T＝0 T＝1 T＝3 T＝6 T＝9 T＝24	233 710 2070 4142	6％ 0％ 0％ 0％	100 376 953 2409 1032 371	0％ 0％ 1％ 3％ 0％ 0％	140 234 1049 1972 1085 159	0％ 0％ 0％ 3％ 0％ 0％	124 336 1299 1623 1268 162	0％ 0％ 0％ 0％ 0％ 0％	104 298 664 2153 1326 229	0％ 3％ 0％ 1％ 0％ 0％

By the mankind contribute the experimenter accept behind the AMD3100 injection 6h the result as seen, the result is very consistent for the multiplication of the maximum of whole five donor's CFU-GM cyclical levels.Before the injection and injection AMD31001,3,6,9 and 24h after, CFU-GM is in slowly or aperiodic state.Chemical compound of the present invention is similar to the AMD3100 performance.

Embodiment 148

The bone marrow stem cell that carries out for myocardial repair activates

Breast is anaesthetized and opened to adult rat.Descending coronarius of ligation left side, and no longer perfusion.4 arrive 6h after the ligation, and the AMD3100 or the AMD3100 that dilute to animal subject injection limit add rhG-CSF.Mus is not handled with actor in contrast.In the interval in 1 week, with echocardiography and MRI monitoring animal.Test is the back end of 2,6 to 12 weeks after operation.Putting to death animal same day, the analyzing blood power function is measured left ventricular end diastolic pressure, left ventricle launches to press the ratio of rising and falling of (developed pressure) and left ventricular pressure.Then heart is stopped to beat at diastole, and pour into from the blood vessel network of cardiac muscle, to flush out residual blood by ventral aorta.In heart, pour into 10% formalin then.Produce several pieces fixedly sections of heart, these sections are with paraffin embedding and section.With section statining and with spectroscopic analysis, to measure the size of treated animal and control animal infraction.The tissue slice of the heart of then obtaining in 2 weeks performing the operation is with the narrow spectrum antibody staining of immature cell, development myocyte and blood vessel protein and with the Laser Scanning Confocal Microscope analysis.This immunohistochemical analysis comprises the discriminating to transcription factor and surface markers, and these transcription factor and surface markers are expressed in early stage that the myocyte forms.The result of this test will show, give AMD3100 actor (simultaneously or do not give simultaneously rhG-CSF) after a few hours bringing out myocardial ischemia, and this actor is the activated bone marrow stem cell rapidly, and will stop heart reconstruction and make dead cardiac muscle regenerate.Chemical compound of the present invention is similar to the AMD3100 performance.

Embodiment 149

The clinical lifting of healthy volunteer WBC level

By 11 initial white cytometries is 4,000-6,500 cells/mm ³Human patients carry out this research.Under the aseptic condition, with AMD3100 (that is, 1,1 '-[1,4-phenylene two (methylene)]-two-1,4,8,11-four-azacyclo-tetradecane) stock solution is prepared into the solution of intravenous injection dosage, and promptly 1mg/ml is with the concentrated solution of 0.9% normal saline (generic physiological saline) dilution in 1: 10.These storing solution equal portions are added in the 50-ml packing of 0.9% normal saline, to be used to obtain the intravenous injection of required dosage level (10 μ g/kg-80 μ g/kg) amount.

The experimenter of present embodiment has accepted to keep somewhere the peripheral vein intubate.The AMD3100 of above-mentioned amount merges in vein with single dose in 15min.Several is until the 24h blood sampling before administration and after the administration.

11 human experimenters accept the AMD3100 intravenously administrable with the dosage of 10,20,40 and 80 μ g/kg.5 experimenters have also accepted the AMD3100 subcutaneous injection of 40 and 80 μ g/kg dosage.The effect that these 11 human experimenters accept the AMD3100 intravenously administrable is seen Fig. 1.3 patients accept 10 μ g/kg dosed administrations (open circles), 3 patients and accept that 20 μ g/kg dosed administrations (filled circles), 3 patients are accepted 40 μ g/kg dosed administrations (hollow triangle), 2 patients accept 80 μ g/kg dosed administrations (solid triangle).

