CN1980916A - Chemokine receptor binding heterocyclic compounds - Google Patents

Chemokine receptor binding heterocyclic compounds Download PDF

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Publication number
CN1980916A
CN1980916A CNA018158021A CN01815802A CN1980916A CN 1980916 A CN1980916 A CN 1980916A CN A018158021 A CNA018158021 A CN A018158021A CN 01815802 A CN01815802 A CN 01815802A CN 1980916 A CN1980916 A CN 1980916A
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solution
methyl
nmr
compound
mixture
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G·布里杰
R·斯基勒
A·卡勒
C·哈维希
D·博古茨基
T·R·威尔逊
J·克劳福德
E·J·麦克阿切
B·阿特斯曼
南思乔
周苑西
D·斯科斯
C·D·史密斯
R·M·迪弗吕
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Anormed Inc
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Anormed Inc
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

Compounds which modulate chemokine receptor activities are disclosed. These compounds are preferably tertiary amines comprising tetrahydroquinoline and benzimidazole.

Description

The heterogeneous ring compound of binding chemotactic factor receptor
According to 35 U.S.C 119 (e), the application requires the right of priority of application of submitting to 15,60/234510,2000 on September of provisional application submission September 22 in 60/232891,2000 of submission on September 15th, 2000 0/233087 and the application of submitting on September 22nd, 2,000 60/234816.This paper will fit into as a reference in these applications.
Technical field
The present invention relates generally to compounds, medical composition and its use.More specifically, the present invention relates to and Chemokine Receptors (comprising CXCR4 and CCR5) bonded novel heterocyclic compounds, and show the provide protection that the opposing target cell is infected by human immunodeficiency virus (HIV).
Background of invention
About 40 kinds of human chemokines have been described, its (to small part) brings into play function by regulating cover biological activity complicated and that interlock, these functions infiltrate and overflow that (to replying of stimulator) is very important (sees to lymphocytic activity and leukocytic tissue, as P.Ponath, Exp.Opin.Invest.Drugs, 7:1-18,1998; Baggiolini, M., " nature " (Nature), 392:565-568 (1998); People such as Locati, Annu.Rev.Med., 50:425-40 (1999)).These chemoattracting cytokings or chemokine constitute class protein, about 8-10kDa size.Chemokine seems has the common structural motif, and the conservative halfcystine of being kept tertiary structure by 4 participations constitutes.Two kinds of main chemokine subclass are arranged: " CC " or beta-chemokine and " CXC " or α-chemokine.By the acceptor classification of the chemokine that constitutes the acceptor native ligand with these chemokines.The acceptor called after " CCR " of beta-chemokine; And the acceptor called after " CXCR " of α-chemokine.
It is believed that chemokine is that (referring to, " chemokine in the disease " (1999) that Humana Press publishes, C.Herbert edits for the main amboceptor that causes and keep inflammation; People such as Murdoch, " blood " (Blood), 95:3032-3043 (2000)).More particularly, found that chemokine has important effect in regulating inner skin cell function, comprise in propagation, migration and the vasculogenesis differentiation and injured after endothelial regeneration (people such as Gupta, Biol.Chem., 7:4282-4287,1998; People such as Volin, Biochem.Biophys Res.Commun., 242:46-53 (1998)).Knownly in the etiology that human immunodeficiency virus (HIV) infects, relate to two kinds of special chemokines.
As a rule, HIV is attached on the CD4 acceptor of target cell by its gp120 envelope protein at first.Show as conformational change taken place in gp120, cause its be incorporated into subsequently Chemokine Receptors (as CCR5) (people such as Wyatt, " science " (Science), 280:1884-1888 (1998); People such as Rizzuto, " science ", 280:1949-1953 (1998); People such as Berger, Annu.Rev.Immunol., 17:657-700 (1999)).The HIV-1 isolate that infects the back generation is attached on the CXCR4 Chemokine Receptors.
After the initial combination of HIV and CD4, then virus-cell of being regulated by the Chemokine Receptors family member just merges, different members serves as the scavenger cell tropism (M-tropism) that causes HIV-1 and the fusion complementary divisor (people such as Carroll of T cell straight line-tropism (T-tropism) isolate, " science ", 276:273-276,1997; People such as Feng, " science ", 272:872-877 (1996); People such as Bleul, " nature ", 382:829-833 (1996); People such as Oberlin, " nature ", 382:833-835 (1996); People such as Cocchi, " science ", 270:1811-1815 (1995); People such as Dragic, " nature ", 381:667-673 (1996); People such as Deng, " nature ", 381:661-666 (1996); People such as Alkhatib, " science ", 272:1955-1958 (1996)).In patient's course of infection, show as most of HIV particle and change into from M-tropism and have more aggressive T-tropism virus phenotype (Blaak waits the people, Proc.Natl.Acad.Sci., 97:1269-1274 (2000); People such as Miedema, Immune.Rev., 140:35 (1994); People such as Simmonds; J.Virol., 70:8355-8360 (1996); People such as Tersmette, J.Virol., 62:2026-2032 (1988); Connor, R.I., Ho.D.D., J.Virol., 68:4400-4408 (1994); People such as Schuitemaker, J.Virol., 66:1354-1360 (1992)).M-tropism virus phenotype be attached to the CCR5 acceptor after virus to enter the ability of cell relevant, and T-tropism's virus phenotype and virus be attached to the CXCR4 acceptor and with its film fusion after virus to enter the ability of cell relevant.Clinical observation shows that the patient with CCR5 genetic mutation can resist infection or few infected (people such as Liu, the Cell 86:367-377 (1996) of HIV; People such as Samson, Nature 382:722-725 (1996); People such as Michael, Nature Med.3:338-340 (1997); People such as Michael, J.Virol.72:6040-6047 (1998); People such as Obrien, Lancet 349:1219 (1997); People such as Zhang, AIDS Res.Hum.Retroviruses 13:1357-1366 (1997); People such as Rana, J.Virol.71:3219-3227 (1997); People such as Theodorou, Lancet349:1219-1220 (1997)).Although it is a lot of that the HIV that has reported mediation enters the Chemokine Receptors quantity of cell, only CCR5 and CXCR4 show as the relevant co-receptor of the physiology that used by various main clinical HIV-1 strains (people such as Zhang, J.Virol., 72:9307-9312 (1998); People such as Zhang, J.Virol., 73:3443-3448 (1999); People such as Simmonds, J.Virol., 72:8453-8457 (1998)).Utilize CXCR4 T-tropism's virus fusion and enter, suppressed by the factor-1 of natural CXC-chemokine stroma cell derivative, utilize CCR5 M-tropism virus fusion and enter by natural CC-chemokine and suppress (promptly to regulate the activation (RANTES) and the macrophage inflammatory protein (MIP-1 α and β) of normal expression and excretory T-cell.
Except the cofactor that enters as HIV, the someone proposes the gp120 of virus and the direct interaction of CXCR4 recently, may cause apoptosis dementia (by induce the apoptosis of neuronal cell) (people such as Hesselgesser, the Curr.Biol.8:595-598 (1998) relevant of CD8+T-cell with AIDS; Hesselgesser waits the people, Curr.Biol.7:112-121 (1997); People such as Hesselgesser, " chemokine in the brain and Chemokine Receptors ", " chemokine in the disease " that Humana Press (1999) publishes, C.Herbert edits; People such as Herbein, Nature 395:189-194 (1998): people such as Buttini, Nature Med.4:441-446 (1998); People such as Ohagen, J.Virol.73:897-906 (1999); People such as Biard-Piechaczyk, Virology268:329-344 (2000); People such as Sanders, J.Neuroscience Res.59:671-679 (2000); People such as Bajetto, Neurochem.73:2348-2357 (1999); People such as Zheng, J.Virol.73:8256-8267 (1999)).
Yet, the mesosome that the binding ratio of Chemokine Receptors and their native ligands only infects as HIV plays a part bigger evolution and center.The factor (PBSF/SDF-1) of native ligand pre-B cell growth-stimulating factor/stroma cell derivative and combining of CXCR-4 Chemokine Receptors, important signal transduction mechanism is provided: the mouse of having rejected CXCR4 or SDF-1 shows the unusual concurrent green tire of cerebellum, heart and intestines and stomach dead (people such as Zou, Nature 393:591-594 (1998); People such as Tachibana, Nature 393:591-594 (1998); People such as Nagasawa, Nature 382:635-638 (1996)).The CXCR4 deficient mice also shows hematopoiesis defective (people such as Nagasawa, Nature 382:635-638 (1996)); The CXCR4 that expresses white corpuscle and hemopoietic progenitor cell shows keeping and CD34 B-clone to the migration of SDF-1 +Archeocyte is located in marrow extremely important (people such as Bleul, J.Exp.Med.187:753-762 (1998); People such as Viardot, Ann.Hematol.77:195-197 (1998); People such as Auiti, J.Exp.Med.185:111-120 (1997); People such as Peled, Science 283:845-848 (1999); People such as Qing, Immunity 10:463-471 (1999); People such as Lataillade, Blood 95:756-768 (1999); People such as Ishii, J.Immunol.163:3612-3620 (1999); People such as Maekawa, Internal Medicine 39:90-100 (2000); People such as Fedyk, J.Leukocyte Biol.66:667-673 (1999); People such as Peled, Blood95:3289-3296 (2000)).
The signal that when combining, provides by SDF-1 with CXCR4, in the hyperplasia of tumour cell and the adjusting vasculogenesis relevant with tumor growth, also may play an important role (referring to, " chemokine and the cancer " that Humana Press (1999) publishes, B.J.Rollins edits; People such as Arenburg, J.Leukocyte Biol.62:554-562 (1997); People such as Moore, J.Invest.Med.46:113-120 (1998); People such as Moore, Trends Cardiovasc.Med.8:51-58 (1998); People such as Seghal, J.Surg.Oncol.69:99-104 (1998)); Known angiogenesis factor VEG-F and bFGF, the last level-off of CXCR4 and SDF-1 can cause intravital neovascularity and generate people such as (, Am.J.Pathol.154:1125-1135 (1999)) Salcedo in the endotheliocyte; Express leukemia cell's migration of CXCR4 and be adsorbed in the lymphoglandula of expressing SDF-1 and marrow stromal cell (people such as Burger, Blood94:3658-3667 (1999); People such as Arai, Eur.J.Haematol.64:323-332 (2000); People such as Bradstock, Leukemia 14:882-888 (2000)).
SDF-1 relates to atherosclerotic morbidity (people such as Abi-Younes with combining of CXCR4, Circ.Res.86:131-138 (2000)), RAT repels (people such as Eitner, Transplantation 66:1551-1557 (1998)), asthma and supersensitivity respiratory inflammation (people such as Yssel, " clinical and test anaphylaxis " (Clinicaland Experimenatl Allergy), 28:104-109 (1998); J.Immunol.164:5935-5943 (2000); People such as Gonzalo, J.Immunol.165:499-508 (2000)), alzheimer's disease (people such as Xia, J.Neurovirology 5:32-41 (1999)) and the pathogeny of sacroiliitis (people such as Nanki, J.Immunol.164:5010-5014 (2000)).
In order to understand the relation between chemokine and their acceptors better, recently by testing with monoclonal antibody or small molecules, block the fusion of HIV by the CXCR4 Chemokine Receptors, enter and duplicate, this may propose a kind of useful therapeutic strategy.(people such as Schols, J.Exp.Med.186:1383-1388 (1997); People such as Schols, Antiviral Research 35:147-156 (1997); People such as Bridger, J.Med.Chem.42:3971-3981 (1999); People such as Bridger, " as bicyclic amide (bicyclam) derivative of hiv inhibitor ", the designs of antiviral, volume 3, the 161-229 pages or leaves, JAI press publishes (1999), E.DeClercq edits).Small molecules (as bicyclic amide (bicyclam)) show as CXCR4 but not the specificity of CCR5 in conjunction with people such as (, Nature Medicine, 4:72-77 (1998)) Donzella.These experimental results show that disturbing external HIV to enter with film is fused to target cell.Recently, bicyclic amide also shows the fusion that suppresses to utilize the feline immunodeficiency virus (FIV) that CXCR4 enters and duplicates people such as (, J.Virol.73:6346-6352 (1999)) Egberink.
Other is tested and shows that bicyclic amide dosage-dependency ground suppresses the SDF-1 of 125I mark and the signal transduction that combines and respond SDF-1 of CXCR4 (increase by intracellular Ca2+ shows).Therefore, bicyclic amide also have as the matrix deutero-factor or SDF-1 α (the natural chemokine of CXCR4) in conjunction with and the function of the antagonist of the signal transduction that produces.Bicyclic amide also suppresses not to be subjected to intracellular HIV gp120 (coating)-inductive apoptosis that HIV infects people such as (, Antimicrobial Agents and Chemother, 44:51-56 (2000)) Blanco.
U.S. Patent No. 5,583,131, No.5,698,546, No.5,817,807, No.5,021,409 and No.6,001,826 (this paper all includes them as a reference in) discloses had anti-HIV-1 and the active ring compound of HIV-2 in vitro test.Subsequently at published PCT application U.S. serial No.09/111,895 and No.60/172, find in 153 (this paper includes it as a reference in) and further disclose these compounds by with combine the demonstration HIV (human immunodeficiency virus)-resistant activity at the Chemokine Receptors CXCR4 of some cell surface expression of immunity system.The HIV that this these target cells of competitive join protection are not utilized the CXCR-4 acceptor to invade infects.In addition; the combination of the native ligand of these compound antagonisms CXCR4 (being the factor 1 α (SDF-1) of chemokine stroma cell derivative), signal produce and chemotaxis, and we find that also these new compounds avoid HIV with the join protection target cell CCR5 acceptor and infect by external.
In addition, we are at U.S. serial No.09/495, disclose cyclic polyamines antiviral drug described in above-mentioned patent in 298 and have had the effect that leukocyte increasing produces and show ntiviral characteristic.Therefore, these medicines can be used for controlling chemotherapy side effect, improve bone marrow transplantation success ratio, accelerating wound healing and burn treatment and in leukemia, resist infectation of bacteria.
Recently, we are at U.S. serial No.09/535, disclose a series of heterogeneous ring compounds in 314, they by with in the Chemokine Receptors CXCR4 of some cell surface expression of immunity system and combining of CCR5, show HIV (human immunodeficiency virus)-resistant activity.The HIV that this these target cells of competitive join protection are not utilized CXCR-4 or CCR5 acceptor to invade infects.In addition, the combination of the native ligand (chemokine RANTES) of the native ligand of these compound antagonisms CXCR4 (being the factor 1 α (SDF-1) of chemokine stroma cell derivative) and/or CCR5, signal produce and chemotaxis.
The invention discloses with the similar mode of previous disclosed macrocylc compound, by combining, show the compounds of target cell being avoided the provide protection that HIV infects with Chemokine Receptors CXCR4 or CCR5.In addition, these compounds also produce antagonistic action to the combination of the native ligand (chemokine RANTES) of the native ligand (factor 1 α (SDF-1) of chemokine stroma cell derivative) of CXCR4 and/or CCR5, the generation and the chemotactic effect of signal.
Quoting as proof not as to the approval for relevant existing field mentioned above of above-mentioned document.The date of these documents of being stated or statement all are based on the obtainable information of the applicant, and the date or any of content exactness that do not constitute these documents admit.This paper all includes all documents that the application quoted as a reference in addition.
Summary of the invention
The invention provides compounds, they combine with Chemokine Receptors and interfere its native ligand and its combine.When these compounds of the present invention were used as medicament, their showed that the protection target cell avoids the effect that HIV infects.Other embodiments of the invention are the compounds that can be used as chemokine receptor anagonists or agonist, and other biologic activity that relates to the ability of these compound chemokine inhibitings and its receptors bind.
Compound of the present invention is the compound of formula (1), comprises its pharmacy acceptable salt and prodrug form thereof.The compound of formula (1) is as follows:
Figure A0181580200101
In the formula:
Ring A randomly contains the heteroatoms that is selected from N, O and S;
It is unsaturated that dotted line is represented to choose wantonly;
R 1, R 2And R 3It is mutual incoherent substituting group;
K is 0-4;
L is 0,1 or 2;
X is C or N unsubstituted or that replace; Or O or S;
Ar is the residue of aromatics or heteroaromatic moiety;
Each n is respectively 0-2;
Each R is respectively H or alkyl (1-6C);
J is 0-3; And
It is as herein described except CR that each Y is respectively 2NR (CR 2) nOptional substituting group beyond the B, wherein B is aromatic ring or hetero-aromatic ring or other heterocycle.
Preferably, each Y is selected from halogen, OH, SH, SO, SO2 respectively; Or do not contain the organic moiety of 1-20 the carbon atom of N, wherein, two such Y can be connected to form condensed ring with Ar; Perhaps Y is selected from following group:
-(CR 2) mCN，
-(CR 2) mNR 5 2，
-(CR 2) mNR(CR 2) mNRR 4，
-(CR 2) mNR(CR 2) mNR(CR 2) mNR 5 2，
-(CR 2) mCO(CR 2) mNR 5 2，
-(CR 2) mCO(CR 2) mNR(CR 2) mNRR 4，
-(CR 2) mCO(CR 2) mNR(CR 2) mNR(CR 2) mNR 5 2，
-(CR 2) mNRCO(CR 2) mNRR 4，
-(CR 2) mNRCO(CR 2) mNR(CR 2) mNR 5 2，
-(CR 2) mNRCO(CR 2) mNR(CR 2) mNR(CR 2) mNR(CR 2) mNR 5 2，
-CH＝N-Z，
-(CR 2) mZ，
-NR(CR 2) mZ，
-(CR 2) mNROH，
(CR 2) mCONROH and
(CR 2) mCR＝NOH，
And Y contains the group of guanidine radicals or NHNHR or amidino groups;
Wherein Z is optional aromatics that contains 5-12 annular atoms or the heteroaromatic moiety that replaces; And
Wherein R as mentioned above; Each m is respectively 0-4; R 4With each R 5Be respectively H, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C) or acyl group (1-6C), randomly replaced separately by one or more non-aromatics, non-heterocyclic substituent, and two R wherein 5Can connect into cyclammonium, randomly contain the extra heteroatoms of one or more N of being selected from, O and S.
Compound of the present invention is CR particularly including Y 2NR (CR 2) nThe embodiment of B, wherein B is aromatic ring or hetero-aromatic ring or other heterocycle.
Described optional substituent definition is as follows.
The present invention includes the pharmaceutical composition that contains formula (1) compound for the treatment of significant quantity; The method of the disease of treatment human body or other mammalian body, these methods comprise and give described pharmaceutical composition; And the bonded method of blocking-up or interference Chemokine Receptors and its native ligand, this method comprises makes described Chemokine Receptors contact with formula (1) compound of significant quantity.
The compound that the invention still further relates to formula 1 is used to prepare a kind of purposes of medicine, this medicament is used for the treatment of disease, wherein advantageously blocking-up or interference Chemokine Receptors combine with its native ligand, and this method can comprise a kind of formula (1) compound compositions for the treatment of significant quantity that contains of preparation.The present invention also provides a kind of protection to contain the method for the target cell of Chemokine Receptors; pathogenic agent can cause sick with combining of this class target cell or pathology takes place, and this method comprises the pharmaceutical composition that contains formula (1) compound for the treatment of significant quantity to mammalian subject.
Compound of the present invention can " prodrug " (being the protection form of these compounds) packaged, this form discharges this compound after giving the patient.For example, a kind of blocking group of described compound portability, this group is hydrolyzed division in body fluid such as blood, thereby discharges active compound, perhaps this blocking group oxidized or reduction in body fluid, thus discharge this compound.About the discussion of prodrug, can be referring to " Smith and Williams are about the introduction of the principle of medicinal design " (Smith and Williams ' Introduction to thePrinciples of Drug Design), H.J.Smith, Wright, second edition, London, 1988.
Acceptable acid salt on the pharmacology, the salt that salt that salt that salt that forms as the salt that forms with mineral alkali and organic bases and mineral acid form and organic acid form and alkalescence or acidic amino acid form etc. also is contained in the present invention.The salt that forms with mineral alkali comprises the salt that forms with basic metal (as sodium, potassium etc.), alkaline-earth metal (as calcium, magnesium etc.), aluminium, ammonium etc.The salt that forms with organic bases comprises and Trimethylamine 99, triethylamine, pyridine, picoline, thanomin, diethanolamine, trolamine, dicyclohexylamine, N the salt that N '-dibenzyl-ethylenediamin etc. form.The example of the salt that forms with mineral acid comprises the salt that forms with hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.The salt that forms with organic acid comprises the acid that forms with formic acid, oxalic acid, acetate, tartrate, methylsulfonic acid, Phenylsulfonic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.The example of the salt that forms with basic aminoacids comprises the salt that forms with arginine, Methionin, ornithine etc.The example of the salt that forms with acidic amino acid comprises the salt that aspartic acid, L-glutamic acid etc. form.Nontoxicity in the teachings herein must be considered as the prognostic of undressed infected patient.
Embodiments of the present invention
The present invention is directed to the compound of formula 1, they can be as the medicament of regulating chemokine receptor activity.These Chemokine Receptors include, but are not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR-4 and CXCR5, are preferably CXR4 and/or CCR5.
These compounds affect native ligand or chemokine and CXCR4 of acceptor such as target cell and/or combining of CCR5.
So these compounds affect Chemokine Receptors, as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5, wherein said Chemokine Receptors connects with many human inflammation and immunomodulatory disease and cancer as important conditioning agent.And these compounds are regulated the activity of these Chemokine Receptors, thereby can be used for treatment or prevent these diseases.
Particularly, formula 1 compound has to protect target cell to avoid the effect that HIV infects with Chemokine Receptors specificity bonded mode.
Term used herein " conditioning agent " comprises antagonist, agonist, partial antagonist and/or partial agonist, inhibitor and activator.In preference of the present invention, the compound exhibits of formula 1 by suppressing HIV and Chemokine Receptors of target cell such as combining of CXCR4 and/or CCR5, thereby play the effect that stops the HIV infection.The present invention includes a kind of method, this method comprises makes target cell contact with the described compound of the bonded of Chemokine Receptors with a certain amount of effective inhibition.
Term " treatment significant quantity " refers to cause in the cell, tissue, organ, system the animal or human who asks for help to investigator, animal doctor, doctor or other clinicist the amount of motif compound of the reaction of biological or medical science.
The term " administration " that is used for motif compound is interpreted as providing compound of the present invention to the individuality of needs treatment, comprises the prodrug of The compounds of this invention.
The The compounds of this invention of chemokine inhibiting acceptor can be used for the prevention and treatment of diseases relevant with hemopoietic, includes, but are not limited to control the treatment of side effect, the healing that improves myelosuppressive success ratio, accelerated in wounds and burn after the chemotherapy and resist infectation of bacteria in leukemia.
The activity of chemokine inhibiting acceptor also can be used for treating the disease relevant with inflammation with the The compounds of this invention of function, these diseases include, but are not limited to inflammation or anaphylactic disease, as asthma, allergic rhinitis, supersensitivity pulmonary disorder, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed type hypersensitivity, interstitial lung disease (ILD) (as congenital pulmonary fibrosis or ILD, systemic lupus erythematous, ankylosing spondylitis, whole body sclerosis, Sjogren ' s syndrome, polymyositis or the dermatomyositis relevant) with rheumatoid arthritis; Systemic anaphylaxis or allergy, drug allergy, sting allergy; Autoimmune disease is as rheumatoid arthritis, psoriasis, systemic lupus erythematous, myasthenia gravis, initial stage diabetes; Glomerulonephritis, autoimmune thyroiditis (throiditis), transplant rejection comprise allograft rejection or graft versus host disease (GVH disease); Inflammatory bowel disease is as Crohn disease and ulcerative colitis; Spondyloarthropathy; Scleroderma; Psoriasis (comprising the psoriasis that T is cell-mediated) and inflammatory skin are sick as dermatitis, eczema, atopic dermatitis, contact dermatitis, urticaria; Vasculitis (as gangrenosum acne, skin and allergic angiitis); Oxyphie myositis (myotis), eosinophilic fasciitis; And cancer.
The compound of the present invention of activation or promotion chemokine receptor function can be used for treating the disease relevant with immunosuppression, stand chemotherapy, radiotherapy, enhancing wound healing and burn treatment, autoimmune disease or other drug treatment (as the corticosteroid treatment) as individuality, or combine with the immunosuppressant traditional drugs that causes that is used for autoimmune disease and allotransplantation/transplant rejection treatment; Because the birth defect of function of receptors or the immunosuppression that other reasons causes; And infectious diseases, as parasitosis, include but not limited to helminth infection, as nematode (roundworm); Pinworm, roundworm, hookworm, quasi-colubriformis, Trichinella spiralis, filaria, fluke, the internal organ worm, visceral larva migrans (as the bow roundworm), eosinophil gastro-enteritis is (as Anisakid nematode, mouse ease constipation nematode (Phocanema spp.)), skin larval migration (ancylostoma braziliense (Ancylostona braziliense), dog hookworm (Ancylostoma canium)), the protozoon Plasmodium vivax (Plasmodium vivax) that causes malaria, human cytomegalic inclusion disease virus, herpesvirus saimiri (Herpesvirus saimiri), with Kaposi sarcoma simplexvirus (being also referred to as human herpes virus 8) and poxvirus MCV (Moluscum contagiosum).
In the compound of formula 1 one or more can use with any other pharmaceutical composition, this combined therapy can be used for regulating chemokine receptor activity, thus the relevant disease of prevention and treatment and hemoposieis, inflammation, autoimmunization, inflammatory skin disease, cancer, inflammatory bowel and immunoregulatory disorder.
Also consider compound of the present invention and following one or more preparations are used in combination, be used for prevention or treatment HIV.The example of these preparations is as follows:
(1) Nucleotide reverse transcriptase inhibitors finalizes polyester (fozivudine todoxil) etc. as Zidovodine, didanosine, lamivudine, zalcitabine, Abacavir, tavudine, A Defuwei (adefovir), A Defuwei two peopentyl esters (adefovir dipivoxil), Fu Xifu;
(2) non-nucleotide reverse transcriptase inhibitors (comprising the medicine that has as the anti-oxidant activity of Yi Minuo card (imminocal), oltipraz etc.) is as nevirapine, U-90152, Ai Fuweien, Luo Weilide (loviride), Yi Minuo card, oltipraz etc.; With
(3) proteinase inhibitor such as Saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, Palinavir (palinavir), LASINAVIR (lasinavir) etc.
The combination of ranges of formula l compound of the present invention and HIV medicament is not limited to (1), (2) and/or (3), and comprises any associating to the useful pharmaceutical composition of treatment HIV in principle.In addition, compound of the present invention and other HIV medicaments can be distinguished or be co-administered in these associatings.In addition, a kind of composition use can before the another kind of pharmacy application, among or afterwards.
But the compound through port of formula 1, parenteral (as in intramuscular, the barrier film, intravenously, intracisternal injection or instillation, subcutaneous injection or implantation), by sucking the drug delivery route of spray, nose, vagina, rectum, hypogloeeis or external application, use separately or together with proper dosage unit formulation (contain acceptable carrier, adjuvant on the conventional nontoxicity pharmacology and be applicable to the vehicle of each drug delivery route).
The compound of formula 1 all is active, and is used for the treatment of animal, comprises mouse, rat, horse, ox, sheep, dog, cat and monkey.It also is effective that compound of the present invention is used for the people.
The compound of formula 1 of the present invention can form hydrate or solvate.The compound of formula 1 of the present invention can any regional isomer, the mixture of configurational isomer, conformer or diastereomeric form exists, and if desired, can separate each isomer with purification process with separation known.When formula 1 compound of the present invention was racemite, it was separable into (S)-compound with general optical resolution and (R)-compound, and each optical isomer and composition thereof comprises within the scope of the invention.
The invention still further relates to pharmaceutical composition, contain formula 1 compound of acceptable carrier on the pharmacology or thinner and significant quantity.Can use the compound of formula 1 separately, or conduct and pharmacology acceptable carrier are (as solid formulation, as tablet, capsule, pill, powder etc.; Liquid formulation such as syrup, injection etc.) mixture oral cavity or non-oral administration.The example of non-oral preparation comprises injection, drops, suppository, hysterophore.
Under treatment or prevention need situation that Chemokine Receptors regulates, the proper dosage level normally every day about 0.01-500 milligram/kg patient body weight, can single agent or multi-agent use.The preferred dosage level is about 0.1-250 milligram/kilogram every day.Concrete dosage level and the dose frequency that should understand any concrete patient can change, and will depend on various factors, the activity that comprises used specific compound, the metabolic stability of this compound effects and length, age, body weight, healthy state, sex, diet, mode of administration and time, discharge rate, medication combined, the severity of particular case and the patient who stands to treat.
The present invention also provides the bonded compounds that combines and disturb itself and native ligand with Chemokine Receptors.Compound of the present invention can be used as and shows that the protection target cell avoids the medicine of HIV infection effect.Compound of the present invention also can be used as the antagonist or the agonist of Chemokine Receptors, and has other biological activitys relevant with the ability of these compound chemokine inhibitings and its receptors bind.
Substituent further definition
In formula 1 compound, R can be the alkyl of straight or branched, perhaps can be cyclic, and can randomly be replaced by 1-2 substituting group that is selected from halogen, hydroxyl, alkoxyl group.Preferably, each R is H or lower straight alkyl (1-4C), is preferably methyl.
In following formula 1, Ar is the residue of aromatics part or heteroaromatic moiety, and this aromatics partly or heteroaromatic moiety contains single or the condensed ring system, and these ring systems contain 5-6 ring members in its single ring system, perhaps contain 9-12 member in its condensed ring system.Described residue can randomly be replaced.Randomly the example of aromatics of Qu Daiing and heteroaromatic group comprises benzene, naphthalene, dihydronaphthalene, naphthane, pyridine, quinoline, isoquinoline 99.9, imidazoles, benzoglyoxaline, azepine benzoglyoxaline, benzotriazole, furans, cumarone, thiazole, benzothiazole,  azoles, benzoxazol, pyrroles, indoles, imidazoles, tetrahydroquinoline, tetrahydroisoquinoline, pyrazoles, thiophene, different  azoles, isothiazole, triazole, tetrazolium,  diazole, thiadiazoles, tetrahydroglyoxaline and chromene.Nitrogenous and hetero-aromatic ring sulfur oxide is also included among the present invention.Particularly preferred Ar form is phenylene, pyridylidene or inferior pyrimidyl.
When the compound of formula (1) contained by " optional replacement " composition, these substituting groups were preferably halogen, nitro, cyano group, carboxylic acid; Optional alkyl, alkenyl or the cycloalkyl that replaces; The optional hydroxyl that replaces; The optional sulfydryl that replaces; The optional amino that replaces; The optional acyl group that replaces; Optional carboxylicesters, carbamate, carboxamide or the sulfanilamide (SN) group that replaces; Or optional aryl or the heterocyclic group that replaces.
The example of halogen comprises fluorine, chlorine, bromine, iodine etc., wherein preferred fluorine and chlorine.
The example that can choose the alkyl of replacement wantonly comprises C 1-10Alkyl comprises methyl, ethyl, propyl group etc., and the example that can choose the alkenyl of replacement wantonly comprises C 2-10Alkenyl, as allyl group, crot(on)yl, pentenyl, 3-hexenyl etc., and the cycloalkyl that can choose replacement wantonly comprises C 3-10Cycloalkyl is as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.In these these examples, C 1-6Alkyl, alkenyl and cycloalkyl are preferred.Optional substituting group can also be can choose replacement wantonly aralkyl (as phenyl C 1-4Alkyl) or assorted alkyl, for example phenyl methyl (benzyl), styroyl, pyridylmethyl, pyridyl ethyl etc.Heterocyclic radical can be to contain 1-4 heteroatomic 5 or 6 yuan of rings.
Can choose the hydroxyl of replacement and the example of sulfydryl wantonly and comprise that those contain the optional alkyl that replaces (as C 1-10Alkyl), as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group etc., preferred (C 1-6) alkyl; The optional cycloalkyl that replaces is (as C 3-7Cycloalkyl etc. are as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.); The optional aralkyl that replaces is (as phenyl-C 1-4Alkyl is as benzyl, styroyl etc.).When having two during in abutting connection with hydroxyl or sulfydryl substituting group, heteroatoms can pass through alkyl, as O (CH 2) nO and S (CH 2) nS (wherein n=1-5) connects.Example comprises methylenedioxy group, ethylenedioxy etc.Also can comprise sulphur-ether oxide groups such as sulfoxide and sulfone.
Other optional hydroxyl examples that replace comprise the optional C of replacement 2-4Alkyloyl (as ethanoyl, propionyl, butyryl radicals, isobutyryl etc.), C 1-4Alkyl sulphonyl (as methylsulfonyl, ethylsulfonyl etc.) and can choose the aromatics and the heterocycle carbonyl of replacement wantonly comprises benzoyl, pyridine carbonyl etc.
Substituting group on the optional amino that replaces can be bonded to each other and form cyclic amino (as 5-6 unit cyclic amino etc., as Pyrrolidine, piperazine, piperidines, tetramethyleneimine, morpholine, thiomorpholine, pyrroles, imidazoles etc.).Described cyclic amino can have substituting group, and substituent example comprises halogen (as fluorine, chlorine, bromine, iodine etc.), nitro, cyano group, hydroxyl, sulfydryl, amino, carboxyl, optional halogenated C 1-4Alkyl (as trifluoromethyl, methyl, ethyl etc.), optional halogenated C 1-4Alkoxyl group (as methoxyl group, oxyethyl group, trifluoromethoxy, trifluoro ethoxy etc.), C 2-4Alkyloyl (as ethanoyl, propionyl etc.), C 1-4Alkyl sulphonyl (as methylsulfonyl, ethylsulfonyl etc.), the number of preferred substituents is 1-3.
Amino can be substituted once or twice (forming secondary amine or tertiary amine), replaces the alkyl of available optional replacement, comprises C 1-10Alkyl (as methyl, ethyl and propyl group etc.); The optional alkenyl that replaces is as allyl group, crot(on)yl, pentenyl, 3-hexenyl etc.; Maybe can choose the cycloalkyl of replacement wantonly, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.Thus, C 1-6Alkyl, alkenyl and cycloalkyl are preferred.Also available aryl of amido or heterocyclic radical, aralkyl are (as phenyl C 1-4Alkyl) or assorted alkyl (as phenyl, pyridine, phenyl methyl (benzyl), styroyl, picolyl, pyridine ethyl etc.) is optional replaces.Heterocyclic group can be to contain 1-4 heteroatomic 5 or 6 yuan of rings.Chosen wantonly the substituting group that " can choose substituted-amino wantonly " is identical with those of " can choose the ring amino of replacement wantonly " defined above.
The amino C that can be able to be chosen wantonly replacement 2-4Alkyloyl (as ethanoyl, propionyl, butyryl radicals, isobutyryl etc.) replaces, or C 1-4Aromatic ring or heterocyclic substituted that alkyl sulphonyl (as methylsulfonyl, ethylsulfonyl etc.) or carbonyl or alkylsulfonyl replace are as benzenesulfonyl, benzoyl, pyridine alkylsulfonyl, pyridine carbonyl etc.The heterocycle definition as above.
The example that can choose the acyl group of replacement wantonly comprise carbonyl or alkylsulfonyl or with hydrogen bonded alkylsulfonyl; The alkyl that can choose replacement wantonly is (as C 1-10Alkyl is such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl etc., preferably rudimentary (C 1-6) alkyl); The cycloalkyl that can choose replacement wantonly is (as C 3-7Cycloalkyl etc. are as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.); The alkenyl that can choose replacement wantonly is (as C 2-10Alkenyl is as allyl group, crot(on)yl, pentenyl etc., preferably rudimentary (C 2-6) alkenyl etc.); The cycloalkenyl that can choose replacement wantonly is (as C 3-7Cycloalkenyls etc. are as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenyl methyl, 2-cyclohexenyl methyl etc.), optional 5-6 unit monocyclic aryl (as phenyl, pyridyl etc.).
The example that can choose the carboxylic acid ester groups (ester group) of replacement wantonly comprises that the alkyl that can choose replacement wantonly is (as C 1-10Alkyl is as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl etc., preferably rudimentary (C 1-6) alkyl etc.); The cycloalkyl that can choose replacement wantonly is (as C 3-7Cycloalkyl etc. are as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.); The alkenyl that can choose replacement wantonly is (as C 2-10Alkenyl is as allyl group, crot(on)yl, pentenyl, 3-hexyl etc., preferably rudimentary (C 2-6) alkenyl etc.); The cycloalkenyl that can choose replacement wantonly is (as C 3-7Cycloalkenyls etc. are as 2-cyclohexenyl methyl etc.), optional aryl (as phenyl, naphthyl etc.) and C 1-4Aryl, for example benzyl, styroyl etc.Also comprise methoxymethyl, methoxy ethyl etc.
Can choose the carboxylic acid amides of replacement and the example of sulfuryl amine group wantonly defines identical with the amine that above limits " can choose the amino of replacement wantonly ".
The example that can choose the aryl of replacement or heterocyclic radical wantonly comprises that phenyl, naphthyl or 5 or 6 yuan contain 1-4 heteroatomic heterocycle.Optional substituting group is identical with above-mentioned listed substituting group in itself.
Uncorrelated each other substituent R 1, R 2And R 3With similar at described in " optional substituting group " those.Preferably, R 1Be selected from above-mentioned optional substituting group, be preferably halogen, replacement or unsubstituted alkyl, replacement or unsubstituted hydroxyl, replacement or unsubstituted amino, replacement or unsubstituted sulfydryl and replacement or unsubstituted acyl.Preferably, k is 0-2, is preferably 0-1, is more preferred from 0.
Substituent R 2And R 3The preferable R that lists above that is selected from 1Preferred embodiment, perhaps, more preferably, they can couple together, and form saturated or unsaturated ring system, are preferably the benzo ring system.
In above-mentioned formula (1), the ring system example that contains the optional replacement that encircles A is dihydroquinoline, tetrahydroquinoline, pyrans pyridine, dihydropyrane pyridine, sulfo-pyrans pyridine, dihydrogen phosphorothioate pyrans pyridine, dihydro naphthyridine (dihydro naphthyridine), tetrahydrochysene naphthyridine.The oxide compound of sulfur heterocyclic ring is also included among the present invention.In containing the above-mentioned ring system of encircling A, optional nitrogen-atoms can perhaps can be the nitrogen-atoms of carboxamide, carbamate or sulfanilamide (SN) by the alkyl of hydrogen, replacement, alkenyl, cycloalkyl or acyl substituted.Preferable l is 1, and it is saturated preferably encircling A.Best composition is a tetrahydroquinoline.
In above-mentioned formula 1, X can be CH (pyrroles), O ( azoles), S (thiazole), NH or NR (imidazoles), and wherein R is C 1-6Alkyl or acyl group, alkylsulfonyl.In formula 1, the R of two vicinities 1And/or R 2And R 3Can link together, form a kind of optional replacement, 5-7 unit condensed ring.The example of condensed ring system includes but not limited to indoles, tetrahydro indole, benzoglyoxaline, Tetrahydrobenzimidazderivative, azepine benzoglyoxaline, benzoxazol, tetrahydro benzo  azoles, benzothiazole, tetrahydro benzothiazol.By R 2And R 3The preferred ring system that produces comprises the ring system that is produced by benzothiazole and benzoglyoxaline.
In the compound of formula 1, preferably, contain (a CR between the ring system of encircling A and ring E 2) nN in the connector is 0, i.e. this connection only is a covalent linkage.(CR in this article 2) nOther preferred embodiment be ethylidene or methylene radical, preferred methylene radical.In most preferred embodiment, nitrogen shown in the formula 1 and the connection of ring between the A are keys, and shown in nitrogen and the connector between the ring E be CH 2As shown, ring E can be by any position and this connector coupling, but preferably passes through position 2,4 or 5, and the best is by position 2.
In the compound of formula 1, the preferred value of j is 0-2, is preferably 1-2.The embodiment of Y can have very big variation, as long as Y does not contain nitrogen.Therefore, Y can be halogen, OH, SH, SO, SO 2Or the like; Perhaps Y is the substituting group of 1-20 carbon atom, for one or more described carbon, randomly contains heteroatoms such as O or S as substituting group.The preferred embodiment that does not contain N in Y comprises halogen, the optional alkyl that replaces, the optional hydroxyl that replaces, the optional sulfydryl that replaces and optional carboxylicesters and the saturated or undersaturated ring that replaces.These substituting groups are exactly substituting group recited above.When containing N among the Y, Y is selected from the above-mentioned part of this paper.In these substituting groups, " Z " is aromatics part or heteroaromatic moiety, contains 5-12 ring members.Therefore, Y can comprise ring single or that merge.The example of the preferred form of " Z " is identical with above-mentioned example about aromatic moieties " Ar ", but it is monovalent.
As shown.In certain embodiments, be defined as the R of H or alkyl (1-6C) by R 4Or R 5Replace R 4Or R 5Have the more definition of wide region, and can comprise the embodiment of the alkenyl, acyl group etc. of R and above-mentioned optional replacement.R 4And R 5Preferred form comprise those forms by R representative and the optional alkenyl that replaces.Preferred two R in addition 5Be connected to form the embodiment of cyclammonium, comprise and contain one or more extra heteroatomss such as the embodiment of N, O and/or S.
When Y contained N, its preferred form was the form of R when all being H or methyl (being preferably methyl) in all examples, is preferably H and two R 5Form during coupling.Particularly preferably be following form:
-(CR 2) mCN，
-(CR 2) mNR 5 2，
-(CR 2) mNR(CR 2) mNRR 4，
-(CR 2) mCO(CR 2) mNR 5 2，
-(CR 2) mZ and
-NR(CR 2) mZ，
And Y contains the form of guanidine radicals or NHNHR or amidino groups; Especially (CR 2) mBe CH 2, CH 2CH 2, or CH 2CH 2CH 2The time form, perhaps m is 0 form; And R 4Or R 5Be H or low alkyl group, alkenyl, or hydrogen, perhaps two R 5Form when identical.
Particularly preferably be-CH 2NH 2, CH 2CH 2NH 2,-CH 2NMe 2,-CH 2CH 2NMe 2,-CONH 2,-CONMe 2Or the like.
Preferred Z is the residue of the optional replacement of benzene,  azoles, imidazoles, thiazole, benzoglyoxaline, benzothiazole, benzoxazol, indoles, thiophene, tetrazine, pyrimidine, pyridine etc.
The compounds of formula 1 of the present invention can be mixed with can following mode administration pharmaceutical composition: the part; Through skin, comprise intravenously; Oral; And, give mammalian subject with other standard way that gives medicament according to the clinical practice of routine.
After the present invention is carried out total description, will be easier to understand above-mentioned identical content in conjunction with following embodiment, these embodiment only are illustrative, except as otherwise noted, otherwise should not think that they have limited the present invention.
Embodiment
Prepare intermediate 8-hydroxyl-5,6,7 according to Bridger etc. in the method described in the U.S. Patent application USSN 09/535314,8-tetrahydroquinoline and 8-amino-5,6,7, the 8-tetrahydroquinoline, this paper includes this patent application as a reference in.According to Bridger etc. at the intermediate of preparation described in U.S. Patent application USSN 60/232891 and the USSN 60/234510 N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1, the 4-benzenedicarboxamide, this paper includes these two patent applications as a reference in.According to An, H., Wang, T., Mohan, V., Griffey, R.H., Cook, P.D. prepare intermediate 1-N-tert-butoxycarbonyl-2-chloromethyl benzimidazole at Tetrahedron 1998,54 described in the 3999-4012.
General procedure:
Use mesylate or alkyl chloride to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-four Hydrogen-quinoline-8-yl)-amine carries out the alkylating general procedure of N-
Mesylate or alkyl chloride (are added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5 as 1-N-tert-butoxycarbonyl-2-chloromethyl benzimidazole (1-1.4 equivalent), 6,7,8-tetrahydrochysene-quinoline-8-yl)-and amine (or amine) (1-1.4 equivalent), N, N-diisopropylethylamine (or K 2CO 3) in the solution of (1.5-2 equivalent) and KI (0.05-0.16 equivalent), stirred the gained mixture 3-25 hour at 50-70 ℃ then, monitor with thin-layer chromatography by analyzing.Reaction mixture is used CH 2Cl 2(10mL/mmol amine) dilution is poured the gained mixture into saturated NaHCO then 3In the aqueous solution or the salt solution (10mL/mmol alcohol).Separate each phase, use CH 2Cl 2(3 * 10mL/mmol amine) extracting water.Dry organic phase (the Na that merges 2SO 4Or MgSO 4), under reduced pressure concentrate.Adopt the thick material of chromatography purification, obtain required N-alkylate.
General flow A: use NaBH 3CN carries out direct reductive amination
At room temperature, a carbonyl compound (～1-2 equivalent) is added in the solution of amine (1 equivalent) in anhydrous methanol that is stirring (concentration～0.1M).In case carbonyl dissolving (～5 minutes) is with 1 part of NaBH 3CN (～2-4 equivalent) adds, and at room temperature stirs gained solution.Under reduced pressure remove and desolvate, with CH 2Cl 2The NaOH aqueous solution of (amine of 20mL/mmol) and salt solution or 1.0M (10mL/mmol amine) is added in the residue.To respectively be separated, use CH 2Cl 2(3 * 10mL/mmol amine) extracting water.Dry organic phase (the Na that merges 2SO 4), under reduced pressure concentrate.Adopt the thick material of chromatography purification.
General flow B: with NaBH (OAc) 3Or NaBH 4Carry out direct reductive amination
At room temperature, with carbonyl compound (～1-2 equivalent), Glacial acetic acid (0-2 equivalent) and NaBH (OAc) 3(～1.5-3 equivalent) is added to the amine (1 equivalent) that stirring at CH 2Cl 2(concentration is～solution in 0.2M) in, at room temperature stir gained solution then.Then reaction mixture is poured into saturated NaHCO 3Or in the 1.0M NaOH aqueous solution (10mL/mmol amine).Isolate each phase, use CH 2Cl 2(3 * 10mL/mmol amine) extracting water.Dry organic phase (the Na that merges 2SO 4), under reduced pressure concentrate.Adopt the thick material of chromatography purification.
Similarly, at room temperature, carbonyl compound (1 equivalent) is added to the amine (1 equivalent) that stirring at anhydrous MeOH (in the solution in the concentration～0.1M).At room temperature stir this solution, perhaps reflux 4-24 hour.Add NaBH 4(1-2 equivalent) at room temperature stirs gained mixture～20 minute.Concentrate this reaction mixture, it is dissolved in CH 2Cl 2In, with saturated NaHCO 3The aqueous solution and saturated NaCl aqueous solution continuous washing.Use CH 2Cl 2(2x) extracting water layer, dry (MgSO 4) and concentrate the organic extract that merges.
General flow C: the reaction of alcohol and methylsulfonyl chloride
At room temperature (or 0 ℃) is added to methylsulfonyl chloride (～1.5 equivalent) alcohol (1 equivalent) and the Et that is stirring 3N (1.5-2 equivalent) is at CH 2Cl 2(or THF) (in the solution in the concentration～0.1M), at room temperature stirred the gained mixture 0.5-1 hour then.Pour reaction mixture into saturated NaHCO 3The aqueous solution or saturated NH 4Among the Cl (10mL/mmol amine).Isolate each phase, use CH 2Cl 2(3 * 10mL/mmol amine) extracting water.Dry organic phase (the Na that merges 2SO 4), under reduced pressure concentrate.Adopt the thick material of chromatography purification, perhaps in the N-alkylation step, need not be further purified and to use.
General flow D: use saturated HBr (g) solution in acetate to form salt
In the Glacial acetic acid (2mL) of alkali-free, be added in saturated HBr (g) solution (2mL) in the acetate.The ether (25mL) that adds large volume then forms solid sediment, and these precipitate are arrived at the bottom of the flask bottle, and decant is removed upper solution.(3 * 25mL) wash the solid of gained to decant ether, remove residual trace solvent under the vacuum.In order to carry out extra purifying, this solid is dissolved in the methyl alcohol, carry out redeposition with a large amount of ether.With ether washing gained solid, follow dry gained solid in vacuum (0.1Torr) by decant, obtain required compound.
Intermediate:
The preparation of 4-methylol phenyl aldehyde
In hydrogenation vessel, mix terephthalic acid two carbonyl aldehyde (30.02g, 224mmol), methyl alcohol (200mL), palladium (on gac) (10%, 3.02g) and 2-(amino methyl) pyridine (2.3mL, 22mol, 0.01 molar equivalent), in the hydrogen of 40psi, in the Parr hydrogenator, shook the gained reaction mixture 2.5 hours.With this mixture of diatomite filtration,, remove the solvent in the elutriant in the vacuum with this filter disc of methanol wash.Adopt column chromatography, purifying crude product on silica gel (EtOAc/ hexane, 1: 1) obtains white solid title compound (23.8g, 78%). 1H?NMR(CDCl 3)δ4.80(s，2H)，7.53(d，2H，J＝9Hz)，7.87(d，2H，J＝9Hz)，10.00(s，1H)。
6, the preparation of 7-dihydro-5H-quinoline-8-ketone
Figure A0181580200221
(85% purity, 82.22g 804mmol) are added to the 8-hydroxyl-5,6,7 that is stirring, and (13.96g is 93.6mmol) at anhydrous CH for the 8-tetrahydroquinoline with activated manganese dioxide 2Cl 2In the solution (400mL).The multiphase mixture of gained was stirred 18 hours, use diatomite filtration gained black slurries afterwards, use CH then 2Cl 2(3 * 50mL) washings.Concentrate the washes that merges, obtain 11.27g (82%) faint yellow solid title compound, this compound need not be further purified and can use in ensuing reaction. 1H?NMR(CDCl 3)δ2.17-2.25(m，2H)，2.82(t，2H，J＝7Hz)，3.04(t，2H，J＝6Hz)，7.37(dd，1H，J＝9，6Hz)，7.66(dd，1H，J＝9，1Hz)，8.71(dd，1H，J＝6，1Hz)； 13C?NMR(CDCl 3)δ22.2，28.6，39.2，126.6，137.3，140.5，147.6，148.6，196.5.ES-MSm/z148(M+H)。
The preparation of (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine:
Adopt the alkylating general flow of N-: with 1-N-tert-butoxycarbonyl-2-chloromethyl benzimidazole (13.22g, 49.6mmol), N, N-diisopropylethylamine (15.5mL, 89.2mmol) and potassiumiodide (0.41g, 8.2mmol) be added to the 8-amino-5,6 that is stirring, 7, (7.34g is 49.6mmol) at anhydrous CH for the 8-tetrahydroquinoline 3In the solution among the CN (250mL), stirred the gained mixture 3.5 hours at 60 ℃ then.Adopt column chromatography, on silica gel, carry out purifying (CH 2Cl 2/ MeOH, then be 97: 3 and 96: 4 at 99: 1), obtain orange viscosity oily intermediate amine (6.38g, 34%). 1H?NMR(CDCl 3)δ1.76(s，9H)，1.81-2.10(m，2H)，2.25-2.37(m，1H)，2.72-2.89(m，2H)，3.77-3.84(m，1H)，4.39(d，1H，J＝15.0Hz)，4.56(d，1H，J＝15.0Hz)，7.00-7.06(m，1H)，7.27-7.37(m，1H)，7.64-7.74(m，1H)，7.90-7.96(d，2H，J＝8.1Hz)，8.34(d，1H，J＝3.0Hz)； 13C?NMR(CDCl 3)δ20.13，28.48，29.00，29.20，47.15，56.89，86.20，115.32，120.28，122.06，124.43，124.85，132.77，133.74，137.01，142.44，147.10，149.22，154.90，157.72；ES-MSm/z279(M+H-boc)。
The preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine:
Figure A0181580200232
With 6,7-dihydro-5H-quinoline-8-ketone (3.99g, 27.1mmol) (5.96g 27.1mmol) in the solution in anhydrous MeOH (225mL), at room temperature stirred this mixture 69 hours then to be added to (2-amino methyl) the benzoglyoxaline dihydrochloride hydrate that is stirring.(2.06g 54.2mmol) is added in the gained solution, stirs the gained mixture 1.5 hours with sodium borohydride in two batches.Concentrate this reaction mixture in the vacuum, use CH then 2Cl 2(150mL) dilution.With saturated sodium bicarbonate aqueous solution (200mL) washing organic layer, use CH 2Cl 2(2 * 50mL) extracting water layers, the dry then organic layer (Na that merges 2SO 4), filter, concentrate in the vacuum.Adopt column chromatography, on silica gel, carry out purifying (CH 2Cl 2/ MeOH, then be 98: 2 and 96: 4 at 99: 1), obtain intermediate amine (3.59g, 50%). 1H?NMR(CDCl 3)δ1.66-1.90(m，3H)，1.91-2.00(m，1H)，2.00-2.17(m，1H)，2.33-2.69(br?m，1H)，3.88-3.96(m，1H)，4.37(d，1H，J＝3.0Hz)，7.18-7.26(m，4H)，7.48(d，1H，J＝6.0Hz)，7.58-7.78(br?m，1H)，8.55-8.58(m，1H)； 13C?NMR(CDCl 3)δ19.66，29.12，30.24，46.62，57.28，122.21，122.83，133.55，138.07，146.98，156.17，157.73。
Embodiment 1
AMD9679:N '-(1H-benzimidazolyl-2 radicals-ylmethyl) N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1, the preparation of 3-benzene dimethylamine
Under the room temperature, (5.69g, 43mmol) (17.0g 80mmol) is added to the 8-amino-5,6,7 that is stirring, and (6.43g is 43mmol) at CH for the 8-tetrahydroquinoline with nitrilotriacetic base sodium borohydride with the 3-cyanobenzaldehyde 2Cl 2In the solution (450mL), stirred this mixture then 16 hours.With 1N NaOH (200mL) stopped reaction, isolate each phase.Dry organic phase (Na 2SO 4), under reduced pressure concentrate, obtain yellow oil (11.7g), adopt flash chromatography, on silica gel, carry out purifying (97: 3 CH 2Cl 2/ CH 3OH), obtain faint yellow solid N-(5,6,7,8-tetrahydrochysene-8-quinolyl)-3-cyano group phenmethyl amine (9.10g, 81%).
The alkylating general flow of N-is carried out in employing: make above-mentioned material (4.17g, 15.8mmol), (130mg, 0.80mmol) and N, (5.2mL is 30mmol) at CH for the N-diisopropylethylamine for potassiumiodide 3Solution among the CN (160mL) and N-(tert-butoxycarbonyl)-2-chloromethyl benzimidazole (as An, H.; Wang, T.; Mohan, V.; Griffey, R.H.; Cook, P.D Tetrahedron 1998,54,3999-4012 is described to be made) (4.22g, 15.8mmol) reaction.Adopt flash chromatography, purifying gained roughage on silica gel (1: 1 EtOAc/ hexane) obtains the alkylating product of yellow spumescence (6.86g, 88%).
