CN101052399A

CN101052399A - Chemical compounds

Info

Publication number: CN101052399A
Application number: CN 200580037876
Authority: CN
Inventors: K·古蒙森; S·D·博格斯
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 2004-09-02
Filing date: 2005-08-31
Publication date: 2007-10-10
Also published as: ZA200701829B; ZA200701827B; CN101052635A

Abstract

The present invention provides novel compounds that demonstrate protective effects on target cells from HIV infection in a manner as to bind to a chemokine receptor, and which affect the binding of the natural ligand or chemokine to a receptor such as CXCR4 of a target cell.

Description

Chemical compound

Invention field

The invention provides to have makes target cell avoid the noval chemical compound of HIV protection against infection effect, they are by playing a role with the bonded mode of chemokine receptors specificity, and this specificity is in conjunction with the receptor that influences native ligand or chemotactic factor and target cell combining of CXCR4 and/or CCR5 for example.

Background of invention

HIV relies on CD4 receptor and at least a coreceptor of expressing at surface of cell membrane, is entered host cell.The M-tropic strain of HIV (close M strain) utilizes chemokine receptor CCR 5, and the T-tropic strain of HIV (close T strain) mainly utilizes CXCR4 to make coreceptor, and the purposes of HIV coreceptor depends primarily on the hypervariable region that is positioned at the V3 circulus on the outer virionic membrane albumen gp120.Gp120 and CD4 combine with suitable coreceptor, cause the structure picture to change, and the second kind of outer virionic membrane albumen that is called gp41 is exposed.Gp41 albumen subsequently with the host cell membrane interaction, cause outer virionic membrane and cell fusion.Subsequently host cell is advanced in viral hereditary information transmission, make the virus replication continuity.Therefore, the host cell of infected by HIV is relevant with the virus that enters cell by the ternary complex acquisition that forms CCR5 or CXCR4, CD4 and gp120 usually.

In independent use or in conjoint therapy, can suppress the interactional medicine of gp120 and CCR5/CD4 or CXCR4/CD4 is effective medicine that treatment is characterised in that the disease, obstacle or the disease that infect M-tropic or T-tropic strain respectively.

In vitro study provides and has given selectivity CXCR4 antagonist and can produce the evidence of effective treatment, and this research confirms, and the selective ligands of CXCR4 and CXCR4-neutralizing antibody is added cell, and HIV virus capable of blocking/host cell merges.In addition, use in human body that selectivity CXCR4 antagonist AMD-3100's studies confirm that this compounds can significantly reduce those pairs preferendum patient or only there is the patient's of T-tropic form virus T-tropic HIV viral load in those.

Except that the cofactor that enters as HIV, circumstantial evidence shows that HIV virus protein gp120 and CXCR4 direct interaction also may be by inducing the neuronal cell apoptosis, causing CD8 recently ⁺The relevant dull-witted reason of T-apoptosis with AIDS.

Also can in the tumor cell proliferation blood vessel hyperplasia relevant with tumor growth, play an important role in conjunction with the signal that provides with CXCR4 by SDF-1 with adjusting; Known angiogenic growth factor VEG-F and bFGF raise the CXCR4 level in the endotheliocyte, and SDF-1 can bring out neovascularization in vivo.In addition, the leukaemia of expression CXCR4 moves and adheres on the marrow stromal cell of lymph node and expression SDF-1.

SDF-1 combines with CXCR4 and also relates to atherosclerosis, renal homotransplantation repulsion, asthma and anaphylaxis airway inflammation, presenile dementia and arthritic pathological changes.

The present invention relates to can be used as the chemical compound of regulating the chemokine receptor activity medicine.This type of chemokine receptors includes but not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5.

The invention provides new chemical compound; this compounds is by combining with the chemokine receptors specificity; generation makes target cell avoid the protective effect that HIV infects, and this specificity is in conjunction with the receptor that influences natural receptor or chemotactic factor and target cell, for example combination of CXCR4 and/or CCR5.

Summary of the invention

The present invention includes formula (I) chemical compound:

Described chemical compound comprises its salt, solvate and physiological functional deriv thereof,

Wherein:

T is 0,1 or 2;

Each R independently be H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl ,-R ^aAy ,-R ^aOR ¹⁰Or-R ^aS (O) _qR ¹⁰

Each R ¹Independent be halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group ,-Ay ,-NHAy ,-Het ,-NHHet ,-OR ¹⁰,-OAy ,-OHet ,-R ^aOR ¹⁰,-NR ⁶R ⁷,-R ^aNR ⁶R ⁷,-R ^aC (O) R ¹⁰,-C (O) R ¹⁰,-CO ₂R ¹⁰,-R ^aCO ₂R ¹⁰,-C (O) NR ⁶R ⁷,-C (O) Ay ,-C (O) Het ,-S (O) ₂NR ⁶R ⁷,-S (O) _qR ¹⁰,-S (O) _qAy, cyano group, nitro or azido;

N is 0,1 or 2, so that R ¹Can shown in the tetrahydroquinoline ring be substituted everywhere;

R ²Be selected from H, alkyl, haloalkyl, cycloalkyl ,-R ^aCycloalkyl, alkenyl, alkynyl ,-R ^aAy ,-R ^aOR ⁵Or-R ^aS (O) _qR ⁵, R wherein ²Do not replaced by amine or alkylamine;

R ³For H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl ,-R ^aAy or-R ^aS (O) _qR ⁵

Each R ⁴Independent be halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group ,-Ay ,-NHAy ,-Het ,-NHHet ,-OR ¹⁰,-OAy ,-OHet ,-R ^aOR ¹⁰,-NR ⁶R ⁷,-R ^aNR ⁶R ⁷,-R ^aC (O) R ¹⁰,-C (O) R ¹⁰,-CO ₂R ¹⁰,-R ^aCO ₂R ¹⁰,-C (O) NR ⁶R ⁷,-C (O) Ay ,-C (O) Het ,-S (O) ₂NR ⁶R ⁷,-S (O) _qR ¹⁰,-S (O) _qAy, cyano group, nitro or azido;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 0 or 1;

Y is-NR ¹⁰-,-O-,-C (O) NR ¹⁰-,-NR ¹⁰C (O)-,-C (O)-,-C (O) O-,-NR ¹⁰C (O) N (R ¹⁰)-,-S (O) _q-,-S (O) _qNR ¹⁰-or-NR ¹⁰S (O) _q-;

X is-N (R ¹⁰) ₂,-R ^aN (R ¹⁰) ₂,-AyN (R ¹⁰) ₂,-R ^aAyN (R ¹⁰) ₂,-AyR ^aN (R ¹⁰) ₂,-R ^aAyR ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂,-HetR ^aN (R ¹⁰) ₂,-R ^aHetR ^aN (R ¹⁰) ₂,-HetR ^aAy or-HetR ^aHet;

Each R ^aIndependent alkylidene, cycloalkylidene, alkylene group, inferior cycloalkenyl group or alkynylene for optional replacement;

Each R ¹⁰Independent be H, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl group ,-R ^aCycloalkyl ,-R ^aOH ,-R ^aOR ⁵,-R ^aNR ⁶R ⁷Or-R ^aHet;

R ⁶And R ⁷Independently be selected from separately H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group ,-R ^aCycloalkyl ,-R ^aOH ,-R ^aOR ⁵,-R ^aNR ⁸R ⁹,-Ay ,-Het ,-R ^aAy ,-R ^aHet or-S (O) _qR ⁵

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Each Het independently represents optional 4 yuan, 5 yuan of replacing or 6 yuan of heterocyclic radicals or heteroaryl.

In one embodiment, t is 1 or 2.Preferred t is 1.In one embodiment, t is 2.

In one embodiment, R is H, alkyl, cycloalkyl or R ^aOR ¹⁰

In one embodiment, R is H or alkyl.Preferred R is H.

In one embodiment, n is 0.

In one embodiment, n is 1, and R ¹Be halogen, haloalkyl, alkyl, OR ¹⁰, NR ⁶R ⁷, CO ₂R ¹⁰, CONR ⁶R ⁷Or cyano group.

In one embodiment, R ²Be H, alkyl, haloalkyl or cycloalkyl.Preferred R ²Be alkyl, haloalkyl or cycloalkyl.

In one embodiment, R ²For H, alkyl, haloalkyl, cycloalkyl or-R ^aOR ⁵In another embodiment, R ²Be R ^aAy or-R ^aCycloalkyl.In one embodiment, R ²Be H, alkyl or cycloalkyl.Preferred R ²Be alkyl.

In one embodiment, R ³Be H, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl.Preferred R ³Be H, alkyl, haloalkyl or cycloalkyl.More preferably R ³Be H or alkyl.More preferably R ³Be H.

In one embodiment, m is 0.

In one embodiment, m is 1 or 2.Preferred m is 1.

When m is not 0, preferred R ⁴Be one or more halogens, haloalkyl, alkyl, OR ¹⁰, NR ⁶R ⁷, CO ₂R ¹⁰, CONR ⁶R ⁷Or cyano group.

In another embodiment, R ^aReplace for alkylidene or ring alkylidene and by one or more alkyl, oxo or hydroxyl.

In one embodiment, p is 0, and X is-R ^aN (R ¹⁰) ₂,-AyR ^aN (R ¹⁰) ₂,-R ^aAyR ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂Or-HetR ^aN (R ¹⁰) ₂Preferred X is-R ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂Or-HetR ^aN (R ¹⁰) ₂More preferably X is-R ^aN (R ¹⁰) ₂,-Het ,-R ^aHet or-HetN (R ¹⁰) ₂In one embodiment, X is Het or HetN (R ¹⁰) ₂In one embodiment, X is-HetN (R ¹⁰) ₂And R ¹⁰Be H or alkyl.

In one embodiment, p is 1; Y is-N (R ¹⁰)-,-O-,-S-,-C (O) NR ¹⁰-,-NR ¹⁰CO-or-S (O) _qNR ¹⁰-; With X be-R ^aN (R ¹⁰) ₂,-AyR ^aN (R ¹⁰) ₂,-R ^aAyR ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂Or-HetR ^aN (R ¹⁰) ₂More preferably Y is-N (R ¹⁰)-,-O-,-C (O) NR ¹⁰,-NR ¹⁰CO-and X are-R ^aN (R ¹⁰) ₂,-Het ,-R ^aHet or-HetN (R ¹⁰) ₂In one embodiment, Y is-N (R ¹⁰)-or-O-and X be Het ,-HetN (R ¹⁰) ₂,-R ^aN (R ¹⁰) ₂Or-R ^aHet.In another embodiment, p is 1, and Y is-N (R ¹⁰)-and X be unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈The Het of cycloalkyl substituted.In one embodiment, p be 0 and X be-HetN (R ¹⁰) ₂In one embodiment, as X be-HetN (R ¹⁰) ₂The time, R ¹⁰Be H or alkyl.

In one embodiment, t is 1 or 2; R is H or alkyl; R ²Be H, alkyl or cycloalkyl; R ³Be H, alkyl, haloalkyl or cycloalkyl; N is 0; With m be 0.In one embodiment, t is 1 or 2; R is H or alkyl; R ²Be H, alkyl or cycloalkyl; R ³Be H, alkyl, haloalkyl or cycloalkyl; N is 0; M is 0; P is 0; With X be-Het or-HetN (R ¹⁰) ₂, and R ¹⁰For H or alkyl and Het are unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.In one embodiment, t is 1 or 2; R is H or alkyl; R ²Be H, alkyl or cycloalkyl; R ³Be H, alkyl, haloalkyl or cycloalkyl; N is 0; M is 0; P is 1; Y is-N (R ¹⁰)-,-O-,-CONR ¹⁰-or-NR ¹⁰CO-; X is-Het or-HetN (R ¹⁰) ₂And Het is unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.In another embodiment, Y is-N (R ¹⁰)-or-O-and X be-Het.

In one embodiment, t is 1 or 2; R is H or alkyl; R ²Be H, alkyl or cycloalkyl; R ³Be H, alkyl, haloalkyl or cycloalkyl; N is 0; M is 0; P be 1 and Y be-N (R ¹⁰)-,-O-,-C (O) NR ¹⁰-or-NR ¹⁰C (O)-; X is-Het or-HetN (R ¹⁰) ₂And Het is unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.

Preferred Het is piperidines, piperazine, azetidine, pyrrolidine, imidazoles, pyridine etc.In one embodiment, Het is piperidines, piperazine or pyrrolidine.In one embodiment, Het is by C ₁-C ₆Piperidines, piperazine or pyrrolidinyl that alkyl replaces.

In one embodiment ,-Het replaces by at least one following group is optional: alkyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino or alkyl amino.In one embodiment ,-Ay replaces by at least one following group is optional: alkyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino or alkyl amino.

In one embodiment, p be 0 and X be-Het.Preferably-Het is unsubstituted or by one or more C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is optional to be replaced

Preferably, substituent group-Y _p-X is positioned on the imidazopyridine ring shown in the structural formula (I '):

Chemical compound of the present invention comprises:

1) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

2) N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

3) N-methyl-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

4) 4-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1-piperazine carboxylic acid 1,1-dimethyl ethyl ester;

5) N-methyl-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

6) N, N, N '-trimethyl-N '-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1;

7) N-{[5-(3,5-dimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

8) N-methyl-N-{[5-(3,4,5-trimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

9) N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

10) N-(1-Methylethyl)-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

11) N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

12) N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

13) methyl N-[(5-{4-[(dimethylamino)] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine; With

14) N-methyl-N-{[5-(4-pyridine radicals) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine.

Preferred compound of the present invention comprises:

4) N-methyl-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

5) N, N, N '-trimethyl-N '-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1;

6) N-{[5-(3,5-dimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

7) N-methyl-N-{[5-(3,4,5-trimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

8) N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

9) N-(1-Methylethyl)-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine; With

10) methyl N-[(5-{4-[(dimethylamino)] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine.

Preferred chemical compound of the present invention comprises:

6) N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine; With

7) N-(1-Methylethyl)-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine.

Chemical compound of the present invention comprises:

9) N-(1-Methylethyl)-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

10) methyl N-[(5-{4-[(dimethylamino)] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

11) N-(1-Methylethyl)-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

12) N-({ 5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

13) N-({ 5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

14) N-{[5-(3-amino-1-azetidinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

15) N-({ 5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

16) N-methyl-N-({ 5-[methyl (1-methyl-3-pyrrolidinyl) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

17) N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

18) N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

19) N-methyl-N-[(5-{4-[2-(methyl oxygen base) ethyl]-the 1-piperazinyl } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

20) N-cyclopropyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

21) N-methyl-N-({ 5-[4-(methylamino)-piperidino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

22) N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

23) N-({ 5-[4-(dimethylamino)-piperidino] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

24) N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

25) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7-dihydro-5H-cyclopenta [b] pyridine-7-amine;

26) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine;

27) (8S)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

28) (8R)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

29) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2-methyl-propyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

30) (8S)-and N-ethyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

31) (8S)-and N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

32) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine;

33) (8S)-and N-(cyclopropyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

34) (8S)-and N-butyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

35) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(phenyl methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

36) (8S)-and N-[(2-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo 1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

37) (8S)-and N-[(3-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

38) (8S)-and N-[(4-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

39) (8S)-and N-[(3-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

40) (8S)-and N-[(4-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

41) (8S)-and the N-[(2-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

42) (8S)-and the N-[(3-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

43) (8S)-and the N-[(4-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

44) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[3-(trifluoromethyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

45) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[4-(trifluoromethyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

46) (8S)-and N-{[2-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

47) (8S)-and N-{[3-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

48) (8S)-and N-{[4-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

49) (8S)-and N-{[4-(1-Methylethyl) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

50) (8S)-and N-(4-xenyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

51) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[4-(2-methyl-propyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

52) 2-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } ethanol;

53) 3-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino }-the 1-propanol;

54) (8S)-and N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

55) N, N, N '-trimethyl-N '-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1;

56) (8S)-N-{[5-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl) imidazo [1,2-a] pyridine-2-yl also] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

57) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

58) (8S)-and N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

59) (8S)-and N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

60) (8S)-N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

61) (8S)-N-methyl-N-(5-[methyl (1-methyl-4-piperidyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

62) (8S)-and N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

63) (8S)-N-methyl-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

64) (8S)-N-(5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

65) (8S)-N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

66) (8S)-N-(5-[(3R)-3-(diethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

67) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-ethyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

68) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine;

69) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

70) (8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine; With

71) (8S)-and N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

72) N, N-dimethyl-N '-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1;

73) (8S)-and N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] amino } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

74) (8S)-and N-methyl-N-[(5-{[2-(piperidino) ethyl] amino } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

75) (8S)-and N-[(5-{[2-(dimethylamino) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

76) (8S)-and N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

77) (8S)-and N-methyl-N-[(5-{[2-(piperidino) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine; Or its pharmaceutically acceptable salt or ester.

Chemical compound of the present invention also comprises:

5) N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

6) N-(1-Methylethyl)-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

7) N-(1-Methylethyl)-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

8) N-({ 5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

9) N-{[5-(3-amino-1-azetidinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

10) N-({ 5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

11) N-methyl-N-({ 5-[methyl (1-methyl-3-pyrrolidinyl) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

12) N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

13) N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

14) N-methyl-N-[(5-{4-[2-(methyl oxygen base) ethyl]-the 1-piperazinyl } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

15) N-cyclopropyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

16) N-methyl-N-({ 5-[4-(methylamino)-piperidino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

17) N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

18) N-({ 5-[4-(dimethylamino)-piperidino] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

19) N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

20) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7-two-hydrogen-5H-cyclopenta [b] pyridine-7-amine;

21) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine;

22) (8S)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

23) (8R)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

24) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2-methyl-propyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

25) (8S)-and N-ethyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

26) (8S)-and N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

27) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine;

28) (8S)-and N-(cyclopropyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

29) (8S)-and N-butyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

30) 2-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } ethanol;

31) 3-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino }-the 1-propanol;

32) (8S)-and N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

33) N, N, N '-trimethyl-N '-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1;

34) (8S)-N-{[5-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl) imidazo [1,2-a] pyridine-2-yl also] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

35) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

36) (8S)-and N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

37) (8S)-and N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

38) (8S)-N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

39) (8S)-N-methyl-N-(5-[methyl (1-methyl-4-piperidyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

40) (8S)-and N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

41) (8S)-N-methyl-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

42) (8S)-N-(5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

43) (8S)-N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

44) (8S)-N-(5-[(3R)-3-(diethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

45) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-ethyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

46) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine;

47) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

48) (8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine; With

49) (8S)-and N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

Or its pharmaceutically acceptable salt or ester.

Chemical compound of the present invention also comprises:

1) (8S)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

2) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2-methyl-propyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

3) (8S)-and N-ethyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

4) (8S)-and N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

5) (8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine;

6) (8S)-and N-(cyclopropyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

7) (8S)-and N-butyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

8) 2-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } ethanol;

9) 3-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino }-the 1-propanol;

10) (8S)-and N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

11) (8S)-N-{[5-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl) imidazo [1,2-a] pyridine-2-yl also] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

12) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

13) (8S)-and N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

14) (8S)-and N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

15) (8S)-N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

16) (8S)-and N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

17) (8S)-N-methyl-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

18) (8S)-N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

19) (8S)-N-(5-[(3R)-3-(diethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

20) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-ethyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

21) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine;

22) (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

23) (8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine; With

24) (8S)-and N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

Or its pharmaceutically acceptable salt or ester.

Chemical compound of the present invention also comprises:

8) (8S)-and N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine;

9) (8S)-and N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

Or its pharmaceutically acceptable salt or ester.

One aspect of the present invention comprises the chemical compound that relates to arbitrary embodiment that defines with preamble basically.

One aspect of the present invention comprises the Pharmaceutical composition that contains one or more The compounds of this invention and pharmaceutically acceptable carrier.

One aspect of the present invention comprises one or more The compounds of this invention as the active treatment material.

One aspect of the present invention comprises the disease that is used for the treatment of or prevents to be caused by unsuitable CXCR4 activity and one or more The compounds of this invention of disease.

One aspect of the present invention comprises the disease that is used for the treatment of or prevents to be caused by unsuitable CCR5 activity and one or more The compounds of this invention of disease.

One aspect of the present invention comprise be used for the treatment of or prevent HIV infect, with the hemopoietic diseases associated; The control chemotherapy side effect; Increase the bone marrow transplantation success rate; Promote wound healing and burn to handle; Bacterial infection in the leukemia; Inflammation; Inflammatory or anaphylactic disease; Asthma; Allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis (autoimmune throiditis), transplant rejection, homograft rejection, graft versus host disease, inflammatory bowel disease, Crohn disease, ulcerative colitis (ulcerativecolitus), spondyloarthropathy, scleroderma, psoriasis, the psoriasis that T-is cell-mediated, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis; Encircle dead property, skin, allergic angiitis; Acidophilia's myositis (eoosinophilicmyotis), eosinophilic fasciitis; One or more The compounds of this invention with brain, mammary gland, prostate, lung or hemopoietic (haematopoetic) tissue cancer.Preferred described disease or disease are HIV infection, rheumatoid arthritis, inflammation or cancer.

One aspect of the present invention comprises that one or more The compounds of this invention are used for the treatment of or prevent to be subjected to purposes in the medicine of disease that chemokine receptors regulates or disease in preparation.Preferred described chemokine receptors is CXCR4 or CCR5.

One aspect of the present invention comprises that one or more The compounds of this invention are used for the purposes of the medicine of following disease in preparation: treatment or prevention HIV infect, with the hemopoietic diseases associated; The control chemotherapy side effect; Increase the bone marrow transplantation success rate; Promote wound healing and burn to handle; Bacterial infection in the leukemia; Inflammation; Inflammatory or anaphylactic disease; Asthma; Allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, homograft rejection, graft versus host disease, inflammatory bowel disease, Crohn disease, ulcerative colitis; Spondyloarthropathy, scleroderma; Psoriasis, the cell-mediated dead property of psoriasis, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, ring, skin, allergic angiitis, acidophilia's myositis, the eosinophilic fasciitis of T-; With brain, mammary gland, prostate, lung or hemopoietic tissue cancer.Preferred described purposes relates to wherein said disease or obstacle is the medicine of HIV infection, rheumatoid arthritis, inflammation or cancer.

One aspect of the present invention comprises that treatment or prevention are subjected to the disease that chemokine receptors regulates or the method for disease, and this method comprises and gives one or more The compounds of this invention.Preferred described chemokine receptors is CXCR4 or CCR5.

One aspect of the present invention comprises the method that is used for following purposes: treatment or prevention HIV infect, with the hemopoietic diseases associated; The control chemotherapy side effect; Increase the bone marrow transplantation success rate; Promote wound healing and burn to handle; Bacterial infection in the leukemia; Inflammation; Inflammatory or anaphylactic disease; Asthma, allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, homograft rejection, graft versus host disease, inflammatory bowel disease, Crohn disease, ulcerative colitis; Spondyloarthropathy, scleroderma; Psoriasis, the cell-mediated dead property of psoriasis, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, ring, skin, allergic angiitis, acidophilia's myositis, the eosinophilic fasciitis of T-; With brain, mammary gland, prostate, lung or hemopoietic tissue cancer, this method comprises and gives one or more The compounds of this invention.

One aspect of the present invention comprises treatment and prevents the method for following disease: HIV infection, rheumatoid arthritis, inflammation or cancer, this method comprise and give one or more The compounds of this invention.

Detailed Description Of The Invention

In the intended scope of its approval, use term.Be intended to illustrate to give a definition, but do not limit defined term.

Term used herein " alkyl " is meant the straight or branched hydrocarbon, and preferred described hydrocarbon has 1-12 carbon atom.The example of " alkyl " used herein includes but not limited to methyl, ethyl, propyl group, isopropyl, isobutyl group, normal-butyl, the tert-butyl group, isopentyl, n-pentyl.

When being used for this specification, preferred atom for example carbon number by for example phrase " C _x-C _yAlkyl " representative, C _x-C _yAlkyl is meant the alkyl that contains this paper definition of specifying carbon number.Similarly term also is applicable to other preferred term and scope.

Term used herein " alkenyl " is meant the straight or branched aliphatic hydrocarbon that contains one or more carbon-to-carbon double bonds.Example includes but not limited to vinyl, pi-allyl etc.

Term used herein " alkynyl " is meant the straight or branched aliphatic hydrocarbon that contains one or more carbon-to-carbon triple bonds.Example includes but not limited to acetenyl etc.

Term used herein " alkylidene " is meant the optional straight or branched bivalent hydrocarbon radical that replaces, and preferred described side chain bivalent hydrocarbon radical has 1-10 carbon atom.The example of " alkylidene " used herein includes but not limited to methylene, ethylidene, inferior n-pro-pyl, inferior normal-butyl etc.Preferred substituted comprises alkyl, oxo and hydroxyl.

Term used herein " alkylene group " is meant the straight or branched bivalent hydrocarbon radical, and preferred described bivalent hydrocarbon radical has 1-10 carbon atom, contains one or more carbon-to-carbon double bonds.Example includes but not limited to vinylene, acrol or 2-allylidene etc.

Term used herein " alkynylene " is meant the straight or branched bivalent hydrocarbon radical, and preferred described bivalent hydrocarbon radical has 1-10 carbon atom, contains one or more carbon-to-carbon triple bonds.Example includes but not limited to ethynylene etc.

Term used herein " cycloalkyl " is meant the optional non-aromatics cyclic hydrocarbon that replaces.Exemplary " cycloalkyl " includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.Term used herein " cycloalkyl " comprises optional condensed polycyclic saturated hydrocarbon and the aromatic ring system that replaces, promptly has polycyclic hydrocarbon less than the maximum number of non-cumulated double bond, for example when saturated hydrocarbons ring (for example cyclopenta ring) and aromatic ring (" aryl " herein be phenyl ring for example) when condensing, for example form for example indane of group.Preferred substituted comprises alkyl, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino and alkyl amino.

Term used herein " cycloalkenyl group " is meant the non-aromatics cyclic hydrocarbon of the optional replacement that contains one or more carbon-to-carbon double bonds, and the optional alkylidene that can be connected with cycloalkenyl group that comprises of described cyclic hydrocarbon is got in touch body.Exemplary " cycloalkenyl group " includes but not limited to cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group and cycloheptenyl.Preferred substituted comprises alkyl, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino and alkyl amino.

Term used herein " cycloalkylidene " is meant the optional non-aromatics cyclic hydrocarbon of bivalence that replaces.Exemplary " cycloalkylidene " includes but not limited to cyclopropylidene, inferior cyclobutyl, cyclopentylene, cyclohexylidene and inferior suberyl.Preferred substituted comprises alkyl, hydroxyl and oxo.

Term used herein " inferior cycloalkenyl group " is meant the non-aromatics bivalence cyclic hydrocarbon of the optional replacement that contains and a plurality of carbon-to-carbon double bonds.Exemplary " inferior cycloalkenyl group " includes but not limited to inferior cyclopropanyl, inferior cyclobutane base, cyclopentenylidene, cyclohexadienylidene and inferior cycloheptenyl.

Term used herein " heterocycle " or " heterocyclic radical " are meant monocycle or the multi-loop system that contains one or more degree of unsaturation and also contain one or more heteroatomic optional replacements.Preferred hetero atom comprises N, O and/or S, comprises N oxide, oxysulfide and dioxide.More preferably described hetero atom is N.

Preferred heterocycle is 3 yuan of-12 yuan of rings saturated fully or that have one or more degrees of unsaturation.This type of ring can be chosen wantonly with one or more other " heterocycles " or cycloalkyl ring and condense.The example of " heterocycle " base includes but not limited to oxolane, pyrans, 1,4-dioxane, 1,3-dioxane, piperidines, piperazine, pyrrolidine, morpholine, tetrahydric thiapyran, azacyclopropane, azetidine and Tetramethylene sulfide.Preferred substituted comprises alkyl, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino and alkyl amino.

Term used herein " aryl " is meant the optional phenyl ring that replaces or the optional condensed phenyl ring system that replaces, for example anthracene, phenanthrene or naphthalene nucleus system.The example of " aryl " includes but not limited to phenyl, 2-naphthyl and 1-naphthyl.Preferred substituted comprises alkyl, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino and alkyl amino.

Term used herein " heteroaryl " is meant optional 5 yuan of-7 yuan of monocyclic aromatic rings that replace, or contains the condensed-bicyclic aromatic ring system of the optional replacement of two these type of aromatic rings.These hetero-aromatic rings contain one or more nitrogen, sulfur and/or oxygen atom, and wherein N oxide, oxysulfide and dioxide can allow hetero atom to replace.Preferred described hetero atom is N.

