CN101370812A

CN101370812A - Fused heterocyclic compound

Info

Publication number: CN101370812A
Application number: CNA2006800523192A
Authority: CN
Inventors: 石川智康; 三轮宪弘; 瀬户雅树; 坂野浩; 川北洋一
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2005-12-02
Filing date: 2006-12-01
Publication date: 2009-02-18
Also published as: ZA200805009B

Abstract

The present invention provides a compound represented by the formula: wherein R<1a>is a hydrogen atom, R<2a> is a C1-6 alkyl group substituted by a group represented by-NR<6a>-CO-(CH2) n-SO2-optionally halogenated C1-4 alkyl wherein n is an integer of 1 to 4, R<6a> is a hydrogen atom or a C 1-4 alkyl group, and -(CH2) n - is optionally substituted by C 1-4 alkyl, R<3a> is a hydrogen atom or a C1-6 alkyl group, R<4a> is a halogen atom or a C 1-6 alkyl group, R<5a> is a halogen atom or a C1-6 alkyl group, and X<a> is a hydrogen atom or a halogen atom, or a salt thereof. The compound of the present invention has a superior tyrosine kinase inhibitory action, is highly safe, and is sufficiently satisfactory as a pharmaceutical product.

Description

The heterogeneous ring compound condensing

Technical field

The present invention relates to have growth factor receptor tyrosine kinase and suppress active condensed pyramidine compounds, it can be used for prevention or treatment cancer, the invention still further relates to Its Preparation Method And Use.

Background technology

The gene of cell growth factor and growth factor receptors is known as proto-oncogene, and plays an important role in the pathology of people's tumour.Epithelial cell growth factor receptor 2 body family (erbB) comprises EGFR, HER2, HER3 and HER4, and it is I receptor type tyrosine kinase.These erbB families are at various cells, and the control of they and Growth of Cells and differentiation and control that necrocytosis suppresses (apoptosis inhibition) closely related.For example, the high expression level of known EGFR and HER2 and the steady state activity of acceptor make cell transformation in experience.

The high expression level of known each these acceptor and simultaneously expressing in different cancer patients as bad prognostic factor also.

These acceptors and multiple peptide part are as combinations such as EGF, TGF α, and the combination of part promotes same dimerization or the allos dimerization of acceptor.This has induced the increase that is derived from the self phosphorylation of acceptor or turns the kinase activity of phosphorylation, and the combination of the tyrosine residues by albumen and specific phosphorylation causes downstream signal approach (MAP, Akt) activation.This is the mechanism of the receptor active of above-mentioned Growth of Cells, differentiation, necrocytosis inhibition etc., and it is considered to increase due to the part of ligand concentration, the reason of acceptor high expression level in the malignization of cancer and cancer.

Many cancers are all relevant to the high expression level of EGFR or HER2.Such as mentioning mammary cancer (20-30%), ovarian cancer (20-40%), nonsmall-cell lung cancer (30-60%), colorectal carcinoma (40-80%), prostate cancer (10-60%), bladder cancer (30-60%), kidney (20-40%) etc.In addition, expression of receptor and prediction are correlated with; And expression of receptor is bad prognostic factor in mammary cancer, nonsmall-cell lung cancer etc.

In recent years, the clinical use of the anti-HER2 antibody of humanization (trastuzumab) in anti-HER2 high expression level mammary cancer, the clinical trial of the clinical trial of anti-EGFR-antibodies and a plurality of lower molecular weight acceptor enzyme inhibitorss has proved that these medicines are for resisting HER2 or EGFR as the possibility of cancer treatment drugs.Although these medicines demonstrate tumor growth restraining effect in clinical and nonclinical test, known they can cause the inhibition of acceptor enzymic activity and the inhibition of downstream signal approach.Therefore, the compound of inhibition EGFR or HER2 kinases or inhibition EGFR or the kinase whose activation of HER2 is effective cancer therapy medicine.

As the compound suppressing by the receptor type tyrosine kinase of HER2/EGFR kinases representative, the known heterogeneous ring compound condensing (for example WO97/13771, WO98/02437, WO00/44728), quinazoline derivant (for example WO02/02552, WO01/98277, WO03/049740, WO03/050108), Thienopyrimidine derivative (for example WO03/053446), aromatic series pyrroles (azole) derivative (such as WO98/03648, WO01/77107, WO03/031442) etc.; Yet, do not have at present HER2 kinase inhibition material to go on the market as novel remedies for cancer.

As pyrrolo-[3,2-d] pyrimidine derivatives; Known following compounds as have cell growth inhibiting activity compound ( khim.-Farm.Zh., 1982,16,1338-1343; collect.Czech.Chem. commun.,2003,68,779-791).

As having receptor type tyrosine kinase, suppress active compound, following pyrrolo-[3,2-d] pyrimidine derivatives is known (WO96/40142, WO98/23613).

In addition, for pyrazolo [4,3-d] pyrimidine derivatives, 3, the trisubstituted pyrazolo of 5,7-[4,3-d] pyrimidine derivatives is the known compound (EP-A-1348707) with CDK restraining effect, cell growth inhibition and/or apoptosis-inducing effect, and 3-sec.-propyl pyrazolo [4,3-d] pyrimidine derivatives is known be have CDK1/ cell periodic protein B suppress active compound ( bioorganic & Medicinal chemistry Letters, 2003,13,2989-2992).In addition, 3-methylpyrazole also [4,3-d] pyrimidine derivatives composite traces ( the Journal of Organic Chemistry,1956,21,833-836) in.

Summary of the invention

The object of the present invention is to provide the compound with excellent tyrosine kinase inhibitory activity, it is hypotoxic, and is foolproof as medicament production

The inventor conducts in-depth research, and attempts to address the above problem, and finds that following formula (Ia)-(Ih) represented compound and salt thereof has excellent tyrosine kinase inhibitory activity.More deep research has been accomplished the present invention.

Therefore, the present invention relates to as follows.

The represented compound or its salt of [1a] following formula:

Wherein

R ^1ahydrogen atom,

R ^2aby-NR ^6a-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4the C that group shown in alkyl replaces _1-6alkyl

Wherein n is the integer of 1-4, R ^6ahydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

R ^3ahydrogen atom or C _1-6alkyl,

R ^4ahalogen atom or C _1-6alkyl,

R ^5ahalogen atom or C _1-6alkyl, and

X ^ahydrogen atom or halogen atom,

Condition is N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] except-2-(methylsulfonyl) ethanamide.

The compound of [2a] above-mentioned [1a], wherein X ^ait is hydrogen atom.

The compound of [3a] above-mentioned [2a], wherein

R ^1ahydrogen atom,

R ^2aby-NR ^6aa-CO-CR ^7ar ^8a-SO ₂-C _1-4the C that group shown in alkyl replaces _1-6alkyl

R wherein ^6aahydrogen atom or methyl, R ^7aand R ^8aidentical or different and each hydrogen atom or methyl naturally,

R ^3ahydrogen atom,

R ^4achlorine atom or methyl, and

R ^5afluorine atom, chlorine atom or methyl.

The compound of [4a] above-mentioned [3a], wherein R ^7aand R ^8ait is methyl.

[5a] is selected from following compound or its salt or its hydrate:

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-methyl-2-(methylsulfonyl) propionic acid amide,

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(ethylsulfonyl) ethanamide,

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-N, 2-dimethyl-2-(methylsulfonyl) propionic acid amide,

N-[2-(the chloro-4-of 4-{[3-(3-methylphenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide,

N-[2-(the chloro-4-of 4-{[3-(3-fluorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide, and

N-[2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-methyl-2-(methylsulfonyl) propionic acid amide.

The prodrug of the compound of [6a] above-mentioned [1a].

The preparation method of the compound or its salt of [7a] above-mentioned [1a], it comprises makes the compound or its salt shown in following formula:

L wherein ^abe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^abe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [8a] comprises above-mentioned [1a] or the medicine of its prodrug (pharmaceuticalagent).

The medicine of [9a] above-mentioned [8a], it is tyrosine kinase inhibitor.

The medicine of [10a] above-mentioned [8a], it is the medicine of prevention or treatment cancer.

The medicine of [11a] above-mentioned [10a], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [12a] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1a] of Mammals effective dosage or its prodrug.

The compound or its salt of [13a] above-mentioned [1a] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The represented compound or its salt of [1b] following formula:

Wherein

W ^bc (R ^1b) or N,

Ring A ^bthe optional pyridine ring replacing,

X ^1bbe-NR ^3b-Y ^1b-,-O-,-S-,-SO-,-SO ₂-or-CHR ^3b-

R wherein ^3bhydrogen atom or the optional aliphatic alkyl replacing, or R ^3boptionally with ring A ^bpyridine ring on carbon atom in conjunction with to form the ring structure of optional replacement, and Y ^1bkey or C _1-4alkylidene group or-O-(C _1-4alkylidene group)-, they are optionally substituted separately, and

R ^1bhydrogen atom, halogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

R ^2bhydrogen atom or the group that passes through the optional replacement of carbon atom or sulphur atom combination, or

R ^1band R ^2b, or R ^2band R ^3boptional combination is to form the ring structure of optional replacement.

The compound of [2b] above-mentioned [1b], it is the compound shown in following formula:

Wherein encircle A ^{b '}further substituted pyridine ring optionally, ring B ^bthe optional C replacing _6-14aryl, and other symbol defines as above-mentioned.

The compound of [3b] above-mentioned [2b], wherein

R ^1bthe C of hydrogen atom, halogen atom, cyano group or optional halo _1-6alkyl,

R ^2bbe selected from the C that following substituting group replaces _1-6alkyl:

(i)-NR ^6ba-CO-(CH ₂) _n1-SO ₂-C _1-4alkyl

R wherein ^6babe hydrogen atom or methyl, n1 is the integer of 1-4, and-(CH ₂) _n1-optionally by C _1-4alkyl replaces,

(ii)-NR ^6bb-CO-(CH ₂) _n2-OH

R wherein ^6bbbe hydrogen atom or methyl, n2 is the integer of 1-4, and-(CH ₂) _n2-optionally by C _1-4alkyl replaces,

(iii)-O-(CH ₂) _n3-OH

Wherein n3 is the integer of 1-4, and-(CH ₂) _n3-optionally by C _1-4alkyl replaces, and

(iv) hydroxyl,

R ^3bhydrogen atom,

Ring A ^{b '}the pyridine ring that is optionally selected from the substituting group replacement of halogen and methyl, and

Ring B ^bthe C that is optionally selected from optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6the phenyl that the substituting group of alkyl-formamyl and halogen replaces.

The compound of [4b] above-mentioned [2b], wherein

Ring A ^{b '}the pyridine ring optionally being replaced by halogen, and

Ring B ^boptionally on 3-position, be selected from the C of optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6the phenyl that the substituting group of alkyl-formamyl and halogen replaces.

[5b] is selected from following compound or its salt:

2-{2-[4-(the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] and pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol,

N-{2-[4-(the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] and pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,

N-{2-[4-(the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] and pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxy-3-methyl butyramide,

N-{2-[4-(the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] and pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide, and

The chloro-5-{[5-of N-(tertiary butyl)-3-[(3-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } pyridine-2-yl) oxygen base] benzamide.

The prodrug of the compound of [6b] above-mentioned [1b].

The preparation method of the compound or its salt of [7b] above-mentioned [1b], it comprises makes the compound or its salt shown in following formula:

L wherein ^bbe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^bbe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [8b] comprises above-mentioned [1b] or the medicine of its prodrug.

The medicine of [9b] above-mentioned [8b], it is tyrosine kinase inhibitor.

The medicine of [10b] above-mentioned [8b], it is the medicine of prevention or treatment cancer.

The medicine of [11b] above-mentioned [10b], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [12b] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1b] of Mammals effective dosage or its prodrug.

The compound or its salt of [13b] above-mentioned [1b] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The compound of [14b] above-mentioned [1b], it is the compound shown in following formula:

Wherein each symbol defines as above-mentioned.

The represented compound or its salt of [1c] following formula:

Wherein

R ^1chydrogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

R ^2cby the group of the optional replacement of carbon atom or sulphur atom combination, or

R ^1cand R ^2c, or R ^2cand R ^3cit is optional in conjunction with to form the ring structure of optional replacement,

R ^3chydrogen atom or the optional aliphatic alkyl replacing, or R ^3coptionally be combined to form the ring structure of optional replacement with the carbon atom on adjacent phenyl ring,

Ring A ^cthe optional phenyl ring replacing,

R ^5cbe

(i) the optional amino replacing,

(ii) the optional formamyl replacing,

(iii) the optional urea groups replacing,

(iv) the optional sulfamyl replacing,

(v) the optional heterocyclic radical replacing,

(vi) the optional C replacing _2-6alkoxyl group,

(vii) the optional aminomethyl replacing,

(viii) the optional carbamyl ylmethyl replacing,

(ix) the optional alkyl sulphonyl replacing, or

(x) cyano group, and

Ring B ^cc _6-14aryl or C _5-8cycloalkyl, except R ^5coutside they are also optionally further substituted separately,

Condition is to get rid of following compound:

The chloro-4-of N-(tertiary butyl)-4-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] benzamide hydrochloride salt,

The chloro-4-of 4-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-N-(2,2-dimethyl propyl) benzamide,

3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzonitrile,

The chloro-4-of 3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] benzonitrile,

The chloro-4-of 3-[2-(6,7-dihydro-9H-Kui Linpyrimido quinoline [4 ', 5 ': 4,5] pyrrolo-es [2,1-c] [Isosorbide-5-Nitrae] oxazine-4-base is amino) phenoxy group] benzonitrile hydrochloride, and

(2E)-N-[(2E)-3-(the chloro-4-of 4-{[3-(3-cyano-benzene oxygen) phenyl] amino }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) third-2-alkene-1-yl]-4-(dimethylamino) but-2-enamides.

The compound of [2c] above-mentioned [1c], wherein R ^1cit is hydrogen atom.

[3c] is selected from following compound or its salt:

2-{2-[4-(the chloro-4-[3-of 3-(1,3-thiazoles-5-yl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol,

The chloro-4-of N-(tertiary butyl)-3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] benzamide,

The chloro-4-of 3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide,

N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide,

N-(3-{2-chloro-4-[(6-cyano group-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } phenyl) cyclopropane carboxamide,

N-(tertiary butyl)-5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-2-fluorobenzamide,

N-{2-[4-(the chloro-4-[3-of 3-(dimethylamino) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxy-3-methyl butyramide,

N-{2-[4-(the chloro-4-[3-of 3-(dimethylamino) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,

N-(tertiary butyl)-2-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] ethanamide,

N-{2-[4-(the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,

N-{2-[4-(the chloro-4-[3-of 3-(2,2-dimethyl propoxy-) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,

2-(methylsulfonyl)-N-{2-[4-(3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } ethanamide,

2-[4-(the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethanol, and

N-[2-(the chloro-4-of 4-{[3-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide.

The prodrug of the compound of [4c] above-mentioned [1c].

The preparation method of the compound or its salt of [5c] above-mentioned [1c], it comprises makes the compound or its salt shown in following formula:

L wherein ^cbe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^cbe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [6c] comprises above-mentioned [1c] or the medicine of its prodrug.

The medicine of [7c] above-mentioned [6c], it is tyrosine kinase inhibitor.

The medicine of [8c] above-mentioned [6c], it is the medicine of prevention or treatment cancer.

The medicine of [9c] above-mentioned [8c], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [10c] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1c] of Mammals effective dosage or its prodrug.

The compound or its salt of [11c] above-mentioned [1c] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The compound of [12c] above-mentioned [1c], it is the compound shown in following formula:

Wherein each symbol defines as above-mentioned.

The compound of [13c] above-mentioned [1c], it is the compound shown in following formula:

Wherein encircle B ^{c '}phenyl or cyclohexyl, except R ^5coutside they are also optionally further substituted separately, and other symbol defines as above-mentioned.

The compound of [14c] above-mentioned [1c], wherein

R ^2coptionally be selected from the C that following substituting group replaces _1-6alkyl:

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

Wherein n is the integer of 1-4, R ^6chydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

The compound of [15c] above-mentioned [1c], wherein

R ^1chydrogen atom or cyano group,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl,

Ring A ^cthe phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl,

R ^5cbe

(i) amino,

(ii) list-C _1-6alkyl-amino,

(iii) two-C _1-6alkyl-amino,

(iv) C of optional halo _1-6alkyloyl-amino,

(v) hydroxyl-C _1-6alkyloyl-amino,

(vi) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vii) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(viii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(ix) C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino,

(x) C _3-7cycloalkyl-carbonyl-amino,

(xi) C _1-6alkoxyl group-carbonyl-amino,

(xii) formamyl,

(xiii) C of optional halo _1-6alkyl-formamyl,

(xiv) hydroxyl-C _1-6alkyl-formamyl,

(xv) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xvi) C _6-14aryl-C _1-6alkyl-formamyl,

(xvii) C _2-6alkynyl-formamyl,

(xviii) piperidyl-C _1-6alkyl-formamyl,

(xix) morpholinyl-C _1-6alkyl-formamyl,

(xx) optionally by C _1-6alkyl or C _2-6the C of alkynyl substituted _3-7cycloalkyl-formamyl,

(xxi) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xxii) urea groups,

(xxiii) C _1-6alkyl-urea groups,

(xxiv) C _3-7cycloalkyl-urea groups,

(xxv) except carbon atom, also contain 1-3 the first heterocycle-urea groups of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,

(xxvi) optionally by C _1-6the sulfamyl that alkyl replaces,

(xxvii) except carbon atom, also contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally selected from the C of optional halo _1-6alkyl and C _1-6the substituting group of alkoxyl group-carbonyl replaces,

(xxviii) be optionally selected from C _3-7cycloalkyl, halogen, C _1-6alkoxyl group and C _1-6the C that the substituting group of alkyl-formamyl replaces _2-6alkoxyl group,

(xxix) optionally by C _1-6the carbamyl ylmethyl that alkyl replaces,

(xxx) optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted,

(xxxi) optionally contain C _3-7the C of cycloalkyl or halogen _1-6alkyl sulphonyl, or

(xxxii) cyano group, and

Ring B ^cc _6-14aryl or C _5-8cycloalkyl, except R ^5coutside they are also optionally selected from the C of optional halo separately _1-6the substituting group of alkyl and halogen further replaces.

The compound of [16c] above-mentioned [1c] or [12c], wherein

R ^5coptionally be selected from the amino that following substituting group replaces:

(i) C _1-6alkyl,

(ii) C of optional halo _1-6alkyloyl,

(iii) hydroxyl-C _1-6alkyloyl,

(iv) C that contains hydroxyl and halogen _1-6alkyloyl,

(v) C _3-7cycloalkyl-C _1-6alkyloyl,

(vi) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl,

(vii) C _1-6alkyl sulphonyl-C _1-6alkyloyl,

(viii) C _3-7cycloalkyl-carbonyl, and

(ix) C _1-6alkoxyl group-carbonyl,

Ring B ^cc _6-14aryl or C _5-8cycloalkyl, except R ^5coutside they are also optionally selected from the C of optional halo separately _1-6the substituting group of alkyl and halogen further replaces,

R ^1chydrogen atom,

R ^2cbe selected from the C that following substituting group replaces _1-6alkyl:

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

Ring A ^cit is the phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl.

The compound of [17c] above-mentioned [1c] or [12c], wherein

R ^5coptionally be selected from the formamyl that following substituting group replaces:

(i) C of optional halo _1-6alkyl,

(ii) hydroxyl-C _1-6alkyl,

(iii) C _1-6alkoxy-C _1-6alkyl,

(iv) C _6-14aryl-C _1-6alkyl,

(v) C _2-6alkynyl,

(vi) piperidyl-C _1-6alkyl,

(vii) morpholinyl-C _1-6alkyl, and

(viii) optionally by C _1-6alkyl or C _2-6the C of alkynyl substituted _3-7cycloalkyl,

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

The compound of [18c] above-mentioned [1c] or [12c], wherein

R ^5cthe urea groups optionally being replaced by following substituting group:

(i) C _1-6alkyl,

(ii) C _3-7cycloalkyl, and

(iii) except carbon atom, also contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

The compound of [19c] above-mentioned [1c] or [12c], wherein

R ^5coptionally by C _1-6the sulfamyl that alkyl replaces,

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

The compound of [20c] above-mentioned [1c] or [12c], wherein

R ^5cbe except carbon atom, also to contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally selected from the C of optional halo _1-6alkyl and C _1-6the substituting group of alkoxyl group-carbonyl replaces,

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

[21c] above-mentioned [16c] is to the compound of [20c] middle any one, wherein

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

R wherein ^7cand R ^8cidentical or different, and each hydrogen atom or C naturally _1-4alkyl,

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

Wherein n2 is the integer of 1-4, R ^6cbhydrogen atom or C _1-4alkyl, and-(CH ₂) _n2-optionally by C _1-4alkyl replaces,

(iii)-O-(CH ₂) _n3-OH

Wherein n3 is the integer of 1-4, and-(CH ₂) _n3-optionally by C _1-4alkyl replaces,

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

The compound of [22c] above-mentioned [1c] or [12c], wherein

R ^2cby-NR ^6ca-CO-(CH ₂) _n1-SO ₂the C of-optional halo _1-4the C that group shown in alkyl replaces _1-6alkyl

Wherein n1 is the integer of 1-4, R ^6cahydrogen atom or C _1-4alkyl, and-(CH ₂) _n1-optionally by C _1-4alkyl replaces,

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(i) amino, optionally (a) optionally contained C _1-6the C of alkyl sulphonyl _1-6alkyloyl is monosubstituted or (b) by C _1-6alkyl list or two replacement,

(ii) optionally by C _1-6the formamyl that alkyl replaces,

(iii) except carbon atom, also contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally by the C of optional halo _1-6alkyl replaces,

(iv) optionally by C _3-7cycloalkyl, halogen, C _1-6alkoxyl group or C _1-6the C that alkyl-formamyl replaces _2-6alkoxyl group,

(v) optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted,

(vi) optionally by C _3-7the C of cycloalkyl substituted _1-6alkyl sulphonyl, or

(vii) cyano group, and

Ring B ^cexcept R ^5coutside be also optionally selected from the C of optional halo _1-6the C that the substituting group of alkyl and halogen further replaces _6-14aryl.

The compound of [23c] above-mentioned [22c], wherein

R ^2cby-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4the C that group shown in alkyl replaces _1-6alkyl

R wherein ^7cand R ^8cidentical or different, and each hydrogen atom or C naturally _1-4alkyl.

The compound of [24c] above-mentioned [1c] or [12c], wherein

R ^2cby-NR ^6cb-CO-(CH ₂) _n2the C that group shown in-OH replaces _1-6alkyl

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(i) amino, its optionally (a) optionally contained the C of hydroxyl _1-6alkyloyl is monosubstituted or (b) by C _1-6alkyl list or two replacement,

(ii) optionally by C _1-6the formamyl that alkyl replaces,

(v) optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted,

(vii) cyano group, and

The compound of [25c] above-mentioned [24c], wherein

R ^2cby-NH-CO-CH ₂-CR ^9cr ^10cthe C that group shown in-OH replaces _1-6alkyl

R wherein ^9cand R ^10cidentical or different, and each C naturally _1-4alkyl.

The compound of [26c] above-mentioned [1c] or [12c], wherein

R ^2cby-O-(CH ₂) _n3the C that group shown in-OH replaces _1-6alkyl

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(i) amino,

(ii) C _1-6alkyl-amino,

(iii) C of optional halo _1-6alkyloyl-amino,

(iv) hydroxyl-C _1-6alkyloyl-amino,

(v) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vi) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(vii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(viii) C _3-7cycloalkyl-carbonyl-amino,

(ix) C _1-6alkoxyl group-carbonyl-amino,

(x) formamyl,

(xi) C of optional halo _1-6alkyl-formamyl,

(xii) hydroxyl-C _1-6alkyl-formamyl,

(xiii) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xiv) C _3-7cycloalkyl-formamyl,

(xv) urea groups,

(xvi) C _1-6alkyl-urea groups,

(xvii) C _3-7cycloalkyl-urea groups,

(xviii) except carbon atom, also contain 1-3 the first heterocyclic radical-urea groups (heterocyclyl-ureido group) of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,

(xix) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xx) except carbon atom, also contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally by the C of optional halo _1-6alkyl or C _1-6alkoxyl group-carbonyl substituted,

(xxi) C of optional halo _2-6alkoxyl group,

(xxii) C _1-6alkyl sulphonyl, or

(xxiii) cyano group, and

The compound of [27c] above-mentioned [1c] or [12c], wherein

R ^2cthe C being replaced by hydroxyl _1-6alkyl,

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(i) amino, optionally (a) optionally contained the C of hydroxyl _1-6alkyloyl is monosubstituted or (b) by C _1-6alkyl list or two replacement,

(ii) optionally by the C of optional halo _1-6the formamyl that alkyl replaces,

(iii) optionally by C _1-6alkyl or C _2-6the C of alkynyl substituted _3-7cycloalkyl-formamyl,

(iv) C _6-14aryl-C _1-6alkyl-formamyl,

(v) hydroxyl-C _1-6alkyl-formamyl,

(vi) morpholinyl-C _1-6alkyl-formamyl,

(vii) C _2-6alkynyl-formamyl,

(viii) optionally by C _1-6the carbamyl ylmethyl that alkyl replaces,

(ix) optionally by C _3-7cycloalkyl, halogen, C _1-6alkoxyl group or C _1-6the C that alkyl-formamyl replaces _2-6alkoxyl group,

(x) optionally by C _1-6the aminomethyl of alkoxyl group-carbonyl substituted, or

(xi) optionally by C _3-7the C of cycloalkyl substituted _1-6alkyl sulphonyl, and

The compound of [28c] above-mentioned [1c] or [12c], wherein

R ^1cthe C of cyano group or optional halo _1-6alkyl,

R ^2cbe

(i) C _1-6alkyl, or

(ii) be selected from the C that following substituting group replaces _1-6alkyl:

(a)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6c-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

R ^3chydrogen atom or C _1-6alkyl,

R ^5cbe

(i) amino,

(ii) C _1-6alkyl-amino,

(iii) C of optional halo _1-6alkyloyl-amino,

(iv) hydroxyl-C _1-6alkyloyl-amino,

(v) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vi) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(vii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(viii) C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino,

(ix) C _3-7cycloalkyl-carbonyl-amino,

(x) C _1-6alkoxyl group-carbonyl-amino,

(xi) formamyl,

(xii) C of optional halo _1-6alkyl-formamyl,

(xiii) hydroxyl-C _1-6alkyl-formamyl,

(xiv) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xv) C _3-7cycloalkyl-formamyl,

(xvi) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xvii) urea groups,

(xviii) C _1-6alkyl-urea groups,

(xix) C _3-7cycloalkyl-urea groups,

(xx) except carbon atom, also contain 1-3 the first heterocycle-urea groups of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,

(xxi) optionally by C _1-6the sulfamyl that alkyl replaces, or

(xxii) except carbon atom, also contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally selected from the C of optional halo _1-6alkyl and C _1-6the substituting group of alkoxyl group-carbonyl replaces, and

[29c] above-mentioned [14c], to the compound of [20c] and [28c] any one, wherein encircles B ^cphenyl or cyclohexyl, except R ^5coutside they are also optionally selected from the C of optional halo separately _1-6the substituting group of alkyl and halogen further replaces, and this phenyl between on position or the β-position of cyclohexyl by R ^5creplace.

[30c] above-mentioned [22c], to the compound of [27c] any one, wherein encircles B ^cexcept R ^5coutside be also optionally selected from the C of optional halo _1-6the phenyl that the substituting group of alkyl and halogen further replaces, between this phenyl, position is upper by R ^5creplace.

Compound or its salt shown in [1d] following formula:

Wherein

R ^1dhydrogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

R ^2dby the group of the optional replacement of carbon atom or sulphur atom combination, or,

R ^1dand R ^2d, or R ^2dand R ^3dit is optional in conjunction with to form the ring structure of optional replacement,

R ^3dhydrogen atom or the optional aliphatic alkyl replacing, or R ^3doptionally be combined to form the ring structure of optional replacement with the carbon atom on adjacent phenyl ring,

Ring A ^dthe optional phenyl ring replacing,

Z ^dthe optional C replacing _1-3alkylidene group,

Ring B ^dthe optional heterocyclic radical replacing,

Condition is to get rid of following compound:

The chloro-4-of 5-[(4-{[3-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-2-ethyl furoate,

The chloro-4-of 5-[(4-{[3-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-2-furancarboxylic acid,

2-[2-(the chloro-4-of 4-{[3-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethanol, and

N-[2-(the chloro-4-of 4-{[3-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide.

The compound of [2d] above-mentioned [1d], it is the compound shown in following formula:

R wherein ^4dacyl group or the optional urea groups replacing, ring B ^{d '}except R ^4doutside the piperidyl that is also optionally further substituted, and other symbol defines as above-mentioned.

[3d] is selected from following compound or its salt:

The chloro-4-of 4-{[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] methyl } piperidines-1-t-butyl formate, and

The chloro-4-{[5-of 4-[(2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) methyl] piperidines-1-t-butyl formate.

The prodrug of the compound of [4d] above-mentioned [1d].

The preparation method of the compound or its salt of [5d] above-mentioned [1d], it comprises makes the compound or its salt shown in following formula:

L wherein ^dbe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^dbe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [6d] comprises above-mentioned [1d] or the medicine of its prodrug.

The medicine of [7d] above-mentioned [6d], it is tyrosine kinase inhibitor.

The medicine of [8d] above-mentioned [6d], it is the medicine of prevention or treatment cancer.

The medicine of [9d] above-mentioned [8d], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [10d] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1d] of Mammals effective dosage or its prodrug.

The compound or its salt of [11d] above-mentioned [1d] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The compound of [12d] above-mentioned [1d], it is the compound shown in following formula:

Wherein each symbol defines as above-mentioned.

The compound of [13d] above-mentioned [2d], wherein

R ^1dthe C of hydrogen atom, cyano group or optional halo _1-6alkyl,

R ^2dbe

(i) C _1-6alkyl, or

(a)-NR ^6d-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6d-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6dhydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

R ^3dhydrogen atom or C _1-6alkyl,

Ring A ^dthe phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl,

Z ^dmethylene radical,

Ring B ^{d '}piperidyl, and

R ^4dc _1-6alkoxyl group-carbonyl, C _5-8cycloalkyl-carbonyl, C _1-6alkyl-urea groups or C _5-8cycloalkyl-urea groups.

The compound of [14d] above-mentioned [2d], wherein

R ^3dhydrogen atom, and

Ring A ^dit is the phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl.

The compound or its salt of [1e] following formula:

Wherein

R ^1ehydrogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

R ^2eby the group of the optional replacement of carbon atom or sulphur atom combination, or,

R ^1eand R ^2e, or R ^2eand R ^3eit is optional in conjunction with to form the ring structure of optional replacement,

R ^3ehydrogen atom or the optional aliphatic alkyl replacing, or R ^3eoptionally be combined to form the ring structure of optional replacement with the carbon atom on adjacent phenyl ring,

Ring A ^ethe optional phenyl ring replacing,

R ^5ebe

(i) straight chained alkyl that the heterocyclic radical being optionally substituted replaces,

(ii) straight chained alkyl that the imino-being optionally substituted replaces,

(iii) straight chained alkyl that the aryl that is optionally substituted replaces, it is optionally further by halo or hydroxylation,

(iv) the optional branched-chain alkyl replacing,

(v) the optional alkenyl replacing,

(vi) hydroxyl that the aryl being optionally substituted replaces,

(vii) by C _1-6the hydroxyl that alkyl replaces,

(viii) by halo C _2-6the hydroxyl that alkyl replaces,

(ix) halo C _2-6alkyl,

(x) the optional cycloalkyl replacing, or

(xi) C that the aryl being optionally optionally substituted replaces _1-6alkyl-carbonyl, and

Ring B ^eexcept R ^5eoutside the C that is also optionally further substituted _6-14aryl,

Condition is to get rid of following compound:

2-(the chloro-4-{4-[3-of 2-{4-[(3-(1H-imidazoles-1-yl) propyl group] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) ethanol dihydrochloride,

2-(the chloro-4-{4-[4-of 2-{4-[(3-(1H-1,2,3-triazol-1-yl) butyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) ethanol, and

The chloro-4-of 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } ethyl ketone.

The compound of [2e] above-mentioned [1e], wherein R ^5edescribed in " straight chained alkyl that the heterocyclic radical that is optionally substituted replaces " be

(i) methyl that the heterocyclic radical being optionally substituted replaces, or

(ii) straight chained alkyl that substituted heterocyclic radical replaces.

[3e] is selected from following compound or its salt:

2-[4-(the chloro-4-[3-of 3-(1,1-, bis-fluoro ethyls) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethanol,

The chloro-4-of (1Z)-1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2,2-dimethyl propylene-1-ketone O-ethyl oxime,

The chloro-4-of 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2,2-dimethyl propylene-1-alcohol,

1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-3,3-dimethyl butyrate-1-ketone,

N-(2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl)-2-(methylsulfonyl) ethanamide, and

N-{2-[4-(the chloro-4-[3-of 3-(1-cyano group cyclopropyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide.

The prodrug of the compound of [4e] above-mentioned [1e].

The preparation method of the compound or its salt of [5e] above-mentioned [1e], it comprises makes the compound or its salt shown in following formula:

L wherein ^ebe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^ebe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [6e] comprises above-mentioned [1e] or the medicine of its prodrug.

The medicine of [7e] above-mentioned [6e], it is tyrosine kinase inhibitor.

The medicine of [8e] above-mentioned [6e], it is the medicine of prevention or treatment cancer.

The medicine of [9e] above-mentioned [8e], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [10e] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1e] of Mammals effective dosage or its prodrug.

The compound or its salt of [11e] above-mentioned [1e] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The compound of [12e] above-mentioned [1e], it is the compound shown in following formula:

Wherein each symbol defines as above-mentioned.

The compound of [13e] above-mentioned [1e], wherein

R ^1ethe C of hydrogen atom, cyano group or optional halo _1-6alkyl,

R ^2ebe

(i) C _1-6alkyl, or

(a)-NR ^6e-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6e-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6ehydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

R ^3ehydrogen atom,

Ring A ^ethe phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl,

R ^5ebe

(i) except carbon atom, also containing 1-3 is selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and optionally contains C _1-65-to 8-unit heterocyclic radical (the heterocyclyl)-straight chain C of alkyl _1-6alkyl,

(ii) by oximino or C _1-6the straight chain C that Alkoximino replaces _1-6alkyl,

(iii) by C _6-14the straight chain C that aryl replaces _1-6alkyl, this group is also optionally by halo or hydroxylation,

(iv) the side chain C of optional halo _3-6alkyl,

(v) C _2-6alkenyl,

(vi) by C _6-14the hydroxyl that aryl replaces,

(vii) by C _1-6the hydroxyl that alkyl replaces,

(viii) by the C of halo _2-6the hydroxyl that alkyl replaces,

(ix) C of halo _2-6alkyl,

(x) optionally by the C of cyano group or formamyl replacement _3-7cycloalkyl, or

(xi) C being optionally substituted by phenyl _1-6alkyl-carbonyl, and

Ring B ^eexcept R ^5eoutside be also optionally selected from the C of optional halo _1-6the C that the substituting group of alkyl and halogen further replaces _6-14aryl.

The compound of [14e] above-mentioned [13e], wherein R ^5edescribed in " except carbon atom, also containing 1-3 is selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and optionally contains C _1-65-to the 8-unit heterocyclic radical-straight chain C of alkyl _1-6alkyl " be:

(i) except carbon atom, also containing 1-3 is selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and optionally contains C _1-65-to the 8-unit heterocyclic radical-methyl of alkyl, or

(ii) except carbon atom, also containing 1-3 is selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and contains C _1-65-to the 8-unit heterocyclic radical-straight chain C of alkyl _1-6alkyl.

The represented compound or its salt of [1f] following formula:

Wherein

R ^1fhydrogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

R ^2fby the group of the optional replacement of carbon atom or sulphur atom combination, or,

R ^1fand R ^2f, or R ^2fand R ^3fit is optional in conjunction with to form the ring structure of optional replacement,

R ^3fhydrogen atom or the optional aliphatic alkyl replacing, or R ^3foptionally be combined to form the ring structure of optional replacement with the carbon atom on adjacent phenyl ring,

Ring A ^fthe optional phenyl ring replacing,

Ring B ^fexcept R ^4foutside the piperidyl that is also optionally further substituted, and

R ^4f(i) optional C replacing _1-6alkyl, or the C (ii) optionally replacing _5-8cycloalkyl.

The compound of [2f] above-mentioned [1f], wherein

R ^1fthe C of hydrogen atom, cyano group or optional halo _1-6alkyl,

R ^2fbe

(i) C _1-6alkyl, or

(a)-NR ^6f-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6f-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6fhydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

R ^3fhydrogen atom or C _1-6alkyl,

Ring A ^fthe phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl,

Ring B ^fpiperidyl, and

The compound of [3f] above-mentioned [1f], wherein

R ^3fhydrogen atom, and

Ring A ^fit is the phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl.

The prodrug of the compound of [4f] above-mentioned [1f].

The preparation method of the compound or its salt of [5f] above-mentioned [1f], it comprises makes the compound or its salt shown in following formula:

L wherein ^fbe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^fbe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [6f] comprises above-mentioned [1f] or the medicine of its prodrug.

The medicine of [7f] above-mentioned [6f], it is tyrosine kinase inhibitor.

The medicine of [8f] above-mentioned [6f], it is the medicine of prevention or treatment cancer.

The medicine of [9f] above-mentioned [8f], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [10f] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1f] of Mammals effective dosage or its prodrug.

The compound or its salt of [11f] above-mentioned [1f] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The compound of [12f] above-mentioned [1f], it is the compound shown in following formula:

Wherein each symbol defines as above-mentioned.

The represented compound or its salt of [1g] following formula:

Wherein

W ^gc (R ^1g) and N,

Ring A ^gthe optional phenyl ring replacing,

Ring B ^gthe optional nitrogen heterocyclic ring replacing,

X ^1gbe-NR ^3g-Y ^1g-,-O-,-S-,-SO-,-SO ₂-or-CHR ^3g-

R wherein ^3ghydrogen atom or the optional aliphatic alkyl replacing, or R ^3goptionally with ring A ^gphenyl ring on carbon atom in conjunction with to form the ring structure of optional replacement, and Y ^1gkey or C _1-4alkylidene group or-O-(C _1-4alkylidene group)-, they are optionally substituted separately, and

R ^1ghydrogen atom, halogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

R ^2ghydrogen atom or the group that passes through the optional replacement of carbon atom or sulphur atom combination, or

R ^1gand R ^2g, or R ^2gand R ^3goptional combination is to form the ring structure of optional replacement.

The compound of [2g] above-mentioned [1g], it is the compound shown in following formula:

R wherein ^4gthe optional alkyl replacing, ring B ^{g '}except R ^4goutside 5 or the 6-member heterocyclic ring containing nitrogen that are also optionally further substituted, and other symbol defines as above-mentioned.

The compound of [3g] above-mentioned [2g], wherein

R ^1gthe C of hydrogen atom, halogen atom, cyano group or optional halo _1-6alkyl,

R ^2ghydrogen atom or the optional C replacing _1-6alkyl,

R ^3ghydrogen atom or C _1-6alkyl,

R ^4g(i) optional C replacing _6-14aryl-C _1-8alkyl, (ii) the optional heterocyclic radical-C replacing _1-8alkyl, (iii) C _1-8alkyl, or the C (iv) optionally replacing _6-14aryl.

The compound of [4g] above-mentioned [2g], wherein

R ^2gbe

(i) hydrogen atom,

(ii) C _1-6alkyl, or

(iii) be selected from the C that following substituting group replaces _1-6alkyl:

(a)-O-(CH ₂) _n-OH，

(b)-NR ^5g-CO-(CH ₂) _n-OH，

(c)-NR ^5g-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(d) hydroxyl, and

(e) amino

Wherein n is the integer of 1-4, R ^5ghydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

R ^3ghydrogen atom or C _1-6alkyl,

Following formula:

or

and

R ^4gthat (i) is optionally selected from halogen, C _1-6alkyl-formamyl and halo C _1-6the C that the substituting group of alkoxyl group replaces _6-14aryl-C _1-8alkyl, (ii) the optional heterocyclic radical-C replacing _1-8alkyl, or the C (iii) optionally replacing _6-14aryl.

[5g] is selected from following compound:

N-[2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide,

N-[2-(4-{[1-(3-luorobenzyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-3-hydroxy-3-methyl butyramide,

N-(tertiary butyl)-3-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] benzamide,

N-(tertiary butyl)-3-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indazole-1-yl) methyl] benzamide, and

N-(tertiary butyl)-6-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] pyridine-2-carboxamide.

The prodrug of the compound of [6g] above-mentioned [1g].

The preparation method of the compound or its salt of [7g] above-mentioned [1g], it comprises makes the compound or its salt shown in following formula:

L wherein ^gbe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^gbe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [8g] comprises above-mentioned [1g] or the medicine of its prodrug.

The medicine of [9g] above-mentioned [8g], it is tyrosine kinase inhibitor.

The medicine of [10g] above-mentioned [8g], it is the medicine of prevention or treatment cancer.

The medicine of [11g] above-mentioned [10g], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [12g] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1g] of Mammals effective dosage or its prodrug.

The compound or its salt of [13g] above-mentioned [1g] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The represented compound or its salt of [1h] following formula:

Wherein

R ^1hthe C of halogen atom or halo _1-6alkyl,

R ^2hhydrogen atom or the group that passes through the optional replacement of carbon atom or sulphur atom combination, or

R ^1hand R ^2h, or R ^2hand R ^3hin conjunction with to form the ring structure of optional replacement,

R ^3hhydrogen atom or the optional aliphatic alkyl replacing, or R ^3hoptionally be combined to form the ring structure of optional replacement with the carbon atom on adjacent phenyl ring,

Z ^hkey or the optional C replacing _1-3alkylidene group,

Ring A ^hthe optional phenyl ring replacing, and

Ring B ^h(i) optional C replacing _6-14aryl, (ii) optional heterocyclic radical replacing, or the C (iii) optionally replacing _5-8cycloalkyl.

The compound of [2h] above-mentioned [1h], it is the compound shown in following formula:

Wherein

R ^5hbe

(i) the optional amino replacing,

(ii) the optional formamyl replacing,

(iii) the optional urea groups replacing,

(iv) the optional sulfamyl replacing,

(v) the optional heterocyclic radical replacing,

(vi) the optional alkyl replacing,

(vii) halogen atom, or

(viii) the optional carboxyl replacing, and

Ring B ^{h '}(i) C _6-14aryl, (ii) heterocyclic radical, or (iii) C _5-8cycloalkyl, they are separately except R ^5houtside be also optionally further substituted, and other symbol defines as above-mentioned.

[3h] is selected from following compound:

N-(the chloro-4-[(6-of 3-{2-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } phenyl) cyclopropane carboxamide,

The chloro-4-[3-of the chloro-N-{3-of 6-(trifluoromethyl) phenoxy group] phenyl }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine,

N-[3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] cyclopropane carboxamide, and

N-(tertiary butyl)-3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide.

The prodrug of the compound of [4h] above-mentioned [1h].

The preparation method of the compound or its salt of [5h] above-mentioned [1h], it comprises makes the compound or its salt shown in following formula:

L wherein ^hbe leavings group, and other symbol define as above-mentioned,

React with the compound or its salt shown in following formula:

G wherein ^hbe hydrogen atom or atoms metal, and other symbol define as above-mentioned.

The compound or its salt that [6h] comprises above-mentioned [1h] or the medicine of its prodrug.

The medicine of [7h] above-mentioned [6h], it is tyrosine kinase inhibitor.

The medicine of [8h] above-mentioned [6h], it is the medicine of prevention or treatment cancer.

The medicine of [9h] above-mentioned [8h], wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of [10h] prevention or treatment mammalian cancer, it comprises to the compound or its salt of above-mentioned [1h] of Mammals effective dosage or its prodrug.

The compound or its salt of [11h] above-mentioned [1h] or its prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer.

The compound of [12h] above-mentioned [1h], it is the compound shown in following formula:

Wherein each symbol defines as above-mentioned.

The compound of [13h] above-mentioned [2h], wherein

R ^1hthe C of halogen atom or optional halo _1-6alkyl,

R ^2hbe

(i) hydrogen atom,

(ii) C _1-6alkyl, or

(a)-O-(CH ₂) _n-OH，

(b)-NR ^6h-CO-(CH ₂) _n-OH，

(c)-NR ^6h-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6hhydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces,

R ^3hhydrogen atom or C _1-6alkyl,

Z ^hkey or methylene radical,

Ring A ^hthe phenyl ring that is optionally selected from the substituting group replacement of halogen and methyl,

R ^5hbe

(i) amino,

(ii) C _1-6alkyl-amino,

(iii) C of optional halo _1-6alkyloyl-amino,

(iv) hydroxyl-C _1-6alkyloyl-amino,

(v) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vi) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(vii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(viii) C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino,

(ix) C _3-7cycloalkyl-carbonyl-amino,

(x) C _1-6alkoxyl group-carbonyl-amino,

(xi) formamyl,

(xii) C of optional halo _1-6alkyl-formamyl,

(xiii) hydroxyl-C _1-6alkyl-formamyl,

(xiv) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xv) C _3-7cycloalkyl-formamyl,

(xvi) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xvii) urea groups,

(xviii) C _1-6alkyl-urea groups,

(xix) C _3-7cycloalkyl-urea groups,

(xx) except carbon atom, also contain 1-3 the first heterocyclic radical-urea groups of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,

(xxi) optionally by C _1-6the sulfamyl that alkyl replaces,

(xxii) except carbon atom, also contain 1-3 the first heterocyclic radical of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally selected from the C of optional halo _1-6alkyl and C _1-6the substituting group of alkoxyl group-carbonyl replaces,

(xxiii) C of optional halo _1-6alkyl,

(xxiv) C _1-6alkoxyl group-carbonyl,

(xxv) halogen atom, or

(xxvi) carboxyl, and

Ring B ^{h '}be phenyl, pyridyl or piperidyl, they are separately except R ^5houtside be also optionally further substituted.

Below each symbol used in this specification sheets is described in detail.

Unless otherwise directed, in this manual, for " halogen atom " (with " halogen " in substituting group), what can mention is fluorine atom, chlorine atom, bromine atoms and iodine atom.

Unless otherwise directed, in this manual, for " alkyl ", what can mention is (for example to have 1-10,1-10,1-8,1-6,2-6,1-4) the straight or branched alkyl of carbon atom, for example, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, 1-ethyl propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, heptyl, octyl group, nonyl, decyl etc.

Unless otherwise directed, in this manual, for " C _1-10alkyl "; what can mention is; for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, 1-ethyl propyl, hexyl, isohexyl, 1; 1-dimethylbutyl, 2; 2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, heptyl, octyl group, nonyl, decyl etc.

Unless otherwise directed, in this manual, for " C _1-8alkyl "; what can mention is; methyl for example; ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, 1-ethyl propyl, hexyl, isohexyl, 1; 1-dimethylbutyl, 2; 2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, heptyl, octyl group etc.

Unless otherwise directed, in this manual, for " C _1-6alkyl "; what can mention is; for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, 1-ethyl propyl, hexyl, isohexyl, 1; 1-dimethylbutyl, 2; 2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl etc.

Unless otherwise directed, in this manual, for " C _2-6alkyl "; what can mention is; for example ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, 1-ethyl propyl, hexyl, isohexyl, 1; 1-dimethylbutyl, 2; 2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl etc.

Unless otherwise directed, in this manual, for " C _1-4alkyl ", can mention such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl etc.

Unless otherwise directed, in this manual, for " alkenyl ", what can mention is (for example to have 2-10,2-10,2-8,2-6,2-4) alkenyl of carbon atom, such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propylene base, 1-butylene base, crotyl, 3-butenyl, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl etc.

Unless otherwise directed, in this manual, for " C _2-10alkenyl ", what can mention is such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propylene base, 1-butylene base, crotyl, 3-butenyl, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl etc.

Unless otherwise directed, in this manual, for " C _2-8alkenyl ", what can mention is such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propylene base, 1-butylene base, crotyl, 3-butenyl, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl etc.

Unless otherwise directed, in this manual, for " C _2-6alkenyl ", what can mention is such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propylene base, 1-butylene base, crotyl, 3-butenyl, 3-methyl-2-butene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl etc.

Unless otherwise directed, in this manual, for " C _2-4alkenyl ", what can mention is such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propylene base, 1-butylene base, crotyl, 3-butenyl etc.

Unless otherwise directed, in this manual, for " alkynyl ", what can mention is (for example to have 2-10,2-10,2-8,2-6,2-4) alkynyl of carbon atom, such as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-heptyne base, 1-octyne base etc.

Unless otherwise directed, in this manual, for " C _2-10alkynyl ", what can mention is such as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-heptyne base, 1-octyne base etc.

Unless otherwise directed, in this manual, for " C _2-8alkynyl ", what can mention is such as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-heptyne base, 1-octyne base etc.

Unless otherwise directed, in this manual, for " C _2-6alkynyl ", what can mention is such as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base etc.

Unless otherwise directed, in this manual, for " C _2-4alkynyl ", what can mention is such as ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl etc.

Unless otherwise directed, in this manual, for " cycloalkyl ", what can mention is (for example to have 3-10,3-10,3-8,3-7,3-6,5-8) cycloalkyl of carbon atom, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two ring [2.2.1] heptyl, two ring [2.2.2] octyl groups, two ring [3.2.1] octyl groups, two ring [3.2.2] nonyls, two ring [3.3.1] nonyls, two ring [4.2.1] nonyls, two ring [4.3.1] decyls, adamantyl etc.

Unless otherwise directed, in this manual, for " C _3-10cycloalkyl ", what can mention is such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two ring [2.2.1] heptyl, two ring [2.2.2] octyl groups, two ring [3.2.1] octyl groups, two ring [3.2.2] nonyls, two ring [3.3.1] nonyls, two ring [4.2.1] nonyls, two ring [4.3.1] decyls, adamantyl etc.

Unless otherwise directed, in this manual, for " C _3-8cycloalkyl ", what can mention is such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two ring [2.2.1] heptyl, two ring [2.2.2] octyl groups, two ring [3.2.1] octyl groups etc.

Unless otherwise directed, in this manual, for " C _3-7cycloalkyl ", what can mention is such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.

Unless otherwise directed, in this manual, for " C _5-8cycloalkyl ", what can mention is such as cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.

Unless otherwise directed, in this manual, for " cycloalkenyl group ", what can mention is the cycloalkenyl group with 3-10 carbon atom, such as 2-cyclopentenes-1-base, 3-cyclopentenes-1-base, 2-tetrahydrobenzene-1-base, 3-tetrahydrobenzene-1-base etc.

Unless otherwise directed, in this manual, for " C _3-10cycloalkenyl group ", what can mention is such as 2-cyclopentenes-1-base, 3-cyclopentenes-1-base, 2-tetrahydrobenzene-1-base, 3-tetrahydrobenzene-1-base etc.

Unless otherwise directed, in this manual, for " cycloalkanes dialkylene ", what can mention is the cycloalkanes dialkylene with 4-10 carbon atom, for example 2, and 4-cyclopentadiene-1-base, 2,4-cyclohexadiene-1-base, 2,5-cyclohexadiene-1-base etc.

Unless otherwise directed, in this manual, for " C _4-10cycloalkanes dialkylene ", what can mention is for example 2,4-cyclopentadiene-1-base, 2,4-cyclohexadiene-1-base, 2,5-cyclohexadiene-1-base etc.

Unless otherwise directed, in this manual, the polyaromatic that term " aryl " has comprised monocyclic aryl and condensed.For " aryl ", what can mention is the aryl for example, with 6-18 (, 6-18,6-14,6-10) carbon atom, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, xenyl etc.

Unless otherwise directed, in this manual, for " C _6-18aryl ", what can mention is such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, xenyl etc.

Unless otherwise directed, in this manual, for " C _6-14aryl ", what can mention is such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, xenyl etc.

Unless otherwise directed, in this manual, for " C _6-10aryl ", what can mention is such as phenyl, naphthyl etc.

Unless otherwise directed, in this manual, for " aralkyl ", what can mention is the aralkyl with 7-16 carbon atom, such as benzyl, styroyl, hydrocinnamyl, menaphthyl, xenyl methyl etc.

Unless otherwise directed, in this manual, for " C _7-16aralkyl ", what can mention is such as benzyl, styroyl, hydrocinnamyl, menaphthyl, xenyl methyl etc.

Unless otherwise directed, in this manual, for " alkyloyl ", that can mention is the alkyloyl for example, with 1-7 (1-7,1-6) carbon atom, for example formyl radical, C _1-6alkyl-carbonyl (such as ethanoyl, propionyl, butyryl radicals, pentanoyl, valeryl) etc.

Unless otherwise directed, in this manual, for " C _1-6alkyloyl ", that can mention is for example formyl radical, C _1-6alkyl-carbonyl (such as ethanoyl, propionyl, butyryl radicals, pentanoyl, valeryl) etc.

Unless otherwise directed, in this manual, for " alkoxyl group ", what can mention is the alkoxyl group for example, with 1-6 (1-6,2-6,1-4) carbon atom, such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.

Unless otherwise directed, in this manual, for " C _1-6alkoxyl group ", what can mention is such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.

Unless otherwise directed, in this manual, for " C _2-6alkoxyl group ", what can mention is such as oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.

Unless otherwise directed, in this manual, for " C _1-4alkoxyl group ", what can mention is such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy etc.

Unless otherwise directed, in this manual, for " alkylidene group ", what can mention is the alkylidene group for example, with 1-4 (1-4,1-3) carbon atom, for example-CH ₂-,-CH ₂cH ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-CH (CH ₃)-,-C (CH ₃) ₂-,-CH (CH ₃) CH ₂-,-CH ₂cH (CH ₃)-,-C (CH ₃) ₂cH ₂-,-CH ₂c (CH ₃) ₂-etc.

Unless otherwise directed, in this manual, for " C _1-4alkylidene group ", that can mention is for example-CH ₂-,-CH ₂cH ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-CH (CH ₃)-,-C (CH ₃) ₂-,-CH (CH ₃) CH ₂-,-CH ₂cH (CH ₃)-,-C (CH ₃) ₂cH ₂-,-CH ₂c (CH ₃) ₂-etc.

Unless otherwise directed, in this manual, for " C _1-3alkylidene group ", that can mention is for example-CH ₂-,-CH ₂cH ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-CH (CH ₃)-,-C (CH ₃) ₂-,-CH (CH ₃) CH ₂-,-CH ₂cH (CH ₃)-etc.

Unless otherwise directed, in this manual, for " alkyl " in " the optional alkyl replacing ", what can mention is such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkanes dialkylene, aryl, aralkyl, aromatic yl alkenyl, cycloalkyl-alkyl etc.Wherein be preferably C _1-10alkyl, C _2-10alkenyl, C _2-10alkynyl, C _3-10cycloalkyl, C _3-10cycloalkenyl group, C _4-10cycloalkanes dialkylene, C _6-14aryl, C _7-16aralkyl, C _8-13aromatic yl alkenyl, C _3-10cycloalkyl-C _1-6alkyl etc.

Above-mentioned C _3-10cycloalkyl, C _3-10cycloalkenyl group and C _4-10cycloalkanes dialkylene optionally condenses with phenyl ring separately, and for such cyclic group that condenses, such as what can mention, is indanyl, dihydro naphthyl, tetralyl, fluorenyl etc.In addition, for above-mentioned alkyl, can also mention crosslinked alkyl, such as norcamphyl, adamantyl etc.

For C _8-13aromatic yl alkenyl, what can mention is such as styryl etc.

For C _3-10cycloalkyl-C _1-6alkyl, what can mention is such as cyclopropyl methyl, cyclohexyl methyl etc.

Above-mentioned C _1-10alkyl, C _2-10alkenyl and C _2-10alkynyl, they optionally have 1 to 3 substituting group separately as the example of " alkyl " on commutable position.

These substituting groups, for example can mention:

(1) optionally by 1 to 3, be selected from the C that following substituting group replaces _3-10cycloalkyl (for example cyclopropyl, cyclohexyl):

Halogen;

Hydroxyl;

Carboxyl;

Sulfo group;

Cyano group;

Azido-;

Nitro;

Nitroso-group;

The C of optional halo _1-4alkyl;

The C of optional halo _2-4alkenyl;

The C of optional halo _2-4alkynyl;

C _3-7cycloalkyl;

C _6-14aryl;

C _7-16aralkyl;

Formyl radical;

The C of optional halo _1-6alkyl-carbonyl;

The C of optional halo _1-6alkoxyl group-carbonyl;

The C of optional halo _1-6alkyl sulphonyl;

Formamyl;

By the C of optional halo _1-6alkyl list or disubstituted formamyl;

Single-or two-C _6-14aryl-formamyl;

Optionally by the C of optional halo _1-6alkyl list or disubstituted thiocarbamoyl;

Optionally by the C of optional halo _1-6alkyl list or disubstituted urea groups;

Single-or two-C _6-14aryl-urea groups;

Optionally by the C of optional halo _1-6alkyl list or disubstituted sulfamyl;

The C of optional halo _1-6alkoxyl group;

The C of optional halo _2-6alkenyloxy;

C _3-10cycloalkyloxy;

C _7-16aralkoxy;

C _6-14aryloxy;

C _1-6alkyl-carbonyl oxygen base;

C _3-10cycloalkyl-C _1-6alkoxyl group;

C _1-6alkylsulfonyloxy;

Sulfydryl;

The C of optional halo _1-6alkylthio;

C _7-16aromatic alkylthio;

C _6-14arylthio;

C _1-6alkyl sulphinyl;

Oxo;

C _1-3alkylenedioxy group (for example methylene radical dioxy base, ethylidene dioxy base);

Optionally by C _1-6the oximino that alkyl replaces;

Deng (S organizes substituting group);

(2) optionally by 1 to 3, be selected from S and organize the C that substituent substituting group replaces _6-14aryl (for example phenyl, naphthyl);

(3) optionally by 1 to 3, be selected from S and organize the heterocyclic radical that substituent substituting group replaces;

(4) optionally by 1 or 2, be selected from the amino that following substituting group replaces:

Optionally be selected from halogen, hydroxyl, C _3-7cycloalkyl, C _1-6alkyl sulphonyl, C _1-6the C that the substituting group of alkoxyl group etc. replaces _1-6alkyl;

The C of optional halo _2-4alkenyl;

The C of optional halo _2-4alkynyl;

C _3-7cycloalkyl;

C _6-14aryl;

C _7-16aralkyl;

4 to 7-unit's (preferably 5 or 6-unit) heterocyclic radicals (nonaromatic heterocycles base for example, as morpholinyl etc.), it also contains 1-4 heteroatoms that is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms as becoming annular atoms except carbon atom;

Formyl radical;

Optionally be selected from halogen, hydroxyl, C _3-7cycloalkyl, C _1-6alkyl sulphonyl, C _1-6the C that the substituting group of alkoxyl group etc. replaces _1-6alkyl-carbonyl;

C _1-6alkoxyl group-carbonyl;

C _6-14aryl-carbonyl (for example benzoyl);

C _7-16aralkyl-carbonyl (for example benzyloxycarbonyl group, styroyl carbonyl);

C _3-7cycloalkyl-carbonyl;

C _1-6alkyl-formamyl (for example methylamino carbonyl, ethylamino carbonyl);

C _6-14aryl-formamyl (for example phenyl amino carbonyl, 1-naphthyl aminocarboxyl, 2-naphthyl aminocarboxyl);

C _7-16aralkyl-formamyl (for example benzylamino carbonyl);

C _1-6alkyl sulphonyl (for example methylsulfonyl, ethylsulfonyl, sec.-propyl alkylsulfonyl);

C _6-14aryl sulfonyl (for example benzenesulfonyl, tosyl group, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base);

C _7-16aralkyl alkylsulfonyl (for example benzyl alkylsulfonyl);

Deng (T organizes substituting group);

(5) amidino groups;

(6) optionally by the C of formylation or halo _1-6alkyl-carbonyl;

(7) C of optional halo _1-6alkoxyl group-carbonyl;

(8) C of optional halo _1-6alkyl sulphonyl (for example methylsulfonyl);

(9) optionally by 1 or 2, be selected from T and organize the formamyl that substituent substituting group replaces;

(10) optionally by the C of optional halo _1-6alkyl list or disubstituted thiocarbamoyl;

(11) optionally by 1 or 2, be selected from T and organize the urea groups that substituent substituting group replaces;

(12) optionally by 1 or 2, be selected from T and organize the sulfamyl that substituent substituting group replaces;

(13) carboxyl;

(14) hydroxyl;

(15) optionally by 1 to 3, be selected from halogen, carboxyl, C _1-6alkoxyl group and C _1-6the C that the substituting group of alkoxyl group-carbonyl replaces _1-6alkoxyl group;

(16) C of optional halo _2-6alkenyloxy (for example vinyloxy group);

(17) C _3-10cycloalkyloxy (for example cyclohexyloxy);

(18) C _7-16aralkoxy (for example benzyloxy);

(19) C _6-14aryloxy (for example phenoxy group, naphthyloxy);

(20) C _1-6alkyl-carbonyl oxygen base (for example acetoxyl group, tertiary butyl carbonyl oxygen base);

(21) sulfydryl;

(22) C of optional halo _1-6alkylthio (for example methylthio group, ethylmercapto group);

(23) C _7-16aromatic alkylthio (for example benzylthio-);

(24) C _6-14arylthio (for example thiophenyl, naphthalene sulfenyl);

(25) sulfo group;

(26) cyano group;

(27) azido-;

(28) nitro;

(29) nitroso-group;

(30) halogen atom;

(31) C _1-6alkyl sulphinyl (for example methylsulfinyl);

(32) oxo group;

(33) C _3-10cycloalkyl-C _1-6alkoxyl group (for example cyclo propyl methoxy);

(34) C _1-3alkylenedioxy group (for example methylene radical dioxy base, ethylidene dioxy base);

(35) optionally by C _1-6the oximino that alkyl replaces;

Deng (U organizes substituting group).When substituent quantity is not less than 2, each substituting group can be identical or different.

Above-mentioned C _3-10cycloalkyl, C _3-10cycloalkenyl group, C _4-10cycloalkanes dialkylene, C _6-14aryl, C _7-16aralkyl, C _8-13aromatic yl alkenyl and C _3-10cycloalkyl-C _1-6alkyl, they optionally have 1 to 3 substituting group separately as the example of " alkyl " on commutable position.

These substituting groups, for example can mention:

(1) be selected from U and organize substituent substituting group;

(2) optionally by 1 to 3, be selected from U and organize the C that substituent substituting group replaces _1-10alkyl;

(3) optionally by 1 to 3, be selected from U and organize the C that substituent substituting group replaces _2-10alkenyl (for example vinyl, 1-propenyl);

(4) optionally by 1 to 3, be selected from U and organize the C that substituent substituting group replaces _7-16aralkyl (for example benzyl);

Deng (V organizes substituting group).When substituent quantity is not less than 2, each substituting group can be identical or different.

Unless otherwise directed, in this manual, for " heterocyclic radical " in " the optional heterocyclic radical replacing ", what can mention is fragrant heterocyclic radical and nonaromatic heterocycles base.

For fragrant heterocyclic radical, what for example can mention is 4 to 7-unit's (preferably 5 or 6-unit) monocycle fragrant heterocyclic radicals, it also contains 1-4 heteroatoms that is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms as becoming annular atoms except carbon atom, and the fragrant heterocyclic radical condensing.For the fragrant heterocyclic radical condensing, what for example can mention is the group derived from fused rings, wherein corresponding to ring and 1 or 2 cyclic condensation that is selected from 5 or the 6-ring that contains 1 or 2 nitrogen-atoms, the 5-ring that contains 1 sulphur atom, phenyl ring etc. of above-mentioned 4 to 7-unit's monocycle fragrant heterocyclic radicals, etc.

For the preferred embodiment of fragrant heterocyclic radical, can mention:

Monocycle fragrant heterocyclic radical is for example

Furyl (2-furyl for example, 3-furyl), thienyl (2-thienyl for example, 3-thienyl), pyridyl (2-pyridyl for example, 3-pyridyl, 4-pyridyl), pyrimidyl (2-pyrimidyl for example, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl), pyridazinyl (3-pyridazinyl for example, 4-pyridazinyl), pyrazinyl (for example 2-pyrazinyl), pyrryl (1-pyrryl for example, 2-pyrryl, 3-pyrryl), imidazolyl (1-imidazolyl for example, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (1-pyrazolyl for example, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (2-thiazolyl for example, 4-thiazolyl, 5-thiazolyl), isothiazolyl (3-isothiazolyl for example, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (2-oxazolyl for example, 4-oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl for example, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (for example 1,2,4-oxadiazolyl-5-base, 1,3,4-oxadiazolyl-2-yl), thiadiazolyl group (for example 1,3,4-thiadiazoles-2-yl), triazolyl (for example 1,2,4-triazol-1-yl, 1,2,4-triazole-3-base, 1,2,3-triazoles-1-base, 1,2,3-triazoles-2-base, 1,2,3-triazoles-4-yl), tetrazyl (tetrazolium-1-base for example, tetrazolium-5-yl), triazinyl (for example 1,2,4-triazine-1-base, 1,2,4-triazine-3-yl) etc.,

The fragrant heterocyclic radical condensing is for example

Quinolyl (2-quinolyl for example, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (for example 3-isoquinolyl), quinazolyl (2-quinazolyl for example, 4-quinazolyl), quinoxalinyl (2-quinoxalinyl for example, 6-quinoxalinyl), benzofuryl (2-benzofuryl for example, 3-benzofuryl), benzothienyl (2-benzothienyl for example, 3-benzothienyl), benzoxazolyl (for example 2-benzoxazolyl), benzoisoxazole base (for example 7-benzoisoxazole base), benzothiazolyl (for example 2-[4-morpholinodithio base), benzimidazolyl-(benzoglyoxaline-1-base for example, benzimidazolyl-2 radicals-Ji, benzoglyoxaline-5-yl), benzotriazole base (for example 1H-1,2,3-benzotriazole-5-yl), indyl (indoles-1-base for example, indoles-2-base, indol-3-yl, indoles-5-yl), indazolyl (for example 1H-indazole-3-yl), Pyrrolopyrazine base (1H-pyrrolo-[2,3-b] pyrazine-2-base for example, 1H-pyrrolo-[2,3-b] pyrazine-6-yl), imidazopyridyl (1H-imidazo [4,5-b] pyridine-2-base for example, 1H-imidazo [4,5-c] pyridine-2-base, 2H-imidazo [1,2-a] pyridin-3-yl), Imidazopyrazines base (for example 1H-imidazo [4,5-b] pyrazine-2-yl), Pyrazolopyridine base (for example 1H-pyrazolo [4,3-c] pyridin-3-yl), pyrazolo thienyl (for example 2H-pyrazolo [3,4-b] thiophene-2-yl), method for preparation of pyrazolotriazine base (for example pyrazolo [5,1-c] [1,2,4] triazine-3-yl) etc.

For nonaromatic heterocycles base, what for example can mention is 4 to 7-unit's (preferably 5 or 6-unit) monocycle nonaromatic heterocycles bases, it also contains 1-4 heteroatoms that is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms as becoming annular atoms except carbon atom, and the nonaromatic heterocycles base condensing.For the nonaromatic heterocycles base condensing, what for example can mention is the group derived from fused rings, wherein corresponding to ring and 1 or 2 cyclic condensation that is selected from 5 or the 6-ring that contains 1 or 2 nitrogen-atoms, the 5-ring that contains 1 sulphur atom, phenyl ring etc. of above-mentioned 4 to 7-unit's monocycle nonaromatic heterocycles bases, etc.

For the preferred embodiment of nonaromatic heterocycles base, can mention:

Monocycle nonaromatic heterocycles base is for example

Oxetanyl (2-oxetanyl for example, 3-oxetanyl), pyrrolidyl (1-pyrrolidyl for example, 2-pyrrolidyl), piperidyl (piperidino-(1-position only) for example, 2-piperidyl, 3-piperidyl, 4-piperidyl), morpholinyl (for example, morpholino), parathiazan base (for example parathiazan generation), piperazinyl (1-piperazinyl for example, 2-piperazinyl, 3-piperazinyl, hexamethyleneimino (for example hexa-methylene imido-1-yl), oxazolidinyl (Li is as oxazolidine-2-yl), thiazolidyl (for example thiazolidine-2-yl), imidazolidyl (imidazolidine-2-base for example, imidazolidine-3-yl), oxazolinyl (Li is as oxazoline-2-yl), thiazolinyl (for example thiazoline-2-yl), imidazolinyl (tetrahydroglyoxaline-2-base for example, tetrahydroglyoxaline-3-yl), dioxa cyclopentenyl (for example 1,3-Dioxol-4-yl), alkyl dioxin (for example 1,3-dioxane-4-yl), Er Qing oxadiazolyl (for example 4,5-dihydro-1,2,4-oxadiazole-3-yl), 2-sulfo--1,3-oxazolidine-5-base (2-thioxo-1,3-oxazolidin-5-yl), pyranyl (for example 4-pyranyl), THP trtrahydropyranyl (2-THP trtrahydropyranyl for example, 3-THP trtrahydropyranyl, 4-THP trtrahydropyranyl), thiapyran base (for example 4-thiapyran base), tetrahydro thiapyran base (2-tetrahydro thiapyran base for example, 3-tetrahydro thiapyran base, 4-tetrahydro thiapyran base), 1-oxidation tetrahydro thiapyran base (1-oxidotetrahydrothiopyranyl) (for example 1-oxidation tetrahydric thiapyran-4-group), 1,1-titanium dioxide tetrahydro thiapyran base (1,1-dioxidotetrahydrothiopyranyl) (for example 1,1-titanium dioxide tetrahydric thiapyran-4-group), tetrahydrofuran base (tetrahydrofuran (THF)-3-base for example, tetrahydrofuran (THF)-2-yl), pyrazolidyl (pyrazolidine-1-base for example, pyrazolidine-3-yl), pyrazolinyl (for example pyrazoline-1-yl), tetrahydro-pyrimidine base (for example tetrahydropyrimidine-1-yl), dihydro triazolyl (for example 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrochysene triazolyl (for example 2,3,4,5-tetrahydrochysene-1H-1,2,3-triazol-1-yl) etc.,

The nonaromatic heterocycles base condensing is for example:

Indolinyl (for example 2,3-dihydro-1H-indoles-1-yl), dihydro-iso indolyl (for example 1,3-dihydro-2H-isoindole-2-yl), dihydro benzo furyl (for example 2,3-dihydro-1-cumarone-5-yl), dihydrobenzo dioxine base (for example 2,3-dihydro-Isosorbide-5-Nitrae-benzo dioxine base), dihydrobenzo dioxa

base (for example 3,4-dihydro-2H-1,5-benzo dioxa base), tetrahydrochysene benzfuran base (for example 4,5,6,7-tetrahydrochysene-1-cumarone-3-yl), chromenyl (for example 4H-chromene-2-base, 2H-chromene-3-yl), dihydroquinoline base (for example 1,2-dihydroquinoline-4-yl), tetrahydric quinoline group (for example 1,2,3,4-tetrahydroquinoline-4-yl), dihydro-isoquinoline base (for example 1,2-dihydro-isoquinoline-4-yl), tetrahydro isoquinolyl (for example 1,2,3,4-tetrahydroisoquinoline-4-yl), dihydro phthalazinyl (for example Isosorbide-5-Nitrae-dihydro phthalazines-4-yl) etc.

" heterocyclic radical " in " the optional heterocyclic radical replacing " optionally has 1 to 3 substituting group in commutable position.These substituting groups, what for example can mention is to be selected from above-mentioned V to organize substituent substituting group.When substituent quantity is not less than 2, each substituting group can be identical or different.

Unless otherwise directed, in this manual, for " aliphatic alkyl " in " the optional aliphatic alkyl replacing ", what can mention is the straight or branched aliphatic alkyl with 1-10 carbon atom (preferably 1-8 carbon atom).For " aliphatic alkyl ", that for example can mention is C _1-10alkyl, C _2-10alkenyl, C _2-10alkynyl and C _3-10cycloalkyl (each group as defined above).

Described " aliphatic alkyl " is optionally selected from V and organizes substituent substituting group and replace, and especially, is selected from following substituting group and replaces: halogen, hydroxyl, C by 1-3 _1-4alkoxyl group, C _1-4alkyl-carbonyl, carboxyl, C _1-4alkoxyl group-carbonyl, cyano group, formamyl, sulfamyl, nitro, amino, C _1-4alkyl-carbonylamino, C _1-4alkoxyl group-carbonylamino and C _1-4alkyl sulfonyl-amino.When substituent quantity is not less than 2, each substituting group can be identical or different.

Unless otherwise directed, in this manual, for described " acyl group ", what for example can mention is-COR ^y1,-CO-OR ^y1,-SO ₂r ^y1,-SOR ^y1,-PO (OR ^y1) (OR ^y2) (R wherein ^y1and R ^y2identical or different, and each hydrogen atom, the optional alkyl replacing or optional heterocyclic radical replacing naturally) etc.

Unless otherwise directed; in this manual, for " urea groups " in " formamyl " in " amino " in " amino of optional replacement ", " formamyl of optional replacement ", " the optional urea groups replacing " and " sulfamyl " in " sulfamyl optionally replacing ", optionally on commutable position, there is 1 or 2 substituting group.For above-mentioned substituting group, such as what can mention, be the optional alkyl replacing, the optional heterocyclic radical replacing, acyl group etc.Wherein, preferably 1 or 2 be selected from T and organize substituent substituting group.When substituent quantity is not less than 2, each substituting group can be identical or different.

When the nitrogen-atoms of the above-mentioned amino of formation, formamyl, urea groups or sulfamyl is replaced by two substituting groups, these substituting groups can be combined to form nitrogen heterocyclic ring with adjacent nitrogen-atoms.For described " nitrogen heterocyclic ring ", what for example can mention is 3 to 8-member heterocyclic ring containing nitrogens, and it also at least contains 1 nitrogen-atoms and in addition optionally contain 1 or 2 heteroatoms that is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms and form into annular atoms except carbon atom.Nitrogenous heterocyclic preferred embodiment, for example can mention be 5 or 6-unit optionally contain the cyclammonium (for example 1-tetramethyleneimine, piperidines, 1-piperazine, morpholine) of Sauerstoffatom.

Unless otherwise directed, in this manual, " imino-" in " the optional imino-replacing " optionally has 1 or 2 substituting group on commutable position.For above-mentioned substituting group, such as what can mention, be the optional alkyl replacing, the optional heterocyclic radical replacing, acyl group etc.Wherein, be preferably selected from T and organize substituent substituting group.When substituent quantity is not less than 2, each substituting group can be identical or different.

Unless otherwise directed, in this manual, for " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination ", that can mention is the group shown in following formula :-X ^x-R ^x, amino and hydroxyl.

In above-mentioned formula, X ^xkey ,-NR ^y-(R wherein ^yhydrogen atom or C _1-6alkyl) or-O-.

In above-mentioned formula, R ^xcyano group or C _1-8alkyl, C _2-8alkenyl, C _2-8alkynyl, formamyl, C _1-8alkyl-carbonyl, C _3-8cycloalkyl, C _6-18aryl, C _6-18aryl-C _1-4alkyl, C _6-18aryl-carbonyl, C _6-18aryl-C _1-4alkyl-carbonyl, heterocyclic radical, heterocyclic radical-C _1-4alkyl, heterocyclic radical carbonyl or heterocyclic radical-C _1-4alkyl-carbonyl, they are optionally substituted separately.

In above-mentioned formula, R ^x" the C representing _1-8alkyl ", " C _2-8alkenyl ", " C _2-8alkynyl ", " formamyl ", " C _1-8alkyl-carbonyl ", " C _3-8cycloalkyl ", " C _6-18aryl ", " C _6-18aryl-C _1-4alkyl ", " C _6-18aryl-carbonyl ", " C _6-18aryl-C _1-4alkyl-carbonyl ", " heterocyclic radical ", " heterocyclic radical-C _1-4alkyl ", " heterocyclic radical carbonyl " and " heterocyclic radical-C _1-4alkyl-carbonyl " substituting group that is optionally for example selected from following (X organizes substituting group) by one or more (preferably 1 to 5, more preferably 1 to 3) replaces:

(a) halogen atom,

(b) oxo group,

(c) C of optional halo _1-4alkyl,

(d)-(CH ₂) _m-Q ^x，

(e)-(CH ₂) _m-Z ^1xthe C of-optional halo _1-4alkyl,

(f)-(CH ₂) _m-Z ^1x-C _3-8cycloalkyl,

(g)-(CH ₂) _m-Z ^2x-(CH ₂) _n-Q ^x，

(h)-(CH ₂) _m-Z ^2x-(CH ₂) _n-Z ^1xthe C of-optional halo _1-4alkyl,

(i)-(CH ₂) _m-Z ^2x-(CH ₂) _n-Z ^1x-C _3-8cycloalkyl,

(j)-(CH ₂) _m-Z ^1x-optional the heterocyclic radical replacing (preferably, heterocyclic radical is to contain 1 to 3 heteroatomic 5 to 8-unit's heterocyclic radical that are selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),

(k)-(CH ₂) _m-Z ^2x-C _1-4alkoxyl group, and

(l)-(CH ₂) _m-Z ^2x-(CH ₂) _n-Z ^1x-(CH ₂) _n-Z ^1x-C _1-4alkyl.

R ^ybe preferably hydrogen atom or methyl, be particularly preferably hydrogen atom.

In above-mentioned formula,

M is the integer of 0-4,

N is the integer of 1-4,

Q ^xhydroxyl, carboxyl, cyano group, nitro ,-NR ^1xr ^2x,-CONR ^1xr ^2xor-SO ₂nR ^1xr ^2x,

Z ^1xbe-O-,-CO-,-C (OH) R ^3x-,-C (=N-OR ^3x)-,-S-,-SO-,-SO ₂-,-N (COR ^3x)-,-N (CO ₂r ^4x)-,-N (SO ₂r ^4x)-,-CO-O-,-O-CO-,-CO-NR ^3x-,-NR ^3x-CO-,-NR ^3x-CO ₂-,-NR ^3x-CO-NH-,-NR ^3x-SO ₂-or-NR ^3x-C (=NH)-NH-,

Z ^2xbe-O-,-CO-,-C (OH) R ^3x-,-C (=N-OR ^3x)-,-S-,-SO-,-SO ₂-,-NR ^3x-,-N (COR ^3x)-,-N (CO ₂r ^4x)-,-N (SO ₂r ^4x)-,-CO-O-,-O-CO-,-CO-NR ^3x-,-NR ^3x-CO-,-NR ^3x-CO ₂-,-NR ^3x-CO-NH-,-NR ^3x-C (=NH)-NH-,-NR ^3x-SO ₂-or-SO ₂-NR ^3x-.

In above-mentioned formula ,-(CH ₂) _m-and-(CH ₂) _n-optionally by one or more (preferably 1 to 5, more preferably 1 to 3), be for example selected from the C of halogen, optional halo _1-4the substituting group of alkyl and hydroxyl replaces, and when m or n are not less than 2 ,-(CH ₂) _m-or-(CH ₂) _n-in-CH ₂cH ₂-optionally by-CH=CH-or-C ≡ C-substitutes.

In above-mentioned formula, R ^1xand R ^2xidentical or different, and each hydrogen atom or C naturally _1-4alkyl, or R ^1xand R ^2xoptional in conjunction with forming ring with nitrogen-atoms.In above-mentioned formula, R ^3xhydrogen atom or C _1-4alkyl, and R ^4xc _1-4alkyl.

Work as R ^1xand R ^2xwhen forming ring with nitrogen-atoms, as this nitrogen heterocyclic ring, what for example can mention is 3 to 8-units' (preferably 5 or 6-unit) saturated or undersaturated (preferably saturated) aliphatics heterocyclic radicals, as azetidine, tetramethyleneimine, piperidines, high piperidines, heptamethylene amine, morpholine, parathiazan, piperazine, homopiperazine etc.

Unless otherwise directed, in this manual, for " group of the optional replacement by carbon atom or sulphur atom combination ", that can mention is C _1-8alkyl, C _2-8alkenyl, C _2-8alkynyl, formamyl, C _1-8alkyl-carbonyl, C _1-8alkylthio, C _1-8alkyl sulphonyl, C _3-8cycloalkyl, C _6-18aryl, C _6-18aryl-C _1-4alkyl, C _6-18aryl-carbonyl, C _6-18aryl-C _1-4alkyl-carbonyl, C _6-18arylthio, C _6-18aryl sulfonyl, heterocyclic radical, heterocyclic radical-C _1-4alkyl, heterocyclic radical carbonyl, heterocyclic radical-C _1-4alkyl-carbonyl, heterocyclic radical sulfenyl and heterocyclic radical-C _1-4alkylthio, they are optionally substituted separately, etc.

Described " C _1-8alkyl ", " C _2-8alkenyl ", " C _2-8alkynyl ", " formamyl ", " C _1-8alkyl-carbonyl ", " C _1-8alkylthio ", " C _1-8alkyl sulphonyl ", " C _3-8cycloalkyl ", " C _6-18aryl ", " C _6-18aryl-C _1-4alkyl ", " C _6-18aryl-carbonyl ", " C _6-18aryl-C _1-4alkyl-carbonyl ", " C _6-18arylthio ", " C _6-18aryl sulfonyl ", " heterocyclic radical ", " heterocyclic radical-C _1-4alkyl ", " heterocyclic radical carbonyl ", " heterocyclic radical-C _1-4alkyl-carbonyl ", " heterocyclic radical sulfenyl " and " heterocyclic radical-C _1-4alkylthio " optionally by one or more (preferably 1 to 5, more preferably 1 to 3), be for example selected from X and organize substituent substituting group and replace.

[compound (Ia)]

The invention provides the compound or its salt shown in formula (Ia) (in this manual, below sometimes referred to as " compound (Ia) ").

Wherein each symbol defines as above-mentioned.

R ^2abe preferably by formula " NR ^6aa-CO-CR ^7ar ^8a-SO ₂-C _1-4alkyl " shown in the C that replaces of group _1-6alkyl (particularly ethyl).

In the formula, R ^6aahydrogen atom or methyl, and R ^7aand R ^8aidentical or different and each hydrogen atom or methyl naturally.R ^7aand R ^8abe preferably methyl.

R ^3abe preferably hydrogen atom.

For R ^4ain " halogen atom ", be preferably chlorine atom.For R ^4ain " C _1-6alkyl ", be preferably methyl.R ^4abe preferably chlorine atom or methyl.

For R ^5ain " halogen atom ", be preferably fluorine atom and chlorine atom.For R ^5ain " C _1-6alkyl ", be preferably methyl.R ^5abe preferably fluorine atom, chlorine atom or methyl.

For X ^ain " halogen atom ", be preferably fluorine atom.X ^abe preferably hydrogen atom or fluorine atom, more preferably hydrogen atom.

For the preferred embodiment of compound (Ia), that can mention is compound (Ia), wherein

R ^1ahydrogen atom,

R ^2aby-NR ^6aa-CO-CR ^7ar ^8a-SO ₂-C _1-4the C that group shown in alkyl replaces _1-6alkyl (particularly ethyl)

R wherein ^6aahydrogen atom or methyl, R ^7aand R ^8aidentical or different and each is hydrogen atom or methyl naturally,

R ^3ahydrogen atom,

R ^4achlorine atom or methyl,

R ^5afluorine atom, chlorine atom or methyl, and

X ^ahydrogen atom or fluorine atom (preferably hydrogen atom).

R ^1ahydrogen atom,

R wherein ^6aahydrogen atom or methyl, R ^7aand R ^8amethyl,

R ^3ahydrogen atom,

R ^4achlorine atom or methyl,

R ^5afluorine atom, chlorine atom or methyl, and

X ^ahydrogen atom or fluorine atom (preferably hydrogen atom).

For compound (Ia), particularly preferably be:

N-[2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-methyl-2-(methylsulfonyl) propionic acid amide,

And salt and hydrate.

[compound (Ib)]

The present invention also provides the compound or its salt shown in formula (Ib) (in this manual, below sometimes referred to as " compound (Ib) ").

Wherein each symbol defines as above-mentioned.

