CN1993362B - Fused heterocyclic compound - Google Patents
Fused heterocyclic compound Download PDFInfo
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- CN1993362B CN1993362B CN2005800261871A CN200580026187A CN1993362B CN 1993362 B CN1993362 B CN 1993362B CN 2005800261871 A CN2005800261871 A CN 2005800261871A CN 200580026187 A CN200580026187 A CN 200580026187A CN 1993362 B CN1993362 B CN 1993362B
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Abstract
A compound represented by the formula (I) [wherein W represents C(R<1>) or N; A represents optionally substituted aryl or optionally substituted heteroaryl; X<1> represents -NR<3>-Y<1>-, -O-, -S-, -SO-, -SO2-, or -CHR<3>- (wherein R<3> represents hydrogen or an optionally substituted aliphatic hydrocarbon group, provided that R<3> may be bonded to A to form an optionally substituted ring structure); R<1> represents hydrogen or an optionally substituted group bonded through a carbon, nitrogen, or oxygen atom; and R<2> represents hydrogen or an optionally substituted group bonded through a carbon or sulfur atom, provided that R<2> may be bonded to R<1> or R<3> to form an optionally substituted ring structure] or a salt of the compound. Also provided is a tyrosinkinase inhibitor or a preventive/therapeutic agent for cancers which each contains the compound or a prodrug thereof.
Description
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, its preparation method method and uses thereof.
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 an I receptor type tyrosine kinase.These erbB families express in various cells, and the control of growth of they and cell and differentiation and necrocytosis to suppress the control of (apoptosis inhibition) closely related.For example, the steady state activity of the high expression level of known EGFR and HER2 and acceptor makes cell transformation in test.
Also the high expression level of known each these acceptor be expressed in different cancer patients simultaneously in for bad prognostic factor.
These acceptors combine with multiple peptide part such as EGF, TGF α etc., and the same dimerization or the allos dimerization in conjunction with the promotion acceptor of part.The increase that this has induced the self phosphorylation that is derived from acceptor or has changeed the kinase activity of phosphorylation, and the tyrosine residues by albumen and specific phosphorylation combine the activation that causes downstream signal approach (MAPK, Akt).This is the mechanism of the receptor active of above-mentioned cell growth, differentiation, necrocytosis inhibition etc., and it is considered to because the part of ligand concentration increases the reason of acceptor high expression level in the malignization of cancer and cancer.
The many cancers all high expression level with EGFR or HER2 are relevant.For example can mention 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 is relevant with prediction, and expression of receptor is bad prognostic factor in mammary cancer, nonsmall-cell lung cancer etc.
In recent years, humanization is anti--the clinical use of HER2 antibody (trastuzumab) in anti-HER2 high expression level mammary cancer, and 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 used to resist HER2 or the EGFR possibility as cancer treatment drugs.Although these medicines demonstrate the tumor growth restraining effect in clinical and nonclinical test, known they can induce the inhibition of acceptor enzymic activity and the inhibition of downstream signal approach.Therefore, suppressing EGFR or HER2 kinases or inhibition EGFR or the kinase whose activatory compound of HER2 is effective cancer therapy medicine.
As the compound that suppresses by the receptor type tyrosine kinase of HER2/EGFR kinases representative, known condensed heterocycle compound (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 pyrrole derivative (for example WO98/03648, WO01/77107, WO03/031442) etc.; Yet, do not have HER2 kinase inhibition material to go on the market at present as novel remedies for cancer.
As pyrrolo-[3,2-d] pyrimidine derivatives, known following compounds as the compound with cell growth inhibiting activity (
Khim.-Farm.Zh., 1982,16,1338-1343; Collect.Czech.Chem.Commun., 2003,68,779-791).
As having the active compound of receptor type tyrosine kinase, following pyrrolo-[3,2-d] pyrimidine derivatives be known (WO96/40142, WO98/23613).
In addition, for pyrazolo [4,3-d] pyrimidine derivatives, 3,5, the trisubstituted pyrazolo of 7-[4,3-d] pyrimidine derivatives is the compound (EP-A-1348707) of the known CDK of having restraining effect, cell growth inhibition and/or apoptosis-inducing effect, and the 3-sec.-propyl also [4,3-d] pyrimidine derivatives is known be have the CDK1/ cell periodic protein B suppress active compound (
Bioorganic﹠amp; Medicinal Chemistry Letters, 2003,13,2989-2992).In addition, the 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 very gratifying as medicament production.
The inventor has carried out deep research, and finds that the compound of following formula (I) representative and salt (being called compound (I) in this manual sometimes) thereof have excellent tyrosine kinase inhibitory activity.Further thereby the present invention has been finished in research.
Therefore, the invention provides
The compound or its salt of following formula representative:
Wherein, W is C (R
1) or N,
A is optional substituted aryl or optional substituted heteroaryl,
X
1For-NR
3-Y
1-,-O-,-S-,-SO-,-SO
2-or-CHR
3,
R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl, or R
3On the optional aryl that is bonded to the A representative or carbon atom on the heteroaryl or the heteroatoms with form optional substituted ring texture and
Y
1Be singly-bound or optional substituted C
1-4Alkylidene group or optional substituted-O-(C
1-4Alkylidene group)-,
R
1For hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded, and R
2For hydrogen atom or by carbon atom or the optional substituted group of sulphur atom bonded, or
R
1And R
2, or R
2And R
3Optional in conjunction with forming optional substituted ring texture, condition is except the compound of following formula representative.
The prodrug of the compound that above-mentioned [1] is put down in writing,
The compound that above-mentioned [1] is put down in writing, wherein W is C (R
1),
The compound that above-mentioned [3] are put down in writing, wherein A is by formula-Y
2Further substituted aryl that-B group replaces, also optional, Y in the formula
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted,
The compound that above-mentioned [3] are put down in writing, wherein R
1Be formula-X
2-R
4Group, X in the formula
2For singly-bound ,-NH-or-O-, and R
4Be hydrogen atom, cyano 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, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted,
The compound that above-mentioned [3] are put down in writing, wherein R
2Be hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted,
The compound that above-mentioned [3] are put down in writing, wherein X
1For-NR
3-, R in the formula
3Be hydrogen atom or optional substituted aliphatic alkyl,
The compound that above-mentioned [3] are put down in writing, wherein A is by formula-Y
2Further substituted aryl that-B group replaces, also optional, Y in the formula
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted;
R
1Be formula-X
2-R
4Group, X in the formula
2For singly-bound ,-NH-or-O-, and R
4Be hydrogen atom, cyano 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, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted;
R
2Be hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted; With
X
1For-NR
3-, R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl,
The compound that above-mentioned [1] is put down in writing, wherein W is N,
The compound that above-mentioned [9] are put down in writing, wherein A is by formula-Y
2Further substituted aryl that-B group replaces, also optional, Y in the formula
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted,
The compound that above-mentioned [9] are put down in writing, wherein R
2Be hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted,
The compound that above-mentioned [9] are put down in writing, wherein X
1For-NR
3-, R in the formula
3Be hydrogen atom or optional substituted aliphatic alkyl,
The compound that above-mentioned [9] are put down in writing, wherein X
1For-NR
3-, R in the formula
3Be hydrogen atom or optional substituted aliphatic alkyl;
A is by formula-Y
2Further substituted aryl that-B group replaces, also optional, Y in the formula
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted;
R
2Be hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted,
The compound that above-mentioned [9] are put down in writing, wherein X
1For-NR
3-;
A is by formula-Y
2Further substituted aryl that-B group replaces, also optional, Y in the formula
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted; With
R
2And R
3In conjunction with forming optional substituted ring texture,
The compound or its salt of following formula representative:
R wherein
1aFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2aChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1aAnd R
2a, or R
2aAnd R
3aOptional combination is chosen substituted ring texture wantonly to form,
R
3aBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3aChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
aFor optional substituted phenyl ring and
C
aBe optional substituted C
6-18Aryl,
The compound or its salt of following formula representative:
R wherein
1bFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2bChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1bAnd R
2b, or R
2bAnd R
3bOptional combination is chosen substituted ring texture wantonly to form,
R
3bBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3bChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
bBe optional substituted phenyl ring,
C
bBe optional substituted C
6-18Aryl and
Z
bBe optional substituted C
1-3Alkylidene group,
The compound or its salt of following formula representative:
R wherein
1cFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2cChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1cAnd R
2c, or R
2cAnd R
3cOptional combination is chosen substituted ring texture wantonly to form,
R
3cBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3cChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
cFor optional substituted phenyl ring and
C
cBe optional substituted heterocyclic radical,
The compound or its salt of following formula representative:
R wherein
1dFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2dChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1dAnd R
2d, or R
2dAnd R
3dOptional combination is chosen substituted ring texture wantonly to form,
R
3dBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3dChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
dBe optional substituted phenyl ring,
C
dFor optional substituted heterocyclic radical and
Z
dBe optional substituted C
1-3Alkylidene group,
The compound or its salt of following formula representative:
R wherein
2eChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
2eAnd R
3eOptional combination is chosen substituted ring texture wantonly to form,
R
3eBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3eChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
eFor optional substituted phenyl ring and
C
eBe optional substituted C
6-18Aryl,
The compound or its salt of following formula representative:
R wherein
2fChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
2fAnd R
3fOptional combination is chosen substituted ring texture wantonly to form,
R
3fBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3fChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
fBe optional substituted phenyl ring,
C
fBe optional substituted C
6-18Aryl and
Z
fBe optional substituted C
1-3Alkylidene group,
The compound or its salt of following formula representative:
R wherein
2gChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
2gAnd R
3gOptional combination is chosen substituted ring texture wantonly to form,
R
3gBe hydrogen atom or optional substituted aliphatic alkyl, or
R
3gChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
gFor optional substituted phenyl ring and
C
gBe optional substituted heterocyclic radical,
(i) 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol,
(ii) 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol,
(iii) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxy-3-methyl butyramide,
(iv) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,
(v) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-methyl-2-(methylsulfonyl) propionic acid amide,
(vi) 5-{2-[2-(tertiary butyl alkylsulfonyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine,
(vii) 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } ethanamide,
(viii) N-[2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide, or
(ix) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,
Or any one salt in them,
The method of the compound or its salt of preparation following formula representative:
Wherein each symbol in above-mentioned [1] definition, described method comprises the compound or its salt that makes the following formula representative:
Wherein L is a leavings group, and the institute's definition in above-mentioned [1] of other symbol, reacts with the compound or its salt of following formula representative:
G-X
1-A (III)
Wherein G is hydrogen atom or atoms metal, and other symbol in above-mentioned [1] definition,
Comprise the compound or its salt of following formula representative or the pharmaceutical preparation of its prodrug:
Wherein, W is C (R
1) or N,
A is optional substituted aryl or optional substituted heteroaryl,
X
1For-NR
3-Y
1-,-O-,-S-,-SO-,-SO
2-or-CHR
3-,
R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl, or R
3On the optional aryl that is bonded to the A representative or carbon atom on the heteroaryl or the heteroatoms with form optional substituted ring texture and
Y
1Be singly-bound or optional substituted C
1-4Alkylidene group or optional substituted-O-(C
1-4Alkylidene group)-,
R
1For hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded, and R
2For hydrogen atom or by carbon atom or the optional substituted group of sulphur atom bonded, or
R
1And R
2, or R
2And R
3Optional in conjunction with forming optional substituted ring texture, condition is except the compound of following formula representative,
The pharmaceutical preparation of above-mentioned [24], it is a tyrosine kinase inhibitor,
The pharmaceutical preparation of above-mentioned [24], it is the medicament of prevention or treatment cancer,
The pharmaceutical preparation of above-mentioned [26], wherein said cancer are mammary cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney,
The method of prevention or treatment mammalian cancer, described method comprises compound or its salt or its prodrug of the following formula representative that delivers medicine to described Mammals significant quantity:
Wherein, W is C (R
1) or N,
A is optional substituted aryl or optional substituted heteroaryl,
X
1For-NR
3-Y
1-,-O-,-S-,-SO-,-SO
2-or-CHR
3-,
R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl, or R
3On the optional aryl that is bonded to the A representative or carbon atom on the heteroaryl or the heteroatoms with form optional substituted ring texture and
Y
1Be singly-bound or optional substituted C
1-4Alkylidene group or optional substituted-O-(C
1-4Alkylidene group)-,
R
1For hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded, and R
2For hydrogen atom or by carbon atom or the optional substituted group of sulphur atom bonded, or
R
1And R
2, or R
2And R
3Optional in conjunction with forming optional substituted ring texture, condition is except the compound of following formula representative,
The compound or its salt of following formula representative or its prodrug are used for preventing or treating the purposes of the medicine of cancer etc. in preparation:
Wherein, W is C (R
1) or N,
A is optional substituted aryl or optional substituted heteroaryl,
X
1For-NR
3-Y
1-,-O-,-S-,-SO-,-SO
2-or-CHR
3-,
R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl, or R
3On the optional aryl that is bonded to the A representative or carbon atom on the heteroaryl or the heteroatoms with form optional substituted ring texture and
Y
1Be singly-bound or optional substituted C
1-4Alkylidene group or optional substituted-O-(C
1-4Alkylidene group)-,
R
1For hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded, and R
2For hydrogen atom or by carbon atom or the optional substituted group of sulphur atom bonded, or
R
1And R
2, or R
2And R
3Optional in conjunction with forming optional substituted ring texture, condition is except the compound of following formula representative.
In addition, the invention provides
The compound that above-mentioned [15] are put down in writing, wherein
R
2aFor
(i) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from following (substituting group group T):
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer,
N is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7,-OCONH
2Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-N
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part (subset)-CH
2CH
2-optional quilt-CH=CH-or-C ≡ C-replacement,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl and
R
9Be C
1-4Alkyl, or
(ii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and these two substituting groups are chosen the selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T wantonly with the optional 3-to 8-of formation of adjacent nitrogen-atoms member,
The compound that above-mentioned [15] are put down in writing, wherein
B
aBe selected from halogen, C for optional by 1-4
1-4Alkyl, hydroxyl-C
1-4Alkyl and C
1-4The phenyl ring that substituting group replaced of alkoxyl group;
C
aBe selected from the following phenyl that substituting group replaced for optional by 1-5,
(i) halogen,
(ii) optional halogenated C
1-4Alkyl,
(iii) hydroxyl-C
1-4Alkyl,
(iv) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(v) optional halogenated C
1-4Alkoxyl group,
(vi) C
1-4Alkyl-carbonyl,
(vii) cyano group,
(viii) optional by C
1-8The formamyl that alkyl replaces and
(ix) C
1-4Alkoxyl group-carbonyl;
R
1aFor
(i) hydrogen atom,
(ii) cyano group, or
(iii) C
1-4Alkyl or C
2-4Alkenyl, the wherein optional quilt-NR of each group
8-CO-(CH
2)
n-NR
6R
7Replace,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces; With
R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH，
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH，
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7，
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, (CH
2)
nOptional by halogenated C
1-4Alkyl or hydroxyl replace, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces;
R
3aBe hydrogen atom or C
1-6Alkyl; Or
R
1aAnd R
2aOptional combination is to form
R
2aAnd R
3aOptional in conjunction with choosing the C that is replaced by imino-wantonly to form
2-4Alkylidene group,
Particularly preferably, R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace),
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7(when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces),
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl,
The compound that above-mentioned [15] are put down in writing, wherein
B
aBe selected from halogen and optional halogenated C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
aFor being selected from the following phenyl that substituting group replaced by 1-5:
(i) halogen,
(ii) optional halogenated C
1-4Alkyl,
(iii) hydroxyl-C
1-4Alkyl,
(iv) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(v) optional halogenated C
1-4Alkoxyl group,
(vi) cyano group and
(vii) optional by C
1-8The formamyl that alkyl replaces;
R
1aBe hydrogen atom;
R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH，
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace;
R
3aBe hydrogen atom or C
1-6Alkyl; Or
R
1aAnd R
2aOptional combination is to form
R
2aAnd R
3aOptional combination is to form C
2-4Alkylidene group,
Particularly preferably, R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl),
4 its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
The compound that above-mentioned [31] are put down in writing, wherein
R
2aThe C that is replaced by hydroxyl for (i)
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH，
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH，
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl,
Particularly preferably, R
2aThe C that is replaced by hydroxyl for (i)
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl,
The compound that above-mentioned [16] are put down in writing, wherein
R
2bBe (i) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from following (substituting group group T):
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7,-OCONH
2Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-or-C ≡ C-replacement,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl, or
(ii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
The compound that above-mentioned [16] are put down in writing, wherein
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen, optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl and cyano group;
R
1bBe (i) hydrogen atom, or
The (ii) optional C that is replaced by hydroxyl
2-4Alkenyl;
R
2bFor
(i) optionally be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d)-O-(CH
2)
n-OH，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-CO-NR
8-(CH
2)
n-OH，
(g)-NR
6R
7And
(h)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(ii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) optional C with hydroxyl
1-4Alkyl,
(b) carboxyl,
(c) C
1-4Alkoxyl group-carbonyl,
(d) have 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is chosen wantonly has the hydroxyl of being selected from and C
1-4The substituting group of alkyl and
(e) optional have a substituent C that is selected from hydroxyl and formamyl
1-4Alkyl-formamyl,
(iii) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-carbonyl,
(iv) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-alkylsulfonyl, or
(v) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl;
R
3bBe hydrogen atom or C
1-6Alkyl; Or
R
2bAnd R
3bOptional combination is to form C
2-4Alkylidene group; With
Z
bBe C
1-3Alkylidene group,
The compound that above-mentioned [16] are put down in writing, wherein
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen and optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl;
R
1bBe hydrogen atom;
R
2bBe selected from the following C that substituting group replaced for choosing wantonly
1-8Alkyl:
(a) hydroxyl,
(b)-O-(CH
2)
n-OH，
(c)-O-(CH
2)
n-O-C
1-4Alkyl,
(d)-CO-NR
8-(CH
2)
n-OH，
(e)-NR
6R
7And
(f)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3bBe hydrogen atom or C
1-6Alkyl; With
Z
bBe C
1-3Alkylidene group,
The compound that above-mentioned [36] are put down in writing, wherein
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen and optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl;
R
1bBe hydrogen atom;
R
2bFor being selected from the following C that substituting group replaced
1-8Alkyl:
(a)-O-(CH
2)
n-OH，
(b)-O-(CH
2)
n-O-C
1-4Alkyl and
(c)-CO-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3bBe hydrogen atom or C
1-6Alkyl; With
Z
bBe methylene radical,
The compound that above-mentioned [17] are put down in writing, wherein
R
2cBe (i) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from following (substituting group group T):
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl, or
(ii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
The compound that above-mentioned [17] are put down in writing, wherein
B
cBe selected from halogen and optional halogenated C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
cFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base (for example pyridyl, pyrimidyl, 4-piperidyl) that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional to be selected from following substituting group by 1-5 and to replace:
(i) halogen,
(ii) C
1-4Alkyl,
(iii) C
1-4Alkyl-carbonyl,
(iv) optional halogenated C
1-4Alkoxyl group-carbonyl,
(v) C
3-8Cycloalkyl-carbonyl and
(vi) choose wantonly and be selected from the following formamyl that substituting group replaced:
(a) optional halogenated C
1-8Alkyl,
(b) C
3-8Cycloalkyl and
(c) optional halogen, the C of being selected from
1-4Alkyl and C
1-4The C that substituting group replaced of alkoxyl group
6-18Aryl;
R
1cBe (i) hydrogen atom,
The (ii) optional C that is replaced by hydroxyl
2-4Alkenyl, or
(iii) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
2cFor
(i) optionally be selected from the following C that substituting group replaced
1-4Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d) carboxyl,
(e) C
1-4Alkoxyl group-carbonyl,
(f)-O-(CH
2)
n-OH，
(g)-O-(CH
2)
n-O-C
1-4Alkyl,
(h)-CO-NR
8-(CH
2)
n-OH and
(i)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(ii) optional by optional C with hydroxyl
1-4The C that alkyl replaced
6-18Aryl-C
1-4Alkyl;
R
3cBe hydrogen atom or C
1-6Alkyl; Or
R
2cAnd R
3cOptional combination is to form C
2-4Alkylidene group,
The compound that above-mentioned [17] are put down in writing, wherein
B
cBe selected from halogen and C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
cFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional to be selected from following substituting group by 1-5 and to replace:
(i) C
1-4Alkyl,
(ii) C
1-4Alkyl-carbonyl,
(iii) optional halogenated C
1-4Alkoxyl group-carbonyl,
(iv) C
3-8Cycloalkyl-carbonyl and
(v) choose wantonly and be selected from the following formamyl that substituting group replaced:
(a) optional halogenated C
1-8Alkyl,
(b) C
3-8Cycloalkyl and
(c) the optional C that is replaced by halogen
6-18Aryl;
R
1cBe hydrogen atom;
R
2cBe selected from the following C that substituting group replaced for choosing wantonly
1-4Alkyl:
(a) hydroxyl,
(b) C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-C
1-4Alkyl and
(e)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3cBe hydrogen atom or C
1-6Alkyl,
The compound that above-mentioned [40] are put down in writing, wherein
R
2cBe selected from the following C that substituting group replaced for choosing wantonly
1-4Alkyl:
(a)-O-(CH
2)
n-OH and
(b)-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer,
The compound that above-mentioned [18] are put down in writing, wherein
B
dBe the optional phenyl ring that is replaced by halogen;
C
dFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
1dBe hydrogen atom;
R
2dFor
(i) optionally be selected from the following C that substituting group replaced
1-4Alkyl:
(a) C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH and
(c)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(ii) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl;
R
3dBe hydrogen atom or C
1-6Alkyl; With
Z
dBe C
1-3Alkylidene group,
The compound that above-mentioned [18] are put down in writing, wherein
B
dBe the optional phenyl ring that is replaced by halogen;
C
dFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
1dBe hydrogen atom;
R
2dFor choosing wantonly by C
1-4The C that alkoxyl group replaced
1-4Alkyl;
R
3dBe hydrogen atom or C
1-6Alkyl; With
Z
dBe methylene radical,
The compound that above-mentioned [19] are put down in writing, wherein
R
2eBe (i) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from following (substituting group group T):
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl, or
(ii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
The compound that above-mentioned [19] are put down in writing, wherein
B
eBe the optional phenyl ring that is replaced by halogen;
C
eChosen wantonly halogenated C for optional
1-4The phenyl that alkyl replaced;
R
2eBe optional quilt-O-(CH
2)
nThe C that-OH replaces
1-4Alkyl, wherein n is 1 to 4 integer,
The compound that above-mentioned [19] are put down in writing, wherein
B
eBe the optional phenyl ring that is replaced by halogen;
C
eChosen wantonly halogenated C for optional
1-4The phenyl that alkyl replaced;
R
2eBe quilt-O-(CH
2)
nThe C that-OH replaced
1-4Alkyl, wherein n is 1 to 4 integer,
The compound that above-mentioned [20] are put down in writing, wherein
R
2fBe (i) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from following (substituting group group T):
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
O be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl, or
(ii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
The compound that above-mentioned [20] are put down in writing, wherein
B
fBe the optional phenyl ring that is replaced by halogen;
C
fBe the optional phenyl that is replaced by halogen;
R
2fFor
(i) optionally be selected from the following C that substituting group replaced by 1-5
1-4Alkyl:
(a) hydroxyl,
(b)-O-(CH
2)
n-OH，
(c)-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and
(e)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
(ii) choose wantonly and be selected from the following C that substituting group replaced by 1-5
6-18Aryl:
(a) optionally be selected from the following C that substituting group replaced
1-4Alkyl: hydroxyl ,-NR
8-(CH
2)
n-OH ,-NR
8-(CH
2)
n-O-C
1-4Alkyl ,-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl and
(b)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) choose wantonly and be selected from the following C that substituting group replaced by 1-5
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3fBe hydrogen atom or C
1-6Alkyl; Or
R
2fAnd R
3fOptional combination is to form C
2-4Alkylidene group; With
Z
fBe C
1-3Alkylidene group,
The compound that above-mentioned [20] are put down in writing, wherein
B
fBe the optional phenyl ring that is replaced by halogen;
C
fBe the optional phenyl that is replaced by halogen;
R
2fBe selected from the following C that substituting group replaced for optional by 1-5
1-4Alkyl:
(a) hydroxyl and
(b)-O-(CH
2)
n-OH, wherein n is 1 to 4 integer;
R
3fBe hydrogen atom or C
1-6Alkyl; With
Z
fBe methylene radical,
The compound that above-mentioned [49] are put down in writing, wherein
R
2fBe quilt-O-(CH
2)
nThe C that-OH replaced
1-4Alkyl, wherein n is 1 to 4 integer,
The compound that above-mentioned [21] are put down in writing, wherein
R
2gBe (i) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from following (substituting group group T):
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl, or
(ii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
The compound that above-mentioned [21] are put down in writing, wherein
B
gFor choosing wantonly by C
1-4The phenyl ring that alkyl replaced;
C
gFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional by C
1-4Alkyl replaces;
R
2gFor
(i) optional by C that hydroxyl replaced
1-4Alkyl,
(ii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) nitro,
(b) amino,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(e)-NR
8-CO-(CH
2)
n-NR
6R
7，
(f)-NR
8-CO-(CH
2)
n-COOH，
(g)-NR
8-CO-(CH
2)
n-CO
2-C
1-4Alkyl and
(h)-NR
8-CO-(CH
2)
m-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3gBe hydrogen atom or C
1-6Alkyl; Or
R
2gAnd R
3gOptional combination is to form C
2-4Alkylidene group,
The compound that above-mentioned [21] are put down in writing, wherein R
2gFor
(i) optionally be selected from the following C that substituting group replaced
6-18Aryl:
(a) nitro,
(b) amino,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(e)-NR
8-CO-(CH
2)
n-NR
6R
7，
(f)-NR
8-CO-(CH
2)
n-COOH，
(g)-NR
8-CO-(CH
2)
n-CO
2-C
1-4Alkyl and
(h)-NR
8-CO-(CH
2)
m-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, or
(ii) be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
The compound that above-mentioned [1] is put down in writing, wherein A is for being selected from the following C that substituting group replaced
6-18Aryl:
(i) optionally be selected from the following phenoxy group that substituting group replaced by 1-5:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl,
(ii) choose wantonly and be selected from following phenyl-C that substituting group replaced by 1-5
1-3Alkoxyl group:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl,
(iii) contain 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base (heterocycleoxy) that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional to be selected from following substituting group by 1-5 and to replace:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl and
(iv) contain 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-3Alkoxyl group, it is optional to be selected from following substituting group by 1-5 and to replace:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl;
Wherein said C
6-18Aryl is optional further to be selected from halogen, C by 1-4
1-4Alkyl, hydroxyl-C
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces;
R
1For
(i) hydrogen atom,
(ii) cyano group, or
(iii) C
1-4Alkyl or C
2-4Alkenyl, the wherein optional quilt-NR of each group
8-CO-(CH
2)
n-NR
6R
7Replace,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces;
R
2For
C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH，
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C1-4 alkyl),
(u)-NR
8-CO-(CH
2)
n-OH，
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7，
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, (CH
2)
nOptional by halogenated C
1-4Alkyl or hydroxyl replace, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces;
R
3Be hydrogen atom or C
1-6Alkyl; Perhaps,
R
1And R
2Optional in conjunction with forming
Or
Or
R
2And R
3Optional in conjunction with choosing the C that is replaced by imino-wantonly to form
2-4Alkylidene group.
Particularly preferably, R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace),
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7(when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces),
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
The compound that above-mentioned [1] is put down in writing, wherein
A is for being selected from the following C that substituting group replaced
6-18Aryl:
(i) be selected from the following phenoxy group that substituting group replaced by 1-5:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl,
(ii) be selected from following phenyl-C that substituting group replaced by 1-5
1-3Alkoxyl group:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl,
(iii) contain 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl and
(iv) contain 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-3Alkoxyl group, it is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl;
Wherein said C
6-18Aryl is optional further to be selected from halogen and optional halogenated C by 1-4
1-4The substituting group of alkyl replaces;
R
1Be hydrogen atom;
R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH，
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace);
R
3Be hydrogen atom or C
1-6Alkyl; Perhaps,
R
1And R
2Optional in conjunction with forming
Or
Or
R
2And R
3Optional combination is to form C
2-4Alkylidene group,
Particularly preferably, R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
The compound that above-mentioned [55] are put down in writing, wherein
R
2The C that is replaced by hydroxyl for (i)
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH，
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH，
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl replaces,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl,
Particularly preferably, R
2For
(i) C that is replaced by hydroxyl
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl,
The compound that above-mentioned [1] is put down in writing, it is for being selected from following (A) compound to (H):
(A) compound (I), wherein
W is CR
1
A is phenoxy group-C
6-18Aryl, wherein said phenoxy group be partly optional to be selected from following substituting group by 1-5 and to replace:
(i) halogen,
(ii) optional halogenated C
1-4Alkyl,
(iii) hydroxyl-C
1-4Alkyl,
(iv) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(v) optional halogenated C
1-4Alkoxyl group,
(vi) C
1-4Alkyl-carbonyl,
(vii) cyano group,
(viii) optional by C
1-8The formamyl that alkyl replaces and
(ix) C
1-4Alkoxyl group-carbonyl and
Described C
6-18Aryl moiety is optional further to be selected from halogen, C by 1-4
1-4Alkyl, hydroxyl-C
1-4Alkyl, C
1-4Alkoxyl group, carboxyl and C
1-4The substituting group of alkoxyl group-carbonyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1For
(i) hydrogen atom,
(ii) cyano group, or
(iii) C
1-4Alkyl or C
2-4Alkenyl, the wherein optional quilt-NR of each group
8-CO-(CH
2)
n-NR
6R
7Replace,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces; And
R
2For (i) hydrogen atom or
(ii) C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH，
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH，
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7，
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, (CH
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces; Or
R
1And R
2Optional in conjunction with forming
Or
R
2And R
3' optional in conjunction with choosing the C that is replaced by imino-wantonly to form
2-4Alkylidene group,
Particularly preferably, R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2) n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace),
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7(when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces),
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(B) compound (I), wherein
W is CR
1
A is phenyl-C
1-3Alkoxy-C
6-18Aryl, wherein said phenyl moiety is optional to be selected from halogen, optional halogenated C by 1-5
1-4The substituting group of alkyl and cyano group replace and
Described C
6-18Aryl moiety optional further by
1-4Individual halogen, the optional C of being selected from hydroxyl
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1Be (i) hydrogen atom,
(ii) C
1-4Alkyl or C
2-4Alkenyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) amino,
(c)-NR
8-CO-(CH
2)
n-NR
6R
7And
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2-CH
2Optional quilt-CH=CH-replaces, or
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) amino,
(b) carboxyl and
(c)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iv) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; With
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d)-O-(CH
2)
n-OH，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-CO-NR
8-(CH
2)
n-OH，
(g)-NR
6R
7And
(h)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) optional C with hydroxyl
1-4Alkyl,
(b) carboxyl,
(c) C
1-4Alkoxyl group-carbonyl,
(d) have 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is chosen wantonly has the hydroxyl of being selected from and C
1-4The substituting group of alkyl and
(e) optional have a substituent C that is selected from hydroxyl and formamyl
1-4Alkyl-formamyl,
(iv) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-carbonyl,
(v) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-alkylsulfonyl, or
(vi) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl; Or
R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group,
(C) compound (I), wherein W is CR
1
A contains 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
6-18Aryl, wherein said heterocyclic oxy group be partly optional to be selected from following substituting group by 1-5 and to replace:
(i) halogen,
(ii) C
1-4Alkyl,
(iii) C
1-4Alkyl-carbonyl,
(iv) optional halogenated C
1-4Alkoxyl group-carbonyl,
(v) C
3-8Cycloalkyl-carbonyl and
(vi) choose wantonly and be selected from the following formamyl that substituting group replaced:
(a) optional halogenated C
1-8Alkyl,
(b) C
3-8Cycloalkyl and
(c) optional halogen, the C of being selected from
1-4Alkyl and C
1-4The C that substituting group replaced of alkoxyl group
6-18Aryl and
Described C
6-18Aryl moiety is optional further to be selected from halogen and optional halogenated C by 1-4
1-4The substituting group of alkyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1Be (i) hydrogen atom,
(ii) C
1-4Alkyl or C
2-4Alkenyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) amino,
(c)-NR
8-CO-(CH
2)
n-NR
6R
7And
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) optional be selected from hydroxyl ,-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl and-NR
8-CO-(CH
2)
n-O-C
1-4The C that substituting group replaced of alkyl
1-4Alkyl,
(b) amino,
(c) C
1-4Alkoxyl group,
(d) carboxyl and
(e)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iv) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; With
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced
1-4Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d) carboxyl,
(e) C
1-4Alkoxyl group-carbonyl,
(f)-O-(CH
2)
n-OH，
(g)-O-(CH
2)
n-O-C
1-4Alkyl,
(h)-CO-NR
8-(CH
2)
n-OH and
(i)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) optional by optional C with hydroxyl
1-4The C that alkyl replaced
6-18Aryl-C
1-4Alkyl; Or R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group,
(D) compound (I), wherein
W is CR
1
A contains 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-3Alkoxy-C
6-18Aryl,
Wherein said C
6-18Aryl moiety is optional further to be replaced by halogen;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1For (i) hydrogen atom or
(ii) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; With
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced
1-4Alkyl:
(a) C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH and
(c)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl,
(E) compound (I), wherein
W is N;
A is phenoxy group-C
6-18Aryl, wherein said phenoxy group are partly optional to be selected from optional halogenated C by 1-5
1-4The substituting group of alkyl and cyano group replace and
Described C
6-18Aryl moiety is optional further to be selected from halogen and C by 1-4
1-4The substituting group of alkyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl; With
R
2For (i) hydrogen atom or
(ii) optional quilt-O-(CH
2)
nThe C that-OH replaces
1-4Alkyl, wherein n is 1 to 4 integer,
(F) compound (I), wherein
W is N;
A is phenyl-C
1-3Alkoxy-C
6-18Aryl, wherein said phenyl moiety is optional replaced by 1-5 substituting group that is selected from halogen and cyano group and
Described C
6-18Aryl moiety is optional further to be selected from halogen and C by 1-4
1-4The substituting group of alkyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl; With
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced by 1-5
1-4Alkyl:
(a) hydroxyl,
(b)-O-(CH
2)
n-OH，
(c)-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and
(e)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
(iii) optional by C
1-4The C that alkyl replaced
6-18Aryl, described C
1-4Alkyl is optional be selected from hydroxyl ,-NR
8-(CH
2)
n-OH ,-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and-NR
8-(CH
2)
n-SO
2-C
1-4The substituting group of alkyl replaces, or
(iv) choose wantonly and be selected from the following C that substituting group replaced by 1-5
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl; Or
R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group,
(G) compound (I), wherein
W is N;
A contains 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
6-18Aryl, wherein said heterocyclic oxy group are partly optional by C
1-4Alkyl replaces and described C
6-18Aryl moiety is optional further by C
1-4Alkyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl; With
R
2Be (i) hydrogen atom,
(ii) choose C wantonly by hydroxyl replaced
1-4Alkyl,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) nitro,
(b) amino,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(e)-NR
8-CO-(CH
2)
n-NR
6R
7，
(f)-NR
8-CO-(CH
2)
n-COOH，
(g)-NR
8-CO-(CH
2)
n-CO
2-C
1-4Alkyl and
(h)-NR
8-CO-(CH
2)
m-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iv) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl); Or R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group,
(H) compound (I), wherein
W is CH;
A is selected from the following C that substituting group replaced for choosing wantonly
6-18Aryl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl,
(c) contain 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom (be preferably optional have 1 or 2 heteroatomic 5-to 8-member who is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom encircle amino-carbonyl), it is optional by C
6-18Aryl-C
1-4Alkyl replaces;
(d) optional by C
6-18Aryl-C
1-4The formamyl that alkyl replaced and
(e) optional by C
6-18Aryl-C
1-4The urea groups that alkyl replaced;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl; And R
2Be hydrogen atom,
The compound that above-mentioned [1] is put down in writing, wherein A is (i) C
6-18Aryl or (ii) contain 1-4 heteroatomic 5-to 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), wherein each group is optional is selected from following substituting group by 1-5 and replaces: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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, C
1-4Alkyl sulfonyl-amino and formula-Y
2-B group,
Y wherein
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-,-NH-or-S-,
B is
(A) (i) C
6-18Aryl, (ii) contain 1-4 heteroatomic 5-to 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), saturated or undersaturated aliphatics heterocyclic radical, (iii) C
3-8Cycloalkyl, (iv) formamyl, (v) C
6-18Aryl-carbonyl or (vi) C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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, or
(B) optional have 1 or 2 C
1-8The urea groups of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said urea groups has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
Wherein, described substituting group group T is:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7,-OCONH
2Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-or-C ≡ C-replacement,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form with nitrogen-atoms and optional to be selected from the following saturated or undersaturated aliphatics heterocyclic radical of 3-to the 8-member that substituting group replaced: halogen, optional halogenated C by 1-5
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl C
1-4Alkyl, 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,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl,
R
3Be (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3Forming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional aryl that is bonded to the A representative or carbon atom on the heteroaryl or the heteroatoms
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,
Y
1Be (i) singly-bound, or
(ii) C
1-4Alkylidene group or-O-(C
1-4Alkylidene group)-, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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,
R
1Be (i) hydrogen atom, or
(ii) formula-X
2-R
4The group of representative,
X wherein
2For singly-bound ,-NH-or-O-and
R
4Be (i) hydrogen atom,
(ii) cyano group,
(iii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, 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 (for example contain 1-4 heteroatomic 5-to the 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), saturated or undersaturated aliphatics heterocyclic radical), heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iv) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
R
2Be (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
1And R
2, or R
2And R
3It is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
The compound that above-mentioned [15] are put down in writing, wherein
R
1aBe (i) hydrogen atom, or
(ii) formula-X
2-R
4The group of representative,
X wherein
2For singly-bound ,-NH-or-O-and
R
4Be (i) hydrogen atom,
(ii) cyano group,
(iii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, 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 (for example contain 1-4 heteroatomic 5-to the 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), saturated or undersaturated aliphatics heterocyclic radical), heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iv) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
R
2aBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
1aAnd R
2a, or R
2aAnd R
3aIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3aBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3aForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
aBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 and
C
aBe selected from the following C that substituting group replaced for optional by 1-5
6-18Aryl: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
The compound that above-mentioned [16] are put down in writing, wherein
R
1bBe (i) hydrogen atom, or
(ii) formula-X
2-R
4The group of representative,
X wherein
2For singly-bound ,-NH-or-O-and
R
4Be (i) hydrogen atom,
(ii) cyano group,
(iii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, 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 (for example contain 1-4 heteroatomic 5-to the 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), saturated or undersaturated aliphatics heterocyclic radical), heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iv) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
R
2bBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
1bAnd R
2b, or R
2bAnd R
3bIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3bBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3bForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
bBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
C
bBe selected from the following C that substituting group replaced for optional by 1-5
6-18Aryl: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 and
Z
bBe selected from the following C that substituting group replaced for optional by 1-3
1-3Alkylidene group: 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,
The compound that above-mentioned [17] are put down in writing, wherein
R
1cBe (i) hydrogen atom, or
(ii) formula-X
2-R
4The group of representative,
X wherein
2For singly-bound ,-NH-or-O-and
R
4Be (i) hydrogen atom,
(ii) cyano group,
(iii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, C
3-8Cycloalkyl, C
6-18Aryl, C
6-18Aryl-C
1-4Alkyl, C
6-18Aryl-carbonyl, C
6-18Aryl-C
1-2Alkyl-carbonyl, heterocyclic radical (for example contain 1-4 heteroatomic 5-to the 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), saturated or undersaturated aliphatics heterocyclic radical), heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iv) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
R
2cBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
1cAnd R
2c, or R
2cAnd R
3cIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3cBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3cForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
cBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 and
C
cFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, described heterocyclic radical is optional to be selected from following substituting group by 1-5 and to replace: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
The compound that above-mentioned [18] are put down in writing, wherein
R
1dBe (i) hydrogen atom, or
(ii) formula-X
2-R
4The group of representative,
X wherein
2For singly-bound ,-NH-or-O-and
R
4Be (i) hydrogen atom,
(ii) cyano group,
(iii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, 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 (for example contain 1-4 heteroatomic 5-to the 8-member heteroaryl as the atom (annular atoms) that constitutes ring system, described heteroatoms is selected from Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms), saturated or undersaturated aliphatics heterocyclic radical), heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iv) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms,
R
2dBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
1dAnd R
2d, or R
2dAnd R
3dIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3dBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3dForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
dBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
C
dFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, described heterocyclic radical is optional to be selected from following substituting group by 1-5 and to replace: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 and
Z
dBe selected from the following C that substituting group replaced for optional by 1-3
1-3Alkylidene group: 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,
The compound that above-mentioned [19] are put down in writing, wherein
R
2eBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
2eAnd R
3eIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3eBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3eForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
eBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 and
C
eBe selected from the following C that substituting group replaced for optional by 1-5
6-18Aryl: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
The compound that above-mentioned [20] are put down in writing, wherein
R
2fBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
2fAnd R
3fIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3fBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3fForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, described heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
fBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
C
fBe selected from the following C that substituting group replaced for optional by 1-5
6-18Aryl: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 and
Z
fBe selected from the following C that substituting group replaced for optional by 1-3
1-3Alkylidene group: 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,
The compound that above-mentioned [21] are put down in writing, wherein
R
2gBe (i) hydrogen atom,
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
1-8Alkyl-carbonyl, C
1-8Alkyl sulphonyl, C
3-8Cycloalkyl, C
6-18Aryl, C
6-18Aryl-C
1-4Alkyl, C
6-18Aryl-carbonyl, C
6-18 aryl-C
1-4Alkyl-carbonyl, C
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is replaced by 1-5 substituting group that is selected from substituting group group T, or
(iii) choose wantonly and have 1 or 2 C
1-8The formamyl of alkyl, described C
1-8The optional selected substituting group from substituting group group T of alkyl replaces,
Wherein said formamyl has two substituting groups, and they are with the optional optional selected saturated or undersaturated aliphatics heterocyclic radical that substituting group replaced from substituting group group T of 3-to 8-member that forms of adjacent nitrogen-atoms, or
R
2gAnd R
3gIt is optional in conjunction with optional by 1-5 saturated or undersaturated 4-to the 8-element heterocycle that substituting group replaced that is selected from substituting group group T to form,
R
3gBe (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl or C
3-8Cycloalkyl, wherein each group is optional is selected from following substituting group by 1-3 and replaces: 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, or
R
3gForming saturated or undersaturated 4-to 8-member nitrogen heterocyclic ring, this heterocycle is optional to be selected from following substituting group by 1-3 and to replace: halogen, hydroxyl, C on the optional carbon atom that is bonded to contiguous phenyl
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,
B
gBe selected from the following phenyl ring that substituting group replaced for optional by 1-5: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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,
C
gFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, described heterocyclic radical is optional to be selected from following substituting group by 1-5 and to replace: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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 etc.
According to the present invention, can provide to have remarkable Tyrosylprotein kinase and suppress active condensed pyramidine compounds, its low toxicity also can be satisfactorily as medicine, its preparation method with and uses thereof.
In this manual, unless specialize, " aryl " in " aromatic yl group " and the substituting group comprises monocyclic aryl and condensed polyaromatic.As " aryl ", for example C that can mention
6-18Aryl.As " C
6-18Aryl ", for example phenyl, xenyl, naphthyl, anthryl, phenanthryl and the acenaphthenyl (acenaphthylenyl) that can mention.
In this manual, as " heterocyclic radical " (with " heterocycle-" in the substituting group), saturated or the undersaturated aliphatics heterocyclic radical of for example 5-to 8-member heteroaryl that can mention, it contains as the atom (annular atoms) that constitutes ring system one or more (preferred 1-4, more preferably 1 or 2) heteroatoms, described heteroatoms is selected from (preferably, Sauerstoffatom, sulphur atom and nitrogen-atoms etc.) such as Sauerstoffatom, the sulphur atom of choosing oxidation wantonly and nitrogen-atoms.
In this manual, unless specialize, as " aliphatic alkyl ", the aliphatic alkyl that can mention for straight or branched with 1-15 carbon atom (preferably, 1-8 carbon atom).For this " aliphatic alkyl ", for example C that can mention
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, C
3-8Cycloalkyl etc.
In this manual, unless specialize, as " heteroaryl ", that can mention is aromatic series monocyclic heterocycles base (for example 5-or 6-person aromatic series monocyclic heterocycles base such as furyl, thienyl, pyrryl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, the furazan base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl etc.) and aromatic series annelated heterocycles base (for example 8 to 12-person's aromatic series annelated heterocycles base such as benzofuryl, isobenzofuran-base, benzothienyl oxazolyl, pseudoindoyl, the 1H-indazolyl, benzo indazolyl benzoxazolyl, 1,2-benzoisoxazole base, benzothiazolyl, benzopyranyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, the β-Ka Lin base, the gamma-carbolines base, acridyl phenoxazinyl, phenothiazinyl, phenazinyl Fei Evil thiophene base (phenoxathiinyl), thianthrenyl, phenanthridinyl, the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl etc.) etc.As aromatic series annelated heterocycles base, two the identical or different heterocyclic fused heterocycles in preferred above-mentioned 5-or 6-person's aromatic series monocyclic heterocycles base and phenyl ring condensed heterocycle and above-mentioned 5-or the 6-person's aromatic series monocyclic heterocycles base.
In this manual, unless specialize, as " aliphatics heterocyclic radical ", the for example 3-to 8-that can mention member (preferred 5-or 6-member) saturated or undersaturated (preferred saturated) aliphatics heterocyclic radical, as Oxyranyle, azetidinyl, oxetanyl, Thietane base, cough up alkyl, tetrahydrofuran base, tetrahydro-thienyl (thiolanyl), piperidyl, THP trtrahydropyranyl, morpholinyl, parathiazan base, piperazinyl, dihydro-1,2,4-oxadiazole base etc.
In this manual, unless specialize, as " C
1-8Alkyl ", for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl and the n-octyl etc. that can mention wherein are preferably C
1-6Alkyl.In addition, in this manual, unless specialize, as " C
1-4Alkyl ", for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl and the isobutyl-that can mention.
In this manual, unless specialize, as " C
2-8Alkenyl ", for example vinyl that can mention, (1-or 2-) propenyl, (1-, 2-or 3-) butenyl, pentenyl, octenyl and (1,3-) butadienyl wherein is preferably C
2-4Alkenyl.
In this manual, unless specialize, as " C
2-8Alkynyl ", for example ethynyl that can mention, (1-or 2-) proyl, (1-, 2-or 3-) butynyl, pentynyl and octyne base wherein are preferably C
2-4Alkynyl.
In this manual, unless specialize, as " C
3-8Cycloalkyl ", for example cyclopropyl that can mention, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group wherein are preferably C
3-6Cycloalkyl.
In this manual, unless specialize, as " C
1-4Alkylidene group ", for example methylene radical, ethylidene, trimethylene, tetramethylene and the propylidene etc. that can mention.
In this manual, unless specialize, as " O-(C
1-4Alkylidene group)-", can mention for example-OCH
2-,-OCH
2CH
2-,-O (CH
2)
3-,-O (CH
2)
4-,-OCH (CH
3)-,-OC (CH
3)
2-,-OCH (CH
3) CH
2-,-OCH
2CH (CH
3)-,-OC (CH
3)
2CH
2-and-OCH
2C (CH
3)
2-etc.
In this manual, unless specialize, as " C
6-18Aryl-carbonyl ", for example benzoyl that can mention, naphthoyl, anthryl carbonyl, phenanthryl carbonyl and acenaphthenyl carbonyl etc.
In this manual, unless specialize, as " C
6-18Aryl-C
1-4Alkyl-carbonyl ", for example benzyloxycarbonyl group that can mention, 3-phenyl propionyl, 2-phenyl propionyl, 4-phenyl butyryl radicals and 5-phenyl pentanoyl etc.
In this manual, unless specialize, as " halogen ", what can mention is fluorine, chlorine, bromine and iodine.
As " containing 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom ", that can mention preferred is " optional have 1 or 2 heteroatomic 5-to 8-member who is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom encircle amino-carbonyl ", for example tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, piperazine-1-base carbonyl, morpholine-4-base carbonyl, parathiazan-4-base carbonyl etc.
In above-mentioned formula, " aryl " as among the A is preferably C
6-18Aryl, and phenyl more preferably.
Described " aryl " is optional by formula-Y
2-B group replaces, wherein Y
2For singly-bound ,-O-,-O-(C
1-3Alkylidene group)-(be preferably-OCH
2-) ,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted.
As Y
2, be preferably singly-bound ,-O-or-OCH
2-, and more preferably-O-or-OCH
2-.
" aryl " as among the B is preferably C
6-18Aryl, and phenyl more preferably.
As " heterocyclic radical " among the B, be preferably above-mentioned " 5 or 6-person's aromatic series monocyclic heterocycles base ", and pyridyl more preferably.
" aryl " among the B, " heterocyclic radical ", " C
6-18Aryl-carbonyl " or " C
6-18Aryl-C
1-4Alkyl-carbonyl " for example can have 1-5 in any commutable position and identical or different be selected from following substituting group: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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.
" aryl " among the A can have the above-mentioned formula-Y of removing in any commutable position
21 to 5 identical or different substituting group the outside-B group.As this substituting group, can mention for to the similar substituting group of those substituting groups of example shown in " aryl " or " heterocyclic radical " of B.
As R
3In " aliphatic alkyl ", be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl and C
3-8Cycloalkyl.
R
3In " aliphatic alkyl " optional be selected from following substituting group by 1-3 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.
Y
1In " C
1-4Alkylidene group " and " O-(C
1-4Alkylidene group)-" optional be selected from following substituting group by 1-3 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.
As X
1, be preferably-NR
3-, R wherein
3As defined above.
As R
1In " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ", that can mention is formula-X
2-R
4Group, X wherein
2For singly-bound ,-NH-or-O-, and R
4Be hydrogen atom, cyano 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, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted.
" C
1-8Alkyl ", " C
2-8Alkenyl ", " C
2-8Alkynyl ", " 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 ", " heterocycle-C
1-4Alkyl ", " heterocycle-carbonyl " and " heterocycle-C
1-4Alkyl-carbonyl " for example optionally be selected from following substituting group by one or more (preferred 1-5, more preferably 1-3) and replace:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl (hereinafter often being called substituting group group T).
In these formulas, m is 0 to 4 integer, and n is 1 to 4 integer, Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7, Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-, and Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8In these formulas, (CH
2)
m(CH
2)
nChoose wantonly by one or more (preferred 1-5, more preferably 1-3) and be selected from for example halogen, optional halogenated C
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-or-C ≡ C-replacement.
In these formulas, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form ring with nitrogen-atoms.In addition, in these formulas, R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.Work as R
6And R
7When forming ring with nitrogen-atoms, as nitrogen heterocycle, for example 3 to 8-members that can mention (preferred 5 or 6-member) saturated or undersaturated (preferred saturated) aliphatics heterocyclic radical is as azetidinyl, pyrrolidyl, piperidyl, homopiperidinyl, suberane imino-, morpholinyl, parathiazan base, piperazinyl, high piperazinyl etc.
As X
2, be preferably singly-bound.
As R
4, be preferably hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
6-18Aryl or heterocyclic radical, wherein each group is optional is substituted.As R
4In " C
6-18Aryl ", be preferably phenyl.As R
4In " heterocyclic radical ", be preferably above-mentioned " 5 or 6-person's aromatic series monocyclic heterocycles base ", and be preferably furyl.
As R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ", that can mention is C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted.
" C
1-8Alkyl ", " C
2-8Alkenyl ", " C
2-8Alkynyl ", " C
1-8Alkyl-carbonyl ", " 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
6-18Aryl-alkylsulfonyl ", " heterocyclic radical ", " heterocycle-C
1-4Alkyl ", " heterocycle-carbonyl " and " heterocycle-C
1-4Alkyl-carbonyl " the optional substituting group that is selected from above-mentioned substituting group group T by for example one or more (preferred 1-5, more preferably 1-3) replaces.
As R
2, be preferably hydrogen atom or C
1-8Alkyl, C
6-18Aryl, C
6-18Aryl-C
1-4Alkyl, C
6-18Aryl-carbonyl, C
6-18Aryl-alkylsulfonyl or heterocycle-C
1-4Alkyl, wherein each group is optional is substituted.
As R
2In " C
6-18Aryl ", be preferably phenyl.As R
2In " C
6-18Aryl-C
1-4Alkyl ", be preferably benzyl.As R
2In " C
6-18Aryl-carbonyl ", be preferably benzoyl.As R
2In " C
6-18Aryl-alkylsulfonyl ", be preferably phenyl sulfonyl.As R
2In " heterocycle-C
1-4Alkyl ", " heterocycle-carbonyl " and " heterocycle-C
1-4Alkyl-carbonyl " in " heterocyclic radical " or " heterocycle-", be preferably above-mentioned " 5 or 6-person's aromatic series monocyclic heterocycles base " or above-mentioned " aliphatics heterocyclic radical ", and be preferably furyl or tetrahydrofuran base.
At R
2In the substituting group that the group of representative can have, work as R
6And R
7Form when ring with nitrogen-atoms, should " ring " optional further have 1-5 (preferred 1-3 is individual) identical or different substituting group.As this substituting group, can mention for to the similar substituting group of those substituting groups of example shown in " aryl " or " heterocyclic radical " of B.
The optional C of above-mentioned " formamyl " and " urea groups " with 1 or 2 optional replacement
1-8Alkyl.Perhaps, should " formamyl " and " urea groups " can have two substituting groups, and they can form optional substituted ring with adjacent nitrogen-atoms.As " ring " in this " optional substituted ring ", can mention for being similar to by R
6And R
7Those rings of institute's example above nitrogen-atoms is formed.As " the optional C that replaces
1-8Alkyl " in " substituting group " and as " substituting group " in " optional substituted ring ", that can mention is similar to substituting group among the above-mentioned substituting group group T for those.
As " the optional formamyl that replaces ", that can mention is formamyl, C
1-8Alkyl-carbamoyl, two (C
1-8Alkyl) formamyl, C
6-18Aryl-C
1-4Alkyl-carbamoyl, azetidine-1-base carbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, piperazine-1-base carbonyl, morpholine-4-base carbonyl, parathiazan-4-base carbonyl, (C
1-4Alkyl) piperidines-1-base carbonyl, (C
6-18Aryl-C
1-4Alkyl) piperidines-1-base carbonyl etc.
As " the optional urea groups that replaces ", that can mention is urea groups, 3-(C
1-8Alkyl) urea groups, 3,3-two (C
1-8Alkyl) urea groups, 3-(C
6-18Aryl-C
1-4Alkyl) urea groups, azetidine-1-base carbonylamino, tetramethyleneimine-1-base carbonylamino, piperidines-1-base carbonylamino, piperazine-1-base carbonylamino, morpholine-4-base carbonylamino, parathiazan-4-base carbonylamino, (C
1-4Alkyl) piperidines-1-base carbonylamino, (C
6-18Aryl-C
1-4Alkyl) piperidines-1-base carbonylamino etc.