The example of " heteroaryl " used herein comprises but should not be limited to furan, thiophene, pyrroles, imidazoles, pyrazoles, triazole, tetrazolium, thiazole,  azoles, different  azoles,  diazole, thiadiazoles, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinolin, benzofuran, benzothiophene, indole, indazole, benzimidazolyl (benzimidizolyl), imidazopyridyl, Pyrazolopyridine base and pyrazolopyrimidine base.Preferred substituted comprises alkyl, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino and alkyl amino.

Term used herein " halogen " is meant fluorine, chlorine, bromine or iodine.

Term used herein " haloalkyl " is meant the alkyl of this paper definition that is replaced by at least one halogen.The example of side chain of Shi Yonging or straight chain " haloalkyl " includes but not limited to by one or more halogens methyl, ethyl, propyl group, isopropyl, normal-butyl and tert-butyl group of independently replacing of fluoro, chloro, bromo and iodo for example in the present invention.Term " haloalkyl " should be interpreted as comprising this type of substituent group such as perfluoroalkyl etc.

Term used herein " alkoxyl " is meant-OR ' group that wherein R ' is defined alkyl.

Term used herein " cycloalkyloxy " is meant-OR ' group that wherein R ' is defined cycloalkyl.

Term used herein " alkoxy carbonyl " is meant group, for example:

Wherein R ' represents alkyl as defined herein.

Term used herein " aryloxycarbonyl " is meant group, for example:

Wherein Ay represents aryl as defined herein.

Term used herein " nitro " is meant-NO ₂Group.

Term used herein " cyano group " is meant-the CN group.

Term used herein " azido " is meant-N ₃Group.

Term amino used herein is meant-NR ' R " group, wherein R ' and R " independent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or the heteroaryl represented.Equally, term " alkyl amino " comprises with the amino alkylidene that is connected and gets in touch thing.The example of " alkyl amino " used herein comprises group, for example-and (CH ₂) _xNH ₂, wherein preferred x is 1-6.

Term used herein " amide " is meant-C (O) NR ' R " group, wherein R ' and R " independent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or the heteroaryl represented.The example of " amide " used herein comprises group, for example-and C (O) NH ₂,-C (O) NH (CH ₃) ,-C (O) N (CH ₃) ₂Deng.

The phrase of Shi Yonging " the optional replacement " or its other version are represented the replacement chosen wantonly to comprise the multistage replacement of carrying out with one or more substituent groups in this specification.This term should accurately or not have described in the ambiguity ground herein interpreted or substitute mode shown in the concrete legend.More precisely, one skilled in the art would recognize that this term comprises provides tangible modification, and this modification is included in the scope of appended claims.

Formula (I) chemical compound can have more than one crystal form, and it is a kind of polymorphic characteristic that is called, and this type of polycrystalline form (polymorph) is in formula (I) scope.Usually Yin Wendu, pressure or the two variation can produce polymorphic.Change method for crystallising and also can produce polymorphic.Can for example x ray diffraction pattern, dissolubility and fusing point be distinguished polymorphic by various physical characteristics as known in the art.

Described herein some chemical compound contains one or more chiral centres, or therefore may have multiple stereoisomer.The scope of the invention comprises the mixture and the pure enantiomer of stereoisomer, or is rich in the mixture of enantiomer and/or diastereomer.Each isomer and any equilibrated wholly or in part mixture thereof of the chemical compound of formula (I) representative are also included within the scope of the invention.The present invention also comprises the mixture of isomers of each isomer and its wherein one or more chiral centres counter-rotatings of the chemical compound that following formula is represented.

In general, but be not absolute, salt of the present invention is pharmaceutically acceptable salt.Be included in salt in the term " pharmaceutically acceptable salt " and be meant the nontoxic salts of The compounds of this invention.The salt of The compounds of this invention can comprise acid-addition salts.Representational salt comprises acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, Ca-EDTA, camsilate, carbonate, Clavulanate, citrate, dihydrochloride, ethanedisulphonate (edisylate), estolate (estolate), esilate, fumarate, gluceptate (gluceptate), gluconate, glutamate, Glu, ethanol based arsanilate (glycollylarsanilate), hexyl resorcin salt (hexylresorcinate), Hai Baming (hydrabamine), hydrobromate, hydrochlorate, Hydroxynaphthoate, iodide, isethionate, lactate, Lactobionate, laruate, malate, maleate, mandelate, mesylate, Methylsulfate, maleic acid one potassium, mucate, naphthalene sulfonate, nitrate, the N-methylglucosamine, oxalates, embonate (pamoate), palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, potassium salt, Salicylate, sodium salt, stearate, basic acetate, succinate, sulfate, tannate, tartrate, the teoclate, toluene fulfonate, triethiodide, trimethylammonium and valerate.Pharmaceutically unacceptable other salt can be used for preparing The compounds of this invention, should be considered as forming another aspect of the present invention.

Term used herein " solvate " is meant the variable stoichiometric complex that is formed by solute (formula I chemical compound itself or salt or physiological functional deriv) in the present invention, and solvent.Be used for the biological activity that this kind solvent of the present invention should not disturb solute.The limiting examples of The suitable solvent includes but not limited to water, methanol, ethanol and acetic acid.Preferred used solvent is pharmaceutically acceptable solvent.The limiting examples of suitable pharmaceutically acceptable solvent comprises water, ethanol and acetic acid.Most preferably, used solvent is a water.

Term used herein " physiological functional deriv " is meant any pharmaceutically acceptable derivates of The compounds of this invention, when giving mammal with it, can (directly or indirectly) provide The compounds of this invention or its active metabolite.Need not inappropriately test, those skilled in the art just can know this analog derivative, for example ester and amide.Can be with reference to Burger ' sMedicinal Chemistry And Drug Discovery, the 5th edition, the 1st volume: the instruction among the Principlesand Practice, the instruction of relevant physiological functional deriv aspect is attached to herein by reference.

The biology that causes tissue, system, animal or human or the medicine of medical response or the amount of medical substance that term used herein " effective dose " expression is being sought by for example research worker or clinicist.Term " treatment effective dose " expression is compared with the respective patient of not accepting this amount, and generation improves treatment, healing, prevention or alleviation disease, disease or side effect or delays disease or any amount of disease development speed.This term is also included within the scope of its amount that effectively strengthens normal physiological function.

Term used herein " regulator " should comprise antagonist, agonist, inverse agonist, partial agonist or partial antagonist, inhibitor and activator.In an embodiment preferred of the present invention, by suppress HIV and chemokine receptors for example CXCR4 and/or the CCR5 of target cell combine, chemical compound confirms to have the protective effect of anti-HIV infection.The present invention comprises and comprises target cell and the method that effectively suppresses the chemical compound of virus and the bonded amount of chemokine receptors of making.

Except that chemokine receptors in HIV infects the role, this receptoroid also relates to a variety of diseases.Therefore, the CXCR4 regulator also has the therapeutical effect of treatment and hemopoietic diseases associated, includes but not limited to control the side effect of chemotherapy, the probability of success that increases bone marrow transplantation, promotion wound healing and burn treating, and the bacterial infection in the opposing leukemia.In addition, these chemical compounds also have the effect of the disease of treatment and inflammation-related, include but not limited to inflammatory or anaphylactic disease, for example asthma, allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD) (for example idiopathic pulmonary fibrosis or ILD, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or the dermatomyositis relevant) with rheumatoid arthritis; Systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy; Autoimmune disease, for example rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes; Glomerulonephritis, autoimmune thyroiditis; The transplant rejection that comprises homograft rejection or graft versus host disease; Enteritis is Crohn disease and ulcerative colitis for example; Spondyloarthropathy; Scleroderma; Psoriasis (comprising the psoriasis that T-is cell-mediated) and inflammatory dermatosis, for example dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis (for example encircling dead property, skin and allergic angiitis); Acidophilia's myositis, eosinophilic fasciitis; And cancer.

When being used for the treatment of, formula (I) chemical compound of treatment effective dose and the form administration that salt, solvate and physiological functional deriv can be used as feed chemicals thereof.Form that can also Pharmaceutical composition provides active component.

Therefore, the present invention also provides formula (I) chemical compound that contains effective dose and the Pharmaceutical composition of salt, solvate and physiological functional deriv and one or more pharmaceutically acceptable carriers, diluent or excipient thereof.Formula (I) chemical compound and salt thereof, solvate and physiological functional deriv are with described herein.According to preparation in other components compatibility and the principle harmless to the receiver of Pharmaceutical composition, examples of such carriers, diluent or excipient must be acceptable.

According to another aspect of the present invention, the method for preparing pharmaceutical formulation also is provided, and this method comprises makes formula (I) chemical compound and salt, solvate and physiological functional deriv mix with one or more pharmaceutically acceptable carriers, diluent or excipient.

The treatment effective dose of The compounds of this invention will depend on multiple factor.For example the character and the route of administration of medication person's kind, age and body weight, the definite disease that needs treatment and seriousness thereof, preparation all are the factors that will consider.The treatment effective dose finally should be judged by attending doctor or veterinary.However, treating the effective dose of weakly people's formula (I) chemical compound usually should be in 0.1-100mg/kg medication person body weight (mammal)/every day scope.More generally, this effective dose should be in 0.1-10mg/kg body weight/every day scope.Therefore, for the 70kg Adult Mammals, one every day actual amount example be generally 7-700mg.Can be by every day single dose or every day (for example 2,3,4,5 or more times) divided dose but total identical mode of daily dose gives this dosage repeatedly.Can be by the effective dose of certain ratio decision salt, solvate or its physiological functional deriv of formula (I) chemical compound of effective dose itself.Similar dosage should be fit to treat other disease that relates to herein.

The unit dosage form that can contain the active component/per unit dosage of scheduled volume provides pharmaceutical preparation.According to the disease of being treated, route of administration and patient's age, body weight and situation, as limiting examples, this unit can contain 0.5mg-1g formula (I) chemical compound.Preferred unit dose formulations is to contain the daily dose or the divided dose of above setting forth, or those of its suitable fractional active component.Can prepare this type of pharmaceutical preparation by any method of knowing in the medicament field.

Can suitably give pharmaceutical preparation by any suitable approach, for example by oral (comprising buccal or Sublingual), rectum, nose, part (comprising buccal, Sublingual or transdermal), vagina or parenteral (comprising subcutaneous, intramuscular, intravenous or Intradermal) approach.Can for example, active component and carrier or excipient prepare this type of preparation by any known method in the medicament field by being combined.Limit example of the present invention as not representing, it is believed that with other approach and compare, preferred The compounds of this invention is to some disease and effective some approach of disease.

Can provide the pharmaceutical preparation of suitable for oral administration administration by following individual, for example capsule or tablet; Powder or granule; The solution or the suspensoid that contain water or on-aqueous liquid separately; Edible foam or whips; Or oil-in-water liquid emulsion or Water-In-Oil liquid emulsion.For example, in the tablet or capsule form of oral administration, active pharmaceutical ingredient can for example ethanol, glycerol, water etc. combine with oral nontoxic pharmaceutically acceptable inert carrier.Usually, can be by compound powder being broken into suitable small volume, and with suitable pharmaceutical carrier for example starch or the mixed preparation of mannitol powder of edible carbohydrate for example.Also can add correctives, antiseptic, dispersant and coloring agent.

Can pass through preparation powder, liquid or suspension mixture, and prepare capsule with gelatin or some other suitable shell matter encapsulate.Can for example silica gel, Pulvis Talci, magnesium stearate, calcium stearate or solid polyethylene glycol add in the mixture encapsulate then with fluidizer and lubricant.Also can add disintegrating agent or solubilizing agent for example agar-agar, calcium carbonate or sodium carbonate,, improve the availability of medicine so that when the digestion capsule.In addition, at needs or also suitable bonding, lubricant, disintegrating agent and coloring agent can be added in the mixture in case of necessity.The example of suitable bonding comprises for example for example arabic gum, Tragacanth or sodium alginate, carboxymethyl cellulose, Polyethylene Glycol, wax etc. of glucose or β lactose, corn sweetener, natural and synthetic colloidal substance of starch, gelatin, natural sugar.The lubricant that is used for these dosage forms comprises for example enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc.Disintegrating agent includes but not limited to starch, methylcellulose, agar, Bentonite, xanthan gum etc.

For example, can granulate or the compression in bulk by the preparation mixture of powders, add lubricant and disintegrating agent, tablet is prepared in compacting in flakes.Can be by chemical compound and diluent or the mixed preparation of the above-mentioned substrate mixture of powders that makes suitable pulverizing.Optional ingredients comprises for example carboxymethyl cellulose, alginate (aliginates), gelatin or polyvinylpyrrolidone, solution blocker paraffin, heavy absorption enhancer for example Bentonite, Kaolin or dicalcium phosphate of quaternary ammonium salt and/or absorbent for example for example of binding agent.Useful binders is the solution of syrup, gelatinized corn starch, arabic gum or cellulose or polymer substance for example, with the mixture of powders wet granulation, exerts pressure then and sieve.As alternative method of granulating, can make mixture of powders fast by tablet machine, form irregular bulk, smash into granule.Can prevent to form towards adhesion by adding stearic acid, stearate, Pulvis Talci or mineral oil lubricated granules with tablet.Then lubrication mixture is pressed into tablet.Also can make The compounds of this invention and free-pouring inert carrier mixed, directly be pressed into tablet without granulating or compressing block process.Clear or the opaque protectiveness coating of being made up of Lac sealing coating, sugar or polymer substance coating and wax polishing coating can be provided.Pigment can be added these coatings, to distinguish different unit dose.

Can with oral fluid for example solution, syrup and elixir make dosage unit form so that the unit of a specified rate contains the chemical compound of scheduled volume.Can be by preparing syrup in the aqueous solution that for example chemical compound is dissolved in suitable flavoring, and elixir can be with nontoxic alcohols solvent preparation.Usually can prepare suspensoid by chemical compound is dispersed in the nontoxic solvent.Can also add solubilizing agent and emulsifying agent, for example the pure and mild polyoxyethylene sorbitan ester of ethoxylation isooctadecane; Antiseptic; The flavoring additive is oleum menthae piperitae for example, or natural sweetener, glucide or other artificial sweetener etc.

Can be as one sees fit with the dosage unit preparations microencapsulation of oral administration.Also can by for example coating or just corpuscle be embedded in and make long-acting said preparation or slow release formulation in polymer, the wax etc.

The form of all right liposome delivery system is small unilamellar vesicle, big unilamellar liposome and multilamelar liposome giving construction (I) chemical compound and salt, solvate and physiological functional deriv for example.Can for example cholesterol, stearylamine or lecithin prepare liposome by multiple phospholipid.

Also can be by using monoclonal antibody conduct and the link coupled separate carrier of compound molecule, delivery type (I) chemical compound and salt thereof, solvate and physiological functional deriv.

Also can be with chemical compound and the soluble polymer coupling that is used as target medicine carrier.This base polymer can comprise polyvinylpyrrolidone (PVP), pyran co-polymer, poly-hydroxypropyl methyl acrylamide-phenol, poly-hydroxyethyl-agedoite phenol or the polyoxyethylene polylysine that is replaced by the palmityl residue.In addition, can make this compounds and the following biodegradable polymer coupling that can be used for realizing the sustained release medicine; Crosslinked or the amphiphilic block copolymer of polylactic acid, poly-epsilon-caprolactone, poly hydroxybutyric acid, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and hydrogel for example.

Can be used as with the epidermis of user keeps the tight separable patch that contacts that the pharmaceutical formulation of suitable transdermal administration is provided.For example, can pass through at Pharmaceutical Research, the ionotherapies of 3 (6), 318 (1986) middle general introductions, by the patch delivering active ingredients, relevant this type of delivery system is attached to herein by reference.

The pharmaceutical formulation of the topical that suits can be mixed with ointment, cream, suspensoid, lotion, powder, solution, paste, gel, spray, aerosol or oil.

When being used for the treatment of eyes or other outside organization for example when oral cavity and skin, this type of preparation can be used as topical ointments or cream uses.In the time of in being formulated in ointment, can be with paraffin or water-can use with active component by miscible ointment base.Perhaps, can be in cream with active component water bag oil matrix or water-in-oil based water plasmogamy.

The pharmaceutical formulation of suitable topical administration eyes comprises that wherein active component is dissolved in or is suspended in appropriate carriers, the especially eye drop in the aqueous solvent.

Suiting, the pharmaceutical formulation of topical comprises lozenge, pastille and collutory in the oral cavity.

The wherein carrier of suitable nasal administration is that solid pharmaceutical formulation comprises having the corase meal of particle diameter in the 20-500 micrometer range.The mode that gives this powder is to go into snuffing, promptly by nose being pressed close to contain the container of powder, therefrom sucks rapidly by nasal meatus.As nose spraying machine or nose drop, the appropriate formulation that gives carrier wherein and be liquid comprises the aqueous or the oily solution of active component.

The pharmaceutical formulation of suitable inhalation comprises can be by the fine dust particles or the mist of various dosing pressure aerosols, aerosol apparatus or insufflator generation.

Available suppository or enema provide the pharmaceutical formulation of suitable rectally.

Available following dosage form provides the pharmaceutical formulation of suitable vagina administration: vaginal suppository, tampon, cream, gel, paste, foam or spray agent.

The pharmaceutical formulation of suitable parenteral comprises water or non-water aseptic injectable solution, and this solution can contain antioxidant, buffer agent, antibacterial and make preparation and expection medication person's the isoosmotic solute of blood; With water that can comprise suspending agent and thickening agent and non-water sterile suspension.Available units dosage or multi-dose container, for example sealed ampoule and pin bottle provide preparation, and can store under lyophilizing (lyophilization) condition, face with before, only need to add for example water for injection of sterile liquid carrier.Can use injection solution by sterilized powder, granule and tablet temporarily.

Except that above-mentioned concrete composition, preparation can comprise other material commonly used of related preparations type in this area.For example, the preparation of suitable for oral administration administration can comprise correctives or coloring agent.

Can use The compounds of this invention and salt, solvate and physiological functional deriv separately or with other medicine gang.Can together or distinguish giving construction (I) chemical compound and other medicines active substance, when the difference administration, can be by any order, while or sequential administration.Answer the amount of selecting type (I) chemical compound and other medicines activating agent and the relative time of administration, so that reach the coordinating effect that needs.Can be by pressing following form, while administering drug combinations formula (I) chemical compound and salt, solvate or its physiological functional deriv and other medicine: (1) contains the single medicine compositions of two kinds of chemical compounds; Or (2) different pharmaceutical composition, contain wherein a kind of chemical compound separately.Perhaps, can give combination medicine respectively by sequential mode, first a kind of medicine wherein, after give another kind, vice versa.The interval of this type of sequential administration is changeable.

The compounds of this invention can be used for treating multiple disease and disease, and same, The compounds of this invention can be used for treating or prevent the suitable drug of those diseases or disease to unite use with multiple other.This compounds can be united use with any other Pharmaceutical composition, and wherein this conjoint therapy can be used for regulating chemokine receptor activity, thereby prevention and treatment inflammatory and/or immune regulative disease.

The present invention can be used for preventing or treating the medication combined use of HIV with one or more.The example of this type of medicine comprises:

Nucleotide reverse transcriptase inhibitors, for example zidovudine, didanosine, lamivudine, zalcitabine, Abacavir, stavudine, adefovirdipivoxil, adefovir dipivoxil, Fu Qifuding, todoxil and similar medicine;

Non-nucleotide reverse transcriptase inhibitors (comprising medicine, for example immunocal, oltipraz etc.), for example nevirapine, dilazep Wei Ding, efavirenz, loviride, immunocal, oltipraz and similar medicine with antioxidant activity;

Protease inhibitor, for example Saquinavir, ritonavir, indinavir, viracept see nelfinaivr, aprenavir, palinavir, LASINAVIR BMS-234475 Lasinavir [INN and similar medicine;

Entry inhibitor, for example T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806,5-spiral elasticity albumen and similar medicine;

Integrin enzyme inhibitor, for example L-870,180 and similar medicine;

Budding inhibitor, for example PA-344 and PA-457 and similar medicine; With

Other CXCR4 and/or CCR5 inhibitor, for example Sch-C, Sch-D, TAK779, UK427,857, TAK449 and in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740 and PCT/US03/39732 those disclosed and similar medicine.

The medication combined scope of The compounds of this invention and HIV be not limited to above-mentioned those, but comprise in principle and any associating that can be used for treating the ingredient of HIV.As described, in this type of associating, can give The compounds of this invention and other HIV medicine separately or together.In addition, a kind of medicine be can before or after giving other medicines, give, or a kind of medicine and other medicines given simultaneously.

Can prepare The compounds of this invention by the several different methods that comprises the standard synthetic method of knowing.Below set forth illustrative general synthetic method, then preparation particular compound of the present invention in work embodiment.

In all following embodiment,, where necessary sensitivity or active group are used blocking group according to the rule of synthetic chemistry.Standard method (T.W.Greenand P.G.M.Wuts (1991) Protecting Groups in Organic Synthesis, JohnWiley ﹠amp according to organic synthesis; Sons, the content of relevant blocking group is attached to herein by reference) the processing blocking group.In the synthetic convenient stage of chemical compound, easily remove these groups with the conspicuous method of those skilled in the art.The selection of their order of method, reaction condition and enforcement is consistent with the method for preparation formula (I) chemical compound.

One skilled in the art will recognize that in formula (I) chemical compound and whether have three-dimensional center.Therefore, the scope of the invention comprises all possible stereoisomer, not only comprises racemic compound, and comprises each enantiomer.When needing the single enantiomer of chemical compound, can pass through stereospecific synthesis; Split end-product or any intermediate easily, or obtain this enantiomer by chiral layers analysis method as known in the art.Can finish by any suitable method as known in the art and split end-product, intermediate or raw material.Referring to for example E.L.Eliel, the Stereochemistry of Organic Compounds (Wiley-Interscience, 1994) of S.H.Wilen and L.N.Mander, relevant stereochemical content is attached to this paper by reference.

Experimental section

Abbreviation:

Symbol used herein and the convention that is used for these methods, flow process and embodiment and present scientific literature, for example those unanimities of using among Journal of the American Chemical Society or the theJournal of Biological Chemistry.Following abbreviation especially can be used for embodiment and description full text:

G (gram); Mg (milligram);

L (liter); ML (milliliter);

μ L (microlitre); Psi (pound/inch ²);

M (mole); MM (mM);

Hz (hertz); MHz (megahertz);

Mol (mole); Mmol (mM);

RT (room temperature); H (hour);

Min (minute); TLC (thin layer chromatography);

Mp (fusing point); RP (anti-phase);

T _r(retention time); TFA (trifluoroacetic acid);

TEA (triethylamine); THF (oxolane);

TFAA (trifluoroacetic anhydride); CD ₃OD (deuterate methanol);

CDCl ₃(deuterate chloroform); DMSO (dimethyl sulfoxide);

SiO ₂(silica gel); Atm (atmospheric pressure);

EtOAc (ethyl acetate); CHCl ₃(chloroform);

HCl (hydrochloric acid); Ac (acetyl group);

DMF (N, dinethylformamide); Me (methyl);

Cs ₂CO ₃(cesium carbonate); EtOH (ethanol);

Et (ethyl); TBu (tert-butyl group);

MeOH (methanol) p-TsOH (p-methyl benzenesulfonic acid);

MP-TsOH (Argonaut Technologies produce with the bonded polystyrene resin of equivalent p-TsOH).

Except that referring else, all temperature with ℃ (degree centigrade) expression.Unless otherwise indicated, respond and all at room temperature carry out.

Record on Varian VXR-300, Varian Unity-300, Varian Unity-400 instrument or General Electric QE-300 ¹The H-NMR spectrum.Count (ppm, δ unit) expression chemical shift very much by hundred.Coupling constant is by hertz (Hz) unit representation.Schizotype illustrates apparent multiplicity, is expressed as s (unimodal), d (doublet), t (triplet), q (quartet), m (multiplet) or br (broad peak).

At Micromass Ltd., Altricham on the Micromass Platform or ZMD mass spectrograph of UK, uses atmospheric pressure chemical ionizing (APCI) or electro-spray ionization (ESI) to obtain mass spectrum.

Examine with the analytical type thin layer chromatography and can't separate them, or their intermediate purity very unstable and that change with reaction process in whole characterization.

Can be by the absolute configuration of Ab Initio Vibrational Circular Dichroism (VCD) spectrum appointed compound.With Bomem Chiral RTM VCD spectrophotometer, 2000 and 800cm ^-1The scope interscan is at CDCl ₃In obtain testing VCD spectrum.Calculate VCD model spectrum with Gaussian 98Suite calculation procedure.By with this experimental spectrum and VCD spectrum contrast, carry out the spatial chemistry ownership by the model structure calculated with (R)-or (S)-configuration.Relevant this spectrographic description has: J.R.Chesseman, and M.J.Frisch, F.J.Devlinand P.J.Stephens, Chem.Phys.Lett.252 (1996) 211; P.J.Stephens andF.J.Devlin, Chirality 12 (2000) 172; And Gaussian 98, Revision A.11.4, M.J.Frisch et al., Gaussian, Inc., Pittsburgh PA, 2002, it is attached to herein by reference.

Can prepare wherein that R is H by flow process 1, t be 1 and all other variable-definitions with formula (I) chemical compound of this paper.

Flow process 1

More particularly, can under reducing condition,, perhaps make formula (III) chemical compound and formula V chemical compound prepared in reaction formula (I) chemical compound (wherein R is that H and t are 1) by making the reaction of formula (II) chemical compound and chemical compound (IV).Can in atent solvent, in the presence of Reducing agent,, carry out reductive amination by with formula (IV) or (V) compound treatment formula (II) or (III) chemical compound.Reactant can be heated to 50-150 ℃ or operation at ambient temperature.Suitable solvent comprises dichloromethane, dichloroethanes, oxolane, acetonitrile, toluene etc.Typical Reducing agent is sodium borohydride, sodium cyanoborohydride, triacetic acid base sodium borohydride etc.Reaction choose wantonly acid for example acetic acid etc. in the presence of carry out.

Can be by preparation formula (II) chemical compound described in the document (J.Org.Chem., 2002,67,2197-2205, relevant this syntheticly be attached to herein by reference).The method that available organic synthesis those skilled in the art know is by with formula (II) chemical compound reductive amination, preparation formula (III) chemical compound.Can method prepares the formula V chemical compound described in the document (J.Heterocyclic Chemistry, 1992,29,691-697, relevant this type of synthetic can being attached to herein by reference) by being similar to.Available method well known to those skilled in the art, by with formula V chemical compound reductive amination, preparation formula (IV) chemical compound.

Bright loud and clear as those skilled in the art institute, wherein R is not that formula (I) chemical compound of H can be as the similar fashion preparation of being summarized in the flow process 1.Those skilled in the art are also bright loud and clear to be, wherein t be 0 or t be that 2 formula (I) chemical compound can be as the similar fashion preparation of being summarized in the flow process 1.

Formula (I) chemical compound, wherein R is H, t is 1, and all variablees can prepare according to flow process 2 as the definition about formula (I):

Flow process 2

Formula (I) chemical compound (wherein R is H, and t is 1) can prepare by formula (III) chemical compound and formula (VI) chemical compound are reacted, wherein LV be leaving group (as, halogen, methanesulfonate, tosylate etc.).Usually in suitable solvent, choose wantonly in the presence of alkali, optional heat is carried out condensation reaction.Suitable solvent comprises oxolane, dioxane, acetonitrile, Nitrocarbol., N, dinethylformamide etc.Suitable alkali comprises triethylamine, pyridine, dimethylamino naphthyridine, N, N-diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate etc.Can react to 30-200 ℃ in room temperature or optional heat.Reaction is chosen wantonly under microwave irradiation and is carried out.Can choose that for example potassium iodide, iodate uncle fourth ammonium etc. add reactant mixture with catalyst wantonly.Can by with these documents (Chem.Pharm.Bull.2000,48,935; Tetrahedron, 1991,47,5173; Tetrahedron Lett.1990,31,3013; J.Heterocyclic Chemistry, 1988,25,129; Chemistry of Heterocyclic compounds, 2002,38,590; Relevant this synthetic document is attached to herein separately by reference) described in similar fashion preparation formula (VI) chemical compound.

Formula (I-A) chemical compound (R wherein ³For H and all other variablees as definition about formula (I)) can be according to flow process 3 preparations:

Flow process 3

More especially, formula (I-A) chemical compound can be by handling formula (X) compound with nucleopilic reagent.Can choose wantonly in the presence of atent solvent, handle formula (X) chemical compound with suitable nucleopilic reagent and carry out this reaction.Reactant can be heated to 50-200 ℃ or operation at ambient temperature.Reaction is chosen wantonly under microwave irradiation and is carried out.Formula (X) chemical compound can prepare by making formula (IX) and formula (III) chemical compound reductive amination.The aldehyde of formula (IX) can by with similarly method preparation described in the document (as J.HeterocyclicChemistry, 1992,29,691-697, relevant this syntheticly be attached to herein by reference).

