TW200817365A - Polyamine compounds - Google Patents

Abstract

This invention relates to methods for treating retinopathy and repairing tissue damage. The methods include administering to a subject in need thereof an effective amount of one or more compounds of the following formula. Each variable in this formula is defined in the specification.

Description

200817365 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to polyamine compounds. [Prior Art]

Chemokines are a family of cytokines that regulate white blood cell adhesion and transendothelial migration during immune or inflammatory responses (Mackay CR·, Nat·I Immunol) (2001) 2:95; Olson et al., Am. J. Physiol. Regul. Integr. C o mp · P hy sio 1 ·, ( 2 0 0 2 ) 2 8 3 ·· R7). Chemokines can also regulate T Cell and B cell movement and homing, and contribute to the development of lymphopoietic systems and hematopoietic systems (Ajuebor et al., Biochem. Pharmacol., (2002) 63 : 1191). About 50 kinds of chemokines have been identified in humans. These chemokines can be divided into four subfamilies, namely CXC, CX3C, CC and C chemokines, mainly based on their N- The position of the conserved cysteine residue at the end (Onuffer et al., Trends Pharmacol Sci., (2002) 23: 459). Chemokines are coupled to the G protein of the cell surface. G protein-coupled receptors ' GPCRs The combination is activated to perform its biological function. Taking the CXCR4 receptor as an example, it can be activated by Streptal-derived factor-1 (SDF-1), a member of the CXC chemotactic hormone. The source was taken from a bone marrow stromal cell line and found to be a growth factor for primordial B cells (Ni shikawa et 200817365 al., Eur. J. Immunol., (1988) 18: 1767). SDF-1 also induces bone marrow colonization of hematopoietic precursor cells during embryogenesis (Bleul et al., J. Exp. Med., (1996) 184: 1101). SDF- The 1 line transmits its physiological function through the CXCR4 receptor. Therefore, mice lacking the SDF-1 or CXCR4 receptor are fatal in bone marrow blastogenesis (myelopoiesis), B cell lymphopoiesis, and cerebellar development. Abnormality (Nagasawa et al., Nature, (1 996) 3 82:63 5; Ma et al., Proc. Natl. Acad· Γ

Sci·, (1 998) 95:9448; Zou et al., Nature (1 998) 3 93:595; Lu et al., Proc. Natl. Acad. Sci. (2002) 99:7090). The CXCR4 receptor is widely expressed in a variety of tissues, especially in the immune and central nervous systems, and is considered to be the major co-receptor of HI V-1/2 on T lymphocytes. Although the initial interest in CRCX4 antagonism is its potential for AIDS treatment (Bleul et al., Nature (1996) 382:829), however, it is now clear that the CXCR4 receptor and SDF-1 also involve other diseases. For example, rheumat 〇 id () arthritis, asthma (asthma) and tumor metastases (Buckley et al, J. Immunol, (2000) 165: 3423). During embryonic development, CXCR4 receptor and SDF-1 m were also found to be present in many tissues. Furthermore, it is also shown that the CXCR4/SDF-1 path is critically involved in the regeneration of some tissue damage patterns. More specifically, the number of SDF-1 is increased at the site of injury, and cells with CXCR4 (CXCR4-positive cells) actively participate in the regeneration of these tissues. 200887365 [Invention] The present invention is based on the following unexpected findings. Polyamines, either alone or in combination with granul〇cyte_c〇l〇ny stimulating factor 'G-CSF, by blocking chemotactic hormone receptors (eg CXCR3 and CXCR4) and their ligands ( Intercourse between ligands) (eg, SDF-1)

Interaction to promote the mobilization of stem cells's stem/progenitor cells 〇 In one aspect, the invention is characterized by a polyamine compound having the following chemical formula: X Ri"

N-Z1 r2 y-z2-n

In the above chemical formula, x is -ch2-, -c2h4-, -c3h6-, -CH2-CH=CH-, _CH=CH-CH2-, _C(0)-, -S02- or removed; Y is Aryl, heteroaryl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 cycloheteroalkyl (C3-C8) Heterocycloalkyl) or C5-C8 heterocycloalkenyl; Z! and Z2 are independently -CH2-, -C2H4-, -C3H6, -CH = CH-, -CH = N-, - CH = N-NR-, -s-, -0-, -NR-, -C(O) - or - SO2-; Ri is H, C1-C10 alkyl, C2-Ci〇, C2-C10 Alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 cycloheteroalkyl, C5-C8 heterocycloalkenyl, aryl or 200817365 Heteroaryl; R2 is · Ai-Bi-Di-Ei; R3 is - A2-B2-D2-E2, removed or together with R 4 is C 4 - C 2 0, and C 4 - C 2 0 loine, C4-C20 hetero, cycloalkyl or C4-C2G heterocycloalkenyl; and if R3 is removed, ζ2·ν is -CH = N·; R4 is ·Α3·Β3-〇3· Ε3 or together with R3 is C4-C20 cycloalkyl, C4-C2G ring, C4-C2G heterocyclic C4-C2G dilute or heterocyclyl group. 'The above Ai, A2 and A3 are each -CH2·, ·<32Η4-, -C3H6-, -C4H8-, -C5H10-, -CH2C(0)-, -C(0)CH2-, -CH2S 〇2-, 〇-so2ch2-, -ch2-ch=ch-, -ch = ch-ch2-, -ch(ch2or)-, -CH(CH2CH2OR)-, -CH(COOR)-, -CH(CH2COOR )·, -(:11((:(0)112)- or removed. The above 31, 62, and 83 are individually 11-, ch2- or removed. The above d!, d2, and d3 are each Others are - CH2-, -C2H4-, -c3h6-, -ch2-ch=ch·, -ch = ch-ch2-, -c(o)-, -so2-, -C(0)-NR-, -C(S)-NR-, -NR-C(o)-, -NR-C(S)-, -CH(OR)-, -CH(CH2OR)-, -CH(CH2CH2OR)-, -CH (COOR)-, 1,1-cyclopropene (1,1-cyclopropylene) or removed. The above E!, E2 and E3 are each C.) Others are H, Ci-Cio alkyl, C2-C1() a C2-C10 alkynyl group, a C3-C8-cyclohexyl group, a fluorenyl-cyclopentene group, a C3-C8 heterocycloalkyl group, a c5-c8 heterocycloalkenyl group, an aryl group or a heteroaryl group. R is H. Ci-Cio alkyl. Referring to the above chemical formula, a subset of the compounds described is where X is -CH2_4-CH(CH3)-' γ is phenyl (phenyi) or 4,4,-biphenyl (4,4 -biphenyl)' Zi is -(^2- -S02-, z2 is -CH2- or -S〇2- or R3 is removed. 5司汇 "alkyl" means a saturated, linear or branched, non-aromatic 8 200817365 fragrance (non- Carbohydrate group of aromatic, such as CH3, -CH2-^ or branched C3H7. Referring to the above chemical formula, -C2h4· and -C3H6• can be straight or branched. The word "alkenyl" is used. Refers to a straight chain or branched, non-aromatic carbohydrate group having at least one double bond, such as -CH=CH2 or -CH=CH. The vocabulary "aikynyl" refers to a straight-chain or a branched, non-aromatic carbohydrate group having at least one key, such as _C = CH or - CsC-. The word "cycloalkyl" C" means a saturated, non-aromatic A cyclic carbohydrate group. The term "cycloalkenyl" refers to a non-aromatic cyclic carbohydrate group having at least one double bond in the ring. The term "heterocycloalkyl" refers to a saturated, non-aromatic cyclic group having at least one ring of heteroatoms (e.g., fluorene, N, and S). The term "heterocycloalkenyl" means a non-aromatic cyclic group having at least one ring heteroatom and having at least one double bond in the ring. The term "aryl" refers to a carbohydrate group, () which has at least one aromatic ring. Examples of the aryl group include a phenyl group, a phenylene group, a biphenyl group, a naphthyl group, a naphthylene group, a pyrenyl group, an anthryl group, and a phenanthryl group ( Phenanthryl). The term "heteroaryl" means having at least one aromatic ring group and having at least one hetero atom. Examples of heteroaryl groups include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazole Imidazolyl, thiazolyl, pyridine 200817365 pyridyl, pyrimidinyi, qUinaz〇iinyi, and indolyl.

The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups described herein include both substituted and unsubstituted groups. Examples of the substituent of the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups include Cl_ClG alkyl, c2_Cl0 alkenyl, C2-C1G alkynyl, (:3_(: 8-cycloalkyl, c5-C8 cycloalkenyl, CrCM alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amine (amino), C1-C1. Acryl group (Ci-C1() alkylamino), C1-C10 dialkylamino group, arylamino group, diarylamino group, miscellaneous Heteroarylamino, diheteroarylamino, C1-C10 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, Ci-C10 alkane Ci-Cio alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, hydroxyl, halogen, mercapto, Ci- CiG hydrogen sulfide (C1-C10 alkylmercapto), arylmercapto, cyano, nitro, hydrazine (acyl), acyloxy, carboxyl, amido, carbamoyl, and carboxylic esters, and deuterated, dilute, and alkynyl Examples of the substituent include all of the above substituents other than the Ci-Cw alkyl group, the C2-C1() alkenyl group, and the C2-C10 alkyne 10 200817365 group. The cycloalkyl group, the heterocycloalkyl group, the aryl group, and the heteroaryl group also include In another aspect, the invention features a polyamine compound having the same chemical formula as described above. With reference to this chemical formula, the same chemical group described above is assigned to each of the different variations, except for X. For _Ch2•, -C2H4· '

-c3H6-, -ch2-ch=ch-, _ch=ch_ch2-, ·δ〇2· or remove; Y

Is aryl, heteroaryl, (: 3-0:8 cycloalkyl, <^5-(:8-cycloalkenyl, <33-(:8-heterocycloalkyl, C"C8 heterocycloalkenyl Or removed; Di, D2 and D3 are individually -CH2-, -C2H4-, -C3H6-, -CH2-CH = CH-, -CH = CH-CH2-, _S02-, -C(0)-NR -, -C(S)-NR-, -NR-C(O)-, _NR-C(S)-, -CH(OR)-, -CH(CH2OR)-, -CH(CH2CH2〇R)- , _CH(COOR)-, l,l-cyclopropene or removed; and hydrazine is H'CrCw alkyl, C2-C1G alkenyl, C2-C1G alkynyl, <:3-(:8-cycloalkyl, C5-C8 cycloalkenyl, C3-C8 heterocyclic, C5-C8 heterocyclic, aryl, 5-membered heteroaryl, fused heteroaryl, substituted six 6-membered heteroaryl, unsubstituted σpyranyl (pryany 1), unsubstituted pyrazinyl, unsubstituted pyrimidinyl or unsubstituted pyridazinyl ( Pyridaziny 1) ° Referring to the above chemical formula, a subset of the compounds is where X is -CH2- or -CH(CH3)-, Y is removed, -Z is -CH2 or Z2 is -C Η 2 - In another aspect, the invention features a method of treating inflammation or immune disease, development A method of developmental or degenerative disease 200817365 disease or tissue &宝 & $ σ. This method comprises administering to an individual in need thereof an effective dose of one or more of the formulas of <&& Compound. With reference to this chemical formula, X is -C Η 2 -, - c 〇Pr 2, -C3H6-, -CH2-CH = CH-, -CH = CH-CH2-, -C(O)-, § 〇 seven gas removal; Y is aryl, heteroaryl, c3-c8 cycloalkyl, C 5 -C 8 cycloalkenyl, C3-C8 heterocycloalkyl, C5-C8 heterocycloalkenyl or removed ; Ζι and Z2 are from w 曰 each is -CH2-, -C2H4-, -C3H6-, -CH = CH-, -CH = N« \ -pu^xt Γ m, -s-, -〇-, - Nr-, ·(:(0)- or -S02-; R i is H, r ^ - r , ^ hG alkyl, C2-C1G alkenyl, c2-c1()alkynyl, c3-c8 , I® 匕5~% alkenyl, c3-c8 heterocycloalkyl, c5_c8 heterocycloalkenyl, aryl or i^ · Norfolk Lane, R2 is -Ai-BrDi-Ei; R3 is -A2-B2- D2-E2, removed or together with R4 is C4-C2 〇cycloalkyl, C4-C20 cycloalkenyl, C4-C20 hetero-alkyl or CVCu heterocycloalkenyl, and if removed, Ζ2-ν For -C Η = · τλ ^ , R4 is -A3-B3-D 3-E3 or together with R3 is a c4-c20 cycloalkyl group, a C4-C2G cycloalkenyl group, a c4-C2G heterocycloalkyl group or a c4-C2〇 heterocycloalkenyl group. The above A!, a2 and a3 are each -CH2-, -C2H4-, -C3H6-, -C4H8-, -c5H10_, _Ch2C(0)·, -c(o)ch2-, -CH2S02-, -S02CH2 -, -CH2-CH = CH-, -ch = ch-ch2-, -ch(ch2or)-, -CH(CH2CH2OR)-, -CH(COOR)-, -CH(CH2COOR)-, -CH(C (〇)NR2) - or remove. The above B!, B2 and B3 are individually -NR-, -ch2- or removed; the above Dl, d2 and d3 are individually - ch2-, -c2h4-, -c3h6-, -ch2-ch = ch -, -ch=ch-ch2-, -c(o)-, -so2-, -C(0)-NR-, -C(S)-NR-, -NR-C(0)-, -NR -C(S)-, -CH(0R)-, -CH(CH2OR)-, -CH(CH2CH2OR)-, -CH(COOR)-, 1,1-cyclopropane 12 200817365 Aene or removed. The above Ei, E2 and E3 are each independently η, CpCio alkyl, C2-C1G alkenyl, C2-C1G alkynyl, C3-C8 cycloalkyl, 05-(:8 cycloalkenyl, C3_C8 heterocycloalkyl, Cs-C8 heterocycloalkenyl, aryl or heteroaryl. The above R is independently hydrazine or Ci-CM alkyl. For example, a compound of the above formula can be administered to an individual suffering from the above diseases. X is -CH2- or -CH(CH3)-, Y is stupid, 4,4'-biphenyl or removed, Ζι is -CH2 - or - S02-, Z2 is - CH2-

Or - S〇2_ or R3 is removed. Among these compounds, e3 is a phenyl group which may be optionally substituted by halo or OR', optionally substituted with hydrazine R, substituted benzoimidazole, and optionally substituted by d-Cw alkyl group. Indole, CyCi〇pentyi combined with phenyl, piperidinyl substituted by aryl or 〇R', and piperidine substituted with CrCioalkyl Or pyrrolidinyl substituted by CrCw alkyl, wherein R' is a hydrocarbyl group. "Treatment" means the administration of one or more polyamines to a subject which has the disease described herein, the symptoms or predisposition of the disease, and the condition of the disease, Providing a therapeutic effect, such as curing, alleviating, altering, influencing, ameliorating or preventing the above-mentioned diseases, symptoms of the disease, or predisposition to rickets. The characteristics of an inflammatory disease can be distinguished by local or systemic, acute or chronic inflammatory responses. Examples include inflammatory retinopathy, such as diabetic retinopathy; dermatoses, such as dermatitis 13 200817365

(dermatitis), eczema, atopic dermatitis, allergic contact dermatitis, urticaria, necrotizing vasculitis, skin Cutaneous vasculitis, hypersensitivity vasculitis, eosinophilic myositis, polymyositis, dermatomyositis, and eosinophilic fasciitis ( Eosin〇philic fasciitis); inflammatory bowel disease, such as Crohn's disease and ulcerative colitis; allergic lung disease, such as hypersensitivity pneumonitis, eosinophilic pneumonia Pneumonia), delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, and rheumatoid arthritis associated with ILD (rheumatoid) Arthritis); asthma (asthma) and allergic rhinitis. When the above polyamine compound is used for the treatment of retinopathy, it is preferred to administer the compound to the eye of the individual. For example, a solution containing the polyamine compound is injected into the eye (e.g., 'vitreal space injected into the eye'). Alternatively, the compound can be applied topically to the eye, for example, by eye drops into the eye or as ointment applied to the peripheral portion of the eye. The characteristics of immune diseases can be distinguished by hyper- or hyper-hypoxia responses. Examples include autoimmune diseases such as rheumatoid arthritis, psoriasis arthritis, systemic erythema 14 200817365 Ο

Systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune thyroiditis, ankylosing spondylitis (ankylosing spondylitis), systemic sclerosis, and multiple sclerosis; acute and chronic inflammatory diseases such as systemic anaphylaxia or hypersensitivity responses, drug-induced Drug allergies, insect sting allergies, graft rejection (including allograft rejection and graft-versus-host disease) ; SjSgren's syndrome; human immunodeficiency virus infection; cancer, such as brain cancer, breast cancer, prostatitis, colorectal cancer, kidney cancer, ovarian cancer, thyroid cancer, lung cancer and hematopoietic cancer (haematopoietic cancer); and cancer metastasis. Developmental diseases refer to conditions associated with growth and differentiation that result in loss of function (l〇ss-of-function) or gain-of-function. Degenerative diseases usually represent changes in the tissue to a lower or less functional state. Examples of developmental or degenerative diseases include spinal muscular atrophy, Duchenne muscular dystrophy, Φ Parkinson's disease, and Alzheimer's disease. Disease). 15

C /: 200817365 Tissue damage can be caused by oxidative stress, such as ischemia-reperfusion in stroke or myocardial infarction; complement activation; graft rejection; Chemical substances, such as mucosal tissue damage during alcohol-induced liver damage or cancer treatment; viral infections such as kidney spheroid damage associated with hepatitis C; and physical external forces such as sports injuries. Examples of tissue damage include brain damage, heart damage, liver damage, skeletal muscle damage, kidney damage, pancreatic damage, lung damage, skin damage, and digestive tract damage. In still another aspect, the invention features a method of treating retinal disease comprising administering an effective amount of one or more compounds of the above formula to the eye of an individual in need thereof. Retinopathy is a non-inflammatory retinal disease, including diabetic retinopathy, proliferative retinopathy, age-related macular degeneration, macular edema, corneal angiogenesis (corneal) Neovascularization) and iris neovascularization. The one or more compounds can be administered to the eye, i.e., directly to the eye or applied to the eye to spread it into the eye. Furthermore, the polyamines described can be used to treat diseases associated with edema or angiogenesis. Methods for repairing tissue damage using one or more of the above compounds are also within the scope of the present invention. Tissue damage refers to an organization or device 16 200817365