As by R
3Be bonded to " ring texture " in the ring texture of formed optional replacement on the aryl of A representative or carbon atom on the heteroaryl or the heteroatoms, that can mention is saturated or undersaturated (preferred saturated) 4-to 8-member (preferred 5-or 6-member) nitrogen heterocyclic ring.Particularly
Should " ring texture " can have 1-5 (preferred 1-3, more preferably 1 or 2) identical or different substituting group in any commutable position.As this substituting group, can mention for to the similar substituting group of those substituting groups of example shown in " aryl " or " heterocyclic radical " of B.
As by R
1And R
2" ring texture " in the ring texture of formed optional replacement of being bonded to each other, that can mention is saturated or undersaturated (preferred saturated) 4-to 8-member (preferred 5-or 6-member) heterocycle.Work as R
1And R
2In conjunction with when forming optional substituted ring texture, can for example mention
Wherein each symbol as defined above, etc.
As by R
2And R
3" ring texture " in the ring texture of formed optional replacement of being bonded to each other, that can mention is saturated or undersaturated (preferred saturated) 4-to 8-member (preferred 5-to 7-member) heterocycle.Work as R
2And R
3In conjunction with when forming optional substituted ring texture, can for example mention
Wherein each symbol as defined above, etc.By R
1And R
2, or R
2And R
3Be bonded to each other formed " ring texture " can have the identical or different substituting group that is selected from above-mentioned substituting group group T of 1-5 (preferred 1-3, more preferably 1 or 2) in any commutable position.
When W is C (R
1) time, compound (I) is by following formula (IA) representative:
Wherein each symbol as defined above.
When W was N, compound (I) was by following formula (IB) or (IC) representative:
Wherein each symbol as defined above.
Especially, as compound (I), preferably use following compounds (Ia)-(Ij) etc.
[compound (Ia)]
The compound of following formula representative, or its salt:
R wherein
1aFor hydrogen atom or by carbon atom, nitrogen-atoms or the optional substituted group of Sauerstoffatom bonded and
R
2aChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1aAnd R
2a, or R
2aAnd R
3aOptional combination is chosen substituted ring texture wantonly to form,
R
3aBe hydrogen atom or optional substituted aliphatic alkyl, or R
3aChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
aBe optional substituted phenyl ring, and C
aBe optional substituted C
6-18Aryl.
As R
1aIn " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ", can use those to be similar to R
1In " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ".
As R
2aIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
1aAnd R
2a, or R
2aAnd R
3aBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
1And R
2, or R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3aIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As R
3aIn pass through be bonded to formed on the carbon atom of contiguous phenyl " the optional ring texture that replaces ", can use those to be similar to R
3In pass through to be bonded to formed on the carbon atom of contiguous phenyl " the optional ring texture that replaces ".
As B
aIn the substituting group of " optional replace phenyl ring ", for example can use 1-5 identical or different to be selected from following substituting group: halogen, optional halogenated C
1-4Alkyl, hydroxyl, optional halogenated C
1-4Alkoxyl group, C
1-4Alkoxy methyl, hydroxyl-C
1-4Alkyl, 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.
As C
a" the optional C that replaces
6-18Aryl " in " C
6-18Aryl ", can use for example phenyl, xenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl etc., wherein be preferably phenyl.
As C
a" the optional C that replaces
6-18Aryl " in " substituting group " can use and be similar to B
a" optional replace phenyl ring " in those substituting groups.
As R
2a, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7,-OCONH
2Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-or-C ≡ C-replacement,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (Ia), preferred following compounds, wherein
B
aBe selected from halogen, C for optional by 1-4
1-4Alkyl, hydroxyl-C
1-4Alkyl and C
1-4The phenyl ring that substituting group replaced of alkoxyl group;
C
aBe selected from the following phenyl that substituting group replaced for optional by 1-5: (i) halogen, (ii) optional halogenated C
1-4Alkyl, (iii) hydroxyl-C
1-4Alkyl, (iv) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.), (v) optional halogenated C
1-4Alkoxyl group, (vi) C
1-4Alkyl-carbonyl, (vii) cyano group is (viii) optional by C
1-8Formamyl that alkyl replaces and (ix) C
1-4Alkoxyl group-carbonyl;
R
1aFor
(i) hydrogen atom,
(ii) cyano group, or
(iii) C
1-4Alkyl or C
2-4Alkenyl, the wherein optional quilt-NR of each group
8-CO-(CH
2)
n-NR
6R
7Replace,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces;
R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH，
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH，
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7，
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, (CH
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces; With
R
3aBe hydrogen atom or C
1-6Alkyl; Or
R
1aAnd R
2aOptional combination is to form
R
2aAnd R
3aOptional in conjunction with choosing the C that is replaced by imino-wantonly to form
2-4Alkylidene group.
As R
8, be preferably hydrogen atom, methyl, ethyl etc., and be preferably hydrogen atom especially.
As R
2a, be preferably C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(f0-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace),
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7(when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces),
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl.
As R
8, be preferably hydrogen atom, methyl, ethyl etc., and be preferably hydrogen atom especially.
In addition, as compound (Ia), preferred following compounds, wherein
B
aBe selected from halogen and optional halogenated C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
aFor being selected from the following phenyl that substituting group replaced: (i) halogen, (ii) optional halogenated C by 1-5
1-4Alkyl, (iii) hydroxyl-C
1-4Alkyl, (iv) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.), (v) optional halogenated C
1-4Alkoxyl group, (vi) cyano group and (vii) optional by C
1-8The formamyl that alkyl replaces;
R
1aBe hydrogen atom;
R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH，
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace;
R
3aBe hydrogen atom or C
1-6Alkyl; Or
R
1aAnd R
2aOptional combination is to form
R
2aAnd R
3aOptional combination is to form C
2-4Alkylidene group.
Wherein, as R
2a, be preferably C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl.
As R
2a, be preferably
(i) C that is replaced by hydroxyl
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH，
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH，
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl,
And, as R
2a, be preferably especially
(i) C that is replaced by hydroxyl
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl, and as R
8, be preferably hydrogen atom, methyl, ethyl etc., and be preferably hydrogen atom especially.
[compound (Ib)]
The compound of following formula representative, or its salt:
R wherein
1bFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2bChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1bAnd R
2b, or R
2bAnd R
3bOptional combination is chosen substituted ring texture wantonly to form,
R
3bBe hydrogen atom or optional substituted aliphatic alkyl, or R
3bChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
bBe optional substituted phenyl ring, C
bBe optional substituted C
6-18Aryl and
Z
bBe optional substituted C
1-3Alkylidene group.
As R
1bIn " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ", can use those to be similar to R
1In " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ".
As R
2bIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
1bAnd R
2b, or R
2bAnd R
3bBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
1And R
2, or R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3bIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As by R
3bWith the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ", can use those to be similar to by R
3With the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ".
As B
bIn " optional replace phenyl ring ", can use those to be similar to B
aIn " optional replace phenyl ring ".
As C
bIn " the optional C that replaces
6-18Aryl ", can use those to be similar to C
aIn " the optional C that replaces
6-18Aryl ".
As Z
b" the optional C that replaces
1-3Alkylidene group " in " C
1-3Alkylidene group ", can use methylene radical, ethylidene, trimethylene and propylidene.
As Z
b" the optional C that replaces
1-3Alkylidene group " in " substituting group ", can use 1-3 to be selected from following substituting group: 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.
As R
2b, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7,-OCONH
2Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-or-C ≡ C-replacement,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (Ib), preferred following compounds, wherein
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen, optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl and cyano group;
R
1bBe (i) hydrogen atom, or
The (ii) optional C that is replaced by hydroxyl
2-4Alkenyl;
R
2bFor
(i) optionally be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d)-O-(CH
2)
n-OH，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-CO-NR
8-(CH
2)
n-OH，
(g)-NR
6R
7And
(h)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(ii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) optional C with hydroxyl
1-4Alkyl,
(b) carboxyl,
(c) C
1-4Alkoxyl group-carbonyl,
(d) have 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is chosen wantonly has the hydroxyl of being selected from and C
1-4The substituting group of alkyl and
(e) optional have a substituent C that is selected from hydroxyl and formamyl
1-4Alkyl-formamyl,
(iii) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-carbonyl,
(iv) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-alkylsulfonyl, or
(v) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl;
R
3bBe hydrogen atom or C
1-6Alkyl; Or
R
2bAnd R
3bOptional combination is to form C
2-4Alkylidene group; With
Z
bBe C
1-3Alkylidene group.
In addition, as compound (Ib), preferred following compounds, wherein
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen and optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl;
R
1bBe hydrogen atom;
R
2bBe selected from the following C that substituting group replaced for choosing wantonly
1-8Alkyl:
(a) hydroxyl,
(b)-O-(CH
2)
n-OH，
(c)-O-(CH
2)
n-O-C
1-4Alkyl,
(d)-CO-NR
8-(CH
2)
n-OH，
(e)-NR
6R
7And
(f)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3bBe hydrogen atom or C
1-6Alkyl; With
Z
bBe C
1-3Alkylidene group.
Especially, as compound (Ib), preferred following compounds, wherein
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen and optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl;
R
1bBe hydrogen atom;
R
2bFor being selected from the following C that substituting group replaced
1-8Alkyl:
(a)-O-(CH
2)
n-OH，
(b)-O-(CH
2)
n-O-C
1-4Alkyl and
(c)-CO-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3bBe hydrogen atom or C
1-6Alkyl; With
Z
bBe methylene radical.
As R
8, be preferably hydrogen atom, methyl, ethyl etc., and preferred especially hydrogen atom.
[compound (Ic)]
The compound of following formula representative, or its salt:
R wherein
1cFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2cChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1cAnd R
2c, or R
2cAnd R
3cOptional combination is chosen substituted ring texture wantonly to form,
R
3cBe hydrogen atom or optional substituted aliphatic alkyl, or R
3cChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
cBe optional substituted phenyl ring, and C
cBe optional substituted heterocyclic radical.
As R
1cIn " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ", can use those to be similar to R
1In " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ".
As R
2cIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
1cAnd R
2c, or R
2cAnd R
3cBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
1And R
2, or R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3cIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As by R
3cWith the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ", can use those to be similar to by R
3With the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ".
As B
cIn " optional replace phenyl ring ", can use those to be similar to B
aIn " optional replace phenyl ring ".
As C
c" optional substituted heterocyclic radical " in " heterocyclic radical ", can use above-mentioned " heterocyclic radical ", and can especially preferably use and have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation.Especially, can use 5 or 6-person's aromatic series monocyclic heterocycles base such as furyl, thienyl, pyrryl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, the furazan base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl etc., 3-to 8-member (preferred 5-or 6-member) saturated or undersaturated (preferred saturated) aliphatics heterocyclic radical such as Oxyranyle, azetidinyl, oxetanyl, the Thietane base, pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, THP trtrahydropyranyl, morpholinyl, the parathiazan base, piperazinyl, dihydro-1,2,4-oxadiazole base etc., and be preferably pyridyl especially, pyrimidyl, piperidyl (particularly 4-piperidyl) etc.
As C
c" optional substituted heterocyclic radical " in " substituting group ", can use those to be similar to C
a" the optional C that replaces
6-18Aryl " in " substituting group ".
As R
2c, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (Ic), be preferably following compounds, wherein
B
cBe selected from halogen and optional halogenated C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
cFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base (for example pyridyl, pyrimidyl, 4-piperidyl) that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional to be selected from following substituting group by 1-5 and to replace:
(i) halogen,
(ii) C
1-4Alkyl,
(iii) C
1-4Alkyl-carbonyl,
(iv) optional halogenated C
1-4Alkoxyl group-carbonyl,
(v) C
3-8Cycloalkyl-carbonyl and
(vi) choose wantonly and be selected from the following formamyl that substituting group replaced:
(a) optional halogenated C
1-8Alkyl,
(b) C
3-8Cycloalkyl and
(c) optional halogen, the C of being selected from
1-4Alkyl and C
1-4The C that substituting group replaced of alkoxyl group
6-18Aryl;
R
1cBe (i) Sauerstoffatom,
The (ii) optional C that is replaced by hydroxyl
2-4Alkenyl, or
(iii) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
2cFor
(i) optionally be selected from the following C that substituting group replaced
1-4Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d) carboxyl,
(e) C
1-4Alkoxyl group-carbonyl,
(f)-O-(CH
2)
n-OH，
(g)-O-(CH
2)
n-O-C
1-4Alkyl,
(h)-CO-NR
8-(CH
2)
n-OH and
(i)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(ii) optional by optional C with hydroxyl
1-4The C that alkyl replaced
6-18Aryl-C
1-4Alkyl; With
R
3cBe hydrogen atom or C
1-6Alkyl; Or
R
2cAnd R
3cOptional combination is to form C
2-4Alkylidene group.
In addition, as compound (Ic), preferred following compound, wherein
B
cBe selected from halogen and C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
cFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional to be selected from following substituting group by 1-5 and to replace:
(i) C
1-4Alkyl,
(ii) C
1-4Alkyl-carbonyl,
(iii) optional halogenated C
1-4Alkoxyl group-carbonyl,
(iv) C
3-8Cycloalkyl-carbonyl and
(v) choose wantonly and be selected from the following formamyl that substituting group replaced:
(a) optional halogenated C
1-8Alkyl,
(b) C
3-8Cycloalkyl and
(c) the optional C that is replaced by halogen
6-18Aryl;
R
1cBe hydrogen atom;
R
2cBe selected from the following C that substituting group replaced for choosing wantonly
1-4Alkyl:
(a) hydroxyl,
(b) C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-C
1-4Alkyl and
(e)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl; With
R
3cBe hydrogen atom or C
1-6Alkyl.Especially, preferred following compound, wherein R
2cBe selected from the following C that substituting group replaced for choosing wantonly
1-4Alkyl:
(a)-O-(CH
2)
n-OH and
(b)-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer.
[compound (Id)]
The compound of following formula representative, or its salt:
Wherein, R
1dFor hydrogen atom or by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded,
R
2dChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
1dAnd R
2d, or R
2dAnd R
3dOptional combination is chosen substituted ring texture wantonly to form,
R
3dBe hydrogen atom or optional substituted aliphatic alkyl, or R
3dChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
dBe optional substituted phenyl ring, C
dFor optional substituted heterocyclic radical and
Z
dBe optional substituted C
1-3Alkylidene group.
As R
1dIn " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ", can use those to be similar to R
1In " by the optional substituted group of carbon atom, nitrogen-atoms or Sauerstoffatom bonded ".
As R
2dIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
1dAnd R
2d, or R
2dAnd R
3dBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
1And R
2, or R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3dIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As by R
3dWith the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ", can use those to be similar to by R
3With the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ".
As B
dIn " optional replace phenyl ring ", can use those to be similar to B
aIn " optional replace phenyl ring ".
As C
dIn " optional substituted heterocyclic radical ", can use those to be similar to C
cIn " optional substituted heterocyclic radical ".
As Z
dIn " the optional C that replaces
1-3Alkylidene group ", can use those to be similar to Z
bIn " the optional C that replaces
1-3Alkylidene group ".
As R
2d, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (Id), preferred following compound, wherein
B
dBe the optional phenyl ring that is replaced by halogen;
C
dFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
1dBe hydrogen atom;
R
2dFor
(i) optionally be selected from the following C that substituting group replaced
1-4Alkyl:
(a) C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH and
(c)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(ii) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl;
R
3dBe hydrogen atom or C
1-6Alkyl; With
Z
dBe C
1-3Alkylidene group.
In addition, as compound (Id), preferred following compound, wherein
B
dBe the optional phenyl ring that is replaced by halogen;
C
dFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
1dBe hydrogen atom,
R
2dFor choosing wantonly by C
1-4The C that alkoxyl group replaced
1-4Alkyl,
R
3dBe hydrogen atom or C
1-6Alkyl; With
Z
dBe methylene radical.
[compound (Ie)]
The compound of following formula representative, or its salt:
R wherein
2eChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
2eAnd R
3eOptional combination is chosen substituted ring texture wantonly to form,
R
3eBe hydrogen atom or optional substituted aliphatic alkyl, or R
3eChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
eBe optional substituted phenyl ring, and C
eBe optional substituted C
6-18Aryl.
As R
2eIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
2eAnd R
3eBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3eIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As by R
3eWith the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ", can use those to be similar to by R
3With the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ".
As B
eIn " optional replace phenyl ring ", can use those to be similar to B
aIn " optional replace phenyl ring ".
As C
eIn " the optional C that replaces
6-18Aryl ", can use those to be similar to C
aIn " the optional C that replaces
6-18Aryl ".
As R
2e, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-optional halogenated C
1-4Alkyl,
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional replaced by-CH=CH-,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (Ie), preferred following compound, wherein
B
eBe the optional phenyl ring that is replaced by halogen;
C
eChosen wantonly halogenated C for optional
1-4The phenyl that alkyl replaced; With
R
2eBe optional quilt-O-(CH
2)
nThe C that-OH replaces
1-4Alkyl, wherein n is 1 to 4 integer.
In addition, as compound (Ie), preferred following compound, wherein
B
eBe the optional phenyl ring that is replaced by halogen;
C
eChosen wantonly halogenated C for optional
1-4The phenyl that alkyl replaced; With
R
2eBe quilt-O-(CH
2)
nThe C that-OH replaced
1-4Alkyl, wherein n is 1 to 4 integer.
[compound (If)]
The compound of following formula representative, or its salt:
R wherein
2fChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
2fAnd R
3fOptional combination is chosen substituted ring texture wantonly to form,
R
3fBe hydrogen atom or optional substituted aliphatic alkyl, or R
3fChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
fBe optional substituted phenyl ring, C
fBe optional substituted C
6-18Aryl and
Z
fBe optional substituted C
1-3Alkylidene group.
As R
2fIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
2fAnd R
3fBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3fIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As by R
3fWith the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ", can use those to be similar to by R
3With the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ".
As B
fIn " optional replace phenyl ring ", can use those to be similar to B
aIn " optional replace phenyl ring ".
As C
fIn " the optional C that replaces
6-18Aryl ", can use those to be similar to C
aIn " the optional C that replaces
6-18Aryl ".
As Z
fIn " the optional C that replaces
1-3Alkylidene group ", can use those to be similar to Z
bIn " the optional C that replaces
1-3Alkylidene group ".
As R
2f, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-optional halogenated C
1-4Alkyl,
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional replaced by-CH=CH-,
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (If), be preferably following compounds, wherein
B
fBe the optional phenyl ring that is replaced by halogen;
C
fBe the optional phenyl that is replaced by halogen;
R
2fFor
(i) optionally be selected from the following C that substituting group replaced by 1-5
1-4Alkyl:
(a) hydroxyl,
(b)-O-(CH
2)
n-OH，
(c)-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and
(e)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
(ii) choose wantonly and be selected from the following C that substituting group replaced by 1-5
6-18Aryl:
(a) optionally be selected from the following C that substituting group replaced
1-4Alkyl: hydroxyl ,-NR
8-(CH
2)
n-OH ,-NR
8-(CH
2)
n-O-C
1-4Alkyl ,-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl and
(b)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) choose wantonly and be selected from the following C that substituting group replaced by 1-5
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxy carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
R
3fBe hydrogen atom or C
1-6Alkyl; With
Z
fBe C
1-3Alkylidene group; Or
R
2fAnd R
3fOptional combination is to form C
2-4Alkylidene group.
As R
8, be preferably hydrogen atom, methyl, ethyl etc., and preferred especially hydrogen atom.
In addition, as compound (If), preferred following compounds, wherein
B
fBe the optional phenyl ring that is replaced by halogen;
C
fBe the optional phenyl that is replaced by halogen;
R
2fBe selected from the following C that substituting group replaced for optional by 1-5
1-4Alkyl:
(a) hydroxyl and
(b)-O-(CH
2)
n-OH, wherein n is 1 to 4 integer;
R
3fBe hydrogen atom or C
1-6Alkyl;
Z
fBe methylene radical.And preferred especially following compounds, wherein R
2fBe quilt-O-(CH
2)
nThe C that-OH replaced
1-4Alkyl, wherein n is 1 to 4 integer.
[compound (Ig)]
The compound of following formula representative, or its salt:
R wherein
2gChoose substituted group wantonly for passing through carbon atom or sulphur atom bonded, or
R
2gAnd R
3gOptional combination is chosen substituted ring texture wantonly to form,
R
3gBe hydrogen atom or optional substituted aliphatic alkyl, or R
3gChoose wantonly on the carbon atom that is bonded to contiguous phenyl and choose substituted ring texture wantonly to form,
B
gBe optional substituted phenyl ring, and C
gBe optional substituted heterocyclic radical.
As R
2gIn " by the optional substituted group of carbon atom or sulphur atom bonded ", can use those to be similar to R
2In " by the optional substituted group of carbon atom or sulphur atom bonded ".
As by R
2gAnd R
3gBe bonded to each other formed " the optional ring texture that replaces ", can use those to be similar to by R
2And R
3Formed " the optional ring texture that replaces " is bonded to each other.
As R
3gIn " optional replace aliphatic alkyl ", can use those to be similar to R
3In " optional replace aliphatic alkyl ".
As by R
3gWith the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ", can use those to be similar to by R
3With the carbon atom of contiguous phenyl formed " the optional ring texture that replaces ".
As B
gIn " optional replace phenyl ring ", can use those to be similar to B
aIn " optional replace phenyl ring ".
As C
gIn " optional substituted heterocyclic radical ", can use those to be similar to C
cIn " optional substituted heterocyclic radical ".
As R
2g, be preferably C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) oxo,
(c) optional halogenated C
1-4Alkyl,
(d)-(CH
2)
m-Q，
(e)-(CH
2)
m-Z
1-(optional halogenated C
1-4Alkyl),
(f)-(CH
2)
m-Z
1-C
3-8Cycloalkyl,
(g)-(CH
2)
m-Z
2-(CH
2)
n-Q，
(h)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(optional halogenated C
1-4Alkyl),
(i)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-C
3-8Cycloalkyl,
(j)-(CH
2)
m-Z
1-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation),
(k)-(CH
2)
m-Z
2-C
1-4Alkoxyl group and
(l)-(CH
2)
m-Z
2-(CH
2)
n-Z
1-(CH
2)
n-Z
1-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer,
Q be hydroxyl, carboxyl, cyano group, nitro ,-NR
6R
7,-CONR
6R
7Or-SO
2NR
6R
7,
Z
1For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-SO
2-or-NR
8-C (=NH)-NH-,
Z
2For-O-,-CO-,-C (OH) R
8-,-C (=N-OR
8)-,-S-,-SO-,-SO
2-,-NR
8-,-N (COR
8)-,-N (CO
2R
9)-,-N (SO
2R
9)-,-CO-O-,-O-CO-,-CO-NR
8-,-NR
8-CO-,-NR
8-CO
2-,-NR
8-CO-NH-,-NR
8-C (=NH)-NH-,-NR
8-SO
2-or-SO
2-NR
8-,
(CH
2)
m(CH
2)
nOptional by individual halogen, the optional halogenated C of being selected from of 1-5
1-4The substituting group of alkyl and hydroxyl replaces, and when m or n are at least 2, (CH
2)
m(CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces.
R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, or R
6And R
7Form the saturated or undersaturated aliphatics heterocyclic radical of 3-to 8-member with the nitrogen-atoms combination,
R
8Be hydrogen atom or C
1-4Alkyl, and R
9Be C
1-4Alkyl.
As compound (Ig), be preferably following compounds, wherein
B
gFor choosing wantonly by C
1-4The phenyl ring that alkyl replaced;
C
gFor having 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is optional by C
1-4Alkyl replaces;
R
2gFor
(i) optional by C that hydroxyl replaced
1-4Alkyl,
(ii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) nitro,
(b) amino,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(e)-NR
8-CO-(CH
2)
n-NR
6R
7，
(f)-NR
8-CO-(CH
2)
n-COOH，
(g)-NR
8-CO-(CH
2)
n-CO
2-C
1-4Alkyl and
(h)-NR
8-CO-(CH
2)
m-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl;
R
3gBe hydrogen atom or C
1-6Alkyl; Or
R
2gAnd R
3gOptional combination is to form C
2-4Alkylidene group.
As compound (Ig), preferred following compounds, wherein
R
2gFor
(i) optionally be selected from the following C that substituting group replaced
6-18Aryl:
(a) nitro,
(b) amino,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(e)-NR
8-CO-(CH
2)
n-NR
6R
7，
(f)-NR
8-CO-(CH
2)
n-COOH，
(g)-NR
8-CO-(CH
2)
n-CO
2-C
1-4Alkyl and
(h)-NR
8-CO-(CH
2)
m-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, or
(ii) be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl.
As R
8, be preferably hydrogen atom, methyl, ethyl etc., and preferred especially hydrogen atom.
[compound (Ih)]
Compound (I), it is selected from following (A)-(H).
(A) compound (I), wherein W is CR
1
A is phenoxy group-C
6-18Aryl, wherein said phenoxy group be partly optional to be selected from following substituting group by 1-5 and to replace:
(i) halogen,
(ii) optional halogenated C
1-4Alkyl,
(iii) hydroxyl-C
1-4Alkyl,
(iv) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(v) optional halogenated C
1-4Alkoxyl group,
(vi) C
1-4Alkyl-carbonyl,
(vii) cyano group,
(viii) optional by C
1-8The formamyl that alkyl replaces and
(ix) C
1-4Alkoxyl group-carbonyl and
Described C
6-18Aryl moiety is optional further to be selected from halogen, C by 1-4
1-4Alkyl, hydroxyl-C
1-4Alkyl, C
1-4Alkoxyl group, carboxyl and C
1-4The substituting group of alkoxyl group-carbonyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1For
(i) hydrogen atom,
(ii) cyano group, or
(iii) C
1-4Alkyl or C
2-4Alkenyl, the wherein optional quilt-NR of each group
8-CO-(CH
2)
n-NR
6R
7Replace,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces;
R
2Be (i) hydrogen atom, or
(ii) C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH，
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH，
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7，
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, (CH
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces; Or
R
1And R
2Optional in conjunction with forming
R
2And R
3' optional in conjunction with choosing the C that is replaced by imino-wantonly to form
2-4Alkylidene group,
Particularly preferably, R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace),
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7(when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces),
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl.
(B) compound (I), wherein W is CR
1
A is phenyl-C
1-3Alkoxy-C
6-18Aryl, wherein said phenyl moiety is optional to be selected from halogen, optional halogenated C by 1-5
1-4The substituting group of alkyl and cyano group replace and
Described C
6-18Aryl moiety is optional further to be selected from halogen, optional C with hydroxyl by 1-4
1-4Alkyl and C
1-4The substituting group of alkoxyl group replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1Be (i) hydrogen atom, or
(ii) C
1-4Alkyl or C
2-4Alkenyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) amino and
(c)-NR
8-CO-(CH
2)
n-NR
6R
7，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) amino,
(b) carboxyl,
(c)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl and
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2-CH
2Optional quilt-CH=CH-replaces, or
(iv) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d)-O-(CH
2)
n-OH，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-CO-NR
8-(CH
2)
n-OH，
(g)-NR
6R
7And
(h)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) optional C with hydroxyl
1-4Alkyl,
(b) carboxyl,
(c) C
1-4Alkoxyl group-carbonyl,
(d) have 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is chosen wantonly has the hydroxyl of being selected from and C
1-4The substituting group of alkyl and
(e) optional have a substituent C that is selected from hydroxyl and formamyl
1-4Alkyl-formamyl,
(iv) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-carbonyl,
(v) optional by C
1-4The C that alkoxyl group replaces
6-18Aryl-alkylsulfonyl, or
(vi) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl; Or
R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group.
(C) compound (I), wherein W is CR
1
A contains 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
6-18Aryl, wherein said heterocyclic oxy group be partly optional to be selected from following substituting group by 1-5 and to replace:
(i) halogen,
(ii) C
1-4Alkyl,
(iii) C
1-4Alkyl-carbonyl,
(iv) optional halogenated C
1-4Alkoxyl group-carbonyl,
(v) C
3-8Cycloalkyl-carbonyl and
(vi) choose wantonly and be selected from the following formamyl that substituting group replaced:
(a) optional halogenated C
1-8Alkyl,
(b) C
3-8Cycloalkyl and
(c) optional halogen, the C of being selected from
1-4Alkyl and C
1-4The C that substituting group replaced of alkoxyl group
6-18Aryl and
Described C
6-18Aryl moiety is optional further to be selected from halogen and optional halogenated C by 1-4
1-4The substituting group of alkyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1Be (i) hydrogen atom,
(ii) C
1-4Alkyl or C
2-4Alkenyl, wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) amino,
(c)-NR
8-CO-(CH
2)
n-NR
6R
7And
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) optional be selected from hydroxyl ,-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl and-NR
8-CO-(CH
2)
n-O-C
1-4The C that substituting group replaced of alkyl
1-4Alkyl,
(b) amino,
(c) C
1-4Alkoxyl group,
(d) carboxyl and
(e)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iv) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced
1-4Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d) carboxyl,
(e) C
1-4Alkoxyl group-carbonyl,
(f)-O-(CH
2)
n-OH，
(g)-O-(CH
2)
n-O-C
1-4Alkyl,
(h)-CO-NR
8-(CH
2)
n-OH and
(i)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) optional by optional C with hydroxyl
1-4The C that alkyl replaced
6-18Aryl-C
1-4Alkyl; Or
R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group.
(D) compound (I), wherein W is CR
1
A contains 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-3Alkoxy-C
6-18Aryl;
Wherein said C
6-18Aryl moiety is optional further to be replaced by halogen;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
1Be (i) hydrogen atom, or
(ii) has 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom;
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced
1-4Alkyl:
(a) C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH and
(c)-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iii) has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-4Alkyl, it is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl.
(E) compound (I), wherein W is N;
A is phenoxy group-C
6-18Aryl, wherein said phenoxy group are partly optional to be selected from optional halogenated C by 1-5
1-4The substituting group of alkyl and cyano group replace and
Described C
6-18Aryl moiety is optional further to be selected from halogen and C by 1-4
1-4The substituting group of alkyl replaces;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
2Be (i) hydrogen atom, or
(ii) optional quilt-O-(CH
2)
nThe C that-OH replaces
1-4Alkyl, wherein n is 1 to 4 integer.
(F) compound (I), wherein W is N;
A is phenyl-C
1-3Alkoxy-C
6-18Aryl, wherein said phenyl moiety is optional replaced by 1-5 substituting group that is selected from halogen and cyano group and
Described C
6-18Aryl moiety is optional further to be selected from halogen and C by 1-5
1-4The substituting group of alkyl replaces;
X
1For-NR
3-', R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
2Be (i) hydrogen atom,
(ii) choose wantonly and be selected from the following C that substituting group replaced by 1-5
1-4Alkyl:
(a) hydroxyl,
(b)-O-(CH
2)
n-OH，
(c)-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and
(e)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
(iii) optional by C
1-4The C that alkyl replaced
6-18Aryl, described C
1-4Alkyl is optional be selected from hydroxyl ,-NR
8-(CH
2)
n-OH ,-NR
8-(CH
2)
n-heterocyclic radical (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and-NR
8-(CH
2)
n-SO
2-C
1-4The substituting group of alkyl replaces, or
(iv) choose wantonly and be selected from the following C that substituting group replaced by 1-5
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl; Or
R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group.
(G) compound (I), wherein W is N;
A contains 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
6-18Aryl, wherein said heterocyclic oxy group are partly optional by C
1-4Alkyl replace and
Described C
6-18Aryl moiety is optional further by C
1-4Alkyl replaces;
X
1For-NR
3', R wherein
3' be hydrogen atom or C
1-6Alkyl;
R
2Be (i) hydrogen atom,
(ii) choose C wantonly by hydroxyl replaced
1-4Alkyl,
(iii) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl:
(a) nitro,
(b) amino,
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
(d)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(e)-NR
8-CO-(CH
2)
n-NR
6R
7，
(f)-NR
8-CO-(CH
2)
n-COOH，
(g)-NR
8-CO-(CH
2)
n-CO
2-C
1-4Alkyl and
(h)-NR
8-CO-(CH
2)
m-O-(CH
2)
n-O-C
1-4Alkyl,
Wherein m is 0 to 4 integer, and n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, or
(iv) choose wantonly and be selected from the following C that substituting group replaced
6-18Aryl-C
1-4Alkyl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl and
(c)-CO-NR
8-(CH
2)
n-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl; With
R
2And R
3' choose combination wantonly to form C
2-4Alkylidene group.
(H) compound (I), wherein W is CH;
A is selected from the following C that substituting group replaced for choosing wantonly
6-18Aryl:
(a) carboxyl,
(b) C
1-4Alkoxyl group-carbonyl,
(c) contain 1 to 3 heteroatomic 5-to 8-element heterocycle-carbonyl that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom (be preferably optional have 1 or 2 heteroatomic 5-to 8-member who is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom encircle amino-carbonyl), it is optional by C
6-18Aryl-C
1-4Alkyl replaces,
(d) optional by C
6-18Aryl-C
1-4The formamyl that alkyl replaced and
(e) optional by C
6-18Aryl-C
1-4The urea groups that alkyl replaced;
X
1For-NR
3'-, be R wherein
3' be hydrogen atom or C
1-6Alkyl; With
R
2Be hydrogen atom.
[compound (II)]
Compound (I), wherein A is for being selected from the following C that substituting group replaced
6-18Aryl:
(i) be selected from the following phenoxy group that substituting group replaced by 1-5:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl,
(ii) be selected from following phenyl-C that substituting group replaced by 1-5
1-3Alkoxyl group:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl,
(iii) contain 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C1-4 alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl and
(iv) contain 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-3Alkoxyl group, it is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl, triazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) C
1-4Alkyl-carbonyl,
(g) cyano group,
(h) optional by C
1-8The formamyl that alkyl replaces and
(i) C
1-4Alkoxyl group-carbonyl;
Wherein said C
6-18Aryl is optional further to be selected from halogen and optional halogenated C by 1-4
1-4The substituting group of alkyl replaces;
R
1Be hydrogen atom;
R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH，
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH，
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7，
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl,
(CH
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace, and when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces;
R
3Be hydrogen atom or C
1-6Alkyl; Or
R
1And R
2Optional in conjunction with forming
Or
Or
R
2And R
3Optional in conjunction with choosing the C that is replaced by imino-wantonly to form
2-4Alkylidene group,
Particularly preferably, R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), wherein each group is optional is selected from following substituting group and is replaced:
(a) hydroxyl,
(b) carboxyl,
(c) cyano group,
(d) optional halogenated C
1-4Alkoxyl group,
(e)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(f)-O-(CH
2)
n-O-CO-NH
2，
(g)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(h)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(i)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(j)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(k)-O-(CH
2)
n-NR
8-CO-C
1-4Alkyl,
(l)-O-(CH
2)
n-NR
8-CO-(CH
2)
n-SO
2-C
1-4Alkyl,
(m)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(n)-CO-NR
8-(CH
2)
n-OH，
(o)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(p)-CO-NR
8-O-C
1-4Alkyl,
(q)-NR
6R
7，
(r)-NR
8-(CH
2)
n-OH，
(s)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(t)-NR
8-CO-(optional halogenated C
1-4Alkyl),
(u)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by optional halogenated C
1-4Alkyl or hydroxyl replace),
(v)-NR
8-CO-(CH
2)
n-CN，
(w)-NR
8-CO-(CH
2)
n-NR
6R
7(when n is at least 2, (CH
2)
nIn group part-CH
2CH
2-optional quilt-CH=CH-replaces),
(x)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(y)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(z)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(aa)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(bb)-NR
8-CO-(CH
2)
n-NR
8-SO
2-C
1-4Alkyl,
(cc)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(dd)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(ee)-NR
8-CO-NH-O-C
1-4Alkyl,
(ff)-NR
8-CO-NH-(CH
2)
n-O-C
1-4Alkyl,
(gg)-NR
8-C (=NH)-NH-C
1-4Alkyl,
(hh)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(ii)-S-(CH
2)
n-OH，
(jj)-SO-(CH
2)
n-OH，
(kk)-SO
2-(CH
2)
n-OH and
(ll)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-O-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl.
[compound (Ij)]
Preferred following compounds (I), wherein
A is for being selected from the following C that substituting group replaced
6-18Aryl:
(i) be selected from the following phenoxy group that substituting group replaced by 1-5:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl,
(ii) be selected from following phenyl-C that substituting group replaced by 1-5
1-3Alkoxyl group:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl,
(iii) contain 1 to 3 heteroatomic 5-to 8-element heterocycle oxygen base that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably 5-to 8-element heterocycle-C
1-4Alkyl, described 5-to 8-element heterocycle have 1 to 3 heteroatoms that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl and
(iv) contain 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
1-3Alkoxyl group, it is selected from following substituting group by 1-5 and replaces:
(a) halogen,
(b) optional halogenated C
1-4Alkyl,
(c) hydroxyl-C
1-4Alkyl,
(d) heterocycle-C
1-4Alkyl (is preferably and has 1 to 3 heteroatomic 5-to 8-element heterocycle-C that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation
1-4Alkyl, for example imidazolyl etc.),
(e) optional halogenated C
1-4Alkoxyl group,
(f) cyano group,
(g) optional by C
1-8The formamyl that alkyl replaces and
(h) C
1-4Alkoxyl group-carbonyl;
Wherein said C
6-18Aryl is optional further to be selected from halogen and optional halogenated C by 1-4
1-4The substituting group of alkyl replaces;
R
1Be hydrogen atom;
R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(i)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH，
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace;
R
3Be hydrogen atom or C
1-6Alkyl; Or
R
1And R
2Optional in conjunction with forming
Or
Or
R
2And R
3Optional combination is to form C
2-4Alkylidene group.
Particularly preferably, R
2Be C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl (C particularly
1-8Alkyl), its each be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl, etc.
[compound (Ik)]
Compound (I), wherein
R
2The C that is replaced by hydroxyl for (i)
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH，
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH，
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl replaces,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl.
Particularly preferably, R
2The C that is replaced by hydroxyl for (i)
5-8Alkyl,
(ii) be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogenated C
1-4Alkoxyl group,
(b)-O-(CH
2)
n-OH ((CH wherein
2)
nChoose wantonly and replaced by hydroxyl),
(c)-O-(CH
2)
n-O-CO-NH
2，
(d)-O-(CH
2)
n-O-(optional halogenated C
1-4Alkyl),
(e)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(f)-O-(CH
2)
n-SO
2-C
6-18Aryl,
(g)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(h)-CO-NR
8-(CH
2)
n-OH，
(i)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(j)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(k)-NR
8-CO-(CH
2)
n-OH ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(l)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(m)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(n)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl) ((CH wherein
2)
nOptional by C
1-4Alkyl replaces),
(o)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(p)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(q)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(r)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(s)-S-(CH
2)
n-OH，
(t)-SO-(CH
2)
n-OH，
(u)-SO
2-(CH
2)
n-OH and
(v)-NR
8-CO-(optional substituted heterocyclic radical) (preferably, described heterocyclic radical is to have 1 to 3 heteroatomic 5-to 8-element heterocycle base that is selected from the sulphur atom of nitrogen-atoms, Sauerstoffatom and optional oxidation, and this heterocyclic radical is optional to be selected from following substituting group and to replace: hydroxyl, C
1-4The C of alkyl, optional oxidation
1-4Alkylthio ,-CO-C
1-4Alkyl ,-CO-NH-C
1-4Alkyl ,-CONH
2,-SO
2-C
1-4Alkyl ,-SO
2-NH-C
1-4Alkyl ,-SO
2NH
2Deng),
Wherein n is 1 to 4 integer, and R
8Be hydrogen atom or C
1-4Alkyl,
The (iii) optional C that is replaced by hydroxyl
2-8Alkenyl, or
The (iv) optional C that is replaced by hydroxyl
2-8Alkynyl.
As the salt of the compound of formula (I) representative, for example, can mention metal-salt, ammonium salt is with the salt of organic bases, with the salt of mineral acid, with organic acid salt, with salt of alkalescence or acidic amino acid etc.As the preferred embodiment of metal-salt, for example, can mention an alkali metal salt such as sodium salt, sylvite etc.; Alkaline earth salt such as calcium salt, magnesium salts, barium salt etc.; Aluminium salt, or the like.As with the preferred embodiment of the salt of organic bases, for example, can mention and Trimethylamine 99, triethylamine, pyridine, picoline, 2,6-lutidine, thanomin, diethanolamine, trolamine, tromethamine[i.e. three (hydroxymethyl) methylamine], TERTIARY BUTYL AMINE, hexahydroaniline, dicyclohexyl amine, N, the salt of N '-dibenzyl-ethylenediamin etc.As with the preferred embodiment of the salt of mineral acid, for example, can mention and hydrochloric acid Hydrogen bromide, nitric acid, sulfuric acid, the salt of phosphoric acid etc.As with the preferred embodiment of organic acid salt, for example, can mention and formic acid acetate, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid, the salt of tosic acid etc.As with the preferred embodiment of the salt of basic aminoacids, for example, can mention and arginine, Methionin, the salt of ornithine etc., and as with the preferred embodiment of the salt of acidic amino acid, for example, can mention and aspartic acid the salt of L-glutamic acid etc.
Wherein, preferred pharmacy acceptable salt.For example, when containing acidic functionality in the compound, can mention inorganic salt such as an alkali metal salt (for example sodium salt, sylvite etc.), alkaline earth salt (for example calcium salt, magnesium salts, barium salt etc.) etc., ammonium salt etc., and when containing basic functionality in the compound, for example, can mention the salt with mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc., or with the salt of organic acid such as acetate, phthalic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, methylsulfonic acid, tosic acid etc.
As compound (I), be preferably such compound, wherein A is by formula-Y
2Further substituted aryl that-B group replaces, also optional, Y in the formula
2For singly-bound ,-O-,-OCH
2-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted.
As a preferred embodiment of compound (I), what can mention is such compound, and wherein, W is C (R
1);
A is by formula-Y
2Further substituted aryl, wherein Y that-B group replaces, also optional
2For singly-bound ,-O-,-OCH
2-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted;
R
1Be formula-X
2-R
4Group, X wherein
2For singly-bound ,-NH-or-O-, and R
4Be hydrogen atom 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, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted;
R
2Be hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted; With
X
1For-NR
3-, R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl.
As another preferred embodiment of compound (I), what can mention is such compound, and wherein W is N;
X
1For-NR
3-, R wherein
3Be hydrogen atom or optional substituted aliphatic alkyl;
A is by formula-Y
2Further substituted aryl, wherein Y that-B group replaces, also optional
2For singly-bound ,-O-,-OCH
2-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted; With
R
2Be hydrogen atom or C
1-8Alkyl, C
2-8Alkenyl, C
2-8Alkynyl, formamyl, C
1-8Alkyl-carbonyl, 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
6-18Aryl-alkylsulfonyl, heterocyclic radical, heterocycle-C
1-4Alkyl, heterocycle-carbonyl or heterocycle-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted.
As another preferred embodiment of compound (I), what can mention is such compound, and wherein W is N;
X
1For-NR
3-;
A is by formula-Y
2Further substituted aryl, wherein Y that-B group replaces, also optional
2For singly-bound ,-O-,-OCH
2-,-NH-or-S-, and B is aryl, heterocyclic radical, C
3-8Cycloalkyl, formamyl, urea groups, C
6-18Aryl-carbonyl or C
6-18Aryl-C
1-4Alkyl-carbonyl, wherein each group is optional is substituted; With
R
2And R
3In conjunction with choosing substituted ring texture wantonly to form.
[preparation method]
The preparation method of compound of the present invention (I) is described below:
Compound of the present invention (I) can pass through for example acquisition such as method shown in the following diagram or method similar with it.
Compound in the diagram (II)-(VIII) comprises salt, as this salt, for example can use similar those salt of the salt that waits with compound (I).
Be obtained from compound in each step can reaction mixture or the form of crude product be used for next step reaction.In addition, also compound can be separated from reaction mixture by ordinary method, and easily by carrying out purifying such as separation means such as recrystallization, distillation, chromatograms.
The diagram reaction formula is as follows, and wherein each symbol in the compound as defined above.
Compound of the present invention (I) can be by for example making the compound or its salt of following formula representative:
Wherein L be leavings group and other symbol as defined above, obtain with the compound or its salt prepared in reaction of following formula representative:
G-X
1A (III)
Wherein G is hydrogen atom or atoms metal, and other symbol as defined above.
Work as X
1For-NR
3-Y
1-,-O-or-during S-, G is mainly hydrogen atom, but can be basic metal such as lithium, sodium, potassium, caesium etc., or is alkaline-earth metal such as magnesium, calcium etc.Work as X
1For-CHR
3In-time, G is preferably metal such as lithium, halo magnesium, copper, zinc etc.
Compound (III) or its salt are preferably with respect to compound (II) 1-5 equivalent, and the normal amount of preferred 1-2 is used, and this reaction is preferably carried out in solvent.In addition, alkali or ammonium salt can about 1-10 equivalents, and the normal amount of preferred 1-2 is used.
In above-mentioned formula,, can use halogen atom such as chlorine, bromine, iodine etc., formula-S (O) as the leavings group of L representative
kR
aGroup, wherein k is 0,1 or 2, and R
aBe rudimentary (C
1-4) alkyl such as methyl, ethyl, propyl group etc., benzyl, C
6-10Aryl such as phenyl, tolyl etc., or formula-OR
aGroup, R wherein
aAs defined above etc.
As the solvent in the above-mentioned reaction, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., alcohol are as methyl alcohol, ethanol, Virahol, the trimethyl carbinol, phenol etc., ether such as ether, tetrahydrofuran (THF), diox etc., acetone, acetonitrile, ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.
As the alkali in the above-mentioned reaction, can use mineral alkali, organic bases etc.Particularly for example sodium hydroxide, potassium hydroxide, yellow soda ash, 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, diazabicyclo undecylene (DBU) etc.
As the ammonium salt in the above-mentioned reaction, can use pyridine hydrochloride, pyridine hydrobromide salt, pyridine right-tosylate, quinoline hydrochloride, isoquinoline hydrochloride, pyrimidine hydrochloride, pyrazine hydrochloride, triazine hydrochloride, trimethylamine hydrochloride, triethylamine hydrochloride, N-ethyl diisopropyl amine hydrochloride etc.
Above-mentioned reaction can the cooling under, at room temperature or the heating under (about 40-200 ℃, preferably about 40-160 ℃) carry out, the reaction times is generally about 1-30 hour, preferably about 1-20 hour, more preferably from about 1-10 hour.
X wherein
1For-SO-or-SO
2-compound (I) can by will be wherein X
1For-the compound (I) of S-carries out oxidizing reaction and prepares.Therefore, as oxygenant, for example can use metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tert-butyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein X
1During for the compound (I) of-SO-, oxygenant to be using with respect to the normal amount of the about 1-1.5 of initial compounds, and when preparing wherein X
1For-SO
2-compound (I) time, oxygenant is to use with respect to the normal amount of the about 2-3 of initial compounds.To not restriction especially of reaction solvent, as long as it not with oxidant reaction, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., pure as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., ether such as ether, tetrahydrofuran (THF), diox etc., carboxylic acid such as acetate, trifluoroacetic acid etc., acetonitrile, ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This is reflected under the cooling, at room temperature or under heating carries out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
Compound in the scope of the invention also can prepare by using known method own, and this method obtains The compounds of this invention (I) 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 converted into 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, and the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and the replacement of the alkylation of amination, hydroxyl, 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 it is essential; by known method own blocking group is incorporated in the active substituent in advance; and after goal response, remove blocking group by known method own; thus, can prepare the interior compound of the scope of the invention.
For the compound (I) of this reaction product can individualized compound or prepare with the form of mixture.
The The compounds of this invention that so obtains (I) can be by known method itself such as solvent extraction, concentrate, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography etc. are handled, thereby target compound can be come out and purifying with high purity separation from reaction mixture.
As this preparation method's initial compounds (III), can use the product that is purchased maybe can be by preparing by known method itself.
Initial compounds among this preparation method (II) can prepare by for example method shown in the following diagram.Wherein, compound (IIa), (IIb), (IIc), (IId) and (IIe) be included in the compound (II).
L wherein
1And L
2Be halogen atom, R
aAs defined above, and t be 1 or 2.
For method A, compound (IIa) can obtain by making compound (IV) and halogenating agent prepared in reaction.
For method B, make compound (IV) with the sulfuration reagent react, obtain compound (V), then in the presence of alkali with compound (V) and R
aL
2The compound reaction of representative obtains compound (IIb), compound (IIb) is further carried out oxidizing reaction obtain compound (IIc).For method C, in the presence of alkali, make compound (IIa) and R
aThe compound reaction of OH representative obtains compound (IId).
As the halogenating agent among the method A, for example can use the normal phosphoryl chloride of about 1-100, phosphorus pentachloride, phosphorus trichloride, thionyl (two) chlorine, SULPHURYL CHLORIDE, phosphorus tribromide etc.In this case, this reaction can be carried out in the presence of alkali such as Diethyl Aniline, xylidine, pyridine etc.Although this reaction can be carried out under the solvent not having,, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1 as reaction solvent, 2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., ether such as ether, tetrahydrofuran (THF), diox etc., acetonitrile, ethyl acetate etc.This is reflected under the cooling, at room temperature or under heating carries out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
Sulfuration reagent as using in the step by compound (IV) preparation compound (V) in method B for example can use the normal Lawesson reagent of about 1-5, thiophosphoric anhydride etc.As reaction solvent, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., ether such as ether, tetrahydrofuran (THF), diox or the like.This reaction at room temperature or under heating is carried out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
As the R that uses in the step in method B by compound (V) preparation compound (IIb)
aL
2For example can use the normal methyl iodide of about 1-5, benzyl chloride, bromotoluene etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, yellow soda ash, 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, diazabicyclo undecylene (DBU) etc.As reaction solvent, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., pure as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., ether such as ether, tetrahydrofuran (THF), diox etc., acetone, acetonitrile, ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This is reflected under the cooling, at room temperature or under heating carries out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
Oxygenant as using in the step by compound (IIb) preparation compound (IIc) in method B for example can use metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, tert-butyl peroxide, Potassium Persulphate, potassium permanganate, sodium perborate, sodium periodate, clorox, halogen etc.When preparing wherein the compound of t=1 (IIc), use with respect to the normal oxygenant of the about 1-1.5 of compound (IIb), and when preparing wherein the compound of t=2 (IIc), use is with respect to the normal oxygenant of the about 2-3 of compound (IIb).Reaction solvent is had no particular limits, as long as it not with oxidant reaction, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., pure as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., ether such as ether, tetrahydrofuran (THF), diox etc., carboxylic acid such as acetate, trifluoroacetic acid etc., acetonitrile, ethyl acetate, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, water or its mixed solvent etc.This is reflected under the cooling, at room temperature or under heating carries out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
As the R that uses in the step in method C by compound (IIa) preparation compound (IId)
aOH, for example can use the normal methyl alcohol of about 1-10, ethanol, phenol etc., and as alkali, for example can use sodium hydroxide, potassium hydroxide, yellow soda ash, 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, diazabicyclo undecylene (DBU) etc.As reaction solvent, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., ether such as ether, tetrahydrofuran (THF), diox etc., acetone, acetonitrile, ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This is reflected under the cooling, at room temperature or under heating carries out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
In addition, compound (IV) can prepare by for example method shown in the following formula:
R wherein
10Be C
1-4Alkyl, and other symbol is as defined above.
Or rather, compound (VI) or its salt are reacted in the presence of the normal carbonamidine of about 1-4, thereby can prepare compound (IV).As reaction solvent, for example can use alcohol as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., ether such as ether, tetrahydrofuran (THF), diox etc., acetone, acetonitrile, ethyl acetate, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This is reflected under the cooling, at room temperature or under heating carries out, and the reaction times is generally about 1-20 hour, preferably about 1-10 hour.
When W is C (R
1) time, compound (II) also can prepare by for example method shown in the following formula:
L wherein
3For halogen atom and other symbol as defined above.
In this method; for step by compound (VII) preparation compound (VIII); this reaction is commonly called the Sonogashira reaction; maybe can use reaction similar with it; and compound (VIII) can make compound (VII) and the normal formula of about 1-3 by in the presence of the alkali, in the presence of normal palladium catalyst of about 0.01-1 and cuprous iodide usually
The compound of representative reacts and prepares.As alkali, for example can use triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazabicyclo undecylene (DBU), yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc.As palladium catalyst, for example can use two (triphenylphosphine) palladium chlorides (II), palladium/carbon, palladium diacetate (II), two (benzonitrile) palladium chloride (II) etc.This reaction can be reacted in the presence of common as the tertiary phosphine compounds of part such as triphenylphosphine, tributylphosphine etc.As reaction solvent, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., ether such as ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc., acetone, acetonitrile, ethyl acetate, N, dinethylformamide, 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, preferably about 1-20 hour.
In this method, for the step by compound (VIII) preparation compound (IIe), cyclization carries out in the presence of normal alkali of about 1-3 or the normal cuprous iodide of about 0.01-1 usually, 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, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, N-ethyl diisopropyl amine, diisopropylamine, pyridine, N, N-dimethyl aminopyridine, diazabicyclo undecylene (DBU) etc.As reaction solvent, for example can use halon such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc., aromatic hydrocarbon such as benzene,toluene,xylene etc., alcohol is as methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., ether such as ether, tetrahydrofuran (THF), diox, 1,2-glycol dimethyl ether etc., acetone, acetonitrile, ethyl acetate, N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, methyl-sulphoxide, hexamethylphosphoramide, water or its mixed solvent etc.This reaction at low temperatures, at room temperature or under heating carry out, and the reaction times is generally about 1-50 hour, preferably about 1-20 hour.
The substituent kind that depends on initial compounds (II), the initial compounds (II) 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, and the reduction amination of carbonyl, the oximate of carbonyl, amino acylation, amino alkylation, reactive halogen is replaced by amine and the replacement of the alkylation of amination, hydroxyl, 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 it is essential; by known method own blocking group is incorporated in the active substituent in advance; and after goal response, remove blocking group by known method own; thus, also can prepare initial compounds (II).
The compound that so obtains (I) can separate and purifying as concentrated, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, phase transition, chromatogram etc. by separation known means own.
If compound (I) obtains with free form, then it can change into required salt by known method own or its process variant; On the contrary, if compound (I) obtains with the form of salt, then it can change into free form or other required salt by known method or its process variant.
When compound (I) comprised isomer as optically active isomer, steric isomer, positional isomers or rotational isomer etc., any isomer and mixture were included in the scope of compound (I).For example, when compound (I) when comprising optically active isomer, the optically active isomer of separating from racemic modification is also contained in the scope of compound (I).These isomer can obtain single product by known synthetic method itself or separation means (concentrate, solvent extraction, column chromatography, recrystallization etc.).
Compound (I) can be crystallization, and single crystallization and crystalline mixture can be included in the scope of compound (I).Crystallization can prepare by crystallization according to known crystallization method itself.