As shown in Figure 2, all demonstrate significantly improving of white blood cell count, and decrescence get back to initial level (though being not that all cases are all like this) at about 24 back WBC countings with all patients 5-10h after administration of all horizontal administrations.Usually, the level of WBC is relevant with compound concentrations level in the blood flow.For example, the patient of a certain acceptance 80 μ g/kg test, its white blood cell count is from 6,000 cell/mm ³19,000 cell/mm when having risen to peak value ³In demonstrating the patient of minimal reaction (giving its 20 μ g/kg medicine), white blood cell count is from 6,300 cell/mm even ³About 9,000 cell/mm have been risen to ³

Therefore, as if AMD3100 can improve the WBC counting consistently in human patients.Chemical compound of the present invention and AMD3100 have similar performance.

Though do not expect to be retrained by any theory, the different chemical compounds with structural formula (1) has the ability and the application thereof that improve the WBC counting and is considered to because this compounds has similar reaction and have similar possible mechanism in improving the WBC counting in antiviral application in different plant species.Chemical compound of the present invention is considered to by suppressing HIV virus second receptor---the combining stoping virus to enter cell of CXCR4 and HIV virus, thus realize its antiviral effect.These concrete receptors comprise mice, rat, cat and the mankind all demonstrating homology in the species widely.

Embodiment 150

The clinical raising of hiv infected patient WBC level

Observed the raising of WBC level in the patient that HIV infects, these patients have accepted AMD3100 until continuous 10 times continuous transfusion (Fig. 3).8 patients have accepted the AMD3100 of 2.5 μ g/kg/h (patient 1-4) and 5.0 μ g/kg/h (patient 5-8) transfusion dosage.The sample and the relatively raising of WBC counting of baseline of (transfusion is carried out before finishing immediately) have been write down the 2nd, 6 and 11 days transfusion stages.The ratio (the 11st day sample) that the WBC counting improves is in 1.4 to 2.8 times of scopes of baseline.The 7d of WBC counting behind discontinuous the carrying out of transfusion gets back to baseline.Thereby result's demonstration gives AMD3100 or transfusion continuously by single dose, all can improve the WBC counting of human patient consistently.Chemical compound of the present invention and AMD3100 have similar performance.

Though do not expect to be retrained by any theory, the different chemical compounds with structural formula (1) has the ability and the application thereof that improve the WBC counting and is considered to because this compounds has similar effect and have similar possible mechanism in improving the WBC counting in antiviral application in different plant species.Chemical compound of the present invention is considered to by suppressing HIV virus second receptor---the combining stoping virus to enter cell of CXCR4 and HIV virus, thus realize its antiviral effect.These concrete receptors comprise mice, rat, cat and the mankind all demonstrating homology in the species widely.

To be understandable that above-mentioned specific descriptions and additional embodiment be just in order illustrating, and scope of the present invention not limited to some extent.The difference of the embodiment that has disclosed changes and improvement, is conspicuous for the those of skill in the art in this area.These variations and improvement relate to chemical constitution, substituent group, derivant, intermedium, synthetic, structural formula and/or use method of the present invention including but not limited to those, can carry out not breaking away under spirit of the present invention and the scope thereof.The United States Patent (USP) and the publication of institute of the present invention reference are classified list of references as jointly at this.

Claims

1. chemical compound, described chemical compound has structure:

L is (CR ³ ₂) ₁Or NR (CR ³ ₂) ₁, alkyl bond wherein can be replaced by chain ethylene linkage or acetylene bond;

Each R wherein ³Be H or alkyl;

1 is 1-6;

2. chemical compound as claimed in claim 1 is characterized in that, the substituent group on the ring that replaces is selected from down group arbitrarily: inorganic part, alkyl (C _1-10), alkenyl (C _2-10), alkynyl group (C _2-10), aryl (5-12 unit), aralkyl, arylalkenyl and sweet-smelling alkynyl, each group can be chosen wantonly and contain the hetero atom that one or more is selected from O, S and N, and each group can further be replaced.

3. chemical compound as claimed in claim 1 is characterized in that A, each ring of B can be independently selected from down group: pyridine, pyrimidine, pyrazine, pyridazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3,5-triazines, 1,2,4, the 5-tetrazine, the pyrroles, imidazoles, pyrazoles, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, thiazole oxazole, isothiazole isoxazole, 1,2, the 3-thiadiazoles, 1,3, the 4-thiadiazoles, 1,2, the 3-oxadiazole, 1,3, the 4-oxadiazole, quinoline, isoquinolin 1,4-Benzodiazine, quinazoline, 2, the 3-benzodiazine, cinnoline, 1,2, the 3-phentriazine, 1,2, the 4-phentriazine, indole, benzimidazole, 1H-indazole benzoxazole, benzothiazole, benzo [d] isoxazole, benzo [d] isothiazole, and purine.