A loss of a certain type or type of cells (eg, is 1 etce 11 s, neura 1 1 ineagece 11 s), hepatocytes, bone cells, muscle cells, blood cells, and epidermal cells Destruction), which leads to dysfunction of the tissue or organ. The term "repair tissue damage" refers to the function of partially or completely restoring a damaged part of a tissue or organ. Many diseases can cause tissue damage, including degenerative diseases such as Alzheimer's disease, Parkinson's disease, osteoarthritis and osteoporosis; tissue ischemia, such as heart hypoxia (cardiac ischemia), limb dyslipidemia, nerve ischemia, liver ischemia, kidney ischemia, pancreatic ischemia, lung hypoxia Lung ischemia) and intestinal hypoxia (intestine ischemia); and autoimmune diseases such as type I diabetes, systemic lupus erythematosus, serrano syndrome, Hashimoto's thyroiditis ), Graves' disease and rheumatoid arthritis. These compounds can also be used to treat the diseases highlighted above. In carrying out the above treatment of the disease or the treatment of tissue damage repair, one or more of the above compounds and one or more other therapeutic agents may be administered simultaneously. Examples of the above therapeutic agents include G-CSF growth factor, steroid- or non-steroidal anti-inflammatory drugs, COX2 inhibitors, leukotriene receptor inhibitors, prostaglandin modulators, TNF modulators, and immunosuppressants (for example, Cyclosporine-A). The term "concurrently administered" as used herein refers to the simultaneous administration or administration of a polyamine compound and one or more other agents at different times during the course of treatment. In a further aspect, the invention features a method of increasing the migration of bone marrow cells into the blood. The method comprises administering an effective amount of one or more compounds of the above formula to a desired one. Referring to the formula, the same chemical group is assigned to each of the different variations of the word "bone marrow-derived cells" (bone marrow) -derived cells) refers to cells from the bone marrow. Examples of such bone marrow-derived cells include, but are not limited to, CD34+ and CD133+ cells. A pharmaceutical composition comprising an effective amount of at least one of the above polyamines and a pharmaceutically acceptable carrier is also within the scope of the present invention. To the extent applicable, the above polyamines include the compounds themselves, as well as salts, prodrugs and solvates thereof, wherein the salts may, for example, be permeating anions and polyamines. Formed by the action of a positive group on the compound (for example, an amine group). The combined anion includes a chloride, a bromide, an iodide, a sulfate, Nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Similarly, salts can be permeable, for example. The action between the cation and the negatively charged group (for example, a carboxyl group) on the clustering compound forms a compound of the compound of the therapeutic derivatization source, and the amine hydrochloride 18 181717365

Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium ions (e.g., tetramethylammonium ions). The above polyamine compounds also include these salts having quaternary nitrogen atoms. The foregoing prodrugs include esters and other pharmaceutically acceptable derivatives which, when administered to a single body, provide an active polyamine compound. The above solvate refers to a complex formed between a reactive polyamine compound and a pharmaceutically acceptable solvent. The pharmaceutically acceptable solvent includes water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. Finally, the scope of the present invention also encompasses a composition having one or more of the above polyamine compounds for use in the treatment of any of the above diseases, and a method of using the composition for the manufacture of the above-described therapeutic method. The detailed description of the present invention will be set forth in the claims and claims [Embodiment] An exemplary compound (Compound 1 -1 4 3 ) of the present invention is shown as follows: 19 200817365

QFs,

Nhk CF3 compound cf3

, F

-HYY

NhK compound compound c, rr ch3 c, whl·7

Nhh\

Cl

NK^ -NI+7 ^

, '_hiT compound compound s 'ch3 NH^ό

Cl ◦κΛ

Cl

Compound FA a compound

0厂/ shouting k, heart ch3 compound compound ch3JD Mh compound

.mj fJ 0H h2n^ Compound /NH2

Compound compound compound

NH /NH

OH compound compound 0, 』d~ compound ch3 compound χη3 20 200817365

Compound compound

Compound

21 200817365 fsiy Μη u

CH3

V

Nt CH,

o, F compound ch3 <NH Cl compound

Eight N / Nh compound

C

JO VO civ, m~nh human compound '▽NbJOw£) compound compound ΊΝί^”S rrF compound

/NH QHs N(^

T

isIH

NH-7

O

,N

Ntl· compound Cl Cl

Ck

Cl

Compound F~

, F

NH /isIH NH .NH

S〇2 NH

S02 NH

S〇2 NH compound /F Cl·, 八/Cl

NH /NH

S〇2 JsIH compound compound ' compound XI Ck compound

Compound compound compound 22 200817365

Compound

Me〇 compound

Compound

Compound

1) Compound

Compound

Compound

Compound

Compound 23 200817365

Compound

Compound C:

Compound

Compound

Compound

Compound

, y丫'~, C1 H〇J compound

Compound

Η /Ν 丫丫C 丨人〇, /,〇H

24 200817365

Compound compound

Compound compound compound 25 200817365

Compound

Compound Η〇 ΝΗ ^

Compound

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Compound L) compound

Cl

Compound

Compound

Compound 26 200817365

Compound: Compound

Compound compound

Compound compound,

Compound compound

Compound compound compound 27 200817365

The polyamine compounds described in the description of the invention can be prepared by conventional techniques, including the synthetic routes disclosed herein. For example, 'Compound 1-11 can be reacted with tris(2-aminoethyl)amine) and three equivalent aldehydes respectively, and then sodium borohydride (s 〇diumb 〇r) 〇 hydride) is prepared by a reduction reaction. In another example, 1,4-dibromoxylene is reacted with two equivalents of bisG-butoxycarbonylaminoethyOamine. Then, the reaction mixture was treated with hydrochloric acid to give the intermediate product, 1,4-bis[2-(ethylamino)aminomethyl]benzene. This intermediate product can be reacted with four equivalents of the corresponding aldehyde compound and sodium borohydride to give the compound 1 2 -1 4 . Alternatively, the intermediate can be reacted with two equivalents of pyridine-2-carbaldehyde followed by reaction with sodium borohydride to give compound 15. 1,4-dibromoxylene can also be equivalent to one equivalent. The bis(tris-butoxycarbonylamineethyl)amine is reacted with one equivalent of another amine compound. Compounds 56-57, 65, 66, 68, 28, 200817365 80, 86, 91, 93-95 can be prepared through this synthetic route followed by a series of treatments with hydrochloric acid, two equivalents of the corresponding aldehydes and sodium borohydride. 106-109, 141 and 142. In the same manner, compound 49 can be passed through 1,4,dibromoxylene and one equivalent of 1,3,8,11-tetrazole protected by tri-butoxycarbonyl. The reaction is carried out by reacting cyclam with one equivalent of bis(2-pyridiyliminoethylamine), followed by reduction reaction using sodium hydride.

In another example, compounds 16-48, 58-64, 69-79, 81-85, 87-90, 92, 96-105, 115, 121, 122, and 125-141 can be used in the following synthetic routes. To synthesize. 4-cyanobenzylbromide is reacted with one equivalent of bis(tertiary-butoxycarbonylamineethyl)amine, followed by treatment with hydrochloric acid to give 4-[bis(2.aminoethyl)amine Methyl]-benzonitrile (4-[bis(2-aminoethyl)aminomethyl]-benzonitrile). The benzonitrile is then treated in two equivalents of genus, shed hydrogenated and diisobuty laluminum to form 4-[bis(2-substituted-aminoethyl)amine oxime. 4-[bis(2-substituted-aminoethyl)aminomethyl]-benzaldeh yde). The compound is prepared by treating the benzaldehyde in succession with one equivalent of the corresponding amine, sodium borohydride and hydrochloric acid. Compounds 1 10 0, 111, 1 16 , 1 17 , 120 , 123 and 124 can be prepared by the same procedure except that one aldehyde is used and one equivalent of ketone is used to treat the benzoquinone. In another example, 4-bromomethylbenzenesulfonyl chloride is reacted with one equivalent of amine 29 200817365 and then reacted with one equivalent of bis(tertiary-butoxycarbonylamine)amine. After the above reaction mixture was treated with hydrochloric acid, an intermediate product was obtained. After the intermediate product is treated with the corresponding aldehyde, and then treated with sodium borohydride, the compound 5 1 - 5 5 can be separately prepared. Compounds 5 0, 67 ' 112 and 11 3 can be prepared in the same manner as in the preparation of compound 5 1 - 5 5 except that the equivalent of bis(tertiary-butoxycarbonylamine ethyl)amine is used to treat 4-bromomethyl Outside of 4-bromomethylbenzenesulfonyl chloride.

另一 In another example, 4-cyanobenzaldehyde with one equivalent of 2-methyl-2-aminoethanol, sodium borohydride, and 2(2- A series of reactions of bromo-ethoxy)-tetrahydro-pyran (2-(2-bromo-ethoxy)-tetrahydro-pyran) to obtain a hydrazine-substituted aminomethane benzonitrile (aminom ethy lbenzonitrile) After the tetrahydropyranyl protecting group, the benzonitrile can be further subjected to a series of mesylated and treated with 2-aminomethylpyridine. After the secondary amine is protected, diisobutylaluminum, one equivalent of the corresponding amine, sodium borohydride, triflic acid and hydrochloric acid can be used to treat the phenylhydrazine. The nitrile to prepare the compound 114, 118 and 119 ° polyamine compound can be further utilized, for example, by column chromatography, high-pressure liquid chromatography or recrystallization 30 Purification was carried out at 200817365 (recrystallization).

Other polyamine compounds can be prepared by the above synthetic routes and other conventional techniques using other suitable starting materials. The above process may add steps to add or remove appropriate protecting groups before or after some of the steps to achieve the purpose of the final synthesis of the polyamine compound. In addition, many synthetic steps can be substituted or altered to achieve the desired compound. It is a well-known technique to effectively use Synthetic chemistry transformations and protective group methodologies (protection and deprotection) applicable to synthetic polyamines, for example, in R. Larock k, Comp re/ Ze nhve Organic Transformations, VCH Publishers (1989), TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd Ed.? John Wiley and Sons (1991) - L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994 Bl L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1 995) and subsequent versions thereof. Polyamines as described herein. It may contain a non-aromatic double bond and one or more asymmetric centers. Therefore, the polyamine compound may use racemates and racemic mixtures, single-mirror Single enantiomers, individual diastereomers, non-mirrors Was present isomeric mixture (diastereomeric 31 200817365 mixtures) and cis (CIS) or trans (trans) isomeric state (is〇meric f〇rms) expected state inclusive of all isomers.

The above pharmaceutical compositions having an effective amount of at least one polyamine compound and a pharmaceutically acceptable carrier are also encompassed by the present invention. Further, the present invention encompasses a method of administering an effective amount of one or more polyamines to a patient having the condition described in the description. The invention also encompasses a method of administering an effective amount of one or more polyamines which enhances the migration of bone marrow-derived cells into the gold solution. "Effective dose (e f f e c t i v e a m 〇 u n t)" refers to a dose required to provide a therapeutic effect when a living polyamine compound is used to treat an individual. Depending on the person skilled in the art, the effective dose will vary depending on the condition being treated, the route of administration, the use of the adjuvant (excipientusage) and co-administration with other therapeutic agents (c 〇- uasge). . When practicing the method of the present invention, a composition having one or more polyamine compounds is permeable to the enteral (e.g., orally, nasally, and rectal), non-intestine Administration by way of enantiomer (parenterally), topical or buccally. The term "parenteral" refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intraserosal. (intrasyno vial), intrasternal, intrathecal, intralesional or intracranial 32 200817365 (intracranial) injection, and other suitable infusion techniques. The above compounds can also be administered in an intravitreally manner. The injectable compositions of sterilized chlorhexidine may be solution or suspended in a non-toxically acceptable parenterally acceptable diluent or solvent, for example, a 1,3 -butanediol- (1,3_butanediol) solution. Among these acceptable carriers and solvents, mannitol, water, Ringer's Solution, and isotonic sodium chloride solution can be used. In addition, fixed oils (" are often used as solvents or suspension matrices, such as synthetic mono- or diglycerides. Fatty acids (eg, oleic acid) and their glycerol derivatives can be used in the preparation of injectables. Pharmaceutically acceptable oils, such as olive oil or castor oil, especially in the form of their polyethylene, the solutions or suspensions of these oils also contain long-chain alcohol dilutions or Dispersing agents, carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as T weens, S pans or other similar emulsifiers or bioavailability enhancers (bi〇availabiHty Q enhancers) It is often used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms. The composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and liquids. Suspensions, dispersions and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricants are also generally added (for example Magnesium stearate. In the case of oral administration in capsule form, useful diluents include lactose and dried corn starch. When a liquid suspension or emulsion is administered orally, the active ingredient will be suspended or dissolved in an emulsified with 33 200817365 The agent or dispersant is combined in the oil phase. If necessary, some sweeteners, flavoring agents or coloring agents may also be added.

鼻 Intranasal spray or inhaled compositions can be prepared according to conventional techniques of pharmaceutical formulation. For example, the above compositions may be prepared using a salt solution in which benzyl alcohol or other suitable preservatives, absorption promoters, and the like are added to improve bioavailability. , fluorocarbons and/or other solubilizers or dispersants. The presence of one or more active polyamines can also be achieved in the form of suppositories»: for rectal administration. The carrier of the pharmaceutical composition must be "acceptable" and compatible with the active ingredients of the composition, and preferably have a function to stabilize the active ingredient' and not deleterious to the individual being treated. result. One or more solubilizing agents may be used as pharmaceutical adjuvants for delivery of the active polyamine compound. Examples of other carriers include c〇u〇idal sHicon oxide, magnesium stearate, cellulose, sodium sulphate lauryl sulfate, and D&C Yellow #10. The above polyamine compound can be tested by a fine, Z/7 vziro assay (refer to the following implementation of 444 α ^ for the treatment of the above diseases, and then using animal experiments and pro > Bin test to confirm. Others, sputum, stomach are the general knowledge of the technical field of the 4 & mosquitoes can think of each. May people also found that the above polyamine compound ΓΎΓΌ Δ can be used as chemotaxis A hormonal antagonist that competes with CXCR4 ligand discrimination (SDF-1) to bind to 34200817365 to the receptor, thereby blocking CXCR4/SDF-1 signaling. This phenomenon is responsible for the migration of stem cells and progenitor cells. Importantly, without being bound by theory, the mode of action of the above polyamines for treating and repairing silver damage may be carried out by the following mechanism of action. By blocking the transmission of CXCR4/SDF-1, The polyamines promote the migration of stem cells and progenitor cells from the bone marrow (the storage of stem cells and progenitor cells) to peripheral blood. Specifically, when SDF-1 is highly expressed in the bone marrow, the stem cells expressing CXCR4 and The progenitor cells are trapped in the bone marrow via the interaction of CXCR4-SDF-1. By blocking the interaction of CXCR4/SDF-1, polyamines release stem cells and primary cells from the bone marrow. In the peripheral blood. % of the stem cells and progenitor cells in the blood are returned to the damaged tissues and organs, and the cells causing the loss of damage are repaired by differentiating into different types of cells. In the case of retinopathy, the glass is broken. The body (vitre〇us) is highly expressed in SDF"1. By binding to CXCR4 expressed by stem cells and primary cells, SDF-1 causes these cells to migrate to the retina, resulting in blood & This phenomenon of neonatal blood plays a key role in the development and progression of retinopathy. Moreover, by blocking the transmission of messages, polyamines prevent stem cells and progenitor cells from returning to the retina, thus effectively treating the visual network. Lesions. Unlike systemic administration, some polyamines can be applied topically to the eyes of patients with retinopathy, while local application will not cause dryness. The cytoplasmic and progenitor cells are displaced from the bone marrow and, therefore, do not contribute to the homing of these cells to the retina. 35 200817365 The following examples (examples) are to be construed as illustrative and not to limit the spirit of the invention. Scope, any person skilled in the art, may make equivalent embodiments when making various changes and retouching.

Example 1: Preparation of Compound 1 : N-(4-Fluoro-indoleylbis-[2-(4-fluoro-benzoguanidino)-ethyl]-ethene-1,2-diamine (N- (4-fluoro-benzyl)-N,9N,-bis-[2-(4-fluoro-benzylamino)-ethyl]-ethane-l?2-diamine) Tris(2-Aminoethyl)amine (0.01 mol And 4-fluoro-benzaldehyde (〇.〇3 mol) was dissolved in decyl alcohol (50 ml). After stirring for 15 hours, NaBH4 (1.90 g, 0.05 mol) was added at 〇 °C. The reaction was stirred for 2 hours at 25 ° C. It was then diluted with dichloromethane (100 mL) and aqueous ammonium chloride (10%, 70 mL). The water (100 mL) was rinsed, dried over magnesium sulfate, and then concentrated under reduced pressure to give an oily product. The original product was subjected to alumina column chromatography (acetic acid ethyl acetate / decyl alcohol = 8: 2) Purification to give the compound 1. LC/MS (M + +1): 471. Example 2: Preparation of compound 2: N-(3-trifluoromethyl-m-methyl)-bishan'- double -[2-(3-Trifluoromethyl-benzylamino)-ethyl]-ethane-1,2-diamine (N-(3-trifluoromethyl-benzyl)-N,?N,-bis- [2 -(3-trifluorome 36 200817365 thyl-benzylamino)-ethyl] - ethane -1,2-diamine) Compound 2 was prepared in a similar manner to Example i. LC/MS (M + +1): 621. Preparation of Compound 3: N-(3,4-Difluoro-benzyl)·ν', Ν,-bis-[2-(3,4-dioxa-benzylamino)-ethyl bethane -N-(3?4-difluoro-benzyl.N,5N,-bis-[2-(354-difluoro-benzy lamino)-ethyl]- ethane -l52-diamine) Prepared by a method similar to that of Example 1. LC/MS (M + + 1 ): 525. Example 4: Preparation of compound 4: N-benzyl-N, N,-bis-(2-benzene Methylamino-ethyl)-ethane-1,2.diamine (N-benzyl-N,?N,-bis-(2-benzylamino-ethyl)-ethane-l?2-dia mine) Prepared by a method similar to that of Example 1.