Compound (I) can be solvate (as hydrate etc.) or non-solvent compound, and the both is included in the scope of compound (I).
With isotropic substance (as
3H,
14C,
35S,
125I etc.) compound of mark is also contained in the scope of compound (I).
The prodrug of compound (I) or its salt (being called compound (I) hereinafter) is meant in vivo under the physiological condition, owing to changing into the compound of compound (I) with reactions such as enzyme, hydrochloric acid in gastric juice, just, the oxidation of this compound by enzyme, reduction, hydrolysis etc. change into compound (I); This compound can be by hydrochloric acid in gastric juice etc. hydrolysis reaction etc. change into compound (I).
Acidylate, alkylation or the phosphorylated that the prodrug of compound (I) can pass through the amino of compound (I) obtains (for example eicosane acidylate, alanylization, amyl group aminocarboxylization, (5-methyl-2-oxo-1,3-Dioxol-4-yl) methoxycarbonylization, tetrahydrofuran baseization, the pyrrolidyl of the amino by compound (I) methylate, oxy acid methyl neopentylization, tert-butylation etc. and the compound that obtains); The compound that acidylate, alkylation, phosphorylated and boron acidylate by the hydroxyl in the compound (I) obtains (for example the acetylize of the hydroxyl by compound (I), palmitoylation, propionylization, pivalylization, succinylation, fumarylization, alanylization, dimethylaminomethyl carbonylation etc. obtain compound); The esterification of the carboxyl by compound (I) or the compound that amidation obtains (for example ethyl-esterification, phenyl-esterification, carboxyl methyl-esterification, dimethylaminomethyl-esterification, oxy acid methyl neopentyl-esterification, the ethyl-esterification of oxyethyl group carbonyl oxygen base, phthalidyl-esterification, (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl-esterification, cyclohexyloxy carbonyl ethyl-esterification and the methyl nitrosoureaization etc. of the carboxyl by compound (I) and the compound that obtains) etc.Any compound in these compounds can be prepared by compound (I) by known method itself.
The prodrug of compound (I) also can be the compound that changes into compound (I) under physiological condition, as
IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Designof Molecules, p.163-198, those that describe among the Published by HIROKAWA SHOTEN (1990).
It is active that compound of the present invention (I) or its salt or its prodrug (compound hereinafter referred to as 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 the disease that increases to feature with the cell proliferation that causes owing to unusual tyrosine kinase activity.And, compound specificity of the present invention ground suppresses HER2 kinases and/or EGFR kinases, and thereby also can be used as the therapeutical agent of the growth of cancers that suppresses HER2 and/or EGFR kinases-expression, or be used to prevent that hormone-dependence cancer is converted into the preventive of hormone-dependent/non-dependent cancer.And this compound useful as drug preparation is because it (for example shows hypotoxicity, acute toxicity, long term toxicity, heredity toxicity, genotoxicity, cardiac toxic, drug interaction, carinogenicity etc.), highly water-soluble, and in stability, pharmacokinetics (absorption, distribution, metabolism is drained etc.) and effect expression aspect excellence.
Therefore, compound of the present invention can be used as prevention or treats because the safe medicament of the caused disease of abnormal cell proliferation, the for example various cancers of described disease (mammary cancer especially, prostate cancer, carcinoma of the pancreas, cancer of the stomach, lung cancer, colorectal carcinoma, the rectum cancer, esophagus cancer, duodenal cancer, tongue cancer, the excuse cancer, the cancer of the brain, the schwann's sheath cancer, nonsmall-cell lung cancer, small cell lung cancer, liver cancer, kidney, cholangiocarcinoma, carcinoma of uterine body, cervical cancer, ovarian cancer, bladder cancer, skin carcinoma, vascular tumor, malignant lymphoma, malignant melanoma, thyroid tumor, bone tumor, the vascular fibroma, cancer eye, penile cancer, the child stage solid carcinoma, the Kaposi sarcoma, by AIDS deutero-Kaposi sarcoma, the jaw knurl, fibrous histiocytoma, leiomyosarcoma, rhabdosarcoma, leukocytosis etc.), arteriosclerosis, vasculogenesis (for example relevant with sarcoma growth vasculogenesis with solid carcinoma, the vasculogenesis relevant with metastases and with diabetic retinopathy relevant vasculogenesis etc.) and virus disease (HIV infect etc.).
Tyrosylprotein kinase-dependence disease also comprises and the unusual relevant cardiovascular disorder of tyrosine kinase activity.Therefore compound of the present invention also can be used as the prevention or the therapeutical agent of cardiovascular disorder such as restenosis.
Compound of the present invention can be used as prevention or treatment cancer, the particularly carcinostatic agent of mammary cancer, prostate cancer, carcinoma of the pancreas, cancer of the stomach, lung cancer, colorectal carcinoma, kidney etc. for example.
Compound exhibits of the present invention goes out hypotoxicity, and can in Mammals (for example people, horse, ox, dog, cat, rat, mouse, rabbit, pig, monkey etc.), be used as pharmaceutical composition with itself, perhaps be used as pharmaceutical composition with mixture with known pharmaceutically acceptable carrier.
Except that compound of the present invention, described pharmaceutical composition can contain other activeconstituentss, for example following hormonotherapy agent, carcinostatic agent (as the medicine of chemotherapeutics, immunotherapeutic agent or the cell growth inhibiting factor or growth factor acceptor effect) etc.
Compound of the present invention can be used as medicament and delivers medicine to Mammals such as people, and this administration for example comprises, with tablet, capsule (comprising soft capsule and microcapsule), powder, the oral administration of forms such as particle, or with injection, suppository, forms such as pellet through administered parenterally.The example of " administered parenterally approach " comprises intravenously, and intramuscular is subcutaneous, and in the tissue, in the nose, intradermal instils, in the brain, and internal rectum, intravaginal, intraperitoneal, in the knurl, near the administration of knurl etc., and to the direct administration that damages.
The dosage of compound of the present invention is with route of administration, symptom etc. and changing.For example, when with its as anticarcinogen when being administered orally in the patient (body weight 40-80kg) who suffers from mammary cancer or prostate cancer, its dosage is, for example the 0.5-100mg/kg body weight/day, be preferably the 1-50mg/kg body weight/day, more preferably 1 or the 25mg/kg body weight/day.This dosage can be administered once every day, perhaps is divided into 2 or 3 parts of administrations every day.
Compound of the present invention can single medicament or (method described in JapanesePharmacopoeia etc.) pharmaceutical composition that contains pharmaceutically acceptable carrier of obtaining according to conventional methods, 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 through administered parenterally (for example, part, rectum, intravenous administration etc.) safely.
And, the combination The compounds of this invention of (1) effective dosage and (2) are 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, for example specifiable is surgical operation, radiotherapy, gene therapy, thermotherapy, psychrotherapy, laser burn etc., and two or more being used in combination in these.
For example, to identical main body, 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 companion's medicine hereinafter) administration together.
Although compound of the present invention has excellent antitumous effect when using with single medicament, by be used in combination (using in the time of various medicaments) with one or more above-mentioned companion's medicines, its effect can obtain bigger enhancing.
Example as described " hormonotherapy agent ", can mention fostestrol, stilboestrol (diethylstilbestrol), Chlortrianisoestrol, Veramix, the acetate megestrol, the acetate Verton, acetate cyproterone salt, danazol, dienogest, asoprisnil, Allyloestrenol, gestrinone, Nomegestrol, Tadenan, Mepartricin, raloxifene, ormeloxifene, Levormeloxifene, estrogen antagonist (for example, citric acid tamoxifen, FC-1157a etc.), ER down regulator (for example fulvestrant etc.), follotropin, follicle stimulating hormone, pill, mepitiostane, testrolactone, amino glutethimide, the LH-RH agonist is (for example, the acetate goserelin, buserelin, Leuprolide etc.), droloxifene, Epitiostanol, sulfonic acid ethinylestradiol, aromatase inhibitor (for example, the fadrozole hydrochloride, Anastrozole, retrozole, Exemestane, vorozole, formestane etc.), androgen antagonist (for example, flutamide, bicartamide, Nilutamide etc.), the 5 inhibitor (for example, finasteride, the dutasteride, epristeride etc.), adrenocortical steroid medicine (for example, dexamethasone, prednisolone, Betamethasone Valerate, triamcinolone etc.), the male sex hormone synthetic inhibitor (for example, Abiraterone etc.), retinoid and delay the metabolic medicine of retinoid (for example, liarozole etc.) etc., and preferred LH-RH agonist (for example, goserelin acetic ester, buserelin, Leuprolide).
The example of described " chemotherapeutic ", can mention for alkylating agent, metabolic antagonist, antitumor antibiotic, plant the anticarcinogen of plant origin etc.
As the example of " alkylating agent ", what can mention is mustargen, mustine hydrochlcride-N-oxide compound, Chlorambucil (chlorambutyl), endoxan, ifosfamide, plug is for group, carboquone, the toluenesulphonic acids improsulfan, busulfan, the nimustine hydrochloride, mitobronitol, melphalan, Dacarbazine, ranomustine, estramustine phosphate sodium, the triethylene trimeric cyanamide, carmustine, lomustine, streptozocin, pipobroman, Etoglucid, carboplatin, cis-platinum, the rice handkerchief, S 254, oxaliplatin, altretamine, ambamustine, dibrospidium chloride, fotemustine, prednimustine, pumitepa, ribomustin, Temozolomide, treosulphan, Z-4828, Zinostatin stimalamer, U 73975, cystemustine, U 77779 etc.
As the example of " metabolic antagonist ", what can mention is mercaptopurine, the Ismipur glycosides, thioinosine, methotrexate, enocitabine, cytosine arabinoside, Cytarbine Ocfostate, Ancitabine, 5-FU medicine (for example, Fluracil, Tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur etc.), aminopterin sodium, Calciumlevofolinate, tablet, 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, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride etc.
As the example of " carcinostatic agent of plant origin ", what can mention is Etoposide, phosphoric acid Etoposide, Vinblastine sulphate, vincristine sulphate, vindesine sulfate, teniposide, taxol, Docetaxel, vinorelbine etc.
As the example of described " immunotherapeutic agent (BRM) ", that can mention eats polysaccharide, ubenimex, interferons, interleukin-, macrophage colony stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, CBP, LEVAMISOLE HCL, polysaccharide K, procodazole etc. for molten chain bacterium, krestin, sizofiran, mill.
" somatomedin " in described " medicine of the effect of the cell growth inhibiting factor or growth factor acceptor " can be mentioned any material that promotes cell proliferation, generally be that molecular weight is no more than 20,000, at lower concentration by showing its active peptide with receptors bind, comprise (1) EGF (Urogastron) or [for example have with it basic identical active material, EGF, heregulin (HER2 part) etc.], (2) Regular Insulin or [for example have with it basic identical active material, Regular Insulin, IGF (rhIGF-1)-1, IGF-2 etc.], (3) FGF (fibroblast growth factor) or [for example have with it basic identical active material, acid FGF, 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.], etc.
As the example of described " growth factor receptors " can mention can with any acceptor of above-mentioned somatomedin bonded, comprise EGF acceptor, heregulin acceptor (HER2), insulin receptor, IGF acceptor, FGF acceptor-1 or FGF acceptor-2 etc.
As the example of described " medicine of the effect of the cell growth inhibiting factor " can mention trastuzumab (Herceptin (trade mark): HER2 antibody), imatinib mesilate, ZD1839 or Cetuximab, to antibody (for example rhuMAb-VEGF), antibody, gefitinib, the erlotinib etc. of VEGF to vegf receptor.
Except that said medicine, can use the altheine enzyme, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury haematoporphyrin sodium, the topoisomerase I inhibitor (for example, irinotecan, Hycamtin etc.), topoisomerase II inhibitor (for example sobuzoxane etc.), differentiation inductor (for example, retinoids, vitamins D etc.), angiogenesis inhibitor (Thalidomide for example, SU11248 etc.), the alpha block agent (for example, the tamsulosin hydrochloride, naftopidil, urapidil, alfuzosin, terazosin, Prazosin, silodosin etc.), the serine/threonine kinase inhibitor, endothelin-receptor antagonists (for example atrasentan etc.), proteasome inhibitor (for example bortezomib etc.), Hsp90 inhibitor (for example 17-AAG etc.), spironolactone, minoxidil, 11 Alpha-hydroxy Progesterone, bone resorption inhibition/transfer inhibitor (Zoledronic acid for example, Alendronic Acid, Pamidronic Acid, etidronic acid, Ibandronic acid, clodronic acid) etc.
Above-mentioned in those, LH-RH agonist (for example, goserelin acetate, buserelin, Leuprolide etc.), trastuzumabs (HER2 antibody) etc. are preferred as companion's medicine.
For companion's being used in combination of medicine, the administration time of compound of the present invention and companion's medicine without limits for compound of the present invention.Compound of the present invention and companion's medicine can deliver medicine to the administration object simultaneously, also can be at different time administrations.The dosage of companion's medicine can be determined according to the dosage of clinical use, and can suitably choose according to administration object, route of administration, disease, combination etc.
Administering mode to compound of the present invention and companion's medicine does not have concrete restriction, as long as compound of the present invention and companion's medicine can combination medicine-feedings.The example of this administering mode comprises following method:
(1) compound of the present invention and companion's medicine prepare simultaneously, to obtain the single preparation of administration.(2) compound of the present invention and companion's prescription solely prepare, to obtain two kinds of preparations with the administration simultaneously of identical route of administration.(3) compound of the present invention and companion's prescription solely prepare, to obtain with identical route of administration two kinds of preparations of administration simultaneously not just.(4) compound of the present invention and companion's prescription solely prepare, to obtain two kinds of preparations with the administration simultaneously of different route of administration.(5) compound of the present invention and companion's prescription solely prepare, to obtain with different route of administration two kinds of preparations of administration simultaneously (for example, compound of the present invention and companion's medicine administration in this order are perhaps by opposite order administration) etc. not.
Embodiment
Specifically describe the present invention by following reference example, embodiment, formulation example and experimental example, but these are not construed as limiting to the present invention.
In reference example and embodiment, the column chromatography wash-out is observed by TLC (thin-layer chromatography) and is carried out.In TLC observed, used TLC plate was the Kieselgel 60F that is made by Fuji Silysia Chemical Ltd.
254Plate (Merck) or NH TLC plate, used developping agent are the solvents that uses as eluent in the column chromatography, and used detection means is the UV detector.As the silica gel of post, use the Kieselgel 60F that makes by Merck
254(70-230 sieve mesh) or the Chromatorex NH DM1020 (alkaline silica gel, 100-200 sieve mesh) that makes by Fuji Silysia Chemical Ltd..The ratio of solvent is the volume ratio of mixed solvent in the silica gel chromatography.In addition, % refers to weight percent, except as otherwise noted.
The NMR spectrum as internal standard substance, is used VARIAN Gemini-200 (200MHz type spectrometer) or Gemini-300 (300MHz type spectrometer) or BRUKER AVANCE300 (300MHz type spectrometer) with tetramethylsilane, shows by proton N MR; The δ value is represented with ppm.
The abbreviation that is used for reference example and embodiment is defined as follows:
S: unimodal, br: broad peak, d: bimodal, t: triplet, q: quartet, dd: doublet of doublet, m: multiplet, J: coupling constant, Hz: hertz, DMSO: methyl-sulphoxide
The genetic manipulation method of describing in following experimental example is based at Maniatis etc., MolecularCloning, Cold Spring Harbor Laboratory, 1989 with and the operation of appendix in the method described.
Reference example 1
2-[(2-chloro-4-nitrophenoxy) methyl] preparation of benzonitrile
, add salt of wormwood (3.7g) in the solution in the dinethylformamide (50mL), and mixture was at room temperature stirred 30 minutes at N to 2-chloro-4-nitrophenols (3.5g) and 2-(brooethyl) benzonitrile (4.0g).After reaction is finished, add entry (50mL), and mixture was stirred 10 minutes.Filter and collect the faint yellow solid that generates.Resistates is washed with Di Iso Propyl Ether, and dry, obtain faint yellow crystalline title compound (5.04g).
1H-NMR(CDCl
3)δ5.44(2H，s)，7.13(1H，d，J＝9.0Hz)，7.51(1H，dt，J＝1.2，7.2Hz)，7.68-7.80(3H，m)，8.19(1H，dd，J＝2.7，9.0Hz)，8.35(1H，d，J＝2.7Hz)。
Reference example 2
2-[(4-amino-2-chlorophenoxy) methyl] preparation of benzonitrile
To 2-[(2-chloro-4-nitrophenoxy) methyl] benzonitrile (2.0g) ethanol/water (9: 1,40mL) add in the solution in calcium chloride (90%, 427mg), and mixture stirred 10 minutes down at 100 ℃.At room temperature add reduced iron (90%, 2.6g), and mixture stirred 3 hours down at 100 ℃.After reaction is finished, reaction mixture is filtered (diatomite), and concentrating under reduced pressure filtrate.Water is joined in the resistates, and mixture is diluted with ethyl acetate, and water and saturated brine washing.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (hexane: ethyl acetate: methylene dichloride=2: 1: 1), obtain the title compound (1.2g) of white solid.
1H-NMR(CDCl
3)δ3.53(2H，br?s)，5.23(2H，s)，6.54(1H，dd，J＝2.7，8.7Hz)，6.76(1H，d，J＝2.7Hz)，6.88(1H，d，J＝8.7Hz)，7.42(1H，dt，J＝0.9，7.8Hz)，7.62-7.70(2H，m)，7.81(1H，d，J＝7.8Hz)。
Reference example 3
2-[(2-methyl-4-nitrophenoxy) methyl] preparation of benzonitrile
React according to the method identical,, obtain the title compound (8.2g) of light yellow solid by using 2-methyl-4-nitrophenols (5.0g) and 2-(brooethyl) benzonitrile (6.4g) with reference example 1.
1H-NMR(CDCl
3)δ2.37(3H，s)，5.36(2H，s)，6.97(1H，d，J＝8.4Hz)，7.50(1H，m)，7.65-7.69(2H，m)，7.76(1H，td，J＝0.9，7.5Hz)，8.09-8.14(2H，m)。
Reference example 4
2-[(4-amino-2-methyl phenoxy group) methyl] preparation of benzonitrile
React according to the method identical, by using 2-[(2-methyl-4-nitrophenoxy with reference example 2) methyl] benzonitrile (6.0g), calcium chloride (and 90%, 1.3g) and reduced iron (90%, 8.3g), obtain the title compound (3.7g) of white solid.
1H-NMR(CDCl
3)δ2.24(3H，s)，3.41(2H，br?s)，5.17(2H，s)，6.48(1H，dd，J＝3.0，8.4Hz)，6.56(1H，d，J＝3.0Hz)，6.73(1H，d，J＝8.4Hz)，7.40(1H，dt，J＝1.2，7.5Hz)，7.59-7.71(3H，m)。
Reference example 5
The preparation of 3-(2-chloro-4-nitrophenoxy) benzonitrile
At N, add salt of wormwood (4.4g) to 2-chloro-1-fluoro-4-oil of mirbane (3.7g) and 3-hydroxy benzonitrile (2.5g) in the solution in the dinethylformamide (50mL), and mixture was stirred 4 hours down at 60 ℃.After reaction is finished, add entry (50mL), and mixture was stirred 10 minutes.Filter and collect the faint yellow solid that generates, with the Di Iso Propyl Ether washing, and dry, obtain faint yellow crystalline title compound (5.3g).
1H-NMR(CDCl
3)δ7.03(1H，d，J＝9.0Hz)，7.27-7.33(2H，m)，7.55-7.56(2H，m)，8.15(1H，dd，J＝2.7，9.0Hz)，8.42(1H，d，J＝2.7Hz)。
Reference example 6
The preparation of 3-(4-amino-2-chlorophenoxy) benzonitrile
To the ethanol/water of 3-(2-chloro-4-nitrophenoxy) benzonitrile (2.0g) (9: 1, add in solution 40mL) calcium chloride (90%, 449mg), and mixture stirred 10 minutes down at 100 ℃.At room temperature add reduced iron (90%, 2.7g), and mixture stirred 5 hours down at 100 ℃.After reaction is finished, reaction mixture is filtered (diatomite), and concentrating under reduced pressure filtrate.Water is joined in the resistates, and mixture is diluted with ethyl acetate, and water and saturated brine washing.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (hexane: ethyl acetate=3: 1), obtain the title compound (1.25g) of white solid.
1H-NMR(CDCl
3)δ3.75(2H，br?s)，6.60(1H，dd，J＝2.7，8.4Hz)，6.80(1H，d，J＝2.7Hz)，6.92(1H，d，J＝8.4Hz)，7.06(1H，m)，7.14(1H，m)，7.30(1H，td，J＝1.2，7.5Hz)，7.37(1H，d，J＝7.5Hz)。
Reference example 7
The preparation of 2-fluoro-5-ethyl nitrobenzoate
Down thionyl (two) chlorine (8.02mL) is added drop-wise in the ethanol (200mL) ice-cooled, and adds 2-fluoro-5-nitrobenzoic acid (13.81g).This mixture was stirred 4 hours down at 80 ℃.And concentrating under reduced pressure.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure obtains the title compound (15.77g) of faint yellow oily thing.
1H-NMR(CDCl
3)δ：1.43(3H，t，J＝7.2Hz)，4.46(2H，q，J＝7.2Hz)，7.32(1H，t，J＝9.1Hz)，8.41(1H，ddd，J＝9.1，4.3，3.0Hz)，8.85(1H，dd，J＝6.1，3.0Hz)。
Reference example 8
The preparation of 5-amino-2-phenoxy benzoic acid ethyl ester
With 2-fluoro-5-ethyl nitrobenzoate (1.07g), phenol (565mg), salt of wormwood (1.38g) and N, the mixture of dinethylformamide (20mL) stirred 4 hours down at 80 ℃.The concentrating under reduced pressure reaction mixture.Water is joined in the resistates, and with the mixture ethyl acetate extraction.Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, ethyl acetate: hexane=20: 80 → 30: 70).Concentrating under reduced pressure target fraction, and ethanol (20mL) and 10% palladium/carbon (1.5g) joined in the resistates (1.54g).Mixture stirred under hydrogen stream spend the night.Leach catalyzer, and concentrated filtrate.The resistates that obtains is passed through silica gel column chromatography purifying (elutriant, ethyl acetate: hexane=20: 80 → 50: 50), and by Di Iso Propyl Ether-hexane recrystallization, obtain the title compound (1.07g) of light brown powder shape.
1H-NMR(CDCl
3)δ：1.12(3H，t，J＝7.2Hz)，3.71(2H，s)，4.17(2H，q，J＝7.2Hz)，6.80-6.87(3H，m)，6.91(1H，d，J＝8.5Hz)，6.97(1H，t，J＝7.3Hz)，7.21-7.30(3H，m)。
Reference example 9
4-{[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } methyl benzoate and 4-{[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } preparation of methyl benzoate
Under ice-cooled, to the N of 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidines (400mg), add 60% sodium hydride (98mg) in the solution of dinethylformamide (8mL), and mixture was at room temperature stirred 10 minutes.Add 4-(brooethyl) methyl benzoate (606mg) down ice-cooled then, and mixture was at room temperature stirred 30 minutes.After reaction is finished, mixture is diluted with ethyl acetate, and wash with saturated sodium bicarbonate aqueous solution and saturated brine.The concentrating under reduced pressure organic layer, and resistates carried out silica gel column chromatography (hexane: ethyl acetate=2: 1 → 1: 2), obtaining all is 4-{[7-(the methylthio group)-1H-pyrazolo [4 of light yellow solid, 3-d] pyrimidine-1-yl] methyl } methyl benzoate (251mg) and 4-{[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } methyl benzoate (450mg).
4-{[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } methyl benzoate:
1H-NMR (CDCl
3) δ 2.71 (3H, s), 3.89 (3H, s), 5.93 (2H, s), 7.22 (2H, d, J=8.1Hz), 7.98 (2H, d, J=8.1Hz), 8.23 (1H, s), 8.80 (1H, s).
4-{[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } methyl benzoate:
1H-NMR (CDCl
3) δ 2.73 (3H, s), 3.92 (3H, s), 5.69 (2H, s), 7.34 (2H, d, J=8.4Hz), 8.03 (2H, d, J=8.4Hz), 8.04 (1H, s), 8.73 (1H, s).
Reference example 10
2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] ethylamino benzonitrile acid esters and 2-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of ethylamino benzonitrile acid esters
N to 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidines (300mg) and 2-iodine ethylamino benzonitrile acid esters (548mg) adds salt of wormwood (374mg) in the solution of dinethylformamide (10mL), and mixture was stirred 1 hour down at 60 ℃.After reaction is finished, water is joined in the reaction mixture.Mixture is diluted with ethyl acetate, and water and saturated brine washing.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (hexane: ethyl acetate=3: 2), obtaining all is 2-[7-(the methylthio group)-1H-pyrazolo [4 of light yellow solid, 3-d] pyrimidine-1-yl] ethylamino benzonitrile acid esters (266mg) and 2-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] ethylamino benzonitrile acid esters (191mg).
2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] the ethylamino benzonitrile acid esters:
1H-NMR (CDCl
3) δ 2.66 (3H, s), 4.78 (2H, t, J=5.4Hz), 5.06 (2H, t, J=5.4Hz), 7.27-7.40 (2H, m), 7.53 (1H, m), 7.85-7.89 (2H, m), 8.20 (1H, s), 8.79 (1H, s).
2-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] the ethylamino benzonitrile acid esters:
1H-NMR (CDCl
3) δ 2.73 (3H, s), 4.80-4.86 (4H, m), 7.40-7.46 (2H, m), 7.58 (1H, m), 7.94-7.97 (2H, m), 8.20 (1H, s), 8.73 (1H, s).
Reference example 11
3-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] propylbenzoic acid ester and 3-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of propylbenzoic acid ester
React according to the method identical with reference example 10, by using 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (600mg), 3-iodine propylbenzoic acid ester (1.15g) and salt of wormwood (748mg), obtaining all is 3-[7-(the methylthio group)-1H-pyrazolo [4 of light yellow solid, 3-d] pyrimidine-1-yl] propylbenzoic acid ester (623mg) and 3-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] propylbenzoic acid ester (556mg).
3-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] the propylbenzoic acid ester:
1H-NMR (CDCl
3) δ 2.40-2.47 (2H, m), 2.66 (3H, s), 4.42 (2H, t, J=5.7Hz), 4.88 (2H, t, J=7.2Hz), 7.42-7.46 (2H, m), 7.57 (1H, m), 7.98-8.02 (2H, m), 8.15 (1H, s), 8.73 (1H, s).
3-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] the propylbenzoic acid ester:
1H-NMR (CDCl
3) δ 2.52-2.58 (2H, m), 2.72 (3H, s), 4.39 (2H, t, J=6.0Hz), 4.65 (2H, t, J=6.9Hz), 7.40-7.46 (2H, m), 7.57 (1H, m), 7.96-8.02 (2H, m), 8.14 (1H, s), 8.71 (1H, s).
Embodiment 1
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (770mg) and 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (2.52g) is dissolved in the 1-Methyl-2-Pyrrolidone (10mL), and with mixture 140 ℃ of following heated and stirred 2.5 hours.After being cooled to room temperature, mixture being diluted with ethyl acetate (300mL), and at room temperature stirred 1 hour.Filter the powder of collecting precipitation, with ethyl acetate (30mL) washing, and drying under reduced pressure, obtain title compound (1.62g).
1H-NMR(DMSO-d
6)δ：5.27(2H，s)，6.63(1H，d，J＝3Hz)，7.0-7.5(5H，m)，7.78(1H，dd，J＝3Hz，9Hz)，8.00(1H，m)，8.15(1H，d，J＝3Hz)，8.79(1H，s)，11.79(1H，br?s)。
Embodiment 2
(4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } phenyl) preparation of methyl alcohol
(i) preparation of { 4-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl] phenyl } methyl alcohol
4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (307mg) are dissolved in N, in the dinethylformamide (2mL), add salt of wormwood (304mg), and mixture was at room temperature stirred 30 minutes.Add 4-hydroxymethylbenzyl chlorine (377mg), and mixture was at room temperature stirred 16 hours.After water (30mL) dilution, mixture is extracted with ethyl acetate/tetrahydrofuran (THF) (3: 1,80mL * 2).With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), obtain pulverous title compound (383mg).
1H-NMR(CDCl
3)δ：2.15(1H，br?s)，4.69(2H，d，J＝4Hz)，5.71(2H，s)，6.76(1H，m)，7.06(2H，d，J＝8Hz)，7.34(2H，d，J＝8Hz)，7.50(1H，d，J＝3Hz)，8.69(1H，s)。
(ii) (4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } phenyl) preparation of methyl alcohol
With { 4-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl] phenyl methyl alcohol (354mg) and 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (488mg) is dissolved in the 1-Methyl-2-Pyrrolidone (2.58mL), and with mixture in 140 ℃ of following heated and stirred 2 hours.After being cooled to room temperature, reaction mixture is diluted with ethyl acetate (80mL), and distribute with saturated sodium bicarbonate aqueous solution (30mL).Organic layer is washed with saturated brine (30mL), through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), obtain pulverous title compound (588mg).
1H-NMR(CDCl
3)δ：4.77(2H，s)，5.07(2H，s)，5.52(2H，s)，6.26(2H，s)，6.64(1H，d，J＝3Hz)，6.81(1H，d，J＝9Hz)，6.9-7.4(8H，m)，7.49(2H，d，J＝8Hz)，8.44(1H，s)。
Embodiment 3
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(3,4-dimethoxy benzoyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
Under ice-cooled, to N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate (150mg) and salt of wormwood (102mg) is at N, add 3 in the suspension in the dinethylformamide (1.5mL), 4-dimethoxy-benzoyl chloride (82mg), and mixture stirred 1 hour down ice-cooled.Mixture is distributed between ethyl acetate (50mL) and water (30mL).Organic layer is washed with saturated brine (30mL), through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → ethyl acetate: methyl alcohol=80: 20), and by the Di Iso Propyl Ether crystallization, obtain title compound (104mg).
1H-NMR(CDCl
3)δ：3.97(3H，s)，4.01(3H，s)，5.14(2H，s)，6.72(1H，d，J＝3Hz)，6.9-7.6(10H，m)，7.88(2H，d，J＝3Hz)，8.63(1H，s)，9.75(1H，br?s)。
Embodiment 4
(4-{[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } phenyl) preparation of methyl alcohol
React according to the method (ii) identical with embodiment 2, by using { 4-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl] phenyl } methyl alcohol (200mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (235mg) and 1-Methyl-2-Pyrrolidone (1.46mL), obtain crystalline title compound (242mg).
1H-NMR(CDCl
3)δ：2.14(3H，s)，2.50(3H，s)，3.01(1H，br?s)，4.75(2H，s)，5.53(2H，s)，6.38(1H，br?s)，6.64(1H，d，J＝3Hz)，6.75(1H，d，J＝9Hz)，6.8-7.2(6H，m)，7.34(2H，d，J＝3Hz)，7.47(1H，d，J＝9Hz)，809(1H，m)，8.46(1H，s)。
Embodiment 5
N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (ii) identical with embodiment 2, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (200mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (418mg) and 1-Methyl-2-Pyrrolidone (2.6mL), obtain crystalline title compound (283mg).
1H-NMR(CDCl
3)δ：2.16(3H，s)，2.51(3H，s)，6.56(1H，d，J＝3Hz)，6.80(1H，d，J＝9Hz)，7.0-7.6(5H，m)，817(1H，m)，8.59(1H，s)，8.76(1H，br?s)，11.08(1H，br?s)。
Embodiment 6
4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } preparation of methyl benzoate
(i) methyl 4-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)] preparation of methyl benzoate
React according to the method identical with embodiment 2 (i), by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (710mg), 4-(brooethyl) methyl benzoate (1.27g), salt of wormwood (703mg) and N, dinethylformamide (9.2mL) obtains pulverous title compound (1.0g).
1H-NMR(CDCl
3)δ：3.90(3H，s)，5.77(2H，s)，6.83(1H，d，J＝3Hz)，7.08(2H，d，J＝8Hz)，7.53(1H，d，J＝3Hz)，8.00(2H，d，J＝8Hz)，8.73(1H，s)。
(ii) 4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } preparation of methyl benzoate
React according to the method (ii) identical with embodiment 2, by using 4-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl] methyl benzoate (1.0g), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (1.25g) and 1-Methyl-2-Pyrrolidone (6.63mL), obtain pulverous title compound (1.35g).
1H-NMR(CDCl
3)δ：3.93(3H，s)，5.07(2H，s)，5.57(2H，s)，6.10(2H，br?s)，6.68(1H，d，J＝3Hz)，6.7-7.4(10H，m)，8.11(2H，d，J＝9Hz)，8.47(1H，s)。
Embodiment 7
4-{[4-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } benzoic preparation
With 4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } methyl benzoate (850mg) is dissolved in ethanol (3.29mL)/tetrahydrofuran (THF) (3.29mL) mixed solvent, add 1N aqueous sodium hydroxide solution (3.29mL), and mixture was at room temperature stirred 20 hours.(3.29mL) joins in the reaction mixture with 1N hydrochloric acid, and mixture water (20mL) is diluted.Filter the crystallization of collecting precipitation, water (10mL) washing, and drying under reduced pressure obtain title compound (738mg).
1H-NMR(DMSO-d
6)δ：5.21(2H，s)，5.94(2H，s)，6.62(1H，d，J＝3Hz)，7.0-7.6(9H，m)，7.84(2H，d，J＝9Hz)，7.91(1H，d，J＝3Hz)，8.40(1H，s)，8.81(1H，br?s)，12.88(1H，br?s)。
Embodiment 8
1-(4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } benzoyl) preparation of piperidines-4-alcohol
At room temperature, to 4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } phenylformic acid (150mg), 4-hydroxy piperidine (33.2mg) and I-hydroxybenzotriazole monohydrate (60mg) be at N, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg) and triethylamine (0.208mL) in the mixture in the dinethylformamide (3mL), and mixture at room temperature stirred spend the night.Mixture is distributed between ethyl acetate (50mL) and water (30mL).Organic layer is washed with saturated brine (30mL), through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=80: 20), and by the Di Iso Propyl Ether crystallization, obtain title compound (168mg).
1H-NMR(CDCl
3)δ：1.4-2.1(5H，m)，3.0-3.7(3H，m)，3.97(1H，m)，4.16(1H，m)，5.08(2H，s)，5.55(2H，s)，6.33(1H，br?s)，6.66(1H，d，J＝3Hz)，6.82(1H，d，J＝9Hz)，6.9-7.5(11H，m)，8.47(1H，s)。
Embodiment 9
6-(3-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) oxygen base 6-chloro-N-{3-methyl-4-[(6-picoline-3-yl)] phenyl }-preparation of 5-nitro-pyrimidine-4-amine hydrochlorate
With 4,6-two chloro-5-nitro-pyrimidines (9.7g) are dissolved in the 1-Methyl-2-Pyrrolidone (25.7mL), under-15 ℃ of coolings, drip 3-methyl-4-[(6-picoline-3-yl) the oxygen base] 1-Methyl-2-Pyrrolidone (10mL) solution of aniline (5.35g), and mixture stirred 1 hour down at-10 ℃ to 0 ℃.Mixture is diluted with ethyl acetate (100mL), and stirred 15 minutes down in 0 ℃.Filter the crystallization of collecting precipitation, with ethyl acetate (30mL) washing, and drying under reduced pressure, obtain title compound (7.34g).
1H-NMR(DMSO-d
6)δ：2.20(3H，s)，2.67(3H，s)，7.0-8.0(5H，m)，8.44(1H，m)，8.55(1H，s)，10.14(1H，br?s)。
(ii) 6-chloro-N4-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } pyrimidine-4, the preparation of 5-diamines
With 6-chloro-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5-nitro-pyrimidine-4-amine hydrochlorate (2.04g) is suspended in the ether (9.45mL), and at ice-cooled concentrated hydrochloric acid (20.17mL) solution that adds tin chloride (IV) dihydrate (9.1g) down.After at room temperature stirring 3 hours, reaction mixture is poured in the frozen water (400mL).Dropwise 5 0% aqueous sodium hydroxide solution (18mL) is to regulate pH to 8.Add ethyl acetate (300mL), and mixture is passed through diatomite filtration.Through dried over mgso, and concentrating under reduced pressure obtains title compound (1.30g) with organic layer.
1H-NMR(CDCl
3)δ：2.23(3H，s)，2.52(3H，s)，6.85(1H，d，J＝9Hz)，7.0-7.5(4H，m)，8.16(1H，s)，8.21(1H，d，J＝3Hz)。
(iii) 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } pyrimidine-4, the preparation of 5-diamines hydriodate
With 6-chloro-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl pyrimidine-4,5-diamines (400mg) is suspended in 55% hydroiodic acid HI (6.16mL), adds sodium iodide (878mg), and with mixture in 70 ℃ of following heated and stirred 10 minutes.After being cooled to room temperature, add entry (40mL)/ethyl acetate (30mL).Regulate its pH after be not less than 7 with sodium bicarbonate aqueous solution, and mixture was at room temperature stirred 15 minutes.Through dried over mgso, and concentrating under reduced pressure obtains title compound (626mg) with organic layer.
1H-NMR(CDCl
3)δ：2.19(3H，s)，2.52(3H，s)，4.23(2H，br?s)，6.81(1H，d，J＝9Hz)，7.0-7.5(5H，m)，7.97(1H，s)，8.18(1H，d，J＝3Hz)。
(iv) 6-[(3-aminophenyl) ethynyl]-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4, the preparation of 5-diamines
With 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines hydriodate (200mg) is dissolved in the mixed solvent of acetonitrile (7.6mL)/triethylamine (5.72mL), add successively 3-ethynyl aniline (0.0574mL), anti--two (triphenylphosphine) palladium chloride (II) (15.4mg) and cuprous iodide (I) (5.3mg), and mixture at room temperature stirred under nitrogen gas stream 1.5 hours.The concentrating under reduced pressure reaction mixture, and separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → ethyl acetate: methyl alcohol=80: 20), obtain title compound (157mg).
1H-NMR(CDCl
3)δ：2.19(3H，s)，2.51(3H，s)，3.65(2H，br?s)，4.37(2H，brs)，6.6-7.5(9H，m)，7.50(1H，br?s)，8.19(1H，d，J＝3Hz)，8.29(1H，s)。
(v) 6-(3-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With the 6-[(3-aminophenyl) ethynyl]-4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines (140mg) is dissolved in N, in the dinethylformamide (0.82mL), add cuprous iodide (I) (6.3mg), and with mixture under nitrogen gas stream in 110 ℃ of following heated and stirred 16 hours.After being cooled to room temperature, reaction mixture being diluted with methylene dichloride (20mL), and pass through diatomite filtration.Concentrating under reduced pressure filtrate, and separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → 85: 15), and by the Di Iso Propyl Ether crystallization, obtain title compound (76mg).
1H-NMR(DMSO-d
6)δ：2.22(3H，s)，2.44(3H，s)，5.32(2H，br?s)，6.65(1H，d，J＝7Hz)，6.76(1H，d，J＝2Hz)，6.9-7.3(6H，m)，7.75(1H，dd，J＝3Hz，9Hz)，7.83(1H，d，J＝2Hz)，8.18(1H，d，J＝3Hz)，8.34(1H，s)，9.14(1H，br?s)，11.47(1H，br?s)。
Embodiment 10
6-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) ethynyl 6-[(4-aminophenyl)]-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4, the preparation of 5-diamines
With 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines hydriodate (270mg) is dissolved in the mixed solvent of acetonitrile (10.3mL)/triethylamine (7.72mL), and add successively 4-ethynyl aniline (80.3mg), anti--two (triphenylphosphine) palladium chloride (II) (20.8mg) and cuprous iodide (I) (7.16mg).React by the method (iv) identical and to obtain pulverous title compound (134mg) with embodiment 9.
1H-NMR(CDCl
3)δ：2.20(3H，s)，2.51(3H，s)，4.00(4H，br?s)，6.60(2H，d，J＝9Hz)，6.83(1H，d，J＝9Hz)，7.0-7.5(6H，m)，8.21(1H，m)，8.29(1H，s)。
(ii) 6-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
According to (v) identical method is reacted with embodiment 9, by using the 6-[(4-aminophenyl) ethynyl]-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines (160mg) and cuprous iodide (I) (7.2mg) obtain pulverous title compound (68mg).
1H-NMR(DMSO-d
6)δ：2.21(3H，s)，2.44(3H，s)，5.58(2H，br?s)，6.70(2H，d，J＝9Hz)，6.99(1H，d，J＝2Hz)，7.20(2H，m)，7.56(1H，d，J＝9Hz)，7.75(1H，dd，J＝2Hz，9Hz)，7.81(1H，d，J＝2Hz)，8.18(1H，d，J＝2Hz)，8.32(1H，s)，9.12(1H，br?s)，11.38(1H，br?s)。
Embodiment 11
2-methoxyl group-N-{4-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] phenyl } preparation of ethanamide
At room temperature, to 6-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (40mg), methoxyacetic acid (0.0145mL) and I-hydroxybenzotriazole monohydrate (38mg) be at N, adds 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (54mg) and triethylamine (0.079mL) in the mixture in the dinethylformamide (1.9mL).After at room temperature stirring is spent the night, reaction mixture is diluted with methylene dichloride (10mL).Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=85: 15), and by the Di Iso Propyl Ether crystallization, obtain title compound (24mg).
1H-NMR(DMSO-d
6)δ：2.21(3H，s)，2.43(3H，s)，3.39(3H，s)，4.04(2H，s)，6.91(1H，d，J＝2Hz)，6.99(1H，d，J＝9Hz)，7.20(2H，m)，7.7-7.9(6H，m)，8.17(1H，d，J＝3Hz)，8.33(1H，s)，9.07(1H，br?s)，9.97(1H，br?s)，11.52(1H，br?s)。
Embodiment 12
6-(4-p-methoxy-phenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate
(i) preparation of 6-(4-p-methoxy-phenyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-alcohol
3-amino-5-(4-p-methoxy-phenyl)-1H-pyrroles-2-carboxyl ethyl ester (7.2g) is dissolved in tetrahydrofuran (THF) (16mL)/ethanol (32mL), adds carbonamidine (3.46g), and mixture was stirred 16 hours down at 90 ℃.After being cooled to room temperature, the reduction vaporization tetrahydrofuran (THF).Resistates is diluted with ethanol (20mL), and filter the powder of collecting precipitation, with ethanol (15mL) washing, and drying under reduced pressure, obtain title compound (769mg).
1H-NMR(DMSO-d
6)δ：3.80(3H，s)，6.76(1H，s)，6.9-7.1(3H，m)，7.7-8.0(2H，m)，11.83(1H，br?s)。
The (ii) preparation of 4-chloro-6-(4-p-methoxy-phenyl)-5H-pyrrolo-[3,2-d] pyrimidine
With 6-(4-p-methoxy-phenyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-alcohol (500mg) is suspended in N, and N-Diethyl Aniline (1.11mL)/1 is in the 2-ethylene dichloride (3.73mL), add phosphoryl chloride (2.29mL), and with mixture in 110 ℃ of following heated and stirred 2 hours.After being cooled to room temperature, reaction mixture is handled with frozen water (20mL), and with ammoniacal liquor be adjusted to pH be 7 or more than.After tetrahydrofuran (THF) (500mL) dilution, mixture is washed with saturated brine (50mL).With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 20: 80), obtain title compound (25mg).
1H-NMR(CDCl
3)δ：3.90(3H，s)，6.92(1H，s)，7.05(2H，d，J＝9Hz)，7.71(2H，d，J＝9Hz)，8.73(1H，s)。
(iii) 6-(4-p-methoxy-phenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate
React according to the method identical with embodiment 1, by using 4-chloro-6-(4-p-methoxy-phenyl)-5H-pyrrolo-[3,2-d] pyrimidine (13mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (16mg) and 1-Methyl-2-Pyrrolidone (0.2mL), obtain crystalline title compound (11mg).
1H-NMR(DMSO-d
6)δ：2.24(3H，s)，2.46(3H，s)，3.86(3H，s)，7.02(1H，s)，7.14(2H，d，J＝9Hz)，7.26(2H，m)，7.80(1H，dd，J＝3Hz，9Hz)，7.90(1H，d，J＝3Hz)，8.11(2H，d，J＝9Hz)，8.22(1H，d，J＝3Hz)，8.72(1H，s)，11.54(1H，brs)。
Embodiment 13
(2E)-and 3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
(i) (2E)-and 5-[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino) pyrimidine-4-yl]-preparation of 2-amylene-4-alkynes-1-alcohol
With 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines hydriodate (507mg) is dissolved in the mixed solvent of acetonitrile (19.4mL)/triethylamine (14.5mL), add successively 2-amylene-4-alkynes-1-alcohol (106mg), anti--two (triphenylphosphine) palladium chloride (II) (38.8mg) and cuprous iodide (I) (13.4mg).React by the method (iv) identical, obtain pulverous title compound (373mg) with embodiment 9.
1H-NMR(DMSO-d
6)δ：2.17(3H，s)，2.43(3H，s)，4.12(2H，m)，5.52(2H，br?s)，6.05(1H，dt，J＝2Hz，16Hz)，6.53(1H，dt，J＝5Hz，16Hz)，6.93(1H，d，J＝9Hz)，7.20(2H，m)，7.63(2H，m)，7.96(1H，s)，8.15(1H，d，J＝3Hz)，8.57(1H，br?s)。
(ii) (2E)-3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
According to (v) identical method is reacted with embodiment 9, by using (2E)-5-[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino) pyrimidine-4-yl]-2-amylene-4-alkynes-1-alcohol (200mg), cuprous iodide (I) are (9.8mg) and N, dinethylformamide (1.29mL), and, obtain title compound (59mg) by the Di Iso Propyl Ether crystallization.
1H-NMR(DMSO-d
6)δ：2.20(3H，s)，2.43(3H，s)，4.22(2H，d，J＝3Hz)，6.45(1H，m)，6.50(1H，s)，6.67(1H，dt，J＝16Hz)，6.98(1H，d，J＝9Hz)，7.19(2H，m)，7.72(1H，dd，J＝3Hz，9Hz)，7.80(1H，d，J＝2Hz)，8.17(1H，d，J＝2Hz)，8.30(1H，s)，9.02(1H，br?s)，11.30(1H，br?s)。
Embodiment 14
6-[3-(amino methyl) phenyl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) 3-{[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino) pyrimidine-4-yl] ethynyl } preparation of benzylamino t-butyl formate
With 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines hydriodate (500mg) is dissolved in the mixed solvent of acetonitrile (14.8mL)/triethylamine (11.0mL), and add successively 3-ethynyl benzylamino t-butyl formate (247mg), anti--two (triphenylphosphine) palladium chloride (II) (31.3mg) and cuprous iodide (I) (10.2mg).React by the method (iv) identical, obtain pulverous title compound (376mg) with embodiment 9.
1H-NMR(CDCl
3)δ：1.47(9H，s)，2.24(3H，s)，2.53(3H，s)，4.00(2H，br?s)，4.32(2H，d，J＝6Hz)，5.04(1H，br?s)，6.87(1H，d，J＝9Hz)，7.01(1H，br?s)，7.09-7.5(9H，m)，8.22(1H，d，J＝2Hz)，8.34(1H，s)。
(ii) 3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of benzylamino t-butyl formate
According to (v) identical method is reacted with embodiment 9, by using 3-{[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl amino) pyrimidine-4-yl] ethynyl benzylamino t-butyl formate (363mg) and cuprous iodide (I) (12.9mg), obtain pulverous title compound (287mg).
1H-NMR(CDCl
3)δ：1.49(9H，s)，2.17(3H，s)，2.51(3H，s)，4.23(2H，br?s)，5.67(1H，br?s)，6.72(1H，s)，6.82(1H，d，J＝8Hz)，6.9-7.7(8H，m)，8.16(1H，brs)，8.60(1H，s)，8.66(1H，br?s)，10.64(1H，br?s)。
(iii) 6-[3-(amino methyl) phenyl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] benzylamino t-butyl formate (230mg) is suspended in the tetrahydrofuran (THF) (2.3mL), add 2N hydrochloric acid (2.3mL), and with mixture in 60 ℃ of following heated and stirred 3 hours.After being cooled to room temperature, add 1N aqueous sodium hydroxide solution (4.6mL), and mixture was at room temperature stirred 5 minutes.Decant removes and desolvates, and resistates is dissolved in the tetrahydrofuran (THF) (30mL), through the salt of wormwood drying, and concentrating under reduced pressure.Resistates is ground with Di Iso Propyl Ether, filter and collect and drying under reduced pressure, obtain title compound (164mg).
1H-NMR(DMSO-d
6)δ：2.18(3H，s)，2.41(3H，s)，3.92(2H，br?s)，4.86(2H，br?s)，6.9-8.2(11H，m)，8.33(1H，s)，9.62(1H，br?s)，12.13(1H，br?s)。
Embodiment 15
2-methoxyl group-N-{3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] benzyl } preparation of ethanamide
React according to the method identical with embodiment 11, by using 6-[3-(amino methyl) phenyl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (50mg), methoxyacetic acid (0.01055mL), I-hydroxybenzotriazole monohydrate (23.2mg), N, dinethylformamide (2.3ml), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (32.9mg) and triethylamine (0.080mL) obtain title compound (56mg).
1H-NMR(DMSO-d
6)δ：2.27(3H，s)，2.52(3H，s)，3.44(3H，s)，3.98(2H，s)，4.56(2H，d，J＝6Hz)，6.65(1H，s)，6.82(1H，d，J＝2Hz)，6.93(1H，d，J＝8Hz)，7.11(2H，m)，7.3-7.9(6H，m)，8.22(1H，m)，8.47(1H，s)，8.82(1H，br?s)，11.26(1H，br?s)。
Embodiment 16
6-(amino methyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) 3-[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino) pyrimidine-4-yl]-preparation of 2-propynyl t-butyl carbamate
With 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines hydriodate (500mg) is dissolved in the mixed solvent of acetonitrile (14.8mL)/triethylamine (11.0mL), and add successively 2-propynyl t-butyl carbamate (166mg), anti--two (triphenylphosphine) palladium chloride (II) (31.3mg) and cuprous iodide (I) (10.2mg).React by the method (iv) identical, obtain pulverous title compound (303mg) with embodiment 9.
1H-NMR(CDCl
3)δ：1.46(9H，s)，2.22(3H，s)，2.52(3H，s)，4.06(2H，br?s)，4.17(2H，d，J＝6Hz)，5.09(1H，br?s)，6.84(1H，d，J＝9Hz)，7.0-7.5(4H，m)，8.20(1H，d，J＝3Hz)，8.25(1H，s)。
(ii) [4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of the methyl carbamic acid tert-butyl ester
According to (v) identical method is reacted with embodiment 9, by using 3-[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl amino) pyrimidine-4-yl]-2-propynyl t-butyl carbamate (286mg) and cuprous iodide (I) (11.8mg), obtain pulverous title compound (212mg).
1H-NMR(CDCl
3)δ：1.38(9H，s)，2.20(3H，s)，2.52(3H，s)，4.30(2H，d，J＝6Hz)，5.38(1H，t，J＝6Hz)，6.32(1H，br?s)，6.83(1H，d，J＝9Hz)，7.07(1H，d，J＝9Hz)，7.1-7.4(4H，m)，7.84(1H，br?s)，8.20(1H，d，J＝2Hz)，8.50(1H，s)，9.95(1H，br?s)。
(iii) 6-(amino methyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (iii) identical with embodiment 14, by using [4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] the methyl carbamic acid tert-butyl ester (165mg), 2N hydrochloric acid (1.92mL) and tetrahydrofuran (THF) (1.92mL), obtain pulverous title compound (160mg).
1H-NMR(DMSO-d
6)δ：2.17(3H，s)，2.42(3H，s)，3.59(2H，t，J＝6Hz)，3.95(2H，s)，6.25(1H，s)，6.86(1H，s)，6.94(1H，d，J＝8Hz)，7.1-7.3(2H，m)，7.78(2H，m)，8.14(1H，d，J＝3Hz)，8.26(1H，s)，9.46(1H，br?s)，11.50(1H，brs)。
Embodiment 17
(2E)-and 4-(dimethylamino)-N-{[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] methyl }-preparation of 2-butylene acid amides
React according to the method identical with embodiment 11, by using 6-(amino methyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (40mg), (2E)-4-(dimethylamino)-2-butylene acid hydrochloride (22mg), I-hydroxybenzotriazole monohydrate (22.5mg), N, dinethylformamide (2.2mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (31.9mg) and triethylamine (0.0928mL) obtain title compound (32mg).
1H-NMR(DMSO-d
6)δ：2.15(6H，s)，2.19(3H，s)，2.43(3H，s)，3.01(2H，d，J＝5Hz)，4.55(2H，d，J＝5Hz)，6.12(1H，d，J＝16Hz)，6.36(1H，d，J＝1Hz)，6.68(1H，m)，6.96(1H，d，J＝8Hz)，7.18(2H，m)，7.74(2H，m)，8.16(1H，d，J＝3Hz)，8.30(1H，s)，8.70(1H，t，J＝5Hz)，9.30(1H，br?s)，11.03(1H，br?s)。
Embodiment 18
6-[(1E)-3-amino-1-propylene-1-yl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) (2E)-and 5-[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino) pyrimidine-4-yl]-preparation of 2-amylene-4-alkynes-1-aminocarbamic acid tert-butyl ester
With 6-iodo-N4-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl } pyrimidine-4,5-diamines hydriodate (500mg) is dissolved in the mixed solvent of acetonitrile (14.8mL)/triethylamine (11.0mL), and add successively (2E)-2-amylene-4-alkynes-1-aminocarbamic acid tert-butyl ester (194mg), anti--two (triphenylphosphine) palladium chloride (II) (31.3mg) and cuprous iodide (I) (10.2mg).By reacting, obtain pulverous title compound (199mg) according to the method (iv) identical with embodiment 9.
1H-NMR(CDCl
3)δ：1.46(9H，s)，2.20(3H，s)，2.52(3H，s)，3.85(2H，m)，4.22(2H，br?s)，5.02(1H，br?s)，5.84(1H，d，J＝16Hz)，6.29(1H，m)，6.84(1H，d，J＝9Hz)，7.0-7.5(5H，m)，8.19(1H，d，J＝2Hz)，8.26(1H，s)。
(ii) (2E)-3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propenyl t-butyl carbamate
According to (v) identical method is reacted with embodiment 9, by using (2E)-5-[5-amino-6-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl amino) pyrimidine-4-yl]-2-amylene-4-alkynes-1-aminocarbamic acid tert-butyl ester (195mg) and cuprous iodide (I) (7.63mg), obtain pulverous title compound (66mg).