In above-mentioned formula (Ib), ring A ^b" pyridine ring " in described " the optional pyridine ring replacing " representing is by for example formula-Y ^2b-B ^{b '}shown group optionally replaces.Y ^2bkey ,-O-,-O-(C _1-3alkylidene group)-,-NR ^zb-(R wherein ^zbhydrogen atom or C _1-6alkyl) or-S-, and B ^{b '}c _6-18aryl (preferred C _6-14aryl, more preferably phenyl), heterocyclic radical (preferably 5 or 6-unit heterocyclic radical, more preferably pyridyl or piperidyl), C _3-8cycloalkyl (preferably cyclohexyl), formamyl, urea groups, C _6-18aryl-carbonyl or C _6-18aryl-C _1-4alkyl-carbonyl, they are optionally substituted separately.

Y ^2bbe preferably key ,-O-or-OCH ₂-, more preferably-O-or-OCH ₂-, be particularly preferably-O-.

B ^{b '}described " the C representing _6-18aryl, heterocyclic radical, C _3-8cycloalkyl, formamyl, urea groups, C _6-18aryl-carbonyl or C _6-18aryl-C _1-4alkyl-carbonyl, they are optionally substituted separately " in described " C _6-18aryl ", " heterocyclic radical ", " C _3-8cycloalkyl ", " formamyl ", " urea groups ", " C _6-18aryl-carbonyl " and " C _6-18aryl-C _1-4alkyl-carbonyl " on any commutable position, optionally there is separately 1 to 5, identical or different substituting group.For described substituting group, what can mention is the substituting group similar to above-mentioned V group substituting group.Wherein, the C of preferably optional halo _1-6alkyl, the C of optional halo _1-6alkoxyl group, C _1-6alkyl-formamyl and halogen.

B ^{b '}be preferably the C of optional replacement _6-14aryl, is more preferably optionally selected from the phenyl that following substituting group replaces: the C of optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6alkyl-formamyl and halogen (are preferably optionally selected from the C of optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group and C _1-6the phenyl that the substituting group of alkyl-formamyl replaces), particularly preferably in the optional selected C from optional halo on 3-position _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6the phenyl that the substituting group of alkyl-formamyl and halogen replaces (the preferred optional selected C from optional halo on 3-position _1-6the C of alkyl, optional halo _1-6alkoxyl group and C _1-6the phenyl that the substituting group of alkyl-formamyl replaces).

Ring A ^bdescribed " pyridine ring " in described " the optional pyridine ring replacing " representing is except by formula-Y ^2b-B ^{b '}outside shown group replaces, on any commutable position, also further optionally there is 1 to 3, identical or different substituting group.For described substituting group, what can mention is the substituting group similar to above-mentioned V group substituting group.Wherein, preferred halogen and methyl.

Ring A ^bbe preferably except by formula :-Y ^2b-B ^{b '}shown group is also further optionally selected from the pyridine ring of the substituting group replacement of halogen and methyl outside replacing, more preferably except formula :-Y ^2b-B ^{b '}the pyridine ring also further optionally being replaced by halogen outside shown group.

R ^3b" aliphatic alkyl " in described " the optional aliphatic alkyl replacing " representing is preferably C _1-6alkyl.

Y ^1bdescribed " the C representing _1-4alkylidene group or-O-(C _1-4alkylidene group)-, they are optionally substituted separately " in " C _1-4alkylidene group " and " O-(C _1-4alkylidene group)-" optionally by 1 to 3, be selected from following substituting group and replace: halogen, hydroxyl, C _1-4alkoxyl group, C _1-4alkyl-carbonyl, carboxyl, C _1-4alkoxyl group-carbonyl, cyano group, formamyl, sulfamyl, nitro, amino, C _1-4alkyl-carbonylamino, C _1-4alkoxyl group-carbonylamino and C _1-4alkyl sulfonyl-amino.

X ^1bbe preferably-NR ^3b-.In the formula, R ^3bbe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

W ^bbe preferably C (R ^1b).

R ^1bdescribed " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination " be preferably cyano group and the optional C replacing _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

For the substituting group of alkyl, what can mention is the substituting group similar to above-mentioned X group substituting group.Preferred halogen wherein.

R ^1bbe preferably the C of hydrogen atom, halogen atom, cyano group or optional halo _1-6alkyl, more preferably hydrogen atom.

R ^2bdescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

For the substituting group of alkyl, what can mention is the substituting group similar to above-mentioned X group substituting group, preferably can use and be selected from following substituting group:

(i)-NR ^6ba-CO-(CH ₂) _n1-SO ₂-C _1-4alkyl

R wherein ^6babe hydrogen atom or methyl, n1 is the integer of 1-4 ,-(CH ₂) _n1-optionally by C _1-4alkyl replaces,

(ii)-NR ^6bb-CO-(CH ₂) _n2-OH

R wherein ^6bbbe hydrogen atom or methyl, n2 is the integer of 1-4 ,-(CH ₂) _n2-optionally by C _1-4alkyl replaces,

(iii)-O-(CH ₂) _n3-OH

Wherein n3 is the integer of 1-4 ,-(CH ₂) _n3-optionally by C _1-4alkyl replaces, and

(iv) hydroxyl.

For by R ^3bwith ring A ^bcarbon atom on the pyridine ring representing in conjunction with and " ring structure " in " the optional ring structure replacing " that form, what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is:

Deng.

Described " ring structure " optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

R ^1band R ^2boptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1band R ^2bbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2band R ^3boptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2band R ^3bbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1band R ^2b, or R ^2band R ^3bdescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Work as W ^bc (R ^1b) time, compound (Ib) is by shown in following formula (IbA):

Wherein each symbol defines as above-mentioned.

Work as W ^bwhile being N, compound (Ib) is by following formula (IbB) or (IbC):

Wherein each symbol defines as above-mentioned.

In said structure formula, partial structural formula

be preferably

Wherein each symbol defines as above-mentioned.

For specific embodiment, what can mention is the compound or its salt shown in following formula (Ib ') (in this manual, below sometimes referred to as " compound (Ib ') "):

Wherein each symbol defines as above-mentioned.

[compound (Iba)]

For the preferred embodiment of compound (Ib), that can mention is the compound or its salt shown in following formula (Iba) (in this manual, below sometimes referred to as " compound (Iba) "):

In above-mentioned formula (Iba), ring A ^{b '}" optionally further substituted pyridine ring " in " pyridine ring ", except by formula-O-B ^boutside shown group replaces, also optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.Wherein preferably halogen and methyl.

Ring A ^bbe preferably except by formula :-O-B ^bshown group is also further optionally selected from the pyridine ring that the substituting group of halogen and methyl replaces outside replacing, more preferably except by formula :-O-B ^bthe pyridine ring that shown group is also further optionally replaced by halogen outside replacing.

Ring B ^bdescribed " the optional C replacing _6-14aryl " in " C _6-14aryl " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.The preferred C of optional halo wherein _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6alkyl-formamyl and halogen.

Ring B ^bbe preferably and be optionally selected from the phenyl that following substituting group replaces: the C of optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6alkyl-formamyl and halogen (are preferably the C that is optionally selected from optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group and C _1-6the phenyl that the substituting group of alkyl-formamyl replaces), the optional selected C from optional halo on 3-position more preferably _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6the phenyl that the substituting group of alkyl-formamyl and halogen replaces (is preferably the optional selected C from optional halo on 3-position _1-6the C of alkyl, optional halo _1-6alkoxyl group and C _1-6the phenyl that the substituting group of alkyl-formamyl replaces).

As the preferred embodiment of compound (Ib), what compound (Iba) can be mentioned is above-mentioned formula (Iba) compound, wherein

(i)-NR ^6ba-CO-(CH ₂) _n1-SO ₂-C _1-4alkyl

(ii)-NR ^6bb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

R ^3bhydrogen atom,

As preferred another embodiment of compound (Ib), that compound (Iba) can be mentioned is above-mentioned formula (Iba), wherein

Ring A ^{b '}the pyridine ring optionally being replaced by halogen, and

Ring B ^bthe optional selected C from optional halo on 3-position _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6the phenyl that the substituting group of alkyl-formamyl and halogen replaces.

Compound (Ib) particularly preferably is:

The chloro-5-{[5-of N-(tertiary butyl)-3-[(3-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } pyridine-2-yl) oxygen base] benzamide,

And salt.

[compound (Ic)]

The present invention also provides the compound or its salt shown in formula (Ic) (in this manual, below sometimes referred to as " compound (Ic) ").

Wherein each symbol defines as above-mentioned.

In above-mentioned formula (Ic), R ^1cdescribed " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination " be preferably cyano group and the optional C replacing _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

R ^1cbe preferably the C of hydrogen atom, cyano group or optional halo _1-6alkyl, more preferably hydrogen atom or cyano group, be particularly preferably hydrogen atom.

R ^2cdescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

More preferably use and be selected from following substituting group:

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

Wherein n3 is the integer of 1-4 ,-(CH ₂) _n3-optionally by C _1-4alkyl replaces,

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

R ^3c" optional replace aliphatic alkyl " in " aliphatic alkyl " be preferably C _1-6alkyl.

R ^3cbe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

For by R ^3ccarbon atom in adjacent phenyl rings is combined and " ring structure " in " optional replace ring structure " that form, and what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is:

Deng.

R ^1cand R ^2coptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1cand R ^2cbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2cand R ^3coptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2cand R ^3cbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1cand R ^2c, or R ^2cand R ^3cdescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Ring A ^c" phenyl ring " in " the optional phenyl ring replacing " representing optionally has 1 to 3, identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.Wherein preferably halogen and methyl.

Ring A ^cbe preferably the phenyl ring of the substituting group replacement that is optionally selected from halogen and methyl.

R ^5c" optional replace amino " be preferably amino, list-or two-C _1-6the C of alkyl-amino, optional halo _1-6alkyloyl-amino, hydroxyl-C _1-6alkyloyl-amino, the C that contains hydroxyl and halogen _1-6alkyloyl-amino, C _3-7cycloalkyl-C _1-6alkyloyl-amino, contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino, C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino, C _3-7cycloalkyl-carbonyl-amino and C _1-6alkoxyl group-carbonyl-amino.

R ^5c" optional replace formamyl " be preferably the C of formamyl, optional halo _1-6alkyl-formamyl, hydroxyl-C _1-6alkyl-formamyl, C _1-6alkoxy-C _1-6alkyl-formamyl, C _6-14aryl-C _1-6alkyl-formamyl, C _2-6alkynyl-formamyl, piperidyl-C _1-6alkyl-formamyl, morpholinyl-C _1-6alkyl-formamyl, optionally by C _1-6alkyl or C _2-6the C of alkynyl substituted _3-7cycloalkyl-formamyl and optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom.

R ^5c" optional replace urea groups " be preferably urea groups, C _1-6alkyl-urea groups, C _3-7cycloalkyl-urea groups and also contain heteroatomic 5-to 8-unit heterocycle-urea groups that 1-3 is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom.

R ^5c" optional replace sulfamyl " be preferably optionally by C _1-6the sulfamyl that alkyl replaces.

R ^5c" optional replace heterocyclic radical " be preferably and except carbon atom, also contain 1-3 heteroatomic 5-to 8-unit heterocyclic radical that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally selected from the C of optional halo _1-6alkyl and C _1-6the substituting group of alkoxyl group-carbonyl replaces.

R ^5c" the optional C replacing _2-6alkoxyl group " be preferably optionally and be selected from C _3-7cycloalkyl, halogen, C _1-6alkoxyl group and C _1-6the C that the substituting group of alkyl-formamyl replaces _2-6alkoxyl group.

R ^5c" optional replace aminomethyl " be preferably optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted.

R ^5c" optional replace carbamyl ylmethyl " be preferably optionally by C _1-6the carbamyl ylmethyl that alkyl replaces.

R ^5c" optional replace alkyl sulphonyl " be preferably and optionally contain C _3-7the C of cycloalkyl or halogen _1-6alkyl sulphonyl.

Ring B ^c" the C being optionally further substituted _6-14aryl " in " C _6-14aryl " be preferably phenyl.

Ring B ^c" the C being optionally further substituted _5-8cycloalkyl " in " C _5-8cycloalkyl " be preferably cyclohexyl.

Except by R ^5coutside replacement, ring B ^c" the C being optionally further substituted _6-14aryl " in " C _6-14aryl " and ring B ^c" the C being optionally further substituted _5-8cycloalkyl " in " C _5-8cycloalkyl " they also optionally have 1 to 5, identical or different substituting group separately on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.The preferred C of optional halo wherein _1-6alkyl and halogen.

In said structure formula, partial structural formula:

be preferably

Wherein each symbol defines as above-mentioned.

For concrete example, can mention be the compound or its salt shown in following formula (Ic ') (in this manual, below sometimes referred to as " compound (Ic ') ") and following formula (Ic ") shown in compound or its salt (in this manual, below sometimes referred to as " compound (Ic ") "):

[compound (Ic ')]

Wherein each symbol defines as above-mentioned.

[compound (Ic ")]

Wherein encircle B ^{c '}except by R ^5cthe phenyl being also optionally further substituted separately outside replacement or cyclohexyl, and other symbol defines as above-mentioned.

As the preferred embodiment of compound (Ic), what compound (Ic) can be mentioned is wherein

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

Wherein n is the integer of 1-4, R ^6chydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces.

As another preferred embodiment of compound (Ic), what compound (Ic) can be mentioned is wherein

R ^1chydrogen atom or cyano group,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl,

R ^5cbe

(i) amino,

(ii) list-C _1-6alkyl-amino,

(iii) two-C _1-6alkyl-amino,

(iv) C of optional halo _1-6alkyloyl-amino,

(v) hydroxyl-C _1-6alkyloyl-amino,

(vi) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vii) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(viii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(ix) C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino,

(x) C _3-7cycloalkyl-carbonyl-amino,

(xi) C _1-6alkoxyl group-carbonyl-amino,

(xii) formamyl,

(xiii) C of optional halo _1-6alkyl-formamyl,

(xiv) hydroxyl-C _1-6alkyl-formamyl,

(xv) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xvi) C _6-14aryl-C _1-6alkyl-formamyl,

(xvii) C _2-6alkynyl-formamyl,

(xviii) piperidyl-C _1-6alkyl-formamyl,

(xix) morpholinyl-C _1-6alkyl-formamyl,

(xxi) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xxii) urea groups,

(xxiii) C _1-6alkyl-urea groups,

(xxiv) C _3-7cycloalkyl-urea groups,

(xxvi) optionally by C _1-6the sulfamyl that alkyl replaces,

(xxix) optionally by C _1-6the carbamyl ylmethyl that alkyl replaces,

(xxx) optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted,

(xxxii) cyano group, and

(i) C _1-6alkyl,

(ii) C of optional halo _1-6alkyloyl,

(iii) hydroxyl-C _1-6alkyloyl,

(iv) C that contains hydroxyl and halogen _1-6alkyloyl,

(v) C _3-7cycloalkyl-C _1-6alkyloyl,

(vi) contain C _3-7cycloalkyl and halogen C _1-6alkyloyl,

(vii) C _1-6alkyl sulphonyl-C _1-6alkyloyl,

(viii) C _3-7cycloalkyl-carbonyl, and

(ix) C _1-6alkoxyl group-carbonyl,

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

In the above-described embodiment, more preferably, R ^2cbe selected from the C that following substituting group replaces _1-6alkyl:

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

(i) C of optional halo _1-6alkyl,

(ii) hydroxyl-C _1-6alkyl,

(iii) C _1-6alkoxy-C _1-6alkyl,

(iv) C _6-14aryl-C _1-6alkyl,

(v) C _2-6alkynyl,

(vi) piperidyl-C _1-6alkyl,

(vii) morpholinyl-C _1-6alkyl, and

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

R ^5coptionally be selected from the urea groups that following substituting group replaces:

(i) C _1-6alkyl,

(ii) C _3-7cycloalkyl, and

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

R ^5coptionally by C _1-6the sulfamyl that alkyl replaces,

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

R ^1chydrogen atom,

(i)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(ii)-NR ^6c-CO-(CH ₂) _n-OH，

(iii)-O-(CH ₂) _n-OH，

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino

R ^3chydrogen atom or C _1-6alkyl, and

(i)-NH-CO-CR ^7cr ^8c-SO ₂-C _1-4alkyl

(ii)-NR ^6cb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

(v)-NR ^6c-CO-C _1-4alkyl,

(vi)-O-C _1-4alkyl,

(vii)-S-C _1-4alkyl,

(viii)-SO ₂-C _1-4alkyl, and

(ix) amino.

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(i) amino, its optionally (a) optionally contained C _1-6the C of alkyl sulphonyl _1-6alkyloyl is monosubstituted or (b) by C _1-6alkyl list or two replacement,

(ii) optionally by C _1-6the formamyl that alkyl replaces,

(v) optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted,

(vii) cyano group, and

In the above-described embodiment, more preferably,

R ^2cby-NR ^6cb-CO-(CH ₂) _n2the C that group shown in-OH replaces _1-6alkyl

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(ii) optionally by C _1-6the formamyl that alkyl replaces,

(v) optionally by C _1-6the aminomethyl of alkyl-carbonyl substituted,

(vii) cyano group, and

Ring B ^cexcept by R ^5coutside replacement, be also optionally selected from the C of optional halo _1-6the C that the substituting group of alkyl and halogen further replaces _6-14aryl.

In the above-described embodiment, more preferably,

R wherein ^9cand R ^10cidentical or different, and each C naturally _1-4alkyl.

R ^2cby-O-(CH ₂) _n3the C that group shown in-OH replaces _1-6alkyl

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(i) amino,

(ii) C _1-6alkyl-amino,

(iii) C of optional halo _1-6alkyloyl-amino,

(iv) hydroxyl-C _1-6alkyloyl-amino,

(v) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vi) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(vii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(viii) C _3-7cycloalkyl-carbonyl-amino,

(ix) C _1-6alkoxyl group-carbonyl-amino,

(x) formamyl,

(xi) C of optional halo _1-6alkyl-formamyl,

(xii) hydroxyl-C _1-6alkyl-formamyl,

(xiii) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xiv) C _3-7cycloalkyl-formamyl,

(xv) urea groups,

(xvi) C _1-6alkyl-urea groups,

(xvii) C _3-7cycloalkyl-urea groups,

(xviii) except carbon atom, also contain 1-3 the first heterocyclic radical-urea groups of heteroatomic 5-to 8-that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,

(xix) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xxi) C of optional halo _2-6alkoxyl group,

(xxii) C _1-6alkyl sulphonyl, or

(xxiii) cyano group, and

R ^2cthe C being replaced by hydroxyl _1-6alkyl,

R ^1chydrogen atom,

R ^3chydrogen atom,

R ^5cbe

(ii) optionally by the C of optional halo _1-6the formamyl that alkyl replaces,

(iv) C _6-14aryl-C _1-6alkyl-formamyl,

(v) hydroxyl-C _1-6alkyl-formamyl,

(vi) morpholinyl-C _1-6alkyl-formamyl,

(vii) C _2-6alkynyl-formamyl,

(viii) optionally by C _1-6the carbamyl ylmethyl that alkyl replaces,

R ^1cthe C of cyano group or optional halo _1-6alkyl,

R ^2cbe

(i) C _1-6alkyl, or

(a)-NR ^6c-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6c-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

R ^3chydrogen atom or C _1-6alkyl,

R ^5cbe

(i) amino,

(ii) C _1-6alkyl-amino,

(iii) C of optional halo _1-6alkyloyl-amino,

(iv) hydroxyl-C _1-6alkyloyl-amino,

(v) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vi) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(vii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(viii) C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino,

(ix) C _3-7cycloalkyl-carbonyl-amino,

(x) C _1-6alkoxyl group-carbonyl-amino,

(xi) formamyl,

(xii) C of optional halo _1-6alkyl-formamyl,

(xiii) hydroxyl-C _1-6alkyl-formamyl,

(xiv) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xv) C _3-7cycloalkyl-formamyl,

(xvi) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xvii) urea groups,

(xviii) C _1-6alkyl-urea groups

(xix) a C _3-7cycloalkyl-urea groups,

(xxi) optionally by C _1-6the sulfamyl that alkyl replaces, or

In the preferred embodiment of above-claimed cpd (Ic), particularly preferably be corresponding compound (Ic ").Particularly preferably:

(i) wherein encircle B ^cphenyl or cyclohexyl, except R ^5coutside they are also optionally selected from the C of optional halo separately _1-6the substituting group of alkyl and halogen further replaces, and this phenyl between on position or the β-position of cyclohexyl by R ^5cthe compound replacing, and

(ii) wherein encircle B ^cexcept R ^5coutside be also optionally selected from the C of optional halo _1-6the phenyl that the substituting group of alkyl and halogen further replaces, between this phenyl, position is upper by R ^5creplace.

Compound (Ic) particularly preferably is:

N-[2-(the chloro-4-of 4-{[3-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide,

And salt.

[compound (Id)]

The present invention also provides the compound or its salt shown in formula (Id) (in this manual, below sometimes referred to as " compound (Id) ").

Wherein each symbol defines as above-mentioned.

In above-mentioned formula (Id), R ^1ddescribed " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination " be preferably cyano group and the optional C replacing _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

R ^1dbe preferably the C of hydrogen atom, cyano group or optional halo _1-6alkyl, more preferably hydrogen atom.

R ^2ddescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

(a)-NR ^6d-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6d-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6dhydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces.

R ^3d" optional replace aliphatic alkyl " in " aliphatic alkyl " be preferably C _1-6alkyl.

R ^3dbe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

For by R ^3dcarbon atom in adjacent phenyl rings is combined and " ring structure " in " optional replace ring structure " that form, and what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is

Deng.

R ^1dand R ^2doptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1dand R ^2dbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2dand R ^3doptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2dand R ^3dbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1dand R ^2dor R ^2dand R ^3ddescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Ring A ^d" optional replace phenyl ring " in " phenyl ring " optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.Wherein preferably halogen and methyl.

Ring A ^dbe preferably the phenyl ring of the substituting group replacement that is optionally selected from halogen and methyl, the phenyl ring more preferably optionally being replaced by halogen.

Ring B ^d" optional replace heterocyclic radical " in " heterocyclic radical " be preferably 5 or 6-unit monocyclic heterocycles base, more preferably piperidyl.

Ring B ^d" optional replace heterocyclic radical " in " heterocyclic radical " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is acyl group and the substituting group similar to above-mentioned V group substituting group.Wherein preferred acyl group and the optionally urea groups of replacement, more preferably C _1-6alkoxyl group-carbonyl, C _5-8cycloalkyl-carbonyl, C _1-6alkyl-urea groups and C _5-8cycloalkyl-urea groups.

Ring B ^dbe preferably optionally by the heterocyclic radical of acyl group or the optional Carbamido substituted replacing (preferably 5 or 6-unit monocyclic heterocycles base, more preferably piperidyl), more preferably optionally by C _1-6alkoxyl group-carbonyl, C _5-8cycloalkyl-carbonyl, C _1-6alkyl-urea groups or C _5-8the heterocyclic radical of cycloalkyl-Carbamido substituted (preferably 5 or 6-unit monocyclic heterocycles base, more preferably piperidyl).

Z ^d" the optional C replacing representing _1-3alkylidene group " in " C _1-3alkylidene group " be preferably methylene radical.

Z ^d" the optional C replacing representing _1-3alkylidene group " in " C _1-3alkylidene group " optionally by 1 to 3, be selected from following substituting group and replace: halogen, hydroxyl, C _1-4alkoxyl group, C _1-4alkyl-carbonyl, carboxyl, C _1-4alkoxyl group-carbonyl, cyano group, formamyl, sulfamyl, nitro, amino, C _1-4alkyl-carbonylamino, C _1-4alkoxyl group-carbonylamino and C _1-4alkyl sulfonyl-amino.

In said structure formula, partial structural formula

be preferably

Wherein each symbol defines as above-mentioned.

For concrete example, what can mention is the compound or its salt (in this manual, below sometimes referred to as " compound (Id) ") shown in following formula (Id '):

[compound (Id ')]

Wherein each symbol defines as above-mentioned.

For the preferred embodiment of compound (Id), that can mention is the compound or its salt shown in following formula (Ida) (in this manual, below sometimes referred to as " compound (Ida) "):

[compound (Ida)]

R wherein ^4dacyl group or the optional urea groups replacing, ring B ^{d '}except by R ^4dthe piperidyl being also optionally further substituted outside replacement, and other symbol defines as above-mentioned.

In above-mentioned formula (Ida), R ^4d" acyl group " be preferably C _1-6alkoxyl group-carbonyl and C _5-8cycloalkyl-carbonyl.

In above-mentioned formula (Ida), R ^4d" optional replace urea groups " be preferably C _1-6alkyl-urea groups and C _5-8cycloalkyl-urea groups.

Ring B ^{d '}" piperidyl being optionally further substituted " in " piperidyl " except by R ^4doutside replacement, optionally on any commutable position, also there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

For the preferred embodiment of compound (Id), that compound (Ida) can be mentioned is above-mentioned formula (Ida), wherein

R ^1dthe C of hydrogen atom, cyano group or optional halo _1-6alkyl,

R ^2dbe

(i) C _1-6alkyl, or

(ii) be selected from the C of following substituting group replacement _1-6alkyl:

(a)-NR ^6d-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6d-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

R ^3dhydrogen atom or C _1-6alkyl,

Z ^dmethylene radical,

Ring B ^{d '}piperidyl, and

For another preferred embodiment of compound (Id), that compound (Ida) can be mentioned is above-mentioned formula (Ida), wherein

R ^3dhydrogen atom, and

Compound (Id) particularly preferably is

The chloro-4-{[5-of 4-[(2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) methyl] piperidines-1-t-butyl formate,

And salt.

[compound (Ie)]

The present invention also provides the compound or its salt shown in formula (Ie) (in this manual, below sometimes referred to as " compound (Ie) ").

Wherein each symbol defines as above-mentioned.

In above-mentioned formula (Ie), R ^1edescribed " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination " be preferably cyano group and the optional C replacing _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

R ^1ebe preferably the C of hydrogen atom, cyano group or optional halo _1-6alkyl, more preferably hydrogen atom or cyano group, be particularly preferably hydrogen atom.

R ^2edescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

(a)-NR ^6e-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6e-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6ehydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces.

R ^3e" optional replace aliphatic alkyl " in " aliphatic alkyl " be preferably C _1-6alkyl.

R ^3ebe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

For by R ^3ecarbon atom in adjacent phenyl rings is combined and " ring structure " in " optional replace ring structure " that form, and what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is

Deng.

R ^1eand R ^2eoptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1eand R ^2ebe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2eand R ^3eoptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2eand R ^3ebe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1eand R ^2eor R ^2eand R ^3edescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Ring A ^e" optional replace phenyl ring " in " phenyl ring " optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.Wherein preferably halogen and methyl.

Ring A ^ebe preferably the phenyl ring of the substituting group replacement that is optionally selected from halogen and methyl.

R ^5ein straight chained alkyl can mention is the straight chained alkyl with 1-10 (preferably 1-8, more preferably 1-6) carbon atom.What can mention particularly, is methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl and decyl.

R ^5ein branched-chain alkyl can mention is the branched-chain alkyl with 3-10 (preferably 3-8, more preferably 3-6) carbon atom.Particularly, what can mention is sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, 1-ethyl propyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl etc.

For R ^5ein " straight chained alkyl that the aryl that is optionally substituted replaces, it is optionally further by halo or hydroxylation ", " hydroxyl that the aryl being optionally substituted replaces " and " C of the aryl replacement being optionally optionally substituted _1-6alkyl-carbonyl " in the substituting group of described " aryl ", what can mention is the substituting group similar to above-mentioned V group substituting group.

For R ^5ein " optional replace branched-chain alkyl ", the substituting group in " the optional alkenyl replacing " and " the optional cycloalkyl replacing ", what can mention is to organize the similar substituting group of substituting group to above-mentioned U.

For R ^5ein " straight chained alkyl that the heterocyclic radical that is optionally substituted replaces ", be preferably and except carbon atom, also contain 1-3 and be selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and optionally contain C _1-65-to the 8-unit heterocyclic radical-straight chain C of alkyl _1-6alkyl.

For R ^5ein " straight chained alkyl that the imino-that is optionally substituted replaces ", be preferably by oximino or C _1-6the straight chain C that Alkoximino replaces _1-6alkyl.

For R ^5ein " straight chained alkyl that the aryl that is optionally substituted replaces, it is optionally further by halo or hydroxylation ", be preferably by C _6-14the straight chain C that aryl replaces _1-6alkyl, it is optionally further by halo or hydroxylation.

For R ^5ein " optional replace branched-chain alkyl ", be preferably the side chain C of optional halo _3-6alkyl.

For R ^5ein " optional replace alkenyl ", be preferably C _2-6alkenyl.

For R ^5ein " hydroxyl that the aryl that is optionally substituted replaces ", be preferably by C _6-14the hydroxyl that aryl replaces.

For R ^5ein " by the C of halo _2-6the hydroxyl that alkyl replaces " in " the C of halo _2-6alkyl " and R ^5ein " the C of halo _2-6alkyl ", what can mention is separately by the ethyl of halo, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl etc.The preferred ethyl of halo wherein.

For R ^5ein " optional replace cycloalkyl " be preferably optionally the C being replaced by cyano group or formamyl _3-7cycloalkyl.

For R ^5ein " the C that the aryl that is optionally optionally substituted replaces _1-6alkyl-carbonyl " be preferably the C being optionally substituted by phenyl _1-6alkyl-carbonyl.

For R ^5ein " straight chained alkyl that the heterocyclic radical that is optionally substituted replaces ", be preferably:

(i) methyl that the heterocyclic radical being optionally substituted replaces, and

(ii) straight chained alkyl that substituted heterocyclic radical replaces.

Except by R ^5coutside replacement, ring B ^e" the C being optionally further substituted _6-14aryl " in " C _6-14aryl " also optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.The preferred C of optional halo wherein _1-6alkyl and halogen.

Ring B ^ebe preferably except R ^5eoutside be also optionally selected from the C of optional halo _1-6the C that the substituting group of alkyl and halogen further replaces _6-14aryl (preferably phenyl).

In said structure formula, partial structural formula

be preferably

Wherein each symbol defines as above-mentioned.

For concrete example, what can mention is the compound or its salt shown in following formula (Ie ') (in this manual, below sometimes referred to as " compound (Ie ') "):

[compound (Ie ')]

Wherein each symbol defines as above-mentioned.

For the preferred embodiment of compound (Ie), what compound (Ie) can be mentioned is wherein

R ^1ethe C of hydrogen atom, cyano group or optional halo _1-6alkyl,

R ^2ebe

(i) C _1-6alkyl, or

(a)-NR ^6e-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6e-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

R ^3ehydrogen atom,

R ^5ebe

(i) except carbon atom, also containing 1-3 is selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and optionally contains C _1-65-to the 8-unit heterocyclic radical-straight chain C of alkyl _1-6alkyl,

(iv) the side chain C of optional halo _3-6alkyl,

(v) C _2-6alkenyl,

(vi) by C _6-14the hydroxyl that aryl replaces,

(vii) by C _1-6the hydroxyl that alkyl replaces,

(viii) by the C of halo _2-6the hydroxyl that alkyl replaces,

(ix) C of halo _2-6alkyl,

(xi) C being optionally substituted by phenyl _1-6alkyl-carbonyl, and

In the preferred embodiment of above-claimed cpd (Ie), preferred such compound, wherein:

R ^5edescribed " except carbon atom, also containing 1-3 is selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom and optionally contains C _1-65-to the 8-unit heterocyclic radical-straight chain C of alkyl _1-6alkyl " be:

Compound (Ie) particularly preferably is:

N-{2-[4-(the chloro-4-[3-of 3-(1-cyano group cyclopropyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,

And salt.

[compound (If)]

The present invention also provides the compound or its salt shown in formula (If) (in this manual, below sometimes referred to as " compound (If) ").

Wherein each symbol defines as above-mentioned.

In above-mentioned formula (If), R ^1fdescribed " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination " be preferably cyano group and the optional C replacing _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

R ^1fbe preferably the C of hydrogen atom, cyano group or optional halo _1-6alkyl, more preferably hydrogen atom or cyano group, be particularly preferably hydrogen atom.

R ^2fdescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

(a)-NR ^6f-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6f-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

Wherein n is the integer of 1-4, R ^6fhydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces.

R ^3f" optional replace aliphatic alkyl " in " aliphatic alkyl " be preferably C _1-6alkyl.

R ^3fbe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

For by R ^3fcarbon atom in adjacent phenyl rings is combined and " ring structure " in " optional replace ring structure " that form, and what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is

Deng.

R ^1fand R ^2foptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1fand R ^2fbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2fand R ^3foptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2fand R ^3fbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1fand R ^2f, or R ^2fand R ^3fdescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Ring A ^f" optional replace phenyl ring " in " phenyl ring " optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.Wherein preferably halogen and methyl.

Ring A ^fbe preferably the phenyl ring of the substituting group replacement that is optionally selected from halogen and methyl.

Except by R ^4foutside replacement, ring B ^f" piperidyl being optionally further substituted " in " piperidyl " optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

For R ^4fin " the optional C replacing _1-6alkyl " in " C _1-6alkyl " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned U group substituting group.

For R ^4fin " the optional C replacing _5-8cycloalkyl " in " C _5-8cycloalkyl " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

In said structure formula, partial structural formula

be preferably

Wherein each symbol defines as above-mentioned.

For concrete example, what can mention is the compound or its salt shown in following formula (If ') (in this manual, below sometimes referred to as " compound (If ') "):

[compound (If ')]

Wherein each symbol defines as above-mentioned.

For the preferred embodiment of compound (If), what compound (If) can be mentioned is wherein

R ^1fthe C of hydrogen atom, cyano group or optional halo _1-6alkyl,

R ^2fbe

(i) C _1-6alkyl, or

(a)-NR ^6f-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(b)-NR ^6f-CO-(CH ₂) _n-OH，

(c)-O-(CH ₂) _n-OH, and

(d) hydroxyl

R ^3fhydrogen atom or C _1-6alkyl,

Ring B ^fpiperidyl, and

For another preferred embodiment of compound (If), what compound (If) can be mentioned is wherein

R ^3fhydrogen atom, and

[compound (Ig)]

The present invention also provides the compound or its salt shown in formula (Ig) (in this manual, below sometimes referred to as " compound (Ig) ").

Wherein each symbol defines as above-mentioned.

In formula (Ig), ring A ^g" optional replace phenyl ring " in " phenyl ring " optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

For ring B ^g" optional replace nitrogen heterocyclic ring " in " nitrogen heterocyclic ring ", can mention such as 3 to 8-units (preferably 5 or 6-unit) aromatic heterocycle or saturated or undersaturated (preferably saturated) aliphatic heterocycle etc.Preferred 3 to 8-units' (preferably 5 or 6-unit) saturated or undersaturated (preferably saturated) aliphatic heterocycle wherein, such as azetidine, tetramethyleneimine, piperidines, high piperidines, heptamethylene amine, morpholine, parathiazan, piperazine, homopiperazine etc.

Described " nitrogen heterocyclic ring " optionally has 1 to 5, identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

R ^3g" optional replace aliphatic alkyl " in " aliphatic alkyl " be preferably C _1-6alkyl.

Y ^1gdescribed " C _1-4alkylidene group or-O-(C _1-4alkylidene group)-, they are optionally substituted separately " in " C _1-4alkylidene group " and " O-(C _1-4alkylidene group)-" optionally by 1 to 3, be selected from following substituting group and replace: halogen, hydroxyl, C _1-4alkoxyl group, C _1-4alkyl-carbonyl, carboxyl, C _1-4alkoxyl group-carbonyl, cyano group, formamyl, sulfamyl, nitro, amino, C _1-4alkyl-carbonylamino, C _1-4alkoxyl group-carbonylamino and C _1-4alkyl sulfonyl-amino.

X ^1gbe preferably-NR ^3g.In the formula, R ^3gbe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

W ^gbe preferably C (R ^1g).

R ^1gdescribed " group of the optional replacement by carbon atom, nitrogen-atoms or Sauerstoffatom combination " be preferably cyano group and the optional C replacing _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

For the substituting group of alkyl, what can mention is the substituting group similar to above-mentioned X group substituting group.

Preferred halogen wherein.

R ^1gbe preferably the C of hydrogen atom, halogen atom, cyano group or optional halo _1-6alkyl, more preferably hydrogen atom.

R ^2gdescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

(a)-O-(CH ₂) _n-OH，

(b)-NR ^5g-CO-(CH ₂) _n-OH，

(c)-NR ^5g-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(d) hydroxyl, and

(e) amino

Wherein n is the integer of 1-4, R ^5ghydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces.

For by R ^3gwith ring A ^gphenyl ring on carbon atom in conjunction with and " ring structure " in " the optional ring structure replacing " that form, what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is

Deng.

R ^1gand R ^2goptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1gand R ^2gbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2gand R ^3goptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2gand R ^3gbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1gand R ^2g, or R ^2gand R ^3gdescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Work as W ^gc (R ^1g) time, compound (Ig) is represented by following formula (IgA):

Wherein each symbol defines as above-mentioned.

Work as W ^gwhile being N, compound (Ig) represents by following formula (IgB) or (IgC):

Wherein each symbol defines as above-mentioned.

[compound (Iga)]

That the preferred embodiment of compound (Ig) can be mentioned is the compound or its salt shown in formula (Iga) (in this manual, below sometimes referred to as " compound (Iga) "):

In above-mentioned formula (Iga), for ring B ^g" 5 or the 6-member heterocyclic ring containing nitrogen that are optionally further substituted " in " 5 or 6-member heterocyclic ring containing nitrogen ", that can mention is ring B ^gdescribed " optional replace nitrogen heterocyclic ring " in " nitrogen heterocyclic ring " among 5 or 6-unit " nitrogen heterocyclic ring ".

R ^4gbe preferably (i) optional C replacing _6-14aryl-C _1-8alkyl, (ii) the optional heterocyclic radical-C replacing _1-8alkyl, (iii) C _1-8alkyl, or the C (iv) optionally replacing _6-14aryl, more preferably (i) is optionally selected from halogen, C _1-6alkyl-formamyl and halo C _1-6the C that the substituting group of alkoxyl group replaces _6-14aryl-C _1-8alkyl, (ii) the optional heterocyclic radical-C replacing _1-8alkyl, or the C (iii) optionally replacing _6-14aryl.

R ^4g" the optional C replacing _6-14aryl-C _1-8alkyl " in " C _6-14aryl-C _1-8alkyl ", R ^4g" optional heterocyclic radical-the C replacing _1-8alkyl " in " heterocyclic radical-C _1-8alkyl " and " the optional C replacing _6-14aryl " in " C _6-14aryl " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

In said structure formula, partial structural formula

Be preferably

or

Wherein each symbol defines as above-mentioned.

For the preferred embodiment of compound (Ig), that compound (Iga) can be mentioned is above-mentioned formula (Iga), wherein

R ^2ghydrogen atom or the optional C replacing _1-6alkyl,

R ^3ghydrogen atom or C _1-6alkyl,

For another preferred embodiment of compound (Ig), that compound (Iga) can be mentioned is above-mentioned formula (Iga), wherein

R ^2gbe

(i) hydrogen atom,

(ii) C _1-6alkyl, or

(a)-O-(CH ₂) _n-OH，

(b)-NR ^5g-CO-(CH ₂) _n-OH，

(c)-NR ^5g-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(d) hydroxyl, and

(e) amino

R ^3ghydrogen atom or C _1-6alkyl,

It is following formula

or and

Compound (Ig) particularly preferably is:

N-(tertiary butyl)-6-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] pyridine-2-carboxamide,

And salt.

[compound (Ih)]

The present invention also provides the compound or its salt shown in formula (Ih) (in this manual, below sometimes referred to as " compound (Ih) ").

Wherein each symbol defines as above-mentioned.

In above-mentioned formula (Ih), R ^2hdescribed " group of the optional replacement by carbon atom or sulphur atom combination " be preferably the C of optional replacement _1-8alkyl.For C _1-8alkyl, is preferably C _1-6alkyl.

(a)-O-(CH ₂) _n-OH，

(b)-NR ^5g-CO-(CH ₂) _n-OH，

(c)-NR ^5g-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl, and

(d) hydroxyl,

Wherein n is the integer of 1-4, R ^6hhydrogen atom or C _1-4alkyl, and-(CH ₂) _n-optionally by C _1-4alkyl replaces.

R ^3h" optional replace aliphatic alkyl " in " aliphatic alkyl " be preferably C _1-6alkyl.

R ^3hbe preferably hydrogen atom or C _1-6alkyl, more preferably hydrogen atom.

For by R ^3hcarbon atom in adjacent phenyl rings is combined and " ring structure " in " optional replace ring structure " that form, and what can mention is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 or 6-unit) nitrogen heterocyclic rings.

Particularly,

Wherein each symbol as defined above, for example, is

Deng.

R ^1hand R ^2hoptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^1hand R ^2hbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

R ^2hand R ^3hoptionally be bonded to each other to form the ring structure of optional replacement.What described " ring structure " can be mentioned is saturated or undersaturated (preferably saturated) 4 to 8-units (preferably 5 to 7-units) heterocycles.

For by R ^2hand R ^3hbe bonded to each other and form described " ring structure " in " the optional ring structure replacing ", what for example can mention is

Deng, wherein each symbol is as defined above.

By R ^1hand R ^2h, or R ^2hand R ^3hdescribed " ring structure " in " the optional ring structure replacing " forming optionally has 1 to 5 (preferably 1 to 3, more preferably 1 or 2), identical or different substituting group on any commutable position.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Ring A ^h" optional replace phenyl ring " in " phenyl ring " optionally on any commutable position, there is 1 to 3, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.Wherein preferably halogen and methyl.

Ring A ^hbe preferably the phenyl ring of the substituting group replacement that is optionally selected from halogen and methyl.

Z ^h" the optional C replacing _1-3alkylidene group " in " C _1-3alkylidene group " be preferably methylene radical.

Z ^h" the optional C replacing _1-3alkylidene group " in " C _1-3alkylidene group " optionally by 1 to 3, be selected from following substituting group and replace: halogen, hydroxyl, C _1-4alkoxyl group, C _1-4alkyl-carbonyl, carboxyl, C _1-4alkoxyl group-carbonyl, cyano group, formamyl, sulfamyl, nitro, amino, C _1-4alkyl-carbonylamino, C _1-4alkoxyl group-carbonylamino and C _1-4alkyl sulfonyl-amino.

Ring B ^h" the optional C replacing _6-14aryl " in " C _6-14aryl " be preferably phenyl.

Ring B ^h" optional replace heterocyclic radical " in " heterocyclic radical " be preferably pyridyl and piperidyl.

Ring B ^h" the optional C replacing _5-8cycloalkyl " in " C _5-8cycloalkyl " be preferably cyclohexyl.

Ring B ^h" the optional C replacing _6-14aryl " in " C _6-14aryl ", ring B ^h" optional replace heterocyclic radical " in " heterocyclic radical " and encircle B ^h" the optional C replacing _5-8cycloalkyl " in " C _5-8cycloalkyl " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

In said structure formula, partial structural formula

be preferably

Wherein each symbol defines as above-mentioned.

For concrete example, what can mention is the compound or its salt shown in following formula (Ih ') (in this manual, below sometimes referred to as " compound (Ih ') "):

[compound (Ih ')]

Wherein each symbol defines as above-mentioned.

That the preferred embodiment of compound (Ih) can be mentioned is the compound or its salt shown in formula (Iha) (in this manual, below sometimes referred to as " compound (Iha) "):

Wherein

R ^5hbe

(i) the optional amino replacing,

(ii) the optional formamyl replacing,

(iii) the optional urea groups replacing,

(iv) the optional sulfamyl replacing,

(v) the optional heterocyclic radical replacing,

(vi) the optional alkyl replacing,

(vii) halogen atom, or

(viii) the optional carboxyl replacing, and

In above-mentioned formula (Iha), R ^5h" optional replace amino " be preferably amino, C _1-6the C of alkyl-amino, optional halo _1-6alkyloyl-amino, hydroxyl-C _1-6alkyloyl-amino, the C that contains hydroxyl and halogen _1-6alkyloyl-amino, C _3-7cycloalkyl-C _1-6alkyloyl-amino, contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino, C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino, C _3-7cycloalkyl-carbonyl-amino and C _1-6alkoxyl group-carbonyl-amino.

R ^5h" optional replace formamyl " be preferably the C of formamyl, optional halo _1-6alkyl-formamyl, hydroxyl-C _1-6alkyl-formamyl, C _1-6alkoxy-C _1-6alkyl-formamyl, C _3-7cycloalkyl-formamyl and optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom.

R ^5h" optional replace urea groups " be preferably urea groups, C _1-6alkyl-urea groups, C _3-7cycloalkyl-urea groups and also contain heteroatomic 5-to 8-unit heterocycle-urea groups that 1-3 is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom.

R ^5h" optional replace sulfamyl " be preferably optionally by C _1-6the sulfamyl that alkyl replaces.

R ^5h" optional replace heterocyclic radical " be preferably and except carbon atom, also contain 1-3 heteroatomic 5-to 8-unit heterocyclic radical that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, this heterocyclic radical is optionally selected from the C of optional halo _1-6alkyl and C _1-6the substituting group of alkoxyl group-carbonyl replaces.

R ^5h" optional replace alkyl " be preferably the C of optional halo _1-6alkyl and C _1-6alkoxyl group-carbonyl.

R ^5h" optional replace carboxyl " be preferably carboxyl.

In above-mentioned formula (Iha), ring B ^{h '}" the optional C replacing _6-14aryl " in " C _6-14aryl " be preferably phenyl.

Ring B ^{h '}" optional replace heterocyclic radical " in " heterocyclic radical " be preferably pyridyl and piperidyl.

Ring B ^{h '}" the optional C replacing _5-8cycloalkyl " in " C _5-8cycloalkyl " be preferably cyclohexyl.

Except by R ^5houtside replacement, ring B ^{h '}" the optional C replacing _6-14aryl " in " C _6-14aryl ", ring B ^{h '}" optional replace heterocyclic radical " in " heterocyclic radical " and encircle B ^{h '}" the optional C replacing _5-8cycloalkyl " in " C _5-8cycloalkyl " optionally on any commutable position, there is 1 to 5, identical or different substituting group.What described substituting group can be mentioned is the substituting group similar to above-mentioned V group substituting group.

Ring B ^{h '}be preferably phenyl, pyridyl or piperidyl, they are separately except R ^5houtside be also optionally further substituted.

For the preferred embodiment of compound (Ih), that compound (Iha) can be mentioned is above-mentioned formula (Iha), wherein

R ^1hthe C of halogen atom or optional halo _1-6alkyl,

R ^2hbe

(i) hydrogen atom,

(ii) C _1-6alkyl, or

(a)-O-(CH ₂) _n-OH，

(b)-NR ^6h-CO-(CH ₂) _n-OH，

(c)-NR ^6h-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl, and

(d) hydroxyl

R ^3hhydrogen atom or C _1-6alkyl,

Z ^hkey or methylene radical,

R ^5hbe

(i) amino,

(ii) C _1-6alkyl-amino,

(iii) C of optional halo _1-6alkyloyl-amino,

(iv) hydroxyl-C _1-6alkyloyl-amino,

(v) C that contains hydroxyl and halogen _1-6alkyloyl-amino,

(vi) C _3-7cycloalkyl-C _1-6alkyloyl-amino,

(vii) contain C _3-7the C of cycloalkyl and halogen _1-6alkyloyl-amino,

(viii) C _1-6alkyl sulphonyl-C _1-6alkyloyl-amino,

(ix) C _3-7cycloalkyl-carbonyl-amino,

(x) C _1-6alkoxyl group-carbonyl-amino,

(xi) formamyl,

(xii) C of optional halo _1-6alkyl-formamyl,

(xiii) hydroxyl-C _1-6alkyl-formamyl,

(xiv) C _1-6alkoxy-C _1-6alkyl-formamyl,

(xv) C _3-7cycloalkyl-formamyl,

(xvi) optionally contain 5 or 6-ring amino-carbonyl of Sauerstoffatom,

(xvii) urea groups,

(xviii) C _1-6alkyl-urea groups,

(xix) C _3-7cycloalkyl-urea groups,

(xxi) optionally by C _1-6the sulfamyl that alkyl replaces,

(xxiii) C of optional halo _1-6alkyl,

(xxiv) C _1-6alkoxyl group-carbonyl,

(xxv) halogen atom, or

(xxvi) carboxyl, and

Compound (Ih) particularly preferably is:

N-(tertiary butyl)-3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide,

And salt.

For the salt of the compound shown in described structural formula, for example, what can mention is metal-salt, ammonium salt, with the salt of organic bases, with the salt of mineral acid, with organic acid salt, with the salt of alkalescence or acidic amino acid etc.

As the preferred embodiment of metal-salt, for example, can mention that an alkali metal salt is as sodium salt, sylvite etc.; Alkaline earth salt is as calcium salt, magnesium salts, barium salt etc.; Aluminium salt, etc.

Preferred embodiment as the salt with organic bases, for example, can mention and Trimethylamine 99, triethylamine, pyridine, picoline, 2,6-lutidine, thanomin, diethanolamine, trolamine, tromethane [i.e. three (hydroxymethyl) methylamine], TERTIARY BUTYL AMINE, hexahydroaniline, dicyclohexyl amine, N, the salt of N '-dibenzyl two quadrols etc.

As the preferred embodiment of the salt with mineral acid, for example, can mention the salt with hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.

As the preferred embodiment with organic acid salt, for example, can mention the salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.

As the preferred embodiment of the salt with basic aminoacids, for example, can mention the salt with arginine, Methionin, ornithine etc.

As the preferred embodiment of the salt with acidic amino acid, for example, can mention the salt with aspartic acid, L-glutamic acid etc.

Wherein, preferred pharmacy acceptable salt.For example, while containing acidic functionality in compound, can mention that inorganic salt are as an alkali metal salt (such as sodium salt, sylvite etc.), alkaline earth salt (such as calcium salt, magnesium salts, barium salt etc.) etc., and when compound contains alkaline functional group, for example, can mention the salt with mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc., or with organic acid as the salt of acetic acid, phthalic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid etc.

[preparation method]

The preparation method of compound of the present invention (Ia) to (Ih) is described below:

[preparation method A]

Compound of the present invention (Ia) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Ia).

Be obtained from compound in each step can reaction mixture or the form of crude product for next step, react.In addition, also compound can be separated from reaction mixture by ordinary method, and easily by separation means such as recrystallization, distillation, chromatogram, be carried out purifying.

Diagram reaction formula is as follows, and wherein each symbol in compound as defined above.

Compound of the present invention (Ia) can be by for example making the compound or its salt of following formula representative:

L wherein ^abe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^abe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

G ^abe mainly hydrogen atom, but can be basic metal as lithium, sodium, potassium, caesium etc., or be that alkaline-earth metal is as magnesium, calcium etc.

Compound (IIIa) or its salt are preferably with respect to compound (IIa) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^athe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zthe group representing, wherein R ^zas defined above etc.

As the solvent in above-mentioned reaction, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.

As the alkali in above-mentioned reaction, can use mineral alkali, organic bases etc.Particularly for example sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU, diazabicycloundecene) etc.

As the ammonium salt in above-mentioned reaction, can use pyridine hydrochloride, pyridine hydrobromide salt, the p-tosylate of pyridine, quinoline hydrochloride, isoquinoline hydrochloride, pyrimidine hydrochloride, pyrazine hydrochloride, triazine hydrochloride, trimethylamine hydrochloride, triethylamine hydrochloride, N-ethyl diisopropyl amine hydrochloride etc.

Above-mentioned reaction can be under cooling, at room temperature or under heating (about 40-200 ℃, preferred about 40-160 ℃) carry out, the reaction times is generally about 1-30 hour, preferred about 1-20 hour, more preferably from about 1-10 hour.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Ia) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

For the compound (Ia) of this reaction product can individualized compound or prepare with the form of mixture.

The compounds of this invention so obtaining (Ia) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIa), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIa) can prepare by for example method shown in following diagram.Wherein, compound (IIaa), (IIab), (IIac) and (IIad) be included in compound (IIa).

L wherein ^1aand L ^2afor halogen atom, R ^zas defined above, and t be 1 or 2 integer.

For method Aa, compound (IIaa) can be by making compound (IVa) react and prepare with halogenating agent.For method Ba, make compound (IVa) and sulfuration reagent react, obtain compound (Va), then under alkali exists by compound (Va) and R ^zl ^2athe compound reaction of representative obtains compound (IIab), compound (IIab) is further carried out to oxidizing reaction and obtain compound (IIac).For method Ca, under existing, alkali makes compound (IIaa) and R ^zthe compound reaction of OH representative obtains compound (IIad).

As the halogenating agent in method Aa, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVa) the sulfuration reagent using in the step of compound (Va) in method Ba, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Va) R using in the step of compound (IIab) in method Ba ^zl ^2asuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIab) oxygenant using in the step of compound (IIac) in method Ba, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIac), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIab), and when preparing wherein the compound of t=2 (IIac), use the oxygenant with respect to the about 2-3 equivalent of compound (IIab).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IIaa) R using in the step of compound (IIad) in method Ca ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVa) can be shown below by example prepares:

R wherein ^10afor C _1-4alkyl, and other symbol is as defined above.

Or rather, make carbonamidine or its reactant salt of compound (VIa) and about 1-4 equivalent, thereby can prepare compound (IVa).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

The method that compound (IIa) also can be shown below by example prepares:

L wherein ^3afor halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIa) by compound (VIIa); can be commonly called the reaction of Sonogashira reaction; maybe can use similar reaction; and compound (VIIIa) can, by under existing at alkali, under the palladium catalyst and cupric iodide (copperiodide) existence of about 0.01-1 equivalent, make the formula of compound (VIIa) and about 1-3 equivalent conventionally

the compound of representative reacts to prepare.As alkali, for example, can use triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU), sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus etc.As palladium catalyst, such as using dichloro two (triphenylphosphines) to close palladium (II), palladium/carbon, palladium diacetate (II), dichloro two (benzonitrile), close palladium (II) etc.This reaction can be in the reaction under common existence as triphenylphosphine, tributylphosphine etc. of the tertiary phosphine compounds as part.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour.

In this method, for prepared the step of compound (IIa) by compound (VIIIa), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIa).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.At low temperatures, under room temperature or under heating, carry out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour in this reaction.

Depend on the substituent kind of initial compounds (IIa), the initial compounds (IIa) with different substituents can be by carrying out the substituting group preparation that is converted by the prepared compound of above-mentioned preparation method as initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIa).

[preparation method B]

Compound of the present invention (Ib) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Ib).

Compound of the present invention (Ib) can be by for example making the compound or its salt of following formula representative:

L wherein ^bbe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^bbe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

Work as X ^1bbe-NR ^3b-Y ^1b-,-O-or-during S-, G ^bbe mainly hydrogen atom, but also can be basic metal, such as lithium, sodium, potassium, caesium etc., or alkaline-earth metal, such as magnesium, calcium etc.

Work as X ^1bbe-CHR ^3b-time, G ^bfor metal, such as lithium, magnesium halide, copper, zinc etc.

Compound (IIIb) or its salt are preferably with respect to compound (IIb) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^bthe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zthe group representing, wherein R ^zas defined above etc.

As the solvent in above-mentioned reaction, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is if benzene,toluene,xylene etc., alcohol are if methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., ether are as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.

As the alkali in above-mentioned reaction, can use mineral alkali, organic bases etc.Particularly for example sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.

X ^1bbe-SO-or-SO ₂-compound (Ib) can be by by X ^1bbe-compound (Ib) of S-carries out oxidizing reaction preparation.As the oxygenant in preparation process, can be such as metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.As preparation X ^1bduring for the compound (Ib) of-SO-, use the oxygenant with respect to the about 1-1.5 equivalent of initial compounds, as preparation X ^1bfor-SO ₂-compound (Ib) time, use the oxygenant with respect to the about 2-3 equivalent of initial compounds.Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Ib) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

For the compound (Ib) of this reaction product can individualized compound or prepare with the form of mixture.

The compounds of this invention so obtaining (Ib) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIb), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIb) can prepare by for example method shown in following diagram.Wherein, compound (IIba), (IIbb), (IIbc), (IIbd) and (IIbe) be included in compound (IIb).

L wherein ^1band L ^2bfor halogen atom, R ^zas defined above, and t be 1 or 2 integer.

For method Ab, compound (IIba) can be by making compound (IVb) react and prepare with halogenating agent.For method Bb, make compound (IVb) and sulfuration reagent react, obtain compound (Vb), then under alkali exists by compound (Vb) and R ^zl ^2bthe compound reaction of representative obtains compound (IIbb), compound (IIbb) is further carried out to oxidizing reaction and obtain compound (IIbc).For method Cb, under existing, alkali makes compound (IIba) and R ^zthe compound reaction of OH representative obtains compound (IIbd).

As the halogenating agent in method Ab, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVb) the sulfuration reagent using in the step of compound (Vb) in method Bb, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Vb) R using in the step of compound (IIbb) in method Bb ^zl ^2bsuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIbb) oxygenant using in the step of compound (IIbc) in method Bb, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIbc), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIbb), and when preparing wherein the compound of t=2 (IIbc), use the oxygenant with respect to the about 2-3 equivalent of compound (IIbb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IIba) R using in the step of compound (IIbd) in method Cb ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVb) can be shown below by example prepares:

R wherein ^10bfor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VIb) and about 1-4 equivalent, thereby can prepare compound (IVb).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

Work as W ^bc (R ^1b) time, the method that compound (IIbe) also can be shown below by example prepares:

L wherein ^3bbe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIb) by compound (VIIb); can be commonly called the reaction of Sonogashira reaction; maybe can use similar reaction; and compound (VIIIb) can, by under existing at alkali, under the palladium catalyst and cupric iodide existence of about 0.01-1 equivalent, make the formula of compound (VIIb) and about 1-3 equivalent conventionally

In this method, for prepared the step of compound (IIbe) by compound (VIIIb), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIbe).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.At low temperatures, under room temperature or under heating, carry out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour in this reaction.

Depend on the substituent kind of initial compounds (IIb), the initial compounds (IIb) with different substituents can be by carrying out the substituting group preparation that is converted by the prepared compound of above-mentioned preparation method as initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIb).

[preparation method C]

Compound of the present invention (Ic) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Ic).

Compound of the present invention (Ic) can be by for example making the compound or its salt of following formula representative:

L wherein ^cbe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^cbe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

G ^cbe mainly hydrogen atom, but also can be basic metal, such as lithium, sodium, potassium, caesium etc., or alkaline-earth metal, such as magnesium, calcium etc.

Compound (IIIc) or its salt are preferably with respect to compound (IIc) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^cthe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zthe group representing, wherein R ^zas defined above etc.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Ic) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

Can individualized compound or prepare with the form of mixture as the compound (Ic) of this reaction product.

The compounds of this invention so obtaining (Ic) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIc), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIc) can prepare by for example method shown in following diagram.Wherein, compound (IIca), (IIcb), (IIcc) and (IIcd) be included in compound (IIc).

L wherein ^1cand L ^2cfor halogen atom, R ^zas defined above, and t be 1 or 2 integer.

For method Ac, compound (IIca) can be by making compound (IVc) react and prepare with halogenating agent.For method Bc, make compound (IVc) and sulfuration reagent react, obtain compound (Vc), then under alkali exists by compound (Vc) and R ^zl ^2cthe compound reaction of representative obtains compound (IIcb), compound (IIcb) is further carried out to oxidizing reaction and obtain compound (IIcc).For method Cc, under existing, alkali makes compound (IIca) and R ^zthe compound reaction of OH representative obtains compound (IIcd).

As the halogenating agent in method Ac, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVc) the sulfuration reagent using in the step of compound (Vc) in method Bc, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Vc) R using in the step of compound (IIcb) in method Bc ^zl ^2csuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIcb) oxygenant using in the step of compound (IIcc) in method Bc, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIcc), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIcb), and when preparing wherein the compound of t=2 (IIcc), use the oxygenant with respect to the about 2-3 equivalent of compound (IIcb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As the R using in the step of preparing compound (IIcd) of compound (IIca) in method Cc ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVc) can be shown below by example prepares:

R wherein ^10cfor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VIc) and about 1-4 equivalent, thereby can prepare compound (IVc).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

The method that compound (IIc) also can be shown below by example prepares:

L wherein ^3cbe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIc) by compound (VIIc); can be commonly called the reaction of Sonogashira reaction; maybe can use similar reaction; and compound (VIIIc) can, by under existing at alkali, under the palladium catalyst and cupric iodide existence of about 0.01-1 equivalent, make the formula of compound (VIIc) and about 1-3 equivalent conventionally

In this method, for prepared the step of compound (IIc) by compound (VIIIc), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIc).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.At low temperatures, under room temperature or under heating, carry out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour in this reaction.

Depend on the substituent kind of initial compounds (IIc), the initial compounds (IIc) with different substituents can be by carrying out the substituting group preparation that is converted by the prepared compound of above-mentioned preparation method as initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIc).

Initial compounds in this preparation method (IIc) also can be used compound (IIc ') to prepare by the method shown in following diagram for example.

Wherein each symbol defines as above-mentioned.

In the method, conventionally use alkali make compound (IIc ') remove proton and be converted into its negatively charged ion, then allow its with there is R ^1ccationoid reaction obtain compound (IIc).As alkali, such as using n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, trimethyl carbinol lithium, di-isopropyl amination lithium etc.As producing cationic reagent, such as using Tosyl chloride, benzene sulfonyl bromine, p-toluenesulfonyl cyanogen, S-(trifluoromethyl) dibenzothiophene fluoroform sulphonate, DMF etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., ether is as ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc., or its mixed solvent etc.This reaction is carried out under cooling, be preferably and be no more than approximately-20 ℃, and the reaction times is generally approximately 15 minutes-50 hours, preferably approximately 30 minutes-4 hours.

[preparation method D]

Compound of the present invention (Id) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Id).

Compound of the present invention (Id) can be by for example making the compound or its salt of following formula representative:

L wherein ^dbe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^dbe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

G ^dbe mainly hydrogen atom, but also can be basic metal, such as lithium, sodium, potassium, caesium etc., or alkaline-earth metal, such as magnesium, calcium etc.

Compound (IIId) or its salt are preferably with respect to compound (IId) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^dthe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zgroup, R wherein ^zas defined above etc.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Id) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

Can individualized compound or prepare with the form of mixture as the compound (Id) of this reaction product.

The compounds of this invention so obtaining (Id) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIId), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IId) can prepare by for example method shown in following diagram.Wherein, compound (IIda), (IIdb), (IIdc) and (IIdd) be included in compound (IId).

L wherein ^1dand L ^2dfor halogen atom, R ^zas defined above, and t be 1 or 2 integer.

For method Ad, compound (IIda) can be by making compound (IVd) react and prepare with halogenating agent.For method Bd, make compound (IVd) and sulfuration reagent react, obtain compound (Vd), then under alkali exists by compound (Vd) and R ^zl ^2dthe compound reaction of representative obtains compound (IIdb), compound (IIdb) is further carried out to oxidizing reaction and obtain compound (IIdc).For method Cd, under existing, alkali makes compound (IIda) and R ^zthe compound reaction of OH representative obtains compound (IIdd).

As the halogenating agent in method Ad, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVd) the sulfuration reagent using in the step of compound (Vd) in method Bd, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Vd) R using in the step of compound (IIdb) in method Bd ^zl ^2dsuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIdb) oxygenant using in the step of compound (IIdc) in method Bd, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIdc), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIdb), and when preparing wherein the compound of t=2 (IIdc), use the oxygenant with respect to the about 2-3 equivalent of compound (IIdb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IIda) R using in the step of compound (IIdd) in method Cd ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVd) can be shown below by example prepares:

R wherein ^10dfor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VId) and about 1-4 equivalent, thereby can prepare compound (IVd).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

The method that compound (IId) also can be shown below by example prepares:

L wherein ^3dbe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIId) by compound (VIId); can be commonly called the reaction of Sonogashira reaction; maybe can use similar reaction; and compound (VIIId) can, by under existing at alkali, under the palladium catalyst and cupric iodide existence of about 0.01-1 equivalent, make the formula of compound (VIId) and about 1-3 equivalent conventionally

In this method, for prepared the step of compound (IId) by compound (VIIId), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IId).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.At low temperatures, under room temperature or under heating, carry out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour in this reaction.

Depend on the substituent kind of initial compounds (IId), the initial compounds (IId) with different substituents can be by carrying out the substituting group preparation that is converted by the prepared compound of above-mentioned preparation method as initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IId).

[preparation method E]

Compound of the present invention (Ie) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Ie).

Compound of the present invention (Ie) can be by for example making the compound or its salt of following formula representative:

L wherein ^ebe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^ebe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

G ^ebe mainly hydrogen atom, but also can be basic metal, such as lithium, sodium, potassium, caesium etc., or alkaline-earth metal, such as magnesium, calcium etc.

Compound (IIIe) or its salt are preferably with respect to compound (IIe) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^ethe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zgroup, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zgroup, R wherein ^zas defined above etc.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Ie) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

Can individualized compound or prepare with the form of mixture as the compound (Ie) of this reaction product.

The compounds of this invention so obtaining (Ie) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIe), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIe) can prepare by for example method shown in following diagram.Wherein, compound (IIea), (IIeb), (IIec) and (IIed) be included in compound (IIe).

L wherein ^1eand L ^2efor halogen atom s, R ^zas defined above, and t be 1 or 2 integer.

For method Ae, compound (IIea) can be by making compound (IVe) react and prepare with halogenating agent.For method Be, make compound (IVe) and sulfuration reagent react, obtain compound (Ve), then under alkali exists by compound (Ve) and R ^zl ^2ethe compound reaction of representative obtains compound (IIeb), compound (IIeb) is further carried out to oxidizing reaction and obtain compound (IIec).For method Ce, under existing, alkali makes compound (IIea) and R ^zthe compound reaction of OH representative obtains compound (IIed).

As the halogenating agent in method Ae, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVe) the sulfuration reagent using in the step of compound (Ve) in method Be, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Ve) R using in the step of compound (IIeb) in method Be ^zl ^2esuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIeb) oxygenant using in the step of compound (IIec) in method Be, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIec), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIeb), and when preparing wherein the compound of t=2 (IIec), use the oxygenant with respect to the about 2-3 equivalent of compound (IIeb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IIea) R using in the step of compound (IIed) in method Ce ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVe) can be shown below by example prepares:

R wherein ^10efor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VIe) and about 1-4 equivalent, thereby can prepare compound (VIe).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

The method that compound (IIe) also can be shown below by example prepares:

L wherein ^3ebe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIe) by compound (VIIe); can be commonly called the reaction of Sonogashira reaction; maybe can use similar reaction; and compound (VIIIe) can, by under existing at alkali, under the palladium catalyst and cupric iodide existence of about 0.01-1 equivalent, make the formula of compound (VIIe) and about 1-3 equivalent conventionally

In this method, for prepared the step of compound (IIe) by compound (VIIIe), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIe).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.At low temperatures, under room temperature or under heating, carry out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour in this reaction.

Depend on the substituent kind of initial compounds (IIe), the initial compounds (IIe) with different substituents can be by carrying out the substituting group preparation that is converted by the prepared compound of above-mentioned preparation method as initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIe).

[preparation method F]

Compound of the present invention (If) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (If).

Compound of the present invention (If) can be by for example making the compound or its salt of following formula representative:

L wherein ^fbe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^fbe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

Compound (IIIf) or its salt are preferably with respect to compound (IIf) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^fthe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zthe group representing, wherein R ^zas defined above etc.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (If) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

Can individualized compound or prepare with the form of mixture as the compound (If) of this reaction product.

The compounds of this invention so obtaining (If) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIf), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIf) can prepare by for example method shown in following diagram.Wherein, compound (IIfa), (IIfb), (IIfc) and (IIfd) be included in compound (IIf).

L wherein ^1fand L ^2ffor halogen atom s, R ^zas defined above, and t be 1 or 2 integer.

For method Af, compound (IIfa) can be by making compound (IVf) react and prepare with halogenating agent.For method Bf, make compound (IVf) and sulfuration reagent react, obtain compound (Vf), then under alkali exists by compound (Vf) and R ^zl ^2fthe compound reaction of representative obtains compound (IIfb), compound (IIfb) is further carried out to oxidizing reaction and obtain compound (IIfc).For method Cf, under existing, alkali makes compound (IIfa) and R ^zthe compound reaction of OH representative obtains compound (IIfd).

As the halogenating agent in method Af, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVf) the sulfuration reagent (thionating agent) using in the step of compound (Vf) in method Bf, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Vf) R using in the step of compound (IIfb) in method Bf ^zl ^2fsuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIfb) oxygenant using in the step of compound (IIfc) in method Bf, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide (t-butylhydroperoxide), Potassium Persulphate (potassium peroxysulfate), potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIfc), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIfb), and when preparing wherein the compound of t=2 (IIfc), use the oxygenant with respect to the about 2-3 equivalent of compound (IIfb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IIfa) R using in the step of compound (IIfd) in method Cf ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVf) can be shown below by example prepares:

R wherein ^10ffor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VIf) and about 1-4 equivalent, thereby can prepare compound (IVf).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

The method that compound (IIf) also can be shown below by example prepares:

L wherein ^3fbe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIf) by compound (VIIf); can be commonly called the reaction of Sonogashira reaction; maybe can carry out similar reaction; and under compound (VIIIf) can exist by the palladium catalyst at alkali, about 0.01-1 equivalent and cupric iodide (copper iodide) conventionally, make the formula of compound (VIIf) and about 1-3 equivalent

In this method, for prepared the step of compound (IIf) by compound (VIIIf), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIf).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is carried out under low temperature, room temperature or under heating, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour.

The substituent kind that depends on initial compounds (IIf), the initial compounds (IIf) with different substituents can be by by carry out the substituting group preparation that is converted as the prepared compound of the above-mentioned preparation method of initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIf).

[preparation method G]

Compound of the present invention (Ig) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Ig).

Compound of the present invention (Ig) can be by for example making the compound or its salt of following formula representative:

L wherein ^gbe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^gbe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

Work as X ^1gbe-NR ^3g-Y ^1g-,-O-or-during S-, G ^gbe mainly hydrogen atom, but also can be basic metal, such as lithium, sodium, potassium, caesium etc., or alkaline-earth metal, such as magnesium, calcium etc.

Work as X ^1gbe-CHR ^3g-time, G ^gcan be metal, such as lithium, magnesium halide, copper, zinc etc.

Compound (IIIg) or its salt are preferably with respect to compound (IIg) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^gthe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zthe group representing, wherein R ^zas defined above etc.

X ^1gbe-SO-or-SO ₂-compound (Ig) can be by by X ^1gbe-compound (Ig) of S-carries out oxidizing reaction preparation.As the oxygenant in preparation process, can be such as metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.As preparation X ^1gduring for the compound (Ig) of-SO-, use the oxygenant with respect to the about 1-1.5 equivalent of initial compounds, as preparation X ^1gfor-SO ₂-compound (Ig) time, use the oxygenant with respect to the about 2-3 equivalent of initial compounds.Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Ig) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl (oximation), amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

Can individualized compound or prepare with the form of mixture as the compound (Ig) of this reaction product.

The compounds of this invention so obtaining (Ig) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIg), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIg) can prepare by for example method shown in following diagram.Wherein, compound (IIga), (IIgb), (IIgc), (IIgd) and (IIge) be included in compound (IIg).

L wherein ^1gand L ^2gfor halogen atom, R ^zas defined above, and t be 1 or 2 integer.

For method Ag, compound (IIga) can be by making compound (IVg) react and prepare with halogenating agent.For method Bg, make compound (IVg) and sulfuration reagent react, obtain compound (Vg), then under alkali exists by compound (Vg) and R ^zl ^2gthe compound reaction of representative obtains compound (IIgb), compound (IIgb) is further carried out to oxidizing reaction and obtain compound (IIgc).For method Cg, under existing, alkali makes compound (IIga) and R ^zthe compound reaction of OH representative obtains compound (IIgd).

As the halogenating agent in method Ag, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVg) the sulfuration reagent using in the step of compound (Vg) in method Bg, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Vg) R using in the step of compound (IIgb) in method Bg ^zl ^2gsuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIgb) oxygenant using in the step of compound (IIgc) in method Bg, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIgc), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIgb), and when preparing wherein the compound of t=2 (IIgc), use the oxygenant with respect to the about 2-3 equivalent of compound (IIgb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As the R using in the step of preparing compound (IIgd) of compound (IIga) in method Cg ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide; 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVg) can be shown below by example prepares:

R wherein ^10gfor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VIg) and about 1-4 equivalent, thereby can prepare compound (IVg).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

Work as W ^gc (R ^1g) time, the method that compound (IIge) also can be shown below by example prepares:

L wherein ^3gbe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIg) by compound (VIIg); can be commonly called the reaction of Sonogashira reaction; maybe can carry out similar reaction; and under compound (VIIIg) can exist by the palladium catalyst at alkali, about 0.01-1 equivalent and cupric iodide conventionally, make the formula of compound (VIIg) and about 1-3 equivalent the compound of representative reacts to prepare.As alkali, for example, can use triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU), sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus etc.As palladium catalyst, such as using dichloro two (triphenylphosphines) to close palladium (II), palladium/carbon, palladium diacetate (II), dichloro two (benzonitrile), close palladium (II) etc.This reaction can be in the reaction under common existence as triphenylphosphine, tributylphosphine etc. of the tertiary phosphine compounds as part.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour.

In this method, for prepared the step of compound (IIge) by compound (VIIIg), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIge).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is carried out under low temperature, room temperature or under heating, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour.

Depend on the substituent kind of initial compounds (IIg), the initial compounds (IIg) with different substituents can be by by carry out the substituting group preparation that is converted as the prepared compound of the above-mentioned preparation method of initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIg).

[preparation method H]

Compound of the present invention (Ih) can be by acquisitions such as the method shown in following diagram or similar methods.

Wherein each symbol defines as above-mentioned.

Each compound in following diagram comprises salt, as this salt, such as using and similar those salt etc. of the salt of compound (Ih).

Compound of the present invention (Ih) can be by for example making the compound or its salt of following formula representative:

L wherein ^hbe leavings group, and other symbol defines as above-mentioned, reacts and prepare with the compound or its salt of following formula representative:

G wherein ^hbe hydrogen atom or atoms metal, and other symbol define as above-mentioned,

G ^hbe mainly hydrogen atom, but also can be basic metal, such as lithium, sodium, potassium, caesium etc., or alkaline-earth metal, such as magnesium, calcium etc.

Compound (IIIh) or its salt are preferably with respect to compound (IIh) 1-5 equivalent, and preferably the amount of 1-2 equivalent is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and preferably the amount of 1-2 equivalent is used.

In above-mentioned formula, as L ^hthe leavings group of representative, can be used halogen atom as chlorine, bromine, iodine etc., formula-S (O) _kr ^zthe group representing, wherein k is 0,1 or 2 integer, and R ^zfor rudimentary (C _1-4) alkyl is as methyl, ethyl, propyl group etc., C _6-10aryl is as phenyl, tolyl etc., or formula-OR ^zthe group representing, wherein R ^zas defined above etc.

As the alkali in above-mentioned reaction, can use mineral alkali, organic bases etc.Concrete example is as sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.

Compound in the scope of the invention also can be by preparing by known method own, and the method obtains the compounds of this invention (Ih) by being converted of substituent introducing and functional group.For substituent conversion, can use known ordinary method.For example; can mention that the hydrolysis by ester is carboxyl; amidation by carboxyl is converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, can prepare the compound in the scope of the invention.

Can individualized compound or prepare with the form of mixture as the compound (Ih) of this reaction product.

The compounds of this invention so obtaining (Ih) can be processed as solvent extraction, concentrated, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. by known method itself, thus can by title compound from reaction mixture with high purity separation out and purifying.

As this preparation method's initial compounds (IIIh), can use the product being purchased maybe can prepare by known method itself.

Initial compounds in this preparation method (IIh) can prepare by for example method shown in following diagram.Wherein, compound (IIha), (IIhb), (IIhc) and (IIhd) be included in compound (IIh).

L wherein ^1hand L ^2hfor halogen atom, R ^zas defined above, and t be 1 or 2 integer.

For method Ah, compound (IIha) can be by making compound (IVh) react and prepare with halogenating agent.For method Bh, make compound (IVh) and sulfuration reagent react, obtain compound (Vh), then under alkali exists by compound (Vh) and R ^zl ^2hthe compound reaction of representative obtains compound (IIhb), compound (IIhb) is further carried out to oxidizing reaction and obtain compound (IIhc).For method Ch, under existing, alkali makes compound (IIha) and R ^zthe compound reaction of OH representative obtains compound (IIhd).

As the halogenating agent in method Ah, such as using phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, sulfuryl chloride, phosphorus tribromide of about 1-100 equivalent etc.In this case, this reaction can be carried out under as existence such as Diethyl Aniline, xylidine, pyridines at alkali.Although this reaction can be carried out under solvent not having, as reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetonitrile, ethyl acetate etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IVh) the sulfuration reagent using in the step of compound (Vh) in method Bh, such as using Lawesson reagent, thiophosphoric anhydride of about 1-5 equivalent etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (Vh) R using in the step of compound (IIhb) in method Bh ^zl ^2hsuch as using methyl iodide, benzyl chloride, bromotoluene of about 1-5 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour; Preferred about 1-10 hour.

As prepare by compound (IIhb) oxygenant using in the step of compound (IIhc) in method Bh, such as using metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tertbutyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIhc), use is with respect to the oxygenant of the about 1-1.5 equivalent of compound (IIhb), and when preparing wherein the compound of t=2 (IIhc), use the oxygenant with respect to the about 2-3 equivalent of compound (IIhb).Reaction solvent is had no particular limits, if it not with oxidant reaction, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Carboxylic acid is as acetic acid, trifluoroacetic acid etc.; Acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

As prepare by compound (IIha) R using in the step of compound (IIhd) in method Ch ^zoH, such as using methyl alcohol, ethanol, phenol of about 1-10 equivalent etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, pyridine, N, N-dimethyl aminopyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

In addition the method that, compound (IVh) can be shown below by example prepares:

R wherein ^10hfor C _1-4alkyl, and other symbol is as defined above.

That is, make carbonamidine or its reactant salt of compound (VIh) and about 1-4 equivalent, thereby can prepare compound (IVh).As reaction solvent, such as using alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Halon is as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Ether is as ether, tetrahydrofuran (THF), diox etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is under cooling, at room temperature or under heating carry out, and the reaction times is generally about 1-20 hour, preferred about 1-10 hour.

The method that compound (IIh) also can be shown below by example prepares:

L wherein ^3hbe halogen atom, and other symbol as defined above.

In this method; for prepared the step of compound (VIIIh) by compound (VIIh); can be commonly called the reaction of Sonogashira reaction; maybe can carry out similar reaction; and conventionally compound (VIIIh) can be by alkali, under the palladium catalyst of about 0.01-1 equivalent and cupric iodide exist, make the formula of compound (VIIh) and about 1-3 equivalent

In this method, for prepared the step of compound (IIh) by compound (VIIIh), cyclization carries out under the alkali of about 1-3 equivalent or the existence of the cupric iodide of about 0.01-1 equivalent conventionally, obtains compound (IIh).As alkali, for example can use potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol caesium, sodium ethylate, potassium hydride KH, sodium hydride, cesium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazo bicyclic undecylene (DBU) etc.As reaction solvent, for example, can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Aromatic hydrocarbon is as benzene,toluene,xylene etc.; Alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Ether as ether,, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc.; Acetone, acetonitrile, ethyl acetate, DMF, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction is carried out under low temperature, room temperature or under heating, and the reaction times is generally about 1-50 hour, preferred about 1-20 hour.

Depend on the substituent kind of initial compounds (IIh), the initial compounds (IIh) with different substituents can be by by carry out the substituting group preparation that is converted as the prepared compound of the above-mentioned preparation method of initiator.For substituent conversion, can use known general method.For example; can mention that hydrolysis and amidation by ester are converted into formamyl; reduction by carboxyl is converted into hydroxymethyl; reduction or alkylation by carbonyl are converted into alkylol cpd, the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and amination, the alkylation of hydroxyl, the replacement of hydroxyl and amination etc.In the conversion process of substituent introducing and functional group; when existence causes the active substituent of non-goal response; if essential; by known method own, blocking group is incorporated in active substituent in advance; and by known method own, remove blocking group after goal response; thus, also can prepare initial compounds (IIh).

Initial compounds in this preparation method (IIh) also can be used compound (IIh ') to prepare by the method shown in following diagram for example.

Wherein each symbol defines as above-mentioned.

In the method, conventionally use alkali make compound (IIh ') remove proton and be converted into its negatively charged ion, then allow its with there is R ^1hcationoid reaction obtain compound (IIh).As alkali, such as using n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, trimethyl carbinol lithium, di-isopropyl amination lithium (lithiumdiisopropylamide) etc.As producing cationic reagent; such as using Tosyl chloride, benzene sulfonyl bromine, p-toluenesulfonyl cyanogen (p-toluenesulfonyl cyanide), S-(trifluoromethyl) dibenzothiophene fluoroform sulphonate (S-(trifluoromethyl) dibenzothiopheniumtrifluoromethanesulfonate), DMF etc.As reaction solvent, for example can use halon as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., ether is as ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc., or its mixed solvent etc.This reaction is carried out under cooling, be preferably and be no more than approximately-20 ℃, and the reaction times is generally approximately 15 minutes-50 hours, preferably approximately 30 minutes-4 hours.

The compound so obtaining (Ia)-(Ih) can be by known method separation and purification itself, such as concentrated, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, phase transition and column chromatography etc.

If compound (Ia)-(Ih) obtains with the form of dissociating, it can be improved one's methods and be converted into the salt needing by known method itself or its; On the contrary, if compound (Ia)-(Ih) obtains with the form of salt, it can be improved one's methods and be converted into free form or other salt needing by fact known method or its.

When compound (Ia)-(Ih) have isomer such as optically active isomer, steric isomer, positional isomers, rotational isomer etc., any isomer and mixture include in compound (Ia)-(Ih).For example, when compound (Ia)-(Ih) have optically active isomer, from racemic modification, separated optically active isomer is also included within compound (Ia)-(Ih).These isomer can obtain with the form of product independently by known synthetic method itself or separation method (concentrated, solvent extraction, column chromatography, recrystallization etc.).

Compound (Ia)-(Ih) can be crystal, and monocrystalline and mixed crystal are included in compound (Ia)-(Ih).Crystal can make by crystallization according to known crystallization method itself.

Compound (Ia)-(Ih) can be solvate (such as hydrate etc.) or non-solvent compound, and they include in compound (Ia)-(Ih).

Mark isotropic substance (for example ³h, ¹⁴c, ³⁵s, ¹²⁵i etc.) compound is also included within compound (Ia)-(Ih).

The prodrug of compound (Ia)-(Ih) or its salt (be called hereinafter compound (Ia)-(Ih)) refers in vivo under physiological condition, owing to reacting the compound that changes into compound (Ia)-(Ih) with enzyme, hydrochloric acid in gastric juice etc., namely, the oxidation by enzyme, reduction, hydrolysis etc. change into the compound of compound (Ia)-(Ih); Hydrolysis reaction by hydrochloric acid in gastric juice etc. etc. changes into the compound of compound (Ia)-(Ih).The prodrug of compound (Ia)-(Ih) can be the compound that obtains through acidylate, alkylation or phosphorylated of the amino of compound (Ia)-(Ih) (for example the amino of compound (Ia)-(Ih) through eicosane acidylate, alanyl, amyl group aminocarboxyl, (5-methyl-2-oxidation-1,3-Dioxol-4-yl) methoxycarbonyl, tetrahydrofuran base, pyrrolidyl methylate, oxy acid methyl neopentyl, tert-butylation etc. and the compound that obtains); The compound that hydroxyl in compound (Ia)-(Ih) obtains through acidylate, alkylation, phosphorylated or boron acidylate (compound obtaining through acetylize, palmitoylation, propionyl, pivalyl, succinylation, fumaryl, alanyl, dimethylaminomethyl carbonylation etc. such as the hydroxyl of compound (Ia)-(Ih)); The compound that the carboxyl of compound (Ia)-(Ih) obtains through over-churning or amidation (compound that for example carbonyl of compound (Ia)-(Ih) obtains through ethyl-ester, phenyl-ester, carboxyl methyl-ester, dimethylaminomethyl-ester, oxy acid methyl neopentyl-ester, oxyethyl group carbonyl oxygen base ethyl-ester, phthalidyl-ester, (5-methyl-2-oxidation-1,3-Dioxol-4-yl) methyl-ester, cyclohexyloxy carbonyl ethyl-ester or methyl nitrosourea etc.) etc.Any compound in these compounds can be by known method own by compound (Ia)-(Ih) preparation.