LC/MS (M + +1): 417.实U"··· Preparation of compound 5: N-(2-chloro-4-fluoro-benzoinyl)·Ν,,Ν,_bis-[2-(2- gas-4-fluoro-benzoguanamine) )--,2-diamine (N-(2-chloro-4-fluoro-benzyl)-N,5N,-bis-[2-(2-chloro»4-fl uoro-benzylamino )-ethyl]-ethane-1,2-diamine) Compound 5 was prepared by a method similar to that of Example 1. LC/MS (M + + 1): 574. 37 200817365 - Example 6: Preparation of compound 6 : N-(2-fluoro-phenylhydrazino)-N', Nf-bis-[2-(2-fluoro-benzylamino)-ethyl]-ethane -1,2-Diamine (N-(2-fluoro-benzyl)-Nf?N,-bis-[2-(2-fluoro-benzylamino)- - e thyl]-eth an e-1,2-diamine Compound 6 was prepared by a method similar to that of Example 1. LC/MS (M + +1): 471.实施 Example 7: Preparation of compound 7: N ·( 5 -methyl-thiophen-2-ylmethyl)-Nf, N'-bis-{2-[(5-methyl-thiophen-2-ylmethyl) )-Amino]-ethyl}•ethane-1,2·diamine (N-(5-methyl-thiophen-2-ylmethyl)-N,5Nf-bis-{2-[(5-methy l- Thiophen-2-ylmethyl)-amino]-ethyl}-ethane -1,2-diamine) Compound 7 was prepared in a similar manner to that of Example 1. LC/MS (M + +1 ): 477.实施 Example 8: Preparation of compound 8: Ν-naphthalen-1-ylindenyl hydrazine, Ν·-bis-{2-[(naphthalen-1-ylmethyl)-amino]-ethyl}-ethane -1,2-Diamine-N-naphthalen-l-ylmethyl-N'?N,-bis-{2-[(naphthalen-l-yl methyl)-amino]-ethyl}-ethane-l,2- Diamine) Compound 8 was prepared in a similar manner to that of Example 1. LC/MS (M + + 1): 567. 38 200817365 Example 9: Preparation of compound 9: N-(2,3-dichloro-benzoinyl)-N',N'-bis-[2-(2,3·dichloro-benzylamino) -ethyl]-ethane-1,2-diamine (N-(253-dichloro-benzyl)-N'?N,-bis-[2-(2?3-dichloro-benzy lamino)-ethyl]- Ethane -1.2-diamine). Compound 9 was prepared by a method similar to that of Example 1. LC/MS (M + +1) ·· 624. ζ^\ Example 10: Preparation of compound 10: Ν-(1Η-吲哚-6-ylmethyl)-Nf,N'-bis-{2-[(1Η-丨哚丨哚-6-ylmethylamine) Ethyl]-ethyl} • ethane-1,2 · ·monoamine (N-(lH-indol-6-ylmethyl)-N,5N'-bis-{2-[(lH-indol-6-ylmet hyl) -amino]-ethyl}- ethane -1,2-diamine) Compound 10 was prepared in a similar manner to that of Example 1. LC/MS (M + +1) ·· 534. I) Example 11: Preparation of compound 11 : N-(l-fluorenyl-1H-indol-2-yl.indolyl)-N',N,-bis-{2-[(1-mercapto-1H-pyrrol-2-yl) Methyl)-amino]-ethyl}-ethylidene~1 5 2 -diamine (N-(l-methyl-lH-pyrrol-2-ylmethyl)-N,?N,-bis-{2-[ (l-methyl-lH-pyrrol-2_ylmethyl)-amino]-ethyl}-ethane-l,2-diami ne) Compound 11 was obtained by a method similar to that of Example 1. LC/MS (M + +1): 426. 39 200817365 'Example 1 2: Preparation of compound 12: 1^-[4-({bis-[2-(2-fluoro-benzyl-amino)-ethyl]-amino}-indenyl)- stupid Methyl]-Nf-(2-fluoro-phenylhydrazinyl)-indole[2-(2-Gas-Butyramine)-Ethyl]-Ethylene-1,2-diamine (N-[4 -( {bis -[2-(2-fluoro-benzylamino)-ethyl]-amino}- met hyl)-benzyl]-Nf-(2-fluoro-benzyl)-N-[2-(2-fluoro-benzyla „ mino)-ethyl]- ethane -1,2-diamine) O 60 0C, 1,4-Dibromoxylene (0.012 mol) as bis (tertiary-butoxyamine B) The amine (0.024 mol) was treated with carbaryl (0.5 mol) in CH3CN (60 mL). After stirring for 12 hours, the solution was cooled to room temperature, filtered and concentrated. The ether is treated and neutralized with potassium carbonate to quantitatively obtain 1, 4-di[2-(ethylamino)aminomethyl]benzene. 〇 will thus give 1,4-bis[bis(2-aminoethyl)amine fluorenyl]benzene (0.01 mo1) (丨 and 4-fluoro-benzaldehyde (0.04 mol) dissolved in A, alcohol (50 mL), stirred at 25 ° C for 15 hours _ Sodium borohydride (2.28 g, 0.06 mol) was added at 0 CC. The reaction was then stirred at 25 ° C for an additional 2 hours, followed by dioxane (CH2C12) (100 mL) and yd. Diluted with aqueous chloride (10%, 70 mL). The organic layer was separated, washed with water (100 mL), dried over magnesium sulfate, and then concentrated to afford oily product. The analytical method (ethyl acetate / methanol = 7:3) was purified to give compound 1 2 40. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; {bis-[2-(4-Fluoro-benzylamino)-ethyl]-amino}-methyl)-benzyl]-indole-(4.fluoro-benzyl)-indole-[ 2-(4-Fluoro-benzylamino)-ethyl]-ethane-1,2-diamine (N-[4-({bis-[2-(4-fluoro-benzylamino)-ethyl]-) Amino}-met hyl)-benzyl]-Nf-(4-fluoro-benzyl)-N-[2-(4-fluoro-benzyla mino)-ethyl]- ethane -1,2-diamine) Prepared in a similar manner to the method of Example 12. LC/MS (M + +1): 741. Example 1 4: Preparation of compound 14. 14 : N-{4-[(bis-{2-[(pyridin-2-ylindenyl)-amino]-ethyl}-amino)-indenyl]-benzene Methyl}-Nf-a is more than 2-methylindolyl-Ν-{2-[(σ-But-2-ylmethyl)-amino]-ethyl}-Ethylene- l,2- 2 Amine (N-{4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino)-methyl]-benzyl}-N,-pyridin-2-ylmethyl-N-{ 2-[(pyridin-2 -ylmethyl)-amino]-ethyl}-ethane -1,2-diamine) Compound 14 was obtained by a method similar to that of Example 12. LC/MS (M + +1): 673. Example 15: Preparation of compound 15: N-(2-amino-ethyl)-N-{4-[((2-amino-ethyl)-{2-[(σ 咬 -2--2-yl) ))-amino]-ethyl}-amino)-methyl]-benzyl}-1^'-° than butyl-2-ylmethyl-ethene-oxime, 2-42 41 200817365 Amine N-(2-amino-ethyl)-N-{4-[((2-amino-ethyl)-{2-[(pyridin-2 . -ylmethyl)-amino]-ethyl }-amino)-methyl]- Benzyl]-N!-pyri din-2-ylmethyl-ethane-l,2-diamine) 1,4-bis[bis(2-aminoethyl)amine fluorenyl]benzene (〇·〇ι m〇i) *0 pyridine-2-carbaldehyde (0.02 mol) was dissolved in methanol (40.mL). After stirring at 25 ° C for 15 hours, sodium borohydride (1.14 g, 0.03 mol) was added at hydrazine. The reaction was then stirred at 25 ° C for an additional 2 hours. It was then diluted with dichloromethane (100 mL) and aqueous ammonium chloride (10%, 70 mL). The organic layer was separated, washed with water (100 mL) and dried over magnesium sulfate. The original product was purified by column chromatography on silica gel (ethyl acetate / methanol = = 6: 4) to afford compound 15. LC/MS (M + +1): 491. () Example 1 6 : Preparation of Compound 16: N-(4-Fluoro-benzyl)-N'-[2-(4-.fluoro-benzoguanidino)·ethyl]-Ν·-{4 -[(4-Fluoro-phenylhydrazino)-methyl]-benzyl}- ethoxy-1,2-diamine (N-(4-fluoro-benzyl)-N,-[2-(4 -fluoro-benzylamino)-ethyl]-N'-{4 -[(4-fluoro-benzylamino)-methyl]-benzyl}- ethane -1? 2-diamine) bis(2-tris-butoxycarbonylamine) Bis(2-ieri-butoxycarbonylaminoethyl)amine (0.01 mol), 42 200817365

4-cyanobenzylbromide (0.01 mol) and sodium carbonate (0.005 mol) were heated in CH3CN (70 mL) at 60 ° C for 10 hours. This product is deprotected with hydrochloric acid/ether by bis(2-/err-butoxycarbonylaminoethylamino-4-methylphen ylcyanide) It was concentrated in 4-fluoro-benzaldehyde (0.02 mol) in methanol. After treatment with sodium borohydride, di-ierr-butyl dicarbonate, and diisobutylaluminum, the bis(2-substituted-amine) is obtained. Ethyl) 4-bis-aminoethylamino-4-methylbenzaldehyd e), which is further concentrated with 4-fluoro-benzylamine to give Schiff base ). Next, the Schiff base is reduced with sodium borohydride and protected by reaction with hydrochloric acid. The obtained original product was purified by oxidative column chromatography (ethyl acetate/methanol = 7:3) to give Compound 16. LC/MS (M + +1 ): 747.实施 Example 1 7: Preparation of compound 17: N-{4-[(3-imidazo-buyl-propylamino)-fluorenyl; I-stupyl}-Ν·-pyridine-2·ylindenyl-Ν -{2·[(pyridin-2-ylindenyl)-amino]-ethyl}••乙烧-1,2-diamine (N-{4-[(3-imidazol-l-yl-propylamino) )-methyl]-benzyl}-N, -pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-et hyl}- ethane -1,2-diamine) Prepared by a method similar to that of Example 16. 43 200817365 LC/MS (M + +1) ·· 513. Example 1 8: Preparation of Compound 18: 1·({4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino)-indenyl]-benzene Methylamino}-mercapto)-cyclohexanol (l-({4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amin o)-methyl]-benzylamino} -methyl)-cyclohexanol) Compound 18 was obtained by a method similar to that of Example 16. LC/MS (M + +1): 517. Example 1 9: Preparation of Compound 19: N-{4-[(3-Folinin-4-yl-propylamino)-indenyl]-benzoinyl N,-acridin-2-ylindenyl- N-{2-[(acridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine (N-{4-[(3-morpholin-4-yl-) Propylamino)-methyl]-benzyl}-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}- ethane -1,2-diamine) Prepared by a method similar to that of Example 16. LC/MS (M + +1 ): 532. Example 20: Preparation of compound 20: N-(4-{[2-(2,5-dimethoxy-phenyl)-ethylamino]-indenyl} methyl group butyl-2-yl hydrazine Base-Ν-{2-[(pyridin-2-ylmethyl)-amino]-ethyl-ethaneethane-1,2-diamine (N-(4-{[2-(255-dimethoxy-phenyl)) )-ethylamino]-methyl}-be 44 200817365 nzyl)-N'-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-a mino]- ethyl}- ethane -1,2- The compound 20 was obtained by a method similar to that of Example 16. 6 LC/MS (M + + 1 ) : 569.

Example 2 1 : Preparation of Compound 21: N-(4-{[2-(4-Fluoro-phenyldimethyl-ethylamino)-indolyl phenylmethyl)-N'-pyridin-2-yl Methyl-N-{2-[(nit ate-2-ylmethyl)-amino]-ethyl}-ethene-1,2-diamine (N-(4-{ [2-(4- Fluoro-phenyl)-l,l-dimethyl-ethylamino]- met hyl}-benzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylme thyl)-amino]-ethyl} - ethane -1,2-diamine) Compound 2 1 was obtained in a similar manner to that of Example 16. 6 LC/MS (M + + 1 ) : 5 5 5. Example 22: Preparation of Compound 22: N-( 4-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-benzyl)-N, acridine-2-ylmethyl-N-{2-[(acridine- 2-(methyl)-amino]-ethyl}-ethane-1,2-diamine (N-(4-{[2-(3-fluoro-phenyl)-ethylamino]-methyl}-benzyl) -Nf-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine) Compound 2 2 was prepared in a similar manner to Example i 6 LC/MS (M + + 1 ) : 527. 45 200817365 Example 23: Preparation of compound 23: Ν-(4·{[(1Η-3 -decyloxybenzimidazole-2-ylmethyl) -amino]-methyl}-benzyl acridine-2-yl ••Ν-{2-[(σ 咬-2-ylmethyl)-amino]-ethyl}-ethene-1,2-diamine (N-(4-{[(lH-3) -methoxybenzoimidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2-y * lmethyl)-amino]- ethyl}- ethane - 1,2-diamine) - Compound 2 3 was prepared in a similar manner to Example 16. C) LC/MS (M + + 1 ): 565. Example 24: Preparation of Compound 24: N-pyridine-2 -ylindolyl-Ν'·{2-[(σ-butyl-2-ylmethyl)-amino]-ethyl}-Nf-(4-{[(obb bit-2-ylmethyl)· Amino]-methyl}•benzyl”-ethane-1,2-diamine (N-pyridin-2-ylmethyl-N,-{2-[(pyridin-2-ylmethyl)-amino] -ethyl }-Nf-(4 -{[(pyridin-2-ylmethyl)-amino]-methyl}-benz yl)-ethane-l,2-diamine) i) Compound 24 was prepared in a similar manner to Example 16 Got it. LC/MS (M + +1) : 496. Example 25: Preparation of compound 25: N-(4-{[(acridin-2-ylmethyl)-amino]-indenyl}-benzyl)-1^-(2,3,5-trigas -Benzyl)_^-[2-(2,3,5-trichloro-benzoguanidino)-ethyl]-ethane-1,2-diamine (N-(4-{[(pyridin) -2-ylmethyl)-amino]-methyl}-benzyl)-N'-(2?3,5-trichloro-benzyl)-N-[2-(2?3,5-trichloro-benzylamino 46 200817365 )-ethyl ]-ethane-l,2-diamine) Compound 2 5 was obtained by a method similar to that of Example 16. LC/MS (M + +1): 488. Example 26: Preparation of compound 26: N-(3,4-difluoro-benzoindolyl)-fluorene-[2-(3,4·difluoro-benzylamino)-ethyl]-Nf- ( 4-{[(Acridine-2.ylmethyl)-amino]-methyl}-phenylindenyl)-ethane-1,2-diamine (N-(3,4-difluoro-benzyl)- N,-[2-(354-difluoro-benzylamino )-ethyl]-Nf-(4-{[(pyridin-2-ylmethyl)-amino]-methyl}-ben zyl)-ethane-l,2-diamine) Compound 26 was prepared by a similar method as in Example 16. LC/MS (M + +l): 566. Example 2 7: Preparation of Compound 27··N-(4-Fluoro-benzyl)-N,-[2-(4-defy-benzylamino)-ethyl]-Ν*-(4-{[ (σι^σ定-2-ylindenyl)-amino]-mercapto}-phenylhydrazine)-ethane-1,2-diamine (N-(4-fluoro-benzyl)-N,-[ 2-(4-fluoro-benzylamino)-ethyl]- N,-(4-{[(pyridin-2-ylmethyl)-amino]-methyl}-benzyl)-etha ne-1,2-diamine) Prepared by a method similar to that of Example 16. LC/MS (M + + 1): 530. Example 2 8: Preparation of Compound 28: N-(4-Gas- azainyl)-N,-[2_(4-47 200817365 chloro-benzoguanidino)-ethyl]-oxime, -(4-{[ (°-pyridin-2-ylindenyl)-amino]-methyl} &quot;* 本 methyl)- 乙院-1,2-diamine (N-(4-chloro-benzyl)-N,- [2-(4-chloro-benzylamino)-ethyl] -N,-(4-{[(pyridin-2-ylmethyl)-amino]-methyl}-benzyl)-eth ane-1,2-diamine) The 8 series was prepared by a method similar to that of Example 16. LC/MS (M + + 1): 5 63.

Example 2 9: Preparation of Compound 29: Ν-(4-{[2-(3·Chloro-phenyl)-ethylamino]-indenyl}•Benzylpyridin-2-ylmethyl·Ν- {2·[(°pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine (N-(4-{[2-(3-chloro-phenyl))) -ethylamino]-methyl}- benzyl)-Nf-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}- ethane -1,2-diamine) Prepared by a method similar to that of Example 16. 6 LC/MS (M + + 1 ) : 543. Example 3 0: Preparation of compound 30: N-(4-{[2-(4- gas-phenyl) -ethylamino]-methylphenylphenyl)-&gt;Γ-acridin-2-ylmethyl-oxime-{2-[(α-pyridin-2-ylmethyl)-amino]-B N-(4-{[2-(4-chloro-phenyl)-ethylamino]-methyl }-benzyl)-N'-pyridin-2-ylmethyl-N- </ RTI> <RTIgt; ) : 543 〇

例. Example 3 1 : Preparation of compound 31: Ν-{4-[(4-fluoro-molenonyl)-methyl]-benzylpyridinyl-2-ylmethylpyridin-2-yl A) Ethyl l-ethyl}-ethane-1,2-diamine (N-{4-[(4-fluoro-benzylamino)-methyl]-benzyl}-N,-pyridi n-2-ylmethyl -N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-et hane-1,2-diamine) Compound 3 1 was obtained by a method similar to that of Example 16. LC/MS (M + +1): 513. Example 3 2: Preparation of compound 32: Ν-(4-{[2-(1Η·吲哚-3-yl)-ethylamino]-indolyl}-phenylhydrazinyl)-fluorene-pyridine-2- Base Ν-Ν-{2·[(pyridine-2-ylindenyl)-amino]•ethyl}-ethane-1,2-diamine (N-(4-{[2-(lH-) Indol-3-yl)-ethylamino]-methyl}-benzyl)-Nf -pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-et hyl}- ethane-1,2 -diamine) Compound 3 2 was obtained by a method similar to that of Example 16. LC/MS (M + +1 ): 548 〇 Example 3 3: Preparation of compound 33: N-(4-{[2-(5-fluoro-1H-.indol-3-yl)-ethylamino] -methyl}-benzylpyridin-2-ylindenyl group 49 200817365 -N-{2-[(Tentidine-2-ylmethyl)-amino]-ethyl}-ethane-1,2 -Diamine (N-(4-{ [2-(5-fluoro-lH-indol-3-yl)-ethylamino]-methyl}-b enzyl)-Nf-pyridin-2-ylmethyl-N-{2- [(pyridin-2-ylmethyl)-amino]-ethyl}-ethane-l?2-diamine) Compound 3 3 was obtained by a method similar to that of Example 16. 6 LC/MS (M + +1 ) : 566. </ RTI> Example 3 4: Preparation of compound 34: Ν-(4-{[2-(5-decyloxy-1Η- 吲哚-3-yl)-ethylamino]-methyl}- Benzoyl)-Ν '-Acridine-2-ylmethyl-indole-{2-[(pyridin-2-ylindenyl)-amino]•ethyl}-ethane-1,2-diamine (N-(4-{[2-(5-methoxy-lH-indol-3-yl)-ethylamino]-methyl}-benzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin -2-ylmethyl)-amino]-ethyl}- ethane -1,2-diamine) Compound 3 4 was obtained by a method similar to that of Example 16. 6 LC/MS (M + +1 ) : 578. Example 3 5: Preparation of compound 35: N-(4-{[2-(6-decyloxy-1H- _ 吲哚-3) -yl)-ethylamino]-methyl}-phenylindolepyridin-2-ylindenyl-indole-{2-[(σιί»pred-2-ylmethyl)-amino]-ethyl} -Ethylene-1,2-diamine (N-(4-{[2-(6-methoxy-lH-indol-3-yl)-ethylamino]-methyl}-benzyl)- N'-pyridin-2- ylmethyl-N-{ 2 -[(pyridin-2-ylmethyl )-amino]- ethyl}- ethane -1,2-diamine) Compound 3 5 was prepared by a method similar to that of Example 16. 50 200817365 LC/ MS (M + + 1 ): 5 7 8.