Perhaps, formula (I-B) chemical compound (promptly wherein all other variablees as the definition about formula (I)) can be according to flow process 4 preparations:

Flow process 4

As illustrated in flow process 4,, formula (X) chemical compound can be converted into formula (I-B) chemical compound by making formula (X) chemical compound and the coupling of formula (XI-B) chemical compound.Below shown in coupling reaction be the Suzuki coupling, other coupling reaction (as Stille) that organic chemistry filed technical staff knows also can be used for preparation formula (I-B) chemical compound.These coupling reactions are that the organic synthesis those skilled in the art know.

Formula (I-C) chemical compound (wherein all other variablees are as the definition about formula (I)) can prepare according to flow process 5:

Flow process 5

Randomly, as shown in the flow process 5, formula (X) chemical compound can with the coupling of formula (XIII) chemical compound to form formula (XII) chemical compound.Make the reduction of formula (XII) chemical compound will obtain formula (I-C) chemical compound.

Formula (I-D) chemical compound (R wherein ³Be H, p is 1, Y is-C (O) NH-(promptly-C (O) NR ¹⁰-, and R ¹⁰Be H) and Pr be suitable blocking group to carboxylic acid, and all other variablees are as the definition about formula (I)) can be according to flow process 6 preparations.

Flow process 6

Formula (I-D) chemical compound can be randomly by formula (XVI) compound formation.Make formula (XVI) chemical compound deprotection, then make the acid of generation and the amines coupling of formula (XVII).The multiple coupling reagent that available organic synthesis those skilled in the art know (for example EDC, HOBt/HBTu; BOPCI) carry out this coupling.This reaction can or be carried out at ambient temperature in heating.The suitable solvent of suitable this reaction comprises acetonitrile, oxolane etc.

Formula (I-E) chemical compound, wherein p is 1, Y is-NHC (O)-(be that Y is-NR ¹⁰C (O)-, and R ¹⁰Be H), and all other variablees can be chosen wantonly described in flow process 7 by formula (XVII) compound formation as the definition about formula (I).

Flow process 7

In more detail, reduction-type (XVIII) chemical compound then experiences the catalytic coupling with benzophenone imines of Pd, obtains formula (XX) chemical compound.This coupling can use various palladium reagents that the organic synthesis those skilled in the art know and part (as, Pd (OAc) ₂And BINAP) carries out.This reaction can or be carried out at ambient temperature in heating.The suitable solvent that is used for this reaction comprises toluene, acetonitrile, oxolane etc.Can use any suitable method for oxidation (as the MnO in dichloromethane ₂Deng) be aldehyde with formula (XX) compound oxidation, then with formula (III) chemical compound reductive amination, obtain formula (XXI) chemical compound.This reductive amination can in the presence of Reducing agent, be handled formula (III) chemical compound with aldehyde and carry out in atent solvent.This reaction can be heated to 50-150 ℃ or carry out at ambient temperature.Suitable solvent comprises dichloromethane, dichloroethanes, oxolane, acetonitrile, toluene etc.Reducing agent is generally sodium borohydride, sodium cyanoborohydride, triacetic acid base sodium borohydride etc.Optional reaction can be carried out as in the presence of the acetic acid etc. in acid.The hydrolysis benzophenone imines obtains formula (XXII) chemical compound.Proper hydrolyzing condition is included in the suitable solvent such as oxolane, with processing formula (XXI) chemical compounds such as hydrochloric acid.With acyl chlorides (XCOCl) or as selecting with acid (XCOOH) at suitable coupling agent (as EDC, HOBt/HBTu; BOPCI) amines of processing formula (XXII) under the existence obtains formula (I-E) chemical compound.The amines of formula (XXII) and the coupling condition of acid or acyl chlorides are that the organic synthesis those skilled in the art know.

Formula (I-F) chemical compound, wherein Z is C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl and all other variablees can be synthetic according to the chirality mode of general introduction in the flow process 8 as the definition about formula (I) chemical compound:

Formula (I-F) chemical compound can be by formula XXXI compound.

With strong acid processing formula (XXXI) chemical compound in suitable solvent is suitable 4-(methoxyl group) phenyl of removing] method of ethyl.Suitable acid comprises trifluoroacetic acid etc.Suitable solvent comprises dichloromethane, dichloroethanes etc.This reaction can be chosen wantonly under heating and carry out.Alternative 4-(methoxyl group) phenyl of removing] method of ethyl comprises and uses Lewis acid (as BCl ₃, AlCl ₃, BBr ₃Deng) or under reducing condition, (as be stated from Pd or PtO on the charcoal ₂, at H ₂Under the atmosphere) the removal blocking group.The amine (formula 1 chemical compound, the wherein R that generate ²Be H) can handle with suitable aldehyde in the reductive amination condition, obtain formula (I-F) chemical compound.Reductive amination can in the presence of Reducing agent, be handled described amine with aldehyde and carry out in atent solvent.This reaction can be heated to 50-150 ℃ or carry out at ambient temperature.Suitable solvent comprises dichloromethane, dichloroethanes, oxolane, acetonitrile, toluene etc.Reducing agent is generally sodium borohydride, sodium cyanoborohydride, triacetic acid base sodium borohydride etc.Optional this reaction can be carried out as in the presence of the acetic acid etc. in acid.

Formula (XXXI) chemical compound can be by formula (XXIX) chemical compound and formula (XXX) compound:

Make formula (XXIX) chemical compound reductive amination obtain formula (XXXI) chemical compound with formula (XXX) chemical compound.Reductive amination can carry out in the presence of Reducing agent in atent solvent.This reaction can be heated to 50-150 ℃ or carry out at ambient temperature.Suitable solvent comprises dichloromethane, dichloroethanes, oxolane, acetonitrile, toluene etc.Reducing agent is generally sodium borohydride, sodium cyanoborohydride, triacetic acid base sodium borohydride etc.Optional this reaction can be carried out as in the presence of the acetic acid etc. in acid.Formula (XXX) chemical compound can be by (S)-(-)-1-(4-methoxyphenyl) ethylamine and 6,7-dihydro-8 (5H)-quinolinone prepares (J.Org.Chem., 2002,67 through reductive amination, 2197-2205 is by being attached to herein with reference to relating to so synthetic document).

Formula (XXIX) chemical compound can be by formula (XXVIII) compound.

Oxidation-type (XXVIII) chemical compound obtains formula (XXIX) chemical compound.Suitable method for oxidation is for using MnO ₂Processing formula (XXVIII) chemical compound in suitable solvent.Suitable solvent comprises dichloromethane, chloroform, dichloroethanes etc.

Several other method for oxidation well known by persons skilled in the art is applicable to this oxidation.

Formula (XXVIII) chemical compound can be by formula (XXVI) compound.

Choose wantonly in suitable solvent, optional heat or in microwave oven is handled formula (XXVI) chemical compound with the piperazine of formula (XXVII) and be can be used for obtaining formula (XXVIII) chemical compound.Perhaps the available strong acid of bridged piperazine derivatives (XXVII) is handled as n-BuLi or LDA, to form salt.At suitable solvent, in oxolane, processing formula (XXVI) chemical compound can be in order to form formula (XXVIII) chemical compound with such salt.Formula (XXVI) chemical compound can be as general introduction in the flow process 8, and the aldehyde by reduction-type (XXV) prepares.The aldehyde of formula (XXV) can prepare with the similar fashion described in the document (as Tetrahedron2002,58,489).

Formula (I-F) chemical compound, wherein Z is C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl and all other variablees can be synthetic according to the chirality mode of general introduction in the flow process 9 as the definition about formula (I) chemical compound.

Flow process 9

Formula (I-F) chemical compound can by formula (XXIX) and (XXXIII) chemical compound prepare through reductive amination.

Reductive amination can carry out in the presence of Reducing agent in atent solvent.This reaction can be heated to 50-150 ℃ or carry out at ambient temperature.Suitable solvent comprises dichloromethane, dichloroethanes, oxolane, acetonitrile, toluene etc.Reducing agent is generally sodium borohydride, sodium cyanoborohydride, triacetic acid base sodium borohydride etc.Optional this reaction can be carried out as in the presence of the acetic acid etc. in acid., then use and be similar to the condition deprotection described in the flow process 8 through reductive amination by formula (XXX) chemical compound, but preparation formula (XXXIII) chemical compound.Formula (XXXIII) chemical compound can be separated or as easy-to-handle salt.Formula (XXIX) chemical compound can prepare with being similar to the mode described in the flow process 8.Bright loud and clear as those skilled in the art institute, other enantiomer can prepare in a similar fashion.

Embodiment

Embodiment 1:5-flumizole is [1,2-a] pyridine-2-formaldehyde also

To 6-fluoro-2-pyridine amine (Tetrahedron, 2002,58,489, be attached to herein by reference) (2.8g adds 1,1 in glycol dimethyl ether 25mmol) (28ml) solution, the 3-trichloroacetone (7.9mL, 75mmol).This mixture was stirred under room temperature 15 hours, and filtration is collected the precipitation that generates and was refluxed 4 hours in ethanol (8ml).Make this reactant mixture be cooled to room temperature, concentrate, be dissolved in dichloromethane and wash with saturated sodium bicarbonate aqueous solution.Separate organic layer, through dried over mgso and concentrated.The solid that generates refluxed in calcium carbonate aqueous solution 2 hours, was cooled to room temperature, and used dichloromethane extraction.Organic layer obtains 1.4g (34% yield) 5-fluoro imidazo [1,2-a] pyridine-2-formaldehyde through dried over mgso and concentrated, is brown solid. ¹H-NMR (CDCl ₃): δ 10.16 (s, 1H), 8.22 (s, 1H), 7.54 (d, 1H), 7.34 (m, 1H), 6.59 (m, 1H); TLC (ammonia spirit of 10%2M in methanol-ethyl acetate) R _f=0.60.

Embodiment 2:5-bromo imidazo [1,2-a] pyridine-2-formaldehyde

To 2-amino-6-pyridine bromide (10g adds 1,1 in glycol dimethyl ether 58mmol) (66mL) solution, the 3-trichloroacetone (18mL, 173mmol).This mixture in 70 ℃ of stirrings 15 hours, is filtered the precipitation of collecting generation and also refluxed 7 hours in ethanol (50mL).Make this reactant mixture be cooled to room temperature, concentrate, be dissolved in dichloromethane, and wash with saturated sodium bicarbonate aqueous solution.Separate organic layer, through dried over mgso and concentrated.The solid that generates refluxed in calcium carbonate aqueous solution 1.5 hours, was cooled to room temperature, and used dichloromethane extraction.Organic layer obtains 6.6g (50% yield) 5-bromo imidazo [1,2-a] pyridine-2-formaldehyde through dried over mgso and concentrated, is orange solids. ¹H-NMR (CDCl ₃): δ 10.16 (s, 1H), 8.37 (s, 1H), 7.69 (d, 1H), 7.22 (m, 1H), 7.16 (m, 1H); TLC (10% ammonium hydroxide-acetonitrile) R _f=0.44.

Embodiment 3:N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In above-mentioned universal method, comprise 6,7-dihydro-8 (5H)-quinolinone (1.5g, (2M is in oxolane to add methyl amine in dichloroethanes 10mmol) (50mL) solution, 10mL, 20mmol), acetic acid (580 μ l, 10mmol) and triacetic acid base sodium borohydride (4.3g, 20mmol).This mixture was stirred under room temperature 15 hours, filter by silica column then and wash with 10% ammonium hydroxide-acetonitrile.Remove and desolvate, residue obtains 1.4g (85% yield) N-methyl-5,6,7 through flash chromatography purification (0-10% ammonium hydroxide-acetonitrile), and 8-tetrahydrochysene-8-quinolinamine is yellow oil.

¹H-NMR(CDCl ₃)：δ8.37(d，1H)，7.36(d，1H)，7.05(t，1H)，3.64(t，1H)，2.75(m，2H)，2.52(s，3H)，2.11(m，1H)，1.96(m，1H)，1.75(m，2H)；MS?m/z?163(M+1).

Embodiment 4:N-[(5-flumizole is [1,2-a] pyridine-2-yl also) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

To N-methyl-5,6,7, (340mg is 2.1mmol) with 5-fluoro imidazo [1,2-a] pyridine-2-formaldehyde (344mg for 8-tetrahydrochysene-8-quinolinamine, 2.1mmol) dichloroethanes (10mL) solution in add acetic acid (120 μ L, 2.1mmol) and triacetic acid base sodium borohydride (1.3g, 6.3mmol).This mixture was stirred under room temperature 2 hours, filter by silica column then and wash with 10% ammonium hydroxide-acetonitrile.Remove and desolvate, residue obtains 0.6g (93% yield) N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl through flash chromatography purification (0-10% ammonium hydroxide-acetonitrile)) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine is brown solid. ¹H-NMR(CDCl ₃)：δ8.53(d，1H)，7.80(s，1H)，7.36(m，2H)，7.13(m，1H)，7.06(m，1H)，6.40(m，1H)，4.10(m，1H)，3.94(s，2H)，2.75(m，2H)，2.43(s，3H)，2.03(m，3H)，1.70(m，1H)；MS?m/z?311(M+1).

Embodiment 5:N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

To N-methyl-5,6,7, (500mg is 3.1mmol) with 5-bromo imidazo [1,2-a] pyridine-2-formaldehyde (770mg for 8-tetrahydrochysene-8-quinolinamine, 3.4mmol) dichloroethanes (17ml) solution in add acetic acid (180 μ l, 3.1mmol) and triacetic acid base sodium borohydride (2.0g, 9.3mmol).This mixture was stirred under room temperature 15 hours, filter by silica column then and wash with 10% ammonium hydroxide-acetonitrile.Remove and desolvate, residue dilutes with dichloromethane, with the saturated sodium bicarbonate aqueous solution washing, and through dried over mgso, obtain 1.1g (99% yield) N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine is orange.

¹H-NMR(CDCl ₃)：δ8.50(d，1H)，7.92(s，1H)，7.49(d，1H)，7.32(d，1H)，7.03(m，2H)，6.96(m，1H)，4.09(m，1H)，3.94(s，2H)，2.72(m，2H)，2.40(s，3H)，2.12(m，1H)，1.99(m，2H)，1.68(m，1H)；MS?m/z?372(M+1).

Embodiment 6:N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

With N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7, (150mg, 0.48mmol) (270 μ l, 2.4mmol) solution in was through 200 ℃ of microwave irradiations 20 minutes at pure 1-methyl piperazine for 8-tetrahydrochysene-8-quinolinamine.Concentrated reaction mixture is through preparation type chromatography purification (0-30% acetonitrile-water; 0.1% trifluoroacetic acid), then with the ethyl acetate dilution,, and, obtain 125mg (67% yield) yellow oil through dried over mgso with the saturated sodium bicarbonate aqueous solution washing.

¹H-NMR(CDCl ₃)：δ8.52(d，1H)，7.70(s，1H)，7.34(m，1H)，7.28(m，1H)，7.10(m，1H)，7.04(m，1H)，6.23(dd，1H)，4.13(m，1H)，3.96(m，2H)，3.13(s，4H)，2.82(m，2H)，2.65(s，4H)，2.40(s，6H)，2.01(m，3H)，1.70(m，1H)；MS?m/z?391(M+1).

Perhaps:

N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine also can prepare through reductive amination.With N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (44mg, 0.27mmol) and 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde (69mg, dichloroethanes 0.30mmol) (1.4ml) solution glacial acetic acid (15 μ l, 0.27mmol) and triacetic acid base sodium borohydride (172mg, 0.81mmol) processing.This mixture was stirred under room temperature 15 hours, filter by silica column then, with the ammonia spirit washing of 10%2M in methanol-ethyl acetate.Concentrated reaction mixture is through preparation type chromatography purification (0-70% acetonitrile-water; 0.1% trifluoroacetic acid), then with the ethyl acetate dilution,, and, obtain 9mg (9% yield) yellow oil through dried over mgso with the saturated sodium bicarbonate aqueous solution washing.This racemic compound also can separate by SFC, obtains described R and S isomer.Racemic N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is analyzed on the SFC at the Berger that is furnished with the HP1100 diode array detector and is separated into R and S isomer.Sample is monitored in 230nm under the following conditions: 15% cosolvent (50/50 MeOH/CHCl that contains 0.5% diisopropylethylamine ₃(v/v)) at CO ₂In, overall flow rate 2mL/ minute, in 1500psi, 27 ℃, on Diacel AD-H post (Chiral Technologies), 4.6 * 250mm, 5um.

Embodiment 7:N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N-ethyl piperazidine prepare N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (24% yield).

¹H-NMR(CDCl ₃)：δ8.49(d，1H)，7.66(s，1H)，7.32(m，1H)，7.27(m，1H)，7.08(m，1H)，7.03(m，1H)，6.21(d，1H)，4.11(m，1H)，3.94(s，2H)，3.12(s，4H)，2.79(m，2H)，2.67(s，4H)，2.51(q，2H)，2.33(s，3H)，2.01(m，3H)，1.66(m，1H)，1.12(t，3H)；MS?m/z?405(M+1).

Embodiment 8:N-methyl-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and isopropyl piperazine prepare N-methyl-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow solid (12% yield).

¹H-NMR(CDCl ₃)：δ8.53(d，1H)，7.74(s，1H)，7.35(m，1H)，7.28(m，1H)，7.11(m，1H)，7.05(m，1H)，6.23(dd，1H)，4.16(m，1H)，4.00(m，2H)，3.14(s，4H)，2.78(m，7H)，2.40(s，3H)，2.01(m，3H)，1.67(m，1H)，1.12(d，6H)；MS?m/z?419(M+1).

Embodiment 9:4-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1-piperazine carboxylic acid 1,1-dimethyl ethyl ester (intermediate)

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N-tert-butoxycarbonyl piperazine prepare 4-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1-piperazine carboxylic acid 1,1-dimethyl ethyl ester obtains brown solid (21% yield).

¹H-NMR(CDCl ₃)：δ8.51(d，1H)，7.75(s，1H)，7.35(m，1H)，7.30(m，1H)，7.11(m，1H)，7.06(m，1H)，6.22(dd，1H)，4.17(m，1H)，4.02(m，2H)，3.66(s，4H)，3.04(s，4H)，2.81(m，2H)，2.39(s，3H)，2.03(m，3H)，1.69(m，1H)，1.49(s，9H)；MS?m/z?477(M+1).

Embodiment 10:N-methyl-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

To 4-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1-piperazine carboxylic acid 1, (20mg adds trifluoroacetic acid (300 μ L) in dichloromethane 0.04mmol) (the 300 μ l) solution to 1-dimethyl ethyl ester.This mixture was stirred under room temperature 2 hours, concentrate, be diluted in 3: 1 dichloromethane: in the isopropyl alcohol,, and, obtain 16mg (100% yield), be brown solid through dried over mgso with the saturated sodium bicarbonate aqueous solution washing.

1H-NMR(CDCl3)：δ8.50(d，1H)，7.74(s，1H)，7.35(m，1H)，7.28(d，1H)，7.12(m，1H)，7.05(m，1H)，6.25(d，1H)，4.22(m，1H)，4.08(m，2H)，3.15(m，8H)，2.75(m，2H)，2.40(s，3H)，2.04(m，3H)，1.68(m，1H)；MS?m/z?377(M+1).

Embodiment 11:N, N, N '-trimethyl-N '-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N, N, N '-trimethyl ethylenediamine prepares N, N, N '-trimethyl-N '-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-1, the 2-ethylenediamine obtains yellow oil (32% yield).

¹H-NMR(CDCl ₃)：δ8.48(d，1H)，7.72(s，1H)，7.33(m，1H)，7.24(m，1H)，7.08(m，1H)，7.02(m，1H)，6.24(dd，1H)，4.09(m，1H)，3.94(s，2H)，3.16(t，2H)，2.83(s，3H)，2.68(m，2H)，2.52(t，2H)，2.32(s，3H)，2.08(m，3H)，1.67(m，1H)；MS?m/z?393(M+1).

Embodiment 12:N-{[5-(3,5-dimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 2,6-two-methyl piperazine prepares N-{[5-(3,5-dimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (64% yield).

¹H-NMR(CDCl ₃)：δ8.49(d，1H)，7.68(s，1H)，7.31(m，1H)，7.25(m，1H)，7.08(m，1H)，7.02(m，1H)，6.20(dd，1H)，4.12(m，1H)，3.96(s，2H)，3.28(m，2H)，3.18(m，2H)，2.73(m，2H)，2.34(s，3H)，2.27(m，2H)，2.04(m，3H)，1.65(m，1H)，1.11(d，3H)，1.01(d，3H)；MS?m/z?405(M+1).

Embodiment 13:N-methyl-N-{[5-(3,4,5-trimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In 0 ℃, to N-{[5-(3,5-dimethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (40mg, 0.10mmol) THF (1ml) solution in add sodium hydride (60% in oil, 10mg, 0.15mmol), this reactant was stirred 10 minutes, (5 μ l 0.50mmol) handle, and disease is spent the night under room temperature with methyl iodide.With saturated sodium bicarbonate aqueous solution quencher reaction, be extracted into 3: 1 dichloromethane: in the isopropyl alcohol,, filter and concentrate through dried over mgso.Residue is through preparation type chromatography purification (0-40% acetonitrile-water; 0.1% trifluoroacetic acid), use 3: 1 dichloromethane then: isopropanol with the saturated sodium bicarbonate aqueous solution washing, and through dried over mgso, obtains 12mg (29% yield) yellow oil.

¹H-NMR(CDCl ₃)：δ8.52(d，1H)，7.71(s，1H)，7.34(m，1H)，7.27(m，1H)，7.10(m，1H)，7.05(m，1H)，6.21(dd，1H)，4.15(m，1H)，3.99(s，2H)，3.28(m，2H)，2.62(m，6H)，2.38(s，3H)，2.36(s，3H)，2.07(m，3H)，1.66(m，1H)，1.15(d，3H)，1.06(d，3H)；MS?m/z?419(M+1).

Embodiment 14:N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-methyl piperazine prepare N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (39% yield).

¹H-NMR(CDCl ₃)：δ8.44(d，1H)，7.64(s，1H)，7.22(m，1H)，7.19(m，1H)，7.05(m，1H)，6.95(m，1H)，6.18(dd，1H)，4.21(m，1H)，3.93(m，2H)，3.16(m，1H)，3.10(s，4H)，2.75(m，2H)，2.67(s，4H)，2.41(s，3H)，1.98(m，3H)，1.62(m，1H)，1.12(dd，6H)；MS?m/z?419(M+1).

Embodiment 15:N-(1-Methylethyl)-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine and isopropyl piperazine prepare N-(1-Methylethyl)-N-({ 5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (43% yield).

¹H-NMR(CDCl ₃)：δ8.44(d，1H)，7.65(s，1H)，7.22(m，1H)，7.19(m，1H)，7.05(m，1H)，6.96(m，1H)，6.17(dd，1H)，4.22(m，1H)，3.94(m，2H)，3.16(m，1H)，3.10(s，4H)，2.77(m，5H)，2.62(m，2H)，2.01(m，3H)，1.63(m，1H)，1.12(m，12H)；MS?m/z?447(M+1).

Embodiment 16:N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-methyl piperazine prepare N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (48% yield).

¹H-NMR(CDCl ₃)：δ8.41(d，1H)，7.61(s，1H)，7.32(m，1H)，7.23(m，1H)，7.10(m，1H)，7.04(m，1H)，6.23(dd，1H)，4.27(m，1H)，4.21(m，1H)，3.99(m，2H)，3.94(m，1H)，3.31(m，1H)，3.15(m，4H)，2.70(m，5H)，2.41(s，3H)，2.20(m，1H)，1.94(m，1H)，1.78(m，2H)；MS?m/z?459(M+1).

Embodiment 17:N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-N-(2, the 2.2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine and isopropyl piperazine prepare N-(5-[4-(1-Methylethyl)-1-piperazinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (43% yield).

¹H-NMR(CDCl ₃)：δ8.41(d，1H)，7.61(s，1H)，7.32(m，1H)，7.22(m，1H)，7.10(m，1H)，7.04(m，1H)，6.22(dd，1H)，4.26(m，1H)，4.22(m，1H)，3.96(m，2H)，3.31(m，1H)，3.14(m，4H)，2.78(m，7H)，2.20(m，1H)，1.95(m，1H)，1.78(m，2H)，1.13(d，6H)；MS?m/z?487(M+1).

Embodiment 18:N-[(5-{4-[(dimethylamino) methyl] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

To N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7, and 8-tetrahydrochysene-8-quinolinamine (75mg, 0.20mmol), potassium carbonate (140mg, 1.02mmol) and 4-(N, the N-dimethylaminomethyl) phenylboric acid (boronic acid) pinacol ester (120mg, 0.46mtnol) add in the suspension in glycol dimethyl ether (2.9mL) four (triphenyl phasphine) palladium (0) (86mg, 0.074mmol) and water (0.11mL).In 80 ℃ of heating 15 hours, dilute with water use ethyl acetate extraction with this reactant, and is concentrated and through preparation type chromatography purification (0-50% acetonitrile-water; 0.1% trifluoroacetic acid).With the product of ethyl acetate dilution purification,, and, obtain 30mg (35% yield) yellow oil then through dried over mgso with the saturated sodium bicarbonate aqueous solution washing.

¹H-NMR(CDCl ₃)：δ8.40(d，1H)，7.79(s，1H)，7.57(m，1H)，7.55(m，1H)，7.50(m，1H)，7.45(m，1H)，7.43(m，1H)，7.31(m，1H)，7.17(m，1H)，7.00(m?1H)，6.67(dd，1H)，4.07(m，1H)，3.90(s，2H)，3.50(s，2H)，2.72(m，2H)，2.31(s，3H)，2.29(s，6H)，2.10(m，1H)，1.99(m，2H)，1.64(m，1H)；MS?m/z?426(M+1).

Embodiment 19:N-methyl-N-{[5-(4-pyridine radicals) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

According to similar fashion as described herein, through the Suzuki coupling, by N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and pyridine-4-boric acid prepares N-methyl-N-{[5-(4-pyridine radicals) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (8% yield).

¹H-NMR(CDCl ₃)：δ8.80(m，2H)，8.44(m，1H)，7.96(s，1H)，7.59(m，3H)，7.35(d，1H)，7.22(m，1H)，7.05(m，1H)，6.77(m，1H)，4.11(m，1H)，3.96(s，2H)，2.75(m，2H)，2.39(s，3H)，2.15(m，1H)，1.99(m，2H)，1.68(m，1H)；MS?m/z?370(M+1).

Embodiment 20:N-methyl-N-{[5-(4-morpholinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by reductive amination, by N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 5-(4-morpholinyl) imidazo [1,2-a] pyridine-2-formaldehyde prepares N-methyl-N-{[5-(4-morpholinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine, obtain yellow oil (7% yield), be separated into trifluoroacetate.

¹H?NMR(400MHz，CDCl ₃)δ8.81(d，J＝5.3Hz，1H)，8.18(s，1H)，8.00(d，J＝8.2Hz，1H)，7.75-7.71(m，1H)，7.67-7.60(m，2H)，6.73(d，J＝7.4Hz，1H)，4.41-4.36(m，2H)，4.20(d，J＝14.8Hz，1H)，3.95(m，4H)，3.20(m，4H)，2.94(m，2H)，2.41(m，1H)，2.35(s，3H)，2.20(m，1H)，2.00-1.84(m，2H)；MSm/z?378(M+1).

Embodiment 21:N-(1-Methylethyl)-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine and piperazine prepare N-(1-Methylethyl)-N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (85% yield).

¹H?NMR(300MHz，CDCl ₃)δ8.49(m，1H)，7.71(s，1H)，7.31-7.28(m，2H)，7.15-7.09(m，1H)，7.02(dd，J＝7.6，4.6Hz，1H)，6.23(d，J＝7.2Hz，1H)，4.26(m，1H)，4.00(d，J＝7.1Hz，2H)，3.19(m，4H)，3.11(m，4H)，2.88-2.78(m，1H)，2.73(m，2H)，2.12-1.99(m，3H)，1.68(m，1H)，1.23(d，J＝5.9Hz，3H)，1.17(m，3H)；MS?m/z?405(M+1).