The prodrug of compound (Ia)-(Ih) can be also the compound that changes into compound (Ia)-(Ih) under physiological condition, as iYAKUHIN no KAIHATSU (Development of Pharmaceuticals),the 7th volume, Design of Molecules, 163-198 page, by HIROKAWA SHOTEN publish (1990) described those.

It is active that compound of the present invention (Ia)-(Ih) or its salt or its prodrug (hereinafter referred to as compound of the present invention) have Tyrosylprotein kinase-inhibition, and can be used to prevention or treat mammiferous Tyrosylprotein kinase-dependence disease.Tyrosylprotein kinase-dependence disease comprises that the cell proliferation to cause due to abnormal tyrosine kinase activity increases to the disease of feature.

Particularly, compound specificity of the present invention ground suppresses HER2 kinases and/or EGFR kinases, and thereby also can be used as suppressing the therapeutical agent of the growth of cancers of HER2 and/or EGFR kinases-expression.And compound of the present invention can be used as preventing hormone-dependence cancer and prevents that hormone-dependence cancer is converted into the preventive of hormone-dependent/non-dependent cancer.

In addition, the compounds of this invention useful as drug preparation, for example, because it (shows hypotoxicity, acute toxicity, long term toxicity, heredity toxicity, genotoxicity, cardiac toxic, drug interaction, carinogenicity etc.), highly water-soluble, and (absorb, distribute in stability, pharmacokinetics, metabolism, excretion etc.) and effect expression aspect excellence.

Therefore, compound of the present invention can be used as prevention or treatment due to the safe medicament of the caused disease of abnormal cell proliferation, and described disease is various cancers (mammary cancer (infitrating ductal carcinoma for example especially for example, ductal carcinoma in situ, inflammatory breast cancer etc.), prostate cancer (hormonal dependent prostate cancer for example, non-hormone dependence prostate cancer etc.), carcinoma of the pancreas (such as pancreas duct carcinoma etc.), cancer of the stomach (adenocarcinoma of nipple (papillary adenocarcinoma) for example, mucinous adenocarcinoma, adenosquamous carcinoma etc.), lung cancer (nonsmall-cell lung cancer for example, small cell lung cancer, malignant mesothelioma etc.), colorectal carcinoma (familial colorectal carcinoma for example, hereditary nonpolyposis colorectal carcinoma, gastrointestinal stromal tumor etc.), colorectal carcinoma (such as gastrointestinal stromal tumor etc.), the rectum cancer (such as gastrointestinal stromal tumor etc.), esophagus cancer, duodenal cancer, tongue cancer, pharynx cancer (nasopharyngeal carcinoma for example, oropharynx cancer, hypopharyngeal cancer (hypopharyngeal cancer) etc.), salivary-gland carcinoma, cerebral tumor (pineal gland astrocytoma for example, pilocytic astrocytoma, diffuse astrocytoma, glioblastoma multiforme etc.), neurocytoma, nonsmall-cell lung cancer, small cell lung cancer, liver cancer (essential liver cancer for example, cholangiocarcinoma etc.), kidney (renal cell carcinoma for example, renal plevis and ureter, transitional cell carcinoma etc.), cholangiocarcinoma, carcinoma of uterine body, carcinoma of endometrium, cervical cancer, ovarian cancer (ovarian epithelium for example, the outer germinocarcinoma of sexual gland, Ovarian Genital Carcinomas, the low malignant tumour of ovary (ovarian lowmalignant potential tumor), bladder cancer, urethral carcinoma, skin carcinoma (eye melanoma for example, Merkel cell carcinoma), vascular tumor, malignant lymphoma, malignant melanoma, thyroid carcinoma (such as medullary thyroid carcinoma etc.), parathyroid carcinoma, CARCINOMA OF THE NASAL CAVITY, nasal sinus cancer, bone tumor (osteosarcoma for example, You Yin (family name) knurl, sarcoma of uterus, soft tissue sarcoma etc.), vascular fibroma, cancer eye (retinoblastoma), penile cancer, child stage solid carcinoma, Kaposi sarcoma, the KapoSi sarcoma being derived by AIDS, jaw knurl, fibrous histiocytoma, leiomyosarcoma, rhabdosarcoma, leukocytosis (acute myeloid leukemia for example, acute lymphoblastic leukemia etc.) etc.), arteriosclerosis, vasculogenesis is (for example, with solid carcinoma and the sarcoma relevant vasculogenesis of growing, the vasculogenesis relevant with metastases and with diabetic retinopathy relevant vasculogenesis etc.) and virus disease (HIV infect etc.).

Tyrosylprotein kinase-dependence disease also comprises the cardiovascular disorder relevant with abnormal tyrosine kinase activity.Therefore compound of the present invention also can be used as cardiovascular disorder as the prevention of restenosis or therapeutical agent.

Compound of the present invention can be used as prevention or treatment cancer, particularly for example mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas, the carcinostatic agent of kidney etc.

Compound of the present invention demonstrates hypotoxicity, and can in Mammals (such as people, horse, ox, dog, cat, rat, mouse, rabbit, pig, monkey etc.), with itself, be used as pharmaceutical composition, or be used as pharmaceutical composition with the mixture with known pharmaceutically acceptable carrier.

Except compound of the present invention, described pharmaceutical composition can contain other activeconstituentss, such as following hormonotherapy agent, carcinostatic agent (as the medicine of chemotherapeutics, immunotherapeutic agent or the cell growth inhibiting factor or growth factor acceptor effect) etc.

As for Mammals as people's medicine, compound of the present invention is tablet for example, capsule (comprising soft capsule and micro-capsule), powder, the oral administration of the forms such as particle, or with injection, suppository, the forms such as pill through administered parenterally.The example of " administered parenterally approach " comprises intravenously, and intramuscular is subcutaneous, in tissue, in nose, intradermal, instils, in brain, and internal rectum, intravaginal, intraperitoneal, in knurl, near the administration (juxtaposition of tumor) of knurl etc., and the direct administration to injury region.

The dosage of compound of the present invention is with route of administration, symptom etc. and changing.For example, when suffer from the patient (during body weight 40-80kg) of mammary cancer or prostate cancer by being administered orally in using it as anticarcinogen, its dosage is, for example 0.5-100mg/kg body weight/day, be preferably 1-50mg/kg body weight/day, more preferably 1 or 25mg/kg body weight/day.This dosage can be administered once every day, or is divided into 2 or 3 parts of administrations every day.

Compound of the present invention can itself or (method described in Japanese Pharmacopoeia etc.) obtain according to conventional methods the pharmaceutical composition that contains pharmaceutically acceptable carrier, as forms such as tablet (comprising that sugar coated tablet, film cover tablet), powder, particle, capsule, solution, emulsion, suspension, injection liquid, suppository, sustained release dosage, paste, per os or for example, through administered parenterally (, part, rectum, intravenous administration etc.) safely.

And, (1) the compounds of this invention of effective dosage and (2) combination is selected from other carcinostatic agent of following 1-3 kind (i) effective dosage, (ii) the hormonotherapy agent of effective dosage and (iii) non-drug therapy can more effectively prevent and/or treat cancer.As non-drug therapy, such as specifiable be surgical operation, radiotherapy, gene therapy, thermotherapy, psychrotherapy, laser burn etc., and two or more being combined with in these.

For example, to identical treatment target, compound of the present invention can with hormonotherapy agent, carcinostatic agent (for example, the medicine of the effect of chemotherapeutic, immunotherapeutic agent or the cell growth inhibiting factor or growth factor acceptor) (these are called as and use medicine hereinafter) combination medicine-feeding.

Although compound of the present invention has excellent antitumous effect when drug use with independent, by above-mentioned with one or more and be used in combination (multi-medicament is used jointly) with medicine, its effect can be enhanced.

As the example of described " hormonotherapy agent ", can mention fostestrol, stilboestrol (diethylstylbestrol), Chlortrianisoestrol, Veramix, acetic acid megestrol, acetic acid Verton, CPA, reach that and tell, dienogest, asoprisnil, Allyloestrenol, gestrinone, Nomegestrol, Tadenan, Mepartricin, raloxifene, ormeloxifene, Levormeloxifene, estrogen antagonist (for example, TAMOXIFEN CITRATE, FC-1157a etc.), ER down regulator (such as fulvestrant etc.), follotropin, follicle stimulating hormone, pill (pill preparations), mepitiostane, testrolactone, aminoglutethimide, exciting (for example, the acetic acid goserelin of LH-RH, buserelin, Leuprolide etc.), droloxifene, Epitiostanol, sulfonic acid ethinylestradiol, aromatase inhibitor (for example, CGS-16949A, Anastrozole, retrozole, Exemestane, vorozole, formestane etc.), androgen antagonist (for example, flutamide, bicartamide, Nilutamide etc.), 5α-reductase inhibitor (for example, finasteride, dutasteride, epristeride etc.), adrenocortical steroid medicine (for example, dexamethasone, prednisolone, Betamethasone Valerate, triamcinolone etc.), male sex hormone synthetic inhibitor (for example, Abiraterone etc.), retinoid and delay the medicine (for example, liarozole etc.) etc. of retinoid metabolism, and preferred LH-RH agonist (for example, goserelin acetic ester, buserelin, Leuprolide).

Described " chemotherapeutic " example, the anticarcinogen for alkylating agent, metabolic antagonist, antitumor antibiotic, plant origin that can mention etc.

Example as " alkylating agent ", what can mention is mustargen, mustine hydrochlcride-N-oxide compound, Chlorambucil (chlorambutyl), endoxan, ifosfamide, phosphinothioylidynetrisaziridine, carboquone, toluenesulphonic acids improsulfan, busulfan, Nimustine, mitobronitol, melphalan, Dacarbazine, ranomustine, estramustine phosphate sodium, Tretamine (triethylenemelamine), carmustine, lomustine, streptozocin, pipobroman, Etoglucid, carboplatin, cis-platinum, Miboplatin, S 254, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribostamycin, Temozolomide, treosulphan, Z-4828, zinostatin (zinostatin stimalamer), U 73975, cystemustine, U 77779 etc.

Example as " metabolic antagonist ", what can mention is mercaptopurine, riboside (6-mercaptopurineriboside), thioinosine, methotrexate, enocitabine, cytosine arabinoside, Cytarbine Ocfostate (cytarabineocfosfate), Ancitabine, 5-FU medicine (for example, Fluracil, Tegafur, UFT, doxifluridine, block not chlorine, gallocitabine, emmitefur etc.), aminopterin sodium, Calciumlevofolinate, tabloid, butocin, Calciumlevofolinate, calcium levofolinate, CldAdo, emitefur, fludarabine, gemcitabine, hydroxyurea, pentostatin, piritrexim, iodoxuridine, mitoguazone, thiazophrine, ambamustine etc.

As the example of " antitumor antibiotic ", can mention for actinomycin D, Actinomycin-C, Mitomycin-C, Toyomycin-A3, Bleocin Hydrochloride, bleomycin sulfate, Peplomycin Sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, THP-adriamycin HCl, epirubicin hydrochloride, neocarzinostatin, Plicamycin, sarkomycin, cardinophyllin, hold in the palm smooth, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride etc.

As the example of " carcinostatic agent of plant origin ", in the time of can mentioning, be Etoposide, etoposide phosphate, Vinblastine sulphate, vincristine sulphate, vindesine sulfate, teniposide, taxol (Taxol (trade mark)), Docetaxel, vinorelbine etc.

As the example of described " immunotherapeutic agent (BRM) ", what can mention is molten chain bacterium, krestin, sizofiran, lentinan, ubenimex, interferons, interleukin-, macrophage colony stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, CBP, LEVAMISOLE HCL, polysaccharide K, procodazole etc.

" somatomedin " in described " medicine of the cell growth inhibiting factor or growth factor acceptor effect " can be mentioned any material that promotes cell proliferation, generally that molecular weight is no more than 20, 000 at lower concentration by showing with receptors bind the peptide that it is active, the material that comprises (1) EGF (Urogastron) or have an activity basic identical with it [for example, EGF, heregulin etc.], (2) Regular Insulin or the material with activity basic identical with it are [for example, Regular Insulin, IGF (rhIGF-1)-1, IGF-2 etc.], (3) FGF (fibroblast growth factor) or the material with activity basic identical with it are [for example, aFGF, basic FGF, KGF (keratinocyte growth factor), FGF-10 etc.], (4) other cell growth factors [for example, CSF (G CFS), EPO (erythropoietin), IL-2 (interleukin II), NGF (nerve growth factor), PDGF (platelet-derived somatomedin), TGF β (transforming growth factor-beta), HGF (pHGF), VEGF (vascular endothelial growth factor) etc.], Deng.

As the example of described " growth factor receptors ", any acceptor that can be combined with above-mentioned somatomedin be can mention, EGF acceptor, heregulin acceptor (HER2), insulin receptor, IGF acceptor, FGF acceptor-1 or FGF acceptor-2 etc. comprised.

As the example of described " medicine of cell growth inhibiting factor effect ", can mention antibody (for example, rhuMAb-VEGF (Avastin trade mark), VEGFR antibody, VEGFR inhibitor, the EGFR inhibitor (Gefitinib (Iressa trade mark), Tarceva (erlotinib) (Tarceva trade mark) etc.) etc. of the antibody (Cetuximab (Erbitux trade mark) etc.) of HER2 antibody (trastuzumab (Herceptin trade mark)), imatinib mesilate, ZD1839 or EGFR, anti-VEGF.

Except said medicine, can use L-ASP, aceglatone, procarbazine hydrochloride, former porphin beautiful jade-cobalt complex salt, mercury haematoporphyrin sodium, topoisomerase I inhibitor (for example, irinotecan, Hycamtin etc.), Topoisomerase II inhibitors (for example, sobuzoxane etc.), differentiation inductor (for example, retinoids, vitamins D etc.), angiogenesis inhibitor (for example, Thalidomide, SU11248 etc.), alpha block agent (for example, tamsulosin hydrochloride, naftopidil, urapidil, alfuzosin, terazosin, Prazosin, silodosin etc.), serine/threonine kinase inhibitor, endothelin-receptor antagonists (such as atrasentan etc.), proteasome inhibitor (such as bortezomib etc.), HSp90 inhibitor (such as 17-AAG etc.), spironolactone, minoxidil, 11 α-hydroxyprogesterone, bone resorption inhibition/transfer inhibitor (such as Zoledronic acid, clinic effect of alendronate, pamidronic acid, etidronic acid, Ibandronic acid, clodronic acid) etc.

Above-mentioned, in those, LH-RH agonist (for example; Goserelin acetate, buserelin, Leuprolide etc.), HER2 antibody (trastuzumab (Herceptin trade mark)), EGFR antibody (Cetuximab (Erbitux trade mark)), EGFR inhibitor (Tarceva (Tarceva trade mark), Gefitinib (gefitinib) (Iressa trade mark) etc.), VEGFR inhibitor or chemotherapeutic (taxol (Taxol (trade mark) etc.) preferably as and use medicine.

Especially, preferred trastuzumab (Herceptin trade mark), Cetuximab (Erbitux trade mark), Tarceva (Tarceva trade mark), Gefitinib (Iressa trade mark), taxol (Taxol (trade mark)) etc.

For compound of the present invention with and with for being used in combination of medicine, compound of the present invention with and with the administration time of medicine, do not limit.Compound of the present invention and and with medicine, can deliver medicine to administration object simultaneously, also can be at different time administrations.And can be according to the dose determination of clinical use with the dosage of medicine, and can suitably choose according to administration object, route of administration, disease, combination etc.

To compound of the present invention and and with the administering mode of medicine, there is no concrete restriction, as long as compound of the present invention and and use the medicine can combination medicine-feeding.The example of this administering mode comprises following method:

(1) compound of the present invention and and with medicine, prepare simultaneously, to obtain the single preparation of administration.(2) compound of the present invention and and with medicine, prepare separately, to obtain two kinds of preparations with the administration simultaneously of identical route of administration.(3) compound of the present invention and and with medicine, prepare separately, to obtain two kinds of preparations of administration when just different with identical route of administration.(4) compound of the present invention and and with medicine, prepare separately, to obtain two kinds of preparations with the administration simultaneously of different route of administration.(5) compound of the present invention and and with medicine, prepare separately, with obtain administration when different with different route of administration two kinds of preparations (for example, compound of the present invention and and with medicine administration in this order, or by contrary pre-order administration) etc.

Embodiment

By the following example, FORMULATION EXAMPLE and experimental example, specifically describe the present invention, but these are not construed as limiting to the present invention.

Embodiment A-1

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

Under ice-cooled; to the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (487mg), 2-methyl-2-(methylsulfonyl) propionic acid (249mg) and I-hydroxybenzotriazole (225mg) be at N; in the solution of dinethylformamide (5.0mL), add triethylamine (0.69mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (316mg), and at room temperature stir this mixture 15 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 90:10), then use ethyl acetate/diisopropyl ether recrystallization, obtain being the title compound (419mg) of clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.70(6H，s)，2.93(3H，s)，3.60-3.80(2H，m)，4.40-4.60(2H，m)，6.46(1H，d，J＝2.8Hz)，6.85-7.00(2H，m)，7.00-7.15(2H，m)，7.15-7.30(2H，m)，7.30-7.40(1H，m)，7.85-7.95(1H，m)，8.00-8.05(1H，m)，8.36(1H，brs)，8.54(1H，s).

Embodiment A-2

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) propionic acid amide

Under ice-cooled, to the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), 2-chloropropionic acid (67mg) and I-hydroxybenzotriazole (90mg) be at N, in the solution of dinethylformamide (4.0mL), add triethylamine (0.29mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (126mg), and at room temperature stir this mixture 17 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is dissolved in DMF (2mL), adds methyl-sulfinic acid sodium (420mg) and pyridine (0.40mL), at 70 ℃, stir this mixture 2 days.Be cooled to after room temperature, water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), then use ethyl acetate/diisopropyl ether recrystallization, obtain being the title compound (97mg) of clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.71(3H，d，J＝7.2Hz)，2.98(3H，s)，3.65-3.75(2H，m)，3.81(1H，q，J＝7.2Hz)，4.45-4.55(2H，m)，6.61(1H，d，J＝3.3Hz)，6.85-6.90(1H，m)，6.90-6.95(1H，m)，7.00-7.10(2H，m)，7.20-7.30(1H，m)，7.30-7.40(1H，m)，7.75-7.85(1H，m)，7.97(1H，d，J＝2.4Hz)，8.28(1H，s)，8.51(1H，s).

Embodiment A-3

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(sec.-propyl alkylsulfonyl) ethanamide

(i) N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(isopropyl sulfenyl) ethanamide

Under ice-cooled, to the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (300mg), Mono Chloro Acetic Acid (87mg) and I-hydroxybenzotriazole (135mg) be at N, in the solution of dinethylformamide (5.0mL), add triethylamine (0.43mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (189mg), and at room temperature stir this mixture 18 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is dissolved in to DMF (2mL)/tetrahydrofuran (THF) (4mL), adds propane-2-sodium mercaptides (sodim propane-2-thiolate) (605mg), and at room temperature stir this mixture 6 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by residue with silica gel column chromatography separated and purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), the title compound (201mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:1.24(6H，d，J＝6.9Hz)，2.80-2.90(1H，m)，3.33(2H，s)，3.60-3.70(2H，m)，4.45-4.55(2H，m)，6.62(1H，d，J＝3.3Hz)，6.85-6.90(1H，m)，6.95-7.00(1H，m)，7.00-7.05(1H，m)，7.07(1H，d，J＝8.7Hz)，7.20-7.30(2H，m)，7.40-7.50(1H，m)，7.73(1H，dd，J＝2.4，8.7Hz)，8.05(1H，d，J＝2.4Hz)，8.51(1H，s).

(ii) N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(sec.-propyl alkylsulfonyl) ethanamide

To N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] add OXONE in methyl alcohol (6mL)/water (1.5mL) solution of-2-(isopropyl sulfenyl) ethanamide single persulphate (monopersulfate) compound (339mg), and at room temperature stir this mixture 21 hours.Water is added in this compound of reaction and use dichloromethane extraction.Anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.Methylene chloride/methanol for residue/diisopropyl ether recrystallization, obtains being the title compound (173mg) of light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:1.23(6H，d，J＝6.9Hz)，3.40-3.65(3H，m)，4.03(2H，s)，4.50-4.70(2H，m)，6.58(1H，s)，6.90-6.95(1H，m)，6.99(1H，s)，7.15-7.25(1H，m)，7.30(1H，d，J＝8.7Hz)，7.40-7.50(1H，m)，7.65-7.75(1H，m)，7.79(1H，s)，7.92(1H，s)，8.53(1H，s)，8.70-8.80(1H，m)，9.28(1H，br?s).

Embodiment A-4

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(ethylsulfonyl) ethanamide

(i) N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(ethylmercapto group) ethanamide

According to method same in embodiment A-1, use the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), ethylenebis dithiocarbamate acetic acid (99mg), I-hydroxybenzotriazole (123mg), triethylamine (0.57mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (173mg) and N, dinethylformamide (4.0mL), the title compound (186mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:1.24(3H，t，J＝7.5Hz)，2.52(2H，q，J＝7.5Hz)，3.32(2H，s)，3.60-3.70(2H，m)，4.45-4.55(2H，m)，6.62(1H，d，J＝3.0Hz)，6.88(1H，d，J＝8.1Hz)，6.95-7.00(1H，m)，7.00-7.10(2H，m)，7.15-7.25(1H，m)，7.40-7.50(1H，m)，7.70-7.80(1H，m)，8.05-8.10(1H，m)，8.50(1H，s)，8.51(1H，s).

(ii) N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(ethylsulfonyl) ethanamide

According to same method in embodiment A-3 (ii), use N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(ethylmercapto group) ethanamide (180mg), OXONE

single persulfate compound (322mg) and methyl alcohol (6mL)/water (1.2mL), obtain being the title compound (149mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:1.21(3H，t，J＝7.2Hz)，3.22(2H，q，J＝7.2Hz)，3.45-3.55(2H，m)，4.03(2H，s)，4.55-4.65(2H，m)，6.55-6.60(1H，m)，6.90-6.95(1H，m)，6.99(1H，s)，7.15-7.20(1H，m)，7.29(1H，d，J＝8.7Hz)，7.41(1H，t，J＝8.2Hz)，7.65-7.75(1H，m)，7.75-7.80(1H，m)，7.93(1H，s)，8.52(1H，s)，8.72(1H，br?s)，9.22(1H，br?s).

Embodiment A-5

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-N-methyl-2-(methylsulfonyl) ethanamide

(i) [2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of the methyl carbamic acid tert-butyl ester

At 80 ℃, the mixture of [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] methyl carbamic acid tert-butyl ester (2.56g), the chloro-4-of 3-(3-chlorophenoxy) aniline (2.51g) and Virahol (25mL) is stirred 18 hours.Be cooled to after room temperature, this mixture is stirred 5 hours.Filter collecting precipitation, and with diisopropyl ether washing, the title compound (3.72g) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:1.52(9H，s)，3.01(3H，s)，3.50-3.60(2H，m)，4.40-4.50(2H，m)，6.60(1H，d，J＝3.0Hz)，6.85-6.95(1H，m)，6.95-7.00(1H，m)，7.00-7.05(1H，m)，7.07(1H，d，J＝9.0Hz)，7.15-7.25(2H，m)，7.90(1H，d，J＝9.0Hz)，8.01(1H，br?s)，8.52(1H，s)，8.83(1H，s).

(ii) the chloro-4-of N-[3-(3-chlorophenoxy) phenyl]-5-[2-(methylamino) ethyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 65 ℃, will [2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] the mixture stirring 24 hours of the methyl carbamic acid tert-butyl ester (3.72g) and 10% (W/W) hydrochloric acid/methyl alcohol (30mL).This reaction mixture of concentrating under reduced pressure, and filter collecting precipitation, with ether washing, obtain being the title compound (2.70g) of light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:2.50-2.60(3H，m)，3.30-3.50(2H，m)，5.00-5.20(2H，m)，6.75(1H，d，J＝3.0Hz)，6.90-7.00(1H，m)，7.02(1H，s)，7.21(1H，d，J＝7.8Hz)，7.32(1H，d，J＝8.7Hz)，7.44(1H，t，J＝8.1Hz)，7.66(1H，d，J＝8.7Hz)，7.93(1H，s)，8.07(1H，d，J＝3.0Hz)，8.73(1H，s)，9.10-9.30(2H，m)，10.17(1H，br?s).

(iii) N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-N-methyl-2-(methylsulfonyl) ethanamide

According to method same in embodiment A-1; use the chloro-4-of N-[3-(3-chlorophenoxy) phenyl]-5-[2-(methylamino) ethyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (200mg), methylsulfonyl acetic acid (83mg), I-hydroxybenzotriazole (87mg), triethylamine (0.28mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (123mg) and N; dinethylformamide (5.0mL), obtains being the title compound (164mg) of clear crystal.

¹H-NMR(CDCl ₃)δ:3.17(3H，s)，3.33(3H，s)，3.70-3.85(2H，m)，4.17(2H，s)，4.45-4.55(2H，m)，6.63(1H，d，J＝3.0Hz)，6.85-6.95(2H，m)，7.00-7.10(2H，m)，7.20-7.30(2H，m)，7.82(1H，dd，J＝2.7Hz，9.0Hz)，7.92(1H，d，J＝2.7Hz)，8.44(1H，s)，8.52(1H，s).

Embodiment A-6

2-(tertiary butyl alkylsulfonyl)-N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of ethanamide

(i) 2-(tertiary butylthio)-N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of ethanamide

Under ice-cooled, to the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), Mono Chloro Acetic Acid (58mg) and I-hydroxybenzotriazole (90mg) be at N, in the solution of dinethylformamide (4.0mL), add triethylamine (0.29mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (126mg), and at room temperature stir this mixture 4 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is dissolved in to DMF (2mL)/tetrahydrofuran (THF) (4mL), adds 2-methylpropane-2-sodium mercaptides (511mg).And at room temperature stir this mixture 2 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by residue with silica gel column chromatography separated and purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), the title compound (159mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:1.30(9H，s)，3.33(2H，s)，3.60-3.70(2H，m)，4.40-4.50(2H，m)，6.61(1H，d，J＝3.3Hz)，6.85-6.90(1H，m)，6.95-7.00(1H，m)，7.00-7.05(1H，m)，7.07(1H，d，J＝9.0Hz)，7.15-7.25(2H，m)，7.45-7.55(1H，m)，7.73(1H，dd，J＝3.0Hz，9.0Hz)，8.06(1H，d，J＝2.7Hz)，8.51(1H，s)，8.56(1H，s).

(ii) 2-(tertiary butyl alkylsulfonyl)-N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of ethanamide

According to same method in embodiment A-3 (ii), use 2-(tertiary butylthio)-N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] ethanamide (159mg), OXONE

single persulfate compound (269mg) and methyl alcohol (5mL)/water (1.5mL), obtain being the title compound (99mg) of light yellow crystal.

¹H-NMR(95％CDCl ₃+5％DMSO-d ₆)δ:1.43(9H，s)，3.50-3.70(2H，m)，4.00(2H，s)，4.60-4.70(2H，m)，6.60(1H，d，J＝3.0Hz)，6.85-6.95(2H，m)，7.05-7.15(2H，m)，7.31(1H，t，J＝8.1Hz)，7.60-7.70(2H，m)，7.92(1H，s)，8.49(1H，s)，8.80-8.90(1H，m)，9.30-9.50(1H，m).

Embodiment A-7

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-N, the preparation of 2-dimethyl-2-(methylsulfonyl) propionic acid amide

Under ice-cooled; to the chloro-4-of N-[3-(3-chlorophenoxy) phenyl]-5-[2-(methylamino) ethyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (200mg) and 2-methyl-2-(methylsulfonyl) propionic acid (100mg) add triethylamine (0.28mL) and diethyl phosphorocyanidate (diethyl cyanophosphonate) (0.097mL) and at room temperature stir this mixture 25 hours in the solution of DMF (5.0mL).Sodium bicarbonate aqueous solution is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 90:10), then use ethyl acetate/diisopropyl ether recrystallization, obtain being the title compound (94mg) of light yellow crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.85(6H，s)，2.97(3H，s)，3.47(3H，s)，3.70-3.80(2H，m)，4.40-4.50(2H，m)，6.63(1H，d，J＝3.6Hz)，6.85-6.95(2H，m)，7.00-7.05(1H，m)，7.06(1H，d，J＝8.7Hz)，7.20-7.30(2H，m)，7.90-8.00(1H，m)，8.01(1H，d，J＝2.4Hz)，8.52(1H，s)，8.69(1H，br?s).

Embodiment A-8

N-[2-(the chloro-4-of 4-{[3-(3-methylphenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

(i) the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-methylphenoxy) phenyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

In the mixture of 80 ℃ of stirrings [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (594mg), the chloro-4-of 3-(3-methylphenoxy) aniline (467mg) and Virahol (10mL) 6 hours.In reaction mixture, add sodium bicarbonate aqueous solution, and be extracted with ethyl acetate this mixture.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained is purification by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0) for residue.By target fraction concentrating under reduced pressure.In methyl alcohol (10mL) solution of residue, add concentrated hydrochloric acid (3mL), and at room temperature mixture is stirred and spent the night, then stir 3 hours at 60 ℃.This reaction mixture of concentrating under reduced pressure.In residue, add Virahol and toluene, and this mixture of concentrating under reduced pressure.Methyl alcohol is added in residue, and this mixture of concentrating under reduced pressure.In residue, add Virahol and diisopropyl ether, filter the solid of collecting precipitation, obtain being the title compound (805mg) of pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:2.31(3H，s)，3.23-3.37(2H，m)，5.04(2H，t，J＝6.2Hz)，6.72-6.80(2H，m)，6.83(1H，m)，6.98(1H，d，J＝7.5Hz)，7.18(1H，d，J＝8.9Hz)，7.29(1H，t，J＝7.8Hz)，7.59(1H，dd，J＝8.8，2.5Hz)，7.87(1H，d，J＝2.5Hz)，8.07(1H，d，J＝3.2Hz)，8.35(3H，br?s)，8.73(1H，s)，10.15(1H，br?s).

(ii) N-[2-(the chloro-4-of 4-{[3-(3-methylphenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

By the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-methylphenoxy) phenyl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (140mg), 2-methyl-2-(methylsulfonyl) propionic acid (75mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is processed (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80) through alkaline silica gel column chromatography.By target fraction concentrating under reduced pressure.Residue is through the crystallization of ethyl acetate-diisopropyl ether, the title compound (155mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:1.69(6H，s)，2.33(3H，s)，2.93(3H，s)，3.61-3.74(2H，m)，4.41-4.51(2H，m)，6.61(1H，d，J＝3.3Hz)，6.75-6.84(2H，m)，6.89(1H，d，J＝7.7Hz)，7.02(1H，d，J＝8.8Hz)，7.16-7.24(2H，m)，7.34(1H，t，J＝5.8Hz)，7.80(1H，dd，J＝8.8Hz，2.5Hz)，7.97(1H，d，J＝2.5Hz)，8.31(1H，brs)，8.51(1H，s).

Embodiment A-9

N-[2-(the chloro-4-of 4-{[3-(3-methylphenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

By the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-methylphenoxy) phenyl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (140mg), methylsulfonyl acetic acid (62mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is processed (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85) through alkaline silica gel column chromatography.By target fraction concentrating under reduced pressure.Residue is through the crystallization of ethyl acetate-diisopropyl ether, the title compound (147mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:2.33(3H，s)，3.13(3H，s)，3.63-3.76(2H，m)，3.70(2H，s)，4.41-4.53(2H，m)，6.58(1H，d，J＝3.3Hz)，6.75-6.84(2H，m)，6.90(1H，d，J＝7.4Hz)，7.01(1H，d，J＝8.7Hz)，7.16-7.24(2H，m)，7.55-7.64(1H，m)，7.69(1H，dd，J＝8.7，2.7Hz)，7.89(1H，d，J＝2.7Hz)，8.14(1H，br?s)，8.48(1H，s).

Embodiment A-10

N-[2-(the chloro-4-of 4-{[3-(3-fluorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

(i) the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-fluorophenoxy) phenyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 80 ℃, the mixture of [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (594mg), the chloro-4-of 3-(3-fluorophenoxy) aniline (475mg) and Virahol (10mL) is stirred 6 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Ethyl acetate layer washs with saturated brine, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.Methyl alcohol (10mL), tetrahydrofuran (THF) (1mL) and concentrated hydrochloric acid (3mL) are added in residue, and at room temperature stir this mixture overnight, then at 60 ℃, stir 3 hours.This reaction mixture of concentrating under reduced pressure.Virahol and toluene are added in residue, and this mixture of concentrating under reduced pressure.Methyl alcohol is added in residue, and this mixture of concentrating under reduced pressure.Virahol and diisopropyl ether are added in residue, filter the solid of collecting precipitation, obtain being the title compound (809mg) of pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:3.22-3.39(2H，m)，5.09(2H，t，J＝6.3Hz)，6.73-6.82(2H，m)，6.83-6.92(1H，m)，6.96-7.05(1H，m)，7.31(1H，d，J＝8.9Hz)，7.39-7.51(1H，m)，7.66(1H，dd，J＝2.4Hz，8.9Hz)，7.93(1H，d，J＝2.4Hz)，8.10(1H，d，J＝3.2Hz)，8.42(3H，br?s)，8.74(1H，s)，10.30(1H，br?s).

(ii) N-[2-(the chloro-4-of 4-{[3-(3-fluorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

By the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-fluorophenoxy) phenyl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (141mg), 2-methyl-2-(methylsulfonyl) propionic acid (75mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue is through the crystallization of ethyl acetate-diisopropyl ether, the title compound (161mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:1.70(6H，s)，2.93(3H，s)，3.63-3.74(2H，m)，4.42-4.53(2H，m)，6.63(1H，d，J＝3.3Hz)，6.64-6.71(1H，m)，6.74-6.82(2H，m)，7.09(1H，d，J＝8.9Hz)，7.19-7.32(2H，m)，7.37(1H，t，J＝5.8Hz)，7.88(1H，dd，J＝2.7Hz，8.9Hz)，8.02(1H，d，J＝2.7Hz)，8.36(1H，br?s)，8.53(1H，s).

Embodiment A-11

N-[2-(the fluoro-4-of 4-{[3-(3-fluorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

By the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-fluorophenoxy) phenyl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (141mg), methylsulfonyl acetic acid (62mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Ethyl acetate layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.Residue is through the crystallization of ethyl acetate-diisopropyl ether, the title compound (146mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:3.14(3H，s)，3.64-3.76(2H，m)，3.98(2H，s)，4.43-4.54(2H，m)，6.59(1H，d，J＝3.3Hz)，6.63-6.70(1H，m)，6.73-6.82(2H，m)，7.08(1H，d，J＝8.9Hz)，7.18-7.31(2H，m)，7.57-7.65(1H，m)，7.75(1H，dd，J＝2.5Hz，8.9Hz)，7.93(1H，d，J＝2.5Hz)，8.19(1H，br?s)，8.49(1H，s).

Embodiment A-12

N-[2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

(i) [2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate

At 80 ℃, stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.0g) and 3-methyl-4-[3-chlorophenoxy] aniline (1.18g) is the solution of Virahol (10mL) 12 hours.Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=8:2 → ethyl acetate), obtain being the title compound (1.7g) of clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.47(9H，s)，2.20(3H，s)，3.48(2H，m)，4.45(2H，m)，5.16(1H，m)，6.57(1H，d，J＝3Hz)，6.80-7.00(4H，m)，7.10-7.30(2H，m)，7.68(2H，m)，8.40(1H，br?s)，8.49(1H，s).

(ii) 5-(2-amino-ethyl)-N-[4-(3-chlorophenoxy)-3-aminomethyl phenyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 60 ℃, stir [2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] mixture 20 hours of t-butyl carbamate (1.6g), 2N hydrochloric acid (23mL) and tetrahydrofuran (THF) (46mL).Pressure reducing and steaming solvent, adds ethanol, and again concentrates this mixture.By filtration, collect gained crystal.With isopropyl ether, wash described crystal, obtain being the title compound (1.35g) of pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:2.19(3H，s)，3.30(2H，m)，5.04(2H，m)，6.72(1H，d，J＝3Hz)，6.80-7.00(2H，m)，7.08(1H，d，J＝9Hz)，7.16(1H，dd，J＝2Hz，8Hz)，7.30-7.50(2H，m)，7.54(1H，m)，8.06(1H，m)，8.40(3H，br?s)，8.68(1H，s)，10.00(1H，br?s).

(iii) N-[2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

By 5-(2-amino-ethyl)-N-[4-(3-chlorophenoxy)-3-aminomethyl phenyl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (167mg), 2-methyl-2-(methylsulfonyl) propionic acid (89mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and DMF (6.9mL) at room temperature stirs 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), obtain being the title compound (179mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:1.42(6H，s)，2.14(3H，s)，2.96(3H，s)，3.47(2H，q，J＝6Hz)，4.56(2H，t，J＝6Hz)，6.45(1H，d，J＝3Hz)，6.80-6.90(2H，m)，7.02(1H，d，J＝9Hz)，7.11(1H，dd，J＝1Hz，8Hz)，7.37(1H，t，J＝8Hz)，7.52(1H，d，J＝3Hz)，7.58(2H，m)，8.20(1H，t，J＝6Hz)，8.28(1H，s)，8.49(1H，br?s).

Embodiment A-13

N-[2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

By 5-(2-amino-ethyl)-N-[4-(3-chlorophenoxy)-3-aminomethyl phenyl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (167mg), methylsulfonyl acetic acid (74mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and DMF (6.9mL) at room temperature stirs 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), obtain being the title compound (177mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:2.13(3H，s)，3.09(3H，s)，3.45(2H，q，J＝6Hz)，4.05(2H，s)，4.55(2H，t，J＝6Hz)，6.46(1H，d，J＝3Hz)，6.80-6.95(2H，m)，7.00(1H，d，J＝9Hz)，7.11(1H，m)，7.37(1H，t，J＝8Hz)，7.56(3H，m)，8.28(1H，s)，8.52(1H，br?s)，8.66(1H，m).

Embodiment A-14

N-[2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) propionic acid amide

By 5-(2-amino-ethyl)-N-[4-(3-chlorophenoxy)-3-aminomethyl phenyl]-5H-pyrrolo-[3,2-d] mixture of pyrimidine-4-amine dihydrochloride (192mg), 2-chloropropionic acid (0.057mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (126mg), I-hydroxybenzotriazole (90mg), triethylamine (0.29mL) and DMF (4mL) at room temperature stirs 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=90:10) of silica gel column chromatography for residue, will be containing the chloro-N-[2-of 2-(4-{[4-(3-chlorophenoxy)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] the fraction concentrating under reduced pressure of propionic acid amide.Residue is dissolved in DMF (4mL) and pyridine (0.4mL), adds methyl-sulfinic acid sodium (420mg), and at 70 ℃, stir this mixture 2 days.Be cooled to after room temperature, water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), obtain being the title compound (116mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:1.36(3H，d，J＝7Hz)，2.13(3H，s)，2.95(3H，s)，3.50(2H，m)，3.82(1H，m)，4.53(2H，m)，6.46(1H，d，J＝3Hz)，6.80-6.90(2H，m)，7.01(1H，d，J＝9Hz)，7.10(1H，d，J＝8Hz)，7.37(1H，t，J＝8Hz)，7.57(3H，m)，8.28(1H，s)，8.49(1H，br?s)，8.59(1H，t，J＝6Hz).

Embodiment A-15

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide tosilate

By ethyl acetate (200mL) and ethanol (70mL) add N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] in-2-methyl-2-(methylsulfonyl) propionic acid amide (9.0g); at 65 ℃, heating is dissolved this mixture, and adds tosic acid monohydrate (3.04g).At room temperature, by standing 23 hours of this mixture lucifuge, by filtration, collect gained crystal.For this crystal, a small amount of ethyl acetate and diisopropyl ether are washed, and obtain being the title compound (11.5g) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:1.40(6H，s)，2.28(3H，s)，2.93(3H，s)，3.50-3.60(2H，m)，4.65-4.75(2H，m)，6.65(1H，d，J＝3.0Hz)，6.90-7.00(1H，m)，7.00-7.05(1H，m)，7.10(2H，d，J＝7.8Hz)，7.20-7.25(1H，m)，7.35(1H，d，J＝9.0Hz)，7.40-7.50(3H，m)，7.60-7.70(1H，m)，7.89(1H，d，J＝3.0Hz)，7.91(1H，d，J＝1.8Hz)，8.15-8.25(1H，m)，8.74(1H，s)，9.80(1H，br?s).

C ₃₂h ₃₃cl ₂n ₅o ₇s ₂ultimate analysis

Calculated value: C, 52.32; H, 4.53; N, 9.53.

Measured value: C, 52.35; H, 4.54; N, 9.49.

mp?217-218℃.

Embodiment A-16

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide tosilate monohydrate

By acetone (20mL) add N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] in-2-methyl-2-(methylsulfonyl) propionic acid amide (500mg); at 40 ℃, heating is dissolved this mixture, and adds tosic acid monohydrate (168mg).At room temperature by standing 4 days of this mixture lucifuge, and concentrating under reduced pressure.In residue, add ethyl acetate (12mL) and ethanol (4mL), and heating is dissolved this mixture at 60 ℃.At room temperature, by standing 17 hours of this mixture lucifuge, by filtration, collect gained crystal.Crystal washs by diisopropyl ether, obtains being the title compound (543mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:1.40(6H，s)，2.29(3H，s)，2.93(3H，s)，3.50-3.60(2H，m)，4.65-4.75(2H，m)，6.65(1H，d，J＝3.0Hz)，6.90-7.00(1H，m)，7.00-7.05(1H，m)，7.10(2H，d，J＝7.8Hz)，7.20-7.25(1H，m)，7.35(1H，d，J＝9.0Hz)，7.40-7.50(3H，m)，7.67(1H，dd，J＝2.4Hz，9.0Hz)，7.88(1H，d，J＝3.0Hz)，7.92(1H，d，J＝2.4Hz)，8.15-8.25(1H，m)，8.73(1H，s)，9.76(1H，br?s).

C ₃₂h ₃₃cl ₂n ₅o ₇s ₂1.0H ₂the ultimate analysis of O

Calculated value: C, 51.06; H, 4.69; N, 9.30.

Measured value: C, 50.49; H, 4.52; N, 9.23.

mp?216-217℃.

Embodiment A-17

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide benzene sulfonate monohydrate

To N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] add ethyl acetate (12mL) and ethanol (4mL) in-2-methyl-2-(methylsulfonyl) propionic acid amide (400mg); and at 60 ℃, heating is dissolved this mixture, adds Phenylsulfonic acid monohydrate (132mg).At room temperature, by standing 17 hours of this mixture lucifuge concentrating under reduced pressure, in residue, add ethyl acetate (10mL).At room temperature, by standing 17 hours of this mixture lucifuge, by filtration, collect gained crystal.Crystal washs by diisopropyl ether, obtains being the title compound (447mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:1.41(6H，s)，2.93(3H，s)，3.50-3.60(2H，m)，4.65-4.75(2H，m)，6.65(1H，d，J＝3.0Hz)，6.95-7.00(1H，m)，7.00-7.05(1H，m)，7.20-7.25(1H，m)，7.25-7.35(3H，m)，7.35(1H，d，J＝8.4Hz)，7.45(1H，t，J＝8.4Hz)，7.55-7.65(2H，m)，7.67(1H，dd，J＝2.4，8.7Hz)，7.88(1H，d，J＝3.0Hz)，7.93(1H，d，J＝2.4Hz)，8.20-8.25(1H，m)，8.73(1H，s)，9.74(1H，br?s).

C ₃₁h ₃₁cl ₂n ₅o ₇s ₂1.0H ₂the ultimate analysis of O

Calculated value: C, 50.41; H, 4.50; N, 9.48.

Measured value: C, 50.53; H, 4.43; N, 9.48.

mp?142-144℃.

Embodiment A-18

N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionamide hydrochloride

By acetone (20mL) add N-[2-(the chloro-4-of 4-{[3-(3-chlorophenoxy) phenyl] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] in-2-methyl-2-(methylsulfonyl) propionic acid amide (400mg), and heating is dissolved this mixture at 40 ℃.Add 4N hydrogenchloride/ethyl acetate solution (0.196mL).At room temperature, by standing 4 days of this mixture lucifuge, by filtration, collect gained crystal.Crystal washs by diisopropyl ether, obtains being the title compound (401mg) of light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:1.40(6H，s)，2.93(3H，s)，3.50-3.65(2H，m)，4.4.70-4.80(2H，m)，6.65(1H，d，J＝3.0Hz)，6.90-7.00(1H，m)，7.00-7.05(1H，m)，7.20-7.25(1H，m)，7.35(1H，d，J＝8.7Hz)，7.45(1H，t，J＝8.1Hz)，7.68(1H，dd，J＝2.4Hz，8.7Hz)，7.89(1H，d，J＝3.0Hz)，7.94(1H，d，J＝2.4Hz)，8.20-8.30(1H，m)，8.73(1H，s)，9.89(1H，br?s).

C ₂₅h ₂₆cl ₃n ₅o ₄the ultimate analysis of S

Calculated value: C, 50.13; H, 4.38; N, 11.69.

Measured value: C, 49.70; H, 4.41; N, 11.48.

mp?194-195℃.

Embodiment A-19

The preparation of N-(2-(4-((the chloro-4-of 3-(the fluoro-3-methylphenoxy of 4-) phenyl) amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl)-2-(methylsulfonyl) ethanamide

At 80 ℃, the mixture of stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.00g), the chloro-4-of 3-(the fluoro-3-methylphenoxy of 4-) aniline (1.51g) and Virahol (10mL) 12 hours.Under ice-cooled, sodium bicarbonate aqueous solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: hexane=60:40 → 100:0), obtain crude product (1.52g) of silica gel column chromatography for residue.Gained crude product (150mg) is dissolved in tetrahydrofuran (THF) (22.2mL).Add 4N hydrogenchloride/ethyl acetate solution (11.5mL), and at 70 ℃, stir this mixture 20 hours.Pressure reducing and steaming solvent.Add ethanol, again concentrated this mixture.Add diisopropyl ether, by filtering the powder of collecting precipitation.At room temperature the mixture of gained powder, methylsulfonyl acetic acid (74mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72mg), triethylamine (0.15mL) and DMF (7.0mL) is stirred 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=90:10), use diisopropyl ether crystallization, obtain being the title compound (116mg) of clear crystal.

¹H-NMR(DMSO-d ₆)δ:2.22(3H，s)，3.10(3H，s)，3.46(2H，q，J＝6.0Hz)，4.04(2H，s)，4.55(2H，t，J＝6.0Hz)，6.49-7.17(5H，m)，7.61-7.93(3H，m)，8.33(1H，s)，8.65-8.66(2H，m).

Embodiment B-1

2-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) the chloro-5-nitro-2-[3-of 3-(trifluoromethyl) phenoxy group] preparation of pyridine

Under argon atmospher, ice-cooled lower to add in tetrahydrofuran (THF) (8.0mL) solution of 3-(trifluoromethyl) phenol (0.42g) sodium hydride (60% dispersion in mineral oil, 0.11g).In ice-cooled lower stirring, after 1 hour, add 2,3-, bis-chloro-5-nitropyridines (0.50g).After at room temperature stirring 2.5 hours, water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer washs and uses dried over mgso with saturated brine.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=9:1 → 3:1), obtain being the title compound (746mg) of colorless oil of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:7.35-7.43(1H，m)，7.45-7.51(1H，m)，7.55-7.65(1H，m)，8.61(1H，d，J＝2.7Hz)，8.88(1H，d，J＝2.7Hz).

(ii) the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] preparation of pyridine-3-amine

At 80 ℃, by the chloro-5-nitro-2-[3-of 3-(trifluoromethyl) phenoxy group] mixture of pyridine (746mg), reduced iron (0.65g), calcium chloride (0.13g) and 15% aqueous ethanol (23mL) stirs 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.In residue, add water, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1), obtain being the title compound (290mg) of brown oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.65(2H，br?s)，7.20(1H，d，J＝2.9Hz)，7.22-7.26(1H，m)，7.27-7.32(1H，m)，7.37-7.40(1H，m)，7.44-7.50(1H，m)，7.59(1H，d，J＝2.9Hz).

(iii) 2-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

At 80 ℃, by phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (100mg) and the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] solution stirring of pyridine-3-amine (100mg) in Virahol (2.0mL) 16 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=1:1 → ethyl acetate) of silica gel column chromatography for residue, obtain phenylformic acid 2-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl ester (130mg), be colourless amorphous.At room temperature, to phenylformic acid 2-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl ester (130mg) adds 1N aqueous sodium hydroxide solution (0.5mL), and stirs this mixture 3 hours in the solution of Virahol-tetrahydrofuran (THF) (3mL-2mL).This reaction mixture dilutes by ethyl acetate, and organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=9:1), obtain being the title compound (72mg) of clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.69-3.80(4H，m)，4.00-4.04(2H，m)，4.54-4.59(2H，m)，6.65(1H，d，J＝3.3Hz)，7.23(1H，d，J＝3.3Hz)，7.31-7.36(1H，m)，7.40-7.55(3H，m)，8.24(1H，d，J＝2.7Hz)，8.47(1H，d，J＝2.7Hz)，8.51(1H，s)，8.83(1H，s).

Embodiment B-2

N-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) preparation of { 2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

At 80 ℃, by [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (189mg) and the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] solution stirring of pyridine-3-amine (184mg) in Virahol (4.0mL) 20 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:1 → ethyl acetate), obtain being the title compound (257mg) of faint yellow solid of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.49(9H，s)，3.43-4.54(2H，m)，4.40-4.51(2H，m)，5.05-5.15(1H，m)，6.60(1H，d，J＝3.0Hz)，7.19(1H，d，J＝3.0Hz)，7.33-7.39(1H，m)，7.41-7.53(3H，m)，8.39(1H，d，J＝2.4Hz)，8.47(1H，s)，8.64(1H，d，J＝2.4Hz)，8.79(1H，s).

(ii) the 5-chloro-6-[3-of (2-amino-ethyl)-N-{5-(trifluoromethyl) phenoxy group] pyridin-3-yl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride

At room temperature, to 2-[4-(the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] and pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } add 2N hydrochloric acid (5.0mL) in tetrahydrofuran (THF) (10mL) solution of t-butyl carbamate (257mg), and at 60 ℃, stir this mixture 20 hours.After concentrating under reduced pressure, in residue, add ethanol, again concentrated this mixture.By filtering the solid of collecting precipitation, and wash this solid by diisopropyl ether, obtain being the title compound (220mg) of faint yellow solid.

¹H-NMR(DMSO-d ₆)δ:3.23-3.37(2H，m)，4.95-5.08(2H，m)，6.74(1H，d，J＝2.7Hz)，7.56(1H，d，J＝8.4Hz)，7.64-7.74(3H，m)，8.06(1H，br?s)，8.23-8.45(5H，m)，8.71(1H，s)，10.15(1H，br?s).

(iii) N-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

At room temperature; by the 5-chloro-6-[3-of (2-amino-ethyl)-N-{5-(trifluoromethyl) phenoxy group] pyridin-3-yl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (95mg), methylsulfonyl acetic acid (47mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (98mg), I-hydroxybenzotriazole (78mg) and the mixture of triethylamine (0.12mL) in DMF (5.0mL) stir 14 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), obtain being the title compound (86mg) of clear crystal.

¹H-NMR(CDCl ₃)δ:3.10(3H，s)，3.62-3.78(2H，m)，3.98(2H，s)，4.41-4.53(2H，m)，6.63(1H，d，J＝3.0Hz)，7.21(1H，d，J＝3.0Hz)，7.29-7.55(5H，m)，8.41-8.50(4H，m).

Embodiment B-3

N-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethyl) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butyramide

According to same method in Embodiment B-2 (iii), use the 5-chloro-6-[3-of (2-amino-ethyl)-N-{5-(trifluoromethyl) phenoxy group] pyridin-3-yl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride (95mg), HMB (46mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (98mg), I-hydroxybenzotriazole (78mg), triethylamine (0.12mL) and N, dinethylformamide (5.0mL), makes the title compound (73mg) that is clear crystal.

¹H-NMR(CDCl ₃)δ:1.33(6H，s)，2.36-2.43(1H，m)，2.48(2H，s)，3.55-3.66(2H，m)，4.41-4.50(2H，m)，6.60(1H，d，J＝3.0Hz)，7.18-7.22(2H，m)，7.34-7.39(1H，m)，7.42-7.53(3H，m)，8.44(1H，d，J＝2.4Hz)，8.47(1H，s)，8.54(1H，d，J＝2.4Hz)，8.97(1H，s).

Embodiment B-4

2-[4-({ the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) the chloro-5-nitro-2-[3-of 3-(trifluoromethoxy) phenoxy group] preparation of pyridine

Under argon atmospher, according to same method in Embodiment B-1 (i), use 3-(trifluoromethoxy) phenol (0.93g), 2,3-bis-chloro-5-nitropyridines (1.0g), sodium hydride (60% dispersion in mineral oil, 0.23g) and tetrahydrofuran (THF) (10mL), make the title compound (1.57g) that is faint yellow oily.

¹H-NMR(CDCl ₃)δ:7.06-7.22(3H，m)，7.49(1H，t，J＝8.3Hz)，8.59(1H，d，J＝2.4Hz)，8.88(1H，d，J＝2.4Hz).

(ii) the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] preparation of pyridine-3-amine

According to same method in Embodiment B-1 (ii), use the chloro-5-nitro-2-[3-of 3-(trifluoromethoxy) phenoxy group] pyridine (1.57g), reduced iron (1.31g), calcium chloride (0.26g) and 15% aqueous ethanol (50mL), make the title compound (1.23g) that is orange oily.

¹H-NMR(CDCl ₃)δ:3.65(2H，br?s)，6.91-7.02(3H，m)，7.18(1H，d，J＝2.7Hz)，7.35(1H，t，J＝8.1Hz)，7.59(1H，d，J＝2.7Hz).

(iii) 2-[4-({ the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

At 80 ℃, stir phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (100mg) and the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] solution of pyridine-3-amine (101mg) in Virahol (2.0mL) 2 days.Reaction mixture is cooled to room temperature, adds wherein 1N aqueous sodium hydroxide solution (1.0mL).At room temperature stir this reaction mixture 4 hours, add wherein water, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=9:1), obtain being the title compound (112mg) of clear crystal.

¹H-NMR(CDCl ₃)δ:4.11-4.19(2H，m)，4.39-4.45(2H，m)，4.83-4.99(1H，m)，6.31(1H，d，J＝3.3Hz)，7.02-7.10(4H，m)，7.36-7.42(1H，m)，8.17(1H，d，J＝2.7Hz)，8.31(1H，s)，8.34(1H，d，J＝2.7Hz)，9.44(1H，s).

Embodiment B-5

N-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) preparation of { 2-[4-({ the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to same method in Embodiment B-2 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (300mg), the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridine-3-amine (308mg) and Virahol (3.0mL), make the title compound (372mg) that is clear crystal.

¹H-NMR(CDCl ₃)δ:1.49(9H，s)，3.45-3.53(2H，m)，4.43-4.49(2H，m)，5.10(1H，t，J＝5.4Hz)，6.60(1H，d，J＝3.0Hz)，7.02-7.12(3H，m)，7.18(1H，d，J＝3.0Hz)，7.36-7.42(1H，m)，8.38(1H，d，J＝2.4Hz)，8.47(1H，s)，8.65(1H，d，J＝2.4Hz)，8.77(1H，br?s).

(ii) the 5-chloro-6-[3-of (2-amino-ethyl)-N-{5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride

According to same method in Embodiment B-2 (ii), use 2-[4-(the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] and pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (350mg), 2N hydrochloric acid (5.0mL) and tetrahydrofuran (THF) (10mL), make the title compound (294mg) that is light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:3.20-3.34(2H，m)，4.91-5.03(2H，m)，6.66-6.76(1H，m)，7.20-7.32(3H，m)，7.59(1H，t，J＝8.1Hz)，8.01(1H，br?s)，8.12-8.37(5H，m)，8.68(1H，br?s)，9.94-10.06(1H，m).

(iii) N-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment B-2 (iii); use the 5-chloro-6-[3-of (2-amino-ethyl)-N-{5-(trifluoromethoxy) phenoxy group] pyridin-3-yl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (90mg), methylsulfonyl acetic acid (43mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (90mg), I-hydroxybenzotriazole monohydrate (72mg), triethylamine (0.12mL) and N; dinethylformamide (5.0mL), makes the title compound (59mg) that is light yellow crystal.

¹H-NMR(CDCl ₃)δ:3.10(3H，s)，3.64-3.75(2H，m)，3.98(2H，s)，4.43-4.53(2H，m)，6.62(1H，d，J＝3.0Hz)，7.03-7.13(3H，m)，7.15-7.23(2H，m)，7.41(1H，t，J＝8.4Hz)，8.42(1H，s)，8.44-8.47(2H，m)，8.49(1H，s).

Embodiment B-6

2-{2-[4-({ the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridin-3-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

According to same method in Embodiment B-4 (iii), use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (100mg), the chloro-6-[3-of 5-(trifluoromethoxy) phenoxy group] pyridine-3-amine (80mg), Virahol (2.0mL) and 1N aqueous sodium hydroxide solution (1.0mL), make the title compound (71mg) that is light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.77(1H，br?s)，3.66-3.80(4H，m)，4.01(2H，t，J＝4.5Hz)，4.56(2H，t，J＝4.5Hz)，6.64(1H，d，J＝3.3Hz)，7.01-7.09(3H，m)，7.22(1H，d，J＝3.3Hz)，7.36-7.42(1H，m)，8.25(1H，d，J＝2.7Hz)，8.47(1H，d，J＝2.7Hz)，8.49(1H，s)，8.83(1H，s).

Embodiment B-7

The chloro-5-{[5-of N-(tertiary butyl)-3-[(3-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } pyridine-2-yl) oxygen base] preparation of benzamide

(i) 3-[(3-chloro-5-nitropyridine-2-yl) oxygen base] preparation of methyl benzoate

According to same method in Embodiment B-1 (i), use 3-methyl hydroxybenzoate (0.83g), 2,3-bis-chloro-5-nitropyridines (1.0g), sodium hydride (60% dispersion in mineral oil, 0.24g) and tetrahydrofuran (THF) (10mL), make the title compound (1.61g) that is colorless oil.

¹H-NMR(CDCl ₃)δ:3.93(3H，s)，7.37-7.41(1H，m)，7.52-7.57(1H，m)，7.84-7.86(1H，m)，7.98-8.02(1H，m)，8.58(1H，d，J＝2.7Hz)，8.86(1H，d，J＝2.7Hz).

(ii) 3-[(3-chloro-5-nitropyridine-2-yl) oxygen base] benzoic preparation

At room temperature, to 3-[(3-chloro-5-nitropyridine-2-yl) oxygen base] methyl benzoate (1.61g) adds 1N aqueous sodium hydroxide solution (6.0mL) in the solution of Virahol (20mL) and tetrahydrofuran (THF) (10mL).After at room temperature stirring 24 hours, in this reaction mixture, add 1N hydrochloric acid (6.0mL), and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by filtration, collect gained crystal.Crystal washs by diisopropyl ether, obtains being the title compound (0.62g) of clear crystal.

¹H-NMR(CDCl ₃)δ:7.42-7.48(2H，m)，7.57-7.63(1H，m)，7.90-7.94(1H，m)，8.06-8.08(1H，m)，8.60-8.61(1H，m)，8.88(1H，d，J＝2.4Hz).

(iii) N-(tertiary butyl)-3-[(3-chloro-5-nitropyridine-2-yl) oxygen base] preparation of benzamide

At room temperature, to 3-[(3-chloro-5-nitropyridine-2-yl) oxygen base] phenylformic acid (0.62g) and DMF (0.1mL) add thionyl chloride (0.23mL) in the solution of tetrahydrofuran (THF) (12mL).At room temperature stir after 2 hours this mixture of concentrating under reduced pressure.At 0 ℃, the tetrahydrofuran (THF) of residue (10mL) solution is added drop-wise to TERTIARY BUTYL AMINE (0.3g) and triethylamine (0.89mL) in the solution of tetrahydrofuran (THF) (5.0mL).After at room temperature stirring 20 hours, water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=9:1 → 2:1), obtain being the title compound (0.61g) of faint yellow solid.

¹H-NMR(CDCl ₃)δ:1.47(9H，s)，5.93(1H，br?s)，7.28-7.32(1H，m)，7.52(1H，t，J＝8.0Hz)，7.57(1H，t，J＝2.1Hz)，7.62-7.65(1H，m)，8.59(1H，d，J＝2.4Hz)，8.87(1H，d，J＝2.4Hz).

(iv) 3-[(5-amino-3-chloropyridine-2-yl) oxygen base] preparation of-N-(tertiary butyl) benzamide

According to same method in Embodiment B-1 (ii), use N-(tertiary butyl)-3-[(3-chloro-5-nitropyridine-2-yl) oxygen base] benzamide (570mg), reduced iron (0.46g), calcium chloride (90mg) and 15% aqueous ethanol (17mL), make the title compound (373mg) that is light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，3.63(2H，br?s)，5.91(1H，br?s)，7.15-7.19(2H，m)，7.36-7.47(3H，m)，7.56(1H，d，J＝2.7Hz).

(v) the chloro-5-{[5-of N-(tertiary butyl)-3-[(3-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } pyridine-2-yl) oxygen base] preparation of benzamide

According to same method in Embodiment B-4 (iii), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (80mg), 3-[(5-amino-3-chloropyridine-2-yl) oxygen base]-N-(tertiary butyl) benzamide (85mg), Virahol (2.0mL) and 1N aqueous sodium hydroxide solution (1.0mL), make the title compound (78mg) that is clear crystal.

¹H-NMR(CDCl ₃)δ:1.49(9H，s)，4.11(2H，t，J＝4.5Hz)，4.41(2H，t，J＝4.5Hz)，5.44-5.56(1H，m)，5.98(1H，s)，6.30(1H，d，J＝3.0Hz)，7.06(1H，d，J＝3.0Hz)，7.20-7.28(1H，m)，7.37-7.43(1H，m)，7.46-7.50(2H，m)，8.09(1H，d，J＝2.7Hz)，8.28(1H，s)，8.31(1H，d，J＝2.7Hz)，9.57(1H，s).

Embodiment C-1

2-{2-[4-({ the chloro-4-[3-of 3-(2-methyl-1 H-imidazole-1-group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of-2-methyl isophthalic acid H-imidazoles

N to 3-(2-methyl-1 H-imidazole-1-group) phenol (1.10g) and the chloro-4-fluoronitrobenzene of 3-(1.28g), in dinethylformamide (10mL) solution, add salt of wormwood (1.31g), and at room temperature stir this mixture 18 hours.Under ice-cooled, in this reaction mixture, add salt solution, and be extracted with ethyl acetate twice, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain being the title compound (1.86g) of faint yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:2.40(3H，s)，7.00-7.25(6H，m)，7.54(1H，t，J＝8.2Hz)，8.12(1H，dd，J＝2.7，9.0Hz)，8.41(1H，d，J＝2.4Hz).

(ii) the chloro-4-[3-of 3-(2-methyl-1 H-imidazole-1-group) phenoxy group] preparation of aniline

Under nitrogen atmosphere, to 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] add 5% platinum-gac (0.37g) in ethyl acetate (30mL)/methyl alcohol (2mL) solution of-2-methyl isophthalic acid H-imidazoles (1.86g).Under room temperature, nitrogen atmosphere, this reaction mixture is stirred 3.5 hours, elimination platinum-gac, filtrate decompression is concentrated.Residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate: hexane=60:40 → 100:0), obtain being the title compound (1.26g) of clear crystal.

¹H-NMR(CDCl ₃)δ:2.34(3H，s)，3.73(2H，br?s)，6.58(1H，dd，J＝2.7，8.7Hz)，6.74(1H，t，J＝2.1Hz)，6.79(1H，d，J＝2.4Hz)，6.9-7.05(5H，m)，7.37(1H，t，J＝8.1Hz).

(iii) 2-{2-[4-({ the chloro-4-[3-of 3-(2-methyl-1 H-imidazole-1-group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

At 120 ℃, by phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (207mg), the chloro-4-[3-of 3-(2-methyl-1 H-imidazole-1-group) phenoxy group] mixture of aniline (180mg), 1-Methyl-2-Pyrrolidone (4.0mL) and pyridine hydrochloride (139mg) stirs 17 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5).In gained compound, add 1N aqueous sodium hydroxide solution (2.6mL) and tetrahydrofuran (THF) (5mL), and at room temperature stir this mixture 3 days.With 1N hydrochloric acid, neutralize this reaction mixture, and add sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), by filtration, collect gained solid, and with diisopropyl ether washing, the title compound (158mg) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:2.35(3H，s)，3.70-3.75(2H，m)，3.75-3.85(2H，m)，4.02(2H，t，J＝4.4Hz)，4.57(2H，t，J＝4.4Hz)，6.64(1H，d，J＝3.0Hz)，6.80-6.85(1H，m)，6.95-7.05(4H，m)，7.11(2H，d，J＝9.0Hz)，7.22(1H，d，J＝3.6Hz)，7.40(1H，t，J＝8.4Hz)，7.64(1H，dd，J＝2.4，9.0Hz)，7.90(1H，d，J＝2.4Hz)，8.53(1H，s)，8.82(1H，s).

Embodiment C-2

2-{2-[4-({ the chloro-4-[3-of 3-(1,3-oxazole-5-yl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) 5-[3-(benzyloxy) phenyl]-1, the preparation of 3-oxazole

Under ice-cooled; in 3-(benzyloxy) phenyl aldehyde (2.12g) and tolysulfonyl ylmethyl isocyanide (p-toluenesulfonylmethyl isocyanide) methyl alcohol (40mL) solution (1.95g), add salt of wormwood (1.66g), and at room temperature stir this mixture 20 minutes and reflux 1 hour.After concentrating under reduced pressure, add water, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by residue with silica gel column chromatography separated and purifying (elutriant: ethyl acetate: hexane=20:80 → 50:50), the title compound (2.04g) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:5.12(2H，s)，6.90-7.00(1H，m)，7.25-7.50(9H，m)，7.91(1H，s).

(ii) preparation of 3-(1,3-oxazole-5-yl) phenol

To 5-[3-(benzyloxy) phenyl]-1, in methyl alcohol (10mL)/tetrahydrofuran (THF) (10mL) solution of 3-oxazole (2.01g), add 10% palladium-gac (0.40g), and under room temperature, nitrogen atmosphere, stir this mixture 5 hours.Palladium-activated-carbon filter is removed to concentrating under reduced pressure filtrate.Throw out washs with diisopropyl ether and hexane, obtains the title compound (1.25g) of light gray crystal.

¹H-NMR(95％CDCl ₃+5％DMSO-d ₆)δ:6.80-6.90(1H，m)，7.10-7.20(2H，m)，7.24(1H，t，J＝8.0Hz)，7.31(1H，s)，7.94(1H，s)，9.13(1H，s).

(iii) 5-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-1, the preparation of 3-oxazole

In DMF (10mL) solution of 3-(1,3-oxazole-5-yl) phenol (1.20g) and the chloro-4-fluoronitrobenzene of 3-(1.45g), add salt of wormwood (1.54g), and at room temperature stir this mixture 18 hours.Under ice-cooled, in this reaction mixture, add salt solution, and be extracted with ethyl acetate, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, ethyl acetate/diisopropyl ether for residue/hexane recrystallization, obtains being the title compound (2.00g) of light yellow crystal.

¹H-NMR(CDCl ₃)δ:6.96(1H，t，J＝9.0Hz)，7.00-7.10(1H，m)，7.35-7.45(2H，m)，7.45-7.60(2H，m)，7.93(1H，s)，8.08(1H，dd，J＝3.0Hz，9.0Hz)，8.40(1H，d，J＝3.0Hz).

(iv) the chloro-4-[3-of 3-(1,3-oxazole-5-yl) phenoxy group] preparation of aniline

According to same method in Embodiment C-1 (ii), use 5-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-1,3-oxazole (1.95g), 5% platinum-gac (0.33g) and ethyl acetate (30mL)/methyl alcohol (5mL), obtain being the title compound (1.80g) of light yellow crystal.

¹H-NMR(95％CDCl ₃+5％DMSO-d ₆)δ:6.8-6.9(2H，m)，6.95-7.05(2H，m)，7.15-7.2(2H，m)，7.3-7.4(3H，m)，7.91(1H，s)，8.09(1H，s).

(v) 2-{2-[4-({ the chloro-4-[3-of 3-(1,3-oxazole-5-yl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

At 80 ℃, by phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (346mg), the chloro-4-[3-of 3-(1,3-oxazole-5-yl) phenoxy group] mixture of aniline (344mg) and Virahol (10mL) stirs 18 hours.Under ice-cooled, sodium bicarbonate aqueous solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5) of silica gel column chromatography for residue.1N aqueous sodium hydroxide solution (0.8mL) and tetrahydrofuran (THF) (4.0mL) are added in gained compound, and at room temperature stir this mixture 2 days.With 1N hydrochloric acid, neutralize this reaction mixture, and add sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, extract anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain being the title compound (26mg) of pale yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.70-3.75(2H，m)，3.75-3.85(2H，m)，4.03(2H，t，J＝4.5Hz)，4.58(2H，t，J＝4.5Hz)，6.64(1H，d，J＝3.0Hz)，6.90-6.95(1H，m)，7.08(1H，d，J＝9.0Hz)，7.22(1H，d，J＝3.3Hz)，7.25-7.30(1H，m)，7.30-7.40(3H，m)，7.61(1H，dd，J＝2.4Hz，9.0Hz)，7.89(2H，d，J＝2.1Hz)，8.53(1H，s)，8.78(1H，s).

Embodiment C-3

2-{2-[4-({ the chloro-4-[3-of 3-(1,3-thiazoles-5-yl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) 5-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of-1,3-thiazoles

According to same method in Embodiment C-1 (i), use 3-(1,3-thiazole-5-yl) phenol (343mg), the chloro-4-fluoronitrobenzene of 3-(429mg), salt of wormwood (401mg) and N, dinethylformamide (5.0mL), makes the title compound (624mg) that is colorless oil.

¹H-NMR(CDCl ₃)δ:6.96(1H，t，J＝9.3Hz)，7.00-7.10(1H，m)，7.30-7.35(1H，m)，7.50-7.55(2H，m)，8.07(1H，d，J＝2.7Hz)，8.10-8.15(1H，m)，8.41(1H，d，J＝2.4Hz)，8.79(1H，d，J＝0.6Hz).

(ii) 2-{2-[4-({ the chloro-4-[3-of 3-(1,3-thiazoles-5-yl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

Will be according to method same in Embodiment C-1 (ii), use 5-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-1, the compound that 3-thiazole (624mg), 5% platinum-gac (312mg) and ethyl acetate (10mL) obtain, phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethyl ester (450mg) and Virahol (10mL) stirs 20 hours at 80 ℃.Under ice-cooled, sodium bicarbonate aqueous solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5) of silica gel column chromatography for residue.In gained compound, add 1N aqueous sodium hydroxide solution (2.2mL) and tetrahydrofuran (THF) (5mL), and at room temperature stir this mixture 2 days.With 1N hydrochloric acid, neutralize this reaction mixture, and add sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by (the elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), and further with diisopropyl ether washing, obtain being the title compound (63.5mg) of pale yellow powder of the separated also purifying of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.70-3.85(4H，m)，4.00-4.10(2H，m)，4.50-4.60(2H，m)，6.64(1H，d，J＝3.0Hz)，6.85-6.95(1H，m)，7.08(1H，d，J＝8.7Hz)，7.20-7.40(4H，m)，7.61(1H，dd，J＝2.4，8.7Hz)，7.90(1H，d，J＝2.4Hz)，8.06(1H，s)，8.53(1H，s)，8.75(1H，s)，8.78(1H，s).

Embodiment C-4

2-{2-[4-({ the chloro-4-[3-of 3-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) 2-(3-p-methoxy-phenyl)-4-methyl isophthalic acid, the preparation of 3-oxazole

At 110 ℃, by 3-methoxy benzamide (4.91g) and monochloroacetone (3.61g), the suspension in toluene (30mL) stirs 2 days.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is used sodium bicarbonate aqueous solution and salt water washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=10:90 → 30:70), obtain being the title compound (1.54g) of yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:2.25(3H，s)，3.88(3H，s)，6.95-7.05(1H，m)，7.35(1H，t，J＝8.0Hz)，7.40-7.45(1H，m)，7.50-7.65(2H，m).

(ii) preparation of 3-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenol

By 2-(3-p-methoxy-phenyl)-4-methyl isophthalic acid, the solution (10mL) of 3-oxazole (1.54g) in 48% Hydrogen bromide refluxes 24 hours.Water is added in this reaction mixture and is extracted with ethyl acetate.Sodium bicarbonate aqueous solution and salt water washing for organic layer, and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by residue with silica gel column chromatography separated and purifying (elutriant: ethyl acetate: hexane=10:90 → 40:60), the title compound (1.14g) of the powder that obtains being white in color.

¹H-NMR(CDCl ₃)δ:2.24(3H，s)，6.09(1H，br?s)，6.90-7.00(1H，m)，7.30(1H，t，J＝8.0Hz)，7.40-7.45(1H，m)，7.50-7.60(2H，m).

(iii) 2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-4-methyl isophthalic acid, the preparation of 3-oxazole

According to same method in Embodiment C-1 (i), use 3-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenol (1.09g), the chloro-4-fluoronitrobenzene of 3-(1.21g), salt of wormwood (1.29g) and N, dinethylformamide (10mL), makes the title compound (1.86g) that is faint yellow oily.

¹H-NMR(CDCl ₃)δ:2.38(3H，s)，6.94(1H，t，J＝9.2Hz)，7.10-7.20(1H，m)，7.40-7.45(1H，m)，7.53(1H，t，J＝8.0Hz)，7.70-7.75(1H，m)，7.85-7.95(1H，m)，8.07(1H，dd，J＝2.6，9.2Hz)，8.40(1H，d，J＝2.6Hz).

(iv) the chloro-4-[3-of 3-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenoxy group] preparation of aniline

According to same method in Embodiment C-1 (ii), use 2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-4-methyl isophthalic acid, 3-oxazole (1.86g), 5% platinum-gac (0.31g) and ethyl acetate (20mL), make title compound (0.41g), be colorless oil.

¹H-NMR(CDCl ₃)δ:2.23(3H，s)，3.69(2H，br?s)，6.58(1H，dd，J＝2.7Hz，9.0Hz)，6.80(1H，d，J＝3.0Hz)，6.96(1H，d，J＝6.9Hz)，6.95-7.00(1H，m)，7.36(1H，t，J＝8.0Hz)，7.35-7.40(1H，m)，7.50-7.55(1H，m)，7.70-7.75(1H，m).

(v) 2-{2-[4-({ the chloro-4-[3-of 3-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

Use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (392mg), the chloro-4-[3-of 3-(4-methyl isophthalic acid, 3-oxazole-2-yl) phenoxy group] aniline (410mg) and Virahol (10mL), react according to same method in Embodiment C-2 (v).Then, use 1N aqueous sodium hydroxide solution (4.7mL) and tetrahydrofuran (THF) (10mL), the compound obtaining is reacted according to same method in Embodiment C-2 (v), make title compound (371mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:2.21(3H，s)，3.65-3.85(4H，m)，4.02(2H，t，J＝4.4Hz)，4.57(2H，t，J＝4.4Hz)，6.62(1H，d，J＝3.2Hz)，7.05-7.15(2H，m)，7.20(1H，d，J＝3.0Hz)，7.30-7.45(2H，m)，7.50-7.55(1H，m)，7.62(1H，dd，J＝2.6Hz，8.8Hz)，7.70-7.75(1H，m)，7.90(1H，d，J＝2.6Hz)，8.52(1H，s)，8.79(1H，s).

Embodiment C-5

2-{2-[4-({ 4-[3-(the 4-tertiary butyl-1,3-oxazole-2-yl) phenoxy group]-3-chloro-phenyl-} amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) the 4-tertiary butyl-2-(3-p-methoxy-phenyl)-1, the preparation of 3-oxazole

According to same method in Embodiment C-4 (i), use 3-methoxy benzamide (1.51g), 1-bromine Pinacolone (2.15g) and toluene (10mL), make title compound (2.01g), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:1.32(9H，s)，3.88(3H，s)，6.96(1H，dd，J＝2.6Hz，8.4Hz)，7.30-7.40(2H，m)，7.55-7.65(2H，m).

(ii) preparation of 3-(the 4-tertiary butyl-1,3-oxazole-2-yl) phenol

According to same method in Embodiment C-4 (ii), use the 4-tertiary butyl-2-(3-p-methoxy-phenyl)-1,3-oxazole (2.01g) and 48% Hydrogen bromide (10mL), make title compound (0.62g), is pale yellow powder.

¹H-NMR(CDCl ₃)δ:1.31(9H，s)，5.20-5.50(1H，m)，6.90(1H，dd，J＝1.8Hz，8.0Hz)，7.31(1H，d，J＝7.6Hz)，7.36(1H，s)，7.45-7.55(1H，m)，7.58(1H，d，J＝7.2Hz).

(iii) the 4-tertiary butyl-2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-1, the preparation of 3-oxazole

According to same method in Embodiment C-1 (i), use 3-(the 4-tertiary butyl-1,3-oxazole-2-yl) phenol (1.48g), the chloro-4-fluoronitrobenzene of 3-(1.26g), salt of wormwood (1.41g) and N, dinethylformamide (12mL), obtain title compound (2.13g), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.31(9H，s)，6.92(1H，t，J＝9.3Hz)，7.10-7.20(1H，m)，7.37(1H，s)，7.51(1H，t，J＝8.1Hz)，7.75-7.80(1H，m)，7.94(1H，t，J＝7.8Hz)，8.06(1H，dd，J＝2.7Hz，9.3Hz)，8.40(1H，d，J＝2.7Hz).

(iv) 4-[3-(the 4-tertiary butyl-1,3-oxazole-2-yl) phenoxy group] preparation of-3-chloroaniline

According to same method in Embodiment C-1 (ii), use the 4-tertiary butyl-2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-1,3-oxazole (1.12g), 5% platinum-gac (0.19g) and ethyl acetate (20mL)/methyl alcohol (4mL), make title compound (985mg), be colorless oil.

¹H-NMR(CDCl ₃)δ:1.30(9H，s)，3.68(2H，br?s)，6.58(1H，dd，J＝2.6，8.4Hz)，6.80(1H，d，J＝2.6Hz)，6.85-6.95(2H，m)，7.33(2H，t，J＝8.4Hz)，7.55-7.60(1H，m)，7.70-7.75(1H，m).

(v) 2-{2-[4-({ 4-[3-(the 4-tertiary butyl-1,3-oxazole 2-yl) phenoxy group]-3-chloro-phenyl-} amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

Use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (444mg), 4-[3-(the 4-tertiary butyl-1,3-oxazole-2-yl) phenoxy group]-3-chloroaniline (660mg) and Virahol (10mL), react according to same method in Embodiment C-2 (v).Then, use 1N aqueous sodium hydroxide solution (6.0mL) and tetrahydrofuran (THF) (12mL), gained compound is reacted according to same method in Embodiment C-2 (v), obtain title compound (316mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.30(9H，s)，3.70-3.80(4H，m)，4.02(2H，t，J＝4.2Hz)，4.56(2H，t，J＝4.2Hz)，6.62(1H，d，J＝3.3Hz)，7.00(1H，dd，J＝2.4Hz，8.4Hz)，7.05(1H，d，J＝8.7Hz)，7.20(1H，d，J＝3.3Hz)，7.34(1H，s)，7.37(1H，t，J＝7.8Hz)，7.59(1H，dd，J＝2.4Hz，9.0Hz)，7.60-7.65(1H，m)，7.75(1H，d，J＝7.8Hz)，7.89(1H，d，J＝2.7Hz)，8.51(1H，s)，8.77(1H，s).

Embodiment C-6

2-{2-[4-({ 4-[3-(the 4-tertiary butyl-1,3-thiazoles-2-yl) phenoxy group]-3-chloro-phenyl-} amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) preparation of 3-anisole thioformamide (3-methoxybenzenecarbothioamide)

At room temperature, by 3-HOMOVERATRONITRILE (9.32g), O, O-diethyl phosphorothioate (11.85mL) and 4N hydrochloric acid (70mL) stir 20 hours.Filter collecting precipitation, by ethyl acetate and diisopropyl ether, obtain title compound (8.51g), be light green powder.

¹H-NMR(CDCl ₃)δ:3.27(2H，br?s)，3.89(3H，s)，7.10-7.20(1H，m)，7.36(1H，t，J＝7.8Hz)，7.40-7.50(1H，m)，7.50-7.60(1H，m).

(ii) preparation of the 4-tertiary butyl-2-(3-p-methoxy-phenyl)-1,3-thiazoles

At room temperature, by ethanol (50mL) solution stirring of 3-anisole thioformamide (4.18g) and 1-bromine Pinacolone (4.48g) 1 hour.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is used sodium bicarbonate aqueous solution and salt water washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=0:100 → 10:90), obtain title compound (4.91g), be colorless oil of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.39(9H，s)，3.88(3H，s)，6.88(1H，s)，6.90-7.00(1H，m)，7.32(1H，t，J＝8.1Hz)，7.50-7.60(2H，m).

(iii) preparation of 3-(the 4-tertiary butyl-1,3-thiazoles-2-yl) phenol

According to same method in Embodiment C-4 (ii), use the 4-tertiary butyl-2-(3-p-methoxy-phenyl)-1,3-thiazoles (4.91g) and 48% Hydrogen bromide (30mL), make title compound (3.59g), be colorless oil.

¹H-NMR(CDCl ₃)δ:1.40(9H，s)，5.08(1H，s)，6.80-6.85(1H，m)，6.89(1H，s)，7.28(1H，t，J＝8.0Hz)，7.45-7.55(2H，m).

(iv) the 4-tertiary butyl-2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of-1,3-thiazoles

According to same method in Embodiment C-1 (i), use 3-(the 4-tertiary butyl-1,3-thiazol-2-yl) phenol (3.13g), the chloro-4-fluoronitrobenzene of 3-(2.48g), salt of wormwood (2.78g) and N, dinethylformamide (24mL), obtain title compound (1.49g), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:1.38(9H，s)，6.93(2H，t，J＝4.6Hz)，7.05-7.15(1H，m)，7.49(1H，t，J＝8.0Hz)，7.75-7.80(1H，m)，7.80-7.90(1H，m)，8.06(1H，dd，J＝2.6，8.8Hz)，8.40(1H，d，J＝2.6Hz).

(v) 4-[3-(the 4-tertiary butyl-1,3-thiazoles-2-yl) phenoxy group] preparation of-3-chloroaniline

According to same method in Embodiment C-1 (ii), use the 4-tertiary butyl-2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-1,3-thiazole (1.49g), 5% platinum-gac (0.25g) and ethyl acetate (10mL), obtain title compound (1.37g), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:1.38(9H，s)，3.68(2H，br?s)，6.58(1H，dd，J＝2.8，8.6Hz)，6.80-6.95(4H，m)，7.30(1H，t，J＝8.1Hz)，7.55-7.65(2H，m).

(vi) 2-{2-[4-({ 4-[3-(the 4-tertiary butyl-1,3-thiazoles-2-yl) phenoxy group]-3-chloro-phenyl-} amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

Use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (277mg), 4-[3-(the 4-tertiary butyl-1,3-thiazol-2-yl) phenoxy group]-3-chloroaniline (359mg) and Virahol (5.04mL), react according to same method in Embodiment C-2 (v).Then, use 1N aqueous sodium hydroxide solution (3.7mL) and tetrahydrofuran (THF) (7.5mL), gained compound is reacted according to same method in Embodiment C-2 (v), obtain title compound (163mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.39(9H，s)，3.70-3.80(4H，m)，4.02(2H，t，J＝4.5Hz)，4.57(2H，t，J＝4.5Hz)，6.63(1H，d，J＝3.3Hz)，6.89(1H，s)，6.92(1H，d，J＝2.4Hz)，7.05(1H，d，J＝9.0Hz)，7.21(1H，d，J＝3.0Hz)，7.34(1H，t，J＝8.4Hz)，7.58(1H，dd，J＝2.4Hz，8.7Hz)，7.65-7.70(2H，m)，7.89(1H，d，J＝2.4Hz)，8.52(1H，s)，8.75(1H，s).