1H-NMR(CDCl
3)δ：1.44(9H，s)，2.12(3H，s)，2.49(3H，s)，3.82(2H，br?s)，5.53(1H，br?s)，6.00(1H，d，J＝16Hz)，6.36(1H，m)，6.77(1H，d，J＝9Hz)，7.0-7.5(4H，m)，8.09(1H，s)，8.43(1H，br?s)，8.51(1H，br?s)，11.00(1H，br?s)。
(iii) 6-[(1E)-3-amino-1-propylene-1-yl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (iii) identical with embodiment 14, by using (2E)-3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-2-propenyl t-butyl carbamate (65mg), 2N hydrochloric acid (0.755mL) and tetrahydrofuran (THF) (0.755mL), obtain pulverous title compound (41mg).
1H-NMR(DMSO-d
6)δ：2.17(3H，s)，2.42(3H，s)，3.41(2H，m)，6.40(1H，s)，6.62(2H，m)，6.96(1H，d，J＝8Hz)，7.17(2H，m)，7.95(2H，m)，8.16(1H，d，J＝3Hz)，8.28(1H，s)，10.09(1H，br?s)，12.43(1H，br?s)。
Embodiment 19
2-methoxyl group-N-{ (2E)-3-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-the 2-propenyl } preparation of ethanamide
React according to the method identical with embodiment 11, by using 6-[(1E)-the amino propylene of 3--1-yl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (50mg), methoxyacetic acid (0.0119mL), I-hydroxybenzotriazole monohydrate (26.2mg), N, dinethylformamide (2.56mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (37.2mg) and triethylamine (0.090mL) obtain title compound (15mg).
1H-NMR(DMSO-d
6)δ：2.20(3H，s)，2.43(3H，s)，3.36(3H，s)，3.88(2H，s)，3.97(2H，t，J＝5Hz)，6.32(1H，m)，6.49(1H，d，J＝1Hz)，6.56(1H，d，J＝17Hz)，6.97(1H，d，J＝9Hz)，7.19(2H，m)，7.75(2H，m)，8.15(1H，d，J＝2Hz)，8.24(1H，t，J＝5Hz)，8.29(1H，s)，9.04(1H，br?s)，11.33(1H，br?s)。
Embodiment 20
(2E)-and 3-[5-ethyl-4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
(i) preparation of 4-iodo-6-phenoxy pyrimidine-5-amine
With 4,6-two iodine pyrimidines-5-amine (2.2g) is dissolved in the 1-Methyl-2-Pyrrolidone (11.5mL), adds phenol (656mg) and salt of wormwood (964mg), and mixture was stirred 16 hours down at 100 ℃.After being cooled to room temperature, mixture is diluted with ethyl acetate (200mL), and water (100mL) and saturated brine (100mL) washing successively.With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 20: 80), obtain buttery title compound (2.0g).
1H-NMR(CDCl
3)δ：4.34(2H，br?s)，7.1-7.5(5H，m)，7.87(1H，s)。
(ii) 4-((3E)-5-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the pirylene base)-preparation of 6-phenoxy pyrimidine-5-amine
4-iodo-6-phenoxy pyrimidine-5-amine (1.0g) is dissolved in the mixed solvent of acetonitrile (53mL)/triethylamine (39mL), and add successively the tertiary butyl (dimethyl) [(2E)-2-amylene-4-alkynyloxy base] silane (753mg), anti--two (triphenylphosphine) palladium chloride (II) (112mg) and cuprous iodide (I) (36.5mg).React by the method (iv) identical, obtain crystalline title compound (1.07g) with embodiment 9.
1H-NMR(CDCl
3)δ：0.09(6H，s)，0.93(9H，s)，4.32(2H，m)，4.42(2H，br?s)，6.08(1H，dt，J＝16Hz，3Hz)，6.48(1H，dt，J＝16Hz，4Hz)，7.1-7.5(5H，m)，8.11(1H，s)。
(iii) 6-((1E)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-propenyl)-preparation of 4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine
According to (v) identical method is reacted with embodiment 9, by use 4-((3E)-5-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the pirylene base)-6-phenoxy pyrimidine-5-amine (950mg) and cuprous iodide (I) (47.4mg), obtain pulverous title compound (409mg).
1H-NMR(CDCl
3)δ：0.12(6H，s)，0.95(9H，s)，4.39(2H，m)，6.44(1H，dt，J＝16Hz，4Hz)，6.67(2H，m)，7.1-7.5(5H，m)，8.48(1H，s)，9.07(1H，br?s)。
(iv) 6-((1E)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-propenyl)-preparation of 5-ethyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine
With 6-((1E)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-propenyl)-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine (100mg) is dissolved in N, in the dinethylformamide (0.786mL), add cesium carbonate (102.6mg), and mixture was at room temperature stirred 20 minutes.Add iodoethane (0.0231mL), and mixture was at room temperature stirred 2 hours, and stirred 4 hours down at 40 ℃.After being cooled to room temperature, reaction mixture is diluted with ethyl acetate (50mL), and water (30mL) and saturated brine (30mL) washing successively.With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 50: 50), obtain buttery title compound (79mg).
1H-NMR(CDCl
3)δ：0.14(6H，s)，0.97(9H，s)，1.44(3H，t，J＝7Hz)，4.44(2H，m)，4.52(2H，q，J＝7Hz)，6.58(1H，dt，J＝15Hz，4Hz)，6.74(1H，s)，6.78(1H，m)，7.2-7.5(5H，m)，8.41(1H，s)。
(v) (2E)-3-[5-ethyl-4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
With 6-((1E)-3-{[tertiary butyl (dimethyl) silyl] the oxygen base }-the 1-propenyl)-5-ethyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidines (78mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] mixture of aniline (61.2mg), pyridine hydrochloride (26mg) and phenol (122mg) is in 120 ℃ of heated and stirred 16 hours.After being cooled to room temperature, mixture is diluted with methylene dichloride (30mL), and wash with saturated sodium bicarbonate aqueous solution (20mL).With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → 80: 20), obtain pulverous title compound (32mg).
1H-NMR(CDCl
3)δ：1.46(3H，t，J＝7Hz)，2.24(3H，s)，2.53(3H，s)，4.31(2H，q，J＝7Hz)，4.42(1H，dd，J＝5Hz，2Hz)，6.54(1H，dt，J＝15Hz，5Hz)，6.66(1H，s)，6.70(1H，d，J＝15Hz)，6.88(1H，d，J＝8Hz)，7.0-7.4(4H，m)，8.20(1H，d，J＝2Hz)，8.46(1H，s)。
Embodiment 21
[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of methylate hydrochlorate
(i) preparation of 3-(5-amino-6-phenoxy pyrimidine-4-yl)-2-propine-1-alcohol
4-iodo-6-phenoxy pyrimidine-5-amine (3.0g) is dissolved in the mixed solvent of acetonitrile (159mL)/triethylamine (117mL), and add successively 2-propine-1-alcohol (0.669mL), anti--two (triphenylphosphine) palladium chloride (II) (336mg) and cuprous iodide (I) (109.5mg).React by the method (iv) identical, obtain crystalline title compound (2.02g) with embodiment 9.
1H-NMR(CDCl
3)δ：3.53(1H，br?s)，4.52(2H，br?s)，4.63(2H，br?s)，7.1-7.5(5H，m)，8.09(1H，s)。
The (ii) preparation of (4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) methyl alcohol
According to (v) identical method is reacted, and by using 3-(5-amino-6-phenoxy pyrimidine-4-yl)-2-propine-1-alcohol (1.98g) and cuprous iodide (I) (156mg), obtains crystalline title compound (1.31g) with embodiment 9.
1H-NMR(DMSO-d
6)δ：4.67(2H，d，J＝5Hz)，5.45(1H，t，J＝5Hz)，6.50(1H，s)，7.2-7.5(5H，m)，8.26(1H，s)，12.15(1H，br?s)。
(iii) [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of methylate hydrochlorate
React according to the method identical with embodiment 1, by using (4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) methyl alcohol (100mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (156mg), pyridine hydrochloride (56.7mg) and 1-Methyl-2-Pyrrolidone (0.828mL), obtain crystalline title compound (142mg).
1H-NMR(DMSO-d
6)δ：4.76(2H，s)，5.27(2H，s)，6.50(1H，d，J＝2Hz)，7.1-7.6(5H，m)，7.73(1H，dd，J＝3Hz，9Hz)，8.12(1H，d，J＝3Hz)，8.77(1H，s)，11.50(1H，br?s)。
Embodiment 22
(2E)-and 3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
(i) (2E)-preparation of 5-(5-amino-6-phenoxy pyrimidine-4-yl)-2-amylene-4-alkynes-1-alcohol
4-iodo-6-phenoxy pyrimidine-5-amine (3.5g) is dissolved in the mixed solvent of acetonitrile (185mL)/triethylamine (136mL), and add successively 2-amylene-4-alkynes-1-alcohol (1.1g), anti--two (triphenylphosphine) palladium chloride (II) (392mg) and cuprous iodide (I) (127mg).React by the method (iv) identical, obtain pulverous title compound (1.79g) with embodiment 9.
1H-NMR(CDCl
3)δ：2.48(1H，br?s)，4.33(2H，dd，J＝5Hz，2Hz)，4.45(2H，br?s)，6.12(1H，dt，J＝2Hz，16Hz)，6.54(1H，dt，J＝16Hz，5Hz)，7.1-7.5(5H，m)，8.11(1H，s)。
The (ii) preparation of (2E)-3-(4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propylene-1-alcohol
According to (v) identical method is reacted, and by using (2E)-5-(5-amino-6-phenoxy pyrimidine-4-yl)-2-amylene-4-alkynes-1-alcohol (1.7g) and cuprous iodide (I) (268mg), obtains crystalline title compound (1.25g) with embodiment 9.
1H-NMR(CDCl
3)δ：2.38(1H，br?s)，4.41(2H，d，J＝4Hz)，6.58(1H，dt，J＝3Hz，16Hz)，6.66(1H，s)，6.75(1H，d，J＝16Hz)，7.2-7.5(5H，m)，8.48(1H，s)，9.73(1H，br?s)。
The (iii) preparation of (2E)-3-(4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propenylbenzene manthanoate
(2E)-3-(4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propylene-1-alcohol (1.0g) is suspended in the tetrahydrofuran (THF) (20mL), and, adds triethylamine (0.651mL) and Benzoyl chloride (0.86mL) successively ice-cooled following.Down mixture was stirred 2 hours ice-cooled, with ethyl acetate (200mL) dilution, and water (50mL) washing.With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), obtain crystalline title compound (1.08g).
1H-NMR(CDCl
3)δ：5.03(2H，d，J＝6Hz)，6.52(1H，m)，6.72(1H，dt，J＝16Hz，2Hz)，6.80(1H，d，J＝16Hz)，7.1-7.7(8H，m)，8.08(2H，m)，8.50(1H，s)，9.27(1H，br?s)。
The (iv) preparation of (2E)-3-(5-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propenylbenzene manthanoate
(2E)-3-(4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propenylbenzene manthanoate (500mg) is dissolved in N, in the dinethylformamide (4mL), and adds salt of wormwood (279mg) and methyl iodide (0.1mL) successively.After at room temperature stirring 4 hours, (30mL) joins in the reaction mixture with water, and mixture is extracted with ethyl acetate (100mL), through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 50: 50), obtain crystalline title compound (301mg).
1H-NMR(CDCl
3)δ：4.14(3H，s)，5.08(2H，dd，J＝6Hz，1Hz)，6.66(1H，m)，6.84(1H，s)，6.85(1H，d，J＝16Hz)，7.2-7.7(8H，m)，8.10(2H，d，J＝9Hz)，8.42(1H，s)。
(v) (2E)-3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
With (2E)-3-(5-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propenylbenzene manthanoate (100mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (130mg), pyridine hydrochloride (36mg) and 1-Methyl-2-Pyrrolidone (0.51gmL) is 140 ℃ of following heated and stirred 4 hours.After being cooled to room temperature, (20mL) joins in the reaction mixture with sodium bicarbonate aqueous solution, and mixture is extracted with ethyl acetate (100mL).With organic layer through dried over mgso, and concentrating under reduced pressure.Resistates is dissolved in tetrahydrofuran (THF) (0.518mL)/ethanol (0.518mL), adds 1N aqueous sodium hydroxide solution (0.518mL), and mixture was at room temperature stirred 2 hours.Add tetrahydrofuran (THF)/ethyl acetate (1: 1,50mL) and saturated brine (30mL), and mixture extracted.With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → 85: 15), obtain crystalline title compound (45mg).
1H-NMR(DMSO-d
6)δ：4.00(3H，s)，4.21(2H，t，J＝4Hz)，5.07(1H，t，J＝5Hz)，5.23(2H，s)，6.58(1H，m)，6.68(1H，s)，6.80(1H，d，J＝16Hz)，7.1-7.8(7H，m)，8.21(1H，s)，8.49(1H，br?s)。
Embodiment 23
(2E)-and 3-[5-methyl-4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl]-preparation of 2-propylene-1-alcohol
According to (v) identical method is reacted with embodiment 22, by using (2E)-3-(5-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-yl)-2-propenylbenzene manthanoate (100mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (111mg), pyridine hydrochloride (36mg) and 1-Methyl-2-Pyrrolidone (0.518mL), obtain crystalline title compound (60mg).
1H-NMR(DMSO-d
6)δ：2.16(3H，s)，2.43(3H，s)，4.02(3H，s)，4.22(2H，brs)，5.07(1H，t，J＝5Hz)，6.60(1H，m)，6.69(1H，s)，6.80(1H，d，J＝16Hz)，6.93(1H，d，J＝9Hz)，7.1-7.6(5H，m)，8.16(1H，d，J＝2Hz)，8.23(1H，s)，8.54(1H，br?s)。
Embodiment 24
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-5-[(3, the 4-Dimethoxyphenyl) alkylsulfonyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate (150mg) is dissolved in N, in the dinethylformamide (1.5mL), and in ice-cooled salt of wormwood (102mg) and (3, the 4-Dimethoxyphenyl) SULPHURYL CHLORIDE (96.9mg) of adding successively down.Mixture was stirred 2 hours down ice-cooled, and at room temperature stirred 1 hour.Mixture is diluted with ethyl acetate (50mL), and water (30mL) is washed twice.With organic layer through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), obtain pulverous title compound (95mg).
1H-NMR(CDCl
3)δ：3.68(3H，s)，3.86(3H，s)，5.16(2H，s)，6.76(IH，d，J＝4Hz)，6.82(1H，d，J＝9Hz)，6.97(1H，d，J＝9Hz)，7.02(1H，m)，7.1-7.4(5H，m)，7.55(1H，dd，J＝9Hz，3Hz)，7.79(1H，d，J＝4Hz)，7.94(1H，d，J＝3Hz)，8.52(1H，s)，9.39(1H，br?s)。
Embodiment 25
5-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl }-preparation of 2-ethyl furoate
(i) methyl 5-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)]-preparation of 2-ethyl furoate
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (500mg), add salt of wormwood (541mg) in dinethylformamide (6.5mL) suspension down ice-cooled, and mixture was stirred 15 minutes, be warmed to room temperature simultaneously.5-(chloromethyl)-2-ethyl furoate (737mg) is joined in the reaction mixture, and mixture was at room temperature stirred 16 hours.Reaction mixture water (20mL) is diluted, and extract with the mixed solvent (40mL * 3) of ethyl acetate/tetrahydrofuran (THF) (1/1).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=80/20 → 10/90).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (825mg) of light yellow solid.
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7.2Hz)，4.36(2H，q，J＝7.2Hz)，5.75(2H，s)，6.30(1H，ddd，J＝0.9，2.1，2.7Hz)，6.80(1H，t，J＝3.9Hz)，7.10(1H，t，J＝3.3Hz)，7.63(1H，dd，J＝2.7，3.3Hz)，8.73(1H，d，J＝3.9Hz)。
(ii) 5-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl }-preparation of 2-ethyl furoate
To 5-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-add 3-chloro-4-[(3-luorobenzyl in 1-Methyl-2-Pyrrolidone (1.3mL) solution of 2-ethyl furoate (200mg)) the oxygen base] aniline (247mg), and with mixture heating up to 140 ℃, and stirred 2 hours.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (20mL * 3) with 5% sodium bicarbonate aqueous solution (20mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: ethyl acetate/methanol=10/0 → 8/2).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (307mg) of light yellow solid.
1H-NMR(CDCl
3)δ1.34(3H，t，J＝7.2Hz)，4.38(2H，q，J＝7.2Hz)，5.14(2H，s)，5.49(2H，s)，6.45(1H，d，J＝3.4Hz)，6.63(1H，d，J＝3.0Hz)，6.94(1H，d，J＝8.8Hz)，7.03(1H，d，J＝9.6Hz)，7.26-7.38(6H，m)，7.43(1H，dd，J＝2.6，8.8Hz)，7.65(1H，d，J＝3.0Hz)，8.50(1H，s)。
Embodiment 26
5-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl }-preparation of pyromucic acid
To 5-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl }-add 1N aqueous sodium hydroxide solution (1.34mL) in the solution of 2-ethyl furoate (280mg) in the mixed solvent of tetrahydrofuran (THF) (1.34mL) and ethanol (1.34mL), and mixture was at room temperature stirred 14 hours.1N hydrochloric acid (1.34mL) and water (10mL) are joined in the reaction mixture, and mixture was at room temperature stirred 30 minutes.Filter and collect the throw out that generates, water (10mL * 3) and Di Iso Propyl Ether (10mL * 3) wash, and drying under reduced pressure (80 ℃), obtain the title compound (178mg) of white powder.
1H-NMR(DMSO-d
6)δ5.24(2H，s)，5.89(2H，s)，6.37(1H，d，J＝3.3Hz)，6.54(1H，d，J＝2.7Hz)，7.10(1H，d，J＝3.3Hz)，7.21(2H，d，J＝9.0Hz)，7.32(2H，t，J＝6.6Hz)，7.48(2H，t，J＝8.1Hz)，7.73(2H，d，J＝9.6Hz)，8.29(1H，s)，8.57(1H，br?s)。
Embodiment 27
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-5-{4-[(is suitable-3,5-lupetazin-1-yl) carbonyl] benzyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
To 4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } N of phenylformic acid (120mg), add suitable-2 in dinethylformamide (2.4mL) solution, 6-lupetazin (95mg) and 1H-1,2,3-benzotriazole-1-alcohol (65mg), and mixture at room temperature stirred 15 minutes.Add N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (92mg) and triethylamine (0.2mL), and mixture at room temperature stirred 12 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (25mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=10/0 → 9/1).Concentrating under reduced pressure target fraction.Chloroform/Di Iso Propyl Ether (3/7) is joined in the resistates, and filter and collect the throw out that generates, and drying under reduced pressure, white powder crystalline title compound (85mg) obtained.
1H-NMR(CDCl
3)δ1.13(6H，d，J＝6.6Hz)，1.66(4H，br?s)，2.69(2H，br)，3.41(1H，brd，J＝6.6Hz)，4.60(1H，brd，J＝13.5Hz)，5.08(2H，s)，5.56(2H，s)，6.28(1H，s)，6.68(1H，dd，J＝2.1，5.4Hz)，6.82(1H，d，J＝9.3Hz)，7.00(2H，dt，J＝2.1，8.7Hz)，7.15-7.21(4H，m)，7.25(1H，d，J＝2.4Hz)，7.30-7.38(4H，m)，7.48(2H，d，J＝8.4Hz)，8.48(1H，s)。
Embodiment 28
N-[3-chloro-4-(pyridine-2-ylmethoxy) phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (0.8mL) solution of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (63mg), add 3-chloro-4-(pyridine-2-ylmethoxy) aniline (149mg), and with mixture heating up to 140 ℃ and stirred 2 hours.Make reaction mixture be cooled to room temperature, dilute, and extract with the mixed solvent (25mL * 3) of ethyl acetate/tetrahydrofuran (THF) (1/1) with 5% sodium bicarbonate aqueous solution (20mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=10/0 → 8/2).Concentrating under reduced pressure target fraction.Chloroform/Di Iso Propyl Ether (1/9) is joined in the resistates, and filter and collect the throw out that generates, and drying under reduced pressure, pale yellow powder shape crystalline title compound (112mg) obtained.
1H-NMR(DMSO-d
6)δ5.27(2H，s)，6.48(1H，d，J＝2.4Hz)，7.25(1H，d，J＝8.7Hz)，7.37(1H，dd，J＝5.1，7.5Hz)，7.55-7.60(2H，m)，7.66(1H，s)，7.89(1H，t，J＝7.5Hz)，8.20(1H，dd，J＝1.5，2.4Hz)，8.35(1H，d，J＝1.5Hz)，8.60(1H，dd，J＝0.6，4.8Hz)，9.25(1H，s)，12.78(1H，s)。
Embodiment 29
5-[(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-preparation of 2-ethyl furoate
To 5-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-add 3-chloro-4-(pyridine-2-ylmethoxy) aniline (360mg) in 1-Methyl-2-Pyrrolidone (2.0mL) solution of 2-ethyl furoate (300mg), and with mixture heating up to 140 ℃ and stirred 1.5 hours.Make reaction mixture be cooled to room temperature, dilute, and extract with the mixed solvent (45mL * 3) of ethyl acetate/tetrahydrofuran (THF) (1/1) with 5% sodium bicarbonate aqueous solution (30mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=10/0 → 8/2).Concentrating under reduced pressure target fraction.Chloroform/Di Iso Propyl Ether (1/9) is joined in the resistates, and filter and collect the throw out that generates, and drying under reduced pressure, pale yellow powder shape crystalline title compound (440mg) obtained.
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7.2Hz)，4.36(2H，q，J＝7.2Hz)，5.33(2H，s)，5.91(2H，s)，6.39(1H，d，J＝3.4Hz)，6.57(1H，d，J＝2.6Hz)，7.12(1H，d，J＝3.4Hz)，7.23(1H，d，J＝9.0Hz)，7.43(1H，dd，J＝4.8，7.8Hz)，7.50(1H，dd，J＝2.2，9.2Hz)，7.61(1H，d，J＝7.8Hz)，7.75(2H，s)，7.90(1H，dt，J＝1.2，7.8Hz)，8.14(1H，d，J＝4.8Hz)，8.30(1H，s)，8.55(1H，br?s)。
Embodiment 30
5-[(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-preparation of pyromucic acid
To 5-[(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl]-add 1N aqueous sodium hydroxide solution (2.0mL) in the solution of 2-ethyl furoate (440mg) in the mixed solvent of tetrahydrofuran (THF) (2.0mL) and ethanol (2.0mL), and mixture was at room temperature stirred 5 hours.1N hydrochloric acid (2.0mL) and water (25mL) are joined in the reaction mixture, and mixture was at room temperature stirred 30 minutes.Filter and collect the throw out that generates, water (10mL * 3) and Di Iso Propyl Ether (10mL * 3) washing, and drying under reduced pressure (80 ℃) obtain white powder crystalline title compound (310mg).
1H-NMR(DMSO-d
6)δ5.27(2H，s)，5.88(2H，s)，6.35(1H，d，J＝3.4Hz)，6.53(1H，d，J＝2.6Hz)，7.08(1H，d，J＝3.4Hz)，7.20(1H，d，J＝9.0Hz)，7.37(1H，dd，J＝4.8，7.8Hz)，7.47(1H，dd，J＝2.2，9.2Hz)，7.58(1H，d，J＝7.8Hz)，7.73(2H，s)，7.88(1H，t，J＝1.2，7.8Hz)，8.27(1H，s)，8.53(1H，br?s)，8.59(1H，d，J＝4.8Hz)。
Embodiment 31
The preparation of 2-(3, the 5-dichlorophenoxy)-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) ethyl benzoate
In 1-Methyl-2-Pyrrolidone (0.8mL) solution of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (61mg), add 5-amino-2-(3, the 5-dichlorophenoxy) ethyl benzoate (186mg), and with mixture heating up to 140 ℃ and stirred 2.5 hours.Make reaction mixture be cooled to room temperature, dilute, and extract with the mixed solvent (25mL * 3) of ethyl acetate/tetrahydrofuran (THF) (1/1) with 5% sodium bicarbonate aqueous solution (20mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: hexane/ethyl acetate=8/2 → 0/10).Concentrating under reduced pressure target fraction.Ethyl acetate is joined in the resistates, and filter and collect the throw out that generates, and drying under reduced pressure, pale yellow powder shape crystalline title compound (149mg) obtained.
1H-NMR(DMSO-d
6)δ1.10(3H，t，J＝7.2Hz)，4.18(2H，q，J＝7.2Hz)，6.52(1H，d，J＝2.8Hz)，6.90(2H，t，J＝3.0Hz)，7.28(1H，dd，J＝1.8，2.8Hz)，7.33(1H，dd，J＝8.8Hz)，7.71(1H，d，J＝2.8Hz)，8.36(2H，d，J＝8.8Hz)，8.39(1H，d，J＝1.8Hz)，9.60(1H，s)，11.15(1H，s)。
Embodiment 32
The benzoic preparation of 2-(3, the 5-dichlorophenoxy)-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino)
To 2-(3, the 5-dichlorophenoxy)-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) adding 1N aqueous sodium hydroxide solution (0.68mL) in the solution of ethyl benzoate (100mg) in the mixed solvent of tetrahydrofuran (THF) (0.68mL) and ethanol (0.68mL), and mixture at room temperature stirred 16 hours.1N hydrochloric acid (0.68mL) and water (5mL) are joined in the reaction mixture, and mixture was at room temperature stirred 30 minutes.Filter and collect the throw out that generates, water (10mL * 3) and Di Iso Propyl Ether (10mL * 3) washing, and drying under reduced pressure (80 ℃) obtain white powder crystalline title compound (76mg).
1H-NMR(DMSO-d
6)δ6.52(1H，d，J＝1.2Hz)，6.90(2H，t，J＝1.2Hz)，7.28(2H，dt，J＝3.0，5.1Hz)，7.71(1H，t，J＝2.7Hz)，8.29(1H，dd，J＝2.7，8.7Hz)，8.37(1H，d，J＝2.7Hz)，8.40(1H，d，J＝1.2Hz)，9.59(1H，s)，11.18(1H，br?s)。
Embodiment 33
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-ethyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-ethyl-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (200mg), add salt of wormwood (269mg) in dinethylformamide (1.3mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.(305mg) joins in the reaction mixture with iodoethane, and mixture was at room temperature stirred 3 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=80/20 → 10/90).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (187mg) of light yellow solid.
1H-NMR(CDCl
3)δ1.52(3H，t，J＝7.2Hz)，4.55(2H，q，J＝7.2Hz)，6.73(1H，d，J＝3.2Hz)，7.51(1H，d，J＝3.2Hz)，8.70(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-ethyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (0.94mL) solution of 4-chloro-5-ethyl-5H-pyrrolo-[3,2-d] pyrimidines (85mg), add 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (177mg).React according to the method identical, obtain the Powdered crystalline title compound of lavender (98mg) with embodiment 29.
1H-NMR(CDCl
3)δ1.56(3H，t，J＝7.4Hz)，4.33(2H，q，J＝7.4Hz)，5.15(2H，s)，6.51(1H，br?s)，6.58(1H，d，J＝3.0Hz)，6.72(2H，s)，6.95(1H，d，J＝8.7Hz)，7.02(1H，m)，7.21(1H，d，J＝8.5Hz)，7.25(1H，d，J＝3.0Hz)，7.33-7.40(2H，m)，7.60(1H，d，J＝2.5Hz)，8.49(1H，br?s)。
Embodiment 34
5-ethyl-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (0.94mL) solution of 4-chloro-5-ethyl-5H-pyrrolo-[3,2-d] pyrimidines (85mg), add 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (150mg).React according to the method identical, obtain white powder crystalline title compound (67mg) with embodiment 29.
1H-NMR(CDCl
3)δ1.57(3H，t，J＝7.4Hz)，2.25(3H，s)，2.53(3H，s)，4.35(2H，q，J＝7.4Hz)，6.58(1H，d，J＝3.0Hz)，6.67(1H，br?s)，6.89(1H，d，J＝8.7Hz)，7.08(1H，d，J＝8.5Hz)，7.13(1H，dd，J＝3.0，8.7Hz)，7.25(1H，d，J＝3.0Hz)，7.34(1H，dd，J＝2.6，8.7Hz)，7.42(1H，d，J＝2.5Hz)，8.23(1H，d，1H，J＝2.5Hz)，8.50(1H，s)。
Embodiment 35
The preparation of N-benzyl-N '-[3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenyl] urea
In 1-Methyl-2-Pyrrolidone (1.3mL) solution of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (100mg), add N-(3-aminophenyl)-N '-benzylurea (220mg), and with mixture heating up to 140 ℃, and stirred 1.5 hours.Make reaction mixture be cooled to room temperature, dilute, and extract with the mixed solvent (30mL * 3) of ethyl acetate/tetrahydrofuran (THF) (1/1) with 5% sodium bicarbonate aqueous solution (20mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=100/0 → 85/15).Concentrating under reduced pressure target fraction.Ethyl acetate is joined in the resistates, and filter and collect the throw out that generates, and drying under reduced pressure, pale yellow powder shape crystalline title compound (97mg) obtained.
1H-NMR(DMSO-d
6)δ4.32(2H，d，J＝5.8Hz)，6.47(1H，s)，6.63(1H，t，J＝5.8Hz)，7.02(1H，d，J＝8.4Hz)，7.16-7.32(6H，m)，7.62(2H，d，J＝8.4Hz)，7.98(1H，s)，8.33(1H，s)，8.63(1H，s)，9.15(1H，s)，11.22(1H，s)。
Embodiment 36
4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl }-preparation of N-(2-hydroxyethyl) benzamide
To 4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } N of phenylformic acid (126mg), add N-[3-(dimethylamino) propyl group in dinethylformamide (1.2mL) solution]-N '-ethyl-carbodiimide hydrochloride (72mg) and 1-hydroxyl pyrrolidine-2,5-diketone (43mg), and mixture at room temperature stirred 3 hours.In this reaction mixture, drip 2-monoethanolamine (23mg) at N, the solution in the mixed solvent of dinethylformamide (1.2mL) and 10% sodium bicarbonate aqueous solution (1.2mL), and mixture at room temperature stirred 48 hours.Reaction mixture water (25mL) is diluted, and extract with ethyl acetate (25mL * 3).Organic layer is washed with saturated brine (25mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=10/0 → 8/2).Concentrating under reduced pressure target fraction.Chloroform/Di Iso Propyl Ether (1/4) is joined in the resistates, and filter and collect the throw out that generates, and drying under reduced pressure, white powder crystalline title compound (105mg) obtained.
1H-NMR(DMSO-d
6)δ3.27(2H，t，J＝5.9Hz)，3.41-3.48(2H，m)，4.68(1H，t，J＝5.9Hz)，5.21(2H，s)，5.84(2H，s)，6.56(1H，d，J＝3.0Hz)，7.06(2H，d，J＝8.1Hz)，7.08(2H，t，J＝7.5Hz)，7.27-7.35(3H，m)，7.46(1H，dt，J＝5.8，8.1Hz)，7.64(1H，d，J＝2.5Hz)，7.73(2H，d，J＝8.3Hz)，7.82(1H，d，J＝3.0Hz)，8.27(2H，s)，8.33(1H，t，J＝5.4Hz)。
Embodiment 37
N-(3-amino-3-oxopropyl)-4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } preparation of benzamide
React according to the method identical with embodiment 27, by using 4-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } phenylformic acid (120mg) and β-alanimamides hydrochloride (45mg), obtain white powder crystalline title compound (83mg).
1H-NMR(DMSO-d
6)δ2.29(1H，t，J＝7.2Hz)，3.37-3.42(4H，m)，5.21(2H，s)，5.83(2H，s)，6.56(1H，d，J＝3.3Hz)，6.80(1H，br?s)，7.06(2H，d，J＝8.3Hz)，7.18(2H，t，J＝9.0Hz)，7.29-7.34(4H，m)，7.46(1H，dt，J＝5.8，7.9Hz)，7.63(1H，d，J＝2.4Hz)，7.71(2H，d，J＝8.3Hz)，7.81(1H，d，J＝3.2Hz)，8.26(1H，d，J＝3.3Hz)，8.40(1H，t，J＝5.7Hz)。
Embodiment 38
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (500mg), add cesium carbonate (1324mg) in dinethylformamide (4.5mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.1-bromo-2-Ethoxyethane (1016mg) is joined in the reaction mixture, and mixture was at room temperature stirred 14 hours.Reaction mixture water (100mL) is diluted, and extract with ethyl acetate (120mL * 3).Organic layer is washed with saturated brine (100mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=85/15 → 20/80).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (697mg) of faint yellow oily thing.
1H-NMR(CDCl
3)δ1.13(3H，t，J＝6.9Hz)，3.43(2H，q，J＝6.9Hz)，3.78(2H，t，J＝5.1Hz)，4.67(2H，t，J＝5.1Hz)，6.71(1H，d，J＝3.0Hz)，7.59(1H，d，J＝3.0Hz)，8.70(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
To 4-chloro-5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] add 3-chloro-4-[(3-luorobenzyl in 1-Methyl-2-Pyrrolidone (0.7mL) solution of pyrimidine (90mg)) the oxygen base] aniline (151mg), and with mixture heating up to 140 ℃ and stirred 7 hours.Make reaction mixture be cooled to room temperature.Reaction mixture is diluted with 5% sodium bicarbonate aqueous solution (20mL), and extract with ethyl acetate (25mL * 3).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=10/0 → 8/2).Concentrating under reduced pressure target fraction.Resistates by the Di Iso Propyl Ether recrystallization, is filtered and collects and drying under reduced pressure, obtain the title compound (90mg) of faint yellow needle crystal.
1H-NMR(CDCl
3)δ1.22(3H，t，J＝7.0Hz)，3.63(2H，q，J＝7.0Hz)，3.90(2H，t，J＝4.4Hz)，4.50(2H，t，J＝4.4Hz)，5.13(2H，s)，6.61(1H，d，J＝3.2Hz)，6.94(1H，d，J＝8.9Hz)，7.01(1H，t，J＝8.1Hz)，7.17-7.25(3H，m)，7.35(1H，dt，J＝5.6，7.9Hz)，7.47(1H，dd，J＝1.3，8.9Hz)，7.64(1H，d，J＝2.6Hz)，8.48(1H，s)，8.79(1H，s)。
Embodiment 39
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (320mg), add salt of wormwood (452mg) in dinethylformamide (2.0mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.(444mg) joins in the reaction mixture with methyl iodide, and mixture was at room temperature stirred 3 hours.Reaction mixture water (25mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=80/20 → 10/90).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (325mg) of light yellow solid.
1H-NMR(CDCl
3)δ4.16(3H，s)，6.70(1H，d，J＝3.9Hz)，7.42(1H，d，J＝3.9Hz)，8.69(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (1.0mL) solution of 4-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidines (100mg), add 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (225mg), and with mixture heating up to 140 ℃ and stirred 1.5 hours.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (30mL * 3) with 5% sodium bicarbonate aqueous solution (25mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 0/100).Concentrating under reduced pressure target fraction.With the mixed solvent recrystallization of resistates by Di Iso Propyl Ether and chloroform, filter and collect and drying under reduced pressure, obtain the Powdered crystalline title compound of lavender (121mg).
1H-NMR(DMSO-d
6)δ4.14(3H，s)，5.24(2H，s)，6.42(1H，d，J＝3.0Hz)，7.16-7.23(2H，m)，7.29-7.34(2H，m)，7.44-7.56(3H，m)，7.78(1H，d，J＝2.4Hz)，8.24(1H，s)，8.36(1H，s)。
Embodiment 40
5-methyl-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (1.0mL) solution of 4-chloro-5-methyl-5H-pyrrolo-[3,2-d] pyrimidines (100mg), add 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (192mg).React according to the method (ii) identical, obtain white powder crystalline title compound (106mg) with embodiment 39.
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.44(3H，s)，4.15(3H，s)，6.43(1H，dd，J＝0.9，3.0Hz)，6.94(1H，d，J＝8.4Hz)，7.18(1H，dd，J＝3.0，8.4Hz)，7.24(1H，d，J＝8.7Hz)，7.51(1H，d，J＝8.7Hz)，7.56(1H，d，J＝3.0Hz)，8.17(1H，d，J＝3.0Hz)，8.25(1H，d，J＝0.9Hz)，8.40(1H，s)，8.63(1H，s)。
Embodiment 41
2-[4-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] the alcoholic acid preparation
(i) preparation of 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl)-4-chloro-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (307mg), add cesium carbonate (977mg) in dinethylformamide (2.0mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add the tertiary butyl (2-iodine oxyethyl group) dimethylsilane (839mg), and mixture was at room temperature stirred 16 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (30mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=85/15 → 10/90).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (591mg) of white solid.
1H-NMR(DMSO-d
6)δ0.95(9H，s)，4.10(2H，t，J＝5.2Hz)，4.76(2H，t，J＝5.2Hz)，6.87(1H，d，J＝3.0Hz)，7.57(1H，d，J＝3.0Hz)，8.85(1H，s)。
(ii) 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) alcoholic acid preparation
Under ice-cooled, to 5-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl)-4-chloro-5H-pyrrolo-[3,2-d] add tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.69mL) in tetrahydrofuran (THF) (1.7mL) solution of pyrimidine (560mg), and mixture was stirred 4 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (30mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: ethyl acetate/methanol=10/0 → 9/1).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (391mg) of white solid.
1H-NMR(CDCl
3)δ2.13(2H，td，J＝6.3，12.6Hz)，4.66(2H，t，J＝6.3Hz)，6.72(1H，d，J＝3.0Hz)，7.57(1H，d，J＝3.0Hz)，8.70(1H，s)。
(iii) 2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] the alcoholic acid preparation
In 1-Methyl-2-Pyrrolidone (1.3mL) solution of 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethanol (130mg), add 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (193mg), and reaction mixture stirred 2 hours down at 120 ℃.Make reaction mixture be cooled to room temperature, and add ethyl acetate (20mL).With the throw out that generates mixed solvent recrystallization by hexane/methanol (3/7), filter and collect and drying under reduced pressure, obtain lavender crystalline title compound (206mg).
1H-NMR(DMSO-d
6)δ3.86(2H，t，J＝4.3Hz)，4.54(2H，m)，5.24(2H，s)，6.23(1H，br?s)，6.53(1H，d，J＝3.2Hz)，7.18(1H，dt，J＝2.6，8.1Hz)，7.25(1H，d，J＝9.0Hz)，7.29-7.34(2H，m)，7.43-7.51(2H，m)，7.70(1H，d，J＝3.2Hz)，7.78(1H，d，J＝2.6Hz)，8.37(1H，br?s)，9.82(1H，br?s)。
Embodiment 42
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-propyl group-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-propyl group-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (150mg), add cesium carbonate (798mg) in dinethylformamide (1.6mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 1-N-PROPYLE BROMIDE (301mg), and mixture was at room temperature stirred 15 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (30mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=90/10 → 20/80).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (161mg) of white solid.
1H-NMR(CDCl
3)δ0.96(3H，t，J＝7.5Hz)，1.86-1.98(2H，m)，4.44(2H，t，J＝7.5Hz)，6.73(1H，t，J＝3.3Hz)，7.48(1H，d，J＝3.3Hz)，8.70(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-propyl group-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (0.8mL) solution of 4-chloro-5-propyl group-5H-pyrrolo-[3,2-d] pyrimidines (80mg), add 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (193mg), and reaction mixture stirred 2 hours down at 120 ℃.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (30mL * 3) with 5% sodium bicarbonate aqueous solution (25mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant: ethyl acetate/methanol=100/0 → 95/5).Concentrating under reduced pressure target fraction.The mixed solvent that in resistates, adds Di Iso Propyl Ether and chloroform.Filter and collect throw out and the drying under reduced pressure that generates, obtain the pulverous title compound of lavender (96mg).
1H-NMR(DMSO-d
6)δ0.85(3H，t，J＝6.0Hz)，1.81(2H，q，J＝6.9Hz)，4.42(2H，t，J＝6.9Hz)，5.18(2H，s)，6.47(1H，dd，J＝1.8，3.0Hz)，7.02(1H，d，J＝8.7Hz)，7.06(1H，d，J＝2.4Hz)，7.21-7.49(4H，m)，7.71(1H，d，J＝2.4Hz)，7.77(1H，br?s)，8.07(1H，br?s)，8.34(1H，d，J＝2.1Hz)。
Embodiment 43
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-isobutyl--5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-isobutyl--5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (150mg), add cesium carbonate (478mg) in dinethylformamide (1.6mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 1-bromo-2-methylpropane (336mg), and mixture was at room temperature stirred 19 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (30mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=90/10 → 20/80).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (210mg) of white solid.
1H-NMR?(CDCl
3)δ0.94(6H，d，J＝6.6Hz)，2.14-2.27(1H，m)，4.26(2H，d，J＝7.5Hz)，6.72(1H，d，J＝2.4Hz)，7.46(1H，d，J＝2.4Hz)，8.70(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-isobutyl--5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (ii) identical, use 1-Methyl-2-Pyrrolidone (0.8mL) solution of 4-chloro-5-isobutyl--5H-pyrrolo-[3,2-d] pyrimidines (90mg), obtain the pulverous title compound of lavender (89mg) with embodiment 42.
1H-NMR(DMSO-d
6)δ0.83(6H，d，J＝6.3Hz)，2.08(1H，m)，4.24(2H，d，J＝7.5Hz)，5.17(2H，s)，6.47(1H，d，J＝2.7Hz)，7.02(2H，d，J＝8.7Hz)，7.22-7.29(2H，m)，7.32(1H，d，J＝3.0Hz)，7.40(1H，dt，J＝6.0，8.1Hz)，7.46(1H，dd，J＝2.7，9.0Hz)，7.73(1H，d，J＝2.7Hz)，7.79(1H，s)，8.09(1H，br?s)。
Embodiment 44
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(tetrahydrofuran (THF)-2-ylmethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-(tetrahydrofuran (THF)-2-ylmethyl)-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (150mg), add cesium carbonate (478mg) in dinethylformamide (1.0mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 2-(brooethyl) tetrahydrofuran (THF) (242mg), and mixture was at room temperature stirred 26 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (30mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=90/10 → 20/80).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (200mg) of colorless oil.
1H-NMR(CDCl
3)δ1.47-1.64(1H，m)，1.85-2.17(3H，m)，3.75-3.90(2H，m)，4.18-4.31(1H，m)，4.42-4.53(1H，m)，4.71(1H，dd，J＝3.4，14.6Hz)，6.74(1H，d，J＝3.0Hz)，7.63(1H，d，J＝3.0Hz)，8.70(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(tetrahydrofuran (THF)-2-ylmethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (ii) identical with embodiment 42, by using 4-chloro-5-(tetrahydrofuran (THF)-2-ylmethyl)-5H-pyrrolo-[3,2-d] 1-Methyl-2-Pyrrolidone (1.6mL) solution of pyrimidine (200mg), obtain the title compound (139mg) of white powder.
1H-NMR(DMSO-d
6)δ1.56-1.65(2H，m)，1.78-1.80(1H，m)，1.97-2.07(1H，m)，3.70(2H，m)，4.17-4.19(1H，m)，4.43(1H，dd，J＝6.0，15.0Hz)，4.67(1H，d，J＝13.8Hz)，5.21(2H，s)，7.14(1H，dd，J＝8.1Hz)，7.20(1H，d，J＝8.1Hz)，7.27-7.48(4H，m)，7.61(1H，d，J＝2.1Hz)，7.78(1H，d，J＝1.5Hz)，8.25(1H，d，J＝1.2Hz)，8.60(1H，d，J＝1.2Hz)，9.03(1H，s)。
Embodiment 45
3-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } preparation of methyl benzoate
(i) methyl 3-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)] preparation of methyl benzoate
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (300mg), add cesium carbonate (955mg) in dinethylformamide (2.0mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 3-(brooethyl) methyl benzoate (671mg), and mixture was at room temperature stirred 4 hours.Reaction mixture water (40mL) is diluted, and extract with the mixed solvent (40mL * 3) of ethyl acetate/tetrahydrofuran (THF) (1/1).Organic layer is washed with saturated brine (120mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=80/20 → 10/90).Concentrating under reduced pressure target fraction.Chloroform/Di Iso Propyl Ether (4/1) is joined in the resistates, and filter and collect the throw out that generates, washing is drying under reduced pressure also, obtains the title compound (319mg) of light brown powder shape.
1H-NMR(CDCl
3)δ3.90(3H，s)，5.77(2H，s)，6.82(1H，d，J＝3.4Hz)，7.19(1H，dd，J＝1.2，7.8Hz)，7.41(1H，t，J＝7.8Hz)，7.54(1H，d，J＝3.4Hz)，7.82(1H，s)，7.98(1H，dt，J＝1.2，7.8Hz)，8.73(1H，s)。
(ii) 3-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } preparation of methyl benzoate
To 3-[(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) methyl] add 3-chloro-4-[(3-luorobenzyl in 1-Methyl-2-Pyrrolidone (3.0mL) solution of methyl benzoate (670mg)) the oxygen base] aniline (549mg), and reaction mixture stirred 1.5 hours down at 120 ℃.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (50mL * 3) with 5% sodium bicarbonate aqueous solution (50mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: hexane/ethyl acetate=9/1 → 0/10).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (1010mg) of yellow oil.
1H-NMR(CDCl
3)δ3.93(3H，s)，5.08(2H，s)，5.60(2H，s)，6.39(1H，s)，6.67(1H，d，J＝3.4Hz)，6.82(1H，d，J＝9.2Hz)，7.01(2H，dd，J＝2.6，8.8Hz)，7.16-7.40(3H，m)，7.56(1H，t，J＝7.8Hz)，7.94(1H，s)，8.09(1H，d，J＝7.8Hz)，8.47(1H，s)。
Embodiment 46
3-{[4-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } benzoic preparation
To 3-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } add 1N aqueous sodium hydroxide solution (4.0mL) in the solution of methyl benzoate (800mg) in the mixed solvent of tetrahydrofuran (THF) (4.0mL) and methyl alcohol (4.0mL), and mixture was at room temperature stirred 12 hours.1N hydrochloric acid (4.0mL) and water (15mL) are joined in the reaction mixture, and mixture was at room temperature stirred 30 minutes.Filter and collect the throw out that generates, water (10mL * 3) and Di Iso Propyl Ether (10mL * 3) wash, and drying under reduced pressure (80 ℃), obtain the title compound (610mg) of white powder.
1H-NMR(DMSO-d
6)δ5.21(2H，s)，5.86(2H，s)，6.57(1H，dd，J＝1.5，3.3Hz)，7.14-7.51(8H，m)，7.58(1H，dd，J＝1.5，2.4Hz)，7.69(1H，s)，7.78(1H，d，J＝6.3Hz)，7.84(1H，d，J＝1.8Hz)，8.27(1H，d，J＝1.5Hz)，8.30(1H，s)。
Embodiment 47
5-(2-ethoxyethyl group)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
To 4-chloro-5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] add 3-methyl-4-[(6-picoline-3-yl in 1-Methyl-2-Pyrrolidone (1.4mL) solution of pyrimidine (160mg)) the oxygen base] aniline (228mg), and reaction mixture stirred 2 hours down at 120 ℃.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (40mL * 3) with 5% sodium bicarbonate aqueous solution (25mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant: hexane/ethyl acetate=90/10 → 0/100).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (191mg) of water white transparency oily thing.
1H-NMR(CDCl
3)δ1.25(3H，dt，J＝2.1，7.2Hz)，2.14(3H，s)，2.52(3H，s)，3.65(2H，q，J＝7.2Hz)，3.92(2H，t，J＝4.5Hz)，4.54(2H，t，J＝4.5Hz)，6.62(1H，d，J＝3.0Hz)，6.91(1H，d，J＝8.4Hz)，7.11(1H，dd，J＝2.7，8.4Hz)，7.20(1H，d，J＝3.0Hz)，7.40(1H，dd，J＝2.7，8.4Hz)，7.51(1H，d，J＝3.0Hz)，8.26(1H，dd，J＝0.6，2.7Hz)，8.50(1H，s)，8.84(1H，br?s)。
Embodiment 48
N-[3-chloro-4-(pyridine-2-ylmethoxy) phenyl]-preparation of 5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
In 1-Methyl-2-Pyrrolidone (1.4mL) solution of 4-chloro-5-(2-ethoxyethyl group)-5H-pyrrolo-[3,2-d] pyrimidines (160mg), add 3-chloro-4-(pyridine-2-ylmethoxy) aniline (250mg).React according to the method (ii) identical, obtain the title compound (160mg) of faint yellow needle crystal with embodiment 42.
1H-NMR(CDCl
3)δ1.23(3H，t，J＝7.2Hz)，3.64(2H，q，J＝7.2Hz)，3.91(2H，t，J＝7.2Hz)，4.51(2H，t，J＝7.2Hz)，5.27(2H，s)，6.12(1H，s)，6.61(1H，d，J＝3.3Hz)，6.97(1H，d，J＝8.7Hz)，7.18(1H，d，J＝3.3Hz)，7.42(1H，dd，J＝2.7，8.7Hz)，7.66(1H，s)，7.69(1H，d，J＝2.1Hz)，7.76(1H，dt，J＝1.5，8.7Hz)，8.49(1H，s)，8.60(1H，d，J＝4.5Hz)，8.81(1H，s)。
Embodiment 49
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(2-fluoro ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-(2-fluoro ethyl)-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (100mg), add cesium carbonate (281mg) in dinethylformamide (0.6mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 1-bromo-2-fluoroethane (124mg), and mixture was at room temperature stirred 5 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (20mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=90/10 → 0/10).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (110mg) of water white transparency oily thing.
1H-NMR(CDCl
3)δ4.64-4.69(1H，m)，4.75-4.79(1H，m)，4.91(2H，d，J＝5.1Hz)，6.77(1H，dd，J＝1.4，3.4Hz)，7.57(1H，d，J＝3.4Hz)，8.73(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(2-fluoro ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (ii) identical with embodiment 39, by using 4-chloro-5-(2-fluoro ethyl)-5H-pyrrolo-[3,2-d] 1-Methyl-2-Pyrrolidone (1.0mL) solution of pyrimidine (110mg), obtain white powder crystalline title compound (124mg).
1H-NMR(CDCl
3)δ4.65(2H，dt，J＝4.0，29.0Hz)，4.90(2H，dt，J＝4.0，47.2Hz)，5.14(2H，s)，6.65(1H，d，J＝3.0Hz)，6.93(1H，d，J＝8.8Hz)，7.04(1H，d，J＝8.8Hz)，7.21-7.41(6H，m)，7.55(1H，s)，8.48(1H，s)。
Embodiment 50
3-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl }-preparation of N-(2-hydroxyethyl) benzamide
React according to the method identical with embodiment 36, by using 3-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] methyl } phenylformic acid (126mg), obtain white powder crystalline title compound (93mg).
1H-NMR(DMSO-d
6)δ3.26-3.48(4H，m)，4.71(1H，t，J＝5.6Hz)，5.21(2H，s)，5.83(2H，s)，6.55(1H，d，J＝2.6Hz)，7.06-7.52(7H，m)，7.61-7.72(4H，m)，7.80(1H，d，J＝3.2Hz)，8.26(2H，s)，8.39(1H，m)。
Embodiment 51
[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethyl acetate
(i) preparation of (4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl acetate
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (200mg), add cesium carbonate (615mg) in dinethylformamide (1.3mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add bromoethyl acetate (326mg), and mixture was at room temperature stirred 2.5 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (20mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=90/10 → 0/10).Concentrating under reduced pressure target fraction is also dry, obtains white powder crystalline title compound (210mg).
1H-NMR(DMSO-d
6)δ1.29(3H，t，J＝7.2Hz)，4.27(2H，q，J＝7.2Hz)，5.21(2H，s)，6.80(1H，d，J＝3.3Hz)，7.45(1H，d，J＝3.3Hz)，8.74(1H，s)。
(ii) [4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethyl acetate
To (4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) add 3-methyl-4-[(6-picoline-3-yl in Virahol (0.6mL) solution of ethyl acetate (140mg)) the oxygen base] aniline (188mg), and mixture stirred 2 hours under 110 ℃ temperature in oil bath.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (25mL * 3) with 5% sodium bicarbonate aqueous solution (20mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=10/0 → 9/1).Concentrating under reduced pressure target fraction.Di Iso Propyl Ether is joined in the resistates, and filter and collect throw out and the drying under reduced pressure that generates, obtain white powder crystalline title compound (210mg).
1H-NMR(CDCl
3)δ1.35(3H，t，J＝7.0Hz)，2.25(3H，s)，2.53(3H，s)，4.35(2H，q，J＝7.0Hz)，4.96(2H，s)，6.64(1H，d，J＝3.4Hz)，6.90(1H，d，J＝8.8Hz)，7.08(1H，d，J＝1.8Hz)，7.09(1H，d，J＝2.6Hz)，7.22(1H，d，J＝3.4Hz)，7.37(1H，d，J＝8.8Hz)，7.44(1H，d，J＝2.6Hz)，8.17(1H，br?s)，8.26(1H，d，J＝1.8Hz)，8.53(1H，s)。
Embodiment 52
[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of acetate
React according to the method identical with embodiment 46, by using [4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl acetate (200mg), obtain the title compound (101mg) of white powder.
1H-NMR(DMSO-d
6)δ2.43(3H，s)，2.51(3H，s)，5.30(2H，s)，6.49(1H，s)，6.92(1H，d，J＝8.8Hz)，7.20-7.25(2H，m)，7.37-7.44(2H，m)，7.62(1H，s)，8.17(1H，s)，8.31(1H，s)。
Embodiment 53
3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of propane-1-alcohol
(i) preparation of 5-(the 3-{[tertiary butyl (dimethyl) silyl] oxygen base } propyl group)-4-chloro-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (400mg), add cesium carbonate (957mg) in dinethylformamide (2.6mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add (3-bromine propoxy-) (tertiary butyl) dimethylsilane (979mg), and mixture was at room temperature stirred 16 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (30mL * 3).Organic layer is washed with saturated brine (30mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=85/15 → 10/90).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (630mg) of white solid.
1H-NMR(CDCl
3)δ0.95(9H，s)，2.83(2H，t，J＝5.2Hz)，4.10(2H，t，J＝5.2Hz)，4.76(2H，t，J＝5.2Hz)，6.87(1H，d，J＝2.8Hz)，7.71(1H，d，J＝2.8Hz)，8.85(1H，s)。
The (ii) preparation of 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) propane-1-alcohol
React according to the method (ii) identical with embodiment 41, by using 5-(the 3-{[tertiary butyl (dimethyl) silyl] oxygen base } propyl group)-4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (600mg), obtain white powder crystalline title compound (320mg).
1H-NMR(CDCl
3)δ2.13(2H，dt，J＝6.3，12.6Hz)，3.65(2H，dd，J＝6.3，10.2Hz)，4.66(2H，t，J＝6.3Hz)，6.72(1H，d，J＝3.0Hz)，7.57(1H，d，J＝3.0Hz)，8.70(1H，s)。
(iii) 3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of propane-1-alcohol
React according to the method (iii) identical,, obtain lavender crystalline title compound (180mg) by using 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) propane-1-alcohol (100mg) with embodiment 41.