Example 3 6: Preparation of Compound 36 ··Ν-(4_{[2·(7-Methyl-1H-indol-3-yl)-ethylamino]•indolyl}-phenylhydrazyl)-Ν· -. Bis-2-ylmethyl-indole-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine (N-(4-{[ 2-(7-methyl-lH-indol-3-yl)-ethylamino]-methyl}-benzyl)-Nf-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]- Ethyl}-ethane -1 ,2-diamine) Compound 3 6 was obtained by a method similar to that of Example 16. LC/MS (M 10 + 1): 562. Example 3 7: Preparation of compound 37: N-{4-[(2-cyclohexyl-1-enyl-ethylamino)-methyl: I-phenylmethyl-N,-pyridin-2-ylmethyl -N-{2-[(.pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine (N-{4-[(2-cyclohex-l-) Enyl-ethylamino)-methyl]-benzyl}-N CJ f-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-e • thyl}- ethane -1,2-diamine Compound 3 7 was prepared by a method similar to that of Example i 6 . LC/MS (M + +1): 513. Preferably, compound 38 is prepared as .m: Ν-{4-[(1Η-吲哚-5-ylamino)-indolyl]-benzoinyl}-N'-pyridin-2-ylmethyl-N- {2-[(pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine 51 200817365 (N-{4-[(lH-indol-5-ylamino)- Methyl]-benzyl}-N,-pyridin-' 2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-etha. ne-1,2-diamine) Compound 3 8 Prepared by a method similar to that of Example 16. - LC/MS (M + +1 ) : 520. Example 3 9: Preparation of compound 39: 2-{4-[(bis-{2-[(pyridin-2-ylindenyl)-amino]-ethyl}-amino)-indenyl]-phenylhydrazine Amino}-4,5,6,7-tetrazole-benzoquinone°Cetene-3-butyric acid (2-{4-[(bis-{2-[(pyridin-2-ylmethyl)-amino) ]-ethyl}-amino )-methyl]-benzylamino}-455,6?7-tetrahydro-benzo[b]thioph ene-3-carboxylic acid ethyl ester) Compound 3 9 was prepared by a method similar to that of Example 1 6 Got it. LC/MS (M + +1): 613. Q Example 40: Preparation of compound 40: N-(4-{[2-(4-fluoro-phenyl)-ethylamino]-indenyl}-benzyl)-^^-° than 唆-2- N-(4-{[2-(4-fluoro-phenyl)-ethylamino]_methyl}-benzyl)-Nf-pyridin -2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}- ethane -1,2-diamine) Compound 40 was obtained by a method similar to that of Example 16. LC/MS (M + +1 ): 527. 52 200817365 Example 4 1 : Preparation of compound 41 : N-(4-{[2-(4-Gas-phenyl)-propylamino]-indenyl}-phenylhydrazinyl-]--{2- [(° ratio bit-2-ylmethyl)·Amino]-ethyl}· Ethylene-1,2-diamine (Ν-(4-{[2-(4-chloro-phenyl)- propyl amino ]-methyl}- benzyl )-N?-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino ]- ethyl}-ethane-1,2-diamine)

Compound 41 was prepared in a similar manner to that in Example 16. LC/MS (M + + 1 ): 5 5 8. Example 42: Preparation of compound 42: N-(4-{[2-(5-methyl-1H-吲σdol-3-yl)-ethylamino]-methyl}-phenylindenyl)-1^ '-°Bite-2-ylindenyl-Ν_{2-[(σΙ0-ylmethyl)-amino]-ethyl}•Ethylene-1,2-diamine (N-(4) -{[2-(5-methyl-lH-indol-3-yl)-ethylamino]-methyl}-benzyl)-Nf-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl) - Amino]-ethyl}- ethane -1,2-diamine) Compound 42 was obtained by a method similar to that of Example 16. LC/MS (M + +1): 562. Example 43: Preparation of compound 43: N-(4-fluoro-benzyl)-N'-[2-(3-fluoro-benzylamino)-ethyl]-Ν'-(4-{[6 -(Acridine-2-yloxy)-acridin-3-ylamino]-methyl}-phenylindenyl)-ethane-1,2-diamine (N-(4-fluoro-benzyl) -N,-[2-(3-fluoro-benzylamino)-ethyl]- 53 200817365

Nt. (4-{[6-(pyridin-2-yloxy)-pyridin-3-ylamino]-methyl}-b enzyl)-ethane -1,2-diamine) Compound 43 is a method similar to that of Example 16. Prepared. LC/MS (M + +1 ): 609. Example 44: Preparation of compound 44: 6-(5-{4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino)-methyl]- Benzylaminodibenzo-di-yloxy)-pyridine-2-carboxylic acid methyl ester (6-(5-{4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]) -ethyl}-ami no)-methyl]-benzylamino}-pyridin-2-yloxy)-pyridine-2-ca rboxylie acid methyl ester) Compound 44 was obtained by a method similar to that of Example 16. LC/MS (M + + 1 ): 63 3. Example 4-5: Preparation of Compound 45 ···N-(4-{[6-(5-Gas-pyridin-2-yloxy)-pyridin-3-ylamino]-fluorenyl}-phenylhydrazine )-N'-Acridine-2-ylindenyl-N-{2-[(pyridine-2-ylindenyl)-amino]-ethyl}-ethane-u-diamine (N-( 4-{[6-(5-chloro-pyridin-2-yloxy)-pyridin-3-ylamino]-methyl }-benzyl)-N,-pyridin-2-ylmethyl-N-{ 2 -[(pyridin-2 -y lmethyl)-aminoethyl}-ethane-1,2-diamine) Compound 4 5 was obtained by a method similar to that of Example 16. LC/MS (M + +1 ): 609. Example 46: Preparation of compound 46: N-pyridin-2-ylindenyl 54 200817365 -Ν,-{2-[(σ-pyridyl-2-ylmethyl)-amino]-ethyl}-Nf-( 4-{[6-(Acridine-2-yloxy)-acridin-3-ylamino]-methyl}-benzyl)-ethane-1,2-diamine (N-pyridin- 2-ylmethyl-N,-{2-[(pyridin-2-ylmethyl)-amino] -ethyl}-N,-(4-{[6-(pyridin-2-yloxy)-pyridin-3-ylamino]- m ethyl}-benzyl)-ethane-l?2-diamine) Compound 4 6 was obtained by a method similar to that of Example 16. LC/MS (M + +1 ): 575.

Example 47: Preparation of compound 47: Ν-(4-{[(1Η-benzimidazolyl-2-ylmethyl)-amino]-indolyl}-benzyl)-Nf-(4-a-phenylene Methyl)-N-[2-(4-fluoroi-phenylhydrazino)-ethyl]-ethene-1,2-diamine (N-(4-{[(lH-benzoimidazol-2-ylmethyl)) )-amino]-methyl}-b enzyl)-Nf-(4-fluoro-benzyl)-N - [2-(4-fluoro-benzyl amino)-ethyl]- ethane -1,2-diamine) Compound 4 7 Prepared by a method similar to that of Example 16. LC/MS (M + + 1): 5 69. Example 48: Preparation of compound 48: 6-{5-[4-({bis-[2-(4-fluoro-benzoguanidino)-ethyl]-amino}-methyl)-benzylamino) ]-yloxy}_pyridine-2-carboxylic acid methyl ester (6-{5-[4-({bis-[2-(4-fluoro-benzylamino)-ethyl]-amino}-m ethyl)-benzylamino ]-pyridin-2-yloxy}- pyridine-2-carboxy ic acid methyl ester) 55 200817365 The compound 4 8 was obtained by a method similar to that of Example 16. LC/MS (M + +1 ): 667. Example 49: Preparation of Compound 49 ···N-Pyridin-2-ylindenyl-N,-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-oxime,-[ 4-(1,4,8,11 tetraazacyclotetradecyl)-benzoinyl]-ethane-I,2-diamine

(N-pyridin-2-ylmethyl-Nr-{2-[(pyridin-2-ylmethyl)-amino] -ethyl}-N,-[4-(l,4,8,1Itetraaza-cyclotetradec - 1-ylmethyl) -benzyl]- ethane -1,2-diamine) 60, potassium carbonate (0. 05 mol) was added to the tri-Boc containing tri-Boc-protected 1,4,8, 11-tetracyclic ring -protected cyclam) (O.Olmole) and 1,4 dibromomethylbenzene (0.01 mol) in CH3CN solution. After 12 hours of scrambling the reactant, tri-Boc-protected bromomethylbenzyl cyclam (0.007 mol) was obtained, followed by tri-Boc-protected bromomethylbenzene (0,7 mol). Bis(2-pyridyliminoethylamine) (0.01 mole) in methyl cyanide (100 mL) containing potassium carbonate (0.05 mol) at 60 °C Carry out the reaction. After stirring for 12 hours, the reaction was filtered and concentrated. At 2 5 . Sterol (50 mL) and sodium borohydride (NaBH4) (0. 〇 3 m〇i) were added sequentially to C, followed by stirring for 2 hours. This solution was separated in ethyl acetate (EtOAc) and water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give residue. This residue was treated with hydrochloric acid/ether and purified using EtOAc EtOAc (EtOAc: EtOAc (EtOAc) LC/MS (M + + 1 ): 5 8 8.

Example 50: Preparation of Compound 50: 4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino)-methyl]-N,N-double- {2-[(〇比 bit-2-ylindenyl)·amino]-ethyl}- benzenesulfonamide (4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-) Ethyl}-amino)-m ethyl]- N,N-bis-{ 2 -[(pyridin-2-ylmethyl)-amino]- ethyl}- be nzene sulfonamide) at 60 ° C, with double (2-3) -Butoxycarbonylamine ethyl)amine (〇·〇2 mol) Treatment of bromomethylbenzenesulfonyl chloride (0.01) in a solution containing potassium carbonate in decyl cyanide (CH3CN) (100 mL) Mol). After stirring for 12 hours, the solution was filtered and concentrated to give a residue which was neutralized with hydrochloric acid/ether to give a polyamine. This polyamine is treated with pyridine-2-carbaldehyde to give a Schiff base. The Schiff base is reduced by the action of sodium borohydride (NaBH4) in methanol. The original product thus obtained was purified by an alumina column chromatography (ethyl acetate / methanol = 1 : 1) to give compound 50. LC/MS (M + + 1): 723. EXAMPLES Preparation of Compound 51 ·· 4-({bis-[2-(3,4-dichloro-benzylamino)-ethyl]-aminophenylindolyl σ-pyridin-2-ylindenyl-benzenesulfonate Amine (4-({ bis -[2-(354-dichloro-benzylamino)-ethyl]-amino}- met 57 200817365 hyl)-N-pyridin-2-ylmethyl-benzene sulfonamide) ' 4-bromodecylbenzene Sulfonium chloride (0.01 m〇l) and 2-aminomethyl pyridine (0.101 mol) were dissolved in ether (100 mL) containing triethylamine (Et3N) (0.02 mol). After stirring at 25 ° (5 °', the solution was rinsed with water 'The obtained product bromosulfamide (0.01 mol) at 60 ° C in a potassium carbonate containing potassium cyanide (CHbCNK100 mL) The solution was treated with bis(2-tris-butoxycarbonylamine ethyl) €)amine (〇·〇1 mol). After stirring for 12 hours, the reaction mixture was passed and concentrated to give a residue. The residue is treated with ether, and a polyamine is obtained after neutralization. The polyamine is treated with 3,4-dichlorobenzaldehyde to obtain a Schiff base. Schiff base acts by sodium borohydride (NaBH4) in furfuryl alcohol. And reduction. The obtained raw product was analyzed by alumina column chromatography. (Ethyl acetate / decyl alcohol = 6:4) was purified to give compound 5 1. LC/MS (M + + l): 680. 〇m... 5 2: Preparation of compound 52: 4- ({double-[ 2-(3,4-Difluoro-benzyl-aminoethyl)-moon-female}-mercapto)-Ν-σί4»Phen-2-ylmethyl-benzophenone A (4-({ Bis-[2-(354-difluoro-benzylamino)-ethyl]-amino}-methyl)-N-pyridin-2-ylmethyl-benzenesulfonamide) Compound 5 2 was obtained by a method similar to that of Example 51. /MS (M + + 1) : 6 1 6. Real-cover Example 53: Preparation of compound 53: 4-({bis-[2-(4-fluoro-benzylamine)_ 58 200817365 ethyl]-amino} -Methyl)-N-»bis-[2-(4-fluoro-benzylamino)-ethyl]-amino}-methyl)-N- Pyridin-2-ylmethyl-benzenesulfonamide) Compound 5 3 was obtained by a method similar to that of Example 51. LC/MS (M + + 1 ): 5 80 〇 Example 5 4: Preparation of compound 54: 4-({bis-[2-(4-chloro-benzylamine)-ethyl]-amino}- -(-bis-[2-(4-chloro-benzylamino)-ethyl]-amino}-methyl)-N-pyridin- 2-ylmethyl-benzenesulfonamide) Compound 5 4 was obtained by a method similar to that of Example 51. LC/MS (M + +1): 612. Example 5 5: Preparation of Compound 55: 4-({bis-[2-(2-Gas-benzylamine)-ethyl]-amino}-indenyl)-indole-σΛσ-decyl-2-ylindenyl - 4-({bis-[2-(2-chl〇ro-benzylamino)-ethyl]-amino}-methyl)-N-pyridin-2-ylmethyl-benzenesulfonamide) Prepared by the method of Example 5 1. LC/MS (M + +1): 612. _盖羞__6: Preparation of compound 56: Ν·[4-(6-methoxy-1,3,4,9-tetrahydro-b-carboline-2-ylindenyl)-benzyl ]-Nf-. Bipyridine-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethylethane-i,2-diamine 59

200817365 (N-[4-(6-methoxy-l?354?9-tetrahydro-b-carbolin-2-ylmethy l)-benzyl]-N,-pyridin-2-ylmethyl-N-{2-[(pyridin Benzyl chloride (CH2C12) (50 mL) In solution, 1,4-dibromoxylene (13.64 mmol) was treated with bis(/eri-butoxyaminoethylamine) (2.7 4 mmol). After stirring for 16 hours, the solution was filtered, concentrated and purified to give a mono-substituted-bromo compound (m ο η 〇 - s u b s t i t u t e d bromide). The mono-substituted-bromide (〇·68 mmol) and 6-decyloxy-1 were reacted in a solution of potassium carbonate (3.39 mmol) in methyl cyanide (CH3CN) (10 mL) at 60 ° , 253,4-tetrahydro-9Η-σ than 哆[3,4-1^]吲〇(6-methoxy-l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (0. 6 8 mmol) was carried out. After stirring for 12 hours, the solution was filtered, and the filtrate was concentrated and purified by chromatography to give a Boc-protected residue (0.57 mmol; 84% yield). This residue (0.26 mmol) was treated with hydrochloric acid/ether and then neutralized to give a polyamine. The polyamine is treated with pyridine-2-formaldehyde to give a Schiff base. The Schiff base is reduced by the action of sodium borohydride (NaBH4) in methanol. The obtained crude product was purified by an alumina column chromatography (ethyl acetate/methanol = 7:3) to give Compounds. LC/MS (M + + 1 ): 5 90. Example 57: Preparation of compound 5 7 : N-pyridin-2-ylmethyl 60 200817365 -Nf-{2-[(pyridin-2-ylindenyl)-amino]-ethyl}-Ν'-[ 4-(1,3,4,9-tetrahydro•-b-carboline-2-ylmethyl)-benzyl]-ethane-1,2-diamine-(N-pyridin-2-ylmethyl -Nf-{2-[(pyridin-2-ylmethyl)-amino] -ethyl}-N'-[4-(l,3,4,9-tetrahydro-b-carbolin-2-ylmethyl)-benzyl]- Ethane -1,2-diamine) • Compound 5 7 was prepared in a similar manner to that of Example 5-6. , LC/MS (M + +1) ·· 560. 〇Example 5 8 : Preparation of compound 58 ··Isonicotinic acid {4-[(bis-{2-[(pyridin-2-ylindenyl)-amino]-ethyl}-amino)-anthracene Isoicotinic acid {4-[(bis -{ 2-[(pyridin-2-ylme thyl)-amino]-ethyl}-am ino)«m ethyl]- benzylidene}- Hydrazide) Bis(2-/Lerr-butoxycarbonylaminoethyl) amine (〇.〇1 mol), Ο 4-cyanobenzylidene (〇.〇) 1 mol) and potassium carbonate (〇·〇5 mol) were added to decyl cyanide (CH3CN) (70 mL), and heated at 60 ° C for 10 hours. The product (bis(2-rer/-butoxycarbonylaminoethyl)amin〇.4-methylphen ylcyanide) is deprotected with hydrochloric acid/ether in methanol In the middle of the pyridine bite _2_ benzoquinone (0 · 0 2 m ο 1 ). After treatment with sodium hydride, di-tertiary-dicarbonate, and isobutyl butyl (DIBAL), the product is double (2_substituted _aminoethyl)amino-4-mercapto Jun · 61 200817365 (bis(2-substituted-aminoethyl)amino-4-methylbenzaldehyd e) and isoicotinic acid hydrazide are concentrated to obtain - Schiff base. The Schiff base was treated with hydrochloric acid/ether. The obtained crude product was purified by an alumina column chromatography (ethyl acetate / methanol = 7:3) to give compound 58. • LC/MS (M + + 1 ): 523. Example 59: Preparation of compound 59: thiophene-2-carboxylic acid {4·[(bis-{2·[(σΑσ定-2-ylmethyl)-amino]-ethyl}-amino)-A Thiophene-2-carboxylie acid {4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino)-m ethyl]- Benzidide}-hydrazide) Compound 5 9 was prepared by a method similar to that of Example 58. LC/MS (M + + 1): 528. Q Example 60: Preparation of compound 60: 1-[bis[(2-(2-pyridinyl)amine)ethyl]]amino-methyl]-4-[2-(3-吲哚)-1 -((5)-hydroxydecyl)ethylaminomethyl] benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[2-(3-indol)-l -((5)-hydroxymethyl)ethylaminomethyl]be nzene) 'Compound 60 was prepared in a similar manner to Example 1 6 (yield: 80%). 62 200817365 LC-MS (C35H43N70.7HC1) (M + +1 -7HC1) : 5 7 8. Example 6 1 • Preparation of Compound 61: 1-[bis[(2-(2-pyridyl-2-ethyl)amineethyl)]amino-indenyl]-4-[2-(3·吲哚)-1-((5)-hydroxyindenyl)ethylamine benzyl] benzene (l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)] amino-methyl ]-4-[2 -(3-indol)-1-((5)-hydroxymethyl) ethylaminomethyl] benzene) Compound 6 1 was obtained by a method similar to that of Example 1 6 (yield: 80%) 〇LC-MS (C35H43N70.7HC1) ) (M + +1 -7HC1) : 606.