Raney nickel (approximately 1g) is added to the above-mentioned material that obtains that is contained in the Parr bottle at NH 3In the solution in the saturated methyl alcohol (100mL), in the Parr hydrogenator, under the hydrogen of 50psi, make this mixture hydrogenation 17 hours then.The products therefrom mixture is filtered on Celite 521, and vacuum is removed the solvent in the elutriant.Adopt flash chromatography, the thick material (5%CH of purifying on silica gel 2Cl 2/ CH 3OH/NH 4OH, then be 18: 1: 1 at 19: 1: 0), obtain xanchromatic spumescence solid AMD9679 (4.36g, 79%). 1H?NMR(CDCl 3)δ1.58-1.75(m，1H)，1.96-2.09(m，2H)，2.24-2.30(m，1H)，2.70-2.94(m，2H)，3.74(s，2H)，3.78(s，2H)，3.94-4.20(m，3H)，7.07(d，1H，J＝7.5Hz)，7.15-7.21(m，4H)，7.30(d，1H，J＝7.5Hz)，7.36(s，1H)，7.43(d，1H，J＝7.5Hz)，7.47(s?br，2H)，8.67(d，1H，J＝4.2Hz)。 13C?NMR(CDCl 3)δ21.77，23.70，29.65，46.47，49.12，54.51，60.78，121.93(2)，122.65，126.45，127.61，127.98，128.83，135.23，137.70，140.08，142.72，147.27，156.35，157.72。ES-MSm/z398(M+H)。C 25H 27N 51.0H 2O0.23CH 2Cl 2Analytical value: C, 69.65; H, 6.82; N, 16.10.Actual value: C, 69.57; H, 6.91; N, 16.30.
Embodiment 2
AMD9720:(1H-benzimidazolyl-2 radicals-ylmethyl)-(2-amino methyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of [1-(tert-butoxycarbonyl)-1H-benzimidazolyl-2 radicals-ylmethyl)]-(2-cyano group-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
Adopt general flow B: with NaBH (OAc) 3(240mg, 1.13mmol) be added to [1-(tert-butoxycarbonyl)-1H-benzimidazolyl-2 radicals-ylmethyl)]-(197mg, 0.523mmol) (91.2mg is 0.695mmol) at CH with the 2-cyanobenzaldehyde for (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine 2Cl 2In the solution (5mL), stirred overnight gained mixture.Adopt oily matter (15g silica gel, 50: 1: 1 the CH of purified by flash chromatography gained 2Cl 2/ CH 3OH/NH 4OH), obtain required intermediate (167mg, 65%). 1H?NMR(CDCl 3)δ1.72(s，9H)，1.91-2.15(m，2H)，2.31-2.42(m，1H)，2.62-2.86(m，2H)，4.12(d，1H，J＝15.6Hz)，4.29(d，1H，J＝15.8Hz)，4.38(dd，1H，J＝9.6，6.1Hz)，4.64(s，2H)，6.93(t，1H，J＝7.6Hz)，7.00(dd，1H，J＝7.5，4.7Hz)，7.14-7.32(m，5H)，7.58-7.69(m，3H)，8.44(d，1H，J＝4.6Hz)。
Raney nickel (200mg) is added to the above-mentioned material that obtains that is contained in the Parr bottle, and (101mg is 0.204mmol) at NH 3In the solution in the saturated methyl alcohol (4mL), in the Parr hydrogenator, under the hydrogen of 50psi, make this mixture hydrogenation 16 hours then.Make the products therefrom mixture at diatomite filtration, vacuum is removed the solvent in the elutriant.Adopt the thick material of purified by flash chromatography (12g silica gel, 50: 1: 1 CH 2Cl 2/ CH 3OH/NH 4OH), obtain de-protected free alkali (freebase) (30mg, 37%).
Adopt general flow D: the amine that obtains is above changed into hydrobromate, obtain AMD9720 (39mg, 77%). 1H?NMR(D 2O)δ1.80-1.97(m，1H)，2.17-2.37(m，2H)，2.42-2.54(m，1H)，2.99-3.08(m，2H)，3.91(d，1H，J＝13.0Hz)，4.16(d，2H，J＝13.7Hz)，4.32-4.41(m，2H)，4.54(d，1H，J＝16.4Hz)，6.89-7.00(m，2H)，7.15(t，1H，J＝7.2Hz)，7.41(d，1H，J＝7.5Hz)，7.48-7.61(m，4H)，7.88(dd，1H，J＝7.7，5.9Hz)，8.36(d，1H，J＝8.0Hz)，8.71(d，1H，J＝5.7Hz)。 13C NMR (D 2O) δ 20.46,20.90,27.92,40.14,48.91,53.45,62.31,113.93 (2 carbon), 126.12,126.79 (2 carbon), 129.35,129.84,129.98,130.67,131.52,131.94,135.10,140.10,141.02,148.08 (2 carbon), 150.57,150.88.ES-MSm/z398(M+H)。C 25H 27N 53.0HBr1.9H 2The analytical value of O: C, 44.52; H, 5.05; N, 10.38; Br, 35.54.Actual value: C, 44.42; H, 4.97; N, 10.15; Br, 35.86.
Embodiment 3
Figure A0181580200261
AMD11090:(2-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(S)-5,6,7, the preparation of 8-tetrahydrochysene-quinoline-8-base-amine (hydrochloride)
The preparation of 2-(phthalyl amido-methyl)-phenyl aldehyde:
In batches with LAH (14.3g, 377mmol) be added to stirring, (10.4g is 79.0mmol) in the solution in anhydrous THF (320mL) for refrigerative (0 ℃) 2-cyanobenzaldehyde.These slurries were at room temperature stirred 15 hours in nitrogen.Use distilled water (15mL) slowly with this stopping of reaction, add 15% (w/v) NaOH (15mL) then, then add more distilled water (45mL).Stirred this mixture 20 minutes, and, removed by filter white floccule thing with ether (200mL) dilution.With filtrate drying (MgSO 4), concentrate in a vacuum then.In ensuing reaction, need not to be further purified the amino alcohol (12.6g) that can use gained.
(12.3g is 83mmol) at 20%MeOH/CHCl with the alcohol that obtains above (general 79mmol) and Tetra hydro Phthalic anhydride 3Solution (200mL) refluxes and stirred 19 hours.With gained mixture cool to room temperature, (8 centimeter inner diameter (id.), 300g silica gel is used 1%MeOH/CH to adopt purified by flash chromatography 2Cl 2Wash-out),, obtains required alcohol, be the solid of baby pink (7.11g, above the yield of two steps be 34%) then with its recrystallization from the methylene dichloride of heat.
In 30 minutes time, (7.11g is 27mmol) at CH with above-mentioned alcohol 2Cl 2Drips of solution (50mL) be added to TPAP (465mg, 1.3mmol), NMO (4.7g, 40mmol) and 3  molecular sieves (14g) at CH 2Cl 2In the solution (220mL).After adding end, in nitrogen, stirred these black slurries 40 minutes, concentrate in a vacuum, adopt purified by flash chromatography (8 centimeter inner diameter, 300g silica gel are used the EtOAc wash-out), obtain pure title compound, be white solid (5.75g, 82%). 1H?NMR(CDCl 3)δ5.38(s，2H)，7.24-7.28(m，1H)，7.44-7.54(m，2H)，7.74-7.78(m，2H)，7.85-7.92(m，3H)，10.35(s，1H)。
(2-amino methyl-benzyl)-(1H-benzyl imidazole-2-ylmethyl)-(S)-5,6,7,8-tetrahydrochysene-quinoline-8-base-amine (hydrochloride) preparation (AMD11090):
Adopt general flow B: make 2-(phthalyl amino-methyl)-phenyl aldehyde of obtaining above (5.44g, 20.5mmol) with S-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (3.34g, 22.6mmol) and NaBH (OAc) 3(21.2, the 100mmol) solution in methylene dichloride (2.0L) reaction.(8 centimeter inner diameter, 250g silica gel is used 5%MeOH/CH to adopt flash chromatography to carry out purifying 2Cl 2) wash-out), obtain purity and be 2 ° amine, be white foam (6.83g, 84%).
With diisopropylethylamine (4.5mL, 26mmol), the 1-boc-2-chloromethyl benzimidazole (5.0g, 19mmol) and potassiumiodide (145mg, (6.83g is 17mmol) in the solution in acetonitrile (170mL) 0.86mmol) to be added to the amine that obtains above.At 60 ℃, at N 2Stirred the gained mixture 15 hours in the atmosphere, then it is cooled to room temperature, and concentrate in a vacuum.The gained residue is distributed in methylene dichloride (200mL) and salt solution (100mL).Dry (MgSO 4) organic layer separated, it is concentrated, (8 centimeter inner diameter, 300g silica gel is used CH to adopt purified by flash chromatography 2Cl 2Wash-out is removed unreacted muriate, adds 2%MeOH/CH then 2Cl 2Wash-out obtains required product), thus pure required amine (7.6g, 70%) obtained.
(2.2g, (4.44g 7.1mmol) at the solution of ethanol (35mL) and methylene dichloride (2mL is used for dissolving), stirred the gained mixture 16 hours 44mmol) to handle the amine that obtains above with a hydrazine hydrate.Concentrate this mixture then in a vacuum, (5 centimeter inner diameter, 80g silica gel is used 3%MeOH/CH to adopt purified by flash chromatography 2Cl 2Wash-out), obtains unprotected amine, be white foam shape solid (2.05g, 73%).
HCl gas is blown into the amine that obtains above, and (2.05g 5.2mmol) in the solution in Glacial acetic acid (20mL) 10 minutes, stirs simultaneously.This solution was at room temperature stirred 5 minutes, slowly it is dripped to then in the ether (200mL), simultaneously vigorous stirring.Make the funnel suction strainer of gained slurries by glass sintering, use then ether washing and filtering sheet (5 * 50mL), be placed in 40 ℃ the vacuum drying oven dry 60 hours then, obtain white solid AMD11090 (2.71g, 96%). 1H NMR (D 2O) δ 1.79-1.97 (m, 1H), 2.17-2.35 (m, 2H), 2.44-2.49 (m, 1H), and 3.00-3.05 (m, 2H), 3.89 (d, 1H, J=13.5Hz), 4.15 (d, 2H, J=14.1Hz), 4.30-4.40 (m, 2H), 4.52 (d, 1H, J=16.4Hz), and 4.73-4.78 (m, 1H), 6.87-6.98 (m, 2H), 7.12 (td, 1H, J=1.2,7.5Hz), 7.38 (d, 1H, J=7.5Hz), 7.47-7.52 (m, 2H), 7.54-7.60 (m, 2H), 7.85-7.90 (m, 1H), 8.36 (d, 1H, J=8.1Hz), 8.71 (d, 1H, J=5.1Hz); 13C NMR (D 2O) δ 20.44,20.86, and 27.91,40.16,48.88,53.52,62.31,113.91 (2 carbon), 126.15,126.80 (2 carbon), 129.33,129.78,129.89,130.58,131.54,131.96,135.01,140.03,141.08,148.19,150.45,150.82.ES-MSm/z398 (M+H).C 25H 27N 53HCl2H 2O0.1CH 3The analytical value of COOH: C, 55.14; H, 6.32; N, 12.76; Cl, 19.38.Actual value: C, 55.47; H, 6.50; N, 12.38; Cl.19.26.
Adopt chirality HPLC, the enantiomeric purity that uses following condition to record AMD11090 is 100%: instrument is Hewlett Packard 1100 HPLC (VWD4); Post is ChiralCelOD, 0.46cm * 25cm; Mobile phase is A:95: 5 hexane/the contain methyl alcohol of 0.1%DEA, B: hexane; Average (Isocratic): 80%A, 20%B; Total run time: 45 minutes; Flow velocity: 0.5mL/ minute; Temperature: 40 ℃; Detector: at the UV of 270 nanometers; Volume injected: 10 μ L.
Residence time=28.7 of S enantiomorph minute.
Residence time=32.6 of R enantiomorph minute.
Embodiment 4
AMD11083:(3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-preparation of methyl alcohol
The preparation of 4-brooethyl-3-cyano group-methyl benzoate:
(0.016mL, (288mg 4.41mmol) in the suspension in THF (1mL), with gained mixture heating up to 70 ℃, kept 10 minutes 0.19mmol) to be added to zinc powder with glycol dibromide.Make the gained mixture be cooled to room temperature, (0.016mL 0.13mmol), at room temperature continues to stir 30 minutes then to add TMSC1.Mixture is cooled to 0 ℃, and (842mg, the 3.68mmol) solution in THF (4mL) continue to stir 2 hours at 0 ℃ to add 4-(brooethyl) methyl benzoate with 2 hours times.The gained mixture is cooled to-78 ℃ then, (571mg, the 3.15mmol) solution in THF (4mL) at room temperature stirred the gained mixture 18 hours to add the tosyl group prussiate.Concentrate this mixture in a vacuum, make residue then at CH 2Cl 2(20mL) with saturated NaHCO 3(aqueous solution) is middle the distribution (20mL).Use CH 2Cl 2(this water of 3 * 10mL) extractings, the dry organic extract (MgSO that merges 4), concentrate in a vacuum.Adopt column chromatography, purifying on silica gel (10%EtOAc/ hexane) obtains colourless crystal (379mg).Adopt 1H NMR records the mixture that this crystal is 3-cyano group-4-methyl-methyl benzoate and unidentified by product, and need not to be further purified this mixture in next step can use.
With the nitrile (379mg) that obtains above, NBS (400mg, 2.25mmol) and AIBN (53mg is 0.32mmol) at CCl 4Mixture reflux (11mL) 4 days makes it be cooled to room temperature then.Filter this mixture, concentrated filtrate in the vacuum.Adopt column chromatography, this thick material of purifying (5%EtOAc/ hexane) on silica gel obtains colourless crystal (100mg, 12%). 1H?NMR(CDCl 3)δ?3.96(s，3H)，4.66(s，2H)，7.65(d，1H，J＝8.1Hz)，8.23(dd，1H，J＝8.1，1.5Hz)，8.33(d，1H，J＝1.5Hz)。
With 2-[(5,6,7,8-tetrahydrochysene-quinoline-8-base is amino)-methyl]-benzoglyoxaline-1-carboxylic acid tertiary butyl ester (175mg, 0.462mmol), 4-brooethyl-3-cyano group-methyl benzoate) 98mg, 0.39mmol), potassiumiodide (4mg, 0.02mmol) and N, (0.10mL, 0.57mmol) mixture in acetonitrile (4.0mL) was 60 ℃ of heating 16 hours for the N-diisopropylethylamine.Heat saturated NaHCO 3(aqueous solution) (15mL) uses CH 2Cl 2(3 * 10mL) extractings.Dry organic extract (MgSO 4), concentrate in the vacuum.The thick material of purifying (500: 5: 1 CH on silica gel 2Cl 2/ MeOH/NH 4OH), obtain yellow oil (213mg, 100%). 1H?NMR(CDCl 3)δ1.73(m，10H)，2.01(m，2H)，2.38(m，1H)，2.76(m，2H)，3.86(s，3H)，4.17(d，1H，J＝17Hz)，4.29(d，1H，J＝17Hz)，4.37(m，1H)，4.58(d，1H，J＝14Hz)，4.69(d，1H，J＝14Hz)，7.01(dd，1H，J＝7.5，4.5Hz)，7.18(m，2H)，7.31(d，1H，J＝7.5Hz)，7.58(m，2H)，7.76(d，2H，J＝1.2Hz)，7.87(s，1H)，8.44(m，1H)。
In room temperature, in hydrogen atmosphere (45psi), make 2-{[(2-cyano group-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl } (213mg is 0.386mmol) at saturated NH for benzoglyoxaline-1-carboxylic acid tertiary butyl ester 3(g)/ solution and Raney among the MeOH (10mL) The suspension of nickel (1.5g) shook 17 hours.Remove by filter crystallization, vacuum concentrated filtrate obtains green foam (195mg).
(220mg 1.01mmol) is added in the solution of thick amine (195mg) in THF (4mL) that obtains above, at room temperature stirs gained solution 3 days with di-t-butyl carbonic acid hydrogen ester.This solution of vacuum concentration is with filtered through silica gel residue (600: 5: 1 CH 2Cl 2/ MeOH/NH 4OH), obtain yellow foam (130mg).
At 0 ℃, with LiAlH 4(1.0M/THF, 0.20mL 0.20mmol) are added in the solution of thick ester (130mg) in THF (2mL) that obtains above, stir the gained mixture 15 minutes at 0 ℃.Add methyl alcohol (1mL), then add 10%HCl (aqueous solution) (1mL).Add saturated NaHCO 3(aqueous solution) (30mL) makes this mixture become alkalescence, uses CH then 2Cl 2(4 * 12mL) extractings.Dry (MgSO 4) organic extract of merging, vacuum concentration obtains yellow foam (116mg).
In room temperature, with the thick alcohol (116mg) that obtains above TFA/CH at 3: 1 2Cl 2Solution stirring (4mL) 50 minutes, vacuum concentration then.Make the gained residue at CH 2Cl 2(10mL), use CH with (15mL) middle distribution of 1N NaOH (aqueous solution) 2Cl 2(2 * 10mL) extracting waters.The dry organic extract that merges, vacuum concentration.Adopt column chromatography, the thick material of purifying is (200: 5: 1-50: 5: 1 CH on silica gel 2Cl 2/ MeOH/NH 4OH), obtain yellow foam AMD11083 (25mg, 12%). 1H?NMR(CDCl 3)δ1.54(m，1H)，1.93(m，2H)，2.19(m，1H)，2.57-2.80(m，2H)，3.52-3.88(m，7H)，4.54(s，2H)，6.93(m，1H)，7.04(d，1H，J＝7.5Hz)，7.15(m，4H)，7.25(m，1H)，7.54(m，2H)，8.39(d，1H，J＝3.6Hz)； 13C?NMR(CDCl 3)δ21.77，21.94，29.47，43.14，49.34，53.99，59.72，64.62，115.42，122.27，122.36，126.33，129.10，131.52，135.04，135.66，137.51，141.25，142.14，147.24，154.27，156.94.?ES-MS?m/z?428?(M+H)。C 26H 29N 5O0.2H 2O1.2CH 2Cl 2Analytical value: C, 61.29; H, 6.01; N, 13.14.Actual value: C, 61.36; H, 6.02; N, 12.84.
Embodiment 5
Figure A0181580200311
AMD11120:(2-amino methyl-3-methoxyl group-benzyl)-and (1H-benzimidazolyl-2 radicals-ylmethyl)-5,6,7,8-tetrahydrochysene-quinoline-8-yl)-preparation of amine (hydrobromate)
(0.467g, (1.23g 6.33mmol) in the solution in anhydrous diethyl ether (58mL), refluxes the mixture heating up of gained 2 hours, is cooled to room temperature then 12.31mmol) to be added to 2-methoxyl group-6-methyl-toluate with LiAlH4.Water (0.45mL), the 15%NaOH aqueous solution (0.45mL) and water (1.35mL) are handled this mixture successively.Use Celite Filter this mixture, (200mL) washs this filter with ether.Concentrated filtrate under reduced pressure obtains yellow solid 2-methoxyl group-6-methylbenzyl alcohol of 0.96g (99%). 1H?NMR(CDCl 3)δ2.27(t，1H，J＝6.3Hz)，2.39(s，3H)，3.86(s，3H)，4.75(d，2H，J＝6.3Hz)，6.76(d，1H，J＝8.4Hz)，6.81(d，1H，J＝7.8Hz)，7.17(dd，1H，J＝7.8，8.4Hz)。
(2.00mL, (0.96g is 6.32mmol) at CH 14.35mmol) to be added to 2-methoxyl group-6-methylbenzyl alcohol with triethylamine 2Cl 2In the solution (35mL), then add methylsulfonyl chloride (0.90mL.11.63mmol), heated the gained solution 45 minutes at 40 ℃, then it is cooled to room temperature.Use CH 2Cl 2(35mL) dilute this mixture, and the water washing of usefulness salt (3 * 15mL), dry (Na 2SO 4), concentrate then, obtain faint yellow solid.This solid (1.12g) is dissolved among the DMF (35mL), and (2.62g 14.15mmol) handles, 80 ℃ of heated overnight with potassium phthalimide.This mixture is cooled to room temperature, with EtOAc (70mL), salt solution (35mL) and water (20mL) dilution.Isolate each phase, with 1.0N NaOH (6 * 10mL) and salt solution (2 * 10mL) wash organic phases.Dry this organic phase (MgSO 4), then it is concentrated, obtain faint yellow solid.With hexane clean this solid (3 * 10mL), obtain white solid (2-methoxyl group-6-methyl-benzyl) phthalamide of 1.18g (66%). 1H?NMR(CDCl 3)δ2.53(s，3H)，3.75(s，3H)，4.89(s，2H)，6.70(d，1H，J＝8.4Hz)，6.80(d，1H，J＝7.5Hz)，7.15(dd，1H，J＝7.5，8.4Hz)，7.66-7.68(m，2H)，7.76-7.80(m，2H)； 13C?NMR(CDCl 3)δ20.27，34.95，55.90，108.61，122.38，123.17，123.41，128.97，132.60，134.07，139.55，158.70，168.36。
(0.177g, (0.286g is 1.02mmol) at CCl 0.99mmol) to be added to (2-methoxyl group-6-methyl-benzyl) phthalamide with the N-bromine succinimide of recrystallization 4In the solution (25mL), then add the peroxidation toluoyl (28mg, 0.11mmol).The mixture of reflux gained 90 minutes is cooled to room temperature with it then.(25mL) dilutes this mixture with ether, uses filter paper filtering, concentrated filtrate.Adopt the thick material of column chromatography purifying (3: 1 hexane-EtOAc), obtain white solid (6-(the brooethyl)-2-methoxy-benzyl) phthalamide of 0.31g (86%). 1H?NMR(CDCl 3)δ3.78(s，3H)，4.90(s，2H)，5.00(s，2H)，6.83(d，1H，J＝8.4Hz)，6.98(d，1H，J＝7.2Hz)，7.25(dd，1H，J＝7.2，8.4Hz)，7.67-7.69(m，2H)，7.78-7.81(m，2H).ES-MSm/z382(M+Na)，384(M+Na)。
With N, N-diisopropylethylamine (0.20mL, 1.15mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(0.202mg is 0.53mmol) in the solution of CH3CN (5mL) for amine, then adding (6-brooethyl)-2-methoxy-benzyl) (0.30g is 0.83mmol) at CH for phthalamide 3Suspension among the CN (5mL).With gained mixture heating up to 60 ℃, kept 18 hours, be cooled to room temperature then.Concentrate the gained mixture, make the gained residue at CH 2Cl 2(40mL) and in the salt solution (10mL) distribute.Isolate each phase, use CH 2Cl 2(3 * 10mL) extracting waters.The dry organic extract (Na that merges 2SO 4), concentrate then.Adopt column chromatography, the thick material of purifying (50: 1 CH on silica gel 2Cl 2-CH 3OH), obtain the white solid of 0.212g (60%).
The solid (0.21g) that obtains above is dissolved in the ethanol (6mL), and (0.31mL 6.4mmol) handles, and at room temperature stirs and spends the night with a hydrazine hydrate.Concentrate this mixture, with CH 2Cl 2(50mL) be added in this residue.Use Celite Filter the suspension of gained, use CH 2Cl 2(50mL) washing and filtering sheet.Under reduced pressure concentrate this filtrate, make this residue then at CH 2Cl 2(40mL) and among the 1.0N NaOH (10mL) distribute.Isolate each phase, use CH 2Cl 2(3 * 10mL) extracting waters.The dry organic extract (Na that merges 2SO 4), concentrate then.Adopt radial chromatography, this thick material of purifying (1mm flat board, 50: 1: 1 CH on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 30mg (22%), be white solid.
Adopt general flow D: (30mg 0.071mmol) changes into hydrobromate, then makes this intermediate precipitation again in methyl alcohol/ether, obtains white solid AMD11120 (34mg, 67%) with the solid that obtains above. 1HNMR (D 2O) δ 1.91-1.99 (m, 1H), 2.20-2.38 (m, 2H), 2.46-2.50 (m, 1H), 3.05-3.13 (m, 2H), 3.38 (s, 3H), 3.90 (d, 1H, J=12.9Hz), 4.11 (d, 1H, J=12.9Hz), 4.16 (d, 1H, J=12.9Hz), 4.29 (d, 1H, J=12.9Hz), 4.34 (d, 1H, J=16.5Hz), 4.54 (d, 1H, J=16.5Hz), (4.74-4.79 m, 1H overlap with HOD), 6.50 (d, 1H, J=8.4Hz), 7.01 (d, 1H, J=7.8Hz), 7.21 (dd, 1H, J=7.8,8.4Hz), 7.52-7.61 (m, 4H), 7.94 (dd, 1H, J=6.0,7.8Hz), 8.42 (d, 1H, J=7.8Hz), 8.77 (d, 1H, J=6.0Hz); 13C NMR (D 2O) δ 20.44,20.98, and 27.93,35.25,48.97,53.77,55.72,62.69,111.43,113.85,119.53,124.35,126.25,126.89,130.42,131.20,136.39,139.95,141.28,148.39,150.35,151.05,157.88. ES-MS m/z 428 (M+H).C 26H 22N 5O3.0HBr2.8H 2The analytical value of O: C, 43.33; H, 5.26; N, 9.72; Br, 33.26.Actual value: C, 43.47; H, 5.14; N, 9.61; Br, 33.00.
Embodiment 6
AMD9903:(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-[(1-amino methyl)-benzoxazol)-3-base-methyl)]-preparation of amine (hydrobromate)
1-[N-(tert-butoxycarbonyl)-amino methyl]-preparation of 3-hydroxymethyl  azoles
Figure A0181580200332
People's such as employing P.Wipf method (A.J.Phillips, Y.Uto, P.Wipf, M.J.Reno and D.R.Williams Org.Lett.2000,2 (8), 1165-1168), with the amino sulphur trifluoride (0.125mL of two (2-methoxy ethyls), 0.677mmol) processing N-(tert-butoxycarbonyl-Gly-Ser-OMe (170mg, 0.615mmol)-20 ℃ of solution in methylene dichloride (5mL).Stirred gained solution 30 minutes at-20 ℃ then.Heat then bromo-trichloromethane (0.212mL, 2.21mmol), then add DBU (0.330mL, 2.21mmol).Make reaction be warming to 0 ℃, and stirred 5 hours, add aqueous ammonium chloride solution then in this temperature.After isolating water layer and organic layer, use twice of methylene dichloride extracting water layer.The organic moiety that merges with anhydrous sodium sulfate drying then, and it is concentrated.Adopt chromatography, carrying out purifying (solution of 2% methyl alcohol in methylene dichloride) on the silica gel, obtain oily matter methyl isophthalic acid-[N-(tert-butoxycarbonyl)-amino methyl]- azoles-3-carboxylicesters (123mg, 78%). 1H?NMR(CDCl 3)δ1.25(s，9H)，3.88(s，3H)，4.51(d，2H，J＝5.8Hz)，5.22(br?s，1H)，8.19(s，1H)。
(solution of 1M in methylene dichloride, 2.08mL 2.08mmol) handle this ester (178mg, 0.695mmol) solution in 0 ℃ methylene dichloride (8mL) with DIBAL-H.Before handling, stirred this mixture 2 hours at 0 ℃ earlier then with 5% sodium tartrate aqueous solutions of potassium (8%).Stir this mixture 30 minutes (becoming clear) fast, then these layers are separated up to water layer and organic layer.With twice of this water layer of methylene dichloride extracting.The organic moiety that merges with anhydrous sodium sulfate drying concentrates it then then.Adopt chromatography,, obtain oily 1-[N-(tert-butoxycarbonyl)-amino methyl carrying out purifying (solution of 5% methyl alcohol in methylene dichloride) on the silica gel]-3-hydroxymethyl  azoles (45mg, 28%). 1H?NMR(CDCl 3)δ1.40(s，9H)，4.43(d，2H，J＝5.6Hz)，4.56(s，2H)，5.37(s，1H)，7.54(s，1H)。
With triethylamine (0.055mL, 0.4mmol) be added to 1-[N-(the tert-butoxycarbonyl)-amino methyl that is stirring]-3-hydroxymethyl  azoles (45mg, 0.197mmol) in the solution of methylene dichloride (5mL), then add methylsulfonyl chloride (0.023mL, 0.3mmol).Before using saturated aqueous ammonium chloride solution (5mL) processing, at room temperature stirred gained solution 20 minutes.With twice of methylene dichloride extracting water layer.The organic moiety that merges with anhydrous sodium sulfate drying then, and it is concentrated, obtaining required mesylate, this product need not be further purified and can directly and be used for ensuing reaction immediately. 1H?NMR(CDCl 3)δ1.45(s，9H)，3.07(s，3H)，4.43(d，2H，J＝5.6Hz)，5.15(s，2H)，7.73(s，1H)。
The alkylating general flow of N-is carried out in employing; make O-methylsulfonyl-1-[N-(tert-butoxycarbonyl)-amino methyl]-3-methylol  azoles (0.197mmol) and diisopropylethylamine (0.05mL; 0.295mmol) and (1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5; 6; 7; 8-tetrahydroquinoline-8-yl)-(95mg 0.25mmol) stirred 4 hours in 60 ℃ acetonitrile (5mL) amine.Make the reactant cooling then, and it is concentrated.In methylene dichloride, obtain residue, use the aqueous ammonium chloride solution extracting, dry, concentrate, adopt chromatography purifying (methylene dichloride of 20: 1: methyl alcohol), obtain [N-(tert-butoxycarbonyl)-benzimidazolyl-2 radicals-Ji-methyl]-(5 on silica gel, 6,7,8-tetrahydroquinoline-8-yl)-{ [1-N-(tert-butoxycarbonyl)-amino methyl]-benzoxazol-3-base-methyl }-amine (23mg, 19%). 1H?NMR(CDCl 3)δ1.46(s，9H)，1.63(s，9H)，1.91(m，1H)，2.02(m，1H)，2.24(dq，1H，J＝6.8，2.1Hz)，2.51(m，1H)，2.61-2.78(m，2H)，4.27(m，1H)，4.43(d，2H，J＝5.8Hz)，4.49(s，2H)，4.73(d，1H，J＝16.1Hz)，5.09(d，1H，J＝16.1Hz)，5.15(m，1H)，6.88(dd，1H，J＝7.1，5.4Hz)，7.13(d，1H，J＝7.1Hz)，7.24(m，2H)，7.61(s，1H)，7.61(m，1H)，7.74(m，1H)，8.23(d，1H，J＝5.4Hz)。
From acetate (1mL), obtain [N-(tert-butoxycarbonyl)-benzimidazolyl-2 radicals-Ji-methyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-{ [1-N-(tert-butoxycarbonyl)-amino methyl]-benzoxazol-3-base-methyl }-amine (23mg, 0.039mmol), the saturated solution (1mL) of HBr in acetate is added in this material.Stir the gained mixture as flow process D then, precipitation is separated, and obtains white crystalline solid AMD9903 (14mg). 1H?NMR(D 2O).δ1.84(m，1H)，2.05(m，2H)，2.21(m，1H)，3.00(m，2H)，3.72(d，1H，J＝14.1Hz)，3.92(d，1H，J＝14.1Hz)，3.99(d，2H，J＝6.0Hz)，4.39(d，1H，J＝16.5Hz)，4.58(d，1H，J＝16.5Hz)，4.72(m，1H)，7.59(m，2H)，7.75(m，2H)，7.84(s，1H)，7.86(m，1H)，8.33(d，1H，J＝8.1Hz)，8.67(d，1H，J＝5.8Hz). 13C?NMR(D 2O)δ20.35，20.57，27.62，35.70，46.40，48.16，60.94，114.15(2C)，125.95，127.06(2C)，139.57，140.46，148.03，151.23，154.96。ES-MSm/z389 (M+H); (C 22H 24N 6O * 4HBr * 2.6H 2O) analytical value: C, 34.82; H, 4.41; N, 11.07; Br42.11.Actual value: C, 35.10; H, 4.44; N, 10.73; Br, 41.80.
Embodiment 7
AMD9986:(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-[(1-(benzyl-2-amino methyl)-imidazoles-5-ylmethyl]-preparation of amine
2, the preparation of 5-two-(hydroxymethyl)-N-benzyl imidazole
Adopt people (S.C.Zimmerman such as S.Zimmerman, K.D.Cramer and A.A.Galan J.Org.Chem.1989,54, method 1256-1264), handle N-benzyl imidazole (15g with formaldehyde (37% aqueous solution of 60mL), 95mmol), Glacial acetic acid (8mL) and sodium-acetate (10.5g) are added in the gained mixture.The mixture that stirs gained is transferred to this mixture in the heavy wall Glass tubing then up to evenly, with this seal of tube, is placed in 140 ℃ the oil bath 12 hours.Cool off this pipe then, concentrate, add 10N NaOH, make it become alkalescence, with 10: 1 Virahol: twice of chloroform mixture extracting.The organic moiety that merges with anhydrous sodium sulfate drying also concentrates then.Adopt chromatography at purifying on the silica gel (solution of 7% methyl alcohol in methylene dichloride), obtain white crystalline solid 2,5-two-(hydroxymethyl)-N-benzyl imidazole (4.9g, 24%). 1H?NMR(CDCl 3)δ4.41(s，2H)，4.48(s，2H)，5.36(s，2H)，6.77(s，1H)，7.00(m，2H)，7.28(m，3H)。
With triethylamine (0.35mL, 2.0mmol) and acetic anhydride (0.19mL 2.0mmol) is added to 2, and (436mg is 2.0mmol) in the solution in methylene dichloride (10mL) for 5-two-(hydroxymethyl)-N-benzyl imidazole.This mixture of stirred overnight at room temperature then.Wash this reactant with ammonium chloride then, isolate each phase.With twice of methylene dichloride extracting water.The organic moiety that merges with anhydrous sodium sulfate drying then, and it is concentrated.Adopt chromatography carrying out purifying (solution of 5% methyl alcohol in methylene dichloride) on the silica gel, obtain the monoacetate (300mg, 58%) of white powder 2-ethoxyl methyl-5-methylol-N-benzoglyoxaline. 1H?NMR(CDCl 3)δ1.83(s，3H)，4.49(s，2H)，5.06(s，2H)，5.33(s，2H)，6.97(m，2H)，7.28(m，3H)。
With triethylamine (0.104mL, 0.75mmol) be added to 2-ethoxyl methyl-5-methylol-N-benzoglyoxaline of stirring (130mg, 0.5mmol) in the solution in methylene dichloride (5mL), then add methylsulfonyl chloride (0.046mL, 0.6mmol).Using before saturated aqueous ammonium chloride solution (5mL) handles, at room temperature stirring the solution 20 minutes of gained.With twice of methylene dichloride extracting water layer.The organic moiety that merges with anhydrous sodium sulfate drying then, and it is concentrated, obtaining required mesylate, this product need not be further purified and can directly and be used for next step reaction immediately. 1H?NMR(CDCl 3)δ1.86(s，3H)，4.44(s，2H)，5.18(s，2H)，5.29(s，2H)，6.97(m，2H)，7.33(m，3H)。
The alkylating general flow of N-is carried out in employing; make O-methylsulfonyl-2-ethoxyl methyl-5-methylol-N-benzoglyoxaline (0.5mmol) and diisopropylethylamine (0.130mL; 0.75mmol) and (1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5; 6; 7; 8-tetrahydroquinoline-8-yl)-(226mg 0.6mmol) stirred 4 hours in 60 ℃ acetonitrile (5mL) amine.Make the reactant cooling then, and it is concentrated.In methylene dichloride, obtain residue, use the aqueous ammonium chloride solution extracting, dry, concentrate, adopt chromatography purifying (methylene dichloride of 20: 1: methyl alcohol), obtain [N-(tert-butoxycarbonyl)-benzimidazolyl-2 radicals-ylmethyl]-(5 on silica gel by dissociating of acetate groups, 6,7,8-tetrahydroquinoline-8-yl)-[(2-ethoxyl methyl-N-benzoglyoxaline-5-yl)-methyl]-amine (mixture, 138mg).
Product mixtures (138mg) with obtaining above the solution-treated of salt of wormwood (100mg) in methyl alcohol (5mL) at room temperature stirred this suspension 8 hours.Filter this mixture then, concentrate, adopt flash chromatography, methylene dichloride with 20: 1: carbinol mixture is an elutriant, and purifying residue on silica gel obtains weak yellow foam shape [1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-[(2-ethoxyl methyl-N-benzyl and imidazoles-5-yl)-methyl]-amine (100mg, two step yield are 43%). 1H?NMR(CDCl 3)δ1.61(m，1H)，1.89(m，2H)，2.15(m，1H)，2.70(m，2H)，3.56(d，1H，J＝15.1Hz)，3.68(d，1H，J＝15.1Hz)，4.00(s，2H)，4.01(m，1H)，4.35(s，2H)，5.28(s，2H)，6.64(m，2H)，6.88(s，1H)，7.07(m，4H)，7.17(m，2H)，7.34(d，1H，J＝7.8Hz)，7.54(br?s，1H)，8.45(d，1H，J＝4.8Hz)。
With triethylamine (0.095mL, 0.68mmol) be added to [1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-[(2-ethoxyl methyl-N-benzyl and imidazoles-5-yl)-methyl]-amine (81mg, 0.17mmol) in the solution in methylene dichloride (5mL), add then methylsulfonyl chloride (0.040mL, 0.50mmol).Stirring at room gained solution 20 minutes, use saturated aqueous ammonium chloride solution (5mL) to handle then.With methylene dichloride extracting water layer 2 times.The organic moiety that merges with anhydrous sodium sulfate drying then, and it is concentrated, obtaining required mesylate, this product need not be further purified and can directly and immediately use in next step reaction.
(33mg 0.51mmol) is added in the solution of this mesylate (0.17mmol) in DMF (2mL) and methylene dichloride (2mL) with sodiumazide.With gained mixture heating up to 50 ℃, kept 2 hours then.After the cooling,, repeat extracting with methylene dichloride with 1N NaOH (5mL) washing gained solution.The organic moiety that merges with anhydrous sodium sulfate drying then, concentrate, adopt flash chromatography, methylene dichloride with 20: 1: carbinol mixture is an elutriant, carries out purifying on silica gel, obtains white foam [1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-[(2-azepine methyl-N-benzyl and imidazoles-5-yl)-methyl]-amine (34mg, two step yield 40%). 1HNMR(CDCl 3)δ1.68(m，1H)，1.95(m，2H)，2.44(m，1H)，2.88(m，2H)，2.64(d，1H，J＝ -16.1Hz)，3.79(s，2H)，4.09(m，1H)，4.11(d，1H，J＝13.8Hz)，4.18(d，1H，J＝13.8Hz)，4.49(d，1H，J＝12.8Hz)，5.71(d，1H，J＝16.1Hz)，6.70(m，2H)，6.90(m，1H)，6.91(s，1H)，7.18(m，2H)，7.20(m，1H)，7.32(m，3H)，7.58(d，1H，J＝8.1Hz)，7.81(m，1H)，8.09(d，1H，J＝4.9Hz)。
Palladium (the Lindlar catalyzer on the lime carbonate of being present in 5%, 30mg) be added to [1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-(34mg is 0.068mmol) in the solution in methyl alcohol (10mL) for [(2-azepine methyl-N-benzyl and imidazoles-5-yl)-methyl]-amine.Then this suspension is placed under the hydrogen pressure of 1atm, at room temperature stirred 12 hours.Filter this mixture then, concentrated filtrate obtains white foam [1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-[(2-amino methyl-N-benzyl and imidazoles-5-yl)-methyl]-amine (23mg, 71%). 1H?NMR(CDCl 3)δ1.68(m，1H)，2.02(m，2H)，2.35(m，1H)，2.64(m，2H)，3.48(br?s，2H，NH 2)，3.80(m，2H)，3.87(s，2H)，4.01(m，1H)，4.16(d，1H，J＝15.3Hz)，4.51(d，1H，J＝15.3Hz)，5.26(d，1H，J＝16.1Hz)，5.73(d，1H，J＝16.1Hz)，6.71(m，2H)，6.94(m，2H)，7.16(m，2H)，7.22(m，2H)，7.24(s，1H)，7.32(m，2H)，7.66(m，1H)，7.85(m，1H)，8.08(d，1H，J＝4.8Hz)。
From acetate (1mL), obtain [1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-[(2-amino methyl-N-benzoglyoxaline-5-yl)-methyl]-amine (23mg, 0.048mmol), add the saturated solution of HBr in acetate (1mL) then.Stir the gained mixture precipitation as flow process D then and separate, obtain white crystalline solid AMD9986 (19mg). 1H NMR (D 2O) δ 1.77 (m, 1H), 2.01 (m, 2H), 2.20 (m, 1H), 2.78 (m, 2H), 3.53 (d, 1H, J=14.8Hz), 4.00 (d, 1H, J=14.8Hz), 4.29 (m, 2H), 4.41 (d, 1H, J=15.3Hz), 4.53 (d, 1H, J=15.3Hz), 4.58 (m, 1H), 5.30 (m, 2H), 6.76 (m, 2H), 7.19 (m, 4H), 7.51 (s, 1H), 7.64 (m, 2H), 7.82 (m, 2H), 8.28 (d, 1H, J=7.8Hz), 8.63 (d, 1H, J=4.9Hz). 13C NMR (D 2O) δ 20.01,20.19, and 27.69,33.06,33.81,45.27,48.21,48.74,59.46,114.36,125.27,125.72,125.89,126.09,127.24,129.02,129.71,130.91,130.99,133.72,138.88,140.95,141.29,148.26,149.94.ES-MSm/z478 (M+H); (C 22H 24N 6O * 4HBr * 2.5H 2The analytical value of O * 0.7HOAc): C, 41.10; H, 4.86; N, 11.04; Br35.98.Actual value: C, 41.16; H, 4.82; N, 11.04; Br, 36.06.
Embodiment 8
The preparation of AMD9813:6-aminomethyl pyridine-3-ylmethyl-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine
The preparation of 3-methylol-6-cyanopyridine:
Figure A0181580200392
With NaBH4 (1.00g, 26.4mmol) be added to 6-cyano group Nikithan (according to T.Sakamoto, S.Kaneda, S.Nishimura and H.Yamanaka Chem.Pharm.Bull.1985,33,565 make) (1.58g 8.97mmol) in MeOH (40ml) solution, at room temperature stirred this reactant 8 hours.Except that after desolvating, from 15%NaOH (5mL), obtain residue, stirred 20 minutes.Use CH then 2Cl 2Repeat this mixture of extracting, dry (Na 2SO 4) organic moiety that merges, filter, under reduced pressure concentrate.Adopt chromatography, on silica gel, carry out purifying (EtOAc/ hexane, 1: 1), obtain 3-methylol-6-cyanopyridine (414mg, 34%). 1H?NMR(CDCl 3)δ5.16(s，2H)，7.69(d，1H，J＝6.8Hz)，7.84(d，1H，J＝6.8Hz)，8.71(s，1H)。
Adopt general flow C: with methylsulfonyl chloride (0.022mL, 0.289mmol) and triethylamine (0.046mL, (30mg is 0.222mmol) at CH 0.333mmol) to be added to 3-methylol-6-cyanopyridine 2Cl 2In the solution (2mL), in stirring at room gained mixture 60 minutes.Adopt chromatography, purifying gained crude product (10: 1 CH on silica gel 2Cl 2/ MeOH), obtain required mesylate (22mg, 47%), be faint yellow solid. 1H?NMR(CDCl 3)δ3.14(s，3H)，5.32(s，2H)，7.75(d，1H，J＝6.8Hz)，7.91(d，1H，J＝6.8Hz)，8.75(s，1H)。
Adopt the alkylating general flow of N-: with (1-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (60mg, 0.156mmol) be added to the mesylate (22mg that obtains above, 0.104mmol), potassiumiodide (3mg, 0.015mmol) and salt of wormwood (22mg is 0.156mmol) at CH 3In the solution among the CN (3mL), heat this mixture to 70 ℃ 4 hours.Adopt chromatography, the thick material of purifying gained (10: 1 CH on silica gel 2Cl 2/ MeOH), obtain 6-cyanopyridine-3-base-(1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (32mg, 63%). 1HNMR(CDCl 3)δ1.68(s，9H)，1.91-2.04(m，2H)，2.22(m，1H)，2.72-2.79(m，2H)，3.80(d，1H，J＝16.1Hz)，3.98(d，1H，J＝16.1Hz)，4.31(dd，1H，J＝12.1，6.2Hz)，4.58(d，1H，J＝16.8Hz)，4.76(d，1H，J＝16.8Hz)，7.02(m，2H)，27.24-7.31(m，3H)，7.61-7.63(m，3H)，8.44(d，1H，J＝5.1Hz)，8.53(d，1H，J＝4.1Hz)。
Raney nickel (65mg 65% aqueous slurry) is added to 6-cyanopyridine-3-base-(1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (32mg, 0.065mmol) in the solution in MeOH (2mL), with anhydrous ammonia that this solution is saturated.At 50psi, this mixture was placed in the Parr bottle hydrogenation 6 hours, with this mixture of diatomite filtration, wash this filter then with MeOH.Under reduced pressure in elutriant, remove and desolvate, adopt the thick material (85%CH of chromatography purifying gained on silica gel 2Cl 2, 12%MeOH, 3%NH 4OH), obtain white foam 6-amino-ethyl pyridin-3-yl-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-ammonia (18mg, 70%). 1H?NMR(CDCl 3)δ1.62(m，1H)，1.94-2.08(m，2H)，2.25-2.31(m，1H)，2.70-2.92(m，2H)，3.49(s，2H)，3.72(s，2H)，3.85(br?s，2H(NH))，4.00(d，2H，J＝16.5Hz)，4.08(dd，1H，.J＝12.1，8.3Hz)，4.13(d，1H，J＝16.5Hz)，7.10-7.22(m，4H)，7.43(d，1H，J＝7.2Hz)，7.53(m，2H)，7.69(d，1H，J＝7.8Hz)，8.58(s，1H)，8.66(d，1H，J＝4.8Hz)。
Adopt general flow D: (18mg 0.045mmol) changes into hydrobromate, obtains white solid AMD9813 (28mg) with the amine that obtains above. 1H NMR (D 2O). δ 1.86 (m, 1H), 2.23 (m, 2H), 2.46 (m, 1H), 3.04 (m, 2H), 3.69 (d, 1H, J=14.9Hz), 3.76 (d, 1H, J=14.9Hz), 3.93 (q, 2H, J=13.4Hz), 4.46 (d, 1H, J=16.8Hz), 4.67 (d, 1H, J=16.8Hz), 4.78 (m, 1H), 7.06 (d, 1H, J=7.8Hz), 7.55 (m, 2H), 7.62 (m, 2H), 7.69 (dd, 1H, J=8.1,6.0Hz), 8.35 (d, 1H, J=1.8Hz), 8.44 (d, 1H, J=8.1Hz), 8.77 (d, 1H, J=4.5Hz). 13C NMR (D 2O) δ 20.38,20.83, and 27.84,42.67,49.63,53.93,62.71,114.05 (2C), 122.99,126.22,127.03 (2C), 130.50,132.87,133.10,139.87 (2C), 141.14,148.41,149.98,150.49,151.44,154.29.ES-MSm/z399 (M+H); (C 24H 26N 6* 3.8HBr * 2.2H 2O) analytical value: C, 38.66; H, 4.62; N, 11.27; Br40.72.Actual value: C, 39.98; H, 4.68; N, 10.97; Br, 40.63.
Embodiment 9
AMD9739:[4-(2-amino-ethyl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of [2-(4-formyl radical-phenyl)-ethyl]-carboxylamine tertiary butyl ester
With 4-(brooethyl) methyl benzoate (10.09g, 44.05mmol), sodium cyanide (6.42g, 131mmol) and cetrimonium bromide (1.59g, 4.36mmol) (2: 1,187.5mL) the mixture reflux in was 5 hours, uses CH then at benzene/water 2Cl 2Extracting (3 * 50mL).Dry organic extract (MgSO 4), filter, under reduced pressure concentrate.Adopt the thick material (35%EtOAc/ hexane) of chromatography purifying gained on silica gel, obtain colorless solid 4-cyano methyl-methyl benzoate (4.64g, 60%). 1H?NMR(CDCl 3)δ3.82(s，2H)，3.93(s，3H)，7.42(d，2H，J＝9Hz)，8.06(d，2H，J＝9Hz)。
Raney nickel (5g) is added to the nitrile that obtains above, and (1.57g is 8.96mmol) at NH 3Saturated CH 3In the solution among the OH (30mL), this solution is contained in the Parr bottle, and in the hydrogen of 45psi, this mixture of hydrogenation is 67 hours in the Parr hydrogenator then.With this product mixtures of diatomite filtration, vacuum is removed the solvent in the elutriant, obtains green liquid (1.30g).(1.90g, 8.71mmol) solution in THF (24mL) is 2 hours, concentrates then at stirring at room di-t-butyl carbonic acid hydrogen ester.Go up the thick material of purifying gained at silica gel (20%EtOAc/ hexane), obtain clear crystal 4-(2-tert-butoxycarbonyl amino-ethyl)-methyl benzoate (1.37g, 55%). 1H?NMR(CDCl 3)δ1.43(s，9H)，2.86(m，2H)，3.39(m，2H)，3.91(s，3H)，4.53(brs，1H)，7.26(d，2H，J＝8.1Hz)，7.98(d，2H，J＝8.1Hz)。
At 0 ℃, ((606mg is 2.17mmol) in the solution in THF (4mL) 13mmol) to be added to the ester that obtains above for 1.0M/THF, 13mL with diisobutylaluminium hydride.In this mixture of stirring at room 1 hour, add entry then, then add the 10%HCl aqueous solution, become acidity (pH1-2) up to solution.Add 1NNaOH (aqueous solution) this solution is become alkalescence, use CH 2Cl 2Extracting.Dry this organic extract (MgSO 4), filter and concentrate.Adopt the thick material (30%EtOAc/ hexane) of chromatography purifying gained on silica gel, obtain clear crystal [2-(4-methylol-phenyl)-ethyl]-carboxylamine tertiary butyl ester (370mg, 68%). 1H?NMR(CDCl 3)δ1.44(s，9H)，2.80(m，2H)，3.37(m，2H)，4.53(br?s，1H)，4.68(d，2H，J＝5.7Hz)，7.19(d，2H，J＝7.8Hz)，7.32(d，2H，J＝7.8Hz)。
With active MnO 2(814mg, (200mg is 0.796mmol) at CH 7.96mmol) to be added to the alcohol that obtains above 2Cl 2In the solution (8mL), then in stirring at room gained mixture 69 hours.With the reaction mixture of diatomite filtration gained, use CH 2Cl 2Wash this diatomite.The solvent in the filtrate is removed in decompression down, obtains required aldehyde, is clear crystal (175mg, 88%). 1H?NMR(CDCl 3)δ1.43(s，9H)，2.89(m，2H)，3.41(m，2H)，4.55(br?s，1H)，7.37(d，2H，J＝8.1Hz)，7.83(d，2H，J＝7.8Hz)，9.99(s，1H)。
Adopt general flow B: with acetate (0.017mL, 0.30mmol) and NaBH (OAc) 3(187mg; 0.882mmol) be added to [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-Ji-methyl)]-(5; 6; 7; 8-tetrahydrochysene-quinoline-8-yl)-amine (102mg; 0.27mmol) and [2-(4-formyl radical-phenyl)-ethyl]-carboxylamine tertiary butyl ester (81mg, 0.32mmol) in the solution in THF (3mL), stirring gained mixture 46 hours.Adopt chromatography this thick yellow oil of purifying (CH of 300: 5: 1 on silica gel 2Cl 2/ MeOH/NH 4OH), obtain colourless foam-like material (153mg).
At room temperature this colourless foam: trifluoroacetic acid/CH with 1: 1 2Cl 2(4mL) solution stirring is 45 minutes, concentrates then.Make residue at CH 2Cl 2(10mL) with saturated NaHCO 3Distribute between the aqueous solution (10mL), use CH 2Cl 2(this water of 3 * 10mL) extractings.Dry organic phase (the MgSO that merges 4), concentrate then.Adopt thick material (100: 5: 1 the EtOAc/MeOH/NH of column chromatography purifying gained on silica gel 4OH), obtain colorless oil (38mg, 35%).
Adopt general flow D: (38mg 0.092mmol) changes into its hydrobromate, obtains colorless solid AMD9739 (50mg, 79%) with the colorless oil that obtains above. 1H?NMR(D 2O)δ1.94(m，1H)，2.26(m，2H)，2.43-2.60(m，5H)，3.03(m，2H)，3.74(d，1H，J＝13Hz)，3.82(d，1H，J＝13Hz)， -4.42(d，1H，J＝16Hz)，4.60(d，1H，J＝16Hz)，4.79(m，1H)，6.85(d，2H，J＝7.8Hz)，7.14(d，2H，J＝7.8Hz)，7.47-7.59(m，4H)，7.91(m，1H)，8.37(d，1H，J＝7.8Hz)，8.75(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ18.88，19.33，26.26，30.88，38.90，48.70，55.03，61.59，112.33，124.34，124.75，127.27，128.98，129.38，133.59，135.32，138.18，139.18，146.31，149.49，150.55.ES-MSm/z412(M+H)。(C 26H 29N 5) 3.0 (HBr), 1.8 (H 2O) analytical value: C, 45.48; H, 5.23; N, 10.20; Br, 34.91.Actual value: C, 45.45; H, 5.13; N, 9.95; Br, 34.94.
Embodiment 10
Figure A0181580200431
AMD9756:[4-(3-amino-propyl group)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Figure A0181580200432
The preparation of 3-(4-chloromethyl-phenyl)-propionitrile
(0.30mL, (solution of 2.4m in hexane, 1.96mL 4.7mmol) in the solution in-78 ℃ anhydrous THF (5mL), stirred 45 minutes then 5.7mmol) to be added to n-Butyl Lithium with acetonitrile.Add α then, (2.485g, the 14.2mmol) solution in-78 ℃ anhydrous THF obtain yellow muddy solution to α '-two chloro-o-Xylol.In this mixture of-78 ℃ of restir 1 hour,, then it is warmed to room temperature with the saturated NaCl aqueous solution (30mL) stopped reaction.Use CH 2Cl 2(this mixture of 3 * 200mL) extractings.Use MgSO 4The dry organic phase that merges concentrates and obtains white solid (2.45g).Adopt column chromatography purifying products therefrom (EtOAc of 10: 1: hexane), obtain required nitrile (1.49g, 60%), be pale yellow syrup on silica gel. 1H?NMR(300MHz，CDCl 3)δ7.37(d，2H，J＝8.1Hz)，7.24(d，2H，J＝8.1Hz)，4.58(s，2H)，2.96(t，2H，J＝7.4Hz)，2.62(t，2H，J＝7.4Hz)。
Adopt alkylating general flow C: with KI (2.6mg, 0.016mmol) and N, N-diisopropylethylamine (0.08mL, 0.48mmol) be added to 3-(4-chloromethyl-phenyl)-propionitrile (63mg that is stirring, 0.35mmol) and (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(121mg is 0.32mmol) at anhydrous CH for amine 3In the solution among the CN (3mL), then with this mixture heating up to 60 ℃ 24 hours.Adopt column chromatography purifying products therefrom (CH of 200: 1: 1 on silica gel 2Cl 2: MeOH: NH 4OH), obtain required coupled product (128mg, 77%), be yellow slurry. 1HNMR(300MHz，CDCl 3)δ8.46(d，1H，J＝3.6Hz)，7.65-7.61(m，1H)，7.55-7.51(m，1H)，7.28(d，1H，J＝9.6Hz)，7.20-7.15(m，4H)，7.04-7.00(m，1H)，6.77(d，2H，J＝8.1Hz)，4.74(d，1H，J＝14.4Hz)，4.66(d，1H，J＝14.4Hz)，4.36-4.30(m，1H)，3.87(d，1H，J＝14.7Hz)，3.73(d，1H，J＝14.7Hz)，2.77-2.63(m，4H)，2.30-2.25(m，3H)，2.02-1.94(m，2H)，1.74-1.71(m，10H)。
Use NH 3(g) make 2-{[[4-(2-cyano group-ethyl)-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(128mg, 0.24mmol) solution in MeOH (10mL) is saturated for benzoglyoxaline-1-carboxylic acid tertiary butyl ester.Clean Raney nickel (～2g, excessive) (3 times) with MeOH, then it is transferred in the hydrogenation flask that contains described nitrile, 45psi hydrogenated mixture 16 hours.With MeOH (100mL) dilution products therefrom mixture, use diatomite filtration, vacuum is removed the solvent in the elutriant.Adopt column chromatography purifying products therefrom (CH of 100: 1: 1 on silica gel 2Cl 2: MeOH: NH 4OH), obtain required amine (51mg, 50%), be white foam. 1H?NMR(300MHz，CDCl 3)δ8.70(d，1H，J＝3.6Hz)，7.59(brs，2H)，7.42(d，1H，J＝8.1Hz)，7.30(d，2H，J＝8.1Hz)，7.20-7.15(m，3H)，7.04(d，2H，J＝7.8Hz)，4.17(d，1H，J＝16.8Hz)，4.12-4.06(m，1H)，3.97(d，1H，J＝16.8Hz)，3.71(s，2H)，2.86-2.74(m，2H)，2.66(t，2H，J＝6.9Hz)，2.56(t，2H，J＝7.8Hz)，2.33-2.24(m，1H)，2.09-1.98(m，2H)，1.73-1.64(m，3H)。
Adopt general flow D: the foam (51mg) that obtains is above changed into hydrobromate, obtain AMD9756. 1H?NMR(300?MHz，D 2O)δ8.75(d，1H，J＝5.7Hz)，8.40(d，1H，J＝7.8Hz)，7.93(dd，1H，J＝7.8，5.7Hz)，7.60-7.56(m，2H)，7.53-7.47(m，2H)，7.11(d，2H，J＝7.8Hz)，6.83(d，2H，J＝8.1Hz)，4.78-4.73(m，1H)，4.62(d，1H，J＝16.5Hz)，4.44(d，1H，J＝16.5Hz)，3.82(d，1H，J＝12.3Hz)，3.75(d，1H，J＝12.3Hz)，3.06-3.03(m，2H)，2.76(t，2H，J＝7.8Hz)，2.46-2.43(m，1H)，2.34-2.17(m，4H)，2.97-1.91(m，1H)，1.46-1.35(m，2H)； 13C?NMR(75.5MHz，D 2O)δ153.8，152.7，150.0，143.1，142.7，141.4，135.8，132.3，132.2，130.3，128.4，127.9，115.7，65.0，58.4，52.1，41.2，33.3，30.4，29.7，22.7，22.3.ES-MSm/z426.3(M+H)。(C 27H 31N 5) 2.9 (HBr), 1.9 (H 2O) analytical value: C, 46.70; H, 5.47; N, 10.08; Br, 33.37.Actual value: C, 46.69; H, 5.14; N, 10.03; Br, 33.43.