Embodiment C-7

2-(the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol

(i) preparation of 2-(3-p-methoxy-phenyl)-4-(trifluoromethyl)-1,3-thiazoles

According to same method in Embodiment C-6 (ii), use 3-anisole thioformamide (4.18g), the bromo-TFK of 3-(4.77g) and ethanol (50mL), obtain title compound (4.29g), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:3.90(3H，s)，6.95-7.05(1H，m)，7.37(1H，d，J＝8.2Hz)，7.50-7.60(2H，m)，7.73(1H，d，J＝1.0Hz).

(ii) 3-[4-(trifluoromethyl)-1,3-thiazoles-2-yl] preparation of phenol

According to same method in Embodiment C-4 (ii), use 2-(3-p-methoxy-phenyl)-4-(trifluoromethyl)-1,3-thiazole (4.23g) and 48% Hydrogen bromide (30mL), obtain title compound (4.61g), is yellow oily.

¹H-NMR(CDCl ₃)δ:5.10-5.50(1H，m)，6.90-7.00(1H，m)，7.33(1H，t，J＝8.1Hz)，7.50-7.60(2H，m)，7.73(1H，s).

(iii) 2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of-4-(trifluoromethyl)-1,3-thiazoles

According to same method in Embodiment C-1 (i), use 3-[4-(trifluoromethyl)-1,3-thiazol-2-yl] phenol (4.00g), the chloro-4-fluoronitrobenzene of 3-(3.01g), salt of wormwood (3.38g) and N, dinethylformamide (20mL), obtain title compound (4.82g), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:6.96(1H，t，J＝9.0Hz)，7.15-7.25(1H，m)，7.55(1H，t，J＝8.1Hz)，7.75-7.80(2H，m)，7.85(1H，t，J＝8.1Hz)，8.09(1H，dd，J＝2.7Hz，9.0Hz)，8.41(1H，d，J＝2.7Hz).

(iv) the chloro-4-{3-[4-of 3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } preparation of aniline

According to same method in Embodiment C-1 (ii), use 2-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-4-(trifluoromethyl)-1,3-thiazole (2.00g), 5% platinum-gac (0.33g) and ethyl acetate (15mL), obtain title compound (1.87g), be colorless oil.

¹H-NMR(CDCl ₃)δ:3.70(2H，br?s)，6.59(1H，dd，J＝2.7Hz，8.7Hz)，6.81(1H，d，J＝2.7Hz)，6.94(2H，d，J＝8.7Hz)，7.36(1H，t，J＝8.1Hz)，7.50-7.55(1H，m)，7.63(1H，d，J＝7.5Hz)，7.73(1H，s).

(v) 2-(the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol

Use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (262mg), the chloro-4-{3-[4-of 3-(trifluoromethyl)-1,3-thiazol-2-yl] phenoxy group } aniline (338mg) and Virahol (5.0mL), react according to same method in Embodiment C-2 (v).Then, use 1N aqueous sodium hydroxide solution (3.4mL) and tetrahydrofuran (THF) (7mL), gained compound reacts according to same method in Embodiment C-2 (v), obtains title compound (173mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:3.70-3.85(4H，m)，4.02(2H，t，J＝4.5Hz)，4.57(2H，t，J＝4.5Hz)，6.63(1H，d，J＝3.3Hz)，7.00-7.10(1H，m)，7.08(1H，d，J＝8.7Hz)，7.21(1H，d，J＝3.0Hz)，7.39(1H，t，J＝8.0Hz)，7.6-7.65(2H，m)，7.67(1H，d，J＝7.8Hz)，7.74(1H，s)，7.91(1H，d，J＝2.7Hz)，8.52(1H，s)，8.79(1H，s).

Embodiment C-8

N-(the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) ethanamide

(i) (the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of t-butyl carbamate

At 80 ℃, by [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.01g), the chloro-4-{3-[4-of 3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } mixture of aniline (1.51g) and Virahol (10mL) stirs 12 hours.Under ice-cooled, in reaction mixture, add sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=60:40 → 100:0) of silica gel column chromatography for residue.Filter and collect gained solid, with diisopropyl ether and hexane washing, obtain title compound (1.88g), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，3.45-3.55(2H，m)，4.45-4.55(2H，m)，5.05-5.15(1H，m)，6.61(1H，d，J＝1.5Hz)，7.00-7.10(2H，m)，7.18(1H，d，J＝2.1Hz)，7.40(1H，t，J＝8.5Hz)，7.65(1H，s)，7.68(1H，d，J＝7.5Hz)，7.74(1H，s)，7.89(1H，d，J＝9.0Hz)，8.03(1H，s)，8.51(1H，s)，8.61(1H，br?s).

(ii) preparation of 5-(2-amino-ethyl)-N-(the chloro-4-{3-[4-of 3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 65 ℃, by (the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazol-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) mixture of t-butyl carbamate (1.70g) and 10% (W/W) hydrochloric acid/methyl alcohol (12mL) stirs 4 hours.This reaction mixture of concentrating under reduced pressure, and filter collecting precipitation, with ether washing, obtain title compound (1.53g), be light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:3.25-3.35(2H，m)，5.00-5.10(2H，m)，6.75(1H，d，J＝3.3Hz)，7.17(1H，dd，J＝2.4，8.1Hz)，7.35(1H，d，J＝8.7Hz)，7.5-7.7(3H，m)，7.78(1H，d，J＝7.8Hz)，7.93(1H，d，J＝2.4Hz)，8.07(1H，d，J＝3.0Hz)，8.20-8.40(3H，m)，8.61(1H，s)，8.72(1H，s)，10.10(1H，br?s).

(iii) N-(the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) ethanamide

Under ice-cooled; to 5-(2-amino-ethyl)-N-(the chloro-4-{3-[4-of 3-(trifluoromethyl)-1; 3-thiazol-2-yl] phenoxy group } phenyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (200mg), methylsulfonyl acetic acid (69mg) and I-hydroxybenzotriazole (75mg) be at N; in the solution of dinethylformamide (5.0mL), add triethylamine (0.23mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (105mg), and at room temperature stir this mixture 6 hours.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), then use ethyl acetate/diisopropyl ether recrystallization, obtain title compound (179mg), be clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.12(3H，s)，3.65-3.75(2H，m)，3.98(2H，s)，4.45-4.55(2H，m)，6.60-6.65(1H，m)，7.08(2H，d，J＝9.0Hz)，7.21(1H，d，J＝3.0Hz)，7.25-7.30(2H，m)，7.42(1H，t，J＝8.0Hz)，7.65-7.75(2H，m)，7.75(1H，s)，7.95(1H，s)，8.20(1H，s)，8.51(1H，s).

Embodiment C-9

The chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide

(i) preparation of 3-hydroxy-benzoic acid diphenyl methyl ester

Under ice-cooled, in acetone (40mL) solution of 3-hydroxy-benzoic acid (2.76g), add diphenyl diazomethane (diphenyldiazomethane) (3.88g), and at room temperature stir the mixture and spend the night.Concentrating under reduced pressure reaction mixture, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=15:85 → 35:65).Concentrating under reduced pressure target fraction, obtains title compound (5.16g), is faint yellow oily.

¹H-NMR(CDCl ₃)δ:5.13(1H，s)，7.03-7.08(1H，m)，7.10(1H，s)，7.25-7.46(11H，m)，7.58-7.62(1H，m)，7.70-7.76(1H，m).

(ii) preparation of 3-(the chloro-4-nitrophenoxy of 2-) phenylformic acid diphenyl methyl ester

At room temperature, stir the mixture overnight of the 2-fluoro-4-oil of mirbane of chloro-1-(2.81g), 3-hydroxy-benzoic acid diphenyl methyl ester (5.16g), salt of wormwood (3.32g) and DMF (50mL).This reaction mixture of concentrating under reduced pressure, adds water and is extracted with ethyl acetate.Ethyl acetate layer washs with saturated brine, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, adds diisopropyl ether in gained residue, filters the solid of collecting precipitation, obtains title compound (6.93g), is colourless powder.

¹H-NMR(CDCl ₃)δ:6.90(1H，d，J＝9.3Hz)，7.12(1H，s)，7.27-7.46(11H，m)，7.55(1H，t，J＝8.0Hz)，7.82(1H，m)，8.02-8.11(2H，m)，8.40(1H，d，J＝2.7Hz).

(iii) preparation of 3-(4-amino-2-chlorophenoxy) phenylformic acid diphenyl methyl ester

In 3-(the chloro-4-nitrophenoxy of 2-) phenylformic acid diphenyl methyl ester (4.60g), add ethyl acetate (80mL) and 5% platinum-gac (50mg), and under nitrogen atmosphere, at room temperature stir this mixture 5 hours.Filtration catalizer, concentrated filtrate, hexane=20:80 → 40:60) and silica gel column chromatography (elutriant: ethyl acetate: hexane=15:85 → 35:65) gained residue is by alkaline silica gel column chromatography (elutriant: ethyl acetate:.Concentrating under reduced pressure target fraction, obtains title compound (3.58g), is colorless solid.

¹H-NMR(CDCl ₃)δ:3.69(2H，br?s)，6.57(1H，dd，J＝2.7Hz，8.6Hz)，6.79(1H，d，J＝2.7Hz)，6.91(1H，d，J＝8.6Hz)，7.04-7.10(2H，m)，7.26-7.44(11H，m)，7.62-7.65(1H，m)，7.78-7.83(1H，m).

(iv) 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } preparation of benzoate hydrochlorate

At 80 ℃, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture overnight of ethyl ester (1.04g), 3-(4-amino-2-chlorophenoxy) phenylformic acid diphenyl methyl ester (1.29g) and Virahol (20mL).Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.In residue, add trifluoroacetic acid (10mL) and methyl-phenoxide (10mL), and at room temperature stir this mixture 4 hours.This reaction mixture of concentrating under reduced pressure.4N hydrogenchloride/ethyl acetate solution is added in residue, and concentrating under reduced pressure mixture.In residue, add ethyl acetate and acetonitrile, filter the solid of collecting precipitation, obtain title compound (1.24g), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:3.76-3.83(2H，m)，3.91(2H，t，J＝4.7Hz)，4.27-4.33(2H，m)，4.89(2H，m)，6.60-6.64(1H，m)，7.22(1H，d，J＝8.8Hz)，7.26-7.75(10H，m)，7.91(1H，d，J＝2.5Hz)，8.01(1H，d，J＝3.0Hz)，8.64(1H，s)，9.91(1H，m).

(v) the chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide

At room temperature, by 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } mixture of benzoate hydrochlorate (183mg), TERTIARY BUTYL AMINE (0.038mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL) and DMF (3mL) stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Ethyl acetate layer washs with saturated brine, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.In residue, add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Ethyl acetate layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-ether, obtains title compound (106mg), and crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，2.36(1H，br?s)，3.69-3.81(4H，m)，3.99-4.05(2H，m)，4.53-4.60(2H，m)，5.96(1H，br?s)，6.61(1H，d，J＝3.0Hz)，7.03(1H，d，J＝8.8Hz)，7.05-7.12(1H，m)，7.21(1H，d，J＝3.0Hz)，7.27-7.37(3H，m)，7.57(1H，dd，J＝2.5Hz，8.8Hz)，7.91(1H，d，J＝2.5Hz)，8.51(1H，s)，8.79(1H，br?s).

Embodiment C-10

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-(2,2-dimethyl propyl) benzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), neopentyl amine (0.042mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (116mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:0.97(9H，s)，2.30(1H，br?s)，3.25(2H，d，J＝6.3Hz)，3.69-3.81(4H，m)，3.99-4.05(2H，m)，4.53-4.60(2H，m)，6.14-6.26(1H，m)，6.61(1H，d，J＝3.3Hz)，7.04(1H，d，J＝8.8Hz)，7.06-7.12(1H，m)，7.21(1H，d，J＝3.3Hz)，7.32-7.44(3H，m)，7.57(1H，dd，J＝2.5Hz，8.8Hz)，7.90(1H，d，J＝2.5Hz)，8.51(1H，s)，8.79(1H，br?s).

Embodiment C-11

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-(2,2,2-trifluoroethyl) benzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), 2, 2, 2-trifluoro ethamine (0.029mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (125mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:2.11(1H，br?s)，3.70-3.82(4H，m)，3.99-4.17(4H，m)，4.54-4.62(2H，m)，6.61(1H，d，J＝3.0Hz)，6.67-6.78(1H，m)，7.03(1H，d，J＝8.8Hz)，7.14-7.20(1H，m)，7.21(1H，d，J＝3.0Hz)，7.33(1H，m)，7.40(1H，t，J＝8.0Hz)，7.46-7.51(1H，m)，7.55(1H，dd，J＝8.8，2.6Hz)，7.88(1H，d，J＝2.6Hz)，8.46(1H，s)，8.78(1H，br?s).

Embodiment C-12

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide

To 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } N of benzoate hydrochlorate (183mg), in dinethylformamide (3mL) solution, add triethylamine (0.050mL) and 1,1 '-carbonyl diurethane (1H-imidazoles) (58mg), and at room temperature stirs this mixture 0.5 hour.Add 7N ammonia hydroxide/methanol (0.086mL), and at room temperature stir this mixture 4 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.In residue, add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Ethyl acetate layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.Residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (95mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:3.49(4H，m)，3.84(2H，t，J＝4.4Hz)，4.65(2H，t，J＝4.4Hz)，4.72(1H，t，J＝4.4Hz)，6.52(1H，d，J＝2.7Hz)，7.08-7.15(1H，m)，7.21(1H，d，J＝8.7Hz)，7.36-7.50(3H，m)，7.58-7.72(3H，m)，7.98-8.08(2H，m)，8.35(1H，s)，8.97(1H，br?s).

Embodiment C-13

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-methyl-benzamide

According to the same method in Embodiment C-12, use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), N, dinethylformamide (3mL), triethylamine (0.050mL), 1,1 '-carbonyl diurethane (1H-imidazoles) (58mg), 2M methylamine/tetrahydrofuran (THF) (0.30mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (114mg), crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:2.76(3H，d，J＝4.5Hz)，3.50(4H，m)，3.84(2H，t，J＝4.4Hz)，4.65(2H，t，J＝4.4Hz)，4.72(1H，t，J＝4.5Hz)，6.52(1H，d，J＝3.0Hz)，7.07-7.15(1H，m)，7.20(1H，d，J＝8.7Hz)，7.34(1H，m)，7.46(1H，t，J＝7.8Hz)，7.52-7.60(1H，m)，7.61-7.73(2H，m)，8.01(1H，d，J＝2.7Hz)，8.35(1H，s)，8.44-8.53(1H，m)，8.97(1H，br?s).

Embodiment C-14

2-{2-[4-({ the chloro-4-[3-of 3-(piperidin-1-yl carbonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylate hydrochlorate

According to the same method in Embodiment C-12, use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), N, dinethylformamide (3mL), triethylamine (0.050mL), 1, 1 '-carbonyl diurethane (1H-imidazoles) (58mg), piperidines (0.059mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make 2-{2-[4-({ the chloro-4-[3-of 3-(piperidin-1-yl carbonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] oxyethyl group } ethanol.This compound is dissolved in ethyl acetate-ethanol, and adds 1N hydrogenchloride/ethyl acetate solution (0.3mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (126mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.34-1.68(6H，m)，3.15-3.75(8H，m)，3.84(2H，t，J＝4.5Hz)，4.81(2H，m)，6.70(1H，d，J＝3.0Hz)，6.86(1H，m)，7.04-7.10(1H，m)，7.12(1H，d，J＝7.7Hz)，7.31(1H，d，J＝8.8Hz)，7.44-7.51(1H，m)，7.64(1H，dd，J＝2.5Hz，8.8Hz)，7.97(1H，d，J＝2.5Hz)，8.02(1H，d，J＝3.3Hz)，8.74(1H，s)，9.90(1H，br?s).

Embodiment C-15

2-{2-[4-({ the chloro-4-[3-of 3-(morpholine-4-base carbonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylate hydrochlorate

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), morpholine (0.031mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make 2-{2-[4-({ the chloro-4-[3-of 3-(morpholine-4-base carbonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] oxyethyl group } ethanol.This compound is dissolved in ethyl acetate-ethanol, and adds 1N hydrogenchloride/ethyl acetate solution (0.3mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (116mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:3.20-3.80(12H，m)，3.85(2H，t，J＝4.4Hz)，4.81(2H，t，J＝4.4Hz)，6.70(1H，d，J＝3.0Hz)，6.94(1H，m)，7.05-7.12(1H，m)，7.15-7.21(1H，m)，7.30(1H，d，J＝8.8Hz)，7.45-7.53(1H，m)，7.64(1H，dd，J＝2.5Hz，8.8Hz)，7.97(1H，d，J＝2.5Hz)，8.02(1H，d，J＝3.3Hz)，8.74(1H，s)，9.90(1H，br?s).

Embodiment C-16

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-(2-methoxy ethyl) benzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), 2-methoxyethyl amine (0.031mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (134mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:2.07-2.31(1H，m)，3.38(3H，s)，3.51-3.66(4H，m)，3.69-3.81(4H，m)，3.99-4.05(2H，m)，4.54-4.60(2H，m)，6.51-6.59(1H，m)，6.62(1H，d，J＝3.3Hz)，7.04(1H，d，J＝8.8Hz)，7.08-7.13(1H，m)，7.21(1H，d，J＝3.3Hz)，7.31-7.46(3H，m)，7.58(1H，dd，J＝8.8，2.8Hz)，7.90(1H，d，J＝2.8Hz)，8.51(1H，s)，8.78(1H，br?s).

Embodiment C-17

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-(3,3,3-trifluoro propyl) benzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), 3, 3, 3-trifluoropropyl amine hydrochlorate (53mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.092mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (150mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:2.08(1H，br?s)，2.37-2.54(2H，m)，3.64-3.83(6H，m)，3.99-4.06(2H，m)，4.55-4.61(2H，m)，6.48-6.58(1H，m)，6.62(1H，d，J＝3.2Hz)，7.04(1H，d，J＝9.0Hz)，7.11-7.17(1H，m)，7.22(1H，d，J＝3.2Hz)，7.27(1H，m)，7.34-7.45(2H，m)，7.57(1H，dd，J＝2.5Hz，9.0Hz)，7.89(1H，d，J＝2.5Hz)，8.50(1H，s)，8.78(1H，br?s).

Embodiment C-18

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-isopropylbenzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), isopropylamine (0.031mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (125mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.25(6H，d，J＝6.6Hz)，2.13-2.37(1H，m)，3.69-3.81(4H，m)，3.99-4.05(2H，m)，4.18-4.31(1H，m)，4.53-4.60(2H，m)，5.92-6.02(1H，m)，6.62(1H，d，J＝3.0Hz)，7.03(1H，d，J＝8.8Hz)，7.06-7.12(1H，m)，7.21(1H，d，J＝3.0Hz)，7.30-7.42(3H，m)，7.56(1H，dd，J＝2.8Hz，8.8Hz)，7.90(1H，d，J＝2.8Hz)，8.50(1H，s)，8.78(1H，br?s).

Embodiment C-19

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-cyclopropyl-phenyl methane amide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), cyclopropylamine (0.025mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (118mg), crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:0.52-0.73(4H，m)，2.76-2.87(1H，m)，3.49(4H，m)，3.84(2H，t，J＝4.6Hz)，4.65(2H，t，J＝4.6Hz)，4.72(1H，t，J＝4.6Hz)，6.52(1H，d，J＝3.2Hz)，7.06-7.12(1H，m)，7.19(1H，d，J＝8.9Hz)，7.35(1H，m)，7.44(1H，t，J＝7.8Hz)，7.52-7.58(1H，m)，7.64(1H，dd，J＝8.9，2.5Hz)，7.69(1H，d，J＝3.2Hz)，8.00(1H，d，J＝2.5Hz)，8.34(1H，s)，8.49(1H，d，J＝4.1Hz)，8.97(1H，br?s).

Embodiment C-20

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-(1,1-dimethyl propyl) benzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), tert.-amylamine (0.042mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (135mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:0.90(3H，t，J＝7.5Hz)，1.40(6H，s)，1.83(2H，q，J＝7.5Hz)，3.70-3.80(4H，m)，3.99-4.05(2H，m)，4.54-4.60(2H，m)，5.84(1H，brs)，6.63(1H，d，J＝3.2Hz)，7.02-7.12(2H，m)，7.21(1H，d，J＝3.2Hz)，7.28-7.39(3H，m)，7.58(1H，dd，J＝8.8，2.7Hz)，7.91(1H，d，J＝2.7Hz)，8.51(1H，s)，8.79(1H，br?s).

Embodiment C-21

The chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide

According to the same method in Embodiment C-9 (v), use 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoate hydrochlorate (183mg), 2-amino-2-methyl-1-propanol (0.034mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), make title compound (106mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.40(6H，s)，3.67(2H，s)，3.69-3.81(4H，m)，3.98-4.05(2H，m)，4.54-4.60(2H，m)，6.23(1H，br?s)，6.62(1H，d，J＝3.0Hz)，7.04(1H，d，J＝8.8Hz)，7.08-7.15(1H，m)，7.21(1H，d，J＝3.0Hz)，7.28(1H，m)，7.32-7.40(2H，m)，7.57(1H，dd，J＝2.5Hz，8.8Hz)，7.90(1H，d，J＝2.5Hz)，8.49(1H，s)，8.80(1H，br?s).

Embodiment C-22

N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) preparation of benzamide hydrochloride salt

(i) 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } preparation of methyl benzoate

At 80 ℃, [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (2.08g), 3-(4-amino-2-chlorophenoxy) methyl benzoate (1.94g) and Virahol (20mL) are stirred and spent the night.In reaction mixture, add sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Ethyl acetate layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.Ethyl acetate and diisopropyl ether are added in residue, by filtering the solid of collecting precipitation, obtain title compound (3.26g), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，3.44-3.54(2H，m)，3.90(3H，s)，4.43-4.53(2H，m)，5.12(1H，t，J＝5.6Hz)，6.60(1H，d，J＝3.2Hz)，7.05(1H，d，J＝8.9Hz)，7.16-7.22(2H，m)，7.39(1H，t，J＝8.0Hz)，7.63(1H，m)，7.74-7.78(1H，m)，7.89(1H，dd，J＝2.7Hz，8.9Hz)，8.03(1H，d，J＝2.7Hz)，8.52(1H，s)，8.61(1H，br?s).

(ii) 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } benzoic preparation

To 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } add methyl alcohol (50mL), tetrahydrofuran (THF) (10mL) and 1N aqueous sodium hydroxide solution (11mL) in methyl benzoate (2.96g), and at 60 ℃, stir this mixture overnight.After concentrating under reduced pressure, add water and acetic acid (0.63mL), and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue, through the crystallization of methyl alcohol-acetonitrile-ether, obtains title compound (2.58g), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.32(9H，s)，3.22-3.32(2H，m)，4.51(2H，t，J＝6.2Hz)，6.49(1H，d，J＝3.0Hz)，7.10-7.20(1H，m)，7.24-7.34(3H，m)，7.52(1H，t，J＝8.0Hz)，7.61(1H，m)，7.67(1H，d，J＝7.7Hz)，7.75-7.84(1H，m)，7.97(1H，m)，8.33(1H，s)，8.66(1H，br?s).

(iii) preparation of 3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy)-N-(tertiary butyl) benzamide dihydrochloride

At room temperature stir 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } mixture overnight of phenylformic acid (524mg), TERTIARY BUTYL AMINE (0.126mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (230mg), I-hydroxybenzotriazole (184mg) and DMF (10mL).Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.In residue, add ethanol (2mL) and 4N hydrogenchloride/ethyl acetate solution (2mL), and at room temperature stir this mixture overnight.In reaction mixture, add ethyl acetate, by filtering the solid of collecting precipitation, obtain title compound (427mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，3.23-3.37(2H，m)，4.96-5.06(2H，m)，6.74(1H，d，J＝3.3Hz)，7.17(1H，dd，J＝2.6Hz，8.1Hz)，7.25(1H，d，J＝8.8Hz)，7.35(1H，m)，7.47(1H，t，J＝7.8Hz)，7.58-7.66(2H，m)，7.85(1H，s)，7.90(1H，m)，8.05(1H，m)，8.27(3H，br?s)，8.74(1H，s)，10.04(1H，br?s).

(iv) N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) preparation of benzamide hydrochloride salt

At room temperature stir 3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy) mixture overnight of-N-(tertiary butyl) benzamide dihydrochloride (166mg), methylsulfonyl acetic acid (62mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL).Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.Residue is dissolved in ethyl acetate-ethanol, and adds 1N hydrogenchloride/ethyl acetate solution (0.3mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (121mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，3.06(3H，s)，3.50-3.61(2H，m)，4.07(2H，s)，4.67-4.77(2H，m)，6.67(1H，d，J＝3.1Hz)，7.13-7.20(1H，m)，7.25(1H，d，J＝8.9Hz)，7.37(1H，m)，7.47(1H，t，J＝8.0Hz)，7.60-7.69(2H，m)，7.85(1H，s)，7.93(1H，d，J＝2.5Hz)，7.96(1H，d，J＝3.1Hz)，8.74(1H，s)，8.78-8.87(1H，m)，9.99(1H，br?s).

Embodiment C-23

The chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-5-(trifluoromethyl) benzamide

(i) preparation of 3-hydroxyl-5-(trifluoromethyl) methyl benzoate

3-amino-5-(trifluoromethyl) phenylformic acid (2.80g) is dissolved in the vitriol oil (50g) and water (50mL), and mixture is cooled to-10 ℃.Add water (120mL), and drip the aqueous solution (20mL) of Sodium Nitrite (0.942g).Add water (10mL), and at-10 ℃, stir this mixture 10min and stir 30min at 0 ℃.The in the situation that of reflux, further stir this mixture 1 hour.After cooling, water added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is dissolved in methyl alcohol (30mL).Add concentrated hydrochloric acid (0.9mL) and the in the situation that of reflux, stir this mixture overnight.This reaction mixture of concentrating under reduced pressure, adds sodium bicarbonate aqueous solution in residue, and is extracted with ethyl acetate.Ethyl acetate layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=10:90 → 30:70).Concentrating under reduced pressure target fraction, obtains title compound (1.86g), is pale yellow powder.

¹H-NMR(CDCl ₃)δ:3.95(3H，s)，5.49(1H，s)，7.29(1H，m)，7.70(1H，m)，7.87(1H，m).

(ii) preparation of 3-(4-amino-2-chlorophenoxy)-5-(trifluoromethyl) methyl benzoate

At room temperature stir the mixture overnight of the fluoro-4-oil of mirbane of the chloro-1-of 2-(1.48g), 3-hydroxyl-5-(trifluoromethyl) methyl benzoate (1.86g), salt of wormwood (1.75g) and DMF (10mL).This reaction mixture of concentrating under reduced pressure, adds water and is extracted with ethyl acetate.Organic layer washs with saturated brine, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=5:95 → 15:85).By target fraction concentrating under reduced pressure.In residue, add ethyl acetate (30mL) and 5% platinum-gac (90mg), and under room temperature, stir this mixture 4 hours under nitrogen atmosphere.Elimination catalyzer, concentrated filtrate and gained residue are by silica gel column chromatography (elutriant: ethyl acetate: hexane=15:85 → 35:65).By target fraction concentrating under reduced pressure.In residue, add hexane, by filtering the solid of collecting precipitation, obtain title compound (2.50g), powder is white in color.

¹H-NMR(CDCl ₃)δ:3.76(2H，br?s)，3.92(3H，s)，6.61(1H，dd，J＝8.6，2.7Hz)，6.81(1H，d，J＝2.7Hz)，6.94(1H，d，J＝8.6Hz)，7.31(1H，m)，7.64(1H，m)，7.95(1H，m).

(iii) 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } preparation of-5-(trifluoromethyl) methyl benzoate

At 80 ℃, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethyl ester (346mg), 3-(4-amino-2-chlorophenoxy)-5-(trifluoromethyl) methyl benzoate (346mg) and Virahol (5mL) 5 hours.Add phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (69mg), and at 80 ℃, this mixture is stirred 3 hours again.This reaction mixture of concentrating under reduced pressure, adds sodium bicarbonate aqueous solution, and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).Concentrating under reduced pressure target fraction, obtains title compound (609mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:3.93(3H，s)，3.95-4.00(2H，m)，4.06-4.12(2H，m)，4.47-4.53(2H，m)，4.56-4.63(2H，m)，6.64(1H，d，J＝3.3Hz)，6.83(1H，d，J＝8.8Hz)，7.24(1H，d，J＝3.3Hz)，7.29-7.43(4H，m)，7.45-7.52(1H，m)，7.69(1H，m)，7.77-7.83(2H，m)，7.92(1H，d，J＝2.5Hz)，8.00(1H，m)，8.52(1H，s)，8.83(1H，br?s).

(iv) the chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] the benzoic preparation of-5-(trifluoromethyl)

To 3-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } add methyl alcohol (12mL) and 1N aqueous sodium hydroxide solution (3mL) in-5-(trifluoromethyl) methyl benzoate (609mg), and at room temperature stir this mixture overnight.Water and 1N hydrochloric acid (3mL) are added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, adds ethanol-acetonitrile-ether in gained residue, by filtering the solid of collecting precipitation, obtains title compound (416mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:3.50(4H，m)，3.85(2H，t，J＝4.4Hz)，4.56-4.88(1H，m)，4.68(2H，t，J＝4.4Hz)，6.54(1H，d，J＝3.0Hz)，7.38(1H，d，J＝8.7Hz)，7.52(1H，m)，7.59-7.80(3H，m)，7.90(1H，m)，8.05(1H，m)，8.40(1H，s)，9.11(1H，br?s).

(v) the chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of-5-(trifluoromethyl) benzamide

At room temperature stir the chloro-4-of 3-[2-(5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] mixture overnight of-5-(trifluoromethyl) phenylformic acid (322mg), TERTIARY BUTYL AMINE (0.126mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (138mg), I-hydroxybenzotriazole (153mg) and DMF (5mL).Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-ether, obtains title compound (247mg), and crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.46(9H，s)，3.70-4.82(4H，m)，4.02(2H，t，J＝4.4Hz)，4.57(2H，t，J＝4.4Hz)，6.00(1H，br?s)，6.61(1H，d，J＝3.2Hz)，7.06(1H，d，J＝8.8Hz)，7.21(1H，d，J＝3.2Hz)，7.29(1H，m)，7.44(1H，m)，7.57(1H，m)，7.62(1H，dd，J＝2.8Hz，8.8Hz)，7.93(1H，d，J＝2.8Hz)，8.51(1H，s)，8.87(1H，br?s).

Embodiment C-24

The chloro-4-[(5-{2-[(3-hydroxy-3-methyl of N-(tertiary butyl)-3-{2-butyryl radicals) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of-5-(trifluoromethyl) benzamide

(i) 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } preparation of-5-(trifluoromethyl) methyl benzoate

Under 80 °, the mixture that stirs [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.48g), 3-(4-amino-2-chlorophenoxy)-5-(trifluoromethyl) methyl benzoate (1.73g) and Virahol (20mL) stirs 5 hours.Add [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (0.30g), and under 80 °, then stir this mixture 3 hours.This reaction mixture of concentrating under reduced pressure, adds sodium bicarbonate aqueous solution and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.In residue, add acetone and diisopropyl ether, by filtering the solid of collecting precipitation, obtain title compound (2.06g), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，3.45-3.55(2H，m)，3.93(3H，s)，4.44-4.54(2H，m)，5.10-5.18(1H，m)，6.61(1H，d，J＝3.2Hz)，7.11(1H，d，J＝8.9Hz)，7.20(1H，d，J＝3.2Hz)，7.39(1H，m)，7.77(1H，m)，7.96(1H，dd，J＝8.9，2.5Hz)，8.00(1H，s)，8.07(1H，d，J＝2.5Hz)，8.53(1H，s)，8.67(1H，br?s).

(ii) 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } the benzoic preparation of-5-(trifluoromethyl)

To 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } add methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and 1N aqueous sodium hydroxide solution (8mL) in-5-(trifluoromethyl) methyl benzoate (2.42g), and at room temperature stir this mixture overnight.In reaction mixture, add water and 1N hydrochloric acid (8mL), and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue, through the crystallization of methyl alcohol-ether, obtains title compound (2.03g), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.32(9H，s)，3.20-3.36(2H，m)，4.53(2H，t，J＝6.4Hz)，6.51(1H，d，J＝3.0Hz)，7.10-7.23(1H，m)，7.39(1H，d，J＝8.7Hz)，7.54(1H，m)，7.63(2H，m)，7.80-7.90(1H，m)，7.90(1H，m)，8.02(1H，m)，8.35(1H，s)，8.73(1H，br?s).

(iii) preparation of 3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy)-N-(tertiary butyl)-5-(trifluoromethyl) benzamide dihydrochloride

At room temperature stir 3-{4-[(5-{2-[(tert-butoxycarbonyl) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-2-chlorophenoxy } mixture overnight of-5-(trifluoromethyl) phenylformic acid (888mg), TERTIARY BUTYL AMINE (0.189mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (345mg), I-hydroxybenzotriazole (276mg) and DMF (10mL).Water is added in this reaction mixture, and be extracted with ethyl acetate.Ethyl acetate layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=70:30 → 100:0 → methyl alcohol: ethyl acetate=10:90).By target fraction concentrating under reduced pressure.In residue, add ethanol (1mL) and 4N hydrogenchloride/ethyl acetate solution (5mL) and at room temperature stir this mixture 2 hours.This reaction mixture of concentrating under reduced pressure, adds ethanol and ether, by filtering the solid of collecting precipitation, obtains title compound (815mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.37(9H，s)，3.23-3.38(2H，m)，5.06(2H，m)，6.76(1H，d，J＝3.0Hz)，7.37-7.44(1H，m)，7.52(1H，m)，7.59(1H，m)，7.66-7.75(1H，m)，7.94-8.55(7H，m)，8.76(1H，s)，9.95-10，04(1H，m).

(iv) the chloro-4-[(5-{2-[(3-hydroxy-3-methyl of N-(tertiary butyl)-3-{2-butyryl radicals) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of-5-(trifluoromethyl) benzamide

At room temperature stir 3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy) mixture overnight of-N-(tertiary butyl)-5-(trifluoromethyl) benzamide dihydrochloride (186mg), HMB (53mg), 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL).Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (152mg), and crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.31(6H，s)，1.48(9H，s)，2.48(2H，s)，3.54-3.66(2H，m)，4.41-4.53(2H，m)，6.01(1H，br?s)，6.57(1H，d，J＝3.3Hz)，7.07(1H，d，J＝9.0Hz)，7.18(1H，d，J＝3.3Hz)，7.25-7.35(2H，m)，7.48(1H，m)，7.62(1H，m)，7.78(1H，dd，J＝2.4Hz，9.0Hz)，8.10(1H，d，J＝2.4Hz)，8.49(1H，s)，8.72(1H，br?s).

Embodiment C-25

N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) preparation of-5-(trifluoromethyl) benzamide

At room temperature stir 3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy) mixture overnight of-N-(tertiary butyl)-5-(trifluoromethyl) benzamide dihydrochloride (186mg), methylsulfonyl acetic acid (62mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole (69mg), triethylamine (0.100mL) and DMF (3mL).Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Ethyl acetate=0:100 → 15:85) and alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90) pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol:.By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (146mg), and crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.48(9H，s)，3.14(3H，s)，3.60-3.74(2H，m)，4.00(2H，s)，4.40-4.54(2H，m)，6.06(1H，br?s)，6.58(1H，d，J＝3.0Hz)，7.08(1H，d，J＝8.8Hz)，7.21(1H，d，J＝3.0Hz)，7.35(1H，m)，7.46(1H，m)，7.58(1H，m)，7.78(1H，dd，J＝2.3Hz，8.8Hz)，7.87-7.96(1H，m)，7.97(1H，d，J＝2.3Hz)，8.29(1H，brs)，9.46(1H，s).

Embodiment C-26

The preparation of N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide

(i) the benzoic preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)

At 80 ℃, stir the mixture overnight of phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (1.51g), 3-(4-amino-2-chlorophenoxy) methyl benzoate (1.39g) and Virahol (20mL).Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.In residue, add methyl alcohol (30mL) and 1N aqueous sodium hydroxide solution (13.5mL) and at room temperature stir this mixture 3 days.This reaction mixture of concentrating under reduced pressure, adds water and 1N hydrochloric acid (13.5mL), and extracts with ethyl acetate-tetrahydrofuran (THF).Extract washes with water, pressure reducing and steaming solvent.Residue, through the crystallization of acetonitrile-ether, obtains title compound (1.88g), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:3.88(2H，m)，4.50-4.60(2H，m)，6.31(1H，br?s)，6.52(1H，d，J＝3.0Hz)，7.23-7.34(3H，m)，7.51(1H，t，J＝8.0Hz)，7.59-7.71(3H，m)，7.99(1H，d，J＝2.7Hz)，8.35(1H，s)，9.90(1H，br?s).

(ii) preparation of N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide

At room temperature stir 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) mixture overnight of phenylformic acid (850mg), TERTIARY BUTYL AMINE (0.420mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (466mg), I-hydroxybenzotriazole (368mg) and DMF (10mL).This reaction mixture of concentrating under reduced pressure, adds water and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Ethyl acetate=0:100 → 20:80) and alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80) pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol:.By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (630mg), and crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，1.66(1H，br?s)，4.08-4.16(2H，m)，4.35-4.42(2H，m)，5.99(1H，br?s)，6.16(1H，d，J＝3.3Hz)，6.98-7.03(2H，m)，7.04-7.12(1H，m)，7.30-7.37(3H，m)，7.41(1H，dd，J＝2.6Hz，8.8Hz)，7.80(1H，d，J＝2.6Hz)，8.23(1H，s)，9.68(1H，br?s).

Embodiment C-27

The preparation of { the chloro-4-of 4-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] cyclohexyl } t-butyl carbamate

At 80 ℃, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture overnight of ethyl ester (300mg), [4-(4-amino-2-chlorophenoxy) cyclohexyl] t-butyl carbamate (384mg) and Virahol (7.0mL).This reaction mixture of concentrating under reduced pressure, adds water and saturated sodium bicarbonate aqueous solution, and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: methyl alcohol=100:0 → 80:20).By target fraction concentrating under reduced pressure.Crude product is dissolved in methyl alcohol (5.0mL) and tetrahydrofuran (THF) (1.0mL), adds 1N aqueous sodium hydroxide solution (2.5mL), and at room temperature stirs this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through ethyl acetate/hexane crystallization, obtains title compound (163mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.20-1.52(4H，m)，1.38(9H，s)，1.82-2.14(4H，m)，3.25-3.32(4H，m)，3.81(2H，t，J＝4.9Hz)，4.15-4.29(1H，m)，4.60-4.72(3H，m)，6.48(1H，d，J＝3Hz)，6.80-6.83(1H，m)，7.17(1H，d，J＝9Hz)，7.46-7.49(1H，m)，7.63(1H，d，J＝3Hz)，7.77(1H，d，J＝3Hz)，8.26(1H，s)，8.68(1H，br?s).

Embodiment C-28

The preparation of { the chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } t-butyl carbamate

According to the same method in Embodiment C-27, use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (165mg), [3-(4-amino-2-chlorophenoxy) phenyl] t-butyl carbamate (200mg), Virahol (7.0mL), methyl alcohol (5.0mL), tetrahydrofuran (THF) (1.0mL) and 1N aqueous sodium hydroxide solution (2.5mL), make the title compound (90mg) that is crystal.

¹H-NMR(DMSO-d ₆)δ:1.45(9H，s)，3.49(4H，s)，3.83(2H，t，J＝4.7Hz)，4.63-4.72(3H，m)，6.51(2H，d，J＝3Hz)，7.12-7.24(4H，m)，7.63-7.69(2H，m)，7.99(1H，s)，8.34(1H，s)，8.93(1H，s)，9.43(1H，s).

Embodiment C-29

[the chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-5-(trifluoromethyl) phenyl] preparation of t-butyl carbamate

According to the same method in Embodiment C-27, use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (206mg), [3-(4-amino-2-chlorophenoxy)-5-(trifluoromethyl) phenyl] t-butyl carbamate (300mg), Virahol (10mL), methyl alcohol (2.0mL), tetrahydrofuran (THF) (1.0mL) and 1N aqueous sodium hydroxide solution (2.0mL), make the title compound (53mg) that is crystal.

¹H-NMR(CDCl ₃)δ:1.53(9H，s)，3.72-3.82(5H，m)，4.02(2H，t，J＝4.9Hz)，4.58(2H，t，J＝4.9Hz)，6.36(1H，d，J＝2.1Hz)，6.58(2H，d，J＝4.7Hz)，6.66(1H，d，J＝3.2Hz)，7.07(1H，d，J＝8.9Hz)，7.23-7.25(2H，m)，7.62(1H，dt，J＝8.9，2.1Hz)，7.87(1H，s)，8.54(1H，s)，8.79(1H，s).

Embodiment C-30

N-[3-(the chloro-4-{[5-of 2-(2-{[2-methyl-2-(methylsulfonyl) propionyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-2, the preparation of 2-dimethyl propylene acid amides

(i) 5-(2-amino-ethyl)-N-[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride

At 120 ℃, 1-Methyl-2-Pyrrolidone (15mL) solution of stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (267mg) and [3-(4-amino-2-chlorophenoxy) phenyl] t-butyl carbamate (430mg) 5 hours.Be cooled to after room temperature, water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.By the separated also purifying (hexane: ethyl acetate=19:1 → 3:2 → ethyl acetate) obtain brown solid of silica gel column chromatography for residue.At room temperature, in tetrahydrofuran (THF) (20mL) solution of gained solid, add 2N hydrochloric acid (10mL), and stir this mixture 20 hours at 60 ℃.After concentrating under reduced pressure, add ethanol, and again concentrate this mixture.Diisopropyl ether is added in residue, filter and collect gained crystal.Use diisopropyl ether washing crystal, obtain title compound (342mg), be light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:3.26-3.34(2H，m)，5.04-5.13(2H，m)，6.76-7.05(4H，m)，7.28-7.69(3H，m)，7.94(1H，s)，8.11(1H，s)，8.45(3H，br?s)，8.76(1H，s)，10.39(2H，br?s).

(ii) N-[3-(the chloro-4-{[5-of 2-(2-{[2-methyl-2-(methylsulfonyl) propionyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-2, the preparation of 2-dimethyl propylene acid amides

By 5-(2-amino-ethyl)-N-[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] mixture of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride (114mg), 2-methyl-2-(methylsulfonyl) propionic acid (210mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (380mg), I-hydroxybenzotriazole (41mg), triethylamine (1.0mL) and tetrahydrofuran (THF) (5.0mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Gained crude product is dissolved in tetrahydrofuran (THF) (5.0mL), adds N-methylmorpholine (1.0mL) and 2,2-dimethyl propylene acyl chlorides (0.25mL), and stir the mixture 1 hour.Under ice-cooled, add saturated sodium bicarbonate aqueous solution, and with this mixture of dichloromethane extraction.Extract is through dried over mgso concentrated, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → ethyl acetate: methyl alcohol=80:20) of silica gel column chromatography for residue, through the crystallization of ether/ethyl acetate, obtain title compound (82mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.19(9H，s)，1.14(6H，s)，2.96(3H，s)，3.39-3.50(2H，m)，4.55-4.59(2H，m)，6.49(1H，d，J＝3.2Hz)，6.66-6.68(1H，m)，7.17-7.74(6H，m)，7.97(1H，s)，8.22(1H，br?s)，8.34(1H，s)，8.65(1H，s)，9.26(1H，s).

Embodiment C-31

N-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

By 5-(2-amino-ethyl)-N-[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] mixture of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride (860mg), 2-methyl-2-(methylsulfonyl) propionic acid (700mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.10g), I-hydroxybenzotriazole (50mg), triethylamine (3.0mL) and tetrahydrofuran (THF) (30mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Gained crude product, through the crystallization of ether/ethyl acetate, obtains title compound (850mg).

¹H-NMR(DMSO-d ₆)δ:1.41(6H，s)，2.96(3H，s)，3.39-3.51(2H，m)，4.54-4.59(2H，m)，5.32(2H，m)，6.07-6.11(2H，m)，6.29(1H，d，J＝8.8Hz)，6.53(1H，d，J＝3.0Hz)，6.94-6.71(1H，m)，7.11(1H，d，J＝8.8Hz)，7.56-7.60(2H，m)，7.70(1H，d，J＝3.0Hz)，8.10(1H，br?s)，8.34(1H，s)，8.91(1H，s).

Embodiment C-32

N-[3-(the chloro-4-{[5-of 2-(2-{[2-methyl-2-(methylsulfonyl) propionyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

According to the same method in Embodiment C-31; use 5-(2-amino-ethyl)-N-[4-(3-amino-benzene oxygen)-3-chloro-phenyl-]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (80mg), 2-methyl-2-(methylsulfonyl) propionic acid (87mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (210mg), I-hydroxybenzotriazole (71mg), triethylamine (0.9mL) and tetrahydrofuran (THF) (8.0mL), make the title compound (89mg) that is crystal.

¹H-NMR(DMSO-d ₆)δ:1.41(6H，s)，1.64(6H，s)，2.96(3H，s)，3.03(3H，s)，3.41-3.52(2H，m)，4.55-4.59(2H，m)，6.49(1H，d，J＝3.2Hz)，6.73-6.76(1H，m)，7.17-7.76(6H，m)，7.99(1H，d.J＝3.2Hz)，8.22(1H，br?s)，8.34(1H，s)，8.66(1H，s)，9.52(1H，s).

Embodiment C-33

N-{2-[4-({ 4-[3-(acetylamino) phenoxy group]-3-chloro-phenyl-} amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

At room temperature stir N-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl]-2-methyl-2-(methylsulfonyl) propionic acid amide (91mg), triethylamine (0.2mL), the mixture of acetic anhydride (0.3mL) and tetrahydrofuran (THF) (7.0mL) 1 hour.Under ice-cooled, add saturated sodium bicarbonate aqueous solution, and with this mixture of dichloromethane extraction.Dried over mgso concentrated for extract, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 80:20), through the crystallization of ether/ethyl acetate, obtain being the title compound (84mg) of crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.41(6H，s)，2.00(3H，s)，2.96(3H，s)，3.39-3.50(2H，m)，4.55-4.59(2H，m)，6.49(1H，d，J＝3.2Hz)，6.63-6.68(1H，m)，7.23-7.30(4H，m)，7.59(1H，s)，7.72-7.75(1H，m)，7.96(1H，s)，8.20(1H，br?s)，8.34(1H，s)，8.65(1H，s)，10.00(1H，s).

Embodiment C-34

2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethanol

Will the chloro-4-of 3-[2-(5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } t-butyl carbamate (120mg) is dissolved in methyl alcohol (7.0mL), add 4N hydrogenchloride/ethyl acetate solution (8.0mL), and stir this mixture 5 hours.Add 8N aqueous sodium hydroxide solution (8.0mL) and water (10mL), mixture dichloromethane extraction.Dried over mgso concentrated for extract, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 80:20), through the crystallization of ether/ethyl acetate, obtain being the title compound (59mg) of crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:3.49(4H，s)，3.81-3.85(2H，m)，4.62-4.65(2H，t，J＝4.8Hz)，4.71(1H，m)，5.32(2H，m)，6.06-6.09(2H，m)，6.27(1H，d，J＝8.8Hz)，6.51(1H，d，J＝3.0Hz)，6.94-6.70(1H，m)，7.11(1H，d，J＝8.8Hz)，7.56-7.60(1H，m)，7.70(1H，d，J＝3.0Hz)，7.95(1H，s)，8.34(1H，s)，8.93(1H，s).

Embodiment C-35

The preparation of N-(tertiary butyl)-N '-{ the chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } urea

(i) phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethyl ester dihydrochloride

At 80 ℃, stir 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethylamino benzonitrile acid esters (206mg), [3-(4-amino-2-chlorophenoxy) phenyl] t-butyl carbamate (300mg) and Virahol (7.0mL) 12 hours.This reaction mixture of concentrating under reduced pressure, adds water and saturated sodium bicarbonate aqueous solution, and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: hexane: ethyl acetate=80:20 → 0:100).By target fraction concentrating under reduced pressure.Crude product is dissolved in to methyl alcohol (8.0mL), and according to the same method in Embodiment C-34, uses 4N hydrogenchloride/ethyl acetate solution (8.0mL), make title compound (370mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.76-3.80(2H，m)，3.87-3.94(2H，m)，4.22-4.35(2H，m)，4.85-4.93(2H，m)，6.62-6.77(3H，m)，6.87-7.18(3H，m)，7.30-7.71(8H，m)，7.90(1H，s)，8.01(1H，s)，8.65(1H，s).

(ii) preparation of N-(tertiary butyl)-N '-{ the chloro-4-of 3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } urea

By phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (200mg) is suspended in toluene (10mL), add triethylamine (0.9mL) and tert-butyl isocyanate (2-isocyanato-2-methylpropane) (0.4mL), and at 120 ℃, stir this mixture 6 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.Residue is dissolved in methyl alcohol (6.0mL) and tetrahydrofuran (THF) (6.0mL).Add 1N aqueous sodium hydroxide solution (3.0mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (74mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.26(9H，s)，3.49(4H，s)，3.83(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.71(1H，m)，5.93(1H，s)，6.43-6.52(2H，m)，6.96-7.21(4H，m)，7.60-7.69(2H，m)，7.98(1H，d，J＝3.0Hz)，8.34(1H，s)，8.35(1H，s)，8.92(1H，s).

Embodiment C-36

The chloro-4-of N-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-3, the preparation of 3-amide dimethyl butyrate

By phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethyl ester dihydrochloride (270mg), triethylamine (1.9mL), 3,3-Dimethylbutyryl chloride (0.3mL) and tetrahydrofuran (THF) (20mL) at room temperature stirs 1 hour.Under ice-cooled, add saturated sodium bicarbonate aqueous solution, and with this mixture of dichloromethane extraction.Dried over mgso concentrated for extract.Residue is by silica gel column chromatography (elutriant: ethyl acetate: methyl alcohol=100:0 → 80:20).By target fraction concentrating under reduced pressure.Residue is dissolved in to methyl alcohol (6.0mL) and tetrahydrofuran (THF) (6.0mL).Add 1N aqueous sodium hydroxide solution (2.0mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (126mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.00(9H，s)，2.15(2H，s)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.66(2H，t，J＝6.0Hz)，4.71(1H，m)，6.52(1H，d，J＝3.0Hz)，6.68-6.70(1H，m)，7.16-7.37(4H，m)，7.61-7.69(2H，m)，7.99(1H，d，J＝3.0Hz)，8.34(1H，s)，8.94(1H，s)，9.85(1H，s).

Embodiment C-37

The chloro-4-of N-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-3-hydroxyl-2, the preparation of 2-dimethyl propylene acid amides

By phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (260mg), 3-hydroxyl-2,2-neopentanoic acid (200mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (621mg), I-hydroxybenzotriazole (70mg), the mixture of triethylamine (2.0mL) and tetrahydrofuran (THF) (15mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Gained crude product is dissolved in to methyl alcohol (6.0mL) and tetrahydrofuran (THF) (6.0mL), adds 1N aqueous sodium hydroxide solution (2.0mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (84mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.30(6H，s)，3.49(4H，s)，3.56(2H，br?s)，3.84(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.71(1H，s)，4.73(1H，m)，6.50(1H，d，J＝3.2Hz)，6.64(1H，d，J＝7.7Hz)，7.15-7.38(4H，m)，7.62-7.70(2H，m)，7.99(1H，d，J＝3.2Hz)，8.34(1H，s)，8.94(1H，s)，9.90(1H，s).

Embodiment C-38

The chloro-4-of N-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of-1-methyl cyclopropane methane amide

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (200mg), 1-methyl cyclopropane carboxylic acid (179mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (600mg), I-hydroxybenzotriazole (70mg), triethylamine (2.3mL), tetrahydrofuran (THF) (20mL), 1N aqueous sodium hydroxide solution (2.0mL), tetrahydrofuran (THF) (6.0mL) and ethanol (6.0mL), make the title compound (69mg) that is crystal.

¹H-NMR(DMSO-d ₆)δ:0.59-0.62(2H，m)，1.04-1.08(2H，m)，1.37(3H，s)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.66(2H，t，J＝6.0Hz)，4.71(1H，m)，6.52(1H，d，J＝3.0Hz)，6.60-6.70(1H，m)，7.15(1H，d，J＝6.0Hz)，7.23-7.41(3H，m)，7.60-7.64(1H，m)，7.70(1H，d，J＝3.0Hz)，7.98(1H，d，J＝3.0Hz)，8.36(1H，s)，8.98(1H，s)，9.22(1H，s).

Embodiment C-39

2-(the chloro-4-{3-[(2 of 2-{4-[(3-, 2-dimethyl propyl) amino] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol

By phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (220mg) is suspended in methylene dichloride (7.0mL), and add acetic acid (0.7mL), molecular sieve 4A (300mg) and pivalyl aldehyde (120mg), stir this mixture 30min.Add sodium triacetoxy borohydride (470mg), then stir this mixture 3 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.Residue is dissolved in methyl alcohol (6.0mL) and tetrahydrofuran (THF) (6.0mL).Add 1N aqueous sodium hydroxide solution (2.0mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (67mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:0.93(9H，s)，2.77(2H，d，J＝6.0Hz)，3.49(4H，s)，3.83(2H，t，J＝4.7Hz)，4.63-4.72(3H，m)，5.63(1H，t，J＝6.0Hz)，6.02-6.05(1H，m)，6.24(1H，t，J＝3.0Hz)，6.34-6.36(1H，m)，6.51(1H，d，J＝3.0Hz)，7.00(1H，t，J＝6.0Hz)，7.08(1H，d，J＝9.0Hz)，7.56-7.60(1H，m)，7.68(1H，d，J＝3.0Hz)，7.95(1H，d，J＝3.0Hz)，8.33(1H，s)，8.91(1H，s).

Embodiment C-40

The chloro-4-of N-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-4,4, the preparation of the fluoro-2-methylbutyryl of 4-tri-amine

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (50mg), 4, 4, the fluoro-2-Methyl Butyric Acid of 4-tri-(47mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (125mg), I-hydroxybenzotriazole (5mg), triethylamine (0.7mL), tetrahydrofuran (THF) (7.0mL), 1N aqueous sodium hydroxide solution (1.5mL), tetrahydrofuran (THF) (3.0mL) and methyl alcohol (2.0mL), make the title compound (25mg) that is crystal.

¹H-NMR(DMSO-d ₆)δ:1.18(3H，d，J＝6.0Hz)，2.26-2.85(3H，m)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.66(2H，t，J＝6.0Hz)，4.71(1H，m)，6.52(1H，d，J＝3.0Hz)，6.68-6.70(1H，m)，7.14-7.38(4H，m)，7.62-7.70(2H，m)，7.99(1H，d，J＝3.0Hz)，8.34(1H，s)，8.95(1H，s)，10.14(1H，s).

Embodiment C-41

The chloro-4-of N-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of-N '-cyclohexyl urea

According to same method in Embodiment C-35 (ii), use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] and ethyl ester dihydrochloride (240mg), toluene (15mL), triethylamine (2.0mL), NSC 87419 (cyclohexylisocyanate) (137mg), 1N aqueous sodium hydroxide solution (3.0mL), tetrahydrofuran (THF) (6.0mL) and methyl alcohol (6.0mL), make title compound (56mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.09-1.82(10H，m)，3.34-3.51(1H，m)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.71(1H，m)，6.00(1H，d，J＝9.0Hz)，6.46-6.52(2H，m)，6.96-7.21(4H，m)，7.61-7.69(2H，m)，7.98(1H，d，J＝2.7Hz)，8.34(1H，s)，8.41(1H，s)，8.93(1H，s).

Embodiment C-42

The chloro-4-of N-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-3,3, the preparation of the fluoro-2-hydroxy-2-methyl of 3-tri-propionic acid amide

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (201mg), 3, 3, the fluoro-2-hydroxy-2-methyl of 3-tri-propionic acid (175mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (415mg), I-hydroxybenzotriazole (47mg), triethylamine (1.8mL), tetrahydrofuran (THF) (28mL), 1N aqueous sodium hydroxide solution (4.0mL), tetrahydrofuran (THF) (6.0mL) and methyl alcohol (6.0mL), make title compound (47mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.01(3H，s)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.65(2H，t，J＝6.0Hz)，4.71(1H，m)，6.52(1H，d，J＝3.0Hz)，6.60-6.70(1H，m)，7.14(1H，d，J＝6.0Hz)，7.22-7.45(3H，m)，7.60-7.65(1H，m)，7.71(1H，d，J＝3.0Hz)，7.98(1H，d，J＝3.0Hz)，8.36(1H，s)，8.98(1H，s)，9.22(1H，s).

Embodiment C-43

The chloro-4-of N-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of-1-(trifluoromethyl) cyclopropane carboxamide

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (220mg), 1-(trifluoromethyl) cyclopropane-carboxylic acid (300mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (450mg), I-hydroxybenzotriazole (110mg), triethylamine (2.6mL), tetrahydrofuran (THF) (15mL), 1N aqueous sodium hydroxide solution (4.0mL), tetrahydrofuran (THF) (6.0mL) and methyl alcohol (6.0mL), make title compound (23mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.14-1.31(2H，m)，1.42-1.45(2H，m)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.71(1H，m)，6.51(1H，d，J＝3.0Hz)，6.70-6.73(1H，m)，7.15-7.41(4H，m)，7.60-7.69(2H，m)，7.99(1H，d，J＝3.0Hz)，8.34(1H，s)，8.95(1H，s)，9.84(1H，s).

Embodiment C-44

The chloro-4-of N-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-N '-(tetrahydrochysene-2H-pyrans-4-yl) urea

To 1, in 1 '-carbonyl diurethane (1H-imidazoles) toluene (10mL) solution (401mg), add tetrahydrochysene-2H-pyrans-4-amine (250mg), and at room temperature stir this mixture 1 hour.Add phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (220mg) and triethylamine (2.0mL) stir this mixture 30min at 70 ℃.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, is dissolved in gained residue in methyl alcohol (8.0mL) and tetrahydrofuran (THF) (2.0mL).Add 1N aqueous sodium hydroxide solution (3.0mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Pressure reducing and steaming solvent, gained residue, through the crystallization of ethyl acetate-hexane, obtains title compound (12mg), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.09-1.82(4H，m)，3.20-3.63(4H，m)，3.33-3.55(1H，m)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.71(1H，m)，6.00(1H，d，J＝9.0Hz)，6.45-6.52(2H，m)，6.97-7.21(4H，m)，7.59-7.71(2H，m)，7.99(1H，d，J＝2.7Hz)，8.34(1H，s)，8.41(1H，s)，8.94(1H，s).

Embodiment C-45

The chloro-4-of N-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of cyclopropane carboxamide

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (200mg), cyclopropane-carboxylic acid (200mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (470mg), I-hydroxybenzotriazole (42mg), triethylamine (2.0mL), tetrahydrofuran (THF) (29mL), 1N aqueous sodium hydroxide solution (3.0mL), tetrahydrofuran (THF) (6.0mL) and methyl alcohol (6.0mL), make title compound (98mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.76-0.78(2H，m)，1.04(2H，d，J＝6.0Hz)，1.71-1.75(1H，m)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.66(2H，t，J＝6.0Hz)，4.71(1H，m)，6.52(1H，d，J＝3.0Hz)，6.62-6.66(1H，m)，7.17(1H，d，J＝9.0Hz)，7.23-7.31(3H，m)，7.61-7.69(2H，m)，7.99(1H，d，J＝3.0Hz)，8.34(1H，s)，8.94(1H，s)，10.25(1H，s).

Embodiment C-46

The chloro-4-of N-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of-3-hydroxy-3-methyl butyramide

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (200mg), HMB (200mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (470mg), I-hydroxybenzotriazole (41mg), triethylamine (1.8mL), tetrahydrofuran (THF) (28mL), 1N aqueous sodium hydroxide solution (2.0mL), tetrahydrofuran (THF) (6.0mL) and methyl alcohol (6.0mL), make title compound (53mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.21(6H，s)，2.38(2H，s)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.71(1H，s)，4.73(1H，m)，6.51(1H，d，J＝3.2Hz)，6.63(1H，d，J＝7.7Hz)，7.15-7.37(4H，m)，7.61-7.69(2H，m)，7.99(1H，d，J＝3.2Hz)，8.34(1H，s)，8.94(1H，s)，9.87(1H，s).

Embodiment C-47

N-(the chloro-4-{3-[(3-of 2-{4-[(3-hydroxyl-2,2-dimethyl propylene acyl group) amino] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-3-hydroxy-3-methyl butyramide

According to method same in Embodiment C-31, using 5-(2-amino-ethyl)-N-[4-(3-amino-benzene oxygen)-3-chloro-phenyl-]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride (150mg), HMB (42mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (357mg), I-hydroxybenzotriazole (18mg) and triethylamine (0.9mL) react in tetrahydrofuran (THF) (4.0mL).According to method same in Embodiment C-31, use crude product and 3-hydroxyl-2 of gained, 2-neopentanoic acid (200mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (460mg), I-hydroxybenzotriazole (150mg), triethylamine (2.0mL) are in tetrahydrofuran (THF) (7.0mL), make title compound (90mg), be crystal.

¹H-NMR(CDCl ₃)δ:1.25(6H，s)，1.32(6H，s)，2.48(2H，s)，2.80(2H，br?s)，3.59(2H，s)，3.57-3.65(2H，m)，4.45-4.51(2H，m)，6.62(1H，d，J＝3.0Hz)，7.05-7.44(8H，m)，7.73(1H，dd，J＝8.7Hz，2.7Hz)，8.03(1H，d，J＝2.7Hz)，8.30(1H，s)，8.50(1H，s).

Embodiment C-48

The chloro-4-of N-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of propionic acid amide

According to method same in Embodiment C-37, use phenylformic acid 2-[2-(4-{[4-(3-amino-benzene oxygen)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester dihydrochloride (200mg), propionic acid (0.5mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (560mg), I-hydroxybenzotriazole (67mg), triethylamine (2.1mL), tetrahydrofuran (THF) (10mL), 1N aqueous sodium hydroxide solution (2.0mL), tetrahydrofuran (THF) (6.0mL) and methyl alcohol (6.0mL), make title compound (70mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.04(3H，t，J＝7.5Hz)，2.28(2H，dd，J＝7.5Hz)，3.49(4H，s)，3.84(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，4.73(1H，m)，6.51(1H，d，J＝3.2Hz)，6.63(1H，d，J＝7.7Hz)，7.15-7.32(4H，m)，7.61-7.69(2H，m)，7.99(1H，d，J＝3.2Hz)，8.34(1H，s)，8.94(1H，s)，9.92(1H，s).

Embodiment C-49

The chloro-4-of 4-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of piperidines-1-t-butyl formate

(i) 4-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of piperidines-1-t-butyl formate

The fluoro-4-oil of mirbane of the chloro-1-of 2-(7.27g) and 4-(3-hydroxyphenyl) piperidines-1-t-butyl formate (11.5g) are dissolved in to N, in dinethylformamide (42mL), add salt of wormwood (8.28g) and at room temperature stir this mixture 16 hours.With ethyl acetate (300mL) diluted reaction mixture water (300mL) washing.Organic layer is through anhydrous magnesium sulfate drying, reduction vaporization.Residue, by silica gel column chromatography (hexane/ethyl acetate=100/0 → 60/40), obtains title compound (17.6g), is oily.

¹H-NMR(CDCl ₃)δ:1.47(9H，s)，1.50-1.70(2H，m)，1.84(2H，d，J＝13Hz)，2.60-2.90(3H，m)，4.23(2H，m)，6.87(1H，d，J＝9Hz)，6.92(2H，m)，7.12(1H，d，J＝8Hz)，7.37(1H，m)，8.04(1H，dd，J＝3Hz，9Hz)，8.38(1H，d，J＝3Hz).

(ii) 4-[3-(4-amino-2-chlorophenoxy) phenyl] preparation of piperidines-1-t-butyl formate

By 4-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] piperidines-1-t-butyl formate (1.9g) is suspended in ethanol (43mL)/water (4.81mL), add wherein calcium chloride (270mg), under 90 ℃ of stirrings, heat and within 10 minutes, make mixture dissolve.Add wherein reduced iron (1.63g), under 90 ℃ of stirrings, heat this mixture 16 hours.Be cooled to after room temperature, reaction mixture is filtered to Sai Lite, concentrating under reduced pressure filtrate.Gained for solid ethyl acetate (150mL) dilute and use saturated brine (80mL) washing.Anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.Residue, through silica gel column chromatography purifying (hexane/ethyl acetate=80/20 → 60/40), obtains title compound (1.71g), is oily.

¹H-NMR(CDCl ₃)δ:1.48(9H，s)，1.50-1.70(2H，m)，1.80(2H，d，J＝13Hz)，2.58(1H，m)，2.77(2H，t，J＝13Hz)，3.69(2H，br?s)，4.22(2H，m)，6.57(1H，dd，J＝3Hz，9Hz)，6.60-6.90(5H，m)，7.20(1H，t，J＝8Hz).

(iii) the chloro-4-of 4-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of piperidines-1-t-butyl formate

At 80 ℃, by phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (150mg), 4-[3-(4-amino-2-chlorophenoxy) phenyl] mixture of piperidines-1-t-butyl formate (260mg) and Virahol (1.5mL) under agitation heats 16 hours.Ethyl acetate for reaction mixture (80mL) dilution, with sodium bicarbonate aqueous solution (40mL) washing.Separated organic layer, with anhydrous magnesium sulfate drying, reduction vaporization.Residue is through purification by silica gel column chromatography (hexane/ethyl acetate=90/10 → 0/100), by target fraction concentrating under reduced pressure.Gained residue is dissolved in methyl alcohol (1.89mL), adds wherein 1N aqueous sodium hydroxide solution (0.433mL), and at room temperature stir this mixture 2 hours.Add 1N hydrochloric acid (0.433mL), ethyl acetate for mixture (30mL) dilution, and wash with saturated brine (30mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure, and residue, by alkaline silica gel column chromatography (ethyl acetate/methanol=100/0 → 85/15), obtains title compound (88mg), is powder.

¹H-NMR(CDCl ₃)δ:1.47(9H，s)，1.50-1.80(2H，m)，1.81(2H，m)，2.61(1H，m)，2.77(2H，m)，3.72(2H，m)，3.79(2H，m)，4.01(2H，t，J＝5Hz)，4.21(2H，m)，4.55(2H，t，J＝5Hz)，6.59(1H，d，J＝3Hz)，6.79(2H，m)，6.90(1H，d，J＝7.5Hz)，7.00(1H，d，J＝9Hz)，7.18-7.30(2H，m)，7.55(1H，dd，J＝3Hz，9Hz)，7.86(1H，d，J＝3Hz)，8.49(1H，s)，8.78(1H，br?s).

Embodiment C-50

N-(the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

According to same method in Embodiment C-8 (iii); use 5-(2-amino-ethyl)-N-(the chloro-4-{3-[4-of 3-(trifluoromethyl)-1; 3-thiazol-2-yl] phenoxy group } phenyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (200mg), 2-methyl-2-(methylsulfonyl) propionic acid (83mg), I-hydroxybenzotriazole (75mg), triethylamine (0.23mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (105mg) and N; dinethylformamide (5.0mL); make title compound (171mg), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:1.70(6H，s)，2.93(3H，s)，3.6-3.75(2H，m)，4.40-4.55(2H，m)，6.63(1H，d，J＝3.3Hz)，7.00-7.10(1H，m)，7.09(1H，d，J＝8.7Hz)，7.21(1H，d，J＝3.0Hz)，7.25-7.45(2H，m)，7.60-7.70(2H，m)，7.75(1H，s)，7.80-7.95(1H，m)，8.04(1H，d，J＝2.4Hz)，8.36(1H，s)，8.53(1H，s).

Embodiment C-51

N-(the chloro-4-{3-[4-of 2-{4-[(3-(trifluoromethyl)-1,3-thiazoles-2-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-3-hydroxy-3-methyl butyramide

According to same method in Embodiment C-8 (iii), use 5-(2-amino-ethyl)-N-(the chloro-4-{3-[4-of 3-(trifluoromethyl)-1,3-thiazol-2-yl] phenoxy group } phenyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), HMB (59mg), I-hydroxybenzotriazole (75mg), triethylamine (0.23mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (105mg) and N, dinethylformamide (5.0mL), make title compound (95.3mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.33(6H，s)，2.48(2H，s)，3.60-3.70(2H，m)，4.40-4.50(2H，m)，6.60(1H，d，J＝3.0Hz)，6.85-6.95(1H，m)，7.00-7.10(2H，m)，7.18(1H，d，J＝3.0Hz)，7.40(1H，t，J＝9.0Hz)，7.60-7.80(4H，m)，8.07(1H，s)，8.52(1H，s)，8.63(1H，s).

Embodiment C-52

N-(3-{2-chloro-4-[(6-cyano group-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } phenyl) preparation of cyclopropane carboxamide

At 0 ℃, in tetrahydrofuran (THF) (15mL) solution of diisopropylamine (545mg), add n-Butyl Lithium (2.9mL).Stir after 30 minutes, mixture is cooled to-78 ℃, and add wherein 4-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine (603mg).Mixture is stirred 1 hour, add p-toluenesulfonyl cyanogen (p-toluenesulfonyl cyanide) (1300mg), with 1 hour, mixture is warming up to-40 ℃.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: hexane: ethyl acetate=80:20 → 30:70).After concentrating under reduced pressure, gained crystal is dissolved in Virahol (7.0mL).Add N-[3-(4-amino-2-chlorophenoxy) phenyl] cyclopropane carboxamide (232mg), and stir this mixture 3 hours at 80 ℃.After concentrating under reduced pressure, add water and saturated sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: hexane: ethyl acetate=80:20 → 0:100).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (103mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:0.77(4H，d，J＝6.1Hz)，1.73-1.81(1H，m)，4.31(3H，s)，6.66-6.70(1H，m)，7.21-7.40(4H，m)，7.53(1H，s)，7.62(1H，d，J＝8.7Hz)，7.90(1H，s)，8.64(1H，s)，9.87(1H，br?s)，10.25(1H，s).

Embodiment C-53

N-{2-[4-({ the chloro-4-[3-of 3,5-bis-(dimethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) 3, the chloro-4-[3-of 5-bis-(dimethylamino) phenoxy group] preparation of aniline

To 3-(dimethylamino) phenol (470mg) and 1, in DMF (15mL) solution of the iodo-5-oil of mirbane of the chloro-2-of 3-bis-(1.00g), add salt of wormwood (850mg) and at room temperature stir this mixture 18 hours.Under ice-cooled, salt solution is added in this reaction mixture, be extracted with ethyl acetate this mixture 2 times, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), gained crude product is dissolved in 15% aqueous ethanol (23mL) of silica gel column chromatography for residue.Add reduced iron (750mg) and calcium chloride (120mg), at 80 ℃, stir this mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1), obtain title compound (402mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:2.85(6H，s)，5.58(2H，s)，5.88(1H，dd，J＝1.9Hz，8.0Hz)，6.19(1H，t，J＝2.2Hz)，6.37(1H，dd，J＝1.9Hz，8.0Hz)，6.69(2H，s)，7.04(1H，t，J＝8.3Hz).

(ii) N-{2-[4-({ the chloro-4-[3-of 3,5-bis-(dimethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

At 80 ℃, stir [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (150mg), 3, the chloro-4-[3-of 5-bis-(dimethylamino) phenoxy group] mixture 12 hours of aniline (150mg) and Virahol (8.0mL).Under ice-cooled, in reaction mixture, add sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=60:40 → 100:0) of silica gel column chromatography for residue, gained crude product (150mg) is dissolved in tetrahydrofuran (THF) (10mL), add 4N hydrogenchloride/ethyl acetate solution (5.0mL), at 70 ℃, stirring the mixture 20 hours.Pressure reducing and steaming solvent, adds ethanol and diisopropyl ether in residue, filters the powder of collecting precipitation, and is dissolved in DMF (7.0mL).Methylsulfonyl acetic acid (70mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (160mg), I-hydroxybenzotriazole (70mg) and triethylamine (0.15mL) are added in mixture, and at room temperature stir this mixture 16 hours.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=90:10), through diisopropyl ether crystallization, obtain title compound (74mg).

¹H-NMR(DMSO-d ₆)δ:2.89(6H，s)，3.11(3H，s)，3.44-3.49(2H，m)，4.06(2H，s)，4.55-4.59(2H，m)，5.89-7.11(5H，m)，7.66-8.69(5H，m)，8.77(1H，s).

Embodiment C-54

N-(tertiary butyl)-3-{2-chloro-4-[(5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of benzamide

(i) 3-{2-chloro-4-[(5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of methyl benzoate

At 80 ℃, stir the mixture overnight of 4-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine (1.01g), 3-(4-amino-2-chlorophenoxy) methyl benzoate (1.39g) and Virahol (10mL).Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=60:40 → 100:0).By target fraction concentrating under reduced pressure.Ethyl acetate-ether is added in residue, by filtering the solid of collecting precipitation, obtain title compound (1.77g), be yellow powder.

¹H-NMR(CDCl ₃)δ:3.90(3H，s)，4.15(3H，s)，6.56(1H，d，J＝3.3Hz)，6.83(1H，br?s)，7.06(1H，d，J＝8.8Hz)，7.16-7.22(2H，m)，7.40(1H，t，J＝8.0Hz)，7.46(1H，dd，J＝2.5Hz，8.8Hz)，7.56-7.60(1H，m)，7.74-7.79(1H，m)，7.81(1H，d，J＝2.5Hz)，8.51(1H，s).

(ii) 3-{2-chloro-4-[(5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } benzoic preparation

To the chloro-4-[(5-methyl-5H-of 3-{2-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } add methyl alcohol (20mL), tetrahydrofuran (THF) (5mL) and 1N aqueous sodium hydroxide solution (8.2mL) in methyl benzoate (1.68g), and at room temperature stir this mixture overnight.This reaction mixture of concentrating under reduced pressure, adds 1N hydrochloric acid (8.2mL), ethyl acetate and diisopropyl ether wherein.Filter the solid of collecting precipitation, water and diisopropyl ether washing, obtain title compound (1.62g), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:4.16(3H，s)，6.45(1H，d，J＝3.0Hz)，7.24-7.32(3H，m)，7.51(1H，t，J＝8.0Hz)，7.60(1H，d，J＝3.0Hz)，7.64-7.73(2H，m)，7.96(1H，d，J＝2.4Hz)，8.32(1H，s)，8.62(1H，br?s).

(iii) N-(tertiary butyl)-3-{2-chloro-4-[(5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of benzamide

By the chloro-4-[(5-methyl-5H-of 3-{2-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } mixture of phenylformic acid (197mg), TERTIARY BUTYL AMINE (0.105mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (92mg) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (215mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，4.15(3H，s)，5.96(1H，br?s)，6.56(1H，d，J＝3.0Hz)，6.85(1H，br?s)，7.02(1H，d，J＝8.5Hz)，7.05-7.10(1H，m)，7.18(1H，d，J＝3.0Hz)，7.31-7.44(4H，m)，7.80(1H，d，J＝2.5Hz)，8.50(1H，s).

Embodiment C-55

N-{2-[4-({ the chloro-4-[3-of 3-(diethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) 3-(4-amino-2-chlorophenoxy)-N, the preparation of N-Diethyl Aniline

Same method according to Embodiment C-6 (iv) and (v), use 3-(diethylamino) phenol (920mg), the chloro-4-fluoronitrobenzene of 3-(1.01g), salt of wormwood (1.38g), N, dinethylformamide (20mL), 5% platinum-gac (300mg), ethyl acetate (10mL) and methyl alcohol (5.0mL), make title compound (954mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.06-1.12(6H，m)，3.25-3.34(4H，m)，5.26(2H，s)，5.94-6.57(4H，m)，6.68(1H，d，J＝2.0Hz)，6.86(1H，d，J＝8.0Hz)，7.12(1H，t，J＝8.3Hz).

(ii) N-{2-[4-({ the chloro-4-[3-of 3-(diethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy)-N, N-Diethyl Aniline (150mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (150mg), Virahol (10mL), tetrahydrofuran (THF) (15mL), 4N hydrogenchloride/ethyl acetate solution (5.0mL), methylsulfonyl acetic acid (190mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (290mg), I-hydroxybenzotriazole (10mg), triethylamine (4.0mL) and N, dinethylformamide (15mL), make title compound (117mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.05-1.10(6H，m)，3.10(3H，s)，3.27-3.34(4H，m)，3.44-3.49(2H，m)，4.05(2H，s)，4.53-4.57(2H，m)，6.00-6.49(4H，m)，7.07-7.91(5H，m)，8.32(1H，s)，8.62-8.68(2H，m).

Embodiment C-56

N-{2-[4-({ the chloro-4-[3-of 3-(diethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butyramide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy)-N, N-Diethyl Aniline (150mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (150mg), Virahol (10mL), tetrahydrofuran (THF) (15mL), 4N hydrogenchloride/ethyl acetate solution (5.0mL), HMB (75mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (191mg), I-hydroxybenzotriazole (5.0mg), triethylamine (0.3mL) and N, dinethylformamide (6mL), make title compound (94mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.05-1.17(12H，m)，2.20(2H，s)，3.24-3.34(4H，m)，3.37-3.44(2H，m)，4.48-4.53(2H，m)，4.65(1H，s)，6.01-6.48(4H，m)，7.06-7.97(5H，m)，8.22-8.26(1H，m)，8.31(1H，s)，8.80(1H，s).

Embodiment C-57

N-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-2, the preparation of 2-dimethyl propylene acid amides

By phenylformic acid N-[3-(4-amino-2-chlorophenoxy) phenyl]-2,2-dimethyl propylene acid amides (70mg) and 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) mixture of ethyl ester (63mg) is dissolved in Virahol (3mL), pyridine hydrochloride (5mg) is added wherein, at 80 ℃, stir this mixture 16 hours.By reaction mixture cool to room temperature, 1N aqueous sodium hydroxide solution (2mL) is added wherein, and at room temperature stir this mixture 9 hours.Saturated aqueous ammonium chloride is added in reaction mixture, and be extracted with ethyl acetate.Saturated brine washing for organic layer, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=10:90 → 0:100 → ethyl acetate: methyl alcohol=90:10), through the crystallization of diisopropyl ether/ethyl acetate, obtain title compound (49mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.16(9H，s)，3.86-3.89(2H，m)，4.52-4.55(2H，m)，6.50-6.66(2H，m)，7.18-7.97(7H，m)，8.33(1H，s)，9.22(1H，s)，9.83(1H，br?s).

Embodiment C-58

2-[4-({ the chloro-4-[3-of 3-(diethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to method same in Embodiment C-57, use phenylformic acid 3-(4-amino-2-chlorophenoxy)-N, N-Diethyl Aniline (112mg), 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (100mg), Virahol (5.0mL), 1N aqueous sodium hydroxide solution (5.0mL) and methyl alcohol (10mL), make title compound (52mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.05-1.09(6H，m)，3.26-3.33(4H，m)，3.85-3.88(2H，m)，4.51-4.54(2H，m)，5.99-6.41(3H，m)，6.49(1H，d，J＝3.0Hz)，7.05-7.94(5H，m)，8.32(1H，s)，9.76(1H，br?s).

Embodiment C-59

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-methylcyclohexyl) benzamide

By 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) mixture of phenylformic acid (170mg), 1-methyl cyclohexane amine hydrochlorate (180mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (92mg), triethylamine (0.170mL) and DMF (5mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Ethyl acetate=0:100 → 20:80) and silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80), and by target fraction concentrating under reduced pressure pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol:.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (92mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.20-1.70(13H，m)，2.05-2.20(2H，m)，4.07-4.17(2H，m)，4.35-4.42(2H，m)，5.86(1H，br?s)，6.14(1H，d，J＝3.3Hz)，6.68(1H，br?s)，6.97-7.12(3H，m)，7.30-7.45(4H，m)，7.81(1H，d，J＝2.4Hz)，8.23(1H，s)，9.69(1H，br?s).

Embodiment C-60

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-phenylcyclohexane methane amide

By 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) mixture of phenylformic acid (170mg), hexahydroaniline (119mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (92mg) and DMF (5mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (178mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.10-1.82(8H，m)，1.95-2.07(2H，m)，3.86-4.01(1H，m)，4.01-4.18(2H，m)，4.37-4.44(2H，m)，6.03(1H，d，J＝8.1Hz)，6.04-6.12(1H，m)，6.22(1H，d，J＝3.0Hz)，6.98-7.11(3H，m)，7.32-7.44(4H，m)，7.79(1H，d，J＝2.7Hz)，8.28(1H，s)，9.57(1H，br?s).

Embodiment C-61

The preparation of N-(tertiary butyl)-3-(4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) benzamide hydrochloride salt

(i) preparation of 3-(2-methyl-4-nitrophenoxy) methyl benzoate

The mixture of 3-methyl hydroxybenzoate (3.04g), the fluoro-5-nitrotoluene of 2-(3.10g), salt of wormwood (4.15g) and DMF (20mL) is at room temperature stirred and spent the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=5:95 → 15:85).Concentrating under reduced pressure target fraction, obtains title compound (5.66g), is faint yellow solid.

¹H-NMR(CDCl ₃)δ:2.41(3H，s)，3.91(3H，s)，6.78(1H，d，J＝8.9Hz)，7.21-7.27(1H，m)，7.49(1H，t，J＝7.8Hz)，7.65-7.68(1H，m)，7.86-7.91(1H，m)，8.01(1H，dd，J＝2.8Hz，8.9Hz)，8.17(1H，d，J＝2.8Hz).

(ii) the benzoic preparation of 3-(2-methyl-4-nitrophenoxy)

In 3-(2-methyl-4-nitrophenoxy) methyl benzoate (5.66g), add Virahol (100mL) and 1N aqueous sodium hydroxide solution (22mL), and at room temperature stir this mixture overnight.In reaction mixture, add 1N hydrochloric acid (25mL), filter the solid of collecting precipitation, wash with water, obtain title compound (4.54g), powder is white in color.

¹H-NMR(CDCl ₃)δ:2.41(3H，s)，6.81(1H，d，J＝8.9Hz)，7.26-7.32(1H，m)，7.52(1H，t，J＝7.9Hz)，7.70-7.74(1H，m)，7.92-7.97(1H，m)，8.02(1H，dd，J＝2.9Hz，8.9Hz)，8.17(1H，d，J＝2.9Hz).

(iii) preparation of N-(tertiary butyl)-3-(2-methyl-4-nitrophenoxy) benzamide

At 80 ℃, the mixture of 3-(2-methyl-4-nitrophenoxy) phenylformic acid (820mg), thionyl chloride (0.438mL), DMF (1) and toluene (10mL) is stirred 2 hours.Add thionyl chloride (0.656mL) and again stir the mixture 1 hour.This reaction mixture of concentrating under reduced pressure, adds toluene, again this mixture of concentrating under reduced pressure.Add TERTIARY BUTYL AMINE (439mg) and triethylamine (0.627mL) in the solution of tetrahydrofuran (THF) (10mL) tetrahydrofuran (THF) of residue (5mL) solution, and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=10:90 → 30:70).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (948mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.47(9H，s)，2.40(3H，s)，5.93(1H，br?s)，6.79(1H，d，J＝8.9Hz)，7.14(1H，ddd，J＝1.2Hz，2.5Hz，7.8Hz)，7.40-7.53(3H，m)，8.00(1H，dd，J＝2.8Hz，8.9Hz)，8.15(1H，d，J＝2.8Hz).

(iv) preparation of 3-(4-amino-2-methyl phenoxy group)-N-(tertiary butyl) benzamide

In ethyl acetate (20mL) solution of N-(tertiary butyl)-3-(2-methyl-4-nitrophenoxy) benzamide (948mg), add 5% platinum-gac (50mg), and under room temperature, stir this mixture 6 hours under nitrogen atmosphere.Elimination catalyzer, concentrated filtrate.Gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=25:75 → 45:55).Concentrating under reduced pressure target fraction, obtains title compound (892mg), is red-violet colour oily.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，2.08(3H，s)，3.56(2H，br?s)，5.89(1H，brs)，6.51(1H，dd，J＝2.5Hz，8.4Hz)，6.58(1H，d，J＝2.5Hz)，6.77(1H，d，J＝8.4Hz)，6.87-6.94(1H，m)，7.22-7.30(3H，m).