1H-NMR(DMSO-d
6)δ1.98(2H，t，J＝6.0Hz)，3.39(2H，t，J＝6.0Hz)，4.66(2H，t，J＝6.0Hz)，5.30(2H，s)，6.66(1H，d，J＝3.2Hz)，7.19(1H，dt，J＝1.9，8.3Hz)，7.29-7.34(3H，m)，7.44-7.52(2H，m)，7.72(1H，d，J＝2.6Hz)，8.00(1H，d，J＝3.2Hz)，8.66(1H，s)，9.97(1H，s)。
Embodiment 54
N-(2-hydroxyethyl)-2-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethanamide
React according to the method identical with embodiment 36, by using [4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) acetate (70mg), obtain the title compound (38mg) of white powder.
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.43(3H，s)，3.24(2H，dd，J＝5.6，11.3Hz)，3.47(2H，dd，J＝5.6，11.3Hz)，4.86(1H，t，J＝5.3Hz)，5.04(2H，s)，6.49(1H，d，J＝3.0Hz)，6.97(1H，d，J＝8.5Hz)，7.15(1H，dd，J＝2.8，8.5Hz)，7.22(1H，d，J＝8.5Hz)，7.54-7.57(3H，m)，8.16(1H，d，J＝2.5Hz)，8.30(1H，s)，8.91(1H，t，J＝5.6Hz)，10.10(1H，s)。
Embodiment 55
N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5-(4,4,4-trifluoro butyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-(4,4,4-trifluoro butyl)-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (250mg), add cesium carbonate (675mg) in dinethylformamide (1.6mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 4-bromo-1,1,1-trifluoro butane (466mg), and mixture at room temperature stirred 15 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (20mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=9/1 → 0/10).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (440mg) of water white transparency oily thing.
1H-NMR(CDCl
3)δ2.17(4H，m)，4.57(2H，t，J＝6.6Hz)，6.76(1H，d，J＝3.3Hz)，7.47(1H，d，J＝3.3Hz)，8.72(1H，s)。
(ii) N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5-(4,4,4-trifluoro butyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method identical,, obtain the title compound (171mg) of colorless oil by using 4-chloro-5-(4,4,4-trifluoro butyl)-5H-pyrrolo-[3,2-d] pyrimidines (150mg) with embodiment 38.
1H-NMR(CDCl
3)δ2.00-2.17(4H，m)，2.25(3H，s)，2.53(3H，s)，4.29(2H，t，J＝6.9Hz)，6.54(1H，br?s)，6.63(1H，d，J＝3.2Hz)，6.88(1H，d，J＝8.5Hz)，7.09(1H，d，J＝8.5Hz)，7.13(1H，dd，J＝2.6，8.5Hz)，7.20(1H，d，J＝2.6Hz)，7.23(1H，d，J＝3.2Hz)，7.26(1H，s)，7.32(1H，d，J＝2.6Hz)，8.23(1H，d，J＝2.6Hz)，8.54(1H，s)。
Embodiment 56
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-5-[2-(2-ethoxy ethoxy) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) 4-chloro-5-[2-(2-ethoxy ethoxy) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (300mg), add cesium carbonate (728mg) in dinethylformamide (2.0mL) suspension down ice-cooled, and mixture is stirred, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 1-bromo-2-(2-ethoxy ethoxy) ethane (496mg), and mixture was at room temperature stirred 20 hours.Reaction mixture water (20mL) is diluted, and extract with ethyl acetate (20mL * 3).Organic layer is washed with saturated brine (20mL * 3), and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (silica gel, elutriant: hexane/ethyl acetate=9/1 → 0/10).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (440mg) of water white transparency oily thing.
1H-NMR(CDCl
3)δ1.17(3H，t，J＝7.1Hz)，3.40-3.58(6H，m)，3.87(2H，t，J＝5.1Hz)，4.69(2H，t，J＝5.1Hz)，6.70(1H，d，J＝3.3Hz)，7.63(1H，d，J＝3.3Hz)，8.69(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-5-[2-(2-ethoxy ethoxy) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
To 4-chloro-5-[2-(2-ethoxy ethoxy) ethyl]-5H-pyrrolo-[3,2-d] add 3-chloro-4-[(3-luorobenzyl in 1-Methyl-2-Pyrrolidone (1.1mL) solution of pyrimidine (150mg)) the oxygen base] aniline (189mg), and reaction mixture stirred 1 hour down at 120 ℃.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (30mL * 3) with 5% sodium bicarbonate aqueous solution (25mL).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=100/0 → 95/5).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (146mg) of colorless oil.
1H-NMR(CDCl
3)δ1.09(3H，t，J＝6.9Hz)，3.36(2H，q，J＝6.9Hz)，3.51(2H，t，J＝4.2Hz)，3.71(2H，t，J＝4.5Hz)，3.98(2H，t，J＝4.5Hz)，4.51(2H，t，J＝4.2Hz)，5.24(2H，s)，6.60(1H，d，J＝3.0Hz)，6.91(2H，d，J＝8.8Hz)，7.00(2H，t，J＝7.2Hz)，7.17-7.37(2H，m)，7.50(1H，dd，J＝2.7，8.8Hz)，7.68(1H，d，J＝3.0Hz)，8.47(1H，s)，8.68(1H，s)。
Embodiment 57
5-[2-(2-ethoxy ethoxy) ethyl]-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method identical, by using 4-chloro-5-[2-(2-ethoxy ethoxy) ethyl with embodiment 47]-5H-pyrrolo-[3,2-d] pyrimidines (150mg), obtain the title compound (98mg) of colorless oil.
1H-NMR(DMSO-d
6)δ0.93(3H，t，J＝7.0Hz)，2.24(3H，s)，2.74(3H，s)，3.23(2H，q，J＝7.0Hz)，3.37-3.40(2H，m)，3.56-3.59(2H，m)，3.86(2H，t，J＝4.5Hz)，4.89(2H，t，J＝4.5Hz)，6.72(1H，d，J＝3.0Hz)，7.22(1H，d，J＝8.7Hz)，7.58-7.66(2H，m)，7.91(1H，d，J＝8.7Hz)，8.05(1H，t，J＝3.0Hz)，8.09(1H，d，J＝3.0Hz)，8.36(1H，d，J＝2.8Hz)，8.73(1H，s)，10.07(1H，br?s)。
Embodiment 58
2-[4-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] the alcoholic acid preparation
React according to the method identical,, obtain white powder crystalline title compound (241mg) by using 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethanol (250mg) with embodiment 47.
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.43(3H，s)，3.87(2H，t，J＝4.5Hz)，4.52(2H，t，J＝4.5Hz)，6.27(1H，br?s)，6.48(1H，dd，J＝1.6，3.0Hz)，6.97(1H，d，J＝9.6Hz)，7.16(1H，ddd，J＝1.6，3.0，8.7Hz)，7.23(1H，d，J＝8.4Hz)，7.53(2H，br?s)，7.63(1H，dd，J＝1.6，3.0Hz)，8.17(1H，d，J＝3.0Hz)，8.28(1H，d，J＝1.6Hz)，9.66(1H，br?s)。
Embodiment 59
4-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-5, the preparation of 6-dihydro-4H-pyrrolo-[3,2,1-de] pteridine
To 2-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] add 1 in ethanol (50mg) and the suspension of tributylphosphine (54mg) in toluene (2.5mL), 1 '-[(E)-diazene-1,2-two basic dicarbapentaborane] two piperidines (67mg), and mixture at room temperature stirred 3 hours.Reaction mixture water (15mL) is diluted, and extract with ethyl acetate (20mL * 3).Organic layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (alkaline silica gel, elutriant: ethyl acetate/methanol=100/0 → 90/10).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (36mg) of white powder.
1H-NMR(CDCl
3)δ2.29(3H，s)，2.54(3H，s)，4.21(2H，t，J＝5.1Hz)，4.41(2H，t，J＝5.1Hz)，6.59(1H，d，J＝2.7Hz)，6.92(1H，d，J＝8.4Hz)，7.11(1H，d，J＝8.4Hz)，7.18(1H，dd，J＝2.7，8.4Hz)，7.23-7.27(2H，m)，7.38(1H，d，J＝2.7Hz)，8.26(1H，d，J＝2.7Hz)，8.49(1H，s)。
Embodiment 60
The preparation of 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) ethyl benzoate
The mixture of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (2.78g), 3-subcutin (4.49g) and 1-Methyl-2-Pyrrolidone (20mL) was stirred 1.5 hours down at 120 ℃.In this reaction mixture, add ethyl acetate, water and saturated sodium bicarbonate aqueous solution.Leach insolubles, and isolate ethyl acetate layer.With the water layer ethyl acetate extraction, and the blended ethyl acetate layer washed with saturated brine, and through anhydrous magnesium sulfate drying.Filtering insolubles is suspended in the methyl alcohol, and adds ethyl acetate and saturated brine.Isolate ethyl acetate layer.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Concentrating under reduced pressure blended ethyl acetate layer, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, ethyl acetate), and, obtain the title compound (2.85g) of light brown powder shape by methyl alcohol-acetone-Di Iso Propyl Ether crystallization.
1H-NMR(CDCl
3)δ：1.39(3H，t，J＝7.2Hz)，4.37(2H，q，J＝7.2Hz)，6.51(1H，d，J＝3.3Hz)，7.28-7.32(1H，m)，7.42(1H，t，J＝8.0Hz)，7.70(1H，d，J＝7.8Hz)，8.09(1H，s)，8.29(1H，d，J＝8.1Hz)，8.49(1H，m)。
Embodiment 61
The benzoic preparation of 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino)
The mixture of 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base amino) ethyl benzoate (3.34g), 1N aqueous sodium hydroxide solution (25mL) and methyl alcohol (50mL) at room temperature stirred spend the night.In this reaction mixture, add 1N hydrochloric acid (25mL), and reduction vaporization methyl alcohol.Filter the crystallization of collecting precipitation, and wash with water, obtain the title compound (3.09g) of light brown powder shape.
1H-NMR(DMSO-d
6)δ：6.50(1H，m)，7.49(1H，t，J＝7.8Hz)，7.60(1H，d，J＝7.8Hz)，7.69(1H，t，J＝2.7Hz)，8.25(1H，d，J＝7.8Hz)，8.39(1H，s)，8.43(1H，s)，9.54(1H，s)，11.24(1H，s)，13.01(1H，br)。
Embodiment 62
N-[3-(piperidines-1-base carbonyl) phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenylformic acid (153mg), piperidines (0.078mL), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (173mg) and N, the mixture of dinethylformamide (10mL) at room temperature stirred 2 hours.Add piperidines (0.078mL) and 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (173mg), and with mixture stirring 1 hour.Add I-hydroxybenzotriazole (138mg), and mixture was stirred 3 days.Saturated brine is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 20: 80).Add Di Iso Propyl Ether, and filter the collecting precipitation thing, obtain the title compound (78mg) of light brown powder shape.
1H-NMR(CDCl
3)δ：1.56(2H，m)，1.73(4H，m)，3.42(2H，m)，3.83(2H，m)，6.58(1H，d，J＝2.4Hz)，6.90(1H，d，J＝7.5Hz)，7.18-7.22(1H，m)，7.23(1H，s)，7.30(1H，t，J＝2.4Hz)，7.88(1H，d，J＝8.3Hz)，8.47(1H，s)，8.70(1H，s)，10.71(1H，s)。
Embodiment 63
N-[3-(parathiazan-4-base carbonyl) phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenylformic acid (153mg), parathiazan (0.091mL), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (173mg) and N, the mixture of dinethylformamide (10mL) at room temperature stirred 2 hours.Add parathiazan (0.030mL) and 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (173mg), and with mixture stirring 1 hour.Add I-hydroxybenzotriazole (138mg), and mixture was stirred 3 days.Saturated brine is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 20: 80).Add Di Iso Propyl Ether, and filter the collecting precipitation thing.Throw out is dissolved in the ethyl acetate that contains methyl alcohol, with the saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and Di Iso Propyl Ether is joined in the resistates of acquisition, and filter the collecting precipitation thing, obtain the title compound (82mg) of light brown powder shape.
1H-NMR(CDCl
3)δ：2.65(2H，m)，2.77(2H，m)，3.78(2H，m)，4.05(2H，m)，6.59(1H，d，J＝3.0Hz)，6.98(1H，d，J＝6.9Hz)，7.33(1H，d，J＝7.8Hz)，7.38(1H，d，J＝3.0Hz)，7.53(1H，s)，7.95(1H，br)，8.48(1H，s)。
Embodiment 64
N-{3-[(4-benzyl piepridine-1-yl) carbonyl] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenylformic acid (153mg), 4-benzyl piepridine (158mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (173mg), I-hydroxybenzotriazole (138mg) and N, the mixture of dinethylformamide (10mL) at room temperature stirred 3 hours.The concentrating under reduced pressure reaction mixture adds entry, and with the ethyl acetate extraction that contains tetrahydrofuran (THF).Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 20: 80).The product that obtains is dissolved in the ethyl acetate that contains methyl alcohol and tetrahydrofuran (THF), with sodium bicarbonate aqueous solution and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and Di Iso Propyl Ether is joined in the resistates of acquisition.Filter the collecting precipitation thing, obtain the title compound (201mg) of light brown powder shape.
1H-NMR(CDCl
3)δ：1.10-2.00(6H，m)，2.86(2H，d，J＝6.9Hz)，2.75-3.05(2H，m)，3.78-3.91(1H，m)，4.68-4.82(1H，m)，6.55(1H，d，J＝3.0Hz)，6.90(1H，d，J＝7.5Hz)，7.10-7.33(7H，m)，7.40(1H，s)，7.72(1H，d，J＝8.1Hz)，8.45(1H，s)，8.77(1H，s)，10.83(1H，s)。
Embodiment 65
The preparation of N-benzyl-3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) benzamide
With 3-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenylformic acid (153mg), benzylamine (96mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (173mg), I-hydroxybenzotriazole (138mg) and N, the mixture of dinethylformamide (10mL) at room temperature stirred 3 days.The concentrating under reduced pressure reaction mixture adds entry, and mixture is used the ethyl acetate extraction that contains tetrahydrofuran (THF).Extraction liquid is washed with saturated sodium bicarbonate aqueous solution and saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 50: 50).Add ethyl acetate and ether, and filter the collecting precipitation thing, obtain the title compound (128mg) of colourless powder shape.
1H-NMR(DMSO-d
6)δ：4.50(2H，d，J＝6.0Hz)，6.49(1H，m)，7.21-7.38(5H，m)，7.46(1H，t，J＝8.0Hz)，7.55(1H，d，J＝8.1Hz)，7.68(1H，t，J＝3.0Hz)，8.19(1H，s)，8.26(1H，d，J＝8.0Hz)，8.37(1H，s)，9.06(1H，t，J＝6.0Hz)，9.41(1H，s)，11.13(1H，s)。
Embodiment 66
The preparation of [2-(benzyloxy)-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenyl] methyl alcohol
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (307mg), [5-amino-2-(benzyloxy) phenyl] methyl alcohol (459mg) and N, the mixture of dinethylformamide (10mL) stirred 4 hours down at 80 ℃.The concentrating under reduced pressure reaction mixture adds sodium bicarbonate aqueous solution, and mixture is used the ethyl acetate extraction that contains tetrahydrofuran (THF).Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 30: 70).Add ethanol and ethyl acetate, and filter the collecting precipitation thing, obtain the title compound (279mg) of brown powder shape.
1H-NMR(DMSO-d
6)δ：4.60(2H，d，J＝5.5Hz)，5.12(2H，s)，5.17(1H，t，J＝5.5Hz)，6.45(1H，m)，7.03(1H，d，J＝8.8Hz)，7.29-7.51(5H，m)，7.62(1H，t，J＝2.9Hz)，7.65(1H，d，J＝2.7Hz)，7.93(1H，dd，J＝8.8，2.7Hz)，8.29(1H，s)，9.08(1H，s)，11.05(1H，s)。
Embodiment 67
N-[4-(benzyloxy)-3-p-methoxy-phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
The mixture of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (200mg), 4-(benzyloxy)-3-anisidine (298mg) and 1-Methyl-2-Pyrrolidone (5mL) was stirred 4 hours down at 80 ℃.Methyl alcohol and gac are joined in the reaction mixture, and mixture is stirred.Leach gac, add sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Extraction liquid is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=10: 80 → 20: 80), and, obtain the pulverous title compound of light gray (269mg) by methyl alcohol-re-crystallizing in ethyl acetate.
1H-NMR(DMSO-d
6)δ：3.82(3H，s)，5.06(2H，s)，6.45(1H，m)，7.03(1H，d，J＝8.9Hz)，7.30-7.49(6H，m)，7.51(1H，d，J＝2.5Hz)，7.63(1H，t，J＝2.9Hz)，8.30(1H，s)，9.07(1H，s)，11.06(1H，s)。
Embodiment 68
N-[4-(benzyloxy)-3-chloro-phenyl-]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
The mixture of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (200mg), 4-(benzyloxy)-3-chloroaniline (365mg) and 1-Methyl-2-Pyrrolidone (3mL) was stirred 4 hours down at 80 ℃.Methyl alcohol and gac are joined in the reaction mixture, and mixture is stirred.Leach gac, add sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.With extraction liquid water and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 15: 75), and, obtain the title compound (226mg) of light brown powder shape by ethanol-re-crystallizing in ethyl acetate.
1H-NMR(CDCl
3)δ：5.15(2H，s)，6.56(1H，s)，6.98(1H，d，J＝8.9Hz)，7.28-7.43(4H，m)，7.48(2H，d，J＝7.5Hz)，7.69(1H，d，J＝8.9Hz)，7.80(1H，d，J＝2.6Hz)，8.50(1H，s)，8.63(1H，s)，10.56(1H，s)。
Embodiment 69
The preparation of 2-phenoxy group-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) ethyl benzoate
The mixture of ethyl 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (461mg), 5-amino-2-phenoxy benzoic acid ester (926mg) and 1-Methyl-2-Pyrrolidone (5mL) was stirred 2 hours down at 80 ℃.Ethanol, water and gac are joined in the reaction mixture, and stir the mixture.Leach gac, and solvent evaporated under reduced pressure.Sodium bicarbonate aqueous solution is joined in the resistates, and with the mixture ethyl acetate extraction.With extraction liquid water and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 20: 80), and, obtain the title compound (572mg) of colourless powder shape by ethanol-re-crystallizing in ethyl acetate.
1H-NMR(CDCl
3)δ：1.12(3H，t，J＝7.1Hz)，4.19(2H，q，J＝7.1Hz)，6.57(1H，d，J＝3.0Hz)，6.84(2H，d，J＝7.7Hz)，6.95(1H，d，J＝8.9Hz)，7.00(1H，t，J＝7.3Hz)，7.19-7.29(2H，m)，7.34(1H，d，J＝3.0Hz)，7.80(1H，dd，J＝8.9，2.8Hz)，8.00(1H，d，J＝2.8Hz)，8.67(1H，s)，8.87(1H，s)，10.89(1H，s)。
Embodiment 70
The benzoic preparation of 2-phenoxy group-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino)
The mixture of 2-phenoxy group-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) ethyl benzoate (899mg), 1N aqueous sodium hydroxide solution (5mL) and methyl alcohol (15mL) was stirred 1.5 hours down at 60 ℃.In this reaction mixture, add 1N hydrochloric acid (5mL), and reduction vaporization methyl alcohol.Filter the crystallization of collecting precipitation, and water and washing with acetone, obtain the title compound (768mg) of light brown powder shape.
1H-NMR(DMSO-d
6)δ：6.50(1H，m)，6.89(2H，d，J＝7.7Hz)，7.04(1H，t，J＝7.3Hz)，7.12(1H，d，J＝8.9Hz)，7.33(2H，t，J＝8.0Hz)，7.69(1H，t，J＝2.9Hz)，8.16(1H，dd，J＝8.9，2.9Hz)，8.31(1H，d，J＝2.9Hz)，8.37(1H，s)，9.46(1H，s)，11.11(1H，s)，12.95(1H，br)。
Embodiment 71
The preparation of [2-phenoxy group-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenyl] methyl alcohol
N to 2-phenoxy group-5-(5H-pyrrolo-[3,2-d] pyrimidine-4-base amino) phenylformic acid (173mg) adds 1 in dinethylformamide (5mL) solution, 1 '-carbonyl dimidazoles (97mg), and mixture at room temperature stirred 1 hour.At room temperature sodium borohydride (38mg) is joined in the reaction mixture, and drip methyl alcohol (1mL).After at room temperature stirring is spent the night, water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.With extraction liquid water and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by silica gel column chromatography purifying (elutriant, methyl alcohol: ethyl acetate=0: 100 → 20: 80), and, obtain the title compound (44mg) of colourless powder shape by methyl alcohol-ethyl acetate crystallization.
1H-NMR(DMSO-d
6)δ：4.50(2H，d，J＝5.1Hz)，5.28(1H，t，J＝5.1Hz)，6.48(1H，m)，6.90(2H，d，J＝7.7Hz)，6.96(1H，d，J＝8.7Hz)，7.06(1H，t，J＝7.3Hz)，7.30-7.40(2H，m)，7.66(1H，t，J＝2.9Hz)，7.85(1H，d，J＝2.7Hz)，8.04(1H，dd，J＝8.7，2.7Hz)，8.34(1H，s)，9.28(1H，s)，11.11(1H，s)。
Embodiment 72
6-(2-furyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 2-cyano group-1-(2-furyl) vinyl 4-toluene sulfonic acide ester
Under ice-cooled, in the mixture of 3-(2-furyl)-3-oxypropionitrile (5.29g), p-toluenesulfonyl chloride (9.00g) and methylene dichloride (60mL), drip triethylamine (5.99g)., after 1.5 hours mixture is diluted with methylene dichloride (100mL) in ice-cooled stirring down.With mixture water (150mL) washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.With resistates by silica gel column chromatography purifying (elutriant, hexane: the title compound (10.48g) that methyl acetate=9: 1 → 3: 1), obtains (E)-type and (Z)-type mixture (3: 1).
1H-NMR(CDCl
3)δ2.47(3/4H，s)，2.49(9/4H，s)，5.27(1/4H，s)，5.63(3/4H，s)，6.47(1/4H，m)，6.53(3/4H，m)，6.86(1/4H，d，J＝3.6Hz)，6.95(3/4H，d，J＝3.6Hz)，7.38(1/2H，d，J＝7.8Hz)，7.42(3/2H，d，J＝7.8Hz)，7.51(3/4H，m)，7.55(1/4H，m)，7.83(1/2H，d，J＝7.8Hz)，7.97(3/2H，d，J＝7.8Hz)。
The (ii) preparation of 3-amino-5-(2-furyl)-1H-pyrroles-2-carboxyl ethyl ester
Under ice-cooled, drip the ethanolic soln (36.9mL) of 20% sodium ethylate in the solution in ethanol (120mL)-tetrahydrofuran (THF) (64mL) mixed solvent to 2-cyano group-1-(2-furyl) vinyl 4-toluene sulfonic acide ester (10.48g) and amidomalonic acid diethyl ester hydrochloride (7.67g).After at room temperature stirring 12 hours, reaction mixture is poured in the frozen water (350mL), and to be adjusted to pH with 1N hydrochloric acid be 7.The reduction vaporization organic solvent, and with resistates ethyl acetate (150mL * 3) extraction.Merge organic layer, with saturated brine (100mL) washing, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, with resistates by the silica gel column chromatography purifying (elutriant, hexane: methyl acetate=3: 1 → 1: 1), and with the solid that obtains by ethyl acetate-hexane recrystallization, obtain title compound (2.66g).
1H-NMR(CDCl
3)δ1.37(3H，t，J＝7.0Hz)，4.34(2H，q，J＝7.0Hz)，4.37(2H，br?s)，5.93(1H，d，J＝2.7Hz)，6.45(1H，dd，J＝3.6，1.8Hz)，6.49(1H，d，J＝3.6Hz)，7.41(1H，d，J＝1.8Hz)，8.35(1H，br?s)。
(iii) 6-(2-furyl)-4, the preparation of 5-dihydro-3H-pyrrolo-[3,2-d] pyrimidin-4-one
In ethanol (35mL) solution of 3-amino-5-(2-furyl)-1H-pyrroles-2-carboxyl ethyl ester (2.58g), add acetate carbonamidine (1.83g), and mixture heating up was refluxed 18 hours.After being cooled to room temperature, filter the solid of collecting precipitation, use washing with alcohol, and, obtain title compound (2.26g) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ6.58(1H，d，J＝2.1Hz)，6.61(1H，dd，J＝3.5，2.1Hz)，7.08(1H，m)，7.76(1H，m)，7.80(1H，d，J＝3.5Hz)，11.91(1H，br?s)，12.50(1H，br?s)。
The (iv) preparation of 4-chloro-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine
With 6-(2-furyl)-4, the mixture of 5-dihydro-3H-pyrrolo-[3,2-d] pyrimidin-4-ones (2.20g) and phosphoryl chloride (10.7g) stirred 20 minutes down at 100 ℃, added diox (30mL), and mixture was stirred 3 hours down at 100 ℃.Behind the concentrating under reduced pressure, saturated sodium bicarbonate aqueous solution is joined in the resistates, and mixture is extracted with ethyl acetate-acetone (155mL * 4).Merge organic layer, with saturated brine (100mL) washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is washed with ethyl acetate-ether, and, obtain title compound (2.19g) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ6.74(1H，dd，J＝3.6，2.1Hz)，6.95(1H，d，J＝1.8Hz)，7.37(1H，dd，J＝3.6，0.6Hz)，7.95(1H，dd，J＝2.1，0.6Hz)，8.60(1H，s)，12.71(1H，br?s)。
(v) 6-(2-furyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine (110mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] mixture of aniline (161mg) and 1-Methyl-2-Pyrrolidone (2.5mL) stirred 2 hours down at 140 ℃, be poured in the water (10mL), and regulate pH to 8 with saturated sodium bicarbonate aqueous solution.Mixture is extracted with ethyl acetate (25mL * 2), and merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=1: 1 → 0: 1).Concentrating under reduced pressure target fraction.Chloroform-Di Iso Propyl Ether is joined in the resistates, and solid filtering is collected, and, obtain title compound (114mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ2.21(3H，s)，2.48(3H，s)，6.72(1H，dd，J＝3.3，1.8Hz)，6.78(1H，d，J＝1.8Hz)，6.98(1H，d，J＝8.4Hz)，7.02(1H，d，J＝3.6Hz)，7.17(1H，dd，J＝8.4，2.7Hz)，7.22(1H，d，J＝8.4Hz)，7.74(1H，dd，J＝8.4，2.7Hz)，7.80(1H，d，J＝2.1Hz)，7.92(1H，dd，J＝1.8，0.9Hz)，8.16(1H，dd，J＝2.7，0.9Hz)，8.33(1H，s)，9.17(1H，br?s)，11.67(1H，br?s)。
Embodiment 73
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine (110mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (189mg) and 1-Methyl-2-Pyrrolidone (2.5mL) stirred 2 hours down at 140 ℃, be poured in the water (10mL), and regulate pH to 8 with saturated sodium bicarbonate aqueous solution.Mixture is extracted with ethyl acetate (30mL * 2).Merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=4: 1 → 1: 1).Concentrating under reduced pressure target fraction.Chloroform-Di Iso Propyl Ether is joined in the resistates, and solid filtering is collected, and, obtain title compound (122mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ5.23(2H，s)，6.71(1H，dd，J＝3.3，2.1Hz)，6.78(1H，d，J＝2.1Hz)，7.02(1H，d，J＝3.3Hz)，7.18(1H，m)，7.25(1H，d，J＝9.0Hz)，7.28-7.33(2H，m)，7.46(1H，m)，7.57(1H，dd，J＝9.0，3.0Hz)，7.92(1H，d，J＝1.8Hz)，8.18(1H，d，J＝2.4Hz)，8.33(1H，s)，9.18(1H，br?s)，11.61(1H，br?s)。
Embodiment 74
N-[3-chloro-4-(pyridine-2-ylmethoxy) phenyl]-preparation of 6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-6-(2-furyl)-5H-pyrrolo-[3,2-d] mixture of pyrimidine (80mg), 3-chloro-4-(pyridine-2-ylmethoxy) aniline (94mg) and 1-Methyl-2-Pyrrolidone (2.5mL) stirred 2 hours down at 140 ℃, be poured in the water (10mL), and regulate pH to 8 with saturated sodium bicarbonate aqueous solution.Mixture is extracted with ethyl acetate (30mL * 2).Merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=1: 1 → 0: 1).Concentrating under reduced pressure target fraction.Chloroform-Di Iso Propyl Ether is joined in the resistates, and solid filtering is collected, and, obtain title compound (71mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ5.27(2H，s)，6.72(1H，m)，6.78(1H，d，J＝1.2Hz)，7.02(1H，d，J＝3.3Hz)，7.26(1H，d，J＝9.0Hz)，7.36(1H，m)，7.53-7.59(2H，m)，7.81(1H，d，J＝8.1Hz)，7.91(1H，s)，8.21(1H，d，J＝2.4Hz)，8.34(1H，s)，8.59(1H，d，J＝5.1Hz)，9.19(1H，br?s)，11.62(1H，br?s)。
Embodiment 75
4-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of benzoate hydrochlorate
(i) 4-(2-cyano group-1-{[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base } vinyl) preparation of methyl benzoate
Under ice-cooled, in the mixture of 4-(cyano group ethanoyl) methyl benzoate (10.29g), p-toluenesulfonyl chloride (11.58g) and methylene dichloride (110mL), drip triethylamine (7.68g)., after 2.5 hours mixture is diluted with methylene dichloride (100mL) in ice-cooled stirring down, water (150mL) washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.With resistates by silica gel column chromatography purifying (elutriant, hexane: the title compound (17.60g) that methyl acetate=9: 1 → 1: 1), obtains (E)-type and (Z)-type mixture (6: 5).
1H-NMR(CDCl
3)δ2.44(18/11H，s)，2.47(15/11H，s)，3.94(18/11H，s)，3.95(15/11H，s)，5.66(6/11H，s)，5.68(5/11H，s)，7.33(12/11H，d，J＝7.8Hz)，7.38(10/11H，d，J＝7.8Hz)，7.62-8.09(6H，m)。
(ii) 3-amino-5-[4-(ethoxy carbonyl) phenyl]-preparation of 1H-pyrroles-2-carboxyl ethyl ester
Ice-cooled down, to 4-(2-cyano group-1-{[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base vinyl) ethanolic soln (50mL) of dropping 20% sodium ethylate in methyl benzoate (17.5g) and the suspension of amidomalonic acid diethyl ester hydrochloride (10.36g) in ethanol (165mL)-tetrahydrofuran (THF) (80mL) mixed solvent.Mixture was at room temperature stirred 21 hours after 1 hour in ice-cooled stirring down.Reaction mixture is poured in the frozen water (400mL), and to be adjusted to pH with 1N hydrochloric acid be 7.The reduction vaporization organic solvent, and with resistates ethyl acetate (250mL * 3) extraction.Merge organic layer, with saturated brine (150mL) washing, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, with resistates by the silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=2: 1 → 1: 1), and with the solid that obtains by re-crystallizing in ethyl acetate, obtain title compound (4.76g).
1H-NMR(CDCl
3)δ1.36-1.43(6H，m)，4.31-4.42(6H，m)，6.11(1H，d，J＝3.0Hz)，7.55(2H，d，J＝8.4Hz)，8.04(2H，d，J＝8.4Hz)，8.40(1H，br?s)。
The (iii) preparation of 4-(4-oxo-4,5-dihydro-3H-pyrrolo-[3,2-d] pyrimidine-6-yl) ethyl benzoate
With 3-amino-5-[4-(ethoxy carbonyl) phenyl]-mixture heating up of 1H-pyrroles-2-carboxyl ethyl ester (3.36g), acetate carbonamidine (1.74g) and ethanol (60mL) refluxed 15 hours.After being cooled to room temperature, filter the solid of collecting precipitation, use washing with alcohol, and, obtain title compound (2.97g) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ1.34(3H，t，J＝7.1Hz)，4.33(2H，q，J＝7.1Hz)，7.04(1H，s)，7.84(1H，d，J＝2.7Hz)，8.00(2H，d，J＝8.1Hz)，8.11(2H，d，J＝8.1Hz)，11.97(1H，br?s)，12.64(1H，br?s)。
The (iv) preparation of 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) ethyl benzoate hydrochloride
The mixture of 4-(4-oxo-4,5-dihydro-3H-pyrrolo-[3,2-d] pyrimidine-6-yl) ethyl benzoate (2.97g) and phosphoryl chloride (16.45g) was stirred 1 hour down at 110 ℃, add diox (10mL), and mixture heating up was refluxed 4 hours.Behind the concentrating under reduced pressure, (30mL) joins in the resistates with ethanol, at room temperature stir 30 minutes after, filter the solid of collecting precipitation.With this solid washing with alcohol, and, obtain title compound (3.34g) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ1.36(3H，d，J＝7.1Hz)，4.36(2H，q，J＝7.1Hz)，7.40(1H，s)，8.09(2H，d，J＝8.7Hz)，8.26(2H，d，J＝8.7Hz)，8.67(1H，s)，12.77(1H，br?s)。
(v) 4-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of benzoate hydrochlorate
With 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) ethyl benzoate hydrochloride (1.297g), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] mixture of aniline (1.00g), diisopropyl ethyl amine (0.834g) and 1-Methyl-2-Pyrrolidone (12.5mL) stirred 3 hours down at 140 ℃, be poured in water (100mL)-ethyl acetate (150mL), and filter the solid of collecting precipitation.This solid is washed with ethyl acetate, and in 60 ℃ of drying under reduced pressure.The solid suspension that obtains in methyl alcohol (40mL), and is added 1N aqueous sodium hydroxide solution (20mL).After at room temperature stirring 12 hours, solvent evaporated under reduced pressure, and resistates is adjusted to pH with 1N hydrochloric acid is 2.Filter the solid of collecting precipitation, wash with water, and, obtain title compound (1.08g) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ2.21(3H，s)，2.44(3H，s)，6.98(1H，d，J＝9.0Hz)，7.15(1H，s)，7.17-7.25(2H，m)，7.76(1H，d，J＝8.7Hz)，7.85(1H，s)，8.01-8.17(5H，m)，8.48(1H，s)，9.99(1H，br?s)，12.47(1H，br?s)。
Embodiment 76
4-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of benzoate hydrochlorate
With 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) ethyl benzoate hydrochloride (517mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (462mg) and 1-Methyl-2-Pyrrolidone (8mL) stirred 5 hours down at 140 ℃, be poured in the water (40mL), and regulate pH to 8 with saturated sodium bicarbonate aqueous solution.Filter the solid of collecting precipitation, wash with water, and be suspended in the methyl alcohol (15mL).After at room temperature stirring 30 minutes, solid filtering is collected, and in 60 ℃ of drying under reduced pressure.The solid suspension that obtains in ethanol (10mL), and is added 1N aqueous sodium hydroxide solution (1.5mL).After at room temperature stirring 6.5 hours, and under 60 ℃, stirred 3.5 hours, mixture is cooled to room temperature.Add 1N hydrochloric acid (155mL), and filter the solid of collecting precipitation, wash with water, and, obtain title compound (498mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ5.24(2H，s)，7.12-7.35(5H，m)，7.48(1H，m)，7.70(1H，d，J＝8.7Hz)，8.01-8.12(4H，m)，8.27(1H，s)，8.37(1H，s)，9.65(1H，br?s)，12.15(1H，br?s)。
Embodiment 77
6-(2-furyl)-5-methyl-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidines (220mg), add salt of wormwood (139mg) and methyl iodide (0.25mL) in dinethylformamide (2.5mL) solution, and mixture was at room temperature stirred 8 hours.Mixture is poured in the water (30mL), and extracts with ethyl acetate (30mL * 3).Merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=4: 1 → 0: 1), obtain title compound (94mg).
1H-NMR(CDCl
3)δ4.29(3H，s)，6.62(1H，dd，J＝3.6，1.8Hz)，6.86(1H，d，J＝3.6Hz)，6.94(1H，s)，7.67(1H，d，J＝1.8Hz)，8.68(1H，s)。
(ii) 6-(2-furyl)-5-methyl-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-6-(2-furyl)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine (92mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] mixture of aniline (102mg) and 1-Methyl-2-Pyrrolidone (2.5mL) stirred 3.5 hours down at 140 ℃, be poured in the water (10mL), and regulate pH to 8 with saturated sodium bicarbonate aqueous solution.Mixture is extracted with ethyl acetate (25mL * 2), and merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=1: 1 → 0: 1).Concentrating under reduced pressure target fraction.Ether is joined in the resistates, and solid filtering is collected, and, obtain title compound (105mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.43(3H，s)，4.12(3H，s)，6.74(1H，dd，J＝3.6，1.2Hz)，6.76(1H，s)，6.93(1H，d，J＝8.7Hz)，7.05(1H，d，J＝3.6Hz)，7.17(1H，dd，J＝8.7，2.4Hz)，7.23(1H，d，J＝8.7Hz)，7.46(1H，dd，J＝8.7，3.0Hz)，7.52(1H，d，J＝2.4Hz)，7.94(1H，d，J＝1.2Hz)，8.16(1H，d，J＝3.0Hz)，8.27(1H，s)，8.71(1H，br?s)。
Embodiment 78
5-(2-ethoxyethyl group)-6-(2-furyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-(2-ethoxyethyl group)-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidines (220mg), add cesium carbonate (489mg) in dinethylformamide (1.2mL) solution down ice-cooled, and mixture was stirred 15 minutes down ice-cooled.Add 2-bromotrifluoromethane ether (0.169mL), and mixture was at room temperature stirred 2 days.Add cesium carbonate (326mg) and 2-bromotrifluoromethane ether (0.113mL), and mixture was at room temperature stirred 1 day.Reaction mixture is poured in the water (30mL), and extracts with ethyl acetate (60mL).With organic layer through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=4: 1 → 1: 4), obtain title compound (76mg).
1H-NMR(CDCl
3)δ1.09(3H，t，J＝6.9Hz)，3.42(2H，q，J＝6.9Hz)，3.82(2H，t，J＝6.3Hz)，4.92(2H，t，J＝6.3Hz)，6.60(1H，dd，J＝3.6，2.1Hz)，6.94(1H，s)，6.98(1H，d，J＝3.6Hz)，7.64(1H，d，J＝2.1Hz)，8.68(1H，s)。
(ii) 5-(2-ethoxyethyl group)-6-(2-furyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-5-(2-ethoxyethyl group)-6-(2-furyl)-5H-pyrrolo-[3,2-d] pyrimidine (76mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] mixture of aniline (67mg) and 1-Methyl-2-Pyrrolidone (1.5mL) stirred 2 hours down at 140 ℃, be poured in the water (8mL), and regulate pH to 8 with saturated sodium bicarbonate aqueous solution.Mixture is extracted with ethyl acetate (20mL * 2), and merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=1: 1 → 0: 1).Concentrating under reduced pressure target fraction.Di Iso Propyl Ether-hexane is joined in the resistates, and solid filtering is collected, and, obtain title compound (78mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ1.08(3H，t，J＝6.9Hz)，2.18(3H，s)，2.43(3H，s)，3.52(2H，q，J＝6.9Hz)，3.95(2H，t，J＝4.4Hz)，4.68(2H，brt，J＝4.4Hz)，6.73(1H，dd，J＝3.6，1.8Hz)，6.84(1H，s)，6.96(1H，d，J＝8.1Hz)，7.01(1H，d，J＝3.6Hz)，7.16(1H，dd，J＝8.4，2.7Hz)，7.22(1H，d，J＝8.4Hz)，7.50-7.55(2H，m)，7.93(1H，d，J＝1.8，Hz)，8.15(1H，d，J＝2.7Hz)，8.31(1H，s)，9.15(1H，br?s)。
Embodiment 79
{ 4-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-and 5H-pyrrolo-[3,2-d] pyrimidine-6-yl] phenyl } preparation of methyl alcohol
To 4-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] add triethylamine (30.5mg) in tetrahydrofuran (THF) (10mL) suspension of phenylformic acid (122mg), after at room temperature stirring 10 minutes, add 1,1 '-carbonyl dimidazoles (49mg), and mixture at room temperature stirred 13 hours.Under ice-cooled, add sodium borohydride (28mg), and further add methyl alcohol (2.5mL).Add entry (1.5mL) in ice-cooled stirring down after 2 hours, and reduction vaporization tetrahydrofuran (THF) and methyl alcohol.Add entry (20mL), and mixture is extracted with ethyl acetate (30mL)-tetrahydrofuran (THF) (15mL).Separate organic layer, and water layer is extracted with ethyl acetate (15mL)-tetrahydrofuran (THF) (5mL).Merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, ethyl acetate: methyl alcohol=99: 1 → 9: 1).Concentrating under reduced pressure target fraction.Resistates by methyl alcohol-re-crystallizing in ethyl acetate, is obtained title compound (65mg).
1H-NMR(DMSO-d
6)δ2.21(3H，s)，2.43(3H，s)，4.57(2H，d，J＝4.8Hz)，5.32(1H，brt，J＝4.8Hz)，6.96(1H，s)，6.99(1H，d，J＝8.4Hz)，7.18(1H，dd，J＝8.7，2.7Hz)，7.23(1H，d，J＝8.7Hz)，7.50(2H，d，J＝7.8Hz)，7.74(1H，dd，J＝8.4，2.7Hz)，7.81-7.85(3H，m)，8.16(1H，d，J＝2.7Hz)，8.34(1H，s)，9.09(1H，br?s)，11.56(1H，br?s)。
Embodiment 80
N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-6-[4-({ [2-(methylsulfonyl) ethyl] amino } methyl) phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
Will 4-[4-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] phenyl } methyl alcohol (96mg), Manganse Dioxide (1.0g) and N, the mixture of dinethylformamide (5mL) at room temperature stirred 12 hours.Behind the diatomite filtration, concentrating under reduced pressure filtrate.Resistates is carried out silica gel column chromatography handle (elutriant, ethyl acetate: methyl alcohol=100: 0 → 9: 1).With the solid, methylsulfonyl ethylamine hydrochloride (27.5mg), the N that obtain, the mixture of dinethylformamide (2mL) and acetate (0.02mL) at room temperature stirred 1 hour, and added sodium triacetoxy borohydride (36.6mg).After at room temperature stirring 4.5 hours, add saturated sodium bicarbonate aqueous solution (10mL), and mixture is extracted with ethyl acetate (25mL * 2).Merge organic layer, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography handle (ethyl acetate: methyl alcohol=10: 0 → 9: 1).Concentrating under reduced pressure target fraction.Chloroform-Di Iso Propyl Ether is joined in the resistates, and solid filtering is collected, and, obtain title compound (28mg) in 60 ℃ of drying under reduced pressure.
1H-NMR(DMSO-d
6)δ2.21(3H，s)，2.44(3H，s)，2.94(2H，t，J＝6.6Hz)，3.00(3H，s)，3.29(2H，t，J＝6.6Hz)，3.78(2H，s)，6.97(1H，s)，7.00(1H，d，J＝8.7Hz)，7.19(1H，dd，J＝8.4，2.7Hz)，7.24(1H，d，J＝8.4Hz)，7.51(2H，d，J＝8.4Hz)，7.77(1H，dd，J＝8.7，2.4Hz)，7.83-7.87(3H，m)，8.18(1H，d，J＝2.4Hz)，8.34(1H，s)，9.23(1H，br?s)，11.73(1H，br?s)。
Embodiment 81
6-(amino methyl)-N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
(i) oxygen base N4-{3-chloro-4-[(3-luorobenzyl)] phenyl }-6-iodine pyrimidine-4, the preparation of 5-diamines
With 5-amino-4,6-two iodine pyrimidines (3.83g) and 3-chloro-4-[(3-luorobenzyl) the oxygen base] 1-Methyl-2-Pyrrolidone (30mL) solution of aniline (2.78g) stirred 14 hours down at 70 ℃.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by column chromatography purifying (elutriant, ethyl acetate: hexane=1: 4 → 2: 3 → 1: 1), obtain brown powder shape crystalline title compound (4.21g).
1H-NMR(CDCl
3)δ：3.47(2H，br?s)，5.13(2H，s)，6.73(1H，br?s)，6.92(1H，d，J＝9.0Hz)，6.96-7.04(1H，m)，7.15-7.25(2H，m)，7.31-7.38(2H，m)，7.64(1H，d，J＝2.7Hz)，8.04(1H，s)。
(ii) 3-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] preparation of Propargyl t-butyl carbamate
At room temperature, to N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4, add in acetonitrile-triethylamine (20mL-15mL) solution of 5-diamines (0.84g) and Propargyl t-butyl carbamate (0.36g) two (triphenylphosphine) palladium chlorides (II) (62.5mg) and cuprous iodide (I) (20.3mg), and mixture at room temperature stirred under argon atmospher 6 hours.Behind the concentrating under reduced pressure, separate resistates, and by column chromatography purifying (elutriant, ethyl acetate: hexane=1: 1 → ethyl acetate), obtain the title compound (766.5mg) of brown solid.
1H-NMR(DMSO-d
6)δ：1.42(9H，s)，4.06(2H，d，J＝5.4Hz)，5.22(2H，s)，5.45(2H，br?s)，7.13-7.23(2H，m)，7.26-7.34(2H，m)，7.42-7.51(2H，m)，7.54-7.60(1H，m)，7.95(2H，s)，8.54(1H，s)。
(iii) [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of the methyl carbamic acid tert-butyl ester
Will (3-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] Propargyl t-butyl carbamate (720mg) and cuprous iodide (I) are (55.2mg) at N, and the mixture in the dinethylformamide (7.0mL) stirred 12 hours down at 80 ℃.Behind the concentrating under reduced pressure, separate resistates, and by column chromatography purifying (alkaline silica gel, elutriant, ethyl acetate → methyl alcohol: ethyl acetate=1: 9), obtain pale yellow powder shape crystalline title compound (604mg).
1H-NMR(DMSO-d
6)δ：1.42(9H，s)，4.33(2H，d，J＝5.7Hz)，5.22(2H，s)，6.29(1H，s)，7.14-7.35(4H，m)，7.41-7.60(3H，m)，8.16(1H，d，J＝2.7Hz)，8.30(1H，s)，9.29(1H，s)，10.96(1H，br?s)。
(iv) 6-(amino methyl)-N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
At room temperature, to [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] add 2N hydrochloric acid (6.0mL) in tetrahydrofuran (THF) (12mL) solution of the methyl carbamic acid tert-butyl ester (500mg).Mixture was stirred 2 hours down at 60 ℃, ethanol is joined in the reaction system, and the concentrating under reduced pressure mixture.Filter and collect the crystallization that generates, and, obtain pale yellow powder shape crystalline title compound (481.4mg) with the Di Iso Propyl Ether washing.
1H-NMR(DMSO-d
6)δ：4.28-4.39(2H，m)，5.28(2H，s)，6.89(1H，s)，7.15-7.25(1H，m)，7.29-7.40(3H，m)，7.45-7.54(1H，m)，7.73-7.80(1H，m)，8.15(1H，s)，8.48-8.65(3H，m)，8.82(1H，s)。
Embodiment 82
(2E)-and N-{[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] methyl }-preparation of 4-(dimethylamino) but-2-enamides
With 6-(amino methyl)-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] N of pyrimidine-4-amine dihydrochloride (150mg), (2E)-4-(dimethylamino) but-2-ene acid hydrochloride (105mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (244mg), I-hydroxybenzotriazole monohydrate (196mg) and triethylamine (0.30mL), dinethylformamide (5mL) solution at room temperature stirred 2 days.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and the separation resistates, and by column chromatography purifying (alkaline silica gel, elutriant, methyl alcohol: ethyl acetate=1: 9 → 1: 4), obtain filbert Powdered crystalline title compound (104.2mg).
1H-NMR(DMSO-d
6)δ：2.14(6H，s)，3.00(2H，d，J＝6.1Hz)，4.54(2H，d，J＝5.7Hz)，5.21(2H，s)，6.11(1H，d，J＝15.3Hz)，6.35(1H，s)，6.66(1H，dt，J＝15.3，6.1Hz)，7.12-7.34(4H，m)，7.41-7.49(1H，m)，7.53-7.60(1H，m)，8.14(1H，d，J＝2.4Hz)，8.29(1H，s)，8.69(1H，t，J＝5.7Hz)，9.34(1H，br?s)，10.99(1H，brs)。
Embodiment 83
6-(3-aminophenyl)-N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) ethynyl 6-[(3-aminophenyl)]-N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl } pyrimidine-4, the preparation of 5-diamines
React according to the method (ii) identical with embodiment 81, by using N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4,5-diamines (1.90g), 3-aminophenyl acetylene (0.41mL), two (triphenylphosphine) palladium chloride (II) (102mg), cuprous iodide (I) (27mg), acetonitrile (24mL) and triethylamine (18mL), obtain brown powder shape crystalline title compound (1.35g).
1H-NMR(CDCl
3)δ：3.65-3.78(4H，m)，5.15(2H，s)，6.59(1H，s)，6.73(1H，d，J＝8.1Hz)，6.90-7.06(4H，m)，7.14-7.41(5H，m)，7.68(1H，d，J＝2.7Hz)，8.35(1H，s)。
(ii) 6-(3-aminophenyl)-N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (iii) identical with embodiment 81, by using the 6-[(3-aminophenyl) ethynyl]-N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl } pyrimidine-4,5-diamines (1.30g), cuprous iodide (I) are (54mg) and N, dinethylformamide (7.0mL) obtains brown powder shape crystalline title compound (673mg).
1H-NMR(DMSO-d
6)δ：5.23(2H，s)，5.31(2H，s)，6.58-6.65(1H，m)，6.75(1H，s)，6.94-7.01(2H，m)，7.13-7.34(5H，m)，7.43-7.50(1H，m)，7.57(1H，dd，J＝8.9，2.6Hz)，8.19(1H，d，J＝2.1Hz)，8.32(1H，s)，9.13(1H，s)，11.40(1H，s)。
Embodiment 84
N-{3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] phenyl }-preparation of 2-methoxyl group ethanamide
React according to the method identical with embodiment 82, by using 6-(3-aminophenyl)-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (80mg), methoxyacetic acid (31mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (67mg), I-hydroxybenzotriazole monohydrate (54mg), triethylamine (0.1mL) and N, dinethylformamide (5mL) obtains filbert Powdered crystalline title compound (42.9mg).
1H-NMR(DMSO-d
6)δ：3.42(3H，s)，4.06(2H，s)，5.24(2H，s)，6.87(1H，s)，7.13-7.36(4H，m)，7.44-7.69(5H，m)，8.19-8.26(2H，m)，8.35(1H，s)，9.25(1H，s)，9.95(1H，s)，11.56(1H，s)。
Embodiment 85
6-(4-aminophenyl)-N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) ethynyl 6-[(4-aminophenyl)]-N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl } pyrimidine-4, the preparation of 5-diamines
React according to the method (ii) identical with embodiment 81, by using N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4,5-diamines (1.50g), 4-aminophenyl acetylene (411mg), two (triphenylphosphine) palladium chloride (II) (112mg), cuprous iodide (I) (36.5mg), acetonitrile (24mL) and triethylamine (18mL), obtain the title compound (1.12g) of yellow solid.
1H-NMR(CDCl
3)δ：3.68(2H，br?s)，3.94(2H，br?s)，5.14(2H，s)，6.58(1H，br?s)，6.65(2H，d，J＝7.8Hz)，6.95(1H，d，J＝9.0Hz)，6.96-7.06(1H，m)，7.19-7.43(6H，m)，7.68(1H，d，J＝2.7Hz)，8.34(1H，s)。
(ii) 6-(4-aminophenyl)-N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (iii) identical with embodiment 81, by using the 6-[(4-aminophenyl) ethynyl]-N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl } pyrimidine-4,5-diamines (1.11g), cuprous iodide (I) are (46mg) and N, dinethylformamide (6.0mL) obtains yellow powder shape crystalline title compound (768.6mg).
1H-NMR(DMSO-d
6)δ：5.22(2H，s)，5.53(2H，s)，6.65-6.70(3H，m)，7.12-7.35(4H，m)，7.42-7.61(4H，m)，8.17(1H，d，J＝2.7Hz)，8.28(1H，s)，8.99(1H，s)，11.21(1H，br?s)。
Embodiment 86
N-{4-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] phenyl }-preparation of 2-methoxyl group ethanamide
With 6-(4-aminophenyl)-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] N of pyrimidine-4-amine (100mg), methoxyacetic acid (29.4mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (94mg), I-hydroxybenzotriazole monohydrate (75mg) and triethylamine (0.23mL), dinethylformamide (5mL) solution at room temperature stirred 20 hours.Methoxyacetic acid (29.4mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (94mg) and I-hydroxybenzotriazole monohydrate (75mg) are joined in the reaction system, and mixture was further stirred 24 hours.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and the separation resistates, and by column chromatography purifying (alkaline silica gel, elutriant, ethyl acetate → methyl alcohol: ethyl acetate=14: 85), obtain filbert Powdered crystalline title compound (63.5mg).
1H-NMR(DMSO-d
6)δ：3.40(3H，s)，4.04(2H，s)，5.23(2H，s)，6.90(1H，s)，7.12-7.21(1H，m)，7.23-7.35(3H，s)，7.43-7.49(1H，m)，7.52-7.60(1H，m)，7.78-7.87(4H，m)，8.19(1H，d，J＝1.8Hz)，8.33(1H，s)，9.07(1H，s)，9.97(1H，s)，11.45(1H，s)。
Embodiment 87
(2E)-and 3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of third-2-alkene-1-alcohol
(i) (2E)-and 5-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] preparation of penta-2-alkene-4-alkynes-1-alcohol
React according to the method (ii) identical with embodiment 81, by using N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4,5-diamines (300mg), 2-amylene-4-alkynes-1-alcohol (58mg), two (triphenylphosphine) palladium chloride (II) (22.5mg), cuprous iodide (I) (7.3mg), acetonitrile (6.0mL) and triethylamine (4.5mL), obtain the title compound (188.2mg) of brown solid.
1H-NMR(DMSO-d
6)δ：4.06-4.15(2H，m)，5.06(1H，t，J＝5.4Hz)，5.21(2H，s)，5.45(2H，br?s)，5.98-6.07(1H，m)，6.46-6.57(1H，m)，7.12-7.34(4H，m)，7.39-7.59(2H，m)，7.92-7.99(2H，m)，8.55(1H，br?s)。
(ii) (2E)-3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of third-2-alkene-1-alcohol
React according to the method (iii) identical with embodiment 81, by using (2E)-5-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] penta-2-alkene-4-alkynes-1-alcohol (170mg), cuprous iodide (I) are (7.6mg) and N, dinethylformamide (1.5mL) obtains pale yellow powder shape crystalline title compound (98mg).