Embodiment 22:N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine and piperazine prepare N-{[5-(1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2,2, the 2-trifluoroethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains white solid (67% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.41(d，J＝4.7Hz，1H)，7.62(s，1H)，7.32(d，J＝7.7Hz，1H)，7.24-7.23(m，1H)，7.13-7.09(m，1H)，7.03(dd，J＝7.6，4.7Hz，1H)，6.23(d，J＝7.2Hz，1H)，4.28(d，J＝16.3Hz，1H)，4.21(dd，J＝10.2，5.8Hz，1H)，4.00-3.89(m，2H)，3.34-3.25(m，1H)，3.16(s，6H)，3.08(m，2H)，2.78-2.66(m，2H)，2.19(m，1H)，1.94(m，1H)，1.83-1.74(m，1H)，1.71-1.65(m，1H)；MS?m/z445(M+1).

Embodiment 23:N-(5-{ (3R)-3-(dimethylamino)-1-pyrrolidinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3R)-(+)-3-(dimethylamino) pyrrolidine prepares N-({ 5-{ (3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (53% yield).

¹H?NMR(300MHz，CDCl ₃)δ8.53(d，J＝4.4Hz，1H)，7.79(m，1H)，7.36(d，J＝7.6Hz，1H)，7.21(d，J＝8.8Hz，1H)，7.10-7.04(m，2H)，6.14(d，J＝7.2Hz，1H)，4.16(m，1H)，4.01(m，2H)，3.60(m，1H)，3.49(m，1H)，3.38-3.27(m，2H)，2.94-2.79(m，2H)，2.73-2.65(m，1H)，2.41(s，3H)，2.32(d，J＝3.1Hz，6H)，2.26-2.14(m，2H)，2.07-1.92(m，3H)，1.69(m，1H)；MS?m/z?405(M+1).

Embodiment 24:N-(5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3S)-(-)-3-(dimethylamino) pyrrolidine prepares N-({ 5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (84% yield).

¹H?NMR(300MHz，CDCl ₃)δ8.54(d，J＝4.5Hz，1H)，7.78(m，1H)，7.36(d，J＝7.7Hz，1H)，7.21(d，J＝8.8Hz，1H)，7.13-7.04(m，2H)，6.15(d，J＝7.2Hz，1H)，4.15(m，1H)，4.00(s，2H)，3.61(m，1H)，3.49(m，1H)，3.38-3.28(m，2H)，2.97-2.79(m，2H)，2.74-2.65(m，1H)，2.41(s，3H)，2.32(m，6H)，2.27-2.13(m，2H)，2.08-1.91(m，3H)，1.70(m，1H)；MS?m/z?405(M+1).

Embodiment 25:N-{[5-(3-amino-1-azetidinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

With N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7, (70mg, (214mg 1.15mmol) handles and in 70 ℃ of heating 15 hours acetonitrile 0.23mmol) (0.5ml) solution 8-tetrahydrochysene-8-quinolinamine with the amino azetidine of 3-N-BOC-.With this reactant with 3: 1 dichloromethane: isopropanol, and wash with saturated sodium bicarbonate aqueous solution.Separate organic layer,, filter, concentrate, through preparation type chromatography purification (0-70% acetonitrile-water through dried over mgso; 0.1% trifluoroacetic acid), use 3: 1 dichloromethane then: isopropanol, wash with saturated sodium bicarbonate aqueous solution, through dried over mgso, obtain 51mg (49% yield) [1-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 3-azetidinyl] carbamic acid 1,1-dimethyl ethyl ester.(50mg 0.11mmol) is dissolved in dichloromethane (0.50ml), handles with trifluoroacetic acid (0.50ml), and stirs 3 hours under room temperature to make the intermediate of this protection.Concentrated reaction mixture, with 3: 1 dichloromethane: isopropanol, and wash with saturated sodium bicarbonate aqueous solution.Separate organic layer,, filter and concentrate, obtain N-{[5-(3-amino-1-azetidinyl) imidazo [1,2-a] pyridine-2-yl through dried over mgso] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (35mg, 88% yield) is yellow oil.

¹H?NMR(300MHz，CDCl ₃)δ8.54(d，J＝4.5Hz，1H)，7.64(s，1H)，7.38(d，J＝7.6Hz，1H)，7.14-7.06(m，3H)，5.84(dd，J＝6.4，1.9Hz，1H)，4.43(m，2H)，4.15(m，1H)，4.05(m，1H)，3.97(s，2H)，3.71(t，J＝6.9Hz，2H)，2.85(m，1H)，2.71(m，1H)，2.38(s，3H)，2.15-1.98(m，3H)，1.71(m，1H)；MS?m/z?363(M+1).

Embodiment 26:N-(5-[3-(dimethylamino)-1-azetidinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

To N-{[5-(3-amino-1-azetidinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7, (31mg adds formaldehyde (21 μ l to 8-tetrahydrochysene-8-quinolinamine in dichloroethanes 0.086mmol) (0.50mL) solution, 0.26mmol, 37% in water), glacial acetic acid (15 μ L, 0.26mmol) and triacetic acid base sodium borohydride (55mg, 0.26mmol).This mixture was stirred under room temperature 15 hours, filter by silica column then, with the acetonitrile solution washing of 10% ammonium hydroxide.Concentrated reaction mixture is with the ethyl acetate dilution, with the saturated sodium bicarbonate aqueous solution washing and through preparation type chromatography purification (0-60% acetonitrile-water; 0.1% trifluoroacetic acid).Separate required product, dilute with ethyl acetate, with saturated sodium bicarbonate aqueous solution washing, through dried over mgso, obtain N-(5-[3-(dimethylamino)-1-azetidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (5mg, 15% yield), be yellow oil.

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.4Hz，1H)，7.74(br，1H)，7.35(d，J＝7.6Hz，1H)，7.09-7.03(m，3H)，5.81(m，1H)，4.23(m，3H)，4.05(br，2H)，3.84(dd，J＝12.7，6.0Hz，2H)，3.24(m，1H)，2.80(m，1H)，2.67(m，1H)，2.43(s，3H)，2.20(s，6H)，2.03-1.97(m，3H)，1.67(m，1H)；MS?m/z?391(M+1).

Embodiment 27:N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping and deprotection, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3R)-(+)-3-(tert-butoxycarbonyl amino) pyrrolidine prepares N-({ 5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (53% yield; 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.48(m，1H)，7.72(s，1H)，7.31(d，J＝7.7Hz，1H)，7.14(d，J＝8.8Hz，1H)，7.06-6.99(m，2H)，6.07(d，J＝7.2Hz，1H)，4.08(m，1H)，3.89(s，2H)，3.74(m，1H)，3.53(m，2H)，3.32(m，1H)，3.15(m，1H)，2.78(m，1H)，2.64(m，1H)，2.30(m，3H)，2.25(m，1H)，2.07(m，1H)，2.00-1.90(m，2H)，1.82(m，1H)，1.63(m，1H)；MS?m/z?377(M+1).

Embodiment 28:N-methyl-N-(5-[methyl (1-methyl-4-piperidyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-methyl-4-(methylamino) piperidines prepare N-methyl-N-({ 5-[methyl (1-methyl-4-piperidyl) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (18% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(m，1H)，7.61(s，1H)，7.34(d，J＝7.6Hz，1H)，7.28-7.25(m，1H)，7.11-7.02(m，2H)，6.27(d，J＝7.1Hz，1H)，4.13(m，1H)，3.98(m，2H)，3.12(m，1H)，2.89-2.66(m，7H)，2.37(s，3H)，2.21(s，3H)，2.13-1.97(m，4H)，1.91-1.65(m，6H)；MSm/z?419(M+1).

Embodiment 29:N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N, N '-dimethyl-3-amino-pyrrolidine prepare N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (29% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.6Hz，1H)，7.71(d，J＝5.7Hz，1H)，7.35(d，J＝7.7Hz，1H)，7.29-7.26(m，1H)，7.11-7.03(m，2H)，6.25(d，J＝7.0Hz，1H)，4.12(m，1H)，4.01(m，1H)，3.93(m，2H)，2.87-2.77(m，2H)，2.74(s，3H)，2.64-2.51(m，4H)，2.40(s，3H)，2.34(d，J＝3.1Hz，3H)，2.17-2.09(m，2H)，2.05-1.99(m，2H)，1.87(m，1H)，1.69(m，1H)；MS?m/z?405(M+1).

Embodiment 30:N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and high piperazine prepare N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (59% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.5Hz，1H)，7.66(s，1H)，7.32(d，J＝7.6Hz，1H)，7.22(d，J＝8.7Hz，1H)，7.09-7.05(m，1H)，7.02(dd，1H)，6.27(d，J＝7.3Hz，1H)，4.09(m，1H)，3.92(s，2H)，3.36-3.27(m，4H)，3.10-3.06(m，4H)，2.78(m，1H)，2.66(m，1H)，2.36(s，3H)，2.10(m，1H)，2.02-1.93(m，4H)，1.66(m，1H)；MS?m/z?391(M+1).

Embodiment 31:N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by reductive amination, by N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and formaldehyde (37% in water) preparation N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains faint yellow oily thing (49% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.50(d，J＝4.4Hz，1H)，7.65(s，1H)，7.32(d，J＝7.7Hz，1H)，7.21(d，J＝8.9Hz，1H)，7.09-7.01(m，2H)，6.24(d，J＝7.2Hz，1H)，4.10(m，1H)，3.92(s，2H)，3.39-3.34(m，4H)，2.82(m，1H)，2.77-2.75(m，4H)，2.66(m，1H)，2.42(s，3H)，2.36(s，3H)，2.11(m，1H)，2.03-1.96(m，4H)，1.67(m，1H)；MS?m/z?405(M+1).

Embodiment 32:N-[(5-{4-[2-(dimethylamino) ethyl]-the 1-piperazinyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by microwave irradiation, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-(2-dimethyl aminoethyl) piperazine prepares N-[(5-{4-[2-(dimethylamino) ethyl]-the 1-piperazinyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (36% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.5Hz，1H)，7.73(s，1H)，7.33(d，J＝7.6Hz，1H)，7.26(d，J＝8.6Hz，1H)，7.11-7.02(m，2H)，6.21(d，J＝7.1Hz，1H)，4.16(m，1H)，4.03-4.01(m，2H)，3.13(s，4H)，2.80(m，2H)，2.72(s，4H)，2.63(m，2H)，2.55(m，2H)，2.38(s，3H)，2.33(s，6H)，2.17(m，1H)，2.02-1.96(m，2H)，1.66(m，1H)；MS?m/z?448(M+1).

Embodiment 33:N-methyl-N-[(5-{4-[2-(methyl oxygen base) ethyl]-the 1-piperazinyl } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-(2-methoxy ethyl) piperazine prepares N-methyl-N-[(5-{4-[2-(methyl oxygen base) ethyl]-the 1-piperazinyl } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (50% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.4Hz，1H)，7.66(s，1H)，7.30(d，J＝7.6Hz，1H)，7.24(d，J＝8.6Hz，1H)，7.09-7.05(m，1H)，7.01(dd，J＝7.5，4.7Hz，1H)，6.19(d，J＝7.1Hz，1H)，4.09(m，1H)，3.93(s，2H)，3.53(m，2H)，3.35(s，3H)，3.12(s，4H)，2.82-2.62(m，8H)，2.35(s，3H)，2.10(m，1H)，2.02-1.92(m，2H)，1.64(m，1H)；MS?m/z?435(M+1).

Embodiment 34:N-cyclopropyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by reductive amination, by N-cyclopropyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde prepares N-cyclopropyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (28% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.6Hz，1H)，7.60(s，1H)，7.31-7.24(m，2H)，7.11-7.07(m，1H)，7.01(dd，J＝7.6，4.6Hz，1H)，6.22(d，J＝7.1Hz，1H)，4.23(m，1H)，4.06(d，J＝4.7Hz，2H)，3.13(s，4H)，2.77(m，2H)，2.66(s，4H)，2.51(m，1H)，2.40(s，3H)，2.11(m，1H)，2.03-1.98(m，2H)，1.66(m，1H)，0.31-0.21(m，4H)；MS?m/z?417(M+1).

Embodiment 35:[1-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 4-piperidyl] carbamic acid 1,1-dimethyl ethyl ester (intermediate)

In similar mode as herein described, by Hot swapping, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 4-(N-BOC-amino) piperidines preparation [1-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 4-piperidyl] carbamic acid 1,1-dimethyl ethyl ester obtains brown solid (49% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.4Hz，1H)，7.61(s，1H)，7.31(d，J＝7.4Hz，1H)，7.26-7.24(m，1H)，7.09-7.05(m，1H)，7.01(dd，J＝7.6，4.6Hz，1H)，6.19(d，J＝7.2Hz，1H)，4.57(s，1H)，4.09(m，1H)，3.93(m，2H)，3.66(m，1H)，3.37(m，2H)，2.81-2.73(m，3H)，2.65(m，1H)，2.36(s，3H)，2.12-1.94(m，5H)，1.69-1，61(m，3H)，1.44(s，9H)；MS?m/z?491(M+1).

Embodiment 36:N-methyl-N-(5-[4-(methylamino)-piperidino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5; 6; 7,8-tetrahydrochysene-8-quinolinamine and 4-(N-BOC-4-N-methylamino) piperidines is by Hot swapping (48% yield) with after trifluoroacetic acid deprotection (51% yield); preparation N-methyl-N-(5-[4-(methylamino)-piperidino] imidazo [1; 2-a] pyridine-2-yl } methyl)-5,6,7; 8-tetrahydrochysene-8-quinolinamine obtains faint yellow oily thing.

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝3.4Hz，1H)，7.58(s，1H)，7.31(d，J＝7.4Hz，1H)，7.25-7.23(m，1H)，7.08-6.99(m，2H)，6.19-6.17(m，1H)，4.09(m，1H)，3.92(s，2H)，3.42(d，J＝10.4Hz，2H)，2.83-2.66(m，4H)，2.58(m，1H)，2.47(s，3H)，2.34(s，3H)，2.10-1.95(m，5H)，1.67-1.54(m，3H)；MSm/z?405(M+1).

Embodiment 37:N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by the trifluoroacetic acid deprotection, by [1-(2-{[methyl (5; 6; 7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 4-piperidyl] carbamic acid 1; 1-dimethyl ethyl ester prepares N-{[5-(4-amino-piperidino) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7; 8-tetrahydrochysene-8-quinolinamine obtains faint yellow oily thing (29% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.2Hz，1H)，7.61(s，1H)，7.34(d，J＝7.6Hz，1H)，7.28-7.26(m，1H)，7.11-7.07(m，1H)，7.04(dd，J＝7.5，4.7Hz，1H)，6.20(d，J＝7.2Hz，1H)，4.11(m，1H)，3.94(s，2H)，3.43(d，J＝11.7Hz，2H)，2.92(m，1H)，2.85-2.65(m，4H)，2.36(s，3H)，2.13(m，1H)，2.04-1.95(m，4H)，1.71-1.60(m，3H)；MS?m/z?391(M+1).

Embodiment 38:N-(5-[4-(dimethylamino)-piperidino] and imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by reductive amination, by N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and formaldehyde (37% in water) preparation N-(5-[4-(dimethylamino)-piperidino] and imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains clarifying grease (73% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝3.3Hz，1H)，7.63(s，1H)，7.33(d，J＝7.7Hz，1H)，7.27-7.25(m，1H)，7.10-7.01(m，2H)，6.19(d，J＝7.1Hz，1H)，4.12(m，1H)，3.95(s，2H)，3.51(d，J＝11.3Hz，2H)，2.80(m，1H)，2.72-2.63(m，3H)，2.37-2.35(m，9H)，2.18-2.10(m，2H)，2.03-1.91(m，4H)，1.82-1.64(m，3H)；MS?m/z?419(M+1).

Embodiment 39:N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) 5,6,7,8-tetrahydrochysene-8-quinolinamine: in the presence of 50mg10%Pd/C, make 6,7-dihydro-8 (5H)-quinoline ketoxime (0.50g, 3.1mmol, Synthetic Communications, 2003,33, the catalytic hydrogenation of 35ml MeOH solution experience 50psi 3497-3502).After 18 hours, use the purging with nitrogen gas reaction vessel, remove catalyst by diatomite filtration, decompression is concentrated into filtrate dried down, obtains 0.42g (92%) 5, and 6,7,8-tetrahydrochysene-8-quinolinamine is purple grease.

¹H?NMR(CDCl ₃)：δ8.39(d，1H)，7.36(d，1H)，7.04(m，1H)，4.00(t，1H)，2.88-2.67(m，2H)，2.18(m，1H)，2.03-1.62(m，5H).

B) N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

To 5,6,7,8-tetrahydrochysene-8-quinolinamine (30mg, 0.20mmol) and 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde (this paper reference) (50mg, 0.20mmol) methanol (2ml) solution in add orthoformic acid trimethyl ester (66 μ l, 0.60mmol).This reactant mixture was stirred 2 hours, and (23mg 0.60mmol), stirs this reactant 1 hour to add sodium borohydride.Reactant mixture concentrates, through preparation type chromatography purification (0-40% acetonitrile-water with saturated aqueous sodium carbonate (1ml) washing; 0.1% trifluoroacetic acid), use 3: 1 dichloromethane then: isopropanol with the saturated sodium bicarbonate aqueous solution washing, through dried over mgso, obtains 18mg (24% yield) yellow oil.

¹H?NMR(400MHz，CDCl ₃)δ8.40(d，J＝4.6Hz，1H)，7.61(s，1H)，7.37(d，J＝7.6Hz，1H)，7.30(d，J＝8.9Hz，1H)，7.16-7.12(m，1H)，7.06(dd，J＝7.7，4.7Hz，1H)，6.26(d，J＝7.2Hz，1H)，4.17(dd，J＝31.6，14.0Hz，2H)，4.01(m，1H)，3.14(s，4H)，2.86-2.72(m，2H)，2.65(s，4H)，2.39(s，3H)，2.22(m，1H)，2.04(m，1H)，1.91(m，1H)，1.75(m，1H)；MS?m/z?377(M+1).

Embodiment 40:N-methyl-N-{[5-(3-pyridine radicals) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by the Suzuki coupling, by N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and pyridine-3-boric acid prepares N-methyl-N-{[5-(3-pyridine radicals) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (7% yield).

¹HNMR(400MHz，CDCl ₃)δ8.84(d，J＝2.3Hz，1H)，8.76(m，1H)，8.49(d，J＝4.4Hz，1H)，8.21-8.13(m，2H)，7.60(d，J＝8.9Hz，1H)，7.55-7.52(m，1H)，7.42-7.40(m，1H)，7.30-7.27(m，1H)，7.15-7.11(m，1H)，6.80(d，J＝7.0Hz，1H)，4.46(br，3H)，2.87-2.67(m，2H)，2.60(s，3H)，2.11-2.00(m，3H)，1.73(m，1H)；MS?m/z?370(M+1).

Embodiment 41:N-[(5-{3-[(dimethylamino) methyl] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by the Suzuki coupling, by N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 3-(N, N-two-methylamino methyl) phenylboric acid pinacol ester (pinocol ester) hydrochlorate prepares the N-[(5-{3-[(dimethylamino) methyl] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (26% yield).

¹H?NMR(400?MHz，CDCl ₃)δ?8.39(d，J＝4.7Hz，1H)，7.77(s，1H)，7.53-7.49(m，3H)，7.46-7.40(m，2H)，7.30(d，J＝7.6Hz，1H)，7.18-7.14(m，1H)，7.01-6.98(m，1H)，6.68(d，J＝7.0Hz，1H)，4.07(m，1H)，3.91(s，2H)，3.47(s，2H)，2.78(m，1H)，2.64(m，1H)，2.31(s，3H)，2.25(s，6H)，2.10(m，1H)，2.02-1.93(m，2H)，1.65(m，1H)；MS?m/z?426(M+1).

Embodiment 42:N-[(5-(2-[(dimethylamino) methyl] phenyl } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by the Suzuki coupling, by N-[(5-bromo imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 2-(N, the N-dimethylaminomethyl) phenylboric acid prepare N-{ (5-(2-[(dimethylamino) methyl] phenyl imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (15% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.36(d，J＝4.4Hz，1H)，7.67-7.58(m，1H)，7.54(d，J＝8.8Hz，1H)，7.50-7.46(m，1H)，7.38-7.33(m，1H)，7.31-7.29(m，2H)，7.26-7.24(m，1H)，7.20-7.16(m，1H)，7.00-6.97(m，1H)，6.63(d，J＝6.8Hz，1H)，4.03(m，1H)，3.95-3.86(m，2H)，3.26-3.12(m，1H)，3.00-2.84(m，1H)，2.81-2.73(m，1H)，2.66-2.60(m，1H)，2.30(s，3H)，2.08(m，1H)，2.00(s，3H)，1.93(m，2H)，1.86(s，3H)，1.62(m，1H)；MS?m/z?426(M+1).

Embodiment 43:N-[(5-aminooimidazole is [1,2-a] pyridine-2-yl also) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) (5-bromo imidazo [1,2-a] pyridine-2-yl) methanol:

In 0 ℃, (6.54g, (1.32g 34.9mmol) handles methanol 29.1mmol) (140mL) solution with sodium borohydride with 5-bromo imidazo [1,2-a] pyridine-2-formaldehyde.Make reactant slowly be warming up to room temperature, stirred 2 hours, the water quencher, and extract with the ethyl acetate solution of 10% methanol.Merge organic layer,, obtain (5-bromo imidazo [1,2-a] pyridine-2-yl) methanol (5.82g, 88% yield), be brown solid through dried over mgso and concentrated. ¹H-NMR(CDCl ₃)：δ7.76(s，1H)，7.55(d，1H)，7.11-7.07(m，1H)，7.03(m，1H)，4.87(s，2H)；MS?m/z?228(M+1)。

B) 5-[(diphenyl methylene) and amino] imidazo [1,2-a] pyridine-2-yl } methanol:

With (5-bromo imidazo [1,2-a] pyridine-2-yl) methanol (1.0g, 4.40mmol), 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (986mg, 1.58mmol) and cesium carbonate (4.30g, toluene 13.2mmol) (20mL) solution is with benzophenone imines (2.22mL, 13.2mmol) and acid chloride (11) (119mg, 0.53mmol) processing.This reactant 100 ℃ of heating 15 hours, is diluted with ethyl acetate, and wash with saturated sodium bicarbonate aqueous solution.Separate organic layer, and water liquid is with other ethyl acetate extraction.Merge organic layer,, filter, concentrate,, obtain 0.80g (56% yield) { 5-[(diphenyl methylene) amino] imidazo [1,2-a] pyridine-2-yl } methanol through flash chromatography purification (0-7.5% ammonium hydroxide is in acetonitrile) through dried over mgso.

¹H?NMR(400MHz，CDCl ₃)δ7.87(d，J＝7.4Hz，2H)，7.68(s，1H)，7.57(m，1H)，7.49-7.45(m，2H)，7.38(m，1H)，7.32-7.28(m，2H)，7.24(m，1H)，7.10(d，J＝7.1Hz，2H)，6.92(m，1H)，5.67(d，J＝7.1Hz，1H)，4.90(s，2H)，3.53(br，1H)；MS?m/z?328(M+1).

C) amino 5-[(diphenyl methylene)] imidazo [1,2-a] pyridine-2-formaldehyde:

Will 5-[(diphenyl methylene) and amino] imidazo [1,2-a] pyridine-2-yl } (100mg, (266mg 3.05mmol) handles and stirred 15 hours under room temperature chloroform 0.305mmol) (3mL) solution methanol with manganese dioxide.Reactant mixture is used the dichloromethane fine laundering by diatomite filtration, concentrates the 5-[(diphenyl methylene that obtains quantitative output (99mg)) amino] imidazo [1,2-a] pyridine-2-formaldehyde.

¹H?NMR(400MHz，CDCl ₃)δ10.15(s，1H)，8.33(s，1H)，7.85(d，J＝7.8Hz，2H)，7.56(t，J＝7.5Hz，1H)，7.47-7.43(m，2H)，7.38(d，J＝7.5Hz，1H)，7.32-7.28(m，3H)，7.08(d，J＝7.5Hz，2H)，7.00(dd，J＝9.0，7.4Hz，1H)，5.73(d，J＝7.1Hz，1H).

D) N-({ 5-[(diphenyl methylene) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In similar mode as herein described, by reductive amination, by N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 5-[(diphenyl methylene) amino] imidazo [1,2-a] pyridine-2-formaldehyde prepares N-({ 5-[(diphenyl methylene) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains the required product of 140mg (99% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.42(m，1H)，7.86(d，J＝7.9Hz，3H)，7.57(t，J＝7.3Hz，1H)，7.46(t，J＝7.7Hz，2H)，7.34(m，2H)，7.24-7.20(m，3H)，7.09(d，J＝7.5Hz，2H)，7.03(dd，J＝7.5，4.7Hz，1H)，6.88(m，1H)，5.67(d，J＝7.1Hz，1H)，4.16(m，1H)，4.03(s，2H)，2.82(m，1H)，2.69(m，1H)，2.45(s，3H)，2.17(m，1H)，2.06-1.96(m，2H)，1.69(m，1H)；MS?m/z472(M+1).

E) methyl N-[(5-aminooimidazole [1,2-a] pyridine-2-yl also)]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In 0 ℃, with N-({ 5-[(diphenyl methylene) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (140mg, handle by being added dropwise to 4N hydrochloric acid (2mL) by oxolane 0.29mmol) (10mL) solution.This reactant was stirred 1.5 hours, dilute, and wash with saturated sodium bicarbonate aqueous solution with ethyl acetate.Separate organic layer, and water liquid is with other ethyl acetate extraction.Merge organic layer, through dried over mgso, filter, concentrate, filter purification by silicagel column and (use 100% ethyl acetate rinse, acetonitrile solution with 10% ammonium hydroxide washes then), obtain also [1,2-a] pyridine-2-yl of 56mg (63% yield) N-[(5-aminooimidazole) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine is brown solid.

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.4Hz，1H)，7.68(s，1H)，7.34(d，J＝7.7Hz，1H)，7.07-6.99(m，3H)，6.01(d，J＝6.9Hz，1H)，4.10(m，1H)，3.90(s，2H)，2.85-2.75(m，1H)，2.71-2.63(m，1H)，2.38(s，3H)，2.17-2.10(m，1H)，2.05-1.90(m，2H)，1.71-1.63(m，1H)；MS?m/z?308(M+1).

Embodiment 44:N-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 3-ascorbyl palmitate

With N-[(5-aminooimidazole also [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (50mg, dichloromethane 0.16mmol) (1mL) solution N, N-diisopropyl ethyl amine (111 μ L, 0.64mmol) and nicotinoyl chlorine hydrochlorate (57mg, 0.32mmol) processing.This reactant was stirred under room temperature 15 hours, the water quencher, and be extracted in the dichloromethane.Merge organic layer,, filter, concentrate and through preparation type chromatography purification (0-50% acetonitrile-water through dried over mgso; 0.1% trifluoroacetic acid), dilute with dichloromethane then, wash with saturated sodium bicarbonate aqueous solution, with through dried over mgso, obtain 27mg (41% yield) N-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 3-ascorbyl palmitate, be yellow solid.

¹H?NMR(400MHz，CDCl ₃)δ9.35(m，1H)，8.65(dd，J＝4.8，1.4Hz，1H)，8.41(m，1H)，8.37(d，J＝4.5Hz，1H)，8.00(s，1H)，7.42-7.37(m，2H)，?7.31(dd，J＝7.9，4.9Hz，1H)，7.22-7.20(m，1H)，7.11-7.06(m，2H)，4.13(m，1H)，4.03-3.97(m，2H)，2.84-2.76(m，1H)，2.73-2.66(m，1H)，2.26(s，3H)，2.14(m，1H)，2.02(m，1H)，1.90(m，1H)，1.68(m，1H)；MSm/z?413(M+1).

Embodiment 45:N-(2-{[methyl (5,6,7,8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine-5-yl)-the 4-ascorbyl palmitate

In similar mode as herein described; by acylation, by N-[(5-aminooimidazole [1,2-a] pyridine-2-yl also) methyl]-N-methyl-5; 6; 7,8-tetrahydrochysene-8-quinolinamine and different nicotinoyl chlorine hydrochlorate prepare N-(2-{[methyl (5,6; 7; 8-tetrahydrochysene-8-quinolyl) amino] methyl } imidazo [1,2-a] pyridine--base)-the 4-ascorbyl palmitate, obtain 7mg (13% yield) yellow solid.

¹H?NMR(400MHz，CDCl ₃)δ8.69-8.68(m，2H)，8.42(d，J＝4.2Hz，1H)，8.02-7.98(m，3H)，7.62(br，1H)，7.45(d，J＝7.7Hz，1H)，7.34(t，J＝8.0Hz，1H)，7.14(dd，J＝7.6，4.8Hz，1H)，7.02(d，J＝8.4Hz，1H)，4.06(m，1H)，3.97-3.86(m，2H)，2.82(m，1H)，2.73(m，1H)，2.28(s，3H)，2.1-2.02(m，2H)，1.98-1.89(m，1H)，1.71(m，1H)；MS?m/z?413(M+1).