Embodiment 11
AMD9768:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-preparation of azanol
In room temperature, with 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl aldehyde (350mg, 0.883mmol) and oxammonium hydrochloride (100mg, 1.44mmol) solution stirring in MeOH (3mL) 45 minutes, vacuum concentration then.Make the gained residue at saturated NaHCO 3(aqueous solution) (15mL) and CH 2Cl 2Distribute (20mL), use CH 2Cl 2(10mL) extracting gained water.Dry organic phase (the MgSO that merges 4), filtering, vacuum concentration obtains yellow solid (363mg).
With NaBH 4(19mg, (90mg 0.22mmol) in the solution in 6: 1 MeOH/THF (2.2mL), uses saturated HCl/1, and 4-two  are adjusted into 4 with the pH of this solution 0.50mmol) to be added to the thick oxime that obtains above.In this mixture of stirring at room 15 minutes, add extra NaBH then 4(19mg 0.50mmol), is adjusted into 4 with the pH of this solution.Stir this mixture 15 minutes, and used 1N NaOH (aqueous solution) that it is adjusted into alkalescence then, use CH 2Cl 2(3 * 15mL) extractings.Dry extract (the MgSO that merges 4), filter vacuum concentration.Adopt the thick material of column chromatography purifying on silica gel (100: 5: 1 CH 2Cl 2/ MeOH/NH 4OH), obtain colourless foam AMD9768 (67mg, 68%). 1H?NMR(CDCl 3)δ1.66(m，1H)，1.99(m，2H)，2.24(m，1H)，2.67-2.90(m，2H)，3.71(s，2H)，3.94(d，1H，J＝17Hz)，3.94(s，2H)，4.07(m，1H)，4.14(d，1H，J＝17Hz)，7.17(m，5H)，7.38(m，3H)，7.55(m，2H)，8.66(d，1H，J＝3.9Hz)； 13C?NMR(CDCl 3)δ21.34，23.30，29.18，48.50，53.81，57.91，60.37，121.87，122.36，128.80，129.06，134.94，136.13，137.55，138.46，146.72，155.89，157.15.ES-MSm/z414(M+H)。C 25H 27N 5O0.3H 2O0.36CH 2Cl 2Analytical value: C, 67.76; H, 6.35; N, 15.58.Actual value: C, 67.85; H, 6.39; N, 15.51.
Embodiment 12
AMD11088:(5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-preparation of methyl alcohol
The preparation of 2-methyl-5-nitro-methyl benzoate:
With 2-methyl-5-nitro phenylformic acid (1.51g, 8.34mmol) and H 2SO 4(catalyzer) solution reflux in MeOH (20mL) 17 hours, vacuum concentration then.The gained residue is dissolved in CH 2Cl 2(40mL), with saturated NaHCO 3(aqueous solution) (3OmL) washs, dry then (MgSO 4), vacuum concentration obtains yellow crystals (1.62g, 99%). 1H?NMR(CDCl 3)δ2.72(s，3H)，3.96(s，3H)，7.44(d，1H，J＝8.7Hz)，8.24(dd，1H，J＝8.7，2.7Hz)，8.78(d，1H，J＝2.7Hz)。
The preparation of 5-amino-2-methyl-methyl benzoate;
Make 2-methyl-5-nitro-methyl benzoate (1.96g, 10.0mmol) solution in 4: 1 MeOH/EtOAc (25mL) room temperature and hydrogen atmosphere (35psi) down and 10%Pd/C (200mg, 0.19mmol) mixture shook 2 hours.Remove by filter catalyzer, vacuum concentrated filtrate obtains orange (1.64g, 99%). 1H?NMR(CDCl 3)δ2.47(s，3H)，3.62(br?s，2H)，3.87(s，3H)，6.75(dd，1H，J＝8.1，2.7Hz)，7.02(d，1H，J＝8.1Hz)，7.25(d，1H，J＝2.7Hz)。
The preparation of 5-cyano group-2-methyl-methyl benzoate:
Figure A0181580200471
In room temperature, (1.00g is 6.05mmol) at H slowly dense HCl (1.5mL) to be added to the 5-amino-2-methyl-methyl benzoate that is stirring 2In the suspension among the O (1.5mL).Add more H 2O (7mL) stirs the gained mixture at 0 ℃ then, drips NaNO simultaneously 2(459mg is 6.65mmol) at H 2Solution among the O (1mL).After this amine dissolves fully, slowly add K at 0 ℃ 2CO 3(s), be neutralized up to this solution.
(651mg, (712mg is 14.5mmol) at H 7.27mmol) to be dissolved in NaCN with cupric cyanide (I) 2In the solution among the O (2.2mL), then this solution is heated to 60 ℃.At 60 ℃, above-mentioned cold neutral diazonium salt solution is added drop-wise in the cyanide solution that vigorous stirring.Heat this mixture to 110 ℃, kept 30 minutes, make it be cooled to room temperature then.(10mL) dilute this mixture with saturated NaHCO3 (aqueous solution), use CH 2Cl 2(4 * 12mL) extractings.The dry organic extract (MgSO that merges 4), vacuum concentration.With this thick material of filtered through silica gel (10%EtOAc/ hexane), obtain yellow crystals (896mg, 85%). 1H?NMR(CDCl 3)δ2.68(s，3H)，3.93(s，3H)，7.37(d，1H，J＝8.1Hz)，7.66(dd，1H，J＝7.8，1.8Hz)，8.22(d，1H，J＝1.8Hz)。
The preparation of 2-brooethyl-5-cyano group-methyl benzoate:
Figure A0181580200472
With 5-cyano group-2-methyl-methyl benzoate (894mg, 5.10mmol), NBS (1.00g, 5.62mmol) and AIBN (125mg is 0.761mmol) at CCl 4Mixture reflux (20mL) 3 days makes it be cooled to room temperature then.Filtering mixt, vacuum concentrated filtrate.Adopt the thick material (5%EtOAc/ hexane) of column chromatography purifying gained on silica gel, obtain yellow crystals (800mg, 62%). 1H?NMR(CDCl 3)δ3.99(s，3H)，4.96(s，2H)，7.61(d，1H，J＝8.1Hz)，7.77(dd，1H，J＝8.1，1.8Hz)，8.27(d，1H，J＝1.8Hz)。
With 2-[(5,6,7,8-tetrahydrochysene-quinoline-8-base is amino)-methyl]-benzoglyoxaline-1-carboxylic acid tertiary butyl ester (253mg, 0.668mmol), 2-brooethyl-5-cyano group-methyl benzoate (170mg, 0.669mmol), potassiumiodide (6mg, 0.04mmol) and N, (0.17mL, 0.98mmol) mixture in acetonitrile (6.7mL) was 60 ℃ of heating 18 hours for the N-diisopropylethylamine.Add saturated NaHCO 3(aqueous solution) (15mL) uses CH 2Cl 2(this mixture of 3 * 15mL) extractings.The dry organic extract (MgSO that merges 4), vacuum concentration.With this thick material of silica gel purification ((500: 5: 1CH 2Cl 2/ MeOH/NH 4OH), obtain yellow foam (360mg, 98%). 1H?NMR(CDCl 3)δ1.74(m，10H)，1.99(m，2H)，2.29(m，1H)，2.74(m，2H)，3.86(s，3H)，4.22(d，1H，J＝17Hz)，4.33(m，1H)，4.36(d，1H，J＝17Hz)，4.59(d，1H，J＝14Hz)，4.65(d，1H，J＝14Hz)，6.98(dd，1H，J＝8.0，4.7Hz)，7.25(m，3H)，7.33(dd，1H，J＝8.1，1.8Hz)，7.50(m，1H)，7.68(m，2H)，8.11(d，1H，J＝8.1Hz)，8.41(m，1H))。
Make 2-{[(4-cyano group-2-methoxycarbonyl-benzyl ((5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl-(356mg is 0.645mmol) at saturated NH for benzoglyoxaline-1-carboxylic acid tertiary butyl ester 3(g)/ solution among the MeOH (20mL) shook 20 hours with the suspension of Raney nickel (1.5g) in room temperature and hydrogen atmosphere (45psi).Remove by filter catalyzer, vacuum concentrated filtrate.With the thick product of filtered through silica gel (100: 5: 1 CH 2Cl 2/ MeOH/NH 4OH), obtain yellow oil (203mg, 69%). 1H?NMR(CDCl 3)δ1.69(m，1H)，2.01(m，2H)，2.27(m，1H)，2.80(m，2H)，3.69(br?s，2H)，3.90(m，5H)，4.10(d，1H，J＝17Hz)，4.15(m，1H)，4.53(d，1H，J＝14Hz)，7.19(m，4H)，7.41(m，1H)，7.47(m，1H)，7.58(m，2H)，7.68(d，1H，J＝7.8Hz)，8.62(m，1H)。
At 0 ℃, with LiAlH 4(1.0M/THF, 0.42mL, 0.42mmol) be added to 5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(192mg 0.421mmol) in the solution in THF (4.2mL), stirred this mixture 15 minutes at 0 ℃ to methyl benzoate then.Water (0.016mL) is added in this mixture, then adds 15% NaOH (aqueous solution) (0.016mL) and water (0.048mL).Make this mixture be warmed to room temperature, filter vacuum concentration then.The crude product of employing column chromatography purifying gained on silica gel (100: 5: 1CH 2Cl 2/ MeOH/NH 4OH), obtain colourless foam AMD11088 (29mg, 15%). 1H?NMR(CDCl 3)δ1.69(m，1H)，2.04(m，2H)，2.36(m，1H)，2.80(m，2H)，3.69(s，2H)，3.78-4.07(m，5H)，4.52(d，1H，J＝12Hz)，4.62(d，1H，J＝12Hz)，6.97(dd，1H，J＝7.5，1.5Hz)，7.13(m，4H)，7.29(d，1H，J＝1.5Hz)，7.44(m，3H)，8.46(m，1H)； 13C?NMR(CDCl 3)δ21.09，21.41，29.05，45.95，49.53，55.39，61.07，62.90，121.81，122.28，126.35，130.44，131.20，134.88，135.67，137.72，140.42，143.53，146.80，153.73，156.25.ES-MSm/z428(M+H)。C 26H 29N 5O0.4H 2O0.3CH 2Cl 2Analytical value: C, 68.64; H, 6.66; N, 15.22.Actual value: C, 68.67; H, 6.67; N, 15.25.
Embodiment 13
Figure A0181580200491
AMD11071:2-amino methyl-5-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of phenol (hydrobromate)
The described method of Makoto Adachi and Tsutomu Sugasawa (" synthesising communication " (SyntheticCommunications), 1990,20,71-84.) of improving prepares 2-hydroxy-4-methyl benzonitrile.(1.00mL 9.56mmol) is added to BCl with pure meta-cresol 3(solution of 1.0M in heptane, 12.0mL 12.0mmol) 1, in cold (0 ℃) solution in the 2-ethylene dichloride, then add CH 3SCN (0.83mL, 12.1mmol) and AlCl3 (1.38g, 10.4mmol).Remove cooling bath,, then it is cooled to room temperature gained mixture heating up to 80 ℃ 3 hours.The gained mixture is poured among the 4N NaOH (35mL), then the gained mixture was heated 45 minutes at 80 ℃, then it is cooled to room temperature.Isolate each phase, use CH 2Cl 2(3 * 50mL) extracting waters.With 6N HCl (30mL) acidifying water, with ether extracting (3 * 50mL).The dry ether extract (MgSO that merges 4), concentrate then.Adopt column chromatography, the crude product of purifying gained ((20: 1 CH on silica gel 2Cl 2-EtOAc) obtain the white solid 2-hydroxy-4-methyl benzonitrile of 1.16g (91%). 1H?NMR(CDCl 3)δ2.36(s，3H)，6.20(br?s，1H)，6.79-6.81(m，2H)，7.38(d，1H，J＝9Hz)。
(0.60mL, (0.563g is 4.23mmol) at CH 6.36mmol) to be added to 2-hydroxy-4-methyl benzonitrile with diacetyl oxide 2Cl 2In the solution (21mL), then add triethylamine (1.20mL, 8.61mmol), stirring at room gained solution 30 minutes.Use CH 2Cl 2(60mL) dilute this mixture, with saturated NaHCO 3(20mL) and salt solution (2 * 20mL) washing.Dry organic phase (Na 2SO 4), concentrate, obtain white solid (2-cyano group-5-methyl-phenyl) acetic ester of 0.72g (97%). 1H?NMR(CDCl 3)δ2.38(s，3H)，2.43(s，3H)，7.08(s，1H)，7.13(d，1H，J＝9Hz)，7.54(d，1H，J＝9Hz)。
(0.767g, (0.72g is 4.11mmol) at CCl 4.31mmol) to be added to (2-cyano group-5-methyl-phenyl) acetic ester with the N-bromine succinimide of recrystallization 4In the solution (10mL), then add benzoyl peroxide (56mg, 0.23mmol).With gained mixture reflux 2.5 hours, be cooled to room temperature then.Dilute this mixture (50mL) with ether, use filter paper filtering, concentrated filtrate.Adopt thick product (6: 1 the hexane-EtOAc), obtain colorless oil (5-brooethyl-2-cyano group-phenyl) acetic ester of 0.31g (30%) of column chromatography purifying. 1H?NMR(CDCl 3)δ2.40(s，3H)，4.45(s，2H)，7.33(s，1H)，7.35(d，1H，J＝9Hz)，7.65(d，1H，J＝9Hz)。
With N, the N-diisopropylethylamine (0.35mL, 2.00mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(0.375g is 0.99mmol) at CH for amine 3In the solution among the CN (5mL), (0.318g is 1.25mmol) at CH then to add (5-brooethyl-2-cyano group-phenyl) acetic ester 3Solution among the CN (5mL).With gained mixture heating up to 60 ℃ 15 hours, be cooled to room temperature then.Concentrate the gained mixture, at CH 2Cl 2(40mL) and between the salt solution (10mL) distribute residue.Isolate each phase, use CH 2Cl 2(3 * 10mL) extracting waters.The dry organic extract (Na that merges 2SO 4), concentrate then.Adopt thick material (20: 1 the CH of column chromatography purifying on silica gel 2Cl 2-CH 3OH), follow in the enterprising conduct of silica gel to chromatography purification (2mm flat board, 2: 1 hexane-EtOAc), obtain the brown foam of 0.28g (51%).
(0.28g 0.51mmol) is dissolved in NH with the foam that obtains above 3In the saturated methyl alcohol (10mL), handle, then at the H of 50psi with Raney nickel (140mg) 2In, shook 17 hours at the Parr wobbler.Use Celite Filtering mixt is with this diatomite of methanol wash.Decompression is concentrate eluant down.Adopt column chromatography purifying crude product (CH of 20: 1: 1 on silica gel 2Cl 2-CH 3OH-NH 4OH), follow in the enterprising conduct of silica gel to chromatography (1mm flat board, 100: 1: 1 CH 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 76mg (33%), be yellow foam.
Adopt general flow D: (72mg 0.16mmol) changes into hydrobromate, then in methyl alcohol/ether the intermediate solid is precipitated again, obtains white solid AMD11071 (73mg, 65%) with the foam that obtains above. 1H NMR (D 2O) δ 1.83-1.95 (m, 1H), 2.19-2.30 (m, 2H), 2.40-2.45 (m, 1H), 3.02-3.04 (m, 2H), 3.55 (s, 2H), 3.72 (d, 1H, J=12.9Hz), 3.77 (d, 1H, J=12.9Hz), 4.44 (d, 1H, J=16.2Hz), 4.62 (d, 1H, J=16.2Hz), 4.72-4.79 (m, 1H, overlapping with HOD), 6.61 (s, 1H), 6.72 (d, 1H, J=7.8Hz), 6.90 (d, 1H, J=7.8Hz), 7.50-7.55 (m, 2H), 7.58-7.62 (m, 2H), 7.92 (dd, 1H, J=6.0,7.8Hz), 8.40 (d, 1H, J=7.8Hz), 8.74 (d, 1H, J=5.1Hz); 13C NMR (D 2O) δ 20.44,20.88, and 27.83,38.85,50.22,56.74,63.17,113.86,116.57,118.99,122.04,126.07,126.69,130.58,131.10,139.63,139.66,140.96,148.21,150.83,151.77,154.96.ES-MSm/z414 (M+H).C 25H 27N 5O3.1HBr2.5H 2The analytical value of O: C, 42.33; H, 4.99; N, 9.87; Br, 34.92.Actual value: C, 42.26; H, 4.94; N, 9.87; Br, 35.06.
Embodiment 14
Figure A0181580200511
AMD11077:(4-amino methyl-3-methoxyl group-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
With lithium hydroxide monohydrate (0.292g, 6.95mmol) be added to 2-hydroxy-4-methyl benzonitrile (0.46g, 3.46mmol) in the solution in THF (17mL), then add methyl-sulfate (0.50mL, 5.28mmol).With the mixture reflux of gained 2 hours, be cooled to room temperature then.(50mL) dilutes this mixture with ether, with saturated NaHCO 3The aqueous solution (3 * 15mL) washings, dry (MgSO 4) and concentrate.Adopt column chromatography purifying (hexane of 4: 1-EtOAc), obtain white solid 2-methoxyl group-4-methyl benzonitrile of 0.456g (90%) on silica gel. 1H?NMR(CDCl 3)δ2.41(s，3H)，3.91(s，3H)，6.77(s，1H)，6.81(d，1H，J＝6Hz)，7.43(d，1H，J＝6Hz).ES-MSm/z148(M+H)。
(0.544g, (0.438g is 2.98mmol) at CCl 3.05mmol) to be added to 2-methoxyl group-4-methyl benzonitrile with the N-bromine succinimide of recrystallization 4In the solution (6mL), then add benzoyl peroxide (47mg, 0.19mmol).The mixture of reflux gained 45 minutes is cooled to room temperature with it then.With ether (30mL) dilution gained mixture, use filter paper filtering, concentrated filtrate.Adopt column chromatography purifying crude product (6: 1 hexane-EtOAc), obtain white solid 4-(brooethyl)-2-HOMOVERATRONITRILE of 0.46g (68%). 1H?NMR(CDCl 3)δ3.96(s，3H)，4.45(s，2H)，6.99(s，1H)，7.03(d，1H，J＝9Hz)，7.53(d，1H，J＝9Hz)。
With N, the N-diisopropylethylamine (0.35mL, 2.00mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(0.386g is 1.02mmol) at CH for amine 3In the solution among the CN (10mL), then add 4-(brooethyl)-2-HOMOVERATRONITRILE (0.363g, 1.60mmol).With gained mixture heating up to 60 ℃ 15 hours, be cooled to room temperature then.Concentrate the gained mixture, make it at CH 2Cl 2(40mL) and between the salt solution (10mL) distribute.Isolate each phase, use CH 2Cl 2(3 * 10mL) extracting waters, the dry organic extract (sodium sulfate) that merges concentrates then.Adopt crude product (20: 1 the CH of column chromatography purifying gained on silica gel 2Cl 2-CH 3OH), follow in the enterprising conduct of silica gel to chromatography purification (2mm flat board, 2: 1 hexane-EtOAc), obtain 0.30g (56% white foam.
(0.29g 0.55mmol) is dissolved in NH with the white foam that obtains above 3In the saturated methyl alcohol (15mL), handle, be placed on the H of 50psi then with Raney nickel (300mg) 2In, in the Parr wobbler 7 hours.Use Celite Filter this mixture, with this filter disc of methanol wash.Decompression is concentrate eluant down.Adopt thick product (10: 1: 1 the CH of column chromatography purifying on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 0.197g (83%), be white solid.
Adopt general flow D: (183mg 0.43mmol) changes into hydrobromate, and then this intermediate solid of reprecipitation in methyl alcohol/ether obtains white solid AMD11077 (268mg, 88%) with the solid that obtains above. 1H NMR (D 2O) δ 1.84-1.97 (m, 1H), 2.20-2.31 (m, 2H), 2.43-2.50 (m, 1H), 3.03-3.06 (m, 2H), 3.55 (s, 2H), 3.73 (s, 3H), 3.82 (d, 1H, J=12.6Hz), 3.88 (d, 1H, J=12.6Hz), 4.45 (d, 1H, J=16.5Hz), 4.63 (d, 1H, J=16.5Hz), 4.72-4.79 (m, 1H, overlapping with HOD), 6.75 (s, 1H), 6.83 (d, 1H, J=7.5Hz), 6.99 (d, 1H, J=7.5Hz), 7.50-7.54 (m, 2H), 7.57-7.61 (m, 2H), 7.93 (dd, 1H, J=6.0,7.5Hz), 8.40 (d, 1H, J=8.1Hz), 8.74 (d, 1H, J=6.0Hz); 13C NMR (D 2O) δ 20.46,20.94, and 27.86,39.08,50.07,55.62,57.24,63.25,112.27,113.78,120.28,122.61,126.16,126.82,130.47,131.11,139.65,140.03,141.06,148.30,150.77,151.78,157.51.ES-MSm/z428 (M+H).C 26H 22N 5O3.0HBr2.4H 2The analytical value of O: C, 43.77; H, 5.20; N, 9.82; Br, 33.60.Actual value: C, 43.61; H, 5.18; N, 9.45; Br, 33.88.
Embodiment 15
AMD9923:(1H-benzimidazolyl-2 radicals-ylmethyl)-(2,4-two-amino methyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of 4-brooethyl-different phthalonitrile:
With solid N-bromine succinimide (1.25g, 7.0mmol) be added to 4-methyl-different phthalonitrile of stirring (as Klement, I.; Lennick, K.; Tucker, C.E.; Knochel, P.Tetrahedron Lett.1993,34,4623-4626 is described to be made) (500mg is 3.52mmol) at CCl 4In the solution (4mL), then heat benzoyl peroxide (8mg, 0.04mmol).The mixture of reflux gained 8 hours is cooled to room temperature with it then, and concentrates in a vacuum.(its mol ratio is 3: 1 for silica gel, 4: 1 hexane-EtOAc), obtain 4-methyl-different phthalonitrile and the 4-brooethyl-different phthalonitrile of 457mg to adopt the thick material of purified by flash chromatography gained.Wherein 4-brooethyl-different phthalonitrile is shown as: 1H NMR (CDCl 3) δ 2.04 (s, 2H), 7.70-7.74 (m, 1H), 7.86-7.74 (m, 1H), 7.96 (s, 1H).
2-{[(2,4-dicyano-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzoglyoxaline-1-carboxylic acid tertiary butyl ester
The alkylating general flow of N-is carried out in employing: the reagent and the solvent that use following amount, with previous step obtain with 3: 1 blended 4-methyl-different phthalonitriles and 4-brooethyl-different O-phthalic mixture of nitriles (457mg) and (1H-N tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (257mg, 0.68mmol) change into corresponding alkylate: diisopropylethylamine (237 μ L, 1.36mmol), CH 3CN (5mL).Reaction times in this example is 3 days, and temperature of reaction is 40 ℃.Adopt thick material (silica gel, 20: 1: 1 the CH of purified by flash chromatography gained 2Cl 2-MeOH-NH 4OH), obtain the 2-{[(2 of 326mg (93%), 4-dicyano-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzoglyoxaline-1-carboxylic acid tertiary butyl ester. 1H?NMR(CDCl 3)δ1.73(s，9H)，1.75-2.20(m，3H)，2.38-2.50(m，1H)，2.65-2.90(m，2H)，4.18(d，2H，J＝6Hz)，4.30-4.40(m，1H)，4.53(d，1H，J＝15Hz)，4.70(d，1H，J＝15Hz)，7.02-7.04(m，1H)，7.23-7.26(m，2H)，7.30-7.32(m，2H)，7.38(s，1H)，7.52-7.70(m，2H)，7.85(d，1H，J＝9Hz)，8.45-8.50(m，1H)。
2-{[[2,4-two-(tert-butoxycarbonyl amino-methyl)-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzoglyoxaline-1-carboxylic acid tertiary butyl ester:
Pack in the hydrogenation flask 50% the slurries of Raney nickel in water (300mg) are used methanol wash (3 * 10mL) then.Add 2-{[(2 then, 4-dicyano-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(326mg, the 0.63mmol) solution in MeOH (10mL) is with NH for benzoglyoxaline-1-carboxylic acid tertiary butyl ester 3Gas blows in this solution 5 minutes.The multiphase mixture of gained is placed Parr wobbler (50psi) go up hydrogenation 18 hours, at this moment, with the crude mixture of diatomite filtration gained, with MeOH (3 * 20mL) washings, vacuum concentration.Adopt material (silica gel, 20: 2: 1 the CH of purified by flash chromatography gained 2Cl 2-MeOH-NH 4OH, 10: 1 MeOH-NH then 4OH), obtain the free alkali of the white solid AMD9923 of 124mg (46%), still, the combustion analysis result discloses, and this material is subjected to the pollution of silica gel, repeats to filter and carry out chromatography purification (diatomite, florisil, silica gel, alkali alumina) all fail to remove this pollutent.Therefore, with this mixture (60mg 0.14mmol) is put in the compound of THF (5mL), MeOH (1mL) and water (3), add then di-t-butyl carbonic acid hydrogen ester (92mg, 0.42mmol).The solution of stirring gained 2 hours at this moment, adds saturated sodium bicarbonate aqueous solution (5mL), uses CH 2Cl 2(3 * 10mL) extracting gained mixtures, the dry organic extract (MgSO that merges 4), vacuum concentration.Adopt the radial chromatography purifying crude product of gained (silica gel, 1mm flat board, 50: 1: 1 CH thus 2Cl 2-MeOH-NH 4OH), obtain 71mg (69% colorless oil 2-{[[2,4-two-(tert-butoxycarbonyl amino-methyl)-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl-benzoglyoxaline-1-carboxylic acid tertiary butyl ester. 1H?NMR(CDCl 3)δ1.44(s，18H)，1.53-1.54(m，1H)，1.69(s，9H)，1.99-2.04(m，1H)，2.17-2.29(m，2H)，2.49-2.54(m，1H)，2.72-2.83(m，1H)，3.84-3.94(m，2H)，4.19(d，2H，J＝5Hz)，4.28-4.54(m，6H)，4.68(br?s，1H)，6.63(dd，1H，J＝8，5Hz)，6.70(dd，1H，J＝18，8Hz)，7.17-7.24(m，3H)，7.36(s，1H)，7.52-7.55(m，1H)，7.67-7.70(m，1H)，8.24(d，1H，J＝4Hz)，8.80(br?s，1H)。
What accompaniment BOC was carried out in employing removes to protect general flow D with the HBr salt formation, and (71mg 0.10mmol), obtains the HBr salt of the AMD9923 of 48mg (60%), is white solid to handle the oily matter that previous step obtains with the saturated acetate (1mL) of HBr. 1H?NMR(CD 3OD)δ1.48-1.59(m，1H)，2.07-2.14(m，2H)，2.29-2.30(m，1H)，2.63(br?d，1H，J＝17Hz)，2.78-2.89(m，1H)，3.76(d，1H，J＝14Hz)，3.74-4.08(m，7H)，4.16(d，1H，J＝13Hz)，6.99(dd，1H，J＝8，5Hz)，7.16-7.20(m，2H)，7.34-7.39(m，3H)，7.54-7.57(m，2H)，7.65(s，1H)，8.31(d，1H，J＝5Hz)； 13C?NMR(CD 3OD)δ21.3，22.6，22.8，41.8，43.6，48.6，55.7，60.9，115.9，123.4，123.8，130.9，133.2，134.2，135.0，135.8，136.4，138.9，140.2，147.5，152.8，156.6.ES-MSm/z427(M+H)。C 26H 30N 64HBr1.5H 2O0.7C 2H 4O 2Analytical value: C, 40.17; H, 4.90; N, 10.26; Br, 39.01.Actual value: C, 40.13; H, 5.15; N, 10.20; Br, 39.08.
Embodiment 16
Figure A0181580200551
AMD11038:5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of methyl benzoate (hydrobromate)
In room temperature, in hydrogen atmosphere (50psi), make 2-{[(4-cyano group-2-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(710mg is 1.29mmol) at saturated NH for benzoglyoxaline-1-carboxylic acid tertiary butyl ester 3(g)/suspension of MeOH (25mL) and Raney nickel (1.2g) shook 17 hours.On diatomite, remove by filter catalyzer, vacuum concentrated filtrate.With filtered through silica gel gained crude product (20: 1: 1 CH 2Cl 2/ MeOH/NH 4OH), obtain white foam (416mg, 71%).
Adopt general flow D: (46mg 0.10mmol) changes into hydrobromate, and then this intermediate solid of reprecipitation from methyl alcohol/ether obtains colorless solid AMD11138 (51mg, 69%) with the white foam that obtains above. 1H?NMR(D 2O)δ1.85-1.99(m，1H)，2.17-2.37(m，2H)，2.40-2.49(m，1H)，3.04(m，2H)，3.63(d，1H，J＝13.5Hz)，3.75(d，1H，J＝13.8Hz)，3.94(s，3H)，4.10(d，1H，J＝12.6Hz)，4.35(d，1H，J＝12.6Hz)，4.44(d，1H，J＝16.2Hz)，4.55(d，1H，J＝16.2Hz)，7.26(dd，1H，J＝8.1，1.8Hz)，7.42(d，1H，J＝8.1Hz)，7.50-7.61(m，5H)，7.92(dd，1H，J＝7.8，6.0Hz)，8.40(d，1H，J＝7.8Hz)，8.77(d，1H，J＝5.1Hz)； 13C?NMR(D 2O)δ20.52，20.95，27.80，42.02，49.21，53.44，54.23，63.26，113.88，126.10，126.89，130.46，130.70，131.45，132.75，133.22，133.67，138.50，139.66，140.83，148.14，150.33，151.34，168.79.ES-MSm/z456(M+H)。C 27H 29N 5O 23.0HBr2.2H 2The analytical value of O: C, 43.95; H, 4.97; N, 9.49; Br, 32.48.Actual value: C, 43.86; H, 4.97; N, 9.35; Br, 32.77.
Embodiment 17
AMD11163:3-amino methyl-4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of phenylformic acid hydrobromate
(77mg, 0.17mmol) solution in THF (2mL) is added to the LiOH that is stirring (41mg is 1.7mmol) in the solution in deionized water (2mL) with AMD11140.With this mixture heating up to 50 ℃, stirred 15 hours, concentrate and remove THF.Slowly add 1N HCl (1.7mL), use CHCl 3(this aqueous solution of 3 * 10mL) extractings.With organic extract that dried over mgso merges, vacuum concentration.(1.5 centimeter inner diameter, 7g silica gel is used 10%NH to adopt flash column chromatography this faint yellow solid of purifying (75mg) 4OH/10%MeOH/CHCl 3Wash-out), obtains required amino-acid, be white solid (32mg).
The saturated solution of HBr in acetate (0.5mL) is added drop-wise to the above-mentioned amino-acid of stirring, and (30mg 0.068mmol) in the solution in acetate (0.5mL), and continues to stir 1 hour.Add ether fast, make the white depositions deposition that is produced.With this ether decant, (5 * 25mL), vacuum is removed residual ether to repeat to clean this white solid with ether.Dried residue is 85 hours in 50 ℃ vacuum drying oven, obtains white solid AMD11163 (35mg, two steps are 28% altogether). 1H NMR (D 2O) δ 1.81-2.01 (m, 1H), 2.20-2.35 (m, 2H), 2.43-2.54 (m, 1H), and 3.00-3.08 (m, 2H), 3.96 (d, 1H, J=15Hz), and 4.19-4.56 (m, 5H), 4.76-4.92 (m, 1H, overlapping with HOD), and 7.42-7.55 (m, 6H), 7.62 (d, 1H, J=8.0Hz), 7.91 (t, 1H, J=6.8Hz), 8.38 (d, 1H, J=8.0Hz), 8.75 (d, 1H, 5.7Hz); 13C NMR (D 2O) δ 20.44,21.15, and 27.94,40.03,49.09,53.60,63.12,113.83 (2 carbon), 126.23,127.06 (2 carbon), 130.39,130.53,130.93,131.85,132.33,140.23,140.38,141.18,148.22,150.33,150.58,169.92.ES-MSm/z442 (M+H).C 26H 27N 5O 23.0HBr2.5H 2The analytical value of O: C, 42.82; H, 4.84; N, 9.60; Br, 32.87.Actual value: C, 42.74; H, 4.55; N, 9.51; Br, 32.53.
Embodiment 18
AMD11177:3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of N-hydroxyl-benzamide hydrobromate
With AMD11140 (159mg, 0.36mmol) and oxammonium hydrochloride (75mg, 1.1mmol) solution in anhydrous methanol (6mL) slowly adds the sodium Metal 99.5 that is stirring (42mg is 1.8mmol) in the solution in anhydrous methanol (6mL).This mixture of reflux stirs in nitrogen atmosphere simultaneously.After 16 hours, concentrate this solution, at CHCl 3The residue that distributes gained (15mL) and between the deionized water (10mL).Use CHCl 3(10mL) this water layer of extracting is with organic extract that dried over mgso merges, vacuum concentration.(3 centimeter inner diameter, 15g silica gel is used 10%NH to the faint yellow solid (185mg) of employing flash column chromatography purifying gained 4OH/10%MeOH/CHCl 3Wash-out), (the 1mm flat board is with 50: 1: 1CH then to adopt radial chromatography to carry out purifying 2Cl 2/ MeOH/NH 4The OH wash-out), obtains required hydroxyl-acid amides, be white solid (63mg).
The saturated solution of HBr in acetate (3mL) is added drop-wise to the above-mentioned hydroxyl-acid amides that is stirring, and (63mg 0.11mmol) in the solution in acetate (3mL), continues to stir 10 minutes.Add ether (50mL) fast, make the white precipitate deposition that is produced.Decant is removed ether, and (5 * 50mL), vacuum is removed residual ether with this white solid of ether repeated washing.Dry gained residue is 42 hours in 50 ℃ vacuum drying oven, obtains white solid AMD11177 (80mg is 28% altogether in two steps). 1H NMR (D 2O) δ 1.74-1.86 (m, 1H), 2.11-2.30 (m, 2H), 2.35-2.44 (m, 1H), and 2.85-2.93 (m, 2H), 3.96 (d, 1H, J=15Hz), and 4.12-4.39 (m, 5H), 4.57-4.62 (m, 1H), 7.31 (s, 1H), 7.38-7.43 (m, 3H), 7.48-7.52 (m, 3H), and 7.59-7.64 (m, 1H), 8.03 (d, 1H, J=8.0Hz), 8.56 (d, 1H, 5.7 Hz); 13C NMR (D 2O) δ 20.73,21.28,28.23,40.14,48.90,54.08,62.97,114.15 (2 carbon), 124.98,125.90 (2 carbon), 127.60,128.81,132.42,132.82,139.26,140.89,142.38,144.62.ES-MSm/z457 (M+H).C 26H 28N 6O 23.2HBr3.0H 2O0.17NH 4The analytical value of Br: C, 39.72; H, 4.86; N, 10.99; Br, 34.25.Actual value: C, 39.34; H, 4.78; N, 11.36; Br, 34.51.
Embodiment 19
AMD11180:3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzamide hydrobromate
3-cyano group-4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl } preparation of benzamide:
With 2-{[(2-cyano group-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzoglyoxaline-1-carboxylic acid tertiary butyl ester (273mg, 0.49mmol) solution in THF (5mL) is added to the LiOH that is stirring (120mg is 5.0mmol) in the solution in deionized water (5mL).With gained mixture heating up to 50 ℃, and stirred 17 hours.This solution is cooled to room temperature, concentrates and remove THF, with 1N HCl neutralization.Use CHCl 3(3 * 25mL), with organic extract that dried over mgso merges, vacuum concentration obtains required acid to the extracting aqueous solution, is yellow solid (224mg).
(0.41mL, (220mg is 0.41mmol) at CH 0.82mmol) to handle the above-mentioned acid of stirring with oxalyl chloride 2Cl 2In the solution (1.6mL), and reflux 1 hour.The solution that this is red is cooled to room temperature, then ammonia is blown in the solution that is stirring 10 minutes.The gained crude mixture is poured in the saturated sodium hydrogen carbonate solution, used CHCl 3Extracting (5 * 10mL).With organic extract that dried over mgso merges, vacuum concentration.Adopt the orange foam of purified by flash chromatography (200mg) (2 centimeter inner diameter.10g silica gel, 5%NH 4OH/5%MeOH/CH 2Cl 2), obtain title compound (106mg is 50% altogether) in two steps, be orange foam. 1H?NMR(CDCl 3)δ1.70-1.93(m?br，1H)，1.99-2.11(m，2H)，2.34-2.38(m，1H)，2.74-2.88(m，2H)，3.88-3.99(m，2H)，4.13-4.28(m，3H)，5.70(s?br，1H)，6.05(s?br，1H)，7.17-7.22(m，3H)，7.46(d，1H，J＝7.5Hz)，7.50-7.68(m?br，2H)，7.79-7.95(m，3H)，8.64(d，1H，J＝3.0Hz)。
3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzamide hydrobromate (AMD11180)
Handle 3-cyano group-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl with Raney nickel (50mg, catalyzer))-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(105mg, the 0.24mmol) solution in MeOH (10mL) place it in the H of 50psi to benzamide then 2On wobbler, placed 3.5 hours down.With diatomite filtration gained slurries, vacuum concentration, (3 centimeter inner diameter, 20g silica gel is used 5%NH to adopt the flash column chromatography purifying 4OH/5%MeOH/CH 2Cl 2Wash-out), obtain required acid amides (35mg).
The saturated solution of HBr in acetate (2mL) is added drop-wise to the above-mentioned acid amides that is stirring, and (35mg 0.079mmol) in the solution in acetate (2mL), continues to stir 10 minutes.Add ether (50mL) fast, make the white precipitate deposition that is produced.Decant is removed ether, and (5 * 50mL), vacuum is removed residual ether with this white solid of ether repeated washing.Dry gained residue is 17 hours in 50 ℃ vacuum drying oven, obtains white solid AMD11180 (49mg is 25% altogether in two steps). 1H NMR (D 2O) δ 1.84-2.00 (m, 1H), 2.19-2.35 (m, 2H), 2.46-2.54 (m, 1H), and 3.00-3.08 (m, 2H), 3.97 (d, 1H, J=15Hz), and 4.21-4.58 (m, 5H), 4.75-4.92 (m, 1H, overlapping with HOD), 7.40 (s, 1H), 7.44-7.55 (m, 6H), 7.93 (t, 1H, J=6.8Hz), 8.40 (d, 1H, J=8.0Hz), 8.77 (d, 1H, 5.5Hz); 13C NMR (D 2O) δ 20.43,21.17, and 27.94,40.12,49.11,53.67,63.17,113.83 (2 carbon), 126.33,127.19 (2 carbon), 128.29,129.24,130.38,132.10,132.51,132.66,139.96,140.12,141.33,148.49,150.15,150.57,170.44.ES-MSm/z441 (M+H).C 26H 28N 6O3.3HBr2.4H 2O0.7NH 4The analytical value of Br: C, 38.11; H, 4.79; N, 11.45; Br, 39.01.Actual value: C, 37.73; H, 4.64; N, 11.56; Br, 39.27.
Embodiment 20
Figure A0181580200601
AMD11190:3-amino methyl-4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenylformic acid hydrazides (hydrobromate)
(2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-5-diazanyl carbonyl-benzyl)-preparation of carboxylamine tertiary butyl ester:
With a hydrazine hydrate (0.5mL, 10.31mmol) be added to (4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(100mg is 0.18mmol) in the solution in ethanol (2mL) for 3-(tert-butoxycarbonyl amino-methyl)-Urethylane.Reacting by heating compound to 80 ℃ spends the night.With its cooling,, use CH then then with saturated sodium bicarbonate (2mL) stopped reaction 2Cl 2Washing (4 * 5mL).The dry organic layer (sodium sulfate) that merges filters, and concentrates, and vacuum-drying obtains yellow oil.(the 1mm flat board uses CH to adopt radial chromatography to carry out purifying on silica gel 3OH/NH 4OH/CH 2Cl 21: 1: 98,2: 1: 97 then), obtaining thick white solid product (60mg), this product need not be further purified and can use. 1H?NMR(CDCl 3)δ1.55(s，9H)，1.61-1.71(m，1H)，189-1.96(m，1H)，2.27(br?s，3H)，2.35(br?m，1H)，2.69-2.90(m，2H)，3.80(q，2H，J＝15Hz)，3.92-4.04(m，4H)，4.41(brm，1H)，7.11-7.18(m，3H)，7.18(s，1H)，7.28-7.42(m，3H)，7.60-7.61(m，1H)，7.72(s，1H)，7.72(br?m，1H)，8.66(d，1H，J＝3.7Hz). ES-MSm/z557[M+H] +。
3-amino methyl-4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of phenylformic acid hydrazides (hydrobromate):
The solution of Hydrogen bromide in acetate (0.5mL) is added to above-mentioned solid, and (30mg 0.054mmol) in the solution in acetate (1mL), stirred the gained reaction mixture 30 minutes.Add ether,, obtain white solid (35mg, 77%) up to the AMD11190 precipitation. 1H?NMR(D 2O)δ1.90-2.00(m，1H)，2.23-2.34(m，2H)，2.48-2.52(m，1H)，3.04(br?s，2H)，3.98(d，1H，J＝13.8Hz)，4.23(d，1H，J＝7.5Hz)，4.29(t，1H，J＝8.7Hz)，4.38(s，1H)，4.45(s，1H)，4.51(d，1H，J＝6.0Hz)，4.57(s，1H)，7.43-7.54(m，7H)，7.92(t，1H，J＝7.5Hz)，8.40(d，1H，J＝7.8Hz)，8.75(d，1H，J＝5.1Hz). 13C?NMR(D 2O)δ20.40，21.09，27.91，39.99，48.94，53.55，62.94，113.90，126.31，127.04，128.04，129.15，130.45，132.47，140.11，140.65，141.31，148.47，150.13，150.53。ES-MSm/z456{M+H] +。C 26H 29N 7-O4.0HBr3.6H 2The analytical value of O: C, 37.00; H, 4.80; N, 11.62; Br, 37.87.Actual value: C, 37.18; H, 4.64; N, 11.31; Br, 37.91.
Embodiment 21
Figure A0181580200611
AMD11175:(2-amino methyl-5-luorobenzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-ammonia (hydrobromate)
The preparation of 4-fluoro-2-methyl benzonitrile:
With CuCN (4.45g, 50.0mmol) and NaCN (3.91g, 80.0mmol) solution in water (15mL) is heated to 60 ℃.With dense HCl (10mL) acidifying 4-fluoro-2-aminotoluene (5.16g, 41.2mmol) suspension in water (20mL).Add extra water (approximately 50mL), the expedite stirring of suspension energy up to gained is cooled to this mixture below 0 ℃ with ice/brine bath.(3.19g, 46.2mmol) solution in water (8mL) drips with trash ice, guarantees always to exist in this diazonium salt solution ice with NaNO2.Stirred this mixture 15 minutes at 0 ℃, then with K 2CO 3(6.62g, 47.9mmol add this solution of neutralization to powder in batches.Then gained bright orange solution was added to about 40 minutes time in batches in 60 ℃ the cyanide solution.With the green suspension of gained be heated to 110 ℃ 45 minutes, in case be cooled to room temperature, promptly add saturated sodium bicarbonate aqueous solution (80mL).Use CH 2Cl 2This thick dark solution of extracting (150mL * 3) does not obtain any required material.
Discovery has orange solids to distil in condenser in the reaction reflux course, uses CH 2Cl 2(100mL) and water (50mL) washing.Use CH 2Cl 2The extracting aqueous solution (25mL * 2), the dry organic solution (sal epsom) that merges is filtered, and decompression concentrates down, obtains yellow solid nitrile (3.00g, 22.2mmol, 54%). 1H NMR (CDCl 3) δ 2.55 (s, 3H), 6.94-7.04 (m, 2H), 7.60 (dd, 1H, J=8.6,5.6Hz) .IR (film, KBr) v2223cm -1
The preparation of 2-brooethyl-4-fluorine benzonitrile:
With NBS (1.33g, 7.47mmol) and AIBN (153mg, (1.62g is 12.0mmol) in the solution in benzene (80mL) 0.93mmol) to be added to adjacent benzyl nitrile.This solution of reflux is 3 hours in nitrogen, add then second section NBS (1.25g, 7.02mmol) and AIBN (150mg, 0.91mmol).Reflux this reactant 2 hours of reheat is once cooling off the washing of water (80mL * 2) and hydrochloric acid (80mL).Dry organic solution (sal epsom) is filtered, and decompression concentrates down.Adopt flash column chromatography on silica gel, to carry out purifying (EtOAc/ hexane, 1: 9), obtain orange solids bromide (721mg, 3.37mmol, 28%). 1H?NMR(CDCl 3)δ4.60(s，2H)，7.13(td，1H，J＝8.2，2.5Hz)，7.28(dd，1H，J＝8.9，2.6Hz)，7.69(dd，1H，J＝8.6，5.3Hz)。
2-{[(2-cyano group-5-luorobenzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzoglyoxaline-1-carboxylic acid tertiary butyl ester:
With bromotoluene (263mg, 1.23mmol), (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (381mg, 1.01mmol), DIPEA (0.26mL, 1.5mmol) and KI (10mg is 0.06mmol) at CH 3Solution among the CN (7mL) stirred 17 hours in nitrogen at 60 ℃.One cool to room temperature just adds saturated sodium hydrogen carbonate solution (10mL), uses CH then 2Cl 2Extracting gained mixture (25mL * 3).The dry organic solution (sal epsom) that merges is filtered, and decompression concentrates down.Adopt flash column chromatography on silica gel, to carry out purifying (EtOAc/ hexane, 1: 1), obtain weak yellow foam tertiary amine (411mg, 0.80mmol, 80%). 1H?NMR(CDCl 3)δ1.75(s，9H)，1.85-2.11(m，3H)，2.31-2.41(m，1H)，2.64-2.92(m，2H)，4.03(d，1H，J＝16.2Hz)，4.18(d，1H，J＝16.2Hz)，4.34(dd，1H，J＝10.2，5.7Hz)，4.62(d，1H，J＝14.1Hz)，4.74(d，1H，J＝14.1Hz)，6.55(td，1H，J＝8.1，2.7Hz)，7.00(dd，1H，J＝7.7，4.7Hz)，7.14(dd，1H，J＝8.4，5.4Hz)，7.20(dd，2H，J＝6.2，3.2Hz)，7.23-7.31(m，1H)，7.56-7.66(m，3H)，8.44(dd，1H，J＝4.5，1.2Hz)。
2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino]-methyl-4-fluorine benzonitrile preparation:
With water (2mL) be added to nitrogen blow the 50mL round-bottomed flask that dashes LiOHH2O (51mg, 1.2mmol) and 10%Pd/C (39mg, 0.04mmol) in.With nitrile (201mg, 0.39mmol) solution in two  alkane (6mL) adds, then add Raney nickel (0.07mL, 0.6mmol) 50% suspension in water (as Klenke, B.; Gilbert, I.H.J.Org.Chem.2001,66,2480-2483 is described).With H 2Be blown in this flask, be heated to then 45 ℃ 15 hours.One cool to room temperature is blown into nitrogen immediately, with this mixture of diatomite filtration, washs with EtOAc.Decompression concentrates this filtrate down, and residue is put into (15mL) in the sodium bicarbonate aqueous solution, uses CH 2Cl 2Extracting (25mL * 3).Dry organic solution (sal epsom) is filtered, and evaporates in the decompression, obtains the free benzoglyoxaline (153mg, 0.37mmol, 95%) of faint yellow solid. 1H?NMR(CDCl 3)δ1.63-1.78(m，1H)，1.93-2.13(m，3H)，2.30-2.42(m，1H)，2.69-2.90(m，2H)，3.88(d，1H，J＝14.9Hz)，3.93(d，1H，J＝14.9Hz)，4.09-4.13(m，1H)，4.21(d，1H，J＝16.1Hz)，4.28(d，1H，J＝16.1Hz)，6.95(td，1H，J＝8.3，2.6Hz)，7.18-7.22(m，3H)，7.45-7.57(m，3H)，7.63-7.67(m，2H)，8.67(dd，1H，J＝4.8，1.5Hz)。
The preparation of AMD11175:
Under the pressure of 50psi, will be present in through NH 3(153mg is 0.37mmol) with Raney nickel hydrogenation 4 hours for nitrile in the saturated MeOH solution (10mL).Use diatomite filtration gained mixture, with the MeOH washing, concentrated filtrate under reduced pressure then.Adopt flash column chromatography on silica gel, to carry out purifying (CH 2Cl 2/ MeOH/NH 4OH, 19: 1: 0.1,9: 1: 0.05 then), obtain white solid primary amine (44mg, 0.11mmol, 29%), and the nitrile (24mg, 0.06mmol, 16%) that reclaims.
The saturated solution (0.5mL) of HBr in HOAc is added to above-mentioned amine, and (42mg is 0.10mmol) in the solution in Glacial acetic acid (1mL), this solution of stirring at room 30 minutes.Add Et 2O (0.5mL) makes the throw out deposition, and decant removes and desolvates.Use Et 2O washs this throw out (1mL * 5), under reduced pressure 90 ℃ of dryings, obtains beige solid AMD11175 (66mg, 0.095mmol, 95%). 1H NMR (D 2O) δ 1.82-1.97 (m, 1H), 2.17-2.36 (m, 2H), 2.41-2.53 (m, 1H), and 2.98-3.08 (m, 2H), 3.91 (d, 1H, J=13.8Hz), 4.16 (d, 2H, J=13.8Hz), 4.32-4.38 (2 * d, 2H, J=16.2 and 13.8Hz), 4.54 (d, 1H, J=16.2Hz), 6.68 (td, 1H, J=8.6,2.7Hz), 7.04 (dd, 1H, J=8.4,6.0Hz), 7.19 (dd, 1H, J=9.9,2.4Hz), 7.51-7.55 (m, 2H), and 7.60-7.63 (m, 2H), 7.89 (t, 1H, J=6.8Hz), 8.37 (d, 1H, J=7.8Hz), 8.72 (d, 1H, J=5.4Hz). 13CNMR (D 2O) δ 20.4,20.9, and 27.9,39.5,48.7,53.3,62.2,113.9,116.1 (d, J=21.7Hz), 118.1 (d, J=22.0Hz), 126.2,127.0,127.6,130.7,132.5 (d, J=8.7Hz), 138.1,140.2,141.1,148.2,150.5 (d, J=20.9Hz). 19F NMR (D 2O) δ-35.9.ES-MS m/z416 (M+H).C 25H 26FN 53.0HBr2.3H 2The analytical value of O: C, 42.92; H, 4.84; N, 10.01; Br, 343.26.Actual value: C, 43.00; H, 4.85; N, 9.71; Br, 34.37.
Embodiment 22
Figure A0181580200641
AMD11140:3-amino methyl-4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of methyl benzoate
The preparation of 4-brooethyl-3-cyano group-methyl benzoate:
With zinc powder (792mg, 12.12mmol) and glycol dibromide (44 μ L, 0.51mmol) suspension in THF (3mL) 70 ℃ the heating 10 minutes.This mixture is cooled to room temperature, add then the chlorine trimethyl silane (45 μ l, 0.36mmol).This mixture is cooled to 0 ℃, and (2.314g, the 10.10mmol) solution in THF (11mL) stirred extra 2 hours at 0 ℃ then to add methyl-4-(brooethyl) benzoic ether at 0 ℃ in 2 hours.Reaction mixture is cooled to-78 ℃, (1.556g, the 8.59mmol) solution in THF (11mL) is then in stirring at room gained mixture 16 hours to add the tolylsulfonyl prussiate.Decompression concentrates this mixture down, uses CH 2Cl 2(100mL), filter then with saturated sodium bicarbonate aqueous solution (15mL) dilution.Isolate each phase, use CH 2Cl 2Extracting water layer (3 * 50mL).The dry organic extract (sal epsom) that merges filters, and decompression concentrates down.Adopting column chromatography to carry out purifying (hexane/EtOAc, 10: 1) on silica gel, obtain required nitrile (973mg), is 16: 1 mixture (required product/by product).