4. chemical compound as claimed in claim 3 is characterized in that, each ring of A, B is pyridine, pyrimidine, imidazoles or benzimidazole.

5. chemical compound as claimed in claim 1 is characterized in that, ring A is identical with ring B.

6. chemical compound as claimed in claim 1, it is characterized in that, ring C is selected from down group: pyrrolidine, piperidines, six hydrogen-1H-azatropylidene, piperazine, morpholine, thiomorpholine, azepan, Azacyclooctane, 2,3,4,7-tetrahydrochysene-1H-azatropylidene, 2,3,6,7-tetrahydrochysene-1H-azatropylidene, the 3-pyrrolin, 1,2,3, the 6-tetrahydropyridine, isoindoline, 1,2,3, the 4-tetrahydroisoquinoline, 2,3,4,5-tetrahydrochysene-1H-benzo [d] azatropylidene, 2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene, Tetramethylene., Pentamethylene., cyclohexane extraction, cycloheptane, cyclooctane, cyclopentenes, cyclohexene, cycloheptene, cyclo-octene, Pentamethylene oxide., tetrahydric thiapyran, oxepane, the thia cycloheptane, oxocane, or thia cyclooctane.

7. chemical compound as claimed in claim 6 is characterized in that, ring C is pyrrolidine, piperidines, piperazine or six hydrogen-1H-azatropylidene.

8. chemical compound as claimed in claim 1 is characterized in that, Y is aromatics, heteroaromatic or heterocyclic part.

9. chemical compound as claimed in claim 8 is characterized in that, Y is phenyl, imidazoles, pyridine, thiophene, pyrrolidine, pyrazoles, piperidines, azetidine, benzimidazole, benzo [d] isoxazole or thiazole.

10. chemical compound as claimed in claim 8, it is characterized in that, Y is replaced by following group is optional: halogen, cyano group, nitro, by carbonyl, annulus or alkyl, alkenyl or the optional assorted moieties that contains one or more N, O, S of alkyl or the optional hydroxyl that replaces of haloalkyl, replacement, each group randomly is an oxide form.

11. chemical compound as claimed in claim 8 is characterized in that, Y is by optional optional replacement of annulus of containing one or more N, O or S.

12. chemical compound as claimed in claim 11 is characterized in that, described annulus is the optional aromatics or the heteroaromatic moiety that contain 5-12 unit ring that replaces.

13. chemical compound as claimed in claim 11 is characterized in that, described annulus is pyridine, phenyl, piperidines or 2H-tetrazolium.

14. chemical compound as claimed in claim 13 is characterized in that, Y is phenyl or imidazoles.

15. chemical compound as claimed in claim 1 is characterized in that, Y is selected from down group:

-(CR ₂) _mNR ₂、

-(CR ₂) _mNR ₂(CR ₃)、

-(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mOR、

-(CR ₂) _mCO(CR ₂) _mOR、

-(CR ₂) _mCO(CR ₂) _mNR ₂、

-(CR ₂) _mCO(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNRCO(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mCO ₂R、

-(CR ₂) _mNR(CR ₂) _mCOR、

-(CR ₂) _mNR(CR ₂) _mSO ₂R、

-(CR ₂) _mNRCO(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNRCO(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR(CR ₂) _mNR ₂、

-(CR ₂) _mNR(CR ₂) _mOR、

-(CR ₂) _mCR＝NOH、

-(CR ₂) _mCONR(CR ₂) _mOR、

-(CR ₂) _mN[(CR ₂) _mCO ₂R] ₂、

-(CR ₂) _mONRCONR ₂、

-(CR ₂) _m-Z、

-(CR ₂) _mNR-(CO) _mZ、

-(CR ₂) _mNR-(CR ₂) _mZ and

-(CR ₂) _m-CR＝N＝Z；

Each R is H or non-interfering substituent group independently, and each m is for being 0-4 independently, and Z is the optional aromatics or the heteroaromatic moiety that contain 5-12 unit ring that replaces.

16. chemical compound as claimed in claim 15 is characterized in that, Y is (CH ₂) ₁NR ₂, wherein R is H or non-interfering substituent group, and 1 is 1-10.

17. chemical compound as claimed in claim 1 is characterized in that, each ring of A, B contains a single substituent group, and this substituent group is positioned at the adjacent of ring A, B and ring C connecting key.