Embodiment 46:N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7-dihydro-5H-cyclopenta [b] pyridine-7-amine

A) 6,7-dihydro-5H-cyclopenta [b] pyridine-7-alcohol:

To 6, (24.50g adds 30% aqueous hydrogen peroxide solution (35ml) and also this mixture was heated 16 hours in 70 ℃ 7-dihydro-5H-cyclopenta [b] pyridine in 100mL glacial acetic acid solution 200mmol).Concentrated reaction mixture is dissolved in the chloroform residue.Adding solid sodium carbonate (100g) also stirs this mixture 16 hours.The elimination solid also concentrates washing liquid.Residue is dissolved in the acetic anhydride (400mL) and with this mixture to be heated 16 hours in 90 ℃.Concentrate this mixture.The careful 500mL aqueous solution that adds potassium carbonate (50g) bubbles with control.Adding other solid carbonic acid potassium is alkalescence until aqueous solution.Add methanol (40mL) and with this mixture heated to 70 ℃ 48 hours.Make this mixture be cooled to room temperature, use dichloromethane extraction 3 times.The organic layer that merges is concentrated into remaining grease, makes it leave standstill crystallization.Make this solid be dissolved in dichloromethane, precipitate with hexane.Solid collected by filtration.By the silicagel column purified product, the methanol of the 2M ammonia solution with 3% and dichloromethane are as co-elute liquid (co-eluent).Concentrate washing liquid, remaining solid recrystallization from dichloromethane and hexane obtains 8.2g (30%) 6,7-dihydro-5H-cyclopenta [b] pyridine-7-alcohol.

¹H?NMR(400MHz，CDCl ₃)δ2.1(m，1H)，2.6(m，1H)，2.8(m，1H)，3.1(m，1H)，3.9(bs，1H)，5.3(t，1H)，7.2(dd，J＝7.5，4.9Hz，1H)，7.6(d，J＝7.7Hz，1H)，8.4(d，J＝5.7Hz，1H).)；MS?m/z?136(M+1).

B) 5,6-dihydro-7H-cyclopenta [b] pyridin-7-one:

To 6,7-dihydro-5H-cyclopenta [b] pyridine-7-alcohol (2.0g, add in 35mL dichloromethane solution 15mmol) manganese dioxide (12g, 130mmol).This mixture was stirred under room temperature 16 hours.By kieselguhr elimination solid and concentrated washing liquid.Residue is used eluent ethyl acetate by the silicagel column purification.Concentrate washing liquid, obtain 1.2g (60%) 5,6-dihydro-7H-cyclopenta [b] pyridin-7-one.

¹H?NMR(400?MHz，CDCl ₃)δ?2.8(m，2?H)，3.2(t，J＝5.7Hz，2H)，7.4(dd，J＝7.9，4.6Hz，1H)，7.9(d，J＝9.3Hz，1H)，8.8(d，J＝4.6Hz，1H).MS?m/z?134(M+1).

C) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7-dihydro-5H-cyclopenta [b] pyridine-7-amine

In similar mode as herein described, by reductive amination, by 5,6-dihydro-7H-cyclopenta [b] pyridin-7-one and methyl amine prepare N-methyl-6,7-dihydro-5H-cyclopenta [d] pyridine-7-amine obtains 27mg (54% yield) crude product yellow oil.In similar mode as herein described, pass through reductive amination, by N-methyl-6,7-dihydro-5H-cyclopenta [b] pyridine-7-amine and 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde prepares N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7-dihydro-5H-cyclopenta [b] pyridine-7-amine obtains 18mg (26% yield) yellow oil.

¹H?NMR(300MHz，CDCl ₃)δ8.52(d，J＝4.7Hz，1H)，7.72(s，1H)，7.54(d，J＝7.5Hz，1H)，7.32(m，1H)，7.17-7.11(m，2H)，6.30(d，J＝7.2Hz，1H)，4.60(m，1H)，4.04(s，2H)，3.19(s，4H)，3.01(m，1H)，2.87(m，1H)，2.72(s，4H)，2.45(s，3H)，2.39(s，3H)，2.34-2.27(m，2H)；MSm/z?377(M+1).

Embodiment 47:N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine

A) 6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-alcohol:

To 6,7,8, (26.32g adds 30% aqueous hydrogen peroxide solution (36mL) and also this mixture was heated 16 hours in 70 ℃ 9-tetrahydrochysene-5H-cyclohepta [b] pyridine in 100ml glacial acetic acid solution 179mmol).Concentrated reaction mixture is dissolved in the chloroform residue.Adding solid sodium carbonate (100g) also stirs this mixture 2 hours.The elimination solid also concentrates washing liquid.Residue is dissolved in the acetic anhydride (400mL) and with this mixture to be heated 48 hours in 90 ℃.Concentrate this mixture, make in the residue water-soluble (500mL), carefully be added dropwise to potassium carbonate (50g).Add methanol (20mL) and with this mixture heated to 70 ℃ 16 hours.Make the cooling of this mixture and with 150mL dichloromethane extraction 3 times.Merge organic layer and concentrated.Residue is through the silica gel column chromatography purification, with the 1%-2% gradient liquid washing of 2M ammonia/methanol in dichloromethane.Concentrate suitable flow point, obtain 6.97g (24%) 6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-alcohol.

¹H?NMR(400MHz，CDCl ₃)δ1.2(m，1H)，1.4(m，1H)，1.8(m，1H)，2.0(m，1H)，2.1(m，1H)，2.2(m，1H)，2.7(m，2H)，4.8(d，J＝11.2Hz，1H)，5.9(s，1H)，7.1(dd，J＝7.5，4.9Hz，1H)，7.4(d，J＝7.3Hz，1H)，8.4(d，J＝4.8Hz，1H)；MS?m/z?164(M+1).

B) 5,6,7,8-tetrahydrochysene-9H-cyclohepta [b] pyridine-9-ketone:

(23mL 46mmol) adds dimethyl sulfoxine (7.1mL, dichloromethane 100mmol) (20mL) solution in the solution in dichloromethane (150mL) to the dichloromethane of-78 ℃ 2M oxalyl chlorides.This mixture was stirred 10 minutes and be added dropwise to 6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-alcohol (6.9g, 30mL dichloromethane solution 42mmol).With this mixture stir be added dropwise in 30 minutes triethylamine (21g, 210mmol).Make this mixture be warmed to room temperature and stirred 1 hour.This mixture is washed with water, through dried over mgso and concentrated.Be concentrated into and form a solid, remove by filter it.Concentrate washing liquid, residue is used eluent ethyl acetate through the silica gel column chromatography purification.Concentrate suitable flow point, obtain 5.12g (74%) 5,6,7,8-tetrahydrochysene-9H-cyclohepta [b] pyridine-9-ketone. ¹H?NMR(400MHz，CDCl ₃)δ1.9(m，4H)，2.8(m，2H)，2.9(m，2H)，7.3(m，1H)，7.6(d，1H)，1.9(d，1H)；MS?m/z?162(M+1)。

C) N-methyl-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine:

In similar mode as herein described, by reductive amination, by 5,6,7,8-tetrahydrochysene-9H-cyclohepta [b] pyridine-9-ketone and methyl amine prepare N-methyl-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine obtains 23mg (38% yield) yellow oil.

¹H?NMR(400MHz，CDCl ₃)δ8.33(m，1H)，7.33(d，J＝7.4Hz，1H)，7.00(dd，J＝7.3，4.9Hz，1H)，3.75(d，J＝9.5Hz，1H)，2.81(m，1H)，2.73(m，1H)，2.59(s，1H)，2.44(s，3H)，1.98(m，2H)，1.77(m，2H)，1.43(m，2H).

D) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine:

In similar mode as herein described, by reductive amination, by N-methyl-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine and 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde prepare N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7,8,9-tetrahydrochysene-5H-cyclohepta [b] pyridine-9-amine obtains the white grease of 34mg (64% yield).

¹H?NMR(300MHz，CDCl ₃)δ8.36(m，1H)，7.53(s，1H)，7.39-7.31(m，2H)，7.15(dd，J＝9.0，7.2Hz，1H)，7.06(dd，J＝7.4，4.9Hz，1H)，6.28(d，J＝7.0Hz，1H)，3.88-3.62(m，4H)，3.19(s，4H)，2.71(s，4H)，2.55(m，1H)，2.45(s，3H)，2.33(s，3H)，2.26(m，2H)，1.95(m，1H)，1.80(m，2H)，1.48(m，1H)；MS?m/z?405(M+1).

Embodiment 48:(8S)-and N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) 6-fluoro-2-pyridine amine:

With 2, (50g, (200ml, 28.0-30.0%) solution played in the shape bottle in sealing ammonium hydroxide 434mmol) the 6-difluoro pyridine, in 105 ℃ of heating 15 hours.This reactant is cooled off in ice bath and filtering-depositing, use cold water washing, drying obtains 6-fluoro-2-pyridine amine (45.8g, 94% yield), is white solid. ¹H-NMR(CDCl ₃)：δ7.53(m，1H)16.36(dd，1H)，6.26(dd，1H)，4.56(s，2H)。

B) 2-(dichloromethyl)-5-fluoro imidazo [1,2-a] pyridine:

(67g, glycol dimethyl ether 0.60mol) (570mL) solution are with 1,1, and (190ml 1.80mol) handles the 3-trichloroacetone, and heats 15 hours in 85 ℃ with 6-fluoro-2-pyridine amine.This reactant is cooled off in ice bath and filtering-depositing, use hexane wash, drying obtains 2-(dichloromethyl)-5-fluoro imidazo [1,2-a] pyridine (85g, 65% yield), is the olive green solid. ¹H-NMR(CDCl ₃)：δ8.18(s，1H)，7.60(s，1H)，7.54-7.46(m，2H)，6.93(m，1H).

C) 5-fluoro imidazo [1,2-a] pyridine-2-formaldehyde:

(103g, (96g 1.17mol) handles and in 60 ℃ of heating 2 hours with sodium acetate for ethanol 470mmol) (300mL) and water (600mL) solution with 2-(dichloromethyl)-5-fluoro imidazo [1,2-a] pyridine.The cooling reactant, through diatomite filtration, vacuum concentration is to remove ethanol.With twice of chloroform extraction water liquid and merge Organic substance, water and salt water washing are through dried over sodium sulfate and concentrate.Residue filters by the silicon dioxide pad, with dichloromethane and ethyl acetate fine laundering, concentrates, and grinds with hexane, filters, and drying obtains 5-fluoro imidazo [1,2-a] pyridine-2-formaldehyde (40g, 52% yield), is brown solid. ¹H-NMR (CDCl ₃): δ 10.17 (s, 1H), 8.22 (s, 1H), 7.57 (d, 1H), 7.38-7.32 (m, 1H), 6.60 (m, 1H); TLC (methanol-ethyl acetate solution of 10%2M ammonia) R _f=0.60.

D) (5-fluoro imidazo [1,2-a] pyridine-2-yl) methanol:

In 0 ℃, (80g, (24g 640mmol) handles methanol 490mmol) (1L) solution by add sodium borohydride in batches with 5-fluoro imidazo [1,2-a] pyridine-2-formaldehyde.Make reactant slowly be warming up to room temperature, stirred 2 hours, the water quencher concentrates, and is dissolved in 3: 1 dichloromethane: in the isopropyl alcohol, and wash with saturated sodium bicarbonate aqueous solution.Separate organic layer, with 3: 1 dichloromethane: isopropanol extraction water liquid 4 times.Merge organic layer,, concentrate, grind, filter and obtain (5-fluoro imidazo [1,2-a] pyridine-2-yl) methanol (76g, 93% yield), be brown solid with hexane through dried over sodium sulfate. ¹H-NMR(CDCl ₃)：δ7.59(s，1H)，7.38(d，1H)，7.21-7.15(m，1H)，6.43(m，1H)，4.85(s，2H)，4.45(s，1H)。

E) [5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methanol:

(76g, 1-methyl piperazine (150mL) solution 460mmol) was in 70 ℃ of heating 15 hours with (5-fluoro imidazo [1,2-a] pyridine-2-yl) methanol.Reaction mixture in the impouring 1.3L saline, is extracted into 3: 1 chloroforms: in the isopropyl alcohol.The extract that merges is through dried over sodium sulfate, and vacuum concentration with the hexane azeotropic, grinds with ether, obtains [5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methanol (101g, 90% yield), is brown solid. ¹H-NMR(CDCl ₃)：δ7.51(s，1H)，7.33(d，1H)，7.21-7.17(m，1H)，6.31(m，1H)，4.87(s，2H)，3.17(s，4H)，2.68(s，4H)，2.42(s，3H)。

F) 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde:

(101g, (360g 4100mmol) handles and stirred 72 hours under room temperature chloroform 410mmol) (1650mL) solution with manganese dioxide with [5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methanol.Reactant mixture with chloroform fine laundering and concentrated, obtains 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde (82g, 82% yield) by diatomite filtration, is golden solid.

¹H-NMR(CDCl ₃)：δ10.17(s，1H)，8.15(s，1H)，7.44(d，1H)，7.31-7.27(m，1H)，6.40(m，1H)，3.16(s，4H)，2.68(s，4H)，2.42(s，3H).

G) (8S)-and N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

With (S)-(-)-1-(4-methoxyphenyl) ethylamine (25g, 166mmol) with 6,7-dihydro-8 (5H)-quinolinone (24g, the glacial acetic acid (14ml of dichloromethane solution 166mmol), 249mmol) (53g 249mmol) handles with triacetic acid base sodium borohydride.This reactant mixture was stirred under room temperature 15 hours, and (106g is 996mmol) with stirring 30 minutes with the sodium carbonate processing.This mixture is diluted with dichloromethane, separate organic layer, with other dichloromethane extraction water liquid.Merge organic layer, through dried over mgso, concentrate, through column chromatography purification (methanol/dichloromethane solution of 0-3%2M ammonia), obtain yellow oil, with its crystallization from hexane, obtain (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine (33g, 70% yield) is transparent crystallization.

¹H-NMR(CDCl ₃)：δ8.40(m，1H)，7.33(m，3H)，7.04(m，1H)，6.84(d，2H)，4.02(m，1H)，3.83-3.78(m，4H)，2.73-2.62(m，2H)，1.82(m，1H)，1.72(m，1H)，1.57(m，2H)，1.43(d，3H).

H) (8S)-and N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

With 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde (2.83g, 11.6mmol) and (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine (3.27g, 11.6mmol) dichloroethanes (40mL) solution with glacial acetic acid (1.0mL, 17.4mmol) and triacetic acid base sodium borohydride (3.68g, 17.4mmol add in batches) handle and under room temperature, stirred 15 hours.Reactant mixture dilutes with dichloromethane, with the saturated sodium bicarbonate aqueous solution washing, separates, and uses other dichloromethane extraction.Merge organic layer, use the salt water washing,, concentrate, through flash chromatography purification (0-4% ammonium hydroxide is in acetonitrile) through dried over sodium sulfate.Residue is dissolved in the dichloromethane, and stir with the methanol solution of 2M ammonia, obtain (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine (5.13g, 87% yield), be the weak yellow foam thing.

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.6Hz，1H)，7.78(s，1H)，7.60-7.58(m，2H)，7.24-7.18(m，2H)，7.09-7.05(m，1H)，6.97(dd，J＝7.6，4.7Hz，1H)，6.84-6.82(m，2H)，6.21(d，J＝7.2Hz，1H)，4.82(m，1H)，4.07(m，1H)，3.91(dd，J＝56.9，17.1Hz，2H)，3.77(s，3H)，3.19-3.13(m，4H)，2.74(s，4H)，2.67-2.53(m，2H)，2.47(s，3H)，2.06(m，1H)，1.85(m，2H)，1.53(m，1H)，1.34(d，J＝6.4Hz，3H)；MS?m/z?511(M+1).

Embodiment 49:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

With (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine (569mg, handle with trifluoroacetic acid (1.11ml) and stirred 4 hours under room temperature by dichloromethane 1.11mmol) (11.1ml) solution.The concentration response thing dilutes with dichloromethane, and washs with saturated sodium bicarbonate aqueous solution.Separate organic layer and water liquid dichloromethane extraction.Merge organic layer,, filter and concentrate, obtain (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl through dried over mgso] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is yellow residue.

¹H-NMR(CDCl ₃)：δ8.41(d，1H)，7.65(s，1H)，7.39(d，1H)，7.31(m，1H)，7.16(m，1H)，7.09(m，1H)，6.27(dd，1H)，4.31-4.17(m，2H)，4.05(m，1H)，3.15(m，4H)，2.88-2.78(m，2H)，2.67(m，4H)，2.41(s，3H)，2.29(m，1H)，2.08(m，1H)，1.96(m，1H)，1.77(m，1H).

Embodiment 50:(8S)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

Make (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is dissolved in dichloroethanes (10ml) and uses formaldehyde (166 μ l, 2.22mmol, 37wt.% aqueous solution), glacial acetic acid (96 μ l, 1.67mmol), (353mg 1.67mmol) handles and stirred 15 hours under room temperature triacetic acid base sodium borohydride.Wash with dichloromethane diluting reaction thing and with saturated sodium bicarbonate aqueous solution.Separate organic layer and water liquid dichloromethane extraction.Merge organic layer, through dried over mgso, filter, concentrate, through flash chromatography purification (0-10% ammonium hydroxide is in acetonitrile), obtain 0.276g (64% derives from (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine) (8S)-N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is faint yellow oily thing.

¹H-NMR(CDCl ₃)：δ8.52(d，1H)，7.70(s，1H)，7.34(d，1H)，7.28(d，1H)，7.10(m，1H)，7.06(m，1H)，6.23(dd，1H)，4.12(m，1H)，3.96(s，2H)，3.14(m，4H)，2.86-2.78(m，2H)，2.71-2.65(m，4H)，2.41(s，3H)，2.39(s，3H)，2.16(m，1H)，2.06-1.97(m，2H)，1.68(m，1H)；MS?m/z391(M+1). ¹³C-NMR(CDCl ₃)：δ158.0，147.0，146.2，145.5，145.2，136.4，134.1，124.7，121.4，111.9，107.9，98.9，62.5，55.0，55.0，53.1，49.5，49.5，46.1，39.0，29.2，24.2，21.1；

HRMS: calculated mass: 391.2610; Actual measurement quality: 391.2614; Formula: C ₂₃H ₃₁N ₆To C ₂₃H ₃₀N ₆The analytical calculation value: C, 70.74; H, 7.74; N, 21.52 measured values: C, 70.36; H., 7.77; N, 21.53.

Perhaps (8S)-N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is can following mode synthetic:

A) 5-bromo imidazo [1,2-a] pyridine-2-formaldehyde:

In reactor, pack into 2-amino-6-pyridine bromide (3.0Kg, 17.3mol) and dimethoxy-ethane (12 liters) and under nitrogen, stirring.With 1,1, (5.6Kg, 30.3mol) disposable joining in 25 ℃ the solution is warmed to 65 ℃ jacket temperature with this reaction solution to the 3-trichloroacetone, and keeps about 2-4 hour until judging that reaction finishes.This reactant is cooled to 10 ℃ and kept about 1 hour and filtered.Wash this solid with dimethoxy-ethane (6 liters).This solid is put back in the reactor and is handled with dimethoxy-ethane (12 liters) and 2N HCI (12 liters), be warmed to about 75 ℃ 16-20 hour or finish until judging to react.Reactant is cooled to about 10 ℃, with 3N NaOH with pH regulator to about 8.Filter the solid that generates, wash with water.This solid in 50 ℃ of dryings 16 hours, is obtained 5-bromo imidazo [1,2-a] pyridine-2-formaldehyde, (2.81Kg, 72% yield) ¹H NMR (400MHz, DMSO-D ₆) δ ppm 10.05 (s, 1H) 8.66 (s, 1H) 7.72 (s, 1H) 7.42 (s, and 1H) 7.35 (s, 1H)

B) 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde

Packing in reactor, (3.1Kg 31mol) and oxolane (10 liters) and stirring, is cooled to-20 ℃ to N methyl piperazine simultaneously under nitrogen.Keeping the speed of-20 ℃ of temperature, (10.4L 26.0mol) joined in the reactant, with this contents stirred 15-30 minute with n-BuLi.To keep reactant in 0 ℃ speed adding 5-bromo imidazo [1,2-a] pyridine-2-formaldehyde (2.79Kg, 12.4mol) slurry in oxolane (10 liters).Wash this slurry with other oxolane (6 liters), this reactant was stirred 30 minutes, and be warmed to-10 ℃ approximately.Make and reach pH 4.0 and come the quencher reaction by adding 6N HCI solution, be maintained at simultaneously≤15 ℃.With heptane (14 liters) diluting reaction thing and separate each layer.Drain following water-bearing layer, and top organic layer washs with 1N HCl (2 * 1.5 liters).In 20 ℃ of water-bearing layers that stir to merge, and be adjusted to pH 9, use 10%iPrOH/CH with 4N NaOH solution ₂Cl ₂(3 * 28 liters) extract the water-bearing layer, and the saturated NaHCO of organic layer that merges ₃Solution (14 liters) washing, be evaporated to about 3 volumes in＜25 ℃, add isopropyl alcohol (28 liters), reactant is evaporated to about 8.5 liters once more, add isopropyl alcohol (17 liters), with the temperature of the speed of keeping good stirring and about 25-40 ℃, usefulness oxalic acid (1.0Kg, isopropyl alcohol 11.1mol) (7 liters) solution-treated reactant.Reaction stirred 30 minutes is filtered and is collected this solid and use isopropyl alcohol (8.5 liters) washing.In 50 ℃ of these solids of drying, obtain 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde, (2.25Kg, 54% yield) ¹H NMR (400MHz, DMSO-D ₆) δ ppm 10.01 (s, 1H) 8.47 (s, 1H) 7.41 (m, 2H) 6.65 (m, 1H) 3.34 (s, and 8H) 2.78 (s, 3H)

C) (8S)-and N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

With triacetic acid base sodium borohydride (4.54Kg, 21.4mol.) slurry in dichloromethane (22 liters) is with 6, (1.8Kg 12.3mol.) handles 7-dihydro-8 (5H)-quinolinone, then with (1S)-1-[4-(methyl oxygen base) phenyl] ethamine (1.8Kg, 11.9mol) .) handle.With this reactant in 22 ℃ of vigorous stirring 24 hours.Making water layer reach pH 8 with 1N NaOH (about 27 liters) reacts with quencher.Separate each phase, make water layer reach pH 11 with 1N sodium hydroxide (about 3.5 liters) and handle.Separate each phase.Then dichloromethane solution is concentrated into minimum volume, handles with heptane (18 liters).Volume is concentrated into about 9 liters once more.When being cooled to 22 ℃, precipitate.Suspension further is cooled to 0 ℃ and filtration.Dry this solid obtains (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl under room temperature, blanket of nitrogen] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine.(2.18Kg，63％)

1H?NMR(400MHz，DMSO-D6)δppm?8.36(m，1H)7.44(m，1H)7.29(m，2H)7.15(m，1H)6.83(m，2H)4.00(m，1H)3.70(s，3H)3.59-3.64(m，1H)2.66(m，1H)2.64(s，1H)2.53(s，1H)1.76(s，1H)1.64(s，1H)1.50(s，1H)1.39(s，1H)1.24(m，3H)

D) (8S)-and N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

With triacetic acid base sodium borohydride (2.44Kg, 11.5molo) and (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl-5,6,7, (2.17Kg, 7.7mol.) slurry in dichloromethane (21.8 liters) is cooled to 5 ℃ to 8-tetrahydrochysene-8-quinolinamine.(37wt.% is in water, and 744ml 10mol.), is lower than 25 ℃ with holding temperature slowly to add formalin.In 22 ℃ with this solution stirring 30 minutes.Slowly add trifluoroacetic acid (7.3 liters 95mol.) are reacted with quencher.Add finish after, this reactant be warmed to be up to 30 ℃ and stirred 16 hours.Add entry (11 liters), separate biphase.With dichloromethane (14 liters) washing water, and the organic facies that merges washes (2 * 5.5 liters) with water.Discard organic facies.Make the pH of water rise to 8.5-9 by adding 6N NaOH, water layer extracts with dichloromethane (3 * 13 liters).Replace isopropyl alcohol with dichloromethane and make the final volume that reaches about 75 liters.(588g, this solution of isopropyl alcohol 6.5Mol.) (2.2 liters) solution-treated is with induced precipitation to use oxalic acid then.Stir after 2 hours, in 22 ℃ of filtering suspension liquids,, obtain (8S)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine oxalates in 22 ℃ of these solids of drying.(1.07Kg, 55% yield) ¹H NMR (300MHz, DMSO-D ₆) δ ppm 9.25 (br s, 1H) 8.52 (s, 1H) 7.69 (s, 1H) 7.39 (s, 1H) 4.39 (s, 1H) 2.82 (s, 2H) 2.65 (s, 3H) 2.50 (s, 1H) 2.32 (s, 1H) 1.99 (s, and 1H) 1.80 (s, 1H);

For (the 8S)-N-methyl-5,6,7 that is free alkali, 8-tetrahydrochysene-8-quinolinamine: ¹H-NMR (CDCl ₃): δ 8.37 (d, 1H), 7.36 (d, 1H), 7.06 (dd, 1H), 3.65 (m, 1H), 2.76 (m, 2H), 2.53 (s, 3H), 2.11 (m, 1H), 1.97 (m, 1H), 1.75 (m, 2H); MS m/z163 (M+1).

E) (8S)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

(0.63g, 2.97mmol) and (8S)-N-methyl-5,6,7, (0.5g, 1.98mmol.) slurry in DCM (50ml.) is in 20 ℃ of stirrings for 8-tetrahydrochysene-8-quinolinamine with triacetic acid base sodium borohydride.(0.84g 2.97mmol.), stirs this reactant 16 hours in 20 ℃ to wherein adding 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde oxalates.Make with 2N NaOH and to reach pH 12 and react with quencher, separate each layer, (3 * 10ml) washings flash to grease with the organic layer that merges with other dichloromethane in the water-bearing layer, it is dry under fine vacuum, obtain (8S)-N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is brown oil (0.6g, 77%) ¹H NMR is in top identical.

Embodiment 51:(8R)-and N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) 2-(chloro methyl)-5-fluoro imidazo [1,2-a] pyridine:

(6.7g, ethyl acetate 60mmol) (30mL) solution be with being dissolved in 1 of ethyl acetate (15mL), and (15g 120mmol) handles and in 65 ℃ of heating 15 hours the 3-dichloroacetone with 6-fluoro-2-pyridine amine.Make this reactant be cooled to room temperature and filtering-depositing, with acetone and ether washing, drying obtains the yellowish-brown solid.Make intermediate water-soluble and handle, filter collecting precipitation thing and dry, obtain 2-(chloro methyl)-5-fluoro imidazo [1,2-a] pyridine (1.9g, 77% yield), be brown solid until pH=7. with saturated sodium bicarbonate aqueous solution. ¹H-NMR(CDCl ₃)：δ7.68(s，1H)，7.42(d，1H)，7.26-7.20(m，1H)，6.47(dd，1H)，4.76(s，2H)。

B) (8R)-and N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In similar mode as herein described, by (1R)-and 1-[4-(methyl oxygen base) phenyl] ethyl } amine and 6,7-dihydro-8 (5H)-quinolinone preparation (8R)-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains transparent crystallization (54% yield).

¹H-NMR(CDCl ₃)：δ8.40(m，1H)，7.34(m，3H)，7.05(m，1H)，6.85(d，2H)，4.04(m，1H)，3.84-3.79(m，4H)，2.73-2.62(m，2H)，1.82(m，1H)，1.72(m，1H)，1.57(m，2H)，1.44(d，3H).

C) (8R)-and N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

To (8R)-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7, (2.32g adds N in acetonitrile 8.23mmol) (40ml) solution, N-diisopropyl ethyl amine (3.15ml to 8-tetrahydrochysene-8-quinolinamine, 18.1mmol), 2-(chloro methyl)-5-fluoro imidazo [1,2-a] pyridine (1.67g, 9.05mmol) and potassium iodide (1.50g, 9.05mmol).This reactant was stirred under room temperature 15 hours, dilute, and wash with saturated sodium bicarbonate aqueous solution with ethyl acetate.Separate organic layer, and the other ethyl acetate extraction of water liquid.Merge organic layer, through dried over mgso, filter, concentrate, through flash chromatography purification (0-5% ammonium hydroxide is in acetonitrile), obtain 2.12g (60% yield) (8R)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is pale solid.