Example 62: Preparation of compound 62: 1-[bis[(2-(2-pyridinyl)aminoethyl)]amino-indenyl]-[4-(phenylhydroxyindoleyl)ethylamine hydrazine Benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[2-(phenyl)-l-((i?)-hydroxymethyl)ethylaminomethyl]be nzene) The title 62 was obtained by a method similar to that of Example 1 6 (yield: 81%). LC-MS (C33H42N60.6HC1) (M + +1 -6HC1) : 53 9 . Example 63: Preparation of compound 63: 1-[bis[(2-(2-pyridylmethyl)amineethyl)]amino-methyl]-4-[2-(phenyl)-1-((5) )-hydroxyindole)ethylaminemethyl]benzene 63 200817365 (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]- 4-[2-(phenyl)-l-((iS ,)-hydroxymethyl)ethylaminomethyl]ben zene) Compound 6 3 was obtained by a method similar to that of Example 1 6 (yield: 85%) </ RTI> </ RTI> LC-MS (C33H42N60.6HC1) (M + +1-6HC1): 539.

Example 64: Preparation of compound 64: 1-[bis[(2-(2-pyridylmethyl)amineethyl)]amino-methyl]-4-[2-(3-吲哚)-l-( (i?)-Hydroxymethyl)ethylaminomethyl] benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]- 4-[2-(3-indol)-l- ((i?)-hydroxymethyl)ethylaminomethyl]be nzene) Compound 64 was obtained by a method similar to that of Example 1 6 (yield: 78%). LC-MS (C35H43N70.7HC1) (M + +1-7HC1) ·· 578. Example 65: Preparation of compound 65: 1-[bis[(2-(2-pyridyl-2-ethyl)amineethyl)]amino-indenyl]-4-[(l,2,3,4 -tetrahydro-9//-. than 哆-6-decyloxy[3,4-6]indol-2-yl)benzene (l-[bis[(2-(2-pyridinyl-2-ethyl) )aminoethyl)]amino-methyl ]-4-[(l,2,3,4_tetrahydro-9ii -pyrido-6-methoxy[3,4-&amp;]indol -2-methyl)benzene] 64 200817365 Compound 6 5 Prepared by a method similar to that of Example 5 6. LC/MS (M + +1): 618 〇 Example 66: Preparation of compound 66: 1-[bis[(2·(2-pyridylmethyl)amine] Ethyl)]aminomethyl]-4-[(1,2,3,4-tetrahydropyridin-6-benzyloxy. [3,4-6] fluoren-2-methyl) benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[(l?2?3?4-tetrahydro-9i7-pyrido-6-benzyloxy[3?4-6] Indol -2-methyl) benzene] Compound 6 6 was obtained by a method similar to that of Example 5 6 LC/MS (M + +1 ) : 666. Example 67: Preparation of compound 67 ·· 1-[double [ (2-(2-Pyridylmethyl)amineethyl)]amino-sulfonyl]-4-(l,2,3,4-tetrahydro-9 ugly-吼哆-6-methoxy[3 , 4-0] 吲哚-2- 曱 base) () (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-sulfonyl ^ ]-4-(l,2,3,4-tetrahydro-9//-pyrido-6-methoxy[3, 4-6]indol-2-ethyl)benzene) Bis(2-terr-butoxycarbonylaminoethylamine) (3.03 g, 0.01 mol) is added to contain 1- &gt;l-bromomethylbenzene-4-sulfonyl chloride (2.6 8 g, 0.01 mol), dichlorodecane (CH2C12) (160 mL) and triethylamine (Et3N) (1.01 65 200817365 g, 0.01 mol) in solution, in hydrazine. 〇: Stir for 2.5 hours. The solvent is then evaporated and the residue is dissolved in methyl cyanide (CH3CN) (180 mL), potassium carbonate (4.14 g5 0.03 mol) and 1,2,3,4-tetrahydro-9//·σΛ 哆-6 - methoxy[3,4-6] 吲哚

(1,2,3,4-tetrahydro-9i/-pyrido-6-methoxy[3,4-6]indole) (1.72 g, 0.01 mol) was stirred at 60 ° C for further 10 hours. Then, the mixture was filtered, concentrated, and treated with a mixture of dichloromethane (EtOAc) (EtOAc) (EtOAc) The reaction was concentrated and stirred with anhydrous EtOAc (EtOAc &lt;RTI ID=0.0&gt;0&gt; The obtained mixture was filtered and concentrated to give the intermediate product 1,1-[bis[(2-aminoethyl)]aminesulfonyl]_4-[(1,2,3,4 -4) in 60% yield. Hydrogen-9 ugly-pyridin-6-methoxy[3,4-6]indole-2-methyl)benzene (1, l-[bis[(2-aminoethyl)]aminosulfonyl]-4-[( l?293,4-tetrahyd r 〇- 9/f-py ri do - 6-methoxy[3,4-i?]indol-2-methyl)benzene] (2.56 g, 0.006 mol) followed by methanol (MeOH The intermediate product was treated with pyridine-2-carboxaldehyde (1.50 g, 0.014 mol) in (40 mL) for 14 hours, followed by sodium borohydride (NaBH4) (1.60 g, 0.04) 2 mol) treatment for 4 hours to obtain intermediate product 2. Intermediate 2 was purified by column chromatography (ethyl acetate / methanol = 7:3) (3·19 g, 0.005 mol, 83% yield) Then, it is treated with hydrochloric acid/ether (125 mL) in di-methane (CH2C12) (50 mL) to give Compound 67. LC-MS (C35H41N7 〇3S.6HCl) (M + +1-6HC1) : 640 66 200817365 Example 6 8 • Preparation of compound 68: Ν-[4·(6-decyloxy-1,3,4,9-tetrahydro-b-flavor-2-ylindenyl)-benzamide Base]-Ν'-t bit-2-ylmethyl -Ν·{2-[(&quot;Bipyridin-2-ylmethyl)-2-hydroxyethylamino]-ethyl}-ethane-1,2-diamine compound 6 8 by compound 5 6 Prepared by selective alkylation (yield: 40%).

LC-MS (C38H47N7 〇 2.7 HCl) (M + +1 -7HC1): 634. Example 6 9: Preparation of compound 69: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-indenyl]-4-[2-(phenyl)-l-(( I〇·hydroxycarbonyl)ethylaminemethyl]benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[2-(phenyl)-l-((i?) -hydroxycarbonyl)ethylaminomethyl]b enzene) Compound 69 was obtained by a method similar to that of Example 1 6 (yield: 70%) 〇LC-MS (C33H40N6 〇2.6HC1) (M + +1-6HC1) : 5 5 3. Example 70: Preparation of compound 70: 1-[bis[(2-(2-pyridinyl)aminoethyl)]amino-methyl]-4-[2-(3-(5-) 〇|〇多)--------------------------------- -l-((i?)-hydroxycarbonyl)ethylam 67 200817365 inomethyl)benzene) Compound 70 was prepared by a method similar to that of Example 1 6 (yield: 75%) 〇LC-MS (C35H41N703.7HC1) (M + +1 -7HC1) ·· 608. • Example 7 1 : Preparation of compound 71 : 1-[bis[(2-(2-pyridylmethyl)amine)ethyl]]amino-methyl]- 4-[2-(3-(7-methyloxime))ethylamine hydrazino]phenylhydrazine (l-[bis[(2-(2-pyrid) Inylmethyl)aminoethyl)]amino-methyl]- 4-[2-(3-(7-methylindol)ethylaminomethyl]benzene) Compound 7 1 was obtained by a method similar to that of Example 1 6 (yield: 70%) 〇LC-MS (C37H47N7.7HC1) (M + +1 -7HC1): 590. Example 72: Preparation of compound 72 ·· 1-[bis[(2-(2-pyridyl-2-ethyl)amine) Amino-methyl]-4-[2-(3-chlorophenyl)ethylaminemethyl]benzene (^(l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)) ]amino-methyl.]-4-[2-(3- chlorophenyl)ethylaminomethyl] benzene) Compound 72 was obtained by a method similar to that of Example 16 (yield: 80%). LC-MS (C34H43C1N6.6HC1) (M + +1 -6HC1): 571. Example 73: Preparation of compound 73: 1-[bis[(2-(2-pyridinyl-2-ethyl)amino)]amino-indenyl]-4-{[(1H-benzo) Imidazol-2-ylmethyl)amine 68 200817365 benzyl]-methyl} benzene (l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)] amino-methyl • ]-4-{[ (lH-benzoimidazol-2-ylmethyl)-amino]-methyl }benz ene) 'Compound 7 3 was obtained by a method similar to that of Example 1 6 (yield: 84%). An LC-MS (C34H42N8.7HC1) (M + +1 -6HC1): 5 63. Example 74: Preparation of compound 74: 1-[bis[(2-(2.pyridinyl)aminoethyl)]amino-indenyl]-4-[(2-phenyl-2-yl)- 1-methoxy]ethylamine benzyl] 1-(bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[(2-phenyl-2-hydroxy-l-methoxymethyl (ethylaminometh yl]benzene) Compound 74 was obtained in a similar manner to that of Example 16 (yield: ί) 71%). • LC-MS (C34H44N6 02.6HC1) (Μ + +1 -6HC1): 569. Example 7 5: Preparation of compound 75: 1-[bis[(2-(2-pyridinyl)aminoethyl)]amino-methyl]-4-[(2-(4-phenylphenyl)- 1-Hydroxy)ethylamine benzyl] 1-(bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[(2-(4-chlorophenyl)-l-hydroxymethyl) Ethylaminomethy 69 200817365 l]benzene) Compound 75 was obtained in a similar manner to that of Example 16 (yield: 70%) 〇LC-MS (C33H41C1N60.6HC1) (M + +1 -6HC1): 573. * Example 76: Preparation of compound 76: 1-[bis[(2-(2•pyridinyl)amine-ethyl)]amino]indolyl]-4-[(2-phenyl-phenyl---) And) _ via methyl) ethyl p-aminomethyl] benzene (1 - [bis [(2-(2-pyridinylmethyl) amino ethyl)] amino-methyl]-4-[(2-phenyl-(2i?)- Hydroxy-(li2)-hydroxymethyl)ethylamin omethyl] benzene) Compound 7 6 was prepared by a method similar to that of Example 1 6 (yield: 68%) 〇LC-MS (C33H42N602.6HC1) (M + +1- 6HC1) : 555. I) Example 77: Preparation of compound 77: 1-[bis[(2-(2-pyridylmethyl)amine•ethyl]&gt;]amino-methylbu 4-[(2-phenyl-(2S) -hydroxy-(1*5)-hydroxymethyl)ethylamine/methyl]benzene (1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]]-amino]methyl]-4-[(2-phenyl-) (2iS,)-hydroxy-(lS,)-hydroxymethyl)ethylamin omethyl] benzene) Compound 77 was obtained by a method similar to that of Example 16 (yield: 70%) 〇70 200817365 LC-MS (C33H42N602.6HC1) (M + +1-6HC1): 555. Example 78: Preparation of compound 78: 1-[bis[(2-(2-pyridinyl)aminoethyl)]amino-methyl]-4-[2 -(4-bromophenyl)-1-((phantom-hydroxycarbonyl)ethylaminemethyl]benzene (1- [bis [(2-(2-pyridinylmethyl)aminoethyl)] amino-methyl]-4-[2 -(4-bromophenyl)-l-((i?)-hydroxycarbonyl)ethylaminomethyl]benzene) Compound 78 was prepared in a similar manner to Example 16 (yield: 77%) 〇LC-MS (C33H39BrN602.6HCl) (M + +1 -6HC1): 631. Example 79: Preparation of compound 79: 2-({4,-[(bis-{2-[(pyridin-2-ylindenyl)-amino]-) }--amino)-methyl]-biphenyl-4-ylindolyl-2-pyridinium-2 Alkyl)-3 - phenyl·&quot;propanol·1 - alcohol (2-({4f-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amin o )-methyl]-biphenyl-4-ylmethyl}-pyridin-2-ylmethyl-amin 〇)-3-phenyl-propan-1-ο 1) Compound 79 was prepared by a method similar to that of Example 16 (yield· 70%) 〇LC-MS (C45H51N70.7HC1) (M + +1-7HC1): 706. Example 80: Preparation of compound 80: N-pyridin-2-ylmethyl 71 200817365 -N'-{2- [(吼唆-2-ylindenyl)_amine-aminoethyl N,/[4 (6-chloro-1,3,4,9-tetrahydro-1)-indolyl-2-ylmethyl)- Phenyl]-ethidin-1,2-diamine (N-pyridin-2-ylmethyl.N^{2-[(pyridin-2-ylmethyl)-amino] -ethyl}-N -[4-(6- Chloro-l,3,4,9-tetrahydro-b-carbolin-2-yl methyl)-benzyl]-ethane-1,2-diamine) Compound 80 was obtained by a procedure similar to that of Example 56. • LC_MS (C35H40C1N7.7HC1) (M + +1 -7HC1) : 594 〇〇Example.g..i.: Preparation of Compound 81:&gt; 1-[4-({ethyl-[2-(7- Mercapto-1H-indol-3-yl)-ethyl]-aminomethylmethylbenzyl]-N,-pyridin-2-ylindenyl-N_{2-[(pyridin-2-ylindole) ()-amino]-ethyl}-ethane-i,2-diamine (N-[4-({ethyl-[2-(7-methyl-lH-indol-3-yl)-ethyl]- Amino}-methyl)-benzyl]-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2-y lmethyl)-amino]-ethyl} - ethane -152-diamine) Prepared in a similar manner to Example 5 6. LC-MS (C37H47N7.7HC1) (M + +1 -7HC1): 590 〇 实施 Example 82: Preparation of compound 82: N-[4-({[2-( 3-Chloro-phenyl)-ethyl]•ethyl-aminopyridylmethyl)-benzoinyl]--acridin-2-ylindenyl-{2-[(pyridin-2-ylmethyl)-amine -ethyl}-ethane-1,2-diamine (Ν-[4 -({[2 -(3- chloro- phenyl)- ethyl]- ethyl -amino}- methyl) -benzyl]-Nf -pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)_amino]-ethyl}-ethane-1,2-diamine) 72 200817365 Compound 82 was prepared in a similar manner to Example 56. LC-MS (C34H43C1N6.6HC1) (M + +1-6HC1): 571. Example 83 • Preparation of compound 83: 1-[bis[(2-(2-pyridinyl)aminoethyl)]amino-indenyl]-4-[(2S) -hydroxymethylpyrrolidinoyl]benzene' (1-[bis[(2 -(2-pyridinylmethyl) ami no ethyl)]]]]]]]]]]]]]]]]]]]] Benzene (1 compound 83 was obtained by a method similar to that of Example 56 (yield: 80%) 〇LC-MS (C29H40N6O.6HCl) (M + + 1 -6HC1): 489. Example 84: Preparation of compound 84: 1-[bis[(2-(2-pyridylmethyl)amineethyl)]amino]indolyl]-4-[(2i?)-hydroxydecylpyrrolidinyl 1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[(2i?)-hydroxymethylpyrrolidine-iV-methyl]benzene) 〇Compound 84 is similar to Example 56 Prepared by the method (yield: '80%) 〇• LC-MS (C29H4〇N6〇.6HC1) (M + +l-6HC1): 489 〇 Example 85: Preparation of Compound 85: 2·( {4 ,-[(bis-{2-[(pyridin-2-ylindenyl)-amino]•ethyl}-amino)-indenyl]&quot;biphenyl-4-ylindenyl}-aminobenzene Base-propanone-1 - drunk (2-((41-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amin 73 200817365 o)-methyl]-biphenyl-4- Ylmethyl}-amino)-3-phenyl-propan-*l-ol). Compound 85 was prepared in a similar manner to that of Example 16. LC-MS (C39H46N60.6HC1) (M + +1 -6HC1) : 615 • Example 86: Preparation of compound 86: N-pyridin-2-ylmethyl-N,-{2-[(pyridin-2-ylindenyl)-amino]-ethyl}-Nf-[4- (6-fluorof)-1,3,4,9-tetrahydro-b-carboline-2-ylmethyl)-benzoinyl]-ethane-1,2-di (N-pyridin-2-ylmethyl-N,-{2-[(pyridin-2-ylmethyl)-amino] ethyl }_Ν· -[4-(6-fluoro-l,3,4,9-tetrahydro-b -carbolin-2-yl methy 1)-benzyl]-ethane-1,2-diamine) Compound 86 was prepared in a similar manner to Example 56. LC-MS (C35H40FN7.7HC1) (M + +1 -7HC1) : 578 〇 Example 87: Preparation of compound 87 : 1·[bis[(2_(2·pyridinemethyl)aminoethyl)]amino-indenyl]-4-[2-(5-chloro-6-) Hydroxyphenyl-1-hydroxycarbonyl)ethylamine