1H-NMR(DMSO-d
6)δ：4.16-4.24(2H，m)，5.02-5.09(1H，m)，5.22(2H，s)，6.40-6.52(2H，m)，6.66(1H，d，J＝15.9Hz)，7.13-7.34(4H，m)，7.41-7.50(1H，m)，7.52-7.60(1H，m)，8.17(1H，d，J＝2.7Hz)，8.29(1H，s)，9.13(1H，br?s)，11.38(1H，br?s)。
Embodiment 88
3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of propane-1-alcohol
(i) 5-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] preparation of penta-4-alkynes-1-alcohol
At room temperature, to N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4, add in acetonitrile-triethylamine (6.0mL-4.5mL) solution of 5-diamines (300mg) and 4-pentyne-1-alcohol (65mg) two (triphenylphosphine) palladium chlorides (II) (22.5mg) and cuprous iodide (I) (7.3mg), and mixture at room temperature stirred under argon atmospher 24 hours.With 4-pentyne-1-alcohol (65mg), two (triphenylphosphine) palladium chloride (II) (22.5mg) and cuprous iodide (I) (7.3mg) join in the reaction system, and mixture was stirred 2 hours down at 60 ℃.Behind the concentrating under reduced pressure, separate resistates, and by column chromatography purifying (alkaline silica gel, elutriant, ethyl acetate → methyl alcohol: ethyl acetate=1: 19), obtain the title compound (157.2mg) of yellow solid.
1H-NMR(DMSO-d
6)δ：1.66-1.79(2H，m)，2.43-2.58(2H，m)，3.53(2H，q，J＝5.4Hz)，4.61(1H，t，J＝5.1Hz)，5.20(2H，s)，5.31(2H，s)，7.11-7.21(2H，m)，7.25-7.33(2H，m)，7.39-7.50(1H，m)，7.55(1H，dd，J＝9.0，2.1Hz)，7.92-7.94(2H，m)，8.50(1H，s)。
(ii) 3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of propane-1-alcohol
With 5-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] penta-4-alkynes-1-alcohol (140mg) and cuprous iodide (I) are (19mg) at N, and the mixture in the dinethylformamide (2.0mL) stirred 5 hours down at 80 ℃.Behind the concentrating under reduced pressure, and separate resistates, and by column chromatography purifying (alkaline silica gel, elutriant, ethyl acetate → methyl alcohol: ethyl acetate=15: 85), obtain filbert Powdered crystalline title compound (95.2mg).
1H-NMR(DMSO-d
6)δ：1.79-1.91(2H，m)，2.84(2H，t，J＝7.8Hz)，3.44-3.52(2H，m)，4.62-4.68(1H，m)，5.22(2H，s)，6.24(1H，s)，7.13-7.35(4H，m)，7.43-7.59(2H，m)，8.17(1H，d，J＝2.7Hz)，8.29(1H，s)，9.01(1H，br?s)，10.94-11.05(1H，m)。
Embodiment 89
4-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of fourth-1-alcohol
(i) 6-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] oneself-preparation of 5-alkynes-1-alcohol
React according to the method (ii) identical with embodiment 81, by using N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4,5-diamines (300mg), 5-hexin-1-alcohol (94.2mg), two (triphenylphosphine) palladium chloride (II) (22.5mg), cuprous iodide (I) (7.3mg), acetonitrile (6.0mL) and triethylamine (4.5mL), obtain the title compound (242mg) of brown solid.
1H-NMR(DMSO-d
6)δ：1.51-1.69(4H，m)，2.39-2.58(2H，m)，3.41-3.47(2H，m)，4.46(1H，t，J＝4.8Hz)，5.20(2H，s)，5.28(2H，br?s)，7.12-7.22(2H，m)，7.25-7.33(2H，m)，7.41-7.49(1H，m)，7.55(1H，dd，J＝8.6，2.9Hz)，7.89-7.96(2H，m)，8.50(1H，s)。
(ii) 4-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of fourth-1-alcohol
React according to the method (iii) identical with embodiment 81, by using 6-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] oneself-5-alkynes-1-alcohol (220mg), cuprous iodide (I) are (9.5mg) and N, dinethylformamide (4.0mL) obtains filbert Powdered crystalline title compound (109mg).
1H-NMR(DMSO-d
6)δ：1.44-1.56(2H，m)，1.67-1.81(2H，m)，2.80(2H，t，J＝7.8Hz)，3.45(2H，t，J＝6.0Hz)，4.40-4.50(1H，m)，5.21(2H，s)，6.22(1H，s)，7.12-7.32(4H，m)，7.42-7.55(2H，m)，8.15(1H，d，J＝2.7Hz)，8.27(1H，s)，8.98(1H，s)，10.93(1H，br?s)。
Embodiment 90
6-[(1E)-3-amino third-1-thiazolinyl]-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) (2E)-and 5-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] preparation of penta-2-alkene-4-alkynyl t-butyl carbamate
React according to the method (ii) identical with embodiment 81, by using N4-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-6-iodine pyrimidine-4,5-diamines (600mg), penta-2-alkene-4-alkynyl t-butyl carbamate (0.26g), two (triphenylphosphine) palladium chloride (II) (44.6mg), cuprous iodide (I) (14.5mg), acetonitrile (12mL) and triethylamine (9mL), obtain the title compound (373.8mg) of yellow solid.
1H-NMR(DMSO-d
6)δ：1.40(9H，s)，3.66-3.75(2H，m)，5.21(2H，s)，5.49(2H，br?s)，5.91(1H，d，J＝10.2Hz)，6.30-6.42(1H，m)，7.12-7.25(3H，m)，7.27-7.36(2H，m)，7.42-7.51(1H，m)，7.54-7.62(1H，m)，7.93-7.99(2H，m)，8.58(1H，s)。
(ii) (2E)-3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] preparation of third-2-alkenyl amino t-butyl formate
React according to the method (iii) identical with embodiment 81, by using (2E)-5-[5-amino-6-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino) pyrimidine-4-yl] penta-2-alkene-4-alkynyl t-butyl carbamate (350mg), cuprous iodide (I) are (12.7mg) and N, dinethylformamide (2.0mL) obtains filbert Powdered crystalline title compound (189mg).
1H-NMR(DMSO-d
6)δ：1.41(9H，s)，3.73-3.85(2H，m)，5.23(2H，s)，6.22-6.36(1H，m)，6.48-6.62(2H，m)，7.14-7.38(5H，m)，7.42-7.50(1H，m)，7.52-7.62(1H，m)，8.18(1H，s)，8.30(1H，s)，9.06(1H，br?s)，11.29(1H，br?s)。
(iii) 6-[(1E)-3-amino third-1-thiazolinyl]-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
At room temperature, to (2E)-3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] add 2N hydrochloric acid (3.0mL) in tetrahydrofuran (THF) (6.0mL) solution of third-2-alkenyl amino t-butyl formate (150mg), and mixture was stirred 2 hours down at 60 ℃.Add the 1N aqueous sodium hydroxide solution so that reaction system is alkalescence.Behind chloroform extraction, with organic layer through dried over sodium sulfate and concentrating under reduced pressure.Filter and collect the crystallization that generates.Crystallization is washed with Di Iso Propyl Ether, obtain filbert Powdered crystalline title compound (104mg).
1H-NMR(DMSO-d
6)δ：3.42(2H，d，J＝4.2Hz)，5.22(2H，s)，6.41-6.50(2H，m)，6.62(1H，d，J＝15.9Hz)，7.12-7.35(4H，m)，7.42-7.50(1H，m)，7.57-7.60(1H，m)，8.18(1H，d，J＝2.1Hz)，8.28(1H，s)，9.20(1H，br?s)，11.39(1H，br?s)。
Embodiment 91
N-{ (2E)-3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] third-2-thiazolinyl }-preparation of 2-methoxyl group ethanamide
React according to the method identical with embodiment 82, by using 6-[(1E)-3-amino third-1-thiazolinyl]-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (30mg), methoxyacetic acid (14mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (55mg), I-hydroxybenzotriazole monohydrate (44mg), triethylamine (0.1mL) and N, dinethylformamide (5mL) obtains filbert Powdered crystalline title compound (23.2mg).
1H-NMR(DMSO-d
6)δ：3.34(3H，s)，3.87(2H，s)，3.95(2H，t，J＝5.4Hz)，5.21(2H，s)，6.35(1H，dt，J＝16.2，5.7Hz)，6.47(1H，s)，6.56(1H，d，J＝16.2Hz)，7.12-7.32(4H，m)，7.41-7.50(1H，m)，7.62(1H，dd，J＝9.0.2.7Hz)，8.16-8.25(2H，m)，8.28(1H，s)，9.37-9.52(1H，m)，11.67-11.84(1H，m)。
Embodiment 92
(2E)-and N-{ (2E)-3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] third-2-thiazolinyl }-preparation of 4-(dimethylamino) but-2-enamides
React according to the method identical with embodiment 82, by using 6-[(1E)-3-amino third-1-thiazolinyl]-N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (40mg), (2E)-4-(dimethylamino) but-2-ene acid hydrochloride (31mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (72mg), I-hydroxybenzotriazole monohydrate (58mg), triethylamine (0.13mL) and N, dinethylformamide (5mL) obtains pale yellow powder shape crystalline title compound (25.6mg).
1H-NMR(DMSO-d
6)δ：2.15(6H，s)，3.00(2H，d，J＝6.3Hz)，3.97-4.06(2H，m)，5.23(2H，s)，6.10(1H，d，J＝15.3Hz)，6.27-6.40(1H，m)，6.51(1H，s)，6.55-6.68(2H，m)，7.14-7.36(4H，m)，7.43-7.60(2H，m)，8.17(1H，d，J＝2.7Hz)，8.31(1H，s)，8.41-8.45(1H，m)，9.01(1H，s)，11.22(1H，s)。
Embodiment 93
2-{[2-chloro-4-(5H-pyrrolo-[3,2-d] pyrimidine-4-base is amino) phenoxy group] methyl } preparation of benzonitrile reacts according to the method (ii) identical with embodiment 2, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (200mg) and 2-[(4-amino-2-chlorophenoxy) methyl] benzonitrile (337mg), obtain title compound (272mg).
1H-NMR(DMSO-d
6)δ5.33(2H，s)，6.49(1H，s)，7.32(1H，d，J＝9.0Hz)，7.57-7.68(3H，m)，7.78-7.80(2H，m)，7.94(1H，d，J＝8.1Hz)，8.20(1H，m)，8.36(1H，s)，9.32(1H，br?s)，11.1(1H，br?s)。
Embodiment 94
3-[2-methyl-4-(5H-pyrrolo-[3,2-d] pyrimidine-4-base amino) phenoxy group] preparation of benzonitrile
React according to the method (ii) identical,, obtain title compound (338mg) by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (200mg) and 3-(4-amino-2-methyl phenoxy group) benzonitrile (292mg) with embodiment 2.
1H-NMR(DMSO-d
6)δ2.16(3H，s)，6.49(1H，s)，7.06(1H，d，J＝9.3Hz)，7.21(1H，m)，7.35(1H，s)，7.51-7.59(2H，m)，7.69(1H，m)，7.80-7.83(2H，m)，8.35(1H，s)，9.26(1H，s)，11.1(1H，br?s)。
Embodiment 95
3-[2-chloro-4-(5H-pyrrolo-[3,2-d] pyrimidine-4-base amino) phenoxy group] preparation of benzonitrile
React according to the method (ii) identical,, obtain title compound (230mg) by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (150mg) and 3-(4-amino-2-chlorophenoxy) benzonitrile (219mg) with embodiment 2.
1H-NMR(DMSO-d
6)δ6.53(1H，s)，7.26(1H，m)，7.32(1H，d，J＝8.7Hz)，7.45(1H，s)，7.58(2H，d，J＝5.7Hz)，7.70-7.73(2H，m)，8.41(2H，s)，9.50(1H，s)，11.1(1H，br?s)。
Embodiment 96
2-{[2-methyl-4-(5H-pyrrolo-[3,2-d] pyrimidine-4-base amino) phenoxy group] methyl } preparation of benzonitrile
React according to the method (ii) identical, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (200mg) and 2-[(4-amino-2-methyl phenoxy group with embodiment 2) methyl] benzonitrile (310mg), obtain title compound (250mg).
1H-NMR(DMSO-d
6)δ2.24(3H，s)，5.26(2H，s)，6.46(1H，t，J＝1.5Hz)，7.08(1H，d，J＝9.0Hz)，7.58-7.68(4H，m)，7.78(2H，d，J＝4.2Hz)，7.94(1H，d，J＝7.5Hz)，8.29(1H，s)，9.02(1H，br?s)，11.1(1H，br?s)。
Embodiment 97
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 1H-pyrazolo [4,3-d] pyrimidine-7-amine
With 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (by document:
J.Am.Chem.Soc----., compound known in 1956,78,2418) (150mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (227mg) and the mixture of pyridine hydrochloride (156mg) in 1-Methyl-2-Pyrrolidone (3mL) stirred 10 hours down at 120 ℃.After reaction is finished, mixture is diluted with ethyl acetate, and wash with saturated sodium bicarbonate aqueous solution and saturated brine.The concentrating under reduced pressure organic layer, and resistates carried out silica gel column chromatography (hexane/ethyl acetate=1/3 → 1/10), obtain the title compound (220mg, yield 61%) of light yellow solid.
1H-NMR(CDCl
3)δ5.15(2H，s)，6.96(1H，d，J＝8.7Hz)，7.03(1H，m)，7.20-7.26(2H，m)，7.36(1H，dt，J＝5.7，8.4Hz)，7.71(1H，dd，J＝2.7，9.0Hz)，7.81(1H，d，J＝2.7Hz)，8.14(1H，s)，8.57(1H，s)。
Embodiment 98
N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 1H-pyrazolo [4,3-d] pyrimidine-7-amine
React according to the method identical with embodiment 97, by using 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (150mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (193mg) and pyridine hydrochloride (156mg), obtain the title compound (195mg) of brown solid.
1H-NMR(CDCl
3)δ2.13(3H，s)，6.89(1H，d，J＝8.4Hz)，7.11(1H，d，J＝8.1Hz)，7.15(1H，dd，J＝2.7，8.4Hz)，7.50(1H，dd，J＝2.7，9.0Hz)，7.68(1H，d，J＝2.7Hz)，8.14(1H，s)，8.25(1H，d，J＝2.7Hz)，8.58(1H，s)。
Embodiment 99
4-{[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } preparation of methyl benzoate
React according to the method identical with embodiment 97, by using 4-{[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } methyl benzoate (120mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (87mg) and pyridine hydrochloride (60mg), obtain the title compound (45mg) of brown solid.
1H-NMR(CDCl
3)δ3.94(3H，s)，5.11(2H，s)，5.90(2H，s)，6.34(1H，br?s)，6.85(1H，d，J＝8.7Hz)，6.94(1H，dd，J＝2.7，8.7Hz)，7.01(1H，m)，7.16-7.22(2H，m)，7.32(2H，d，J＝8.7Hz)，7.35(1H，m)，8.14(2H，d，J＝8.7Hz)，8.18(1H，s)，8.51(1H，s)。
Embodiment 100
4-{[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } preparation of methyl benzoate
React according to the method identical with embodiment 97, by using 4-{[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } methyl benzoate (150mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (109mg) and pyridine hydrochloride (75mg), obtain the title compound (140mg) of light yellow solid.
1H-NMR(CDCl
3)δ3.92(3H，s)，5.16(2H，s)，5.62(2H，s)，6.97(1H，d，J＝8.8Hz)，7.02(1H，m)，7.18-7.42(4H，m)，7.55-7.68(2H，m)，8.00-8.08(4H，m)，8.50(1H，s)。
Embodiment 101
4-{[7-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } benzoic preparation
To 4-{[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } methyl benzoate (25mg) is the mixed solvent of tetrahydrofuran (THF)/methyl alcohol (1: 1, add 1N aqueous sodium hydroxide solution (0.5mL) in the solution 1mL), and mixture was at room temperature stirred 1 hour.After reaction is finished, add 1N aqueous hydrochloric acid (0.5mL) and water (1mL) down ice-cooled, and mixture was at room temperature stirred 1 hour.Filter and collect the solid that generates, and wash and drying, obtain faint yellow crystalline title compound (16mg) with Di Iso Propyl Ether.
1H-NMR(DMSO-d
6)δ5.24(2H，s)，6.10(2H，s)，7.13-7.31(5H，m)，7.42-7.47(2H，m)，7.70(1H，m)，7.83-7.91(2H，m)，8.27(1H，s)，8.35(1H，s)，8.81(1H，s)，12.9(1H，br?s)。
Embodiment 102
4-{[7-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } benzoic preparation
React according to the method identical with embodiment 101, by using 4-{[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } methyl benzoate (150mg) and 1N aqueous sodium hydroxide solution (6mL), obtain faint yellow crystalline title compound (130mg).
1H-NMR(DMSO-d
6)δ5.26(2H，s)，5.85(2H，s)，7.15-7.32(4H，m)，7.41(2H，d，J＝8.1Hz)，7.45(1H，m)，7.72(1H，dd，J＝2.4，8.7Hz)，7.94(2H，d，J＝8.1Hz)，8.06(1H，d，J＝2.1Hz)，8.65(1H，s)，8.85(1H，s)，11.4(1H，br?s)。
Embodiment 103
4-{[7-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } benzoic preparation
React according to the method identical with embodiment 97, by using 4-{[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } methyl benzoate (120mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (87mg) and pyridine hydrochloride (60mg), obtain 4-{[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] methyl } mixture of methyl benzoate and 1-Methyl-2-Pyrrolidone.
React according to the method identical,, obtain the title compound (20mg) of yellow crystal by using said mixture and 1N aqueous sodium hydroxide solution (1mL) with embodiment 101.
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.43(3H，s)，6.12(2H，s)，6.91(2H，d，J＝8.7Hz)，7.12-7.24(4H，m)，7.38-7.47(2H，m)，7.85(2H，d，J＝8.1Hz)，8.16(1H，d，J＝2.4Hz)，8.28(1H，s)，8.35(1H，s)，8.81(1H，s)。
Embodiment 104
4-{[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } preparation of methyl benzoate
React according to the method identical with embodiment 97, by using 4-{[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } methyl benzoate (150mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (93mg) and pyridine hydrochloride (75mg), obtain faint yellow crystalline title compound (160mg).
1H-NMR(CDCl
3)δ2.27(3H，s)，2.52(3H，s)，3.91(3H，s)，5.60(2H，s)，6.90(1H，d，J＝8.7Hz)，7.08-7.09(2H，m)，7.31(1H，s)，7.66(1H，dd，J＝3.0，9.0Hz)，7.76(1H，d，J＝2.4Hz)，7.86(1H，m)，8.02(2H，s)，8.04(1H，s)，8.25(1H，m)，8.51(1H，s)。
Embodiment 105
4-{[7-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } benzoic preparation
React according to the method identical with embodiment 101, by using 4-{[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } methyl benzoate (150mg) and 1N aqueous sodium hydroxide solution (3mL), obtain the title compound (120mg) of white crystals.
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.43(3H，s)，5.80(2H，s)，6.93(1H，d，J＝8.7Hz)，7.13-7.23(2H，m)，7.37(2H，d，J＝7.8Hz)，7.84(1H，dd，J＝2.1，9.0Hz)，7.92-7.97(2H，m)，8.15(1H，d，J＝2.1Hz)，8.32(1H，s)，8.67(1H，s)，10.09(1H，s)，13.0(1H，br?s)。
Embodiment 106
4-{[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl }-preparation of N-(2-methoxy ethyl) benzamide
With 4-{[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } phenylformic acid (45mg), 2-methoxy ethyl amine (9mg), I-hydroxybenzotriazole (18mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (26mg) and triethylamine (0.08mL) are at N, and the solution in the dinethylformamide (2mL) at room temperature stirred 30 hours.After reaction is finished, the concentrating under reduced pressure reaction soln, and resistates is carried out silica gel column chromatography handle (alkaline silica gel; Ethyl acetate), obtain the title compound (115mg) of light yellow solid.
1H-NMR(CDCl
3)δ3.38(3H，s)，3.54-3.57(2H，m)，3.63-3.68(2H，m)，5.12(2H，s)，5.60(2H，s)，6.53(1H，br?s)，6.97(1H，d，J＝8.7Hz)，7.02(1H，m)，7.20-7.40(3H，m)，7.31(1H，d，J＝8.4Hz)，7.64(1H，d，J＝8.7Hz)，7.65(1H，d，J＝8.4Hz)，7.79(1H，d，J＝8.4Hz)，8.00-8.01(2H，m)，8.50(1H，s)。
Embodiment 107
N-(2-methoxy ethyl)-4-{[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } preparation of benzamide
React according to the method identical with embodiment 106, by using 4-{[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl } phenylformic acid (45mg), 2-methoxy ethyl amine (10mg), I-hydroxybenzotriazole (20mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (28mg) and triethylamine (0.08mL), obtain the title compound (30mg) of white crystals.
1H-NMR(CDCl
3)δ2.29(3H，s)，2.53(3H，s)，3.38(3H，s)，3.54-3.57(2H，m)，3.63-3.68(2H，m)，5.62(2H，s)，6.51(1H，br?s)，6.93(1H，d，J＝8.7Hz)，7.09-7.10(2H，m)，7.34(2H，d，J＝8.1Hz)，7.62-7.69(2H，m)，7.76(1H，m)，7.80(1H，d，J＝8.1Hz)，8.02(1H，s)，8.26(1H，m)，8.51(1H，s)。
Embodiment 108
N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 2-(4-nitrophenyl)-2H-pyrazolo [4,3-d] pyrimidine-7-amine
(i) preparation of 7-(methylthio group)-2-(4-nitrophenyl)-2H-pyrazolo [4,3-d] pyrimidine
Under ice-cooled, to the N of 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidines (500mg), add potassium tert.-butoxide (405mg) in dinethylformamide (10mL) solution, and mixture was at room temperature stirred 10 minutes.Subsequently, add 1-fluoro-4-oil of mirbane (465mg), and mixture was stirred 30 minutes down at 70 ℃.After reaction is finished, water is joined in the reaction mixture, and mixture was at room temperature stirred 30 minutes.Filter and collect the solid that generates, wash and drying, obtain brown crystalline title compound (860mg) with Di Iso Propyl Ether.
1H-NMR(DMSO-d
6)δ2.72(3H，s)，8.39(2H，d，J＝8.7Hz)，8.46(2H，d，J＝8.7Hz)，8.76(1H，s)，9.64(1H，s)。
(ii) N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 2-(4-nitrophenyl)-2H-pyrazolo [4,3-d] pyrimidine-7-amine
React according to the method identical with embodiment 97, by using 7-(methylthio group)-2-(4-nitrophenyl)-2H-pyrazolo [4,3-d] pyrimidine (430mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (321mg) and pyridine hydrochloride (259mg), obtain the title compound (667mg) of light yellow solid.
1H-NMR(CDCl
3)δ2.32(3H，s)，2.54(3H，s)，6.95(1H，d，J＝9.0Hz)，7.07-7.15(2H，m)，7.71(1H，dd，J＝2.7，8.4Hz)，7.80-7.81(2H，m)，8.12(2H，d，J＝9.3Hz)，8.25(1H，dd，J＝0.6，2.7Hz)，8.45(2H，d，J＝9.3Hz)，8.55(1H，s)，8.57(1H，s)。
Embodiment 109
2-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 2H-pyrazolo [4,3-d] pyrimidine-7-amine
To N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-2-(4-nitrophenyl)-2H-pyrazolo [4,3-d] pyrimidine-7-amine (200mg) is the mixed solvent of ethanol/water (9: 1, add calcium chloride (90% in the solution 6mL), 28mg), and with mixture stirred 10 minutes down at 100 ℃.At room temperature add reduced iron (90%, 164mg), and mixture stirred 5 hours down at 100 ℃.After reaction is finished, reaction mixture is filtered (diatomite), and concentrating under reduced pressure filtrate.Water is joined in the resistates, and mixture is diluted with ethyl acetate, and water and saturated brine washing.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Resistates by silica gel column chromatography purifying (ethyl acetate/dichloromethane=10/1), is obtained the title compound (140mg) of white solid.
1H-NMR(DMSO-d
6)δ2.20(3H，s)，2.44(3H，s)，5.55(2H，s)，6.71-6.74(2H，m)，6.95-6.98(1H，m)，7.18-7.23(2H，m)，7.73-7.76(2H，m)，7.901(1H，m)，8.03(1H，br?s)，8.18(1H，br?s)，8.34(1H，br?s)，8.94(1H，br?s)，10.05(1H，br?s)。
Embodiment 110
2-methoxyl group-N-{4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } preparation of ethanamide
React according to the method identical with embodiment 106, by using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-2H-pyrazolo [4,3-d] pyrimidine-7-amine (100mg), methoxyacetic acid (30mg), I-hydroxybenzotriazole (48mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (68mg) and triethylamine (0.20mL), obtain the title compound (64mg) of white crystals.
1H-NMR(CDCl
3)δ2.26(3H，s)，2.53(3H，s)，3.55(3H，s)，4.07(2H，s)，6.92(1H，d，J＝8.7Hz)，7.12-7.25(2H，m)，7.35-7.45(3H，m)，7.70-7.83(4H，m)，8.19(1H，d，J＝2.4Hz)，8.44(2H，s)，8.50(1H，s)。
Embodiment 111
2-(N, N-dimethylamino)-N-{4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } preparation of ethanamide
React according to the method identical with embodiment 106, by using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-2H-pyrazolo [4,3-d] pyrimidine-7-amine (100mg), N, N-dimethyl glycine hydrochloride (46mg), I-hydroxybenzotriazole (48mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (68mg) and triethylamine (0.20mL), obtain the title compound (60mg) of white crystals.
1H-NMR(CDCl
3)δ2.31(3H，s)，2.43(6H，s)，2.53(3H，s)，3.14(2H，s)，6.95(1H，d，J＝9.0Hz)，7.09-7.11(2H，m)，7.70-7.76(2H，m)，7.81-7.85(5H，m)，8.27(1H，m)，8.43(1H，s)，8.55(1H，s)，9.35(1H，br?s)。
Embodiment 112
4-({ 4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } amino)-preparation of 4-ketobutyric acid methyl esters
React according to the method identical with embodiment 106, by using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-2H-pyrazolo [4,3-d] pyrimidine-7-amine (150mg), monomethyl succinate (66mg), I-hydroxybenzotriazole (72mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (102mg) and triethylamine (0.30mL), obtain the title compound (175mg) of white crystals.
1H-NMR(CDCl
3)δ2.30(3H，s)，2.53(3H，s)，2.73-2.75(2H，m)，2.79-2.81(2H，m)，3.75(3H，s)，6.94(1H，d，J＝8.7Hz)，7.10-7.12(2H，m)，7.69-7.74(3H，m)，7.79-7.82(4H，m)，8.08(1H，br?s)，8.27(1H，dd，J＝0.6，2.4Hz)，8.42(1H，s)，8.53(1H，s)。
Embodiment 113
4-({ 4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } amino)-preparation of 4-ketobutyric acid
React according to the method identical with embodiment 101, by using 4-({ 4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } amino)-4-ketobutyric acid methyl esters (175mg) and 1N aqueous sodium hydroxide solution (0.5mL), obtain the title compound (98mg) of white crystals.
1H-NMR(DMSO-d
6)δ2.21(3H，s)，2.44(3H，s)，2.50-2.61(4H，m)，6.97(1H，d，J＝8.4Hz)，7.20-7.22(2H，m)，7.81-7.93(4H，m)，8.03-8.09(3H，m)，8.18(1H，m)，8.36(1H，s)，9.13(1H，s)，10.2(1H，br?s)，10.3(1H，s)。
Embodiment 114
2-(2-methoxy ethoxy)-N-{4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } preparation of ethanamide
React according to the method identical with embodiment 106, by using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-2H-pyrazolo [4,3-d] pyrimidine-7-amine (130mg), (2-methoxy ethoxy) acetate (58mg), I-hydroxybenzotriazole (62mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (88mg) and triethylamine (0.26mL), obtain the title compound (88mg) of white crystals.
1H-NMR(CDCl
3)δ2.30(3H，s)，2.53(3H，s)，3.52(3H，s)，3.63-3.66(2H，m)，3.80-3.82(2H，m)，4.16(2H，s)，6.94(1H，d，J＝8.7Hz)，7.07-7.10(2H，m)，7.71(1H，d，J＝8.7Hz)，7.80(1H，m)，7.83(4H，s)，8.27(1H，s)，8.43(1H，s)，8.54(1H，s)，9.16(1H，s)。
Embodiment 115
4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of methyl benzoate
(i) 4-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of methyl benzoate
In 1-Methyl-2-Pyrrolidone (2mL) solution of 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidines (100mg) and 4-fluorophenyl carbamate (102mg), add salt of wormwood (125mg), and mixture was stirred 3 hours down at 120 ℃.After reaction is finished, water is joined in the reaction mixture, and mixture was at room temperature stirred 30 minutes.Filter and collect the solid that generates, wash and drying, obtain the title compound (90mg) of yellow crystal with Di Iso Propyl Ether.
1H-NMR(CDCl
3)δ2.76(3H，s)，3.98(3H，s)，8.04(2H，d，J＝8.4Hz)，8.24(2H，d，J＝8.4Hz)，8.63(1H，s)，8.77(1H，s)。
(ii) 4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of methyl benzoate
React according to the method identical with embodiment 97, by using 4-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl benzoate (115mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (82mg) and pyridine hydrochloride (66mg), obtain the title compound (135mg) of light yellow solid.
1H-NMR(CDCl
3)δ2.32(3H，s)，2.54(3H，s)，3.99(3H，s)，6.95(1H，d，J＝8.7Hz)，7.10-7.12(2H，m)，7.73(1H，dd，J＝2.7，8.7Hz)，7.81-7.82(2H，m)，8.00(2H，d，J＝8.4Hz)，8.26(2H，d，J＝8.4Hz)，8.27(1H，s)，8.55(1H，s)，8.56(1H，s)。
Embodiment 116
4-[7-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] benzoic preparation
React according to the method identical with embodiment 101, by using 4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] methyl benzoate (110mg) and 1N aqueous sodium hydroxide solution (0.4mL), obtain the title compound (91mg) of white crystals.
1H-NMR(DMSO-d
6)δ2.21(3H，s)，2.44(3H，s)，6.98(1H，d，J＝9.0Hz)，7.21-7.26(2H，m)，7.90(1H，dd，J＝2.7，8.7Hz)，8.03(1H，m)，8.12-8.22(6H，m)，8.38(1H，s)，9.30(1H，s)，10.3(1H，br?s)。
Embodiment 117
N-(2-methoxy ethyl)-4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of benzamide
React according to the method identical with embodiment 106, by using 4-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenylformic acid (75mg), 2-methoxy ethyl amine (17mg), I-hydroxybenzotriazole (34mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (48mg) and triethylamine (0.14mL), obtain the title compound (63mg) of white crystals.
1H-NMR(CDCl
3)δ2.31(3H，s)，2.54(3H，s)，3.43(3H，s)，3.60-3.63(2H，m)，3.69-3.74(2H，m)，6.61(1H，br?s)，6.96(1H，d，J＝8.7Hz)，7.10-7.12(2H，m)，7.72(1H，dd，J＝2.4，8.4Hz)，7.81(1H，t，J＝3.3Hz)，8.00(4H，s)，8.27(1H，m)，8.53(1H，s)，8.55(1H，s)。
Embodiment 118
{ 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-and 2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } preparation of methyl alcohol
(i) 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of phenyl aldehyde
React according to the method identical with embodiment 115 (i), by using N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-1H-pyrazolo [4,3-d] pyrimidine-7-amine (100mg) and 4-fluorobenzaldehyde (37mg), obtain faint yellow crystalline title compound (60mg).
1H-NMR(DMSO-d
6)δ5.26(2H，s)，7.16-7.35(4H，m)，7.46(1H，m)，7.93(1H，dd，J＝2.6，8.8Hz)，8.18(2H，d，J＝8.4Hz)，8.30(1H，d，J＝2.2Hz)，8.38-8.43(3H，m)，9.40(1H，s)，10.1(1H，s)，10.3(1H，s)。
(ii) { 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-and 2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl } preparation of methyl alcohol
Ice-cooled down, to 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] add sodium borohydride (2mg) in methyl alcohol (2mL) solution of phenyl aldehyde (50mg), and mixture was stirred 30 minutes.After reaction is finished, the concentrating under reduced pressure reaction soln, and resistates is carried out silica gel column chromatography handle (tetrahydrofuran (THF)/ethyl acetate=1/1), obtain the title compound (20mg) of white solid.
1H-NMR(DMSO-d
6)δ4.60(2H，d，J＝5.8Hz)，5.25(2H，s)，5.38(1H，t，J＝5.8Hz)，7.16-7.35(3H，m)，7.49(1H，m)，7.56(2H，d，J＝8.8Hz)，7.93(1H，m)，8.09(2H，d，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，8.38(1H，s)，9.22(1H，s)，10.2(1H，s)。
Embodiment 119
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-2-[4-({ [2-(methylsulfonyl) ethyl] amino } methyl) phenyl]-preparation of 2H-pyrazolo [4,3-d] pyrimidine-7-amine
To 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4; 3-d] pyrimidine-2-base] N of phenyl aldehyde (80mg) and 2-(methylsulfonyl) ethylamine hydrochloride (40mg); add acetate (0.02mL) in dinethylformamide (2mL) solution, and mixture was at room temperature stirred 1 hour.Subsequently, add sodium triacetoxy borohydride (54mg), and mixture was stirred 2 hours under uniform temp.After reaction is finished, add saturated sodium bicarbonate aqueous solution, and the concentrating under reduced pressure mixture.With the resistates ethyl acetate extraction, and with organic layer water and saturated salt washing and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography handle (ethyl acetate/methanol=5/1), obtain the title compound (70mg) of white solid.
1H-NMR(CDCl
3)δ3.02(3H，s)，3.22(4H，s)，3.92(2H，s)，5.17(2H，s)，6.98-7.04(2H，m)，7.21-7.26(3H，m)，7.36(1H，m)，7.52(2H，d，J＝8.1Hz)，7.68-7.71(2H，m)，7.84(2H，d，J＝8.1Hz)，8.05(1H，d，J＝2.4Hz)，8.45(1H，s)，8.54(1H，s)。
Embodiment 120
2-(4-[7-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] benzyl } amino) the alcoholic acid preparation
React according to the method identical with embodiment 119, by using 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl aldehyde (120mg), thanomin (23mg) and sodium triacetoxy borohydride (134mg), obtain faint yellow crystalline title compound (83mg).
1H-NMR(DMSO-d
6)δ2.59(2H，t，J＝6.0Hz)，3.48(2H，m)，3.80(2H，s)，4.51(1H，br?s)，5.25(2H，s)，7.16-7.34(5H，m)，7.46(1H，m)，7.57(2H，d，J＝7.8Hz)，7.91(1H，dd，J＝1.8，9.0Hz)，8.07(2H，d，J＝7.8Hz)，8.30(1H，d，J＝1.8Hz)，8.38(1H，s)，9.21(1H，s)，10.2(1H，s)。
Embodiment 121
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-2-(4-{[(2-morpholine-4-base ethyl) amino] methyl } phenyl)-preparation of 2H-pyrazolo [4,3-d] pyrimidine-7-amine
React according to the method identical with embodiment 119, by using 4-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] phenyl aldehyde (80mg), N-(2-amino-ethyl) morpholine (33mg) and sodium triacetoxy borohydride (54mg), obtain faint yellow crystalline title compound (68mg).
1H-NMR(CDCl
3)δ2.44(4H，t，J＝4.5Hz)，2.53(2H，t，J＝6.0Hz)，2.74(2H，t，J＝6.0Hz)，3.70(4H，t，J＝4.5Hz)，3.91(2H，s)，5.16(2H，s)，6.98(1H，d，J＝8.7Hz)，7.02(1H，m)，7.19-7.25(3H，m)，7.35(1H，m)，7.52(2H，d，J＝8.7Hz)，7.67-7.71(2H，m)，7.82(2H，d，J＝8.7Hz)，8.04(1H，d，J＝2.4Hz)，8.43(1H，s)，8.52(1H，s)。
Embodiment 122
2-[7-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] the alcoholic acid preparation
React according to the method identical with embodiment 97, by using 2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] ethyl benzoate (130mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (104mg) and pyridine hydrochloride (72mg), obtain 2-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] mixture of ethylamino benzonitrile acid esters and 1-Methyl-2-Pyrrolidone.
React according to the method identical,, obtain the title compound (60mg) of light yellow solid by using said mixture and 1N aqueous sodium hydroxide solution (0.2mL) with embodiment 101.
1H-NMR(DMSO-d
6)δ3.87-3.93(2H，m)，4.75(2H，t，J＝5.7Hz)，5.24(2H，s)，6.27(1H，t，J＝3.9Hz)，7.13-7.32(4H，m)，7.48(1H，m)，7.55(1H，dd，J＝2.4，9.3Hz)，7.86(1H，d，J＝1.8Hz)，8.17(1H，s)，8.36(1H，s)，9.85(1H，s)。
Embodiment 123
2-[7-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] the alcoholic acid preparation
React according to the method identical with embodiment 97, by using 2-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] ethylamino benzonitrile acid esters (120mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (96mg) and pyridine hydrochloride (66mg), obtain 2-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] mixture of ethylamino benzonitrile acid esters and 1-Methyl-2-Pyrrolidone.
React according to the method identical,, obtain the title compound (86mg) of light yellow solid by using said mixture and 1N aqueous sodium hydroxide solution (0.2mL) with embodiment 101.
1H-NMR(DMSO-d
6)δ3.88-3.93(2H，m)，4.50(2H，t，J＝5.4Hz)，5.04(1H，t，J＝5.7Hz)，5.23(2H，s)，7.14-7.32(4H，m)，7.46(1H，m)，7.88(1H，dd，J＝2.7，9.0Hz)，8.28(1H，d，J＝1.8Hz)，8.31(1H，s)，8.45(1H，s)，10.12(1H，s)。
Embodiment 124
2-[7-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] the alcoholic acid preparation
React according to the method identical with embodiment 101, by using 2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] ethylamino benzonitrile acid esters (190mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (129mg) and pyridine hydrochloride (105mg), obtain 2-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] mixture of ethylamino benzonitrile acid esters and 1-Methyl-2-Pyrrolidone.
React according to the method identical,, obtain the title compound (88mg) of light yellow solid by using said mixture and 1N aqueous sodium hydroxide solution (0.3mL) with embodiment 101.
1H-NMR(CDCl
3)δ2.22(3H，s)，2.48(3H，s)，4.25(2H，br?s)，4.76(2H，brs)，6.01(1H，br?s)，6.86(1H，d，J＝8.7Hz)，7.08(1H，d，J＝8.7Hz)，7.16(1H，dd，J＝3.0，8.7Hz)，7.45(1H，dd，J＝2.7，8.7Hz)，7.56(1H，d，J＝2.7Hz)，8.05(1H，d，J＝3.0Hz)，8.37(1H，s)，9.88(1H，s)。
Embodiment 125
2-[7-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] the alcoholic acid preparation
React according to the method identical with embodiment 97, by using 2-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] ethylamino benzonitrile acid esters (115mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (78mg) and pyridine hydrochloride (63mg), obtain 2-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] mixture of ethylamino benzonitrile acid esters and 1-Methyl-2-Pyrrolidone.
React according to the method identical,, obtain the title compound (95mg) of light yellow solid by using said mixture and 1N aqueous sodium hydroxide solution (0.3mL) with embodiment 101.
1H-NMR(CDCl
3)δ2.24(3H，s)，2.52(3H，s)，4.16(2H，t，J＝4.5Hz)，4.26(1H，br?s)，4.50-4.53(2H，m)，6.86(1H，d，J＝8.7Hz)，7.05-7.12(2H，m)，7.57-7.61(2H，m)，7.69(1H，d，J＝2.7Hz)，7.97(1H，s)，8.23(1H，m)，8.34(1H，s)。
Embodiment 126
3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] preparation of propyl alcohol
React according to the method identical with embodiment 122, by using 3-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] propylbenzoic acid ester (623mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (477mg) and pyridine hydrochloride (329mg) and 1N aqueous sodium hydroxide solution (0.5mL), obtain the title compound (240mg) of light yellow solid.
1H-NMR(DMSO-d
6)δ1.97-2.04(2H，m)，3.25-3.28(2H，m)，4.71(2H，t，J＝6.6Hz)，5.27(2H，s)，5.44(1H，t，J＝4.8Hz)，7.16-7.34(4H，m)，7.48(1H，m)，7.57(1H，dd，J＝2.7，9.0Hz)，7.82(1H，d，J＝2.4Hz)，8.19(1H，s)，8.35(1H，s)，9.22(1H，s)。
Embodiment 127
3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] preparation of propyl alcohol
React according to the method identical with embodiment 123, by using 3-[7-(methylthio group)-2H-pyrazolo [4,3-d] pyrimidine-2-base] propylbenzoic acid ester (556mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] aniline (426mg), pyridine hydrochloride (293mg) and 1N aqueous sodium hydroxide solution (10mL), obtain the title compound (512mg) of light yellow solid.
1H-NMR(DMSO-d
6)δ2.06-2.13(2H，m)，3.41-3.46(2H，m)，4.53(2H，t，J＝6.9Hz)，4.70(1H，t，J＝5.4Hz)，5.24(2H，s)，7.16-7.33(4H，m)，7.46(1H，m)，7.89(1H，dd，J＝2.4，9.0Hz)，8.28(1H，d，J＝2.4Hz)，8.32(1H，s)，8.51(1H，s)，10.12(1H，s)。
Embodiment 128
4-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-5, the preparation of 6-dihydro-4H-pyrazolo [4,5,1-de] pteridine
With 2-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] tetrahydrofuran (THF) (2mL) solution of ethanol (40mg), 1,1 '-(azo dicarbapentaborane) two piperidines (48mg) and tributylphosphine (40mg) at room temperature stirred 15 hours.After reaction is finished, water is joined in the reaction mixture, and mixture is diluted with ethyl acetate, and wash with saturated brine.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Resistates by silica gel column chromatography purifying (hexane/ethyl acetate=4/1 → 1/4), is obtained the title compound (31mg) of white solid.
1H-NMR(CDCl
3)δ4.32(2H，dd，J＝5.0，6.6Hz)，4.62(2H，dd，J＝5.0，6.6Hz)，5.19(2H，s)，7.04(1H，d，J＝9.2Hz)，7.05(1H，m)，7.18-7.26(2H，m)，7.32-7.43(2H，m)，7.55(1H，d，J＝2.6Hz)，8.09(1H，s)，8.51(1H，s)。
Embodiment 129
4-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-5, the preparation of 6-dihydro-4H-pyrazolo [4,5,1-de] pteridine
React according to the method identical with embodiment 128, by using 2-[7-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] ethanol (30mg), 1,1 '-(azo dicarbapentaborane) two piperidines (40mg) and tributylphosphine (32mg) obtain the title compound (21mg) of light yellow solid.
1H-NMR(CDCl
3)δ2.34(3H，s)，2.55(3H，s)，4.36(2H，t，J＝5.7Hz)，4.64(2H，t，J＝5.7Hz)，6.92(1H，d，J＝8.4Hz)，7.13(1H，d，J＝8.4Hz)，7.20(1H，dd，J＝2.7，8.4Hz)，7.27(1H，dd，J＝2.4，8.4Hz)，7.41(1H，d，J＝2.4Hz)，8.09(1H，s)，8.30(1H，d，J＝2.7Hz)，8.53(1H，s)。
Embodiment 130
6-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-6,7,8,9-tetrahydrochysene-1,3,5,6, the preparation of 9a-pentaaza benzo [cd] Azulene
React according to the method identical with embodiment 128, by using 3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] propyl alcohol (60mg), 1,1 '-(azo dicarbapentaborane) two piperidines (70mg) and tributylphosphine (57mg) obtain the title compound (29mg) of light yellow solid.
1H-NMR(CDCl
3)δ2.49-2.56(2H，m)，4.03(2H，m)，4.62(2H，t，J＝5.7Hz)，5.19(2H，s)，7.02(1H，d，J＝8.7Hz)，7.05(1H，m)，7.15(1H，dd，J＝2.7，9.0Hz)，7.21-7.26(2H，m)，7.35-7.42(2H，m)，8.12(1H，s)，8.37(1H，s)。
Embodiment 131
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 2-(3-{[2-(methylsulfonyl) ethyl] amino } propyl group)-2H-pyrazolo [4,3-d] pyrimidine-7-amine
With 3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4; 3-d] pyrimidine-2-base] propyl alcohol (50mg), N-[2-(methylsulfonyl) ethyl]-tetrahydrofuran (THF) (2mL) solution of 2-nitrobenzene sulfonamide (47mg), 1,1 '-(azo dicarbapentaborane) two piperidines (59mg) and tributylphosphine (47mg) at room temperature stirred 4 hours.After reaction is finished, water is joined in the reaction mixture, and mixture is diluted with ethyl acetate, and wash with saturated brine.Organic layer through anhydrous magnesium sulfate drying, is filtered and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (ethyl acetate/methanol=4/1 → 1/4); obtain N-{3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] propyl group }-N-[2-(methylsulfonyl) ethyl]-the 2-nitrobenzene sulfonamide.In tetrahydrofuran (THF) (2mL) solution of this compound, add 2 mercapto ethanol (12mg) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (23mg), and mixture at room temperature stirred 3 hours.After reaction is finished, the concentrating under reduced pressure reaction mixture, and with resistates by silica gel column chromatography purifying (ethyl acetate/methanol=10/1), obtain the title compound (34mg) of white solid.
1H-NMR(CDCl
3)δ2.05-2.14(2H，m)，2.57(2H，t，J＝6.3Hz)，3.08(3H，s)，3.14-3.16(2H，m)，3.22-3.26(2H，m)，4.54(2H，t，J＝6.3Hz)，5.16(2H，s)，6.97(1H，d，J＝8.7Hz)，7.02(1H，m)，7.20-7.26(3H，m)，7.36(1H，dt，J＝6.3，7.8Hz)，7.71(1H，dd，J＝2.7，9.0Hz)，7.99(2H，s)，8.09(1H，d，J＝2.7Hz)，8.49(1H，s)。
Embodiment 132
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-2-{3-[(2-morpholine-4-base ethyl) amino] propyl group }-preparation of 2H-pyrazolo [4,3-d] pyrimidine-7-amine
React according to the method identical with embodiment 131, by using 3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] propyl alcohol (60mg), N-(2-morpholine-4-base ethyl)-2-nitrobenzene sulfonamide (53mg), 1,1 '-(azo dicarbapentaborane) two piperidines (71mg), tributylphosphine (57mg), 2 mercapto ethanol (12mg) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (23mg) obtain the title compound (32mg) of light yellow solid.
1H-NMR(CDCl
3)δ2.42-2.51(8H，m)，2.59-2.72(4H，m)，3.70(4H，t，J＝4.8Hz)，4.51(2H，t，J＝6.8Hz)，5.15(2H，s)，6.97(1H，d，J＝8.8Hz)，7.02(1H，m)，7.19-7.26(2H，m)，7.31-7.42(2H，m)，7.66(2H，m)，7.98(1H，s)，8.01(1H，d，J＝2.8Hz)，8.49(1H，s)。
Embodiment 133
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-the 2-{3-[(2-methoxy ethyl) amino] propyl group }-preparation of 2H-pyrazolo [4,3-d] pyrimidine-7-amine
React according to the method identical with embodiment 131, by using 3-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-2H-pyrazolo [4,3-d] pyrimidine-2-base] propyl alcohol (60mg), N-(2-methoxy ethyl)-2-nitrobenzene sulfonamide (44mg), 1,1 '-(azo dicarbapentaborane) two piperidines (71mg), tributylphosphine (57mg), 2 mercapto ethanol (12mg) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (23mg) obtain the title compound (26mg) of light yellow solid.
1H-NMR(CDCl
3)δ2.14-2.18(2H，m)，2.61(2H，t，J＝6.6Hz)，2.76(2H，t，J＝5.1Hz)，3.37(3H，s)，3.50(2H，t，J＝5.1Hz)，4.52(2H，t，J＝6.6Hz)，5.15(2H，s)，6.97(1H，d，J＝9.0Hz)，7.01(1H，m)，7.18-7.26(4H，m)，7.35(1H，m)，7.58(1H，br?s)，7.65(1H，dd，J＝2.4，8.7Hz)，7.99-8.00(2H，m)，8.48(1H，s)。
Embodiment 134
2-{[2-chloro-4-(1H-pyrazolo [4,3-d] pyrimidin-7-yl amino) phenoxy group] methyl } preparation of benzonitrile
React according to the method identical with embodiment 97, by using 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (80mg), 2-[(4-amino-2-chlorophenoxy) methyl] benzonitrile (125mg) and pyridine hydrochloride (83mg), obtain the title compound (96mg) of light yellow solid.
1H-NMR(DMSO-d
6)δ2.23(3H，s)，5.26(2H，s)，7.09(1H，d，J＝8.7Hz)，7.54-7.77(5H，m)，7.92(1H，d，J＝8.7Hz)，8.20(1H，br?s)，8.34(1H，br?s)，9.45(1H，br?s)，12.8(1H，br?s)。
Embodiment 135
2-{[2-methyl-4-(1H-pyrazolo [4,3-d] pyrimidin-7-yl amino) phenoxy group] methyl } preparation of benzonitrile
React according to the method identical with embodiment 97, by using 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (80mg), 2-[(4-amino-2-methyl phenoxy group) methyl] benzonitrile (115mg) and pyridine hydrochloride (83mg), obtain the title compound (110mg) of light yellow solid.
1H-NMR(DMSO-d
6)δ2.23(3H，s)，5.26(2H，s)，7.09(1H，d，J＝8.7Hz)，7.54-7.77(5H，m)，7.92(1H，d，J＝8.7Hz)，8.20(1H，br?s)，8.34(1H，br?s)，9.45(1H，br?s)，12.8(1H，br?s)。
Embodiment 136
3-[2-chloro-4-(1H-pyrazolo [4,3-d] pyrimidin-7-yl amino) phenoxy group] preparation of benzonitrile
React according to the method identical with embodiment 97, by using 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (80mg), 3-(4-amino-2-chlorophenoxy) benzonitrile (117mg) and pyridine hydrochloride (83mg), obtain the title compound (89mg) of light yellow solid.
1H-NMR(DMSO-d
6)δ7.26-7.35(2H，m)，7.46(1H，m)，7.55-7.59(2H，m)，7.89(1H，m)，8.39(1H，br?s)，8.46(2H，s)，10.16(1H，br?s)，12.6(1H，br?s)。
Embodiment 137
3-[2-methyl-4-(1H-pyrazolo [4,3-d] pyrimidin-7-yl amino) phenoxy group] preparation of benzonitrile
React according to the method identical with embodiment 97, by using 7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine (80mg), 3-(4-amino-2-methyl phenoxy group) benzonitrile (108mg) and pyridine hydrochloride (83mg), obtain the title compound (98mg) of light yellow solid.
1H-NMR(DMSO-d
6)δ2.18(3H，s)，7.09(1H，d，J＝8.7Hz)，7.24(1H，m)，7.37(1H，m)，7.53-7.59(2H，m)，7.86(1H，d，J＝8.7Hz)，7.93(1H，br?s)，8.32(1H，br?s)，8.42(1H，br?s)，9.85(1H，br?s)，12.2(1H，br?s)。
Embodiment 138
2-{2-[4-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
(i) 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethylamino benzonitrile acid esters
Under ice-cooled, to 2,2 '-oxygen di-ethanol (add benzoyl oxide (4.52g) with small portion in the pyridine of 2,2 '-oxydiethanol) (2.12g) (20mL) solution, and stirred reaction mixture, be warmed to room temperature simultaneously 18 hours.The reduction vaporization pyridine, and with the resistates that obtains ether (20mL) dilution.Add 5% sodium bicarbonate aqueous solution (100mL), and mixture is extracted with ether (100mL * 3).Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 40/60).Concentrating under reduced pressure target fraction is also dry, obtains 2-(2-hydroxyl-oxethyl) ethylamino benzonitrile acid esters (2.21g).Under ice-cooled, in the solution of 2-(2-hydroxyl-oxethyl) ethylamino benzonitrile acid esters (2.10g) in methylene dichloride (10mL) that obtains, add 1-iodol alkane-2 with small portion, 5-diketone (2.70g) and triphenylphosphine (3.14g), and with mixture stirring 14 hours.Reaction mixture is poured in 5% sodium bicarbonate aqueous solution (100mL), and extracts with ethyl acetate (120mL * 3).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel chromatography handle (elutriant: hexane/ethyl acetate=100/0 → 60/40).Concentrating under reduced pressure target fraction is also dry, obtains 2-(2-iodine oxyethyl group) the ethylamino benzonitrile acid esters (2.05g) of water white transparency oily thing.
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (0.659g), add cesium carbonate (3.13g) in dinethylformamide (5.0mL) suspension down ice-cooled, and stirred reaction mixture, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add as above 2-(2-iodine oxyethyl group) the ethylamino benzonitrile acid esters (1.45g) of preparation, and mixture was at room temperature stirred 15 hours.Reaction mixture is poured in 5% sodium bicarbonate aqueous solution (100mL), and extracts with ethyl acetate (150mL * 3).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 60/40).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (0.822g) of water white transparency oily thing.
1H-NMR(CDCl
3)δ3.718(2H，dt，J＝3.0，6.6Hz)，3.887(2H，t，J＝5.1Hz)，4.412(2H，dt，J＝3.0，6.6Hz)，4.680(2H，t，J＝5.1Hz)，6.566(1H，d，J＝3.3Hz)，7.404-7.462(2H，m)，7.542-7.600(2H，m)，7.944-7.982(2H，m)，8.665(1H，s)。
(ii) 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylamino benzonitrile acid esters
To 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] add 3-chloro-4-[(3-luorobenzyl in 1-Methyl-2-Pyrrolidone (8.0mL) solution of ethylamino benzonitrile acid esters (802mg)) the oxygen base] aniline (745mg), and mixture stirred 2 hours under 100 ℃ temperature in oil bath.Make reaction mixture be cooled to room temperature, dilute, and extract with the mixed solvent (50mL * 3) of ethyl acetate/tetrahydrofuran (THF) (3/1) with 5% sodium bicarbonate aqueous solution (25mL).Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 0/100).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (1141mg) of yellow amorphous solid.
1H-NMR(CDCl
3)δ3.901-3.931(2H，m)，4.036(2H，t，J＝4.2Hz)，4.452-4.483(2H，m)，4.540(2H，t，J＝4.2Hz)，5.033(2H，s)，6.590(1H，d，J＝3.0Hz)，6.704(1H，d，J＝9.0Hz)，7.005(1H，td，J＝1.8，7.5Hz)，7.164-7.372(7H，m)，7.511(1H，tt，J＝1.8，7.5Hz)，7.679(1H，d，J＝3.0Hz)，7.769(1H，t，J＝1.8Hz)，7.788(1H，t，J＝0.6Hz)，8.431(1H，s)，8.511(1H，s)。
(iii) 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
To 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } add 1N aqueous sodium hydroxide solution (7.0mL) in tetrahydrofuran (THF) (7.0mL) solution of ethylamino benzonitrile acid esters (760mg), and mixture was at room temperature stirred 14 hours.(7.0mL) joins in the reaction mixture with 1N hydrochloric acid, and mixture was at room temperature stirred 10 minutes.And extract with ethyl acetate/tetrahydrofuran (THF) (1/1) mixed solvent (100mL * 3).Organic layer is washed with 5% sodium bicarbonate aqueous solution and saturated brine successively, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel column chromatography handle (elutriant: ethyl acetate/methanol=100/0 → 90/10).Concentrating under reduced pressure target fraction.The mixed solvent of ethanol/isopropyl ether (1/4) is joined in the resistates, and with mixture heating up to 80 ℃, and be cooled to room temperature then.Filter and collect throw out and the drying under reduced pressure that generates, obtain white powder crystalline title compound (431mg).