¹HNMR(400MHz，CDCl ₃)δ8.47(d，J＝4.5Hz，1H)，7.80(s，1H)，7.54-7.52(m，2H)，7.26(d，J＝8.9Hz，1H)，7.20(d，J＝7.6Hz，1H)，7.12-7.07(m，1H)，6.96(dd，J＝7.6，4.7Hz，1H)，6.86-6.84(m，2H)，6.38(dd，J＝7.4，5.0Hz，1H)，4.95(m，1)，4.05-3.95(m，2H)，3.79-3.75(m，4H)，2.68-2.52(m，2H)，2.05(m，1H)，1.86-1.73(m，2H)，1.51(m，1H)，1.28(d，J＝6.7Hz，3H)；MS?m/z?431(M+1).

D) (8R)-and N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

With (8R)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7, (1.0g, 1-methyl piperazine (10ml.) solution 2.32mmol) was in 100 ℃ of heating 48 hours for 8-tetrahydrochysene-8-quinolinamine.Dilute this reactant and wash with dichloromethane with saturated sodium bicarbonate aqueous solution.Separate organic layer, and water liquid is with other dichloromethane extraction.Merge organic layer, through dried over mgso, filter, concentrate, through flash chromatography purification (0-8% ammonium hydroxide is in acetonitrile), obtain quantitative output (1.2g) (8R)-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine is yellow oil.

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.5Hz，1H)，7.78(s，1H)，7.62-7.60(m，2H)，7.24-7.19(m，2H)，7.08(dd，J＝8.9，7.2Hz，1H)，6.98(dd，J＝7.7，4.7Hz，1H)，6.86-6.84(m，2H)，6.21(d，J＝7.0Hz，1H)，4.84(m，1H)，4.07(m，1H)，3.91(dd，J＝61.8，17.4Hz，2H)，3.79(s，3H)，3.21-3.14(m，4H)，2.76(s，4H)，2.68-2.54(m，2H)，2.48(s，3H)，2.07(m，1H)，1.86(m，2H)，1.54(m，1H)，1.35(d，J＝6.9Hz，3H)；MS?m/z?511(M+1).

Embodiment 52:(8R)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination, by (8R)-N-{ (1R)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6; 7; 8-tetrahydrochysene-8-quinolinamine and prepared formaldehyde (8R)-N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6; 7; 8-tetrahydrochysene-8-quinolinamine obtains faint yellow oily thing (53% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.52(d，1H)，7.68(s，1H)，7.33(d，1H)，7.28(d，1H)，7.10(dd，1H)，7.04(dd，1H)，6.23(dd，1H)，4.12(m，1H)，3.96(s，2H)，3.13(m，4H)，2.85-2.77(m，2H)，2.70-2.65(m，4H)，2.39(s，3H)，2.37(s，3H)，2.14(m，1H)，2.05-1.96(m，2H)，1.68(m，1H)；MS?m/z391(M+1).

Embodiment 53:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2-methyl-propyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

With (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine (600mg, handle with trifluoroacetic acid (2mL) and stirred 2.5 hours under room temperature by dichloromethane 1.17mmol) (4ml) solution.The concentration response thing with the dichloromethane dilution, washs with saturated aqueous sodium carbonate.Separate organic layer,, filter and concentrate, obtain intermediate (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1, the 2-a] pyridine-2-yl of rough deprotection through dried over mgso] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine.Make this intermediate (73mg, 0.195mmol) be dissolved in dichloroethanes (1mL) and with isobutylaldehyde (36 μ l, 0.39mmol), glacial acetic acid (17 μ l, 0.29mmol) and triacetic acid base sodium borohydride (62mg 0.29mmol) handles and stirred 15 hours under room temperature.This reactant is washed with the dichloromethane dilution and with saturated aqueous sodium carbonate.Separate organic layer and water liquid dichloromethane extraction.Merge organic layer,, filter, concentrate and through preparation type chromatography purification (0-60% acetonitrile-water through dried over mgso; 0.1% trifluoroacetic acid), dilute with dichloromethane then, with the saturated aqueous sodium carbonate washing with through dried over mgso, obtain 24mg (29% yield, 2 steps) (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(2-methyl-propyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine is yellow oil.

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.5Hz，1H)，7.78(s，1H)，7.30(d，J＝7.5Hz，1H)，7.26-7.24(m，1H)，7.11-7.07(m，1H)，7.01(dd，J＝7.7，4.7Hz，1H)，6.22(d，J＝7.2Hz，1H)，4.14(m，1H)，4.01(dd，J＝71.6，16.0Hz，2H)，3.17(s，4H)，2.78-2.58(m，7H)，2.46-2.41(m，4H)，2.12(m，1H)，1.99-1.88(m，2H)，1.77-1.62(m，2H)，0.87(d，J＝6.7Hz，6H)；MS?m/z?433(M+1).

Embodiment 54:(8S)-and N-ethyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by deprotection and reductive amination, by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine and acetaldehyde preparation (8S)-N-ethyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain faint yellow oily thing (19% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.4Hz，1H)，7.65(s，1H)，7.29(d，J＝7.7Hz，1H)，7.24-7.23(m，1H)，7.10-7.06(m，1H)，7.00(dd，J＝7.6，4.7Hz，1H)，6.21(d，J＝7.2Hz，1H)，4.21(m，1H)，4.01-3.83(m，2H)，3.12(s，4H)，2.90-2.82(m，2H)，2.79-2.72(m，2H)，2.66(s，4H)，2.40(s，3H)，2.14(m，1H)，2.02-1.88(m，2H)，1.64(m，1H)，1.07(t，J＝7.0Hz，3H)；MS?m/z?405(M+1).

Embodiment 55:(8S)-and N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and acetone preparation (8S)-N-(1-Methylethyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain faint yellow oily thing (50% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.44(d，J＝4.5Hz，1H)，7.64(s，1H)，7.24-7.18(m，2H)，7.06-7.02(m，1H)，6.96(dd，J＝7.6，4.7Hz，1H)，6.17(d，J＝7.1Hz，1H)，4.22(m，1H)，3.92(dd，J＝29.9，16.6Hz，2H)，3.20-3.14(m，1H)，3.10(s，4H)，2.81-2.73(m，2H)，2.66(s，4H)，2.41(s，3H)，2.03-1.93(m，3H)，1.63(m，1H)，1.12(m，6H)；MS?m/z?419(M+1).

Embodiment 56:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by deprotection and reductive amination, by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine and propionic aldehyde preparation (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-propyl group-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain faint yellow oily thing (40% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.4Hz，1H)，7.67(s，1H)，7.28(d，J＝7.6Hz，1H)，7.24-7.22(m，1H)，7.08-7.04(m，1H)，6.99(dd，J＝7.6，4.7Hz，1H)，6.20(d，J＝7.2Hz，1H)，4.16(m，1H)，3.94(dd，J＝62.0，15.2Hz，2H)，3.12(s，4H)，2.77-2.60(m，8H)，2.39(s，3H)，2.11(m，1H)，1.99-1.86(m，2H)，1.47(m，2H)，1.62(m，1H)，0.81(t，J＝7.3Hz，3H)；MS?m/z?419(M+1).

Embodiment 57:(8S)-and N-(cyclopropyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and cyclopanecarboxaldehyde preparation (8S)-N-(cyclopropyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain faint yellow oily thing (14% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.5Hz，1H)，7.72(s，1H)，7.30-7.26(m，2H)，7.08(dd，J＝8.9，7.2Hz，1H)，7.00(dd，J＝7.5，4.7Hz，1H)，6.22(d，J＝7.2Hz，1H)，4.36(m，1H)，4.17-3.94(m，2H)，3.13(s，4H)，2.81-2.74(m，2H)，2.67(s，4H)，2.57-2.51(m，2H)，2.40(s，3H)，2.18(m，1H)，2.00-1.88(m，2H)，1.65(m，1H)，0.95(m，1H)，0.44-0.37(m，2H)，0.11-0.05(m，2H)；MS?m/z?431(M+1).

Embodiment 58:(8S)-and N-butyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by deprotection and reductive amination, by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine and butyraldehyde preparation (8S)-N-butyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellow oil (37% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.4Hz，1H)，7.66(s，1H)，7.28(d，J＝7.5Hz，1H)，7.24-7.22(m，1H)，7.09-7.05(m，1H)，6.99(dd，J＝7.6，4.7Hz，1H)，6.20(d，J＝7.2Hz，1H)，4.16(m，1H)，3.93(dd，J＝61.9，15.1Hz，2H)，3.12(s，4H)，2.80-2.72(m，4H)，2.68-2.60(m，4H)，2.40(s，3H)，2.10(m，1H)，1.99-1.86(m，2H)，1.63(m，1H)，1.48-1.42(m，2H)，1.29-1.21(m，2H)，0.79(t，J＝7.3Hz，3H)；MS?m/z?433(M+1).

Embodiment 59:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-(phenyl methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and benzaldehyde preparation (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-(phenyl methyl)-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (88% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.4Hz，1H)，7.73(s，1H)，7.52-7.50(m，2H)，7.28-7.22(m，4H)，7.14(m，1H)，7.08-7.04(m，1H)，7.00(dd，J＝7.7，4.7Hz，1H)，6.18(d，J＝7.4Hz，1H)，4.16(m，1H)，4.11-3.77(m，4H)，3.10(s，4H)，2.80-2.72(m，2H)，2.66(s,4H)，2.42(s，3H)，2.15(m，1H)，2.00-1.91(m，2H)，1.62(m，1H)；MS?m/z?467(M+1).

Embodiment 60:(8S)-and N-[(2-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 2-Fluorobenzaldehyde. preparation (8S)-N-[(2-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (80% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ?8.51(d，J＝4.4Hz，1H)，7.83(t，J＝7.5Hz，1H)，7.70(s，1H)，7.30(d，J＝7.6Hz，1H)，7.25-7.23(m，1H)，7.14-7.01(m，4H)，6.92(m，1H)，6.20(d，J＝7.2Hz，1H)，4.18(m，1H)，4.11-3.95(m，4H)，3.11(s，4H)，2.82-2.75(m，2H)，2.67(s，4H)，2.43(s，3H)，2.18(m，1H)，2.01-1.90(m，2H)，1.65(m，1H)；MS?m/z?485(M+1).

Embodiment 61:(8S)-and N-[(3-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 3-Fluorobenzaldehyde. preparation (8S)-N-[(3-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (73% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.53(d，J＝4.3Hz，1H)，7.78(s，1H)，7.43(d，J＝10.2Hz，1H)，7.30(d，J＝7.6Hz，1H)，7.26-7.23(m，1H)，7.20-7.15(m，2H)，7.10-7.06(m，1H)，7.03(dd，J＝7.7，4.6Hz，1H)，6.83(m，1H)，6.21(d，J＝7.2Hz，1H)，4.16(m，1H)，4.12-3.95(m，3H)，3.80(d，J＝14.6Hz，1H)，3.13(s，4H)，2.82-2.63(m，6H)，2.44(s，3H)，2.20(m，1H)，2.00-1.90(m，2H)，1.65(m，1H)；MS?m/z?485(M+1).

Embodiment 62:(8S)-and N-[(4-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 4-Fluorobenzaldehyde. preparation (8S)-N-[(4-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (50% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.4Hz，1H)，7.67(s，1H)，7.48-7.45(m，2H)，7.29(d，J＝7.5Hz，1H)，7.23(d，J＝8.7Hz，1H)，7.07(dd，J＝8.9，7.3Hz，1H)，7.01(dd，J＝7.5，4.6Hz，1H)，6.92-6.88(m，2H)，6.19(d，J＝7.1Hz，1H)，4.15(m，1H)，4.03-3.91(m，3H)，3.74(d，J＝14.1Hz，1H)，3.10(s，4H)，2.79-2.72(m，2H)，2.66(s，4H)，2.42(s，3H)，2.15(m，1H)，1.99-1.91(m，2H)，1.62(m，1H)；MS?m/z?485(M+1).

Embodiment 63:(8S)-and N-[(2-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 2-bromobenzene prepared formaldehyde (8S)-N-[(2-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (68% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.50(d，J＝4.3Hz，1H)，7.99(d，J＝7.5Hz，1H)，7.63(s，1H)，7.39(d，J＝8.0Hz，1H)，7.30(d，J＝7.7Hz，1H)，7.24-7.18(m，2H)，7.08-7.00(m，2H)，6.98-6.94(m，1H)，6.16(d，J＝7.4Hz，1H)，4.20(m，1H)，4.13-4.01(m，4H)，3.05(s，4H)，2.83-2.75(m，2H)，2.68-2.60(m，4H)，2.41(s，3H)，2.25(m，1H)，2.01-1.92(m，2H)，1.66(m，1H)；MS?m/z546(M+1).

Embodiment 64:(8S)-and N-[(3-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 3-bromobenzene prepared formaldehyde (8S)-N-[(3-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (76% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.52-8.51(m，1H)，7.80(s，1H)，7.73(s，1H)，7.34-7.18(m，4H)，7.10-7.00(m，3H)，6.20(d，J＝7.1Hz，1H)，4.14(m，1H)，4.06-3.93(m，3H)，3.74(m，1H)，3.11(s，4H)，2.76-2.60(m，6H)，2.43(s，3H)，2.17(m，1H)，1.99-1.89(m，2H)，1.63(m，1H)；MS?m/z?546(M+1).

Embodiment 65:(8S)-and N-[(4-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 4-bromobenzene prepared formaldehyde (8S)-N-[(4-bromo phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (75% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51-8.49(m，1H)，7.62(s，1H)，7.40-7.21(m，6H)，7.10-7.00(m，2H)，6.20-6.15(m，1H)，4.14(m，1H)，4.03-3.92(m，3H)，3.72(m，1H)，3.09(s，4H)，2.80-2.72(m，2H)，2.64(s，4H)，2.43(s，3H)，2.16(m，1H)，1.99-1.90(m，2H)，1.62(m，1H)；MS?m/z?546(M+1).

Embodiment 66:(8S)-and the N-[(2-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and neighbour-tolualdehyde preparation (8S)-N-[(2-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (71% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.6Hz，1H)，7.74(d，J＝7.4Hz，1H)，7.66(s，1H)，7.30(d，J＝7.6Hz，1H)，7.24-7.22(m，1H)，7.14-7.00(m，5H)，6.19(d，J＝7.2Hz，1H)，4.21-4.12(m，2H)，3.99-3.87(m，3H)，3.10(s，4H)，2.78(m，1H)，2.66(s，4H)，2.54(s，1H)，2.43(s，3H)，2.32(s，3H)，2.16(m，1H)，2.01-1.95(m，2H)，1.63(m，1H)；MS?m/z?481(M+1).

Embodiment 67:(8S)-and the N-[(3-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and-tolualdehyde preparation (8S)-N-[(3-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (69% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.52(d，J＝4.6Hz，1H)，7.74(s，1H)，7.34-7.23(m，4H)，7.16-6.96(m，4H)，6.21(d，J＝7.3Hz，1H)，4.17(m，1H)，4.09-3.76(m，4H)，3.13(s，4H)，2.81-2.62(m，6H)，2.44(s，3H)，2.31(s，3H)，2.17(m，1H)，2.01-1.94(m，2H)，1.64(m，1H)；MS?m/z?481(M+1).

Embodiment 68:(8S)-and the N-[(4-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and right-tolualdehyde preparation (8S)-N-[(4-aminomethyl phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (67% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.52(d，J＝4.5Hz，1H)，7.73(s，1H)，7.42(d，J＝7.7Hz，2H)，7.29(d，J＝7.5Hz，1H)，7.26-7.23(m，1H)，7.10-7.05(m，3H)，7.02(dd，J＝7.5，4.7Hz，1H)，6.20(d，J＝7.2Hz，1H)，4.17(m，1H)，4.07-3.74(m，4H)，3.12(s，4H)，2.82-2.74(m，2H)，2.70-2.61(m，4H)，2.44(s，3H)，2.28(s，3H)，2.16(m，1H)，2.00-1.93(m，2H)，1.63(m，1H)；MS?m/z?481(M+1).

Embodiment 69:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[2-(trifluoromethyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 2-(trifluoromethyl) benzaldehyde preparation (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-{[2-(trifluoromethyl) phenyl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (82% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.1Hz，1H)，8.41(d，J＝7.6Hz，1H)，7.66(s，1H)，7.48(d，J＝7.7Hz，1H)，7.43(t，J＝7.5Hz，1H)，7.30(d，J＝7.5Hz，1H)，7.25-7.23(m，1H)，7.17(t，J＝7.6Hz，1H)，7.09-7.00(m，2H)，6.17(d，J＝7.2Hz，1H)，4.20(m，1H)，4.05(s，2H)，4.00(d，J＝3.1Hz，2H)，3.23(s，1H)，3.06(s，4H)，2.79(m，1H)，2.69-2.61(m，4H)，2.42(s，3H)，2.24(m，1H)，2.01-1.91(m，2H)，1.65(m，1H)；MSm/z?535(M+1).

Embodiment 70:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[3-(trifluoromethyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 3-(trifluoromethyl) benzaldehyde preparation (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-{[3-(trifluoromethyl) phenyl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (74% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝3.9Hz，1H)，7.95(s，1H)，7.74(s，1H)，7.59(d，J＝7.5Hz，1H)，7.35(d，J＝7.7Hz，1H)，7.30-7.21(m，3H)，7.09-7.05(m，1H)，7.01(dd，J＝7.4，4.6Hz，1H)，6.19(d，J＝7.1Hz，1H)，4.16(m，1H)，4.05-3.97(m，3H)，3.79(d，J＝14.6Hz，1H)，3.10(s，4H)，2.80-2.72(m，2H)，2.66(s，4H)，2.42(s，3H)，2.18(m，1H)，2.03-1.91(m，2H)，1.64(m，1H)；MS?m/z?535(M+1).

Embodiment 71:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[4-(trifluoromethyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 4-(trifluoromethyl) benzaldehyde preparation (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-{[4-(trifluoromethyl) phenyl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain orange (86% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.52-8.46(m，1H)，7.65-7.59(m，3H)，7.47-7.40(m，2H)，7.31-7.19(m，2H)，7.10-6.98(m，2H)，6.21-6.15(m，1H)，4.18-4.07(m，2H)，4.00-3.94(m，2H)，3.81(m，1H)，3.07(s，4H)，2.80-2.72(m，2H)，2.63(s，4H)，2.42-2.37(m，3H)，2.18(m，1H)，2.01-1.92(m，2H)，1.64(m，1H)；MS?m/z?535(M+1).

Embodiment 72:(8S)-and N-{[2-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and neighbour-anisaldehyde preparation (8S)-N-{[2-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine quinolinamine; obtain yellowish-brown grease (68% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.2Hz，1H)，7.92(d，J＝7.3Hz，1H)，7.72(s，1H)，7.27(d，J＝7.6Hz，1H)，7.22(d，J＝8.9Hz，1H)，7.13-7.09(m，1H)，7.07-7.05(m，1H)，6.99(dd，J＝7.5，4.6Hz，1H)，6.91(t，J＝7.4Hz，1H)，6.74(d，J＝8.1Hz，1H)，6.16(d，J＝7.0Hz，1H)，4.19(m，1H)，4.09-3.89(m，4H)，3.75(s，3H)，3.07(s，4H)，2.92(s，1H)，2.78(m，1H)，2.62(s，4H)，2.40(s，3H)，2.20(m，1H)，2.00-1.95(m，2H)，1.62(m，1H)；MS?m/z?497(M+1).

Embodiment 73:(8S)-and N-{[3-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and m-anisaldehyde preparation (8S)-N-{[3-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (72% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.50(d，J＝4.4Hz，1H)，7.72(s，1H)，7.30-7.27(m，2H)，7.25-7.23(m，1H)，7.13-6.98(m，4H)，6.67(m，1H)，6.19(d，J＝7.1Hz，1H)，4.17(m，1H)，4.03-3.92(m，3H)，3.80-3.70(m，4H)，3.08(s，4H)，2.80-2.73(m，2H)，2.65(s，4H)，2.41(s，3H)，2.17(m，1H)，2.00-1.91(m，2H)，1.62(m，1H)；MS?m/z?497(M+1).

Embodiment 74:(8S)-and N-{[4-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and right-anisaldehyde preparation (8S)-N-{[4-(methyl oxygen base) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (60% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(m，1H)，7.69(s，1H)，7.41(d，J＝8.0Hz，2H)，7.28(d，J＝7.4Hz，1H)，7.23(d，J＝9.0Hz，1H)，7.07(m，1H)，7.01(m，1H)，6.77(d，J＝7.9Hz，2H)，6.19(d，J＝7.2Hz，1H)，4.16(m，1H)，4.02-3.89(m，3H)，3.73-3.68(m，4H)，3.11(s，4H)，2.85-2.72(m，2H)，2.66(s，4H)，2.42(s，3H)，2.13(m，1H)，1.99-1.92(m，2H)，1.62(m，1H)；MS?m/z?497(M+1).

Embodiment 75:(8S)-and N-{[4-(1-Methylethyl) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 4-cumene prepared formaldehyde (8S)-N-{[4-(1-Methylethyl) phenyl] methyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (60% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.2Hz，1H)，7.77(s，1H)，7.44(d，J＝7.9Hz，2H)，7.28(d，J＝7.5Hz，1H)，7.23(d，J＝9.2Hz，1H)，7.11-7.05(m，3H)，7.00(dd，J＝7.7，4.7Hz，1H)，6.19(d，J＝7.1Hz，1H)，4.18(m，1H)，4.08-4.02(m，2H)，3.94(d，J＝15.5Hz，1H)，3.77(d，J＝14.2Hz，1H)，3.12(s，4H)，2.86-2.72(m，3H)，2.68(s，4H)，2.44(s，3H)，2.15(m，1H)，1.99-1.93(m，2H)，1.62(m，1H)，1.19(d，J＝6.9Hz，6H)；MS?m/z509(M+1).

Embodiment 76:(8S)-and N-(4-xenyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 4-xenyl benzaldehyde preparation (8S)-N-(4-xenyl methyl)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (52% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.54(d，J＝4.0Hz，1H)，7.74(s，1H)，7.59(d，J＝7.9Hz，2H)，7.53(d，J＝7.3Hz，2H)，7.47(d，J＝8.1Hz，2H)，7.41-7.37(m，2H)，7.31-7.24(m，3H)，7.08(dd，J＝8.9，7.3Hz，1H)，7.03(dd，J＝7.6，4.6Hz，1H)，6.19(d，J＝7.0Hz，1H)，4.22(m，1H)，4.16-3.97(m，3H)，3.86(d，J＝14.5Hz，1H)，3.10(s，4H)，2.82-2.75(m，2H)，2.65(s，4H)，2.40(s，3H)，2.20(m，1H)，2.03-1.96(m，2H)，1.65(m，1H)；MS?m/z?543(M+1).

Embodiment 77:(8S)-and N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-{[4-(2-methyl-propyl) phenyl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and 4-isobutyl-benzene prepared formaldehyde (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-N-{[4-(2-methyl-propyl) phenyl] methyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellowish-brown grease (42% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.3Hz，1H)，7.76(s，1H)，7.41(d，J＝7.8Hz，2H)，7.28(d，J＝7.4Hz，1H)，7.23(d，J＝8.2Hz，1H)，7.07(dd，J＝8.7，7.3Hz，1H)，7.02-6.99(m，3H)，6.19(d，J＝7.1Hz，1H)，4.17(m，1H)，4.08-4.02(m，2H)，3.94(d，J＝15.2Hz，1H)，3.78(d，J＝14.3Hz，1H)，3.12(s，4H)，2.79-2.72(m，2H)，2.67(s，4H)，2.44(s，3H)，2.39(d，J＝7.4Hz，2H)，2.15(m，1H)，1.99-1.93(m，2H)，1.79(sept，J＝6.7Hz，1H)，1.62(m，1H)，0.85(d，J＝6.7Hz，6H)；MS?m/z?523(M+1).

Embodiment 78:2-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } ethanol

With (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine (300mg, handle with trifluoroacetic acid (1mL) and stirred 2.5 hours under room temperature by dichloromethane 0.59mmol) (2ml) solution.The concentration response thing with the dichloromethane dilution, washs with saturated aqueous sodium carbonate.Separate organic layer,, filter and concentrate, obtain intermediate (8S)-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1, the 2-a] pyridine-2-yl of rough deprotection through dried over mgso] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine.Make this intermediate (111mg, 0.295mmol) be dissolved in acetonitrile (1.5mL) and with (2-bromo the ethyoxyl)-tert-butyl group-dimethylsilane (70 μ l, 0.325mmol), N, N-diisopropyl ethyl amine (125 μ l, 0.715mmol) and potassium iodide (54mg, 0.325mmol) processing.Under room temperature, stirred this reactant 15 hours, stirred 24 hours in 50 ℃ then.Wash with ethyl acetate diluting reaction thing and with saturated aqueous sodium carbonate.Separate organic layer, concentrate and through preparation type chromatography purification (0-90% acetonitrile-water; 0.1% trifluoroacetic acid), deprotection taking place, with the dichloromethane dilution, with the saturated aqueous sodium carbonate washing, through dried over mgso, obtains 28mg (23% yield) orange then.

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.6Hz，1H)，7.85(s，1H)，7.35(d，J＝7.6Hz，1H)，7.25(d，J＝8.2Hz，1H)，7.12-7.06(m，2H)，6.21(d，J＝7.3Hz，1H)，4.17-4.04(m，3H)，3.63(m，1H)，3.47(m，1H)，3.12(s，4H)，2.83-2.75(m，4H)，2.65(s，4H)，2.40(s，3H)，2.31(m，1H)，2.00(m，1H)，1.80(m，1H)，1.67(m，1H)；MS?m/z?421(M+1).

Embodiment 79:3-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl } [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino }-the 1-propanol

In similar mode as herein described; by deprotection and alkylation; by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and (3-bromo the propoxyl group)-tert-butyl group-dimethylsilane prepare 3-{{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1; 2-a] pyridine-2-yl] methyl } [(8S)-5; 6; 7,8-tetrahydrochysene-8-quinolyl] amino }-the 1-propanol, obtain 13mg (10% yield) orange.

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.5Hz，1H)，7.88(s，1H)，7.36(d，J＝7.7Hz，1H)，7.26-7.24(m，1H)，7.13-7.06(m，2H)，6.21(d，J＝7.3Hz，1H)，4.22(m，1H)，3.94(dd，J＝49.9，15.3Hz，2H)，3.82(m，1H)，3.57(m，1H)，3.15(s，4H)，2.91-2.78(m，4H)，2.73-2.66(m，4H)，2.42(s，3H)，2.28(m，1H)，2.03(m，1H)，1.93(m，1H)，1.82(m，1H)，1.68(m，1H)，1.54(m，1H)；MS?m/z?435(M+1).

Embodiment 80:(8S)-and N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) (8S)-and N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In similar mode as herein described, by reductive amination, by (8S)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine and 5-fluoro imidazo [1,2-a] pyridine-2-formaldehyde preparation (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains brown solid (98% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.3Hz，1H)，7.80(s，1H)，7.53(d，J＝8.4Hz，2H)，7.28-7.24(m，1H)，7.20(d，J＝7.5Hz，1H)，7.09(m，1H)，6.96(dd，J＝7.6，4.6Hz，1H)，6.85(d，J＝8.6Hz，2H)，6.38(dd，J＝7.3，4.8Hz，1H)，4.95(m，1H)，4.05-3.95(m，2H)，3.78(s，4H)，2.67-2.52(m，2H)，2.05(m，1H)，1.87-1.73(m，2H)，1.51(m，1H)，1.28(d，J＝6.6Hz，3H)；MS?m/z?431(M+1).

B) (8S)-and N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In similar mode as herein described, by deprotection and reductive amination, by (8S)-N-[(5-fluoro imidazo [1; 2-a] pyridine-2-yl) methyl]-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5; 6,7,8-tetrahydrochysene-8-quinolinamine and prepared formaldehyde (8S)-N-[(5-fluoro imidazo [1; 2-a] pyridine-2-yl) methyl]-N-methyl-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellow oil (88% yield, 2 steps).

¹H?NMR(400MHz，CDCl ₃)δ8.52(d，J＝4.3Hz，1H)，7.79(s，1H)，7.36(m，2H)，7.13(m，1H)，7.05(dd，J＝7.7，4.7Hz，1H)，6.39(dd，J＝7.3，4.9Hz，1H)，4.07(m，1H)，3.92(s，2H)，2.76(m，2H)，2.43(s，3H)，2.02(m，3H)，1.70(m，1H)；MS?m/z?311(M+1).