(v) preparation of N-(tertiary butyl)-3-(4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) benzamide hydrochloride salt

At 80 ℃, the mixture of phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (121mg), 3-(4-amino-2-methyl phenoxy group)-N-(tertiary butyl) benzamide (119mg) and Virahol (5mL) is stirred and spent the night.Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=60:40 → 100:0).By target fraction concentrating under reduced pressure.Residue is through the crystallization of ethyl acetate-diisopropyl ether and filter collection.In gained powder, add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue is dissolved in to ethyl acetate-ethanol, and adds 1N hydrogenchloride/ethyl acetate solution (0.4mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (139mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，2.20(3H，s)，3.90(2H，t，J＝4.4Hz)，4.69(2H，t，J＝4.4Hz)，6.30-6.55(1H，m)，6.69(1H，d，J＝3.0Hz)，7.02-7.12(2H，m)，7.28-7.32(1H，m)，7.43(1H，t，J＝8.0Hz)，7.48-7.59(3H，m)，7.81(1H，br?s)，7.99(1H，d，J＝3.0Hz)，8.72(1H，s)，10.77(1H，br?s).

Embodiment C-62

The preparation of N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-methyl-benzamide

(i) preparation of 3-(the chloro-4-nitrophenoxy of 2-) methyl benzoate

According to same method in Embodiment C-61 (i), use 3-methyl hydroxybenzoate (8.20g), the fluoro-4-oil of mirbane of the chloro-1-of 2-(9.46g), salt of wormwood (11.2g) and N, dinethylformamide (50mL), make title compound (16.0g), be faint yellow solid.

¹H-NMR(CDCl ₃)δ:3.92(3H，s)，6.91(1H，d，J＝9.1Hz)，7.29(1H，ddd，J＝0.8Hz，2.6Hz，8.0Hz)，7.52(1H，t，J＝8.0Hz)，7.70-7.73(1H，m)，7.91-7.97(1H，m)，8.07(1H，dd，J＝2.8Hz，9.1Hz)，8.39(1H，d，J＝2.8Hz).

(ii) the benzoic preparation of 3-(the chloro-4-nitrophenoxy of 2-)

According to same method in Embodiment C-61 (ii), use 3-(the chloro-4-nitrophenoxy of 2-) methyl benzoate (7.08g), Virahol (150mL), tetrahydrofuran (THF) (50mL) and 1N aqueous sodium hydroxide solution (25.3mL), make title compound (5.31g), powder is white in color.

¹H-NMR(CDCl ₃)δ:6.94(1H，d，J＝9.0Hz)，7.31-7.37(1H，m)，7.56(1H，t，J＝8.0Hz)，7.76-7.79(1H，m)，7.97-8.03(1H，m)，8.09(1H，dd，J＝2.6Hz，9.0Hz)，8.40(1H，d，J＝2.6Hz).

(iii) preparation of N-(tertiary butyl)-3-(the chloro-4-nitrophenoxy of 2-)-N-methyl-benzamide

According to same method in Embodiment C-61 (iii), use 3-(the chloro-4-nitrophenoxy of 2-) phenylformic acid (881mg), thionyl chloride (1.09mL), N, dinethylformamide (1), toluene (10mL), tetrahydrofuran (THF) (5mL), N-methyl-TERTIARY BUTYL AMINE (523mg), triethylamine (0.627mL) and tetrahydrofuran (THF) (10mL), make title compound (1.14g), be colorless oil.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，2.87(3H，s)，6.92(1H，d，J＝9.1Hz)，7.08-7.16(2H，m)，7.30-7.35(1H，m)，7.45(1H，t，J＝7.8Hz)，8.06(1H，dd，J＝2.6Hz，9.1Hz)，8.38(1H，d，J＝2.6Hz).

(iv) preparation of 3-(4-amino-2-chlorophenoxy)-N-(tertiary butyl)-N-methyl-benzamide

According to same method in Embodiment C-61 (iv), use N-(tertiary butyl)-3-(the chloro-4-nitrophenoxy of 2-)-N-methyl-benzamide (1.14g), ethyl acetate (20mL) and 5% platinum-gac (50mg), make title compound (868mg), be yellow powder.

¹H-NMR(CDCl ₃)δ:1.48(9H，s)，2.84(3H，s)，3.69(2H，br?s)，6.55(1H，dd，J＝2.8Hz，8.7Hz)，6.76(1H，d，J＝2.8Hz)，6.86-6.93(3H，m)，7.03-7.08(1H，m)，7.27(1H，t，J＝7.8Hz).

(v) preparation of N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-methyl-benzamide

At 80 ℃, the mixture of phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (121mg), 3-(4-amino-2-chlorophenoxy)-N-(tertiary butyl)-N-methyl-benzamide (133mg) and Virahol (5mL) is stirred and spent the night.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=60:40 → 100:0).By target fraction concentrating under reduced pressure.In residue, add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (173mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.48(9H，s)，2.86(3H，s)，4.09(2H，t，J＝4.5Hz)，4.38(2H，t，J＝4.5Hz)，6.19(1H，d，J＝3.3Hz)，6.50-6.90(1H，m)，6.95-7.03(4H，m)，7.04-7.09(1H，m)，7.26-7.39(2H，m)，7.82(1H，d，J＝2.5Hz)，8.26(1H，s)，9.73(1H，br?s).

Embodiment C-63

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-ethynyl cyclohexyl) benzamide hydrochloride salt

By 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) mixture of phenylformic acid (170mg), 1-ethynyl hexahydroaniline (148mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (92mg) and DMF (5mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue is dissolved in to ethyl acetate-ethanol, and 1N hydrogenchloride/ethyl acetate solution (0.4mL) is added wherein.Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (160mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.20-1.37(1H，m)，1.43-1.64(5H，m)，1.71-1.88(2H，m)，2.04-2.18(2H，m)，3.16(1H，s)，3.85-3.95(2H，m)，4.64-4.74(2H，m)，6.20-6.40(1H，m)，6.70(1H，d，J＝3.0Hz)，7.17(1H，dd，J＝2.3Hz，8.1Hz)，7.27-7.35(2H，m)，7.48(1H，t，J＝8.0Hz)，7.57-7.65(2H，m)，7.94(1H，d，J＝2.5Hz)，7.98-8.03(1H，m)，8.17(1H，br?s)，8.76(1H，s)，10.76-10.86(1H，m).

Embodiment C-64

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1,1-dimethyl propylene-2-alkynes-1-yl) benzamide

According to method same in Embodiment C-59, use 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenylformic acid (170mg), 3-amino-3-methyl isophthalic acid-butine (120mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (92mg) and N, dinethylformamide (5mL), make title compound (155mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.75(6H，s)，2.37(1H，s)，4.13(2H，t，J＝4.3Hz)，4.39(2H，t，J＝4.3Hz)，6.15(1H，d，J＝3.3Hz)，6.25(1H，br?s)，6.45(1H，br?s)，6.98-7.03(2H，m)，7.08-7.14(1H，m)，7.31-7.45(4H，m)，7.78(1H，d，J＝2.5Hz)，8.23(1H，s)，9.62(1H，br?s).

Embodiment C-65

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-ethyl cyclohexyl) benzamide

According to method same in Embodiment C-59, use 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenylformic acid (170mg), 1-ethyl cyclohexylamine (153mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (92mg) and N, dinethylformamide (5mL), make title compound (136mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:0.84(3H，t，J＝7.4Hz)，1.20-1.70(8H，m)，1.88(2H，q，J＝7.4Hz)，2.10-2.21(2H，m)，4.12(2H，t，J＝4.5Hz)，4.38(2H，t，J＝4.5Hz)，5.70(1H，br?s)，6.15(1H，d，J＝3.0Hz)，6.50(1H，br?s)，6.99(1H，d，J＝3.0Hz)，7.02(1H，d，J＝8.8Hz)，7.04-7.11(1H，m)，7.30-7.44(4H，m)，7.80(1H，d，J＝2.5Hz)，8.23(1H，s)，9.64(1H，br?s).

Embodiment C-66

3-{2-chloro-4-[(5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of-N-(1-methylcyclohexyl) benzamide hydrochloride salt

According to method same in Embodiment C-63, use the chloro-4-[(5-methyl-5H-of 3-{2-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } phenylformic acid (197mg), 1-methyl cyclohexane amine hydrochlorate (150mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (144mg), I-hydroxybenzotriazole monohydrate (115mg), triethylamine (0.139mL) and N, dinethylformamide (5mL), make title compound (178mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.18-1.57(8H，m)，1.31(3H，s)，2.13-2.29(2H，m)，4.29(3H，s)，6.62-6.65(1H，m)，7.16(1H，dd，J＝2.6Hz，8.1Hz)，7.28(1H，d，J＝8.8Hz)，7.33(1H，m)，7.48(1H，t，J＝8.0Hz)，7.55-7.68(3H，m)，7.91-7.98(2H，m)，8.71(1H，s)，9.78-9.94(1H，m).

Embodiment C-67

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-methylcyclopentyl) benzamide

According to method same in Embodiment C-59, use 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenylformic acid (212mg), 1-methyl cyclopentamine hydrochloride (136mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (144mg), I-hydroxybenzotriazole (101mg), triethylamine (0.139mL) and N, dinethylformamide (5mL), make title compound (162mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.50(3H，s)，1.65-1.82(6H，m)，1.98-2.13(2H，m)，4.12(2H，t，J＝4.4Hz)，4.39(2H，t，J＝4.4Hz)，6.06(1H，br?s)，6.17(1H，d，J＝3.0Hz)，6.52(1H，br?s)，7.00(1H，d，J＝3.0Hz)，7.01(1H，d，J＝8.8Hz)，7.05-7.12(1H，m)，7.30-7.37(3H，m)，7.41(1H，dd，J＝2.6Hz，8.8Hz)，7.80(1H，d，J＝2.6Hz)，8.24(1H，s)，9.66(1H，br?s).

Embodiment C-68

N-{2-[4-({ the chloro-4-[3-of 3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) the chloro-4-[3-of 3-(3-methyl butoxy) phenoxy group] preparation of aniline

In DMF (20mL) solution of 3-(the chloro-4-nitrophenoxy of 2-) phenol (1.0g) and the iodo-3-methylbutane of 1-(1.0mL), add cesium carbonate (1.6g), and at room temperature stir this mixture 2 hours.Under ice-cooled, water is added in this reaction mixture, be extracted with ethyl acetate organic layer anhydrous magnesium sulfate drying 2 times.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in 15% aqueous ethanol (25mL), adds reduced iron (1.60g) and calcium chloride (220mg), at 80 ℃, stir this mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1), obtain title compound (806mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.89-0.92(6H，m)，1.53-1.60(2H，m)，1.70-1.79(1H，m)，3.91-3.95(2H，m)，5.33(2H，s)，6.31-6.33(2H，m)，6.53-6.60(2H，m)，6.71-6.72(1H，m)，6.88-6.91(1H，m)，7.14-7.20(1H，m).

(ii) N-{2-[4-({ the chloro-4-[3-of 3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use the chloro-4-[3-of 3-(3-methyl butoxy) phenoxy group] aniline (250mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (250mg), Virahol (20mL), ethyl acetate (10mL), 4N hydrogenchloride/ethyl acetate solution (15mL), methylsulfonyl acetic acid (72mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (187mg), I-hydroxybenzotriazole (10mg), triethylamine (1.5mL) and tetrahydrofuran (THF) (10mL), make title compound (277mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.91-0.93(6H，m)，1.56-1.78(3H，m)，3.10(3H，s)，3.42-3.49(2H，m)，3.95-4.05(4H，m)，4.52-4.60(2H，m)，6.43-6.70(4H，m)，7.16-7.94(5H，m)，8.34(1H，s)，8.64-8.68(2H，m).

Embodiment C-69

N-(the chloro-4-{3-[(3-methyl but-2-ene-1-of 2-{4-[(3-yl) oxygen base] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) ethanamide

(i) the chloro-4-{3-[(3-methyl but-2-ene-1-of 3-yl) oxygen base] phenoxy group } aniline

N to 3-(the chloro-4-nitrophenoxy of 2-) phenol (1.0g) and the bromo-3-methyl of 1-but-2-ene (1.5mL), in dinethylformamide (20mL) solution, add cesium carbonate (1.8g), and at room temperature stir this mixture 2 hours.Under ice-cooled, water is added in this reaction mixture, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in to 15% aqueous ethanol (25mL), adds reduced iron (1.60g) and calcium chloride (220mg), at 80 ℃, stir this mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1), obtain title compound (730mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.62-1.71(6H，m)，4.42-4.47(2H，m)，5.32-5.36(1H，m)，6.32-6.35(2H，m)，6.56-6.59(2H，m)，6.71-6.72(1H，m)，6.87-6.90(1H，m)，7.13-7.19(1H，m).

(ii) N-(the chloro-4-{3-[(3-methyl but-2-ene-1-of 2-{4-[(3-yl) oxygen base] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use the chloro-4-{3-[(3-methyl but-2-ene-1-of 3-yl) oxygen base] phenoxy group } aniline (150mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (150mg), Virahol (16mL), ethyl acetate (10mL), 4N hydrogenchloride/ethyl acetate solution (5mL), methylsulfonyl acetic acid (120mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (470mg), I-hydroxybenzotriazole (10mg), triethylamine (1.5mL) and N, dinethylformamide (15mL), make title compound (108mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.75-1.79(6H，m)，3.10(3H，s)，3.40-3.52(2H，m)，4.03(2H，s)，4.47-4.60(4H，m)，5.40-5.51(1H，m)，6.40-6.70(4H，m)，7.15-7.95(5H，m)，8.35(1H，s)，8.62-8.70(2H，m).

Embodiment C-70

N-(the chloro-4-{3-[(2 of 2-{4-[(3-, 2-dimethyl propyl) amino] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) ethanamide

(i) preparation of 3-(the chloro-4-nitrophenoxy of 2-)-N-(2,2-dimethyl propyl) aniline

3-(the chloro-4-nitrophenoxy of 2-) anilinechloride (1.98g) is suspended in tetrahydrofuran (THF) (80mL), add wherein triethylamine (0.87mL), acetic acid (6.0mL) and pivalyl aldehyde (2.10g), stir this mixture 30 minutes.Add sodium triacetoxy borohydride (470mg), and stir the mixture again 2 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, separating obtained residue is also used alkaline silica gel column chromatography purification (elutriant: hexane: ethyl acetate=95:5 → 1:1), obtain title compound (1.79g), be brown oily.

¹H-NMR(CDCl ₃)δ:0.99(9H，s)，2.89(2H，s)，6.31-6.54(3H，m)，6.89-7.26(3H，m)，8.01-8.09(1H，m)，8.37(1H，s).

(ii) the chloro-4-{3-[(2 of 3-, 2-dimethyl propyl) amino] phenoxy group } preparation of aniline

By 3-(the chloro-4-nitrophenoxy of 2-)-N-(2,2-dimethyl propyl) aniline (1.0g) is dissolved in 15% aqueous ethanol (30mL), add reduced iron (800mg) and calcium chloride (100mg), and at 80 ℃, stir this mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1), obtain title compound (737mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.95(9H，s)，2.78-2.82(2H，m)，6.31-6.54(3H，m)，6.89-7.26(3H，m)，8.01-8.09(1H，m)，8.37(1H，s).

(iii) N-(the chloro-4-{3-[(2 of 2-{4-[(3-, 2-dimethyl propyl) amino] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use the chloro-4-{3-[(2 of 3-, 2-dimethyl propyl) amino] phenoxy group } aniline (73mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (71mg), Virahol (5mL), ethyl acetate (10mL), 4N hydrogenchloride/ethyl acetate solution (10mL), methylsulfonyl acetic acid (61mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (220mg), I-hydroxybenzotriazole (5.0mg), triethylamine (1.5mL) and N, dinethylformamide (7.0mL), make title compound (48mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.93(9H，s)，2.76-2.79(2H，m)，3.10(3H，s)，3.42-3.48(2H，m)，4.05(2H，s)，4.53-4.59(2H，m)，5.61-6.50(5H，m)，6.98-7.12(2H，m)，7.61-7.91(3H，m)，8.33(1H，s)，8.64-8.68(2H，m).

Embodiment C-71

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-methyl isophthalic acid-phenylethyl) benzamide

According to method same in Embodiment C-59, use 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino phenoxy group) phenylformic acid (170mg), cumyl amine (cumylamine) (108mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole (81mg) and N, dinethylformamide (5mL), make title compound (139mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.79(6H，s)，4.02(2H，t，J＝4.5Hz)，4.32(2H，t，J＝4.5Hz)，6.16(1H，d，J＝3.0Hz)，6.50(1H，br?s)，6.95-7.00(2H，m)，7.07-7.13(1H，m)，7.17-7.46(9H，m)，7.77(1H，d，J＝2.5Hz)，8.22(1H，s)，9.66(1H，brs).

Embodiment C-72

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(2-hydroxy-2-methyl propyl group) benzamide

(i) preparation of 3-(the chloro-4-nitrophenoxy of 2-)-N-(2-hydroxy-2-methyl propyl group) benzamide

3-(the chloro-4-nitrophenoxy of 2-) phenylformic acid (500mg) is dissolved in to tetrahydrofuran (THF) (5mL)/N, in dinethylformamide (5mL) mixed solvent, add successively 1-amino-2-methyl propan-2-ol (199mg), I-hydroxybenzotriazole (347mg), triethylamine (0.7mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (496mg), and at room temperature stir this mixture 2.5 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=33:67 → 0:100), obtain title compound (448mg), powder is white in color of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.30(6H，s)，3.48(2H，d，J＝5.8Hz)，6.60(1H，br?s)，6.92(1H，d，J＝9.1Hz)，7.19-7.25(1H，m)，7.47-7.58(2H，m)，7.61-7.69(1H，m)，8.07(1H，dd，J＝2.8Hz，9.1Hz)，8.39(1H，d，J＝2.8Hz).

(ii) preparation of 3-(4-amino-2-chlorophenoxy)-N-(2-hydroxy-2-methyl propyl group) benzamide

3-(the chloro-4-nitrophenoxy of 2-)-N-(2-hydroxy-2-methyl propyl group) benzamide (446mg) is dissolved in ethanol (13.5mL)/water (1.5mL) mixed solvent, add reduced iron (347mg) and calcium chloride (68mg), the in the situation that of reflux, stir this mixture 15 hours.By reaction mixture filtration over celite, concentrating under reduced pressure filtrate.Residue is dissolved in ethyl acetate, and solution is water and saturated brine washing successively, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=33:67 → 0:100), obtain title compound (349mg), be colorless oil of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.27(6H，s)，2.38(1H，br?s)，3.44(2H，d，J＝6.0Hz)，3.71(2H，br?s)，6.53-6.64(1H，m)，6.57(1H，dd，J＝2.8Hz，8.7Hz)，6.78(1H，d，J＝2.8Hz)，6.90(1H，d，J＝8.7Hz)，6.97-7.03(1H，m)，7.29-7.37(2H，m)，7.38-7.44(1H，m).

(iii) preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(2-hydroxy-2-methyl propyl group) benzamide

By phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) mixture of ethyl ester (84.3mg) and 3-(4-amino-2-chlorophenoxy)-N-(2-hydroxy-2-methyl propyl group) benzamide (110mg) is dissolved in Virahol (2mL), the pyridine hydrochloride that adds wherein catalytic amount, and at 70 ℃, stir the mixture 16 hours.Be cooled to after room temperature, 1N aqueous sodium hydroxide solution (1mL) is added wherein, and at room temperature stir this mixture 9 hours.Saturated aqueous ammonium chloride is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=10:90 → 0:100 → ethyl acetate: methyl alcohol=90:10), through the crystallization of diisopropyl ether/ethyl acetate, obtain title compound (99.7mg), crystal is white in color of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.09(6H，s)，3.23(2H，d，J＝6.0Hz)，3.87(2H，t，J＝4.5Hz)，4.47-4.61(3H，m)，6.30(1H，br?s)，6.51(1H，d，J＝3.0Hz)，7.05-7.13(1H，m)，7.24(1H，d，J＝8.9Hz)，7.36-7.42(1H，m)，7.46(1H，t，J＝7.9Hz)，7.56-7.64(2H，m)，7.66(1H，d，J＝3.0Hz)，7.98(1H，d，J＝2.6Hz)，8.31(1H，t，J＝6.0Hz)，8.34(1H，s)，9.87(1H，br?s).

Embodiment C-73

The preparation of N-(tertiary butyl)-5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-2-fluorobenzamide

According to method same in Embodiment C-57, use 5-(4-amino-2-chlorophenoxy)-N-(tertiary butyl)-2-fluorobenzamide (260mg), phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (150mg), Virahol (7.0mL), 1N aqueous sodium hydroxide solution (4.0mL) and methyl alcohol (10mL), make title compound (285mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.33(9H，s)，3.85-3.89(2H，m)，4.51-4.54(2H，m)，6.50-7.29(5H，m)，7.58-7.97(4H，m)，8.33(1H，s)，9.76(1H，br?s).

Embodiment C-74

The chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(methylthio group) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide hydrochloride salt

(i) the chloro-5-[2-of 4-(methylthio group) ethyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine

The mixture of the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine (768mg), 2-chloroethyl Dimethyl sulfide (664mg), cesium carbonate (1.95g) and DMF (10mL) is at room temperature stirred and spent the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent.In the mixture of gained residue, drip cesium carbonate (3.91g) and N, DMF (3mL) solution of dinethylformamide (10mL) and 2-chloroethyl Dimethyl sulfide (553mg), and at room temperature stir this mixture overnight.Drip again DMF (3mL) solution of 2-chloroethyl Dimethyl sulfide (553mg), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=40:60 → 60:40).Concentrating under reduced pressure target fraction, obtains title compound (880mg), is faint yellow solid.

¹H-NMR(CDCl ₃)δ:2.04(3H，s)，2.95(2H，t，J＝6.9Hz)，4.67(2H，t，J＝6.9Hz)，6.75(1H，d，J＝3.2Hz)，7.56(1H，d，J＝3.2Hz)，8.71(1H，s).

(ii) the chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(methylthio group) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide hydrochloride salt

At 80 ℃, by the chloro-5-[2-of 4-(methylthio group) ethyl] mixture of-5H-pyrrolo-[3,2-d] pyrimidine (455mg), 3-(4-amino-2-chlorophenoxy)-N-(tertiary butyl) benzamide (638mg) and Virahol (10mL) stirs and spends the night.Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).Concentrating under reduced pressure target fraction, obtains being the chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(methylthio group) ethyl]-5H-pyrrolo-[3, the 2-d] pyrimidine-4-yl } amino) phenoxy group of amorphous powder] benzamide (1.00g).By the chloro-4-of the N-of gained (tertiary butyl)-3-[2-(5-[2-(methylthio group) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] benzamide (200mg) is dissolved in ethyl acetate-ethanol, and adds 1N hydrogenchloride/ethyl acetate solution (0.5mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (138mg), is pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，1.99(3H，s)，2.88(2H，t，J＝6.4Hz)，4.92(2H，t，J＝6.4Hz)，6.69(1H，d，J＝3.2Hz)，7.16(1H，dd，J＝3.0Hz，7.7Hz)，7.24(1H，d，J＝8.8Hz)，7.36-7.39(1H，m)，7.47(1H，t，J＝8.0Hz)，7.57-7.65(2H，m)，7.84(1H，br?s)，7.92(1H，d，J＝2.5Hz)，8.06(1H，d，J＝3.2Hz)，8.73(1H，s)，10.06(1H，br?s).

Embodiment C-75

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1,1-dimethyl-2-(piperidin-1-yl) ethyl) benzamide dihydrochloride

According to method same in Embodiment C-63, use 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenylformic acid (170mg), 2-methyl isophthalic acid-(piperidin-1-yl) third-2-amine (125mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole (81mg) and N, dinethylformamide (5mL), make title compound (136mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.33-2.00(6H，m)，1.51(6H，s)，2.91-3.09(2H，m)，3.27-3.62(4H，m)，3.90(2H，t，J＝4.5Hz)，4.71(2H，t，J＝4.5Hz)，6.30-6.65(1H，m)，6.71(1H，d，J＝3.0Hz)，7.15(1H，dd，J＝2.3，7.8Hz)，7.30(1H，d，J＝8.9Hz)，7.45-7.53(2H，m)，7.62(1H，dd，J＝2.5Hz，8.9Hz)，7.73(1H，d，J＝7.7Hz)，7.96(1H，d，J＝2.5Hz)，8.02(1H，d，J＝3.0Hz)，8.17(1H，br?s)，8.76(1H，s)，9.70(1H，br?s)，10.88(1H，br?s).

Embodiment C-76

The preparation of 5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-cyclopropyl-2-fluorobenzamide

(i) 5-[4-({ 5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-2-chlorophenoxy] preparation of-2-fluorophenyl carbamate

According to same method in Embodiment C-2 (v), use 5-(4-amino-2-chlorophenoxy)-2-fluorophenyl carbamate (1.50g), phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (1.53g) and Virahol (15mL), make title compound (2.12g), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.80(3H，s)，4.54-4.57(2H，m)，4.94-4.97(2H，m)，6.56(1H，s)，7.21-7.79(12H，m)，8.32(1H，s)，8.78(1H，br?s).

(ii) preparation of 5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-cyclopropyl-2-fluorobenzamide

According to same method in Embodiment C-2 (v), using 5-[4-({ 5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-2-chlorophenoxy]-2-fluorophenyl carbamate (200mg), 1N aqueous sodium hydroxide solution (3.0mL) and tetrahydrofuran (THF) (10mL) make compound.Gained compound reacts according to the same method in Embodiment C-9 (v), and use cyclopropylamine (60mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (200mg), I-hydroxybenzotriazole (5.0mg), triethylamine (1.5mL) and N, dinethylformamide (5.0mL), obtain title compound (101mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.52-0.71(4H，m)，2.77-2.83(1H，m)，3.86-3.89(2H，m)，4.52-4.55(2H，m)，6.15-6.51(2H，m)，7.01-7.97(7H，m)，8.33(1H，s)，8.37-8.38(1H，m)，9.84(1H，br?s).

Embodiment C-77

The preparation of 5-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy)-N-cyclopropyl-2-fluorobenzamide

At 80 ℃, the mixture of [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (286mg), 5-(4-amino-2-chlorophenoxy)-N-cyclopropyl-2-fluorobenzamide (310mg) and Virahol (5.0mL) is stirred 12 hours.Under ice-cooled, sodium bicarbonate aqueous solution added in reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: hexane=60:40 → 100:0) of silica gel column chromatography for residue.Gained crude product is dissolved in methyl alcohol (10mL), adds 4N hydrogenchloride/ethyl acetate solution (5.0mL), at 70 ℃, stir the mixture 20 hours.Add ethyl acetate and saturated sodium bicarbonate aqueous solution, organic layer dried over mgso.By the separated also purifying (hexane: ethyl acetate=10:90 → 0:100 → ethyl acetate: methyl alcohol=90:10), through the crystallization of diisopropyl ether/ethyl acetate, obtain title compound (356mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.53-0.70(4H，m)，2.77-2.85(1H，m)，3.06(2H，brs)，4.36(2H，br?s)，5.95(2H，br?s)，6.48-8.01(8H，m)，8.31(1H，s)，8.37-8.38(1H，m).

Embodiment C-78

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1,1-dimethyl-2-(morpholine-4-yl) ethyl) benzamide dihydrochloride

According to method same in Embodiment C-63, use 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenylformic acid (170mg), 2-methyl isophthalic acid-(morpholine-4-yl) third-2-amine (127mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole (81mg) and N, dinethylformamide (5mL), make title compound (128mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.52(6H，s)，3.00-4.20(12H，m)，4.70(2H，m)，6.20-6.70(1H，m)，6.71(1H，d，J＝3.0Hz)，7.15(1H，dd，J＝2.5Hz，7.8Hz)，7.29(1H，d，J＝8.8Hz)，7.44-7.54(2H，m)，7.62(1H，dd，J＝2.5Hz，8.8Hz)，7.68-7.76(1H，m)，7.95(1H，d，J＝2.7Hz)，8.01(1H，d，J＝2.7Hz)，8.15(1H，brs)，8.75(1H，s)，10.38(1H，br?s)，10.85(1H，br?s).

Embodiment C-79

The preparation of 5-(the chloro-4-{[5-of 2-(2-methoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-cyclopropyl-2-fluorobenzamide

According to same method in Embodiment C-22 (i), use 5-(4-amino-2-chlorophenoxy)-N-cyclopropyl-2-fluorobenzamide (100mg), the chloro-5-of 4-(2-methoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidine (66mg) and Virahol (5.0mL), make title compound (131mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.52-0.71(4H，m)，2.77-2.83(1H，m)，3.31(3H，s)，3.72-3.75(2H，m)，4.64-4.67(2H，m)，6.50-7.95(8H，m)，8.34(1H，s)，8.37-8.39(1H，m)，9.97(1H，br?s).

Embodiment C-80

5-[4-({ 5-[2-(acetylamino) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-2-chlorophenoxy] preparation of-N-cyclopropyl-2-fluorobenzamide

According to same method in Embodiment C-23 (v), use 5-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy)-N-cyclopropyl-2-fluorobenzamide (100mg), acetic acid (40mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (120mg), I-hydroxybenzotriazole (5.0mg), triethylamine (0.5mL) and N, dinethylformamide (5.0mL), make title compound (71mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.52-0.71(4H，m)，1.79(3H，s)，2.79-2.82(1H，m)，3.33-3.39(2H，m)，4.48-4.53(2H，m)，6.49-6.50(1H，m)，7.02-7.32(4H，m)，7.63-8.43(6H，m)，8.79(1H，s).

Embodiment C-81

The preparation of 5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) the fluoro-N-of-2-(1-methylcyclohexyl) benzamide

According to same method in Embodiment C-2 (v), using 5-[4-({ 5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-2-chlorophenoxy]-2-fluorophenyl carbamate (150mg), 1N aqueous sodium hydroxide solution (3.0mL) and tetrahydrofuran (THF) (10mL) make compound.Gained compound reacts according to the same method in Embodiment C-9 (v), and use 1-methyl cyclohexylamine (110mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (250mg), I-hydroxybenzotriazole (5.0mg), triethylamine (1.5mL) and N, dinethylformamide (5.0mL), obtain title compound (82mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.20-1.51(13H，m)，2.14-2.18(1H，m)，3.86-3.89(2H，m)，4.52-4.56(2H，m)，6.49-6.51(1H，m)，7.17-7.68(7H，m)，7.98(1H，s)，8.34(1H，br?s)，9.85(1H，br?s).

Embodiment C-82

The preparation of 5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-2-fluorobenzamide

According to same method in Embodiment C-2 (v), using 5-[4-({ 5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-2-chlorophenoxy]-2-fluorophenyl carbamate (150mg), 1N aqueous sodium hydroxide solution (3.0mL) and tetrahydrofuran (THF) (10mL) make compound.Gained compound reacts according to the same method in Embodiment C-9 (v), and use 30% ammonia hydroxide/methanol (5.0mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (300mg), I-hydroxybenzotriazole (30mg), triethylamine (1.5mL) and N, dinethylformamide (10mL), obtain title compound (58mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.86-3.89(2H，m)，4.52-4.56(2H，m)，6.50-6.51(1H，m)，7.22-8.04(9H，m)，8.34(1H，br?s)，9.86(1H，br?s).

Embodiment C-83

The preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-cyano group-1-methylethyl) benzamide

(i) N-[3-(the chloro-4-nitrophenoxy of 2-) benzoyl] preparation of-2-methylalanine methyl esters

At 80 ℃, the mixture of 3-(the chloro-4-nitrophenoxy of 2-) phenylformic acid (1.47g), thionyl chloride (1.00mL), DMF (1) and toluene (20mL) is stirred 2 hours.After concentrating under reduced pressure, add toluene and by mixture concentrating under reduced pressure again.Under ice-cooled, the tetrahydrofuran (THF) of residue (5mL) solution is added in the mixture of 2-aminoisobutyric acid methyl ester hydrochloride (922mg), triethylamine (1.67mL) and tetrahydrofuran (THF) (10mL), and within 1 hour, then at room temperature stir and spend the night at this mixture of ice-cooled lower stirring.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=20:80 → 40:60).Concentrating under reduced pressure target fraction, obtains title compound (1.72g), and solid is white in color.

¹H-NMR(CDCl ₃)δ:1.69(6H，s)，3.79(3H，s)，6.84(1H，br?s)，6.92(1H，d，J＝9.2Hz)，7.20-7.25(1H，m)，7.48-7.54(2H，m)，7.61-7.66(1H，m)，8.08(1H，dd，J＝2.7Hz，9.2Hz)，8.40(1H，d，J＝2.7Hz).

(ii) N-[3-(the chloro-4-nitrophenoxy of 2-) benzoyl] preparation of-2-methylalanine

To N-[3-(the chloro-4-nitrophenoxy of 2-) benzoyl] add Virahol (20mL), tetrahydrofuran (THF) (5mL) and 1N aqueous sodium hydroxide solution (6mL) in-2-methylalanine methyl esters (1.72g), and at room temperature stir this mixture overnight.1N hydrochloric acid (6.6mL) is added in reaction mixture to pressure reducing and steaming solvent.Add water, filter the solid of collecting precipitation, wash with water, obtain title compound (1.53g), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.45(6H，s)，7.08(1H，d，J＝9.1Hz)，7.39(1H，dd，J＝2.5Hz，8.0Hz)，7.61(1H，t，J＝8.0Hz)，7.68(1H，m)，7.83(1H，d，J＝8.0Hz)，8.20(1H，dd，J＝2.7Hz，9.1Hz)，8.50(1H，d，J＝2.7Hz)，8.55(1H，br?s).

(iii) preparation of 3-(the chloro-4-nitrophenoxy of 2-)-N-(1-cyano group-1-methylethyl) benzamide

Under ice-cooled; to N-[3-(the chloro-4-nitrophenoxy of 2-) benzoyl] N of-2-methylalanine (1.52g); in dinethylformamide (20mL) solution, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (920mg) and I-hydroxybenzotriazole (649mg), and in this mixture of ice-cooled lower stirring 1 hour.28% ammoniacal liquor (1.4mL) is added in reaction mixture, and within 1 hour, then at room temperature stir and spend the night at this mixture of ice-cooled lower stirring.This reaction mixture of concentrating under reduced pressure, adds water and is extracted with ethyl acetate.Organic layer washs with aqueous sodium hydroxide solution and saturated brine successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is through ethyl acetate crystallization.Gained powder is by alkaline silica gel column chromatography (elutriant: ethyl acetate).Concentrating under reduced pressure target fraction, obtains N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(the chloro-4-nitrophenoxy of 2-) benzamide (0.95g), and powder is white in color.Under ice-cooled, to gained N-, (2-amino-1,1-dimethyl-2-oxoethyl) in tetrahydrofuran (THF) (30mL) solution of-3-(the chloro-4-nitrophenoxy of 2-) benzamide (0.95g) and triethylamine (1.12mL), drip tetrahydrofuran (THF) (5mL) solution of trifluoacetic anhydride (0.556mL), and at room temperature stir this mixture overnight.Under ice-cooled, in reaction mixture, add again triethylamine (0.697mL) and trifluoacetic anhydride (0.348mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=15:85 → 50:50).Concentrating under reduced pressure target fraction, obtains title compound (419mg), and amorphous powder is white in color.

¹H-NMR(CDCl ₃)δ:1.82(6H，s)，6.21(1H，br?s)，6.93(1H，d，J＝9.1Hz)，7.22-7.27(1H，m)，7.48-7.55(2H，m)，7.58-7.63(1H，m)，8.08(1H，dd，J＝2.6，9.1Hz)，8.39(1H，d，J＝2.6Hz).

(iv) preparation of 3-(4-amino-2-chlorophenoxy)-N-(1-cyano group-1-methylethyl) benzamide

Under nitrogen atmosphere, in ethyl acetate (10mL) solution of 3-(the chloro-4-nitrophenoxy of 2-)-N-(1-cyano group-1-methylethyl) benzamide (419mg), add 5% platinum-gac (20mg), and at room temperature stir this mixture 6 hours.Elimination catalyzer, concentrated filtrate.Gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=30:70 → 60:40).Concentrating under reduced pressure target fraction, obtains title compound (283mg), is yellow-green colour amorphous powder.

¹H-NMR(CDCl ₃)δ:1.80(6H，s)，3.72(2H，br?s)，6.15(1H，br?s)，6.58(1H，dd，J＝2.7Hz，8.4Hz)，6.78(1H，d，J＝2.7Hz)，6.90(1H，d，J＝8.4Hz)，7.00-7.10(1H，m)，7.25-7.40(3H，m).

(v) preparation of 3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-N-(1-cyano group-1-methylethyl) benzamide

According to same method in Embodiment C-62 (v), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (121mg), 3-(4-amino-2-chlorophenoxy)-N-(1-cyano group-1-methylethyl) benzamide (132mg), Virahol (5mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.8mL), make title compound (68mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.80(6H，s)，4.13(2H，t，J＝4.3Hz)，4.38(2H，t，J＝4.3Hz)，6.24(1H，d，J＝3.0Hz)，6.50(1H，br?s)，6.97(1H，d，J＝9，1Hz)，7.06(1H，d，J＝3.0Hz)，7.13-7.20(1H，m)，7.28-7.44(4H，m)，7.76(1H，d，J＝2.7Hz)，8.24(1H，s)，9.58(1H，br?s).

Embodiment C-84

The chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(methylsulfonyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide

Under ice-cooled, to the chloro-4-of N-(tertiary butyl)-3-[2-({ 5-[2-(methylthio group) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] add OXONE in methyl alcohol (2mL) solution of benzamide (255mg)

the solution of single persulfate compound (615mg) in water (1mL).Methyl alcohol (18mL) and water (9mL) are added wherein, and at room temperature stir this mixture overnight.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with 5% sodium thiosulfate solution and saturated brine successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=60:40 → 100:0 → methyl alcohol: ethyl acetate → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (207mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.46(9H，s)，2.73(3H，s)，3.67(2H，t，J＝6.2Hz)，4.87(2H，t，J＝6.2Hz)，5.95(1H，br?s)，6.74(1H，d，J＝3.4Hz)，7.00-7.12(2H，m)，7.31-7.40(4H，m)，7.48(1H，dd，J＝2.7Hz，8.7Hz)，7.86(1H，d，J＝2.7Hz)，7.97(1H，br?s)，8.56(1H，s).

Embodiment C-85

The preparation of N-(tertiary butyl)-5-(the chloro-4-{[5-of 2-(2-methoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group)-2-fluorobenzamide

According to same method in Embodiment C-22 (i), use 5-(4-amino-2-chlorophenoxy)-N-(tertiary butyl)-2-fluorobenzamide (60mg), the chloro-5-of 4-(2-methoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidine (38mg) and Virahol (3.0mL), make title compound (84mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.32(9H，s)，3.72-3.76(2H，m)，3.80(3H，s)，4.64-4.68(2H，m)，6.51-7.99(8H，m)，8.36(1H，s)，9.01(1H，s)，9.97(1H，br?s).

Embodiment C-86

N-{2-[4-({ the chloro-4-[3-of 3-(dimethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butyramide

(i) preparation of 3-(4-amino-2-chlorophenoxy)-DMA

Same method according to Embodiment C-1 (i) and (ii), use 3-(dimethylamino) phenol (5.0g), the chloro-4-fluoronitrobenzene of 3-(6.38g), salt of wormwood (5.38g), N, dinethylformamide (100mL), 5% platinum-gac (0.73g) and ethyl acetate (75mL), make title compound (8.95g).

¹H-NMR(DMSO-d ₆)δ:2.84(6H，s)，5.27(2H，s)，5.95-6.55(4H，m)，6.69(1H，d，J＝2.0Hz)，6.86(1H，d，J＝8.0Hz)，7.04(1H，t，J＝8.3Hz).

(ii) N-{2-[4-({ the chloro-4-[3-of 3-(dimethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butyramide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy)-N, accelerine (100mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (89mg), Virahol (5.0mL), ethyl acetate (5.0mL), 4N hydrogenchloride/ethyl acetate solution (5.0mL), HMB (54mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (136mg), I-hydroxybenzotriazole (5.0mg), triethylamine (1.0mL) and tetrahydrofuran (THF) (10mL), make title compound (67mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.13(6H，s)，2.20(2H，s)，2.89(6H，s)，3.38-3.44(2H，m)，4.49-4.53(2H，m)，4.66(1H，s)，6.09-7.15(6H，m)，7.62-8.26(4H，m)，8.31(1H，s)，8.81(1H，s).

Embodiment C-87

N-{2-[4-({ the chloro-4-[3-of 3-(dimethylamino) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy)-N, accelerine (100mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (89mg), Virahol (5.0mL), ethyl acetate (5.0mL), 4N hydrogenchloride/ethyl acetate solution (5.0mL), methylsulfonyl acetic acid (52mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (141mg), I-hydroxybenzotriazole (5.0mg), triethylamine (1.0mL) and tetrahydrofuran (THF) (10mL), make title compound (74mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:2.89(6H，s)，3.09(3H，s)，3.44-3.47(2H，m)，4.04(2H，s)，4.51-4.59(2H，m)，6.08-7.16(6H，m)，7.60-7.91(3H，m)，8.32(1H，s)，8.61-8.69(2H，m).

Embodiment C-88

The preparation of 5-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) the fluoro-N-of-2-(2,2,2-trifluoroethyl) benzamide

According to same method in Embodiment C-2 (v), using 5-[4-({ 5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-2-chlorophenoxy]-2-fluorophenyl carbamate (100mg), 1N aqueous sodium hydroxide solution (2.0mL) and tetrahydrofuran (THF) (5.0mL) make compound.Gained compound reacts according to the same method in Embodiment C-9 (v), and use 2,2,2-trifluoro ethamine (70mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (220mg), I-hydroxybenzotriazole (5.0mg), triethylamine (0.5mL) and N, dinethylformamide (5.0mL), obtain title compound (52mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.86-3.90(2H，m)，3.99-4.10(2H，m)，4.52-4.56(2H，m)，6.15-6.52(1H，m)，7.24-7.99(7H，m)，8.34(1H，s)，9.13-9.17(1H，m)，9.87(1H，br?s).

Embodiment C-89

N-(tertiary butyl)-2-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of ethanamide

(i) preparation of [3-(the chloro-4-nitrophenoxy of 2-) phenyl] jasmal

According to same method in Embodiment C-1 (i), use (3-hydroxyphenyl) jasmal (2.50g), the chloro-4-fluoronitrobenzene of 3-(1.83g), salt of wormwood (1.90g) and N, dinethylformamide (20mL), make title compound (1.21g), be brown oily.

¹H-NMR(DMSO-d ₆)δ:3.81(2H，s)，5.12(2H，s)，7.00-7.25(4H，m)，7.31-7.37(5H，m)，7.43-7.48(1H，m)，8.14-8.18(1H，m)，8.46-8.47(1H，m).

(ii) 2-[3-(4-amino-2-chlorophenoxy) phenyl] preparation of-N-(tertiary butyl) ethanamide

In [3-(the chloro-4-nitrophenoxy of 2-) phenyl] jasmal (1.00g), add 1N aqueous sodium hydroxide solution (5.3mL) and tetrahydrofuran (THF) (4mL), and at room temperature stir this mixture 21 hours.1N hydrochloric acid neutralization for reaction mixture, adds sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.According to the same method in Embodiment C-9 (v), gained residue, 2-methyl-prop-2-amine (1.1mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.11g), I-hydroxybenzotriazole (30mg), triethylamine (3.5mL) and DMF (10mL) are reacted.According to the same method in Embodiment C-1 (ii), gained compound, 5% platinum-gac (130mg) and ethyl acetate (10mL) are reacted, obtain title compound (340mg), be faint yellow oily.

¹h-NMR (DMSO-d ₆) δ: 1.21 (9H, s), 3.61 (2H, s), 5.27 (2H, s), 5.92-6.59 (4H, m), 6.65-6.69 (1H, m), 6.87 (1H, d, J=8.0Hz), 7.13 (1H, t, J=8.3Hz). (iii) N-(tertiary butyl)-2-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of ethanamide

According to method same in Embodiment C-57, use 2-[3-(4-amino-2-chlorophenoxy) phenyl]-N-(tertiary butyl) ethanamide (330mg), phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (270mg), Virahol (20mL), 1N aqueous sodium hydroxide solution (2.0mL) and methyl alcohol (6.0mL), make title compound (115mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.22(9H，s)，3.34-3.40(2H，m)，3.84-3.92(2H，m)，4.51-4.57(2H，m)，6.30(1H，br?s)，6.51-7.30(6H，m)，7.56-7.96(4H，m)，8.36(1H，s)，9.91(1H，br?s).

Embodiment C-90

N-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzyl]-2, the preparation of 2-dimethyl propylene acid amides

(i) N-[3-(4-amino-2-chlorophenoxy) benzyl]-2, the preparation of 2-dimethyl propylene acid amides

According to same method in Embodiment C-53 (i), use N-(3-acrinyl)-2,2-dimethyl propylene acid amides (2.07g), the chloro-4-fluoronitrobenzene of 3-(1.79g), N, dinethylformamide (40mL), salt of wormwood (1.78g), 15% aqueous ethanol (23mL), reduced iron (750mg) and calcium chloride (120mg), make title compound (1.73g), be brown oily.

¹H-NMR(DMSO-d ₆)δ:1.09(9H，s)，4.21-4.25(2H，m)，5.26(2H，s)，5.90-6.58(4H，m)，6.64-6.68(1H，m)，6.85-6.98(1H，m)，7.13(1H，t，J＝8.3Hz).

(ii) N-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzyl]-2, the preparation of 2-dimethyl propylene acid amides

According to method same in Embodiment C-57, use N-[3-(4-amino-2-chlorophenoxy) benzyl]-2,2-dimethyl propylene acid amides (190mg), phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (172mg), Virahol (5.0mL), 1N aqueous sodium hydroxide solution (2.0mL) and methyl alcohol (5.0mL), make title compound (121mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.07(9H，s)，3.86-3.89(2H，m)，4.21-4.23(2H，m)，4.51-4.55(2H，m)，6.51-7.32(6H，m)，7.56-8.06(4H，m)，8.33(1H，s)，9.82(1H，br?s).

Embodiment C-91

N-[3-(the chloro-4-{[5-of 2-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzyl]-2, the preparation of 2-dimethyl propylene acid amides

According to same method in Embodiment C-53 (ii), use N-[3-(4-amino-2-chlorophenoxy) benzyl]-2, 2-dimethyl propylene acid amides (350mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (312mg), Virahol (11mL), tetrahydrofuran (THF) (17mL), 4N hydrogenchloride/ethyl acetate solution (7.0mL), methylsulfonyl acetic acid (220mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (380mg), I-hydroxybenzotriazole (20mg), triethylamine (4.0mL) and N, dinethylformamide (15mL), make title compound (263mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.08(9H，s)，3.10(3H，s)，3.45-3.49(2H，m)，4.04(2H，s)，4.22-4.24(2H，m)，4.54-4.59(2H，m)，6.48-7.33(6H，m)，7.62-8.08(4H，m)，8.34(1H，s)，8.67(1H，br?s).

Embodiment C-92

N-{2-[4-({ the chloro-4-[3-of 3,5-bis-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) preparation of phenylformic acid 3-(the chloro-4-nitrophenoxy of 2,6-bis-) phenyl ester

In the solution of the DMF (15mL) of phenylformic acid 3-oxybenzene ester (675mg) and the iodo-5-oil of mirbane of the chloro-2-of 1,3-bis-(1.0g), add salt of wormwood (1.25g), and at room temperature stir this mixture 18 hours.Under ice-cooled, in reaction mixture, add salt solution, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1), obtain title compound (269mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:6.90-6.97(2H，m)，7.07-7.10(1H，m)，7.44-7.77(4H，m)，8.10-8.12(2H，m)，8.55(2H，s).

(ii) 3, the chloro-4-[3-of 5-bis-(cyclo propyl methoxy) phenoxy group] preparation of aniline

In phenylformic acid 3-(the chloro-4-nitrophenoxy of 2,6-bis-) phenyl ester (269mg), add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent.In DMF (15mL) solution of gained residue and 1-(brooethyl) cyclopropane (0.78mL), add salt of wormwood (430mg), and at room temperature stir this mixture 18 hours.Under ice-cooled, salt solution is added in this reaction mixture, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in to 15% aqueous ethanol (10mL), adds reduced iron (250mg) and calcium chloride (70mg), at 80 ℃, stir this mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 0:1), obtain title compound (112mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.30-0.57(4H，m)，1.11-1.35(1H，m)，3.79-3.81(2H，m)，5.56(2H，s)，5.90(1H，dd，J＝2.0Hz，8.0Hz)，6.22(1H，t，J＝2.2Hz)，6.36(1H，dd，J＝2.0Hz，8.0Hz)，6.71(2H，s)，7.05(1H，t，J＝8.3Hz).

(iii) N-{2-[4-({ the chloro-4-[3-of 3,5-bis-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use 3, the chloro-4-[3-of 5-bis-(cyclo propyl methoxy) phenoxy group] aniline (110mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (101mg), Virahol (5.0mL), methyl alcohol (10mL), 4N hydrogenchloride/ethyl acetate solution (3.0mL), methylsulfonyl acetic acid (90mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (120mg), I-hydroxybenzotriazole (5.0mg), triethylamine (0.8mL) and N, dinethylformamide (5mL), make title compound (43mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.30-0.57(4H，m)，1.11-1.35(1H，m)，3.11(3H，s)，3.40-3.50(2H，m)，3.79-3.81(2H，m)，4.07(2H，s)，4.54-4.59(2H，m)，6.32-6.67(4H，m)，7.19-7.67(2H，m)，8.02(2H，s)，8.41(1H，s)，8.68(1H，br?s)，8.80(1H，s).

Embodiment C-93

N-{2-[4-({ the chloro-4-[3-of 3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butanamide hydrochloride

(i) the chloro-4-nitro-1-[3-of 2-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] preparation of benzene

By the chloro-4-fluoronitrobenzene of 3-(5g) and 3-(1,1,2,2-tetrafluoro oxyethyl group) phenol (6g) is dissolved in N, in dinethylformamide (28mL), salt of wormwood (5.92g) is added wherein, and at room temperature stir this mixture 15 hours.Water (200mL) adds in reaction mixture, and is extracted with ethyl acetate (200mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=90:10 → 60:40), obtain title compound (10g), be yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:5.91(1H，tt，J＝3.0Hz，53.0Hz)，6.90-7.10(3H，m)，7.10-7.15(1H，m)，7.44(1H，t，J＝8.0Hz)，8.10(1H，dd，J＝3.0Hz，9.0Hz)，8.39(1H，d，J＝3.0Hz).

(ii) the chloro-4-[3-of 3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] preparation of aniline

Under 90 ℃ of heating, stir the chloro-4-nitro-1-[3-(1 of 2-, 1,2,2-tetrafluoro oxyethyl group) phenoxy group] benzene (10g), reduced iron (10.2g) and the mixture of calcium chloride (1.7g) in ethanol (270mL)/water (30mL) 16 hours.Be cooled to after room temperature, by mixture filtration over celite.Concentrating under reduced pressure filtrate, residue distributes in ethyl acetate (300mL)/saturated brine (200mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=90:10 → 60:40), obtain title compound (7.91g) and be clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.70(2H，br?s)，5.87(1H，tt，J＝3.0Hz，53.0Hz)，6.58(1H，dd，J＝3.0Hz，8.0Hz)，6.70-6.85(3H，m)，6.85-7.00(2H，m)，7.26(1H，t，J＝8.0Hz).

(iii) preparation of { 2-[4-({ the chloro-4-[3-of 3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

By [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.0g) and the chloro-4-[3-(1 of 3-, 1,2,2-tetrafluoro oxyethyl group) phenoxy group] aniline (1.70g) is dissolved in Virahol (10mL), stirs the mixture 20 hours at 80 ℃.Saturated sodium bicarbonate aqueous solution (50mL) is added in reaction mixture, and be extracted with ethyl acetate (100mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure. by the separated also purifying (hexane: ethyl acetate=80:20 → 0:100), obtain title compound (2.04g), be oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.49(9H，s)，3.40-3.60(2H，m)，4.40-4.60(2H，m)，5.11(1H，t，J＝6.0Hz)，5.89(1H，tt，J＝3.0Hz，53.0Hz)，6.60(1H，d，J＝3.0Hz)，6.80-7.00(3H，m)，7.09(1H，d，J＝9.0Hz)，7.19(1H，d，J＝3.0Hz)，7.31(1H，t，J＝8.0Hz)，7.89(1H，dd，J＝3.0Hz，9.0Hz)，8.03(1H，d，J＝3.0Hz)，8.52(1H，s)，8.64(1H，br?s).

(iv) the chloro-4-[3-of 5-(2-amino-ethyl)-N-{3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

By { ({ the chloro-4-[3-of 3-(1 for 2-[4-, 1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (1.98g) is dissolved in tetrahydrofuran (THF) (47.2mL), 2N hydrochloric acid (23.6mL) is added wherein, at 60 ℃, stir the mixture 15 hours.This reaction mixture of concentrating under reduced pressure, is dissolved in residue in ethanol (50mL), again this mixture of concentrating under reduced pressure.Twice of repetitive operation.Residual solids filters and is dried with Virahol, obtains title compound (1.65g), is pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:3.20-3.40(2H，m)，5.00-5.10(2H，m)，6.60-7.00(4H，m)，7.35(1H，d，J＝9.0Hz)，7.51(1H，t，J＝9.0Hz)，7.60-7.70(1H，m)，7.94(1H，d，J＝2.4Hz)，8.11(1H，d，J＝3.0Hz)，8.40(3H，br?s)，8.75(1H，s).

(v) N-{2-[4-({ the chloro-4-[3-of 3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butanamide hydrochloride

At room temperature stir the chloro-4-[3-(1 of 5-(2-amino-ethyl)-N-{3-, 1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (204mg), HMB (63.5mg), DMF (6.9mL), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg) 16 hours.Mixture distributes in ethyl acetate (80mL)/water (50mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Methyl alcohol=100:0 → 85:15) and alkaline silica gel column chromatography purification (ethyl acetate: methyl alcohol=100:0 → 85:15) residue is separated and by silica gel column chromatography (ethyl acetate:.Residue is dissolved in ethyl acetate (5mL), with 4N hydrogenchloride/ethyl acetate solution (0.18mL), processes, through the crystallization of diisopropyl ether/ethyl acetate, obtain title compound (134mg), crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.11(6H，s)，2.20(2H，s)，3.44-3.56(2H，m)，4.68(2H，t，J＝6.0Hz)，6.60-7.10(5H，m)，7.35(1H，d，J＝9.0Hz)，7.51(1H，t，J＝8.0Hz)，7.73(1H，dd，J＝3.0Hz，9.0Hz)，7.98(2H，dd，J＝3.0Hz，7.0Hz)，8.43(1H，m)，8.74(1H，s).

Embodiment C-94

N-{2-[4-({ the chloro-4-[3-of 3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

At room temperature stir the chloro-4-[3-(1 of 5-(2-amino-ethyl)-N-{3-; 1; 2; 2-tetrafluoro oxyethyl group) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (204mg), methylsulfonyl acetic acid (74.2mg), DMF (6.9mL), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg) 16 hours.Mixture distributes in ethyl acetate (80mL)/water (50mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Methyl alcohol=100:0 → 85:15) and alkaline silica gel column chromatography purification (ethyl acetate: methyl alcohol=100:0 → 85:15), obtain title compound (140mg), be light yellow crystal residue is separated and by silica gel column chromatography (ethyl acetate:.

¹H-NMR(DMSO-d ₆)δ:3.10(3H，s)，3.40-3.50(2H，m)，4.05(2H，s)，4.56(2H，t，J＝7.0Hz)，6.50(1H，d，J＝3.0Hz)，6.60-7.10(4H，m)，7.29(1H，d，J＝9.0Hz)，7.47(1H，t，J＝8.0Hz)，7.63(1H，d，J＝3.0Hz)，7.76(1H，dd，J＝2.0Hz，9.0Hz)，7.98(1H，d，J＝3.0Hz)，8.35(1H，s)，8.68(1H，m)，8.71(1H，br?s).

Embodiment C-95

2-{2-[4-({ the chloro-4-[3-of 3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

At 80 ℃, by phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (150mg) and the chloro-4-[3-(1,1 of 3-, 2,2-tetrafluoro oxyethyl group) phenoxy group] aniline (217mg) stirs 16 hours in Virahol (3mL).Saturated sodium bicarbonate aqueous solution (40mL) is added in reaction mixture, and be extracted with ethyl acetate (80mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=90:10 → 0:100) of silica gel column chromatography for residue.Gained oily residue is dissolved in methyl alcohol (1.89mL), adds 1N aqueous sodium hydroxide solution (0.433mL), and at room temperature stir this mixture 1 hour.1N hydrochloric acid (0.433mL) is added in mixture, and distribute in ethyl acetate (50mL) and saturated brine (20mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Methyl alcohol=100:0 → 90:10) and alkaline silica gel column chromatography purification (ethyl acetate: methyl alcohol=100:0 → 90:10), obtain title compound (136mg), crystal is white in color residue is separated and by silica gel column chromatography (ethyl acetate:.

¹H-NMR(DMSO-d ₆)δ:3.49(4H，br?s)，3.83(2H，t，J＝4.5Hz)，4.64(2H，t，J＝4.5Hz)，4.73(1H，t，J＝4.5Hz)，6.52(1H，d，J＝3.0Hz)，6.76(1H，m)，6.79(1H，tt，J＝3.0Hz，52.0Hz)，6.91(1H，dd，J＝2.0Hz，8.0Hz)，7.02(1H，d，J＝9.0Hz)，7.27(1H，d，J＝9.0Hz)，7.47(1H，t，J＝8.0Hz)，7.60-7.70(2H，m)，8.01(1H，d，J＝2.0Hz)，8.34(1H，s)，8.99(1H，br?s).

Embodiment C-96

N-[2-(the chloro-4-of 4-{[3-(3-isobutoxy phenoxy group) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

(i) preparation of the chloro-4-of 3-(3-isobutoxy phenoxy group) aniline

N to 3-(the chloro-4-nitrophenoxy of 2-) phenol (1.00g) and the iodo-2-methylpropane of 1-(1.5mL), in dinethylformamide (15mL) solution, add salt of wormwood (1.50g), and at room temperature stir this mixture 12 hours.Under ice-cooled, salt solution is added in this reaction mixture, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in 15% aqueous ethanol (30mL), adds reduced iron (750mg) and calcium chloride (70mg), at 80 ℃, stir the mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 0:1), obtain title compound (390mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.94-0.96(6H，m)，1.90-2.01(1H，m)，3.67-3.69(2H，m)，5.33(2H，s)，6.32-7.34(2H，m)，6.53-6.59(2H，m)，6.71-6.72(1H，m)，6.89-6.91(1H，m)，7.14-7.20(1H，m).

(ii) N-[2-(the chloro-4-of 4-{[3-(3-isobutoxy phenoxy group) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use the chloro-4-of 3-(3-isobutoxy phenoxy group) aniline (1.00g), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.02g), Virahol (25mL), methyl alcohol (35mL), 4N hydrogenchloride/ethyl acetate solution (10mL), methylsulfonyl acetic acid (870mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.50g), I-hydroxybenzotriazole (100mg), triethylamine (4.1mL) and N, dinethylformamide (100mL), make title compound (933mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.95-0.97(6H，m)，1.95-2.04(1H，m)，3.09(3H，s)，3.40-3.50(2H，m)，3.72-3.74(2H，m)，4.04(2H，s)，4.54-4.59(2H，m)，6.44-7.27(6H，m)，7.61-7.75(2H，m)，7.94(1H，s)，8.33(1H，s)，8.66(2H，s).

Embodiment C-97

N-{2-[4-({ the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) the chloro-1-[3-of 2-(cyclo propyl methoxy) phenoxy group] preparation of-4-oil of mirbane

In DMF (10.9mL) solution of 3-(the chloro-4-nitrophenoxy of 2-) phenol (2.92g), add cesium carbonate (5.39g) and 1-(brooethyl) cyclopropane (1.6mL) and at room temperature stir this mixture 16 hours.Mixture distributes in ethyl acetate (150mL)/water (80mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=100:0 → 70:30), obtain title compound (3.17g), crystal is white in color of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:0.30-0.40(2H，m)，0.60-0.70(2H，m)，1.20-1.40(1H，m)，3.79(2H，d，J＝7.0Hz)，6.60-6.70(2H，m)，6.70-6.82(1H，m)，6.92(1H，d，J＝9.0Hz)，7.29(1H，m)，8.00-8.10(1H，m)，8.36(1H，d，J＝3.0Hz).

(ii) the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] preparation of aniline

By the chloro-1-[3-of 2-(cyclo propyl methoxy) phenoxy group]-4-oil of mirbane (3.1g) is dissolved in ethanol (97mL)/water (11mL), add wherein reduced iron (3.61g) and calcium chloride (717mg), and at 90 ℃, stir the mixture 16 hours.By filtration over celite, remove solid, and concentrating under reduced pressure filtrate.Ethyl acetate (150mL) is added in residue, and wash this mixture with saturated brine (100mL).Organic layer dried over mgso, concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=90:10 → 60:40), obtain title compound (2.50g), be oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:0.20-0.40(2H，m)，0.50-0.70(2H，m)，1.10-1.30(1H，m)，3.66(2H，br?s)，3.74(2H，d，J＝7.0Hz)，6.40-6.50(2H，m)，6.50-6.60(2H，m)，6.76(1H，d，J＝3.0Hz)，6.85(1H，d，J＝9.0Hz)，7.10-7.20(1H，m).

(iii) preparation of { 2-[4-({ the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

By [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (0.5g) and the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] aniline (732mg) is dissolved in Virahol (5mL), and at 80 ℃, stirs the mixture 20 hours.Saturated sodium bicarbonate aqueous solution (60mL) is added in reaction mixture, and be extracted with ethyl acetate (80mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=90:10 → 0:100), obtain title compound (742mg), powder is white in color of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:0.30-0.40(2H，m)，0.60-0.70(2H，m)，1.10-1.30(1H，m)，1.49(9H，s)，3.40-3.60(2H，m)，3.76(2H，d，J＝7.0Hz)，4.40-4.50(2H，m)，5.21(1H，t，J＝5.0Hz)，6.50-6.70(4H，m)，7.04(1H，d，J＝9.0Hz)，7.10-7.30(2H，m)，7.82(1H，dd，J＝2.0Hz，9.0Hz)，7.98(1H，d，J＝3.0Hz)，8.49(1H，s)，8.59(1H，br?s).

(iv) the 5-chloro-4-[3-of (2-amino-ethyl)-N-{3-(cyclo propyl methoxy) phenoxy group] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

Will 2-[4-(the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (700mg) is dissolved in tetrahydrofuran (THF) (18mL), add wherein 2N hydrochloric acid (9.0mL), and at 60 ℃, stir the mixture 15 hours.This reaction mixture of concentrating under reduced pressure, is dissolved in ethanol (50mL) by residue, again this solution of concentrating under reduced pressure.Repeat twice of this operation.Also dry with the solid of Virahol collecting precipitation, obtain title compound (599mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:0.20-0.40(2H，m)，0.50-0.60(2H，m)，1.10-1.40(1H，m)，3.20-3.40(2H，m)，3.80(2H，d，J＝7.0Hz)，5.00-5.10(2H，m)，6.40-6.60(2H，m)，6.60-6.80(2H，m)，7.10-7.30(2H，m)，7.50-7.70(1H，m)，7.88(1H，m)，8.08(1H，m)，8.37(3H，br?s)，8.73(1H，s)，10.19(1H，br?s).

(v) N-{2-[4-({ the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

At room temperature stir the 5-chloro-4-[3-of (2-amino-ethyl)-N-{3-(cyclo propyl methoxy) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (187mg), methylsulfonyl acetic acid (74.2mg), DMF (6.9mL), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg) 16 hours.This mixture distributes in ethyl acetate (80mL)/water (50mL).Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Methyl alcohol=100:0 → 85:15) and alkaline silica gel column chromatography purification (ethyl acetate: methyl alcohol=100:0 → 85:15) residue is separated and by silica gel column chromatography (ethyl acetate:.Gained compound is dissolved in ethyl acetate (4mL), processes, and through the crystallization of diisopropyl ether/ethyl acetate, obtain title compound (167mg) with 4N hydrogenchloride/ethyl acetate solution (0.18mL), and crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:0.20-0.40(2H，m)，0.50-0.60(2H，m)，1.10-1.40(1H，m)，3.05(3H，s)，3.50-3.60(2H，m)，3.80(2H，d，J＝7.0Hz)，4.07(2H，s)，4.73(1H，t，J＝7.0Hz)，6.40-6.55(2H，m)，6.60-6.75(2H，m)，7.20-7.30(2H，m)，7.63(1H，dd，J＝2.0Hz，9.0Hz)，7.90(1H，d，J＝2.0Hz)，7.96(1H，d，J＝3.0Hz)，8.72(1H，s)，8.87(1H，m)，10.05(1H，br?s).

Embodiment C-98

N-{2-[4-({ the chloro-4-[3-of 3-(2,2-dimethyl propoxy-) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) the chloro-1-[3-of 2-(2,2-dimethyl propoxy-) phenoxy group] preparation of-4-oil of mirbane

N to 3-(the chloro-4-nitrophenoxy of 2-) phenol (1.0g), in dinethylformamide (10mL) solution, add potassium hydroxide (423mg) and three (dimethylaminos) (2,2-dimethyl propoxy-) Phosphonium hexafluorophosphate (tris (dimethylamino) (2,2-dimethylpropoxy) phosphoniumhexafluorophosphate) (2.99g), and at 180 ℃, stir this mixture 30 minutes.Under ice-cooled, water is added in this reaction mixture, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1), obtain title compound (180mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.03(9H，s)，3.58(2H，s)，6.63-6.65(2H，m)，6.80-6.94(2H，m)，7.30-7.34(1H，m)，8.04-8.08(1H，m)，8.37-8.38(1H，m).

(ii) the chloro-4-[3-of 3-(2,2-dimethyl propoxy-) phenoxy group] preparation of aniline

By the chloro-1-[3-(2 of 2-, 2-dimethyl propoxy-) phenoxy group]-4-oil of mirbane (210mg) is dissolved in 15% aqueous ethanol (7mL), add reduced iron (150mg) and calcium chloride (20mg), and at 80 ℃, stir the mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 0:1), obtain title compound (75mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.98(9H，s)，3.92(2H，s)，5.34(2H，s)，6.31-7.33(2H，m)，6.52-6.58(2H，m)，6.70-6.72(1H，m)，6.88-6.92(1H，m)，7.13-7.20(1H，m).

(iii) N-{2-[4-({ the chloro-4-[3-of 3-(2,2-dimethyl propoxy-) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use the chloro-4-[3-(2 of 3-, 2-dimethyl propoxy-) phenoxy group] aniline (75mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (73mg), Virahol (10mL), methyl alcohol (10mL), 4N hydrogenchloride/ethyl acetate solution (5mL), methylsulfonyl acetic acid (50mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (120mg), I-hydroxybenzotriazole (10mg), triethylamine (0.7mL) and N, dinethylformamide (10mL), make title compound (62mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.98(9H，s)，3.09(3H，s)，3.45-3.49(2H，m)，3.62(2H，s)，4.05(2H，s)，4.54-4.59(2H，m)，6.44-7.28(6H，m)，7.66-7.94(3H，m)，8.39(1H，s)，8.67(1H，br?s)，8.81(1H，s).

Embodiment C-99

N-[2-(the chloro-4-of 4-{[3-(3-isobutoxy phenoxy group) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

According to same method in Embodiment C-53 (ii), use the chloro-4-of 3-(3-isobutoxy phenoxy group) aniline (180mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (185mg), Virahol (5.0mL), methyl alcohol (6.0mL), 4N hydrogenchloride/ethyl acetate solution (3.0mL), 2-methyl-2-(methylsulfonyl) propionic acid (160mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (320mg), I-hydroxybenzotriazole (20mg), triethylamine (1.0mL) and N, dinethylformamide (25mL), make title compound (146mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:0.95-0.97(6H，m)，1.41(6H，s)，1.95-2.04(1H，m)，2.95(3H，s)，3.40-3.50(2H，m)，3.72-3.74(2H，m)，4.54-4.59(2H，m)，6.44-7.27(6H，m)，7.56-7.97(3H，m)，8.19-8.22(1H，m)，8.33(1H，s)，8.65(1H，s).

Embodiment C-100

N-{2-[4-({ the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

Under ice-cooled; to the 5-chloro-4-[3-of (2-amino-ethyl)-N-{3-(cyclo propyl methoxy) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] N of pyrimidine-4-amine dihydrochloride (200mg), 2-methyl-2-(methylsulfonyl) propionic acid (170mg) and I-hydroxybenzotriazole (20mg); in dinethylformamide (25mL) solution, add triethylamine (0.87mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (320mg), and at room temperature stir this mixture 15 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by residue with silica gel column chromatography separated and purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 90:10), then use ethyl acetate/diisopropyl ether recrystallization, obtain title compound (160mg) and be clear crystal.

¹H-NMR(DMSO-d ₆)δ:0.29-0.58(4H，m)，1.11-1.28(1H，m)，1.41(6H，s)，2.95(3H，s)，3.44-3.50(2H，m)，3.78-3.80(2H，m)，4.55-4.59(2H，m)，6.32-6.68(4H，m)，7.16-7.96(5H，m)，8.20(1H，br?s)，8.33(1H，s)，8.65(1H，br?s).

Embodiment C-101

N-[2-(the chloro-4-of 4-{[3-(3-isobutoxy phenoxy group) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) acetamide hydrochloride

By N-[2-(the chloro-4-of 4-{[3-(3-isobutoxy phenoxy group) phenyl] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide (1.00g) is dissolved in ethyl acetate (10mL); 4N hydrogenchloride/ethyl acetate solution (5.0mL) is added wherein, filter the solid of collecting precipitation.Solid washs by diisopropyl ether, obtains title compound (1.03g) and is clear crystal.

¹H-NMR(DMSO-d ₆)δ:0.95-0.98(6H，m)，1.92-2.04(1H，m)，3.05(3H，s)，3.40-3.56(2H，m)，3.72-3.75(2H，m)，4.07(2H，s)，4.71-4.75(2H，m)，6.47-7.32(6H，m)，7.62-7.97(3H，m)，8.73(1H，s)，8.83-8.88(1H，m)，10.03(1H，s).

Embodiment C-102

N-{2-[4-({ the chloro-4-[3-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butyramide

Under ice-cooled, to the 5-chloro-4-[3-of (2-amino-ethyl)-N-{3-(cyclo propyl methoxy) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] add triethylamine (0.3mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (216mg) in tetrahydrofuran (THF) (15mL) solution of pyrimidine-4-amine dihydrochloride (100mg), HMB (293mg) and I-hydroxybenzotriazole (10mg), and at room temperature stir this mixture 3 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 90:10), then use ethyl acetate/diisopropyl ether recrystallization, obtain title compound (66mg) and be clear crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.29-0.58(4H，m)，1.11-1.28(1H，m)，1.16(6H，s)，2.20(2H，s)，3.35-3.41(2H，m)，3.78-3.80(2H，m)，4.49-4.54(2H，m)，4.66(1H，s)，6.43-7.26(6H，m)，7.63-8.00(3H，m)，8.25(1H，br?s)，8.32(1H，s)，8.86(1H，br?s).

Embodiment C-103

N-(tertiary butyl)-2-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenoxy group] preparation of ethanamide

(i) 2-[3-(4-amino-2-chlorophenoxy) phenoxy group] preparation of-N-(tertiary butyl) ethanamide

In DMF (10mL) solution of 3-(the chloro-4-nitrophenoxy of 2-) phenol (1.0g), add bromoethyl acetate (1.26g) and salt of wormwood (1.20g), and at room temperature stir this mixture 18 hours.Under ice-cooled, salt solution is added in this reaction mixture, be extracted with ethyl acetate this mixture, and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is dissolved in tetrahydrofuran (THF) (20mL), 1N aqueous sodium hydroxide solution (5.0mL) is added wherein, and at room temperature stir this mixture 12 hours.1N hydrochloric acid neutralization for reaction mixture, adds sodium bicarbonate aqueous solution and salt solution wherein.Mixture is extracted with ethyl acetate, anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.Under ice-cooled, in tetrahydrofuran (THF) (15mL) solution of gained residue, 2-methyl-prop-2-amine (1.0mL) and I-hydroxybenzotriazole (10mg), add triethylamine (1.3mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.50g), and at room temperature stir this mixture 3 hours.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in to 15% aqueous ethanol (23mL), reduced iron (550mg) and calcium chloride (70mg) is added wherein, and at 80 ℃, stir the mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 0:1), obtain title compound (375mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.29(9H，s)，4.35(2H，s)，5.35(2H，s)，6.31-7.34(2H，m)，6.52-6.58(2H，m)，6.70-6.72(1H，m)，6.88-6.93(1H，m)，7.13-7.20(1H，m).

(ii) N-(tertiary butyl)-2-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenoxy group] preparation of ethanamide

According to method same in Embodiment C-57, use 2-[3-(4-amino-2-chlorophenoxy) phenoxy group]-N-(tertiary butyl) ethanamide (100mg), phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (87mg), Virahol (5.0mL), 1N aqueous sodium hydroxide solution (2.0mL) and methyl alcohol (5.0mL), make title compound (73mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.27(9H，s)，3.86-3.89(2H，m)，4.37(2H，s)，4.51-4.55(2H，m)，6.48-7.66(9H，m)，7.95-8.97(1H，m)，8.33(1H，s)，9.87(1H，br?s).

Embodiment C-104

2-[4-({ 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) 2-methyl-4-nitro-1-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] preparation of benzene

By the fluoro-5-nitrotoluene of 2-(2.10g) and 3-(1,1,2,2-tetrafluoro oxyethyl group) mixture of phenol (3.01g) is dissolved in N, in dinethylformamide (13mL), salt of wormwood (3.04g) is added wherein, and at room temperature stir this mixture 15 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, anhydrous magnesium sulfate drying, and concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=100:0 → 80:20), obtain title compound (4.05g), be yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:2.39(3H，s)，5.91(1H，tt，J＝2.8Hz，53.0Hz)，6.87(1H，d，J＝9.0Hz)，6.89-6.98(2H，m)，7.02-7.14(1H，m)，7.41(1H，t，J＝8.2Hz)，8.04(1H，dd，J＝2.6Hz，9.0Hz)，8.18(1H，d，J＝2.6Hz).

(ii) 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] preparation of aniline

According to same method in Embodiment C-72 (ii), use 2-methyl-4-nitro-1-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] benzene (4.04g), reduced iron (3.45g), calcium chloride (691mg) and ethanol (108mL)/water (12mL), make title compound (3.45g), be brown oily.

¹H-NMR(CDCl ₃)δ:2.09(3H，s)，3.59(2H，br?s)，5.86(1H，tt，J＝2.9Hz，53.0Hz)，6.53(1H，dd，J＝3.0Hz，8.7Hz)，6.59(1H，d，J＝3.0Hz)，6.67(1H，t，J＝2.2Hz)，6.72-6.77(1H，m)，6.80(1H，d，J＝8.7Hz)，6.81-6.86(1H，m)，7.19-7.27(1H，m).

(iii) 2-[4-({ 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to same method in Embodiment C-72 (iii), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (102mg), 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] aniline (110mg), Virahol (3mL) and 1N aqueous sodium hydroxide solution (1.5mL), make title compound (114mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:2.23(3H，s)，4.14(2H，t，J＝4.5Hz)，4.32-4.42(2H，m)，5.89(1H，tt，J＝2.9Hz，53.0Hz)，6.15(1H，d，J＝3.4Hz)，6.75-7.02(5H，m)，7.20-7.34(1H，m)，7.40-7.52(2H，m)，8.24(1H，s)，9.30(1H，s).

Embodiment C-105

2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of acetamide hydrochloride

(i) preparation of { 2-[4-({ 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

By [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (304mg) and 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] aniline (331mg) is dissolved in Virahol (10mL), stirs the mixture 20 hours at 70 ℃.Saturated sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=67:33 → 10:90), obtain title compound (540mg), be colorless oil of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.46(9H，s)，2.21(3H，s)，3.43-3.57(2H，m)，4.40-4.54(2H，m)，5.00(1H，t，J＝5.5Hz)，5.88(1H，tt，J＝2.9Hz，53.0Hz)，6.59(1H，d，J＝3.0Hz)，6.75-6.80(1H，m)，6.82-6.93(2H，m)，6.94-7.02(1H，m)，7.16(1H，d，J＝3.0Hz)，7.27(1H，t，J＝8.1Hz)，7.64-7.74(2H，m)，8.36(1H，br?s)，8.50(1H，s).

(ii) 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

By { ({ 3-methyl-4-[3-(1 for 2-[4-, 1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (537mg) is dissolved in tetrahydrofuran (THF) (2mL), 6N hydrochloric acid (0.8mL) is added wherein, at 50 ℃, stir the mixture 15 hours.This reaction mixture of concentrating under reduced pressure, is dissolved in ethanol by residue, again this mixture of concentrating under reduced pressure.Filter collecting precipitation, obtain title compound (460mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:2.19(3H，s)，3.22-3.48(2H，m)，4.99(2H，t，J＝6.1Hz)，6.72(1H，d，J＝3.2Hz)，6.76(1H，t，J＝2.3Hz)，6.80(1H，tt，J＝3.1Hz，52Hz)，6.90-6.96(1H，m)，7.00-7.07(1H，m)，7.11(1H，d，J＝8.7Hz)，7.47(1H，dd，J＝2.5Hz，8.7Hz)，7.49(1H，t，J＝8.3Hz)，7.54(1H，d，J＝2.5Hz)，8.03(1H，d，J＝3.2Hz)，8.29(3H，br?s)，8.68(1H，s)，9.87(1H，br?s).

(iii) 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of acetamide hydrochloride

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(1, 1, 2, 2-tetrafluoro oxyethyl group) phenoxy group] phenyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (121mg), methylsulfonyl acetic acid (48.8mg), tetrahydrofuran (THF) (0.6mL)/N, dinethylformamide (0.6mL), I-hydroxybenzotriazole (47mg), triethylamine (0.3mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (64.3mg), make 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(1, 1, 2, 2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] ethyl } ethanamide.This compound is dissolved in ethyl acetate, with 4N hydrogenchloride/ethyl acetate solution, processes, and through ethyl acetate/alcohol crystal, obtain title compound (104mg), be light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:2.19(3H，s)，3.05(3H，s)，3.49-3.60(2H，m)，4.07(2H，m)，4.70(2H，t，J＝6.4Hz)，6.61-6.99(1H，m)，6.64(1H，d，J＝3.2Hz)，6.76(1H，t，J＝2.3Hz)，6.91-6.96(1H，m)，6.99-7.07(1H，m)，7.12(1H，d，J＝8.5Hz)，7.44-7.61(3H，m)，7.91(1H，d，J＝3.2Hz)，8.68(1H，s)，8.78(1H，t，J＝5.7Hz)，9.85(1H，s).

Embodiment C-106

3-hydroxy-3-methyl-N-{2-[4-({ 3-methyl-4-[3-(1,1,2,2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of butanamide hydrochloride

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(1, 1, 2, 2-tetrafluoro oxyethyl group) phenoxy group] phenyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (120mg), HMB (40.5mg), tetrahydrofuran (THF) (0.6mL)/N, dinethylformamide (0.6mL), I-hydroxybenzotriazole (47.6mg), triethylamine (0.3mL) and 1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide hydrochloride (66.1mg), make 3-hydroxyl-3 '-methyl-N-{2-[4-({ 3-methyl-4-[3-(1, 1, 2, 2-tetrafluoro oxyethyl group) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] ethyl } butyramide.This compound is dissolved in ethyl acetate, processes, and through the crystallization of diisopropyl ether/ethyl acetate, obtain title compound (108mg) with 4N hydrogenchloride/ethyl acetate solution, crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.11(6H，s)，2.18(3H，s)，2.20(2H，s)，3.44-3.56(2H，m)，4.65(2H，t，J＝6.8Hz)，6.60-6.99(1H，m)，6.65(1H，d，J＝3.0Hz)，6.75(1H，t，J＝2.3Hz)，6.91-6.96(1H，m)，6.99-7.06(1H，m)，7.11(1H，d，J＝8.7Hz)，7.49(1H，t，J＝8.3Hz)，7.54(1H，dd，J＝2.5Hz，8.7Hz)，7.60(1H，d，J＝2.5Hz)，7.95(1H，d，J＝3.0Hz)，8.37(1H，t，J＝5.5Hz)，8.68(1H，s)，10.16(1H，s).

Embodiment C-107

N-{2-[4-({ the chloro-3-of the chloro-4-[4-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) the chloro-3-of the chloro-4-[4-of 3-(cyclo propyl methoxy) phenoxy group] preparation of aniline

To the chloro-4-fluoronitrobenzene of 3-(5.00g), 4-chlorobenzene-1, adds salt of wormwood (5.50g) in DMF (35mL) solution of 3-glycol (4.11g), and at room temperature stirs this mixture 5 hours.Under ice-cooled, salt solution is added in this reaction mixture, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in DMF (15mL), 1-(brooethyl) cyclopropane (1.3mL) and salt of wormwood (1.50g) is added wherein, and at room temperature stir this mixture 12 hours.Under ice-cooled, salt solution is added in this reaction mixture, be extracted with ethyl acetate this mixture, organic layer anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=1:0 → 1:1) of silica gel column chromatography for residue.Gained crude product is dissolved in to 15% aqueous ethanol (30mL), reduced iron (550mg) and calcium chloride (70mg) is added wherein, and at 80 ℃, stir the mixture 8 hours.Solids removed by filtration, concentrating under reduced pressure filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=4:1 → 0:1), obtain title compound (868mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:0.35-0.68(4H，m)，0.84-0.90(1H，m)，3.87(2H，d，J＝6.7Hz)，5.36(2H，s)，6.33-7.34(1H，m)，6.52-6.58(2H，m)，6.69-6.71(1H，m)，6.86-6.92(1H，m)，7.13-7.21(1H，m).

(ii) N-{2-[4-({ the chloro-3-of the chloro-4-[4-of 3-(cyclo propyl methoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use the chloro-3-of the chloro-4-[4-of 3-(cyclo propyl methoxy) phenoxy group] aniline (200mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (183mg), Virahol (9mL), methyl alcohol (15mL), 4N hydrogenchloride/ethyl acetate solution (8.0mL), methylsulfonyl acetic acid (170mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (300mg), I-hydroxybenzotriazole (50mg), triethylamine (1.1mL) and N, dinethylformamide (10mL), make title compound (61mg), be crystal.

¹H-NMR(CDCl ₃)δ:0.36-0.42(2H，m)，0.62-0.68(2H，m)，0.86-0.90(1H，m)，3.13(3H，s)，3.68-3.72(2H，m)，3.86(2H，d，J＝6.7Hz)，3.98(2H，s)，4.45-4.52(2H，m)，6.43-7.28(6H，m)，7.50(1H，br?s)，7，68-7.72(1H，m)，7.92(1H，s)，8.18(1H，br?s)，8.49(1H，s).

Embodiment C-108

2-[4-({ 4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) preparation of 3-(2-methyl-4-nitrophenoxy) phenol

According to same method in Embodiment C-104 (i), use the fluoro-5-nitrotoluene of 2-(10.0g), Resorcinol (24.8g), salt of wormwood (31.3g) and N, dinethylformamide (120mL), makes title compound (7.19g), is yellow oily.

¹H-NMR(CDCl ₃)δ:2.39(3H，s)，5.12(1H，s)，6.52(1H，t，J＝2.3Hz)，6.55-6.61(1H，m)，6.64-6.70(1H，m)，6.84(1H，d，J＝9.0Hz)，7.24(1H，t，J＝8.1Hz)，7.99(1H，dd，J＝2.8Hz，9.0Hz)，8.14(1H，d，J＝2.8Hz).

(ii) 1-[3-(cyclo propyl methoxy) phenoxy group] preparation of-2-methyl-4-oil of mirbane

According to same method in Embodiment C-104 (i), use 3-(2-methyl-4-nitrophenoxy) phenol (939mg), 1-(brooethyl) cyclopropane (0.55mL), salt of wormwood (963mg) and N, dinethylformamide (10mL), make title compound (1.02g), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:0.28-0.42(2H，m)，0.58-0.71(2H，m)，1.17-1.36(1H，m)，2.39(3H，s)，3.78(2H，d，J＝7.2Hz)，6.53-6.63(2H，m)，6.71-6.78(1H，m)，6.82(1H，d，J＝8.8Hz)，7.27(1H，t，J＝8.1Hz)，7.98(1H，dd，J＝2.8Hz，8.8Hz)，8.14(1H，d，2.8Hz).