With the nitrile (973mg) that obtains above, N-bromine succinimide (1.087g, 6.11mmol) and AIBN (137mg is 0.83mmol) at CCl 4Vlil (18.5mL) 4 days.Reaction mixture is cooled to room temperature, filters, decompression concentrates down.Adopt the yellow slurry (hexane/EtOAc, 20: 1,40: 3 then) of column chromatography purifying gained on silica gel, obtain required bromide (800mg obtains 37% altogether in two steps), be white solid. 1H?NMR(CDCl 3)δ3.96(s，3H)，4.66(s，2H)，7.65(d，1H，J＝8.1Hz)，8.23(dd，1H，J＝8.1，1.8Hz)，8.33(d，1H，J＝1.5Hz)。
2-{[(2-cyano group-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzoglyoxaline-1-carboxylic acid tertiary butyl ester:
With 4-brooethyl-3-cyano group-methyl benzoate (800mg, 3.15mmol), 2-[(5,6,7,8-tetrahydrochysene-quinoline-8-base is amino)-methyl]-benzoglyoxaline-1-carboxylic acid tertiary butyl ester (1.253g, 3.15mmol), KI (26mg, 0.16mmol) and DIPEA (0.82mL is 4.72mmol) at CH 3Solution among the CN (31.5mL) is 60 ℃ of heated overnight.Reaction mixture is cooled to room temperature, and decompression concentrates down.Use CH 2Cl 2(100mL) the brown slurries of dilution gained are used saturated sodium chloride aqueous solution (30mL) washing then.Use CH 2Cl 2(2 * 50mL), the dry organic extract (sal epsom) that merges filters the extracting water, and decompression concentrates down.Adopt column chromatography purifying gained brown foam ((CH on silica gel 2Cl 2/ MeOH, 20: 1), obtain required methyl esters (1.74g, 100%), be cream-coloured foam. 1H?NMR(CDCl 3)δ1.69-1.78(m，10H)，1.95-2.09(m，2H)，2.36-2.41(m，1H)，2.63-2.85(m，2H)，3.86(s，3H)，4.17(d，1H，J＝16.2Hz)，4.20(d，1H，J＝15.9Hz)，4.35-4.40(m，1H)，4.58(d，1H，J＝14.4Hz)，4.69(d，1H，J＝14.4Hz)，7.01(dd，1H，J＝7.8，4.8Hz)，7.13-7.23(m，2H)，7.31(d，1H，J＝7.5Hz)，7.55-7.61(m，2H)，7.76(d，2H，J＝1.2Hz)，7.87(s，1H)，8.44(d，1H，J＝4.5Hz)。
With 2-{[(2-cyano group-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(1.23g 2.23mmol) is dissolved in NH to benzoglyoxaline-1-carboxylic acid tertiary butyl ester 3Saturated MeOH (～15mL) in, handle with Raney nickel (excessive), be placed on the H of 45psi then 2On the Parr wobbler, shook 16 hours down.With MeOH dilution gained mixture, use diatomite filtration.Wash this filter cake with MeOH, decompression concentrates the filtrate that merges down.Filter the slurries ((CH of gained with silica gel plug 2Cl 2/ MeOH/NH 4OH, 100: 2: 1), obtaining required amine (720mg), this amine need not be further purified and can use in next step reaction.
TFA (1mL) is added to the amine (64mg) that obtains above at CH 2Cl 2In the solution (1mL), stir the gained mixture in ambient temperature overnight then.Decompression concentrates this mixture down, and the gained slurry dissolved in water, is alkalized with 1N NaOH (pH8).Add CHCl 3(75mL), isolate each phase, use CHCl 3Extracting water layer (2 * 75mL).The dry organic extract (sal epsom) that merges, decompression concentrates down.Adopt the yellow foam (CH of radial chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 1: 1,200: 3: 1 then), obtain white foam AMD11140 (39mg is 43% altogether) in two steps. 1H?NMR(CDCl 3)δ1.55-1.73(m，1H)，1.92-2.07(m，2H)，2.23-2.35(m，1H)，2.63-2.89(m，2H)，3.74-4.02(m，10H)，7.06(dd，1H，J＝7.5，4.8Hz)，7.16-7.19(m，2H)，7.35(d，1H，J＝7.5Hz)，7.47(d，1H，J＝7.8Hz)，7.57(br?s，2H)，7.79-7.82(m，1H)，7.93(br?s，1H)，8.49(d，1H，J＝3.9Hz)； 13C?NMR(CDCl 3)δ21.75，22.72，29.47，43.47，49.67，52.47，53.72，60.08，122.16，122.49，128.59，130.22，131.01，131.25，135.03，137.53，142.15，142.66，147.34，154.59，156.99，167.19. ES-MSm/z456.4(M+H)。C 27H 29N 5O 21.0H 2The analytical value of O: C, 68.48; H, 6.60; N, 14.79 actual values: C, 68.54; H, 6.52; N, 14.51.
Embodiment 23
AMD11158:(2-amino methyl-4-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
2-{[[2-(tert-butoxycarbonyl amino-methyl)-4-methylol-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzoglyoxaline-1-carboxylic acid tertiary butyl ester:
With 2-{[(2-amino methyl-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(1.23g 2.23mmol) is dissolved in NH to benzoglyoxaline-1-carboxylic acid tertiary butyl ester 3Saturated MeOH (～15mL) in, handle with Raney nickel (excessive), then the gained mixture is placed on the H of 45psi 2On the Parr wobbler, shook 16 hours down.Dilute this mixture with MeOH, use diatomite filtration.Wash this filter cake with MeOH, decompression concentrates the filtrate that merges down.Filter the slurries (CH of gained with silica gel plug 2Cl 2/ MeOH/NH 4OH, 100: 2: 1), obtaining required amine (720mg), this amine need not be further purified and can use in next step reaction.
(solution of 1.0M in THF, 1.80mL 1.80mmol) are added drop-wise to being cooled in 0 ℃ the solution of amine (500mg) in THF (7.2mL) of obtaining above with LiAlH4.This mixture of stirring at room 15 minutes.Add MeOH (2mL), concentrate this mixture, repeat again twice.The weak yellow foam of gained (410mg) need not be further purified and can use in next step reaction.
With BOC 2O (205mg, 0.94mmol) in the solution of alcohol (330mg) in THF (2mL) that the solution in THF (4mL) obtains above being added to, stirring at room gained mixture 3 days.Decompression is concentrated gained reaction mixture down.Adopt the yellow foam (CH of column chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 2: 1), obtain required amine (230mg is 30% altogether) in two steps, be weak yellow foam. 1H?NMR(CDCl 3)δ1.44(s，9H)，1.65-1.70(m，10H)，1.96-2.08(m，1H)，2.16-2.27(m，2H)，2.46-2.57(m，1H)，2.71-2.85(m，1H)，3.86-3.97(m，2H)，4.31(d，1H，J＝15.0Hz)，4.38-4.48(m，2H)，4.54-4.59(m，4H)，6.63(dd，1H，J＝7.2，4.5Hz)，6.98(d，1H，J＝7.8Hz)，7.13-7.24(m，4H)，7.45(s，1H)，7.53-7.56(m，1H)，7.68-7.71(m，1H)，8.24(d，1H，J＝3.9Hz)，8.82-8.87(m，1H)。
With 2-{[[2-(tert-butoxycarbonyl amino-methyl)-4-methylol-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzoglyoxaline-1-carboxylic acid tertiary butyl ester (230mg, 0.37mmol) and NaH (60% is dispersed in the mineral oil, 13.3mg 0.56mmol) solution in DMF (2.0mL) was stirring at room 30 minutes.The adding methyl iodide (0.12mL, 1.85mmol), stirring at room gained mixture 1 hour.This mixture of vacuum concentration with EtOAc dilution, is used saturated sodium bicarbonate aqueous solution (2 * 5mL) and saturated sodium chloride aqueous solution (10mL) washing successively.Dry organic layer (sal epsom), decompression concentrates down.Adopt the yellow foam (CH of column chromatography purifying on silica gel 2Cl 2/ MeOH/NH 4OH, 200: 1: 1,200: 2: 1 then), obtaining required product (97mg), this product need not be further purified and can use in next step reaction.
TFA (1mL) is added to the amine (96mg) that obtains above at CH 2Cl 2In the solution (1mL), ambient temperature overnight stirs the gained mixture.Decompression concentrates this mixture down, in water, uses 1NNaOH (pH8) with its alkalization the gained slurry dissolved.Add CHCl 3(75mL), isolate each phase, use CHCl 3Extracting water layer (2 * 75mL).The dry organic extract (sal epsom) that merges filters, and decompression concentrates down.Adopt the yellow foam (CH of radial chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 1: 1,200: 3: 1 then), (20.2 mg obtain 13% altogether in two steps to obtain white solid AMD11158. 1HNMR(CD 3OD)δ1.52-1.66(m，1H)，2.04-2.25(m，3H)，2.61-2.71(m，1H)，2.82-2.93(m，1H)，3.60-3.65(m，1H)，3.72-3.75(m，4H)，3.81(d，1H，J＝12.9Hz)，3.91-3.98(m，3H)，4.13(d，1H，J＝13.2Hz)，4.53(s，2H)，7.02(dd，1H，J＝7.5，4.5Hz)，7.14-7.27(m，4H)，7.33-7.40(m，3H)，7.54-7.56(m，1H)，8.32-8.36(m，1H)； 13C?NMR(CD 3OD)δ23.27，23.34，30.59，31.18，44.23，48.33，55.77，60.96，65.21，111.37，119.67，123.44，123.69，124.30，127.17，130.03，132.72，136.74，136.87，138.48，142.81，143.24，148.08，153.81，158.22.ES-MSm/z442.4(M+H)。C 27H 31N 5O1.2CH 4O0.2CH 2Cl 2Analytical value: C, 68.63; H, 7.34; N, 14.09.Actual value: C, 69.03; H, 7.09; N, 13.79.
Embodiment 24
Figure A0181580200681
AMD9852:N-(2-{[1H-benzimidazolyl-2 radicals-Ji-methyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-preparation of guanidine
With N, N '-two tert-butoxycarbonyls-pyrazoles-1-carbonyl amidine (60mg, 0.187mmol) and salt of wormwood (35mg, 0.25mmol) be added to (1H-benzimidazolyl-2 radicals-ylmethyl)-(2-amino methyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (referring to AMD9720) (50mg, 0.125mmol) in the solution in THF (5mL), this mixture of stirred overnight.Use NH 4The Cl aqueous solution (5mL) dilution gained reactant is with ethyl acetate extracting (3 * 10mL).The dry organic moiety (sodium sulfate) that merges concentrates, and adopts chromatography to carry out purifying (5%MeOH/CH on silica gel 2Cl 2), obtain the required product of canescence foamy (51mg, 64%), 1H NMR (CDCl 3) δ 1.47 (s, 9H), 1.48 (s, 9H), 1.81 (m, 1H), 2.00 (m, 2H), 2.26 (m, 2H), 2.71-2.88 (m, 2H), 3.89-4.05 (m, 5H), 4.73 (dd, 1H, J=15.5,5.1Hz), 4.96 (dd, 1H, J=15.5,5.7Hz), 7.12 (m, 7H), and 7.36-7.44 (m, 3H), 7.55 (br s, 1H (NH)), (8.55 m, 1H (NH)), 8.66 (d, 1H, J=5.1Hz).
Adopt general flow D: (51mg 0.08mmol) changes into hydrobromate, obtains white solid AMD9852 (108mg) with the foam that obtains above. 1H NMR (D 2O). δ 1.88 (m, 1H), 2.21 (m, 2H), 2.43 (m, 1H), 3.01 (m, 2H), 3.81 (d, 1H, J=13.5Hz), 4.01 (d, 1H, J=13.5Hz), 4.34 (d, 1H, J=16.2Hz), 4.38 (d, 1H, J=14.4Hz), 4.44 (d, 1H, J=14.4Hz), 4.55 (d, 1H, J=16.2Hz), 4.78 (m, 1H), 6.99 (m, 2H), 7.10 (dt, 1H, J=7.2,1.2Hz), 7.40 (d, 1H, J=6.9Hz), 7.55 (m, 2H), 7.62 (m, 2H), 7.87 (dd, 1H, J=7.8,5.7Hz), 8.35 (d, 1H, J=7.8Hz), 8.68 (d, 1H, J=5.1Hz). 13C NMR (D 2O) δ 18.03,18.26, and 25.51,40.78,46.69,50.49,59.14,111.69 (2C), 123.74,124.50 (2C), 126.48,126.65,126.74,128.35,128.98,132.04,137.48,138.22,145.85,150.02.ES-MSm/z440 (M+H); (C 26H 29N 7* 3.0HBr * 3.0H 2O) analytical value: C, 42.41; H, 5.07; N, 13.32; Br32.55.Actual value: C, 42.67; H, 5.07; N, 13.24; Br, 32.77.
Embodiment 25
Figure A0181580200691
AMD9596:N-(4-{[(1H-benzimidazolyl-2 radicals-Ji-methyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-preparation of guanidine (hydrobromate)
With N, N '-two tert-butoxycarbonyls-pyrazoles-1-carbonyl amidine (370mg, 1.2mmol) and salt of wormwood (207mg, 1.5mmol) be added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1,4-xylylene amine (benzenedimethanamine) (397mg, 1.0mmol) in the solution in THF (10mL), this mixture of stirring at room 16 hours.Use NH 4The Cl aqueous solution (15mL) dilutes this reactant, with this mixture of ethyl acetate extracting.The dry organic moiety (sodium sulfate) that merges is filtered, and concentrates, and adopts chromatography purifying (CH of 19: 1 on silica gel 2Cl 2/ MeOH), obtain canescence foam N ', N " two tert-butoxycarbonyls-N-(4-{[1H-benzimidazolyl-2 radicals-ylmethyl)--(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-guanidine (426mg, 67%). 1H?NMR(CDCl 3)δ1.25(s，9H)，1.44(s，9H)，1.65(m，1H)，1.99(m，2H)，2.04(m，1H)，2.72-2.79(m，2H)，3.73(s，2H)，3.94(d，1H，J＝16.1Hz)，4.07(m，1H)，4.11(d，1H，J＝16.1Hz)，4.51(d，2H，J＝6.2Hz)，7.14(m，4H)，7.39(m，3H)，7.55(m，1H)，7.63(m，1H)，8.47(m，1H(NH))，8.66(d，1H，J＝4.8Hz)。
Adopt general flow D: by removing the Boc group simultaneously, (106mg 0.1mmol) changes into hydrobromate, obtains white crystalline solid AMD9596 (108mg) with the material that obtains above. 1H NMR (D 2O). δ 1.88 (m, 1H), 2.21 (m, 2H), 2.43 (m, 1H), 3.01 (m, 2H), 3.78 (d, 1H, J=12.6Hz), 3.83 (d, 1H, J=12.6Hz), 3.89 (s, 2H), 4.45 (d, 1H, J=16.5Hz), 4.60 (d, 1H, J=16.5Hz), 4.79 (m, 1H), 6.89 (d, 2H, J=7.8Hz), 7.15 (d, 2H, J=7.8Hz), 7.50 (m, 2H), 7.57 (m, 2H), 7.91 (dd, 1H, J=8.1,6.0Hz), 8.39 (d, 1H, J=8.1Hz), 8.73 (d, 1H, J=6.0Hz). 13C NMR (D 2O) δ 20.46,20.87, and 27.83,43.90,50.31,56.69,63.17,113.76 (2C), 126.04,126.62 (2C), 127.03 (2C), 130.52 (2C), 135.98,136.24,139.58,140.92,148.20,150.93,151.86.ES-MSm/z440 (M+H); (C 26H 29N 7* 3.2HBr * 2.2H 2O) analytical value: C, 42.31; H, 5.00; N, 13.28; Br33.64.Actual value: C, 42.48; H, 5.05; N, 13.15; Br, 32.64.
Embodiment 26
Figure A0181580200701
AMD9735:N '-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-N, the preparation of N-dimethyl-guanidine (hydrobromate)
Hydrochloric acid N, the preparation of N-dimethyl-1H-pyrazoles-1-carbonyl amidine
(4.0N is 1, the solution in the 4-two  alkane, 3.8mL with hydrochloric acid, 15.2mmol) be added to pyrazoles (1.01g, 14.8mmol) (1.20mL is 14.8mmol) 1 with the dimethyl cyanamide, in the solution in the 4-two  alkane (15mL), then reflux gained mixture is 3 hours.This reaction mixture is cooled to room temperature,, is settled out yellow solid with anhydrous ether (15mL) dilution.(spending the night), decant upper solution then at the bottom of the throw out of gained is deposited to bottle.This solid of vacuum-drying obtains title compound (2.01g, 78%).ES-MSm/z139(M+H)。
With hydrochloric acid N, N '-dimethyl-1H-pyrazoles-1-carbonyl amidine (0.250g, 1.18mmol) and N, (0.70mL 4.02mmol) is added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5 to the N-diisopropylethylamine, 6,7,8-tetrahydrochysene-8-quinolyl)-1,4-xylylene amine (0.221g, 0.56mmol) in the solution in DMF (1mL), stirring at room gained mixture 19 hours.Water (5mL) and CH 2Cl 2(25mL) dilute this reaction mixture, with diluted hydrochloric acid aqueous solution (1N, 3mL) pH with water adjust to～4.Isolate each phase, use CH 2Cl 2Extracting water (3 * 10mL).Decompression is concentrated water down, and the colorless oil of gained is dissolved among the 10N NaOH (4mL).Use CH 2Cl 2(4 * 10mL), the dry organic extract (sodium sulfate) that merges concentrates this alkaline aqueous solution of extracting.Adopt the radial chromatography thick material of purifying gained (1mm flat board, CH of 1: 1: 1 on silica gel 3CN-CH 3OH-NH 4OH), obtain white solid (147mg).
Adopt general flow D: above-mentioned free alkali (124mg) is changed into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9735 (121mg). 1H NMR (D 2O) δ 1.84-1.98 (m, 1H), 2.20-2.34 (m, 2H), 2.40-2.47 (m, 1H), and 2.99-3.06 (m, 8H), 3.77 (d, 1H, J=12.6Hz), 3.84 (d, 1H, J=12.6Hz), 3.96 (s, 2H), 4.47 (d, 1H, J=16.5Hz), 4,65 (d, 1H, J=16.5Hz), 4.72-4.79 (m, 1H, overlapping with HOD), 6.93 (d, 2H, J=7.8Hz), 7.18 (d, 2H, J=7.8Hz), 7.50-7.53 (m, 2H), 7.58-7.63 (m, 2H), 7.93 (dd, 1H, J=6.6,7.2Hz), 8.39 (d, 1H, J=7.8Hz), 8.77 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.29,20.70, and 27.67,37.99,44.43,50.09,56.39,62.91,113.65,125.86,126.39,126.86,130.33,130.36,135.80,136.43,139.47,140.75,148.01,150.75,151.75,155.99; ES-MSm/z468 (M+H).C 28H 33N 73.2HBr2.6H 2O1.4NH 4The analytical value of Br: C, 36.94; H, 5.20; N, 12.92; Br, 40.37.Actual value: C, 36.94; H, 5.06; N, 12.88; Br, 40.45.
Embodiment 27
AMD9777:[4-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-8-yl)-amino methyl benzyl]-N, the preparation of N '-dimethyl carbonamidine (hydrobromate)
With 2-pyridine SULPHURYL CHLORIDE (41mg, 0.23mmol) solution stirring in DMF (0.75mL) 10 minutes, add N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5 afterwards, 6,7,8-tetrahydrochysene-8-quinolyl)-1,4-xylylene amine (62mg, 0.16mmol) in the solution in DMF (0.8mL), then stirring at room gained reactant 3 hours.Decompression concentrates this reactant down, uses CH 2Cl 2(5mL) with saturated wet chemical (5mL) dilution.Isolate each phase, dry then organic phase (sal epsom) is filtered, and concentrates, and adopts column chromatography to carry out purifying (5%MeOH/CH on silica gel 2Cl 2), obtain required N, N-dimethyl carbonamidine (23mg, 32%). 1H?NMR(CDCl 3)δ1.67(m，1H)，2.03(m，2H)，2.24(m，1H)，2.70(m，1H)，2.84(m，1H)，2.84(s，6H)，3.71(s，2H)，3.96(d，1H，J＝15.0Hz)，4.07(m，1H)，4.15(d，1H，J＝18.0Hz)，4.36(s，2H)，7.16(m，5H)，7.31(s，1H)，7.35(d，2H，J＝7.8Hz)，7.42(d，1H，J＝7.8Hz)，7.51(br，1H)，7.64(br，1H)，8.68(d，1H，J＝3.5Hz)。
Adopt general flow D: the material (23mg) that obtains is above changed into hydrobromate, obtain white solid AMD9777 (38mg). 1H?NMR(D 2O)δ1.91(br?m，1H)，2.26(m，2H)，2.45(br?m，1H)，2.97(s，3H)，3.03(br?m，2H)，3.24(s，3H)，3.78(d，1H，J＝12.9Hz)，3.85(d，1H，J＝12.9Hz)，4.04(s，2H)，4.45(d，1H，J＝16.5Hz)，4.63(d，1H，J＝16.5Hz)，4.80(m，1H)，6.90(d，2H，J＝8.1Hz)，7.18(d，2H，J＝7.8Hz)，7.52(dd，2H，J＝3.0，6.3Hz)，7.59(dd，2H，J＝3.0，6.3Hz)，7.64(s，1H(NCHN))，7.94(t，1H，J＝6.9Hz)，8.41(d，1H，J＝7.8Hz)，8.76(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.47，20.92，27.85，36.27，43.38，49.66，50.21，56.67，63.21，113.87(2C)，126.09，126.50(2C)，127.63(2C)，130.61(2C)，136.44(2C)，139.65，141.01，148.27(2C)，150.90，151.94，156.35(2C).ES-MSm/z453(M+H)。C 28H 32N 63.3HBr2.3H 2The analytical value of O: C, 44.29; H, 5.30; N, 11.07; Br, 34.46.Actual value: C, 44.36; H, 5.14; N, 10.74; Br, 34.44.
Embodiment 28
AMD9783:N-(4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-preparation of benzonitrile (hydrobromate)
Hydrogen bromide S-dibenzylsulfide is for the preparation of benzonitrile:
(0.26mL, (0.307g is 2.24mmol) at CH 2.19mmol) to be added to thiobenzamide with bromotoluene 2Cl 2In the solution (11mL), with gained vlil 2 hours.This mixture is cooled to room temperature, and decompression concentrates down.Vacuum-drying gained yellow solid obtains Hydrogen bromide S-dibenzylsulfide for benzonitrile (0.573g, 85%). 1H?NMR(DMSO-d 6)δ4.76(s，2H)，7.34-7.44(m，3H)，7.51-7.54(m，2H)，7.61-7.66(m，2H)，7.78-7.83(m，1H)，7.88-7.91(m，2H)，11.92(br?s，1H)。
With Hydrogen bromide S-dibenzylsulfide for benzonitrile (0.100g, 0.33mmol) be added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1,4-xylylene amine (0.130g, 0.33mmol) in the solution in ethanol (2mL), stirring at room gained mixture 45 minutes.Handle this mixture with the saturated acetate of HBr (3mL).Add ether (50mL), white solid is deposited on bottle at the bottom of on, with the upper solution decant.(3 * 50mL), the ether of residual trace is removed in decompression down to wash this solid with ether.Make this solid sodium hydroxide solution (10N, 5mL) and CH 2Cl 2Distribute (20mL).Isolate each phase, use CH 2Cl 2Extracting water (4 * 10mL).The dry organic extract (sodium sulfate) that merges concentrates.Adopt the radial chromatography thick material of purifying gained (1mm flat board, 20: 1: 1 CH on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 50mg (32%), be white solid.
Adopt general flow D: (50mg) changes into hydrobromate with above-mentioned free alkali, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9783 (56mg). 1H NMR (D 2O) δ 1.83-1.97 (m, 1H), 2.20-2.35 (m, 2H), 2.42-2.48 (m, 1H), 3.04 (br s, 2H), 3.79 (d, 1H, J=12.3Hz), 3.87 (d, 1H, J=12.3Hz), 4.21 (s, 2H), 4.47 (d, 1H, J=16.5Hz), 4.65 (d, 1H, J=16.5Hz), 4.74-4.79 (m, 1H, overlapping with HOD), 7.02 (d, 2H, J=7.8Hz), 7.22 (d, 2H, J=7.8Hz), 7.29 (dd, 2H, J=3.0,6.0Hz), 7.54 (dd, 2H, J=3.0,6.0Hz), 7.62-7.64 (m, 4H), 7.74-7.78 (m, 1H), 7.91 (dd, 1H, J=6.3,7.2Hz), 8.39 (d, 1H, J=8.1Hz), 8.76 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.47,20.93, and 27.86,45.43,50.31,56.67,63.26,113.73,126.07,126.55,127.64,128.09,128.89,129.83,130.50,130.67,134.41,136.54,139.65,140.99,148.23,150.92,151.93,164.65; ES-MSm/z501 (M+H).C 32H 32N 63.0HBr2.4H 2The analytical value of O: C, 48.86; H, 5.10; N, 10.68; Br, 30.47.Actual value: C, 48.97; H, 4.89; N, 10.62; Br, 30.30.
Embodiment 29
Figure A0181580200741
AMD9784:N-(4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-preparation of ethanamidine (hydrobromate)
Hydrogen bromide S-dibenzylsulfide pursues the preparation of acetate (acetimidate) for imido:
(0.76mL, (0.478g is 6.36mmol) at CHCl 6.39mmol) to be added to thioacetamide with bromotoluene 3In the solution (16mL), with the vlil of gained 2 hours.This mixture is cooled to room temperature.Add ether (50mL), this mixture of cooling is settled out white solid in ice-water-bath.The decant upper solution is washed this solid (2 * 50mL) with ether.This solid of vacuum-drying, the white solid Hydrogen bromide S-dibenzylsulfide that obtains 1.44g (92%) pursues acetate for imido. 1H?NMR(DMSO-d 6)δ2.63(s，3H)，4.61(s，2H)，7.34-7.46(m，5H)，11.89(br?s，1H)。
Hydrogen bromide S-dibenzylsulfide is pursued acetate (0.099g for imido, 0.40mmol) be added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1, (0.154g 0.39mmol) in the solution in ethanol (2mL), stirs the gained mixture in ambient temperature overnight to 4-xylylene amine.Handle this mixture with the saturated acetate of HBr (3mL).Decompression concentrates down this mixture, make residue sodium hydroxide solution (10N, 5mL) and CH 2Cl 2Distribute (10mL).Isolate each phase, use CH 2Cl 2Extracting water (3 * 10mL).The dry organic extract (sodium sulfate) that merges concentrates.Adopt thick material (1mm flat board, 1: 1: 1 the CH of radial chromatography purifying on silica gel 3CN-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 97mg (57%), be white solid.
Adopt general flow D: (97mg) changes into hydrobromate with above-mentioned free alkali, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9784 (113mg). 1H NMR (D 2O) δ 1.83-1.98 (m, 1H), 2.17-2.33 (m, 5H), 2.41-2.47 (m, 1H), and 3.03-3.05 (m, 2H), 3.78 (d, 1H, J=12.3Hz), 3.85 (d, 1H, J=12.3Hz), 3.96 (s, 2H), 4.46 (d, 1H, J=16.5Hz), 4.64 (d, 1H, J=16.5Hz), 4.74-4.79 (m, 1H, overlapping with HOD), 6.91 (d, 2H, J=7.8Hz), 7.18 (d, 2H, J=7.8Hz), 7.49-7.60 (m, 4H), 7.92 (dd, 1H, J=6.0,7.8Hz), 8.39 (d, 1H, J=7.5Hz), 8.75 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 18.91,20.47, and 20.91,27.86,44.99,50.26,56.65,63.18,113.84,126.08,126.63,127.58,130.52,130.60,134.29,136.43,139.64,140.99,148.25,150.91,151.90,164.99; ES-MSm/z439 (M+H).C 27H 30N 63.1HBr2.2H 2The analytical value of O: C, 44.48; H, 5.18; N, 11.53; Br, 33.98.Actual value: C, 44.49; H, 5.19; N, 11.25; Br, 34.13.
Embodiment 30
Figure A0181580200751
AMD9689:N-isobutyl--N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1, the preparation of 4-xylylene amine (hydrobromate)
Be used in anhydrous CH 3N ' among the OH (5mL)-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1, (152mg, 0.382mmol) (0.1mL, 1.1mmol) condensation is 17 hours, uses NaBH with isobutyl-aldehyde for 4-xylylene amine 4(81mg, 2.14mmol) imines 1 hour (referring to general flow A and B) of reduction gained.Adopt thick material (2mm TLC flat board, 50: 1: 1 the CH of radial chromatography purifying gained 2Cl 2/ CH 3OH/NH 4OH), obtain free amine (43mg, 25%).
Adopt general flow D: the material (43mg) that obtains is above changed into hydrobromate, obtain white solid AMD9689 (52mg, 75%). 1H NMR (D 2O) δ 0.88 (d, 6H, J=6.1Hz), 1.82-1.96 (m, 2H), 2.17-2.34 (m, 2H), 2.40-2.50 (m, 1H), 2.63 (d, 2H, J=7.6Hz), 3.01-3.08 (m, 2H), 3.65 (s, 2H), 3.81 (d, 1H, J=12.7Hz), 3.88 (d, 1H, J=12.7Hz), 4.46 (d, 1H, J=16.6Hz), 4.64 (d, 1H, J=16.1Hz), 7.02 (d, 2H, J=7.9Hz), 7.23 (d, 2H, J=8.0Hz), 7.51 (dd, 2H, J=6.2,3.1Hz), 7.59 (dd, 2H, J=6.0,3.6Hz), 7.94 (dd, 1H, J=8.1,6.0Hz), 8.41 (d, 1H, J=7.9Hz), 8.76 (d, 1H, J=5.7Hz). 13C (D 2O) δ 19.67 (2 carbon), 20.64,21.12,25.95,28.04,50.35,50.67,54.46,56.86,63.38,114.11 (2 carbon), 126.30, (126.90 2 carbon), 130.35 (2 carbon), 130.75,130.93 (2 carbon), 138.13,139.87,141.21, (148.46 2 carbon), 151.03,151.95.ES-MSm/z454 (M+H).C 29H 35N 53.0HBr1.9H 2The analytical value of O: C, 47.68; H, 5.77; N, 9.59; Br, 32.81.Actual value: C, 47.53; H, 5.68; N, 9.46; Br, 32.94.
Embodiment 31
AMD9776:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-piperidines-2-base benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The 4-[(1-tert-butoxycarbonyl)-piperidines-2-yl]-preparation of phenyl aldehyde:
Figure A0181580200762
With PtO 2(57mg, 0.251mmol) be added to 4-pyridine-2-base-phenyl aldehyde of being contained in the Parr hydrogenation flask (1.0368,5.65mmol) EtOH (95%, 3.1mL) and in the solution in the concentrated hydrochloric acid (0.48mL), then at the H of 50psi 2Middle this mixture of hydrogenation 40 hours.With this mixture of diatomite filtration, wash this filter cake with MeOH, the solvent in the elutriant is removed in decompression down.The yellow solid of gained is dissolved among the 1N NaOH (30mL), with ether extracting (4 * 50mL).The dry organic phase (sodium sulfate) that merges is filtered, and decompression concentrates down, obtains thick white solid 1-(methylol)-4-(piperidines-2-yl)-benzene (0.988).With two-tert-butyl carbonic acid hydrogen ester (1.51g 6.92mmol) is added in the solution of this solid in THF (25mL), triethylamine (10) and water (10), with this reactant stirring at room 20 hours.Decompression concentrates this mixture down then, from CH 2Cl 2Obtain residue (100mL), with salt water washing (3 * 75mL).Dry organic phase (sodium sulfate) is filtered, and decompression concentrates down, obtains thick oily matter 1-(methylol)-4-[(1-butoxy carbonyl)-piperidines-2-yl]-benzene (1.878).
With MnO 2(85%, 5.90g 57.7mmol) is added to the oily matter (1.87g) that obtains above at CH 2Cl 2In the solution (100mL), and this reactant of stirring at room 18 hours.With this mixture of diatomite filtration, the solvent in the elutriant is removed in decompression down.Adopt thick product (1.50g) (38g silica gel, 99: 1CH of purified by flash chromatography 2Cl 2: CH 3OH), obtain title compound (0.98g, 60%). 1H?NMR(CDCl 3)δ1.25-1.69(m，13H)，1.95(tt，1H，J＝13.4，4.6Hz)，2.31(d，1H，J＝12.9Hz)，2.77(td，1H，J＝12.4，4.3Hz)，4.09(d，1H，J＝13.7Hz)，5.44(s，1H)，7.39(d，2H，J＝7.7Hz)，7.87(d，2H，J＝8.2Hz)，10.00(s，1H)。
Adopt general flow B: with NaBH (OAc) 3(219mg 1.03mmol) is added to the 4-[(1-tert-butoxycarbonyl)-piperidines-2-yl]-(189mg is 0651mmol) with [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(5 for phenyl aldehyde, 6,7,8-tetrahydrochysene-quinoline-8-yl)-(138mg is 0.366mmol) at CH for amine 2Cl 2In the solution (8mL), this reactant stirring is spent the night.Adopt this thick oily matter of column chromatography purifying (12g silica gel, 40: 1: 1 CH 2Cl 2: CH 3OH: NH 4OH), then adopt radial chromatography purifying (1mm TLC flat board, 100: 1: 1CH 2Cl 2: CH 3OH: NH 4OH), obtain required free alkali (59mg, 29%).
Adopt general flow D: the oily matter (59mg) that obtains is above changed into hydrobromate, obtain AMD9776 (59mg, 75%). 1H NMR (D 2O) δ 1.07-1.22 (m, 1H), 1.24-1.40 (m, 1H), 1.43-1.68 (m, 2H), and 1.81-1.98 (m, 3H), 2.18-2.36 (m, 2H), 2.40-2.51 (m, 1H), 2.95-3.10 (m, 3H), 3.35 (d, 1H, J=13.3Hz), 3.75-3.92 (m, 3H), 4.48 (dd, 1H, J=16.7,8.7Hz), 4.66 (dd, 1H, J=16.7,5.7Hz), 7.01 (d, 2H, J=7.5Hz), 7.26 (dd, 2H, J=7.8,4.9Hz), 7.48-7.54 (m, 2H), 7.55-7.61 (m, 2H), and 7.91-7.97 (m, 1H), 8.41 (d, 1H, J=8.3Hz), 8.75-8.80 (m, 1H). 13C NMR (D 2O) δ 20.48,20.97, and 21.84,22.29,27.88,29.86,45.87,50.32,50.49,56.61,60.24,63.27,63.37,113.94 (2 carbon), 126.14,126.71 (2 carbon), 127.06 (2 carbon), 130.46, (131.03 2 carbon), 136.85,137.49,139.71,141.02,148.30 (2 carbon), 150.83,151.88.ES-MSm/z452 (M+H).C 29H 33N 53.0HBr2.0H 2The analytical value of O: C, 47.69; H, 5.52; N, 9.59; Br, 32.82.Actual value: C, 47.54; H, 5.42; N, 9.48; Br, 33.09.
Embodiment 32
AMD9713:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-piperidines-1-ylmethyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow A: with piperidines (0.040mL, 0.40mmol) and sodium cyanoborohydride (44mg, 0.70mmol) be added to the 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl that is stirring)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(144mg 0.36mmol) in the solution in anhydrous MeOH (5mL), stirred this mixture 5 hours to phenyl aldehyde (AMD9882).Adopt crude product (1mm flat board, the CH of radial chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH, 50: 1: 1), obtain required adducts (50mg, 30%), be white foam.
Adopt general flow D: (25mg 0.053mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains yellow solid AMD9713 (40mg, 98%) with the foam that obtains above. 1HNMR (D 2O) δ 1.32-1.57 (m, 3H), 1.70-1.93 (m, 4H), 2.22-2.31 (m, 2H), and 2.44-2.48 (m, 1H), 2.65 (brt, 2H, J=11.4Hz), 3.01-3.03 (br m, 4H), 3.75 (s, 2H), 3.81 (d, 1H, J=12.6Hz), 3.89 (d, 1H, J=12.6Hz), 4.48 (d, 1H, J=16.5Hz), 4.67 (d, 1H, J=16.5Hz), 4.77-4.79 (m, 1H, overlapping with HOD), 7.04 (d, 2H, J=7.8Hz), 7.25 (d, 2H, J=7.8Hz), 7.51 (dd, 2H, J=6.3,3Hz), 7.59 (dd, 2H, J=6.3,3Hz), 7.94 (dd, 1H, J=7.5,6.3Hz), 8.41 (d, 1H, J=8.1Hz), 8.78 (d, 1H, J=5.4Hz); 13C NMR (D 2O) δ 20.30,20.82, and 21.25,22.91,27.71,50.19,52.80,56.58,59.44,63.22,113.70,125.98,126.62,128.69,130.29,130.58,131.14,138.14,139.55,140.92,148.17,150.66,151.68.ES-MSm/z466 (M+H).C 30H 35N 53.2HBr1.5H 2The analytical value of O: C, 47.94; H, 5.53; N, 9.32; Br, 34.02.Actual value: C, 47.72; H, 5.54; N, 9.22; Br, 34.32.
Embodiment 33
AMD9722:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-methylamino methyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: with the methylamine (solution of 2.0M in methyl alcohol, 1mL, 2.00mmol) be added to 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl aldehyde (AMD9882) (120mg, 0.30mmol) in the solution in MeOH (2mL), stirring at room gained solution 5 hours.With solid NaBH 4(18mg 0.48mmol) is added in this solution, room temperature restir gained mixture 30 minutes.Adopt thick material (1mm flat board, 50: 1: 1 the CH of radial chromatography purifying gained on silica gel 2Cl 2/ CH 3OH/NH 4OH), obtain the free alkali (74mg, 59%) of title compound, be white solid.
Adopt general flow D: the free alkali (74mg) that obtains is above changed into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9722 (111mg). 1H NMR (D 2O) δ 1.84-1.97 (m, 1H), 2.21-2.47 (m, 6H), 3.04 (br s, 2H), 3.66 (s, 2H), 3.81 (d, 1H, J=12.6Hz), 3.88 (d, 1H, J=12.6Hz), 4.46 (d, 1H, J=16.5Hz), 4.64 (d, 1H, J=16.5Hz), 4.77-4.79 (m, 1H, overlapping with HOD), 7.01 (d, 2H, J=8.1Hz), 7.24 (d, 2H, J=8.1Hz), 7.49-7.53 (m, 2H), 7.56-7.60 (m, 2H), 7.93 (dd, 1H, J=6.0,7.5Hz), 8.40 (d, 1H, J=8.1Hz), 8.76 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 18.71,19.20, and 26.11,30.37,48.50,49.69,54.93,61.49,112.19,124.37,124.95,128.27,128.77,128.84,129.07,136.21,137.94,139.28,146.54,149.08,150.08; ES-MSm/z412 (M+H).C 26H 29N 53.0HBr2.0H 2The analytical value of O: C, 45.24; H, 5.26; N, 10.15; Br, 34.73.Actual value: C, 45.13; H, 5.20; N, 10.02; Br, 34.81.
Embodiment 34
AMD9724:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-piperazine-1-ylmethyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
2,2, preparation (Xu, the D. of 2-three fluoro-1-piperazines-1-base-ethane ketone (ethanone); Repic, O.; Blacklock, J.Tetrahedron Lett.1995,41,7357-7360):
With Trifluoroacetic Acid Ethyl Ester (2.0mL, 16.8mmol) be added to piperazine (1.444g, 16.8mmol) in the solution in MeOH (10mL), this mixture overnight of stirring at room.Concentrate this reactant, adopt column chromatography on silica gel, to carry out purifying (CH 2Cl 2/ MeOH, 9: 1), obtain required single piperazine synthetics of protecting (1.77g, 58%), be faint yellow oily thing. 1H?NMR(CDCl 3)δ1.70(br?s，1H)，2.90-2.94(m，4H)，3.56-3.59(m，2H)，3.64-3.67(m，2H)。
Adopt general flow A: with 2,2,2-three fluoro-1-piperazines-1-base-ethane ketone (172mg, 0.95mmol) and sodium cyanoborohydride (54mg 0.86mmol) is added to 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl aldehyde (AMD9882) (262mg, 0.66mmol) in the solution in MeOH (10mL), stirred overnight gained mixture.Adopt column chromatography this thick product (CH of purifying on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 1: 1), then adopt radial chromatography on silica gel, to carry out purifying (2mm flat board, CH 2Cl 2/ MeOH/NH 4OH, 50: 1: 1), obtain required adducts (68mg, 18%), be white foam.
(55mg, (68mg 0.12mmol) in the solution in MeOH (3mL), stirred down reflux gained mixture 1.5 hours, spent the night under the room temperature then 0.40mmol) to be added to the adducts of the TFA protection that obtains above with potassium carbonate powder.Use CH 2Cl 2(30mL) and water (20mL) diluting reaction thing, isolate each phase, use CH 2Cl 2Extracting water (2 * 15mL).Dry (Na 2SO 4) organic extract of merging, filter vacuum concentration.Adopt radial chromatography purifying crude product (1mm flat board, CH on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 1: 1,50: 1: 1 then), obtain required adducts (54mg, 97%), be purified oily matter.
Adopt general flow D: (23mg 0.049mmol) changes into hydrobromate, and then reprecipitation goes out the intermediate solid in methyl alcohol/ether, obtains white solid AMD9724 (35mg, 85%) with the foam that obtains above. 1H NMR (D 2O) δ 1.89-1.93 (m, 1H), 2.21-2.33 (m, 2H), 2.42-2.48 (m, 1H), 3.03-3.05 (m, 2H), 3.24-3.28 (m, 4H), 3.42-3.44 (m, 4H), 3.82 (d, 1H, J=12.9Hz), 3.87 (s, 2H), 3.90 (d, 1H, J=12.6 Hz), 4.46 (d, 1H, J=16.5Hz), (4.65 d, 1H, J=16.5 Hz), 4.77-4.79 (m, 1H, overlapping with HOD), 7.07 (d, 2H, J=7.8 Hz), 7.27 (d, 2H, J=7.8Hz), 7.51 (dd, 2H, J=6,3Hz), 7.59 (dd, 2H, J=6,3Hz), 7.94 (dd, 1H, J=7.2,6.6Hz), 8.41 (d, 1H, J=8.1Hz), 8.78 (d, 1H, J=6.2Hz); 13C NMR (D 2O) δ 20.45,20.97, and 27.87,41.14,48.19,50.17,56.75,59.92,63.27,113.97,126.15,126.68,128.00,130.53,130.94,131.34,138.82,139.74,141.09,148.33,150.78,151.81.ES-MSm/z467 (M+H).C 29H 34N 64HBr2.5H 2The analytical value of O: C, 41.70; H, 5.19; N, 10.06; Br, 38.26.Calculated value: C, 41.72; H, 5.16; N, 9.82; Br, 38.41.
Embodiment 35
AMD9733:[4-(4-allyl group-piperazine-1-ylmethyl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of 1-allyl group-piperazine:
With allyl bromide 98 (0.32mL, 3.7mmol) and potassium carbonate powder (0.78g, 5.65mmol) be added to stirring 2,2, (515mg is 2.83mmol) at anhydrous CH for 2-three fluoro-1-piperazines-1-base-ethane ketone 3In the solution among the CN (6mL), this mixture of stirred overnight.Decompression concentrates this reactant down, uses CH 2Cl 2(30mL) and water (30mL) dilution.Use CH 2Cl 2Extracting water layer (2 * 20mL).The dry organic extract (sodium sulfate) that merges filters, and vacuum concentration obtains two piperazines of protecting (0.554g), and this product need not be further purified and can use in next step reaction.
(0.689g 5.0mmol) is added in the solution of piperazine (0.554g) in MeOH (10mL) of the TFA protection that obtains above, and stirring and refluxing gained mixture 1.5 hours makes it in ambient temperature overnight with potassium carbonate powder.Use CH 2Cl 2(30mL) and water (20mL) dilute this reactant, isolate each phase, use CH 2Cl 2Extracting water layer (2 * 15mL).Dry (Na 2SO 4) organic extract of merging, filtering, vacuum concentration obtains title compound (0.132g, 42%), is faint yellow oily thing. 1H?NMR(CDCl 3)δ?1.96(br?s，1H)，2.39-2.44(brm，4H)，2.89-2.92(m，4H)，2.98(d，2H，J＝6Hz)，5.13-5.21(m，2H)，5.79-5.93(m，1H)。
Adopt general flow B: with NaBH (OAc) 3(184mg 0.87mmol) is added to 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(262mg, 0.66mmol) (132mg is 1.05mmol) at CH with 1-allyl group-piperazine for phenyl aldehyde (AMD9882) 2Cl 2In the solution (6mL), stirring at room gained compound 2 hours.Adopt thick the material ((CH of column chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH, 95: 4: 1), obtain required adducts (267mg), be purified oily matter.
Adopt general flow D: the oily matter (233mg) that obtains is above changed into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains AMD9733 (335mg is 56% altogether) in two steps, is yellow solid. 1H NMR (D 2O) δ 1.89-1.94 (m, 1H), 2.21-2.33 (m, 2H), 2.42-2.46 (m, 1H), and 3.03-3.05 (m, 2H), 3.30-3.34 (m, 4H), 3.44-3.51 (m, 4H), 3.80-3.90 (m, 6H), 4.47 (d, 1H, J=16.5Hz), 4.65 (d, 1H, J=16.5Hz), 4.77-4.79 (m, 1H, overlapping with HOD), 5.62 (d, 1H, J=17.1Hz), 5.64 (d, 1H, J=9.6Hz), 5.81-5.91 (m, 1H), 7.07 (d, 2H, J=7.8Hz), 7.28 (d, 2H, J=7.8Hz), 7.50 (dd, 2H, J=6,3Hz), 7.59 (dd, 2H, J=6,3Hz), 7.95 (dd, 1H, J=7.8,6Hz), 8.42 (d, 1H, J=7.8Hz), 8.78 (d, 1H, J=5.5Hz); 13C NMR (D 2O) δ 20.72,21.26, and 28.15,48.52,48.64,50.48,56.99,59.47,59.73,63.48,114.29,125.18,126.44,126.97,127.79,128.76,130.70,131.28,131.71,139.20,140.03,141.33,148.62,150.97,152.01.ES-MSm/z507 (M+H).C 32H 38N 63.9HBr2.7H 2O0.4C 4H 10The analytical value of O: C, 44.81; H, 5.74; N, 9.33; Br, 34.60.Actual value: C, 44.62; H, 5.49; N, 9.26; Br, 34.84.
Embodiment 36
AMD9734:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-dimethylaminomethyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: make 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl aldehyde (AMD9882) (157mg, 0.40mmol) and dimethylamine (solution of 2.0M in THF, 0.4mL, 0.80mmol) and CH 2Cl 2NaBH (4mL) (OAc) 3(0.179g, 0.84mmol) reaction overnight then adopt crude product (2mm flat board, 50: 1: 1 the CH of radial chromatography purifying gained on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali (72mg, 43%) of title compound, be colorless oil.
Adopt general flow D: the free alkali (72mg) that obtains is above changed into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains AMD9734 (77mg), is white solid. 1H NMR (D 2O) δ 1.86-1.98 (m, 1H), 2.20-2.48 (m, 9H), 3.05 (br s, 2H), 3.80 (s, 2H), 3.81 (d, 1H, J=12.6 Hz), 3.90 (d, 1H, J=12.6Hz), 4.50 (d, 1H, J=16.5Hz), 4.68 (d, 1H, J=16.5Hz), 4.78-4.83 (m, 1H, overlapping with HOD), 7.06 (d, 2H, J=7.8Hz), 7.28 (d, 2H, J=7.8Hz), 7.48-7.52 (m, 2H), 7.57-7.61 (m, 2H), 7.95 (dd, 1H, J=6.0,7.5Hz), 8.42 (d, 1H, J=7.8Hz), 8.79 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.47,21.03, and 27.90,42.16,50.41,56.77,60.12,63.45,113.98,126.18,126.85,129.16,130.43,130.91,131.12,138.45,139.74,141.11,148.37,150.77,151.99; ES-MSm/z426 (M+H).C 27H 31N 53.2 HBr2.2 H 2The analytical value of O: C, 44.78; H, 5.37; N, 9.67; Br, 35.31.Actual value: C, 44.76; H, 5.27; N, 9.52; Br, 35.29.
Embodiment 37
Figure A0181580200831
AMD9775:(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-preparation of [4-(1,2,4-triazoles-4-base iminomethyl)-benzyl]-amine (hydrobromate)
Adopt general flow B: make 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl-phenyl aldehyde (AMD9882) (206mg, 0.52mmol) and 4-amino-1,2, the 4-triazole (70mg, 0.82mmol) with at CH 2Cl 2(4mL) and the NaBH (OAc) in the acetate (0.12mL) 3(0.223g, 1.05mmol) reaction overnight then adopt crude product (2mm flat board, 100: 1: 1 the CH of radial chromatography purifying gained on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 87mg (36%), be colourless oily matter.
Adopt general flow D: top acquisition free alkali (87mg) is changed into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9775 (83mg). 1H NMR (D 2O) δ 1.85-1.99 (m, 1H), 2.20-2.34 (m, 2H), 2.45-2.49 (m, 1H), 3.06 (s, 2H), 3.82 (d, 1H, J=12.6Hz), 3.91 (d, 1H, J=12.6Hz), 4.46 (d, 1H, J=16.5Hz), 4.65 (d, 1H, J=16.5Hz), 4.79-4.83 (m, 1H, overlapping with HOD), 7.27-7.32 (m, 2H), and 7.36-7.44 (m, 4H), 7.50-7.56 (m, 2H), 7.95 (dd, 1H, J=6.3,7.5Hz), 8.41-8.43 (m, 2H), 8.79 (d, 1H, J=5.4Hz), 9.07 (br s, 2H); 13C NMR (D 2O) δ 20.44,21.04, and 27.86,50.24,56.96,63.44,113.90,113.97,126.21,126.53,126.82,129.02,129.99,130.44,130.69,130.84,135.15,139.77,141.11,141.88,144.07,148.36,1 50.67,151.27,151.54,160.78,195.56; ES-MSm/z463 (M+H).C 27H 26N 83.0 HBr1.8 H 2The analytical value of O: C, 43.96; H, 4.45; N, 15.19; Br, 32.49.Actual value: C, 43.99; H, 4.40; N, 14.83; Br, 32.61.
Embodiment 38
Figure A0181580200841
AMD9671:N '-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-ethane-1, the preparation of 2-diamines (hydrobromate)
Adopt general flow B: with NaBH (OAc) 3(173mg, 0.816mmol) be added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5 that is stirring, 6,7,8-tetrahydrochysene-8-quinolyl)-1, (250mg is 0.629mmol) with (2-oxo-ethyl)-carboxylamine tertiary butyl ester (100mg for 4-xylylene amine, 0.628mmol) in the solution in THF (6.3mL), stirring at room gained mixture 22 hours.Adopt thick material (200: 5: 1 the CH of column chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH), obtain colourless oily matter (47mg).
Adopt general flow D: (47mg 0.11mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains colorless solid AMD9671 (72mg, 14%) with the oily matter that obtains above. 1HNMR(D 2O)δ?1.88(m，1H)，2.24(m，2H)，2.42(m，1H)，3.01(m，2H)，3.25(m，4H)，3.73(m，2H)，3.82(dd，2H，J＝19，12Hz)，4.40(d，1H，J＝16Hz)，4.59(d，1H，J＝16Hz)，4.75(m，1H)，7.03(d，2H，J＝7.8Hz)，7.23(d，2H，J＝7.8Hz)，7.48(m，2H)，7.55(m，2H)，7.88(dd，1H，J＝7.8，6.0Hz)，8.35(d，1H，J＝7.8Hz)，8.73(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.46，20.91，27.85，35.73，43.93，50.12，50.82，56.63，63.00，114.01，126.02，126.50，130.05，130.86，138.33，139.77，140.88，148.06，150.92，151.74.ES-MSm/z441(M+H)。C 27H 32N 63.9HBr2.5H 2The analytical value of O: C, 40.48; H, 5.15; N, 10.49; Br, 38.90.Actual value: C, 40.35; H, 4.96; N, 10.25; Br, 39.04.
Embodiment 39
Figure A0181580200851
AMD9701:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-butyl amino methyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
With N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1,4-xylylene amine (165mg, 0.415mmol) and butyraldehyde (50mg, 0.69mmol) the solution reflux in MeOH (4mL) refluxed 30 minutes.This solution is cooled to room temperature, and (20mg 0.019mmol), stirred this mixture 20 hours in room temperature in hydrogen atmosphere (latm) to add 10%Pd/C.With this mixture of diatomite filtration, decompression removes from filtrate down and desolvates.Adopted the thick product of column chromatography purifying on silica gel ((200: 5: 1CH 2Cl 2/ MeOH/NH 4OH), obtain colourless foam AMD9701 (16mg, 8%). 1H?NMR(CDCl 3)δ0.87(m，3H)，1.24-1.49(m，4H)，1.68(m，1H)，2.02(m，2H)，2.26(m，1H)，2.56(m，2H)，2.79(m，2H)，3.68(s，2H)，3.73(s，2H)，3.97(d，1H，J＝17Hz)，4.08(m，1H)，4.17(d，1H，J＝17Hz)，7.18(m，5H)，7.35(m，2H)，7.42(m，1H)，7.58(m，2H)，8.69(d，1H，J＝3.9Hz)； 13C?NMR(CDCl 3)δ14.39，20.84，21.79，23.77，29.63，32.57，48.88，49.53，54.11，60.58，111.30，119.11，121.68，122.04，122.60，128.47，128.99，135.09，137.55，138.30，139.82，147.33，156.73，157.89.ES-MS?m/z454(M+H)。C 29H 35N 51.3H 2The analytical value of O: C, 73.02; H, 7.94; N, 14.68.Actual value: C, 73.06; H, 7.70; N, 14.32.
Embodiment 40
AMD9725:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-diallyl amino methyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
With N, (65 μ L 0.37mmol) are added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1 to the N-diisopropylethylamine, and (156mg is 0.39mmol) at CH for 4-xylylene amine 2Cl 2In the solution (4mL).Drip allyl bromide 98 (35 μ L, 0.40mmol), in stirring at room gained mixture 3 days.Use CH 2Cl 2(50mL) dilute this reaction mixture, water (2 * 5mL), saturated sodium bicarbonate aqueous solution (5mL) and saturated sodium chloride aqueous solution (5mL) wash successively.Use CH 2Cl 2(20mL) extracting water layer, the dry organic extract (sal epsom) that merges, decompression concentrates down, obtains light yellow foam (100mg).Adopt column chromatography on silica gel, carry out purifying (200: 1: 1, then 100: 1: 1 CH 2Cl 2: MeOH: NH 4OH), follow in the enterprising conduct of silica gel to chromatography purification (1000: 1: 1 EtOAc: MeOH: NH 4OH), obtain light yellow foam AMD9725 (24.5mg, 14%). 1H?NMR(CDCl 3)δ1.62-1.75(m，1H)，1.97-2.08(m，2H)，2.22-2.30(m，1H)，2.66-2.77(m，1H)，2.77-2.92(m，1H)，3.01(d，4H，J＝6.3Hz)，3.48(s，2H)，3.74(s，2H)，3.99(d，1H，J＝16.8Hz)，4.07-4.12(m，1H)，4.18(d，1H，J＝16.8Hz)，5.09-5.17(m，4H)，5.83(ddt，2H，J＝16.8，10.2，6.3Hz)，7.15-7.20(m，5H)，7.34(d，2H，J＝7.8Hz)，7.41(d，1H，J＝7.8Hz)，7.48-7.56(m，1H)，7.60-7.69(m，1H)，8.69(d，1H，J＝4.2Hz)； 13C?NMR(CDCl 3)δ19.69，21.65，27.53，46.90，52.08，54.63，55.44，58.47，109.24，115.61，117.04，119.79，120.49，126.67，127.13，132.99，134.17，135.45，136.13，136.56，145.22，154.64，155.80.ES-MSm/z478.4(M+H)。C 31H 35N 50.5H 2The analytical value of O: C, 76.51; H, 7.46; N, 14.39.Actual value: C, 76.67; H, 7.45; N, 14.18.