C) (8S)-and N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine:

With (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine (94mg, 0.30mmol) acetonitrile (1mL) solution (300mg 1.50mmol) handles and in 50 ℃ of heating 15 hours with in 70 ℃ of heating 24 hours with 4-(N-BOC-amino) piperidines.With dichloromethane diluting reaction thing; with the saturated aqueous sodium carbonate washing, separate, concentrate; through flash chromatography purification (0-10% ammonium hydroxide is in acetonitrile); obtain 117mg (80% yield) { 1-[2-({ methyl [(8S)-5,6,7; 8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1; 2-a] pyridine-5-yl]-the 4-piperidyl } carbamic acid 1,1-dimethyl ethyl ester is the intermediate of protection.Make this intermediate be dissolved in dichloromethane (1mL), handle and under room temperature, stirred 2 hours with trifluoroacetic acid (0.50mL).The concentration response thing with the dichloromethane dilution, washs with saturated aqueous sodium carbonate.Separate organic layer, concentrate, through flash chromatography purification (0-10% ammonium hydroxide is in acetonitrile), obtain 72mg (77% yield) (8S)-N-{[5-(4-amino-piperidino) imidazo [1,2-a] pyridine-2-yl] methyl-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine is yellow oil.

¹HNMR(400MHz，CDCl ₃)δ8.49(d，J＝3.5Hz，1H)，7.59(s，1H)，7.31(d，J＝7.7Hz，1H)，7.24(d，J＝8.5Hz，1H)，7.06(m，1H)，7.01(m，1H)，6.18(d，J＝7.4Hz，1H)，4.09(m，1H)，3.92(s，2H)，3.40(d，J＝11.1Hz，2H)，2.90(m，1H)，2.81-2.63(m，4H)，2.34(s，3H)，2.10(m，1H)，2.02-1.93(m，4H)，1.68-1.57(m，3H)；MS?m/z?391(M+1).

Embodiment 81:N, N, N '-trimethyl-N '-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N, N, N '-trimethyl ethylenediamine prepares N, N, N '-trimethyl-N '-[({ methyl is [(8S)-5,6 for 2-, 7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1, the 2-ethylenediamine obtains yellow oil (64% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.46(d，J＝4.4Hz，1H)，7.70(s，1H)，7.30(d，J＝7.7Hz，1H)，7.22(d，J＝8.9Hz，1H)，7.06(dd，J＝8.7，7.3Hz，1H)，7.00(dd，J＝7.3，4.8Hz，1H)，6.22(d，J＝7.3Hz，1H)，4.05(m，1H)，3.91(s，2H)，3.14(m，2H)，2.82(s，3H)，2.77(m，1H)，2.63(m，1H)，2.49(t，J＝7.2Hz，2H)，2.34(s，3H)，2.17(s，6H)，2.07-1.95(m，3H)，1.63(m，1H)；MS?m/z?393(M+1).

Embodiment 82:(8S)-N-{[5-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl) imidazo [1,2-a] pyridine-2-yl also] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1,4-diazabicylo [4.3.0] nonane preparation (8S)-N-{[5-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl) imidazo [1,2-a] pyridine-2-yl also] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (82% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.47(s，1H)，7.66(d，J＝4.8Hz，1H)，7.29(d，J＝7.6Hz，1H)，7.23(d，J＝8.9Hz，1H)，7.07-7.03(m，1H)，7.01-6.98(m，1H)，6.21(d，J＝7.0Hz，1H)，4.08(m，1H)，3.92(s，2H)，3.47(d，J＝10.8Hz，1H)，3.38(d，J＝11.9Hz，1H)，3.13-3.05(m，2H)，2.92-2.73(m，2H)，2.66-2.48(m，3H)，2.34(s，3H)，2.28-2.20(m，2H)，2.09(m，1H)，2.00-1.92(m，2H)，1.86-1.60(m，4H)，1.41(m，1H)；MS?m/z417(M+1).

Embodiment 83:(8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinoline

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3R)-(+)-3-dimethylamino pyrrolidine preparation (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (73% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.46(d，J＝4.4Hz，1H)，7.76(s，1H)，7.30(d，J＝7.6Hz，1H)，7.13(d，J＝8.8Hz，1H)，7.05-6.98(m，2H)，6.07(d，J＝7.3Hz，1H)，4.10(m，1H)，3.97(m，2H)，3.54(m，1H)，3.42(m，1H)，3.30-3.22(m，2H)，2.87-2.73(m，2H)，2.62(m，1H)，2.35(s，3H)，2.26(m，6H)，2.17-2.10(m，2H)，1.98-1.86(m，3H)，1.62(m，1H)；MS?m/z?405(M+1).

Embodiment 84:(8S)-and N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and high piperazine preparation (8S)-N-{[5-(six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (70% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.46(d，J＝4.2Hz，1H)，7.64(s，1H)，7.29(d，J＝7.4Hz，1H)，7.20(d，J＝8.9Hz，1H)，7.06-7.02(m，1H)，6.99(dd，J＝7.5，4.7Hz，1H)，6.24(d，J＝7.3Hz，1H)，4.07(m，1H)，3.89(s，2H)，3.30-3.24(m，4H)，3.08-3.03(m，4H)，2.77(m，1H)，2.62(m，1H)，2.33(s，3H)，2.07(m，1H)，1.99-1.90(m，4H)，1.63(m，1H)；MS?m/z?391(M+1).

Embodiment 85:(8S)-and N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7, the high piperazine preparation of 8-tetrahydrochysene-8-quinolinamine and 1-methyl (8S)-N-methyl-N-{[5-(4-methyl six hydrogen-1H-1,4-diaza -1-yl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (71% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.1Hz，1H)，7.64(s，1H)，7.32(d，J＝7.5Hz，1H)，7.21(d，J＝8.9Hz，1H)，7.08-7.00(m，2H)，6.23(d，J＝7.1Hz，1H)，4.09(m，1H)，3.92(s，2H)，3.38-3.34(m，4H)，2.85-2.63(m，6H)，2.42(s，3H)，2.36(s，3H)，2.10(m，1H)，2.03-1.95(m，4H)，1.66(m，1H)；MS?m/z?405(M+1).

Embodiment 86:(8S)-N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N, N '-dimethyl-3-amino-pyrrolidine preparation (8S)-N-methyl-N-(5-[methyl (1-methyl-3-pyrrolidinyl) amino] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (54% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.4Hz，1H)，7.67(d，J＝4.8Hz，1H)，7.31(d，J＝7.7Hz，1H)，7.24(d，J＝8.7Hz，1H)，7.06(dd，J＝8.7，7.3Hz，1H)，7.01(dd，J＝7.6，4.7Hz，1H)，6.22(d，J＝7.2Hz，1H)，4.09(m，1H)，3.97(m，1H)，3.90(d，J＝5.0Hz，2H)，2.78(m，2H)，2.71(s，3H)，2.63-2.48(m，4H)，2.33(s，3H)，2.30(d，J＝3.2Hz，3H)，2.13-1.95(m，4H)，1.84(m，1H)，1.66(m，1H)；MS?m/z?405(M+1).

Embodiment 87:(8S)-N-methyl-N-(5-[methyl (1-methyl-4-piperidyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-methyl-4-(methylamino) piperidines preparation (8S)-N-methyl-N-(5-[methyl (1-methyl-4-piperidyl) amino] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,5,7,8-tetrahydrochysene-8-quinolinamine obtains orange (19% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.47(m，1H)，7.57(s，1H)，7.33(d，J＝7.3Hz，1H)，7.26(m，1H)，7.08(m，1H)，7.02(m，1H)，6.26(m，1H)，4.11(m，1H)，3.95(m，2H)，3.09(m，1H)，2.92-2.84(m，3H)，2.76(s，3H)，2.66(m，1H)，2.31(s，3H)，2.20(s，3H)，2.12-1.94(m，4H)，1.91-1.63(m，6H)；MS?m/z?419(M+1).

Embodiment 88:(8S)-and N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N-ethyl piperazidine preparation (8S)-N-{[5-(4-ethyl-1-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (87% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.4Hz，1H)，7.67(s，1H)，7.30(d，J＝7.6Hz，1H)，7.26-7.24(m，1H)，7.07(m，1H)，7.01(m，1H)，6.20(d，J＝7.2Hz，1H)，4.09(m，1H)，3.93(s，2H)，3.11(s，4H)，2.78(m，2H)，2.66(s，4H)，2.51(q，J＝7.2Hz，2H)，2.35(s，3H)，2.11(m，1H)，2.00-1.92(m，2H)，1.64(m，1H)，1.12(t，J＝7.0Hz，3H)；MS?m/z?405(M+1).

Embodiment 89:(8S)-N-methyl-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-isopropyl piperazine preparation (8S)-N-methyl-N-(5-[4-(1-Methylethyl)-1-piperazinyl] and imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains pale solid (76% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.5Hz，1H)，7.68(s，1H)，7.30(d，J＝7.6Hz，1H)，7.25-7.23(m，1H)，7.07(m，1H)，7.00(m，1H)，6.19(d，J＝7.0Hz，1H)，4.10(m，1H)，3.94(s，2H)，3.10(s，4H)，2.79-2.62(m，7H)，2.34(s，3H)，2.11(m，1H)，2.01-1.91(m，2H)，1.64(m，1H)，1.09(d，J＝6.7Hz，6H)；MS?m/z?419(M+1).

Embodiment 90:N-{ (3R)-1-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } acetamide

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3R)-3-acetylamino pyrrolidine prepares N-{ (3R)-1-[2-, and ({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } acetamide, obtain pale solid (84% yield).

¹H?NMR(400?MHz，CDCl ₃)δ8.42(d，J＝4.3Hz，1H)，7.74(s，1H)，7.32-7.31(m，2H)，7.13(d，J＝8.7Hz，1H)，7.03-6.99(m，2H)，6.02(d，J＝7.1Hz，1H)，4.63(m，1H)，4.04(m，1H)，3.89(d，J＝4.0Hz，2H)，3.64(m，1H)，3.45(m，1H)，3.27(m，1H)，3.04(m，1H)，2.77(m，1H)，2.63(m，1H)，2.29(s，3H)，2.06(m，1H)，2.01-1.97(m，7H)，1.60(m，1H)；MS?m/z419(M+1).

Embodiment 91:(8S)-N-(5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3S)-(-)-3-dimethylamino pyrrolidine preparation (8S)-N-(5-[(3S)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains red oil (81% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.5Hz，1H)，7.72(s，1H)，7.30(d，J＝7.7Hz，1H)，7.15(d，J＝8.7Hz，1H)，7.06-6.99(m，2H)，6.08(d，J＝7.2Hz，1H)，4.09(m，1H)，3.93(s，2H)，3.55(m，1H)，3.43(m，1H)，3.29-3.23(m，2H)，2.87-2.75(m，2H)，2.64(m，1H)，2.34(s，3H)，2.25(s，6H)，2.19-2.05(m，2H)，1.98-1.86(m，3H)，1.64(m，1H)；MS?m/z?405(M+1).

Embodiment 92:(8S)-N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) (3R)-1-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } carbamic acid 1,1-dimethyl ethyl ester:

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3R)-(+)-3-(tert-butoxycarbonyl) amino-pyrrolidine preparation (3R)-({ methyl is [(8S)-5 for 1-[2-, 6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } carbamic acid 1,1-dimethyl ethyl ester obtains brown solid (84% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.52(d，J＝4.6Hz，1H)，7.86(br，1H)，7.35(d，J＝7.3Hz，1H)，7.21(d，J＝8.8Hz，1H)，7.10-7.03(m，2H)，6.11(d，J＝7.2Hz，1H)，4.94(m，1H)，4.39(m，1H)，4.16(m，1H)，3.98(s，2H)，3.70(m，1H)，3.52(m，1H)，3.24(m，1H)，3.10(m，1H)，2.82(m，1H)，2.68(m，1H)，2.42(s，3H)，2.34(m，1H)，2.14(m，1H)，2.04-1.94(m，3H)，1.67(m，1H)，1.47(s，9H)；MS?m/z477(M+1).

B) (8S)-N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In similar mode as herein described, by the trifluoroacetic acid deprotection, by (3R)-({ methyl is [(8S)-5 for 1-[2-; 6; 7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } carbamic acid 1; 1-dimethyl ethyl ester preparation (8S)-N-(5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7; 8-tetrahydrochysene-8-quinolinamine obtains pink grease (68% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.2Hz，1H)，7.76(s，1H)，7.31(d，J＝7.5Hz，1H)，7.14(d，J＝8.8Hz，1H)，7.06-6.99(m，2H)，6.07(d，J＝7.2Hz，1H)，4.09(m，1H)，3.91(s，2H)，3.71(m，1H)，3.57-3.49(m，2H)，3.32(m，1H)，3.10(m，1H)，2.78(m，1H)，2.64(m，1H)，2.34(s，3H)，2.26(m，1H)，2.08(m，1H)，2.01-1.92(m，2H)，1.76(m，1H)，1.64(m，1H)；MS?m/z?377(M+1).

Embodiment 93:(8S)-N-(5-[(3R)-3-(diethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by reductive amination, by (8S)-N-({ 5-[(3R)-3-amino-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and acetaldehyde preparation (8S)-N-(5-[(3R)-3-(diethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (52% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.2Hz，1H)，7.71(s，1H)，7.32(d，J＝7.6Hz，1H)，7.16(d，J＝9.1Hz，1H)，7.08-7.00(m，2H)，6.10(d，J＝7.3Hz，1H)，4.09(m，1H)，3.93(s，2H)，3.52(m，1H)，3.44-3.38(m，2H)，3.33-3.27(m，2H)，2.84-2.74(m，2H)，2.67-2.62(m，4H)，2.34(s，3H)，2.20(m，1H)，2.09(m，1H)，2.01-1.90(m，3H)，1.65(m，1H)，1.04(t，J＝7.2Hz，6H)；MS?m/z?433(M+1).

Embodiment 94: methyl (3R)-1-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } carbamic acid 1,1-dimethyl ethyl ester (intermediate)

In similar mode as herein described, through the sodium hydride alkylation, by (3R)-({ methyl is [(8S)-5 for 1-[2-, 6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } carbamic acid 1,1-dimethyl ethyl ester and methyl iodide prepare methyl (3R)-1-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-the 3-pyrrolidinyl } carbamic acid 1,1-dimethyl ethyl ester (intermediate) obtains yellow oil (79% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.46(d，J＝4.3Hz，1H)，7.72(s，1H)，7.30(d，J＝7.5Hz，1H)，7.18(d，J＝8.8Hz，1H)，7.07-6.99(m，2H)，6.10(d，J＝7.3Hz，1H)，4.90(br，1H)，4.09(m，1H)，3.94(s，2H)，3.48(m，1H)，3.35-3.31(m，2H)，3.19(m，1H)，2.89(s，3H)，2.77(m，1H)，2.63(m，1H)，2.35(s，3H)，2.23(m，1H)，2.09-1.94(m，4H)，1.63(m，1H)，1.45(s，9H)；MS?m/z?491(M+1).

Embodiment 95:(8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, pass through Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine and (3R)-(+)-3-dimethylamino pyrrolidine preparation (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains pink grease (89% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.47(d，J＝4.2Hz，1H)，7.91(s，1H)，7.55(d，J＝8.5Hz，2H)，7.20(d，J＝7.4Hz，1H)，7.08-7.00(m，2H)，6.95(dd，J＝7.6，4.7Hz，1H)，6.82-6.80(m，2H)，6.05(d，J＝6.7Hz，1H)，4.04(m，1H)，4.87(m，1H)，3.86(m，2H)，3.75(s，3H)，3.58-3.51(m，2H)，3.45(m，1H)，3.34(m，1H)，2.91(m，1H)，2.63(m，1H)，2.52(m，1H)，2.34(s，6H)，2.26(m，1H)，2.06-1.98(m，2H)，1.84-1.77(m，2H)，1.48(m，1H)，1.29(d，J＝7.1Hz，3H)；MS?m/z?525(M+1).

Embodiment 96:(8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-ethyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-({ 5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and acetaldehyde preparation (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-ethyl-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellow oil (48% yield, two steps).

¹H?NMR(400MHz，CDCl ₃)δ8.46(d，J＝4.2Hz，1H)，7.72(s，1H)，7.29(d，J＝7.4Hz，1H)，7.14(d，J＝8.8Hz，1H)，7.06-6.98(m，2H)，6.09(d，J＝7.1Hz，1H)，4.17(m，1H)，3.88(dd，J＝64.6，15.1Hz，2H)，3.57(m，1H)，3.42(m，1H)，3.34-3.27(m，2H)，2.89-2.61(m，5H)，2.29(s，6H)，2.22(m，1H)，2.10(m，1H)，1.98-1.85(m，3H)，1.62(m，1H)，1.05(t，J＝7.0Hz，3H)；MS?m/z?419(M+1).

Embodiment 97:(8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-propyl group-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-({ 5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and propionic aldehyde preparation (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-propyl group-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellow oil (65% yield, two steps).

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.2Hz，1H)，7.78(s，1H)，7.27(d，J＝7.4Hz，1H)，7.12(d，J＝8.8Hz，1H)，7.05-7.01(m，1H)，6.98(dd，J＝7.6，4.8Hz，1H)，6.07(d，J＝7.3Hz，1H)，4.14(m，1H)，3.91(dd，J＝68.5，15.3Hz，2H)，3.56(m，1H)，3.43(m，1H)，3.36-3.28(m，2H)，2.87(m，1H)，2.78-2.69(m，2H)，2.64-2.57(m，2H)，2.29(s，6H)，2.21(m，1H)，2.09(m，1H)，1.98-1.84(m，3H)，1.61(m，1H)，1.49-1.42(m，2H)，0.79(t，J＝7.4Hz，3H)；MSm/z?433(M+1).

Embodiment 98:(8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-N-(1-Methylethyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-({ 5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and acetone preparation (8S)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-(1-Methylethyl)-5; 6,7,8-tetrahydrochysene-8-quinolinamine; obtain yellow oil (49% yield, two steps).

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.3Hz，1H)，7.84(s，1H)，7.24(m，1H)，7.10-7.02(m，2H)，7.00-6.95(m，1H)，6.05(d，J＝7.1Hz，1H)，4.23(m，1H)，3.89(dd，J＝41.0，16.5Hz，2H)，3.55(m，1H)，3.44-3.28(m，2H)，3.14(m，1H)，2.91-2.84(m，2H)，2.76(m，1H)，2.61(m，1H)，2.30(s，6H)，2.23(m，1H)，2.03(m，1H)，1.99-1.89(m，3H)，1.61(m，1H)，1.12-1.09(m，6H)；MS?m/z?433(M+1).

Embodiment 99:(8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described; by deprotection and reductive amination; by (8S)-N-({ 5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-N-{ (1S)-1-[4-(methyl oxygen base) phenyl] ethyl }-5; 6; 7; 8-tetrahydrochysene-8-quinolinamine and cyclopanecarboxaldehyde preparation (8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1; 2-a] pyridine-2-yl } methyl)-5; 6; 7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (75% yield.Two steps).

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.4Hz，1H)，7.77(s，1H)，7.27(d，J＝7.8Hz，1H)，7.13(d，J＝8.7Hz，1H)，7.05-7.01(m，1H)，6.97(dd，J＝7.5，4.8Hz，1H)，6.07(d，J＝7.3Hz，1H)，4.30(m，1H)，4.09(d，J＝15.0Hz，1H)，3.87(d，J＝15.0Hz，1H)，3.56(m，1H)，3.41(m，1H)，3.35-3.26(m，2H)，2.86(m，1H)，2.76-2.68(m，2H)，2.61(m，1H)，2.47(m，1H)，2.28(s，6H)，2.20(m，1H)，2.11(m，1H)，1.96-1.83(m，3H)，1.61(m，1H)，0.91(m，1H)，0.39-0.33(m，2H)，0.06-0.01(m，2H)；MS?m/z?445(M+1).

Embodiment 100:(8S)-and N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine

A) 1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl ketone:

In 0 ℃, (150mg, (407 μ l 1.22mmol) handle and stir 15 hours to oxolane 0.61mmol) (3ml) solution with methyl-magnesium-bromide with 5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-formaldehyde.With dichloromethane diluting reaction thing, with the saturated aqueous sodium carbonate washing, separation also concentrates, and obtains 1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethanol.Make this intermediate be dissolved in chloroform (3ml), (530mg 6.1mmol) handles and stirred 15 hours with manganese dioxide.Reactant is used the dichloromethane fine laundering by diatomite filtration, concentrates, and through flash chromatography purification (0-7.5% ammonium hydroxide is in acetonitrile), obtains 79mg (50% yield, 2 steps) 1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl ketone.

¹HNMR(400MHz，CDCl ₃)δ8.10(s，1H)，7.40(d，J＝9.1Hz，1H)，7.24(m，1H)，6.35(d，J＝7.1Hz，1H)，3.14(s，4H)，2.71(s，3H)，2.66(s，4H)，2.40(s，3H).

B) (8S)-and N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine:

In similar mode as herein described, by reproducibility amine, by (8S)-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl ketone preparation (8S)-N-methyl-N-{1-[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] ethyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (47% yield).

¹H?NMR(400MHz，CD ₃OD)δ8.40(m，1H)，7.82(d，J＝7.0Hz，1H)，7.45(d，J＝7.7Hz，1H)，7.27-7.21(m，2H)，7.16-7.12(m，1H)，6.43(d，J＝6.5Hz，1H)，4.35-4.03(m，2H)，3.14(s，4H)，2.86-2.78(m，2H)，2.70(s，4H)，2.40(d，J＝2.8Hz，3H)，2.18-2.09(m，3H)，2.01-1.92(m，3H)，1.65(m，1H)，1.53(t，J＝7.0Hz，3H)；MS?m/z?405(M+1).

Embodiment 101:N, N-dimethyl-N '-[2-({ methyl [(8S)-5,6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and N, N '-dimethyl-ethylenediamine prepares N, and N-dimethyl-N '-[({ methyl is [(8S)-5 for 2-, 6,7,8-tetrahydrochysene-8-quinolyl] amino } methyl) imidazo [1,2-a] pyridine-5-yl]-1, the 2-ethylenediamine obtains yellow oil (64% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.4Hz，1H)，7.62(s，1H)，7.28(d，J＝7.5Hz，1H)，7.09-7.04(m，1H)，7.00-6.95(m，2H)，5.75(d，J＝7.2Hz，1H)，5.00(m，1H)，4.10(m，1H)，3.89(s，2H)，3.22-3.18(m，2H)，2.76(m，1H)，2.65-2.58(m，3H)，2.35(s，3H)，2.23(s，6H)，2.10(m，1H)，1.99-1.87(m，2H)，1.62(m，1H)；MS?m/z?379(M+1).

Embodiment 102:(8S)-and N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] amino } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-(2-amino-ethyl) pyrrolidine preparation (8S)-N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] amino } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange (49% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.49(d，J＝4.4Hz，1H)，7.62(s，1H)，7.31(d，J＝7.4Hz，1H)，7.11-7.07(m，1H)，7.02-6.96(m，2H)，5.78(d，J＝7.4Hz，1H)，5.00(m，1H)，4.11(m，1H)，3.90(s，2H)，3.29-3.26(m，2H)，2.83-2.75(m，4H)，2.57-2.47(m，4H)，2.36(s，3H)，2.12(m，1H)，2.02-1.90(m，2H)，1.81-1.73(m，4H)，1.64(m，1H)；MS?m/z?405(M+1).

Embodiment 103:(8S)-and N-methyl-N-[(5-{[2-(piperidino) ethyl] amino } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by Hot swapping, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-(2-amino-ethyl) piperidines preparation (8S)-N-methyl-N-[(5-{[2-(piperidino) ethyl] amino } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains orange solids (67% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.48(d，J＝4.2Hz，1H)，7.57(s，1H)，7.31(d，J＝7.4Hz，1H)，7.10-7.06(m，1H)，7.00(dd，J＝7.8，4.6Hz，1H)，6.97-6.95(m，1H)，5.77(d，J＝7.4Hz，1H)，5.14(s，1H)，4.10(m，1H)，3.91(s，2H)，3.27-3.23(m，2H)，2.79(m，1H)，2.67-2.63(m，3H)，2.43-2.37(m，4H)，2.34(s，3H)，2.11(m，1H)，2.02-1.90(m，2H)，1.64(m，1H)，1.59-1.53(m，4H)，1.45-1.39(m，2H)；MS?m/z?419(M+1).

Embodiment 104:(8S)-and N-[(5-{[2-(dimethylamino) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine

In 0 ℃, to 2-(dimethylamino) ethanol (64 μ l, add in oxolane 0.64mmol) (3.2mL) solution sodium hydride (60% in oil, 43mg, 0.64mmol).This reactant was stirred 30 minutes, with (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7, (100mg 0.32mmol) handles 8-tetrahydrochysene-8-quinolinamine, stirs 15 hours under room temperature.With saturated aqueous sodium carbonate quencher reactant, be extracted in the ethyl acetate also concentrated.Residue is through flash chromatography purification (0-10% ammonium hydroxide is in acetonitrile), obtain 95mg (79% yield) (8S)-N-[(5-{[2-(dimethylamino) ethyl] the oxygen base imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine is yellow oil.

¹H?NMR(400MHz，CDCl ₃)δ8.45(d，J＝4.4Hz，1H)，7.71(s，1H)，7.28(d，J＝7.7Hz，1H)，7.13-7.11(m，1H)，7.06-7.02(m，1H)，6.98(dd，J＝7.6，4.7Hz，1H)，5.93(d，J＝7.4Hz，1H)，4.23(m，2H)，4.04(m，1H)，3.86(s，2H)，2.80(t，J＝5.8Hz，2H)，2.74(m，1H)，2.62(m，1H)，2.33(s，3H)，2.32(s，6H)，2.06(m，1H)，2.00-1.89(m，2H)，1.62(m，1H)；MS?m/z?380(M+1).

Embodiment 105:(8S)-and N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by alkylation, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and pyrrolidino ethanol preparation (8S)-N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains pink grease (80% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.51(d，J＝4.5Hz，1H)，7.77(s，1H)，7.33(d，J＝7.6Hz，1H)，7.17-7.15(m，1H)，7.11-7.07(m，1H)，7.03(dd，J＝7.6，4.6Hz，1H)，5.98(d，J＝7.2Hz，1H)，4.33(t，J＝5.8Hz，2H)，4.09(m，1H)，3.91(d，J＝4.4Hz，2H)，3.01(t，J＝5.9Hz，2H)，2.82(m，1H)，2.71-2.64(m，4H)，2.57(m，1H)，2.40(s，3H)，2.13(m，1H)，2.06-1.97(m，2H)，1.82-1.77(m，4H)，1.67(m，1H)；MS?m/z?406(M+1).

Embodiment 106:(8S)-and N-methyl-N-[(5-{[2-(piperidino) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine

In similar mode as herein described, by alkylation, by (8S)-N-[(5-fluoro imidazo [1,2-a] pyridine-2-yl) methyl]-N-methyl-5,6,7,8-tetrahydrochysene-8-quinolinamine and 1-piperidines ethanol preparation (8S)-N-methyl-N-[(5-{[2-(piperidino) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine obtains yellow oil (76% yield).

¹H?NMR(400MHz，CDCl ₃)δ8.50(d，J＝4.3Hz，1H)，7.75(s，1H)，7.32(d，J＝7.6Hz，1H)，7.16-7.14(m，1H)，7.09-7.05(m，1H)，7.02(dd，J＝7.5，4.7Hz，1H)，5.96(d，J＝7.4Hz，1H)，4.30(t，J＝5.9Hz，2H)，4.08(m，1H)，3.90(s，2H)，2.87(t，J＝5.9Hz，2H)，2.79(m，1H)，2.66(m，1H)，2.54-2.49(m，4H)，2.37(s，3H)，2.11(m，1H)，2.03-1.94(m，2H)，1.66(m，1H)，1.59-1.54(m，4H)，1.45-1.40(m，2H)；MS?m/z?420(M+1).

Biological part retinal diseases

Merge and measure

Plasmid propagation

With clone's HIV-1 tat (GenBank searching number X07861) and the sequence of rev (GenBank searching number M34378) are cloned into respectively in the pcDNA3.1 expression vector and hygromycin drug resistant gene that contains G418 fully.The complete cloned sequence (the nucleotide base 6225-8795 searching number K03455 of GenBank) of HIV-1 (HXB2 strain) gp160 env gene is cloned in the pCRII-TOPO plasmid.Under the control of CMV promoter transcription, again these three kinds of HIV genes are inserted baculovirus and pass among the shuttle carrier pFastBacMam1.By contain the pcDNA3.1 of G418 hygromycin drug resistant gene with Nru I and Bam HI digestion, remove the CMV promoter, prepare and entangle the pHIV-I LTR member that contains the NFkB sequence of suddenling change that the plain enzyme reporter gene of light is connected.Then LTR-luc is cloned on the Nru I/Bam HI site of this plasmid vector.After plasmid is bred in escherichia coli (Escherichia coli) strain DH5-α, preparation plasmid preparation.With ABI Prism Model 377 automatic sequencers, by the fidelity of double chain nucleotide order-checking conclusive evidence insertion sequence.