(iii) 4-[3-(cyclo propyl methoxy) phenoxy group] preparation of-3-monomethylaniline

According to same method in Embodiment C-72 (ii), use 1-[3-(cyclo propyl methoxy) phenoxy group]-2-methyl-4-oil of mirbane (1.01g), reduced iron (964mg), calcium chloride (196mg) and ethanol (36mL)/water (4mL), make title compound (809mg), darkly brown oily.

¹H-NMR(CDCl ₃)δ:0.26-0.38(2H，m)，0.55-0.68(2H，m)，1.13-1.34(1H，m)，2.09(3H，s)，3.54(2H，br?s)，3.73(2H，d，J＝6.9Hz)，6.37-6.45(2H，m)，6.47-6.54(2H，m)，6.57(1H，d，J＝2.5Hz)，6.78(1H，d，J＝8.5Hz)，7.07-7.16(1H，m).

(iv) 2-[4-({ 4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to same method in Embodiment C-72 (iii), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (99.7mg), 4-[3-(cyclo propyl methoxy) phenoxy group]-3-monomethylaniline (98.7mg), Virahol (3mL) and 1N aqueous sodium hydroxide solution (1.5mL), make title compound (106mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:0.29-0.39(2H，m)，0.58-0.70(2H，m)，1.17-1.33(1H，m)，2.24(3H，s)，3.77(2H，d，J＝7.0Hz)，4.08-4.17(2H，m)，4.37(2H，t，J＝4.4Hz)，6.13(1H，d，J＝3.0Hz)，6.47-6.62(3H，m)，6.94(1H，d，J＝3.0Hz)，6.97(1H，d，J＝8.5Hz)，7.17(1H，t，J＝8.1Hz)，7.37-7.48(2H，m)，8.23(1H，s)，9.28(1H，s).

Embodiment C-109

The preparation of 2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethanol

(i) preparation of 1-(3-isobutoxy phenoxy group)-2-methyl-4-oil of mirbane

According to same method in Embodiment C-104 (i), use 3-(2-methyl-4-nitrophenoxy) phenol (822mg), isobutyl bromide (0.55mL), salt of wormwood (834mg) and N, dinethylformamide (10mL), make title compound (884mg), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:1.02(6H，d，J＝6.8Hz)，1.97-2.18(1H，m)，2.40(3H，s)，3.70(2H，d，J＝6.4Hz)，6.52-6.64(2H，m)，6.71-6.78(1H，m)，6.82(1H，d，J＝9.1Hz)，7.22-7.33(1H，m)，7.99(1H，dd，J＝3.0Hz，9.1Hz)，8.14(1H，d，J＝3.0Hz).

(ii) preparation of 4-(3-isobutoxy phenoxy group)-3-monomethylaniline

According to same method in Embodiment C-72 (ii), use 1-(3-isobutoxy phenoxy group)-2-methyl-4-oil of mirbane (879mg), reduced iron (823mg), calcium chloride (162mg) and ethanol (27mL)/water (3mL), make title compound (756mg), be brown oily.

¹H-NMR(CDCl ₃)δ:1.00(6H，d，J＝6.6Hz)，1.95-2.10(1H，m)，2.11(3H，s)，3.55(2H，br?s)，3.66(2H，d，J＝6.3Hz)，6.35-6.44(2H，m)，6.49-6.52(1H，m)，6.52-6.55(1H，m)，6.58(1H，d，J＝3.0Hz)，6.80(1H，d，J＝8.5Hz)，7.12(1H，t，J＝8.1Hz).

(iii) preparation of 2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethanol

According to same method in Embodiment C-72 (iii), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (110mg), 4-(3-isobutoxy phenoxy group)-3-monomethylaniline (103mg), Virahol (3mL) and 1N aqueous sodium hydroxide solution (1.5mL), make title compound (116mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.02(6H，d，J＝6.8Hz)，1.97-2.16(1H，m)，2.25(3H，s)，3.70(2H，d，J＝6.4Hz)，4.12(2H，t，J＝4.3Hz)，4.35(2H，t，J＝4.3Hz)，6.10(1H，d，J＝3.2Hz)，6.45-6.54(2H，m)，6.54-6.62(1H，m)，6.91(1H，d，J＝3.2Hz)，6.97(1H，d，J＝8.5Hz)，7.17(1H，t，J＝8.3Hz)，7.37-7.48(2H，m)，8.21(1H，s)，9.31(1H，s).

Embodiment C-110

N-{2-[4-({ 4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) preparation of { 2-[4-({ 4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to same method in Embodiment C-105 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (402mg), 4-[3-(cyclo propyl methoxy) phenoxy group]-3-monomethylaniline (395mg) and Virahol (15mL), make title compound (710mg), be light orange powder.

¹H-NMR(CDCl ₃)δ:0.27-0.39(2H，m)，0.54-0.69(2H，m)，1.16-1.32(1H，m)，1.46(9H，s)，2.22(3H，s)，3.41-3.58(2H，m)，3.76(2H，d，J＝6.8Hz)，4.39-4.53(2H，m)，4.99(1H，d，J＝9.5Hz)，6.46-6.63(4H，m)，6.95(1H，d，J＝9.5Hz)，7.09-7.20(2H，m)，7.55-7.73(2H，m)，8.28(1H，br?s)，8.49(1H，s).

(ii) 5-(2-amino-ethyl)-N-{4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to same method in Embodiment C-105 (ii), use 2-[4-(4-[3-(cyclo propyl methoxy) phenoxy group] and-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (707mg), 6N hydrochloric acid (1mL) and ethanol (3mL), make title compound (578mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:0.25-0.36(2H，m)，0.49-0.62(2H，m)，1.12-1.27(1H，m)，2.19(3H，s)，3.20-3.33(2H，m)，3.79(2H，d，J＝6.9Hz)，5.01(2H，t，J＝6.1Hz)，6.40-6.49(2H，m)，6.62-6.69(1H，m)，6.71(1H，d，J＝3.0Hz)，7.01(1H，d，J＝8.5Hz)，7.19-7.29(1H，m)，7.40(1H，dd，J＝2.5Hz，8.5Hz)，7.49(1H，d，J＝2.5Hz)，8.04(1H，d，J＝3.0Hz)，8.33(3H，br?s)，8.67(1H，s)，9.90(1H，br?s).

(iii) N-{2-[4-({ 4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-72 (i); use 5-(2-amino-ethyl)-N-{4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (120mg), methylsulfonyl acetic acid (50.5mg), tetrahydrofuran (THF) (0.6mL)/N; dinethylformamide (0.6mL), I-hydroxybenzotriazole (51.5mg), triethylamine (0.35mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (116mg); make title compound (72.4mg), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:0.28-0.39(2H，m)，0.57-0.70(2H，m)，1.17-1.34(1H，m)，2.24(3H，s)，3.08(3H，s)，3.62-3.75(2H，m)，3.77(2H，d，J＝7.0Hz)，3.93(2H，s)，4.38-4.53(2H，m)，6.45-6.63(4H，m)，6.95(1H，d，J＝8.5Hz)，7.11-7.23(2H，m)，7.36-7.50(2H，m)，7.57(1H，d，J＝2.1Hz)，7.83(1H，s)，8.47(1H，s).

Embodiment C-111

N-{2-[4-({ 4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butyramide

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-{4-[3-(cyclo propyl methoxy) phenoxy group]-3-aminomethyl phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (121mg), HMB (46.2mg), tetrahydrofuran (THF) (0.6mL)/N, dinethylformamide (0.6mL), I-hydroxybenzotriazole (59.8mg), triethylamine (0.35mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (88.0mg), make title compound (60.0mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:0.29-0.38(2H，m)，0.58-0.68(2H，m)，1.17-1.33(1H，m)，1.30(6H，s)，2.24(3H，s)，2.44(2H，s)，3.56-3.70(2H，m)，3.77(2H，d，J＝7.0Hz)，4.41-4.53(2H，m)，6.48-6.62(4H，m)，6.86-6.93(1H，m)，6.95(1H，d，J＝8.7Hz)，7.11-7.22(2H，m)，7.54(1H，dd，J＝2.5Hz，8.7Hz)，7.62(1H，d，J＝2.5Hz)，8.32(1H，s)，8.47(1H，s).

Embodiment C-112

N-[2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) [2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

According to same method in Embodiment C-105 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (307mg), 4-(3-isobutoxy phenoxy group)-3-monomethylaniline (304mg) and Virahol (12mL), make title compound (504mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.01(6H，d，J＝6.8Hz)，1.46(9H，s)，1.97-2.14(1H，m)，2.23(3H，s)，3.41-3.58(2H，m)，3.68(2H，d，J＝6.4Hz)，4.39-4.54(2H，m)，5.01(1H，t，J＝5.5Hz)，6.45-6.63(4H，m)，6.96(1H，d，J＝8.7Hz)，7.09-7.21(2H，m)，7.58-7.71(2H，m)，8.32(1H，br?s)，8.49(1H，s).

(ii) 5-(2-amino-ethyl)-N-[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to same method in embodiment 105 (ii), use [2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (499mg), 6N hydrochloric acid (1mL) and ethanol (3mL), make title compound (429mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:0.96(6H，d，J＝6.6Hz)，1.91-2.08(1H，m)，2.20(3H，s)，3.21-3.85(2H，m)，3.73(2H，d?J＝6.4Hz)，5.02(2H，t，J＝6.1Hz)，6.40-6.52(2H，m)，6.64-6.70(1H，m)，6.72(1H，d，J＝3.2Hz)，7.02(1H，d，J＝8.7Hz)，7.26(1H，t，J＝8.2Hz)，7.41(1H，dd，J＝2.5Hz，8.7Hz)，7.50(1H，d，J＝2.5Hz)，8.05(1H，d，J＝3.2Hz)，8.37(3H，br?s)，8.68(1H，s)，9.94(1H，br?s).

(iii) N-[2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) acetamide hydrochloride

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl]-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (119mg), methylsulfonyl acetic acid (50.3mg), tetrahydrofuran (THF) (0.6mL)/N, dinethylformamide (0.6mL), I-hydroxybenzotriazole (50.1mg), triethylamine (0.35mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (82.7mg), make N-[2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide.This compound is dissolved in ethyl acetate, with 4N hydrogenchloride/ethyl acetate solution, processes, filter collecting precipitation, obtain title compound (104mg), crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:0.96(6H，d，J＝6.6Hz)，1.88-2.09(1H，m)，2.20(3H，s)，3.06(3H，s)，3.54(2H，q，J＝6.0Hz)，3.73(2H，d，J＝6.6Hz)，4.06(2H，s)，4.69(2H，t，J＝6.0Hz)，6.39-6.52(2H，m)，6.64(1H，d，J＝3.2Hz)，6.65-6.72(1H，m)，7.02(1H，d，J＝8.8Hz)，7.26(1H，t，J＝8.2Hz)，7.45(1H，dd，J＝2.5Hz，8.8Hz)，7.52(1H，d，J＝2.5Hz)，7.90(1H，d，J＝3.2Hz)，8.67(1H，s)，8.77(1H，t，J＝6.0Hz)，9.82(1H，s).

Embodiment C-113

3-hydroxy-n-[2-(4-{[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-methylbutyryl amine

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-[4-(3-isobutoxy phenoxy group)-3-aminomethyl phenyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (120mg), HMB (46.1mg), tetrahydrofuran (THF) (0.6mL)/N, dinethylformamide (0.6mL), I-hydroxybenzotriazole (50.2mg), triethylamine (0.35mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (82.7mg), make title compound (91.0mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:1.01(6H，d，J＝6.6Hz)，1.30(6H，s)，1.97-2.15(1H，m)，2.25(3H，s)，2.44(2H，s)，3.57-3.67(2H，m)，3.69(2H，d，J＝6.6Hz)，4.41-4.54(2H，m)，6.44-6.63(4H，m)，6.84(1H，t，J＝5.9Hz)，6.95(1H，d，J＝8.7Hz)，7.11-7.21(2H，m)，7.55(1H，dd，J＝2.5Hz，8.7Hz)，7.63(1H，d，J＝2.5Hz)，8.31(1H，s)，8.48(1H，s).

Embodiment C-114

2-[4-({ 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) 2-methyl-4-nitro-1-[3-(2,2,2-trifluoro ethoxy) phenoxy group] preparation of benzene

According to same method in Embodiment C-104 (i), use 3-(2-methyl-4-nitrophenoxy) phenol (797mg), 1,1, the fluoro-2-iodoethane of 1-tri-(0.5mL), salt of wormwood (903mg) and N, dinethylformamide (10mL), make title compound (780mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:2.39(3H，s)，4.35(2H，q，J＝8.0Hz)，6.64(1H，t，J＝2.4Hz)，6.67-6.74(1H，m)，6.74-6.81(1H，m)，6.84(1H，d，J＝9.0Hz)，7.34(1H，t，J＝8.3Hz)，8.02(1H，dd，J＝2.8Hz，9.0Hz)，8.16(1H，d，J＝2.8Hz).

(ii) 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] preparation of aniline

According to same method in Embodiment C-72 (ii), use 2-methyl-4-nitro-1-[3-(2,2,2-trifluoro ethoxy) phenoxy group] benzene (774mg), reduced iron (685mg), calcium chloride (138mg) and ethanol (22.5mL)/water (2.5mL), make title compound (529mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:2.08(3H，s)，3.57(2H，br?s)，4.28(2H，q，J＝8.0Hz)，6.43(1H，t，J＝2.5Hz)，6.48-6.56(3H，m)，6.58(1H，d，J＝2.8Hz)，6.78(1H，d，J＝8.5Hz)，7.17(1H，t，J＝8.3Hz).

(iii) 2-[4-({ 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to same method in Embodiment C-72 (iii), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (101mg), 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] aniline (100mg), Virahol (3mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (63.9mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:2.23(3H，s)，4.13(2H，t，J＝4.4Hz)，4.25-4.43(4H，m)，6.13(1H，d，J＝3.2Hz)，6.54(1H，t，J＝2.3Hz)，6.56-6.68(2H，m)，6.94(1H，d，J＝3.2Hz)，6.98(1H，d，J＝8.5Hz)，7.23(1H，t，J＝8.3Hz)，7.39-7.49(2H，m)，8.23(1H，s)，9.32(1H，s).

Embodiment C-115

2-[4-({ 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) preparation of 2-methyl isophthalic acid-[3-(3-methyl butoxy) phenoxy group]-4-oil of mirbane

According to same method in Embodiment C-104 (i), use 3-(2-methyl-4-nitrophenoxy) phenol (855mg), the iodo-3-methylbutane of 1-(0.8mL), salt of wormwood (968mg) and N, dinethylformamide (10mL), make title compound (983mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:0.96(6H，d，J＝6.6Hz)，1.67(2H，q，J＝6.6Hz)，1.74-1.93(1H，m)，2.40(3H，s)，3.97(2H，t，J＝6.6Hz)，6.55-6.62(2H，m)，6.71-6.79(1H，m)，6.82(1H，d，J＝9.0Hz)，7.24-7.33(1H，m)，8.00(1H，dd，J＝2.6Hz，9.0Hz)，8.15(1H，d，J＝2.6Hz).

(ii) 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] preparation of aniline

According to same method in Embodiment C-72 (ii), use 2-methyl isophthalic acid-[3-(3-methyl butoxy) phenoxy group]-4-oil of mirbane (978mg), reduced iron (879mg), calcium chloride (176mg) and ethanol (27mL)/water (3mL), make title compound (835mg), be brown oily.

¹H-NMR(CDCl ₃)δ:0.94(6H，d，J＝6.7Hz)，1.64(2H，q，J＝6.7Hz)，1.72-1.90(1H，m)，2.10(3H，s)，3.55(2H，br?s)，3.93(2H，t，J＝6.7Hz)，6.36-6.44(2H，m)，6.48-6.55(2H，m)，6.58(1H，d，J＝2.8Hz)，6.80(1H，d，J＝8.3Hz)，7.06-7.18(1H，m).

(iii) 2-[4-({ 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to same method in Embodiment C-72 (iii), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (105mg), 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] aniline (102mg), Virahol (3mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (91.5mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:0.96(6H，d，J＝6.7Hz)，1.66(2H，q，J＝6.7Hz)，1.75-1.92(1H，m)，2.25(3H，s)，3.96(2H，t，J＝6.7Hz)，4.12(2H，t，J＝4.4Hz)，4.31-4.41(2H，m)，6.11(1H，d，J＝3.2Hz)，6.46-6.54(2H，m)，6.54-6.62(1H，m)，6.92(1H，d，J＝3.2Hz)，6.97(1H，d，J＝8.3Hz)，7.12-7.22(1H，m)，7.36-7.50(2H，m)，8.22(1H，s)，9.29(1H，s).

Embodiment C-116

2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of acetamide hydrochloride

(i) preparation of { 2-[4-({ 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to same method in Embodiment C-105 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (305mg), 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] aniline (326mg) and Virahol (12mL), make title compound (489mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.46(9H，s)，2.21(3H，s)，3.42-3.58(2H，m)，4.31(2H，q，J＝8.1Hz)，4.41-4.55(2H，m)，5.03(1H，t，J＝5.0Hz)，6.53(1H，t，J＝2.4Hz)，6.56-6.67(3H，m)，6.91-7.02(1H，m)，7.16(1H，d，J＝3.2Hz)，7.21(1H，t，J＝8.2Hz)，7.56-7.77(2H，m)，8.38(1H，br?s)，8.49(1H，s).

(ii) 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to same method in Embodiment C-105 (ii), use { 2-[4-({ 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (484mg), 6N hydrochloric acid (1mL) and ethanol (3mL), make title compound (423mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:2.20(3H，s)，3.21-3.33(2H，m)，4.78(2H，q，J＝8.9Hz)，5.01(2H，t，J＝6.1Hz)，6.56(1H，dd，J＝2.0Hz，8.0Hz)，6.64(1H，t，J＝2.0Hz)，6.72(1H，d，J＝3.2Hz)，6.81(1H，dd，J＝2.0Hz，8.0Hz)，7.04(1H，d，J＝8.7Hz)，7.33(1H，t，J＝8.0Hz)，7.43(1H，dd，J＝2.5Hz，8.7Hz)，7.52(1H，d，J＝2.5Hz)，8.04(1H，d，J＝3.2Hz)，8.34(3H，br?s)，8.68(1H，s)，9.92(1H，br?s).

(iii) 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(2,2,2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of acetamide hydrochloride

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(2, 2, 2-trifluoro ethoxy) phenoxy group] phenyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (152mg), methylsulfonyl acetic acid (64.5mg), tetrahydrofuran (THF) (0.8mL)/N, dinethylformamide (0.8mL), I-hydroxybenzotriazole (70.6mg), triethylamine (0.4mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (93.8mg), make 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(2, 2, 2-trifluoro ethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] ethyl } ethanamide.This compound is dissolved in ethyl acetate, with 4N hydrogenchloride/ethyl acetate solution, processes, filter collecting precipitation, obtain title compound (132mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:2.20(3H，s)，3.05(3H，s)，3.49-3.60(2H，m)，4.07(2H，s)，4.69(2H，t，J＝6.5Hz)，4.77(2H，q，J＝8.9Hz)，6.52-6.59(1H，m)，6.61-6.68(2H，m)，6.81(1H，dd，J＝2.3Hz，8.1Hz)，7.04(1H，d，J＝8.7Hz)，7.33(1H，t，J＝8.1Hz)，7.47(1H，dd，J＝2.5Hz，8.7Hz)，7.54(1H，d，J＝2.5Hz)，7.91(1H，d，J＝3.0Hz)，8.67(1H，s)，8.79(1H，t，J＝5.5Hz)，9.85(1H，s).

Embodiment C-117

N-{2-[4-({ 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) preparation of { 2-[4-({ 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to same method in Embodiment C-105 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (400mg), 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] aniline (408mg) and Virahol (15mL), make title compound (692mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:0.95(6H，d，J＝6.6Hz)，1.46(9H，s)，1.61-1.71(2H，m)，1.74-1.91(1H，m)，2.23(3H，s)，3.42-3.58(2H，m)，3.95(2H，t，J＝6.6Hz)，4.39-4.54(2H，m)，5.01(1H，t，J＝6.1Hz)，6.45-6.62(4H，m)，6.96(1H，d，J＝8.9Hz)，7.10-7.22(2H，m)，7.57-7.74(2H，m)，8.33(1H，br?s)，8.49(1H，s).

(ii) 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to same method in Embodiment C-105 (ii), use 2-[4-(3-methyl-4-[3-(3-methyl butoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (685mg), 6N hydrochloric acid (1mL) and ethanol (3mL), make title compound (602mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:0.92(6H，d，J＝6.6Hz)，1.59(2H，q，J＝6.6Hz)，1.67-1.86(1H，m)，2.20(3H，s)，3.20-3.33(2H，m)，3.97(2H，t，J＝6.6Hz)，5.01(2H，t，J＝6.2Hz)，6.40-6.52(2H，m)，6.68(1H，dd，J＝2.0Hz，8.3Hz)，6.72(1H，d，J＝3.0Hz)，7.02(1H，d，J＝8.7Hz)，7.26(1H，t，J＝8.3Hz)，7.41(1H，dd，J＝2.5Hz，8.7Hz)，7.50(1H，d，J＝2.0Hz)，8.05(1H，d，J＝3.0Hz)，8.35(3H，br?s)，8.67(1H，s)，9.91(1H，br?s).

(iii) N-{2-[4-({ 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (150mg), methylsulfonyl acetic acid (60.9mg), tetrahydrofuran (THF) (0.8mL)/N, dinethylformamide (0.8mL), I-hydroxybenzotriazole (68.1mg), triethylamine (0.4mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (92.2mg), make N-{2-[4-({ 3-methyl-4-[3-(3-methyl butoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide.This compound is dissolved in ethyl acetate, with 4N hydrogenchloride/ethyl acetate solution, processes, filter collecting precipitation, obtain title compound (116mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:0.92(6H，d，J＝6.6Hz)，1.59(2H，q，J＝6.6Hz)，1.67-1.84(1H，m)，2.20(3H，s)，3.05(3H，s)，3.54(2H，q，J＝6.0Hz)，3.97(2H，t，J＝6.6Hz)，4.06(2H，s)，4.69(2H，t，J＝6.0Hz)，6.40-6.52(2H，m)，6.64(1H，d，J＝3.2Hz)，6.66-6.72(1H，m)，7.02(1H，d，J＝8.7Hz)，7.26(1H，t，J＝8.2Hz)，7.45(1H，dd，J＝2.5Hz，8.7Hz)，7.52(1H，d，J＝2.5Hz)，7.90(1H，d，J＝3.2Hz)，8.67(1H，s)，8.78(1H，t，J＝6.0Hz)，9.83(1H，s).

Embodiment C-118

N-{2-[4-({ 4-[3-(2-methoxy ethoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

(i) 1-[3-(2-methoxy ethoxy) phenoxy group] preparation of-2-methyl-4-oil of mirbane

According to same method in Embodiment C-104 (i), use 3-(2-methyl-4-nitrophenoxy) phenol (806mg), the bromo-2-methyl ethyl ether of 1-(0.5mL), salt of wormwood (910mg) and N, dinethylformamide (10mL), make title compound (855mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:2.39(3H，s)，3.45(3H，s)，3.69-3.80(2H，m)，4.06-4.15(2H，m)，6.57-6.65(2H，m)，6.75-6.80(1H，m)，6.82(1H，d，J＝9.0Hz)，7.24-7.33(1H，m)，7.99(1H，dd，J＝2.8Hz，9.0Hz)，8.15(1H，d，J＝2.8Hz).

(ii) 4-[3-(2-methoxy ethoxy) phenoxy group] preparation of-3-monomethylaniline

According to same method in Embodiment C-72 (ii), use 1-[3-(2-methoxy ethoxy) phenoxy group]-2-methyl-4-oil of mirbane (850mg), reduced iron (825mg), calcium chloride (167mg) and ethanol (27mL)/water (3mL), make title compound (707mg), be brown oily.

¹H-NMR(CDCl ₃)δ:2.09(3H，s)，3.43(3H，s)，3.56(2H，br?s)，3.67-3.76(2H，m)，4.02-4.09(2H，m)，6.35-6.63(5H，m)，6.79(1H，d，J＝8.3Hz)，7.13(1H，t，J＝8.3Hz).

(iii) preparation of { 2-[4-({ 4-[3-(2-methoxy ethoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to same method in Embodiment C-105 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (358mg), 4-[3-(2-methoxy ethoxy) phenoxy group]-3-monomethylaniline (364mg) and Virahol (15mL), make title compound (563mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.46(9H，s)，2.22(3H，s)，3.44(3H，s)，3.45-3.56(2H，m)，3.69-3.77(2H，m)，4.04-4.10(2H，m)，4.40-4.52(2H，m)，5.01(1H，t，J＝5.7Hz)，6.49-6.65(4H，m)，6.91-6.99(1H，m)，7.12-7.23(2H，m)，7.53-7.73(2H，m)，8.31(1H，br?s)，8.49(1H，s).

(iv) 5-(2-amino-ethyl)-N-{4-[3-(2-methoxy ethoxy) phenoxy group]-3-aminomethyl phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to same method in Embodiment C-105 (ii), use 2-[4-(4-[3-(2-methoxy ethoxy) phenoxy group] and-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (558mg), 6N hydrochloric acid (1mL) and ethanol (4mL), make title compound (471mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:2.19(3H，s)，3.21-3.38(2H，m)，3.29(3H，s)，3.58-3.69(2H，m)，4.00-4.13(2H，m)，5.00(2H，t，J＝6.0Hz)，6.44-6.54(2H，m)，6.65-6.71(1H，m)，6.72(1H，d，J＝3.2Hz)，7.03(1H，d，J＝8.7Hz)，7.20-7.33(1H，m)，7.41(1H，dd，J＝2.5Hz，8.7Hz)，7.50(1H，d，J＝2.5Hz)，8.04(1H，d，J＝3.2Hz)，8.32(3H，br?s)，8.68(1H，s)，9.88(1H，br?s).

(v) N-{2-[4-({ 4-[3-(2-methoxy ethoxy) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-72 (i); use 5-(2-amino-ethyl)-N-{4-[3-(2-methoxy ethoxy) phenoxy group]-3-aminomethyl phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (151mg), methylsulfonyl acetic acid (67.3mg), tetrahydrofuran (THF) (0.8mL)/N; dinethylformamide (0.8mL), I-hydroxybenzotriazole (94.2mg), triethylamine (0.4mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (122mg); make title compound (98.4mg), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:2.23(3H，s)，3.08(3H，s)，3.44(3H，s)，3.63-3.78(4H，m)，3.93(2H，s)，4.04-4.13(2H，m)，4.38-4.54(2H，m)，6.51(1H，t，J＝2.4Hz)，6.53-6.66(3H，m)，6.94(1H，d，J＝8.7Hz)，7.13-7.23(2H，m)，7.44(1H，dd，J＝2.0Hz，8.7Hz)，7.51(1H，t，J＝5.7Hz)，7.56(1H，d，J＝2.0Hz)，7.83(1H，s)，8.46(1H，s).

Embodiment C-119

N-{2-[4-({ 4-[3-(2,2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) 1-[3-(2,2-dimethyl propoxy-) phenoxy group] preparation of-2-methyl-4-oil of mirbane

According to same method in Embodiment C-104 (i), use 3-(2-methyl-4-nitrophenoxy) phenol (803mg), 1-iodo-2,2-dimethylpropane (0.75mL), salt of wormwood (911mg) and N, dinethylformamide (10mL), make title compound (826mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.03(9H，s)，2.40(3H，s)，3.57(2H，s)，6.55-6.62(2H，m)，6.73-6.79(1H，m)，6.82(1H，d，J＝9.0Hz)，7.28(1H，t，J＝8.5Hz)，8.00(1H，dd，J＝2.5Hz，9.0Hz)，8.15(1H，d，J＝2.5Hz).

(ii) 4-[3-(2,2-dimethyl propoxy-) phenoxy group] preparation of-3-monomethylaniline

According to same method in Embodiment C-72 (ii), use 1-[3-(2,2-dimethyl propoxy-) phenoxy group]-2-methyl-4-oil of mirbane (821mg), reduced iron (876mg), calcium chloride (147mg) and ethanol (27mL)/water (3mL), make title compound (745mg), be brown oily.

¹H-NMR(CDCl ₃)δ:1.01(9H，s)，2.11(3H，s)，3.53(2H，s)，3.54(2H，br?s)，6.35-6.41(1H，m)，6.43(1H，t，J＝2.4Hz)，6.48-6.56(2H，m)，6.59(1H，d，J＝2.8Hz)，6.80(1H，d，J＝8.0Hz)，7.12(1H，t，J＝8.0Hz).

(iii) preparation of { 2-[4-({ 4-[3-(2,2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to same method in Embodiment C-105 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (351mg), 4-[3-(2,2-dimethyl propoxy-) phenoxy group]-3-monomethylaniline (357mg) and Virahol (15mL), make title compound (592mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.02(9H，s)，1.46(9H，s)，2.24(3H，s)，3.42-3.55(2H，m)，3.56(2H，s)，4.39-4.55(2H，m)，5.02(1H，t，J＝5.8Hz)，6.44-6.65(4H，m)，6.96(1H，d，J＝8.5Hz)，7.09-7.22(2H，m)，7.56-7.72(2H，m)，8.32(1H，br?s)，8.49(1H，s).

(iv) 5-(2-amino-ethyl)-N-{4-[3-(2,2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to same method in Embodiment C-105 (ii), { ({ 4-[3-(2 for 2-[4-in use, 2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (586mg), 6N hydrochloric acid (1mL) and ethanol (4mL), make title compound (369mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:0.98(9H，s)，2.20(3H，s)，3.18-3.36(2H，m)，3.62(2H，s)，4.99(2H，t，J＝6.2Hz)，6.40-6.55(2H，m)，6.63-6.77(2H，m)，7.02(1H，d，J＝8.5Hz)，7.26(1H，t，J＝8.2Hz)，7.41(1H，dd，J＝2.3Hz，8.5Hz)，7.50(1H，d，J＝2.3Hz)，8.03(1H，d，J＝3.2Hz)，8.29(3H，br?s)，8.67(1H，s)，9.86(1H，brs).

(v) N-{2-[4-({ 4-[3-(2,2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

According to same method in Embodiment C-72 (i), use 5-(2-amino-ethyl)-N-{4-[3-(2, 2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl }-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (152mg), methylsulfonyl acetic acid (63.0mg), tetrahydrofuran (THF) (0.8mL)/N, dinethylformamide (0.8mL), I-hydroxybenzotriazole (86.5mg), triethylamine (0.4mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (125mg), ({ 4-[3-(2 to make N-{2-[4-, 2-dimethyl propoxy-) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3, 2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide.This compound is dissolved in ethyl acetate, with 4N hydrogenchloride/ethyl acetate solution, processes, filter collecting precipitation, obtain title compound (126mg), be yellow crystals.

¹H-NMR(DMSO-d ₆)δ:0.98(9H，s)，2.20(3H，s)，3.05(3H，s)，3.54(2H，q，J＝6.0Hz)，3.61(2H，s)，4.07(2H，s)，4.70(2H，t，J＝6.0Hz)，6.40-6.53(2H，m)，6.64(1H，d，J＝3.0Hz)，6.69(1H，dd，J＝1.7Hz，8.0Hz)，7.02(1H，d，J＝8.5Hz)，7.26(1H，t，J＝8.0Hz)，7.45(1H，dd，J＝2.0Hz，8.5Hz)，7.53(1H，d，J＝2.0Hz)，7.91(1H，d，J＝3.0Hz)，8.67(1H，s)，8.80(1H，t，J＝6.0Hz)，9.86(1H，s).

Embodiment C-120

The chloro-4-{3-[(2 of 2-{4-[(3-, 2,2-trifluoroethyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

(i) the chloro-4-nitro-1-{3-[(2 of 2-, 2,2-trifluoroethyl) sulfenyl] phenoxy group } preparation of benzene

At room temperature in DMF (20mL) solution of 3-mercapto-phenol (2.0g) and triethylamine (2.70mL), add the fluoro-1-iodoethane of 2,2,2-tri-(1.72mL).At room temperature stirred reaction mixture is 4 hours, and the chloro-4-fluoronitrobenzene of 3-(2.77g) and salt of wormwood (2.18g) are added wherein.At room temperature stirred reaction mixture is 20 hours, and water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=19:1 → 3:1), obtain title compound (4.27g), be yellow oily.

¹H-NMR(CDCl ₆)δ:3.48(2H，q，J＝9.6Hz)，6.91(1H，d，J＝9.0Hz)，6.98-7.02(1H，m)，7.19-7.21(1H，m)，7.34-7.44(2H，m)，8.09(1H，dd，J＝2.7Hz，9.0Hz)，8.40(1H，d，J＝2.7Hz).

(ii) the chloro-4-nitro-1-{3-[(2 of 2-, 2,2-trifluoroethyl) alkylsulfonyl] phenoxy group } preparation of benzene

At 0 ℃, to the chloro-4-nitro-1-{3-[(2 of 2-, 2,2-trifluoroethyl) sulfenyl] phenoxy group } add 70% 3-chlorine peroxybenzoic acid (2.80g) in ethyl acetate (20mL) solution of benzene (2.0g).At 0 ℃, stirred reaction mixture 2 hours, then at room temperature stirs 4 days, sodium thiosulfate solution is added in reaction mixture and stir the mixture 1 hour.Mixture is extracted with ethyl acetate, and organic layer washs with sodium bicarbonate aqueous solution and saturated brine successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=9:1 → 2:3), obtain title compound (2.34g), be clear crystal.

¹H-NMR(CDCl ₃)δ:3.94(2H，q，J＝8.7Hz)，7.01(1H，d，J＝9.0Hz)，7.38-7.43(1H，m)，7.60-7.62(1H，m)，7.66-7.71(1H，m)，7.81-7.85(1H，m)，8.15(1H，dd，J＝2.7Hz，9.0Hz)，8.43(1H，d，J＝2.7Hz).

(iii) the chloro-4-{3-[(2 of 3-, 2,2-trifluoroethyl) alkylsulfonyl] phenoxy group } preparation of aniline

Under refluxing, add the chloro-4-nitro-1-{3-[(2 of 2-; 2,2-trifluoroethyl) alkylsulfonyl] phenoxy group } benzene (2.34g), reduced iron (1.54g) and the mixture of calcium chloride (0.31g) in 15% aqueous ethanol (70mL) 10 hours.Remove by filter insolubles, concentrating under reduced pressure filtrate.Sodium bicarbonate aqueous solution is added in residue and is extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=3:1 → 3:7), obtain title compound (892mg), be yellow solid.

¹H-NMR(CDCl ₃)δ:3.77(2H，br?s)，3.87(2H，q，J＝9.0Hz)，6.60(1H，dd，J＝2.7，8.7Hz)，6.79(1H，d，J＝2.7Hz)，6.85(1H，d，J＝8.7Hz)，7.20-7.25(1H，m)，7.35-7.37(1H，m)，7.51(1H，t，J＝8.1Hz)，7.61(1H，d，J＝8.1Hz).

(iv) the chloro-4-{3-[(2 of 2-{4-[(3-, 2,2-trifluoroethyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

At 80 ℃, stir 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-5H-pyrrolo-[3 of-4-; 2-d] pyrimidine (100mg) and the chloro-4-{3-[(2 of 3-; 2,2-trifluoroethyl) alkylsulfonyl] phenoxy group } Virahol (3.0mL) solution 4 days of aniline (117mg).After concentrating under reduced pressure, methyl alcohol (5.0mL) and 6N hydrochloric acid (1.0mL) are added in residue.At room temperature stir the mixture 4 hours, sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=9:1), obtain title compound (99mg), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:3.90(2H，q，J＝9.0Hz)，4.16-4.25(2H，m)，4.43-4.50(2H，m)，4.91-5.02(1H，m)，6.32(1H，d，J＝3.0Hz)，7.08(1H，d，J＝3.0Hz)，7.11(1H，d，J＝8.7Hz)，7.27-7.33(1H，m)，7.42-7.47(1H，m)，7.52-7.58(2H，m)，7.64-7.67(1H，m)，7.83(1H，d，J＝2.7Hz)，8.35(1H，s)，9.45(1H，s).

Embodiment C-121

2-[4-({ the chloro-4-[3-of 3-(methylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) the chloro-1-[3-of 2-(methylthio group) phenoxy group] preparation of-4-oil of mirbane

At 0 ℃, in DMF (30mL) solution of 3-mercapto-phenol (3.0g) and triethylamine (3.64mL), add methyl-iodide (1.48mL).At 0 ℃, stirred reaction mixture 1 hour, then at room temperature stirs 30 minutes.The chloro-4-fluoronitrobenzene of 3-(4.18g) and salt of wormwood (3.29g) are added in reaction mixture.At room temperature stirred reaction mixture is 14 hours, water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=19:1 → 3:1), obtain title compound (2.84g), be yellow oily.

¹H-NMR(CDCl ₃)δ:2.49(3H，s)，6.80-6.84(1H，m)，6.91(1H，d，J＝9.3Hz)，6.96-6.97(1H，m)，7.11-7.15(1H，m)，7.32-7.37(1H，m)，8.07(1H，dd，J＝2.7Hz，9.3Hz)，8.39(1H，d，J＝2.7Hz).

(ii) the chloro-1-[3-of 2-(methylsulfonyl) phenoxy group] preparation of-4-oil of mirbane

At 0 ℃, to the chloro-1-[3-of 2-(methylthio group) phenoxy group] add 70% 3-chlorine peroxybenzoic acid (5.21g) in ethyl acetate (50mL) solution of-4-oil of mirbane (2.84g).At 0 ℃, stirred reaction mixture 1 hour, adds sodium thiosulfate solution in reaction mixture, and at room temperature stirs this mixture 1 hour.Mixture is extracted with ethyl acetate, and organic layer washs with sodium bicarbonate aqueous solution and saturated brine successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=4:1 → 2:3), obtain title compound (2.79g), be clear crystal.

¹H-NMR(CDCl ₃)δ:3.09(3H，s)，7.02(1H，d，J＝8.7Hz)，7.32-7.36(1H，m)，7.61-7.67(2H，m)，7.79-7.83(1H，m)，8.13(1H，dd，J＝2.4Hz，8.7Hz)，8.42(1H，d，J＝2.7Hz).

(iii) the chloro-4-[3-of 3-(methylsulfonyl) phenoxy group] preparation of aniline

According to same method in Embodiment C-120 (iii); use the chloro-1-[3-of 2-(methylsulfonyl) phenoxy group]-4-oil of mirbane (2.90g), reduced iron (2.50g), calcium chloride (0.50g) and 15% aqueous ethanol (90mL); make title compound (2.29g), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:3.03(3H，s)，3.74(2H，br?s)，6.59(1H，dd，J＝2.7Hz，8.4Hz)，6.78(1H，d，J＝2.7Hz)，6.93(1H，d，J＝8.4Hz)，7.13-7.17(1H，m)，7.36-7.38(1H，m)，7.44-7.50(1H，m)，7.56-7.60(1H，m).

(iv) 2-[4-({ the chloro-4-[3-of 3-(methylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

At 80 ℃, stir phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (100mg) and the chloro-4-[3-of 3-(methylsulfonyl) phenoxy group] Virahol (2.0mL) solution of aniline (98.3mg) 3 days.By reaction mixture cool to room temperature, 1N aqueous sodium hydroxide solution (1.0mL) is added wherein.At room temperature stirred reaction mixture is 2 hours, adds wherein water, and is extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=9:1), obtain title compound (116mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:3.06(3H，s)，4.18(2H，t，J＝4.7Hz)，4.44(2H，t，J＝4.7Hz)，6.27(1H，d，J＝3.0Hz)，7.05(1H，d，J＝3.0Hz)，7.11(1H，d，J＝9.0Hz)，7.22-7.28(1H，m)，7.43-7.45(1H，m)，7.50-7.55(2H，m)，7.61-7.64(1H，m)，7.83(1H，d，J＝2.7Hz)，8.31(1H，s)，9.50(1H，s).

Embodiment C-122

2-{2-[4-({ the chloro-4-[3-of 3-(methylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

According to same method in Embodiment C-121 (iv); use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-; 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (100mg), the chloro-4-[3-of 3-(methylsulfonyl) phenoxy group] aniline (86.1mg), Virahol (2.0mL) and 1N aqueous sodium hydroxide solution (1.0mL); make title compound (117mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.78-1.85(1H，m)，3.05(3H，s)，3.78-3.84(4H，m)，4.03(2H，t，J＝4.4Hz)，4.59(2H，t，J＝4.4Hz)，6.64(1H，d，J＝3.3Hz)，7.09(1H，d，J＝9.0Hz)，7.22-7.27(2H，m)，7.39-7.41(1H，m)，7.48-7.53(1H，m)，7.61(1H，s)，7.63(1H，dd，J＝2.7Hz，9.0Hz)，7.94(1H，d，J＝2.7Hz)，8.53(1H，s)，8.85(1H，s).

Embodiment C-123

2-[4-({ the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) the chloro-1-[3-of 2-(isopropyl sulfenyl) phenoxy group] preparation of-4-oil of mirbane

At room temperature, in DMF (25mL) solution of 3-mercapto-phenol (1.5g) and sodium tert-butoxide (1.37g), add 2-N-PROPYLE BROMIDE (1.23mL).At room temperature stirred reaction mixture is 16 hours, sodium tert-butoxide (1.37g) and the chloro-4-fluoronitrobenzene of 3-(1.88g) is added in reaction mixture, and stir the mixture 4 hours.Again the chloro-4-fluoronitrobenzene of 3-(0.17g) is added in reaction mixture, and at room temperature stir this mixture 2 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=19:1 → 4:1), obtain title compound (3.36g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.32(6H，d，J＝6.9Hz)，3.42(1H，quintet，J＝6.9Hz)，6.88-6.92(2H，m)，7.07-7.08(1H，m)，7.21-7.27(1H，m)，7.32-7.37(1H，m)，8.06(1H，dd，J＝2.7Hz，9.3Hz)，8.38(1H，d，J＝2.7Hz).

(ii) the chloro-1-[3-of 2-(sec.-propyl alkylsulfonyl) phenoxy group] preparation of-4-oil of mirbane

According to same method in Embodiment C-121 (ii), use the chloro-1-[3-of 2-(isopropyl sulfenyl) phenoxy group]-4-oil of mirbane (3.36g), 70% 3-chlorine peroxybenzoic acid (5.63g) and ethyl acetate (50mL), make title compound (3.36g), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.32(6H，d，J＝6.9Hz)，3.22(1H，quintet，J＝6.9Hz)，6.99(1H，d，J＝9.0Hz)，7.33-7.37(1H，m)，7.54-7.55(1H，m)，7.61-7.66(1H，m)，7.74-7.77(1H，m)，8.13(1H，dd，J＝2.7Hz，9.0Hz)，8.41(1H，d，J＝2.7Hz).

(iii) the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] preparation of aniline

According to same method in Embodiment C-120 (iii); use the chloro-1-[3-of 2-(sec.-propyl alkylsulfonyl) phenoxy group]-4-oil of mirbane (3.30g), reduced iron (2.59g), calcium chloride (0.52g) and 15% aqueous ethanol (100mL); make title compound (3.00g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.28(6H，d，J＝6.9Hz)，3.16(1H，quintet，J＝6.9Hz)，3.73(2H，br?s)，6.59(1H，dd，J＝2.7Hz，8.7Hz)，6.78(1H，d，J＝2.7Hz)，6.93(1H，d，J＝8.7Hz)，7.14-7.19(1H，m)，7.28-7.30(1H，m)，7.44-7.54(2H，m).

(iv) 2-[4-({ the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to same method in Embodiment C-121 (iv); use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-; 2-d] pyrimidine-5-yl) ethyl ester (100mg), the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] aniline (140mg), Virahol (2.0mL) and 1N aqueous sodium hydroxide solution (1.0mL); make title compound (127mg), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.30(6H，d，J＝6.9Hz)，3.19(1H，quintet，J＝6.9Hz)，4.16(2H，t，J＝4.5Hz)，4.43(2H，t，J＝4.5Hz)，5.30-5.71(1H，m)，6.26(1H，d，J＝3.0Hz)，7.05(1H，d，J＝3.0Hz)，7.10(1H，d，J＝8.7Hz)，7.23-7.30(1H，m)，7.35-7.37(1H，m)，7.48-7.61(3H，m)，7.84(1H，d，J＝2.4Hz)，8.31(1H，s)，9.53(1H，s).

Embodiment C-124

2-{2-[4-({ the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylate hydrochlorate

According to same method in Embodiment C-121 (iv); use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-; 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (100mg), the chloro-4-[3-of 3-(sec.-propyl alkylsulfonyl) phenoxy group] aniline (113mg), Virahol (2.0mL) and 1N aqueous sodium hydroxide solution (1.0mL), make faint yellow oily matter.At room temperature in ethanol (5.0mL) solution of gained oily matter, add 4N hydrogenchloride/ethyl acetate solution (0.50mL).Concentrating under reduced pressure mixture, filters and collects gained crystal.Crystal washs by ethyl acetate, obtains title compound (130mg), is light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:1.15(6H，d，J＝6.9Hz)，3.38-3.54(5H，m)，3.82-3.89(2H，m)，4.75-4.83(2H，m)，6.69(1H，d，J＝3.0Hz)，7.23-7.25(1H，m)，7.39-7.44(2H，m)，7.61-7.75(3H，m)，7.99-8.03(2H，m)，8.73(1H，s)，9.84(1H，br?s).

Embodiment C-125

The chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

(i) the chloro-1-{3-[(cyclopropyl of 2-methyl) sulfenyl] phenoxy group } preparation of-4-oil of mirbane

At room temperature, in DMF (15mL) solution of 3-mercapto-phenol (1.5g) and sodium tert-butoxide (1.26g), add 1-(brooethyl) cyclopropane (1.27mL).At room temperature stirred reaction mixture is 16 hours, sodium tert-butoxide (1.27g) and the chloro-4-fluoronitrobenzene of 3-(1.88g) is added in reaction mixture, and stir the mixture 3 days.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=19:1 → 4:1), obtain title compound (2.93g), be yellow oily.

¹H-NMR(CDCl ₃)δ:0.25-0.30(2H，m)，0.58-0.64(2H，m)，0.99-1.13(1H，m)，2.89(2H，d，J＝7.2Hz)，6.84-6.89(1H，m)，6.90(1H，d，J＝9.0Hz)，7.05(1H，t，J＝2.1Hz)，7.20-7.24(2H，m)，7.31-7.36(1H，m)，8.06(1H，dd，J＝2.7Hz，9.0Hz)，8.39(1H，d，J＝2.7Hz).

(ii) the chloro-1-{3-[(cyclopropyl of 2-methyl) alkylsulfonyl] phenoxy group } preparation of-4-oil of mirbane

According to same method in Embodiment C-121 (ii), use the chloro-1-{3-[(cyclopropyl of 2-methyl) sulfenyl] phenoxy group }-4-oil of mirbane (2.93g), 70% 3-chlorine peroxybenzoic acid (4.73g) and ethyl acetate (60mL), make title compound (2.90g), be clear crystal.

¹H-NMR(CDCl ₃)δ:0.14-0.20(2H，m)，0.57-0.63(2H，m)，0.95-1.09(1H，m)，3.05(2H，d，J＝7.2Hz)，7.00(1H，d，J＝9.0Hz)，7.33-7.36(1H，m)，7.59-7.66(2H，m)，7.78-7.82(1H，m)，8.13(1H，dd，J＝2.7Hz，9.0Hz)，8.41(1H，d，J＝2.7Hz).

(iii) the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } preparation of aniline

According to same method in Embodiment C-120 (iii); use the chloro-1-{3-[(cyclopropyl of 2-methyl) alkylsulfonyl] phenoxy group }-4-oil of mirbane (2.84g), reduced iron (2.57g), calcium chloride (0.51g) and 15% aqueous ethanol (85mL); make title compound (2.60g), be yellow oily.

¹H-NMR(CDCl ₃)δ:0.10-0.16(2H，m)，0.52-0.58(2H，m)，0.90-1.06(1H，m)，2.99(2H，d，J＝7.5Hz)，3.74(2H，br?s)，6.59(1H，dd，J＝2.7Hz，8.7Hz)，6.78(1H，d，J＝2.7Hz)，6.93(1H，d，J＝8.7Hz)，7.15-7.19(1H，m)，7.34-7.35(1H，m)，7.44-7.49(1H，m)，7.55-7.59(1H，m).

(iv) the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

According to same method in Embodiment C-121 (iv); use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-; 2-d] pyrimidine-5-yl) ethyl ester (100mg), the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } aniline (123mg), Virahol (2.0mL), 1-Methyl-2-Pyrrolidone (2.0mL) and 1N aqueous sodium hydroxide solution (1.0mL); make title compound (126mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:0.11-0.19(2H，m)，0.53-0.63(2H，m)，0.94-1.05(1H，m)，3.01(2H，d，J＝7.2Hz)，4.13-4.21(2H，m)，4.39-4.47(2H，m)，5.11-5.31(1H，m)，6.29(1H，d，J＝3.3Hz)，7.06(1H，d，J＝3.3Hz)，7.10(1H，d，J＝8.7Hz)，7.24-7.30(1H，m)，7.40-7.42(1H，m)，7.48-7.54(2H，m)，7.60-7.63(1H，m)，7.83(1H，d，J＝2.4Hz)，8.32(1H，s)，9.48(1H，s).

Embodiment C-126

2-[4-({ the chloro-4-[3-of 3-(isobutyl-alkylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) the chloro-1-[3-of 2-(isobutyl-sulfenyl) phenoxy group] preparation of-4-oil of mirbane

At room temperature in DMF (15mL) solution of 3-mercapto-phenol (1.5g) and sodium tert-butoxide (1.26g), add the bromo-2-methylpropane of 1-(1.42mL).At room temperature stirred reaction mixture is 2 days, sodium tert-butoxide (1.26g) and the chloro-4-fluoronitrobenzene of 3-(2.08g) is added in reaction mixture, and stir the mixture 6 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=19:1 → 3:1), obtain title compound (3.63g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.04(6H，d，J＝6.6Hz)，1.83-1.96(1H，m)，2.82(2H，d，J＝6.3Hz)，6.81-6.84(1H，m)，6.89(1H，d，J＝9.0Hz)，6.99-7.01(1H，m)，7.15-7.19(1H，m)，7.29-7.34(1H，m)，8.05(1H，dd，J＝2.4Hz，9.0Hz)，8.37(1H，d，J＝2.4Hz).

(ii) the chloro-1-[3-of 2-(isobutyl-alkylsulfonyl) phenoxy group] preparation of-4-oil of mirbane

According to same method in Embodiment C-121 (ii), use the chloro-1-[3-of 2-(isobutyl-sulfenyl) phenoxy group]-4-oil of mirbane (3.63g), 70% 3-chlorine peroxybenzoic acid (5.80g) and ethyl acetate (50mL), make title compound (3.88g), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.08(6H，d，J＝6.6Hz)，2.20-2.23(1H，m)，3.00(2H，d，J＝6.6Hz)，7.00(1H，d，J＝9.0Hz)，7.31-7.35(1H，m)，7.58(1H，t，J＝2.1Hz)，7.60-7.66(1H，m)，7.76-7.80(1H，m)，8.13(1H，dd，J＝2.7Hz，9.0Hz)，8.41(1H，d，J＝2.7Hz).

(iii) the chloro-4-[3-of 3-(isobutyl-alkylsulfonyl) phenoxy group] preparation of aniline

According to same method in Embodiment C-120 (iii); use the chloro-1-[3-of 2-(isobutyl-alkylsulfonyl) phenoxy group]-4-oil of mirbane (3.88g), reduced iron (2.93g), calcium chloride (0.58g) and 15% aqueous ethanol (120mL); make title compound (3.40g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.04(6H，d，J＝6.6Hz)，2.13-2.28(1H，m)，2.96(2H，d，J＝6.6Hz)，3.74(2H，br?s)，6.60(1H，dd，J＝2.7Hz，8.7Hz)，6.79(1H，d，J＝2.7Hz)，6.93(1H，d，J＝8.7Hz)，7.13-7.18(1H，m)，7.34(1H，t，J＝2.1Hz)，7.47(1H，t，J＝8.0Hz)，7.54-7.57(1H，m).

(iv) 2-[4-({ the chloro-4-[3-of 3-(isobutyl-alkylsulfonyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to same method in Embodiment C-121 (iv); use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-; 2-d] pyrimidine-5-yl) ethyl ester (100mg), the chloro-4-[3-of 3-(isobutyl-alkylsulfonyl) phenoxy group] aniline (123mg), Virahol (5.0mL) and 1N aqueous sodium hydroxide solution (2.0mL); make title compound (112mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.06(6H，d，J＝6.9Hz)，2.18-2.29(1H，m)，2.98(2H，d，J＝6.6Hz)，4.12-4.21(2H，m)，4.39-4.48(2H，m)，5.45-5.60(1H，m)，6.25(1H，d，J＝3.0Hz)，7.04(1H，d，J＝3.0Hz)，7.09(1H，d，J＝8.7Hz)，7.23-7.27(1H，m)，7.39-7.41(1H，m)，7.48-7.53(2H，m)，7.57-7.61(1H，m)，7.83(1H，d，J＝2.4Hz)，8.30(1H，s)，9.50(1H，s).

Embodiment C-127

The chloro-4-{3-[(2 of 2-{4-[(3-, 2-dimethyl propyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

(i) the chloro-1-{3-[(2 of 2-, 2-dimethyl propyl) sulfenyl] phenoxy group } preparation of-4-oil of mirbane

At room temperature to adding in DMF (15mL) solution of 3-mercapto-phenol (1.5g) and sodium tert-butoxide (1.26g) 1-bromo-2,2-dimethylpropane (1.64mL).After 70 ℃ are stirred 24 hours, by mixture cool to room temperature, sodium tert-butoxide (1.26g) and the chloro-4-fluoronitrobenzene of 3-(2.08g) are added wherein, and at room temperature stir this mixture 3 days.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: hexane: ethyl acetate=19:1 → 7:3), obtain title compound (2.80g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.05(9H，s)，2.89(2H，s)，6.80-6.84(1H，m)，6.88(1H，d，J＝9.0Hz)，7.02-7.04(1H，m)，7.18-7.22(1H，m)，7.28-7.33(1H，m)，8.05(1H，dd，J＝3.0Hz，9.0Hz)，8.37(1H，d，J＝3.0Hz).

(ii) the chloro-1-{3-[(2 of 2-, 2-dimethyl propyl) alkylsulfonyl] phenoxy group } preparation of-4-oil of mirbane

According to same method in Embodiment C-121 (ii), use the chloro-1-{3-[(2 of 2-, 2-dimethyl propyl) sulfenyl] phenoxy group }-4-oil of mirbane (2.80g), 70% 3-chlorine peroxybenzoic acid (4.32g) and ethyl acetate (56mL), make title compound (3.04g), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.20(9H，s)，3.05(2H，s)，7.00(1H，d，J＝9.0Hz)，7.30-7.34(1H，m)，7.59-7.66(2H，m)，7.77-7.81(1H，m)，8.13(1H，dd，J＝2.7Hz，9.0Hz)，8.42(1H，d，J＝2.7Hz).

(iii) the chloro-4-{3-[(2 of 3-, 2-dimethyl propyl) alkylsulfonyl] phenoxy group } preparation of aniline

According to same method in Embodiment C-120 (iii); use the chloro-1-{3-[(2 of 2-; 2-dimethyl propyl) alkylsulfonyl] phenoxy group }-4-oil of mirbane (3.0g), reduced iron (2.18g), calcium chloride (0.43g) and 15% aqueous ethanol (90mL); make title compound (2.34g), be faint yellow amorphous.

¹H-NMR(CDCl ₃)δ:1.17(9H，s)，3.01(2H，s)，3.73(2H，br?s)，6.59(1H，dd，J＝2.7Hz，9.0Hz)，6.78(1H，d，J＝2.7Hz)，6.92(1H，d，J＝9.0Hz)，7.08-7.14(1H，m)，7.35-7.36(1H，m)，7.42-7.47(1H，m)，7.53-7.57(1H，m).

(iv) the chloro-4-{3-[(2 of 2-{4-[(3-, 2-dimethyl propyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

According to same method in Embodiment C-121 (iv); use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-; 2-d] pyrimidine-5-yl) ethyl ester (100mg), the chloro-4-{3-[(2 of 3-; 2-dimethyl propyl) alkylsulfonyl] phenoxy group } aniline (140mg), Virahol (3.0mL) and 1N aqueous sodium hydroxide solution (1.5mL); make title compound (131mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.19(9H，s)，3.04(2H，s)，4.11-4.20(2H，m)，4.35-5.46(2H，m)，5.81-5.96(1H，m)，6.20(1H，d，J＝3.3Hz)，7.02(1H，d，J＝3.3Hz)，7.08(1H，d，J＝8.7Hz)，7.20-7.27(1H，m)，7.41-7.43(1H，m)，7.46-7.52(2H，m)，7.56-7.63(1H，m)，7.83(1H，d，J＝2.7Hz)，8.27(1H，s)，9.55(1H，s).

Embodiment C-128

N-(the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) (the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of t-butyl carbamate

At 80 ℃, stir [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (1.00g) and the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } Virahol (10mL) solution 14 hours of aniline (1.14g).Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with column chromatography purification (elutriant: hexane: ethyl acetate=1:1 → ethyl acetate → ethyl acetate: methyl alcohol=9:1), obtain title compound (1.86g), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:0.10-0.20(2H，m)，0.54-0.61(2H，m)，0.92-1.06(1H，m)，1.50(9H，s)，3.01(2H，d，J＝6.9Hz)，3.43-3.53(2H，m)，4.43-4.52(2H，m)，5.02-5.10(1H，m)，6.61(1H，d，J＝3.0Hz)，7.09(1H，d，J＝9.0Hz)，7.19(1H，d，J＝3.0Hz)，7.21-7.28(1H，m)，7.46-7.52(2H，m)，7.60-7.63(1H，m)，7.91(1H，dd，J＝2.7Hz，9.0Hz)，8.06(1H，d，J＝2.7Hz)，8.51(1H，s)，8.62(1H，br?s).

(ii) 5-(2-amino-ethyl)-N-(the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } phenyl) preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 60 ℃, stir (the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) mixture 3 days of t-butyl carbamate (1.86g), 6N hydrochloric acid (5.0mL) and ethanol (20mL).After concentrating under reduced pressure, ethanol is added in residue.Concentrating under reduced pressure mixture, filters and collects gained crystal, and with diisopropyl ether washing, obtains title compound (1.66g), is light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:0.09-0.14(2H，m)，0.41-0.48(2H，m)，0.76-0.88(1H，m)，3.22-3.38(4H，m)，4.94-5.05(2H，m)，6.74(1H，d，J＝2.7Hz)，7.30-7.45(3H，m)，7.61-7.74(3H，m)，7.92-7.97(1H，m)，8.00-8.08(1H，m)，8.23-8.32(3H，m)，8.72(1H，s)，9.99(1H，br?s).

(iii) N-(the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) acetamide hydrochloride

At room temperature stir 5-(2-amino-ethyl)-N-(the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } phenyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (100mg), methylsulfonyl acetic acid (48.4mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (101mg), I-hydroxybenzotriazole monohydrate (80mg) and the mixture of triethylamine (0.073mL) in DMF (5.0mL) 20 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), obtain faint yellow amorphous.At room temperature in the unbodied ethanol of gained (5.0mL) solution, add 4N hydrogenchloride/ethyl acetate solution (0.5mL), and at room temperature stir 1 hour, filter and collect gained crystal, and wash by ethyl acetate, obtain title compound (81mg), be clear crystal.

¹H-NMR(DMSO-d ₆)δ:0.06-0.13(2H，m)，0.40-0.47(2H，m)，0.75-0.90(1H，m)，3.06(3H，s)，3.30(2H，d，J＝6.9Hz)，3.49-3.60(2H，m)，4.06(2H，s)，4.64-4.73(2H，m)，6.66(1H，d，J＝2.7Hz)，7.30-7.44(3H，m)，7.65-7，74(3H，m)，7.91-7.99(2H，m)，8.68-8.79(2H，m)，8.86(1H，br?s).

Embodiment C-129

N-(the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

At room temperature stir 5-(2-amino-ethyl)-N-(the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } phenyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (120mg), 2-methyl-2-(methylsulfonyl) propionic acid (52mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (90mg), I-hydroxybenzotriazole monohydrate (72mg) and the mixture of triethylamine (0.088mL) in DMF (5.0mL) 2 days.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), obtain title compound (120mg), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:0.11-0.18(2H，m)，0.54-0.61(2H，m)，0.92-1.07(1H，m)，1.70(6H，s)，2.93(3H，s)，3.01(2H，d，J＝7.2Hz)，3.64-3.74(2H，m)，4.43-4.52(2H，m)，6.64(1H，d，J＝3.3Hz)，6.99(1H，d，J＝9.0Hz)，7.21(1H，d，J＝3.3Hz)，7.22-7.32(2H，m)，7.42-7.44(1H，m)，7.51(1H，t，J＝8.1Hz)，7.60-7.64(1H，m)，7.89(1H，dd，J＝2.7Hz，9.0Hz)，8.07(1H，d，J＝2.7Hz)，8.37(1H，s)，8.53(1H，s).

Embodiment C-130

N-(the chloro-4-{3-[(cyclopropyl of 2-{4-[(3-methyl) alkylsulfonyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-3-hydroxy-3-methyl butyramide mesylate

At room temperature stir 5-(2-amino-ethyl)-N-(the chloro-4-{3-[(cyclopropyl of 3-methyl) alkylsulfonyl] phenoxy group } phenyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (120mg), HMB (49.7mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (121mg), I-hydroxybenzotriazole monohydrate (97mg) and the mixture of triethylamine (0.090mL) in DMF (5.0mL) 20 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=4:1), obtain colourless amorphous.At room temperature in the unbodied ethyl acetate of gained (5.0mL) solution, add methylsulfonic acid (12.4 μ L).At room temperature stir 1 hour, filter and collect gained crystal, and with ethyl acetate washing, obtain title compound (116mg), be clear crystal.

¹H-NMR(DMSO-d ₆)δ:0.08-0.14(2H，m)，0.41-0.47(2H，m)，0.75-0.88(1H，m)，1.12(6H，s)，2.20(2H，s)，2.30(3H，s)，3.29(2H，d，J＝7.2Hz)，3.43-3.56(2H，m)，4.62(2H，t，J＝7.5Hz)，6.66(1H，d，J＝3.0Hz)，7.31-7.45(3H，m)，7.64-7.76(3H，m)，7.93-8.01(2H，m)，8.34(1H，t，J＝5.4Hz)，8.72(1H，s)，10.14(1H，br?s).

Embodiment C-131

N-[2-(the chloro-4-of 4-{[3-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy) benzonitrile (115mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (125mg), Virahol (2.0mL), methyl alcohol (2mL), 4N hydrogenchloride/ethyl acetate solution (3.0mL), methylsulfonyl acetic acid (170mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (360mg), I-hydroxybenzotriazole (15mg), triethylamine (0.86mL) and N, dinethylformamide (15mL), make title compound (169mg), be clear crystal.

¹H-NMR(DMSO-d ₆)δ:3.10(3H，s)，3.44-3.49(2H，m)，4.05(2H，s)，4.55-4.60(2H，m)，6.51-6.52(1H，m)，7.24-8.01(8H，m)，8.38(1H，s)，8.66-8.69(1H，m)，8.81(1H，s).

Embodiment C-132

N-[2-(the chloro-4-of 4-{[3-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-methyl-2-(methylsulfonyl) propionic acid amide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy) benzonitrile (115mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (125mg), Virahol (2.0mL), methyl alcohol (2mL), 4N hydrogenchloride/ethyl acetate solution (3.0mL), 2-methyl-2-(methylsulfonyl) propionic acid (210mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (370mg), I-hydroxybenzotriazole (40mg), triethylamine (1.0mL) and N, dinethylformamide (20mL), make title compound (173mg), be light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:1.41(6H，s)，2.95(3H，s)，3.42-3.49(2H，m)，4.58-4.62(2H，m)，6.50-6.51(1H，m)，7.24-8.00(8H，m)，8.20(1H，br?s)，8.40(1H，s)，8.88(1H，s).

Embodiment C-133

N-[2-(the chloro-4-of 4-{[3-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butyramide

According to same method in Embodiment C-53 (ii), use 3-(4-amino-2-chlorophenoxy) benzonitrile (115

Mg), [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (125mg), Virahol (2.0mL), methyl alcohol (2mL), 4N hydrogenchloride/ethyl acetate solution (3.0mL), HMB (190mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (320mg), I-hydroxybenzotriazole (15mg), triethylamine (0.5mL) and N, dinethylformamide (20mL), make title compound (115mg), be light yellow crystal.

¹H-NMR(DMSO-d ₆)δ:1.13(6H，s)，2.20(2H，s)，3.42-3.49(2H，m)，4.50-4.55(2H，m)，4.66(1H，s)，6.50-6.51(1H，m)，7.24-8.06(8H，m)，8.24(1H，br?s)，8.35(1H，s)，8.92(1H，s).

Embodiment D-1

The chloro-4-of 4-{[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] methyl } preparation of piperidines-1-t-butyl formate

At 80 ℃, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (156mg), 4-[(4-amino-2-chlorophenoxy) methyl] mixture overnight of piperidines-1-t-butyl formate (200mg) and Virahol (15mL).After concentrating under reduced pressure, water and saturated sodium bicarbonate aqueous solution are added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: methyl alcohol=100:0 → 80:20).By target fraction concentrating under reduced pressure.Crude product is dissolved in methyl alcohol (5.0mL), adds tetrahydrofuran (THF) (4.0mL) and 1N aqueous sodium hydroxide solution (3.0mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through ethyl acetate/hexane crystallization, obtains title compound (74mg), is crystal.

¹H-NMR(DMSO-d ₆)δ:1.13-1.27(2H，m)，1.40(9H，s)，1.76-1.80(2H，m)，1.86-2.03(1H，m)，2.65-2.86(2H，m)，3.47(4H，s)，3.78-4.01(6H，m)，4.60-4.68(3H，m)，6.47(1H，d，J＝3.1Hz)，7.12(1H，d，J＝9.1Hz)，7.50(1H，dd，J＝9.1，2.7Hz)，7.63(1H，d，J＝3.1Hz)，7.78(1H，d，J＝2.7Hz)，8.26(1H，s)，8.68(1H，br?s).

Embodiment D-2

The chloro-4-{[5-of 4-[(2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) methyl] preparation of piperidines-1-t-butyl formate

At 80 ℃, stir phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (200mg), 4-[(4-amino-2-chlorophenoxy) methyl] mixture overnight of piperidines-1-t-butyl formate (293mg) and Virahol (5.0mL).After concentrating under reduced pressure, water and saturated sodium bicarbonate aqueous solution are added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: methyl alcohol=100:0 → 80:20).By target fraction concentrating under reduced pressure.Crude product is dissolved in methyl alcohol (5.0mL), tetrahydrofuran (THF) (4.0mL) and 1N aqueous sodium hydroxide solution (4.0mL) is added in mixture, and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through ethyl acetate/hexane crystallization, obtains title compound (147mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.13-1.27(2H，m)，1.40(9H，s)，1.76-1.80(2H，m)，1.86-2.03(1H，m)，2.65-2.86(2H，m)，3.83-4.01(6H，m)，4.50(2H，t，J＝4.1Hz)，6.18-6.21(1H，m)，6.46(1H，d，J＝3.1Hz)，7.13(1H，d，J＝9.1Hz)，7.46(1H，dd，J＝9.1，2.7Hz)，7.60(1H，d，J＝3.1Hz)，7.75(1H，d，J＝2.7Hz)，8.26(1H，s)，9.53(1H，br?s).

Embodiment E-1

2-(the chloro-4-{3-[(2-methyl-1 H-imidazole-1-group of 2-{4-[(3-) methyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol

(i) preparation of [3-(the chloro-4-nitrophenoxy of 2-) phenyl] methyl alcohol

At room temperature, in DMF (50mL) solution of 3-(methylol) phenol (6.21g) and the chloro-4-fluoronitrobenzene of 3-(9.24g), add salt of wormwood (10.37g), and stir the mixture 4 hours.Under ice-cooled, salt solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=20:80 → 40:60), obtain title compound (5.55g), be pale yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.78(1H，t，J＝5.7Hz)，4.74(2H，d，J＝5.7Hz)，6.90(1H，d，J＝9.0Hz)，6.95-7.05(1H，m)，7.12(1H，s)，7.25-7.30(1H，m)，7.43(1H，t，J＝8.0Hz)，8.05-8.10(1H，m)，8.35-8.40(1H，m).

(ii) 1-[3-(the chloro-4-nitrophenoxy of 2-) benzyl] preparation of-2-methyl isophthalic acid H-imidazoles

Under ice-cooled, in tetrahydrofuran (THF) (30mL) solution of [3-(the chloro-4-nitrophenoxy of 2-) phenyl] methyl alcohol (1.12g), add triethylamine (0.67mL) and methylsulfonyl chloride (0.33mL), and at 0 ℃, stir this mixture 1 hour.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.Glyoxal ethyline (328mg), salt of wormwood (829mg) and DMF (10mL) are added in gained residue, and at room temperature stir this mixture 15 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate), obtain title compound (0.96g), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:2.35(3H，s)，5.08(2H，s)，6.75-6.9(3H，m)，6.90-7.05(3H，m)，7.41(1H，t，J＝7.8Hz)，8.06(1H，dd，J＝2.7Hz，9.0Hz)，8.38(1H，d，J＝2.7Hz).

(iii) the chloro-4-{3-[(2-methyl-1 H-imidazole-1-group of 3-) methyl] phenoxy group } preparation of aniline

Under nitrogen atmosphere, to 1-[3-(the chloro-4-nitrophenoxy of 2-) benzyl] add 5% platinum-gac (192mg) in methyl alcohol (10mL) solution of-2-methyl isophthalic acid H-imidazoles (0.96g).Reaction mixture is stirred under room temperature 19 hours under nitrogen atmosphere, then elimination 5% platinum-gac.Concentrating under reduced pressure filtrate is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate: hexane=60:40 → 100:0), obtain title compound (494mg), powder is white in color by residue.

¹H-NMR(CDCl ₃)δ:2.32(3H，s)，3.69(2H，br?s)，4.99(2H，s)，6.56(1H，dd，J＝2.7Hz，9.0Hz)，6.60-6.70(2H，m)，6.70-6.85(3H，m)，6.87(1H，d，J＝9.0Hz)，6.93(1H，d，J＝1.2Hz)，7.22(1H，t，J＝7.6Hz).

(iv) 2-(the chloro-4-{3-[(2-methyl-1 H-imidazole-1-group of 2-{4-[(3-) methyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol

At 120 ℃, by phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (207mg), the chloro-4-{3-[(2-methyl-1 H-imidazole-1-group of 3-) methyl] phenoxy group } mixture of aniline (154mg), 1-Methyl-2-Pyrrolidone (5.0mL) and pyridine hydrochloride (139mg) stirs 22 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5).In gained mixture, add 1N aqueous sodium hydroxide solution (2.3mL) and tetrahydrofuran (THF) (4mL), and at room temperature stir this mixture 21 hours.1N hydrochloric acid neutralization for reaction mixture, then adds sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain title compound (119mg), be pale yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:2.21(3H，s)，3.70-3.85(4H，m)，4.02(2H，t，J＝4.2Hz)，4.57(2H，t，J＝4.2Hz)，5.01(2H，s)，5.99(1H，s)，6.63(1H，d，J＝3.3Hz)，6.75-6.85(1H，m)，6.83(1H，d，J＝8.1Hz)，6.92(1H，d，J＝9.0Hz)，6.95-7.05(1H，m)，7.21(1H，d，J＝3.0Hz)，7.25-7.30(1H，m)，7.32(1H，t，J＝8.0Hz)，7.65(1H，dd，J＝2.4Hz，9.0Hz)，8.02(1H，d，J＝2.4Hz)，8.54(1H，s)，8.98(1H，s).

Embodiment E-2

(1E) the chloro-4-of-1-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of ethyl ketone O-ethyl oxime

(i) (1E)-1-[3-(4-amino-2-chlorophenoxy) phenyl] preparation of ethyl ketone O-ethyl oxime

To 1-[3-(4-amino-2-chlorophenoxy) phenyl] add O-ethyl hydroxylamine hydrochloride (2.44g) and sodium acetate (2.05g) in ethanol (50mL) solution of ethyl ketone (1.31g), and at room temperature stir this mixture overnight.This reaction mixture of concentrating under reduced pressure, adds water wherein, and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=20:80 → 40:60).Concentrating under reduced pressure target fraction, obtains title compound (1.54g), is orange oily.

¹H-NMR(CDCl ₃)δ:1.31(3H，t，J＝7.0Hz)，2.19(3H，s)，3.66(2H，br?s)，4.22(2H，q，J＝7.0Hz)，6.56(1H，dd，J＝2.8Hz，8.7Hz)，6.77-6.83(2H，m)，6.89(1H，d，J＝8.7Hz)，7.21-7.28(2H，m)，7.29-7.35(1H，m).

(ii) the chloro-4-of (1E)-1-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of ethyl ketone O-ethyl oxime

At 80 ℃, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (173mg), (1E)-1-[3-(4-amino-2-chlorophenoxy) phenyl] mixture overnight of ethyl ketone O-ethyl oxime (153mg) and Virahol (3mL).Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).By target fraction concentrating under reduced pressure.In residue, add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (134mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.32(3H，t，J＝7.1Hz)，1.88-2.04(1H，m)，2.21(3H，s)，3.70-3.82(4H，m)，3.99-4.05(2H，m)，4.24(2H，q，J＝7.1Hz)，4.53-4.59(2H，m)，6.61(1H，d，J＝3.0Hz)，6.86-6.92(1H，m)，7.01(1H，d，J＝8.9Hz)，7.20(1H，d，J＝3.0Hz)，7.27-7.40(3H，m)，7.56(1H，dd，J＝2.7Hz，8.9Hz)，7.87(1H，d，J＝2.7Hz)，8.51(1H，s)，8.75(1H，br?s).

Embodiment E-3

2-[2-(4-{[4-(3-tertiary butyl phenoxy group)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethanol

According to the same method in embodiment E-2 (ii), use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (173mg), 4-(3-tertiary butyl phenoxy group)-3-chloroaniline (138mg), Virahol (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (189mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.32(9H，s)，1.95-2.30(1H，m)，3.70-3.82(4H，m)，3.99-4.05(2H，m)，4.52-4.59(2H，m)，6.60(1H，d，J＝3.0Hz)，6.68-6.74(1H，m)，6.99(1H，d，J＝8.9Hz)，7.08-7.15(2H，m)，7.14-7.28(2H，m)，7.54(1H，dd，J＝2.5Hz，8.9Hz)，7.86(1H，d，J＝2.5Hz)，8.49(1H，s)，8.73(1H，br?s).

Embodiment E-4

(1E) the chloro-4-of-1-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of ethyl ketone oxime hydrochloride

(i) phenylformic acid 2-[2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethyl ester

At 80 ℃, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (1.04g), 1-[3-(4-amino-2-chlorophenoxy) phenyl] mixture overnight of ethyl ketone (785mg) and Virahol (10mL).Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).Concentrating under reduced pressure target fraction, obtains title compound (1.59g), is yellow solid.

¹H-NMR(CDCl ₃)δ:2.59(3H，s)，3.93-3.99(2H，m)，4.05-4.12(2H，m)，4.46-4.52(2H，m)，4.55-4.62(2H，m)，6.63(1H，d，J＝3.2Hz)，6.82(1H，d，J＝8.8Hz)，7.07-7.12(1H，m)，7.22(1H，d，J＝3.2Hz)，7.29-7.54(6H，m)，7.63-7.69(1H，m)，7.75-7.82(2H，m)，7.89(1H，d，J＝2.7Hz)，8.50(1H，s)，8.77(1H，br?s).

(ii) the chloro-4-of (1E)-1-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of ethyl ketone oxime hydrochloride

To phenylformic acid 2-[2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) oxyethyl group] add hydroxylamine hydrochloride (104mg) and sodium acetate (123mg) in ethanol (5mL) solution of ethyl ester (171mg), and at room temperature stir this mixture 4 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, then adds methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL) in gained residue.Mixture is at room temperature stirred and spent the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue is dissolved in ethyl acetate-ethanol, then adds wherein 1N hydrogenchloride/ethyl acetate solution (0.3mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of Ethanol-Acetic Acid ethyl ester, obtains title compound (75mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:2.14(3H，s)，3.40-3.54(4H，m)，3.81-3.89(2H，m)，4.76-4.85(2H，m)，6.69(1H，d，J＝3.0Hz)，7.00-7.06(1H，m)，7.22(1H，m)，7.27(1H，d，J＝8.7Hz)，7.37-7.48(2H，m)，7.62(1H，dd，J＝2.5Hz，8.7Hz)，7.96(1H，d，J＝2.5Hz)，8.01(1H，m)，8.73(1H，s)，9.80-9.90(1H，m)，11.31(1H，s).

Embodiment E-5

2-[2-(the chloro-4-of 4-{[3-(3-phenoxy-phenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethylate hydrochlorate

(i) preparation of the chloro-4-nitro-1-of 2-(3-phenoxy-phenoxy) benzene

The fluoro-4-oil of mirbane of the chloro-1-of 2-(0.943g) and 3-phenoxy phenyl (1g) are dissolved in DMF (5.4mL), and salt of wormwood (1.07g) is added wherein.Mixture is at room temperature stirred 16 hours.Ethyl acetate for reaction mixture (80mL) dilution, and water (70mL) washing.Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue, by silica gel column chromatography (hexane/ethyl acetate=100/0 → 70/30), obtains title compound (1.75g), is oily.

¹H-NMR(CDCl ₃)δ:6.73(1H，t，J＝2Hz)，6.78(1H，m)，6.89(1H，m)，6.95(2H，d，J＝9Hz)，7.05(2H，m)，7.16(1H，m)，7.37(3H，m)，8.07(1H，dd，J＝3Hz，9Hz)，8.37(1H，d，J＝3Hz).

(ii) preparation of the chloro-4-of 3-(3-phenoxy-phenoxy) aniline

2-chloro-4-nitro-1-(3-phenoxy-phenoxy) benzene (1.7g) is suspended in ethanol (49mL)/water (5.45mL), calcium chloride (306mg) is added wherein, and by within 10 minutes, making this mixture dissolve 90 ℃ of heated and stirred.Add reduced iron (1.85g), in this mixture of 90 ℃ of heated and stirred 16 hours.Be cooled to after room temperature, by reaction mixture filtration over celite, and concentrating under reduced pressure filtrate.Residual ethyl acetate for solid (200mL) dilution, saturated brine (100mL) washing.Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue, through silica gel column chromatography purifying (hexane/ethyl acetate=80/20 → 60/40), obtains title compound (1.58g), is oily.

¹H-NMR(CDCl ₃)δ:3.67(2H，br?s)，6.50-6.70(4H，m)，6.76(1H，d，J＝3Hz)，6.92(1H，d，J＝9Hz)，7.01(2H，m)，7.10(1H，m)，7.20(1H，m)，7.33(2H，m).

(iii) 2-[2-(the chloro-4-of 4-{[3-(3-phenoxy-phenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethylate hydrochlorate

At 140 ℃ of heated and stirred phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethyl ester (150mg), the chloro-4-of 3-(3-phenoxy-phenoxy) aniline (201mg) and 1-Methyl-2-Pyrrolidone (0.863mL) 3 hours.Ethyl acetate for reaction mixture (80mL) dilution, sodium bicarbonate aqueous solution (30mL) washing.Organic layer is through anhydrous magnesium sulfate drying, concentrating under reduced pressure.Ethyl acetate=90:10 → 0:100), and by target fraction concentrating under reduced pressure residue is through purification by silica gel column chromatography (hexane:.Gained residue is dissolved in methyl alcohol (1.89mL), 1N aqueous sodium hydroxide solution (0.433mL) is added wherein, and at room temperature stir this mixture 2 hours.Add 1N hydrochloric acid (0.433mL), ethyl acetate for mixture (80mL) dilution, saturated brine (30mL) washing.Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue is by silica gel column chromatography (ethyl acetate: methyl alcohol=100:0 → 85:15).Concentrating under reduced pressure, containing the fraction of title compound, is dissolved in residue in ethyl acetate (4mL).4N hydrochloric acid (0.125mL) is added in mixture, and through the crystallization of isopropyl ether/ethyl acetate, obtain title compound (129mg).

¹H-NMR(DMSO-d ₆)δ:3.46(4H，d，J＝2Hz)，3.84(2H，br?s)，4.85(2H，brs)，6.60(1H，s)，7.07(2H，d，J＝8Hz)，7.18(2H，t，J＝8Hz)，7.29(1H，d，J＝8Hz)，7.30-7.50(3H，m)，7.64(1H，d，J＝9Hz)，7.96(1H，d，J＝1Hz)，8.04(1H，d，J＝3Hz)，8.74(1H，s)，10.02(1H，br?s).

Embodiment E-6

N-[2-(the chloro-4-of 4-{[3-(3-phenoxy-phenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butanamide hydrochloride

(i) [2-(the chloro-4-of 4-{[3-(3-phenoxy-phenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

At 80 ℃, Virahol (5mL) solution of stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (0.5g) and the chloro-4-of 3-(3-phenoxy-phenoxy) aniline (786mg) 12 hours.Sodium bicarbonate aqueous solution (30mL) is added in reaction mixture, and be extracted with ethyl acetate (80mL).Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=7:3 → ethyl acetate), obtain title compound (713mg), be clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.48(9H，s)，3.48(2H，m)，4.46(2H，m)，5.12(1H，t，J＝5Hz)，6.59(1H，d，J＝3Hz)，6.69(3H，m)，7.00-7.40(8H，m)，7.85(1H，dd，J＝3Hz，9Hz)，7.98(1H，d，J＝3Hz)，8.50(1H，s)，8.58(1H，br?s).

(ii) the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-phenoxy-phenoxy) phenyl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 60 ℃, stir [2-(the chloro-4-of 4-{[3-(3-phenoxy-phenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] mixture 20 hours of t-butyl carbamate (683mg), 2N hydrochloric acid (8.46mL) and tetrahydrofuran (THF) (16.9mL).Pressure reducing and steaming solvent, adds ethanol, and again concentrates this mixture.Filter the powder of collecting precipitation.With isopropyl ether, wash powder, obtain title compound (622mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:3.30(2H，m)，5.08(2H，m)，6.60(1H，t，J＝2Hz)，6.73(3H，m)，7.06(2H，m)，7.18(1H，m)，7.29(1H，d，J＝9Hz)，7.41(3H，m)，7.64(1H，dd，J＝3Hz，9Hz)，7.90(1H，d，J＝3Hz)，8.10(1H，d，J＝3Hz)，8.42(3H，br?s)，8.73(1H，s).

(iii) N-[2-(the chloro-4-of 4-{[3-(3-phenoxy-phenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butanamide hydrochloride

By the chloro-4-of 5-(2-amino-ethyl)-N-[3-(3-phenoxy-phenoxy) phenyl]-5H-pyrrolo-[3,2-d] mixture of pyrimidine-4-amine dihydrochloride (195mg), HMB (0.058mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and DMF (6.9mL) at room temperature stirs 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15).The fraction that concentrating under reduced pressure contains title compound, is dissolved in residue in ethyl acetate (4mL).Add 4N hydrochloric acid (0.169mL), mixture, through ethyl acetate crystallization, obtains title compound (176mg).

¹H-NMR(DMSO-d ₆)δ:1.10(6H，s)，2.19(2H，s)，3.48(2H，q，J＝6Hz)，4.66(2H，t，J＝6Hz)，6.60(1H，t，J＝3Hz)，6.67(1H，d，J＝3Hz)，6.72(2H，dt，J＝3Hz，9Hz)，7.06(2H，d，J＝8Hz)，7.17(1H，t，J＝7Hz)，7.29(1H，d，J＝9Hz)，7.40(3H，m)，7.67(1H，dd，J＝3Hz，9Hz)，7.92(1H，d，J＝3Hz)，7.98(1H，d，J＝3Hz)，8.40(1H，m)，8.71(1H，s).

Embodiment E-7

2-{2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

(i) 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-2, the preparation of 2-dimethyl propylene-1-ketone

By the fluoro-4-oil of mirbane of the chloro-1-of 2-(2.63g), 1-(3-hydroxyphenyl)-2, the mixture of 2-dimethyl propylene-1-ketone (2.55g), salt of wormwood (2.97g) and DMF (20mL) at room temperature stirs and spends the night.This reaction mixture of concentrating under reduced pressure, adds water and is extracted with ethyl acetate.Organic layer washs with saturated brine, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=2:98 → 15:85).Concentrating under reduced pressure target fraction, obtains title compound (5.17g), is pistac oily.