Embodiment 41
AMD9726:(4-allyl amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
With N, (90 μ L 0.52mmol) are added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1 to the N-diisopropylethylamine, and (200mg is 0.39mmol) at CH for 4-xylylene amine 2Cl 2In the solution in the (～0.4mL).(35 μ L 0.40mmol) are dissolved in CH with allyl bromide 98 2Cl 2In the (～9.6mL), with 5.5mL/ hour speed it is added in the above-mentioned amine mixt then.In stirring at room gained mixture 24 hours.Use CH 2Cl 2(50mL) diluted reaction mixture, water (5mL), saturated sodium bicarbonate aqueous solution (5mL) and saturated sodium chloride aqueous solution (5mL) washing successively.Use CH 2Cl 2(20mL) extracting water layer, the dry organic extract (sal epsom) that merges, decompression concentrates down.Adopt column chromatography on silica gel, to carry out purifying ((200: 1: 1 then EtOAc of 100: 1: 1: MeOH: NH 4OH), then adopt radial chromatography on silica gel, to carry out purifying (250: 1: 1 EtOAc: MeOH: NH 4OH), obtain light yellow foam AMD9725 (36mg, 21%). 1H?NMR(CDCl 3)δ1.56-1.75(m，1H)，1.97-2.08(m，2H)，2.24-2.31(m，1H)，2.65-2.77(m，1H)，2.77-2.91(m，1H)，3.21(d，2H，J＝5.7Hz)，3.69(s，2H)，3.73(s，2H)，3.97(d，1H，J＝16.8Hz)，4.04-4.16(m，1H)，4.17(d，1H，J＝16.8Hz)，5.07(d，1H，J＝9.9Hz)，5.15(dd，1H，J＝17.1，1.2Hz)，5.88(ddt，1H，J＝17.1，10.5，6.0Hz)，7.10-7.19(m，5H)，7.35(d，2H，J＝7.8Hz)，7.42(d，1H，J＝7.5Hz)，7.45-7.57(m，1H)，7.58-7.68(m，1H)，8.69(d，1H，J＝4.2Hz)； 13C?NMR(CDCl 3)δ?20.83，22.89，28.67，47.95，51.11，52.33，53.17，59.68，110.37，115.39，118.11，120.91，121.66，127.59，128.07，134.13，136.17，136.60，137.48，138.56，146.38，155.80，156.94.ES-MSm/z438.3(M+H)。C 28H 31N 50.8H 2The analytical value of O: C, 74.40; H, 7.27; N, 15.49.Calculated value: C, 74.36; H, 7.25; N, 15.31.
Embodiment 42
AMD9754:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-tetramethyleneimine-1-ylmethyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
Adopt general flow B: with NaBH (OAc) 3(235mg, 1.11mmol) be added to the 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl that is stirring)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl-phenyl aldehyde (150mg, 0.37mmol), tetramethyleneimine (30 μ L, 0.36mmol) and AcOH (20 μ L, 0.37mmol) in the solution in THF (4mL), then in stirring at room gained mixture 1.5 hours.Adopt thick white foam (205mg) (100: 1: 1 the CH of column chromatography purifying gained on silica gel 2Cl 2: MeOH: NH 4OH), obtain required product (160mg, 96%), be white foam.
Adopt general flow D: the foam that obtains is above changed into hydrobromate, obtain white solid AMD9754. 1H?NMR(CD 3OD)δ1.82-1.98(m，3H)，1.98-2.15(m，2H)，2.18-2.36(m，2H)，2.42-2.53(m，1H)，2.85-2.97(m，2H)，3.03-3.14(m，4H)，3.85(d，1H，J＝12.9Hz)，3.94(d，1H，J＝12.9Hz)，4.07(s，2H)，4.45(d，1H，J＝16.5Hz)，4.66(d，1H，J＝16.2Hz)，4.74-4.79(m，1H)，7.27(d，2H，J＝7.8Hz)，7.55(dd，2H，J＝6.3，3.3Hz)，7.63(d，2H，J＝7.8Hz)，7.77(dd，2H，J＝6.3，3.3Hz)，7.97(dd，1H，J＝7.8，6.0Hz)，8.42(d，1H，J＝8.1Hz)，9.01(d，1H，J＝5.4Hz)； 13C?NMR(D 2O)δ20.47，21.05，22.81，27.90，50.46，53.75，56.76，57.26，63.49，113.98，126.18，126.74，130.31，130.42，130.62，130.94，138.04，139.76，141.10，148.36，150.77，152.06.ES-MSm/z452.3(M+H)。C 29H 33N 53.0HBr2.1H 2The analytical value of O: C, 47.57; H, 5.53; N, 9.57; Br, 32.74.Actual value: C, 47.69; H, 5.53; N, 9.48; Br, 32.48.
Embodiment 43
Figure A0181580200891
AMD9723:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-morpholine-4-ylmethyl-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow A: (O.068mL with morpholine, 0.78mmol) and sodium cyanoborohydride (0.107g, 1.7mmol) be added to 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(0.285g 0.72mmol) in the solution of anhydrous MeOH (5mL), at room temperature stirred this mixture 24 hours to phenyl aldehyde.Adopt the crude product (CH of radial chromatography purifying gained on 2mm TLC level silica gel plate 2Cl 2/ MeOH/NH 4OH, 100: 1: 1), obtain required product (23mg, 7%), be colourless oily matter.
Adopt general flow D: (23mg 0.049mmol) changes into hydrobromate, obtains white solid AMD9723 (36mg) with the oily matter that obtains above. 1H NMR (D 2O) δ 1.79-2.03 (br m, 1H), 2.14-2.38 (br m, 2H), 2.38-2.54 (br m, 1H), 2.83-3.15 (m, 6H), 3.51-3.71 (m, 2H), 3.76-4.10 (m, 6H), 4.48 (d, 1H, J=16.5Hz), 4.66 (d, 1H, J=16.8Hz), 7.07 (d, 2H, J=7.8Hz), 7.27 (d, 2H, J=7.5Hz), 7.12-7.68 (m, 4H), 7.94 (t, 1H, J=6.3Hz), 8.41 (d, 1H, J=7.8Hz), 8.78 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.45,20.99, and 27.87,50.33, (51.31 2 carbon), 56.75,59.89,63.39, (63.98 2 carbon), 113.92 (2 carbon), 126.13,126.66 (2 carbon), 127.83,130.56,130.84 (2 carbon), 131.47 (2 carbon), 138.67,139.75,141.07,148.27,150.81,151.94; ES-MSm/z468 (M+H); C 29H 33N 5O3.0HBr2.0H 2The analytical value of O: C, 46.67; H, 5.40; N, 9.38; Br, 32.12.Actual value: C, 46.71; H, 5.34; N, 9.22; Br, 32.17.
Embodiment 44
AMD9698:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(4-thiomorpholine-4-ylmethyl-benzyl)-amine
Adopt general flow A: use sodium cyanoborohydride (63mg, 1.0mmol), MeOH (3mL), with 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl-phenyl aldehyde (200mg, 0.50mmol) and thiomorpholine (51 μ L 0.50mmol) change into corresponding reductive amination product.Reaction times in this example is 5 hours.Adopt the thus obtained crude product of radial chromatography purifying (silica gel, 1mm flat board, 50: 2: 1 CH 2Cl 2-MeOH-NH 4OH) obtain the white foam AMD9698 of 63mg (26%). 1H?NMR(CDCl 3)δ?1.67-1.72(m，1H)，2.02-2.09(m，2H)，2.25-2.27(m，1H)，2.62(s，8H)，2.68-2.73(m，1H)，2.80-2.85(m，1H)，3.40(s，2H)，3.74(s，2H)，3.98(d，1H，J＝16Hz)，4.10(dd，1H，J＝9，6Hz)，4.19(d，1H，J＝16Hz)，7.14-7.20(m，5H)，7.35(d，2H，J＝8Hz)，7.42(dd，1H，J＝8，1Hz)，7.53-7.63(m，2H)，8.70(dd，1H，J＝5，1Hz)； 13C?NMR(CDCl 3)δ?21.3，23.4，27.9，29.1，48.5，53.6，54.8，60.2，63.3，110.8，118.6，121.3，122.2，128.3，128.9，134.6，136.9，137.1，138.1，146.9，156.3，157.4.ES-MSm/z484(M+H)。C 29H 33N 5S0.1CH 2Cl 2.0.3H 2The analytical value of O: C, 70.25; H, 6.85; N, 14.08; S, 6.44.Actual value: C, 70.42; H, 6.90; N, 13.70; S, 6.29.
Embodiment 45
Figure A0181580200902
AMD11173:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(2-cyclopropyl amino methyl-benzyl)-amine (HBr salt)
Adopt general flow B (to use NaBH (OAc) 3Carry out direct reductive amination): (0.960g, 7.16mmol) (0.991g is 3.58mmol) with NaBH (OAc) with (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine to make phthalic acid dicarboxyl aldehyde 3(3.24g is 15.3mmol) at CH 2Cl 2Reaction is 65 hours (20mL), then stirs in THF (10mL) and 4N HCl (20mL), obtains crude product.Adopt thick product (37g silica gel, 30: 1 the CH of column chromatography purifying on silica gel 2Cl 2: CH 3OH), obtain benzyl aldehyde and the benzyl alcohol mixture of products of 1.21g (45%).
(1.21g 3.04mmol) is dissolved in CH with pure mixture with this aldehyde 2Cl 2(20mL), use MnO 2(1.990g 19.5mmol) handles, and stirs then 48 hours.With this suspension of diatomite filtration, concentrate and obtain thick product.Adopt column chromatography on silica gel, to carry out purifying (51g silica gel, 60: 1 CH 2Cl 2: CH 3OH), obtain the adjacent benzyl aldehyde intermediate of 942mg (is 66% altogether) in two steps, be yellow foam.
(0.119g, 0.300mmol) (32 μ L are 0.461mmol) at CH with cyclopropylamine with the aldehyde that obtains above 3Stirred 1 hour among the OH (2.5mL), use NaBH then 4(18mg 0.475mmol) handles.After 1 hour this mixture is concentrated.Use CH 2Cl 2(20mL) dilution gained residue is with salt water washing (3 * 10mL).Use CH 2Cl 2The water (1 * 15mL) that extracting merges.The dry organic phase (sodium sulfate) that merges is filtered, and concentrates and obtains crude product.Adopt radial chromatography on silica gel, to carry out purifying (1mm flat board, 100: 1: 1 CH 2Cl 2: CH 3OH: NH 4OH), obtain the white foam of 0.066g (50%).
Adopt general flow D: (66mg 0.151mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD11173 (100mg, 92%) with the foam that obtains above. 1H?NMR(D 2O)δ?0.63-0.79(m，4H)，1.83-1.98(m，1H)，2.18-2.30(m，1H)，2.31-2.41(m，1H)，2.43-2.58(m，2H)，2.98-3.13(m，2H)，3.92(d，1H，J＝13.7Hz)，4.14(d，1H，J＝13.2Hz)，4.24(d，1H，J＝13.6Hz)，4.41(d，1H，J＝16.6Hz)，4.48(d，1H，J＝13.1Hz)，4.59(d，1H，J＝16.4Hz)，6.92(t，1H，J＝7.5Hz)，7.00(d，1H，J＝7.4Hz)，7.19(t，1H，J＝7.0Hz)，7.41(d，1H，J＝7.4Hz)，7.51-7.56(m，2H)，7.58-7.63(m，2H)，7.91(dd，1H，J＝7.7，6.1Hz)，8.40(d，1H，J＝7.9Hz)，8.74(d，1H，J＝5.22)； 13C?NMR(D 2O)δ?3.53，20.43，20.93，27.92，30.04，48.44，49.35，53.22，62.29，113.95，126.24，126.91，129.42，129.54，130.32，130.60，131.16，132.17，135.58，139.96，141.16，148.33，150.52，150.89.ES-MS?m/z?438(M+H)。C 28H 31N 53.0HBr2.2H 2The analytical value of O: C, 46.71; H, 5.38; N, 9.73; Br, 33.30.Actual value C, 46.72; H, 5.36; N, 9.59; Br, 33.21.
Embodiment 46
Figure A0181580200921
AMD11173:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(2-allyl amino methyl-benzyl)-amine (HBr salt)
Adopt general flow B (to use NaBH (OAc) 3Carry out direct reductive amination): (0.9608,7.16mmol) (0.991g is 3.58mmol) with NaBH (OAc) with (1H-benzoglyoxaline-1-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine to make phthalic acid dicarboxyl aldehyde 3(3.248,15.3mmol) at CH 2Cl 2Reaction is 65 hours (20mL), then stirs in THF (10mL) and 4N HCl (20mL), obtains crude product.Adopt thick product (37g silica gel, 30: 1 the CH of column chromatography purifying on silica gel 2Cl 2: CH 3OH), obtain benzyl aldehyde and the benzyl alcohol mixture of products of 1.21g (45%).(1.21g 3.04mmol) is dissolved in CH with pure mixture with this aldehyde 2Cl 2(20mL), use MnO 2(1.9908,19.5mmol) handle, stirred then 48 hours.With this suspension of diatomite filtration, concentrate and obtain thick product.Adopt column chromatography on silica gel, to carry out purifying (51g silica gel, 60: 1 CH 2Cl 2: CH 3OH), obtain the adjacent benzyl aldehyde intermediate of 942mg (is 66% altogether) in two steps, be yellow foam.
(0.1508,0.378mmol) (42 μ L are 0.968mmol) at CH with allyl amine with the aldehyde that obtains above 3Stirred 18 hours among the OH (2.5mL), use NaBH then 4(24mg 0.634mmol) handles.After 1 and a half hours this mixture is concentrated.Use CH 2Cl 2(30mL) dilution gained residue is with salt water washing (3 * 15mL).Use CH 2Cl 2The water (1 * 15mL) that extracting merges.The dry organic phase (sodium sulfate) that merges is filtered, and concentrates and obtains crude product.Adopt radial chromatography on silica gel, to carry out purifying (2mm flat board, 100: 1: 1 CH 2Cl 2: CH 3OH: NH 4OH), obtain the white foam of 53mg (32%).
Adopt general flow D: (53mg 0.121mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD11174 (77mg, 88%) with the foam that obtains above. 1H?NMR(D 2O)δ1.83-1.99(m，1H)，2.19-2.40(m，2H)，2.45-2.55(m，1H)，2.99-3.12(m，2H)，3.61(d，2H，J＝6.5Hz)，3.92(d，1H，J＝13.5Hz)，4.12-4.20(m，2H)，4.36-4.43(m，2H)，4.58(d，1H，J＝16.3Hz)，5.44(s，1H)，5.89(d，1H，J＝5.2Hz)，5.77-5.91(m，1H)，6.93(t，1H，J＝7.5?Hz)，7.02(d，1H，J＝7.9Hz)，7.18(t，1H，J＝7.7Hz)，7.43(d，1H，J＝7.9Hz)，7.51-7.56(m，2H)，7.58-7.64(m，2H)，7.92(t，1H，J＝6.8Hz)，8.41(d，1H，J＝8.4Hz)，8.75(d，1H，J＝5.8Hz)； 13CNMR(D 2O)δ?20.43，20.96，27.90，47.07，49.16，49.69，53.30，62.33，113.95，124.80，126.25，126.93，127.51，129.38，129.67，130.31，130.53，130.96，132.10，135.49，139.88，141.18，148.44，150.41，150.73.ES-MSm/z438(M+H)。C 28H 31N 53.0HBr2.2H 2The analytical value of O: C, 46.71; H, 5.38; N, 9.73; Br, 33.30.Actual value: C, 46.79; H, 5.27; N, 9.62; Br, 33.17.
Embodiment 47
Figure A0181580200931
AMD11133:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of [2-(R)-(2-amino propionamido-methyl)-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Successively with diisopropylethylamine (0.08mL, 0.468mmol), I-hydroxybenzotriazole ((HOBT, 32mg, 0.234mmol), (1H-benzimidazolyl-2 radicals-ylmethyl)-(2-amino methyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (62mg, 0.156mmol) and hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDAC, 45mg, 0.234mmol) (37mg is 0.195mmol) in the solution in methylene dichloride (5mL) to be added to N-tert-butoxycarbonyl-l-L-Ala.Then at the solution of room temperature stirred overnight gained in nitrogen.Use this solution of aqueous ammonium chloride solution extracting then, drying concentrates, and adopts flash chromatography, methylene dichloride with 20: 1: methanol solution is that elutriant carries out purifying on silica gel, obtain (1H-benzimidazolyl-2 radicals-ylmethyl)-{ 2-(R)-[2-(N-tert-butoxycarbonyl)-amino propionamido-methyl]-benzyl }-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine, this product is the mixture of two kinds of diastereomers, is total to 61mg, and yield is 69%. 1H NMR (CDCl 3) δ 1.14 and 1.56 (d, 3H altogether, J=6.9Hz), 1.370 and 1.483 (s, 9H altogether), 1.88 (m, 1H), 1.93 (m, 1H), 2.03 (m, 1H), 2.36 (m, 1H), 2.75-2.86 (m, 2H), 3.74 (m, 3H), 3.91 (m, 2H), 4.05 and 4.41 (m, 1H altogether), 4.66 (m, 1H), 5.34 (m, 1H), 7.13 (m, 5H), 7.29-7.44 (m, 4H), 7.68 (br s, 1H (NH)), 8.38 and 8.56 (m, 1H altogether), 8.59 and 8.76 (d, 1H altogether, J=4.9Hz).
Absorb this (1H-benzimidazolyl-2 radicals-ylmethyl)-{ 2-(R)-[2-(N-tert-butoxycarbonyl)-amino propionamido-methyl]-benzyl }-(5 with acetate (1mL), 6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (61mg, 0.107mmol), then the saturated solution of HBr in acetate (1mL) is added in the gained mixture.Stir this mixture then, as described in flow process D, make its precipitation and separate, obtain white crystalline solid AMD11133, obtain 64mg. 1H NMR (D 2O). δ 1.43 and 1.46 (d is total to 3H, J=6.9Hz), 1.88 (m, 1H), 2.28 (m, 2H), 2.46 (m, 1H), 3.00 (m, 2H), 3.81 (d, 1H, J=12.8Hz), 4.03 (m, 2H), 4.21 (d, 1H, J=12.8Hz), 4.43-4.77 (m, 4H), 6.68 (m, 2H), 6.91 (m, 1H), 7.25 (t, 1H, J=6.1Hz), 7.51 (m, 4H), 7.88 (m, 1H), 8.28 (m, 1H), 8.68 (d, 1H, J=4.8Hz). 13C NMR (D 2O) 17.01,20.43 and 20.67 (1C altogether), 27.89,40.78,48.93 with 49.22 (1C altogether), 49.43,53.87 and 54,46 (1C altogether), 62.01 with 62.15 (1C altogether), 113.92 and 113.97 (2C altogether), 126.08,126.74 (2C), 128.03,129.13,131.45,131.55,133.92,136.00,139.91,140.78,148.19 with 148.27 (1C altogether), 150.25 and 150.43 (1C altogether), 170.69 and 170.91 (1C altogether) .ES-MSm/z469 (M+H); (C 28H 32N 6O * 3.1HBr * 1.1H 2The analytical value of O * 1.0HOAc): C, 45.04; H, 5.21; N, 10.53; Br 31.04.Actual value: C, 45.04; H, 5.19; N, 10.53; Br, 31.04.
Embodiment 48
AMD9872:(1H-benzimidazolyl-2 radicals-ylmethyl)-[2-(1H-benzimidazolyl-2 radicals-ylmethyl)-aminobenzyl]-preparation of (5,6,7,8-tetrahydroquinoline-8-yl)-amine
The preparation of (5,6,7,8-tetrahydroquinoline-8-yl)-(2-aminobenzyl)-amine:
Adopt general flow B: with NaBH (OAc) 3(0.92g, (0.36g, 2.9mmol) with 6, (0.43g is 2.9mmol) at CH for 7-dihydro-5H-quinoline-8-ketone 4.4mmol) to be added to 2-aminobenzyl amine 2Cl 2In the solution (15mL), then in stirring at room gained mixture 64 hours.Adopt the crude product (2%MeOH/CH of column chromatography purifying gained on silica gel 2Cl 2), obtain yellow oil (5,6,7,8-tetrahydroquinoline-8-yl)-(2-aminobenzyl)-amine (0.39g, 52%). 1H?NMR(CDCl 3)δ1.80(m，1H)，1.94(m，2H)，2.17(m，1H)，2.79(m，2H)，3.84(m，1H)，3.87(d，1H，J＝11.7Hz)，4.02(d，1H，J＝12.0Hz)，6.64(d，1H，J＝7.8Hz)，6.67(t，1H，J＝7.8Hz)，7.09(m，3H)，7.38(d，1H，J＝3.0Hz)，8.38(d，1H，J＝3.9Hz)。
Adopt the alkylating general flow of N-: make CH 3Among the CN (6mL) (5,6,7,8-tetrahydroquinoline-8-yl)-and (2-aminobenzyl)-amine (0.16g, 0.6mmol), N, N-diisopropylethylamine (0.32mL, 1.8mmol) and potassiumiodide (10mg, 40 μ mol) (0.32g 1.2mmol) 70 ℃ of reactions 16 hours, adopts column chromatography to be purified (CH on silica gel afterwards with 1-(N-tert-butoxycarbonyl)-2-chloromethyl benzimidazole 2Cl 2/ MeOH, 250: 1), obtain the alkylating product of N-(0.16g, 37%), be faint yellow solid. 1H?NMR(CDCl 3)δ?1.56(s，9H)，1.70(s，10H)，1.95(m，2H)，2.48(m，1H)，2.65(m，2H)，4.23(d，1H，J＝3.0Hz)，4.27(d，1H，J＝8.1Hz)，4.29(m，1H)，4.48(d，1H，J＝3.0Hz)，4.53(d，1H，J＝8.4Hz)，4.93(m，2H)，6.55(m，2H)，6.98(m，2H)，7.10(d，1H，J＝7.8Hz)，7.20-7.32(m，4H)，7.55(m，1H)，7.68(m，1H)，7.82(m，2H)，7.90(m，1H)，8.44(d，1H，J＝3.2Hz)。
(0.17g is 0.24mmol) at CH with the product that obtains above 2Cl 2(1: 1,2mL) solution stirring in was 0.5 hour, then concentrated gained solution under the decompression for/TFA.Make this reactant at 15% aqueous sodium hydroxide solution (5mL) and CH 2Cl 2Distribute (5mL), isolate each phase, dry then organic extract (sal epsom) filters, and concentrates, and adopts radial chromatography purifying ((MeOH/NH on silica gel 4OH/CH 2Cl 21: 1: 98), obtain faint yellow solid AMD9872 (48mg, 40%). 1H?NMR(CDCl 3)δ1.71(br，1H)，2.09(m，2H)，2.29(br，1H)，2.73(m，1H)，2.85(m，1H)，3.81(d，1H，J＝12.9Hz)，3.90(d，1H，J＝12.6Hz)，4.06(d，2H，J＝6.9Hz)，4.09(m，1H)，4.77(s，2H)，6.50(d，1H，J＝8.1Hz)，6.62(t，1H，J＝7.4Hz)，6.94(br，1H)，7.04(t，1H，J＝7.8Hz)，7.05-7.25(br?m，6H)，7.43(d，1H，J＝7.8Hz)，7.66(br，3H)，8.41(d，1H，J＝3.9?Hz). 13C?NMR(CDCl 3)δ?21.45，21.80，29.23，42.32，48.18，54.10，59.88，110.27(2C)，117.06(2C)，121.71，122.25(5C)，122.48(2C)，129.23(2C)，130.91(2C)，135.18，137.70(2C)，146.91(2C)，147.16，154.00，154.19，1?57.03.ES-MSm/z514(M+H)。C 32H 31N 71.0CH 2C1 20.3C 6H 14Analytical value: C, 66.57; H, 5.98; N, 15.60.Actual value: C, 66.61; H, 5.78; N, 15.51.
Embodiment 49
The AMD9883:(2-aminobenzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydroquinoline-8-yl)-amine
Adopt the alkylating general flow of N-: make CH 3Among the CN (8mL) (5,6,7,8-tetrahydroquinoline-8-yl)-and (2-aminobenzyl)-amine (0.20g, 0.8mmol), N, N-diisopropylethylamine (0.14mL, 0.8mmol) and potassiumiodide (5mg, 30 μ mol) (0.145g 0.55mmol) 70 ℃ of reactions 16 hours, adopts radial chromatography to be purified (MeOH/NH on silica gel afterwards with 1-(N-tert-butoxycarbonyl)-2-chloromethyl benzimidazole 4OH/CH 2Cl 2, 1: 1: 98), obtain the alkylating product of single N-(65mg, 25%), be faint yellow solid. 1H?NMR(CDCl 3)δ1.61(s，10H)，1.94(m，2H)，2.03(br，1H)，2.67(m，2H)，3.98(d，1H，J＝12.3Hz)，4.22(m，1H)，4.30(d，2H，J＝9.9Hz)，4.37(d，1H，J＝11.1Hz)，5.44(br，2H)，6.53(m，2H)，6.90(m，1H)，6.97(t，1H，J＝6.7Hz)，7.06(d，1H，J＝7.5Hz)，7.17(d，1H，J＝7.5Hz)，7.25(d，2H，J＝7.2Hz)，7.61(m，1H)，7.81(m，1H，J＝3.6Hz)，8.40(d，1H，J＝4.5Hz)。
(65mg is 0.13mmol) at CH with the product that obtains above 2Cl 2(1: 1,1mL) solution stirring in was 0.5 hour, then concentrated gained solution under the decompression for/TFA.Make this reactant at 15% aqueous sodium hydroxide solution (3mL) and CH 2Cl 2Distribute (5mL), isolate each phase, dry then organic extract (sal epsom) filters, and concentrates, and adopts radial chromatography purifying ((MeOH/NH on silica gel 4OH/CH 2Cl 21: 1: 150), obtain faint yellow solid AMD9883 (33mg, 64%). 1H?NMR(CDCl 3)δ1.71(br，1H)，2.05(m，2H)，2.32(br，1H)，2.70(m，1H)，2.85(m，1H)，3.65(d，1H，J＝12.6Hz)，3.80(d，1H，J＝12.6Hz)，4.05(m，1H)，4.08(d，2H，J＝4.8Hz)，6.63(t，1H，J＝8.7Hz)，6.64(t，1H，J＝6.6Hz)，7.03(t，2H，J＝7.2Hz)，7.1?7(m，3H)，7.42(d，1H，J＝7.2Hz)，7.54(br，2H)，8.53(d，1H，J＝4.2Hz). 13C?NMR(CDCl 3)δ?21.64，21.91，29.55，48.22，53.20，60.93，111.08，116.59，118.09，119.14，122.05(4C)，122.52，122.83，129.19，131.83，135.22，137.98，147.09，147.17，156.04，157.47.ES-MSm/z384(M+H)。C 24H 25N 50.6CH 2Cl 2Analytical value: C, 67.49; H, 6.04; N, 15.97.Actual value: C, 67.60; H, 6.21; N, 15.57.
Embodiment 50
AMD9736:(1H-benzimidazolyl-2 radicals-ylmethyl)-(2-cyano group-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
(72mg 0.145mmol) refluxed 16 hours in 6N HCl (5mL) with intermediate [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(2-cyano group-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (referring to AMD9720).Decompression removes down and desolvates, with the salt of gained be dissolved in distilled water (0.8mL) and ethanol (95%, 0.8mL) in, use sodium hydroxide (0.148g, 3.69mmol) processing then.With this mixture heating up to 90 ℃ 2 hours, then stirring at room 64 hours.Water (4mL) dilutes this two-phase system, uses ether extracting (3 * 10mL) then.The dry organic phase (sodium sulfate) that merges is filtered, and decompression concentrates down, obtains white powder.Adopt this solid of radial chromatography purifying (1mm TLC flat board, 60: 1: 1 CH 2Cl 2/ CH 3OH/NH 4OH), obtain required free alkali (48mg, 84%).
Adopt general flow D: the product (48mg) that obtains is above changed into hydrobromate, obtain AMD9736 (45mg, 64%). 1H NMR (D 2O) δ 1.85-2.01 (m, 1H), 2.17-2.52 (m, 3H), 2.98-3.14 (m, 2H), 3.95 (d, 1H, J=13.2Hz), 4.1 5 (d, 1H, J=13.2Hz), 4.46 (d, 1H, J=16.3Hz), 4.63 (d, 1H, J=16.6Hz), 6.96 (t, 1H, J=7.7Hz), 7.27 (t, 1H, J=7.7Hz), 7.35 (t, 1H, J=8.1Hz), 7.49-7.60 (m, 4H), 7.92 (dd, 1H, J=7.9,5.5Hz), 8.40 (d, 1H, J=-7.8Hz), 8.71 (d, 1H, J=5.8 Hz). 13C NMR (D 2O) δ 18.14,18.68, and 25.56,47.43,53.07,60.81,109.76,111.60 (2 carbon), 116.68,123.81,124.55 (2 carbon), 126.70,128.29,129.19,131.29,131.46,137.66,137.84,138.58,145.88,147.73,148.64. IR (CsI) v 2224 (C ≡ N) .ES-MSm/z394 (M+H).C 25H 23N 52.0HBr1.3H 2The analytical value of O: C, 51.88; H, 4.81; N, 12.10; Br, 27.61.Actual value: C, 51.86; H, 4.86; N, 11.78; Br, 27.78.
Embodiment 51
AMD11091:2-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl]-methyl }-preparation of 6-methoxyl group-ethyl benzoate (hydrobromate)
With lithium hydroxide monohydrate (0.594g, 14.2mmol) be added to 6-cresotinic acid acetoacetic ester (1.27g, 6.97mmol) in the solution in THF (35mL), then add methyl-sulfate (1.00mL, 10.6mmol).Reflux gained mixture 1 hour is cooled to room temperature with it then.With ether (70mL) dilution gained mixture, with saturated sodium bicarbonate aqueous solution washing (4 * 10mL), drying (MgSO 4), concentrate.Adopt thick material (9: 1 the hexane/EtOAc), obtain white solid 2-methoxyl group-6-tolyl acid ethyl ester of 1.23g (91%) of column chromatography purifying gained on silica gel. 1H?NMR(CDCl 3)δ1.38(t，3H，J＝7.2Hz)，2.30(s，3H)，3.82(s，3H)，4.40(q，2H，J＝7.2Hz)，6.76(d，1H，J＝8.4Hz)，6.79(d，1H，J＝7.8Hz)，7.23(dd，1H，J＝7.8，8.4Hz)。
(0.751g, (0.813g is 4.19mmol) at CCl 4.22mmol) to be added to 2-methoxyl group-6-tolyl acid ethyl ester with the N-bromine succinimide of recrystallization 4In the solution (8mL), then add benzoyl peroxide (52mg, 0.22mmol).The gained mixture heating up was refluxed 90 minutes, be cooled to room temperature then.(50mL) dilutes this mixture with ether, uses filter paper filtering, concentrated filtrate.Adopt thick material (8: 1 the hexane-EtOAc), obtain colorless oil 6-(the brooethyl)-O-Anisic Acid ethyl ester of 0.68g (60%) of column chromatography purifying gained. 1H?NMR(CDCl 3)δ1.42(t，3H，J＝7.2Hz)，3.84(s，3H)，4.45(q，2H，J＝7.2Hz)，4.50(s，2H)，6.89(d，1H，J＝8.4Hz)，7.01(d，1H，J＝7.2Hz)，7.34(dd，1H，J＝7.2，8.4Hz)。
With N, the N-diisopropylethylamine (0.38mL, 2.18mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(0.409g is 1.08mmol) at CH for amine 3In the solution among the CN (5mL), (0.454g is 1.66mmol) at CH then to add 6-(brooethyl)-O-Anisic Acid ethyl ester 3In the solution among the CN (6mL).With gained mixture heating up to 60 ℃ 22 hours, be cooled to room temperature then.Concentrate the gained mixture, make residue at CH 2Cl 2(50mL) and between the salt solution (10mL) distribute.Isolate each phase, use CH 2Cl 2Extracting water (3 * 10mL).The dry organic extract (sodium sulfate) that merges concentrates.Adopt column chromatography purifying gained crude product (CH of 25: 1 on silica gel 2Cl 2-CH 3OH), then adopt column chromatography on silica gel, carry out further chromatography purification (2: 1 hexane-EtOAc), and in the enterprising conduct of silica gel to chromatography purification (2mm flat board, 100: 1: 1 CH 2Cl 2-CH 3OH-NH 4OH), obtain the white solid of 0.38g (62%).
Adopt general flow D: when removing the BOC-blocking group, (55mg 0.10mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains golden solid AMD11091 (35mg, 51%) with the solid that obtains above. 1H?NMR(D 2O)δ1.23(t，3H，J＝7.2Hz)，1.82-1.90(m，1H)，2.17-2.28(m，2H)，2.34-2.40(m，1H)，3.00(br?s，2H)，3.45(s，3H)，3.69(d，1H，J＝12.6Hz)，3.82(d，1H，J＝12.6Hz)，4.25-4.37(m，2H)，4.40(d，1H，J＝15.9Hz)，4.52(d，1H，J＝15.9Hz)，4.68(dd，1H，J＝6.0，9.3Hz)，6.54(d，1H，J＝8.4Hz)，6.99(d，1H，J＝7.5Hz)，7.15(dd，1H，J＝7.5，8.4Hz)，7.50-7.53(m，2H)，7.59-7.62(m，2H)，7.90(dd，1H，J＝6.3，7.5Hz)，8.36(d，1H，J＝7.8Hz)，8.77(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ?13.77，20.42，20.79，27.77，49.29，53.67，56.45，62.55，63.59，112.11，113.95，123.03，123.84，126.07，126.74，130.62，131.76，134.36，139.77，140.89，148.12，150.49，150.81，156.10，169.70.ES-MSm/z471(M+H)。C 28H 30N 4O 32.2HBr1.7H 2The analytical value of O: C, 49.52; H, 5.28; N, 8.25; Br, 25.88.Actual value: C, 49.89; H, 5.33; N, 8.19; Br, 25.53.
Embodiment 52
AMD9837:(6-aminopyridine-3-ylmethyl)-(benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
The preparation of 6-(N-tert-butoxycarbonyl amino)-3-4-hydroxymethylpiperidine:
(2.0g, 14.4mmol) vlil in the anhydrous EtOH (70mL) and the vitriol oil (14mL) is 16 hours with the 6-amino-nicotinic acid.Decompression concentrates this solution down, with saturated aqueous sodium carbonate (50mL) neutralization, uses CH then 2Cl 2(3 * 50mL) extractings.The dry organic phase (sal epsom) that merges is filtered, and concentrates, and obtains the amino niacin ethyl ester (2.18g, 92%) of 6-, is white powder. 1H?NMR(CDCl 3)δ1.37(t，3H，J＝6.0Hz)，4.34(q，2H，J＝7.0Hz)，4.89(br?s，2H(NH2))，6.46(d，1H，J＝7.5Hz)，8.02(d，1H，J＝7.5Hz)，8.73(s，1H)。
At 0 ℃, (0.41g, 10.6mmol) solution in THF (12mL) was added to 6-amino-nicotinic acid ethyl ester (1.18g 7.1mmol) in the solution in anhydrous THF (24mL), stirred the gained mixture 1.5 hours then with lithium aluminum hydride with 10 minutes.Successively the aqueous sodium hydroxide solution of 0.5mL water, 0.5mL 15% and the water of 1.5mL are added in this reactant, filter the gained slurries then.Dried filtrate (sal epsom) is filtered, and concentrates, and adopts column chromatography purifying (10%MeOH/CH 2Cl 2), obtain clear crystal 6-amino-3-4-hydroxymethylpiperidine (0.61g, 69%). 1H?NMR(MeOD)δ3.31(s，1H(OH))，4.43(s，2H)，6.58(d，1H，J＝8.4Hz)，7.48(d，1H，J＝8.7Hz)，7.85(s，1H)。
(0.58g, (0.30g, 2.4mmol) (12.4g 16mL) in the solution in, then stirred the gained mixture 16 hours at 40 ℃ at the colourless trimethyl carbinol 2.7mmol) to be added to 6-amino-3-4-hydroxymethylpiperidine with di-t-butyl carbonic acid hydrogen ester.Decompression concentrates this reactant down, adopts the column chromatography thick residue of purifying gained (MeOH/CH of 7.5% on silica gel 2Cl 2), obtain white solid title alcohol (0.42g, 77%). 1H?NMR(CDCl 3)δ1.54(s，9H)，1.74(t，1H(OH)，J＝6.0Hz)，4.65(d，2H，J＝6.0Hz)，7.68(d，1H，J＝9.0Hz)，7.83(br?s，1H(NH)，7.95(d，1H，J＝9.0Hz)，8.24(s，1H)。
Adopt general flow C: with methylsulfonyl chloride (0.20mL), 2.4mmol) be added to 6-(N-tert-butoxycarbonyl amino)-3-4-hydroxymethylpiperidine (0.42g, 1.9mmol) and triethylamine (0.40mL is 2.8mmol) at CH 2Cl 2In the solution (19mL), stirring at room gained mixture is 1 hour then.Adopt column chromatography purifying gained crude product (MeOH/CH of 4% on silica gel 2Cl 2), obtain required mesylate (0.23g, 42%). 1H?NMR(CDCl 3)δ1.54(s，9H)，3.37(s，3H)，4.40(s，2H)，7.68(d，1H，J＝9.0Hz)，7.95(d，1H，J＝9.0Hz)，8.11(br?s，1H)，8.25(s，1H)。
Adopt the alkylating general flow of N-: make the mesylate that obtains above (0.22g, 0.8mmol), N, the N-diisopropylethylamine (0.20mL, 1.2mmol) and Repone K (10mg is 0.04mmol) at CH 3(0.30g is 0.8mmol) 70 ℃ of reactions 16 hours with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine for solution among the CN (8mL).Adopt the thick material (MeOH/NH of radial chromatography purifying gained on silica gel 4OH/CH 2Cl 21: 1: 98), obtain flaky white solid, i.e. the alkylating product of N (180mg, 40%). 1H?NMR(CDCl 3)δ1.49(s，9H)，1.70(br?s，10H)，1.96(m，2H)，2.13(m，1H)，2.70(m，2H)，3.76(d，1H，J＝15.0Hz)，4.03(d，1H，J＝15.0Hz)，4.25(m，1H)，4.58(s，2H)，7.00(m，1H)，7.20(m，2H)，7.30(s，1H)，7.66(m，4H)，8.04(s，2H)，8.43(dd，1H，J＝3.0Hz)。
Adopt general flow D: when removing the Boc group, the solid (30mg) that obtains is above changed into hydrobromate, obtain white solid AMD9837 (0.034g). 1H?NMR(D 2O)δ1.90(br?m，1H)，2.20(m，2H)，2.40(br?m，1H)，3.02(br?m，2H)，3.70(d，1H，J＝13.5Hz)，3.83(d，1H，J＝13.5Hz)，4.37(d，1H，J＝15.9Hz)，4.58(d，1H，J＝16.2Hz)，4.75(m，1H)，6.62(d，1H，J＝9.3Hz)，7.53(d，1H，J＝1.5Hz)，7.57(dd，2H，J＝3.0，6.0Hz)，7.68(d，1H，J＝2.1Hz)，7.70(m，2H)，7.92(dd，1H，J＝6.0，7.8Hz)，8.40(d，1H，J＝7.2Hz)，8.75(d，1H，J＝4.8Hz)； 13C?NMR(D 2O)δ?20.38，20.92，27.86，49.32，53.02，62.53，114.11(4C)，121.78，126.19，127.24(2C)，130.91，134.41，140.07(2C)，141.11，145.36，148.33，1?50.36，151.7?2.ES-MSm/z385(M+H)。C 23H 24N 62.9HBr2.1H 2The analytical value of O: C, 42.21; H, 4.78; N, 12.84; Br, 35.10.Actual value: C, 42.29; H, 4.71; N, 12.58; Br, 35.09.
Embodiment 53
Figure A0181580201011
AMD9840:(2-aminopyridine-3-ylmethyl)-(benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-8-quinolyl)-amine (hydrobromate)
The preparation of the amino cigarette aldehyde of 2-:
(2.0g, 14.4mmol) vlil in the anhydrous EtOH (70mL) and the vitriol oil (14mL) is 16 hours with the 2-amino-nicotinic acid.Decompression concentrates this solution down, with saturated yellow soda ash (50mL) neutralization, uses CH 2Cl 2Extracting (3 * 50mL).The dry organic phase (sal epsom) that merges is filtered, and concentrates, and obtains 2-amino-nicotinic acid ethyl ester, for yellow solid ((1.74 g, 74%). 1H NMR (CDCl 3) δ 1.40 (t, 3H, J=6.0Hz), 4.34 (q, 2H, J=7.0Hz), 6.41 (br s, 2H (NH 2)), 6.63 (m, 1H), 8.14 (d, 1H, J=7.8Hz), 8.22 (s, 1H).
At 0 ℃, (0.60g, 15.7mmol) solution in THF (17mL) was added to 2-amino-nicotinic acid ethyl ester (1.74g 10.5mmol) in the solution in anhydrous THF (35mL), stirred the gained mixture 1.5 hours then with lithium aluminum hydride with 15 minutes.Successively the aqueous sodium hydroxide solution of 0.6mL water, 0.6mL 15% and the water of 1.8mL are added in the above-mentioned reactant, filter the slurries of gained then.Dried filtrate (sal epsom) is filtered, and concentrates, and adopts column chromatography purifying (10%MeOH/CH 2Cl 2), obtain 2-amino-3-4-hydroxymethylpiperidine (1.03g, 79%), be the yellow crystal solid. 1H?NMR(CDCl 3)δ?3.14(br?s，1H(OH)，4.60(s，2H)，5.00(br?s，1H(NH)，6.59(t，1H，J＝6.0Hz)，7.28(d，1H，J＝7.5Hz)，7.94(d，1H，J＝7.5Hz)。
(0.10g 0.8mmol) is dissolved in CH with the alcohol that obtains above 2Cl 2(8mL), use active MnO 2(0.70g 8mmol) handles, then stirring at room 1.5 hours.Use celite Filter this mixture, use CH 2Cl 2Wash this filter disc.The solvent in the filtrate is removed in decompression down, obtains the amino cigarette aldehyde (0.10g, 99%) of 2-, is light yellow crystalline solid. 1H?NMR(CDCl 3)δ?6.75(t，1H，J＝6.0Hz)，7.81(d，1H，J＝7.5Hz)，8.27(d，1H，J＝4.5Hz)，9.86(s，1H，(CHO))。
Adopt general flow B: with sodium triacetoxy borohydride (126mg, 0.59mmol) be added to the amino cigarette aldehyde of 2-(47mg, 0.4mmol) and (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(132mg is 0.35mmol) at CH for amine 2Cl 2In the solution (4mL), then in stirring at room gained mixture 16 hours.Adopt column chromatography purifying gained crude product (2%MeOH/CH on silica gel 2Cl 2), obtain required N-alkylate (68mg, 40%), be white solid. 1HNMR(CDCl 3)δ1.58(s，9H)，1.62(m，1H)，1.91(m，2H)，2.17(m，1H)，2.64(m，2H)，3.93(d，1H，J＝12.0Hz)，4.15(m，1H)，4.26(d，2H，J＝3.0Hz)，4.38(d，1H，J＝12.0Hz)，6.40(t，1H，J＝4.5Hz)，6.47(br?s，2H)，6.97(m，1H)，7.27(m，4H)，7.61(m，1H)，7.84(m，2H)，8.40(d，1H，J＝3.0Hz)。
Adopt general flow D: when removing the Boc group, the material that obtains is above changed into hydrobromate, obtain white solid AMD9840 (0.025g). 1H?NMR(D 2O)δ?1.87(br?m，1H)，2.18(m，2H)，2.46(br?m，1H)，2.98(br?m，2H)，3.95(d，1H，J＝14.1Hz)，4.07(d，1H，J＝14.1Hz)，4.33(d，1H，J＝16.2Hz)，4.49(d，1H，J＝15.9Hz)，4.74(m，1H)，6.64(t，1H，J＝6.9Hz)，7.25(dd，1H，J＝1.5，6.3Hz)，7.55(m，2H)，7.66(m，2H)，7.83(t，1H，J＝6.9Hz)，7.93(dd，1H，J＝1.5，7.4Hz)，8.28(d，1H，J＝7.2Hz)，8.70(d，1H，J＝5.1?Hz)； 13C?NMR(D 2O)δ20.45，20.68，27.95，48.36，52.51，62.20，113.24，114.03(2C)，120.49，120.73，126.09，127.17(2C)，130.89，135.44，140.70，140.81，146.12(2C)，147.61，150.32，150.71.ES-MSm/z385(M+H)。C 23H 24N 63.0HBr2.2H 2The analytical value of O: C, 41.49; H, 4.74; N, 12.62; Br, 35.95.Actual value: C, 41.56; H, 4.61; N, 12.38; Br, 35.94.
Embodiment 54
AMD9681:N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-preparation of guanidine (hydrobromate)
With N, N '-two-(tert-butoxycarbonyl)-1H-pyrazoles-1-carbonyl amidine (Tetrahedron Lett.1993,34,3389) is added to 4-aminobenzyl alcohol (0.127g, 1.03mmol) in the solution in anhydrous THF (1mL), then in stirring at room gained mixture 26 hours.(1mL) dilutes this mixture with hexane, filters (100% hexane then is 1: 1 a hexane/ethyl acetate) with short silicagel column.Concentrate suitable cut, " (4-methylol-phenyl)-guanidine (0.309g, 85%) that obtains white solid N.N '-two-(tert-butoxycarbonyl)-N.
(0.282g 0.771mmol) is dissolved in CH with the alcohol that obtains above 2Cl 2(7mL), use active MnO 2(0.696g 8.01mmol) handles, and stirs in ambient temperature overnight.Use celiite Filter this mixture, use CH 2Cl 2Wash this filter disc.The solvent in the filtrate is removed down in decompression, " (4-formyl radical-phenyl)-guanidine (0.260g, 93%) that obtains white solid N, N '-two-(tert-butoxycarbonyl)-N. 1H?NMR(CDCl 3)δ1.53(s，9H)，1.55(s，9H)，7.85(s，4H)，9.93(s，1H)，10.34(br?s，1H)。
Adopt general flow B: make N; N '-two-(tert-butoxycarbonyl)-N " (4-formyl radical-phenyl)-guanidine (0.167g; 0.49mmol) (0.151g is 0.42mmol) with NaBH (OAc) with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5; 6; 7; 8-tetrahydrochysene-quinoline-8-yl)-amine 3(0.184g is 0.87mmol) at CH 2Cl 2Solution reaction (4mL) 4.5 hours then adopts the radial chromatography thick material of purifying gained (2m flat board, 20: 1: 1 CH on silica gel 2Cl 2/ CH 3OH/NH 4OH), obtain required tertiary amine (0.101g, 33%), be white solid.
Adopt general flow D: when removing the BOC-blocking group, the white solid (101mg) that obtains is above changed into hydrobromate, then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9681 (66mg). 1H NMR (D 2O) δ 1.81-1.92 (m, 1H), 2.19-2.30 (m, 2H), 2.41-2.46 (m, 1H), 3.01 (br s, 2H), 3.78 (d, 1H, J=12.9Hz), 3.84 (d, 1H, J=12.9Hz), 4.43 (d, 1H, J=16.5Hz), 4.62 (d, 1H, J=16.5Hz), 4.72-4.79 (m, 1H, overlapping with HOD), 6.84 (d, 2H, J=8.1Hz), 7.21 (d, 2H, J=8.1Hz), 7.49-7.53 (m, 2H), 7.56-7.60 (m, 2H), 7.91 (dd, 1H, J=6.0,7.8Hz), 8.38 (d, 1H, J=7.8Hz), 8.73 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.43,20.86, and 27.83,50.03,56.40,62.98,113.84,124.65,126.08,126.76,130.47,131.50,134.21,135.70,139.65,141.00,148.26,148.28,150.83,151.77; ES-MSm/z426 (M+H).C 25H 27N 73.0 HBr3.4 H 2The analytical value of O: C, 41.16; H, 5.08; N, 13.44; Br, 32.86.Actual value: C, 41.12; H, 4.86; N, 13.32; Br, 32.81.
Embodiment 55
AMD9730:(4-amino-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of (4-formyl radical-phenyl)-carboxylamine tertiary butyl ester:
In room temperature, (607mg, 4.93mmol) (1.3g, 6.0mmol) solution stirring in THF (16mL) is 24 hours, concentrates then with di-t-butyl carbonic acid hydrogen ester with the 4-aminobenzyl alcohol.The thick material of purifying gained (30%EtOAc/ hexane) obtains colorless oil (906mg, 82% on silica gel. 1H?NMR(CDCl 3)δ1.52(s，9H)，4.63(d，2H，J＝5.7Hz)，6.48(br?s，1H)，7.32(m，4H)。
With active MnO 2(916mg, (200mg is 0.896mmol) at CH 8.96mmol) to be added to top alcohol 2Cl 2In the solution (9mL), stir the gained mixture in ambient temperature overnight then.With this reaction mixture of diatomite filtration, use CH 2Cl 2Wash this filter disc.The solvent in the filtrate is removed in decompression down, obtains clear crystal shape title compound (170mg, 86%). 1H?NMR(CDCl 3)δ1.54(s，9H)，6.73(br?s，1H)，7.54(d，2H，J＝9Hz)，7.83(d，2H，J＝9Hz)，9.90(s，1H)。
Adopt general flow B: with acetate (0.017mL, 0.30mmol) and NaBH (OAc) 3(190mg; 0.896mmol) be added to [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(5; 6; 7; 8-tetrahydrochysene-quinoline-8-yl)-amine (83mg; 0.22mmol) and (4-formyl radical-phenyl)-carboxylamine tertiary butyl ester (66mg, 0.30mmol) in the solution in THF (3mL), stirring at room gained mixture is 4 hours then.Adopt thick yellow oil (300: 5: 1 the CH of chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH), obtain colourless foam (128mg).
The foam that obtains on stirring at room was at trifluoroacetic acid/CH of 1: 1 2Cl 2Solution (4mL) 45 minutes concentrates then.Make residue at CH 2Cl 2(10mL) and between the saturated sodium bicarbonate aqueous solution (10mL) distribute, use CH then 2Cl 2The extracting water.The dry organic phase (sal epsom) that merges is filtered, and decompression concentrates down.Adopt the chromatography thick material of purifying gained (EtOAc/MeOH/NH of 600: 5: 1 on silica gel 4OH), obtain colourless foam (49mg, 53%).
Adopt general flow D: (49mg 0.13mmol) changes into hydrobromate, obtains yellow solid AMD9730 (56mg, 67%) with the colourless foam that obtains above. 1H?NMR(D 2O)δ1.88(m，1H)，2.26(m，2H)，2.44(m，1H)，3.02(m，2H)，3.83(d，1H，J＝13Hz)，3.89(d，1H，J＝13Hz)，4.46(d，1H，J＝16Hz)，4.64(d，1H，J＝16Hz)，4.79(m，1H)，6.95(d，2H，J＝8.1Hz)，7.29(d，2H，J＝8.4Hz)，7.51-7.63(m，4H)，7.91(m，1H)，8.38(d，1H，J＝7.8Hz)，8.74(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.45，20.86，27.85，50.06，56.31，62.82，113.94，122.85，126.12，126.85，130.03，130.50，131.58，137.51，139.70，140.98，148.28，150.75，151.51.ES-MSm/z384(M+H)。(C 24H 25N 5) 3.0 (HBr), 1.6 (H 2O) analytical value: C, 44.01; H, 4.80; N, 10.69; Br, 36.59.Actual value: C, 43.84; H, 4.86; N, 10.40; Br, 36.85.
Embodiment 56
AMD9774:N '-({ [(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino]-methyl }-phenyl)-N, the preparation of N-dimethyl carbonamidine
The preparation of O-methylsulfonyl-4-(tert-butoxycarbonyl)-aminobenzyl alcohol:
Adopt general flow C: with methylsulfonyl chloride (0.23mL, 3mmol) and triethylamine (0.56mL, (446mg is 2mmol) at CH 4mmol) to be added to 4-(tert-butoxycarbonyl)-aminobenzyl alcohol 2Cl 2In the solution (10mL).Stirring at room gained solution 60 minutes.Adopt chromatography purifying gained crude product (2%MeOH/CH on silica gel 2Cl 2), obtain oily title compound (320mg, 56%). 1H?NMR(CDCl 3)δ3.14(s，3H)，4.39(s，2H)，6.53(br?s，1H(NH))，7.31(m，4H)。
Adopt the alkylating general flow of N-: with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (210mg, 0.55mmol) be added to the mesylate (213mg that obtains above, 0.75mmol) and N, (0.178mL is 1.0mmol) at CH for the N-diisopropylethylamine 3In the solution among the CN (10mL), stirred the gained mixture 4 hours at 60 ℃ then.Adopt chromatography purifying gained crude product (CH of 20: 1 on silica gel 2Cl 2/ MeOH), obtain (1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-[4-(tert-butoxycarbonyl amino)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (126mg, 39%). 1H?NMR(CDCl 3)δ1.41(s，9H)，1.68(s，9H)，2.03(m，3H)，2.20(m，1H)，2.75(m，2H)，3.83(m，1H)，3.99(m，1H)，4.30(dd，1H，J＝8.4，6.5Hz)，4.61(m，2H)，6.26(br?s，1H(NH))，7.04(m，2H)，7.26(m，5H)，7.3?1(m，2H)，7.63(m，2H)，8.44(m，1H)。
Trifluoroacetic acid (1mL) is added to (1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-[4-(tert-butoxycarbonyl amino)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-(62mg is 0.106mmol) at CH for amine 2Cl 2In the solution (2mL).Stirring at room gained mixture 2 hours concentrates it then.The gained residue is added to CH 2Cl 2In, with 15%NaOH (3mL) washing, use CH 2Cl 2Repeat extracting.With the organic moiety that anhydrous sodium sulfate drying merges, filter, concentrate then.(27mg is 0.15mmol) in the solution in DMF (1mL) then thick (1H-benzimidazolyl-2 radicals-ylmethyl)-[4-aminobenzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine to be added to 2-pyridine SULPHURYL CHLORIDE.Stirring at room gained solution 30 minutes.Concentrate this mixture then, it is added to CH 2Cl 2In, wash with wet chemical.Use the anhydrous sodium sulfate drying organic moiety then, filter, concentrate, adopt chromatography on silica gel to its purifying (CH of 10: 1: 0.1 2Cl 2: MeOH: MH 4OH), obtain N '-({ [(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino]-methyl }-phenyl)-N, N-dimethyl carbonamidine (21mg, 47%). 1H?NMR(CDCl 3)δ1.69(m，1H)，2.01(m，3H)，2.25(m，1H)，2.73(m，2H)，2.93(s，3H)，3.60(s，3H)，3.62(d，1H，J＝13.2Hz)，3.68(d，1H，J＝13.2Hz)，3.98(d，1H，J＝16.2Hz)，4.01(m，1H)，4.12(d，1H，J＝16.2Hz)，6.80(d，2H，J＝8.1Hz)，7.16(m，4H)，7.26(d，1H，J＝8.1Hz)，7.38(m，2H)，7.40(br?s，1H)，8.55(d，1H，J＝4.8Hz)。
Adopt general flow D: with N '-({ [(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino]-methyl }-phenyl)-N, N-dimethyl carbonamidine (21mg 0.047mmol) changes into hydrobromate. obtain white solid AMD9774 (14mg). 1H NMR (D 2O). δ 1.91 (m, 1H), 2.29 (m, 2H), 2.43 (m, 1H), 3.05 (m, 2H), 3.13 (s, 3H), 3.37 (s, 3H), 3.79 (d, 1H, J=12.3Hz), 3.86 (d, 1H, J=12.3Hz), 4.44 (d, 1H, J=16.5Hz), 4.63 (d, 1H, J=16.5Hz), 4.82 (m, 1H), 6.82 (d, 2H, J=8.1Hz), 7.22 (d, 2H, J=8.1Hz), 7.50-7.63 (m, 4H), 7.95 (dd, 1H, J=7.8,5.7Hz), 8.41 (d, 1H, J=7.8Hz), 8.78 (d, 1H, J=5.7Hz). 13C NMR (D 2O) δ 20.45,21.01, and 27.86,37.17,44.08,50.20,54.46,63.43,114.05,119.10,126.14,126.49,130.54,131.70,134.46,136.98,139.73,142.33,148.32,152.16,152.94.ES-MSm/z439 (M+H); (C 27H 30N 6* 3.2HBr * 0.6H 2The analytical value of O * 0.6HOAc): C, 45.51; H, 4.98; N, 11.29; Br 34.35.Actual value: C, 45.28; H, 5.13; N, 11.14; Br, 34.32.