The BacMam baculovirus is gone down to posterity

With the cellular matrix Bac-to-Bac system of antibacterial, pass shuttle plasmid construction reorganization BacMam baculovirus by pFastBacMam.According to the scheme of generally acknowledging, propagative viruses in Sf9 (Spodoptera frugiperda) cell of Hink ' the s TNM-FH Insect culture medium culturing that replenishes 10% (v/v) hyclone and 0.1% (v/v) poly alcohol F-68.

Cell culture

Entangle human osteosarcoma (HOS) cell of the plain enzyme plasmid transfection nature of light expressing human CXCR4 with FuGENE 6 transfection reagents and people CCR5, people CD4 and pHIV-LTR-.Separate unicellularly, it is grown under alternative condition, so that produce stable HOS (hCXCR4/hCCR5/hCD4/pHIV-LTR-entangles the plain enzyme of light) cloned cell line.In replenishing the Dulbeccos improvement Eagles culture medium of 10% hyclone (FCS), G418 (400ug/ml), puromycin (1ug/ml), mycophenolic acid (40ug/ml), xanthine (250ug/ml) and hypoxanthine (13.5ug/ml), preserve cell, entangle the cell of the plain enzyme of light, hCCR5 and hCD4 for expressing LTR-respectively, keep selection pressure.With huge human embryo kidney (HEK-293) cell (category-A, 1 type of having a liking for cell removing receptor of the expressing human of stable transfection; GenBank searching number D90187) is kept in the DMEM/F-12 culture medium (1: 1) of replenishing 10%FCS and 1.5ug/ml puromycin.Strengthen itself and the adhesion of the plastics of handling through tissue culture medium (TCM) by this receptor of HEK-293 cellular expression.

Transfection HEK-293 cell

With the cell dissociation buffer results HEK-293 cell that does not contain enzyme.This cell resuspending in the DMEM/F-12 culture medium of replenishing 10%FCS and 1.5ug/ml, is counted.Directly add cell by the BacMam baculovirus that will contain the insect cell culture medium, implement transfection.Simultaneously with the BacMam baculovirus infection cell of expressing HIV-1 tat, HIV-1 rev and HIV-1 gp160 (from the HXB2HIV strain).As usual, the MOI with 10 kinds of viruses adds this phase cell respectively, the protein expression in the increase infection cell.Subsequently that these cells are mixed, by 3,000 ten thousand cell/T225 density, in culture bottle, inoculate.Under 37 ℃, 5%CO ₂Under 95% humidity,, make protein expression with cell incubation 24h down.

Cell/cell fusion is measured mode

In the DMEM/F-12 culture medium that contains 2%FCS with contain results HEK and HOS cell in the DMEM culture medium of 2%FCS, reagent does not bring Selection In respectively.Press the 1ul/ hole, the 100%DMSO solution of chemical compound is added in the 96 hole CulturPlate plates.Earlier HOS cell (50ul) is added in each hole, add HEK cell (50ul) then immediately.The final concentration of every type cell is 20,000 cells/well.After these addings, cell is put back to (37 ℃ of incubator for tissue cultures; 5%CO ₂/ 95% air), preserve 24h again.

What measure to produce entangles the plain enzyme of light

Behind the 24h incubation, (Packard, Meridien CT) measure total cellularity and entangle the plain enzymatic activity of light to measure test kit with LucLite Plus.In brief, this reagent of 100ul is added in each hole.Shrouding, mixed.These plates are placed the dark about 10min in place, and observation is luminous on Packard TopCount then.

Functional examination

Cell culture

By above-mentioned preservation and results human embryo kidney (HEK-293) cell.By 40,000 cells/well concentration, in the plate of the 96 hole black transparent primary coat cloth polylysines that contain people CXCR4 BacMam (MOI=25) and Gqi5BacMam (MOI=12.5), final volume is 100ul with cell inoculation.With cell under 37 ℃, at 5%CO ₂Down, incubation 24h under 95% humidity.Functional FLIPR measures

The incubation that arrival needs contains the DMEM/F12 culture medium washed cell that or not serum of 4-(dipropyl sulfamoyl) benzoic acid (probenicid) after the time with the 50ul new system.Then with 50ul dye solution (Calcium Plus Assay Kit Dye; Molecular Devices) adds cell, be dissolved in 4-(dipropyl sulfamoyl) benzoic acid/BSA that contains culture medium more than the 200ml, incubation 1h.Cell plates are put into Fluormetric Imaging Plate Reader (FLIPR).After the adding, measure chemical compound to [Ca ²⁺] _iThe influence that changes, detection compound are the agonist or the antagonisies (ability of retardance SDF-1 alpha active) of CXCR4 receptor.Measure IC ₅₀Value is with following Leff and Dougall Equation for Calculating pK _bValue: K _B=IC ₅₀/ ((2+ ([agonist]/EC ₅₀^b) ^1/b-1), IC wherein ₅₀By antagonist concentration-response curve definition, [agonist] is the EC of used agonist ₈₀Concentration, EC ₅₀Be that b is the slope of agonist concentration-response curve by the concentration of agonist concentration-response curve definition.

HOS HIV-1 infectiousness is measured

Preparation HIV virus

The sight of two kinds of HIV-1 viruses of observation chemical compound opposing, M-tropic (CCR5 utilizes) Ba-L strain and T-tropic (CXCR4 utilizes) IIIB strain.Two kinds of viruses are bred in the human peripheral blood lymphocytes ball.Test compounds blocks the ability of HIV-1 Ba-L or HIV-1 IIIB infection HOS cell line (express hCXCR4/hCCR5/hCD4/pHIV-LTR-and entangle the plain enzyme of light) therein.Simultaneously do not adding under the virus cytotoxicity of test compounds.

HOS HIV-1 infectiousness is measured mode

Results HOS cell C expresses hCXCR4/hCCR5/hCD4/pHIV-LTR-and entangles the plain enzyme of light) and use the Dulbeccos improvement Eagles culture medium of replenishing 2%FCS and non essential amino acid to be diluted to 60,000 cells/ml concentration.Cell inoculation in 96 orifice plates (100ul/ hole), is put into (37 ℃ of incubator for tissue cultures with plate; 5%CO ₂/ 95% air) in, preserves 24h.

Subsequently, the drug solution that 50ul is needed (final concentration 4 times) adds in each hole, and plate is put back to (37 ℃ of incubator for tissue cultures; 5%CO ₂/ 95% air), preserve 1h.Through behind this incubation, the culture fluid of 50ul virus dilution is added each hole (about 200 ten thousand viral RLU/ hole).Plate is put back to (37 ℃ of incubator for tissue cultures; 5%CO ₂/ 95% air) in, incubation 96h again.

Through behind this incubation, add Steady-Glo Luciferase measure system's reagent (Promega, Madison, WI) after, the terminal point of the culture of viral infection is quantized.(Promega, Madison WI), measure cell survival or do not infect culture to measure system with CellTiter-Glo luminescent cell viability.All (Packard, Meridien CT) carry out at the Topcount luminescence detector in all luminous observations.

Table 1

Table 2

^*" A " expression HOS HIV is anti--and infectiousness is lower than the activity level of 100nM in measuring.

" B " expression HOS HIV is anti--infectiousness measure in the activity level of 100nM-500nM.

" C " expression HOS HIV is anti--infectiousness measure in the activity level of 500nM-10 μ M.

Chemical compound of the present invention is at the IC of the about 50 μ M of about 1nM- ₅₀Demonstrate the anti-HIV activity in the scope.In one aspect of the invention, chemical compound of the present invention has the anti-HIV activity in the scope that is up to about 100nM.In others of the present invention, chemical compound of the present invention has the anti-HIV activity in the scope of the about 500nM of about 100nM-.In others of the present invention, chemical compound of the present invention has the anti-HIV activity in the scope of about 500nM-10 μ M.In others of the present invention, chemical compound has the anti-HIV activity in the scope of the about 50 μ M of about 10 μ M-.

Compound exhibits of the present invention goes out required usefulness.Antiviral activity is different with cytotoxicity.In addition, believe that chemical compound of the present invention can provide required pharmacokinetics pattern.Also believe chemical compound of the present invention provide required auxiliary biology pattern.One aspect of the present invention comprises the have required physicochemical property The compounds of this invention of (solid state properties as required).

Use the test compound of free form or salt form.

Laboratory animal protection philosophy (NIH publication No. 85-23,1985 revisions) is observed in all research and GlaxoSmithKline uses the policy of animal.

Though the present invention is not limited at this for example and describe specific embodiments of the present invention in detail.Provide above-mentioned detailed description only in order to demonstrate the invention, and should not to be considered as be that the present invention is constituted any restriction.Modification will be apparent to those skilled in the art, and do not deviate from spirit of the present invention all modify and all to think and be included in the scope of appended claim.

Claims

1. formula (I) chemical compound or its pharmaceutically acceptable salt or ester:

Wherein:

T is 0,1 or 2;

Each R ¹Independent be halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group ,-Ay ,-NHAy ,-Het ,-NHHet ,-OR ¹⁰,-OAy ,-OHet ,-R ^aOR ¹⁰,-NR ⁶R ⁷,-R ^aNR ⁶R ⁷,-R ^aC (O) R ¹⁰,-C (O) R ¹⁰,-CO ²R ¹⁰,-R ^aCO ₂R ¹⁰,-C (O) NR ⁶R ⁷,-C (O) Ay ,-C (O) Het ,-S (O) ₂NR ⁶R ⁷,-S (O) _qR ¹⁰,-S (O) _qAy, cyano group, nitro or azido;

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 0 or 1;

Each R ^aIndependent is by the optional alkylidene that replaces of one or more alkyl, oxo or hydroxyl, by optional cycloalkylidene, the alkylene group that replaces of one or more alkyl, oxo or hydroxyl, inferior cycloalkenyl group, or alkynylene;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Each Het independently represents optional 4-, the 5-that replaces or 6-unit's heterocyclic radical or heteroaryl.

2. the chemical compound of claim 1, wherein-Het is selected from by at least one that following group is optional to be replaced: alkyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino, or alkyl amino.

3. the chemical compound of claim 1, wherein-Ay is selected from by at least one that following group is optional to be replaced: alkyl, alkoxyl, hydroxyl, halogen, haloalkyl, cycloalkyl, cycloalkyloxy, cyano group, amide, amino, or alkyl amino.

4. the chemical compound of claim 1, wherein t is 1.

5. the chemical compound of claim 1, wherein t is 2.

6. the chemical compound of claim 1, wherein R is H, alkyl, cycloalkyl or R ^aOR ¹⁰

7. the chemical compound of claim 1, wherein R is H or alkyl.

8. the chemical compound of claim 7, wherein R is H.

9. the chemical compound of claim 1, wherein n is 0.

10. the chemical compound of claim 1, wherein n is 1 and R ¹Be halogen, haloalkyl, alkyl, OR ¹⁰, NR ⁶R ⁷, CO ₂R ¹⁰, CONR ⁶R ⁷Or cyano group.

11. the chemical compound of claim 1, wherein R ²Be H, alkyl, haloalkyl, R ^aOR ⁵Or cycloalkyl.

12. the chemical compound of claim 1, wherein R ²Be R ^aAy or R ^aCycloalkyl.

13. the chemical compound of claim 11, wherein R ²Be H, alkyl or cycloalkyl.

14. the chemical compound of claim 11, wherein R ²Be alkyl.

15. the chemical compound of claim 1, wherein R ³Be H, alkyl, haloalkyl, cycloalkyl, alkenyl or alkynyl.

16. the chemical compound of claim 15, wherein R ³Be H, alkyl, haloalkyl or cycloalkyl.

17. the chemical compound of claim 16, wherein R ³Be H or alkyl.

18. the chemical compound of claim 17, wherein R ³Be H.

19. the chemical compound of claim 1, wherein m is 0.

20. the chemical compound of claim 1, wherein m is 1 or 2.

21. the chemical compound of claim 20, wherein m is 1.

22. the chemical compound of claim 21, wherein R ⁴Be halogen, haloalkyl, alkyl, OR ¹⁰, NR ⁶R ⁷, CO ₂R ¹⁰, CONR ⁶R ⁷Or cyano group.

23. the chemical compound of claim 1, wherein p be 0 and X be-R ^aN (R ¹⁰) ₂,-AyR ^aN (R ¹⁰) ₂,-R ^aAyR ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂Or-HetR ^aN (R ¹⁰) ₂

24. the chemical compound of claim 23, wherein X is-R ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂Or-HetR ^aN (R ¹⁰) ₂

25. the chemical compound of claim 24, wherein X is-R ^aN (R ¹⁰) ₂,-Het ,-R ^aHet or-HetN (R ¹⁰) ₂

26. the chemical compound of claim 1, wherein

P is 1;

Y is-N (R ¹⁰)-,-O-,-S-,-C (O) NR ¹⁰,-NR ¹⁰C (O)-or-S (O) qNR ¹⁰-; With

X is-R ^aN (R ¹⁰) ₂,-AyR ^aN (R ¹⁰) ₂,-R ^aAyR ^aN (R ¹⁰) ₂,-Het ,-R ^aHet ,-HetN (R ¹⁰) ₂,-R ^aHetN (R ¹⁰) ₂Or-HetR ^aN (R ¹⁰) ₂

27. the chemical compound of claim 26, wherein

Y is-N (R ¹⁰)-,-O-,-C (O) NR ¹⁰-or-NR ¹⁰C (O)-; With

X is-R ^aN (R ¹⁰) ₂,-Het ,-R ^aHet or-HetN (R ¹⁰) ₂

28. the chemical compound of claim 1, wherein t is 1 or 2; R is H or alkyl; R ²Be H, alkyl or cycloalkyl; R ³Be H, alkyl, haloalkyl or cycloalkyl; N is 0; M is 0.

29. the chemical compound of claim 28, wherein p be 0 and X for-Het or-HetN (R ¹⁰) ₂, R ¹⁰For H or alkyl and Het are unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.

30. the chemical compound of claim 28, wherein p is 1; Y is-N (R ¹⁰)-,-O-,-CONR ¹⁰-or-NR ¹⁰CO-; X is-Het or-HetN (R ¹⁰) ₂And Het is unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.

31. the chemical compound of claim 30, wherein Y is-N (R ¹⁰)-or-O-and X be-Het.

32. the chemical compound of claim 1, wherein p is 0; X is-HetN (R ¹⁰) ₂And R ¹⁰Be H or alkyl.

33. the chemical compound of claim 1, wherein p be 1 and Y be-N (R ¹⁰)-,-O-,-C (O) NR ¹⁰-or-NR ¹⁰C (O)-; X is-Het or-HetN (R ¹⁰) ₂And Het is unsubstituted or by C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.

34. the chemical compound of claim 1, wherein substituent group-Y _p-X is positioned on the imidazopyridine ring shown in the structural formula (I '):

35. the chemical compound of claim 1, wherein Het is piperidines, piperazine, azetidine, pyrrolidine, imidazoles or pyridine.

36. the chemical compound of claim 1, wherein p be 0 and X be-Het.

37. the chemical compound of claim 36, wherein-Het is unsubstituted or by one or more C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl substituted.

38. one kind is selected from following chemical compound;

16) N-methyl-N-({ 5-[methyl (1-methyl-3-pyrrolidinyl) amino] imidazo [1,2-a] pyridine 2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

36) (8S)-and N-[(2-fluoro phenyl) methyl]-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,6,7,8-tetrahydrochysene-8-quinolinamine;

73) (8S)-and N-methyl-N-[(5-{[2-(1-pyrrolidinyl) ethyl] amino) imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

77) (8S)-and N-methyl-N-[(5-{[2-(piperidino) ethyl] the oxygen base } imidazo [1,2-a] pyridine-2-yl) methyl]-5,6,7,8-tetrahydrochysene-8-quinolinamine;

And pharmaceutically acceptable salt or ester.

39. one kind is selected from following chemical compound:

20) N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-6,7-dihydro-5H-cyclopenta [b] pyridine-7-amine;

22) (8S)-and N-methyl-N-{[5-(4-methyl isophthalic acid-piperazinyl) imidazo [1,2-a] pyridine-2-yl] methyl }-5,67,8-tetrahydrochysene-8-quinolinamine;

48) (8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

And pharmaceutically acceptable salt or ester.

40. one kind is selected from following chemical compound:

23) (8S)-N-(cyclopropyl methyl)-N-(5-[(3R)-3-(dimethylamino)-1-pyrrolidinyl] imidazo [1,2-a] pyridine-2-yl } methyl)-5,6,7,8-tetrahydrochysene-8-quinolinamine;

And pharmaceutically acceptable salt or ester.

41. one kind is selected from following chemical compound:

And pharmaceutically acceptable salt or ester.

42. each chemical compound among the claim 1-41, described chemical compound are gone up substantially as aforementioned definition to arbitrary embodiment.

43. a pharmaceutical composition, described compositions contain among the claim 1-41 each chemical compound and pharmaceutically acceptable carrier.

44. the compositions of claim 43, wherein said compositions contains at least a following other medicine that is selected from: nucleotide reverse transcriptase inhibitors, for example zidovudine, didanosine, lamivudine, zalcitabine, Abacavir, stavudine, adefovirdipivoxil, adefovir dipivoxil, Fu Qifuding, todoxil and similar medicine; Non-nucleotide reverse transcriptase inhibitors (comprising medicine, for example immunocal, oltipraz etc.), for example nevirapine, dilazep Wei Ding, efavirenz, loviride, immunocal, oltipraz and similar medicine with antioxidant activity; Protease inhibitor, for example Saquinavir, ritonavir, indinavir, viracept see nelfinaivr, aprenavir, palinavir, LASINAVIR BMS-234475 Lasinavir [INN and similar medicine; Entry inhibitor, for example T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806,5-spiral elasticity albumen and similar medicine; Integrin enzyme inhibitor, for example L-870,180 and similar medicine; The budding inhibitor is PA-344 and PA-457 and similar medicine for example; With other CXCR4 and/or CCR5 inhibitor, for example Sch-C, Sch-D, TAK779, UK427,857, TAK449 and similar medicine.

45. each chemical compound among the claim 1-41, described chemical compound is as the active treatment material.

46. disease and disease that each chemical compound among the claim 1-41, described chemical compound are used for the treatment of or prevent to be caused by unsuitable CXCR4 activity.

47. each chemical compound among the claim 1-41, described chemical compound is used for: treatment or prevention HIV infect, with the hemopoietic diseases associated; The control chemotherapy side effect; Increase the bone marrow transplantation success rate; Promote wound healing and burn to handle; Bacterial infection in the leukemia; Inflammation; Inflammatory or anaphylactic disease; Asthma; Allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, homograft rejection, graft versus host disease, inflammatory bowel disease, Crohn disease, ulcerative colitis, spondyloarthropathy, scleroderma, psoriasis, the psoriasis that T-is cell-mediated, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis; Encircle dead property, skin, allergic angiitis; Acidophilia's myositis, eosinophilic fasciitis; With brain, mammary gland, prostate, lung or hemopoietic tissue cancer.

48. the chemical compound of claim 47, wherein said disease or disease are HIV infection, rheumatoid arthritis, inflammation or cancer.

49. being HIV, the chemical compound of claim 47, wherein said disease or disease infect.

50. among the claim 1-41 each chemical compound preparation be used for the treatment of or the medicine of the disease of preventing to regulate or disease by chemokine receptors in purposes.

51. the purposes of the chemical compound of claim 50, wherein said chemokine receptors is CXCR4.

52. among the claim 1-41 each chemical compound preparation be used for the treatment of or prevent purposes in the medicine of following disease: HIV infect, with the hemopoietic diseases associated; The control chemotherapy side effect; Increase the bone marrow transplantation success rate; Promote wound healing and burn to handle; Bacterial infection in the leukemia; Inflammation; Inflammatory or anaphylactic disease; Asthma; Allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, homograft rejection, graft versus host disease, inflammatory bowel disease, Crohn disease, ulcerative colitis, spondyloarthropathy, scleroderma, psoriasis, the psoriasis that T-is cell-mediated, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis; Encircle dead property, skin, allergic angiitis; Acidophilia's myositis, eosinophilic fasciitis; With brain, mammary gland, prostate, lung or hemopoietic tissue cancer.

53. the purposes of the chemical compound of claim 52, wherein said disease or disease are HIV infection, rheumatoid arthritis, inflammation or cancer.

54. being HIV, the purposes of the chemical compound of claim 52, wherein said disease or disease infect.

55. the disease that treatment or prevention are regulated by chemokine receptors or the method for disease, described method comprise the chemical compound that gives among the claim 1-41 each.

56. the method for claim 55, wherein said chemokine receptors is CXCR4.

57. the method that is used for the treatment of or prevents following disease a: HIV infects, with the hemopoietic diseases associated; The control chemotherapy side effect; Increase the bone marrow transplantation success rate; Promote wound healing and burn to handle; Bacterial infection in the leukemia; Inflammation; Inflammatory or anaphylactic disease; Asthma; Allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia, delayed hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic lupus erythematosus (sle), ankylosing spondylitis, Sjogren's syndrome, siogren's syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or anaphylaxis, drug allergy, sting allergy, autoimmune disease, rheumatoid arthritis, arthritic psoriasis, systemic lupus erythematosus (sle), myasthenia gravis, juvenile diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, homograft rejection, graft versus host disease, inflammatory bowel disease, Crohn disease, ulcerative colitis, spondyloarthropathy, scleroderma, psoriasis, the psoriasis that T-is cell-mediated, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis; Encircle dead property, skin, allergic angiitis; Acidophilia's myositis, eosinophilic fasciitis; With brain, mammary gland, prostate, lung or hemopoietic tissue cancer, described method comprises the chemical compound that gives among the claim 1-41 each.

58. a treatment or prevention HIV infection, rheumatoid arthritis, inflammation or method for cancer, described method comprise the chemical compound that gives among the claim 1-41 each.

59. the method that treatment or prevention HIV infect, described method comprise the chemical compound that gives among the claim 1-41 each.

60. the method that treatment or prevention human virus infect, described method comprise that giving described people contains each chemical compound and the compositions of another kind of medicine among the claim 1-41.

61. the method for claim 60, wherein said medicine is selected from nucleotide reverse transcriptase inhibitors, for example zidovudine, didanosine, lamivudine, zalcitabine, Abacavir, stavudine, adefovirdipivoxil, adefovir dipivoxil, Fu Qifuding, todoxil and similar medicine; Non-nucleotide reverse transcriptase inhibitors (comprising medicine, for example immunocal, oltipraz etc.), for example nevirapine, dilazep Wei Ding, efavirenz, loviride, immunocal, oltipraz and similar medicine with antioxidant activity; Protease inhibitor, for example Saquinavir, ritonavir, indinavir, viracept see nelfinaivr, aprenavir, palinavir, LASINAVIR BMS-234475 Lasinavir [INN and similar medicine; Entry inhibitor, for example T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806,5-spiral elasticity albumen and similar medicine; Integrin enzyme inhibitor, for example L-870,180 and similar medicine; The budding inhibitor is PA-344 and PA-457 and similar medicine for example; With other CXCR4 and/or CCR5 inhibitor, for example Sch-C, Sch-D, TAK779, UK427,857, TAK449 and similar medicine.

62. the method for a preparation formula (I) chemical compound

Wherein

T is 1; Each R is H;

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 0 or 1;

Y is-NR ¹⁰-,-O-,-C (O) NR ¹⁰-,-NR ¹⁰C (O)-,-C (O)-,-C (O) O-,-NR ¹⁰C (O) N (R ¹⁰) ₂-,-S (O) _q-,-S (O) _qNR ¹⁰-or-NR ¹⁰S (O) _q-;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Each Het independently represents optional 4-, the 5-that replaces or 6-unit's heterocyclic radical or heteroaryl;

Described method is included under the reductive amination condition, makes formula (II) chemical compound

React with formula (IV) chemical compound

Obtain the step of formula (I) chemical compound.

63. the method for a preparation formula (I) chemical compound

Wherein

T is 1;

Each R independently is H;

N is 0,1 or 2;

R ²Be selected from H, alkyl, haloalkyl, cycloalkyl ,-R ^aCycloalkyl, alkenyl, alkynyl ,-R ^aAy ,-R _aOR ⁵Or-R ^aS (O) _qR ⁵, R wherein ²Do not replaced by amine or alkylamine;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 0 or 1;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Described method is included under the reductive amination condition, makes formula (III) chemical compound

R wherein ¹, R ²With n as definition to formula (I), react with the formula V chemical compound

Obtain the step of formula (I) chemical compound.

64. the method for a preparation formula (I) chemical compound

Wherein

T is 1;

Each R independently is H;

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 0 or 1;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Described method comprises makes formula (III) chemical compound

R wherein ¹, R ²With n as definition to formula (I), react with formula (VI) chemical compound

R wherein ³, R ⁴, Y, X, p and m be leaving group as definition and LV to formula (I), obtains the step of formula (I) chemical compound.

65. the method for a preparation formula (I-A) chemical compound

Wherein

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 0 or 1;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Described method comprises with nucleopilic reagent handles formula (X) chemical compound

R wherein ¹, R ², R ³, R ⁴, m and n be as the definition to formula (I-A), obtains the step of formula (I-A) chemical compound.

66. the method for a preparation formula (I-C) chemical compound

Wherein

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Said method comprising the steps of: in the presence of catalyst, make formula (X) chemical compound

R wherein ¹, R ², R ³, R ⁴, n and m be as the definition to formula (I-C), react with formula (XIII) chemical compound

Production (XII) chemical compound

R wherein ¹, R ², R ³, n and m be as the definition to formula (I-C), and reduction-type (XII) chemical compound obtains formula (I-C) chemical compound.

67. the method for a preparation formula (I-D) chemical compound

Wherein

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 1;

Y is-C (O) NR ¹⁰-;

Each R ^aIndependently serve as reasons-individual or a plurality of alkyl, the optional alkylidene that replaces of oxo or hydroxyl, by optional cycloalkylidene, the alkylene group that replaces of one or more alkyl, oxo or hydroxyl, inferior cycloalkenyl group, or alkynylene;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Said method comprising the steps of: make formula (XVI) chemical compound deprotection

R wherein ¹, R ², R ³, R ⁴, n and m be as the definition to formula (I-D), forms carboxylic acid compounds, then makes this carboxylic acid compounds and amine coupling, forms formula (I-D) chemical compound.

68. the method for a preparation formula (I-E) chemical compound

Each R wherein ¹Independent be halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group ,-Ay ,-NHAy ,-Het ,-NHHet ,-OR ¹⁰,-OAy ,-OHet ,-R ^aOR ¹⁰,-NR ⁶R ⁷,-R ^aNR ⁶R ⁷,-R ^aC (O) R ¹⁰,-C (O) R ¹⁰,-CO ₂R ¹⁰,-R ^aCO ₂R ¹⁰,-C (O) NR ⁶R ⁷,-C (O) Ay ,-C (O) Het ,-S (O) ₂NR ⁶R ⁷,-S (O) _qR ¹⁰,-S (O) _qAy, cyano group, nitro or azido;

N is 0,1 or 2;

M is 0,1 or 2;

Each R ⁵Independent be H, alkyl, alkenyl, alkynyl, cycloalkyl or-Ay;

P is 1;

Y is-NR ¹⁰C (O)-;

R ⁸And R ⁹Independently be selected from H or alkyl separately;

Each q independently is 0,1 or 2;

Each Ay independently represents the optional aryl that replaces; And

Described method comprises the amine that makes formula (XXII)

R wherein ¹, R ², R ³, R ⁴, n and m be as the definition to formula (I-E), with the carboxylic acid derivates coupling, forms the step of formula (I-E) chemical compound.

69. the method for a preparation formula (XXXI) chemical compound

Wherein Z is C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl, described method is included under the reductive amination condition, makes formula (XXIX) chemical compound

Wherein Z is C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is reacted with formula (XXX) chemical compound

Obtain the step of formula (XXXI) chemical compound.

70. the method for a preparation formula (I-F) chemical compound

Wherein Z is C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl said method comprising the steps of, and removes 4-(methyl oxygen base phenyl) ethyl from formula (XXXI) chemical compound

Wherein Z is C ₁-C ₆Alkyl or C ₃-C ₈Cycloalkyl is then used the aldehyde reductive amination, obtains formula (I-F) chemical compound.