18. chemical compound as claimed in claim 17 is characterized in that, described substituent group is identical on ring A and B.

19. one kind is suppressed the method that HIV infects, this method comprises chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose that needs this kind inhibition.

20. a method of improving the receptor-mediated condition of illness of CXCR4, this method comprise chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose that needs this kind improvement.

21. a method for the treatment of inflammatory conditions, this method comprise chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose that needs this kind treatment.

22. method as claimed in claim 21 is characterized in that, described inflammatory conditions is a rheumatoid arthritis.

23. a method for the treatment of asthma, this method comprise chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose that needs this kind treatment.

24. a method for the treatment of tumor condition of illness, this method comprise chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose that needs this kind treatment.

25. a method for the treatment of rheumatoid arthritis, this method comprise chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose that needs this kind treatment.

26. further comprising, method as claimed in claim 19, described method give the additional treatment of described experimenter HIV effective function thing.

27. method as claimed in claim 24 is characterized in that, described tumor is the tumor of brain, mammary gland, prostate, lung or hemopoietic tissue.

28. method for the treatment of the non-anticipation condition of illness of the mankind or animal individual, this method comprises according to clinical effective therapy, by clinical acceptable route of administration, need chemical compound as claimed in claim 1 or its pharmaceutical composition of the individual effective dose of this kind treatment, wherein said condition of illness is asthma, allergic rhinitis, the hypersensitivity pulmonary disease, the hypersensitivity pneumonia, the eosinophilic pneumonia, delayed hypersensitivity, interstitial lung disease, systemic anaphylaxis or allergy, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, allograft rejection, the anti-host disease of mortifier, inflammatory bowel disease, the Crohn disease, ulcerative colitis, spondyloarthropathy, scleroderma, psoriasis, dermatitis, eczema, atopic dermatitis, contact dermatitis, urticaria, vasculitis, acidophil myositis, eosinophilic fasciitis or cancer.

29. method as claimed in claim 20 is characterized in that, described condition of illness is relevant with immunosuppressant.

30. method as claimed in claim 29 is characterized in that, described individuality is through the treatment of chemotherapy, radiotherapy, wound healing, burn treatment or autoimmune disease.

31. a pharmaceutical composition, described compositions contain the effective dose chemical compound as claimed in claim 1 of unit dosage form, to improve individual white blood cell count.

32. a method that influences the individual heart tissue regeneration, this method are by giving described individuality with a certain amount of chemical compound with structural formula (1) as claimed in claim 1, described amount is for can effectively influencing the amount of described individual heart tissue regeneration.

33. method as claimed in claim 32 is characterized in that, described chemical compound is to give described experimenter by intravenous or subcutaneous route or oral route.

34. method as claimed in claim 33 is characterized in that, described chemical compound is that by oral route gives described experimenter.

35. method as claimed in claim 32 is characterized in that, the chemical compound that will have a structural formula (1) gives described individuality with the dosage range of about 0.1 μ g/kg-5mg/kg body weight.

36. a method that improves individual CFU-GM and/or stem cell population, this method comprises:

Give described individuality chemical compound as claimed in claim 1 or its pharmaceutical composition;

With the described CFU-GM of the described individuality of effective raising and/or the amount administration of stem cell population.

37. method as claimed in claim 36 is characterized in that, individuality demonstrates the hemopoietic defective that causes because of chemotherapy or radiotherapy.

38. method as claimed in claim 36 is characterized in that, individuality has the condition of illness of the group of being selected from down: aplastic anemia, leukemia and drug induced anemia.

39. method as claimed in claim 36 is characterized in that, and is individual for transplanting the receiver.

40. method as claimed in claim 36 is characterized in that, individuality is healthy stem cell donor.

41. method as claimed in claim 36 is characterized in that, described CFU-GM and/or stem cell promote wound healing.

42. method as claimed in claim 36 is characterized in that, described CFU-GM and/or stem cell are improved bacterial inflammation.

43. method as claimed in claim 36 is characterized in that, the organ-tissue that described CFU-GM and/or stem cell regenerating are impaired.

44. method as claimed in claim 36 is characterized in that, described chemical compound gives described individuality by intravenous or subcutaneous route or oral route.

45. method as claimed in claim 44 is characterized in that, described chemical compound by oral route gives described individuality.