Benzene (1-[bis[(2-(2- pyridinylmethyl)amino ethyl)] ami no-methyl]-4-[2-(5-chloro-6-hydroxyphenyl-l-hydroxycarbonyl)ethyla minomethyl] benzene) Compound 87 was obtained by a method similar to that of Example 16 (yield: 76%) 〇LC-MS (C33H39C1N603.6HC1) (M + +1-6HC1): 603. 74 200817365 Example 8 8 : Preparation of compound 88 ·· 1-[bis[(2-(2-pyridinyl)aminoethyl)]amino-methyl]-4-[(2-thiophene-1-hydroxyl) Carbonyl)ethylaminomethyl]benzene (1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]]-amino]]-[(2-thiophene-l-hydroxycarbonyl)ethylaminomethyl]ben zene) Prepared by a method similar to that of Example 16 (yield: 70%) 〇LC-MS (C31H38C1N602S.6HC1) (M + +1 -6HC1): 559. Example 89: Preparation of compound 89: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-methyl]-4-{[2-(4-chlorophenyl)-2 -cyclopropyl]ethylamine methyl} benzene (1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]]-amino]-4-{[2-(4-chlorophenyl)-2-cyclopropyl] Ethylaminomethyl}benzene) Compound 89 was obtained by a method similar to that of Example 16 (yield: 78%) 〇LC-MS (C34H41C1N6.6HC1) (M + +1 -6HC1) ·· 569. Example 90: Preparation of compound 90: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-methyl]-4-{[2-(3-chloro-6-methoxy) Phenyl)]ethylaminomethyl}benzene (1-[bis[(2-(2-pyidinylmethyl)aminoethyl)]amino-methyl]- 75 200817365 4-{[2-(3-chloro-6-methoxyphenyl)] Ethylaminomethyl}benz ene) Compound 90 was obtained in a similar manner to that of Example 16 (yield: 80%), LC-MS (C33H41C1N60.6HC1) (M + +1 -6HC1): 573. Example 91: Preparation of compound 91: N-pyridin-2-yl-2-ethyl-:^-{2-[(acridin-2-ylindenyl)-amino]-ethyl}-:^- [4-(6-Methoxy-1,3,4,9-tetrahydro-b-oxalin-2-ylmethyl)-benzoinyl]-ethane-1,2-diamine (N- Pyridin-2-yl-2-ethyl-N,-{2-[(pyridin-2-ylmethyl)-amin o]- ethyl}- Nf -[4-(6-methoxy -1 ?354?9-tetrahydro- B-carbolin-2-ylmethyl)-benzyl]- ethane -1,2-diamine) Compound 9 1 was obtained by a method similar to that of Example 56 (yield: 65%) 〇LC-MS (C37H45N70.7HC1) (M.+ 1-7HC1) : 604. Example 92: Preparation of compound 92: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-indenyl]-4-[(2-thiophene-2-hydroxycarbonyl)ethylamine Benzene (1 - [bis [(2-(2-pyridinylmethyl)aminoethyl)] amino-methy 1]-4-[(2-thiophene-2-hydroxycarbonyl)ethylaminomethyl]ben zene) Prepared by the method of Example 1 6 (yield: 8 5%) 〇76 200817365 LC-MS (C31H38N602S.6HC1) (M + +1 -6HC1): 559. Example 93: Preparation of compound 93: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-indenyl]-4-[3-methyl-(5)-1, 2,3,4-tetrahydroisoindole-iV-ylindenyl] benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[3-hydroxym ethyl -2 , 3,4-tetrahydroiso quinoline-ylmethyl] benzene) Compound 93 was prepared by a method similar to that of Example 56. LC-MS (C34H42N60.6HC1) (M + + 1 -6HC1) ·· 551. Example 94: Preparation of compound 94: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-indenyl]-4-(4-hydroxy-4-piperidinylmethyl) Benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-(4-hydroxy-4-phenylpiperidine-iV-ylmethyl)benzene) Compound 94 is similar to Example 56 The method is prepared. LC-MS (C35H44N60.6HC1) (M + +1 -6HC1): 565 〇 Example 95: Preparation of compound 95: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino- Methyl]-4-[4-hydroxy-4-(4-chloropiperidinyl)methyl]benzene (1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]- 4- [4-hydroxy-4-(4-chlorophenylpiperidine)-iVr-ylmethyl]be 77 200817365 nzene) - Compound 95 was obtained by a method similar to that of Example 56. LC-MS (C35H43C1N60.6HC1) (M + +1-6HC1): 599. Example 96: Preparation of compound 96: 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-methylindanylmethyl)benzene (l-[bis[(2) '(2-pyridinylmethyl)aminoethyl)]amino-methyl]-(y 4-(1-indanaminomethyl)benzene) Compound 96 was prepared in a similar manner to that in Example 16. LC-MS (C33H40N6.6HC1) ( M + +1-6HC1): 521. Example 97: Preparation of compound 97: 1-[bis[(2-(2-pyridylmethyl)amineethyl)]amino-indenyl]-4-(3, 4-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-(3,4-dichlorophenylmethylaminomethyl)benzene) Prepared by a method similar to that of Example 1 6 LC-MS (C31H36C12N6.6HC1) (M + +1-6HC1): 563. Example 98: Preparation of compound 98: 1·[bis[(2-(2-pyridine) Methyl)aminoethyl)]amino-mercapto]-4-(3-chlorobenzylaminemethyl)benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]- 4-(3-chlorophenylmethylaminomethyl)benzene) Compound 9 8 was prepared by a method similar to that of Example 16. 78 200817365 LC-MS (C31H37CIN6.6HCI) (M + +1-6HC1) : 52 9 〇 Example 91 = Preparation of compound 99 : 1-[bis[(2-(2-pyridylmethyl)amineethyl)]amino-methyl]-4-[4-hydroxybenzene (hydroxyl-yl) 1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[4-hydroxyphenyl(l-hydroxymethyl)ethylaminomethyl)b enzene] The method of Example 16 was prepared. LC-MS (C33H42N602.6HC1) (M + +1-6HC1): 555. Paste Example 100: Preparation of Compound 100: N-(4-{[2-(7-Methyl-1H-indol-3-yl)-1-(hydroxycarbonylindolyl)ethylamino]-methyl} -Benzyl)-Ν^吼吼-2-ylindenyl)-amino]-ethyl}-ethene-1,2-diamine (N-(4-{[2-(7) -methyl-lH-indol-3-yl)-l-(hydroxycarbonylme thyl)ethylamino] - methyl} - benzyl)-Nf-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl) - amino ]-ethyl}-ethane-l, 2-dia mine) Compound 1 00 was obtained by a method similar to that of Example 16. LC-MS (C37H45N702.6HC1) (M + +1 (6HC1): 620 〇 Example 1 0 1 : Preparation of compound 101 : N-(4-{[2-(7-methyl-1H- 吲哚-3) -yl)-1-(hydroxyethyl)ethylamino]-methylbufenyl)-Nf-pyridine-2- 79 200817365 benzyl-N-{2-[(pyridin-2-yl) Indenyl)-amino]-ethyl}-ethane-1,2-di'amine (N-(4-{[2-(7-methyl-lH-indol-3-yl)-l-(hydroxyethyl) )ethyl amino] - methyl} - benzyl)-N?-pyridin-2-ylmethyl-N-{2-[(pyr • idin-2-ylmethyl)-amino]-ethyl}- ethane -l?2-diamine) Compound 1 0 1 was obtained by a method similar to that of Example 16. 6 LC-MS (C37H47N70.7HC1) (M + +1 (7HC1): 606. 〇 Example 102: Preparation of Compound 102: 1-[Doub [(2-(2-Pyridinyl)aminoethyl)]amino-indenyl]-4-{[2-(3-chloro-4-ethylphenyl)]ethylaminemethyl}benzene (1- [bis [(2-(2-pyridinylmethyl)aminoethyl)] amino-methyl]-4 -{[2-(3- chloro-4-ethylphenyl)]ethylaminomethyl} benzene ) Compound 1 02 is similar to Example 1 6 The method was prepared (yield: 80%) 〇(I LC-MS (C33H41C1N60.6HC1) (M + +1 -6HC1): 573. Example 103: Preparation of Compound 103 ·· N- (4-{[2-(7-Methyl-1H.indol-3-yl)ethylamino]-methyl-p-benzyl)_N*·pyridin-2-ylmethyl-Ν-{2 -[(σ 唆 _ _ _ _ _ ) ) ) ) ) ) ) -1 -1 -1 -1 -1 N N N N N N N N N N N N N N N N N N N 3-yl)ethylamino]-methyl}-b enzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]- ethyl}- propane -1,3-diamine 80 200817365 Compound 1 03 was prepared by a method similar to that of Example 16. LC-MS (C36H45N7.7HC1) (M + +1-7HC1): 576. Example 104: Preparation of Compound 104: N-(4-{[2-(3-Chlorophenyl)ethylamino]methyl-p-benzoyl)-indole--acridin-2-ylmethyl·Ν- {2-[(Acridine-2-ylindenyl)-amino]-ethyl}-propan-1,3-diamine (N-(4-{[2-(3-chlorophenyl)ethylamino) methyl) }-benzyl)-N'-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-et hyl}-propane-1,3-diamine) Compound 1 04 is similarly implemented The method of Example 1 was prepared. LC-MS (C33H41C1N6.6HC1) (M + +1-6HC1) ·· 557 〇 Example 105: Preparation of compound 105: Ν-(4-{[(1Η-benzimidazol-2-yl-indenyl)amine ]]-methyl}-benzyl)-N'-acridin-2-ylindenyl nitr-2-ylmethyl)-amino]-ethyl}-propan-1,3-diamine (N-(4-{[(l H-benzo imi dazo 1-2-yl-methyl) amino] - methyl} - b enzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin -2-ylmethyl)-amino]-ethyl}-propane-1,3-diamine) Compound 1 05 was obtained by a method similar to that of Example 16. LC-MS (C33H40N8.7HC1) (M + +1 -7HC1): 549. Example 106: Preparation of compound 106: N-pyridin-2-yl-hydroxyethyl•&gt;^-{2-[(acridin-2-ylmethyl)-amino]-ethyl}^'-[ 4-(6-decyloxy 81 200817365 -1,3,4,9-tetrahydro-b-carboline-2-ylmethyl)-benzyl]-ethane-1,2-diamine (N -pyridin-2-yl-hydroxyethyl-Nf-{2-[(pyridin-2-ylmethyl)-amino]- ethyl}- Ν' -[4-(6-methoxy-l,3,4,9-tetrahydro- B-car bolin-2-ylmethyl)-benzyl]- ethane -1,2-diamine) Compound 106 was obtained by a method similar to that of Example 56 (yield: 65%) 〇LC-MS (C37H45N702.7HC1) (M + +1-7HC1) : 620. Example 107: Preparation of Compound 107: 1-[Bis[(2·(2·pyridinyl)aminoethyl)]amino-methyl]-4·(2-oxopyrrolidine-indole-methyl Benzene (l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-(2-methoxymethylpyrrolidine-N-methylbenzene) Compound 1 07 was prepared by a method similar to that of Example 5 6 ( Yield: 82%) 〇LC-MS (C30H42N6O.6 HCl) (M + + 1-6HC1): 503. Example 1 0 8 : Preparation of compound 1 〇 8 : N·pyridin-2-yl-hydroxyethyl- N*-{2-[(0-But-2-ylindenyl)-amine]-ethyl}-Ν*-[4-(1-pyridyl-6-decyloxy-1,3,4 , 9_tetrahydro-1&gt;-吟^^yl-mercapto)-phenylhydrazinyl]-ethene-1,2-diamine (N-pyridin-2-yl-hydroxyethyl-N,-{2 -[(pyridin-2-ylmethyl)-amino]-ethyl}-N,-[4-(l-hydroxymethyl-6-methoxy-l?3,4?9-tetrahydro-b-carbolin-2-yl-methyl -benzyl]-ethane-l, 2-di 82 200817365 amine) Compound 1 08 was obtained by a procedure similar to Example 56. LC-MS (C37H45N702.7HC1) (M + +1 -7HC1): 620. Example 109 • Preparation of Compound 109 ···N-Pyridin-2-yl-hydroxyethyl-Ν*-{2·[(σΛ °定-2-ylindenyl)amine ]ethyl}-Nf-[4_(4-phenyl 1,2,3,6-tetrahydropyridine-1-methyl)-benzyl]-ethane·1,2-diamine (N-pyridin -2-yl-hydroxyethyl-N,-{2-[(pyridin-2-ylmethyl)-amino]-ethyl }-Nf-[4-(4-phenyl-l?2,3 ?6-tetrahydropyridine -l- Methyl)-benzyl]- ethane -1,2-diamine) Compound 1 09 was prepared in a similar manner to Example 56. LC-MS (C35H42N6.6HC1) (M + +1 -6HC1) ·· 547. Example 110: Preparation of compound 110: N-pyridin-2-yl-2 -ethyl 11-precipitate-2-yl-ethyl)-amino]-ethyl}-4-(murine thiol)-B -1,2-Amine.SHCUN-pyridind-yU-ethyl-N'-P-Kpyridinj-yl-ethyl )-amino]- ethyl }-4-(cyanobenzyl)-ethane-l,2-diamine .5HC1 ) at 60 ° C, containing bis(2-tris-butoxycarbonylaminoethyl)amine (0.01 mol), 4-cyanobenzyl group A mixture of (4-cyanobenzyl-bromide) (0.01 mol), sodium carbonate (0.05 mol) and methyl cyanide (CH3CN) (7 〇 mL) was heated at 10 hours 83 200817365. The product bis(2-tert-butoxycarbonylamineethyl)amine-4-indolephenyl^^^^^^^^^^ cyanide (bis(2-ieri-butoxycarbonylaminoethyl)amino-) with hydrochloric acid/ether 4-methylphen }^1〇5^111(16) deprotected by 2-ethylindole 0 唆(2-&amp;〇615^1卩)^14(11116)(0.01 mol) in decyl alcohol Concentration, followed by reduction with sodium borohydride. After sequential treatment with pyridine-2-carboxaldehyde, sodium borohydride (NaBH4) and hydrochloric acid, the compound was obtained in 75% overall yield. 1 10 • c \I# c LC-MS (C25H3 〇N6.5HCl) (M + +1-5HC1): 415. Example 111: Preparation of compound 111: N-pyridin-2-yl-2-ethyl ^^-{2-[(orridin-2-ylindolyl)-amino]-ethyl}-^-[4-(111-benzimidazol-2-yl-methyl)-amine fluorenyl Benzoyl]-ethene-1,2-diamine (N-pyridin-2-yl-2-ethyl-N,-{2-[(pyridin-2-ylmethyl)-amin o]-ethyl}- N,-[4-(lH-benzimidazol-2-yl-methyl)-aminometh yl]benzyl)-ethane-1,2-diamine) will contain bis(2-tris-butoxycarbonyl) at 60 °C Bis(2-ier/-butoxycarbonylaminoethyl)amine (0.01 mol), 4-cyanobenzoyl-independent (4-cyan) A mixture of obenzyl-bromide (0.01 mol), carbonic acid unloaded (0.05 mol) and mercapto cyanide (CH3CN) (70 mL) was heated for 10 hours. Deprotect the product bis(2-ier/L-butoxycarbonylaminoethylamino-4-methylphen ylcyanide) with hydrochloric acid/ether to 2 - 2-acetyl pyridine (0.01 84 200817365 mol) was concentrated in methanol, followed by reduction with sodium borohydride. In the order of pyridine-2-carboxaldehyde, NaBKU, di-ieri-butyl dicarbonate and diisobutyl sulphate After the treatment with (diisobutylaluminum), the obtained acid was further concentrated by 2-aminomethylbenzimidazole to obtain a Schiff base. The Schiff base was reduced with sodium borohydride (NaBH4) and deprotected with hydrochloric acid to give compound 111 in 45% overall yield. 〇 LC-MS (C33H40N8.7HC1) (M + +1-7HC1): 549. Example 112: Preparation of Compound 112 ·· 1-[bis[(2-(2-pyridylmethyl)aminoethyl)]amino-indenyl]-4_[4-hydroxy-4-(4-methoxy) 1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]]-amino]]-[4-hydroxy-4-(4-methoxyphenylpiperidine)- 7V-yl-methyl] benzene) () Compound 112 was obtained by a method similar to that of Example 67. LC-MS (C36H46N602.6HC1) (M + +1 -6HC1) ·· 5 95. Paste Example 11 3 : Preparation of Compound 113 : 1-[Bis[(2_(2_pyridinemethyl)aminoethyl)]amino-indenyl]-4-[4-hydroxy-4·(2-oxo) 1-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino-methyl]-4-[4-hydroxy-4-(2-methoxyphenylpiperidine)-7^- Yl-methyl] 85 200817365 benzene) Compound 11 3 was obtained by a method similar to that of Example 5 6. LC-MS (C36H46N6 〇 2.6 HCl) (M + + 1-6HC1): 595. Example 11 4: Preparation Compound 114 : N_(4-{[2-(7-fluorenyl-1H-indol-3-yl)ethylamino]-indenyl}-benzyl)-N'-acridin-2-yl -N-{2-[(acridin-2-ylmethyl)-amino]-ethyl b- 1 -decylethane-1,2-diamine (N-(4-{[2-( 7-methyl-lH-indol-3-yl)ethylamino]-methyl}-b enzyl)-N'-pyridin-2-ylmethyl_N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl} -1 -methylethane-1,2-diamine) Treatment with 2-methyl-2-aminoethanol (0.01 mol) in methanol (MeOH) (20 mL) at 60 °C -Cyanobenzaldehyde (4-cyanobenzaldehyde> (0. 01 mol) for 12 hours. At 0 °C, NaHH4 (1.90 g, 0.05 mol) was added. Into the above solution, the reaction mixture was stirred for another 2 hours at 25 ° C. Then, it was diluted with dichlorohydrazine (CH 2 CI 2 KIOO mL) and an aqueous solution of ammonium chloride (10%, 70 mL). The organic layer was separated, washed with water (1 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give an oily intermediate product. Next, methyl cyanide containing potassium carbonate (〇. 5 mmol) (CH3CN) (30 mL) solution, this oily intermediate and 2-(2-bromo-ethoxy)-tetrahydro-pyran (2-(2-bromo-ethoxy)-tetrahydro-pyran) 0.01 mol) was subjected to shaking. After deprotection, the resulting radical was mesylated, 86 200817365 and reacted with 2-aminomethylpyridine. The resulting secondary amine is then protected with a Boc group. Therefore, the cyanide group is treated with diisobutylaluminum, and the obtained aldehyde is sequentially introduced with 6-mercapto-3-amine ethyl hydrazide (aminoethylindol), sodium borohydride (NaBH4), Treatment with triflic acid and hydrochloric acid gave compound 114 〇 LC-MS (C36H45N7.6HC1) (M + +1 -6HC1): 576 in an overall yield of 60%.