¹H-NMR(CDCl ₃)δ:1.35(9H，s)，6.92(1H，d，J＝9.1Hz)，7.18(1H，ddd，J＝1.1Hz，2.6Hz，8.1Hz)，7.37(1H，m)，7.45-7.52(1H，m)，7.56-7.60(1H，m)，8.08(1H，dd，J＝2.7Hz，9.1Hz)，8.40(1H，d，J＝2.7Hz).

(ii) the chloro-1-[3-of 2-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] preparation of-4-oil of mirbane

Under reflux, stir 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-2, methylene dichloride (100mL) solution of 2-dimethyl propylene-1-ketone (3.34g) and diethylamino sulfur trifluoride (6.85g) spends the night.Ice and sodium bicarbonate aqueous solution are added in reaction mixture, with this mixture of dichloromethane extraction.Dichloromethane layer washs with saturated brine, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=2:98 → 15:85).Concentrating under reduced pressure target fraction, obtains title compound (3.63g), is colorless oil.

¹H-NMR(CDCl ₃)δ:1.05(9H，s)，6.87(1H，d，J＝9.1Hz)，7.11-7.18(2H，m)，7.31-7.37(1H，m)，7.44-7.52(1H，m)，8.07(1H，dd，J＝2.7Hz，9.1Hz)，8.40(1H，d，J＝2.7Hz).

(iii) the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] preparation of aniline

Under reflux, stir the chloro-1-[3-(1 of 2-, 1-bis-is fluoro-2,2-dimethyl propyl) phenoxy group] mixture 7 hours of-4-oil of mirbane (712mg), reduced iron (372mg), calcium chloride (123mg) and 10% aqueous ethanol (20mL).In addition, under reflux, stir the chloro-1-[3-of 2-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] mixture overnight of-4-oil of mirbane (3.00g), reduced iron (1.57g), calcium chloride (520mg) and 10% aqueous ethanol (100mL).By their merging, solids removed by filtration.Concentrated filtrate, adds water in gained residue, and is extracted with ethyl acetate.Ethyl acetate layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=15:85 → 30:70).Concentrating under reduced pressure target fraction, obtains title compound (2.40g), is light brown solid.

¹H-NMR(CDCl ₃)δ:1.02(9H，s)，3.68(2H，br?s)，6.57(1H，dd，J＝2.7Hz，8.8Hz)，6.79(1H，d，J＝2.7Hz)，6.87-6.95(3H，m)，7.05-7.11(1H，m)，7.28-7.33(1H，m).

(iv) 2-{2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethanol

According to the same method in embodiment E-2 (ii), use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (173mg), the chloro-4-[3-(1 of 3-, 1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] aniline (163mg), Virahol (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (198mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.04(9H，s)，2.05(1H，br?s)，3.70-3.84(4H，m)，4.02(2H，t，J＝4.3Hz)，4.56(2H，t，J＝4.3Hz)，6.61(1H，d，J＝3.2Hz)，6.94-7.08(3H，m)，7.13(1H，d，J＝7.7Hz)，7.20(1H，d，J＝3.2Hz)，7.32(1H，t，J＝8.0Hz)，7.58(1H，dd，J＝2.6Hz，8.9Hz)，7.89(1H，d，J＝2.6Hz)，8.51(1H，s)，8.78(1H，br?s).

Embodiment E-8

2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

At 80 ℃, stir phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (151mg), the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] mixture 9 hours of aniline (163mg) and Virahol (3mL).Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=60:40 → 100:0).By target fraction concentrating under reduced pressure.In residue, add methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), and at room temperature stir this mixture 4 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (191mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.05(9H，s)，4.11-4.18(2H，m)，4.33-4.40(2H，m)，6.09(1H，d，J＝3.3Hz)，6.50(1H，br?s)，6.95(1H，d，J＝3.3Hz)，6.97-7.08(3H，m)，7.14(1H，d，J＝7.7Hz)，7.34(1H，t，J＝8.0Hz)，7.47(1H，dd，J＝2.5Hz，8.8Hz)，7.82(1H，d，J＝2.5Hz)，8.21(1H，s)，9.56(1H，br?s).

Embodiment E-9

N-(the chloro-4-{3-[(1E of 2-{4-[(3-)-N-oxyethyl group imido ethyl (N-ethoxyacetoimidoyl)] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-3-hydroxy-3-methyl butanamide hydrochloride

(i) [2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

At 80 ℃, stir [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (890mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl] mixture overnight of ethyl ketone (785mg) and Virahol (10mL).Sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0).Concentrating under reduced pressure target fraction, residue, through the crystallization of acetone-ether, obtains title compound (1.14g), is pale yellow powder.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，2.59(3H，m)，3.44-3.55(2H，m)，4.44-4.53(2H，m)，5.08(1H，t，J＝5.6Hz)，6.61(1H，d，J＝3.3Hz)，7.05(1H，d，J＝8.9Hz)，7.15-7.21(2H，m)，7.41(1H，t，J＝8.0Hz)，7.56(1H，m)，7.66(1H，d，J＝7.7Hz)，7.89(1H，dd，J＝2.7Hz，8.9Hz)，8.03(1H，d，J＝2.7Hz)，8.52(1H，s)，8.60(1H，br?s).

(ii) N-[2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butyramide

To [2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] add ethanol (2mL) and 4N hydrogenchloride/ethyl acetate solution (5mL) in t-butyl carbamate (1.10g), and at room temperature stir this mixture overnight.This reaction mixture of concentrating under reduced pressure.N to gained residue, in dinethylformamide (20mL) solution, add HMB (374mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (607mg), I-hydroxybenzotriazole monohydrate (485mg) and triethylamine (0.882mL), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=50:50 → 100:0 → methyl alcohol: ethyl acetate=20:80 and alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 10:90).Concentrating under reduced pressure target fraction, obtains title compound (596mg), and amorphous powder is white in color.

¹H-NMR(CDCl ₃)δ:1.32(6H，s)，2.48(2H，s)，2.59(3H，s)，3.58-3.68(2H，m)，4.44-4.54(2H，m)，6.59(1H，d，J＝3.3Hz)，7.05(1H，d，J＝8.8Hz)，7.09-7.22(3H，m)，7.42(1H，t，J＝7.8Hz)，7.57(1H，m)，7.64-7.69(1H，m)，7.74(1H，dd，J＝2.6Hz，8.8Hz)，8.07(1H，d，J＝2.6Hz)，8.50(1H，s)，8.66(1H，brs).

(iii) N-(the chloro-4-{3-[(1E of 2-{4-[(3-)-N-oxyethyl group acetylimino-] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-3-hydroxy-3-methyl butanamide hydrochloride

To N-[2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] add O-ethyl hydroxylamine hydrochloride (88mg) and sodium acetate (74mg) in ethanol (5mL) solution of-3-hydroxy-3-methyl butyramide (157mg), and at room temperature stir this mixture overnight.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 15:85).By target fraction concentrating under reduced pressure.Residue is dissolved in to ethyl acetate-ethanol, adds 1N hydrogenchloride/ethyl acetate solution (0.3mL).Pressure reducing and steaming solvent, gained residue, through the crystallization of ethyl acetate-ether, obtains title compound (91mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.11(6H，s)，1.25(3H，t，J＝7.1Hz)，2.18(3H，s)，2.20(2H，s)，3.43-3.55(2H，m)，4.17(2H，q，J＝7.1Hz)，4.66(2H，t，J＝6.7Hz)，6.67(1H，d，J＝3.2Hz)，6.95-7.02(1H，m)，7.22(1H，d，J＝8.9Hz)，7.33(1H，m)，7.40-7.49(2H，m)，7.67(1H，dd，J＝2.5Hz，8.9Hz)，7.94(1H，d，J＝2.5Hz)，7.98(1H，d，J＝3.2Hz)，8.40(1H，t，J＝5.6Hz)，8.72(1H，s)，10.28(1H，br?s).

Embodiment E-10

N-(the chloro-4-{3-[(1E of 2-{4-[(3-)-N-isobutoxy acetylimino-] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-3-hydroxy-3-methyl butanamide hydrochloride

According to the same method in embodiment E-9 (iii); use N-[2-(4-{[4-(3-ethanoyl phenoxy group)-3-chloro-phenyl-] amino }-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl]-3-hydroxy-3-methyl butyramide (157mg), ethanol (5mL), O-isobutyl-hydroxylamine hydrochloride (113mg), sodium acetate (74mg) and 1N hydrogenchloride/ethyl acetate solution (0.3mL); make title compound (87mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:0.92(6H，d，J＝6.9Hz)，1.11(6H，s)，1.90-2.05(1H，m)，2.20(5H，s)，3.44-3.54(2H，m)，3.91(2H，d，J＝6.6Hz)，4.66(2H，t，J＝6.7Hz)，6.67(1H，d，J＝3.0Hz)，6.94-7.02(1H，m)，7.22(1H，d，J＝8.9Hz)，7.32(1H，m)，7.40-7.48(2H，m)，7.67(1H，dd，J＝2.5Hz，8.9Hz)，7.94(1H，d，J＝2.5Hz)，7.99(1H，d，J＝3.0Hz)，8.40(1H，t，J＝5.5Hz)，8.72(1H，s)，10.29(1H，br?s).

Embodiment E-11

N-{2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butanamide hydrochloride

(i) preparation of { 2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to the same method in embodiment E-9 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (594mg), the chloro-4-[3-(1 of 3-, 1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] aniline (652mg) and Virahol (10mL), make title compound (1.15g), be faint yellow amorphous powder.

¹H-NMR(CDCl ₃)δ:1.04(9H，s)，1.49(9H，s)，3.42-3.54(2H，m)，4.41-4.52(2H，m)，5.20(1H，t，J＝5.4Hz)，6.58(1H，d，J＝3.3Hz)，6.96-7.08(3H，m)，7.12(1H，d，J＝7.7Hz)，7.17(1H，d，J＝3.3Hz)，7.32(1H，t，J＝8.0Hz)，7.84(1H，dd，J＝2.5Hz，8.8Hz)，8.01(1H，d，J＝2.5Hz)，8.50(1H，s)，8.61(1H，brs).

(ii) the chloro-4-[3-of 5-(2-amino-ethyl)-N-{3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

To { 2-[4-({ the chloro-4-[3-(1 of 3-, 1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } add methyl alcohol (10mL) and concentrated hydrochloric acid (2mL) in t-butyl carbamate (1.15g), at room temperature stir this mixture overnight, then at 60 ℃, stir 3 hours.This reaction mixture of concentrating under reduced pressure, adds Virahol and methyl alcohol wherein, again this mixture of concentrating under reduced pressure.Virahol and diisopropyl ether are added in residue, filter and collect crystal, obtain title compound (1.09g), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:0.99(9H，s)，3.24-3.36(2H，m)，5.01(2H，t，J＝6.1Hz)，6.73(1H，d，J＝3.1Hz)，6.93(1H，m)，7.11(1H，dd，J＝2.4Hz，8.0Hz)，7.19(1H，d，J＝8.1Hz)，7.27(1H，d，J＝8.9Hz)，7.51(1H，t，J＝8.0Hz)，7.62(1H，dd，J＝2.4Hz，8.9Hz)，7.90(1H，d，J＝2.4Hz)，8.05(1H，d，J＝3.1Hz)，8.23-8.33(3H，m)，8.71(1H，s)，10.06(1H，br?s).

(iii) N-{2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-3-hydroxy-3-methyl butanamide hydrochloride

By the chloro-4-[3-(1 of 5-(2-amino-ethyl)-N-{3-, 1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] mixture of pyrimidine-4-amine dihydrochloride (168mg), HMB (53mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole monohydrate (69mg), triethylamine (0.100mL) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue is dissolved in ethyl acetate-ethanol, adds 1N hydrogenchloride/ethyl acetate solution (0.3mL).Pressure reducing and steaming solvent, gained residue, through ethyl acetate crystallization, obtains title compound (134mg), and powder is white in color.

¹H-NMR(DMSO-d ₆)δ:0.99(9H，s)，1.11(6H，s)，2.20(2H，s)，3.44-3.54(2H，m)，4.66(2H，t，J＝7.0Hz)，6.67(1H，d，J＝3.2Hz)，6.92(1H，m)，7.13(1H，dd，J＝2.3Hz，8.1Hz)，7.20(1H，d，J＝7.7Hz)，7.29(1H，d，J＝8.9Hz)，7.52(1H，t，J＝8.0Hz)，7.70(1H，dd，J＝2.5Hz，8.9Hz)，7.96(1H，d，J＝2.5Hz)，7.99(1H，d，J＝3.2Hz)，8.41(1H，t，J＝5.1Hz)，8.73(1H，s)，10.28(1H，brs).

Embodiment E-12

N-{2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-2,2-dimethyl propyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) ethanamide

By the chloro-4-[3-(1 of 5-(2-amino-ethyl)-N-{3-; 1-bis-fluoro-2; 2-dimethyl propyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (168mg), methylsulfonyl acetic acid (62mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg), I-hydroxybenzotriazole monohydrate (69mg), triethylamine (0.100mL) and DMF (3mL) at room temperature stirs and spends the night.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, gained residue is by alkaline silica gel column chromatography (elutriant: methyl alcohol: ethyl acetate=0:100 → 20:80).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (153mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:1.04(9H，s)，3.14(3H，s)，3.65-3.75(2H，m)，3.98(2H，s)，4.44-4.53(2H，m)，6.59(1H，d，J＝3.0Hz)，6.98-7.04(2H，m)，7.07(1H，m)，7.15(1H，d，J＝7.7Hz)，7.21(1H，d，J＝3.0Hz)，7.34(1H，d，J＝8.0Hz)，7.62(1H，t，J＝5.5Hz)，7.72(1H，dd，J＝2.5Hz，8.9Hz)，7.94(1H，d，J＝2.5Hz)，8.18(1H，br?s)，8.50(1H，s).

Embodiment E-13

The chloro-4-of 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2, the preparation of 2-dimethyl propylene-1-ketone

(i) 1-[3-(4-amino-2-chlorophenoxy) phenyl]-2, the preparation of 2-dimethyl propylene-1-ketone

Under reflux, stir 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-2, the mixture overnight of 2-dimethyl propylene-1-ketone (1.03g), reduced iron (575mg), calcium chloride (190mg) and 10% aqueous ethanol (30mL).By mixture solids removed by filtration, concentrated filtrate.Water is added in residue, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=20:80 → 40:60).Concentrating under reduced pressure target fraction, obtains title compound (708mg), is brown oily.

¹H-NMR(CDCl ₃)δ:1.31(9H，s)，3.69(2H，br?s)，6.58(1H，dd，J＝2.7Hz，8.5Hz)，6.79(1H，d，J＝2.7Hz)，6.91(1H，d，J＝8.5Hz)，6.94-7.00(1H，m)，7.16(1H，m)，7.26-7.35(2H，m).

(ii) the chloro-4-of 1-{3-[2-({ 5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2, the preparation of 2-dimethyl propylene-1-ketone

According to the same method in embodiment E-2 (ii), use phenylformic acid 2-[2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) oxyethyl group] ethyl ester (734mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl]-2,2-dimethyl propylene-1-ketone (645mg), Virahol (10mL), methyl alcohol (25mL), tetrahydrofuran (THF) (5mL) and 1N aqueous sodium hydroxide solution (5mL), make title compound (858mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.33(9H，s)，3.70-3.82(4H，m)，4.02(2H，t，J＝4.4Hz)，4.55(2H，t，J＝4.4Hz)，6.58(1H，d，J＝3.3Hz)，7.00-7.06(2H，m)，7.19(1H，d，J＝3.3Hz)，7.22(1H，m)，7.28-7.39(2H，m)，7.57(1H，dd，J＝2.6Hz，8.8Hz)，7.89(1H，d，J＝2.6Hz)，8.48(1H，s)，8.81(1H，br?s).

Embodiment E-14

The chloro-4-of (1z)-1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2, the preparation of 2-dimethyl propylene-1-ketone O-methyloxime hydrochloride

According to the same method in embodiment E-9 (iii), the chloro-4-of use 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2,2-dimethyl propylene-1-ketone (204mg), ethanol (5mL), O-methyl hydroxylamine hydrochloride (100mg), sodium acetate (98mg) and 1N hydrogenchloride/ethyl acetate solution (0.4mL), make title compound (201mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.10(9H，s)，3.41-3.51(4H，m)，3.65(3H，s)，3.84(2H，t，J＝4.4Hz)，4.78-4.85(2H，m)，6.62(1H，m)，6.69(1H，d，J＝3.0Hz)，6.82(1H，d，J＝7.7Hz)，6.94(1H，dd，J＝2.5Hz，8.0Hz)，7.22(1H，d，J＝8.9Hz)，7.42(1H，t，J＝8.0Hz)，7.61(1H，dd，J＝2.5Hz，8.9Hz)，7.95(1H，d，J＝2.5Hz)，8.02(1H，d，J＝3.0Hz)，8.73(1H，s)，9.92(1H，br?s).

Embodiment E-15

2-[4-({ the chloro-4-[3-of 3-(1,1-, bis-fluoro ethyls) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of ethyl ketone

According to the same method in embodiment E-7 (i), use the 2-fluoro-4-oil of mirbane of chloro-1-(3.51g), 3 '-hydroxy acetophenone (2.72g), salt of wormwood (4.15g) and N, dinethylformamide (20mL), make title compound (5.60g), solid is white in color.

¹H-NMR(CDCl ₃)δ:2.62(3H，s)，6.92(1H，d，J＝9.1Hz)，7.28-7.33(1H，m)，7.56(1H，t，J＝8.0Hz)，7.65(1H，m)，7.82-7.88(1H，m)，8.09(1H，dd，J＝2.6Hz，9.1Hz)，8.41(1H，d，J＝2.6Hz).

(ii) the chloro-1-[3-of 2-(1,1-, bis-fluoro ethyls) phenoxy group] preparation of-4-oil of mirbane

At 50 ℃, stir 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] ethyl ketone (2.92g), diethylamino sulfur trifluoride (8.06g) 1,2-glycol dimethyl ether (10mL) solution 5 days.Reaction mixture is poured in ice, wherein added 8N aqueous sodium hydroxide solution (20mL).Add ethyl acetate, separated organic layer, with saturated brine washing, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=0:100 → 20:80).Concentrating under reduced pressure target fraction, obtains title compound (2.75g), is orange solids.

¹H-NMR(CDCl ₃)δ:1.93(3H，t，J＝18.1Hz)，6.92(1H，d，J＝9.1Hz)，7.11-7.17(1H，m)，7.25(1H，m)，7.38-7.44(1H，m)，7.51(1H，t，J＝7.8Hz)，8.08(1H，dd，J＝2.7Hz，9.1Hz)，8.40(1H，d，J＝2.7Hz).

(iii) the chloro-4-[3-of 3-(1,1-, bis-fluoro ethyls) phenoxy group] preparation of aniline

According to the same method in embodiment E-13 (i), use the chloro-1-[3-(1 of 2-, 1-bis-fluoro ethyls) phenoxy group]-4-oil of mirbane (2.51g), reduced iron (1.99g), calcium chloride (493mg) and 10% aqueous ethanol (100mL), make title compound (1.81g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.89(3H，t，J＝18.1Hz)，3.69(2H，br?s)，6.58(1H，dd，J＝2.7Hz，8.6Hz)，6.79(1H，d，J＝2.7Hz)，6.86-6.92(1H，m)，6.91(1H，d，J＝8.6Hz)，7.04(1H，m)，7.13-7.18(1H，m)，7.32(1H，t，J＝8.0Hz).

(iv) 2-[4-({ the chloro-4-[3-of 3-(1,1-, bis-fluoro ethyls) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to the same method in embodiment E-8, use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (151mg), the chloro-4-[3-(1 of 3-, 1-bis-fluoro ethyls) phenoxy group] aniline (142mg), Virahol (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (149mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.92(3H，t，J＝18.1Hz)，4.10-4.18(2H，m)，4.32-4.39(2H，m)，6.06(1H，d，J＝3.2Hz)，6.72(1H，br?s)，6.93(1H，d，J＝3.2Hz)，6.97-7.02(1H，m)，7.05(1H，d，J＝8.8Hz)，7.13(1H，m)，7.20(1H，d，J＝8.0Hz)，7.36(1H，t，J＝7.8Hz)，7.47(1H，dd，J＝2.5Hz，8.8Hz)，7.81(1H，d，J＝2.5Hz)，8.18(1H，s)，9.61(1H，br?s).

Embodiment E-16

2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-3,3-dimethylbutyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-3, the preparation of 3-dimethyl butyrate-1-ketone

According to the same method in embodiment E-7 (i), use the 2-fluoro-4-oil of mirbane of chloro-1-(1.76g), 1-(3-hydroxyphenyl)-3,3-dimethyl butyrate-1-ketone (1.92g), salt of wormwood (2.07g) and N, dinethylformamide (10mL), make title compound (3.24g), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.07(9H，s)，2.85(2H，s)，6.90(1H，d，J＝9.1Hz)，7.25-7.30(1H，m)，7.54(1H，t，J＝8.0Hz)，7.63(1H，m)，7.80-7.86(1H，m)，8.08(1H，dd，J＝2.7Hz，9.1Hz)，8.41(1H，d，J＝2.7Hz).

(ii) the chloro-1-[3-of 2-(1,1-bis-fluoro-3,3-dimethylbutyl) phenoxy group] preparation of-4-oil of mirbane

According to the same method in embodiment E-15 (ii), use 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-3,3-dimethyl butyrate-1-ketone (1.90g), diethylamino sulfur trifluoride (5.0mL) and 1,2-glycol dimethyl ether (10mL), make title compound (52mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.02(9H，s)，2.07(2H，t，J＝19.1Hz)，6.88(1H，d，J＝9.3Hz)，7.09-7.15(1H，m)，7.21(1H，m)，7.38(1H，d，J＝7.7Hz)，7.49(1H，t，J＝7.8Hz)，8.08(1H，dd，J＝2.7Hz，9.3Hz)，8.40(1H，d，J＝2.7Hz).

(iii) the chloro-4-[3-of 3-(1,1-bis-fluoro-3,3-dimethylbutyl) phenoxy group] preparation of aniline

According to the same method in embodiment E-13 (i), use the chloro-1-[3-(1 of 2-, 1-bis-fluoro-3,3-dimethylbutyl) phenoxy group]-4-oil of mirbane (130mg), reduced iron (99mg), calcium chloride (25mg) and 10% aqueous ethanol (10mL), make title compound (100mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:0.99(9H，s)，2.04(2H，t，J＝18.9Hz)，3.69(2H，br?s)，6.58(1H，dd，J＝2.7Hz，8.6Hz)，6.79(1H，d，J＝2.7Hz)，6.85-6.90(1H，m)，6.90(1H，d，J＝8.6Hz)，7.00(1H，m)，7.12(1H，d，J＝7.7Hz)，7.30(1H，t，J＝8.1Hz).

(iv) 2-[4-({ the chloro-4-[3-of 3-(1,1-bis-fluoro-3,3-dimethylbutyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to the same method in embodiment E-8, use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (121mg), the chloro-4-[3-(1 of 3-, 1-bis-fluoro-3,3-dimethylbutyl) phenoxy group] aniline (100mg), Virahol (5mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (67mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.01(9H，s)，2.07(2H，t，J＝19.0Hz)，4.11-4.18(2H，m)，4.33-4.40(2H，m)，6.09(1H，d，J＝3.3Hz)，6.49(1H，br?s)，6.94(1H，d，J＝3.3Hz)，6.95-7.01(1H，m)，7.04(1H，d，J＝8.7Hz)，7.10(1H，m)，7.17(1H，d，J＝7.7Hz)，7.35(1H，t，J＝8.0Hz)，7.47(1H，dd，J＝2.6Hz，8.7Hz)，7.81(1H，d，J＝2.6Hz)，8.20(1H，s)，9.55(1H，br?s).

Embodiment E-17

2-[4-({ the chloro-4-[3-of 3-(the fluoro-2-phenylethyl of 1,1-bis-) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

(i) 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of-2-Phenyl ethyl ketone

According to the same method in embodiment E-7 (i), use the 2-fluoro-4-oil of mirbane of chloro-1-(702mg), 1-(3-hydroxyphenyl)-2-Phenyl ethyl ketone (849mg), salt of wormwood (829mg) and N, dinethylformamide (10mL), make title compound (725mg), be faint yellow oily.

¹H-NMR(CDCl ₃)δ:4.26(2H，s)，6.86(1H，d，J＝9.1Hz)，7.20-7.36(6H，m)，7.53(1H，t，J＝8.0Hz)，7.65(1H，m)，7.86-7.92(1H，m)，8.05(1H，dd，J＝2.6Hz，9.1Hz)，8.39(1H，d，J＝2.6Hz).

(ii) the chloro-1-[3-of 2-(the fluoro-2-phenylethyl of 1,1-bis-) phenoxy group] preparation of-4-oil of mirbane

According to the same method in embodiment E-15 (ii), use 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-2-Phenyl ethyl ketone (478mg), diethylamino sulfur trifluoride (2.0mL) and 1,2-glycol dimethyl ether (5mL), make title compound (372mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:3.41(2H，t，J＝15.4Hz)，6.59(1H，d，J＝9.1Hz)，6.91(1H，m)，7.01-7.13(3H，m)，7.20-7.29(4H，m)，7.44(1H，t，J＝8.0Hz)，7.99(1H，dd，J＝2.5Hz，9.1Hz)，8.35(1H，d，J＝2.5Hz).

(iii) the chloro-4-[3-of 3-(the fluoro-2-phenylethyl of 1,1-bis-) phenoxy group] preparation of aniline

According to the same method in embodiment E-13 (i), use the chloro-1-[3-(1 of 2-, the fluoro-2-phenylethyl of 1-bis-) phenoxy group]-4-oil of mirbane (372mg), reduced iron (186mg), calcium chloride (62mg) and 10% aqueous ethanol (10mL), make title compound (200mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:3.36(2H，t，J＝15.9Hz)，3.67(2H，br?s)，6.54(1H，dd，J＝2.7Hz，8.8Hz)，6.77(1H，d，J＝2.7Hz)，6.78-6.84(2H，m)，6.85-6.91(1H，m)，6.98(1H，d，J＝8.0Hz)，7.05-7.12(2H，m)，7.20-7.30(4H，m).

(iv) 2-[4-({ the chloro-4-[3-of 3-(the fluoro-2-phenylethyl of 1,1-bis-) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanol

According to the same method in embodiment E-8, use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (169mg), the chloro-4-[3-(1 of 3-, the fluoro-2-phenylethyl of 1-bis-) phenoxy group] aniline (200mg), Virahol (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (171mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:3.39(2H，t，J＝15.8Hz)，4.10-4.19(2H，m)，4.32-4.40(2H，m)，6.09(1H，d，J＝3.3Hz)，6.53(1H，br?s)，6.90-7.14(7H，m)，7.20-7.38(4H，m)，7.45(1H，dd，J＝2.5Hz，8.8Hz)，7.80(1H，d，J＝2.5Hz)，8.21(1H，s)，9.57(1H，br?s).

Embodiment E-18

1-[3-(4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) phenyl] preparation of cyclopropane carboxamide

(i) preparation of 1-(3-p-methoxy-phenyl) cyclopropane formonitrile HCN

60% sodium hydride (2.72g) is suspended in DMF (80mL), and mixture is cooled to 0 ℃.DMF (20mL) solution of (3-p-methoxy-phenyl) acetonitrile (4.00g) is added drop-wise in mixture, at 0 ℃, stirs the mixture 1 hour.Glycol dibromide (3.5mL) is added drop-wise in reaction mixture, and at room temperature stirs this mixture 17 hours.Saturated aqueous ammonium chloride is added in reaction mixture, use extracted with diethyl ether mixture.Organic layer is water and saturated brine washing successively, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=100:0 → 80:20), obtain title compound (2.76g), be yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.36-1.44(2H，m)，1.67-1.75(2H，m)，3.81(3H，s)，6.77-6.89(3H，m)，7.21-7.29(1H，m).

(ii) preparation of 1-(3-p-methoxy-phenyl) cyclopropane carboxamide and 1-(3-p-methoxy-phenyl) cyclopropane-carboxylic acid

1-(3-p-methoxy-phenyl) cyclopropane formonitrile HCN (2.75g) is dissolved in ethanol (100mL)/water (50mL) mixed solvent, potassium hydroxide (8.94g) is added wherein, under reflux, stir the mixture 5 hours.This reaction mixture of concentrating under reduced pressure, is adjusted to pH1-2 with 6N hydrochloric acid by residue, and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=50:50 → 0:100) of silica gel column chromatography for residue, obtain 1-(3-p-methoxy-phenyl) cyclopropane carboxamide (762mg) and 1-(3-p-methoxy-phenyl) cyclopropane-carboxylic acid (1.78g), be greenish orange look crystal.

1-(3-p-methoxy-phenyl) cyclopropane carboxamide

¹H-NMR(DMSO-d ₆)δ:0.91-0.98(2H，m)，1.26-1.34(2H，m)，3.75(3H，s)，6.11(1H，br?s)，6.79-6.96(3H，m)，7.02(1H，br?s)，7.25(1H，t，J＝8.0Hz).

1-(3-p-methoxy-phenyl) cyclopropane-carboxylic acid

¹H-NMR(DMSO-d ₆)δ:1.02-1.20(2H，m)，1.33-1.50(2H，m)，3.73(3H，s)，6.71-7.00(3H，m)，7.20(1H，t，J＝7.8Hz)，12.27(1H，br?s).

(iii) preparation of 1-(3-hydroxyphenyl) cyclopropane carboxamide

By 1-(3-p-methoxy-phenyl) cyclopropane carboxamide (756mg) be dissolved in phenylfluoroform (benzotrifluoride) (20mL) in, at 0 ℃, 1N boron tribromide/dichloromethane solution (10mL) is added wherein, and at room temperature stir this mixture 2 days.Reaction mixture is ice-cooled, add saturated sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=67:33 → 0:100), obtain title compound (350mg), powder is white in color of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.85-0.95(2H，m)，1.22-1.32(2H，m)，6.04(1H，brs)，6.59-6.71(1H，m)，6.71-6.82(2H，m)，7.02(1H，br?s)，7.12(1H，t，J＝7.8Hz)，9.40(1H，s).

(iv) 1-[3-(2-methyl-4-nitrophenoxy) phenyl] preparation of cyclopropane carboxamide

The mixture of 1-(3-hydroxyphenyl) cyclopropane carboxamide (345mg) and the fluoro-5-nitrotoluene of 2-(347mg) is dissolved in to N, in dinethylformamide (5mL), salt of wormwood (588mg) is added wherein, and at room temperature stir this mixture 19 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=67:33 → 10:90), obtain title compound (561mg), powder is white in color of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.11(2H，q，J＝3.9Hz)，1.58-1.70(2H，m)，2.41(3H，s)，5.35(1H，br?s)，5.56(1H，br?s)，6.80(1H，d，J＝9.0Hz)，6.93-7.00(1H，m)，7.13(1H，t，J＝2.1Hz)，7.27-7.33(1H，m)，7.41(1H，t，J＝7.8Hz)，8.02(1H，dd，J＝2.0Hz，9.0Hz)，8.18(1H，d，J＝2.0Hz).

(v) 1-[3-(4-amino-2-methyl phenoxy group) phenyl] preparation of cyclopropane carboxamide

By 1-[3-(2-methyl-4-nitrophenoxy) phenyl] cyclopropane carboxamide (556mg) is suspended in ethanol (18mL)/water (2mL) mixed solvent, reduced iron (615mg) and calcium chloride (105mg) are added wherein, under reflux, stir this mixture 4 hours.By reaction mixture filtration over celite (celite), concentrating under reduced pressure filtrate.Residue is dissolved in to ethyl acetate, and solution is water and saturated brine washing successively, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=50:50 → 0:100), obtain title compound (433mg), be brown oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.03-1.11(2H，m)，1.54-1.63(2H，m)，2.09(3H，s)，3.59(2H，br?s)，5.38(2H，br?s)，6.49-6.56(1H，m)，6.60(1H，d，J＝2.8Hz)，6.72-6.82(2H，m)，6.89-6.94(1H，m)，7.01-7.07(1H，m)，7.23(1H，t，J＝8.4Hz).

(vi) 1-[3-(4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) phenyl] preparation of cyclopropane carboxamide

By phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (113mg) and 1-[3-(4-amino-2-methyl phenoxy group) phenyl] mixture of cyclopropane carboxamide (108mg) is dissolved in Virahol (3mL), stirs the mixture 21 hours at 70 ℃.By reaction mixture cool to room temperature, 1N aqueous sodium hydroxide solution (1mL) is added wherein, and at room temperature stir this mixture 1 hour.Saturated aqueous ammonium chloride is added in reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=20:80 → 0:100 → ethyl acetate: methyl alcohol=90:10), and through ethyl acetate crystallization, obtain title compound (110mg), crystal is white in color of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:.0.90-0.98(2H，m)，1.25-1.33(2H，m)，2.16(3H，s)，3.87(2H，t，J＝4.5Hz)，4.52(2H，t，J＝4.5Hz)，6.25(2H，br?s)，6.48(1H，d，J＝3.0Hz)，6.74-6.82(1H，m)，6.82-6.87(1H，m)，6.96-7.09(3H，m)，7.30(1H，t，J＝7.9Hz)，7.47-7.56(2H，m)，7.62(1H，d，J＝3.0Hz)，8.27(1H，s)，9.61(1H，br?s).

Embodiment E-19

1-[3-(4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) phenyl] preparation of cyclopropane formonitrile HCN

(i) preparation of 1-(3-hydroxyphenyl) cyclopropane formonitrile HCN

According to the same method in embodiment E-18 (iii), use 1-(3-p-methoxy-phenyl) cyclopropane formonitrile HCN (1.28g), toluene (75mL) and 1N boron tribromide/dichloromethane solution (25mL), make title compound (1.11g), be colorless oil.

¹H-NMR(CDCl ₃)δ:1.37-1.46(2H，m)，1.69-1.77(2H，m)，5.16(1H，s)，6.70-6.81(2H，m)，6.83(1H，t，J＝2.1Hz)，7.21(1H，t，J＝7.8Hz).

(ii) 1-[3-(2-methyl-4-nitrophenoxy) phenyl] preparation of cyclopropane formonitrile HCN

According to the same method in embodiment E-18 (iv), use the fluoro-5-nitrotoluene of 2-(409mg), 1-(3-hydroxyphenyl) cyclopropane formonitrile HCN (450mg), salt of wormwood (731mg) and N, dinethylformamide (8mL), make title compound (776mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.38-1.47(2H，m)，1.72-1.82(2H，m)，2.40(3H，s)，6.78(1H，d，J＝9.0Hz)，6.88-6.95(1H，m)，7.01(1H，t，J＝2.1Hz)，7.10-7.17(1H，m)，7.38(1H，t，J＝8.0Hz)，8.01(1H，dd，J＝2.8Hz，9.0Hz)，8.12-8.22(1H，m).

(iii) 1-[3-(4-amino-2-methyl phenoxy group) phenyl] preparation of cyclopropane formonitrile HCN

According to the same method in embodiment E-18 (v), use 1-[3-(2-methyl-4-nitrophenoxy) phenyl] cyclopropane formonitrile HCN (771mg), reduced iron (847mg), calcium chloride (151mg) and ethanol (27mL)/water (3mL), make title compound (665mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.36-1.39(2H，m)，1.67-1.71(2H，m)，2.09(3H，s)，3.57(2H，br?s)，6.52(1H，dd，J＝2.7Hz，8.7Hz)，6.59(1H，d，J＝2.7Hz)，6.67-6.70(1H，m)，6.75-6.79(2H，m)，6.93-6.96(1H，m)，7.21(1H，t，J＝8.1Hz).

(iv) 1-[3-(4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) phenyl] preparation of cyclopropane formonitrile HCN

According to the same method in embodiment E-18 (vi), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (127mg), 1-[3-(4-amino-2-methyl phenoxy group) phenyl] cyclopropane formonitrile HCN (130mg), Virahol (3mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (115mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.38-1.45(2H，m)，1.69-1.76(2H，m)，2.24(3H，s)，4.08-4.18(2H，m)，4.31-4.43(2H，m)，6.12(1H，d，J＝3.3Hz)，6.35(1H，br?s)，6.80(1H，dd，J＝1.9Hz，8.0Hz)，6.88-7.03(4H，m)，7.25(1H，t，J＝8.0Hz)，7.38-7.51(2H，m)，8.22(1H，s)，9.31(1H，m).

Embodiment E-20

The chloro-4-of (1z)-1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2, the preparation of 2-dimethyl propylene-1-ketone O-ethyl oxime hydrochloride

According to the same method in embodiment E-9 (iii), the chloro-4-of use 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2,2-dimethyl propylene-1-ketone (255mg), ethanol (5mL), O-ethyl hydroxylamine hydrochloride (146mg), sodium acetate (123mg) and 1N hydrogenchloride/ethyl acetate solution (0.5mL), make title compound (144mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.07(3H，t，J＝7.0Hz)，1.10(9H，s)，3.40-3.50(4H，m)，3.84(2H，t，J＝4.5Hz)，3.92(2H，q，J＝7.0Hz)，4.82(2H，t，J＝4.5Hz)，6.61(1H，m)，6.69(1H，d，J＝3.0Hz)，6.82(1H，d，J＝7.4Hz)，6.93-6.99(1H，m)，7.19(1H，d，J＝8.8Hz)，7.42(1H，t，J＝7.8Hz)，7.61(1H，dd，J＝2.5Hz，8.8Hz)，7.95(1H，d，J＝2.5Hz)，8.01(1H，d，J＝3.0Hz)，8.71(1H，s)，9.92(1H，br?s).

Embodiment E-21

The chloro-4-of 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl] and-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2, the preparation of 2-dimethyl propylene-1-alcohol

To the chloro-4-of 1-{3-[2-(5-[2-(2-hydroxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl }-2, in methyl alcohol (5mL) solution of 2-dimethyl propylene-1-ketone (255mg), add sodium borohydride (38mg), and at room temperature stir this mixture 4 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue, through the crystallization of ethyl acetate-diisopropyl ether, obtains title compound (206mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:0.92(9H，s)，2.02(1H，br?s)，2.12(1H，br?s)，3.69-3.80(4H，m)，4.01(2H，t，J＝4.4Hz)，4.36(1H，s)，4.55(2H，t，J＝4.4Hz)，6.59(1H，d，J＝3.0Hz)，6.82-6.88(1H，m)，6.92(1H，m)，6.96-7.04(2H，m)，7.19(1H，d，J＝3.0Hz)，7.24(1H，t，J＝7.8Hz)，7.54(1H，dd，J＝2.5Hz，8.8Hz)，7.85(1H，d，J＝2.5Hz)，8.47(1H，s)，8.73(1H，br?s).

Embodiment E-22

1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-3, the preparation of 3-dimethyl butyrate-1-ketone

(i) 1-[3-(4-amino-2-chlorophenoxy) phenyl]-3, the preparation of 3-dimethyl butyrate-1-ketone

To 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-3, in ethyl acetate (20mL) solution of 3-dimethyl butyrate-1-ketone (1.04g), add 5% platinum-gac (50mg), and under room temperature, stir this mixture 3 hours under nitrogen atmosphere.Elimination catalyzer, concentrated filtrate.Gained residue is by silica gel column chromatography (elutriant: ethyl acetate: hexane=15:85 → 35:65), concentrating under reduced pressure target fraction, obtains title compound (964mg), is brown oily.

¹H-NMR(CDCl ₃)δ:1.04(9H，s)，2.80(2H，s)，3.69(2H，br?s)，6.57(1H，dd，J＝2.7Hz，8.7Hz)，6.78(1H，d，J＝2.7Hz)，6.90(1H，d，J＝8.7Hz)，7.05(1H，ddd，J＝0.9Hz，2.6Hz，8.1Hz)，7.34(1H，t，J＝8.0Hz)，7.41(1H，m)，7.55-7.59(1H，m).

(ii) 1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-3, the preparation of 3-dimethyl butyrate-1-ketone

According to the same method in embodiment E-8, use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (754mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl]-3,3-dimethyl butyrate-1-ketone (795mg), Virahol (5mL), methyl alcohol (10mL), tetrahydrofuran (THF) (2mL) and 1N aqueous sodium hydroxide solution (2.5mL), make title compound (878mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.06(9H，s)，2.84(2H，s)，4.13(2H，t，J＝4.4Hz)，4.37(2H，t，J＝4.4Hz)，6.09(1H，d，J＝3.2Hz)，6.58(1H，br?s)，6.95(1H，d，J＝3.2Hz)，7.04(1H，d，J＝8.8Hz)，7.13-7.18(1H，m)，7.39(1H，t，J＝8.0Hz)，7.46(1H，dd，J＝2.6Hz，8.8Hz)，7.50(1H，m)，7.62(1H，d，J＝7.7Hz)，7.81(1H，d，J＝2.6Hz)，8.19(1H，s)，9.59(1H，br?s).

Embodiment E-23

1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-3, the preparation of 3-dimethyl butyrate-1-alcohol

According to the same method in embodiment E-21, use 1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-3,3-dimethyl butyrate-1-ketone (239mg), methyl alcohol (5mL) and sodium borohydride (38mg), make title compound (234mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.00(9H，s)，1.61(1H，dd，J＝3.4Hz，14.5Hz)，1.74(1H，dd，J＝8.3Hz，14.5Hz)，1.91(1H，br?s)，4.13(2H，t，J＝4.5Hz)，4.36(2H，t，J＝4.5Hz)，4.82(1H，dd，J＝3.4Hz，8.3Hz)，6.09(1H，d，J＝3.0Hz)，6.52(1H，br?s)，6.85(1H，dd，J＝2.5Hz，8.0Hz)，6.95(1H，d，J＝3.0Hz)，7.00-7.08(3H，m)，7.28(1H，t，J＝7.8Hz)，7.45(1H，dd，J＝2.6Hz，8.8Hz)，7.80(1H，d，J＝2.6Hz)，8.19(1H，s)，9.56(1H，br?s).

Embodiment E-24

1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of-2-Phenyl ethyl ketone

(i) 1-[3-(4-amino-2-chlorophenoxy) phenyl] preparation of-2-Phenyl ethyl ketone

According to the same method in embodiment E-22 (i), use 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl]-2-Phenyl ethyl ketone (240mg), ethyl acetate (10mL) and 5% platinum-gac (12mg), make title compound (192mg), be colorless oil.

¹H-NMR(CDCl ₃)δ:3.70(2H，br?s)，4.21(2H，s)，6.57(1H，dd，J＝2.7Hz，8.8Hz)，6.78(1H，d，J＝2.7Hz)，6.89(1H，d，J＝8.8Hz)，7.06-7.11(1H，m)，7.19-7.40(6H，m)，7.46(1H，m)，7.64-7.69(1H，m).

(ii) 1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of-2-Phenyl ethyl ketone

According to the same method in embodiment E-8, use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (166mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl]-2-Phenyl ethyl ketone (186mg), Virahol (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (123mg), be light brown powder.

¹H-NMR(CDCl ₃)δ:4.14(2H，t，J＝4.5Hz)，4.25(2H，s)，4.38(2H，t，J＝4.5Hz)，6.15(1H，d，J＝3.2Hz)，6.19(1H，br?s)，6.97(1H，d，J＝3.2Hz)，7.05(1H，d，J＝8.7Hz)，7.17-7.37(6H，m)，7.42(1H，t，J＝8.0Hz)，7.49(1H，dd，J＝2.7Hz，8.7Hz)，7.54(1H，m)，7.72(1H，d，J＝7.7Hz)，7.82(1H，d，J＝2.7Hz)，8.24(1H，s)，9.55(1H，br?s).

Embodiment E-25

1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of-2-phenylethyl alcohol

According to the same method in embodiment E-21, use 1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl]-2-Phenyl ethyl ketone (60mg), methyl alcohol (2mL) and sodium borohydride (10mg), make title compound (24mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:2.08(1H，br?s)，2.98(1H，dd，J＝8.2Hz，13.7Hz)，3.05(1H，dd，J＝4.9Hz，13.7Hz)，4.14(2H，t，J＝4.6Hz)，4.38(2H，t，J＝4.6Hz)，4.89(1H，dd，J＝4.9Hz，8.2Hz)，6.07(1H，br?s)，6.15(1H，d，J＝3.3Hz)，6.87-6.93(1H，m)，6.96-7.02(3H，m)，7.08(1H，d，J＝7.7Hz)，7.17-7.35(6H，m)，7.45(1H，dd，J＝2.5Hz，8.8Hz)，7.79(1H，d，J＝2.5Hz)，8.24(1H，s)，9.48(1H，br?s).

Embodiment E-26

2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

(i) preparation of 3-(2-methyl-4-nitrophenoxy) phenyl aldehyde

According to the same method in embodiment E-18 (iv), use the fluoro-5-nitrotoluene of 2-(3.00g), 3-hydroxy benzaldehyde (2.59g), salt of wormwood (4.58g) and N, dinethylformamide (30mL), make title compound (4.14g), be faint yellow solid.

¹H-NMR(CDCl ₃)δ:2.40(3H，s)，6.85(1H，d，J＝9Hz)，7.28-7.36(1H，m)，7.46-7.54(1H，m)，7.60(1H，t，J＝7.8Hz)，7.68-7.76(1H，m)，8.04(1H，dd，J＝2.8Hz，9.0Hz)，8.19(1H，d，J＝2.8Hz)，10.00(1H，s).

(ii) preparation of 2-methyl isophthalic acid-{ 3-[3-methyl but-1-ene-1-yl] phenoxy group }-4-oil of mirbane

Bromination isobutyl-triphenyl phosphonium (Isobutyltriphenylphosphonium bromide) (1.86g) is suspended in tetrahydrofuran (THF) (20mL), and suspension is cooled to 0 ℃.Drip 1.6M n-Butyl Lithium/hexane solution (3.5mL), at 0 ℃, stir the mixture 1 hour.Tetrahydrofuran (THF) (10mL) solution of 3-(2-methyl-4-nitrophenoxy) phenyl aldehyde (1.00g) is added drop-wise in reaction mixture, and at room temperature stirs this mixture 2 hours.Saturated aqueous ammonium chloride is added in reaction mixture, use extracted with diethyl ether mixture.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=100:0 → 90:10), obtain title compound (1.09g, E/Z=approximately/5), be yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.03(5H，d，J＝6.5Hz)，1.09(1H，d，J＝6.5Hz)，2.41(3H，s)，2.40-2.51(0.17H，m)，2.77-2.92(0.83H，m)，5.51(0.83H，dd，J＝10.3Hz，11.6Hz)，6.15-6.38(1.17H，m)，6.72-6.96(2.83H，m)，7.03(0.17H，t，J＝7.7Hz)，7.11(0.83H，d，J＝7.7Hz)，7.20(0.17H，d，J＝7.7Hz)，7.28-7.41(1H，m)，7.94-8.06(1H，m)，8.11-8.21(1H，m).

(iii) 3-methyl-4-{3-[3-methyl but-1-ene-1-yl] phenoxy group } preparation of aniline

According to the same method in embodiment E-18 (v), use 2-methyl isophthalic acid-{ 3-[3-methyl but-1-ene-1-yl] phenoxy group }-4-oil of mirbane (1.08g), reduced iron (1.01g), calcium chloride (205mg) and ethanol (36mL)/water (4mL), make title compound (821mg, E/Z=approximately 1/5), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.00(5H，d，J＝6.6Hz)，1.07(1H，d，J＝6.6Hz)，2.12(3H，s)，2.36-2.52(0.17H，m)，2.74-2.96(0.83H，m)，3.55(2H，br?s)，5.43(0.83H，dd，J＝10.2Hz，11.6Hz)，6.08-6.33(1.17H，m)，6.47-6.92(5.83H，m)，6.95-7.01(0.17H，m)，7.16(0.17H，t，J＝8.0Hz)，7.19(0.83H，t，J＝8.0Hz).

(iv) 3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } preparation of aniline

By 3-methyl-4-{3-[3-methyl but-1-ene-1-yl] phenoxy group } aniline (815mg) is dissolved in tetrahydrofuran (THF) (15mL), add diphenyl disulfide (diphenyl disulfide) (133mg) He 2,2 '-azo two (butyronitrile) (103mg), under reflux, stir the mixture 3 days.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=90:10 → 50:50), obtain title compound (181mg), be orange oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.06(6H，d，J＝6.9Hz)，2.11(3H，s)，2.35-2.53(1H，m)，3.55(2H，br?s)，6.13(1H，dd，J＝6.3Hz，16.0Hz)，6.25(1H，d，J＝16.0Hz)，6.51(1H，dd，J＝3.0Hz，8.4Hz)，6.59(1H，d，J＝3.0Hz)，6.65(1H，dd，J＝2.6Hz，8.0Hz)，6.78(1H，d，J＝8.4Hz)，6.81-6.86(1H，m)，6.97(1H，d，J＝8.0Hz)，7.15(1H，t，J＝8.0Hz).

(v) 2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

According to the same method in embodiment E-18 (vi), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (69.6mg), 3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } aniline (65.0mg), Virahol (2mL) and 1N aqueous sodium hydroxide solution (1mL), make title compound (47.7mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.09(6H，d，J＝6.8Hz)，2.26(3H，s)，2.36-2.56(1H，m)，4.13(2H，t，J＝4.5Hz)，4.31-4.42(2H，m)，6.12(1H，d，J＝3.2Hz)，6.19(1H，dd，J＝6.6Hz，16.2Hz)，6.30(1H，d，J＝16.2Hz)，6.72-6.81(1H，m)，6.90-6.99(3H，m)，7.04(1H，d，J＝8.0Hz)，7.21(1H，t，J＝8.0Hz)，7.37-7.48(2H，m)，8.23(1H，s)，9.28(1H，s).

Embodiment E-27

N-(2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) (2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of t-butyl carbamate

By [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (120mg) and 3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } mixture of aniline (109mg) is dissolved in Virahol (5mL), stirs 22 hours at 70 ℃.By saturated, sodium bicarbonate aqueous solution is added in reaction mixture, and be extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=67:33 → 10:90), obtain title compound (186mg), powder is white in color of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.08(6H，d，J＝6.6Hz)，1.46(9H，s)，2.24(3H，s)，2.35-2.55(1H，m)，3.42-3.58(2H，m)，4.40-4.52(2H，m)，4.95-5.08(1H，m)，6.18(1H，dd，J＝6.6Hz，16.2Hz)，6.29(1H，d，J＝16.2Hz)，6.58(1H，d，J＝3.0Hz)，6.73-6.81(1H，m)，6.90-6.98(2H，m)，7.03(1H，d，J＝8.0Hz)，7.16(1H，d，J＝3.0Hz)，7.20(1H，t，J＝8.0Hz)，7.58-7.70(2H，m)，8.32(1H，br?s)，8.49(1H，s).

(ii) 5-(2-amino-ethyl)-N-(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

By (2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) t-butyl carbamate (180mg) is dissolved in ethanol (1mL), 6N hydrochloric acid (0.3mL) is added wherein, at 50 ℃, stir the mixture 12 hours.This reaction mixture of concentrating under reduced pressure, is dissolved in residue in ethanol, again concentrating under reduced pressure mixture.Filter collecting precipitation, obtain title compound (158mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.05(6H，d，J＝6.8Hz)，2.22(3H，s)，2.37-2.54(1H，m)，3.18-3.32(2H，m)，5.00(2H，t，J＝6.1Hz)，6.22-6.41(2H，m)，6.67-6.79(2H，m)，6.92-7.04(2H，m)，7.16(1H，d，J＝7.9Hz)，7.31(1H，t，J＝7.9Hz)，7.39(1H，dd，J＝2.0Hz，8.6Hz)，7.49(1H，d，J＝2.0Hz)，8.03(1H，d，J＝3.2Hz)，8.31(3H?br?s)，8.67(1H，s)，9.87(1H，br?s).

(iii) N-(2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) acetamide hydrochloride

By 5-(2-amino-ethyl)-N-(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl)-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine dihydrochloride (74.8mg) and methylsulfonyl acetic acid (31.1mg) is dissolved in tetrahydrofuran (THF) (0.4mL)/N; in dinethylformamide (0.4mL); add successively wherein I-hydroxybenzotriazole (32.5mg), triethylamine (0.2mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (45.0mg), and at room temperature stir this mixture 24 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=20:80 → 0:100 → ethyl acetate: methyl alcohol=90:10) of silica gel column chromatography for residue; obtain N-(2-{4-[(3-methyl-4-{3-[(1E)-3-methyl but-1-ene-1-yl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl)-2-(methylsulfonyl) ethanamide.This compound is dissolved in ethyl acetate, with 4N hydrogenchloride/ethyl acetate solution, processes, filter collecting precipitation, obtain title compound (32.5mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.05(6H，d，J＝6.8Hz)，2.22(3H，s)，2.36-2.55(1H，m)，3.06(3H，s)，3.47-3.62(2H，m)，4.06(2H，s)，4.69(2H，t，J＝6.4Hz)，6.20-6.42(2H，m)，6.64(1H，d，J＝3.0Hz)，6.69-6.78(1H，m)，6.93-7.03(2H，m)，7.16(1H，d，J＝8.0Hz)，7.31(1H，t，J＝8.0Hz)，7.44(1H，dd，J＝2.5Hz，8.6Hz)，7.53(1H，d，J＝2.5Hz)，7.90(1H，d，J＝3.0Hz)，8.67(1H，s)，8.79(1H，t，J＝5.6Hz)，9.85(1H，s).

Embodiment E-28

N-(2-{4-[(4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-aminomethyl phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) 1-{3-[2-cyclopropyl vinyl] phenoxy group } preparation of-2-methyl-4-oil of mirbane

According to the same method in embodiment E-26 (ii), use bromination (cyclopropyl methyl) triphenyl phosphonium ((cyclopropylmethyl) triphenylphosphonium bromide) (1.86g), tetrahydrofuran (THF) (30mL), 1.6M n-Butyl Lithium/hexane solution (3.5mL) and 3-(2-methyl-4-nitrophenoxy) phenyl aldehyde (1.00g), make title compound (1.15g, E/Z=approximately 1/2), be yellow oily.

¹H-NMR(CDCl ₃)δ:0.43-0.56(2H，m)，0.76-0.89(2H，m)，1.50-1.63(0.33H，m)，1.75-1.91(0.67H，m)，2.40(1H，s)，2.41(2H，s)，5.10(0.67H，dd，J＝10Hz，11.5Hz)，5.72(0.33H，dd，J＝8.9Hz，15.7Hz)，6.30(0.67H，d，J＝11.5Hz)，6.43(0.33H，d，J＝15.7Hz)，6.76(0.33H，d，J＝9.0Hz)，6.80(0.67H，d，J＝9.0Hz)，6.79-6.84(0.33H，m)，6.84-6.90(0.67H，m)，6.96(0.33H，t，J＝1.9Hz)，7.09(0.67H，t，J＝1.9Hz)，7.13(0.33H，d，J＝8.0Hz)，7.27(0.67H，d，J＝8.0Hz)，7.30(0.33H，t，J＝8.0Hz)，7.36(0.67H，t，J＝8.0Hz)，7.93-8.02(1H，m)，8.09(1H，m).

(ii) 1-{3-[(E)-2-cyclopropyl vinyl] phenoxy group } preparation of-2-methyl-4-oil of mirbane

According to the same method in embodiment E-26 (iv), use 1-{3-[2-cyclopropyl vinyl] phenoxy group }-2-methyl-4-oil of mirbane (1.14g), tetrahydrofuran (THF) (25mL), diphenyl disulfide (172mg) and 2,2 '-azo two (butyronitrile) (134mg), make title compound (734mg), be orange oily.

¹H-NMR(CDCl ₃)δ:0.47-0.55(2H，m)，0.79-0.89(2H，m)，1.50-1.63(1H，m)，2.41(3H，s)，5.73(1H，dd，J＝9.0Hz，15.7Hz)，6.44(1H，d，J＝15.7Hz)，6.77(1H，d，J＝9.0Hz)，6.80-6.85(1H，m)，6.97(1H，t，J＝2.0Hz)，7.14(1H，d，J＝7.7Hz)，7.30(1H，t，J＝7.7Hz)，7.98(1H，dd，J＝2.2Hz，9.0Hz)，8.15(1H，d，J＝2.2Hz).

(iii) 4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group } preparation of-3-monomethylaniline

According to the same method in embodiment E-18 (v), use 1-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-2-methyl-4-oil of mirbane (729mg), reduced iron (712mg), calcium chloride (156mg) and ethanol (18mL)/water (2mL), make title compound (352mg), be brown oily.

¹H-NMR(CDCl ₃)δ:0.44-0.53(2H，m)，0.75-0.85(2H，m)，1.44-1.63(1H，m)，2.10(3H，s)，3.54(2H，br?s)，5.67(1H，dd，J＝9.0Hz，15.7Hz)，6.39(1H，d，J＝15.7Hz)，6.51(1H，dd，J＝2.7Hz，8.7Hz)，6.59(1H，d，J＝2.7Hz)，6.61-6.67(1H，m)，6.75-6.82(2H，m)，6.92(1H，d，J＝7.8Hz)，7.14(1H，t，J＝7.8Hz).

(iv) (2-{4-[(4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-aminomethyl phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of t-butyl carbamate

According to the same method in embodiment E-27 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (352mg), 4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-monomethylaniline (347mg) and Virahol (15mL), make title compound (540mg), solid is white in color.

¹H-NMR(CDCl ₃)δ:0.47-0.55(2H，m)，0.75-0.87(2H，m)，1.46(9H，s)，1.50-1.61(1H，m)，2.23(3H，s)，3.43-3.56(2H，m)，4.39-4.54(2H，m)，4.98(1H，t，J＝5.9Hz)，5.71(1H，dd，J＝9.0Hz，15.7Hz)，6.41(1H，d，J＝15.7Hz)，6.59(1H，d，J＝3.2Hz)，6.75(1H，dd，J＝1.6Hz，8.2Hz)，6.87-7.01(3H，m)，7.12-7.23(2H，m)，7.57-7.71(2H，m)，8.31(1H，br?s)，8.50(1H，s).

(v) 5-(2-amino-ethyl)-N-(4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-aminomethyl phenyl) preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to the same method in embodiment E-27 (ii), use (2-{4-[(4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-aminomethyl phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) t-butyl carbamate (536mg), 6N hydrochloric acid (1mL) and ethanol (4mL), make title compound (399mg), be yellow solid.

¹H-NMR(DMSO-d ₆)δ:0.47-0.55(2H，m)，0.74-0.84(2H，m)，1.49-1.64(1H，m)，2.21(3H，s)，3.21-3.34(2H.m)，5.02(2H，t，J＝6.2Hz)，5.85(1H，dd，J＝9.4Hz，15.7Hz)，6.44(1H，d，J＝15.7Hz)，6.66-6.74(2H，m)，6.90-6.99(2H，m)，7.09(1H，d，J＝7.8Hz)，7.27(1H，t，J＝7.8Hz)，7.38(1H，dd，J＝2.6Hz，8.7Hz)，7.48(1H，d，J＝2.5Hz)，8.04(1H，d，J＝3.3Hz)，8.37(3H，br?s)，8.66(1H，s)，9.93(1H，br?s).

(vi) N-(2-{4-[(4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-aminomethyl phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of-2-(methylsulfonyl) acetamide hydrochloride

According to the same method in embodiment E-27 (iii), use 5-(2-amino-ethyl)-N-(4-{3-[(E)-2-cyclopropyl vinyl] phenoxy group }-3-aminomethyl phenyl)-5H-pyrrolo-[3, 2-d] pyrimidine-4-amine dihydrochloride (149mg), methylsulfonyl acetic acid (85.1mg), tetrahydrofuran (THF) (0.8mL)/N, dinethylformamide (0.8mL), I-hydroxybenzotriazole (118mg), triethylamine (0.4mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (178mg) and 4N hydrogenchloride/ethyl acetate solution, make title compound (123mg), be yellow crystals.

¹H-NMR(DMSO-d ₆)δ:0.47-0.56(2H，m)，0.74-0.86(2H，m)，1.47-1.66(1H，m)，2.22(3H，s)，3.06(3H，m)，3.49-3.63(2H，m)，4.06(2H，s)，4.69(2H，t，J＝6.2Hz)，5.86(1H，dd，J＝9.2Hz，15.8Hz)，6.44(1H，d，J＝15.8Hz)，6.64(1H，d，J＝3.0Hz)，6.70(1H，dd，J＝1.8Hz，8.0Hz)，6.90-7.00(2H，m)，7.10(1H，d，J＝8.0Hz)，7.28(1H，t，J＝8.0Hz)，7.43(1H，dd，J＝2.5Hz，8.6Hz)，7.52(1H，d，J＝2.5Hz)，7.90(1H，d，J＝3.0Hz)，8.66(1H，s)，8.79(1H，t，J＝5.7Hz)，9.85(1H，br?s).

Embodiment E-29

N-{2-[4-({ 4-[3-(1-cyano group cyclopropyl) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) preparation of { 2-[4-({ 4-[3-(1-cyano group cyclopropyl) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to the same method in embodiment E-27 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (350mg), 1-[3-(4-amino-2-methyl phenoxy group) phenyl] cyclopropane formonitrile HCN (351mg) and Virahol (10mL), make title compound (590mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.35-1.43(2H，m)，1.47(9H，s)，1.66-1.75(2H，m)，2.21(3H，s)，3.43-3.57(2H，m)，4.41-4.53(2H，m)，5.01(1H，t，J＝5.8Hz)，6.59(1H，d，J＝3.2Hz)，6.76-6.83(1H，m)，6.86-6.95(2H，m)，6.98-7.05(1H，m)，7.16(1H，d，J＝3.2Hz)，7.24(1H，t，J＝7.9Hz)，7.58-7.76(2H，m)，8.35(1H，brs)，8.50(1H，s).

(ii) 1-[3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) phenyl] preparation of cyclopropane formonitrile HCN dihydrochloride

According to the same method in embodiment E-27 (ii), use 2-[4-(4-[3-(1-cyano group cyclopropyl) phenoxy group] and-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (586mg), 6N hydrochloric acid (1mL) and ethanol (6mL), make title compound (478mg), crystal is white in color.

¹H-NMR(DMSO-d ₆)δ:1.47-1.58(2H，m)，1.71-1.82(2H，m)，2.21(3H，s)，3.19-3.49(2H，m)，4.98(2H，t，J＝6.1Hz)，6.71(1H，d，J＝3.0Hz)，6.80(1H，dd，J＝2.3Hz，7.7Hz)，6.98(1H，t，J＝2.3Hz)，7.01(1H，d，J＝8.7Hz)，7.04-7.09(1H，m)，7.39(1H，t，J＝7.7Hz)，7.42(1H，dd，J＝2.3Hz，8.7Hz)，7.51(1H，d，J＝2.3Hz)，8.01(1H，d，J＝3.0Hz)，8.26(3H，br?s)，8.66(1H，s)，9.81(1H，br?s).

(iii) N-{2-[4-({ 4-[3-(1-cyano group cyclopropyl) phenoxy group]-3-aminomethyl phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

According to the same method in embodiment E-27 (iii), use 1-[3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl] amino }-2-methylphenoxy) phenyl] cyclopropane formonitrile HCN dihydrochloride (150mg), methylsulfonyl acetic acid (65.2mg), tetrahydrofuran (THF) (0.8mL)/N, dinethylformamide (0.8mL), I-hydroxybenzotriazole (82.1mg), triethylamine (0.4mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (117mg) and 4N hydrogenchloride/ethyl acetate solution, make title compound (133mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.49-1.57(2H，m)，1.73-1.81(2H，m)，2.21(3H，s)，3.05(3H，s)，3.49-3.60(2H，m)，4.06(2H，s)，4.70(2H，t，J＝6.2Hz)，6.63(1H，d，J＝3.0Hz)，6.79(1H，dd，J＝2.5Hz，8.0Hz)，6.98(1H，t，J＝2.5Hz)，7.01(1H，d，J＝8.0Hz)，7.03-7.09(1H，m)，7.38(1H，t，J＝8.0Hz)，7.46(1H，dd，J＝2.6Hz，8.7Hz)，7.54(1H，d，J＝2.6Hz)，7.90(1H，d，J＝3.0Hz)，8.66(1H，s)，8.81(1H，t，J＝5.5Hz)，9.87(1H，s).

Embodiment E-30

N-{2-[4-({ the chloro-4-[3-of 3-(1-cyano group cyclopropyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

(i) 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of cyclopropane formonitrile HCN

According to the same method in embodiment E-18 (iv), use the chloro-4-fluoronitrobenzene of 3-(362mg), 1-(3-hydroxyphenyl) cyclopropane formonitrile HCN (350mg), salt of wormwood (493mg) and N, dinethylformamide (7mL), make title compound (650mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.39-1.48(2H，m)，1.74-1.84(2H，m)，6.90(1H，d，J＝9Hz)，6.95-7.01(1H，m)，7.04(1H，t，J＝2.0Hz)，7.20(1H，d，J＝8.0Hz)，7.42(1H，t，J＝8.0Hz)，8.08(1H，dd，J＝2.6Hz，9.0Hz)，8.40(1H，d，J＝2.6Hz).

(ii) 1-[3-(4-amino-2-chlorophenoxy) phenyl] preparation of cyclopropane formonitrile HCN

According to the same method in embodiment E-18 (v), use 1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] cyclopropane formonitrile HCN (643mg), reduced iron (570mg), calcium chloride (113mg) and ethanol (18mL)/water (2mL), make title compound (508mg), be yellow oily.

¹H-NMR(CDCl ₃)δ:1.34-1.41(2H，m)，1.66-1.74(2H，m)，3.68(2H，br?s)，6.57(1H，dd，J＝2.8Hz，8.5Hz)，6.68-6.74(1H，m)，6.78(1H，d，J＝2.8Hz)，6.80(1H，t，J＝2.1Hz)，6.88(1H，d，J＝8.5Hz)，6.95-7.01(1H，m)，7.23(1H，t，J＝8.0Hz).

(iii) preparation of { 2-[4-({ the chloro-4-[3-of 3-(1-cyano group cyclopropyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to the same method in embodiment E-27 (i), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (350mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl] cyclopropane formonitrile HCN (349mg) and Virahol (8mL), make title compound (632mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.36-1.45(2H，m)，1.50(9H，s)，1.66-1.77(2H，m)，3.43-3.57(2H，m)，4.40-4.55(2H，m)，5.07(1H，t，J＝5.5Hz)，6.60(1H，d，J＝3.0Hz)，6.84(1H，dd，J＝2.2Hz，8.0Hz)，6.91(1H，t，J＝2.2Hz)，7.03(1H，d，J＝9.1Hz)，7.05-7.11(1H，m)，7.18(1H，d，J＝3.0Hz)，7.28(1H，t，J＝8.0Hz)，7.87(1H，dd，J＝2.7Hz，9.1Hz)，8.02(1H，d，J＝2.7Hz)，8.51(1H，s)，8.58(1H，s).

(iv) 1-[3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy) phenyl] preparation of cyclopropane formonitrile HCN dihydrochloride

Will 2-[4-(the chloro-4-[3-of 3-(1-cyano group cyclopropyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (627mg) is dissolved in ethanol (7mL)/tetrahydrofuran (THF) (1mL) mixed solvent, 6N hydrochloric acid (1mL) is added wherein, at 50 ℃, stir the mixture 14 hours.This reaction mixture of concentrating under reduced pressure, is dissolved in residue in concentrated hydrochloric acid (2mL), and at room temperature stirs this mixture 10min.Ethanol is added in reaction mixture, filter and collect gained precipitation, obtain title compound (433mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.48-1.60(2H，m)，1.72-1.84(2H，m)，3.21-3.37(2H，m)，5.01(2H，t，J＝6.4Hz)，6.74(1H，d，J＝3.0Hz)，6.85(1H，dd，J＝8.0Hz，2.2Hz)，7.03(1H，t，J＝2.2Hz)，7.08-7.15(1H，m)，7.23(1H，d，J＝8.9Hz)，7.42(1H，t，J＝8.0Hz)，7.61(1H，dd，J＝2.5Hz，8.9Hz)，7.90(1H，d，J＝2.5Hz)，8.05(1H，d，J＝3.0Hz)，8.29(3H，br?s)，8.71(1H，s)，10.05(1H，br?s).

(v) N-{2-[4-({ the chloro-4-[3-of 3-(1-cyano group cyclopropyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of-2-(methylsulfonyl) acetamide hydrochloride

According to the same method in embodiment E-27 (iii), use 1-[3-(4-{[5-(2-amino-ethyl)-5H-pyrrolo-[3, 2-d] pyrimidine-4-yl] amino }-2-chlorophenoxy) phenyl] cyclopropane formonitrile HCN dihydrochloride (149mg), methylsulfonyl acetic acid (60.0mg), tetrahydrofuran (THF) (0.8mL)/N, dinethylformamide (0.8mL), I-hydroxybenzotriazole (77.4mg), triethylamine (0.4mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (110mg) and 4N hydrogenchloride/ethyl acetate solution, make title compound (131mg), powder is white in color.

¹H-NMR(DMSO-d ₆)δ:1.50-1.60(2H，m)，1.74-1.83(2H，m)，3.06(3H，s)，3.54(2H，q，J＝6.0Hz)，4.06(2H，s)，4.70(2H，t，J＝6.0Hz)，6.66(1H，d，J＝3.0Hz)，6.85(1H，dd，J＝2.2Hz，8.0Hz)，7.02(1H，t，J＝2.2Hz)，7.08-7.14(1H，m)，7.24(1H，d，J＝9.0Hz)，7.41(1H，t，J＝8.0Hz)，7.64(1H，dd，J＝2.5Hz，9.0Hz)，7.92(1H，d，J＝2.5Hz)，7.93(1H，d，J＝3.0Hz)，8.71(1H，s)，8.77(1H，t，J＝5.8Hz)，9.91(1H，br?s).

Embodiment E-31

N-(tertiary butyl)-1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of cyclopropane carboxamide

(i) preparation of N-(tertiary butyl)-1-(3-p-methoxy-phenyl) cyclopropane carboxamide

1-(3-p-methoxy-phenyl) cyclopropane-carboxylic acid (400mg) is dissolved in tetrahydrofuran (THF) (6mL), the DMF of catalytic amount and thionyl chloride (0.4mL) is added wherein, and at room temperature stir this mixture 6 hours.This reaction mixture of concentrating under reduced pressure, is dissolved in residue in tetrahydrofuran (THF) (4mL).This solution is added drop-wise in the mixture of the TERTIARY BUTYL AMINE (0.25mL), triethylamine (1mL) and the tetrahydrofuran (THF) (3mL) that are cooled to 0 ℃, and at room temperature stirs this mixture 2 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer washs with saturated brine, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (hexane: ethyl acetate=95:5 → 67:33), obtain title compound (477mg), be faint yellow oily of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:0.97(2H，q，J＝3.7Hz)，1.22(9H，s)，1.52(2H，q，J＝3.7Hz)，3.82(3H，s)，5.22(1H，br?s)，6.81-6.87(1H，m)，6.90-6.94(1H，m)，6.95-7.01(1H，m)，7.27(1H，t，J＝7.9Hz).

(ii) preparation of N-(tertiary butyl)-1-(3-hydroxyphenyl) cyclopropane carboxamide

According to the same method in embodiment E-18 (iii), use N-(tertiary butyl)-1-(3-p-methoxy-phenyl) cyclopropane carboxamide (470mg), phenylfluoroform (10mL) and 1N boron tribromide/dichloromethane solution (4mL), make title compound (245mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:0.95-1.04(2H，m)，1.22(9H，s)，1.50-1.58(2H，m)，5.36(1H，br?s)，6.13(1H，br?s)，6.76-6.88(2H，m)，6.90-6.98(1H，m)，7.19-7.29(1H，m).

(iii) N-(tertiary butyl)-1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] preparation of cyclopropane carboxamide

According to the same method in embodiment E-18 (iv), use N-(tertiary butyl)-1-(3-hydroxyphenyl) cyclopropane carboxamide (242mg), the chloro-4-fluoronitrobenzene of 3-(237mg), salt of wormwood (223mg) and N, dinethylformamide (5mL), make title compound (397mg), crystal is white in color.

¹H-NMR(CDCl ₃)δ:0.96-1.01(2H，m)，1.23(9H，s)，1.52-1.59(2H，m)，5.08(1H，br?s)，6.88(1H，d，J＝9.1Hz)，6.98-7.04(1H，m)，7.08-7.13(1H，m)，7.27-7.32(1H，m)，7.43(1H，t，J＝8.0Hz)，8.07(1H，dd，J＝2.8Hz，9.1Hz)，8.40(1H，d，J＝2.8Hz).

(iv) 1-[3-(4-amino-2-chlorophenoxy) phenyl] preparation of-N-(tertiary butyl) cyclopropane carboxamide

By N-(tertiary butyl)-1-[3-(the chloro-4-nitrophenoxy of 2-) phenyl] cyclopropane carboxamide (392mg) is dissolved in methyl alcohol (7.5mL)/ethyl acetate (7.5mL) mixed solvent, add wherein 5% platinum-gac (44.4mg), under nitrogen atmosphere, under room temperature, stir the mixture 1.5 hours.By reaction mixture filtration over celite, concentrating under reduced pressure filtrate.By the separated also purifying (hexane: ethyl acetate=95:5 → 50:50), obtain title compound (324mg), be colorless oil of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:0.91-0.98(2H，m)，1.21(9H，s)，1.45-1.52(2H，m)，3.70(2H，s)，5.17(1H，br?s)，6.59(1H，dd，J＝2.7Hz，8.6Hz)，6.79(1H，d，J＝2.7Hz)，6.81-6.87(2H，m)，6.91(1H，d，J＝8.6Hz)，6.99-7.06(1H，m)，7.21-7.31(1H，m).

(v) N-(tertiary butyl)-1-[3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of cyclopropane carboxamide

According to the same method in embodiment E-18 (vi), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (120mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl]-N-(tertiary butyl) cyclopropane carboxamide (160mg), Virahol (4mL) and 1N aqueous sodium hydroxide solution (1.5mL), make title compound (155mg), powder is white in color.

¹H-NMR(CDCl ₃)δ:0.96(2H，q，J＝3.7Hz)，1.21(9H，s)，1.49(2H，q，J＝3.7Hz)，4.14-4.22(2H，m)，4.37-4.46(2H，m)，5.19(1H，s)，6.06(1H，br?s)，6.19(1H，d，J＝3.2Hz)，6.89-6.98(2H，m)，7.02(1H，d，J＝3.2Hz)，7.04-7.11(2H，m)，7.31(1H，t，J＝7.8Hz)，7.52(1H，dd，J＝2.5Hz，8.7Hz)，7.81(1H，d，J＝2.5Hz)，8.29(1H，s)，9.58(1H，s).

Embodiment G-1

N-[1-(3-luorobenzyl)-1H-indazole-5-yl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate

At 120 ℃, stir DMF (2mL) solution 2.5 hours of the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine (153mg) and 1-(3-luorobenzyl)-1H-indazole-5-amine (362mg).By reaction mixture cool to room temperature, add wherein ethyl acetate (30mL), and at room temperature stir this mixture 30min.Filter and collect gained crystal, with ethyl acetate washing drying under reduced pressure, obtain title compound (361mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:5.70(2H，s)，6.57(1H，d，J＝2Hz)，7.00-7.20(3H，m)，7.36(1H，m)，7.70-7.90(3H，m)，8.17(1H，s)，8.41(1H，m)，8.59(1H，s)，10.97(1H，br?s)，12.58(1H，br?s).

Embodiment G-2

2-[2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethanol

Under 140 ℃ of heating, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethyl ester (150mg), 1-(3-luorobenzyl)-1H-indazole-5-amine (156mg) and 1-Methyl-2-Pyrrolidone (0.863mL) 2 hours.Ethyl acetate for reaction mixture (80mL) dilution, sodium bicarbonate aqueous solution for organic layer (30mL) washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue through purification by silica gel column chromatography (hexane: ethyl acetate=70:30 → 0:100), by target fraction concentrating under reduced pressure.Gained residue is dissolved in methyl alcohol (1.89mL), adds 1N aqueous sodium hydroxide solution (0.433mL), and at room temperature stir this mixture 2 hours.By in 1N hydrochloric acid (0.433mL) mixture, and by ethyl acetate (80mL), dilute saturated brine washing (30mL) for organic layer, anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue is by silica gel column chromatography (ethyl acetate: methyl alcohol=100:0 → 90:10), through isopropyl ether crystallization, obtain title compound (153mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.50(4H，br?s)，3.84(2H，t，J＝4Hz)，4.64(2H，t，J＝4Hz)，4.69(1H，m)，5.69(2H，s)，6.47(1H，d，J＝3Hz)，7.00-7.20(3H，m)，7.36(1H，m)，7.53(1H，d，J＝9Hz)，7.60-7.70(2H，m)，8.05(1H，s)，8.09(1H，s)，8.23(1H，s)，8.76(1H，br?s).

Embodiment G-3

N-[2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

(i) [2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

At 80 ℃, Virahol (5mL) solution of stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (0.5g) and 1-(3-luorobenzyl)-1H-indazole-5-amine (608mg) 12 hours.Sodium bicarbonate aqueous solution (30mL) is added in reaction mixture, and be extracted with ethyl acetate (80mL).Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.After concentrating under reduced pressure, by residue with silica gel column chromatography separated and purifying (elutriant: hexane: ethyl acetate=7:3 → ethyl acetate), obtain title compound (820mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.44(9H，s)，3.50(2H，m)，4.46(2H，m)，5.07(1H，m)，5.58(2H，s)，6.57(1H，d，J＝3Hz)，6.80-7.00(3H，m)，7.14(1H，d，J＝3Hz)，7.20-7.40(2H，m)，7.74(1H，dd，J＝2Hz，9Hz)，7.99(1H，s)，8.05(1H，d，J＝1Hz)，8.45(1H，s)，8.53(1H，br?s).

(ii) 5-(2-amino-ethyl)-N-[1-(3-luorobenzyl)-1H-indazole-5-yl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride

At 60 ℃, stir [2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (780mg), the mixture of 2N hydrochloric acid (11.1mL) and tetrahydrofuran (THF) (22.2mL) 20 hours.Pressure reducing and steaming solvent, adds ethanol in mixture, and again concentrated.Filter the powder of collecting precipitation, with isopropyl ether washing, obtain title compound (668mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:3.32(2H，m)，5.08(2H，m)，5.74(2H，s)，6.72(1H，d，J＝3Hz)，7.00-7.20(3H，m)，7.38(1H，m)，7.52(1H，dd，J＝2Hz，9Hz)，7.80(1H，d，J＝9Hz)，7.91(1H，d，J＝2Hz)，8.07(1H，m)，8.20(1H，s)，8.45(3H，brs)，8.60(1H，s).

(iii) N-[2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-2-(methylsulfonyl) ethanamide

By 5-(2-amino-ethyl)-N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5H-pyrrolo-[3; 2-d] mixture of pyrimidine-4-amine tri hydrochloride (183mg), methylsulfonyl acetic acid (74.2mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and DMF (6.9mL) at room temperature stirs 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=90:10), through isopropyl ether crystallization, obtain title compound (134mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.07(3H，s)，3.48(2H，q，J＝6Hz)，4.04(2H，s)，4.56(2H，t，J＝6Hz)，5.69(2H，s)，6.45(1H，d，J＝3Hz)，7.00-7.20(3H，m)，7.30-7.40(1H，m)，7.57(2H，m)，7.68(1H，d，J＝9Hz)，7.95(1H，m)，8.10(1H，s)，8.21(1H，s)，8.58(1H，br?s)，8.65(1H，t，J＝6Hz).

Embodiment G-4

N-[1-(3-luorobenzyl)-1H-indoles-5-yl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate

At 120 ℃, DMF (2mL) solution of the stirring chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine (153mg) and 1-(3-luorobenzyl)-1H-indoles-5-amine (360mg) 2 hours.By reaction mixture cool to room temperature, ethyl acetate (30mL) is added wherein, and at room temperature stir this mixture 30min.Filter and collect gained crystal, with ethyl acetate washing drying under reduced pressure, obtain title compound (377mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:5.46(2H，s)，6.53(2H，d，J＝3Hz)，7.05(3H，m)，7.36(1H，m)，7.49(2H，m)，7.56(1H，d，J＝3Hz)，7.79(1H，br?s)，8.16(1H，brs)，8.51(1H，s)，10.61(1H，br?s)，12.45(1H，br?s).

Embodiment G-5

N-[2-(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butyramide

By 5-(2-amino-ethyl)-N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5H-pyrrolo-[3,2-d] mixture of pyrimidine-4-amine tri hydrochloride (183mg), HMB (0.058mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and DMF (6.9mL) at room temperature stirs 4 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), through isopropyl ether crystallization, obtain title compound (100mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.12(6H，s)，2.20(2H，s)，3.44(2H，q，J＝7Hz)，4.52(2H，t，J＝7Hz)，4.69(1H，s)，5.69(2H，s)，6.44(1H，d，J＝3Hz)，7.00-7.20(3H，m)，7.30-7.40(1H，m)，7.50-7.70(3H，m)，8.00(1H，d，J＝2Hz)，8.09(1H，s)，8.20(1H，s)，8.23(1H，t，J＝7Hz)，8.76(1H，br?s).

Embodiment G-6

2-[2-(4-{[1-(3-luorobenzyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethanol

Under 140 ℃ of heating, stir phenylformic acid 2-[2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethyl ester (150mg), 1-(3-luorobenzyl)-1H-indoles-5-amine (155mg) and 1-Methyl-2-Pyrrolidone (0.863mL) 2 hours.Ethyl acetate for reaction mixture (80mL) is diluted and is used sodium bicarbonate aqueous solution (30mL) to wash.Separated organic layer, anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residue through purification by silica gel column chromatography (hexane: ethyl acetate=70:30 → 0:100 → ethyl acetate: methyl alcohol=95:5), by target fraction concentrating under reduced pressure.Gained residue is dissolved in methyl alcohol (1.89mL), 1N aqueous sodium hydroxide solution (0.433mL) is added wherein, and at room temperature stir this mixture 2 hours.1N hydrochloric acid (0.433mL) is added in mixture, and dilute by ethyl acetate (80mL).Saturated brine washing (30mL) for organic layer, dried over mgso concentrating under reduced pressure.Residue is by silica gel column chromatography (ethyl acetate: methyl alcohol=100:0 → 90:10), through the crystallization of isopropyl ether/ethyl acetate, obtain title compound (107mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:3.49(4H，br?s)，3.83(2H，t，J＝4Hz)，4.61(2H，t，J＝4Hz)，4.67(1H，t，J＝4Hz)，5.45(2H，s)，6.44(1H，dd，J＝1.5Hz，3Hz)，6.47(1H，d，J＝3Hz)，6.90-7.10(3H，m)，7.25(1H，d，J＝9Hz)，7.3-7.5(2H，m)，7.51(1H，d，J＝3Hz)，7.59(1H，d，J＝3Hz)，7.81(1H，s)，8.17(1H，s)，8.58(1H，brs).

Embodiment G-7

N-[2-(4-{[1-(3-luorobenzyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butyramide

(i) [2-(4-{[1-(3-luorobenzyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

At 80 ℃, Virahol (5mL) solution of stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (0.5g) and 1-(3-luorobenzyl)-1H-indoles-5-amine (606mg) 12 hours.Sodium bicarbonate aqueous solution (30mL) is added in reaction mixture, and be extracted with ethyl acetate (80mL).Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.After concentrating under reduced pressure, by the separated also purifying (elutriant: hexane: ethyl acetate=7:3 → ethyl acetate → ethyl acetate: methyl alcohol=95:5), obtain title compound (840mg), be clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.42(9H，s)，3.45(2H，m)，4.38(2H，t，J＝7Hz)，5.17(1H，m)，5.29(2H，s)，6.51(1H，dd，J＝1Hz，3Hz)，6.53(1H，d，J＝3Hz)，6.78(1H，d，J＝9Hz)，6.80-7.00(2H，m)，7.10(2H，t，J＝3Hz)，7.18-7.30(2H，m)，7.47(1H，d，J＝9Hz)，7.89(1H，br?s)，8.20(1H，br?s)，8.43(1H，s).