1H-NMR(DMSO-d
6)δ3.471-3.478(4H，m)，3.817(2H，t，J＝4.6Hz)，4.616(2H，t，J＝4.6Hz)，4.681-4.712(1H，m)，5.234(2H，s)，6.480(1H，d，J＝3.2Hz)，7.173-7.212(2H，m)，7.289-7.339(2H，m)，7.433-7.523(2H，m)，7.641(1H，d，J＝3.2Hz)，7.829(1H，d，J＝3.2Hz)，8.271(1H，s)，8.698(1H，s)。
Fusing point: 168-169 ℃
Embodiment 139
4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of fourth-1-alcohol
(i) preparation of 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) butylacetic acid ester
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (0.768g), add cesium carbonate (2.01g) in dinethylformamide (10mL) suspension down ice-cooled, and stirred reaction mixture, be warmed to room temperature simultaneously 15 minutes.4-brombutyl acetic ester (1.26g) is added drop-wise in the reaction mixture, and mixture was at room temperature stirred 30 hours.Reaction mixture is poured in 5% sodium bicarbonate aqueous solution (80mL), and extracts with ethyl acetate (100mL * 3).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 0/100).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (1.084g) of water white transparency oily thing.
1H-NMR(CDCl
3)δ1.636-1.730(2H，m)，1.874-1.971(2H，m)，2.047(3H，s)，4.098(2H，t，J＝6.3Hz)，4.512(2H，t，J＝6.3Hz)，6.718(1H，d，J＝3.3Hz)，7.482(1H，d，J＝3.3Hz)，8.690(1H，s)。
(ii) 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of butylacetic acid ester
To 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) add 3-chloro-4-[3-(trifluoromethyl) phenoxy group in Virahol (2.24mL) solution of butylacetic acid ester (302mg)] aniline (421mg), and mixture stirred 3.5 hours under 100 ℃ temperature in oil bath.Make reaction mixture be cooled to room temperature, add 5% sodium bicarbonate aqueous solution (35mL), and mixture is extracted with ethyl acetate (50mL * 3).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 20/80).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (293mg) of white powder.
1H-NMR(CDCl
3)δ1.624-1.714(2H，m)，1.924-2.005(2H，m)，2.005(3H，s)，4.108(2H，t，J＝6.0Hz)，4.342(2H，t，J＝6.0Hz)，6.573(1H，d，J＝3.3Hz)，7.054(1H，s)，7.083-7.471(7H，m)，7.793(1H，d，J＝3.3Hz)，8.526(1H，s)。
(iii) 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of fourth-1-alcohol
To 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] add 1N aqueous sodium hydroxide solution (2.8mL) in tetrahydrofuran (THF) (4.0mL) solution of butylacetic acid ester (281mg), and mixture was at room temperature stirred 4.5 hours.Add 1N aqueous hydrochloric acid (2.8mL), and mixture was stirred 15 minutes.Reaction mixture is poured in the water (50mL), and mixture is extracted with ethyl acetate (50mL * 3).Organic layer is washed with 5% sodium bicarbonate aqueous solution, water and saturated brine successively, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 0/100).Concentrating under reduced pressure target fraction is also dry.Ethanol/Di Iso Propyl Ether (5/95) is joined in the resistates, and mixture is stirred under being heated to 80 ℃, make it be cooled to room temperature, and leave standstill.Filter and collect the throw out that generates.The precipitation that obtains is washed and drying under reduced pressure with Di Iso Propyl Ether, obtain white powder crystalline title compound (214mg).
1H-NMR(DMSO-d
6)δ1.240-1.331(2H，m)，1.690-1.782(2H，m)，3.324-3.361(2H，m)，4.473(1H，br?s)，4.540(2H，t，J＝6.0Hz)，6.492(1H，d，J＝3.0Hz)，7.200-7.254(2H，m)，7.303(1H，d，J＝9.0Hz)，7.472(1H，d，J＝9.0Hz)，7.621(1H，t，J＝9.0Hz)，7.653-7.713(2H，m)，7.970(1H，s)，8.351(1H，s)，8.632(1H，s)。
Embodiment 140
The preparation of 3-(2-chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzonitrile
(i) 2-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) preparation of ethylamino benzonitrile acid esters
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (141mg), add cesium carbonate (358mg) in dinethylformamide (2.5mL) suspension down ice-cooled, and stirred reaction mixture, be warmed to room temperature simultaneously 15 minutes.In this reaction mixture, add 2-iodine ethylamino benzonitrile acid esters (298mg), and mixture was at room temperature stirred 15 hours.Reaction mixture is poured in 5% sodium bicarbonate aqueous solution (50mL), and extracts with ethyl acetate (50mL * 3).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 60/40).Concentrating under reduced pressure target fraction is also dry, obtains 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) the ethylamino benzonitrile acid esters (205mg) of water white transparency oily thing.
React according to the method (ii) identical with embodiment 42, by using 3-(4-amino-2-chlorophenoxy) benzonitrile (211mg) and 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) 1-Methyl-2-Pyrrolidone (1.3mL) solution of ethylamino benzonitrile acid esters (205mg), obtain the title compound (311mg) of yellow solid.
1H-NMR(CDCl
3)δ4.693(4H，s)，6.688(1H，d，J＝3.0Hz)，7.086-7.497(8H，m)，7.609-7.727(2H，m)，7.962(2H，d，J＝6.9Hz)，8.024(2H，d，J＝6.9Hz)，8.569(1H，s)。
The (ii) preparation of 3-(2-chloro-4-{[5-(2-hydroxyethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) benzonitrile
React according to the method (iii) identical with embodiment 138, by use 2-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethylamino benzonitrile acid esters (310mg), obtain the title compound (187mg) of pale yellow powder.
1H-NMR(DMSO-d
6)δ3.977-3.990(2H，m)，4.542(2H，br?s)，6.470(1H，d，J＝3.0Hz)，7.162-7.24(3H，m)，7.421-7.625(3H，m)，7.645(1H，d，J＝7.2Hz)，7.989(1H，d，J＝3.0Hz)，8.078(1H，d，J＝3.0Hz)，8.368(1H，s)，10.10(1H，brs)。
Embodiment 141
3-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzonitrile
(i) 2-[2-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethylamino benzonitrile acid esters
React according to the method (ii) identical with embodiment 138, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (130mg) and 3-(4-amino-2-chlorophenoxy) benzonitrile (112mg), obtain filbert solid title compound (117mg).
1H-NMR(CDCl
3)δ4.051-4.077(2H，m)，4.206(2H，t，J＝4.2Hz)，4.582-4.599(2H，m)，4.610(2H，t，J＝4.2Hz)，6.781(1H，d，J＝3.0Hz)，6.904(1H，d，J＝9.0Hz)，7.195(1H，td，J＝1.8，7.5Hz)，7.360-7.568(7H，m)，7.709(1H，tt，J＝1.8，7.5Hz)，7.872(1H，d，J＝3.0Hz)，7.975(1H，t，J＝1.8Hz)，7.968(1H，t，J＝0.6Hz)，8.531(1H，s)，8.671(1H，s)。
(ii) 3-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzonitrile
React according to the method (iii) identical with embodiment 138, by use 2-[2-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (92mg), obtain the title compound (52mg) of pale yellow powder.
1H-NMR(DMSO-d
6)δ3.578-3.693(4H，m)，3.617(2H，t，J＝4.8Hz)，4.515(2H，t，J＝4.8Hz)，4.589-4.699(1H，m)，6.378(1H，d，J＝3.0Hz)，7.153-7.181(3H，m)，7.411-7.461(1H，m)，7.553-7.663(2H，m)，7.840(1H，d，J＝3.2Hz)，8.049(1H，d，J＝3.2Hz)，8.377(1H，s)，8.879(1H，s)。
Embodiment 142
2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-preparation of N-(2-hydroxyethyl) ethanamide
(i) [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethyl acetate
To (4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) add 3-chloro-4-[(3-luorobenzyl in Virahol (4.0mL) solution of ethyl acetate (530mg)) the oxygen base] aniline (695mg), and mixture stirred 2.5 hours under 100 ℃ temperature in oil bath.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (30mL * 3) with 5% sodium bicarbonate aqueous solution (25mL).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 20/80).Concentrating under reduced pressure target fraction is also dry, obtains the title compound (743mg) of white solid.
1H-NMR(CDCl
3)δ1.298-1.344(3H，m)，4.338(2H，q，J＝7.2Hz)，4.938(2H，s)，5.132(2H，s)，6.616(1H，d，J＝3.4Hz)，6.935(1H，d，J＝8.8Hz)，6.979-7.056(1H，m)，7.190-7.263(3H，m)，7.301-7.426(2H，m)，7.638(1H，t，J＝2.4Hz)，8.200(1H，s)，8.499(1H，br?s)。
(ii) [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of acetate
React according to the method identical with embodiment 46, by using [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl acetate (730mg), obtain the pulverous title compound of lavender (504mg).
1H-NMR(DMSO-d
6)δ5.223(2H，s)，5.282(2H，s)，6.480(1H，d，J＝3.0Hz)，7.137-7.525(7H，m)，7.603(1H，d，J＝3.0Hz)，7.666(1H，d，J＝3.0Hz)，8.299(1H，s)。
(iii) 2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-preparation of N-(2-hydroxyethyl) ethanamide
React according to the method identical with embodiment 36, by using [4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] acetate (103mg), obtain the title compound (39mg) of pale yellow powder.
1H-NMR(DMSO-d
6)δ3.23(2H，m)，3.46(2H，m)，4.89(1H，t，J＝4.5Hz)，5.04(2H，s)，5.22(2H，s)，6.48(1H，d，J＝3.0Hz)，7.14-7.24(2H，m)，7.29-7.33(2H，m)，7.43-7.53(2H，m)，7.56(1H，d，J＝3.0Hz)，7.85(1H，d，J＝3.0Hz)，8.29(1H，s)，8.97(1H，br?s)，10.08(1H，br?s)。
Embodiment 143
3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of propane-1-alcohol
To embodiment 53 (ii) in synthetic 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) add 3-chloro-4-[3-(trifluoromethyl) phenoxy group in the propane-solution of 1-alcohol (201mg) in Virahol (2.5mL)] aniline (381mg), and mixture stirred 2.0 hours under 100 ℃ temperature in oil bath.Make reaction mixture be cooled to room temperature, dilute, and extract with ethyl acetate (30mL * 3) with 5% sodium bicarbonate aqueous solution (25mL).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel chromatography handle (elutriant: hexane/ethyl acetate=95/5 → 20/80).Concentrating under reduced pressure target fraction is also dry.Ethanol/Di Iso Propyl Ether (1/9) is joined in the resistates, and mixture is stirred under being heated to 80 ℃, make it be cooled to room temperature, and leave standstill.Filter and collect the throw out that generates.The precipitation that obtains is washed and drying under reduced pressure with Di Iso Propyl Ether, obtain white powder crystalline title compound (375mg).
1H-NMR(DMSO-d
6)δ1.953(2H，t，J＝5.7Hz)，3.380(2H，t，J＝5.7Hz)，4.545(2H，t，J＝6.6Hz)，5.372(1H，br?s)，6.527(1H，d，J＝3.0Hz)，7.198-7.327(3H，m)，7.470(1H，d，J＝7.5Hz)，7.592-7.707(3H，m)，7.981(1H，d，J＝3.0Hz)，8.354(1H，s)，9.038(1H，br?s)。
Embodiment 144
2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethyl carbamate hydrochloride
Under ice-cooled; to 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] oxyethyl group } add trichloroacetyl isocyanate (22 μ L) in the solution of ethanol (84mg) in the mixed solvent (1.0mL) of toluene/methylene dichloride (1/1), and mixture was stirred 3 hours.In this reaction mixture, add methyl alcohol (0.2mL) and salt of wormwood (71mg), and mixture was at room temperature stirred 12 hours.Reaction mixture is poured in 5% sodium bicarbonate aqueous solution (25mL), and extracts with ethyl acetate (30mL * 3).With organic layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel chromatography handle (elutriant: ethyl acetate/methanol=100/0 → 95/5).Concentrating under reduced pressure target fraction is also dry, obtains 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3, the 2-d] pyrimidine-5-yl of water white transparency oily thing] oxyethyl group } ethyl carbamate (83mg).4N hydrochloric acid/ethyl acetate solution is joined in the water white transparency oily thing of acquisition.After at room temperature stirring 3 hours, filter and collect the throw out that generates,, and, obtain the title compound (57mg) of pale yellow powder in 60 ℃ of drying under reduced pressure with Di Iso Propyl Ether, ethyl acetate and frozen water washing.
1H-NMR(DMSO-d
6)δ3.57(2H，t，J＝3.0Hz)，3.79(2H，t，J＝3.0Hz)，3.96(2H，t，J＝6.0Hz)，4.64(2H，t，J＝6.0Hz)，6.48(2H，br?s)，6.56(1H，s)，7.15-7.23(2H，m)，7.30-7.34(2H，m)，7.41(1H，dd，J＝3.0，9.0Hz)，7.47(1H，dt，J＝6.0，9.0Hz)，7.63(1H，d，J＝3.0Hz)，7.82(1H，s)，8.28(1H，s)，8.56(1H，s)。
Embodiment 145
2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] the alcoholic acid preparation
With 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethylamino benzonitrile acid esters (302mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] mixture of aniline (288mg) and 1-Methyl-2-Pyrrolidone (3mL) stirred 2 hours down at 120 ℃.Water and saturated sodium bicarbonate aqueous solution are joined in the reaction mixture, and with the mixture ethyl acetate extraction.With ethyl acetate layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, ethyl acetate: hexane=20: 80 → 100: 0).Concentrating under reduced pressure target fraction.Ether joined in the resistates so that its crystallization, and add Di Iso Propyl Ether, subsequent filtration obtains white powder (286mg).In methyl alcohol (5mL) solution of this white powder (221mg), add 1N aqueous sodium hydroxide solution (0.8mL), and mixture was at room temperature stirred 2 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and ethyl acetate and Di Iso Propyl Ether joined in the resistates of acquisition, subsequent filtration obtains the title compound (160mg) of white powder.
1H-NMR(CDCl
3)δ4.16(2H，t，J＝4.4Hz)，4.38(2H，t，J＝4.4Hz)，6.12(1H，d，J＝3.2Hz)，6.97(1H，d，J＝3.2Hz)，7.09(1H，d，J＝8.8Hz)，7.10-7.17(1H，m)，7.21(1H，s)，7.32(1H，d，J＝7.7Hz)，7.43(1H，t，J＝8.0Hz)，7.52(1H，dd，J＝8.8，2.6Hz)，7.84(1H，d，J＝2.6Hz)，8.24(1H，s)，9.59(1H，br?s)。
Embodiment 146
2-[2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] the alcoholic acid preparation
With 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethylamino benzonitrile acid esters (346mg), 3-chloro-4-(3-chlorophenoxy) aniline (280mg) and 1-Methyl-2-Pyrrolidone (3mL) stirred 2 hours down at 120 ℃.Water and saturated sodium bicarbonate aqueous solution are joined in the reaction mixture, and with the mixture ethyl acetate extraction.With ethyl acetate layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, ethyl acetate: hexane=30: 70 → 100: 0).Concentrating under reduced pressure target fraction.In methyl alcohol (10mL) solution of resistates (431mg), add 1N aqueous sodium hydroxide solution (1mL), and mixture was at room temperature stirred 4 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by ethyl acetate-ether crystallization, obtain the title compound (312mg) of white powder.
1H-NMR(CDCl
3)δ2.05(1H，br?s)，3.71-3.84(4H，m)，4.03(2H，t，J＝4.5Hz)，4.57(2H，t，J＝4.5Hz)，6.61(1H，d，J＝3.0Hz)，6.83-6.88(1H，m)，6.92(1H，t，J＝2.2Hz)，7.01-7.06(1H，m)，7.06(1H，d，J＝8.9Hz)，7.19-7.27(2H，m)，7.61(1H，dd，J＝8.9，2.6Hz)，7.89(1H，d，J＝2.6Hz)，8.52(1H，s)，8.82(1H，br?s)。
Embodiment 147
2-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
With 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (1.037g), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] mixture of aniline (863mg) and 1-Methyl-2-Pyrrolidone (10mL) stirred 1.5 hours down at 120 ℃.Water and saturated sodium bicarbonate aqueous solution are joined in the reaction mixture, and with the mixture ethyl acetate extraction.With ethyl acetate layer water successively and saturated brine washing, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, ethyl acetate: hexane=50: 50 → 100: 0).Concentrating under reduced pressure target fraction.In methyl alcohol (30mL) solution of resistates (1.420g), add 1N aqueous sodium hydroxide solution (3mL), and mixture was at room temperature stirred 1 hour.The concentrating under reduced pressure reaction mixture joins water in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 5: 95).Concentrating under reduced pressure target fraction.Filter the crystallization of collecting precipitation, and wash with ether.Coarse crystallization by ethyl acetate-Di Iso Propyl Ether recrystallization, is obtained the title compound (933mg) of white powder.
1H-NMR(CDCl
3)δ1.94(1H，br?s)，3.71-3.85(4H，m)，4.03(2H，t，J＝4.4Hz)，4.57(2H，t，J＝4.4Hz)，6.63(1H，d，J＝3.2Hz)，7.07(1H，d，J＝8.9Hz)，7.08-7.14(1H，m)，7.19(1H，s)，7.22(1H，d，J＝3.2Hz)，7.31(1H，d，J＝7.7Hz)，7.42(1H，t，J＝8.0Hz)，7.63(1H，dd，J＝8.9，2.6Hz)，7.91(1H，d，J＝2.6Hz)，8.52(1H，s)，8.83(1H，br?s)。
Fusing point: 130-132 ℃
Embodiment 148
2-{2-[4-(3-chloro-4-[3-(trifluoromethoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 146, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (346mg), 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] aniline (334mg) and 1-Methyl-2-Pyrrolidone (3mL), obtain the title compound (293mg) of white powder.
1H-NMR(CDCl
3)δ1.95(1H，br?s)，3.71-3.84(4H，m)，4.03(2H，t，J＝4.5Hz)，4.57(2H，t，J＝4.5Hz)，6.62(1H，d，J＝3.2Hz)，6.80-6.95(3H，m)，7.08(1H，d，J＝8.8Hz)，7.21(1H，d，J＝3.2Hz)，7.30(1H，t，J＝8.2Hz)，7.62(1H，dd，J＝8.8，2.6Hz)，7.90(1H，d，J＝2.6Hz)，8.52(1H，s)，8.82(1H，br?s)。
Embodiment 149
1-{3-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } preparation of ethyl ketone
React according to the method identical with embodiment 146, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (692mg), 1-[3-(4-amino-2-chlorophenoxy) phenyl] ethyl ketone (576mg) and 1-Methyl-2-Pyrrolidone (5mL), obtain the title compound (493mg) of white powder.
1H-NMR(CDCl
3)δ1.97(1H，br?s)，2.58(3H，s)，3.71-3.84(4H，m)，4.03(2H，t，J＝4.4Hz)，4.58(2H，t，J＝4.4Hz)，6.63(1H，d，J＝3.2Hz)，7.06(1H，d，J＝8.9Hz)，7.15-7.20(1H，m)，7.22(1H，d，J＝3.2Hz)，7.41(1H，t，J＝7.9Hz)，7.48-7.51(1H，m)，7.61(1H，dd，J＝8.9，2.6Hz)，7.62-7.67(1H，m)，7.90(1H，d，J＝2.6Hz)，8.52(1H，s)，8.80(1H，br?s)。
Embodiment 150
1-{3-[2-chloro-4-(5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } the alcoholic acid preparation
To 1-{3-[2-chloro-4-(5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] phenyl } add sodium borohydride (38mg) in methyl alcohol (5mL) solution of ethyl ketone (233mg), and mixture was at room temperature stirred 2 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with the resistates that obtains by ethyl acetate-ether crystallization, obtain the title compound (225mg) of white powder.
1H-NMR(CDCl
3)δ2.47(3H，d，J＝6.4Hz)，3.67-3.77(4H，m)，4.00(2H，t，J＝4.4Hz)，4.58(2H，t，J＝4.4Hz)，4.84(1H，q，J＝6.4Hz)，6.62(1H，d，J＝3.3Hz)，6.85-6.90(1H，m)，6.96-7.00(1H，m)，7.01-7.09(2H，m)，7.24-7.32(2H，m)，7.52(1H，dd，J＝8.9，2.6Hz)，7.86(1H，d，J＝2.6Hz)，8.45(1H，s)。
Embodiment 151
2-[2-(4-{[3-chloro-4-(pyrimidine-5-base oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] the alcoholic acid preparation
React according to the method identical with embodiment 146, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (346mg), 3-chloro-4-(pyrimidine-5-base oxygen base) aniline (360mg) and 1-Methyl-2-Pyrrolidone (3mL), obtain the title compound (63mg) of white powder.
1H-NMR(CDCl
3)δ2.08(1H，br?s)，3.72-3.84(4H，m)，4.03(2H，t，J＝4.4Hz)，4.58(2H，t，J＝4.4Hz)，6.63(1H，d，J＝3.1Hz)，7.12(1H，d，J＝8.7Hz)，7.23(1H，d，J＝3.1Hz)，7.67(1H，dd，J＝8.7，2.6Hz)，7.95(1H，d，J＝2.6Hz)，8.43(2H，s)，8.52(1H，s)，8.89(1H，br?s)，8.94(1H，s)。
Embodiment 152
2-(2-{4-[(3-chloro-4-{[2-(trifluoromethyl) benzyl] the oxygen base } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) the alcoholic acid preparation
React according to the method identical with embodiment 146, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (277mg), 3-chloro-4-{[2-(trifluoromethyl) benzyl] the oxygen base } aniline (241mg) and 1-Methyl-2-Pyrrolidone (3mL), obtain the title compound (276mg) of white powder.
1H-NMR(CDCl
3)δ2.02(1H，br?s)，3.68-3.81(4H，m)，4.00(2H，t，J＝4.4Hz)，4.53(2H，t，J＝4.4Hz)，5.34(2H，s)，6.58(1H，d，J＝3.2Hz)，6.93(1H，d，J＝8.8Hz)，7.17(1H，d，J＝3.2Hz)，7.42(1H，t，J＝7.7Hz)，7.49(1H，dd，J＝8.8，2.6Hz)，7.60(1H，t，J＝7.7Hz)，7.69(1H，d，J＝7.7Hz)，7.76(1H，d，J＝2.6Hz)，7.89(1H，d，J＝7.7Hz)，8.46(1H，s)，8.57(1H，br?s)。
Embodiment 153
2-(2-{4-[(3-chloro-4-{[3-(trifluoromethyl) benzyl] the oxygen base } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) the alcoholic acid preparation
React according to the method identical with embodiment 146, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (346mg), 3-chloro-4-{[3-(trifluoromethyl) benzyl] the oxygen base } aniline (302mg) and 1-Methyl-2-Pyrrolidone (3mL), obtain the title compound (393mg) of white powder.
1H-NMR(CDCl
3)δ2.03(1H，br?s)，3.68-3.80(4H，m)，4.00(2H，t，J＝4.4Hz)，4.54(2H，t，J＝4.4Hz)，5.17(2H，s)，6.59(1H，d，J＝3.1Hz)，6.95(1H，d，J＝8.8Hz)，7.17(1H，d，J＝3.1Hz)，7.48-7.62(3H，m)，7.66-7.76(3H，m)，8.46(1H，s)，8.58(1H，br?s)。
Embodiment 154
5-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of penta-1-alcohol
(i) preparation of 5-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) amyl group acetic ester
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (0.50g), 5-bromine amyl group acetic ester (0.71mL), cesium carbonate (1.59g) and N, the mixture of dinethylformamide (5.0mL) stirred 4 days down at 40 ℃.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: hexane=1: 3 → 6: 4), obtain the title compound (637mg) of white solid.
1H-NMR(CDCl
3)δ：1.33-1.46(2H，m)，1.61-1.72(2H，m)，1.84-1.97(2H，m)，2.04(3H，s)，4.05(2H，t，J＝6.6Hz)，4.48(2H，t，J＝7.5Hz)，6.71(1H，d，J＝3.3Hz)，7.46(1H，d，J＝3.3Hz)，8.69(1H，s)。
(ii) 5-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of penta-1-alcohol
With 5-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) amyl group acetic ester (200mg) and 3-chloro-4-[3-(trifluoromethyl) phenoxy group] Virahol (3.5mL) solution of aniline (265mg) stirred 14 hours down at 80 ℃.Add 1N aqueous sodium hydroxide solution (2.1mL) down at 0 ℃, and mixture was at room temperature stirred 1 hour.(2.0mL) joins in the reaction system with 1N hydrochloric acid, and with the mixture ethyl acetate extraction.Organic layer is washed with sodium bicarbonate aqueous solution and saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=1: 19), obtain colorless solid.By ethyl acetate-hexane recrystallization, obtain the title compound (275mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.35(1H，t，J＝4.7Hz)，1.50-1.69(4H，m)，1.92-2.05(2H，m)，3.63-3.71(2H，m)，4.32(2H，t，J＝7.4Hz)，6.59(1H，d，J＝3.3Hz)，6.70(1H，s)，7.08(1H，d，J＝8.7Hz)，7.09-7.12(1H，m)，7.15-7.27(2H，m)，7.30-7.35(1H，m)，7.40-7.43(1H，m)，7.47(1H，dd，J＝8.7，2.7Hz)，7.82(1H，d，J＝2.7Hz)，8.53(1H，s)。
Embodiment 155
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-hydroxyl acetamide
(i) preparation of [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate
React according to the method identical with embodiment 154 (i), by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (0.50g), 2-bromotrifluoromethane t-butyl carbamate (0.95g), cesium carbonate (1.59g) and N, dinethylformamide (10mL) obtains the title compound (687mg) of colorless solid.
1H-NMR(CDCl
3)δ：1.31-1.46(9H，m)，3.55(2H，dt，J＝6.0，6.0Hz)，4.51-4.68(3H，m)，6.74(1H，d，J＝3.2Hz)，7.47(1H，d，J＝3.2Hz)，8.71(1H，s)。
The (ii) preparation of { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate
With [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (712mg) and 3-chloro-4-[3-(trifluoromethyl) phenoxy group] Virahol (7.1mL) solution of aniline (830mg) stirred 12 hours down at 80 ℃.Sodium bicarbonate aqueous solution is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=1: 1 → ethyl acetate), obtain the title compound (1.12g) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.49(9H，s)，3.43-3.54(2H，m)，4.43-4.51(2H，m)，5.10(1H，t，J＝5.6Hz)，6.60(1H，d，J＝3.3Hz)，7.07(1H，m)，7.09-7.14(1H，m)，7.16-7.22(2H，m)，7.25-7.30(1H，m)，7.37-7.45(1H，m)，7.89(1H，dd，J＝8.7，2.4Hz)，8.02(1H，d，J＝2.4Hz)，8.50(1H，s)，8.64(1H，br?s)。
(iii) 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
Will { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (1.12g), the mixture of 2N hydrochloric acid (15mL) and tetrahydrofuran (THF) (30mL) stirred 20 hours down at 60 ℃.Solvent evaporated under reduced pressure adds ethanol, and mixture is further concentrated.Filter the crystallization of collecting precipitation, and this crystallization is washed with ethyl acetate, obtain faint yellow crystalline title compound (1.07g).
1H-NMR(DMSO-d
6)δ：3.21-3.35(2H，m)，4.92-5.02(2H，m)，6.71-6.76(1H，m)，7.24-7.32(2H，m)，7.37(1H，d，J＝9.0Hz)，7.50-7.56(1H，m)，7.64-7.71(2H，m)，7.91-7.97(1H，m)，7.98-8.06(1H，m)，8.13-8.26(3H，m)，8.71(1H，br?s)，9.88-9.99(1H，m)。
(iv) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-hydroxyl acetamide
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (105mg), oxyacetic acid (44mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (167mg), I-hydroxybenzotriazole monohydrate (133mg), triethylamine (0.40mL) and N, the mixture of dinethylformamide (5.0mL) at room temperature stirred 3 days.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → methyl alcohol: ethyl acetate=1: 9), obtain the title compound (108mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：2.93-3.09(1H，m)，3.59-3.73(2H，m)，4.24(2H，s)，4.43-4.53(2H，m)，6.59(1H，d，J＝3.3Hz)，7.07(1H，d，J＝8.7Hz)，7.09-7.46(6H，m)，7.72(1H，dd，J＝8.7，2.4Hz)，8.06(1H，d，J＝2.4Hz)，8.49(1H，s)，8.57(1H，s)。
Embodiment 156
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
(i) preparation of { 2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate
With [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (100mg), 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] Virahol (1.5mL) solution of aniline (153mg) stirred 12 hours down at 80 ℃.Sodium bicarbonate aqueous solution is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=1: 1 → ethyl acetate), obtain the title compound (173mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.50(9H，s)，3.45-3.54(2H，m)，4.43-4.52(2H，m)，5.01-5.08(1H，m)，6.61(1H，d，J＝3.0Hz)，6.80-6.95(3H，m)，7.09(1H，d，J＝8.7Hz)，7.19(1H，d，J＝3.0Hz)，7.29-7.34(1H，m)，7.90(1H，dd，J＝8.7，2.7Hz)，8.03(1H，d，J＝2.7Hz)，8.52(1H，s)，8.62(1H，br?s)。
(ii) 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
Will { 2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (173mg), the mixture of 2N hydrochloric acid (2.5mL) and tetrahydrofuran (THF) (5.0mL) stirred 6 hours down at 60 ℃.Ethanol is joined in the reaction system.Solvent evaporated under reduced pressure.Ethanol is joined in the enriched material, and with the further concentrating under reduced pressure of mixture.Filter and collect remaining crystallization, and crystallization is washed with ethyl acetate, obtain faint yellow crystalline title compound (155mg).
1H-NMR(DMSO-d
6)δ：3.21-3.34(2H，m)，4.89-5.00(2H，m)，6.74(1H，d，J＝2.4Hz)，6.94-7.01(2H，m)，7.16(1H，d，J＝8.7Hz)，7.36(1H，d，J＝9.0Hz)，7.51-7.57(1H，m)，7.62-7.69(1H，m)，7.90-7.95(1H，m)，7.99-8.05(1H，m)，8.12-8.27(3H，m)，8.71(1H，s)，9.92(1H，br?s)。
(iii) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (160mg), 2-(methylsulfonyl) acetate (82.3mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (171mg), I-hydroxybenzotriazole monohydrate (137mg), triethylamine (0.42mL) and N, the mixture of dinethylformamide (5.0mL) at room temperature stirred 20 hours.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=4: 1), and by ethanol-ethyl acetate-Di Iso Propyl Ether crystallization, obtain faint yellow crystalline title compound (112mg).
1H-NMR(CDCl
3)δ：3.12(3H，s)，3.64-3.76(2H，m)，3.99(2H，s)，4.34-4.52(2H，m)，6.62(1H，d，J＝3.0Hz)，6.81-6.84(1H，m)，6.86-6.95(2H，m)，7.08(1H，d，J＝8.7Hz)，7.17-7.24(2H，m)，7.29-7.34(1H，m)，7.76(1H，dd，J＝8.7，2.7Hz)，7.95(1H，d，J＝2.7Hz)，8.18(1H，s)，8.51(1H，s)。
Fusing point: 133-135 ℃
Embodiment 157
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-methoxyl group ethanamide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), methoxyacetic acid (52mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (166mg), I-hydroxybenzotriazole monohydrate (133mg), triethylamine (0.40mL) and N, dinethylformamide (5.0mL) obtains the title compound (120mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：3.44(3H，s)，3.60-3.71(2H，m)，4.00(2H，s)，4.44-4.53(2H，m)，6.62(1H，d，J＝3.0Hz)，7.02-7.15(3H，m)，7.19(1H，d，J＝3.0Hz)，7.22-7.35(2H，m)，7.38-7.45(1H，m)，7.74(1H，dd，J＝8.7，2.4Hz)，8.07(1H，d，J＝2，4Hz)，8.52(1H，s)，8.55(1H，s)。
Embodiment 158
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-hydroxy-3-methyl butyramide
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), 3-hydroxy-3-methyl butyric acid (68mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (166mg), I-hydroxybenzotriazole monohydrate (133mg), triethylamine (0.40mL) and N, the mixture of dinethylformamide (5.0mL) at room temperature stirred 5 days.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=9: 1).By ethyl acetate-Di Iso Propyl Ether crystallization, obtain the title compound (122mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.33(6H，s)，2.49(2H，s)，2.65-2.77(1H，m)，3.57-3.68(2H，m)，4.44-4.53(2H，m)，6.61(1H，d，J＝3.0Hz)，6.93-7.01(1H，m)，7.07(1H，d，J＝9.0Hz)，7.09-7.15(1H，m)，7.19(1H，d，J＝3.0Hz)，7.23-7.35(2H，m)，7.40-7.45(1H，m)，7.77(1H，dd，J＝9.0，2.7Hz)，8.08(1H，d，J＝2.7Hz)，8.52(1H，s)，8.66(1H，s)。
Fusing point: 167-169 ℃
Embodiment 159
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-hydroxy-2-methyl propionic acid amide
At room temperature, to 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl-add in tetrahydrofuran (THF) (5.0mL) suspension of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg) and triethylamine (0.40mL) 1-chloroformyl-1-ethyl methyl acetic acid ester (0.12mL).After at room temperature stirring 3 days, add sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure.At room temperature in ethanol (3.0mL) solution of resistates, add 1N aqueous sodium hydroxide solution (1.5mL).After at room temperature stirring 24 hours, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and separation resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=9: 1), obtain the title compound (133mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.49(6H，s)，2.12-2.27(1H，m)，3.56-3.67(2H，m)，4.42-4.52(2H，m)，6.61(1H，d，J＝3.3Hz)，7.06(1H，d，J＝9.0Hz)，7.08-7.14(1H，m)，7.15-7.43(5H，m)，7.86(1H，dd，J＝9.0，2.7Hz)，8.10(1H，d，J＝2.7Hz)，8.51(1H，s)，8.72(1H，s)。
Embodiment 160
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (150mg), 2-(methylsulfonyl) acetate (79.6mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (166mg), I-hydroxybenzotriazole monohydrate (133mg), triethylamine (0.40mL) and N, the mixture of dinethylformamide (5.0mL) at room temperature stirred 20 hours.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=4: 1).By ethyl acetate-Di Iso Propyl Ether crystallization, obtain colourless powder shape crystalline title compound (128mg).
1H-NMR(CDCl
3)δ：3.12(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)，7.07(1H，d，J＝9.0Hz)，7.09-7.15(1H，m)，7.18-7.33(4H，m)，7.40-7.45(1H，m)，7.77(1H，dd，J＝9.0，2.7Hz)，7.96(1H，d，J＝2.7Hz)，8.19(1H，s)，8.51(1H，s)。
Fusing point: 177-178 ℃
Embodiment 161
5-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-3-methylpentane-1, the preparation of 3-glycol
(i) 3, the preparation of 5-dihydroxyl-3-methyl amyl benzoic ether
With the 3-methyl isophthalic acid, 3, acetonitrile (200mL) solution of 5-penta triol (21.9g), benzoyl oxide (7.39g), pyridine (4.0mL) and 4-(N, N-dimethylamino) pyridine (0.39g) at room temperature stirred 2 days.Behind the concentrating under reduced pressure, add entry, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=1: 1 → ethyl acetate), obtain the title compound (4.27g) of colorless oil.
1H-NMR(CDCl
3)δ：1.36(3H，s)，1.72-1.81(1H，m)，1.86-2.13(3H，m)，2.47(1H，t，J＝4.7Hz)，2.89(1H，s)，3.85-4.02(2H，m)，4.52(2H，t，J＝6.8Hz)，7.42-7.48(2H，m)，7.54-7.60(1H，m)，8.00-8.04(2H，m)。
The (ii) preparation of 5-bromo-3-hydroxy-3-methyl amylbenzene manthanoate
Under ice-cooled,, drip tetrahydrofuran (THF) (10mL) solution of triphenylphosphine (2.20g) in tetrahydrofuran (THF) (30mL) solution of 5-dihydroxyl-3-methyl amyl benzoic ether (1.0g) and carbon tetrabromide (2.78g) to 3.After at room temperature stirring 3 days, add entry, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=9: 1 → 6: 4), obtain the title compound (979mg) of colorless oil.
1H-NMR(CDCl
3)δ：1.32(3H，s)，1.78(1H，s)，1.97-2.02(2H，m)，2.11-2.23(2H，m)，3.53(2H，t，J＝8.1Hz)，4.51(2H，t，J＝6.5Hz)，7.42-7.48(2H，m)，7.55-7.60(1H，m)，8.00-8.04(2H，m)。
The (iii) preparation of 5-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)-3-hydroxy-3-methyl amylbenzene manthanoate
React according to the method identical with embodiment 154 (i), by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (400mg), 5-bromo-3-hydroxy-3-methyl amylbenzene manthanoate (979mg), cesium carbonate (0.94g) and N, dinethylformamide (10mL) obtains the title compound (773mg) of colorless oil.
1H-NMR(CDCl
3)δ：1.41(3H，s)，1.91(1H，s)，2.01-2.13(4H，m)，4.54(2H，t，J＝6.6Hz)，4.59-4.76(2H，m)，6.71(1H，d，J＝3.0Hz)，7.40-7.46(2H，m)，7.51(1H，d，J＝3.0Hz)，7.54-7.60(1H，m)，7.98-8.01(2H，m)，8.69(1H，s)。
(iv) 5-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-3-methylpentane-1, the preparation of 3-glycol
React according to the method (ii) identical with embodiment 154, by using 5-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)-3-hydroxy-3-methyl amylbenzene manthanoate (250mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (230mg), Virahol (1.5mL) and 1N aqueous sodium hydroxide solution (2.0mL), obtain the title compound (223mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.35(3H，s)，1.62-1.71(1H，m)，1.89-2.22(4H，m)，3.93-4.18(2H，m)，4.54-4.65(3H，m)，6.56(1H，d，J＝3.0Hz)，7.04(1H，d，J＝8.7Hz)，7.08-7.14(1H，m)，7.19-7.25(2H，m)，7.29-7.35(1H，m)，7.39-7.44(1H，m)，7.61(1H，dd，J＝8.7，2.7Hz)，7.93(1H，d，J＝2.7Hz)，8.49(1H，s)，8.52(1H，brs)。
Embodiment 162
2-(2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } sulfenyl) the alcoholic acid preparation
(i) sulfenyl 2-[(2-hydroxyethyl)] preparation of ethylamino benzonitrile acid esters
With the N of 2 mercapto ethanol (1.52mL), 2-iodine ethylamino benzonitrile acid esters (6.00g) and ethyl diisopropyl amine (4.53mL), dinethylformamide (60mL) solution stirred 3 days down at 40 ℃.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=4: 1 → 3: 7), obtain orange buttery title compound (3.77g).
1H-NMR(CDCl
3)δ：2.15(1H，t，J＝6.0Hz)，2.83(2H，t，J＝5.9Hz)，2.92(2H，t，J＝6.8Hz)，3.79(2H，dt，J＝6.0，6.0Hz)，4.50(2H，t，J＝6.8Hz)，7.43-7.48(2H，m)，7.55-7.61(1H，m)，8.03-8.08(2H，m)。
(ii) 2-[(2-bromotrifluoromethane) sulfenyl] preparation of ethyl benzoate
React according to the method (ii) identical with embodiment 161, by using the 2-[(2-hydroxyethyl) sulfenyl] ethylamino benzonitrile acid esters (1.0g), carbon tetrabromide (2.20g), triphenylphosphine (1.74g) and methylene dichloride (50mL), obtain the title compound (966mg) of colorless oil.
1H-NMR(CDCl
3)δ：2.95(2H，t，J＝6.8Hz)，3.02-3.08(2H，m)，3.50-3.56(2H，m)，4.49(2H，t，J＝6.8Hz)，7.43-7.48(2H，m)，7.55-7.61(1H，m)，8.03-8.06(2H，m)。
(iii) 2-{[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] sulfenyl } preparation of ethylamino benzonitrile acid esters
React according to the method identical with embodiment 154 (i), by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (420mg), 2-[(2-bromotrifluoromethane) sulfenyl] ethylamino benzonitrile acid esters (966mg), cesium carbonate (1.34g) and N, dinethylformamide (4.2mL) obtains the title compound (790mg) of colorless oil.
1H-NMR(CDCl
3)δ：2.81(2H，t，J＝6.8Hz)，3.08(2H，t，J＝6.9Hz)，4.45(2H，t，J＝6.8Hz)，4.69(2H，t，J＝6.9Hz)，6.73(1H，d，J＝3.3Hz)，7.39-7.46(2H，m)，7.53-7.62(2H，m)，7.96-8.06(2H，m)，8.71(1H，s)。
(iv) 2-({ 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } sulfenyl) alcoholic acid preparation
React according to the method (ii) identical with embodiment 154, by using 2-{[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] sulfenyl } ethylamino benzonitrile acid esters (505mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (480mg), Virahol (10mL) and 1N aqueous sodium hydroxide solution (3.0mL), obtain the title compound (420mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.92-2.00(1H，m)，2.52(2H，t，J＝5.6Hz)，3.13(2H，t，J＝6.5Hz)，3.65-3.75(2H，m)，4.61(2H，t，J＝6.5Hz)，6.67(1H，d，J＝3.3Hz)，7.08(1H，d，J＝8.7Hz)，7.09-7.13(1H，m)，7.18-7.23(1H，m)，7.29(1H，d，J＝3.3Hz)，7.32-7.35(1H，m)，7.41-7.46(1H，m)，7.51(1H，dd，J＝8.7，2.7Hz)，7.77(1H，d，J＝2.7Hz)，7.80(1H，s)，8.55(1H，s)。
Embodiment 163
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-methyl-2-(methylsulfonyl) ethanamide
(i) preparation of [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] methyl carbamic acid tert-butyl ester
At room temperature, in tetrahydrofuran (THF) (10mL) solution of 2-(methylamino) ethanol (1.00g), add two carbonic acid, two-tert-butyl esters (3.60mL).After at room temperature stirring 2 hours, the concentrating under reduced pressure mixture.In tetrahydrofuran (THF) (50mL) solution of resistates and triethylamine (3.71mL), dripping methylsulfonyl chloride (1.55mL) under 0 ℃, and mixture was being stirred 1 hour down at 0 ℃.Sodium bicarbonate aqueous solution is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, obtain colorless oil.React according to the method identical with embodiment 154 (i), by using oily matter, the 4-chloro-5H-pyrrolo-[3 that obtains, 2-d] pyrimidine (1.34g), cesium carbonate (5.69g) and N, dinethylformamide (20mL) obtains the title compound (902mg) of faint yellow oily thing.
1H-NMR(CDCl
3)δ：1.12(4.5H，s)，1.43(4.5H，m)，2.55(1.5H，s)，2.81(1.5H，s)，3.58-3.60(2H，m)，4.54-4.69(2H，m)，6.73(1H，d，J＝3.0Hz)，7.29-7.35(0.5H，m)，7.38-7.46(0.5H，m)，8.71(1H，s)。
The (ii) preparation of { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } methyl carbamic acid tert-butyl ester
React according to the method (ii) identical with embodiment 155, by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] the methyl carbamic acid tert-butyl ester (450mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (500mg) and Virahol (4.5mL), obtain the title compound (622mg) of colourless amorphous solid.
1H-NMR(CDCl
3)δ：1.51(9H，s)，3.01(3H，s)，3.51-3.59(2H，m)，4.41-4.51(2H，m)，6.60(1H，d，J＝3.0Hz)，7.06(1H，d，J＝8.7Hz)，7.08-7.13(1H，m)，7.15-7.24(2H，m)，7.30(1H，d，J＝8.4Hz)，7.38-7.44(1H，m)，7.85-7.93(1H，m)，7.99-8.04(1H，m)，8.50(1H，s)，8.82(1H，s)。
(iii) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(methylamino) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
React according to the method (iii) identical with embodiment 155, by using { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } the methyl carbamic acid tert-butyl ester (622mg), 2N hydrochloric acid (10mL) and tetrahydrofuran (THF) (20mL), obtain faint yellow crystalline title compound (538mg).
1H-NMR(DMSO-d
6)δ：2.54(3H，t，J＝5.3Hz)，3.32-3.44(2H，m)，5.01-5.15(2H，m)，6.74(1H，d，J＝3.3Hz)，7.22-7.27(2H，m)，7.36(1H，d，J＝8.7Hz)，7.51(1H，d，J＝8.4Hz)，7.60-7.69(2H，m)，7.91-7.96(1H，m)，8.01-8.07(1H，m)，8.72(1H，s)，9.00-9.18(2H，m)，10.06(1H?br?s)。
(iv) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-methyl-2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(methylamino) ethyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (170mg), 2-(methylsulfonyl) acetate (88mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (183mg), I-hydroxybenzotriazole monohydrate (146mg), triethylamine (0.44mL) and N; dinethylformamide (5.0mL) obtains the title compound (131mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：3.17(3H，s)，3.34(3H，s)，3.75-3.84(2H，m)，4.18(2H，s)，4.43-4.52(2H，m)，6.64(1H，d，J＝3.0Hz)，7.08(1H，d，J＝8.7Hz)，7.10-7.16(1H，m)，7.17-7.25(2H，m)，7.32-7.37(1H，m)，7.41-7.46(1H，m)，7.86(1H，dd，J＝8.7，2.7Hz)，7.96(1H，d，J＝2.7Hz)，8.46(1H，s)，8.53(1H，s)。
Embodiment 164
2-(2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } sulfinyl) the alcoholic acid preparation
Under-78 ℃, in methylene dichloride (10mL) solution of 2-({ 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } sulfenyl) ethanol (100mg), drip methylene dichloride (5.0mL) solution of 70% 3-chlorine peroxybenzoic acid (58mg).Mixture was stirred 1 hour down at-78 ℃, and add sodium thiosulfate solution.After at room temperature stirring 0.5 hour, with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=4: 1), obtain the title compound (87mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：2.78-3.01(2H，m)，3.27-3.40(1H，m)，3.42-3.58(1H，m)，3.71-3.79(2H，m)，4.80-4.90(2H，m)，5.02-5.09(1H，m)，6.58-6.63(1H，m)，7.16-7.25(2H，m)，7.27-7.31(1H，m)，7.44-7.50(1H，m)，7.59-7.64(1H，m)，7.66-7.72(1H，m)，7.74-7.82(1H，m)，7.96-8.03(1H，m)，8.37(1H，s)，9.38(1H，s)。
Embodiment 165
2-(2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } alkylsulfonyl) the alcoholic acid preparation
2-({ 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } sulfenyl) ethanol (150mg), tetraisopropoxy titanium (43 μ L), methyl alcohol (24 μ L) and the solution of water (10 μ L) in methylene dichloride were at room temperature stirred 30 minutes.The 70% tert-butyl peroxide aqueous solution (0.12mL) is joined in the reaction system, and mixture was at room temperature stirred 2 days.Sodium thiosulfate solution is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=4: 1), obtain the title compound (118mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：3.09-3.15(2H，m)，3.62-3.75(4H，m)，4.92-5.02(2H，m)，5.09-5.15(1H，m)，6.50-6.57(1H，m)，7.16-7.32(3H，m)，7.45-7.48(1H，m)，7.58-7.74(3H，m)，7.91-7.97(1H，m)，8.37(1H，br?s)，8.69-8.79(1H，m)。
Embodiment 166
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-methyl-2-(methylsulfonyl) ethanamide
(i) preparation of { 2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } methyl carbamic acid tert-butyl ester
React according to the method (ii) identical with embodiment 155, by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] the methyl carbamic acid tert-butyl ester (463mg), 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] aniline (679mg) and Virahol (5.0mL), obtain the title compound (665mg) of colourless amorphous solid.
1H-NMR(CDCl
3)δ：1.51(9H，s)，3.01(3H，s)，3.48-3.61(2H，m)，4.42-4.50(2H，m)，6.60(1H，d，J＝3.2Hz)，6.80-6.83(1H，m)，6.86-6.95(2H，m)，7.08(1H，d，J＝8.7Hz)，7.20(1H，d，J＝3.2Hz)，7.28-7.33(1H，m)，7.85-7.95(1H，m)，7.99-8.05(1H，m)，8.51(1H，s)，8.81(1H，br?s)。
(ii) N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5-[2-(methylamino) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
React according to the method (iii) identical with embodiment 155, by using { 2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } the methyl carbamic acid tert-butyl ester (665mg), 2N hydrochloric acid (10mL) and tetrahydrofuran (THF) (20mL), obtain faint yellow crystalline title compound (557mg).
1H-NMR(DMSO-d
6)δ：2.52-2.66(2H，m))，3.29-3.45(2H，m)，5.03-5.15(2H，m)，6.75(1H，d，J＝3.0Hz)，6.91-7.00(2H，m)，7.11-7.18(1H，m)，7.35(1H，d，J＝8.7Hz)，7.51-7.57(1H，m)，7.63-7.69(1H，m)，7.91-7.96(1H，m)，8.06(1H，d，J＝3.3Hz)，8.73(1H，s)，9.06-9.26(2H，m)，10.11(1H，br?s)。
(iii) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-methyl-2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5-[2-(methylamino) ethyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (170mg), 2-(methylsulfonyl) acetate (87mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (179mg), I-hydroxybenzotriazole monohydrate (143mg), triethylamine (0.43mL) and N; dinethylformamide (5.0mL) obtains the title compound (147mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：3.17(3H，s)，3.34(3H，s)，3.75-3.84(2H，m)，4.18(2H，s)，4.43-4.52(2H，m)，6.64(1H，d，J＝3.0Hz)，7.08(1H，d，J＝8.7Hz)，7.10-7.16(1H，m)，7.17-7.25(2H，m)，7.32-7.37(1H，m)，7.41-7.46(1H，m)，7.86(1H，d，J＝8.7，2.7Hz)，7.96(1H，d，J＝2.7Hz)，8.46(1H，s)，8.53(1H，s)。
Embodiment 167
N-{3-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group }-preparation of 2-(methylsulfonyl) acetamide hydrochloride
(i) preparation of [3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) propyl group] t-butyl carbamate
React according to the method identical with embodiment 154 (i), by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (500mg), 3-bromopropyl t-butyl carbamate (1.00g), cesium carbonate (1.59g) and N, N-N,N-DIMETHYLACETAMIDE (5.0mL) obtains the title compound (1.04g) of colorless oil.
1H-NMR(CDCl
3)δ：1.46(9H，s)，2.02-2.12(2H，m)，3.13-3.25(2H，m)，4.50-4.66(3H，m)，6.78(1H，d，J＝3.0Hz)，7.61-7.69(1H，m)，8.71(1H，s)。
The (ii) preparation of { 3-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group } t-butyl carbamate
React according to the method (ii) identical with embodiment 155, by using [3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) propyl group] t-butyl carbamate (546mg), 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] aniline (640mg) and Virahol (10mL), obtain the title compound (398mg) of colourless amorphous solid.
1H-NMR(CDCl
3)δ：1.42(9H，s)，2.10-2.21(2H，m)，3.17-3.27(2H，m)，4.40(2H，t，J＝7.5Hz)，4.69-4.79(1H，m)，6.62(1H，d，J＝3.0Hz)，6.81(1H，brs)，6.85-6.95(2H，m)，7.04-7.13(2H，m)，7.29-7.34(2H，m)，7.54-7.60(1H，m)，7.89(1H，d，J＝3.0Hz)，8.52(1H，s)。
(iii) 5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
React according to the method (iii) identical with embodiment 155, by using { 3-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group } t-butyl carbamate (398mg), 2N hydrochloric acid (10mL) and tetrahydrofuran (THF) (20mL), obtain colourless powder shape crystalline title compound (355mg).
1H-NMR(DMSO-d
6)δ：2.03-2.16(2H，m)，2.61-2.75(2H，m)，4.86(2H，t，J＝6.6Hz)，6.70(1H，d，J＝3.0Hz)，6.94-7.01(2H，m)，7.11-7.19(1H，m)，7.37(1H，d，J＝8.7Hz)，7.52-7.58(1H，m)，7.67(1H，dd，J＝8.7，2.7Hz)，7.95(1H，d，J＝2.1Hz)，7.96-815(4H，m)，8.72(1H，s)，9.96(1H，br?s)。
(iv) N-{3-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group }-preparation of 2-(methylsulfonyl) acetamide hydrochloride
React according to the method (iv) identical with embodiment 155; by using 5-(3-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (170mg); 2-(methylsulfonyl) acetate (85.0mg); 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (177mg); I-hydroxybenzotriazole monohydrate (141mg); triethylamine (0.43mL) and N; dinethylformamide (5.0mL); obtain N-{3-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group }-2-(methylsulfonyl) ethanamide.At room temperature; to N-{3-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] propyl group }-add 4N hydrochloric acid-ethyl acetate (0.50mL) in ethyl acetate (1.0mL) solution of 2-(methylsulfonyl) ethanamide, and mixture was at room temperature stirred 1 hour.Behind the concentrating under reduced pressure, add Di Iso Propyl Ether, and filter the crystallization of collecting precipitation.Crystallization is washed with Di Iso Propyl Ether, obtain colourless powder shape crystalline title compound (128mg).