Example 115: Preparation of compound 115: 2-{4-[(bis-{2-[(pyridin-2-ylindenyl)-amino]-ethyl-amino)-methyl]-benzylamine -1-(3-chloro-phenyl)-ethanol (2-{4-[(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino )-methyl]-benzylamino }-l - (3-chloro-phenyl)-ethanol) Compound 11 5 was obtained by a method similar to that of Example 16 (yield: 77%) 〇() LC-MS (M + +1 ) : 5 59 〇 Example 11 6_: Preparation of compound 116: Ν-(4-{[(1Η-benzimidazol-2-&lt;ylmethyl)-amino]-methylbufenyl)-N,-piperidyl Aridin-4-yl-N-{2-bubidin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine (N-(4-{[(lH-) Benzomidazol-2-ylmethyl)-amino]-methyl }-b enzyl)-N,-piperidin-4.yl.N.{2-[(pyridin-2-ylmethyl)-amin o]-ethyl}-ethane-1 , 2-diamine) 87 200817365 Compound 1 1 6 was obtained by a method similar to that of Example 111 (yield: 70%): LC-MS (M + +1): 527. Tube 117: Preparation of Compound 117 : N-(4-{[2-(7-Methyl-1H- • π丨ϋ丨ϋ多-3-yl)-ethylamino]-methyl}-benzyl)-Ν'-(1- σ than bite-2 -yl-ethyl)-Ν-{2-[(pyridyl) Pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine () (N-(4-{[2-(7-methyl-lH-indol-3-yl) )-ethylamino]-methyl}- benzyl)-N,-(l-pyridin-2-yl-ethyl)-N-{2-[(pyridin-2-ylmeth yl)-amino]-ethyl}-ethane-1 , 2-diamine) Compound 11 7 was obtained by a method similar to that of Example 111 (yield: 70%). LC-MS (M + +1) : 576 〇 Example 1 1 8 : Preparation of Compound 118 : Ν 2 -(4-{[(1Η-benzimidazole Ij _2·ylindenyl)-amino]-methyl}-phenylindenyl)-N 1 - ° than 唆-2-ylindenyl-N2-{2 -[(pyridin-2-ylmethyl)-amino]-ethyl}propane-1,2-diamine (N2-(4-{[(lH-benzoimidazol-2-ylmethyl)-amino]-methyl} -benzyl)-Nl-pyridin-2-ylmethyl-N2-{2-[(pyridin-2-ylmethy l)-amino]-ethyl}-propane-1,2-diamine) Compound 1 1 8 series similar examples Prepared by the method of 1 1 4 (yield: 68%). LC-MS (M + +l): 549. 88 200817365 • Example 1 1 9 : Preparation of compound 1 19 : N2-(4-{[2-(3-chloro-phenyl)-, ethylamino]-methyl} • phenylhydrazinyl)-N1-pyridine -2-ylmethyl-Ν2-{2·[(pyridin-2-ylmethyl)-amino]•ethyl}-propanone-1,2 --amine (N2-(4-{[2- (3-chloro-phenyl)-ethylamino]-methyl}- benzyl . )-Nl-pyridin-2-ylmethyl-N2-{2-[(pyridin-2-ylmethyl)-ami no]-ethyl}-propane-1 , 2-diamine) Compound 11 9 was obtained by a method similar to that of Example 11 (yield: 69%) 〇LC-MS (M + +1 ) : 557. Example 1 20: Preparation of compound 120: 1^-ethyl-1^'-(4-{[2-(7-fluorenyl-1H-indol-3-yl)-ethylamino]methyl}- Benzyl)_N-pyridin-2-ylmethyl-N, {2-[(pyridin-2-ylindenyl)-amino]•ethyl}•ethane·1,2-diamine (N- Ethyl-Ν'-(4 -{[2-(7-methy 1 -1 H-indol-3 - y 1)-ethy 1 amino] -〇methyl }-benzyl)-N-pyridin-2-ylmethyl-N ,-{ 2 -[(pyridin-2-y lmethyl)-amino]- ethyl}- ethane -l?2-diamine) After reacting with acetaldehyde and sodium borohydride (NaBHU), compound 120 is similar Prepared by the method of Example 111 (yield: 75%) 〇LC-MS (M + +1): 590 〇 Example 1 2 1 : Preparation of compound 121 : 3-{4-[double-{2-[ (pyridine-2-89 200817365 fluorenyl)-amino]•ethyl}-amino)-methyl]-benzoguanamine-chloro-phenyl)-propanol-1 - alcohol (3-{4- [(bis-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-amino )- methyl]- benzylamino}-! -(3- chloro-phenyl)- propan -1-〇1) Compound 1 2 1 was prepared by a method similar to acetaldehyde Example 16 (yield: 70%) 〇 LC-MS (M + +1 ) : 573 〇 Example 122: Preparation of Compound 12 2: 1-(3-Benzyloxy-phenyl)-3-{4·[(bis-{2-[(.pyridin-2-ylindenyl)-amino]-ethyl}-amino group )-Methyl]-benzylamine}-propane·1-alcohol (1-(3-benzyloxy-phenyl)-3-{4-[(bis-{2-[(pyridin-2-ylmeth yl)-amino ]-ethyl }-amino)-methyl]-benzylamino}-propan - Ιοί) Compound 1 22 was obtained by a method similar to acetaldehyde (1%) (yield: 67%). LC-MS (M + +1) ·· 645 〇 Example 123: Preparation of compound 123: 3-[2-((4-{[2_(7-methyl-111-indol-3-yl)-) Amino]-methyl}benzyl)-{2·[(acridin-2-ylindenyl)-amino]-ethyl-amino)-ethylamino]-3-pyridin-2-yl -propan-1-ol (3-[2-((4-{[2-(7-methyl-lH-indol-3-yl)-ethylamino]-methy 1}- benzyl) -{ 2-[(pyridin -2-ylmethyl)-amino]-ethyl}-amino) 90 200817365 -ethylamino]-3-pyridin-2-yl-propan-l-ol) Compound 1 2 3 was prepared by a method similar to that of Example 1 11 (Yield: 73%) 〇LC-MS (M + +1): 606 〇 Example 124: Preparation of compound 124: 3-[2-((4-{[(1Η·benzimidazol-2-yl) ()-amino]-mercaptopurine methyl)-{2-[(acridin-2-ylmethyl)-amino]-ethyl}-amino)ethylamino]-3 - 17 ratio唆-2 -yl-propan-1-ol (3-[2-((4-{[(1 H-benzoimidazol-2-ylmethyl)-amino] - methyl }-benzyl)-{2 - [(pyri Thy-2-ylm on thy 1)-amino]-ethyl}-amino)-ethylamino]-3-pyri din-2-y 1-propan-1-ol) Compound 124 was prepared in a similar manner to Example 111. (Yield: 60%) · LC-MS (M + +1): 579 〇 Example 12 5: Preparation of compound 125: &gt; 1-(4-{[(111-benzimidazol-2-ylindenyl)-amino]-indolyl phenylmethyl)-N'vnpyridin-2-yl Methyl-N-{2-[(pyridin-2-ylindenyl)-amino]-ethyl}-ethane-1,2-diamine (N-(4-{[(1 H-benzoimidazol-) 2-ylmethyl)-amino] - methyl} -b enzyl)-Nf-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}-ethane-1,2-diamine Compound 1 25 was obtained by a method similar to that of Example 16 (yield: 70%) 〇91 200817365 LC-MS (M + +1) ·· 535 〇 Example 126: Preparation of Compound 126: N-( 4-{[3-(3-Gas-phenyl)-propylamino]-methyl} ~N-methyl)-N1 - 〇bite-2 -ylmethyl-N-{2-[(0 唆· 2 *~ Methyl)-amino]-ethyl}-ethane-1,2-diamine (N-(4- {[ 3-(3- chloro-phenyl)-propylamino]- methyl}- Benzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2-ylmethyl)-amino]-ethyl}- ethane -1,2-diamine) Compound 1 26 is similar to Example 1 6 Prepared by the method (yield: 85%) 〇LC-MS (M + +1): 557 〇 Example 127: Preparation of Compound 127: N-(4-{[2-(3-chloro-phenyl) -

Ethylamino]-methylbufenylpyridin-2-ylindenyl-N-{2-[(acridin-2-ylmethyl)-amino]-ethyl}-ethane-1, 2-Diamine (N-(4 -{[2-(3- chloro-phenyl)-ethylamino]-methyl}- benzyl)-N,-pyridin-2-ylmethyl-N-{2-[(pyridin-2 -ylmethyl)-amino]-ethyl}-ethane-1,2-diamine) Compound 1 27 was obtained by a method similar to that of Example 1 6 (yield: 80%) 〇LC-MS (M + + l) : 543 〇Improvement. Example 1 2 8 : Preparation of compound 128 : (lR, 2S)-2-(4-((double 92 200817365 (2-(pyridin-2-ylindenyl)))) ) hydrazino) phenylamino)-1-phenylpropanone-1,3-diol ((lR,2S)-2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl))) Am ino)methyl)benzylamino)-l-phenylpropane-l53-diol) Compound 128 was obtained by a method similar to that of Example 16 (yield: 6 8%) 〇LC-MS (C33H42N602) (M + +1) : 555 〇 Example 129: Preparation of Compound 129: (lS,2R)-2-(4-((bis(2-(acridin-2-ylindoleamino)-ethyl)amino)methyl)phenylhydrazine Amino,-1-phenylpropane-; i,3, diol ((lS,2R)-2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)am ino)methyl)benzylam Ino)· 1-phenylpropane-1,3-diol) Compound 1 2 9 was obtained by a method similar to that of Example 1 6 (yield: 70%). LC-MS (C33H42N6〇2) (M + +1) : 555 〇 Example 130: Preparation of Compound 130 ·· 2-(4-((bis(2-(pyridin-2-ylindolyl)ethyl)-amino)methyl)phenyl)amino)) -(4-chlorophenyl)propanol (2-(4-((bis(2-(pyridin-2-ylmethylamino)ethyl)-amino)meth yl)benzylamino)-3-(4-chlorophenyl)propan- L-〇l) Compound 1 30 was prepared by a method similar to that of Example 1 6 (yield 93 200817365 rate: 70%) 〇LC-MS (C33H41C1N60) (Μ + +1 ) : 573. Example 1 3 1 : Preparation of Compound 131: (S)-4-(2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino)methyl)benzylamine (3-(4-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amin - o)methyl)benzylamino)-3 -hydroxypropyl)phenol) (Compound 1 3 1 was obtained by a method similar to that of Example 16. 6 LC-MS (C33H42N602) (M + +1 ): 555. Example 1 32: Preparation of Compound 132: 3-( 2-(4-((bis(2-(pyridin-2-ylindolyl)-ethyl)amino)methyl)phenylhydrazinyl)-1-hydroxyethyl)phenol (3-(2-) (4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino)m ethyl) benzyl amino)-1-hydroxy ethyl) phenol) Compound 132 was prepared by a method similar to that of Example 16 (J rate: 70%) 〇; LC-MS (C32H40N6O2) (M + +1) : 541 〇 Example 1 3 3 : Preparation of compound 133: 2-(4-((bis(2-(pyridine-2) Methylamino)-ethyl)amino)mercapto)benzylamino)-1-(3-chlorophenyl)ethanol (2-(4-((bis(2-(pyridin-2-ylmethylamino))) -ethyl)amino)meth yl)benzylamino)-l-(3-chlorophenyl)ethanol) Prepared by the method of Example 1 6 (yield 94 200817365 rate: 73%) 〇LC-MS (C32H39C1N60) (Μ + +1): 559. Example 134: Preparation of compound 134 : 1-(3-(phenylhydrazine) Oxy)phenyl)-2-(4-((bis(2-(acridin-2-ylmethylamino)ethyl)amino)methyl)benzylamino)ethanol (1-(3-) Benzyloxy)phenyl)-2-(4-((bis(2-(pyridin-2-ylmethyl))) eth y 1) am i no) me thy l)benzyl amino) ethanol) Prepared by the method of Example 1 (yield: 67 〇 / 〇) 〇 LC-MS (C39H46N602) (M + +1): 631. Example 1 3 5 : Preparation of Compound 135: 2-(4-((bis(2-(pyridin-2-ylindolyl)-ethyl)amino)methyl)phenyl)amino)-1-( 3-phenoxyphenyl)ethanol

(2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino)meth yl)benzylamino)-1-(3-phenoxy phenyl) ethanol) Compound 135 is a method similar to that of Example 16. Prepared (yield: 67%) 〇LC-MS (C38H44N602) (M + +1): 617. Example 136: Preparation of Compound 136: N 1-(4-((5-Methoxy-1H-benzimidazol-2-yl)decylamino)methyl)phenylhydrazinyl)-indole 2 (Acridine) -2-ylmethyl 95 200817365 yl)-Nl-(2-(pyridin-2-ylmethylamino)-ethyl)ethane-1,2-diamine (Nl-(4-((5-methoxy) -lH-benzo[d]imidazol-2-yl)methylami no)methyl)benzyl)-N2-(pyridin-2-ylmethyl)-Nl-(2-(pyridi n-2-methylmethylamino)-ethyl)ethane -1 , 2-diamine) Compound 136 was obtained by the method of Example 16 (yield: 73%) 〇LC-MS (C33H40N8O) (M + +1) ··566. Example 1 3 7 : Preparation of Compound 137 : (S)-2-(4-((bis(2-(pyridine-2-ylmethylamino)-ethyl)amino)methyl)benzylamino)- 3-(7-methyl-1H-indol-3-yl)propan-1-ol ((S)-2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino)) Methyl)benzylamino)-3-(7-methyl-lH-indol-3-yl)propan-Ιοί) Compound 137 was prepared in a similar manner to Example 16 (yield: 78%) 〇LC-MS (C36H45N70) ) (Μ + +1) ·· 592. Cyanide Example 1 3 8 : Preparation of Compound 138 : (R)-2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino)indolyl)benzamide )-3-( 1H-indol-3-yl)propanone-1 -ol ((R)-2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino) methy l )benzylamino)-3 - (1 H-indol-3 - yl)propan-1 - ol) 96

The compound 1 3 8 was prepared by a method similar to that of Example 1 6 (yield: 78%) 〇 LC-MS (C35H43N70) (M + +1): 578. Implementation of IU 9 : Preparation of Compound 139 ··(S)-2-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino))indolyl)phenylhydrazinyl)- 3-(111-indol-3-yl)propanone·1-alcohol ((S)-2 - (4-((bis(2-(py)))) Methyl)benzylamino)-3 - (1H-indol-3 - yl)propan-1 - 〇l) Compound 1 3 9 was prepared by a method similar to that of Example 1 6 (yield: 80%) 〇LC -MS (C35H43N70) (M + +1) : 578. Example 140: Preparation of Compound 140: Ν1·(4-((2-(7-fluorenyl-1H-indol-3-yl)ethylamino)methyl)phenyl))-pyridyl 2-(pyridine- 2-ylindenyl)-indole 1-(2-(pyridin-2-ylmethylamino)-ethyl)ethane-1,2-diamine (Nl-(4-((2-(7-methyl)) -lH-indol-3-yl)ethylamino)methyl)be nzyl)-N2-(pyridin-2-ylmethyl)-Nl-(2-(pyridin-2-ylmethyla mino)-ethyl) ethane-1,2-diamine Compound 140 was prepared in a similar manner to that of Example 16 (yield: 80%) 〇LC-MS (C35H43N7) (M + +1): 562. 97 200817365 Camp 141: Preparation of Compound 141 : Nl_(4-((2,3-Dihydro-1H-indol-1-ylamino)methyl)phenyl)-N2-(Acridine-2- Methyl)-indole 1-(2-(acridin-2-ylmethylamino)ethyl)ethane-1,2-diamine (Nl-(4-((253-dihydro-lH-inden-l) -ylamino)methyl)benzyl)-N2-(pyridin-2-ylmethyl)-Nl-(2-(pyridin-2-ylmethylamino)ethyl)ethane-1,2-diamine) Compound 141 is a method similar to that of Example 16. Prepared. LC-MS (C33H40N6) (M + +1): 521. Paste Example 142: Preparation of Compound 142: N1-(4-((6-methoxy-3,4-dihydro-lH-α) 哆[3,4-b]吲哚-2(9H)-yl )methyl)benzyl)-N2-(mouthpyridin-2-ylmethyl)-indole 1-(2-(pyridin-2-ylguanidino)-ethyl)ethane-1,2-di Amine (Nl-(4-((6-methoxy-3,4-dihydro -1 H-pyrido[354-b]indol-2( 9H)-yl)methyl)benzyl)-N2-(pyridin-2-ylmethyl) -Nl-(2-(py ridin-2-ylmethylamino)-ethyl)ethane-l,2-diamine) at 0 ° C in dichloromethane containing triethylamine (Et3N) (2.74 mmol) ((:112(:12)(5〇1111〇, 1,4-dibromoxylene (13.64 111111〇1) as bis(iii-butoxyamineethyl)amine (bis(ieri-butoxyaminoethyl)) Treatment with amine) (2.74 mmol). After stirring for 16 hours, the solution was filtered, concentrated and purified to give mono-substituted bromide. At 60 ° C, containing potassium carbonate (3.39 mmol) ) in methyl cyanide (CH3CN) (10 mL), this single-pass 98

200817365 Substituted bromide (〇·68 mmol) and 6-decyloxy-1,2,3,4-tetrahydro-911-pyridinium [3,4-b] fluorene (6-methoxy-l, 2 3,4-tetrahydro-9H-pyrido[3,4-b]indole) (〇· 6 8 mmol) was reacted. After stirring for 12 hours, the solution was filtered, and the filtrate was concentrated and purified by chromatography to give a Boc-protected residue (0.57 mmol; 84% yield). The residue (0.26 mmol) was treated with hydrochloric acid / ether and neutralized to give a polyamine. This polyamine was treated with pyridine-2-carbaldehyde to give a Schiff base. The Schiff base is reduced by the action of sodium borohydride (NaBH4) in methanol. The obtained crude product was purified by an alumina column chromatography (ethyl acetate/methanol = 7:3) to afford compound 1 42. LC-MS (C36H43N70) (M + +1): 590. Paste Example 143: Preparation of Compound 143: (S)-(l-(4-((bis(2-(pyridin-2-ylindolyl)-ethyl)amino)methyl)phenyl)) (S)-(l-(4-((bis(2-(pyridin-2-ylmethylamino)-ethyl)amino)methyl)benzyl)pyrrolidin-2-yl)methanol) Compound 141 was prepared by a method similar to that of Example 142 (yield: 80%) 〇LC-MS (C29H4 〇N60) (M + +l): 489 ο Paste Example 1 44: GTP-binding test ( GTP-binding assay) Using the DELFIA GTP' binding assay kit (Wallac Oy, Turku, 99 Ο

200817365

Finland) The binding efficacy analysis of compounds 1-126 and 1 37-143 with the CXCR4 receptor. The DELFIA GTP-binding assay is a time-resolved fluorometric assay based on the principle that when a G protein-coupled receptor is activated by its agonist, This in turn causes a GDP-GTP conversion on the G-protein subunit. In this assay, Eu-GTP from Wallac Oy was used to provide detection of G-protein agonist-dependent activation. Stimulation of the CXCR4 receptor by SDF-1 results in the replacement of GDP on the G_protein alpha subunit by GTP, while the GTP-Ga complex ij represents the activation form of the G-protein. Eu-GTP is a non-hydrolysable analog of GTP that can be used to quantify the amount of G-protein activated (Peltonen et al., Eur J. Pharmacol. (1 998) 355:275). The cell membrane of HEK293 expressing CXCR4 was suspended in a test buffer (50 mM sodium chloride, 100 pg/mL saponin, 3 mM magnesium chloride, 3 μΜ GDP, 5% BSA, and 50 mM HEPES; pH 7.4). An equal amount of sample (4 gg protein) was then added to each well of AcroPlate (Pall Life Sciences, Ann Arbor, MI). And after adding the test compound (ΙΟμΜ dissolved in 0.1% DMSO) and matrix-derived factor-1 (SDF_1) (4 ηΜ dissolved in the test buffer), the test tray was placed in a dark room. Gently shake for 10 minutes at room temperature. Eu-GTP was then added to each well of the test tray and incubated for an additional 60 minutes. Finally, the washing solution cleaning test provided by the test kit 100

200817365 Two times to terminate the test. Thus, the combination of 'Eu-GTP' can be determined by the fluorescent signal read by the Victor 2 multi-label reader. Unexpectedly, all test compounds have IC5 values below 10 μΜ. More specifically, there are 104 test compounds with IC5 〇 values below 1 μΜ, of which 63 have ICso values between 0.004 μΜ and 0·1 μΜ. Example 145: Radiodiol ligand binding assay Competitive binding assays between test compounds and human matrix-derived factor 1 were performed using glass fiber filter plates (Millipore, Billerica, ΜΑ). Binding assays). The glass fiber was first passed through a furnace, and the disk was pre-coated with 90 μΐ of 〇·2% polyethyleneimine for 30 minutes, and rinsed with 100 μM of distilled water four times to reduce non-specific binding. Human CXCR4-transfected (70X1 transfected) in 70μl assay buffer (50 mM HEPES, pH 7.4, 0.5% bovine serum albumin, 90 mM sodium chloride, 5 mM magnesium sulphate and imM calcium chloride) Cell membrane of HEK293 cells (5-10 pg protein/well) in U-bottom test dish (Corning, Corning, NY) with 20 μΐ of each test substance and 1 μ〇 of [125I]-SDF-1 (final concentration is 150 pM) for culture. After 120 minutes of incubation at room temperature, 80 μM of the reaction mixture was added to each well of the glass fiber filter disc to terminate the incubation step, and vacuum filtration (Multiscreen Vacuum Maniford, Millip0re) was used for the 101 200817365 filtration step. . The filter discs were then washed four times with 80 μM wash buffer (20 mMHEPES, pH 7.4 and 90 mM sodium chloride) per well. Next, after the test tray was air-dried overnight, a 3 5 μM Super mix cocktail was added to each well, and the radioactive dose remaining on the coffin was read using Trilux MicroBeta (PerkimElmer, Boston, MA). Compounds 94 and 1 37-1 were tested. Surprisingly, in the radioligand binding assay, all test compounds had IC5G values between 1 1-84 nM.实_1A6: Synergistic effect of compounds 125 and 135 with G-CSF in stem cell and endothelial progenitor (EPC) displacement (Synergistic effect) Animal studies have shown that compounds 1 2 5 and 136 can be fast CD34 + 〇k cells are generated to produce stem cells and CD133+EPCS enters the peripheral blood. The in vivo efficacy of this two compound mobile stem cells was tested in male BALB/c mice without specific pathogen (SPF). Different concentrations of the test compound were prepared and administered to the test rats via an intravenous or intramuscular route of administration, and rats receiving physiological saline were used as a control group. After 3 hours of intravenous injection or 6 hours of intramuscular injection, whole blood of the mice was collected by cardiac puncture. All white blood cells were suspended in PBS and the number of cells was estimated by trypan blue exclusion. The number of cells was then adjusted to 6 χΙΟ 4 cells in 〇1 mL PBS for antibody staining. Cxcr4 + cells, CD34 + cells and CD 133 cells were measured by surface staining and flow cytometry analysis. The experimental data is averaged over four independent experiments.