46. method as claimed in claim 36 is characterized in that, the chemical compound that will have a structural formula (1) gives described individuality with the dosage range of about 0.1 μ g/kg-5mg/kg body weight.

47. method that improves CFU-GM in peripheral blood or the bone marrow and/or stem cell population, this method comprises that with described peripheral blood of compound treatment as claimed in claim 1 or bone marrow the amount of compound used therefor is for can effectively improving the amount of CFU-GM described in described peripheral blood or the bone marrow and/or stem cell population.

48. further comprising with macrophage inflammatory protein, method as claimed in claim 47, described method handle described peripheral blood or bone marrow.

49. method as claimed in claim 47 is characterized in that, described processing is carried out external.

50. method as claimed in claim 47 is characterized in that, described peripheral blood or derived from bone marrow are in the experimenter who treated with G-CSF.

51. a pharmaceutical composition, it comprises the chemical compound as claimed in claim 1 of the effective dose of single dose, to improve the quantity of individual CFU-GM and/or stem cell.

52. pharmaceutical composition as claimed in claim 51, described pharmaceutical composition further comprise the relevant oncogene of one or more G-CSF, granulocyte-macrophage colony stimutaing factor (GM-CSF), il-1 (IL-1), interleukin-3 (IL-3), interleukin-8 (IL-8), PIXY-321 (GM-CSF/IL-3 fusion rotein), macrophage inflammatory protein, stem cell factor, thrombopoietin and/or growth.

53. comprising, a method that improves individual CFU-GM and/or stem cell population, this method give described individuality a certain amount of chemical compound that combines with chemokine receptors CXCR4, with described CFU-GM of effective raising and/or stem cell population.

54. method that improves CFU-GM in peripheral blood or the bone marrow and/or stem cell population, this method comprise with effective dose with described peripheral blood of the bonded compound treatment of chemokine receptors CXCR4 or bone marrow, to improve the amount of CFU-GM described in described peripheral blood or the bone marrow and/or stem cell population.

55. comprising, a method that influences the individual heart tissue regeneration, this method need this regenerated individuality with effective dose and the bonded chemical compound of chemokine receptors CXCR4, with the described heart tissue of regenerating.

56. a method for the treatment of the experimenter, described experimenter will benefit from the raising of leukocyte (WBC) counting, and this method comprises:

Give the chemical compound as claimed in claim 1 of described individual effective dose, to improve the described WBC counting of described individuality.

57. method as claimed in claim 56 is characterized in that, described experimenter demonstrates the hemopoietic defective that chemotherapy or radiotherapy cause,

Wherein said experimenter has the condition of illness of the group of being selected from down: aplastic anemia, leukemia and drug induced anemia, or

Wherein said experimenter is for transplanting the receiver.

58. method as claimed in claim 56 is characterized in that, the raising of described WBC counting promotes wound healing, or

The raising of wherein said WBC counting improves bacterial inflammation.

59. method as claimed in claim 56 is characterized in that, described chemical compound gives described individuality by intravenous or subcutaneous route or oral route.

60. method as claimed in claim 59 is characterized in that, described chemical compound by oral route gives described individuality.

61. method as claimed in claim 56 is characterized in that, the chemical compound that will have a structural formula (1) gives described individuality with the dosage range of about 0.1 μ g/kg-5mg/kg body weight.

62. chemical compound as claimed in claim 1 is characterized in that, R ¹And R ²Be the alkyl of non-replacement independently.

63. chemical compound as claimed in claim 1 is characterized in that, R ¹And R ²Be positioned at the adjacent of the key that links to each other with ring C.

64. chemical compound as claimed in claim 1 is characterized in that, ring C is saturated or contains a two key.

65. chemical compound as claimed in claim 1 is characterized in that, described chemical compound is selected from the chemical compound described in the embodiment 1-142.

66. a pharmaceutical composition, described pharmaceutical composition comprise chemical compound and at least a excipient as claim as active component.

67. the purposes of chemical compound according to claim 1, it is used to prepare the medicine for the treatment of HIV.

68. the purposes of chemical compound according to claim 1, it is used to prepare the medicine of treatment by chemokine receptor mediated condition of illness.

69. the purposes of chemical compound according to claim 1, it is used to prepare the medicine for the treatment of inflammatory conditions.

70., it is characterized in that described inflammatory conditions is a rheumatoid arthritis as the described purposes of claim 69.

71. as the purposes of the chemical compound in the purposes as described in the claim 69, it is used to prepare the medicine of treatment tumor condition of illness.