Embodiment 57
AMD9685:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzaldoxime
With solid tungsten hydrochlorate dihydrate (332mg, 1.0mmol) be added to N '-(1H-benzimidazolyl-2 radicals-ylmethyl)-N '-(5,6,7,8-tetrahydrochysene-8-quinolyl)-1, (200mg is 0.50mmol) in the solution in MeOH (5mL) for 4-xylylene amine, then add 35wt% aqueous hydrogen peroxide solution (2.9mL, 30mmol).Stir gained suspension 3 hours, and added saturated sodium bicarbonate aqueous solution (5mL) then.Isolate each phase, use CH 2Cl 2The extracting water layer (3 * 10mL), use organic extract 1 time that salt solution (10mL) washing merges then, dry (sal epsom), vacuum concentration.Adopt thick material (silica gel, 75: 1: 1 the CH of purified by flash chromatography 2Cl 2/ MeOH/NH 4OH), obtain white solid title compound (130mg, 63%). 1H?NMR(CDCl 3)δ1.63-1.66(m，1H)，1.97-2.07(m，2H)，2.25-2.27(m，1H)，2.66-2.72(m，1H)，2.80-2.85(m，1H)，3.65(d，1H，J＝14Hz)，3.71(d，1H，J＝14Hz)，5.03(d，1H，J＝16Hz)，4.14(dd，1H，J＝9，7Hz)，4.21(d，1H，J＝16Hz)，7.11-7.19(m，3H)，7.41-7.48(m，6H)，7.65(br?d，1H，J＝5Hz)，8.18(s，1H)，8.67(dd，1H，J＝5，1Hz)； 13C?NMR(CDCl 3)δ?22.2，23.9，30.2，49.5，55.0，61.2，112.1，119.4，122.7，123.3，127.8，130.1，133.0，136.2，138.7，141.4，147.8，150.0，1?56.2，157.7.ES-MSm/z412(M+H)。C 25H 25N 5O0.4H 2O.0.3CH 2Cl 2Analytical value: C, 68.41; H, 5.99; N, 15.77.Actual value: C, 68.57; H, 5.86; N, 15.48.
Embodiment 58
Figure A0181580201091
AMD9773:[4-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino methyl]-preparation of benzamidine (hydrobromate)
Adopt general flow B: with NaBH (OAc) 3(0.36g, (0.15g is 1.1mmol) with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(0.38g is 1.0mmol) at CH for amine 1.7mmol) to be added to the 4-cyanobenzaldehyde 2Cl 2In the solution (10mL), then in stirring at room gained mixture 6 hours.Adopt the thick material (2%MeOH/CH of column chromatography purifying gained on silica gel 2Cl 2), obtain the alkylating product of N-(0.26g, 72%), be white solid. 1H?NMR(CDCl 3)δ1.74(s，10H)，1.95(m，1H)，2.02(m，1H)，2.30(m，1H)，2.75(m，2H)，3.80(d，1H，J＝15.0Hz)，3.97(d，1H，J＝15.0Hz)，4.31(m，1H)，4.65(d，1H，J＝12.0Hz)，4.75(d，1H，J＝12.0Hz)，7.04(m，1H)，7.16(d，1H，J＝7.2Hz)，7.22-7.30(m，5H)，7.51(m，1H)，7.61(m，1H)，8.45(d，1H，J＝3.5Hz)。
HCl gas is blown into the material that obtains above (0.26g, 0.53mmol) in the solution in 0 ℃ anhydrous EtOH (3.5mL) 30 minutes, restir gained mixture 4 hours at room temperature then.Decompression concentrates down this reactant, and (3 * 20mL), vacuum-drying obtains the hydrochloride of required oxyethyl group imines, and this salt can directly use in next step reaction with ether washing gained residue. 1H?NMR(D 2O)δ1.54(t，3H，J＝6.9Hz)，1.91(m，1H)，2.23(m，2H)，2.47(m，1H)，3.04(m，2H)，3.88(d，1H，J＝12.9Hz)，3.96(d，1H，J＝13.2Hz)，4.44(d，1H，J＝15.6Hz)，4.46(q，2H，J＝6.9Hz)，4.63(d，1H，J＝16.5Hz)，4.78(m，1H)，7.35(d，2H，J＝8.4Hz)，7.47-7.58(m，5H)，7.95(t，1H，J＝6.2Hz)，8.41(d，1H，J＝6.2Hz)，8.82(d，1H，J＝3.5Hz)。
(0.24g 2.5mmol) is added in hydrochloric acid (N-tert-butoxycarbonyl benzimidazolyl-2 radicals-ylmethyl)-(4-oxyethyl group imonium the benzyl)-solution of (5,6,7,8-tetrahydroquinoline-8-yl)-amine (top acquisition) in anhydrous EtOH (3mL) with volatile salt.Decompression concentrates this reactant down, adopts chromatography, carries out purifying ((MeOH/NH by a silica gel plug 4OH/CH 2Cl 2, 15: 10: 75), obtain required benzyl amidine, be white powder (0.10g obtains 48% altogether in two steps). 1H?NMR(CDCl 3)δ1.68(m，1H)，2.03(m，2H)，2.27(m，1H)，2.78(m，2H)，3.78(s，2H)，3.92(d，1H，J＝15.0Hz)，4.09(m，1H)，4.20(d，1H，J＝15.0Hz)，5.68(br，1H)，6.12(br，1H)，7.18(m，3H)，7.46(m，3H)，7.57(m，2H)，7.65(d，2H，J＝7.2Hz)，8.71(d，1H，J＝3.5Hz)。
Adopt general flow D: the material (100mg) that obtains is above changed into hydrobromate, obtain white solid AMD9773 (70mg). 1H?NMR(D 2O)δ1.88(br?m，1H)，2.25(m，2H)，2.45(brm，1H)，3.03(br?m，2H)，3.88(d，1H，J＝12.9Hz)，3.95(d，1H，J＝12.9Hz)，4.45(d，1H，J＝16.2Hz)，4.63(d，1H，J＝16.2Hz)，4.79(m，1H)，7.36(s，4H)，7.47(dd，2H，J＝3.0，6.3Hz)，7.58(dd，2H，J＝3.0，6.3Hz)，7.93(t，1H，J＝6.9Hz)，8.40(d，1H，J＝8.1Hz)，8.77(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.43，21.00，27.87，50.12，56.72，63.21，113.97(2C)，126.17，126.67，126.87(2C)，127.56(2C)，130.61，130.85(2C)，139.85，141.09，143.36(2C)，148.27，150.71，151.44，165.18.ES-MSm/z411(M+H)。C 25H 26N 62.9HBr2.0H 2The analytical value of O: C, 43.89; H, 4.85; N, 12.28; Br, 34.34.Actual value: C, 43.97; H, 4.90; N, 12.02; Br, 34.35.
Embodiment 59
Figure A0181580201101
AMD9717:4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzylalcohol
In argon gas atmosphere, with 4-methylol phenyl aldehyde (7.22g 52.5mmol) is added to the 8-amino-5,6,7 that is stirring, the 8-tetrahydroquinoline (5.56g, 37.5mmol) in the solution in anhydrous MeOH (150mL), this mixture of stirred overnight at room temperature then.With 45 minutes in three batches with sodium borohydride (2.85g, 75mmol) be added in the gained solution, stirred reaction mixture is 24 hours then, obtains a light yellow oil, and this oily matter need not be further purified and can use (referring to general flow B) in next step reaction.
General-N, and the N-diisopropylethylamine (10mL, 57mmol), (0.24g, 1.4mmol) (7.98g is 29.9mmol) at CH with 1-N-tert-butoxycarbonyl-2-chloromethyl benzimidazole for potassiumiodide 3Solution among the CN (50mL) is added to the above-mentioned oily matter (7.64g) that stirring at anhydrous CH 3In the solution among the CN (100mL).Stirred overnight gained mixture in 60 ℃, argon gas atmosphere.Vacuum concentration gained reaction mixture is used CH 2Cl 2(100mL) dilution is washed with saturated aqueous ammonium chloride solution (150mL).Use CH 2Cl 2(2 * 50mL), the dry organic layer (sodium sulfate) that merges filters vacuum concentration to the extracting water layer.
In room temperature with the thick material that obtains above at CH 2Cl 2(2: 1,30mL) solution stirring in was 3 hours for/trifluoroacetic acid.Use CH 2Cl 2(30mL) dilution gained reaction mixture concentrates then in a vacuum.Use CH 2Cl 2(50mL) dilution gained residue is with 1N NaOH (50mL) washing.Use CH 2Cl 2(2 * 30mL), the dry organic layer (sodium sulfate) that merges filters extracting gained water layer, and vacuum concentration obtains the brown foam.Adopt radial chromatography, a fraction of thick material of purifying (111mg) (CH on 1mm TLC level silica-gel plate 2Cl 2/ MeOH/NH 4OH, 100: 1: 1), obtain free alkali AMD9717, (31.4mg, 28%) is white foam. 1H NMR (CDCl 3) δ 1.68-1.77 (br m, 1H), 1.97-2.08 (m, 2H), 2.24-2.28 (m, 1H), 2.70-2.91 (m, 2H), 3.75 (s, 2H), 3.95 (d, 1H, J=16.8Hz), 4.09 (m, 1H), 4.17 (d, 1H, J=16.8Hz), 4.59 (s, 2H), 7.14-7.24 (m, 6H), and 7.38-7.45 (m, 3H), 7.49-7.51 (m, 1H), 7.61-7.65 (m, 1H), 8.70 (d, 1H, J=4.8Hz); 13C NMR (CDCl 3) δ 20.24,21.78,28.17,47.73,52.85,59.21,63.41,120.42,121.11,125.75,127.78,133.84,136.27,137.16,139.22,145.76,154.60,156.10; ES-MSm/z399 (M+H); C 25H 26N 4O0.3 CH 2Cl 20.25H 2The analytical value of O: C, 70.92; H, 6.37; N, 13.08 actual values: C, 71.25; H, 6.53; N, 12.68.
Embodiment 60
AMD9882:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of phenyl aldehyde
With MnO 2(20.3g 233mmol) is added to the above-mentioned pure 4-{[1H-benzimidazolyl-2 radicals-ylmethyl that is stirring)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzylalcohol (AMD9717) is (9.29g) at anhydrous CH 2Cl 2In the solution (200mL), then in stirring at room gained mixture 4 hours.Add other MnO then 2(8.5g, 97.8mmol), ambient temperature overnight stirs the gained mixture.Use the Celite pad filter reaction mixture, use CHCl 3Wash this pad, vacuum concentration gained filtrate.Adopt the thick product (CH of column chromatography purifying on silica gel 2Cl 2/ MeOH, 97: 3 96: 4 then), obtain described aldehyde (5.08g is 34% altogether in 5 steps), be light yellow solid. 1H NMR (CDCl 3) δ 1.56-1.74 (br m, 2H), 1.92-2.09 (m, 2H), 2.28-2.32 (m, 1H), 2.70-2.94 (m, 2H), 3.84 (s, 2H), 3.94 (d, 1H, J=16.5Hz), 4.08-4.14 (m, 1H), 4.23 (d, 1H, J=16.5Hz), 7.18-7.26 (m, 4H), 7.45 (d, 1H, J=7.8Hz), 7.56 (m, 4H), 7.76 (d, 2H, J=8.1Hz), 8.72 (d, 1H, J=4.2Hz), 9.92 (s, 1H). 13C NMR (CDCl 3) δ 21.29,23.73,29.11,48.90,53.90,60.56, (121.85 2 carbon), 122.53 (2 carbon), 129.04 (2 carbon), (129.86 2 carbon), 134.89,135.58, (137.57 2 carbon), 146.69,146.85,155.58,156.99,191.85.ES-MSm/z397 (M+H).C 25H 34N 4O0.15CH 2Cl 2Analytical value: C, 73.82; H, 5.98; N, 13.69.Actual value: C, 73.69; H, 6.16; N, 13.78.
Embodiment 61
Figure A0181580201121
AMD9711:4-{[-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of methyl benzoate
Adopt general flow B: with NaBH (OAc) 3(763mg, 3.6mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(680mg, 1.8mmol) (295mg is 1.8mmol) at CH with the 4-acyl radical methyl benzoate for (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine 2Cl 2In the solution (10mL), stirred the gained mixture then 18 hours.The thick material of gained is added among the pure TFA (2mL), stirred then 3 hours.Add saturated sodium bicarbonate aqueous solution (10mL) carefully, use CH 2Cl 2(mixture of 3 * 20mL) extracting gained, the dry organic extract (sal epsom) that merges, vacuum concentration.Adopt thick material (silica gel, 50: 2: 1CH of purified by flash chromatography gained 2Cl 2/ MeOH/NH 4OH), obtain title compound (565mg, 74%), be white solid. 1H?NMR(CDCl 3)δ1.64-1.75(m，1H)，2.01-2.08(m，2H)，2.26-2.28(m，1H)，2.74-2.76(m，1H)，2.81-2.86(m，1H)，3.81(s，2H)，3.86(s，3H)，3.94(d，1H，J＝17Hz)，4.09(dd，1H，J＝9，7Hz)，4.21(d，1H，J＝17Hz)，7.1?8-7.22(m，3H)，7.44(br?d，1H，J＝8Hz)，7.49(d，2H，J＝8Hz)，7.50-7.53(m，1H)，7.64-7.66(m，1H)，7.91(d，2H，J＝8Hz)，8.70(dd，1H，J＝5，1Hz)； 13C?NMR(CDCl 3)δ21.2，23.6，29.0，48.7，51.9，53.7，111.0，118.6，121.5，122.3，129.3，128.9，129.5，134.7，137.2，144.8，146.8，155.7，157.1，166.8. ES-MSm/z427(M+H)。C 26H 26N 4O 20.6H 2O.0.3CH 2Cl 2Analytical value: C, 68.26; H, 6.05; N, 12.11.Actual value: C, 68.57; H, 6.12; N, 11.75.
Embodiment 62
AMD9738:(R, S)-4-{[1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of N-hydroxybenzamide
With oxammonium hydrochloride (32mg, 0.46mmol) be added to the 4-{[-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5 that is stirring, 6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-methyl benzoate (AMD9711) (120mg, 0.23mmol) in the solution in anhydrous MeOH (3mL), then add potassium hydroxide (39mg, 0.69mmol).Stir gained solution 18 hours, and added entry (5mL) and CH this moment 2Cl 2(5mL).Isolate each phase, add saturated ammonium hydroxide aqueous solution its pH is adjusted into 7, use CH then 2Cl 2Extracting (3 * 10mL).The dry organic extract (sal epsom) that merges filters, and concentrates in the vacuum.Adopt thick material (1mm flat board, 10: 1: 1 the CH of radial chromatography purifying gained 2Cl 2/ MeOH/NH 4OH), obtain title compound (52mg, 43%), be white solid. 1H?NMR(CDCl 3)δ1.58-1.61(m，1H)，1.87-1.91(m，2H)，2.12-2.14(m，1H)，2.61-2.66(m，1H)，2.73-2.77(m，1H)，3.55(br?s，2H)，3.79(br?d，1H，J＝16Hz)，3.98-4.00(m，1H)，4.09(br?d，1H，J＝16Hz)，7.08-7.11(m，3H)，7.23-7.26(m，2H)，7.38(br?d，1H，J＝8Hz)，7.48-7.51(m，4H)，8.60(br?d，1H，J＝4Hz)； 13C?NMR(CDCl 3)δ21.2，23.1，29.1，48.6，53.9，60.5，121.9，122.4，127.0，128.8，130.7，135.1，137.7，142.9，146.7，155.2，156.7，166.3.ES-MSm/z428(M+H)。C 25H 25N 5O0.8CH 2Cl 2Analytical value: C, 64.63; H, 5.59; N, 14.61.Actual value: C, 64.94; H, 5.69; N, 14.23.
Embodiment 63
Figure A0181580201141
AMD9743:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-and (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino] methyl }-preparation of phenylformic acid hydrazides
With a hydrazine hydrate (0.5mL, 10.3mmol) be added to the 4-{[-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5 that is stirring, 6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-methyl benzoate (AMD9711) (140mg, 0.33mmol) in the solution in dehydrated alcohol (3mL), then in 80 ℃ of heating gained mixtures 24 hours.Add saturated sodium bicarbonate aqueous solution (5mL), isolate each phase, use CH 2Cl 2The extracting water layer (3 * 10mL), the dry organic extract (sal epsom) that merges, vacuum concentration.Adopt thick material (1mm flat board, 75: 1: 1CH of radial chromatography purifying 2Cl 2-MeOH-NH 4OH), obtain title compound (89mg, 61%), be white solid. 1H?NMR(CDCl 3)δ1.64-1.68(m，1H)，1.94-2.04(m，2H)，2.20-2.24(m，1H)，2.66-2.72(m，1H)，2.78-2.83(m，1H)，3.73(s，2H)，3.93(d，1H，J＝16Hz)，4.00-4.12(m，3H)，4.15(d，1H，J＝16Hz)，7.14-7.18(m，3H)，7.40(d，2H，J＝8Hz)，7.50(br?d，1H，J＝7Hz)，7.58(d，2H，J＝8Hz)，7.62(br?d，1H，J＝7Hz)，8.06(s，1H)，8.66(dd，1H，J＝5，1Hz)； 13C?NMR(CDCl 3)δ21.2，23.6，29.0，48.7，53.7，60.4，11?1.4，118.4，121.5，122.3，126.9，128.6，131.5，134.7，137.3，143.5，146.8，155.8，157.1，168.4.ES-MSm/z427(M+H)。C 25H 26N 6O0.5CH 2Cl 2Analytical value: C, 65.31; H, 5.80; N, 17.92.Actual value: C, 65.22; H, 5.77; N, 17.97.
Embodiment 64
AMD9769:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of phenylformic acid (hydrobromate)
(3.5m, 0.30mL 1.05mmol) are added to 4-{[-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5 with aqueous sodium hydroxide solution, 6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-(90mg is 0.21mmol) in the solution in MeOH (2.5mL) for methyl benzoate (AMD9711).Heated these reaction mixtures 16 hours at 40 ℃, concentrate gained solution afterwards,, use CH with saturated sodium bicarbonate aqueous solution (10mL) washing 2Cl 2Extracting (2 * 50mL).With the 10%HCl aqueous solution pH of this water layer is acidified to 4, makes it saturated, use CH with NaCl (s) 2Cl 2Extracting products therefrom (3 * 75mL).With organic extract that dried over mgso merges, concentrate and obtain light yellow foam. 1HNMR(300MHz，CDCl 3)δ?8.71(d，1H，J＝5.8Hz)，7.84(d，2H，J＝8.1Hz)，7.62(br?s，2H)，7.52(d，1H，J＝8.1Hz)，7.35(d，2H，J＝8.1Hz)，7.23-7.17(m，3H)，4.29-4.21(m，2H)，3.95(d，1H，J＝16.2Hz)，3.74(s，2H)，2.95-2.86(m，1H)，2.79-2.74(m，1H)，2.37-2.25(m，1H)，2.18-2.11(m，2H)，1.83-1.74(m，1H)。
Adopt general flow D: the foam that obtains is above changed into hydrobromate, obtain AMD9769. 1H?NMR(300MHz，D 2O)δ8.77(d，1H，J＝6.0Hz)，8.41(d，1H，J＝7.8Hz)，7.94(dd，1H，J＝7.5，5.7Hz)，7.53-7.42(m，6H)，7.22-7.19(m，2H)，4.78-4.73(m，1H)，4.62(d，1H，J＝16.2Hz)，4.43(d，1H，J＝16.2Hz)，3.87(d，1H，J＝12.9Hz)，3.78(d，1H，J＝12.9Hz)，3.05-3.03(m，2H)，2.47-2.43(m，1H)，2.32-2.21(m，2H)，1.93-1.87(m，1H)； 13C?NMR(75.5MHz，D 2O)δ172.1，153.5，152.9，150.4，144.2，143.2，141.8，132.6，132.3，131.7，131.2，128.9，128.3，115.9，65.6，58.9，52.4，30.0，23.1，22.5.ES-MSm/z413.2(M+H).。C 25H 24N 4O 2) analytical value of 2 (HBr) 1.3 (H2O): C, 50.24; H, 4.82; N, 9.37; Br, 26.74.Actual value: C, 50.58; H, 4.96; N, 9.00; Br, 26.35.
Embodiment 65
AMD9770:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of benzamide
The preparation of 4-formyl radical benzamide:
(1.94mL, (2.0g is 13mmol) at anhydrous CH 27mmol) to be added drop-wise to the 4-formyl radical phenylformic acid that is stirring with pure thionyl chloride 2Cl 2In the suspension (50mL).The slurries of stirring gained 18 hours, solvent removed in vacuo and excessive thionyl chloride at this moment.Residual solid is dissolved among the anhydrous THF (50mL), then ammonia was fed in this solution 15 minutes, formed white depositions thus.This mixture is poured in the saturated sodium bicarbonate aqueous solution (30mL), added chloroform (100mL) then.Isolate each phase, use CHCl 3Extracting water layer (3 * 30mL).The dry organic extract (sal epsom) that merges filters vacuum concentration.Adopt thick material ((20: 1: 1 CH of flash chromatography purifying gained on silica gel 2Cl 2-MeOH-NH 4OH), obtain title compound (85mg, 4%), be white solid. 1H?NMR(CDCl 3)δ5.96(br?s，1H)，6.19(br?2，1H)，7.97(s，4H)，10.09(s，1H)。
Adopt general flow B: (242mg 1.14mmol) is added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6 with the triethoxy sodium borohydride; 7; 8-tetrahydrochysene-quinoline-8-yl)-(216mg, 0.57mmol) (85mg is 0.57mmol) at CH with 4-formyl radical benzamide for amine 2Cl 2In the solution (5mL), stirred this reactant then 18 hours.The thick material of gained is added among the pure TFA (2mL), stirred then 3 hours.Add saturated sodium bicarbonate aqueous solution (10mL) carefully, use CH 2Cl 2(3 * 20mL), the dry then organic extract (sal epsom) that merges filters vacuum concentration to the mixture of extracting gained.Adopt thick material (1mm flat board, 50: 1: 1 CH of radial chromatography purifying gained on silica gel 2Cl 2-MeOH-NH 4OH), obtain title compound (66mg, 28%), be white solid. 1H?NMR(CDCl 3)δ1.67-1.73(m，1H)，2.00-2.08(m，2H)，2.26-2.30(m，1H)，2.71-2.76(m，1H)，2.82-2.87(m，1H)，3.80(s，2H)，3.92(d，1H，J＝16Hz)，4.09(dd，1H，J＝9，7Hz)，4.20(d，1H，J＝16Hz)，5.56(br?s，1H)，6.01(br?s，1H)，7.17-7.22(m，3H)，7.43-7.53(m，4H)，7.65-7.67(m，3H)，8.70(dd，1H，J＝5，1Hz)； 13C?NMR(CDCl 3)δ21.3，23.7，29.1，48.7，53.7，60.5，121.7，122.4，127.4，128.7，132.3，134.8，137.4，143.8，146.9，155.8，157.1，169.1. ES-MSm/z412(M+H)。C 25H 25N 5O1.45H 2O0.6CH 2C1 2Analytical value: C, 63.84; H, 6.34; N, 13.76.Actual value: C, 64.03; H, 5.95; N, 13.37.
Embodiment 66
AMD11130:(6-amino-pyridine-2-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-4-base)-amine (hydrobromate)
Adopt the alkylating general flow of N-: with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (0.176g, 0.47mmol), N, the N-diisopropylethylamine (0.20mL, 1.15mmol) and potassiumiodide (12mg, 0.048mmol) be added to N-[6-(the brooethyl)-2-pyridyl that is stirring] pivalyl amine (according to Harata, M.; Hasegawa, K.; Jitsukawa, K.; Masuda, H.; Einaga, H.Bull.Chem.Soc.Jpn 1998,71,1031-1038) described making) (0.129g is 0.45mmol) at CH 3In the solution among the CN (10mL).Under argon gas atmosphere, 60 ℃ condition, stirred the gained mixture 3.75 hours.Adopt the thick material (CH of column chromatography purifying gained on silica gel 2C1 2/ MeOH, then be 96: 4 at 98: 2), obtain alkylating product (0.148g, 54%), be brown oil.
Adopt general flow D: when removing the Boc group, (43mg 0.074mmol) changes into hydrobromate, obtains yellow solid AMD11130 (41mg, 84%) with the amine that obtains above. 1H NMR (D 2O) δ 1.86-1.92 (m, 1H), 2.15-2.26 (m, 2H), 2.40-2.45 (m, 1H), 3.00-3.01 (m, 2H), 3.99 (d, 1H, J=14.4Hz), 4.15 (d, 1H, J=14.7Hz), 4.36 (d, 1H, J=15.9Hz), 4.52 (d ,-1H, J=15.9Hz), 4.76-4.79 (m, 1H, overlapping with HOD), 6.45 (d, 1H, J=9Hz), 6.70 (d, 1H, J=6.9Hz), 7.43 (dd, 1H, J=9,7.5Hz), 7.57 (dd, 2H, J=6.3,3Hz), 7.67 (dd, 2H, J=6.3,3Hz), 7.89 (dd, 1H, J=7.8,6Hz), 8.37 (d, 1H, J=7.5Hz), 8.74 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.30,20.86, and 27.81,48.12,54.65,62.49,113.24,113.78,114.19,126.26,127.22,127.36,130.88,140.30,141.10,143.85,144.14,148.38,149.38,149.63; ES-MSm/z385 (M+H); C 23H 24N 63.0 HBr1.8H 2The analytical value of O: C, 41.88; H, 4.68; N, 12.74; Br, 36.34.Actual value: C, 41.85; H, 4.61; N, 12.45; Br, 36.44.
Embodiment 67
Figure A0181580201181
AMD11157:(2-{[(1H benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-preparation of methyl alcohol (free alkali)
Adopt general flow B (to use NaBH (OAc) 3Carry out direct reductive amination): (0.139g, 1.04mmol) (0.183g is 0.48mmol) with NaBH (OAc) with (1-tert-butoxycarbonyl-1H-benzoglyoxaline-1-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine to make phthalic acid dicarboxyl aldehyde 3(0.504g is 2.38mmol) at CH 2Cl 2Reaction is 20 hours (5mL), then adopts the thick product of radial chromatography purifying on silica gel (2mm flat board, 100: 1 CH 2Cl 2: CH 3OH), obtain the white foam of 0.108g (45%).(0.108g 0.22mmol) is dissolved in CH with this foam 2Cl 2(2mL), use trifluoroacetic acid (1mL) to handle then.Stirring at room gained solution 90 minutes, decompression concentrated down then.The gained residue is dissolved in CH 2Cl 2(10mL) and NaOH (1.0M ,～10mL) in, this water becomes alkalescence (pH14) like this.Isolate each phase, use CH 2Cl 2Extracting water (3 * 10mL).The dry organic extract (sodium sulfate) that merges concentrates then.Adopt thick material (1mm flat board, 100: 1: 1 CH of radial chromatography purifying gained on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the white solid AMD 11157 of 0.079g (91%).
1H?NMR(CDCl 3)δ1.61-1.76(m，2H)，1.89-2.02(m，1H)，2.07-2.13(m，1H)，2.33-2.40(m，1H)，2.69-2.90(m，2H)，3.81(d，1H，J＝15.0Hz)，3.82(d，1H，J＝1?2.6?Hz)，3.95(d，1H，J＝15.0Hz)，3.98(t，1H，J＝8.1Hz)，4.06(d，1H，J＝12.6Hz)，4.50(d，1H，J＝11.7Hz)，4.63(d，1H，J＝11.7Hz)，7.06-7.21(m，6H)，7.38-7.46(m，3H)，7.62(br?s，1H)，8.09(br?s，1H)，8.44(br?d，1H，J＝4.2?Hz)； 13CNMR(CDCl 3)δ20.90，21.40，29.04，49.28，55.26，60.09，62.90，111.04，118.81，121.48，122.23，127.93，128.50，130.95，131.83，134.83，137.27，137.63，140.38，146.78，153.60，156.28. ES-MSm/z399(M+H)。C 25H 26N 4O1.0H 2The analytical value of O: C, 72.09; H, 6.78; N, 13.45.Actual value: C, 72.15; H, 6.43; N, 13.29.
Embodiment 68
AMD11156:O-(2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-preparation of azanol (hydrobromate)
2-(2-brooethyl-benzyl oxygen base)-isoindole-1, the preparation of 3-diketone:
Figure A0181580201192
With α, α '-two bromo-o-dimethylbenzene (3.30g, 0.0125mol) be added to the N-hydroxyphthalimide that stirring (0.60g, 3.68mmol) and Et 3(0.60mL is 4.30mmol) in the solution in DMF (6mL), then in stirring at room gained mixture 4 hours for N.Filter the brown throw out of gained, use CH 2Cl 2Washing.With EtOAc (40mL) and water (30mL) dilution filtrate, (1 * 30mL), dry (sodium sulfate) concentrates under the decompression with salt water washing organic phase.(4: 1 hexane/EtOAc), obtain title compound (581mg, 46%) is white solid to the yellow oil of employing column chromatography purifying gained on silica gel. 1H?NMR(CDCl 3)δ4.99(s，2H)，5.37(s，2H)，7.27-7.40(m，2H)，7.41-7.45(m，2H)，7.73-7.76(m，2H)，7.81-7.84(m，2H)。
Adopt alkylating general flow: with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-and amine (0.274g, 0.725mmol), N, N-diisopropylethylamine (0.21mL, 1.21mmol) and potassiumiodide (12mg, 0.048mmol) being added to 2-(2-brooethyl-benzyl oxygen the base)-isoindole-1 that is stirring, (0.308g is 0.89mmol) at anhydrous CH for the 3-diketone 3In the solution among the CN (10mL).Under argon gas atmosphere, 60 ℃ condition, stirred the gained mixture 2.75 hours.Adopt the thick material (CH of column chromatography purifying gained on silica gel 2Cl 2/ MeOH, 98: 2, then 96: 4), obtain alkylate (0.32g, 69%), be white foam.
With a hydrazine hydrate (0.10mL, 2mmol) be added to above-mentioned foam (219mg, 0.34mmol) EtOH (96%, 5mL) in the solution in, then stirring at room gained solution 3 days.Filter this mixture (removing the white solid of gained), use CH then 2Cl 2Washing.Decompression is concentrated filtrate down, adopts radial chromatography purifying (1mm flat board, CH on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 1: 1), obtain required going and protect amine (44mg, 31%), be white foam.
Adopt general flow D: (39mg 0.094mmol) changes into hydrobromate, obtains white solid AMD11156 (59mg, 90%) with the amine that obtains above. 1H NMR (D 2O) δ 1.88-1.93 (m, 1H), 2.19-2.32 (m, 2H), 2.45-2.49 (m, 1H), and 3.03-3.04 (m, 2H), 3.85 (d, 1H, J=13.5Hz), 4.17 (d, 1H, J=13.5Hz), 4.36 (d, 1H, J=16.2Hz), 4.55 (d, 1 H, J=16.2Hz), 4.76-4.79 (m, 1H, overlapping with HOD), 5.10 (d, 1H, J=10.8Hz), 5.24 (d, 1H, J=10.8Hz), 6.91 (t, 1H, J=7.5Hz), 7.07 (d, 1H, J=6.9Hz), 7.14 (t, 1H, J=7.5Hz), 7.42 (d, 1H, J=7.5Hz), 7.5 1 (dd, 2H, J=6.3,3Hz), 7.58 (dd, 2H, J=6.3,3Hz), 7.90 (dd, 1H, J=7.8,6Hz), 8.38 (d, 1H, J=7.5Hz), 8.73 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.42,20.80, and 27.88,48.98,52.84,62.08,74.83,113.93,126.16,126.81,128.85,130.56,131.21,131.52,131.87,136.51,139.88,141.13,148.36,150.49,150.80; ES-MSm/z414 (M+H); C 25H 27N 5O3.0HBr2.2H 2The analytical value of O: C, 43.15; H, 4.98; N, 10.06; Br, 34.45.Actual value C, 43.37; H, 5.05; N, 9.87; Br, 34.33.
Embodiment 69
AMD11191:(4-amino-pyridine-3-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: with NaBH (OAc) 3(243mg, 1.15mmol) be added to (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine of stirring (252mg, 0.91mmol) and (3-formyl radical-pyridin-4-yl)-amino acid t-butyl ester (according to Venuti, M.C.; Stephenson, R.A.et al.J.Med.Chem.1988,31,2136-2145 is described to be made) (206mg is 0.93mmol) at CH 2Cl 2In the solution (9mL), then in stirring at room gained mixture 16 hours.(1: 1,6mL) solution stirring in was 3 days at 5NHCl/THF with the thick yellow foam (0.30g) of gained.Water (10mL) and CH 2Cl 2(25mL) dilution gained mixture becomes alkalescence with 10N NaOH (10mL) with it.Isolate each layer, use CH 2Cl 2Extracting water (3 * 10mL).The dry organic extract (sodium sulfate) that merges, decompression concentrates down, adopts radial chromatography purifying (2mm flat board, CH on silica gel 2Cl 2/ MeOH/NH 4OH, 100: 1: 1,50: 1: 1 then, 20: 1: 1 then), obtain free amine (100mg obtains 29% altogether in 2 steps), be purified oily matter.
Adopt general flow D: (73mg 0.19mmol) changes into hydrobromate, obtains white solid AMD11191 (120mg, 90%) with the amine that obtains above. 1H NMR (D 2O) δ 1.87-1.91 (m, 1H), 2.15-2.26 (m, 2H), 2.45-2.50 (m, 1H), and 3.00-3.02 (m, 2H), 4.02 (d, 1H, J=14.1Hz), 4.13 (d, 1H, J=14.1Hz), 4.34 (d, 1H, J=16.2Hz), 4.45 (d, 1H, J=16.2Hz), 4.76-4.79 (m, 1H, overlapping with HOD), 6.40 (d, 1H, J=6.9Hz), 7.38 (d, 1H, J=6.9Hz), 7.56 (dd, 2H, J=6.3,3Hz), 7.66 (dd, 2H, J=6.3,3Hz), 7.89 (dd, 1H, J=7.8,6Hz), 8.08 (s, 1H), 8.35 (d, 1H, J=7.8Hz), 8.74 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.41 (2 carbon), 27.92,48.03,51.51,61.78,109.58,114.04,11 5.89,126.30,127.34,130.58,138.61,140.26,140.69,141.07,148.25,149.82,150.33,158.82; ES-MSm/z385 (M+H); C 23H 24N 63.1HBr1.8H 2O0.5C 4H 10The analytical value of O: C, 42.60; H, 5.11; N, 11.92; Br, 35.15.Actual value: C, 42.91; H, 5.01; N, 11.88; Br, 34.76.
Embodiment 70
AMD11065:2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-preparation of 5-cyano group-methyl benzoate
The preparation of 2-methyl-5-nitro-methyl benzoate:
(1.91g 10.6mmol) and the vlil of sulfuric acid (catalyzer) in MeOH (25mL) 16 hours, concentrates in the vacuum then with 2-methyl-5-nitro phenylformic acid.The gained residue is dissolved in CH 2Cl 2(50mL), (2 * 40mL), dry (sal epsom) then filters, and vacuum concentration obtains yellow crystals (1.50g, 73%) with saturated sodium bicarbonate aqueous solution washing. 1H?NMR(CDCl 3)δ2.72(s，3H)，3.96(s，3H)，7.44(d，1H，J＝9.0Hz)，8.24(dd，1H，J＝9.0，3.0Hz)，8.78(d，1H，J＝3.0Hz)。
The preparation of 5-amino--methyl-methyl benzoate:
(1.50g, 7.8mmol) (175mg 0.17mmol) shook 17 hours under the condition of hydrogen atmosphere (35psi), room temperature for solution in 4: 1 MeOH/EtOAc (20mL) and 10%Pd/C to make 2-methyl-5-nitro-methyl benzoate.Remove by filter catalyzer on diatomite, vacuum concentrated filtrate obtains faint yellow oily thing (1.29g, 99%). 1H?NMR(CDCl 3)δ2.46(s，3H)，3.63(br?s，2H)，3.87(s，3H)，6.74(dd，1H，J＝9.0，3.0Hz)，7.02(d，1H，J＝6.0Hz)，7.25(d，1H，J＝3.0Hz)。
The preparation of 5-cyano group-2-methyl-methyl benzoate:
In room temperature, (1.29g is 7.80mmol) in the suspension in water (2.0mL) lentamente concentrated hydrochloric acid (2.0mL) to be added to the 5-amino-2-methyl-methyl benzoate that is stirring.Add more water (15mL), stir the gained mixture, drip NaNO simultaneously at 0 ℃ 2(592mg, 8.58mmol) solution in water (2.2mL).After this amine dissolves fully, slowly add solid carbonic acid potassium at 0 ℃, be neutralized up to this solution.
(838mg, (918mg 18.7mmol) in the solution in water (2.9mL), is heated to 60 ℃ with this solution then 9.36mmol) to be dissolved in NaCN with cupric cyanide (I).Cold above-mentioned neutral diazonium salt solution is added drop-wise in 60 ℃ the cyanide solution that vigorous stirring.With this mixture heating up to 110 ℃ 1 hour, make it be cooled to room temperature then then.(15mL) dilutes this mixture with saturated sodium bicarbonate aqueous solution, uses CH 2Cl 2Extracting (3 * 20mL).The dry organic extract (sal epsom) that merges filters vacuum concentration.With this thick material of filtered through silica gel (20%EtOAc/ hexane), obtain yellow crystals (990mg, 72%). 1H?NMR(CDCl 3)δ2.68(s，3H)，3.93(s，3H)，7.38(d，1H，J＝9.0Hz)，7.66(dd，1H，J＝9.0，3.0Hz)，8.22(d，1H，J＝1.5Hz)。
The preparation of 2-brooethyl-5-cyano group-methyl benzoate:
Figure A0181580201231
With 5-cyano group-2-methyl-methyl benzoate (913mg, 5.21mmol), NBS (1.02g, 5.73mmol) and AIBN (128mg is 0.780mmol) at CCl 4Mixture heating up (20mL) refluxed 24 hours, made it be cooled to room temperature then.Filter this mixture, concentrate gained filtrate in the vacuum.Adopt the thick material (10%EtOAc/ hexane) of column chromatography purifying on silica gel, obtain xanchromatic crystal (720mg, 55%). 1H?NMR(CDCl 3)δ3.99(s，3H)，4.96(s，2H)，7.62(d，1H，J＝9.0Hz)，7.77(dd，1H，J＝9.0，3.0Hz)，8.27(d，1H，J＝3.0Hz)。
With 2-[(5,6,7,8-tetrahydrochysene-quinoline-8-base is amino)-methyl]-benzoglyoxaline-1-carboxylic acid tertiary butyl ester) 762mg, 2.01mmol), 2-brooethyl-5-cyano group-methyl benzoate (511mg, 2.01mmol), potassiumiodide (19mg, 0.10mmol) and N, (0.53mL, 3.02mmol) mixture in acetonitrile (16mL) was 60 ℃ of heating 16 hours for the N-diisopropylethylamine.The vacuum concentration reaction mixture is used CH 2Cl 2(25mL) with saturated sodium bicarbonate aqueous solution (30mL) dilution gained residue.Isolate each layer, use CH 2C1 2Extracting gained water layer (2 * 20mL).The dry organic extract (sal epsom) that merges filters vacuum concentration.Thick material ((500: 10: 1 CH of purifying gained on the silica gel 2Cl 2/ MeOH/NH 4OH), obtain white foam (935mg, 84%).
(50mg 0.11mmol) is dissolved in anhydrous CH with the material of the purifying that obtains above 2Cl 2(1.5mL), drip trifluoroacetic acid (2.0mL) then.In stirring at room gained mixture 2.5 hours.Use CH 2Cl 2Diluted reaction mixture (15mL), vacuum concentration is removed any excessive trifluoroacetic acid then.Use CH 2Cl 2(20mL) and the enriched material of 1N NaOH (20mL) dilution gained.Isolate each layer, use CH 2Cl 2(2 * 15mL), the dry then organic layer (sodium sulfate) that merges filters extracting gained water layer, and vacuum concentration obtains yellow foam AMD11165. 1H?NMR(CDCl 3)δ1.62-1.79(m，1H)，1.92-2.10(m，2H)，2.26-2.34(m，1H)，2.69-2.93(m，2H)，3.89(s，3H)，3.89(d，1H，J＝16.5Hz)，3.95(d，1H，J＝16.2Hz)，4.13(m，1H)，4.16(d，1H，J＝16.5Hz)，4.57(d，1H，J＝15.9Hz)，7.12-7.23(m，3H)，7.43(d，1H，J＝7.8Hz)，7.48(br?m，1H)，7.58(dd，2H，J＝7.8，1.5Hz)，7.94(d，1H，J＝1.8Hz)，8.00(d，1H，J＝8.1Hz)，8.62(d，1H，J＝5.1Hz). 13C?NMR(CDCl 3)δ21.72，24.40，29.46，50.21，53.01，53.07，111.08，118.26，122.28，122.88，130.88，131.50，134.05，135.12，135.20，137.97，147.17，147.26，155.56，157.27，166.75.ES-MSm/z452(M+H)。C 27H 25N 5O 20.05CH 2Cl 20.8H 2The analytical value of O: C, 69.10; H, 5.72; N, 14.89.Actual value: C, 69.44; H, 5.87; N, 14.61.
Embodiment 71
AMD11179:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino]-methyl }-preparation of 3-cyano group-benzamide
With 2-{[(2-cyano group-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amino]-methyl }-(0.55g, 1mmol) solution in methyl alcohol (25mL) is added in the Raney nickel of 0.5mL in water benzoglyoxaline-1-carboxylic acid tertiary butyl ester.Made this solution saturated 10 minutes with ammonia then.In hydrogen atmosphere (40psi), acutely shook reaction vessel 16 hours.Filter the gained mixture with Celite pad, then concentrated gained filtrate under the decompression.Adopt the thick residue of column chromatography purifying gained (88: 12 CH 2Cl 2: MeOH), obtain described amine (0.20g, 36%). 1HNMR(CDCl 3)δ1.73(m，1H)，2.01(m，2H)，2.35(m，1H)，2.85(m，2H)，3.88(t，2H，J＝15.9Hz)，4.16(m，1H)，4.21(d，1H，J＝9.6Hz)，4.26(d，1H，J＝7.8Hz)，5.71(br，1H，NH)，6.12(br，1H，NH)，7.19(m，3H)，7.46(d，1H，J＝7.8Hz)，7.55(br，2H)，7.80(d，1H，J＝8.1Hz)，7.87(d，1H，J＝8.1Hz)，7.96(s，1H)，8.64(dd，1H，J＝4.5Hz). 13C?NMR(CDCl 3)δ21.71，24.65，29.44，49.92，53.09，61.84，112.81，117.49，122.30(4C)，122.97，130.44(2C)，131.98，132.32，133.56，135.37，138.05(2C)，147.13，147.29，155.27，156.87，167.82.ES-MSm/z437(M+H)。C 26H 24N 6O0.6CH 2Cl 2Analytical value: C, 65.54; H, 5.21; N, 17.24.Actual value: C, 65.93; H, 5.51; N, 17.44.
Embodiment 72
Figure A0181580201251
AMD9643:[(3-(1H-benzimidazolyl-2 radicals-yl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
3-(preparation of benzimidazolyl-2 radicals-yl)-benzylalcohol:
(1.00g, 5.6mmol) solution in thionyl chloride (12mL) stirred 3.5 hours at 80 ℃ with different terephthalic acid mono-methyl.Decompression removes down and desolvates, and obtains the different terephthalic acid mono-methyl of chlorination (1.06g, 97%). 1H?NMR(CDCl 3)δ3.98(s，3H)，7.63(t，1H，J＝7.8Hz)，8.30(d，1H，J＝7.8Hz)，8.35(d，1H，J＝7.8Hz)，8.78(s，1H)。
With the 2-N-methyl-p-nitroaniline (0.62g, 4.5mmol) and the different terephthalic acid mono-methyl of chlorination (1.06g, 5.3mmol) in the solution in THF (5.6mL) and pyridine (1.1mL) stirring at room 2 hours.Saturated sodium bicarbonate aqueous solution (20mL) is added in this mixture, uses this mixture (3 * 20mL) of ethyl acetate extracting then.The dry organic extract (sal epsom) that merges filters, and concentrates, and adopts column chromatography purifying (5%MeOH/CH on silica gel 2Cl 2), obtain (2-nitrophenyl)-different terephthalic acid methyl esters (0.70g, 52%), be yellow solid. 1H?NMR(CDCl 3)δ3.99(s，3H)，7.27(t，1H，J＝7.8Hz)，7.65(t，1H，J＝7.8Hz)，7.75(t，1H，J＝7.8Hz)，8.17(d，1H，J＝7.8Hz)，8.30(t，2H，J＝7.8Hz)，8.67(s，1H)，8.99(d，2H，J＝7.8Hz)。
(＜5 μ m orders, 0.35g are added to 6.3mmol) (2-nitrophenyl)-different terephthalic acid methyl esters that (0.70g 2.3mmol) in the solution in Glacial acetic acid (8mL), reflux to stir the gained mixture 1.5 hours then with iron powder.Cool off this mixture, stirring at room 1 hour, decompression concentrated down.The gained residue is distributed in saturated sodium bicarbonate (20mL) and ethyl acetate (20mL), isolate each phase, with saturated sodium bicarbonate (20mL) washing organic layer.Dry organic extract (sal epsom) filters, and concentrates, obtain cyclic 3-(benzimidazolyl-2 radicals-yl)-methyl benzoate (0.59g, 100%). 1H NMR (CDCl 3) δ 3.93 (s, 3H), 7.30 (m, 2H), 7.57 (t, 2H, J=7.8Hz), 7.88 (br, 1H), 8.12 (d, 1H, J=7.8Hz), 8.35 (d, 1H, J=7.8Hz), 8.64 (s, 1H), 10.10 (br, 1H (NH)).
(4.0mL, the 1.0M solution in THF, solution 4.0mmol) are added to 3-, and ((0.20g is 0.8mmol) in the solution in-78 ℃ THF (8mL) for the benzoic ether of benzimidazolyl-2 radicals-yl) with DIBAL-H.Make this reactant be warmed to room temperature, stirred 0.5 hour, with saturated sodium tartrate potassium solution (15mL) stopped reaction.This biphase mixture of vigorous stirring 1 hour is isolated each phase, and dry organic layer (sal epsom) filters, and concentrates, and obtains 3-(benzimidazolyl-2 radicals-yl)-benzylalcohol (0.12g, 67%). 1H?NMR(CD 4OD 3)δ4.73(s，2H)，7.26(m，2H)，7.52(m，2H)，7.57(m，2H)，7.99(m，1H)，8.10(s，1H)。
Adopt general flow C: with methylsulfonyl chloride (55 μ L, 0.7mmol) be added to 3-(benzimidazolyl-2 radicals-yl)-benzylalcohol (0.12g, 0.5mmol) and triethylamine (0.11mL is 0.8mmol) in the solution in THF (5mL), then in stirring at room gained mixture 1 hour.The mesylate (0.15g, 91%) that need not be further purified gained in next step reaction can use. 1H?NMR(CDCl 3)δ3.14(s，3H)，5.38(s，2H)，7.27(m，2H)，7.62(m，4H)，8.12(m，1H)，8.19(s，1H)。
Adopt alkylating general flow: make the mesylate that obtains above (0.15g, 0.5mmol), N, the N-diisopropylethylamine (0.12mL, 0.7mmol) and potassiumiodide (6mg, 30 μ mol) at CH 3(0.18g is 0.5mmol) 60 ℃ of reactions 3 hours with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine for solution among the CN (5mL).Adopt the thick material (2%MeOH/CH of column chromatography purifying gained on silica gel 2Cl 2), obtain required N-alkylate (0.17g, 60%), be flaky white solid. TH?NMR(CDCl 3)δ1.68(s，10H)，2.05(m，2H)，2.30(m，1H)，2.80(m，2H)，3.69(d，1H，J＝12.0Hz)，3.87(d，1H，J＝15.0Hz)，4.30(d，1H，J＝15.0Hz)，4.45(m，1H)，4.61(d，1H，J＝15.0Hz)，7.08(m，1H)，7.15-7.30(m，7H)，7.35(d，1H，J＝7.8Hz)，7.67(d，2H，J＝7.8Hz)，7.70(m，3H)，8.09(d，1H，J＝7.8Hz)，8.49(d，1H，J＝3.5Hz)，9.06(s，1H)。
Adopt general flow D: the material (50mg) that obtains is above changed into hydrobromate, obtain beige solid AMD9575 (0.062g). 1H?NMR(D 2O)δ1.91(br?m，1H)，2.25(m，2H)，2.45(brm，1H)，3.04(br?m，2H)，3.79(d，1H，J＝12.9Hz)，3.94(d，1H，J＝13.2Hz)，4.42(d，1H，J＝16.2Hz)，4.62(d，1H，J＝16.2Hz)，4.78(m，1H)，7.14(d，2H，J＝5.4Hz)，7.14(m，2H)，7.41(m，2H)，7.48(d，2H，J＝6.9Hz)，7.59(dd，2H，J＝3.0，6.3Hz)，7.73(dd，2H，J＝3.0，6.0Hz)，7.95(t，1H，J＝6.9Hz)，8.41(d，1H，J＝8.1Hz)，8.79(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.43，21.15，27.88，50.15，56.67，63.59，113.41(2C)，114.16(2C)，122.13，126.26，126.54(2C)，126.69，127.03(2C)，127.46，130.33，130.83，131.71，135.08，138.72，139.91(2C)，141.14，147.47，148.41(2C)，150.54，151.56.ES-MSm/z485(M+H)。C 31H 28N 63.0HBr2.9H 2The analytical value of O: C, 48.35; H, 5.09; N, 10.37; Br, 29.60.Actual value: C, 48.35; H, 4.96; N, 10.31; Br, 29.59.
Embodiment 73
Figure A0181580201271
AMD9902:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydroquinoline-8-yl)-(imidazoles-2-yl)-methylamine (hydrobromate)
The reductive amination condition A of employing standard, make 1H-(benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (207mg, 0.75mmol) with imidazoles-2-carboxylic aldehyde (96mg, 1.0mmol) and sodium cyanoborohydride (95mg, 1.5mmol) solution stirring in methyl alcohol (5mL) is 48 hours.Concentrate this solution then.The gained residue is added in the methylene dichloride, wash with 1N sodium hydroxide (3mL), use anhydrous sodium sulfate drying then, concentrate, adopt chromatography purifying (methylene dichloride of 20: 1: methyl alcohol), obtain (1H-benzimidazolyl-2 radicals-ylmethyl)-(5 on silica gel, 6,7,8-tetrahydroquinoline-8-yl)-(imidazoles-2-yl)-methylamine (69mg, 56%). 1H?NMR(CDCl 3)δ1.64(m，1H)，1.86(m，1H)，2.00(m，1H)，2.68(m，1H)，2.86(m，1H)，3.64(d，1H，J＝14.6Hz)，3.79(d，1H，J＝15.4Hz)，3.90(m，1H)，3.91(d，1H，J＝15.4Hz)，3.94(d，1H，J＝14.6Hz)，6.97(s，1H)，7.18(m，3H)，7.55(d，1H，J＝9.0Hz)，7.60(m，2H)，8.47(d，1H，J＝4.9Hz)。
(56mg 0.156mmol) is added in the acetate (1mL), then the saturated solution of HBr in acetate (1mL) is added in the solution of gained with (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-(imidazoles-2-yl)-methylamine.Stir the gained mixture then, it is precipitated, separate, obtain white crystalline solid AMD9902 (39mg) according to flow process D. 1H NMR (D 2O). δ 1.88 (m, 1H), 2.09 (m, 1H), 2.39 (m, 1H), 3.02 (m, 2H), 4.31 (d, 1H, J=15.6Hz), 4.42 (d, 1H, J=12.6Hz), 4.48 (d, 1H, J=12.6Hz), 4.53 (d, 1H, J=15.6Hz), 4.63 (m, 1H), 7.19 (s, 1H), 7.58 (m, 2H), 7.73 (m, 2H), 7.87 (dd, 1H, J=7.8,4.9Hz), 8.67 (d, 1H, J=4.9Hz). 13C NMR (D 2O) δ 19.83,20.26, and 20.94,27.30,27.71,47.37,48.09,61.93,114.33,120.20,126.27,126.64,127.36,131.08,140.35,140.98,142.76,148.42,149.03,151.26,154.87.ES-MSm/z359 (M+H); (C 21H 22N 6* 2.7HBr * 1.9H 2The analytical value of O * 0.3HOAc): C, 40.86; H, 4.87; N, 12.88; Br 36.73.Actual value: C, 41.11; H, 4.73; N, 12.87; Br, 36.39.
Embodiment 74
Figure A0181580201281
AMD9592:4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-2, the preparation of 6-dichloropyridine (hydrobromate)
Methylsulfonic acid 2, the preparation of 6-two chloro-pyridin-4-yl methyl esters
With BH 3-THF (solution of 1M in THF, 5.8mL, 5.8mmol) be added drop-wise to stirring 2, (280mg 1.5mmol) in the solution in THF (7.5mL), reflux to stir this mixture 65 hours to the 6-dichloro-isonicotinic acid then.The cooling reactant, with MeOH (10mL) stopped reaction, decompression concentrates down.MeOH (10mL) is added in the residue of gained, with this solution reconcentration.Repeat above-mentioned flow process 5 times, gained white solid (230mg, 89%) need not be further purified and can use in next step reaction.
Adopt general flow C: with methylsulfonyl chloride (0.10mL, 0.3mmol) be added to the material that obtains above that stirring (230mg, 1.3mmol) and triethylamine (0.50mL is 3.9mmol) at CH 2Cl 2In the ice-cold solution (13mL), stirred the gained mixture 30 minutes at 0 ℃ then.Obtain required thick mesylate (340mg), be light yellow solid, and in next step reaction, need not be further purified and to use.
Adopt the alkylating general flow of N-: (330mg, 1.3mmol) and N, (0.45mL is 2.6mmol) at CH for the N-diisopropylethylamine to make the material that obtains above 3Solution among the CN (13mL) and (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (470mg, 1.2mmol) reaction overnight.Adopt the thick material (3: 1 EtOAc/ hexanes) of flash chromatography purifying gained on silica gel, obtain required amine (400mg, 58%), be faint yellow solid.
Adopt general flow D: when removing N-tert-butoxycarbonyl blocking group, (264mg 0.49mmol) changes into hydrobromate, obtains white powder AMD9592 (280 mg, 92%) with the material that obtains above. 1H?NMR(D 2O)δ1.80-1.97(m，1H)，2.12-2.21(m，2H)，2.33-2.45(m，1H)，2.97-3.01(m，2H)，3.83(q，2H，J＝15Hz)，3.78(dd，2H，J＝66，15Hz)，4.73(m，1H)，7.18(s，2H)，7.47-7.51(m，2H)，7.5-7.62(m，2H)，7.86(t，1H，J＝6Hz)，8.32(d，1H，J＝7.5Hz)，8.72(d，1H，J＝6?Hz). 13C?NMR(CDCl 3)δ25.12，25.90，32.66，54.46，60.32，67.92，118.95(2)，128.83(2)，131.11，132.05(2)，135.43，144.95，146.02，153.17，154.63，154.87，155.07，157.53.ES-MSm/z439(M+H)。C 23H 21N 5Cl 21.0H 2The analytical value of O2.0HBr: C, 44.69; H, 4.08; N, 11.33; Br, 25.85; Cl, 11.47.Calculated value: C, 44.56; H, 4.22; N, 11.41; Br, 25.83; Cl, 11.46.