200817365 Value &amp; Benchmark (S Ε Μ) to present. The number of cells in different groups was compared using One-way ANOVA, while the P value of the field &lt; 0·05 was considered to be significantly different. The results showed that Compounds 125 and 136 increased cell cycle of CD34+ cells and CD133+ by up to 6 to 8.5 times within 3 hours after single intravenous stenciling. These results are summarized in Table 1 below. Table 1: Compounds 125 and 136 significantly increase the circulation of stem cells and progenitor cells. Increased fold at maximum tolerated dose (MTD) at compound 1 mg/kg (CD34 + CD133 + CD34 + CD133 + 125 3.99 2.24 6.58 5.77 136 2.63 3.17 5.66 8·49 MTD of compound 125·· 15 mg/kg MTD of Compound 136: 30 mg/Kg G-CSF stem cells and a growth factor of EPCs, which are used today to improve the hematopoietic function of cancer patients after chemotherapy. When Compound 125 was used in combination with G-CSF, it showed a synergistic effect on stem cell and EPC movement. Specifically, the combination of Compound 125 and g_Csf significantly increased the cycle by a factor of 38 for C D 1 3 4+ cells, and 64 times for CD 1 3 3 + cells. These results are summarized in the following table. ^ 103 200817365 Table 2 · Compound 125 and G-CSF for dry-loop increase multiples CD34 + CD 1 3 3 + Compound 125 (15 mg/Kg) ___ 7.1 6.0 G-CSF ( 50 ug/kg/d x4) ~__8.4 26.2 — G-CSF + compound 125 38.1 64.3 He's combination. The disclosed technical features may be replaced by technical features that provide the same, equal or similar purpose. Therefore, unless expressly stated in the specification, each technical feature is merely an exemplification of a group of equal or similar technical features. While the invention has been described above in terms of several embodiments, other embodiments can be obtained by those skilled in the art without departing from the spirit and scope of the invention. The scope is defined. For example, the above-mentioned polyamine compound can be used to treat an inflammatory inflammatory disease by a mechanism other than binding to the CXCR4 receptor. Further, other uses of the above compounds are also encompassed within the scope of the present invention. [Simple description of the diagram] None [Key component symbol description] None 104

Claims (1)

N-Z, Ο 200817365 X. Patent Application Range: 1 · A method for treating retinopathy comprising at least: administering an effective dose of one of the following chemical formulas to an eye of an individual in need of such treatment: /4 - Ζ 2 - R3 where X is -CH2-, -c2H4-, -C3H6-, ·ς:Η2-(:Η = (:Η-, -CH = CH-CH2-, -c(0)-, -S〇2 - or removed; Y is aryl, heteroaryl, C3_C8 cycloalkyl, C5-C8 cycloalkenyl, (: 3-&lt;:8 heterocycloalkyl (C3_C8 heterocycloalkyl), c5-c8 heterocycle Alkenyl (05-(:81^161:〇〇&gt;^1〇&amp;11€611丫1) or removed; Zi and Z2 are individually -ch2_, _c2H4-, -C3H6-, -CH = CH -, -CH=N-, -CH = N-NR-, -s-, -0-, -NR_, _C(0)_ or -S02-; Ri is H, (VCm alkyl, c2"C10 Glycosyl, C2-C1()alkynyl, C3-C8 cycloalkyl, Cs-c:8 cycloalkenyl, C3_C8 heterocycloalkyl, c5-c8 heterocycloalkenyl, aryl or heteroaryl; R2 is · Ai-Bb d"Ei; R3 is -A2-B2-D2_e2, removed or together with R4 is 匕^^cycloalkyl C4 C2G, gynecyl, C4-C2G heterocycloalkyl or c4-C2 Heterocyclenyl, and if R3 is removed, -ZpN- is -CH=N-; and R4 is -A3_b3-d3-E3 or together with r3 is c4_C2〇cycloalkyl, 105 200817365 C4_C2G cycloalkenyl, C4-C2G heterocycloalkyl or C4-C2g heterocycloalkenyl; the above Ai, A2 and A3 are each independently -CH2-, -C2H4-, -C3H6-, -c4h8-, -c5h10-, -ch2c(o )-, -c(o)ch2-, -ch2so2-, -S02CH2-, -ch2-ch = ch·, -ch = ch-ch2-, -CH(CH2OR)-, -CH(CH2CH2OR)-, - CH(COOR)-, -CH(CH2COOR)-, -ch(c(o)nr2)· or removed; the above Bi, B2 and B3 are individually _NR-, -CH2- or removed; !, D2 and 〇3 are each -0:112-, -(:2114-, _(:3116-, -CH2-CH = CH-, -CH = CH-CH2·, -c(0)- , -S〇2-, -C(0)-NR-, -C(S)-NR-, -NR-C(0)_, -NR-C(s)-, -CH(OR)-, -CH(CH2OR&gt;-, _CH(CH2CH2OR)·, -CH(COOR)·, 1,1_cyclopropene (l,l-cyclopropylene) or removed; the above Ε!, E2 and E3 are each η, Cl-Cl〇alkyl, C2_Cldecenyl, C2-Ci()alkynyl, (3-(:8-cycloalkyl, c5-C8-cycloalkyl, C3-C8 heterocycloalkyl, Cs-C8) Cycloalkenyl, aryl or hetero Group; and the above-described respective R independently is alkyl Η or CVCw. 2. The method of claim 1, wherein X is _Ch2-, -c2h4-, -c3H6-, -Ch2-CH=CH', -ch=Ch-ch2·, -so2- or shift Except; Y is aryl, heteroaryl, C^C8 cycloalkenyl or removed; Zl and Z2 are _CH2_, _C3H6_, _CH = CH-, -CH=N-NR·, -NR- , .C(〇)u〇2_; 106 200817365 R1 is C2-C1G alkynyl, c3-c8 cycloalkyl, c5-c8 cycloalkenyl, c3-c8-heterocycloalkyl, aryl or heteroaryl; • R3 is -A2-B2-D2-E2, removed or together with r4 is c4-C20 cycloalkyl or C4-c2〇 heterocycloalkenyl; • R4 is -a3-b3-D3_E3 or together with r3 When it is c4-c20 heterocycloalkyl A or C4-C2 fluorenylheterocyclene; • The Al, A2 and A3 are each independently - CH2-, -C2H4-, -C3H6-, f, -ch2S〇2- - -SO2CH2- ' -CH2-CH = CH- ' -CH = CH-CH2- 'CH(CH2〇R)-, _CH(CH2CH2OR)-, -CH(COOR)-, -CH(CH2CO〇R)- Or removed; the Di, D2 and D3 are _ch2_, -C2H4-, -C3H6-, -CH2-CH = CH_, _CH = CH_CH2·, _c(0)-, _S〇2_, -CH ( OR)-, -CH(COOR)-, 1,1-cyclopropene or removal; and the Ei, E2 and E3 are each Is Η, C3-C8 cycloalkyl, C5-C8-yl women soil, burned group, an aryl group or a heteroaryl group. Lj 3 The method of claim 2, wherein X is -CH2·, -C2H4·, C3H6-, -S〇2- or removed; Y is aryl, heteroaryl or removed Z! and z2 alone or _ S Ο 2 -, Ri is a C3-C8 heterocycloalkyl, aryl or heteroaryl; the Αι, A2 and A3 are individually CHCH, ... C3H6_, 107 200817365 - CH2SO2- '-SO2CH2- '-CH(CH2〇R). &gt; -CH(CH2CH20R)- '-CH(COOR)·, -CH(CH2C00R)· or remove; the Bi, B2 and B3 are different Is -NH• or removed; and the Di, D2, and D3 are individually CH2c2H4 ' Ah, -C(O)-, -S02-, -CH(0R)-, _CH(C00R)_,! The method of claim 3, wherein X is _ca_ or _CH(CH3)_; Y is removed; Z1 is -CH 2 ·; Z2 is -CH2 - 5. The method of claim 3, wherein χ -CH(CH3)·, Y is phenyl, Ζι is -called _ or, fCH2· or 〇 or -S〇2_» B is -ch2- 6 · as described in the third paragraph of the patent application, 苴 4 ^ ', 八 4 -ch2-, 丫 4,4, _ biphenyl (4,4,_1^1) 11 1), 21 is {112· 厶 is -CH2· 〇7. The method described in claim 3, wherein -CH, -, y is phenyl, and r3 is removed. 108 200817365 8. The method of claim 4, wherein R3 is -a2-b2-d2-e2, r4 is _a3_B3_D3_E3, Αι is -C2H4_ or removed, A: is removed, &amp; To remove ' &amp; for removal, I is removed, ... is _cH2-, D2 is removed, h is -CH2·, El is aryl or heteroaryl, E2aH, and e3 is aryl or hetero Aryl. 9. The method of claim 5, wherein 3 is • a2-b2-d2-e2 or together with R4 is c4_C2〇heterocycloalkyl or c4_C2〇heterocyclenyl; A! is -C2H4 - or -CH(CH3)CH2·; A2 is -C2H4 - or removed; A3 is -CH2-, _C2H4-, -C3H6-, -CH(CH2OH)-, -CH(COOH)-, -CH(CH2OCH3 )-, -CH(CH2CH2OH)-, -CH(CH2COOH)- or removed; Bi is -NH-, -N(CH2CH2OH)- or -N(CH2CH3)-; Di is -CH2-, _ch(ch3) _, _ch(ch2oh)-, -CH(CH2CH2OH)- or removed; D2 is -CH2- or removed; D3 is -CH2-, -CH(OH)-, -CH(COOH)-, 1,1 - cyclopropene or removed; E! is hydrazine, C3-C8 heterocycloalkyl, aryl or heteroaryl; E2 is fluorenyl, aryl or heteroaryl; and Ε3 is a square or heteroaryl, c3 - C g 炫 * *, C5 - C g ring dilute or 109 200817365 c3-c8 heterocycloalkyl. 10 · If the patent application scope is 6-A 2 &quot; Β 2 ~ D 2 ~ Ε 2 &gt; R4 is - A3-B3-D3-E3; Αι is - C2H4-, A2 is removed; A3 is -CH ( CH2OH)-; Bi is -NH-; B2 is removed; b3 is removed; the method described, wherein R3 is Di is -CH2-, D2 is -CH2- or removed; D3 is -CH2-; Ei is a heteroaryl group; ο E2 is an anthracene or a heteroaryl group; and Ε 3 is an aryl group. 11. The method of claim 7, wherein Ri is a heteroaryl group; R4 is -A3-B3-D3-E3, Αι is -C2H4-, A3 is removed; Bi is -NH-; B3 Is -NH- 200817365 Di is -CH2-; D3 is -C(O)-; Ε! is heteroaryl; and E3 heteroaryl. 12. The method of claim 9, wherein the E3 is a halo or OR'-selectively substituted phenyl group, an OR' selectively substituted benzoimidazole, via Ci -Cr-alkyl group optionally substituted, indol or cyclophenyl group of phenyl; the above R' is hydrazine or CrCio alkyl 0 1 3 · as described in claim 12 The method wherein the compound is one of the compounds 127-141. 14. The method of claim 9, wherein E3 is an aryl or OR' substituted piperidinyl, and a piperidinyl group substituted with a Ci-Ci oxime Or a pyrrolidinyl substituted by a Ci-Cio alkyl group; wherein R' is hydrazine or a Ci-Ci fluorene group. The method of claim 14, wherein the compound is compound 142 or 143. 1 6. The method of claim 1, wherein the retinal disease 111 200817365 becomes diabetic retinopathy, proliferative retinopathy, age-related macular degeneration (age-related) Macular degeneration), macular edema, corneal blood genus (〇〇rnea 1 neovascu 1 arizati ο η ) or iris neovascularization. The method of claim i, further comprising administering to the individual an effective amount of G-CSF growth factor. The method of claim 1, wherein the chemical enters the eye by injection. The method of claim 18, wherein the compound is injected into a vitreal space of the eye. </ RTI> The method of claim 1, wherein the compound is applied topically to the eye. The method of claim 2, wherein the compound is formulated as an ointment or ophthalmic solution. 22. The method of claim 2, wherein the compound is applied to a peripheral portion of the eye. 112 200817365 23 - A method of repairing tissue damage comprising administering to an individual in need of such repair an effective dose of a compound of the formula: Wherein X is -ch2-, _c2H4-, _c3H6 CH2_CH=CH_, -CH=CH-CH2-...s〇2- or removed; Γ, Y is aryl, heteroaryl, C^C8 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 heterocycloalkyl, c5-c8 heterocycloalkenyl or removed; Ζι and Z2 are each _ch2·, _C2h4_, _c3h6_, -CH = CH-, -c( 0)- or -S02-; -CH = N-, -CH = N-NR...-s., -〇·, -NR- Ri are H, Ci-Cu alkyl, C2_Cl nonenyl, C2_Ci() Alkynyl, c3_C8 cycloalkyl, CVC8 cycloalkenyl, CrCg heterocycloalkyl, C5-C8 heterocycloalkenyl, aryl or heteroaryl; ί) R*2 is -; R3 is -a2-b2-d2 -e2, removed or together with R4 is C4_C2〇cycloalkyl, C4-C2Gcycloalkenyl, C4-C2〇heterocycloalkyl or c4-C2〇heterocyclenyl, and if R3 is removed, - Z2-N- is -CH=N-; and R4 is -A3-B3-D3-E3 or together with r3 is c4-C20 cycloalkyl, cvcw cycloalkenyl, cu-Cm heterocycloalkyl or C4-C2G Heterocyclenyl; the above A!, A2 and A3 are each independently -CH2_, -C2h4_...c3H6-, -C4H8-, -C5H10-, -CH2C(0)_, -c(0)CH2-, -CH2S 〇2-, 113 200817365 -S02CH2·, -CH2_CH = CH-, -CH = CH-CH2-, -CH(CH2OR)- -CH(CH2CH2OR)-, -CH(COOR)-, -CH(CH2COOR)-, -CHCCCCONF^)- or remove; 'The above, B2 and B3 are individually -NR-, -CH2- or removed • The above Di, D2 and D3 are individually -CH2 -, -C2H4-, -C3H6-, r -CH2-CH = CH-, -CH = CH-CH2-, -C(O)-, -S 〇2-, -C(0)-NR-, • -C(S)-NR-, -NR-C(O)-, _NR-C(S)-, -CH(OR)-, (-ch (ch2〇r)-, _CH(CH2CH2〇R)-, -CH(COOR)-, 1,1_cyclopropene or removal; the above E 1, E 2 and E3 are H, Ci-Ci Tertiary base, C 2 -C 1 decenyl, C2-C1G alkynyl, C3-C8 cycloalkyl, (: 5-(^8 cycloalkenyl, C3-C8 heterocycloalkyl, C5-C8 heterocycle) Alkenyl, aryl or heteroaryl; and R as described above are each independently or only CVCw alkyl. The method of claim 23, wherein the tissue damage CJ is caused by islet cells, neural lineage cells, hepatocytes, bone cells, muscle cells, blood cells or epidermal cells. damage. The method of claim 23, wherein the tissue damage is caused by a degenerative disease. The method of claim 24, wherein the degenerative disease is selected from the group consisting of Alzheimer's disease (Alzheimer, s 114 200817365 disease), Parkinson's disease ( Parkins〇n, s disease), osteoarthritis (osteoarthritis) and osteoporosis (〇ste〇p〇r〇sis). 27. The method of claim 23, wherein the tissue damage is caused by tissue isehemia. 28. The method of claim 27, wherein the hypoxia is selected from the group consisting of cardiac ischemia, limb ischemia, and neuronal hypoxia (nerve) Isehemia), liver ischemia, kidney ischemia, pancreatic ischemia, lung ischemia, and intestinal hypoxia. The method of claim 23, wherein the tissue damage is caused by an autoimmune disease, wherein the method of claim 29, wherein the method of claim 29, wherein The autoimmune disease is type I diabetes, systemic lupus erythematosus (SLE), Sjdgren's syndrome, Hashimoto's thyroiditis, and Gray. Graves' disease and rheumatoid arthritis. 3 1. The method of claim 23, further comprising administering an effective amount of G-CSF growth factor to the individual at the same time as 115 200817365. 3. The method of claim 23, wherein the compound is administered by injection or instillation in an enteral or parenterally manner. 3 3 · A compound having the following chemical formula: 116 200817365 VII. Designation of representative representatives: (1) The representative representative of the case is: no picture. (2) The symbolic representation of the symbol of the representative figure is as follows: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4