(ii) 5-(2-amino-ethyl)-N-[1-(3-luorobenzyl)-1H-indoles-5-yl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

At 60 ℃, stir [2-(4-{[1-(3-luorobenzyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] mixture 20 hours of t-butyl carbamate (830mg), 2N hydrochloric acid (11.8mL) and tetrahydrofuran (THF) (23.6mL).Pressure reducing and steaming solvent, adds ethanol in mixture, and again concentrated.Filter the powder of collecting precipitation, with isopropyl ether washing, obtain title compound (828mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:3.27(2H，m)，5.07(2H，m)，5.43(2H，s)，6.50-6.70(2H，m)，6.80-7.30(4H，m)，7.37(1H，m)，7.68(1H，m)，7.86(1H，s)，8.04(1H，d，J＝3Hz)，8.44(1H，s)，8.50(3H，br?s)，8.55(1H，s)，10.01(1H，br?s).

(iii) N-[2-(4-{[1-(3-luorobenzyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of-3-hydroxy-3-methyl butyramide

By 5-(2-amino-ethyl)-N-[1-(3-luorobenzyl)-1H-indoles-5-yl]-5H-pyrrolo-[3,2-d] mixture of pyrimidine-4-amine dihydrochloride (183mg), HMB (0.058mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (103mg), I-hydroxybenzotriazole (72.5mg), triethylamine (0.15mL) and DMF (6.9mL) at room temperature stirs 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses anhydrous magnesium sulfate drying.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: ethyl acetate → ethyl acetate: methyl alcohol=85:15), through isopropyl ether crystallization, obtain title compound (43mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.12(6H，s)，2.20(2H，s)，3.44(2H，q，J＝7Hz)，4.50(2H，t，J＝7Hz)，4.70(1H，br?s)，5.46(2H，s)，6.41(1H，d，J＝3Hz)，6.47(1H，d，J＝3Hz)，6.9-7.2(3H，m)，7.20-7.50(3H，m)，7.52(2H，t，J＝3Hz)，7.76(1H，s)，8.15(1H，s)，8.19(1H，t，J＝6Hz)，8.57(1H，br?s).

Embodiment G-8

3-hydroxy-3-methyl-N-[2-(4-{[1-(pyridine-2-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of butyramide

(i) preparation of 5-nitro-1-(pyridine-2-ylmethyl)-1H-indoles

Under ice-cooled, N to 5-nitroindoline (1.62g) and 2-(chloromethyl) pyridine hydrochloride (1.80g), in dinethylformamide (20mL) solution, add salt of wormwood (3.46g), and at room temperature stir this mixture 16 hours.Under ice-cooled, water added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue, through ethyl acetate/diisopropyl ether recrystallization, obtains title compound (2.05g), is yellow crystals.

¹H-NMR(CDCl ₃)δ:5.49(2H，s)，6.75-6.80(2H，m)，7.15-7.25(1H，m)，7.32(1H，d，J＝9.0Hz)，7.36(1H，d，J＝3.3Hz)，7.58(1H，dt，J＝2.1Hz，7.8Hz)，8.07(1H，dd，J＝2.1Hz，9.0Hz)，8.55-8.65(2H，m).

(ii) preparation of 1-(pyridine-2-ylmethyl)-1H-indoles-5-amine

Under nitrogen atmosphere, in ethyl acetate (10mL)/methyl alcohol (2mL) solution of 5-nitro-1-(pyridine-2-ylmethyl)-1H-indoles (507mg), add 5% platinum-gac (84.5mg).Stirred reaction mixture 6 hours under room temperature under nitrogen atmosphere.Remove by filter platinum-gac, concentrating under reduced pressure filtrate.By the separated also purifying (elutriant: ethyl acetate: hexane=70:30 → 100:0), then through ethyl acetate/hexane recrystallization, obtain title compound (357mg), be light peachiness powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.48(2H，br?s)，5.38(2H，s)，6.39(1H，d，J＝3.0Hz)，6.55-6.70(2H，m)，6.94(1H，s)，7.03(1H，d，J＝8.7Hz)，7.10-7.20(2H，m)，7.49(1H，t，J＝7.8Hz)，8.57(1H，d，J＝4.2Hz).

(iii) [2-(4-{[1-(pyridine-2-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

At 80 ℃, the mixture of stirring [2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (297mg), 1-(pyridine-2-ylmethyl)-1H-indoles-5-amine (246mg) and Virahol (5.0mL) 16 hours.Under ice-cooled, sodium bicarbonate aqueous solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 90:10), obtain title compound (498mg), be lavender powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.43(9H，s)，3.45-3.55(2H，m)，4.35-4.45(2H，m)，4.9-5.0(1H，m)，5.45(2H，s)，6.53(1H，d，J＝3.0Hz)，6.55(1H，d，J＝3.0Hz)，6.71(1H，d，J＝8.1Hz)，7.10-7.30(4H，m)，7.40-7.50(1H，m)，7.52(1H，dt，J＝1.8，7.8Hz)，7.90(1H，s)，8.17(1H，br?s)，8.44(1H，s)，8.58(1H，d，J＝4.2Hz).

(iv) 5-(2-amino-ethyl)-N-[1-(pyridine-2-ylmethyl)-1H-indoles-5-yl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine four hydrochlorides

At 65 ℃, stir [2-(4-{[1-(pyridine-2-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] mixture 18 hours of t-butyl carbamate (439mg) and 10% (W/W) hydrochloric acid/methyl alcohol (5mL).This reaction mixture of concentrating under reduced pressure, filters collecting precipitation, with ether washing, obtains title compound (422mg), is light green crystal.

¹H-NMR(DMSO-d ₆)δ:3.2-3.4(2H，m)，4.90-5.10(2H，m)，5.63(2H，s)，6.57(1H，d，J＝3.3Hz)，6.69(1H，d，J＝3.3Hz)，7.08(1H，d，J＝7.2Hz)，7.20(1H，d，J＝8.7Hz)，7.35-7.45(1H，m)，7.52(1H，d，J＝8.7Hz)，7.61(1H，d，J＝3.3Hz)，7.67(1H，s)，7.85-7.95(1H，m)，8.01(1H，d，J＝2.7Hz)，8.25-8.4(3H，m)，8.56(1H，s)，8.61(1H，d，J＝5.1Hz)，9.97(1H，s).

(v) 3-hydroxy-3-methyl-N-[2-(4-{[1-(pyridine-2-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of butyramide

Under ice-cooled, to 5-(2-amino-ethyl)-N-[1-(pyridine-2-ylmethyl)-1H-indoles-5-yl]-5H-pyrrolo-[3,2-d] N of pyrimidine-4-amine four hydrochlorides (200mg), HMB (67mg) and I-hydroxybenzotriazole (85mg), in dinethylformamide (5.0mL) solution, add triethylamine (0.52mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (120mg), and at room temperature stir this mixture 16 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 70:30), then use ethyl acetate/diisopropyl ether recrystallization, obtain title compound (85.3mg), be clear crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.26(6H，s)，2.37(2H，s)，3.55-3.7(2H，m)，4.35-4.45(2H，m)，5.45(2H，s)，6.55(2H，dd，J＝3.3Hz，7.8Hz)，6.73(1H，d，J＝7.8Hz)，6.75-6.85(1H，m)，7.1-7.25(3H，m)，7.39(1H，dd，J＝1.8Hz，8.7Hz)，7.53(1H，dt，J＝1.8Hz，7.8Hz)，7.87(1H，d，J＝1.5Hz)，8.22(1H，s)，8.43(1H，s)，8.58(1H，d，J＝4.8Hz).

Embodiment G-9

3-hydroxy-3-methyl-N-{2-[4-({ 1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of butyramide

(i) 5-nitro-1-[3-(trifluoromethoxy) benzyl] preparation of-1H-indoles

According to the same method of embodiment G-8 (i), use 5-nitroindoline (538mg), 1-(brooethyl)-3-(trifluoromethoxy) benzene (0.96g), salt of wormwood (551mg) and N, dinethylformamide (8.0mL), make title compound (0.95g), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:5.39(2H，s)，6.76(1H，d，J＝3.3Hz)，6.90-7.00(2H，m)，7.15(1H，d，J＝8.1Hz)，7.20-7.30(2H，m)，7.35(1H，t，J＝8.1Hz)，8.09(1H，dd，J＝2.1Hz，9.0Hz)，8.62(1H，d，J＝2.4Hz).

(ii) 1-[3-(trifluoromethoxy) benzyl] preparation of-1H-indoles-5-amine

According to the same method of embodiment G-8 (ii), use 5-nitro-1-[3-(trifluoromethoxy) benzyl]-1H-indoles (504mg), 5% platinum-gac (84mg) and ethyl acetate (15mL), make title compound (466mg), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:3.50(2H，br?s)，5.26(2H，s)，6.37(1H，d，J＝3.0Hz)，6.62(1H，dd，J＝2.4Hz，8.7Hz)，6.90-7.10(5H，m)，7.08(1H，d，J＝8.7Hz)，7.25-7.35(1H，m).

(iii) preparation of { 2-[4-({ 1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate

According to the same method of embodiment G-8 (iii), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (405mg), 1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-amine (459mg) and Virahol (8.0mL), make title compound (692mg), be white in color amorphous.

¹H-NMR(CDCl ₃)δ:1.42(9H，s)，3.45-3.55(2H，m)，4.35-4.45(2H，m)，4.93(1H，br?s)，5.33(2H，s)，6.52(1H，d，J＝3.3Hz)，6.55(1H，d，J＝3.0Hz)，6.95-7.05(2H，m)，7.10-7.25(4H，m)，7.30(1H，t，J＝8.2Hz)，7.45-7.55(1H，m)，7.90(1H，s)，8.18(1H，br?s)，8.44(1H，s).

(iv) 5-(2-amino-ethyl)-N-{1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to the same method of embodiment G-8 (iv), use 2-[4-(1-[3-(trifluoromethoxy) benzyl] and-1H-indoles-5-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (675mg), 10% (W/W) hydrochloric acid/methyl alcohol (8.0mL) and methyl alcohol (6.0mL), make title compound (568mg), be orange powder.

¹H-NMR(DMSO-d ₆)δ:3.20-3.35(2H，m)，4.90-5.10(2H，m)，5.54(2H，s)，6.55(1H，d，J＝3.3Hz)，6.68(1H，d，J＝3.0Hz)，7.15-7.30(4H，m)，7.46(1H，t，J＝7.8Hz)，7.53(1H，d，J＝8.7Hz)，7.63(1H，d，J＝3.3Hz)，7.67(1H，s)，8.01(1H，d，J＝3.0Hz)，8.25-8.45(3H，m)，8.55(1H，s)，9.93(1H，s).

(v) 3-hydroxy-3-methyl-N-{2-[4-({ 1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of butyramide

According to the same method of embodiment G-8 (v), use 5-(2-amino-ethyl)-N-{1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), HMB (62mg), I-hydroxybenzotriazole (76mg), triethylamine (0.48mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (106mg) and N, dinethylformamide (5.0mL), make title compound (143mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.26(6H，s)，2.38(2H，s)，3.55-3.70(2H，m)，4.35-4.50(2H，m)，5.32(2H，s)，6.54(2H，t，J＝3.6Hz)，6.80-6.90(1H，m)，6.95-7.05(2H，m)，7.10-7.20(3H，m)，7.20-7.45(3H，m)，7.88(1H，s)，8.25(1H，s)，8.43(1H，s).

Embodiment G-10

N-(tertiary butyl)-3-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of benzamide

(i) 3-[(5-nitro-1H-indoles-1-yl) methyl] preparation of methyl benzoate

According to the same method of embodiment G-8 (i), use 5-nitroindoline (0.87g), 3-(brooethyl) methyl benzoate (1.35g), salt of wormwood (0.89g) and N, dinethylformamide (10mL), make title compound (0.83g), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:3.89(3H，s)，5.41(2H，s)，6.75(1H，d，J＝3.3Hz)，7.20-7.35(3H，m)，7.39(1H，t，J＝7.8Hz)，7.88(1H，s)，7.97(1H，d，J＝7.8Hz)，8.07(1H，dd，J＝2.4Hz，9.1Hz)，8.60(1H，d，J＝1.8Hz).

(ii) 3-[(5-nitro-1H-indoles-1-yl) methyl] benzoic preparation

To 3-[(5-nitro-1H-indoles-1-yl) methyl] add 1N aqueous sodium hydroxide solution (12mL) in methyl alcohol (12mL) suspension of methyl benzoate (0.75g), and at room temperature stir this mixture 1.5 hours.Tetrahydrofuran (THF) (12mL) is added in mixture, and at room temperature stir this mixture 5 hours.Under ice-cooled, 1N hydrochloric acid (12mL) is added in reaction mixture to concentrating under reduced pressure mixture.Filter collecting precipitation, with ethanol and diisopropyl ether washing, obtain title compound (621mg), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:5.55(2H，s)，6.80(1H，d，J＝2.4Hz)，7.15-7.35(2H，m)，7.67(1H，d，J＝9.0Hz)，7.70-7.85(3H，m)，7.99(1H，d，J＝7.8Hz)，8.57(1H，s).

(iii) N-(tertiary butyl)-3-[(5-nitro-1H-indoles-1-yl) methyl] preparation of benzamide

Under ice-cooled, to 3-[(5-nitro-1H-indoles-1-yl) methyl] N of phenylformic acid (600mg) and TERTIARY BUTYL AMINE (222mg), in dinethylformamide (5.0mL) suspension, add triethylamine (0.45mL) and diethyl phosphorocyanidate (0.49mL), and at room temperature stir this mixture 21 hours.TERTIARY BUTYL AMINE (0.32mL) is added in mixture, and at room temperature stir this mixture 20 hours.Sodium bicarbonate aqueous solution is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=35:65 → 70:30), obtain title compound (266mg), be pale yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，5.39(2H，s)，5.87(1H，br?s)，6.70-6.75(1H，m)，7.10(1H，d，J＝7.8Hz)，7.25-7.30(2H，m)，7.33(1H，t，J＝7.8Hz)，7.55(1H，d，J＝7.8Hz)，7.67(1H，s)，8.06(1H，dd，J＝2.1Hz，9.0Hz)，8.60(1H，d，J＝2.1Hz).

(iv) 3-[(5-amino-1H-indoles-1-yl) methyl] preparation of-N-(tertiary butyl) benzamide

According to the same method of embodiment G-8 (ii), use N-(tertiary butyl)-3-[(5-nitro-1H-indoles-1-yl) methyl] benzamide (263mg), 5% platinum-gac (44mg) and ethyl acetate (10mL), make title compound (241mg), be faint yellow amorphous.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，3.50(2H，br?s)，5.28(2H，s)，5.84(1H，brs)，6.37(1H，d，J＝3.0Hz)，6.62(1H，dd，J＝2.4Hz，8.7Hz)，6.94(1H，d，J＝2.1Hz)，7.00-7.15(3H，m)，7.25-7.35(1H，m)，7.54(1H，d，J＝7.5Hz)，7.60(1H，s).

(v) N-(tertiary butyl)-3-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of benzamide

At 80 ℃, stir phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (105mg), 3-[(5-amino-1H-indoles-1-yl) methyl] mixture 16 hours of-N-(tertiary butyl) benzamide (123mg) and Virahol (5.0mL).Under ice-cooled, sodium bicarbonate aqueous solution added in reaction mixture, and be extracted with ethyl acetate.Organic layer concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5) of silica gel column chromatography for residue.In gained compound, add 1N aqueous sodium hydroxide solution (1.5mL) and tetrahydrofuran (THF) (3.0mL), and at room temperature stir this mixture 18 hours.1N hydrochloric acid neutralization for reaction mixture, adds sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.Residue, through ethyl acetate/methanol recrystallization, obtains title compound (90mg), is light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.46(9H，s)，4.00-4.10(2H，m)，4.25-4.35(2H，m)，5.33(2H，s)，5.90(1H，br?s)，6.14(1H，d，J＝3.0Hz)，6.52(1H，d，J＝2.7Hz)，6.87(1H，d，J＝3.0Hz)，7.10-7.35(5H，m)，7.54(1H，d，J＝7.5Hz)，7.63(1H，s)，7.76(1H，s)，8.19(1H，s)，9.15(1H，s).

Embodiment G-11

2-methyl-2-(methylsulfonyl)-N-{2-[4-({ 1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of propionic acid amide

According to the same method of embodiment G-8 (v); use 5-(2-amino-ethyl)-N-{1-[3-(trifluoromethoxy) benzyl]-1H-indoles-5-yl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (200mg), 2-methyl-2-(methylsulfonyl) propionic acid (87mg), I-hydroxybenzotriazole (76mg), triethylamine (0.48mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (106mg) and N; dinethylformamide (5.0mL); obtain title compound (100mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.61(6H，s)，2.84(3H，s)，3.65-3.75(2H，m)，4.35-4.45(2H，m)，5.34(2H，s)，6.55(1H，d，J＝3.0Hz)，6.60(1H，d，J＝3.0Hz)，7.00-7.45(9H，m)，7.86(1H，s)，7.91(1H，br?s)，8.46(1H，s).

Embodiment G-12

2-{4-[(1-{[1-(2,2-dimethyl propylene acyl group) piperidin-4-yl] methyl }-1H-indoles-5-yl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

(i) 4-[(5-nitro-1H-indoles-1-yl) methyl] preparation of piperidines-1-t-butyl formate

Under ice-cooled, in tetrahydrofuran (THF) (30mL) solution of 4-(methylol) piperidines-1-t-butyl formate (1.29g) and triethylamine (1.17mL), drip methylsulfonyl chloride (0.56mL), and at room temperature stir this mixture 1 hour.Under ice-cooled, sodium bicarbonate aqueous solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure, obtain yellow oil.Under ice-cooled, in DMF (5.0mL) solution of 5-nitroindoline (811mg), add sodium hydride (in 60% oil (220mg)), and at 0 ℃ of 10min that stirs the mixture.Under ice-cooled, DMF (5.0mL) solution of the yellow oil of gained above dripping in reaction mixture, and at room temperature stir this mixture 1 hour, then at 60 ℃, stir 18 hours.Under ice-cooled, water added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.By (the elutriant: ethyl acetate: hexane=30:70 → 50:50), obtain title compound (1.79g), be yellow amorphous of the separated also purifying of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.15-1.30(2H，m)，1.45(9H，s)，1.50-1.60(2H，m)，1.90-2.05(1H，m)，2.55-2.70(2H，m)，4.00-4.20(4H，m)，6.69(1H，d，J＝3.0Hz)，7.20(1H，d，J＝3.0Hz)，7.34(1H，d，J＝9.0Hz)，8.12(1H，dd，J＝2.1Hz，9.0Hz)，8.60(1H，d，J＝2.1Hz).

(ii) 4-[(5-amino-1H-indoles-1-yl) methyl] preparation of piperidines-1-t-butyl formate

According to the same method of embodiment G-8 (ii), use 4-[(5-nitro-1H-indoles-1-yl) methyl] piperidines-1-t-butyl formate (0.90g), 5% platinum-gac (0.15g) and ethyl acetate (10mL), make title compound (0.83g), be incarnadine amorphous.

¹H-NMR(CDCl ₃)δ:1.10-1.25(2H，m)，1.44(9H，s)，1.50-1.60(2H，m)，1.90-2.05(1H，m)，2.55-2.70(2H，m)，3.91(2H，d，J＝7.2Hz)，4.00-4.20(2H，m)，6.28(1H，d，J＝3.0Hz)，6.67(1H，dd，J＝2.1Hz，8.7Hz)，6.92(1H，d，J＝2.1Hz)，6.96(1H，d，J＝3.3Hz)，7.12(1H，d，J＝8.7Hz).

(iii) 4-{[5-({ 5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-1H-indoles-1-yl] methyl } piperidines-1-t-butyl formate

At 80 ℃, stir phenylformic acid 2-(the chloro-5H-pyrrolo-of 4-[3,2-d] pyrimidine-5-yl) ethyl ester (686mg), 4-[(5-amino-1H-indoles-1-yl) methyl] mixture 12 hours of piperidines-1-t-butyl formate (824mg) and Virahol (20mL).Under ice-cooled, sodium bicarbonate aqueous solution added in reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain title compound (1.04g), be yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.15-1.30(2H，m)，1.45(9H，s)，1.50-1.60(2H，m)，1.95-2.10(1H，m)，2.55-2.70(2H，m)，3.98(2H，d，J＝7.5Hz)，4.05-4.20(2H，m)，4.55-4.70(4H，m)，6.43(1H，d，J＝3.3Hz)，6.63(1H，d，J＝3.3Hz)，7.04(1H，d，J＝3.3Hz)，7.25-7.35(3H，m)，7.35-7.45(3H，m)，7.50-7.65(2H，m)，7.90-8.00(2H，m)，8.48(1H，s).

(iv) preparation of phenylformic acid 2-(4-{[1-(piperidin-4-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl ester dihydrochloride

To 4-{[5-(5-[2-(benzoyloxy) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-1H-indoles-1-yl] methyl } add 10% (W/W) hydrochloric acid/methyl alcohol (10mL) in methyl alcohol (10mL) solution of piperidines-1-t-butyl formate (820mg), and at room temperature stir this mixture 17 hours.This reaction mixture of concentrating under reduced pressure, adds ethanol wherein, again enriched mixture.Repeat twice of this operation.Add diisopropyl ether enriched mixture.Filter and collect gained powder, with diisopropyl ether washing, obtain title compound (621mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:1.35-1.55(2H，m)，1.60-1.70(2H，m)，2.05-2.20(1H，m)，2.70-2.90(2H，m)，3.20-3.30(2H，m)，4.14(2H，d，J＝6.9Hz)，4.60-4.70(2H，m)，5.10-5.20(2H，m)，6.45(1H，d，J＝3.0Hz)，6.65(1H，d，J＝2.7Hz)，7.15(1H，d，J＝9.6Hz)，7.40-7.50(3H，m)，7.55(1H，d，J＝8.7Hz)，7.66(1H，t，J＝7.5Hz)，7.81(2H，d，J＝8.1Hz)，8.07(1H，d，J＝3.0Hz)，8.53(1H，s)，8.55-8.70(1H，br?m)，8.90-9.00(1H，br?m)，9.90(1H，br?s).

(v) 2-{4-[(1-{[1-(2,2-dimethyl propylene acyl group) piperidin-4-yl] methyl }-1H-indoles-5-yl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } preparation of ethanol

Under ice-cooled, to phenylformic acid 2-(4-{[1-(piperidin-4-ylmethyl)-1H-indoles-5-yl] amino-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) drip triethylamine (0.23mL) and 2,2-dimethyl propylene acyl chlorides (0.045mL) in tetrahydrofuran (THF) (5.0mL) suspension of ethyl ester dihydrochloride (200mg).At 0 ℃, stir the mixture and then at room temperature stir 30 minutes for 30 minutes.Under ice-cooled, water added in this reaction mixture, and be extracted with ethyl acetate.Salt water washing concentrating under reduced pressure for organic layer.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5) of silica gel column chromatography for residue.In gained compound, add 1N aqueous sodium hydroxide solution (1.5mL) and tetrahydrofuran (THF) (4.0mL), and at room temperature stir this mixture 15 hours.1N hydrochloric acid neutralization for reaction mixture, adds sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.Residue, through ethyl acetate/methanol/diisopropyl ether recrystallization, obtains title compound (104mg), is light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.10-1.30(2H，m)，1.27(9H，s)，1.55-1.70(2H，m)，2.05-2.20(1H，m)，2.60-2.75(2H，m)，3.98(2H，d，J＝7.2Hz)，4.05-4.15(2H，m)，4.30-4.50(4H，m)，6.10(1H，d，J＝3.0Hz)，6.46(1H，d，J＝3.0Hz)，6.85(1H，d，J＝3.0Hz)，7.04(1H，d，J＝3.0Hz)，7.25-7.35(1H，m)，7.35-7.45(1H，m)，7.75(1H，s)，8.18(1H，s)，9.27(1H，br?s).

Embodiment G-13

N-(tertiary butyl)-4-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of piperidines-1-methane amide

Under ice-cooled, in tetrahydrofuran (THF) (5.0mL) suspension of phenylformic acid 2-(4-{[1-(piperidin-4-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl ester dihydrochloride (200mg), drip triethylamine (0.23mL) and tert-butyl isocyanate

(2-isocyanate-2-methylpropane)(0.045mL)。At room temperature stirred reaction mixture is 1.5 hours, lower water is added to reaction mixture, and be extracted with ethyl acetate ice-cooled.Salt water washing concentrating under reduced pressure for organic layer.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5) of silica gel column chromatography for residue.In gained compound, add 1N aqueous sodium hydroxide solution (1.6mL) and tetrahydrofuran (THF) (4.0mL), and at room temperature stir this mixture 15 hours.1N hydrochloric acid neutralization for reaction mixture, adds sodium bicarbonate aqueous solution and salt solution.Mixture is extracted with ethyl acetate, and organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.Residue, through ethyl acetate/methanol/diisopropyl ether recrystallization, obtains title compound (112mg), is light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.15-1.30(2H，m)，1.34(9H，s)，1.50-1.65(2H，m)，1.95-2.10(1H，m)，2.55-2.70(2H，m)，3.85-3.95(2H，m)，3.99(2H，d，J＝7.2Hz)，4.05-4.15(2H，m)，4.29(1H，s)，4.30-4.40(2H，m)，6.19(1H，d，J＝3.0Hz)，6.45-6.50(1H，m)，6.90-6.95(1H，m)，7.05-7.10(1H，m)，7.25-7.45(2H，m)，7.75(1H，s)，8.23(1H，s)，9.20(1H，br?s).

Embodiment G-14

N-(tertiary butyl)-3-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indazole-1-yl) methyl] preparation of benzamide

(i) 3-[(5-nitro-1H-indazole-1-yl) methyl] preparation of methyl benzoate

Under ice-cooled, N to 5-nitro indazole (816mg) and 3-(brooethyl) methyl benzoate (2.29g), in dinethylformamide (10mL) solution, add salt of wormwood (2.07g), and at room temperature stir this mixture 2 hours.Under ice-cooled, water added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: hexane=20:80 → 50:50), obtain title compound (805mg), be light yellow crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.90(3H，s)，5.68(2H，s)，7.30-7.45(3H，m)，7.90-8.00(2H，m)，8.23(1H，dd，J＝1.8Hz，9.0Hz)，8.20-8.25(1H，m)，8.74(1H，d，J＝1.8Hz).

(ii) 3-[(5-nitro-1H-indazole-1-yl) methyl] benzoic preparation

According to the same method of embodiment G-10 (ii), use 3-[(5-nitro-1H-indazole-1-yl) methyl] methyl benzoate (0.79g), 1N aqueous sodium hydroxide solution (12mL), methyl alcohol (15mL) and tetrahydrofuran (THF) (15mL), make title compound (732mg), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:5.86(2H，s)，7.40-7.55(2H，m)，7.75-7.90(2H，m)，8.00(1H，d，J＝9.3Hz)，8.25(1H，dd，J＝2.1Hz，9.3Hz)，8.48(1H，s)，8.86(1H，d，J＝2.1Hz)，13.07(1H，br?s).

(iii) N-(tertiary butyl)-3-[(5-nitro-1H-indazole-1-yl) methyl] preparation of benzamide

To 3-[(5-nitro-1H-indazole-1-yl) methyl] add N in tetrahydrofuran (THF) (10mL) suspension of phenylformic acid (595mg), dinethylformamide (1) and thionyl chloride (0.144mL), and at room temperature stir this mixture 3.5 hours.Under ice-cooled, in DMF (4.0mL) solution of TERTIARY BUTYL AMINE (0.73g) and triethylamine (0.25g), add above-mentioned reaction mixture, and at room temperature stir this mixture 4.5 hours.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.After concentrating under reduced pressure, by the separated also purifying (elutriant: ethyl acetate: hexane=30:70 → 50:50), obtain title compound (0.56g), be faint yellow amorphous of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，5.66(2H，s)，5.88(1H，br?s)，7.20-7.30(1H，m)，7.35(1H，t，J＝7.5Hz)，7.40(1H，d，J＝9.0Hz)，7.56(1H，d，J＝7.5Hz)，7.73(1H，s)，8.23(1H，dd，J＝2.1Hz，9.0Hz)，8.25(1H，s)，8.74(1H，d，J＝2.1Hz).

(iv) 3-[(5-amino-1 h-indazole-1-yl) methyl] preparation of-N-(tertiary butyl) benzamide

According to the same method of embodiment G-8 (ii), use N-(tertiary butyl)-3-[(5-nitro-1H-indazole-1-yl) methyl] benzamide (0.55g), 5% platinum-gac (92mg) and ethyl acetate (20mL), make title compound (0.47g), powder is white in color.

¹H-NMR(CDCl ₃)δ:1.44(9H，s)，3.61(2H，br?s)，5.55(2H，s)，5.86(1H，brs)，6.81(1H，d，J＝9.0Hz)，6.95-7.00(1H，m)，7.14(1H，d，J＝8.7Hz)，7.20(1H，d，J＝7.5Hz)，7.30(1H，t，J＝7.5Hz)，7.56(1H，d，J＝8.1Hz)，7.63(1H，s)，7.83(1H，s).

(v) N-(tertiary butyl)-3-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indazole-1-yl) methyl] preparation of benzamide

According to the same method of embodiment G-10 (v), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (151mg), 3-[(5-amino-1 h-indazole-1-yl) methyl]-N-(tertiary butyl) benzamide (177mg), Virahol (8.0mL), 1N aqueous sodium hydroxide solution (2.0mL) and tetrahydrofuran (THF) (4.0mL), make title compound (169mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，4.05-4.15(2H，m)，4.30-4.40(2H，m)，5.59(2H，s)，5.92(1H，br?s)，6.18(1H，d，J＝3.0Hz)，6.93(1H，d，J＝3.6Hz)，7.25-7.35(4H，m)，7.40-7.50(1H，m)，7.56(1H，d，J＝7.2Hz)，7.65(1H，s)，7.88(1H，s)，7.98(1H，s)，8.22(1H，s)，9.33(1H，br?s).

Embodiment G-15

The preparation of N-(tertiary butyl)-3-(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) benzamide

(i) preparation of 3-(5-nitro-1H-indoles-1-yl) ethyl benzoate

At 120 ℃, stir 5-nitroindoline (1.62g), 3-iodo ethyl benzoate (3.04g), N, N-dimethylene diamines (N, N-dimethylenediamine) (0.97g), salt of wormwood (1.66g), cupric iodide (I) is (0.19g) and the mixing solutions of toluene (10mL) 24 hours.Under ice-cooled, water added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: hexane=20:80 → 40:60), obtain title compound (0.95g), be pale yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.43(3H，t，J＝7.0Hz)，4.44(2H，q，J＝7.0Hz)，6.89(1H，d，J＝3.3Hz)，7.50-7.55(2H，m)，7.60-7.75(2H，m)，8.10-8.20(3H，m)，8.66(1H，d，J＝2.4Hz).

(ii) the benzoic preparation of 3-(5-nitro-1H-indoles-1-yl)

According to the same method of embodiment G-10 (ii), use 3-(5-nitro-1H-indoles-1-yl) ethyl benzoate (0.95g), 1N aqueous sodium hydroxide solution (15mL), ethanol (15mL) and tetrahydrofuran (THF) (15mL), make title compound (0.71g), be yellow powder.

¹H-NMR(DMSO-d ₆)δ:6.95-7.05(1H，m)，7.60-7.75(2H，m)，7.83(1H，d，J＝7.2Hz)，7.90-8.10(4H，m)，8.68(1H，s).

(iii) preparation of N-(tertiary butyl)-3-(5-nitro-1H-indoles-1-yl) benzamide

According to the same method of embodiment G-14 (iii), use 3-(5-nitro-1H-indoles-1-yl) phenylformic acid (565mg), thionyl chloride (0.144mL), tetrahydrofuran (THF) (10mL), TERTIARY BUTYL AMINE (0.73g), triethylamine (0.25g) and N, dinethylformamide (4.0mL), make title compound (0.32g), be yellow powder.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，5.99(1H，br?s)，6.89(1H，d，J＝3.3Hz)，7.50-7.65(4H，m)，7.65-7.75(1H，m)，7.93(1H，s)，8.13(1H，dd，J＝2.1Hz，9.0Hz)，8.66(1H，d，J＝2.4Hz).

(iv) preparation of 3-(5-amino-1H-indoles-1-yl)-N-(tertiary butyl) benzamide

According to the same method of embodiment G-8 (ii), use N-(tertiary butyl)-3-(5-nitro-1H-indoles-1-yl) benzamide (0.32g), 5% platinum-gac (0.05g) and ethyl acetate (20mL), make title compound (253mg), be light peachiness amorphous.

¹H-NMR(CDCl ₃)δ:1.49(9H，s)，3.58(2H，br?s)，5.94(1H，br?s)，6.51(1H，d，J＝3.0Hz)，6.68(1H，dd，J＝2.1Hz，8.7Hz)，6.96(1H，d，J＝2.1Hz)，7.20-7.30(1H，m)，7.37(1H，d，J＝8.7Hz)，7.50-7.65(3H，m)，7.84(1H，s).

(v) preparation of N-(tertiary butyl)-3-(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) benzamide

According to the same method of embodiment G-10 (v), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (164mg), 3-(5-amino-1H-indoles-1-yl)-N-(tertiary butyl) benzamide (200mg), Virahol (8.0mL), 1N aqueous sodium hydroxide solution (2.5mL) and tetrahydrofuran (THF) (5.0mL), make title compound (154mg), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.51(9H，s)，4.10-4.15(2H，m)，4.35-4.45(2H，m)，6.03(1H，br?s)，6.17(1H，d，J＝3.3Hz)，6.67(1H，d，J＝3.3Hz)，6.91(1H，d，J＝3.3Hz)，7.30-7.40(2H，m)，7.50-7.70(4H，m)，7.80-7.85(1H，m)，7.89(1H，s)，8.23(1H，s)，9.24(1H，br?s).

Embodiment G-16

3-hydroxy-3-methyl-N-[2-(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of butyramide

(i) preparation of 5-nitro-1-(1,3-thiazoles-4-ylmethyl)-1H-indoles

According to the same method of embodiment G-8 (i), use 5-nitroindoline (1.62g), 4-(chloromethyl)-1,3-thiazole hydrochloride (1.87g), salt of wormwood (4.15g) and N, dinethylformamide (20mL), make title compound (1.98g), be yellow powder.

¹H-NMR(CDCl ₃)δ:5.54(2H，s)，6.74(1H，d，J＝3.3Hz)，6.95-7.00(1H，m)，7.30-7.45(2H，m)，8.10(1H，dd，J＝2.1Hz，9.0Hz)，8.60(1H，d，J＝2.1Hz)，8.81(1H，d，J＝2.1Hz).

(ii) preparation of 1-(1,3-thiazoles-4-ylmethyl)-1H-indoles-5-amine

Under nitrogen atmosphere, in ethyl acetate (20mL)/methyl alcohol (4mL) solution of 5-nitro-1-(1,3-thiazoles-4-ylmethyl)-1H-indoles (519mg), add 5% platinum-gac (87mg).Stirred reaction mixture 3 days under room temperature under nitrogen atmosphere.Under nitrogen atmosphere, add 10% palladium/charcoal (87mg), and under room temperature, stir this mixture 9 hours under nitrogen atmosphere.Elimination catalyzer, concentrating under reduced pressure filtrate.By the separated also purifying (elutriant: ethyl acetate: hexane=60:40 → 100:0), obtain title compound (424mg), oily takes on a red color of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.50(2H，br?s)，5.44(2H，s)，6.37(1H，d，J＝3.3Hz)，6.64(1H，dd，J＝2.1Hz，8.4Hz)，6.75-6.80(1H，m)，6.94(1H，d，J＝2.1Hz)，7.10-7.15(2H，m)，8.77(1H，d，J＝1.8Hz).

(iii) [2-(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate

According to the same method of embodiment G-8 (iii), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (446mg), 1-(1,3-thiazole-4-yl methyl)-1H-indoles-5-amine (414mg) and Virahol (10mL), make title compound (697mg), be incarnadine amorphous.

¹H-NMR(CDCl ₃)δ:1.43(9H，s)，3.45-3.55(2H，m)，4.35-4.45(2H，m)，4.92(1H，br?s)，5.51(2H，s)，6.51(1H，d，J＝3.0Hz)，6.56(1H，d，J＝3.0Hz)，6.81(1H，s)，7.13(1H，d，J＝3.3Hz)，7.20(1H，d，J＝3.0Hz)，7.28(1H，d，J＝8.7Hz)，7.48(1H，d，J＝7.2Hz)，7.88(1H，s)，8.18(1H，br?s)，8.44(1H，s)，8.79(1H，d，J＝2.1Hz).

(iv) 5-(2-amino-ethyl)-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indoles-5-yl] preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride

According to the same method of embodiment G-8 (iv), [(4-{[1-(1 for 2-in use, 3-thiazole-4-yl methyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (675mg), 10% (W/W) hydrochloric acid/methyl alcohol (10mL) and methyl alcohol (8.0mL), make title compound (610mg), be light green powder.

¹H-NMR(DMSO-d ₆)δ:3.25-3.35(2H，m)，4.90-5.10(2H，m)，5.57(2H，s)，6.50(1H，d，J＝3.3Hz)，6.69(1H，d，J＝3.0Hz)，7.20(1H，dd，J＝1.8Hz，8.4Hz)，7.50-7.65(4H，m)，8.01(1H，d，J＝3.0Hz)，8.25-8.45(3H，m)，8.55(1H，s)，9.05(1H，d，J＝1.8Hz)，9.97(1H，s).

(v) 3-hydroxy-3-methyl-N-[2-(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indoles-5-yl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of butyramide

According to the same method of embodiment G-8 (v), use 5-(2-amino-ethyl)-N-[1-(1,3-thiazole-4-yl methyl)-1H-indoles-5-yl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), HMB (71mg), I-hydroxybenzotriazole (88mg), triethylamine (0.56mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (123mg) and N, dinethylformamide (5.0mL), make title compound (118mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.27(6H，s)，2.38(2H，s)，3.55-3.70(2H，m)，4.35-4.50(2H，m)，5.50(2H，s)，6.50-6.60(2H，m)，6.65-6.75(1H，m)，6.82(1H，s)，7.13(1H，d，J＝3.3Hz)，7.15-7.45(4H，m)，7.83(1H，s)，8.25(1H，s)，8.42(1H，s)，8.78(1H，d，J＝1.5Hz).

Embodiment G-17

The chloro-5-{[5-of N-(tertiary butyl)-3-[(7-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of benzamide

(i) preparation of the chloro-5-nitro of 7-indoline

The mixing solutions of 5-nitro indoline (3.28g), N-chloro-succinimide (2.94g) and acetonitrile (100mL) is refluxed 19 hours.Water is added in this reaction mixture, and be extracted with ethyl acetate.Organic layer salt water washing, anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: hexane=30:70 → 50:50), obtain title compound (2.09g), be yellow powder of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:3.23(2H，t，J＝8.7Hz)，3.84(2H，t，J＝8.7Hz)，4.68(1H，br?s)，7.85-7.90(1H，m)，8.05-8.10(1H，m).

(ii) preparation of the chloro-5-nitro-1H-of 7-indoles

In ethyl acetate (100mL) solution of the chloro-5-nitro of 7-indoline (2.09g), add manganese oxide (9.13g), at 60 ℃, stir the mixture 15 hours.Remove by filter manganese oxide, concentrating under reduced pressure filtrate.By the separated also purifying of silica gel column chromatography (elutriant: ethyl acetate), with hexane washing, obtain title compound (1.92g), be light brown powder for residue.

¹H-NMR(CDCl ₃)δ:6.79-6.82(1H，m)，7.40-7.45(1H，m)，8.15(1H，d，J＝1.8Hz)，8.53(1H，d，J＝1.8Hz)，8.65-8.85(1H，m).

(iii) the chloro-5-nitro-1H-of 3-[(7-indoles-1-yl) methyl] preparation of methyl benzoate

According to the same method of embodiment G-8 (i), use 7-chloro-5-nitro-1H-indoles (950mg), 3-(brooethyl) methyl benzoate (1.22g), salt of wormwood (0.80g) and N, dinethylformamide (15mL), make title compound (1.43g), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:3.89(3H，s)，5.84(2H，s)，6.80(1H，d，J＝3.3Hz)，7.13(1H，dd，J＝0.9Hz，7.8Hz)，7.25-7.30(1H，m)，7.38(1H，t，J＝7.8Hz)，7.79(1H，s)，7.95(1H，d，J＝8.1Hz)，8.07(1H，d，J＝2.1Hz)，8.50(1H，d，J＝2.1Hz).

(iv) the chloro-5-nitro-1H-of 3-[(7-indoles-1-yl) methyl] benzoic preparation

According to the same method of embodiment G-10 (ii), use the chloro-5-nitro-1H-of 3-[(7-indoles-1-yl) methyl] methyl benzoate (1.30g), 1N aqueous sodium hydroxide solution (20mL), methyl alcohol (20mL) and tetrahydrofuran (THF) (30mL), make title compound (1.20g), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:5.92(2H，s)，6.99(1H，d，J＝3.0Hz)，7.26(1H，d，J＝7.5Hz)，7.44(1H，t，J＝7.5Hz)，7.56(1H，s)，7.82(1H，d，J＝7.5Hz)，7.88(1H，d，J＝3.0Hz)，7.98(1H，d，J＝1.8Hz)，8.62(1H，d，J＝1.8Hz)，12.90-13.10(1H，br).

(v) the chloro-5-nitro-1H-of N-(tertiary butyl)-3-[(7-indoles-1-yl) methyl] preparation of benzamide

According to the same method of embodiment G-14 (iii), use the chloro-5-nitro-1H-of 3-[(7-indoles-1-yl) methyl] phenylformic acid (595mg), thionyl chloride (0.13mL), tetrahydrofuran (THF) (10mL), TERTIARY BUTYL AMINE (0.66g), triethylamine (0.23g) and N, dinethylformamide (4.0mL), make title compound (460mg), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，5.83(2H，s)，5.86(1H，br?s)，6.79(1H，t，J＝3.3Hz)，7.02(1H，d，J＝7.8Hz)，7.20-7.30(1H，m)，7.33(1H，t，J＝7.8Hz)，7.53(1H，d，J＝7.8Hz)，7.58(1H，s)，8.07(1H，d，J＝2.4Hz)，8.49(1H，d，J＝2.4Hz).

(vi) the chloro-1H-indoles-1-of 3-[(5-amino-7-yl) methyl] preparation of-N-(tertiary butyl) benzamide

By the chloro-5-nitro-1H-of N-(tertiary butyl)-3-[(7-indoles-1-yl) methyl] benzamide (212mg) is suspended in ethanol (10mL)/water (1mL), adds calcium chloride (30.5mg), by mixture 90 ℃ of dissolvings.Reduced iron (184mg) is added in mixture, and stir 4 hours at 90 ℃.Allow reaction mixture return to room temperature, remove by filter insolubles.Concentrating under reduced pressure filtrate, ethyl acetate adds wherein, uses salt solution purging compound.Mixture, through anhydrous magnesium sulfate drying concentrating under reduced pressure, obtains title compound (203mg), is yellow amorphous.

¹H-NMR(CDCl ₃)δ:1.44(9H，s)，3.45-3.60(2H，br)，5.69(2H，s)，5.84(1H，br?s)，6.37(1H，d，J＝3.3Hz)，6.61(1H，d，J＝2.0Hz)，6.82(1H，d，J＝2.0Hz)，6.95-7.05(1H，m)，7.02(1H，d，J＝3.3Hz)，7.29(1H，t，J＝7.8Hz)，7.50-7.55(1H，m)，7.53(1H，d，J＝7.8Hz).

(vii) the chloro-5-{[5-of N-(tertiary butyl)-3-[(7-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of benzamide

According to the same method of embodiment G-10 (v), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (151mg), the chloro-1H-indoles-1-of 3-[(5-amino-7-yl) methyl]-N-(tertiary butyl) benzamide (196mg), Virahol (8.0mL), 1N aqueous sodium hydroxide solution (2.0mL) and tetrahydrofuran (THF) (4.0mL), make title compound (157mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.45(9H，s)，4.05-4.15(2H，m)，4.30-4.40(2H，m)，5.75(2H，s)，5.89(1H，s)，6.17(1H，d，J＝3.0Hz)，6.53(1H，d，J＝3.0Hz)，6.92(1H，d，J＝3.0Hz)，7.05(1H，d，J＝7.2Hz)，7.09(1H，d，J＝3.0Hz)，7.25-7.35(2H，m)，7.50-7.55(2H，m)，7.65-7.70(1H，m)，8.22(1H，s)，9.22(1H，s).

Embodiment G-18

N-(tertiary butyl)-6-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of pyridine-2-carboxamide

(i) preparation of 6-(methylol) pyridine-2-ethyl formate

To pyridine-2, in ethanol (50mL) solution of 6-dicarboxylate (4.46g), add sodium borohydride (454mg), and at room temperature stir this mixture 3 hours.This reaction mixture of concentrating under reduced pressure, adds salt solution wherein, and is extracted with ethyl acetate.Water layer is saltoutd (salt out), and be extracted with ethyl acetate.Merge organic layer, and with anhydrous magnesium sulfate drying, concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: hexane=50:50 → 100:0), obtain title compound (2.42g), be clear crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.44(3H，t，J＝7.2Hz)，3.53(1H，t，J＝5.4Hz)，4.46(2H，q，J＝7.2Hz)，4.86(2H，d，J＝5.4Hz)，7.49(1H，d，J＝7.8Hz)，7.84(1H，t，J＝7.8Hz)，8.02(1H，d，J＝7.8Hz).

(ii) 6-[(5-nitro-1H-indoles-1-yl) methyl] preparation of pyridine-2-ethyl formate

Under ice-cooled, in tetrahydrofuran (THF) (20mL) solution of 6-(methylol) pyridine-2-ethyl formate (1.00g) and triethylamine (0.84mL), drip methylsulfonyl chloride (0.43mL), and at room temperature stir this mixture 1.5 hours.Under ice-cooled, in reaction mixture, add sodium bicarbonate aqueous solution and salt solution, and be extracted with ethyl acetate.Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.In gained compound, add 5-nitroindoline (757mg), salt of wormwood (0.97g) and DMF (10mL) and at room temperature stir this mixture 24 hours, at 60 ℃, stirring 20 hours, then at 80 ℃, stirring 1 hour.Under ice-cooled, water added in this reaction mixture, and be extracted with ethyl acetate.Water layer is saltoutd, and be extracted with ethyl acetate.Merge organic layer, and with anhydrous magnesium sulfate drying, concentrating under reduced pressure, residue, through re-crystallizing in ethyl acetate, obtains title compound (1.31g), is pale yellow powder.

¹H-NMR(CDCl ₃)δ:1.47(3H，t，J＝7.2Hz)，4.51(2H，q，J＝7.2Hz)，5.62(2H，s)，6.76(1H，d，J＝7.8Hz)，6.79(1H，d，J＝3.0Hz)，7.30(1H，d，J＝9.0Hz)，7.36(1H，d，J＝3.0Hz)，7.70(1H，t，J＝7.8Hz)，8.02(1H，d，J＝7.8Hz)，8.08(1H，dd，J＝2.1Hz，9.0Hz)，8.63(1H，d，J＝2.1Hz).

(iii) 6-[(5-nitro-1H-indoles-1-yl) methyl] preparation of pyridine-2-formic acid

According to the same method of embodiment G-10 (ii), use 6-[(5-nitro-1H-indoles-1-yl) methyl] pyridine-2-ethyl formate (1.20g), 1N aqueous sodium hydroxide solution (20mL), ethanol (20mL) and tetrahydrofuran (THF) (40mL), make title compound (1.01g), be pale yellow powder.

¹H-NMR(DMSO-d ₆)δ:5.68(2H，s)，6.80-6.85(1H，m)，6.89(1H，d，J＝7.2Hz)，7.67(1H，d，J＝8.1Hz)，7.70-7.90(3H，m)，7.99(1H，d，J＝9.0Hz)，8.60(1H，s).

(iv) N-(tertiary butyl)-6-[(5-nitro-1H-indoles-1-yl) methyl] preparation of pyridine-2-carboxamide

According to the same method of embodiment G-14 (iii), use 6-[(5-nitro-1H-indoles-1-yl) methyl] pyridine-2-carboxylic acids (0.95g), thionyl chloride (0.23mL), tetrahydrofuran (THF) (20mL), TERTIARY BUTYL AMINE (1.17g), triethylamine (0.40g) and N, dinethylformamide (8.0mL), make title compound (636mg), be pale yellow powder.

¹H-NMR(CDCl ₃)δ:1.41(9H，s)，5.51(2H，s)，6.78(1H，d，J＝3.3Hz)，6.98(1H，d，J＝7.8Hz)，7.30-7.40(2H，m)，7.66(1H，br?s)，7.76(1H，t，J＝7.8Hz)，8.05-8.15(2H，m)，8.63(1H，d，J＝2.1Hz).

(v) 6-[(5-amino-1H-indoles-1-yl) methyl] preparation of-N-(tertiary butyl) pyridine-2-carboxamide

Under nitrogen atmosphere, to N-(tertiary butyl)-6-[(5-nitro-1H-indoles-1-yl) methyl] add 5% platinum-gac (35mg) in ethyl acetate (8.0mL) solution of pyridine-2-carboxamide (211mg).Stirred reaction mixture 5 hours under room temperature under nitrogen atmosphere.Under nitrogen atmosphere, 10% palladium/charcoal (69mg) is added in reaction mixture, then under room temperature, stir the mixture 2.5 hours under nitrogen atmosphere.Elimination catalyzer, concentrating under reduced pressure filtrate.By the separated also purifying (elutriant: ethyl acetate: hexane=50:50 → 80:20), obtain title compound (160mg), be light peachiness amorphous of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.48(9H，s)，3.52(2H，br?s)，5.39(2H，s)，6.41(1H，d，J＝3.0Hz)，6.64(1H，dd，J＝2.4Hz，8.7Hz)，6.82(1H，d，J＝8.1Hz)，6.97(1H，d，J＝2.4Hz)，7.00-7.10(1H，m)，7.11(1H，d，J＝3.0Hz)，7.68(1H，t，J＝7.5Hz)，7.89(1H，br?s)，8.03(1H，d，J＝7.5Hz).

(vi) N-(tertiary butyl)-6-[(5-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of pyridine-2-carboxamide

According to the same method of embodiment G-10 (v), use phenylformic acid 2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl ester (136mg), 6-[(5-amino-1H-indoles-1-yl) methyl]-N-(tertiary butyl) pyridine-2-carboxamide (160mg), Virahol (8.0mL), 1N aqueous sodium hydroxide solution (2.0mL) and tetrahydrofuran (THF) (4.0mL), make title compound (137mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.50(9H，s)，4.05-4.15(2H，m)，4.30-4.40(2H，m)，5.46(2H，s)，6.16(1H，d，J＝3.0Hz)，6.57(1H，d，J＝3.0Hz)，6.85-6.90(2H，m)，7.19(1H，d，J＝3.0Hz)，7.20-7.30(1H，m)，7.35(1H，d，J＝9.0Hz)，7.69(1H，t，J＝7.5Hz)，7.81(1H，s)，7.92(1H，s)，8.04(1H，d，J＝7.5Hz)，8.20(1H，s)，9.15(1H，br?s).

Embodiment G-19

N-(tertiary butyl)-3-({ 5-[(5-{2-[(3-hydroxy-3-methyl butyryl radicals) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-1H-indoles-1-yl } methyl) preparation of benzamide

(i) (the 2-{4-[(1-{3-[(tertiary butyl amino) carbonyl] benzyl }-1H-indoles-5-yl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) preparation of t-butyl carbamate

According to the same method of embodiment G-8 (iii), use [2-(the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (297mg), 3-[(5-amino-1H-indoles-1-yl) methyl]-N-(tertiary butyl) benzamide (354mg) and Virahol (8.0mL), make title compound (478mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.43(9H，s)，1.46(9H，s)，3.45-3.55(2H，m)，4.35-4.50(2H，m)，4.93(1H，br?s)，5.33(2H，s)，5.88(1H，s)，6.49(1H，d，J＝3.0Hz)，6.55(1H，d，J＝2.4Hz)，7.10-7.30(4H，m)，7.30(1H，t，J＝7.8Hz)，7.40-7.50(1H，m)，7.54(1H，d，J＝8.1Hz)，7.64(1H，s)，7.86(1H，s)，8.16(1H，br?s)，8.43(1H，s).

(ii) 3-[(5-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of-N-(tertiary butyl) benzamide dihydrochloride

According to the same method of embodiment G-8 (iv), use (the 2-{4-[(1-{3-[(tertiary butyl is amino) carbonyl] benzyl }-1H-indoles-5-yl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl) t-butyl carbamate (449mg) and 10% (W/W) hydrochloric acid/methyl alcohol (5.0mL), make title compound (400mg), be light orange powder.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，3.25-3.35(2H，m)，4.90-5.05(2H，m)，5.51(2H，s)，6.56(1H，d，J＝3.0Hz)，6.69(1H，d，J＝3.3Hz)，7.20(1H，d，J＝9.0Hz)，7.29(1H，d，J＝7.2Hz)，7.37(1H，t，J＝7.8Hz)，7.51(1H，d，J＝9.0Hz)，7.62(1H，d，J＝3.0Hz)，7.65-7.70(2H，m)，7.68(1H，s)，7.99(1H，d，J＝3.0Hz)，8.15-8.30(3H，m)，8.58(1H，s)，9.89(1H，s).

(iii) N-(tertiary butyl)-3-({ 5-[(5-{2-[(3-hydroxy-3-methyl butyryl radicals) amino] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-1H-indoles-1-yl } methyl) preparation of benzamide

According to the same method of embodiment G-8 (v), use 3-[(5-{[5-(2-amino-ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl]-N-(tertiary butyl) benzamide dihydrochloride (150mg), HMB (48mg), I-hydroxybenzotriazole (59mg), triethylamine (0.38mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (83mg) and N, dinethylformamide (4.0mL), make title compound (80mg), be light yellow crystal.

¹H-NMR(CDCl ₃)δ:1.25(6H，s)，1.46(9H，s)，2.44(2H，s)，3.55-3.65(2H，m)，4.45-4.55(2H，m)，5.30(2H，s)，5.99(1H，s)，6.51(1H，d，J＝3.0Hz)，6.57(1H，d，J＝3.3Hz)，7.10-7.35(6H，m)，7.55(1H，d，J＝8.1Hz)，7.64(1H，s)，7.75-7.80(1H，m)，8.05-8.10(1H，m)，8.28(1H，s)，9.55-9.65(1H，br).

Embodiment G-20

N-(tertiary butyl)-3-[(5-{[5-(2-{[2-methyl-2-(methylsulfonyl) propionyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl] preparation of benzamide

According to the same method of embodiment G-8 (v); use 3-[(5-{[5-(2-amino-ethyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-yl] amino }-1H-indoles-1-yl) methyl]-N-(tertiary butyl) benzamide dihydrochloride (150mg), 2-methyl-2-(methylsulfonyl) propionic acid (68mg), I-hydroxybenzotriazole (59mg), triethylamine (0.38mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (83mg) and N; dinethylformamide (4.0mL); make title compound (91mg), be clear crystal.

¹H-NMR(CDCl ₃)δ:1.46(6H，s)，1.60(9H，s)，2.84(3H，s)，3.60-3.75(2H，m)，4.30-4.45(2H，m)，5.34(2H，s)，5.90(1H，s)，6.51(1H，d，J＝2.7Hz)，6.55-6.60(1H，m)，7.00-7.10(1H，m)，7.10-7.40(6H，m)，7.53(1H，d，J＝7.5Hz)，7.65(1H，s)，7.81(1H，s)，7.89(1H，s)，8.44(1H，s).

Embodiment H-1

N-(the chloro-4-[(6-of 3-{2-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } phenyl) preparation of cyclopropane carboxamide

(i) 4, the preparation of 6-bis-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine

At 0 ℃, in tetrahydrofuran (THF) (12mL) solution of diisopropylamine (540mg), add n-Butyl Lithium (2.7mL), stir after 30 minutes, mixture is cooled to-78 ℃, 4-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine (500mg) is added wherein.Reaction mixture is stirred 1 hour, Tosyl chloride (690mg) is added wherein, with 1 hour, allow mixture be warming up to-40 ℃.Water is added in this reaction mixture and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: hexane: ethyl acetate=80:20 → 30:70).After concentrating under reduced pressure, filter and collect gained crystal, with diisopropyl ether washing, obtain title compound (191mg), be crystal.

¹H-NMR(CDCl ₃)δ:4.13(3H，s)，6.72(1H，s)，8.68(1H，s).

(ii) N-(the chloro-4-[(6-of 3-{2-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } phenyl) preparation of cyclopropane carboxamide

At 80 ℃, stir 4,6-bis-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine (98mg), N-[3-(4-amino-2-chlorophenoxy) phenyl] mixture of cyclopropane carboxamide (167mg) and Virahol (7.0mL) 3 hours.This reaction mixture of concentrating under reduced pressure, adds water and saturated sodium bicarbonate aqueous solution wherein, and is extracted with ethyl acetate.Organic layer washs and uses anhydrous magnesium sulfate drying with saturated brine.Pressure reducing and steaming solvent, gained residue is by silica gel column chromatography (elutriant: hexane: ethyl acetate=80:20 → 0:100).By target fraction concentrating under reduced pressure.Residue, through the crystallization of ethyl acetate-hexane, obtains title compound (146mg), and powder is white in color.

¹H-NMR(CDCl ₃)δ:0.78-0.84(2H，m)，0.99-1.05(2H，m)，1.47-1.54(1H，m)，4.07(3H，s)，6.60(1H，s)，6.75-6.77(2H，m)，7.01-7.04(2H，m)，7.20-7.26(3H，m)，7.62(1H，s)，8.10(1H，br?s)，8.47(1H，s).

Embodiment H-2

The chloro-4-[3-of the chloro-N-{3-of 6-(trifluoromethyl) phenoxy group] phenyl } preparation of-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine

According to the same method of embodiment H-1 (ii), use 4, the chloro-5-methyl-5H-of 6-bis-pyrrolo-[3,2-d] pyrimidine (70mg), the chloro-4-[3-of 3-(trifluoromethyl) phenoxy group] aniline (109mg) and Virahol (7.0mL), make title compound (61mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:4.07(3H，s)，6.73(1H，s)，7.21-7.33(3H，m)，7.46-7.67(3H，m)，7.93(1H，br?s)，8.40(1H，br?s)，8.97(1H，br?s).

Embodiment H-3

The chloro-5-methyl-N-{3-of 6-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } preparation of-5H-pyrrolo-[3,2-d] pyrimidine-4-amine

According to the same method of embodiment H-1 (ii), use 4, the chloro-5-methyl-5H-of 6-bis-pyrrolo-[3,2-d] pyrimidine (150mg), 3-methyl-4-[(6-picoline-3-yl) oxygen base] aniline (160mg) and Virahol (8.0mL), make title compound (116mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:2.17(3H，s)，2.43(3H，s)，4.04(3H，s)，6.65(1H，s)，6.94(1H，d，J＝8.3Hz)，7.16-7.25(2H，m)，7.44-7.51(2H，m)，7.16(1H，d，J＝2.7Hz)，8.28(1H，s)，8.57(1H，s).

Embodiment H-4

The chloro-4-of the chloro-N-[3-of 6-(pyridine-2-ylmethoxy) phenyl] preparation of-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine

According to the same method of embodiment H-1 (ii), use 4, the chloro-5-methyl-5H-of 6-bis-pyrrolo-[3,2-d] pyrimidine (150mg), the chloro-4-of 3-(pyridine-2-ylmethoxy) aniline (210mg) and Virahol (10mL), make title compound (170mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:4.03(3H，s)，5.27(2H，s)，6.64(1H，s)，7.20-7.91(6H，m)，8.25(1H，s)，8.54(1H，br?s)，8.58-8.62(1H，m).

Embodiment H-5

N-[3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of cyclopropane carboxamide

(i) preparation of 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-5H-pyrrolo-of-4-[3,2-d] pyrimidine

By the chloro-5H-pyrrolo-[3 of 4-, 2-d] pyrimidine (2.00g), (2-bromine oxethyl) (tertiary butyl) dimethylsilane (4.00g) and cesium carbonate (6.40g) be dissolved in N, in dinethylformamide (10mL), and at room temperature stir this mixture 4 hours.Under ice-cooled, salt solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is through anhydrous magnesium sulfate drying concentrating under reduced pressure.By the separated also purifying (elutriant: ethyl acetate: hexane=20:80 → 40:60), obtain title compound (3.02g), be brown solid of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:-0.24(6H，s)，0.69(9H，s)，3.90-3.93(2H，m)，4.61-4.64(2H，m)，6.76(1H，s)，8.00(1H，s)，8.61(1H，s).

(ii) N-[3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) phenyl] preparation of cyclopropane carboxamide

According to embodiment H-1 (i) and (ii) same method, use diisopropylamine (2.20g), 1.6M n-Butyl Lithium (14mL), tetrahydrofuran (THF) (50mL), 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-5H-pyrrolo-[3 of-4-, 2-d] pyrimidine (500mg), Tosyl chloride (6.10g), N-[3-(4-amino-2-chlorophenoxy) phenyl] cyclopropane carboxamide (190mg) and Virahol (10mL), make compound.Gained compound is dissolved in methyl alcohol (10mL), 4N hydrogenchloride/ethyl acetate solution (3.0mL) is added wherein, at 80 ℃, stir the mixture 18 hours.Under ice-cooled, in reaction mixture, add sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain title compound (73mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:0.75-0.77(4H，m)，1.69-1.75(1H，m)，3.88-3.91(2H，m)，4.53-4.55(2H，m)，6.62-6.68(1H，m)，6.72(1H，s)，7.20-7.96(6H，m)，8.37(1H，s)，9.87-9.97(1H，m)，10.24(1H，s).

Embodiment H-6

The chloro-4-[(3-luorobenzyl of the chloro-N-{3-of 6-) oxygen base] phenyl } preparation of-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine

According to the same method of embodiment H-1 (ii), use 4, the chloro-5-methyl-5H-of 6-bis-pyrrolo-[3,2-d] pyrimidine (150mg), the chloro-4-[(3-luorobenzyl of 3-) oxygen base] aniline (167mg) and Virahol (10mL), make title compound (61mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:4.03(3H，s)，5.24(2H，s)，6.64(1H，s)，7.14-7.50(6H，m)，7.71-7.72(1H，m)，8.26(1H，s)，8.52(1H，s).

Embodiment H-7

3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzoic preparation

According to embodiment H-1 (i), (ii) and the same method of embodiment H-5 (ii), use diisopropylamine (2.00g), 1.6M n-Butyl Lithium (13mL), tetrahydrofuran (THF) (50mL), 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-5H-pyrrolo-[3 of-4-, 2-d] pyrimidine (450mg), Tosyl chloride (6.01g), 3-(4-amino-2-chlorophenoxy) methyl benzoate (190mg), Virahol (10mL), methyl alcohol (10mL) and 4N hydrogenchloride/ethyl acetate solution (3.0mL), make compound.In gained compound, add 1N aqueous sodium hydroxide solution (0.8mL) and tetrahydrofuran (THF) (4.0mL), and at room temperature stir this mixture 2 days.1N hydrochloric acid neutralization for reaction mixture, adds sodium bicarbonate aqueous solution and salt solution wherein.Mixture is extracted with ethyl acetate, anhydrous magnesium sulfate drying concentrating under reduced pressure for organic layer.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain title compound (127mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:3.83-3.91(2H，m)，4.54-4.57(2H，m)，6.49(1H，brs)，6.73(1H，s)，7.24-7.68(6H，m)，7.98(1H，s)，9.97(1H，s)，13.14(1H，br?s).

Embodiment H-8

N-(tertiary butyl)-chloro-4-[(6-of 3-{2-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino] phenoxy group } preparation of benzamide

According to the same method of embodiment H-1 (ii), use 4, the chloro-5-methyl-5H-of 6-bis-pyrrolo-[3,2-d] pyrimidine (110mg), 3-(4-amino-2-chlorophenoxy)-N-(tertiary butyl) benzamide (197mg) and Virahol (10mL), prepare title compound (86mg), be crystal.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，4.06(3H，s)，6.69(1H，s)，7.06-7.64(6H，m)，7.81(1H，s)，7.89(1H，br?s)，8.34(1H，s)，8.81(1H，s).

Embodiment H-9

The preparation of N-(tertiary butyl)-3-(the chloro-5-of the chloro-4-{[6-of 2-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide

According to embodiment H-1 (i) and (ii) same method, use diisopropylamine (2.80g), 1.6M n-Butyl Lithium (16mL), tetrahydrofuran (THF) (50mL), 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-5H-pyrrolo-[3 of-4-, 2-d] pyrimidine (800mg), Tosyl chloride (7.10g), 3-(4-amino-2-chlorophenoxy)-N-(tertiary butyl) benzamide (811mg) and Virahol (16mL), make compound.Gained compound is dissolved in methyl alcohol (10mL), 4N hydrogenchloride/ethyl acetate solution (10mL) is added wherein, at 80 ℃, agitate compounds is 18 hours.Under ice-cooled, in reaction mixture, add sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain title compound (576mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(DMSO-d ₆)δ:1.36(9H，s)，3.88-3.91(2H，m)，4.53-4.57(2H，m)，6.72(1H，s)，7.06-7.61(6H，m)，7.81(1H，s)，7.96-7.97(1H，m)，8.37(1H，s)，9.52-10.53(1H，m).

Embodiment H-10

The preparation of N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-6-(trifluoromethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide

(i) preparation of 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-6-of-4-(trifluoromethyl)-5H-pyrrolo-[3,2-d] pyrimidine

At 0 ℃, in tetrahydrofuran (THF) (20mL) solution of diisopropylamine (300mg), add 1.6M n-Butyl Lithium (2.0mL).Stir after 30 minutes, mixture is cooled to-78 ℃, 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-5H-pyrrolo-of-4-[3,2-d] pyrimidine (520mg) is added wherein.Reaction mixture is stirred 1 hour, S-(trifluoromethyl) dibenzothiophene fluoroform sulphonate (2.00g) is added wherein, with 1 hour, allow mixture be warming up to-40 ℃.Water is added in this compound of reaction and is extracted with ethyl acetate.Organic layer is water and saturated brine washing successively, and uses dried over mgso.After concentrating under reduced pressure, residue is separated also with alkaline silica gel column chromatography purification (elutriant: hexane: ethyl acetate=80:20 → 30:70).After concentrating under reduced pressure, filter and collect gained crystal, with diisopropyl ether washing, obtain title compound (29mg), be crystal.

¹H-NMR(CDCl ₃)δ:0.02(6H，s)，0.74(9H，s)，3.92-3.96(2H，m)，4.74-4.78(2H，m)，7.17(1H，s)，8.79(1H，s).

(ii) preparation of N-(tertiary butyl)-3-(the chloro-4-{[5-of 2-(2-hydroxyethyl)-6-(trifluoromethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzamide

According to the same method of embodiment H-2 (ii), use 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) the chloro-6-of-4-(trifluoromethyl)-5H-pyrrolo-[3,2-d] pyrimidine (25mg), 3-(4-amino-2-chlorophenoxy)-N-(tertiary butyl) benzamide (26mg) and Virahol (1.5mL), make compound.Gained compound is dissolved in methyl alcohol (2.0mL), 4N hydrogenchloride/ethyl acetate solution (1.0mL) is added wherein, at 80 ℃, stir the mixture 18 hours.Under ice-cooled, sodium bicarbonate aqueous solution added in this reaction mixture, and be extracted with ethyl acetate.Organic layer is with salt water washing and use anhydrous magnesium sulfate drying.By the separated also purifying (elutriant: ethyl acetate: methyl alcohol=100:0 → 95:5), obtain title compound (9.2mg), be crystal of silica gel column chromatography for residue.

¹H-NMR(CDCl ₃)δ:1.36(9H，s)，3.92-3.96(2H，m)，4.61-4.64(2H，m)，7.06-7.45(5H，m)，7.55-7.61(2H，m)，7.82(1H，s)，7.97(1H，s)，8.44(1H，s)，9.50-10.55(1H，m).

FORMULATION EXAMPLE 1 (amount of every)

(1) the compound 10.0mg obtaining in embodiment A-1

(2) lactose 60.0mg

(3) W-Gum 35.0mg

(4) gelatin 3.0mg

(5) Magnesium Stearate 2.0mg

The mixture of the compound obtaining in 10.0mg embodiment A-1,60.0mg lactose and 35.0mg W-Gum is utilized to the 10 % by weight aqueous gelatin solutions (3.0mg gelatin) of 0.03ml, by the granulation of 1mm-mesh screen, subsequently particle be dried at 40 ℃ and again sieve.The particle obtaining is thus mixed and suppressed with 2.0mg Magnesium Stearate.Gained label is carried out to dressing with the sugar-coat of the suspension that contains sucrose, titanium dioxide, talcum and gum arabic, and use beeswax polishing, obtain the tablet of sugar-coat.

FORMULATION EXAMPLE 2 (amount of every)

(1) the compound 10.0mg obtaining in embodiment A-1

(2) lactose 70.0mg

(3) W-Gum 50.0mg

(4) Zulkovsky starch 7.0mg

(5) Magnesium Stearate 3.0mg

By the compound obtaining in 10.0mg embodiment A-1 and the aqueous solution (7.0mg Zulkovsky starch) granulation of 0.07ml Zulkovsky starch for 3.0mg Magnesium Stearate, subsequently by these particle dryings, and mix with 70.0mg lactose and 50.0mg W-Gum.Suppress this mixture, obtain tablet.

The clone of experimental example 1A people HER2 gene and the preparation of recombinant baculovirus

Total RNA that use is prepared by MCF7 cell is as template, by the RT-PCR HER2 gene of cloning people.Primer for RT-PCR is preparation like this: by nucleotide sequence (the Genbank accession number M11730) information of HER2 gene, by the nucleotide sequence of encoding D YKDDDD peptide and restriction enzyme recognition sequence being added to the nucleotide sequence (2176-3918 of GenbankAccession accession number M11730) in coding HER2 cell intracellular domain district, make described albumen contain N-end DYKDDDD peptide sign.Described primer nucleotide sequence is as follows.

HER2-U:5 '-AATTAAGTCGACATGGACTACAAAGACGATGACGACAAGCGACGGCAGCAGAAGAT CCGGAAGTAC-3 ' (recognition sequence number: 1)

With

HER2-L:

5 '-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTACTC-3 ' (recognition sequence number: 2)

Use SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen) to carry out this RT reaction, and use KOD-plus test kit (TOYOBO) to carry out this PCR reaction.Make the PCR product obtaining at the upper electrophoresis of sepharose (1%), the DNA fragmentation by pcr amplification, by reclaiming on gel, is then digested with restriction enzyme Sal I and Sph I.To use the DNA of restriction enzyme treatment at the upper electrophoresis of sepharose (1%), and the DNA fragmentation obtaining is reclaimed, and be connected to the plasmid pFASTBAC1 (Invitrogen) with restriction enzyme Sal I and Sph I digestion, obtain expression plasmid pFB-HER2.Confirm the nucleotide sequence of Insert Fragment, and find that it is consistent with the nucleotide sequence (2176-3918 of Genbank accession number M11730) of HER2 cell intracellular domain.In addition, use BAC-TO-BAC baculovirus expression system (Baculovirus Expression System) (Invitrogen), to prepare recombinant baculovirus BAC-HER2.

The preparation of experimental example 1B HER2 cell intracellular domain albumen

By SF-21 cell with 1 * 10 ⁶individual cell/mL is inoculated in the Sf-900IISFM substratum (1L containing 10% foetal calf serum (trace), 50mg/L gentamicin (Invitrogen) and 0.1% Pluronic F-68 (Invitrogen), and use the Erlenmeyer flask of 2L volume with 100rpm, to carry out wave and culture at 27 ℃ Invitrogen).After cultivating 24 hours, add recombinant baculovirus BAC-HER2 (13.4mL), and mixture is further cultivated 3 days.By this substratum with 2000rpm centrifugal 5 minutes, obtain the cell of virus infection.By phosphate buffered saline(PBS) for cell (Invitrogen) washing of this infection, centrifugal under the same conditions, and by this cell-80 ℃ of preservations.Cryopreserved cell is thawed in ice, be suspended in buffer A (the 50mM Tris damping fluid (30mL that contains 20% glycerine, 0.15MNaCl that is supplemented with adequate proteins enzyme inhibitors (Boehringer), pH7.4)) in, and with Polytron homogenizer (Kinematica) with 20000rpm, within 30 seconds, under condition, break 3 times.By the medium breaking by within centrifugal 30 minutes, make its clarification with 40000rpm, and with the filter filtration of 0.45 μ m.Filtrate is passed through to use the post of Anti-FLAG M2 Affinity Gel (4mL, Sigma) filling with the flow velocity of about 0.5mL/ minute.This post is washed by buffer A, and with containing the buffer A wash-out of 100 μ g/mL FLAG peptides.The Vivaspin 20 (Vivascience) that elutant is held back with the molecular weight with 30K is concentrated.Concentrated solution is carried out to purifying by use with the gel-filtration of the Hi Load Superdex 200pg 16/60 (AmershamBioscience) of buffer A balance.Collect the fraction containing HER2 cell intracellular domain, add the final concentration of glycerine to 50%, and-80 ℃ of stored refrigerated.

Determining of experimental example 1C HER2 kinase inhibiting activity

To be dissolved in damping fluid (50mM Tris-HCl (pH7.5), 5mM MgCl for kinase reaction for test compound in methyl-sulphoxide (DMSO) ₂, 5mM MnCl ₂, 2mM dithiothreitol (DTT), 0.01% Tween-20) and dilution.In this compound solution (10 μ L), add the damping fluid (20 μ L) for kinase reaction, in this damping fluid, contain the peptide substrate poly-Glu:Tyr (4:1) of the HER2 cell intracellular domain that obtains in 5 μ g/mL experimental example 1B and 12.5 μ g/mL (Sigma).In the mixture obtaining to this, add 20 μ L ATP solution (1.25 μ M ATP, 0.05 μ Ci[γ- ³²p] ATP), make mixture 25 ℃ of reactions 10 minutes, and this reaction stopped with the 20% TCA solution of 50 μ L.By this reaction soln in 4 ℃ standing 20 minutes, and use cell harvester (PerkinElmer) that the insoluble part of acid is transferred to GF/C strainer (PerkinElmer), and wash with 250mM phosphoric acid solution.After washing, this plate is dried to 60 minutes at 45 ℃, and adds the MicroScinti 0 (PerkinElmer) of 35 μ L.Use TopCount (PerkinElmer) to measure radioactivity.Calculate according to the following formula the HER2 kinase inhibition rate (%) of test compound:

Inhibiting rate (%)=(1-(counting-blank of test compound) ÷ (contrast-blank)) * 100

Use the counting of the solution that does not add compound reaction as " contrast ", and use the counting of the solution that there is no compound and HER2 cell intracellular domain as " blank ".The results are shown in table 1 of the inhibiting rate of compound.

By above-mentioned, show that compound of the present invention suppresses the kinase whose activity of HER2 consumingly.

Table 1

The In-vitro Inhibitory Effect of 2 pairs of breast cancer cell BT-474 propagation of experimental example

The suspension of human breast cancer cell BT-474 (100 μ l (6000 cells)) is inoculated to be attached in the microtest plate of 96-hole, and cultivate in incubator (37 ℃, 5% carbonic acid gas).Second day, adds the 100 μ l solution of each test compound of 2 times of the serial dilutions dosage to obtain indicating in advance, and by cell cultures 5 days.After the substratum of removing containing test compound, cell is washed and fixed with 50% trichoroacetic acid(TCA), add 0.4% (w/v) SRB solution (being dissolved in 1% acetic acid) with staining cell albumen (Skehan etc. thereafter, Journal of the National Cancer Institute, the 82nd volume, 1107-1112 page, 1990).With after 1% acetic acid solution washing, add 100 μ l Tris solution (10mM) to extract pigment, and at the wavelength place of 550nm, measure absorbancy and using the amount of quantitative cell as protein content.To there is no protein content in the control group of reception test compound solution as 100%, measure the ratio of the residual protein content of each treatment group, and the content that calculate to suppress residual cell to reach with respect to contrast be the required compound concentration (IC of 50% inhibition ₅₀value).The results are shown in table 2.

Table 2

工业实用性

根据本发明，提供了吡咯并[3，2-d]嘧和吡唑并[4，3-d]嘧化合物，它们的制备方法它们的用途。这些稠合的嘧化合物具有优异的酪氨酸酶抑制作用、高度的安全性、并且作为药物产品是十分令人满意的。

Number of patent application 2005-349858 and the 2006-060648 of the application based on submitting in Japan, its content is incorporated herein by reference.

Sequence table

Claims

1. the represented compound or its salt of following formula:

Wherein

R ^1ahydrogen atom,

R ^2athe C being replaced by the group shown in following formula _1-6alkyl :-NR ^6a-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

R ^3ahydrogen atom or C _1-6alkyl,

R ^4ahalogen atom or C _1-6alkyl,

R ^5ahalogen atom or C _1-6alkyl, and

X ^ahydrogen atom or halogen atom,

2. the compound of claim 1, wherein X ^ait is hydrogen atom.

3. the compound of claim 2, wherein

R ^1ahydrogen atom,

R ^2aby-NR ^6aa-CO-CR ^7ar ^8a-SO ₂-C _1-4the C that group shown in alkyl replaces _1-6alkyl,

R ^3ahydrogen atom,

R ^4achlorine atom or methyl, and

R ^5afluorine atom, chlorine atom or methyl.

4. the compound of claim 3, wherein R ^7aand R ^8ait is methyl.

5. be selected from following compound or its salt or their hydrate:

6. the represented compound or its salt of following formula:

Wherein

W ^bc (R ^1b) or N,

Ring A ^bthe optional pyridine ring replacing,

X ^1bbe-NR ^3b-Y ^1b-,-O-,-S-,-SO-,-SO ₂-or-CHR ^3b-

R wherein ^3bhydrogen atom or the optional aliphatic alkyl replacing, or R ^3boptionally with ring A ^bpyridine ring on carbon atom in conjunction with to form the ring structure of optional replacement, and Y ^1bkey or C _1-4alkylidene group or-O-(C _1-4alkylidene group)-, they are optionally substituted separately,

And R ^1bhydrogen atom, halogen atom or the group that passes through the optional replacement of carbon atom, nitrogen-atoms or Sauerstoffatom combination,

7. the compound of claim 6, it is the compound shown in following formula:

Wherein encircle A ^{b '}further substituted pyridine ring optionally, ring B ^bthe optional C replacing _6-14aryl, other symbol is as the definition in claim 6.

8. the compound of claim 7, wherein

(i)-NR ^6ba-CO-(CH ₂) _n1-SO ₂-C _1-4alkyl

(ii)-NR ^6bb-CO-(CH ₂) _n2-OH

(iii)-O-(CH ₂) _n3-OH

(iv) hydroxyl,

R ^3bhydrogen atom,

Ring B ^boptionally be selected from the phenyl that following substituting group replaces: the C of optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6alkyl-formamyl and halogen.

9. the compound of claim 7, wherein

Ring A ^{b '}the pyridine ring optionally being replaced by halogen, and

Ring B ^bthe optional selected phenyl replacing from following substituting group on 3-position: the C of optional halo _1-6the C of alkyl, optional halo _1-6alkoxyl group, C _1-6alkyl-formamyl and halogen.

10. be selected from following compound or its salt:

11. the compound or its salt that following formula is represented:

Wherein

Ring A ^cthe optional phenyl ring replacing,

R ^5cbe

(i) the optional amino replacing,

(ii) the optional formamyl replacing,

(iii) the optional urea groups replacing,

(iv) the optional sulfamyl replacing,

(v) the optional heterocyclic radical replacing,

(vi) the optional C replacing _2-6alkoxyl group,

(vii) the optional aminomethyl replacing,

(viii) the optional carbamyl ylmethyl replacing,

(ix) the optional alkyl sulphonyl replacing, or

(x) cyano group, and

Ring B ^cc _6-14aryl or C _5-8cycloalkyl, except by R ^5coutside replacement, they are also optionally further substituted separately,

Condition is to get rid of following compound:

The compound of 12. claims 11, wherein R ^1cit is hydrogen atom.

13. are selected from following compound or its salt:

14. the compound or its salt shown in following formula:

Wherein

Ring A ^dthe optional phenyl ring replacing,

Z ^dthe optional C replacing _1-3alkylidene group,

Ring B ^dthe optional heterocyclic radical replacing,

Condition is to get rid of following compound:

The compound of 15. claims 14, it is the compound shown in following formula:

R wherein ^4dacyl group or the optional urea groups replacing, ring B ^{d '}except by R ^4dthe piperidyl being also optionally further substituted outside replacement, and other symbol is as the definition in claim 14.

16. are selected from following compound or its salt:

The compound or its salt of 17. following formulas:

Wherein

Ring A ^ethe optional phenyl ring replacing,

R ^5ebe

(i) straight chained alkyl, the heterocyclic radical that it is optionally substituted replaces,

(ii) straight chained alkyl, the imino-that it is optionally substituted replaces,

(iii) straight chained alkyl, the aryl that it is optionally substituted replaces, and optionally further by halo or hydroxylation,

(iv) the optional branched-chain alkyl replacing,

(v) the optional alkenyl replacing,

(vi) hydroxyl, the aryl that it is optionally substituted replaces,

(vii) by C _1-6the hydroxyl that alkyl replaces,

(viii) hydroxyl, it is by the C of halo _2-6alkyl replaces,

(ix) C of halo _2-6alkyl,

(x) the optional cycloalkyl replacing, or

(xi) C optionally being replaced by aryl _1-6alkyl-carbonyl, described aryl is optionally substituted, and

Ring B ^eexcept by R ^5ethe C being also optionally further substituted outside replacement _6-14aryl,

Condition is to get rid of following compound:

18. be selected from following compound or its salt:

19. the compound or its salt that following formula is represented:

Wherein

W ^gc (R ^1g) or N,

Ring A ^gthe optional phenyl ring replacing,

Ring B ^gthe optional nitrogen heterocyclic ring replacing,

X ^1gbe-NR ^3g-Y ^1g-,-O-,-S-,-SO-,-SO ₂-or-CHR ^3g-

The compound of 20. claims 19, it is the compound shown in following formula:

R wherein ^4gthe optional alkyl replacing, ring B ^{g '}except by R ^4g5 or the 6-member heterocyclic ring containing nitrogen that outside replacement, are also optionally further substituted, and other symbol is as the definition in claim 19.

The compound of 21. claims 20, wherein

R ^2ghydrogen atom or the optional C replacing _1-6alkyl,

R ^3ghydrogen atom or C _1-6alkyl,

The compound of 22. claims 20, wherein

R ^2gbe

(i) hydrogen atom,

(ii) C _1-6alkyl, or

(a)-O-(CH ₂) _n-OH，

(b)-NR ^5g-CO-(CH ₂) _n-OH，

(c)-NR ^5g-CO-(CH ₂) _n-SO ₂the C of-optional halo _1-4alkyl,

(d) hydroxyl, and

(e) amino

R ^3ghydrogen atom or C _1-6alkyl,

Following formula:

or

And

23. are selected from following compound or its salt:

The compound or its salt that 24. following formulas are represented:

Wherein

R ^1hthe C of halogen atom or halo _1-6alkyl,

Z ^hkey or the optional C replacing _1-3alkylidene group,

Ring A ^hthe optional phenyl ring replacing, and

The compound of 25. claims 24, it is the compound shown in following formula:

Wherein

R ^5hbe

(i) the optional amino replacing,

(ii) the optional formamyl replacing,

(iii) the optional urea groups replacing,

(iv) the optional sulfamyl replacing,

(v) the optional heterocyclic radical replacing,

(vi) the optional alkyl replacing,

(vii) halogen atom, or

(viii) the optional carboxyl replacing, and

Ring B ^{h '}(i) C _6-14aryl, (ii) heterocyclic radical, or (iii) C _5-8cycloalkyl, they are separately except by R ^5houtside replacement, be also optionally further substituted, and other symbol is as the definition in claim 24.

26. are selected from following compound or its salt:

The prodrug of the compound of any one in 27. claims 1 to 26.

The medicine of 28. compound or its salts that comprise any one in claim 1 to 26 or their prodrug.

The medicine of 29. claims 28, it is tyrosine kinase inhibitor.

The medicine of 30. claims 28, it is the medicine of prevention or treatment cancer.

The medicine of 31. claims 30, wherein said cancer is mammary cancer, ovarian cancer, colorectal carcinoma, cancer of the stomach, esophagus cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.

The method of 32. preventions or treatment mammalian cancer, it comprises to the compound or its salt of any one in the claim 1 to 26 of Mammals effective dosage or their prodrug.

33. the compound or its salt of any one or their prodrug are for the preparation of the purposes of the medicine of prevention or treatment cancer in claim 1 to 26.