Embodiment 75
Figure A0181580201291
AMD9782:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of benzoxazol-5-ylmethyl-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
The preparation of 5-brooethyl-benzoxazol
With 5-methyl benzoxazol (200mg, 1.50mmol), N-bromine succinimide (321mg, 1.80mmol) and 2,2 '-(37mg is 0.23mmol) at CCl for azo diisobutyl nitrile 4Mixture heating up (3mL) refluxed 22 hours.Filter the gained mixture, decompression is concentrated gained filtrate down.The thick material of purifying gained (5%EtOAc/ hexane) obtains title compound on silica gel, is clear crystal (126mg, 39%). 1H?NMR(CDCl 3)δ4.64(s，2H)，7.46(dd，1H，J＝8.6，1.7Hz)，7.57(d，1H，J＝8.4Hz)，7.83(d，1H，J＝1.2Hz)，8.12(s，1H)。
Adopt the alkylating general flow of N-: make 5-brooethyl-benzoxazol (94mg, 0.44mmol), (3mg, 0.02mmol) and N, (0.10mL is 0.57mmol) at CH for the N-diisopropylethylamine for potassiumiodide 3(152mg is 0.402mmol) 60 ℃ of reactions 22 hours with (1-tert-butoxycarbonyl-1H-2-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine among the CN (4mL).Adopt the thick material (400: 5: 1 EtOAc/MeOH/NH4OH) of flash chromatography purifying gained on silica gel, obtain yellow foam (124mg, 60%).
(40mg is 0.078mmol) at 3: 1 trifluoroacetic acid: CH at the above-mentioned yellow foam of stirring at room 2Cl 2Solution (4mL) 1 hour concentrates it then.The residue that makes gained is at CH 2Cl 2With the protection sodium bicarbonate aqueous solution in distribute, use CH then 2Cl 2Extracting gained water.The dry organic phase (sal epsom) that merges is filtered, and concentrates, and obtains title compound, is yellow foam (32mg, 89%). 1H?NMR(CDCl 3)δ1.68(m，1H)，2.04(m，2H)，2.28(m，1H)，2.71(m，1H)，2.86(m，1H)，3.86(s，2H)，3.98(d，1H，J＝17Hz)，4.09(m，1H)，4.22(d，1H，J＝17Hz)，7.19(m，3H)，7.44(m，3H)，7.58(m，2H)，7.87(s，1H)，8.02(s，1H)，8.73(d，1H，J＝4.2Hz)； 13C?NMR(CDCl 3)δ21.77，23.76，29.58，48.77，54.24，60.59，110.95，120.86，122.08，122.75，126.73，135.19，136.57，137.77，140.56，147.38，149.70，153.13，156.32，157.63.ES-MSm/z410(M+H)。(C 25H 23N 5O) 0.23 (H 2O) 0.53 (CH 2Cl 2) analytical value: C, 66.86; H, 5.39; N, 15.27.Actual value: C, 66.99; H, 5.55; N, 14.90.
Embodiment 76
AMD9786: the preparation of pyridine-2-ylmethyl (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine
Adopt the alkylating general flow of N-: (104mg, 0.413mmol) and N, (0.092mL is 0.516mmol) at CH for the N-diisopropylethylamine with hydrochloric acid 2-bromo methyl cycloheptapyridine 3Stirred 10 minutes among the CN (5mL).Add then salt of wormwood (71mg, 0.516mmol) and (1-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (130mg, 0.344mmol), and with gained mixture heating up to 60 ℃ 2 hours.Cooling gained dark solution concentrates, and the gained residue is dissolved in CH 2Cl 2In, wash with ammonium carbonate solution then.Adopt chromatography purifying gained residue (10%MeOH/CH on silica gel 2Cl 2), obtain producing pyridine-2-ylmethyl-(1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (32mg, 20%), be white foam. 1H?NMR(CDCl 3)δ1.62(s，9H)，1.88-2.20(m，4H)，2.69-2.78(m，2H)，3.95(d，1H，J＝16.1Hz)，4.13(d，1H，J＝16.1Hz)，4.36(t，1H，J＝6.8Hz)，4.63(d，1H，J＝12.8Hz)，4.77(d，1H，J＝12.8Hz)，6.86(m，1H)，6.96(m，1H)，7.22-7.29(m，3H)，7.38(t，1H，J＝7.8Hz)，7.62(m，2H)，7.74(m，1H)，8.30(d，1H，J＝6.0Hz)，8.43(d，1H，J＝5.2Hz)。
Adopt general flow D: (32mg 0.068mmol) changes into hydrobromate, obtains white solid AMD9786 (28mg) with the foam that obtains above. 1H NMR (D 2O). δ 1.81 (m, 1H), 2.19 (m, 2H), 2.45 (m, 1H), 3.00 (m, 2H), 4.23 (d, 1H, J=9.0Hz), 4.38 (s, 1H), 4.43 (s, 1H), 4.59 (d, 1H, J=9.0Hz), 4.77 (m, 1H), 7.46 (dd, 1H, J=5.3,6.8Hz), 7.53 (m, 2H), 7.63 (m, 2H), 7.72 (d, 1H, J=8.1Hz), 7.86 (dd, 1H, J=7.8,5.7Hz), 8.04 (dt, 1H, J=7.8,1.5Hz), 8.34 (d, 1H, J=7.8Hz), 8.49 (d, 1H, J=5.1Hz), 8.70 (d, 1H, J=6.0Hz). 13C NMR (D 2O) δ 20.32,21.06,27.74,48.17,55.59,62.28,114.23 (2C), 126.86,126.16,126.87,127.16 (2C), 131.05,140.23,140.95,144.03,144.78,148.10,149.33,149.68,152.40.ES-MSm/z440 (M+H); (C 23H 23N 5* 2.9 HBr * 1.7H 2O) analytical value: C, 43.52; H, 4.65; N, 11.03; Br36.51.Actual value: C, 43.50; H, 4.68; N, 10.96; Br, 36.58.
Embodiment 77
Figure A0181580201321
AMD9787:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of benzoxazol-6-ylmethyl-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
The preparation of 6-brooethyl-benzoxazol:
Figure A0181580201322
With 6-methyl benzoxazol (422mg, 3.17mmol), N-bromine succinimide (677mg, 3.80mmol) and 2,2 '-(78mg is 0.48mmol) at CCl for azo diisobutyl nitrile 4Mixture heating up (6.3mL) refluxed 22 hours.Filter the gained mixture, decompression is concentrated gained filtrate down.The thick material of purifying gained (4%EtOAc/ hexane) obtains title compound on silica gel, is clear crystal (257mg, 38%). 1H?NMR(CDCl 3)δ4.64(s，2H)，7.42(dd，1H，J＝8.1，1.5Hz)，7.64(d，1H，J＝1.2Hz)，7.76(d，1H，J＝8.4Hz)，8.12(s，1H)。
Adopt the alkylating general flow of N-: make 6-brooethyl-benzoxazol (113mg, 0.533mmol), (4mg, 0.02mmol) and N, (0.12mL is 0.69mmol) at CH for N-di-isopropyl imines for potassiumiodide 3(168mg is 0.444mmol) 60 ℃ of reactions 16 hours with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine for solution among the CN (4.4mL).Adopt flash chromatography on silica gel, to carry out purifying.The thick material of purifying (600: 5: 1 EtOAc: MeOH: NH on silica gel 4OH), obtain yellow oil (179mg, 79%).
(173mg is 0.339mmol) at trifluoroacetic acid/CH of 3: 1 in the above-mentioned yellow oil of stirring at room 2Cl 2Solution (4mL) 1 hour concentrates then.Make the gained residue at CH 2Cl 2With distribute in the saturated sodium bicarbonate aqueous solution, use CH then 2Cl 2Extracting gained water.The dry organic phase (sal epsom) that merges is filtered, and concentrates, and obtains title compound AMD9787, is yellow foam (118mg, 79%). 1HNMR(CDCl 3)δ1.70(m，1H)，2.04(m，2H)，2.29(m，1H)，2.73(m，1H)，2.87(m，1H)，3.88(s，2H)，3.98(d，1H，J＝17Hz)，4.11(m，1H)，4.22(d，1H，J＝17Hz)，7.19(m，3H)，7.42(m，2H)，7.62(m，3H)，7.71(s，1H)，8.01(s，1H)，8.73(d，1H，J＝4.2?Hz)； 13C?NMR(CDCl 3)δ21.23，23.36，29.06，48.47，53.88，60.16，110.74，119.94，121.52，122.26，125.07，134.68，137.25，137.65，139.20，146.86，150.08，152.34，155.73，157.13.ES-MSm/z410(M+H)。(C 25H 23N 5O) 0.6 (H 2O) analyte of 0.2 (EtOAc): C, 70.76; H, 5.94; N, 15.99.Actual value: C, 70.88; H, 5.83; N, 16.07.
Embodiment 78
AMD9829:(1H-benzoglyoxaline-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of 4-methyl isophthalic acid H-benzoglyoxaline
With tri-methyl ortho formate (4.5mL, 41mmol) and trifluoroacetic acid (0.32mL, 4.1mmol) be added to stirring 2, (1.00g is 8.2mmol) at CH for the 3-diaminotoluene 2Cl 2In the solution (82mL),, use CH afterwards in stirring at room gained mixture 24 hours 2Cl 2(200mL) dilution gained reaction mixture is used the washing of saturated aqueous sodium carbonate (40mL) and water (40mL) then successively.Use CH 2Cl 2Extracting gained water layer (2 * 100mL) again.With organic extract that dried over mgso merges, concentrate and obtain rusty-brown solid (1.07g, 97%). 1H?NMR(300MHz，CDCl 3)δ8.08(s，1H)，7.49(d，1H，J＝8.1Hz)，7.23-7.18(m，1H)，7.10(d，1H，J＝7.5Hz)，2.64(s，3H)。
The preparation of 4-brooethyl-benzoglyoxaline-1-carboxylic acid tertiary butyl ester:
(4.4g, 20mmol) solution in THF (6mL) is added to the 4-methyl isophthalic acid H-benzoglyoxaline that is stirring (1.05g is 7.9mmol) in the solution in THF (10mL) with di-t-butyl carbonic acid hydrogen ester.After 18 hours, concentrate this reaction mixture, obtain the brown slurries.Adopt column chromatography on silica gel, to carry out purifying (20: 3 hexane: EtOAc), obtain required product, be yellow slurry (1.66g, 91%). 1H?NMR(300MHz，CDCl 3)δ8.41(s，1H)，7.81(d，1H，J＝8.1Hz)，7.31-7.26(m，1H)，7.16(d，1H，J＝7.5Hz)，2.67(s，3H)，1.70(s，9H)。
With N-bromine succinimide (730mg, 4.1mmol) and 2,2 '-(84mg, (800mg is 3.4mmol) at CCl 0.51mmol) to be added to the 4-methyl-benzoglyoxaline-1-carboxylic acid tertiary butyl ester that is stirring for azo two (2-methyl propionitrile) 4In the solution (7mL).The gained mixture heating up was refluxed 18 hours, filter afterwards, concentrate, obtain yellow/orange slurries and crystal (1.4g).Adopt column chromatography on silica gel, to carry out purifying (200: 15 hexane: EtOAc), obtain required title compound, be yellow slurry (635mg, 60%). 1H?NMR(300MHz，CDCl 3)δ8.48(s，1H)，7.95(dd，1H，J＝7.8，1.5Hz)，7.42-7.34(m，2H)，4.96(s，2H)，1.71(s，9H)。
Adopt alkylating general flow: with KI (3mg, 0.02mmol) and N, N-diisopropylethylamine (0.1mL, 0.6mmol) be added to (the 1-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5 that is stirring, 6,7,8-tetrahydroquinoline-8-yl)-amine (153mg, 0.40mmol) and 4-brooethyl-benzimidazolyl-2 radicals-carboxylic acid tertiary butyl ester (167mg is 0.48mmol) at CH 3In the solution among the CN (5mL), then the gained reaction mixture is heated to 60 ℃ 3 days.The gained foam is dissolved in CH 2Cl 2(2mL) and in the mixture of TFA (2mL).Concentrate gained solution after 3 hours, with its be dissolved in again water (～1mL) in, with 1N NaOH alkalization.Use CH 2Cl 2Extracting gained water (3 * 50mL).Organic extract with dried over mgso merges concentrates then, obtains light brown foam.Adopt column chromatography on silica gel, to carry out purifying (200: 3: 2 CH 2Cl 2: MeOH: NH 4OH), use radial chromatography purifying (1 millimeter flat board, CH of 100: 1: 1 on silica gel then 2Cl 2: MeOH: NH 4OH), obtain required compound, be light yellow foam (38mg, 23%). 1HNMR(300MHz，CDCl 3)δ8.59(d，1H，J＝3.6Hz)，8.00(s，1H)，7.72(d，1H，J＝7.0Hz)，7.58-7.35(m，3H)，7.20-7.13(m，5H)，4.19-4.08(m，3H)，3.97(d，1H，J＝15Hz)，3.84(d，1H，J＝13.5Hz)，2.90-2.75(m，2H)，2.54-2.50(m，1H)，2.15-2.11(m，1H)，2.04-1.92(m，1H)，1.79-65(m，1H)。
Adopt general flow D: the foam (38mg) that obtains is above changed into hydrobromate, obtain AMD9829. 1H?NMR(300MHz，D 2O)δ9.15(s，1H)，8.78(dd，1H，J＝5.7，1.2Hz)，8.39(d，1H，J＝8.1Hz)，7.92(dd，1H，J＝7.8，6.0Hz)，7.49-7.42(m，3H)，7.41-7.36(m，2H)，7.28(t，1H，J＝8.1Hz)，7.15(d，1H，J＝8.1Hz)，4.89-4.83(m，1H)，4.54(d，1H，J＝16.5Hz)，4.40(d，1H，J＝13.5Hz)，4.34(d，1H，J＝16.2Hz)，4.16(d，1H，J＝13.5Hz)，3.06-3.03(m，2H)，2.56-2.52(m，1H)，2.31-2.22(m，2H)，1.97-1.94(m，1H)； 13C?NMR(75.5MHz，D 2O)δ150.4，148.2，141.0，140.1，140.0，130.5，130.0，128.4，126.9，126.1，123.7，114.1，113.6，66.5，63.1，52.8，49.1，27.9，21.0，20.5.ES-MSm/z409.3(M+H)。(C 25H 24N 6) 2.9 (HBr), 2.2 (H 2O) analytical value: C, 43.98; H, 4.62; N, 12.31; Br, 33.94.Actual value: C, 44.22; H, 4.75; N, 12.11; Br, 33.75.
Embodiment 79
AMD9780:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of pyridin-4-yl methyl-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
Adopt general flow B: (136mg 0.64mmol) is added to (1-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-(5,6 with the triethoxy sodium borohydride, 7,8-tetrahydroquinoline-8-yl)-(120mg, 0.32mmol) (30mg is 0.32mmol) at CH with 4-pyridine carboxylic aldehyde for amine 2Cl 2In the solution (5mL), stirred this reactant then 18 hours.The gained crude product adds among the pure TFA (1mL) and stirred 3 hours.Add saturated sodium bicarbonate aqueous solution (5mL), use CH 2Cl 2The mixture of extracting gained (3 * 10mL), the dry then organic extract (sal epsom) that merges, vacuum concentration.Adopt radial chromatography to carry out purifying (1mm flat board, 50: 1: 1CH 2Cl 2-MeOH-NH 4OH), obtain title compound (83mg, 70%), be white solid. 1H?NMR(CDCl 3)δ1.68-1.72(m，1H)，1.97-2.06(m，2H)，2.26-2.30(m，1H)，2.74-2.77(m，1H)，2.80-2.86(m，1H)，3.77(s，2H)，3.92(d，1H，J＝16Hz)，4.09(dd，1H，J＝9，7Hz)，4.17(d，1H，J＝16Hz)，7.18-7.22(m，3H)，7.36(d，2H，J＝6Hz)，7.44(dd，1H，J＝7，1Hz)，7.52(br?d，1H，J＝7Hz)，7.66(br?d，1H，J＝7Hz)，8.46(dd，2H，J＝5，2Hz)，8.70(dd，1H，J＝5，1Hz)； 13C?NMR(CDCl 3)δ21.2，23.8，29.0，49.1，53.0，60.5，110.9，118.8，121.4，121.9，122.5，123.3，133.7，134.7，137.4，144.2，146.9，148.7，149.8，155.4，156.9.ES-MSm/z370(M+H)。C 23H 23N 50.2H 2O0.2CH 2Cl 2Analytical value: C, 71.44; H, 6.1 5; N, 17.95.Actual value: C, 71.63; H, 6.30; N, 17.77.
Embodiment 80
AMD9781:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (benzo [1,3] dioxy base-4-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl) amine
Adopt general flow B: with NaBH (OAc) 3(107mg 0.505mmol) is added to 2,3-(methylene radical dioxy base)-phenyl aldehyde (57mg, 0.379mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(140mg is 0.371mmol) at CH for amine 2Cl 2In the solution (5mL), stirred overnight gained reactant then.Adopt oily matter (2mm TLC, 100: 1: 1 the CH of radial chromatography purifying gained on silica gel 2Cl 2: CH 3OH: NH 4OH), obtain the alkylating amine of N (105mg).With TFA (2mL) solution stirring of this amine 1 hour, decompression concentrated down then, makes the thick material of gained at CH 2Cl 2(15mL) and in the saturated sodium bicarbonate aqueous solution (15mL) distribute.Isolate each phase, dry organic layer (sodium sulfate) filters, and concentrates, and adopts radial chromatography to carry out purifying (1mm TLC flat board, 125: 1: 1CH 2Cl 2: CH 3OH: NH 4OH), obtain AMD9781 (being 45% altogether) in two steps. 1H NMR (CDCl 3) δ 1.61-1.76 (m, 1H), 1.93-2.09 (m, 2H), 2.21-2.31 (m, 1H), and 2.64-2.90 (m, 2H), 3.67 (d, 1H, J=14.0Hz), 3.92 (d, 1H, J=13.8Hz), 4.03 (d, 1H, J=16.5Hz), 4.11 (dd, 1H, J=9.2,6.8Hz), 4.21 (d, 1H, J=16.7Hz), 5.89 (s, 2H), 6.64 (d, 1H, J=7.0Hz), 6.71 (t, 1H, J=7.7Hz), 6.98 (d, 1H, J=8.1Hz), 7.11-7.23 (m, 3H), 7.40 (d, 1H, J=7.6Hz), 7.55-7.63 (m, 2H), 8.64 (d, 1H, J=3.6Hz). 13C NMR (CDCl 3) δ 21.54,24.21,29.31,29.84,47.82,49.15,60.63,100.74, (107.42 2 carbon), 120.85,121.70,121.74 (2 carbon), (122.34 2 carbon), 122.76 (2 carbon), 134.80, (137.34 2 carbon), 145.98,146.95 (2 carbon), 147.07,156.34,157.45.ES-MSm/z413 (M+H).C 25H 24N 4O 20.8H 2The analytical value of O: C, 70.34; H, 6.04; N, 13.12.Actual value: C, 70.44; H, 5.98; N, 12.88.
Embodiment 81
AMD9789: the preparation of benzo [1,3] dioxy base-5-ylmethyl-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
Adopt general flow B: with NaBH (OAc) 3(210mg, 0.99mmol) be added to [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (125mg, 0.33mmol), piperonylaldehyde (50mg, 0.33mmol) and AcOH (0.02mL, 0.33mmol) in the solution in THF (3.3mL), then stirring at room gained suspension 16 hours.The gained crude product is dissolved in CH 2Cl 2(～2mL) and trifluoroacetic acid are (in～2mL) the mixed solution.1.5 after hour, concentrate this reaction mixture, with its be dissolved in again water (～2mL) in, with 1N NaOH alkalization.Use CH 2Cl 2The extracting obtained aqueous solution (3 * 50mL), with organic extract that dried over mgso merges, concentrate and obtain yellow slurry.Adopt column chromatography purifying products therefrom (100: 1: 1-EtOAc: MeOH: NH on silica gel 4OH), obtain title compound, be white foam (45mg, 33%). 1H?NMR(300MHz，CDCl 3)δ8.69(d，1H，J＝3.3Hz)，7.58(brs，2H)，7.43(d，1H，J＝7.2Hz)，7.21-7.16(m，3H)，6.99(d，1H，J＝1.5Hz)，6.79(dd，1H，J＝8.1，1.5Hz)，6.65(d，1H，J＝7.8Hz)，5.86-5.85(m，2H)，4.15(d，1H，J＝16.5Hz)，4.09-4.06(m，1H)，3.98(d，1H，J＝16.8Hz)，3.64(s，2H)，2.91-2.80(m，1H)，2.74-2.67(m，1H)，2.27-2.17(m，1H)，2.06-1.64(m，2H)，1.75-1.64(m，1H)； 13C?NMR(75.5MHz，CDCl 3)δ159.2，158.0，149.4，148.7，148.5，139.0，136.5，135.0，124.0，123.5，123.3，110.7，109.5，102.5，61.8，55.5，49.9，31.0，25.0，23.1.ES-MSm/z413.3(M+H)。(C 25H 24N 4O 2) 0.8 (H 2O) analytical value: C, 70.34; H, 6.04; N, 13.12.Actual value: C, 70.29; H, 5.99; N, 12.75.
Embodiment 82
Figure A0181580201381
AMD9817:(1 H-benzimidazolyl-2 radicals-ylmethyl)-(2,3-dihydro-cumarone-7-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: with NaBH (OAc) 3(112mg 0.528mmol) is added to 2, and (53.6mg is 0.362mmol) with [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(136mg is 0.361mmol) at CH for amine for 3-Dihydrobenzofuranes-7-carboxylic aldehyde 2Cl 2In the solution (5mL), stirred overnight gained mixture.Adopt radial chromatography purifying gained crude product (1mm TLC flat board, 125: 1: 1 CH on silica gel 2Cl 2: CH 3OH: NH 4OH), obtain required radical (48mg, 33%).
Adopt general flow D: the amine (28mg, 38%) that obtains is above transformed, obtain AMD9817. 1H NMR (D 2O) δ 1.84-2.01 (m, 1H), 2.08-2.29 (m, 2H), 2.34-2.54 (m, 2H), and 2.70-2.83 (m, 1H), 2.95-3.12 (m, 2H), 3.39 (d, 1H, J=12.7Hz), 3.57 (d, 1H, J=12.6Hz), 4.37 (d, 1H, J=16.2Hz), 4.48-4.73 (m, 3H) [4.60 (d, 1H, J=15.5Hz)], 6.52-6.56 (m, 2H), 6.91 (dd, 1H, J=6.1,2.7Hz), 7.50 (dd, 2H, J=6.3,2.8Hz), 7.58 (dd, 2H, J=6.6,3.0Hz), 7.93 (dd, 1H, J=7.9,5.9Hz), 8.39 (d, 1H, J=7.0Hz), 8.73 (d, 1H, J=5.0Hz). 13C NMR (D 2O) δ 20.48,20.86, and 27.43,28.73,50.35,51.50,63.64,72.17, (113.74 2 carbon), 117.76,121.22,125.49,126.17,126.64,127.73 (2 carbon), 129.77,130.53,138.83 (2 carbon), 140.34,147.8 5.150.58,151.78,157.51.ES-MSm/z411 (M+H).C 26H 26N 4O2.2HBr2.1H 2The analytical value of O: C, 49.86; H, 5.21; N, 8.94; Br, 28.07.Actual value: C, 50.16; H, 5.02; N, 9.03; Br, 27.68.
Embodiment 83
AMD9818:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of pyridin-3-yl methyl-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: with NaBH (OAc) 3(98mg, 0.462mmol) be added to 3-pyridine-carboxylic aldehyde (29mg, 0.271mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(103mg is 0.273mmol) at CH for amine 2Cl 2In the solution (5mL), stirred overnight gained reactant then.Adopt the thick material of radial chromatography purifying gained (1mm TLC flat board, 80: 1: 1 CH 2Cl 2: CH 3OH: NH 4OH), obtain required radical (64mg, 50%).
Adopt general flow B: the amine (64mg) that obtains is above changed into hydrobromate, obtain AMD9818 ((69mg, 78%). 1H NMR (D 2O) δ 1.80-1.96 (m, 1H), 2.16-2.31 (m, 2H), 2.43-2.54 (m, 1H), and 3.01-3.08 (m, 2H), 4.10 (d, 1H, J=14.1Hz), 4.24 (d, 1H, J=13.9Hz), 4.43 (d, 1H, J=16.4Hz), 4.61 (d, 1H, J=15.6Hz), 4.72-4.75 (m, 1H), 7.58 (dd, 2H, J=6.5,3.3Hz), 7.69 (dd, 2H, J=6.4,3.4Hz), 7.81 (dd, 1H, J=8.2,6.0Hz), 7.91 (dd, 1H, J=8.1,6.0Hz), 8.36-8.41 (m, 2H), 8.54 (d, 1H, J=8.0Hz), 8.74-8.79 (m, 2H). 13C NMR (D 2O) δ 14.54,20.29, and 20.76,27.83,48.39,53.46,61.54,66.47, (114.23 2 carbon), 126.30,127.29 (2 carbon), 127.42,130.76,137.43,140.23,141.21,141.25,141.63,147.43,148.44,149.92,1 50.13. ES-MS m/z370 (M+H).C 23H 23N 53.0HBr1.8H 2The analytical value of O: C, 42.85; H, 4.63; N, 10.86; Br, 37.19.Actual value C, 43.22; H, 4.66; N, 10.69; Br, 36.85.
Embodiment 84
AMD9828:(1H-benzoglyoxaline-5-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of 1H-benzoglyoxaline-5-carbonyl aldehyde (carbaldehyde)
Figure A0181580201401
With LiAlH 4((500mg is 3.08mmol) in the suspension in 0 ℃ THF (20mL) 10mmol) to be added drop-wise to 5-benzoglyoxaline carboxylic acid for the solution of 1.0m in THF, 10mL.This reaction mixture is warming to room temperature, stirred 24 hours, then extra 24 hours of 50 ℃ of heating.Adding MeOH (4 * 5mL), between each the adding, concentrate gained solution.Vacuum-drying gained brown slurries 3 hours.With the CH of this slurry dissolved at 100: 1 2Cl 2: among the MeOH, use diatomite filtration, concentrate, obtain light brown foam (300mg, 66%).With manganese oxide (IV) (85%, 2.05g, (300mg is 2.0mmol) at CH 20mmol) to be added to the above-mentioned thick alcohol that is stirring 2Cl 2(10mL) and in the solution among the MeOH (0.8mL).With gained suspension be heated to 40 ℃ 18 hours, be cooled to room temperature, use diatomite filtration.Concentrate gained filtrate, obtain light yellow foam (260mg).Adopt column chromatography purifying gained crude product (EtOAc of 200: 1: 1: MeOH: NH on silica gel 4OH), obtain title compound, be white powder (139mg, 60%). 1H?NMR(300MHz，CD 3OD)δ10.0(s，1H)，8.38(s，1H)，8.20(s，1H)，7.87(d，1H，J＝9.0Hz)，7.75(d，1H，J＝9.0Hz)。
Adopt general flow BA: with NaBH (OAc) 3(353mg, 1.65mmol) be added to [1-(tert-butoxycarbonyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (215mg, 0.57mmol), 1H-benzoglyoxaline-5-carbonyl aldehyde (81mg, 0.57mmol) and AcOH (0.03mL, 0.55mmol) in the solution in THF (5.5mL), stirring at room gained suspension 24 hours.The gained crude product is dissolved in CH 2Cl 2(～2mL) and trifluoroacetic acid are (in～2mL) the mixed liquid.After 3 hours, concentrated reaction mixture, with the gained enriched material be dissolved in again water (～2mL) in, then with 1N NaOH alkalization.Use CH 2Cl 2(3 * 50mL) extracting obtained aqueous solutions with organic extract that dried over mgso merges, concentrate and obtain yellow foam.Adopt column chromatography purifying products therefrom (EtOAc of 100: 2: 1: MeOH: NH on silica gel 4OH), obtain title compound, be light yellow foam (52mg, 24%). 1H?NMR(300MHz，CDCl 3)δ8.68(d，1H，J＝3.3Hz)，7.95(s，1H)，7.56(br?s，4H)，7.41(d，1H，J＝6.6Hz)，7.27(d，1H，J＝7.5Hz)，7.18-7.14(m，3H)，4.15(d，1H，J＝16.8Hz)，4.10-4.06(m，1H)，4.00(d，1H，J＝16.8Hz)，3.85(d，1H，J＝13.2Hz)，3.77(d，1H，J＝13.5Hz)，2.90-2.73(m，1H)，2.73-2.68(m，1H)，2.26-2.21(m，1H)，2.08-2.00(m，2H)，1.79-1.64(m，1H)。
Adopt general flow D: the foam (52mg) that obtains is above changed into hydrobromate, obtain AMD9828. 1H?NMR(300MHz，D 2O)δ8.81-8.78(m，2H)，8.43(d，1H，J＝6.9Hz)，7.95(dd，1H，J＝8.1，6Hz)，7.54-7.51(m，2H)，7.44-7.35(m，5H)，4.85-4.79(m，1H)，4.64(d，1H，J＝16.2Hz)，4.46(d，1H，J＝16.2Hz)，4.07(d，1H，J＝12.9Hz)，4.00(d，1H，J＝12.9Hz)，3.08-3.05(m，2H)，2.51-2.48(m，1H)，2.35-2.22(m，2H)，1.98-1.93(m，1H)； 13C?NMR(75.5MHz，D 2O)δ151.7，150.6，148.4，141.1，139.9，136.8，135.8，130.1，129.8，129.5，128.9，126.8，126.2，115.2，114.7，113.4，63.5，57.3，50.0，27.9，21.1，20.5.ES-MSm/z409.3(M+H)。(C 25H 24N 6) 2.9 (HBr), 3.0 (H 2O) analytical value: C, 43.07; H, 4.76; N, 12.05; Br, 33.24.Actual value: C, 43.12; H, 4.65; N, 11.71; Br, 33.39.
Embodiment 85
AMD9844: the preparation of two-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt the alkylating general flow of N-: with 1-N-tert-butoxycarbonyl-2-chloromethyl benzimidazole (115mg, 0.41mmol), N, N-diisopropylethylamine (0.13mL), 0.74mmol) and potassiumiodide (3mg, 0.02mmol) be added to (the 1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7 that is stirring, 8-tetrahydrochysene-quinoline-8-yl)-(7.64g is 28.5mmol) at anhydrous CH for amine 3In the solution among the CN (3mL), in argon gas atmosphere, stirred the gained mixture 4 hours then at 60 ℃.The yellow oil that gained is thick is dissolved in anhydrous CH 2Cl 2(2mL), drip trifluoroacetic acid (1mL) then.Ambient temperature overnight stirs the gained mixture.Use CH 2Cl 2(10mL) dilution gained reaction mixture, vacuum concentration is removed any excessive trifluoroacetic acid then.Use CH 2Cl 2(20mL) dilution gained enriched material is with 1N NaOH (30mL) extracting.Use CH 2Cl 2(2 * 15mL), the dry then organic layer (sodium sulfate) that merges filters vacuum concentration to the washing water layer.Adopt radial chromatography on 2mm TLC level silica gel plate, to carry out purifying (CH 2Cl 2/ MeOH/NH 4OH, 100: 1: 1, then 50: 1: 1), obtain bisbenzimidazole adducts (134mg obtains 49% altogether in two steps), be colorless oil.
Adopt general flow D: (134mg 0.33mmol) changes into hydrobromate, obtains beige solid AMD9844 (192mg) with the free alkali that obtains above. 1H?NMR(D 2O)δ1.87-2.04(br?m，1H)，2.15-2.37(m，2H)，2.41-2.55(br?m，1H)，2.99-3.12(m，2H)，4.46(d，2H，J＝15.6Hz)，4.65(d，2H，J＝15.6Hz)，4.92(dd，1H，J＝10.2，6.3Hz)，7.34-7.44(m，8H)，7.90(dd，1H，J＝8.1，6.0Hz)，8.38(d，1H，J＝7.8Hz)，8.76(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.29，21.27，27.77，48.75，63.05，113.81，126.33，127.28，130.82，140.52，141.10，148.45，148.80，148.92；ES-MSm/z409(M+H)。C 25H 24N 63.0HBr1.8H 2O0.3C 4H 10The analytical value of O: C, 44.58; H, 4.80; N, 11.91; Br, 33.96.Actual value: C, 44.52; H, 4.68; N, 11.91; Br, 33.94.
Embodiment 86
AMD9875:(1H-benzimidazolyl-2 radicals-ylmethyl)-(3H-imidazol-4 yl methyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: (0.055g, 0.57mmol) (0.164g is 0.43mmol) with NaBH (OAc) with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine to make 4 (5)-imidazoles carboxylic aldehyde 3(0.154g is 0.73mmol) at CH 2Cl 2Reaction is 24 hours (4mL), then adopts thick material (2mm flat board, 20: 1: 1 the CH of radial chromatography purifying gained on silica gel 2Cl 2: CH 3OH: NH 4OH), obtain the required tertiary amine of 0.099g (50%), be white solid.
Adopt general flow D: when removing the BOC-blocking group, the white solid that obtains is above changed into hydrobromate, then reprecipitation intermediate solid in methyl alcohol/ether obtains AMD9875 (97mg), is white solid. 1H?NMR(D 2O)δ1.83-1.97(m，1H)，2.15-2.26(m，2H)，2.39-2.46(m，1H)，3.03-3.05(m，2H)，4.05(d，1H，J＝15.0Hz)，4.21(d，1H，J＝15.0Hz)，4.44(d，1H，J＝16.2Hz)，4.59(d，1H，J＝16.2Hz)，4.75(dd，1H，J＝6.0，10.2Hz)，7.35(s，1H)，7.59-7.65(m，2H)，7.73-7.78(m，2H)，7.90(dd，1H，J＝6.6，7.2Hz)，8.38(d，1H，J＝8.1Hz)，8.48(s，1H)，8.72(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.32，20.66，27.72，46.28，48.05，61.54，1?14.16，118.98，126.13，127.27，129.11，130.73，134.90，140.07，140.87，148.31，149.87，150.31；ES-MSm/z359(M+H)。C 21H 22N 63.0 HBr2.6 H 2The analytical value of O: C, 38.92; H, 4.70; N, 12.97; Br, 36.99.Actual value: C, 39.02; H, 4.59; N, 12.72; Br, 37.02.
Embodiment 87
AMD9575:[4-(1H-benzimidazolyl-2 radicals-yl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
4-(preparation of benzimidazolyl-2 radicals-yl)-phenyl aldehyde:
With 2-nitro L-Ala (0.41g, 3.0mmol) and the chloroformyl methyl benzoate of 4-(0.65g, 3.3mmol) solution in THF (3.7mL) and pyridine (0.8mL) was stirring at room 2 hours.Dilute this reactant with saturated sodium bicarbonate (10mL) and EtOAc (15mL), isolate each phase, with EtOAc extracting (2 * 10mL).The dry organic extract (sodium sulfate) that merges filters, and decompression concentrates down, obtains (2-nitrophenyl)-terephthalic acid methyl esters, is yellow solid (0.70g, 78%). 1H?NMR(CDCl 3)δ3.97(s，3H)，7.25(t，1H，J＝7.8Hz)，7.74(t，1H，J＝7.8Hz)，8.04(d，2H，J＝7.8Hz)，8.20(s，1H(NH))，8.20(d，2H，J＝7.8Hz)，8.30(d，1H，J＝7.8Hz)，8.99(d，1H，J＝7.8Hz)。
((0.23g 0.76mmol) in the solution in glacial acetic acid (2.5mL), refluxes then and stirred this mixture 1 hour 2.1mmol) to be added to (2-nitrophenyl)-terephthalic acid methyl esters for＜5 μ m orders, 0.12g with iron powder.Cool off this mixture, stirring at room 2 hours, decompression concentrated down.The gained residue is distributed in saturated sodium bicarbonate (10mL) and ethyl acetate (10mL), isolate each phase, with saturated sodium bicarbonate (10mL) washing organic layer.Dry organic extract (sal epsom) filters, and concentrates, and obtains the 4-(benzimidazolyl-2 radicals-yl)-methyl benzoate (0.163g, 86%) of cyclisation. 1H?NMR(CDCl 3)δ3.96(s，3H)，7.32(m，2H)，7.53(br，1H)，7.84(br，1H)，8.17(m，4H)，9.65(br，1H(NH))。
(5.0mL, 1.0M in THF, (benzimidazolyl-2 radicals-yl)-(0.23g is 0.9mmol) in the solution in 0 ℃ THF (10mL) for methyl benzoate 5.0mmol) to be added to 4-with DIBAL-H solution.Make this reactant be warmed to room temperature, stirred 1 hour, use saturated sodium tartrate potassium solution (20mL) stopped reaction then.This biphase mixture of vigorous stirring 1 hour is isolated each phase, and dry organic layer (sal epsom) filters, and concentrates, and adopts column chromatography to carry out purifying ((7%MeOH/CH on silica gel 2Cl 2), obtain 4-(benzimidazolyl-2 radicals-yl)-benzylalcohol (0.175g, 87%). 1H?NMR(CD 4OD)δ3.30(s，1H(OH))，4.69(s，2H)，7.26(m，2H)，7.53(d，2H，J＝8.4Hz)，7.60(m，2H)，8.07(d，2H，J＝8.1Hz)。
(benzimidazolyl-2 radicals-yl)-(0.175g 0.78mmol) is dissolved in CH to benzylalcohol with the 4-that obtains above 2Cl 2(5mL) and CH 2Cl 2(5mL) and among the THF (8mL), use active MnO 2(0.68g 7.8mmol) handles, then stirring at room 1.5 hours.With diatomite filtration gained mixture, use CH 2Cl 2Washing gained filter disc, decompression are removed the solvent in the elutriant down, obtain 4-(benzimidazolyl-2 radicals-yl)-phenyl aldehyde (92mg, 42%). 1H?NMR(CD 4OD)δ7.28(m，2H)，7.60(br，1H(NH))，7.65(d，2H，J＝7.8Hz)，8.09(d，2H，J＝7.8Hz)，8.30(d，2H，J＝9.0Hz)，10.08(s，1H(CHO))。
Adopt general flow B: with acetate (90 μ L) and triethoxy sodium borohydride (68mg, 0.32mmol) be added to 4-(benzimidazolyl-2 radicals-yl)-phenyl aldehyde (39mg, 0.175mmol) and (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(60mg 0.16mmol) in the solution in THF (2mL), stirred the gained mixture 3 hours at 60 ℃ to amine then.Adopt radial chromatography purifying gained crude product (0.7%MeOH/0.5%NH on silica gel 4OH/CH 2Cl 2), obtain required [4-(1H-benzimidazolyl-2 radicals-yl)-benzyl]-(N-tert.-butoxy benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (30mg, 39%), be the sheet white solid. 1H?NMR(CDCl 3)δ1.72(s，10H)，1.97(m，2H)，2.26(m，1H)，2.73(m，2H)，3.80(d，1H，J＝15.0Hz)，4.00(d，1H，J＝15.0Hz)，4.35(m，1H)，4.71(s，2H)，7.00(m，1H)，7.14(m，2H)，7.24(m，3H)，7.33(d，2H，J＝7.2Hz)，7.47(br，1H)，7.53(d，1H，J＝7.2Hz)，7.63(d，1H，J＝7.8Hz)，7.67(d，2H，J＝7.8Hz)，7.79(br，1H)，8.39(d，1H，J＝3.5Hz)，9.92(br，1H(NH))。
Adopt general flow D: the material (30mg) that obtains is above changed into hydrobromate, obtain white solid AMD9575 (0.026g). 1H?NMR(D 2O)δ1.92(br?m，1H)，2.25(m，2H)，2.47(brm，1H)，3.06(br?m，2H)，3.78(d，1H，J＝12.9Hz)，3.92(d，1H，J＝12.6Hz)，4.44(d，1H，J＝16.5Hz)，4.63(d，1H，J＝15.9Hz)，4.80(m，1H)，7.01(dd，2H，J＝6.0，3.2Hz)，7.37(d，2H，J＝8.1Hz)，7.43(dd，2H，J＝3.2，6.0Hz)，7.54(d，2H，J＝8.1Hz)，7.58(dd，2H，J＝3.0，6.3Hz)，7.74(dd，2H，J＝3.0，6.3Hz)，7.97(t，1H，J＝6.9Hz)，8.44(d，1H，J＝7.8Hz)，8.81(d，1H，J＝5.4Hz)； 13C?NMR(D 2O)δ19.74，20.48，27.23，49.56，55.99，62.95，113.15(2C)，113.40(2C)，120.78(2C)，125.49(2C)，125.62，126.33(2C)，126.41(2C)，129.83，130.79(2C)，139.23(2C)，140.50，141.69，146.89，147.76(2C)，149.95，150.89.ES-MSm/z485(M+H)。C 31H 28N 63.0HBr3.6H 2The analytical value of O: C, 46.90; H, 4.86; N, 10.59; Br, 30.35.Actual value: C, 46.93; H, 4.74; N, 10.41; Br, 30.34.
Embodiment 88
AMD9719:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-pyridine-2-base-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: with NaBH (OAc) 3(192mg is added to 0.906mmol) (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine that (174mg, 0.462mmol) (161mg is 0.879mmol) at CH with 4-pyridine-2-base-benzene carboxylic aldehyde 2Cl 2In the solution (5mL), stirred overnight gained mixture then.Adopt the thick material of radial chromatography purifying gained (2mm TLC flat board, 100: 1: 1CH 2Cl 2/ CH 3OH/NH 4OH), obtain free alkali (0.135g, 66%).
Adopt general flow D: the material (135mg) that obtains is above changed into hydrobromate, obtain AMD9719 (0.154g, 69%). 1H NMR (D 2O) δ 1.86-2.00 (m, 1H), 2.19-2.37 (m, 2H), 2.44-2.54 (m, 1H), and 3.03-3.11 (m, 2H), 3.90 (d, 1H, J=12.7Hz), 3.98 (d, 1H, J=13.2Hz), 4.50 (d, 1H, J=16.4Hz), 4.68 (d, 1H, J=16.6Hz), 7.29 (dd, 2H, J=6.4,3.3Hz), 7.40-7.48 (m, 4H), 7.53 (dd, 2H, J=6.2,3.1Hz), 7.69 (d, 1H, J=8.5Hz), 7.90-7.99 (m, 2H), 8.44 (d, 1H, J=7.9Hz), 8.51 (t, 1H, J=8.0Hz), 8.62 (d, 1H, J=5.6Hz), 8.81 (d, 1H, J=5.3Hz). 13C NMR (D 2O) δ 19.95,20.58, and 27.38,49.79,56.32,63.04,113.36 (2 carbon), 125.41,125.71,125.78,126.21 (2 carbon), 127.29 (2 carbon), 129.66,129.93,130.91 (2 carbon), 139.31,140.63,140.95,146.80 (2 carbon), 147.89 (2 carbon), 150.18,150.59,151.15.ES-MSm/z446 (M+H).C 29H 27N 53.1HBr2.0H 2The analytical value of O: C, 47.56; H, 4.69; N, 9.56; Br, 33.82.Actual value: C, 47.60; H, 4.76; N, 9.44; Br, 33.93.
Embodiment 89
Figure A0181580201461
AMD9750:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of [4-( azoles-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
4-( azoles-2-yl)-benzylalcohol (preparation of (B.A.Anderson et al. J.Org.Chem.1997,62,8634):
With n-Butyl Lithium (the 2.4M solution of 1.83mL in hexane, 4.4mmol) (0.285mL 4mmol) in the solution in-78 ℃ THF (40mL), stirred the gained reactant 30 minutes at-78 ℃ then to be added to the  azoles, add then zinc chloride (the 1M solution of 12mL in THF, 12mmol).Make the gained mixture slowly be warming to 0 ℃ then, stirred 45 minutes.Add methyl-4-bromo-benzoate (0.860g, 4mmol) the solution in THF (10mL), then add two-(triphenylphosphine)-Palladous chloride (II) (140mg, 0.2mmol) and n-Butyl Lithium (the 2.4M solution of 0.17mL in hexane, 0.4mmol) solution in THF (4mL).With the warm backflow of dun mixture of gained, and stirred 1 hour.After the cooling, with ethyl acetate (30mL) dilution gained reaction mixture, then water (1 * 20mL) and salt solution (1 * 20mL) washs.Dry organic layer (sodium sulfate) filters, and concentrates, and adopts chromatography to carry out purifying (98: 2 CH on silica gel 2Cl 2/ MeOH), obtain required methyl-4-( azoles-2-yl)-benzoic ether (340mg, 42%), be yellow oil. 1H?NMR(CDCl 3)δ3.94(s，3H)，7.28(s，1H)，7.76(m，1H)，8.09(m，4H)。
(the 1.0M solution of 4mL in methylene dichloride 4mmol) was added to that methyl-4-( azoles-2-yl)-(0.203g is 1mmol) at CH for benzoic ether with DIBAL-H with 10 minutes 2Cl 2In the solution (10mL).Stir the gained reaction soln at 0 ℃, use saturated sodium tartrate potassium solution (20mL) stopped reaction then, stir the two-phase mixture 60 minutes of gained fast.Isolate each phase, use CH 2Cl 2Extracting gained water layer (3 * 10mL).The dry organic moiety (sodium sulfate) that merges is filtered, and concentrates, and adopts chromatography purifying (CH of 10: 1 on silica gel 2Cl 2: MeOH), obtain the alcohol (0.156g, 89%) of title. 1H?NMR(CDCl 3)δ3.42(t，1H，J＝6.0Hz(OH))，4.77(s，2H，J＝6.0Hz)，7.24(s，1H)，7.47(d，2H，J＝7.8Hz)，7.71(s，1H)，8.05(d，2H，J＝7.8Hz)。
Adopt general flow C: with methylsulfonyl chloride (0.102mL, 1.34mmol) and triethylamine (0.250mL 1.79mmol) is added to that 4-( azoles-2-yl)-(156mg is 0.89mmol) at CH for benzylalcohol 2Cl 2In the solution (10mL), then in stirring at room gained mixture 30 minutes.The mesylate that is obtained is white fine-powder, need not be further purified directly to use in next step reaction. 1H?NMR(CDCl 3)δ3.00(s，3H)，3.67(s，2H)，7.26(s，1H)，7.51(d，2H，J＝8.1Hz)，7.74(s，1H)，8.07(d，2H，J＝8.1Hz)。
Adopt alkylating general flow: with (1-tert-butoxycarbonyl-1 H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (113mg, 0.3mmol) be added to the mesylate (56mg that obtains above, 0.22mmol), salt of wormwood (60mg, 0.44mmol) and KI (2mg is 0.01mmol) at CH 3In the solution among the CN (10mL), stirred the gained mixture 16 hours at 60 ℃ then.Adopt chromatography purifying gained crude product (10: 1 CH on silica gel 2Cl 2/ MeOH), obtain N-alkylate (89mg, 93%). 1H?NMR(CDCl 3)δ1.73(s，9H)，2.03(m，3H)，2.20(m，1H)，2.75(m，2H)，3.81(d，1H，J＝16.1Hz)，4.04(d，1H，J＝16.1Hz)，4.34(dd，1H，J＝9.1，6.2Hz)，4.67(s，2H)，7.03(m，1H)，7.11-7.17(m，2H)，7.26(m，4H)，7.57-7.68(m，5H)，8.44(d，1H，J＝5.1Hz)。
Adopt general flow D: (89mg 0.020mmol) changes into hydrobromate, obtains white solid AMD9750 (14mg) with the amine that obtains above. 1H NMR (D 2O). δ 2.07 (m, 1H), 2.26 (m, 2H), 2.44 (m, 1H), 3.05 (m, 2H), 3.81 (m, 3H), 4.42 (d, 1H, J=16.2Hz), 4.63 (d, 1H, J=16.2Hz), 7.18 (s, 1H), 7.24 (m, 2H), 7.43 (m, 2H), 7.83 (s, 1H), 7.83 (t, 1H, J=7.8Hz), 8.43 (d, 1H, J=8.4Hz), 8.82 (d, 1H, J=5.2Hz). 13C NMR (D 2O) δ 20.42,21.07, and 27.83,50.22,56.69,63.49,113.67 (2C), 125.02,126.14 (2C), 126.23 (2C), 126.69,140.41,130.81 (2C), 139.74,140.35,141.01,148.33,150.69,151.41,156.23,161.09.ES-MSm/z436 (M+H); (C 27H 25N 5O * 2.9 HBr * 2.0 H 2O) analytical value: C, 45.92; H, 4.55; N, 9.92; Br 32.81.Actual value: C, 46.01; H, 4.65; N, 9.55; Br, 32.75.
Embodiment 90
Figure A0181580201481
AMD9755:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-imidazoles-1-base-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt general flow B: (0.075g, 0.44mmol) (0.107g is 0.29mmol) with NaBH (OAc) with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine to make 4-(imidazoles-1-yl) phenyl aldehyde 3(0.171g is 0.81mmol) at CH 2Cl 2Reaction is 24 hours (3mL), then adopts the column chromatography thick material of purifying gained (CH of 25: 1: 1 on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the required tertiary amine of 0.091g (58%), be white solid.
Adopt general flow D: when removing the BOC-blocking group, (91mg) changes into hydrobromate with above-mentioned white solid, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9755 (89 mg). 1H NMR (D 2O) δ 1.86-2.02 (m, 1H), 2.22-2.36 (m, 2H), 2.48-2.52 (m, 1H), and 3.06-3.08 (m, 2H), 3.90 (d, 1H, J=12.6Hz), 3.98 (d, 1H, J=12.6Hz), 4.90 (d, 1H, J=16.5Hz), 4.69 (d, 1H, J=16.5Hz), 4.79-4.87 (m, 1H, overlapping with HOD), 7.22 (d, 2H, J=8.7Hz), 7.31 (dd, 1H, J=1.2,1.5Hz), 7.39-7.46 (m, 4H), 7.54-7.61 (m, 3H), 7.98 (dd, 1H, J=6.0,7.8Hz), 8.45 (d, 1H, J=7.5Hz), 8.67 (s, 1H), 8.82 (d, 1H, J=5.4Hz); 13C NMR (D 2O) δ 21.03,21.67, and 28.46,50.80,57.18,64.09,114.49,121.28,121.87,122.61,126.80,127.32,131.06,132.52,134.10,134.84,139.32,140.40,141.74,148.99,151.26,152.38; ES-MSm/z435 (M+H).C 27H 26N 63.2HBr3.4 H 2The analytical value of O: C, 42.97; H, 4.81; N, 11.14; Br, 33.88.Actual value: C, 43.00; H, 4.61; N, 10.89; Br, 33.93.
Embodiment 91
AMD9757:[4-(thiazol-2-yl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
The preparation of 4-(2-thiazolyl)-phenyl aldehyde:
With tetrakis triphenylphosphine palladium (0) (0.09g; 0.08mmol) and salt of wormwood (0.33g, (0.26g is 1.6mmol) with 4-formyl radical phenyl-boron dihydroxide (0.48g 2.4mmol) to be added to the 2-bromo thiazole; 3.2mmol) in the solution in toluene (16mL), reflux and stirred gained solution 16 hours.This reactant is cooled to room temperature, water (50mL) and ethyl acetate (50mL) dilution.Isolate organic layer, with salt solution (30mL) washing, dry (sal epsom) filters, and concentrates, and adopts column chromatography purifying (2%MeOH/CH on silica gel 2Cl 2), obtain 4-(2-thiazolyl)-phenyl aldehyde (45mg, 15%). 1H?NMR(CDCl 3)δ7.45(d，1H，J＝3.0Hz)，7.90(d，1H，J＝3.0Hz)，7.97(d，2H，J＝7.8Hz)，8.1?5(d，2H，J＝7.2Hz)，1?0.07(s，1H(CHO))。
Adopt general flow B: with NaBH (OAc) 3(77mg, 0.36mmol) be added to 4-(2-thiazolyl)-phenyl aldehyde (45mg, 0.24mmol) and (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(81mg is 0.21mmol) in the solution in methylene dichloride (2.5mL), then in stirring at room gained mixture 16 hours for amine.Adopt radial chromatography at silicon ' the thick material (MeOH/NH of purifying gained on the glue 4OH/CH 2Cl 2, 1: 1: 98), obtain required amine (34mg, 28%), be sheet white solid basis. 1H?NMR(CDCl 3)δ1.73(m，10H)，1.97(m，2H)，2.25(m，1H)，2.75(m，2H)，3.84(d，1H，J＝15.0Hz)，4.03(d，1H，J＝15.0Hz)，4.32(m，1H)，4.68(s，2H)，7.02(m，1H)，7.10(t，1H，J＝7.2Hz)，7.18(t，1H，J＝7.2Hz)，7.27(m，4H)，7.58(d，2H，J＝7.8Hz)，7.60(m，2H)，7.78(d，1?H，J＝3.0Hz)，8.45(d，1H，J＝3.5Hz)。
Adopt general flow D: the solid (34mg) that obtains is above changed into hydrobromate, obtain white solid AMD9757 (34mg). 1H?NMR(D 2O)δ1.86(br?m，1H)，2.23(m，2H)，2.43(brm，1H)，3.03(br?m，2H)，3.70(d，1H，J＝12.6Hz)，3.84(d，1H，J＝12.6Hz)，4.42(d，1H，J＝16.5Hz)，4.62(d，1H，J＝16.5Hz)，4.77(m，1H)，7.21(d，2H，J＝12.6Hz)，7.22(d，2H，J＝8.7Hz)，7.40(d，2H，J＝8.1Hz)，7.45(dd，2H，J＝3.0，6.0Hz)，7.66(d，1H，J＝3.3Hz)，7.83(d，1H，J＝3.6Hz)，7.94(t，1H，J＝6.9Hz)，8.40(d，1H，J＝7.5Hz)，8.78(d，1H，J＝5.1Hz)； 13C?NMR(D 2O)δ20.43，21.07，27.85，50.29，56.73，63.57，113.70(2C)，121.82，126.19，126.58(4C)，130.42，131.10(2C)，139.75(2C)，140.01，140.13(2C)，141.08，148.36(2C)，150.78，151.54.ES-MSm/z452(M+H)。C 27H 25N 5S3.0HBr2.0H 2The analytical value of O: C, 44.21; H, 4.41; N, 9.55; Br, 33.04.Actual value: C, 44.26; H, 4.37; N, 9.29; Br, 33.04.
Embodiment 92
Figure A0181580201501
AMD9595:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of [4-(benzothiazole-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
The preparation of 4-(benzothiazole-2-yl)-benzylalcohol
With 10 minutes with DIBAL-H (the 1.0M solution of 20mL in THF, 20mmol) be added to methyl-4-(benzothiazole-2-yl)-benzoic ether of 0 ℃ (according to A.Brembilla, D.Roizard and P.Lochonsynth.Commun.1990,20,3379 make) (1.08g is in the solution in THF (20mL) 4mmol).Stir gained solution 2 hours at 0 ℃, add the saturated aqueous solution of sodium-potassium tartrate then, stirred this biphase mixture fast 60 minutes.Isolate each phase, with this water layer (3 * 20mL) of ether extracting.The dry organic moiety (sodium sulfate) that merges concentrates, and adopts column chromatography to carry out purifying (10: 1 CH on silica gel 2Cl 2/ MeOH), obtain title compound (0.69g, 75%). 1H?NMR(CD 3OD)δ4.69(s，2H)，7.43(t，1H，J＝7.8Hz)，7.53(m，3H)，7.99(m，1H)，8.06(m，3H)。
Adopt general flow C: with methylsulfonyl chloride (0.092mL, 1.2mmol) and triethylamine (0.210mL 1.5mmol) is added to that 4-(benzothiazole-2-yl)-(227mg is 1.0mmol) at CH for benzylalcohol 2Cl 2In the solution (10mL), then in stirring at room gained mixture 30 minutes.The mesylate that collect to obtain is trickle white powder, can use in next step reaction and need not be further purified. 1H?NMR(CDCl 3)δ3.06(s，3H)，5.28(s，2H)，7.38(t，1H，J＝6.2Hz)，7.49(t，1H，J＝6.2Hz)，7.52(d，2H，J＝7.1Hz)，7.90(d，1H，J＝6.2Hz)，8.05(d，1H，J＝6.2Hz)，8.1?1(d，2H，J＝7.1Hz)。
Adopt alkylating general flow: with mesylate (1mmol), the N that obtains above, the N-diisopropylethylamine (0.093mL, 1.2mmol).(13mg is 0.10mmol) with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(400mg is 1.1mmol) at CH for amine for potassiumiodide 3Solution among the CN (10mL) stirred 3 hours at 70 ℃.Adopt thick material (10: 1 the CH of column chromatography purifying gained on silica gel 2Cl 2/ MeOH), obtain alkylating product (1H-N-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-[4-(benzothiazole-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (354mg, 71%). 1H?NMR(CDCl 3)δ1.63(s，9H)，2.06(m，3H)，2.25(m，1H)，2.75(m，2H)，3.81(d，1H，J＝16.1Hz)，4.02(d，1H，J＝16.1Hz)，4.34(dd，1H，J＝8.3，6.8Hz)，4.65(d，1H，J＝13.2Hz)，4.69(d，1H，J＝13.2Hz)，7.03(m，1H)，7.09-7.11(m，2H)，7.30(m，4H)，7.46(t，1H，J＝8.1Hz)，7.62(t，2H，J＝6.1Hz)，7.69(d，1H，J＝6.1Hz)，7.85(d，1H，J＝6.1Hz)，8.00(d，1H，J＝6.1Hz)，8.44(d，1H，J＝4.8Hz)。
Adopt general flow D: when removing N-tert-butoxycarbonyl blocking group, the material (80mg) that obtains is above changed into hydrobromate, obtain white crystalline solid AMD9595 (14mg). 1H NMR (D 2O). δ 1.85 (m, 1H), 2.18 (m, 2H), 2.41 (m, 1H), 3.08 (m, 2H), 3.48 (m, 1H), 3.54 (dd, 1H, J=14.1,7.2Hz), 3.71 (d, 1H, J=11.7Hz), 4.40 (d, 1H, J=15.9Hz), 4.60 (d, 1H, J=15.9Hz), 7.00 (dd, 1H, J=6.0,3.0Hz), 7.11 (d, 2H, J=7.8Hz), 7.41 (m, 4H), 7.50 (d, J=7.8Hz), 7.55 (t, 1H, J=7.2Hz), 7.89 (d, 1H, J=8.1Hz), 7.97 (m, 2H), 8.43 (d, 1H, J=8.1Hz), 8.79 (d, 1H, J=5.1Hz). 13C NMR (D 2O) δ 20.46,21.08,26.83,51.44,56.69,62.35,113.56 (2C), 121.81,122.57,126.26,126.44,126.94,130.27,130.61,139.73,140.02,148.43,151.69,151.44,158.83.ES-MSm/z501 (M+H); (C 31H 27N 5S * 3 HBr * 3H 2O) analytical value: C, 46.63; H, 4.54; N, 8.77; Br 30.02.Actual value: C, 46.88; H, 4.46; N, 8.66; Br, 29.84.
Embodiment 93
Figure A0181580201521
AMD9615:[4-(benzoxazol-2-yl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
The preparation of 4-(benzoxazol-2-yl)-benzylalcohol:
With the 2-nitrophenols (0.50g, 3.6mmol) and the chloroformyl methyl benzoate of 4-(0.79g, 4.0mmol) solution in THF (4.5mL) and pyridine (0.9mL) was stirring at room 1 hour.With the reactant of saturated sodium bicarbonate (10mL) and EtOAc (15mL) dilution gained, isolate each phase, with EtOAc extracting gained water (2 * 10mL).The dry organic extract (sodium sulfate) that merges filters, and decompression concentrates down, obtains (2-nitrophenyl)-bis--terephthalate, is yellow solid (1.03g, 96%). 1H?NMR(CDCl 3)δ3.98(s，3H)，7.40(d，1H，J＝7.8Hz)，7.47(t，1H，J＝7.8Hz)，7.74(t，1H，J＝7.2Hz)，8.18(d，1H，J＝7.2Hz)，8.19(d，2H，J＝7.8Hz)，8.27(d，2H，J＝7.8Hz)。
((1.02g 3.3mmol) in the solution in Glacial acetic acid (11mL), refluxes then and stirred the gained mixture 1.5 hours 9.0mmol) to be added to (2-nitrophenyl)-bis--terephthalate for＜5 μ m orders, 0.51g with iron powder.Cool off this mixture, stirring at room 2 hours, decompression concentrates down then.The gained residue is distributed in saturated sodium bicarbonate (25mL) and ethyl acetate (25mL), isolate each phase, with saturated sodium bicarbonate (25mL) washing organic layer.Dry organic extract (sal epsom) filters, and concentrates, and adopts column chromatography to carry out purifying (2%MeOH/CH on silica gel 2Cl 2), obtain (2-hydroxy phenyl)-terephthalic acid methyl esters (0.37g, 44%). 1H?NMR(CDCl 3)δ3.98(s，3H)，6.95(t，1H，J＝7.8Hz)，7.07(d，1H，J＝7.8Hz)，7.19(t，1H，J＝7.8Hz)，7.28(d，1H，J＝7.8Hz)，7.98(d，2H，J＝8.4Hz)，8.18(d，2H，J＝7.8Hz)。
With (2-hydroxy phenyl)-terephthalic acid methyl esters (0.35g, 1.3mmol) Tripyrophosphoric acid (～5mL) vlil 3 hours.Gained solution being cooled to 0 ℃, adding entry (100mL) and solid carbonic acid potassium, is 7-9 up to its pH.With ethyl acetate extracting gained residue, dry organic extract (sal epsom), filter, concentrate, obtain 4-(benzoxazol-2-the yl)-methyl benzoate (0.15g, 45%) of cyclisation, be cream-coloured powder. 1H?NMR(CDCl 3)δ3.98(s，3H)，7.40(m，2H)，7.61(m，1H)，7.81(m，1H)，8.20(d，2H，J＝7.8Hz)，8.34(d，2H，J＝7.8Hz)。
((0.20g is 0.8mmol) in the solution in THF (8mL) 4.0mmol) to be added to 4-(benzoxazol-2-yl)-methyl benzoate for 4.0mL, the 1.0M solution in THF with DIBAL-H.Make this reactant be warmed to room temperature, stirred 1 hour, use saturated sodium tartrate potassium solution (15mL) stopped reaction then.The biphase mixture of vigorous stirring gained 1 hour.Isolate each phase, dry organic layer (sal epsom) filters, and concentrates, and obtains the alcohol (0.16g, 89%) of title. 1H?NMR(CDCl 3)δ1.80(t，1H(OH))，4.82(d，2H，J＝6.0Hz)，7.36(m，2H)，7.55(d，2H，J＝8.4Hz)，7.60(m，1H)，7.78(m，1H)，8.26(d，2H，J＝8.4Hz)。
Adopt general flow C: with methylsulfonyl chloride (75 μ L, 1.0mmol) be added to 4-(benzoxazol-2-yl)-benzylalcohol (0.16g, 0.7mmol) and triethylamine (0.15mL is 1.1mmol) in the solution in THF (7mL), then in stirring at room gained mixture 0.5 hour.(10mL) ends this reaction with saturated sodium bicarbonate aqueous solution, uses CH 2Cl 2Extracting water (3 * 10mL).The dry organic extract (sal epsom) that merges filters, and concentrates, and obtains mesylate (0.20g, 93%), is faint yellow crystalline solid. 1H?NMR(CDCl 3)δ3.00(s，3H)，5.33(s，2H)，7.38(m，2H)，7.60(m，3H)，7.78(m，1H)，8.32(d，2H，J＝7.8Hz)。
Adopt alkylating general flow: make the mesylate that obtains above (0.20g, 0.66mmol), N, the N-diisopropylethylamine (0.17mL, 1.0mmol) and potassiumiodide (6mg, 30 μ mol) at CH 3(0.27g is 0.72mmol) 60 ℃ of reactions 4 hours with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine among the CN (7mL).Adopt column chromatography purifying gained crude product (4%MeOH/CH on silica gel 2Cl 2), obtain the alkylating product of N (0.23g, 59%), be the sheet white solid. 1HNMR(CDCl 3)δ1.74(s，10H)，2.01(m，2H)，2.26(m，1H)，2.74(m，2H)，3.87(d，1H，J＝15Hz)，4.08(d，1H，J＝15Hz)，4.35(m，1H)，4.70(s，2H)，7.00-7.20(m，3H)，7.30-7.40(m，5H)，7.55-7.65(m，3H)，7.68(m，1H)，7.87(d，2H，J＝7.8Hz)，8.42(d，1H，J＝3.5Hz)。
Adopt general flow D: the material (90mg) that obtains is above changed into hydrobromate, obtain light brown solid AMD9615 (0.10g). 1H?NMR(D 2O)δ1.86(br?m，1H)，2.08(m，2H)，2.34(br?m，1H)，3.00(br?m，2H)，3.04(d，1H)，3.50(d，1H，J＝12.3Hz)，4.30(d，1H，J＝16.2Hz)，4.52(d，1H，J＝16.2Hz)，4.66(m，1H)，6.91(br?d，2H，J＝7.2Hz)，6.95(d，2H，J＝8.1Hz)，7.30(br?s，2H)，7.32(s，2H)，7.35(d，2H，J＝8.7Hz)，7.49(brm，2H)，7.98(t，1H，J＝6.8Hz)，8.44(d，1H，J＝7.8Hz)，8.76(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ20.32，21.00，27.87，50.20，55.90，63.25，111.25，113.57(2C)，119.04，124.64，125.47，126.12(2C)，126.26(2C)，126.99(2C)，130.29(2C)，139.68(2C)，139.87，140.26，141.00，148.49(2C)，149.88，150.63，151.29，162.00.ES-MSm/z486(M+H)。C 31H 27N 5O2.1HBr0.9H 2The analytical value of O: C, 55.18; H, 4.62; N, 10.38; Br, 25.28.Actual value: C, 55.18; H, 4.65; N, 10.39; Br, 25.28.
Embodiment 94
Figure A0181580201541
AMD9716:[4-(1H-imidazoles-2-yl)-benzyl]-preparation of (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydroquinoline-8-yl)-amine (hydrobromate)
The preparation of [(N-sulfonic acid dimethylformamide base)-imidazoles-2-yl]-benzylalcohol:
N-Butyl Lithium (3.2mL, the 2.42M solution in THF) is added to imidazoles-1-sulfonic acid dimethylformamide, and (1.03g 5.9mmol) in the solution in-78 ℃ THF (5.9mL), stirred gained solution 15 minutes at-78 ℃ then.(0.80g, 5.9mmol)-78 ℃ of solution in THF (4.4mL) are added in this mixture, the gained reactant is warmed to room temperature, and stirred 0.5 hour with zinc chloride.With tetrakis triphenylphosphine palladium (0) (0.27g, 0.2mmol), 4-methyl-bromobenzoate (0.85g, 3.9mmol) (1.6g 11.8mmol) is added in the gained mixture, and reflux gained reactant is 6 hours then for solution in THF (2.6mL) and zinc chloride.With saturated NH 4Cl (50mL) stopped reaction is isolated each layer, and (1 * 30mL), dry (sal epsom) filters, and concentrates, and adopts column chromatography to carry out purifying (2%MeOH/CH on silica gel with salt water washing organic layer 2Cl 2), obtain [(N-sulfonic acid dimethylformamide base)-imidazoles-2-yl]-methyl benzoate (0.56g, 47%), be brown solid. 1H?NMR(CDCl 3)δ2.53(s，6H)，3.95(s，3H)，7.14(s，1H)，7.48(s，1H)，7.79(d，1H，J＝7.8Hz)，8.12(d，1H，J＝7.8Hz)。
DIBAL-H (9.1mL, the 1.0M solution in THF) is added to [(N-sulfonic acid dimethylformamide base)-imidazoles-2-yl]-methyl benzoate, and (0.56g is 1.8mmol) in the solution in-78 ℃ THF (18mL).Make this reactant be warming to room temperature, stirred 1 hour, add saturated sodium-potassium tartrate (25mL) stopped reaction then.The biphase mixture of vigorous stirring gained 1 hour is isolated each phase, and dry organic layer (sal epsom) filters, and concentrates, and obtains methyl [(N-sulfonic acid dimethylformamide base)-imidazoles-2-yl]-benzylalcohol (0.39g, 76%). 1H?NMR(CDCl 3)δ2.49(s，6H)，4.72(s，2H)，7.10(s，1H)，7.36(d，2H，J＝7.2Hz)，7.45(s，1H)，7.61(d，2H，J＝7.2Hz)。
Adopt general flow C: with methylsulfonyl chloride (0.15mL, 1.9mmol) be added to the alcohol that obtains above (0.39g, 1.4mmol) and triethylamine (0.30mL is 2.1mmol) in the solution in THF (14mL), then in stirring at room gained mixture 1 hour.Gained mesylate (0.50g) need not be further purified and can use in next step reaction. 1H?NMR(CDCl 3)δ2.54(s，6H)，3.00(s，3H)，3.68(s，2H)，7.13(s，1H)，7.46(s，1H)，7.48(d，2H，J＝7.8Hz)，7.75(d，2H，J＝7.8Hz)。
Adopt alkylating general flow: make the mesylate that obtains above (0.29g, 0.8mmol), N, the N-diisopropylethylamine (0.21mL, 1.2mmol) and potassiumiodide (10mg, 10 μ mol) at CH 3(0.31g is 0.8mmol) 60 ℃ of reactions 16 hours with (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine among the CN (9mL).Adopt the thick material (6%MeOH/CH of column chromatography purifying gained on silica gel 2Cl 2), obtain required amine (0.25g, 48%), be the sheet white solid. 1H?NMR(CDCl 3)δ1.72(s，10H)，1.93(m，2H)，2.13(m，1H)，2.27(s，6H)，2.74(m，2H)，3.90(d，1H，J＝15Hz)，4.25(d，1H，J＝15Hz)，4.26(m，1H)，4.55(d，1H，J＝15Hz)，4.65(d，1H，J＝15Hz)，7.00(m，2H)，7.26(m，4H)，7.44(m，4H)，7.66(m，1H)，7.75(m，1H)，8.44(d，1H，J＝3.5Hz)。
(0.25g, 0.5mmol) vlil in 2M HCl (4mL) is 16 hours with protected imidazolyl-amine of obtaining above.With the 15%NaOH aqueous solution (20mL) dilution gained mixture, use CH then 2Cl 2(2 * 20mL) extractings.Isolate organic layer, dry (sal epsom) filters, and concentrates, and adopts column chromatography to carry out purifying (5%MeOH/CH on silica gel 2Cl 2), obtain required amine (0.10g, 60%), be white solid. 1H?NMR(CDCl 3)δ1.60(m，1H)，1.85(m，2H)，2.1?3(m，1H)，2.74(m，2H)，3.52(d，1H，J＝13.5Hz)，3.62(d，1H，J＝13.5Hz)，3.88(d，1H，J＝16.5Hz)，4.00(m，1H)，4.06(d，1H，J＝16.5Hz)，7.02(s，2H)，7.15-7.25(m，5H)，7.38(d，1H，J＝7.8Hz)，7.57(m，2H)，7.66(d，2H，J＝8.1Hz)，8.63(d，1H，J＝4.2Hz)。
Adopt general flow D: the solid (100mg) of above-mentioned acquisition is changed into hydrobromate, obtain white solid AMD9716 (0.125 g). 1H?NMR(D 2O)δ1.87(br?m，1H)，2.26(m，2H)，2.47(brm，1H)，3.05(br?m，2H)，3.87(d，1H，J＝12.6Hz)，3.94(d，1H，J＝12.9Hz)，4.45(d，1H，J＝16.2Hz)，4.64(d，1H，J＝16.2Hz)，4.75(m，1H)，7.25(dd，2H，J＝3.0，6.0Hz)，7.37(s，4H)，7.42(s，2H)，7.47(dd，2H，J＝3.0，6.0Hz)，7.95(t，1H，J＝8.4Hz)，8.42(d，1H，J＝8.1Hz)，8.80(d，1H，J＝5.7Hz)； 13C?NMR(D 2O)δ28.72，29.38，36.15，58.51，65.13，71.86，122.09(2C)，128.20(2C)，130.21，134.22(2C)，134.43(3C)，138.98，139.62(2C)，148.16(2C)，149.34(2C)，156.51(2C)，159.04，159.98.ES-MSm/z435(M+H)。C 27H 26N 63.2HBr1.4H 2The analytical value of O: C, 45.61; H, 4.74; N, 11.34; Br, 34.64.Actual value: C, 45.61; H, 4.81; N, 11.37; Br, 34.65.
Embodiment 95
Figure A0181580201561
AMD9841: preparation that will (2 '-amino methyl-xenyl-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
Adopt alkylating general flow: with N, the N-diisopropylethylamine (0.30mL, 1.72mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(0.194g is 0.51mmol) at CH for amine 3In the solution among the CN (5mL), then add 4 '-brooethyl-2-cyanobiphenyl (0.303g, 1.11mmol), with gained mixture heating up to 60 ℃ 25 hours.Adopt the column chromatography thick material of purifying gained (CH of 10: 1: 1 on silica gel 2Cl 2-CH 3OH-NH 4OH), then adopt radial chromatography on silica gel, to carry out purifying (2mm flat board, 100: 1: 1 CH 2Cl 2-CH 3OH-NH 4OH), obtain brown foam (79mg).
(79mg 0.14mmol) is dissolved in the NH that is contained in the Parr hydrogenation bottle with the intermediate that obtains above 3In the saturated methyl alcohol (3mL).Clean Raney nickel (50mg) (3 times) with MeOH, it is added in the hydrogenation bottle that contains nitrile then, under the pressure of 50psi, make this mixture hydrogenation 24 hours.Use Celite Filter the gained mixture, use the methanol wash filter disc.Decompression is concentrate eluant down.Adopt thick material (1mm flat board, 50: 1: 1 CH of radial chromatography purifying gained on silica gel 2Cl 2-CH 3OH-NH 4OH), obtain the free alkali of the title compound of 36mg (54%), be white foam.
Adopt general flow D: (36mg) changes into hydrobromate with above-mentioned white foam, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9841 (35mg). 1H NMR (D 2O) δ 1.87-2.00 (m, 1H), 2.22-2.39 (m, 2H), 2.45-2.51 (m, 1H), and 3.06-3.09 (m, 2H), 3.84-3.96 (m, 4H), 4.53 (d, 1H, J=16.5Hz), 4.70 (d, 1H, J=16.5Hz), 4.78-4.85 (m, 1H, overlapping with HOD), 6.26 (d, 1H, J=7.2Hz), 6.96 (d, 2H, J=7.8Hz), 7.3 1 (d, 2H, J=7.8Hz), 7.34-7.43 (m, 3H), 7.51-7.55 (m, 2H), 7.60-7.64 (m, 2H), 7.96 (dd, 1H, J=6.0,8.1Hz), 8.44 (d, 1H, J=7.8Hz), 8.79 (d, 1H, J=5.4Hz); 13C NMR (D 2O) δ 20.50,21.00, and 27.90,40.58,50.45,56.75,63.43,113.93,126.12,126.78,128.91,128.99,129.14,129.36,130.05,130.55,130.57,131.06,135.97,139.48,139.71,141.05,141.20,148.30,150.94,152.15; ES-MSm/z474 (M+H)..C 31H 31N 53.0HBr2.2 H 2The analytical value of O: C, 49.25; H, 5.12; N, 9.26; Br, 31.71.Actual value: C, 49.31; H, 5.21; N, 9.13; Br, 31.62.
Embodiment 96
Figure A0181580201571
AMD9785:(1H-benzimidazolyl-2 radicals-ylmethyl)-(2 '-methoxyl group-xenyl-4-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
2 '-preparation of methoxyl group-xenyl-4-carboxylic aldehyde:
Sodium carbonate solution (1.6mL) and Pd (PPh with 2M 3) 4(63mg, (218mg, 1.18mmol) (188mg is 1.24mmol) in the liquid solution that degass among the DME/THF (5mL, 4: 1) (degassed solution) with the 2-methoxyphenylboronic acid 0.055mmol) to be added to the 4-bromobenzaldehyde that is stirring.Brush this reaction mixture with argon gas, and this mixture is maintained under the argon gas, simultaneously 85 ℃ of heating of spending the night.Cool off this mixture then, with EtOAc (25mL) and water (25mL) dilution.(2 * 10mL), the dry organic extract (sodium sulfate) that merges filters, and concentrates with EtOAc washing gained water layer.Adopt the oily matter (hexane/Et of column chromatography purifying gained on silica gel 2O, 80: 20), obtain title compound (230mg, 92%), be purified oily matter. 1H?NMR(CDCl 3)δ3.84(s，3H)，7.01-7.09(m，2H)，7.33-7.39(m，2H)，7.71(d，2H，J＝6Hz)，7.93(d，2H，J＝6Hz)，10.05(s，1H)。
Adopt general flow B: with NaBH (OAc) 3(83mg, 0.39mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine of stirring (95mg, 0.25mmol) and 2 '-(55mg is 0.26mmol) at CH for methoxyl group-xenyl-4-carboxylic aldehyde 2Cl 2In the solution (5mL), stir the gained mixture in ambient temperature overnight then.Adopt the radial chromatography thick material of purifying gained (1mm flat board, CH of 50: 1: 1 on silica gel 2Cl 2-MeOH-NH 4OH), obtain required amine (75mg, 52%), be purified oily matter.
Adopt general flow D: when removing N-tert-butoxycarbonyl blocking group; (34mg 0.059mmol) changes into hydrobromate, then reprecipitation intermediate solid in methyl alcohol/ether with the oily matter that obtains above; obtain white solid AMD9785 (25mg, 63%). 1H NMR (D 2O) δ 1.89-1.94 (m, 1H), 2.20-2.27 (m, 2H), 2.31-2.44 (m, 1H), 3.03-3.05 (m, 2H), 3.68 (s, 3H), 3.76 (d, 1H, J=12.3Hz), 3.84 (d, 1H, J=12.3Hz), 4.47 (d, 1H, J=16.5Hz), 4.63 (d, 1H, J=16.5Hz), 4.74-4.89 (m, 1H, overlapping with HOD), 6.36 (d, 1H, J=7.5Hz), 6.96 (t, 1H, J=7.5Hz), and 7.02-7.05 (m, 3H), 7.19 (d, 2H, J=7.8Hz), 7.33 (dd, 1H, J=8.1,7.8Hz), 7.44 (dd, 2H, J=6,3Hz), 7.56 (dd, 2H, J=6,3Hz), 7.93 (dd, 1H, J=7.2,6.6Hz), 8.40 (d, 1H, J=7.8Hz), 8.76 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 19.71,20.15, and 27.08,49.63,55.13,55.91,62.54,11 1.67,113.02,120.58,125.29,125.91,128.68,129.09,129.32,129.76,130.34,134.47,137.26,138.86,140.17,147.45,150.22,151.23,155.17.ES-MSm/z475 (M+H).C 31H 30N 4O2.1HBr1.3H 2The analytical value of O: C, 55.74; H, 5.24; N, 8.39; Br, 25.12.Actual value: C, 55.67; H, 5.26; N, 8.27; Br.25.30.
Embodiment 97
AMD9791:(1H-benzimidazolyl-2 radicals-ylmethyl)-(4- azoles-5-base-benzyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
The preparation of 4-( azoles-5-yl)-phenyl aldehyde:
With active MnO 2(1.01g, 11.6mmol) be added to 4-( azoles-5-yl) benzylalcohol that stirring (according to Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H.J.Med.Chem.1998,41,2390-2410 makes) (0.23g is 1.31mmol) at CH 2CL 2/ MeOH (20: 1,10.5mL) in the solution in, in stirring at room gained mixture overnight.Use CH then 2Cl 2(10mL) dilute this reactant, use Celite then Filter, use CHCl 3Washing.Concentrate gained filtrate, obtain thick aldehyde, be beige solid (0.164g), in next step reaction, need not be further purified and to use this aldehyde. 1H?NMR(CDCl 3)δ7.52(s，1H)，7.82(d，2H，J＝9Hz)，7.95(d，2H，J＝9Hz)，7.99(s，1H)，10.02(s，1H)。
Adopt general flow B: with NaBH (OAc) 3(107mg, 0.50mmol) be added to (1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine of stirring (1 33mg, 0.35mmol) and 4-( azoles-5-yl) phenyl aldehyde (80mg is 0.45mmol) at CH 2Cl 2In the solution (10mL), ambient temperature overnight stirs the gained mixture then.The thick oily matter of gained is dissolved in CH 2Cl 2/ TFA (1: 1,2mL) in, stirred the gained mixture 2 hours.Concentrate this reactant then, use CH 2Cl 2(30mL) with 1N NaOH (30mL) dilution.Use CH 2Cl 2(2 * 10mL), the dry organic extract (sodium sulfate) that merges filters the washing water layer, concentrates.Adopt thick foam (2mm flat board, 50: 1: 1 the CH of radial chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH), obtain unhindered amina (50mg is 33% altogether) in 2 steps, be yellow foam.
Adopt general flow D: (50mg 0.11mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains yellow solid AMD9791 (70mg, 87%) with the foam that obtains above. 1H NMR (D 2O) δ 1.86-1.90 (m, 1H), 2.16-2.27 (m, 2H), 2.38-2.43 (m, 1H), and 2.99-3.02 (m, 2H), 3.60 (d, 1H, J=12.3Hz), 3.76 (d, 1H, J=12.3Hz), 4.38 (d, 1H, J=16.5Hz), 4.57 (d, 1H, J=16.5Hz), 4.72-4.79 (m, 1H, overlapping with HOD), 7.12-7.19 (m, 5H), 7.23 (dd, 2H, J=6,3Hz), 7.43 (dd, 2H, J=6,3Hz), 7.92 (dd, 1H, J=7.8,5.7Hz), 8.16 (s, 1H), 8.37 (d, 1H, J=7.2Hz), 8.76 (d, 1H, J=5.7Hz); 13C NMR (D 2O) δ 20.43,21.01, and 27.83,50.22,56.66,63.41,113.62,120.71,124.26,126.12,126.36,126.78,130.44,130.76,137.01,139.68,140.96,148.27,150.79,151.60,152.13.ES-MSm/z436 (M+H).C 27H 25N 5O2.8HBr1.9H 2The analytical value of O: C, 46.57; H, 4.57; N, 10.6; Br, 32.13.Actual value: C, 46.56; H, 4.61; N, 9.73; Br, 32.14.
Embodiment 98
Figure A0181580201601
AMD9792:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of (5,6,7,8-tetrahydrochysene-quinoline-8-yl)-(4-thiophene-2-base-benzyl)-amine (hydrobromate)
The preparation of 4-thiophene-2-benzaldehyde:
With 2M Na 2CO 3Solution (3.0mL) and Pd (PPh 3) 4(110mg, 0.095mmol) be added to the 4-bromobenzaldehyde that stirring (371mg, 2.00mmol) and thiophene-2-boric acid (287mg is 2.24mmol) in the no gas solution of DME/THF (5mL, 4: 1).Brush this reaction mixture with argon gas, and it is maintained under the argon gas, simultaneously 85 ℃ of heating 2 days.Then with this mixture cooling, with EtOAc (35mL) and water (30mL) dilution.(2 * 10mL), the dry organic extract (sodium sulfate) that merges filters, and concentrates to wash water layer with EtOAc.Adopt the oily matter (hexane/EtOAc, 4: 1) of column chromatography purifying gained on silica gel, obtain title compound (293mg, 78%), be yellow solid. 1H?NMR(CDCl 3)δ7.14(dd，1H，J＝5.1，3.6Hz)，7.40(dd，1H，J＝5.1，0.9Hz)，7.46(dd，1H，J＝3.6，0.9Hz)，7.76(d，2H，J＝8.4Hz)，7.88(d，2H，J＝8.4Hz)，10.00(s，1H)。
Adopt general flow B: with NaBH (OAc) 3(160mg, (144mg, 0.52mmol) (100mg is 0.53mmol) at CH with 4-thiophene-2-base-phenyl aldehyde 0.75mmol) to be added to (1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-the yl)-amine that is stirring 2Cl 2In the solution (5mL), stir the gained mixture in ambient temperature overnight then.Adopt thick material (2mm flat board, 50: 1: 1CH of radial chromatography purifying gained on silica gel 2Cl 2/ MeOH/NH 4OH), obtain required amine (133mg, 57%), be yellow foam.
Adopt general flow D: (115mg 0.26mmol) changes into hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains yellow solid AMD9792 (134mg, 82%) with the foam that obtains above. 1H?NMR(D 2O)δ1.73-1.77(m，1H)，2.00-2.11(m，2H)，2.24-2.28(m，1H)，2.84-2.88(m，2H)，3.12(d，1H，J＝12.3Hz)，3.45(d，1H，J＝12.3Hz)，4.20(d，1H，J＝16.5Hz)，4.37(d，1H，J＝16.5Hz)，4.46(dd，1H，J＝10.2，6Hz)，6.85(d，2H，J＝8.1Hz)，6.90-6.97(m，4H)，7.17(dd，2H，J＝6，3Hz)，7.26(d，1H，J＝5.1Hz)，7.37(dd，2H，J＝6，3Hz)，7.84(dd，1H，J＝7.8，5.7Hz)，8.25(d，1H，J＝7.8Hz)，8.66(d，1H，J＝4.7Hz)； 13C?NMR(D 2O)δ20.39，20.85，27.77，50.08，56.18，63.03，113.58，124.19，125.34，126.05，126.12，126.63，128.72，130.36，130.67，133.71，135.22，139.52，140.76，142.84，148.28，150.66，151.42. ES-MSm/z451(M+H)。C 28H 26N 4S2.0HBr0.9H 2The analytical value of O: C, 53.50; H, 4.78; N, 8.91; Br, 25.42.Actual value: C, 53.65; H, 4.98; N, 8.66; Br, 25.32.
Embodiment 99
AMD9778:(1H-benzimidazolyl-2 radicals-ylmethyl)-preparation of [4-(2-methyl-2H-tetrazolium-5-yl)-benzyl]-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine (hydrobromate)
With 4-(2-methyl-2H-tetrazolium-5-yl) phenyl aldehyde (according to Bold, G.; Fassler, A.; Capraro, H.-G.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rosel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hurlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang, M.J.Med.Chem.1998,41,3387-3401 is described to be made) (220mg, 1.17mmol) be added to the 8-amino-5,6 that is stirring, 7, the 8-tetrahydroquinoline (170mg, 1.15mmol) in the solution in anhydrous MeOH (10mL), this solution of stirring at room 1.5 hours.After during this period of time, be initially yellow-orange suspension and become dark orange uniform solution.This mixture of vacuum concentration adopts 1H NMR analyzes, and it is dissolved among the MeOH (10mL) again.With NaBH 4(85mg 2.25mmol) is added in this solution, stirs the gained mixture 1 hour.This reactant of vacuum concentration is used CH 2Cl 2(40mL), use CH with saturated sodium bicarbonate aqueous solution (40mL) dilution 2Cl 2(2 * 10mL) washing waters are used Na 2SO 4The dry organic extract that merges filters, and concentrates, and obtains orange-brown oil (422mg), and this product does not need purifying to use in next step reaction.
Adopt alkylating general flow: with N, N-diisopropylethylamine (0.23mL, 1.32mmol), KI (24mg, 0.14mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl) benzoglyoxaline (165mg, 0.62mmol) (205mg is 0.64mmol) at CH to be added to the secondary amine that obtains above that is stirring 3In the solution among the CN (5mL).Stirred the gained mixture 3 hours at 60 ℃.Adopt column chromatography purifying gained brown oil (CH on silica gel 2Cl 2/ MeOH, 98: 2,96: 4 then), then adopt radial chromatography on silica gel, to carry out purifying (1mm flat board, CH 2Cl 2/ MeOH, 98: 2) obtain required alkylating amine (44mg is 43% altogether) in 2 steps, be the brown foam.
Adopt general flow D: when removing N-tert-butoxycarbonyl blocking group; (44mg 0.08mmol) changes into hydrobromate, then reprecipitation intermediate solid in methyl alcohol/ether with the foam that obtains above; obtain light brown solid AMD9778 (45mg, 87%). 1H NMR (D 2O) δ 1.89-1.94 (m, 1H), 2.19-2.27 (m, 2H), 2.43-2.47 (m, 1H), and 3.03-3.05 (m, 2H), 3.72 (d, 1H, J=12.6Hz), 3.84 (d, 1H, J=12.6Hz), 4.35 (s, 2H), 4.43 (d, 1H, J=16.5Hz), 4.61 (d, 1H, J=16.5Hz), 4.79-4.89 (m, 1H, overlapping with HOD), 7.15 (dd, 2H, J=6,3Hz), 7.24 (d, 2H, J=8.1Hz), 7.41 (dd, 2H, J=6,3Hz), 7.46 (d, 2H, J=8.1Hz), 7.95 (dd, 1H, J=7.5,6.3Hz), 8.41 (d, 1H, J=8.1Hz), 8.79 (d, 1H, J=5.1Hz); 13C NMR (D 2O) δ 20.45,21.07, and 27.86,40.01,50.30,56.78,63.54,113.67,125.64,126.18,126.32,126.42,130.42,130.91,139.31,139.75,141.04,148.33,150.77,151.62,163.70.ES-MSm/z451 (M+H).C 26H 26N 82.1HBr1.5H 2The analytical value of O: C, 48.23; H, 4.84; N, 17.31; Br, 25.92.Actual value: C, 48.49; H, 4.72; N, 17.05; Br, 25.63.
Embodiment 100
Figure A0181580201631
The preparation of AMD9715:(1H-benzimidazolyl-2 radicals-ylmethyl-[4-(5-phenyl  azoles-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine
The preparation of methyl-N-(2-oxygen base-2-styroyl)-terephthalate:
With 10 minutes with methyl-4-chloroformyl-benzoic ether (594mg, 3.0mmol) be added drop-wise to 2-amino ethoxy benzene ketone (516mg, 3.0mmol) and triethylamine (0.84mL is 6mmol) at 0 ℃ CH 2Cl 2In the solution (20mL).Make this solution be warmed to room temperature then, and stirred 90 minutes.With saturated NH 4The Cl aqueous solution (20mL) washs this solution, uses CH 2Cl 2Extracting gained water layer (2 * 20mL).The dry organic extract (sodium sulfate) that merges filters, and vacuum concentration obtains required methyl-N-(2-oxygen base-2-styroyl)-terephthalate, is light yellow crystal (835mg, 94%). 1H?NMR(CDCl 3)δ3.94(s，3H)，4.97(d，2H，J＝5.4Hz)，7.35(br?s，1H)，7.50(m，2H)，7.53(m，1H)，7.92(d，2H，J＝6.6Hz)，8.04(d，2H，J＝6.6Hz)，8.11(d，2H，J＝6.9Hz)。
The preparation of methyl-4-(5-phenyl  azoles-2-yl)-benzoic ether (as .Wipf, P., Miller, C.P.J.Org.Chem.1993,58,3604 is described):
With iodine (480mg, 1.9mmol) be added to triphenylphosphine (524mg, 2.0mmol) and triethylamine (0.56mL is 4.0mmol) at CH 2Cl 2In the solution (10mL), stirred the gained mixture then 15 minutes.With methyl-N-(2-oxygen base-2-styroyl)-(297mg is 1.0mmol) at CH for terephthalate 2Cl 2Solution (5mL) adds, and stirs the gained mixture in ambient temperature overnight then.With 5% sodium thiosulfate solution (1 * 15mL) and saturated sodium bicarbonate (1 * 15mL) washing gained organic phase is dried (sodium sulfate) then, filters vacuum concentration.(1: 1 hexane/EtOAc), obtain required product, promptly methyl-4-(5-phenyl  azoles-2-yl)-benzoic ether is yellow oil (69mg, 24%) the oily residue of employing column chromatography concentrated gained on silica gel. 1H?NMR(CDCl 3)δ3.86(s，3H)，7.20(m，1H)，7.23(t，1H，J＝6.3Hz)，7.41(s，1H)，7.64(m，2H)，8.04(m，4H).ES-MSm/z280(M+H)。
(1mL is at CH with DIBAL-H 2Cl 2In 1.0M solution, (56mg is 0.19mmol) at-78 ℃ CH 1.0mmol) to be added to methyl-4-(5-phenyl  azoles-2-yl)-benzoic ether 2Cl 2In the solution (8mL), stirred gained solution 90 minutes at-78 ℃ then.Saturated sodium tartrate aqueous solutions of potassium (5mL) is added in this reactant, makes the gained mixture be warmed to room temperature.The biphase mixture of stirring gained is 60 minutes fast, isolates each layer, uses CH 2Cl 2Extracting water layer (2 * 10mL).The dry organic moiety (sodium sulfate) that merges is filtered, and concentrates in the vacuum, obtains required alcohol, and promptly 2-(4-hydroxymethyl phenyl)-5-phenyl  azoles is faint yellow oily thing (46mg, 96%). 1H?NMR(CDCl 3)δ3.41(t，1H(OH)，J＝7.0Hz)，4.77(d，2H，J＝7.0Hz)，7.33(m，1H)，7.45(m，5H)，7.72(d，2H，J＝6.4Hz)，8.08(d，2H，J＝8.1Hz)。
Adopt general flow C: with methylsulfonyl chloride (0.05mL, 0.65mmol) be added to the alcohol that obtains above (123mg, 0.5mmol) and triethylamine (0.105mL is 0.75mmol) at CH 2Cl 2In the solution (8mL), then in the mixture of stirring at room gained 10 minutes.Obtain required thick 2-(4-(methylsulfonic acid ylmethyl phenyl))-5-phenyl  azoles, be faint yellow oily thing, this oily matter need not be further purified and directly use in next step reaction.
Adopt alkylating general flow: with N, N-diisopropylethylamine (0.145mL, 0.8mmol) and potassiumiodide (8mg, 0.05mmol) be added to the mesylate (0.5mmol) and (the 1-tert-butoxycarbonyl-1H-benzimidazolyl-2 radicals-ylmethyl)-(5 that obtain above, 6,7,8-tetrahydrochysene-quinoline-8-yl)-(264mg is 0.7mmol) at CH for amine 3In the solution among the CN (8mL), then gained mixture heating up to 60 ℃ is spent the night.Adopt the thick residue (CH of column chromatography purifying gained on silica gel 2Cl 2/ MeOH, 95: 5), obtain required tertiary amine (1H-1-tert-butoxycarbonyl-benzimidazolyl-2 radicals-ylmethyl)-[4-(5-phenyl  azoles-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinoline-8-yl)-amine, be weak yellow foam (209mg, 68%). 1H?NMR(CDCl 3)δ1.63(s，9H)，2.01(m，2H)，2.26(m，1H)，2.69-2.82(m，3H)，3.83(d，1H，J＝16.1Hz)，4.05(d，1H，J＝16.1Hz)，4.32(m，1H)，4.69(s，2H)，7.12(m，1H)，7.15-7.20(m，3H)，7.33-7.46(m，6H)，7.58-7.73(m，6H)，8.44(d，1H，J＝4.9Hz).ES-MS?m/z?612(M+H)。
Adopt general flow D: (31mg 0.05mmol) transforms hydrobromate, and then reprecipitation intermediate solid in methyl alcohol/ether obtains white solid AMD9715 (28mg) with the foam that obtains above. 1H?NMR(D 2O)δ1.93(m，1H)，2.07(m，2H)，2.40(m，1H)，3.05(m，2H)，3.37(m，1H)，3.56(m，1H)，4.35(d，1H，J＝16.5Hz)，4.58(d，1H，J＝16.5Hz)，4.77(m，1H)，7.04(m，4H)，7.30-7.37(m，6H)，7.49(t，2H，J＝7.2Hz)，7.64(m，2H)，7.92(dd，1H，J＝7.8，5.4Hz)，8.44(d，1H，J＝7.8Hz)，8.77(d，1H，J＝5.4Hz)； 13C?NMR(D 2O)δ21.93，22.13，29.24，50.89，57.87，63.37，115.13(2C)，124.32，125.65(2C)，127.33，127.43(2C)，127.83(2C)，128.11，130.40，130.60(2C)，132.33(2C)，133.04，140.22，141.84，144.99，147.24，149.33，153.14，154.87.ES-MSm/z512(M+H)。C 33H 29N 5O2.8HBr2H 2The analytical value of O: C, 51.20; H, 4.66; N, 9.05; Br, 28.90.Actual value: C, 51.16; H, 4.59; N, 8.87; Br, 28.76.
Embodiment 101
The inhibition of the chemokine inductive Ca stream that on FLIPR (molecular device), records
Reagent:
The application of sample dyestuff: with Fluo-3, AM (molecular probe F-1241) is dissolved among the anhydrous DMSO, is divided into the freezing storage of equal portions.In order to improve the solubleness of dyestuff in the application of sample medium, face and use preceding the storage in the solution to add the compound acid of 10% (w/v) (pluronic acid) (Molecular Probes F-127) at once at Fluo-3.
Damping fluid flows:
HBSS+20mM Hepes damping fluid+0.2%BSA, pH7.4.Phenol red and the sodium bicarbonate (Gibco 14 065-049) of HBSS 10x[(w/o]; Hepes damping fluid 1M (Gibco15 630-056), BSA (SigmaA3675).The damping fluid that flows is somebody's turn to do in vacuum filtration, refrigerates maximum 5 days.Before in experiment, using, in water-bath that damping fluid is warm at 37 ℃.
Antagonist:
With mobile damping fluid dilution test compounds, and be added in 4 holes of black microtiter plate (every kind compound horizontal survey 4 times).Used following control wells: 100% response contrast (unrestraint) adds the damping fluid that flows; 100% suppresses contrast: extraordinarily go into chemokine to induce 5 of the required concentration of Ca stream.
The preparation of agonist (chemokine) plate
With mobile damping fluid chemokine is diluted to the high 4 times concentration of the concentration more required than irritation cell (promptly for SDF-1 α, 2.5nM).In Sero hole, untreated 96-hole compound flat board (International Medical, Sterilincode 611F96), add chemokine.In negative control hole (baseline monitoring), add flow damping fluid rather than chemokine.Positive control as checking dyestuff load efficient has also added 20 μ M digitonins (ultimate density).In FLIPR (37 ℃), cultivated agonist dull and stereotyped 15-30 minute.
Be used for measuring the cell load scheme that SUP-T1 cell SDF-1 α inductive Ca stream suppresses
At the following centrifugal SUP-T1 cell of room temperature (RT), be suspended in again the load nutrient solution (RPMI-1640 contains 2%FBS and 4 μ M Fluo-3, AM) in.Room temperature was cultivated cell 45 minutes, with the damping fluid washing 2 times of flowing, cultivated 10 minutes under the room temperature in the damping fluid that flows then then.Eccentric cell is with 3 * 10 6The density of cells/ml is suspended in the damping fluid that flows again.The cell suspension (3 * 10 that in each black microtiter plate (Costar 3603) hole, adds 100 microlitre equal portions 5Cell), the solution (concentration is 3 times of required final compound concentration) of 50 microlitre test compounds has been contained in each hole.Slow centrifugal microtiter plate under the room temperature then.Confirm the cell uniform spreading in the bottom of micro titer plate well with microscope, test is preceding cultivated microtiter plate 10 minutes in FLIPR (37 ℃).
On FLIPR as the fluorescence measurement value of the function of time
Regulate FLIPR set(ting)value (camera exposure time and laser power), obtain 8 000-10, the initial fluorescent value between 000 unit.After monitoring 20 seconds baselines,, add agonist (chemokine) (50 microlitre) by having the automatization transfer pipet of black dropper head.Microtiter plate porose in every 2 seconds (beginning 2 minutes), measure fluorescence simultaneously every 6 seconds (2 minutes in addition) then.With the average Ca stream in every group of 4 same holes of FLIPR computed in software (1 specimen).
Adopt aforesaid method, record compound of the present invention under the fixed concentration that is suppressed at 5 μ g/mL of SDF-1 α inductive Ca-stream in the SUP-T1 cell between 0-100%.
Embodiment 102
In the MT-4 cell, suppress the test that HIV-1 (NL4.3) duplicates
(people such as Bridger, J.Med.Chem.1999,42,3971-3981 as previously mentioned; People such as De Clercq, Proc.Natl.Acad.Sci.1992,89,5286-5290; People such as De Clercq, Antimicrob.AgentsChemother.1994,38,668-674; People such as Bridger, J.Med.Chem.1995,38,366-378) carry out the inhibition test that HIV-1 NL4.3 (or IIIB) duplicates.Parallel HIV (human immunodeficiency virus)-resistant activity and the cytotoxicity of carrying out measured.They are based in the presence of the test compounds of different concns, the survival rate of the MT-4 cell of infected by HIV.After the MT-4 cell proliferation 5 days, use colour developing bromination 3-(4,5-dimethylthiazole-2-yl)-2, the quantity of 5-phenylbenzene tetrazolium bromination  (MTT) method quantitative assay survivaling cell in the microtiter plate of 96-hole based on tetrazolium ().In all these tests, (the virus infection plural number is 0.01 MO1), or 50% cell cultures infective dose (CCID in the virus input 50) 100 times.EC 50The cell that is defined as protection 50% virus infection is not subjected to virus to make the cell required concentration of causing a disease.
The test compound of the present invention to the MT-4 cell in HIV-1 NL4.3 or III BDuring the inhibition situation of duplicating, found that their inhibition EC 50Be 0.002-20.0 μ g/ml.
Also to have prepared the following compound of formula 1 with aforementioned similar mode:
(4-amino methyl-pyridin-3-yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(3-amino methyl-pyridin-4-yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
1-(3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-ethane ketone (ethanone)
1-(5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-ethane ketone
3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzene sulfanilamide (SN)
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzene sulfanilamide (SN)
N-(3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-hydroxyl 1 amine
N-(5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-hydroxyl 1 amine
N-(3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-O-methyl-hydroxyl 1 amine
N-(5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-O-methyl-hydroxyl 1 amine
(4-amino methyl-2-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
N-(2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-methane amide
N-(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-methane amide
N-(2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-hydroxyl 1 amine
(1H-benzimidazolyl-2 radicals-ylmethyl)-(2,6-bis-amino methyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(3-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-methyl alcohol
(2-amino methyl-6-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
N-(3-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-hydroxyl 1 amine
N-(3-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-O-methyl-hydroxyl 1 amine
[2-amino methyl-4-(1H-imidazoles-2-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(1-methyl isophthalic acid H-imidazoles-2-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(2H-pyrazole-3-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(1-methyl isophthalic acid H-pyrazole-3-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(1H-[1,2,4] triazole-3-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(1-methyl isophthalic acid H-[1,2,4] triazole-3-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-azoles-2-base-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-furans-2-base-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(tetrahydrochysene-furans-2-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-thiazol-2-yl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(1H-tetrazolium-5-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
[2-amino methyl-4-(2-methyl-2H-tetrazolium-5-yl)-benzyl]-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-pyridine-2-base-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-piperidines-2-base-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-3-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-methyl alcohol
(2-amino methyl-5-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-5-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-pyridine-2-yl)-methyl alcohol
(4-amino methyl-6-methoxymethyl-pyridin-3-yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(1H-benzimidazolyl-2 radicals-ylmethyl)-(4,6-bis-amino methyl-pyridin-3-yl methyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-allyl amino methyl-2-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-allyl amino methyl-4-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-cyclopropyl amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-2-cyclopropyl amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-5-chloro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-5-bromo-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-5-nitro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
4-amino methyl-3-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzonitrile
(5-amino-2-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-5-trifluoromethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-fluoro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-chloro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-bromo-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-nitro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzonitrile
(4-amino-2-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-trifluoromethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-2-fluoro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-2-chloro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-2-bromo-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-2-nitro-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzonitrile
(2-amino-4-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-2-trifluoromethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-amino methyl-thiophene-2-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-thiene-3-yl-methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-amino methyl-furans-3-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-aminomethyl-1,2 H-pyrroles-3-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-aminomethyl-1,2-methyl isophthalic acid H-pyrroles-3-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-aminomethyl-1,2 H-pyrazole-3-yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-aminomethyl-1,2-methyl isophthalic acid H-pyrazole-3-yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(3-aminomethyl-1,2 H-pyrazoles-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(3-aminomethyl-1,2-methyl isophthalic acid H-pyrazoles-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-amino methyl-3H-imidazol-4 yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-aminomethyl-1,2-methyl isophthalic acid H-imidazol-4 yl methyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-amino methyl-thiazole-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-amino methyl-pyrimidine-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-amino methyl-pyridazine-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(5-allyl amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-methyl alcohol
(3-allyl amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenyl)-methyl alcohol
(4-allyl amino methyl-2-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(3-allyl amino methyl-4-methoxymethyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-5-cyclopropyl amino methyl-phenyl)-methyl alcohol
(4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-3-cyclopropyl amino methyl-phenyl)-methyl alcohol
(1H-benzimidazolyl-2 radicals-ylmethyl)-(4-cyclopropyl amino methyl-2-methoxymethyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(1H-benzimidazolyl-2 radicals-ylmethyl)-(2-cyclopropyl amino methyl-4-methoxymethyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzamide
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-N-hydroxyl-benzamide
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-the phenylformic acid hydrazides
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-phenylformic acid
(1H-benzimidazolyl-2 radicals-ylmethyl)-(2,4-bis-allyl amino methyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-allyl amino methyl-2-cyclopropyl amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-allyl amino methyl-4-cyclopropyl amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(1H-benzimidazolyl-2 radicals-ylmethyl)-(2,4-bis-cyclopropyl amino methyl-benzyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(2-amino methyl-4-propyl group-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-allyl group-2-amino methyl-benzyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
Acetate 3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl ester
Acetate 5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl ester
Acetate 4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-the interior basic amino methyl-benzyl ester of 3-ring
Acetate 2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-5-cyclopropyl amino methyl-benzyl ester
Acetate 3-allyl amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl ester
Acetate 5-allyl amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl ester
5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzaldoxime
3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzaldoxime
N-(5-amino methyl-2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-ethanamide
N-(3-amino methyl-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-ethanamide
N-(3-(acetylamino-methyl)-4-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-ethanamide
N-(2-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amino]-methyl }-benzyl)-ethanamide
(6-aminomethyl-1,2,3-dihydro-isobenzofuran-5-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(4-aminomethyl-1,2,3-dihydro-isobenzofuran-5-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine
(7-aminomethyl-1,2,3-dihydro-isobenzofuran-4-ylmethyl)-(1H-benzimidazolyl-2 radicals-ylmethyl)-(5,6,7,8-tetrahydrochysene-quinoline-8-yl)-amine.

Claims (15)

1. the compound of following formula and salt thereof and prodrug form:
Figure A018158020002C1
Ring A randomly contains the heteroatoms that is selected from N, O and S;
It is unsaturated that dotted line is represented to choose wantonly;
R 1, R 2And R 3It is mutual incoherent substituting group;
K is 0-4;
L is 0,1 or 2;
X is C or N unsubstituted or that replace; Or O or S;
Ar is the residue of aromatics or heteroaromatic moiety;
Each n is respectively 0-2;
Each R is respectively H or alkyl (1-6C);
J is 0-3; And
Each Y is respectively CR 2NR (CR 2) nOptional and mutual incoherent substituting group beyond the B, wherein B is aromatic ring or hetero-aromatic ring or other heterocycle.
2. compound as claimed in claim 1 is characterized in that, described each Y is respectively halogen, OH, SH, SO, SO 2Or the organic moiety that does not contain N of 1-20 carbon atom, wherein two such Y can be connected to form condensed ring with Ar; Perhaps be selected from following group:
-(CR 2) mCN，
-(CR 2) mNR 5 2，
-(CR 2) mNR(CR 2) mNRR 4，
-(CR 2) mNR(CR 2) mNR(CR 2) mNR 5 2，
-(CR 2) mCO(CR 2) mNR 5 2，
-(CR 2) mCO(CR 2) mNR(CR 2) mNRR 4，
-(CR 2) mCO(CR 2) mNR(CR 2) mNR(CR 2) mNR 5 2，
-(CR 2) mNRCO(CR 2) mNRR 4，
-(CR 2) mNRCO(CR 2) mNR(CR 2) mNR 5 2，
-(CR 2) mNRCO(CR 2) mNR(CR 2) mNR(CR 2) mNR(CR 2) mNR 5 2，
-CH＝N-Z，
-(CR 2) mZ，
-NR(CR 2) mZ，
-(CR 2) mNROH，
(CR 2) mCONROH and
(CR 2) mCR＝NOH，
And Y contains the group of guanidine radicals or NHNHR or amidino groups;
Wherein Z is optional aromatic ring or the hetero-aromatic ring part that replaces, and contains 5-12 annular atoms;
Wherein R such as claim 1 definition; Each m is respectively 0-4; R 4With each R 5Be respectively H, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C) or acyl group (1-6C), randomly replaced separately by one or more non-aromatics, non-heterocyclic substituent, and two R wherein 5Can connect into cyclammonium, randomly contain the extra heteroatoms of one or more N of being selected from, O and S.
3. compound as claimed in claim 1 is characterized in that, described ring E in the position 2 with the remaining part coupling of described molecule.
4. compound as claimed in claim 3 is characterized in that, described R 2And R 3Form the benzo substituting group together.
5. compound as claimed in claim 4 is characterized in that described X is N, and described ring E contains the π key that is coupled to a N.
6. compound as claimed in claim 1 is characterized in that, described ring A is a saturated rings, and 1 is 1.
7. compound as claimed in claim 6 is characterized in that described k is 0-1.
8. compound as claimed in claim 7 is characterized in that, the described ring system that comprises A is tetrahydroquinoline or its replacement form.
9. compound as claimed in claim 1 is characterized in that (CR 2) a n(CR 2) b nIn one be CH 2, another is a key.
10. compound as claimed in claim 9 is characterized in that (CR 2) a nBe key, (CR 2) b nBe CH 2
11. compound as claimed in claim 1 is characterized in that, at least one Y is-CH 2NH 2
12. compound as claimed in claim 1 is characterized in that, described Ar is the residue of benzene, benzoglyoxaline, benzothiazole, imidazoles,  azoles, benzotriazole, thiazole, pyridine or pyrimidine.
13. a pharmaceutical composition of regulating chemokine receptor activity is characterized in that, this pharmaceutical composition contains each described compound among the claim 1-12 that treats significant quantity.
14. the purposes of each described compound is characterized in that among the claim 1-12, is used for the treatment of chemokine receptor mediated disease.
15. the purposes of each described compound is characterized in that among the claim 1-12, is used for the treatment of HIV or FIV.
CNA018158021A 2000-09-15 2001-09-19 Chemokine receptor binding heterocyclic compounds Pending CN1980916A (en)

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