1H-NMR(DMSO-d
6)δ：1.88-2.00(2H，m)，2.97-3.08(2H，m)，3.11(3H，s)，4.04(2H，s)，4.63-4.72(2H，m)，6.67(1H，d，J＝3.0Hz)，6.94-7.01(2H，m)，7.13-7.21(1H，m)，7.36(1H，d，J＝9.0Hz)，7.49-7.65(2H，m)，7.91(1H，d，J＝2.4Hz)，7.96(1H，d，J＝3.0Hz)，8.45-8.52(1H，m)，8.70(1H，s)，9.67(1H，br?s)。
Embodiment 168
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-(methylsulfonyl) propionic acid amide
(i) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-(methylthio group) propionic acid amide
Under ice-cooled, to 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-add 3-(methylthio group) propionyl chloride (0.15mL) in tetrahydrofuran (THF) (8.0mL) mixture of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (230mg) and triethylamine (0.61mL).After at room temperature stirring 20 hours, add entry, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure, and separation resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=9: 1), obtain the title compound (133mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：2.13(3H，s)，2.59(2H，t，J＝6.9Hz)，2.83(2H，t，J＝6.9Hz)，3.57-3.69(2H，m)，4.45-4.55(2H，m)，6.39-6.47(1H，m)，6.62(1H，d，J＝3.0Hz)，7.08(1H，d，J＝8.7Hz)，7.09-7.14(1H，m)，7.20(1H，d，J＝3.0Hz)，7.23-7.27(1H，m)，7.29-7.34(1H，m)，7.39-7.47(1H，m)，7.83(1H，dd，J＝8.7，2.7Hz)，8.12(1H，d，J＝2.7Hz)，8.523(1H，s)，8.63(1H，s)。
(ii) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-(methylsulfonyl) propionic acid amide
React according to the method identical with embodiment 165, by using N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-(methylthio group) propionic acid amide (150mg), tetraisopropoxy titanium (40.3 μ L), methyl alcohol (22.2 μ L), water (9.3 μ L), the 70% tert-butyl peroxide aqueous solution (0.12mL) and methylene dichloride (8.0mL), obtain the title compound (97mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：2.41-2.57(2H，m)，2.95(3H，s)，3.26(2H，t，J＝7.5Hz)，3.35-3.45(2H，m)，4.48-4.58(2H，m)，6.51(1H，d，J＝3.0Hz)，7.18-7.32(3H，m)，7.43-7.50(1H，m)，7.58-7.67(2H，m)，7.73-7.82(1H，m)，8.02-8.07(1H，m)，8.34-8.45(2H，m)，8.75(1H，s)。
Embodiment 169
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) 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, to 2-methyl-2-(methylsulfonyl) propionic acid (115mg) and N, add thionyl (two) chlorine (0.10mL) in tetrahydrofuran (THF) (5.0mL) solution of dinethylformamide (catalytic amount).After at room temperature stirring 3 hours, the concentrating under reduced pressure mixture.At room temperature, tetrahydrofuran (THF) (10mL) drips of solution of resistates is added to 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl-tetrahydrofuran (THF) (10mL) suspension of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (180mg) and triethylamine (0.48mL) in.After at room temperature stirring 20 hours, water is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=9: 1), obtain the title compound (205mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.70(6H，s)，2.93(3H，s)，3.63-3.73(2H，m)，4.43-4.52(2H，m)，6.64(1H，d，J＝3.3Hz)，7.09(1H，d，J＝8.7Hz)，7.10-7.16(1H，m)，7.18-7.24(2H，m)，7.27-7.35(2H，m)，7.40-7.47(1H，m)，7.90(1H，dd，J＝8.7，2.7Hz)，8.05(1H，d，J＝2.7Hz)，8.38(1H，s)，8.54(1H，s)。
Fusing point: 167-168 ℃
Embodiment 170
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) 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, to 2-methyl-2-(methylsulfonyl) propionic acid (92mg) and N, add thionyl (two) chlorine (80 μ L) in tetrahydrofuran (THF) (5.0mL) solution of dinethylformamide (catalytic amount).After at room temperature stirring 3 hours, the concentrating under reduced pressure mixture.At room temperature, the drips of solution of resistates in tetrahydrofuran (THF)-methylene dichloride (10mL-10mL) is added to 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg) and the suspension of triethylamine (0.39mL) in tetrahydrofuran (THF) (10mL) in.After at room temperature stirring 20 hours, sodium bicarbonate aqueous solution is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through dried over mgso, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=9: 1), obtain faint yellow crystalline title compound (108mg).
1H-NMR(CDCl
3)δ：1.70(6H，s)，2.93(3H，s)，3.62-3.73(2H，m)，4.42-4.51(2H，m)，6.64(1H，d，J＝3.3Hz)，6.82-6.86(1H，m)，6.88-6.96(2H，m)，7.09(1H，d，J＝9.0Hz)，7.21(1H，d，J＝3.3Hz)，7.26-7.35(2H，m)，7.89(1H，dd，J＝9.0，2.6Hz)，8.04(1H，d，J＝2.6Hz)，8.37(1H，s)，8.54(1H，s)。
Embodiment 171
N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(2-methoxy ethoxy) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (500mg) is dissolved in N, in the dinethylformamide (10mL), and add salt of wormwood (830mg) and 2-(2-methoxy ethoxy) ethyl 4-toluene sulfonic acide ester (920mg), and mixture was at room temperature stirred 12 hours.Down saturated sodium bicarbonate aqueous solution is joined in the reaction mixture ice-cooled, and with the mixture ethyl acetate extraction.Organic layer is also concentrated through dried over mgso.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=50: 50 → 0: 100).The oily matter that obtains is dissolved in the Virahol (10mL), and adds 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline.Down mixture was stirred 4 hours down at 90 ℃ ice-cooled, saturated sodium bicarbonate aqueous solution is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso.Separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10), and by 4N hydrochloric acid-ethyl acetate solution/hexane crystallization, obtain title compound (277mg).
1H-NMR(DMSO-d
6)δ∶3.06(3H，s)，3.33-3.35(2H，m)，3.55-3.61(2H，m)，3.83-3.86(2H，m)，4.83-4.86(2H，m)，6.71(1H，d，J＝3Hz)，7.24-7.72(7H，m)，7.99-8.04(2H，m)，8.77(1H，s)，9.92(1H，s)。
Embodiment 172
N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(methylsulfonyl) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(methylthio group) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
Down the compound (150mg) of embodiment 147 is dissolved in the tetrahydrofuran (THF) (10mL), and adds triethylamine (1.50mL) and methylsulfonyl chloride (0.70mL) ice-cooled, and with mixture stirring 1 hour.Down saturated sodium bicarbonate aqueous solution is joined in this reaction soln ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and resistates is dissolved in N, in the mixed solvent of dinethylformamide (5.0mL) and tetrahydrofuran (THF) (4.0mL).Add sodium methyl mercaptide (180mg), and mixture was at room temperature stirred 1 hour.Down saturated sodium bicarbonate aqueous solution is joined in the reaction mixture ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso.Separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10), obtain title compound (123mg).
1H-NMR(CDCl
3)δ：2.02(3H，s)，2.66-2.73(2H，m)，3.74-3.78(2H，m)，3.98-4.01(2H，m)，4.55-4.58(2H，m)，6.66(1H，d，J＝3Hz)，7.07-7.63(6H，m)，7.88(1H，br?s)，8.02(1H，s)，8.55(1H，s)，8.74(1H，s)。
(ii) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(methylsulfonyl) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(methylthio group) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (70.0mg) is dissolved in the methylene dichloride (5.0mL), add tetraisopropoxy titanium (0.10mL), methyl alcohol (0.50mL) and the 70% tert-butyl peroxide aqueous solution (8.0mL), and mixture was at room temperature stirred 1 hour.Under ice-cooled, saturated sodium thiosulfate solution joined in the reaction mixture, and mixture was at room temperature stirred 1 hour, and use dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10).By ether/ethyl acetate/hexane crystallization, obtain title compound (62.5mg).
1H-NMR(CDCl
3)δ：2.62(3H，s)，4.57-4.61(2H，m)，6.68(1H，d，J＝3Hz)，4.16(1H，m)，5.08(2H，s)，5.55(2H，s)，6.33(1H，br?s)，6.66(1H，d，J＝3Hz)，7.09-7.60(7H，m)，7.86(1H，d，J＝3Hz)，8.11(1H，s)，8.55(1H，s)。
Embodiment 173
N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(2,2, the 2-trifluoro ethoxy) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine hydrochlorate
React according to the method identical with embodiment 172 (i), under 50 ℃ temperature of reaction, pass through to use the compound (200mg), 2 of embodiment 147,2,2-trifluoroethanol sodium (1.20g), tetrahydrofuran (THF) (7.0mL) and N, dinethylformamide (10mL), and, obtain crystalline title compound (107mg) by 4N hydrochloric acid-ethyl acetate solution/hexane crystallization.
1H-NMR(DMSO-d
6)δ：3.09(4H，m)，3.30-3.39(2H，m)，4.61(2H，br?s)，5.12(2H，br?s)，6.53(1H，d，J＝3Hz)，7.20-8.56(10H，m)。
Embodiment 174
The preparation of 2-(methylsulfonyl) ethyl { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } carbamate
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (64.1mg) and triethylamine (1.0mL) be dissolved in the methylene dichloride (5.0mL); add 1-({ [2-(methylsulfonyl) oxyethyl group] carbonyl } oxygen base) tetramethyleneimine-2; 5-diketone (45.6mg), and mixture at room temperature stirred 2 hours.Down saturated sodium bicarbonate aqueous solution is joined in the reaction mixture ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=95: 5).By the ether/hexane crystallization, obtain title compound (61.0mg).
1H-NMR(CDCl
3)δ：3.10(3H，s)，3.48-3.52(2H，m)，3.70-3.75(2H，m)，4.62-4.68(2H，m)，4.75-4.79(2H，m)，5.57(1H，m)，6.78(1H，d，J＝3Hz)，7.22-7.61(6H，m)，7.92(1H，m)，8.11(1H，m)，8.20(1H，s)，8.68(1H，s)。
Embodiment 175
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N '-[2-(methylsulfonyl) ethyl] urea
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (54.1mg) and triethylamine (0.7mL) be dissolved in the methylene dichloride (10mL), add 1,1 '-carbonyl two (1H-imidazoles), and mixture at room temperature stirred.After 1 hour, add 2-(methylsulfonyl) ethamine (1.0mL), and mixture was further stirred 1 hour.Down saturated sodium bicarbonate aqueous solution is joined in the reaction mixture ice-cooled, and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10).By ether/ethyl acetate/hexane crystallization, obtain title compound (37.6mg).
1H-NMR(CDCl
3)δ：2.84(3H，s)，3.11-3.17(2H，m)，3.40-3.50(2H，m)，3.66-3.72(2H，m)，4.39-4.44(2H，m)，5.55(2H，m)，6.47(1H，d，J＝3Hz)，7.00-7.39(6H，m)，7.81-7.88(1H，m)，7.99(1H，m)，8.40(1H，s)，8.73(1H，s)。
Embodiment 176
5-{2-[2-(tertiary butyl alkylsulfonyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) 5-{2-[2-(tertiary butyl sulfenyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol (150mg) is dissolved in the tetrahydrofuran (THF) (6.0mL), and at ice-cooled triethylamine (1.00mL) and the methylsulfonyl chloride (0.59mL) of adding down, and with mixture stirring 1 hour.Down saturated sodium bicarbonate aqueous solution is joined in this reaction soln ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and resistates is dissolved in N, in the mixed solvent of dinethylformamide (4.0mL) and tetrahydrofuran (THF) (6.0mL).Add 2-methylpropane-2-sodium mercaptides (220mg), and mixture was at room temperature stirred 1 hour.Down saturated sodium bicarbonate aqueous solution is joined in the reaction mixture ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso.Separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10), obtain title compound (143mg).
1H-NMR(CDCl
3)δ：1.23(9H，s)，2.69-2.73(2H，m)，3.73-3.78(2H，m)，3.97-3.99(2H，m)，4.54-4.57(2H，m)，6.66(1H，d，J＝3Hz)，7.07-7.45(6H，m)，7.64-7.68(1H，m)，7.89(1H，d，J＝3Hz)，8.55(1H，s)，8.77(1H，s)。
(ii) 5-{2-[2-(tertiary butyl alkylsulfonyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 5-{2-[2-(tertiary butyl sulfenyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (140mg) is dissolved in the methylene dichloride (5.0mL), add tetraisopropoxy titanium (0.90mL), methyl alcohol (0.20mL) and the 70% tert-butyl peroxide aqueous solution (7.0mL), and mixture was at room temperature stirred 1 hour.Down saturated sodium thiosulfate solution is joined in the reaction mixture ice-cooled, and mixture was at room temperature stirred 1 hour, and use dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10).By ether/ethyl acetate/hexane crystallization, obtain title compound (10.6mg).
1H-NMR(CDCl
3)δ：1.24(9H，s)，3.00-3.04(2H，m)，3.97-4.08(4H，m)，4.49-4.52(2H，m)，6.59(1H，d，J＝3Hz)，7.00-7.56(7H，m)，7.84(1H，d，J＝3Hz)，8.27(1H，s)，8.48(1H，s)。
Fusing point: 79.5-81.5 ℃
Embodiment 177
N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(phenyl sulfonyl) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(phenyl sulfenyl) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method identical with embodiment 172 (i), by using compound (100mg), benzenethiol sodium (200mg), tetrahydrofuran (THF) (5.0mL) and the N of embodiment 147, dinethylformamide (4.0mL) obtains title compound (96.4mg).
1H-NMR(CDCl
3)δ：3.06-3.10(2H，m)，3.75-3.79(2H，m)，3.94-3.97(2H，m)，4.52-4.55(2H，m)，6.66(1H，d，J＝3Hz)，7.01-7.56(12H，m)，7.88(1H，d，J＝3Hz)，8.56(1H，s)，8.71(1H，s)。
(ii) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(phenyl sulfonyl) oxyethyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method (ii) identical with embodiment 172, by using N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-{2-[2-(phenyl sulfenyl) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (60mg), methylene dichloride (5.0mL), N, dinethylformamide (2.0mL), tetraisopropoxy titanium (0.90mL), methyl alcohol (0.20mL) and the 70% tert-butyl peroxide aqueous solution (4.0mL) obtain title compound (7.2mg).
1H-NMR(CDCl
3)δ：3.23-3.27(2H，m)，3.88-4.00(4H，m)，4.42-4.45(2H，m)，6.58(1H，d，J＝3Hz)，7.00-7.70(12H，m)，7.79(1H，d，J＝3Hz)，8.13(1H，s)，8.47(1H，s)。
Embodiment 178
2-[(2-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl) sulfinyl] the alcoholic acid preparation
React according to the method identical with embodiment 172 (i), by using compound (200mg), 2-hydroxyl ethane sodium mercaptides (2.02g), tetrahydrofuran (THF) (6.0mL) and the N of embodiment 147, dinethylformamide (5.0mL) is dissolved in the methylene dichloride (7.0mL), obtains compound (120mg).Add metachloroperbenzoic acid (110mg) down at-18 ℃, and mixture was stirred 5 hours.Down saturated sodium bicarbonate aqueous solution is joined in the reaction mixture ice-cooled, and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=80: 20).By ether/ethyl acetate/hexane crystallization, obtain title compound (97.0mg).
1H-NMR(CDCl
3)δ：2.66-2.73(2H，m)，2.90-2.98(2H，m)，3.93-4.13(6H，m)，4.56-4.62(2H，m)，6.68(1H，d，J＝3Hz)，7.08-7.59(7H，m)，7.83(1H，d，J＝3Hz)，8.37(1H，m)，8.55(1H，s)。
Embodiment 179
2-[(2-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl) alkylsulfonyl] the alcoholic acid preparation
React according to the method (ii) identical with embodiment 172, by using compound (87.0mg), methylene dichloride (4.0mL), the N of embodiment 178, dinethylformamide (2.0mL), tetraisopropoxy titanium (0.90mL), methyl alcohol (0.50mL) and the 70% tert-butyl peroxide aqueous solution (5.0mL) obtain crystalline title compound (60.2mg).
1H-NMR(CDCl
3)δ：2.78-2.82(2H，m)，3.34-3.38(2H，m)，3.79(2H，m)，4.03-4.13(4H，m)，4.57-4.60(2H，m)，6.68(1H，d，J＝3Hz)，7.07-7.57(7H，m)，7.80(1H，d，J＝3Hz)，8.23(1H，m)，8.54(1H，s)。
Embodiment 180
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 1-(methylsulfonyl) Toluidrin
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (245mg) and N-methylmorpholine (1.0mL) be dissolved in the methylene dichloride (6.0mL); drip (methylsulfonyl) methylsulfonyl chloride (0.40mL) down ice-cooled, and mixture was stirred 1 hour.Add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=80: 20).By ether/ethyl acetate crystallization, obtain crystalline title compound (79.4mg).
1H-NMR(CDCl
3)δ：3.60(3H，br?s)，3.83-3.92(4H，m)，4.82(2H，br?s)，6.68(1H，d，J＝3Hz)，7.24-7.99(8H，m)，8.73(1H，s)，8.73(1H，s)，9.72(1H，s)。
Embodiment 181
3-[2-chloro-4-(6,7-dihydro-9H-Mi Dingbing [4 ', 5 ': 4,5] pyrrolo-[2,1-c] [1,4] oxazine-4-base is amino) phenoxy group] preparation of benzonitrile hydrochloride
(i) 4-phenoxy group-6,7-dihydro-9H-Mi Dingbing [4 ', 5 ': 4,5] pyrrolo-[2, the 1-c] [preparation of 1,4] oxazine
The compound (130mg) that embodiment 21 is obtained in (ii) is dissolved in N, in the dinethylformamide (2.16mL), and adds cesium carbonate (1.05g) and glycol dibromide (0.255mL) successively.Mixture was at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate (30mL), and water (20mL) washing.Separate organic layer, through dried over mgso, and concentrating under reduced pressure.Resistates is dissolved in N, in the dinethylformamide (1.08mL), adds potassium tert.-butoxide (90.5mg), and mixture was at room temperature stirred 1 hour.Add ethyl acetate (30mL)/water (20mL), and with organic layer through dried over mgso, and concentrating under reduced pressure.Resistates by silica gel column chromatography purifying (hexane/ethyl acetate=70/30 → 0/100), is obtained title compound (76mg).
1H-NMR(CDCl
3)δ4.20(2H，t，J＝5Hz)，4.55(2H，t，J＝5Hz)，5.06(2H，s)，6.40(1H，s)，7.2-7.5(5H，m)，8.44(1H，s)。
(ii) 3-[2-chloro-4-(6,7-dihydro-9H-Mi Dingbing [4 ', 5 ': 4,5] pyrrolo-[2,1-c] [1,4] oxazine-4-base is amino) phenoxy group] preparation of benzonitrile hydrochloride
With 4-phenoxy group-6,7-dihydro-9H-Mi Dingbing [4 ', 5 ': 4,5] pyrrolo-[2,1-c] [mixture of 1,4] oxazine (69mg), 3-(4-amino-2-chlorophenoxy) benzonitrile (95mg), pyridine hydrochloride (75mg) and 1-Methyl-2-Pyrrolidone (1mL) stirred 14 hours down at 140 ℃.After reaction is finished, mixture is diluted with ethyl acetate, and wash with saturated sodium bicarbonate aqueous solution and saturated brine.With organic layer through dried over mgso.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (hexane/ethyl acetate=50/50 → 0/100).The fraction that collection obtains, and concentrate, and resistates is dissolved in the ethyl acetate (2mL), and handle with 4N hydrochloric acid/ethyl acetate (0.13mL), crystallization title compound (81mg) obtained as hydrochloride.
1H-NMR(DMSO-d
6)δ4.17(2H，t，J＝5Hz)，4.75(2H，m)，5.07(2H，s)，6.55(1H，s)，7.2-7.7(6H，m)，7.94(1H，m)，8.70(1H，s)，9.91(1H，br?s)。
Embodiment 182
N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5-(2-{[2-(methylsulfonyl) ethyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
(i) preparation of 4-chloro-5-(2,2-diethoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidine
4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (1g) are dissolved in N, in the dinethylformamide (13mL), add cesium carbonate (6.37g) and 2-bromo-1 successively, 1-diethoxyethane (2.94mL), and mixture stirred 4.5 hours down at 80 ℃.Reaction mixture is diluted with ethyl acetate (100mL), and water (80mL) washing.Separate organic layer, through dried over mgso and reduction vaporization.Resistates by silica gel column chromatography purifying (hexane/ethyl acetate=50/50 → 0/100), is obtained the title compound (1.26g) of yellow oil.
1H-NMR(CDClC
3)δ1.14(6H，t，J＝6Hz)，3.40(2H，m)，3.72(2H，m)，4.08(1H，m)，4.56(2H，d，J＝5Hz)，6.71(1H，d，J＝3Hz)，7.55(1H，d，J＝3Hz)，8.69(1H，s)。
The (ii) preparation of 4-phenoxy group-5-(2,2-diethoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidine
The mixture of 4-chloro-5-(2,2-diethoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidines (1g), phenol (420mg), salt of wormwood (617mg) and 1-Methyl-2-Pyrrolidone (6.74mL) was stirred 6 hours down in 140 ℃ of heating.Reaction mixture is diluted with ethyl acetate (100mL), and water (80mL) washing.Separate organic layer, through dried over mgso and reduction vaporization.Resistates by silica gel column chromatography purifying (hexane/ethyl acetate=90/10 → 40/60), is obtained the title compound (1.15g) of yellow oil.
1H-NMR(CDCl
3)δ1.13(6H，t，J＝7Hz)，3.40(2H，m)，3.69(2H，m)，4.51(2H，d，J＝6Hz)，4.76(1H，t，J＝6Hz)，6.65(1H，d，J＝3Hz)，7.2-7.5(6H，m)，8.45(1H，s)。
(iii) 2-(4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethane-1, the preparation of 1-glycol
4-phenoxy group-5-(2,2-diethoxy ethyl)-5H-pyrrolo-[3,2-d] pyrimidines (1.1g) are dissolved in methylene dichloride (4.53mL)/trifluoroacetic acid (4.53mL), and mixture was at room temperature stirred 16 hours.The concentrating under reduced pressure reaction mixture, and resistates is dissolved in the ethyl acetate (100mL).With mixture with saturated sodium bicarbonate aqueous solution (80mL) washing, and with organic layer through dried over mgso, and concentrating under reduced pressure obtains the title compound (826mg) of white solid.
1H-NMR(DMSO-d
6)δ4.35(2H，d，J＝6Hz)，5.17(1H，t，J＝6Hz)，6.14(2H，d，J＝6Hz)，6.59(1H，d，J＝3Hz)，7.2-7.6(5H，m)，7.75(1H，d，J＝3Hz)，8.28(1H，s)。
(iv) 2-(methylsulfonyl)-N-[2-(4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of ethamine
With 2-(4-phenoxy group-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethane-1; 1-glycol (500mg) and 2-(methylsulfonyl) ethamine (341mg) are dissolved in N, in dinethylformamide (29mL)/acetate (2.9mL), and mixture are at room temperature stirred 1.5 hours.Add sodium triacetoxy borohydride (579mg), and mixture was at room temperature stirred 16 hours.The concentrating under reduced pressure reaction mixture, and with resistates by silica gel column chromatography purifying (ethyl acetate/methanol=100/0 → 70/30), obtain the title compound (508mg) of rock sugar shape material.
1H-NMR(CDCl
3)δ2.84(3H，s)，3.0-3.2(6H，m)，4.54(2H，t，J＝6Hz)，6.66(1H，d，J＝3Hz)，7.2-7.5(6H，m)，8.45(1H，s)。
(v) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5-(2-{[2-(methylsulfonyl) ethyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 2-(methylsulfonyl)-N-[2-(4-phenoxy group-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl] ethamine (500mg) is dissolved in the tetrahydrofuran (THF) (5mL); and add tert-Butyl dicarbonate (0.478mL) and triethylamine (0.29mL), and mixture was at room temperature stirred 3 hours.The concentrating under reduced pressure reaction mixture, and with resistates by silica gel column chromatography purifying (hexane/ethyl acetate=80/20 → 0/100).With a part (243mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group in the resistates (491mg) that obtains] mixture of aniline (228mg), pyridine hydrochloride (183mg) and phenol (406mg) is 140 ℃ of stirrings 14 hours down.After reaction is finished, mixture is diluted with methylene dichloride (50mL), and wash with saturated sodium bicarbonate aqueous solution (30mL).With organic layer through dried over mgso.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (ethyl acetate/methanol=100/0 → 70/30), and, obtain title compound (123mg) by the Di Iso Propyl Ether crystallization.
1H-NMR(DMSO-d
6)δ2.88(3H，s)，2.89(2H，m)，2.99(2H，m)，3.16(2H，t，J＝6Hz)，4.50(2H，m)，6.51(1H，d，J＝3Hz)，7.22(2H，m)，7.31(1H，d，J＝9Hz)，7.46(1H，d，J＝8Hz)，7.5-7.7(3H，m)，8.04(1H，d，J＝2Hz)，8.35(1H，s)。
Embodiment 183
2-[2-(4-{[4-[(6-picoline-3-yl) oxygen base]-3-(trifluoromethyl) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] the alcoholic acid preparation
With 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl benzoate (150mg), 4-[(6-picoline-3-yl) the oxygen base]-mixture of 3-(trifluoromethyl) aniline (175mg) and 1-Methyl-2-Pyrrolidone (0.863mL) stirred 2.5 hours under 140 ℃ of heating.Reaction mixture is diluted with ethyl acetate (80mL), and wash with sodium bicarbonate aqueous solution (30mL).Separate organic layer, through dried over mgso, and reduction vaporization.Resistates is passed through silica gel column chromatography purifying (ethyl acetate/methanol=100/0 → 90/10).Concentrating under reduced pressure target fraction.The resistates that obtains is dissolved in the methyl alcohol (1.9mL), adds 1N sodium hydroxide (0.433mL), and mixture was at room temperature stirred 1.5 hours.Add 1N hydrochloric acid (0.433mL), and mixture is diluted with ethyl acetate (80mL), and wash with saturated brine (30mL).With organic layer through dried over mgso.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (ethyl acetate/methanol=100/0 → 90/10), and, obtain title compound (118mg) by the Di Iso Propyl Ether crystallization.
1H-NMR(DMSO-d
6)δ2.46(3H，s)，3.47(4H，br?s)，3.82(2H，m)，4.66(3H，m)，6.51(1H，d，J＝3Hz)，7.10(1H，d，J＝9Hz)，7.31(2H，m)，7.68(1H，d，J＝3Hz)，7.90(1H，dd，J＝3Hz，9Hz)，8.10(1H，d，J＝3Hz)，8.24(1H，d，J＝3Hz)，8.30(1H，s)，8.99(1H，br?s)。
Embodiment 184
2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl benzoate (100mg), 3-chloro-4-(3-chlorophenoxy) aniline (126mg) and 1-Methyl-2-Pyrrolidone (0.66mL), obtain the title compound (81mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.87(2H，m)，4.53(2H，t，J＝4.5Hz)，6.31(1H，br?s)，6.51(1H，d，J＝3Hz)，6.88(1H，d，J＝9Hz)，6.95(1H，s)，7.15(1H，d，J＝9Hz)，7.28(1H，d，J＝9Hz)，7.38(1H，t，J＝9Hz)，7.60(1H，dd，J＝2Hz，9Hz)，7.66(1H，d，J＝3Hz)，7.97(1H，d，J＝2Hz)，8.34(1H，s)，9.89(1H，br?s)。
Embodiment 185
2-{2-[4-(3-methoxyl group-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl benzoate (150mg), 3-methoxyl group-4-[3-(trifluoromethyl) phenoxy group] aniline (185mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (80mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.52(4H，m)，3.74(3H，s)，3.85(2H，t，J＝5Hz)，4.65(2H，t，J＝5Hz)，4.76(1H，t，J＝5Hz)，6.51(1H，d，J＝3Hz)，7.13(3H，m)，7.35(2H，m)，7.49(1H，d，J＝2Hz)，7.55(1H，t，J＝8Hz)，7.68(1H，d，J＝3Hz)，8.32(1H，s)，8.90(1H，br?s)。
Embodiment 186
2-{2-[4-(3-(hydroxymethyl)-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl benzoate (150mg), { 5-amino-2-[3-(trifluoromethyl) phenoxy group] phenyl } methyl alcohol (184mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (175mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.52(4H，m)，3.74(3H，s)，3.85(2H，t，J＝5Hz)，4.65(2H，t，J＝5Hz)，4.76(1H，t，J＝5Hz)，6.51(1H，d，J＝3Hz)，7.13(3H，m)，7.35(2H，m)，7.49(1H，d，J＝2Hz)，7.55(1H，t，J＝8Hz)，7.68(1H，d，J＝3Hz)，8.32(1H，s)，8.90(1H，br?s)。
Embodiment 187
2-{2-[4-(3-methyl-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl benzoate (150mg), 3-methyl-4-[3-(trifluoromethyl) phenoxy group] aniline (174mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (98mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ2.13(3H，s)，3.51(4H，m)，3.84(2H，t，J＝4.5Hz)，4.63(2H，t，J＝4.5Hz)，4.74(1H，t，J＝4.5Hz)，6.49(1H，d，J＝3Hz)，7.04(1H，d，J＝9Hz)，7.16(2H，m)，7.41(1H，d，J＝8Hz)，7.5-7.7(4H，m)，8.29(1H，s)，8.83(1H，br?s)。
Embodiment 188
2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide
(i) preparation of { 2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate
With [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (297mg), 3-methyl-4-[3-(trifluoromethyl) phenoxy group] mixture of aniline (401mg) and Virahol (2.97mL) stirred 16 hours down at 80 ℃.Reaction mixture is diluted with ethyl acetate (80mL), and wash with sodium bicarbonate aqueous solution (30mL).Separate organic layer, through dried over mgso and reduction vaporization.Resistates by silica gel column chromatography purifying (hexane/ethyl acetate=90/10 → 0/100), is obtained the title compound (528mg) of white powder.
1H-NMR(CDCl
3)δ1.47(9H，s)，2.21(3H，s)，3.50(2H，m)，4.46(2H，m)，5.11(1H，m)，6.58(1H，d，J＝3Hz)，6.97(1H，d，J＝9Hz)，7.0-7.2(3H，m)，7.27(1H，m)，7.39(1H，t，J＝8Hz)，7.69(2H，m)，8.45(1H，br?s)，8.50(1H，s)。
(ii) 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
Will 2-[4-(3-methyl-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (494mg) is dissolved in the methylene dichloride (6.4mL), add trifluoroacetic acid (4.8mL), and mixture was at room temperature stirred 1 hour.The concentrating under reduced pressure reaction mixture, and with resistates with ethyl acetate (50mL) dilution, and wash with sodium bicarbonate aqueous solution (30mL).Separate organic layer, through dried over mgso, and concentrating under reduced pressure, obtain pulverous title compound (442mg).
1H-NMR(CDCl
3)δ2.20(3H，s)，3.30(2H，t，J＝5Hz)，4.46(2H，t，J＝5Hz)，6.61(1H，d，J＝3Hz)，6.95(1H，d，J＝9Hz)，7.0-7.5(6H，m)，7.51(1H，d，J＝3Hz)，8.50(1H，s)。
(iii) 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide
React according to the method (iv) identical with embodiment 155; by using 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine (196mg), 2-(methylsulfonyl) acetate (64mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (133mg), I-hydroxybenzotriazole monohydrate (94mg), triethylamine (0.319mL) and N; dinethylformamide (5.0mL) obtains colourless powder shape crystalline title compound (89mg).
1H-NMR(DMSO-d
6)δ2.14(3H，s)，3.09(3H，s)，3.45(2H，m)，4.05(2H，s)，4.56(2H，t，J＝7Hz)，6.47(1H，d，J＝3Hz)，7.04(1H，d，J＝9Hz)，7.17(2H，m)，7.47(1H，m)，7.59(4H，m)，8.29(1H，s)，8.55(1H，br?s)，8.67(1H，t，J＝5.5Hz)。
Embodiment 189
2-{2-[4-(3-methyl-4-[3-(trifluoromethoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl benzoate (150mg), 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] aniline (184mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (128mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ2.12(3H，s)，3.51(4H，m)，3.84(2H，t，J＝5Hz)，4.63(2H，t，J＝5Hz)，4.73(1H，t，J＝5Hz)，6.49(1H，d，J＝3Hz)，6.87(2H，m)，7.04(2H，m)，7.47(1H，t，J＝8Hz)，7.59(2H，m)，7.66(1H，d，J＝3Hz)，8.29(1H，s)，8.82(1H，br?s)。
Embodiment 190
2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide
(i) preparation of { 2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate
With [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (297mg) and 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] aniline (425mg) is dissolved in the Virahol (2.97mL), and mixture was stirred 16 hours down at 80 ℃.After being cooled to room temperature, mixture is diluted with ethyl acetate (60mL), and wash with sodium bicarbonate aqueous solution (30mL).With organic layer through dried over mgso, and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), obtain the title compound (563mg) of white powder.
1H-NMR(CDCl
3)δ1.47(9H，s)，2.20(3H，s)，3.49(2H，m)，4.46(2H，m)，5.08(1H，m)，6.59(1H，d，J＝3Hz)，6.78(1H，m)，6.86(2H，m)，6.97(1H，m)，7.16(1H，d，J＝3Hz)，7.27(2H，m)，7.69(2H，m)，8.43(1H，br?s)，8.50(1H，s)。
(ii) 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
Will 2-[4-(3-methyl-4-[3-(trifluoromethoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (523mg) is dissolved in the methylene dichloride (6.4mL), add trifluoroacetic acid (4.8mL), and mixture was at room temperature stirred 2 hours.The concentrating under reduced pressure reaction mixture, and with resistates with ethyl acetate (50mL) dilution, and wash with sodium bicarbonate aqueous solution (40mL).Separate organic layer, through dried over mgso, and concentrating under reduced pressure, obtain the title compound (420mg) of white powder.
1H-NMR(CDCl
3)δ2.20(3H，s)，3.30(2H，t，J＝4.5Hz)，4.46(2H，t，J＝4.5Hz)，6.62(1H，d，J＝3Hz)，6.85(3H，m)，6.96(1H，d，J＝9Hz)，7.19(1H，d，J＝3Hz)，7.27(1H，m)，7.44(1H，dd，J＝2Hz，9Hz)，7.50(1H，d，J＝3Hz)，8.50(1H，s)。
(iii) 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide
With 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine (174mg), 2-(methylsulfonyl) acetate (54mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (112mg), I-hydroxybenzotriazole monohydrate (79mg) and triethylamine (0.273mL) are at N, and the solution in the dinethylformamide (7.69mL) at room temperature stirred 16 hours.Reaction mixture is diluted with ethyl acetate (80mL), and water (60mL) washing.With organic layer through dried over mgso, and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography handle (elutriant, ethyl acetate: methyl alcohol=100: 0 → 92: 8), and, obtain the title compound (92mg) of colourless crystallization by the Di Iso Propyl Ether crystallization.
1H-NMR(DMSO-d
6)δ2.14(3H，s)，3.10(3H，s)，3.46(2H，q，J＝6Hz)，4.06(2H，s)，4.56(2H，t，J＝6Hz)，6.48(1H，d，J＝3Hz)，6.89(2H，m)，7.06(2H，m)，7.48(1H，t，J＝8Hz)，7.59(3H，m)，8.30(1H，s)，8.55(1H，br?s)，8.67(1H，t，J＝6Hz)。
Fusing point: 106-108 ℃
Embodiment 191
N-[2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-preparation of 2-(methylsulfonyl) ethanamide
(i) 2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl) amino)-and 5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of the ethyl carbamic acid tert-butyl ester
The mixture of 2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) the ethyl carbamic acid tert-butyl ester (1.19g), 3-chloro-4-(3-chlorophenoxy) aniline (1.22g) and Virahol (12.0mL) was stirred 15 hours down at 80 ℃.Add sodium bicarbonate aqueous solution down ice-cooled, and with the mixture ethyl acetate extraction.With organic layer salt water washing, and through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent, and with resistates by silica gel chromatography purifying (elutriant: hexane/ethyl acetate=50/50 → 100/0), and, obtain crystalline title compound (1.69g) with Di Iso Propyl Ether-hexane wash.
1H-NMR(CDCl
3)δ：1.50(9H，s)，3.4-3.6(2H，m)，4.4-4.6(2H，m)，5.0-5.1(1H，m)，6.61(1H，d，J＝2.6Hz)，6.85-7.05(2H，m)，7.07(2H，d，J＝8.8Hz)，7.18(1H，d，J＝2.6Hz)，7.2-7.3(1H，m)，7.85-7.95(1H，m)，8.0-8.05(1H，m)，8.52(1H，s)，8.62(1H，br?s)。
(ii) 5-(2-amino-ethyl)-N-[3-chloro-4-(3-chlorophenoxy) phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
To 2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) add 2N hydrochloric acid (16mL) in tetrahydrofuran (THF) (32mL) solution of the ethyl carbamic acid tert-butyl ester (1.69g).Reaction mixture was stirred 18 hours down and concentrates at 65 ℃.Add ethanol, and mixture is concentrated once more.Ethyl acetate and Di Iso Propyl Ether are joined in the resistates, and filter the collecting precipitation thing, and, obtain crystalline title compound (1.50g) with the Di Iso Propyl Ether washing.
1H-NMR(DMSO-d
6+CDCl
3)δ：3.3-3.6(4H，m)，5.0-5.15(2H，m)，6.71(1H，d，J＝3.2Hz)，6.9-7.0(2H，m)，7.1-7.2(1H，m)，7.22(1H，d，J＝8.8Hz)，7.3-7.45(1H，m)，7.6-7.7(1H，m)，7.87(1H，d，J＝2.6Hz)，8.05(1H，d，J＝2.4Hz)，8.2-8.4(2H，m)，8.71(1H，s)。
(iii) N-[2-(4-{[3-chloro-4-(3-chlorophenoxy) 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-[3-chloro-4-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3; 2-d] N of pyrimidine-4-amine dihydrochloride (200mg), 2-(methylsulfonyl) acetate (113mg) and I-hydroxybenzotriazole (122mg); add triethylamine (419mg) at N in dinethylformamide (5.0mL) solution, the solution in dinethylformamide (1.25mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (173mg).After at room temperature reaction mixture being stirred 16 hours, under ice-cooled, add entry, and with twice of ethyl acetate extraction of mixture.Collected organic layer is through anhydrous magnesium sulfate drying and concentrated.Resistates is passed through silica gel column chromatography purifying (elutriant: ethyl acetate/methanol=100/0 → 80/20), and by ethanol-ethyl acetate-Di Iso Propyl Ether recrystallization, obtain crystalline title compound (151mg).
1H-NMR(CDCl
3)δ：3.13(3H，s)，3.6-3.8(2H，m)，3.99(2H，s)，4.4-4.6(2H，m)，6.62(1H，d，J＝3.4Hz)，6.85-6.95(2H，m)，7.0-7.1(2H，m)，7.2-7.3(2H，m)，7.7-7.8(1H，m)，7.95-8.0(1H，m)，8.19(1H，s)，8.52(1H，s)。
Fusing point: 206-207 ℃
Embodiment 192
2-[{3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group } (methyl) amino] preparation of ethanol dihydrochloride
(i) preparation of 4-chloro-5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidine
To the N of 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (1.54g), add cesium carbonate (4.89g) in dinethylformamide (20mL) solution down ice-cooled, and mixture was stirred 20 minutes down ice-cooled.Add 1-bromo-3-chloropropane (1.89g), and mixture is stirred 1 hour down, and at room temperature stirred 32 hours ice-cooled.Reaction mixture is poured in the water (40mL), and mixture is extracted with ethyl acetate (60mL * 2).Merge organic layer, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 50: 50), obtain title compound (1.87g).
1H-NMR(CDCl
3)δ：2.35(2H，m)，3.49(2H，t，J＝6.0Hz)，4.69(2H，t，J＝6.6Hz)，6.73(1H，d，J＝3.0Hz)，7.56(1H，d，J＝3.0Hz)，8.70(1H，s)。
(ii) N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-preparation of 5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidines (839mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (1.10g) and Virahol (5mL) stirred 1.5 hours down at 80 ℃.The concentrating under reduced pressure mixture, (30mL) joins in the resistates with saturated sodium bicarbonate aqueous solution, and mixture is extracted with ethyl acetate (30mL * 3).Merge organic layer, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 20: 80), obtain title compound (1.19g).
1H-NMR(CDCl
3)δ：2.36(2H，m)，3.56(2H，t，J＝5.7Hz)，4.47(2H，t，J＝6.9Hz)，5.14(2H，s)，6.60(1H，d，J＝3.3Hz)，6.73(1H，br?s)，6.94(1H，d，J＝8.7Hz)，7.02(1H，m)，7.19-7.40(5H，m)，7.65(1H，d，J＝3.3Hz)，8.49(1H，s)。
(iii) 2-[{3-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propyl group } (methyl) amino] preparation of ethanol dihydrochloride
With N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (634mg), 2-methylamino ethanol (534mg) and N, the mixture of dinethylformamide (5mL) at room temperature stirred 64 hours.Behind the concentrating under reduced pressure, (10mL) joins in the resistates with saturated sodium bicarbonate aqueous solution, and mixture is extracted with ethyl acetate (55mL * 2).With organic layer through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is passed through alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100).4N hydrogenchloride-ethyl acetate solution (10mL) is joined in the amorphous solid of acquisition, behind the concentrating under reduced pressure, resistates by ethanol-re-crystallizing in ethyl acetate, is obtained title compound (523mg).
1H-NMR(DMSO-d
6)δ：2.16-2.32(2H，m)，2.74(3H，s)，2.94-3.40(4H，m)，3.62-3.80(2H，m)，4.74-4.84(2H，m)，5.31(2H，s)，6.69(1H，m)，7.20(1H，m)，7.29-7.36(5H，m)，7.43-7.50(2H，m)，7.71(1H，m)，8.03(1H，br?s)，8.64(1H，s)，9.84(1H，br?s)，10.12(1H，br?s)。
Embodiment 193
N-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-5-[3-(dimethylamino) propyl group]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
With N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (560mg) is dissolved in 2.0M dimethyl amine-tetrahydrofuran solution (5mL), and mixture at room temperature stirred 26 hours.Further add 2.0M dimethyl amine-tetrahydrofuran solution (5mL), and mixture was at room temperature stirred 20 hours.Further add 2.0M dimethyl amine-tetrahydrofuran solution (10mL), and mixture was at room temperature stirred 24 hours.Behind the concentrating under reduced pressure reaction mixture, (20mL) joins in the resistates with saturated sodium bicarbonate aqueous solution, and mixture is extracted with ethyl acetate (35mL * 2).With organic layer through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.With resistates by alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 20: 80), and 4N hydrogenchloride-ethyl acetate solution (10mL) joined in the amorphous solid of acquisition.Behind the concentrating under reduced pressure, resistates by ethanol-re-crystallizing in ethyl acetate, is obtained title compound (428mg).
1H-NMR(DMSO-d
6)δ：2.18-2.26(2H，m)，2.70(6H，s)，2.94-3.04(2H，m)，4.77-4.84(2H，m)，5.30(2H，s)，6.67(1H，m)，7.19(1H，m)，7.28-7.34(4H，m)，7.43-7.51(2H，m)，7.71(1H，m)，8.04(1H，m)，8.63(1H，s)，9.87(1H，br?s)，10.74(1H，br?s)。
Embodiment 194
6-{3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl }-6,7,8,9-tetrahydrochysene-3,5,6, the 9a-tetrazine be the preparation of [cd] Azulene also
With N-{3-chloro-4-[(3-luorobenzyl) the oxygen base] phenyl }-5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (839mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (1.10g) and 1-Methyl-2-Pyrrolidone (5mL) stirred 1 hour down at 140 ℃.Reaction mixture is poured in the water (10mL), and regulates pH to 8 with saturated sodium bicarbonate aqueous solution.Mixture is extracted with ethyl acetate (40mL * 3), and merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out the silica gel column chromatography processing, and (elutriant, hexane: ethyl acetate=60: 40 → 50: 50), the step of going forward side by side carries out the alkaline silica gel column chromatography and handles (elutriant, hexane: ethyl acetate=80: 20 → 0: 100).Concentrating under reduced pressure target fraction.Chloroform-Di Iso Propyl Ether is joined in the resistates, and solid filtering is collected and drying.By re-crystallizing in ethyl acetate, obtain title compound (74.5mg).
1H-NMR(DMSO-d
6)δ：2.31(2H，m)，3.88(2H，m)，4.31(2H，m)，5.27(2H，s)，6.47(1H，d，J＝3.0Hz)，7.14-7.36(5H，m)，7.42(1H，d，J＝2.4Hz)，7.47(1H，m)，7.65(1H，d，J＝3.0Hz)，8.02(1H，s)。
Embodiment 195
6-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-6,7,8,9-tetrahydrochysene-3,5,6, the 9a-tetrazine be the preparation of [cd] Azulene also
(i) 5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
With 4-chloro-5-(3-chloropropyl)-5H-pyrrolo-[3,2-d] pyrimidines (789mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] mixture of aniline (1.09g) and Virahol (5mL) stirred 4.5 hours down at 80 ℃.The concentrating under reduced pressure mixture, (30mL) joins in the resistates with saturated sodium bicarbonate aqueous solution, and mixture is extracted with ethyl acetate (40mL * 3).Merge organic layer, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 20: 80), obtain title compound (1.46g).
1H-NMR(CDCl
3)δ：2.39(2H，m)，3.60(2H，t，J＝5.6Hz)，4.53(2H，t，J＝6.9Hz)，6.62(1H，d，J＝3.3Hz)，6.96(1H，br?s)，7.07(1H，d，J＝8.7Hz)，7.08-7.49(6H，m)，7.87(1H，m)，8.55(1H，s)。
(ii) 6-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-6,7,8,9-tetrahydrochysene-3,5,6, the 9a-tetrazine be the preparation of [cd] Azulene also
With 5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] mixture of pyrimidine-4-amine (470mg), salt of wormwood (270mg) and ethylene glycol (10mL) at room temperature stirred 18.5 hours, and stirred 4 hours down in 60 ℃.Reaction mixture is poured in the sodium bicarbonate aqueous solution (20mL), and mixture is extracted with ethyl acetate (50mL * 2).Merge organic layer, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.With resistates by the silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 0: 100), and with the solid that obtains by the alcohol-water recrystallization, obtain title compound (116mg).
1H-NMR(DMSO-d
6)δ：2.45(2H，m)，3.99(2H，t，J＝4.8Hz)，4.34(2H，t，J＝5.4Hz)，6.65(1H，d，J＝3.0Hz)，7.06(1H，d，J＝9.0Hz)，7.16-7.22(2H，m)，7.28(1H，m)，7.33(1H，d，J＝3.0Hz)，7.37(1H，m)，7.42(1H，d，J＝2.4Hz)，7.46(1H，m)，8.36(1H，s)。
Embodiment 196
2-{2-[7-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl } oxyethyl group } the alcoholic acid preparation
(i) 2-{2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] oxyethyl group } preparation of ethylamino benzonitrile acid esters
With 7-(methylthio group)-1H-pyrazolo [4; 3-d] pyrimidine (747mg), 2-{2-[(methylsulfonyl) the oxygen base] oxyethyl group } ethylamino benzonitrile acid esters (1.43g), salt of wormwood (931mg) and N, the mixture of dinethylformamide (12mL) stirred 4 hours down at 60 ℃.Reaction mixture is poured in the water (30mL), and mixture is extracted with ethyl acetate (50mL * 2).Merge organic layer, with the saturated brine washing, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 20: 80), and further pass through alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 40: 60), obtain title compound (533mg).
1H-NMR(CDCl
3)δ：2.67(3H，s)，3.75(2H，m)，4.01(2H，m)，4.38(2H，m)，4.87(2H，t，J＝5.8Hz)，7.38-7.48(3H，m)，7.91-7.95(2H，m)，8.11(1H，s)，8.71(1H，s)。
(ii) 2-{2-[7-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] oxyethyl group } the alcoholic acid preparation
With 2-{2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] oxyethyl group } ethylamino benzonitrile acid esters (200mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (140mg), pyridine hydrochloride (96mg) and 1-Methyl-2-Pyrrolidone (5mL) stirred 16.5 hours down at 140 ℃.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution (30mL), and extracts with ethyl acetate (30mL * 3).Merge organic layer, with the saturated brine washing, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=90: 10 → 20: 80).Concentrating under reduced pressure target fraction, and resistates is dissolved in the methyl alcohol (5mL).Add 1N aqueous sodium hydroxide solution (1mL), and mixture was at room temperature stirred 11.5 hours.Behind the concentrating under reduced pressure reaction mixture, add entry (30mL), and mixture is extracted with ethyl acetate (45mL * 2).With organic layer through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), and by ethanol-re-crystallizing in ethyl acetate, obtain title compound (78mg).
1H-NMR(DMSO-d
6)δ：3.30-3.55(4H，m)，3.87(2H，m)，4.67(1H，m)，4.86(2H，m)，5.26(2H，s)，7.14-7.35(4H，m)，7.46(1H，m)，7.60(1H，d，J＝8.4Hz)，7.92(1H，m)，8.18(1H，s)，8.35(1H，s)，8.99(1H，br?s)。
Embodiment 197
2-{2-[7-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] oxyethyl group } the alcoholic acid preparation
With 2-{2-[7-(methylthio group)-1H-pyrazolo [4,3-d] pyrimidine-1-yl] oxyethyl group } ethylamino benzonitrile acid esters (328mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] mixture of aniline (264mg), pyridine hydrochloride (159mg) and 1-Methyl-2-Pyrrolidone (7.5mL) stirred 33.5 hours down at 140 ℃.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution (15mL), and extracts with ethyl acetate (35mL * 2).Merge organic layer, and through anhydrous magnesium sulfate drying.Behind the concentrating under reduced pressure, resistates is carried out silica gel column chromatography handle (elutriant, hexane: ethyl acetate=80: 20 → 0: 100).Concentrating under reduced pressure target fraction, and resistates is dissolved in the methyl alcohol (5mL).Add 1N aqueous sodium hydroxide solution (1mL), and mixture was at room temperature stirred 2 hours.Behind the concentrating under reduced pressure reaction mixture, add entry (30mL), and mixture is extracted with ethyl acetate (40mL * 2).With organic layer through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 0: 100), and by ethyl acetate-hexane recrystallization, obtain title compound (50mg).
1H-NMR(DMSO-d
6)δ：3.40-3.55(4H，m)，3.88(2H，m)，4.68(1H，m)，4.89(2H，m)，7.20-7.24(2H，m)，7.33(1H，d，J＝8.7Hz)，7.47(1H，d，J＝7.5Hz)，7.62(1H，m)，7.77(1H，m)，8.13(1H，s)，8.22(1H，s)，8.44(1H，m)，9.23(1H，br?s)。
Embodiment 198
2-{2-[4-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-6-methyl-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
(i) preparation of 4-phenoxy group-6-third-1-alkynes-1-yl pyrimidines-5-amine
4-iodo-6-phenoxy pyrimidine-5-amine (5.00g) is dissolved in N, in the mixed solvent of dinethylformamide (100mL)/triethylamine (50mL), and add successively 1-(trimethyl silyl)-1-propine (3.3mL), anti--two (triphenylphosphine) palladium chloride (II) (557.7mg), triphenylphosphine (421.1mg), cuprous iodide (I) (303.0mg) and Potassium monofluoride (1.29g).Mixture was being stirred 16 hours under argon gas stream under 60 ℃.Reaction mixture is handled with saturated sodium bicarbonate aqueous solution, and used extracted with diethyl ether.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 50: 50), obtain the title compound (2.64g) of orange solids.
1H-NMR(CDCl
3)δ：2.19(3H，s)，4.36(2H，br?s)，7.07-7.22(2H，m)，7.22-7.34(1H，m)，7.35-7.54(2H，m)，8.08(1H，s)。
The (ii) preparation of 6-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine
4-phenoxy group-6-third-1-alkynes-1-yl pyrimidines-5-amine (776.0mg) is dissolved in the tetrahydrofuran (THF) (30mL), and is cooled to 0 ℃.In this solution, drip the tetrahydrofuran solution (4mL) of 1.0M potassium tert.-butoxide, and mixture was at room temperature stirred 30 minutes.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=67: 33 → 20: 80), obtain the title compound (578.6mg) of white solid.
1H-NMR(CDCl
3)δ：2.54(3H，s)，6.44(1H，q，J＝1.0Hz)，7.21-7.30(3H，m)，7.41-7.48(2H，m)，8.47(1H，s)，8.55(1H，br?s)。
(iii) 2-[2-(6-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethylamino benzonitrile acid esters
With 6-methyl-4-phenoxy group-5H-pyrrolo-[3; 2-d] pyrimidine (299.9mg) and 2-{2-[(methylsulfonyl) the oxygen base] oxyethyl group } ethylamino benzonitrile acid esters (464.1mg) is dissolved in N; in the dinethylformamide (7mL), add salt of wormwood (431mg), and mixture was stirred 21 hours down at 60 ℃.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 20: 80), obtain the title compound (517.8mg) of yellow oil.
1H-NMR(CDCl
3)δ：2.50(3H，s)，3.62-3.74(2H，m)，3.92(2H，t，J＝5Hz)，4.33-4.44(2H，m)，4.57(2H，t，J＝5Hz)，6.36(1H，s)，7.15-7.34(3H，m)，7.34-7.51(4H，m)，7.51-7.65(1H，m)，7.87-8.00(2H，m)，8.40(1H，s)。
(iv) 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-6-methyl-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylamino benzonitrile acid esters
With 2-[2-(6-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (92.3mg), 3-chloro-4-[(3-luorobenzyl) the oxygen base] mixture of aniline (86.3mg), pyridine hydrochloride (81.6mg) and phenol (156.1mg) stirred 3 hours down at 120 ℃, and stirred 5.5 hours down in 140 ℃.In addition, add pyridine hydrochloride (77.6mg) and phenol (188.7mg), and mixture was stirred 22.5 hours down at 140 ℃.Reaction mixture is diluted with methylene dichloride, with the saturated brine washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=50: 50 → 0: 100), obtain purple buttery title compound (33.3mg).
1H-NMR(CDCl
3)δ：2.43(3H，s)，3.88-3.97(2H，m)，4.00(2H，t，J＝4.4Hz)，4.42-4.55(4H，m)，5.04(2H，s)，6.38(1H，s)，6.71(1H，d，J＝8.8Hz)，6.93-7.09(1H，m)，7.13-7.42(6H，m)，7.46-7.58(1H，m)，7.65(1H，d，J＝2.6Hz)，7.74-7.85(2H，m)，8.40(1H，s)，8.48(1H，s)。
(v) 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-6-methyl-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
With 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-6-methyl-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethylamino benzonitrile acid esters (90.0mg) is dissolved in the methyl alcohol (1mL), add 1N aqueous sodium hydroxide solution (0.3mL), and mixture was at room temperature stirred 5 hours.Reaction mixture is neutralized with 1N hydrochloric acid, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=33: 67 → 0: 100), obtain the title compound (43.9mg) of pale yellow powder.
1H-NMR(DMSO-d
6)δ2.45(3H，s)，3.46-3.52(4H，m)，3.82(2H，t，J＝4.7Hz)，4.52(2H，t，J＝4.3Hz)，4.64-4.80(1H，m)，5.23(2H，s)，6.30(1H，s)，7.10-7.24(2H，m)，7.26-7.38(2H，m)，7.41-7.55(2H，m)，7.82(1H，d，J＝2.8Hz)，8.21(1H，s)，8.68(1H，s)。
Embodiment 199
2-{2-[4-(3-chloro-4-[3-(trifluoromethoxy) phenoxy group] and phenyl } amino)-6-methyl-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
(i) 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylamino benzonitrile acid esters
React according to the method (iv) identical with embodiment 198, by using 2-[2-(6-methyl-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (271.0mg), 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] aniline (297.3mg), pyridine hydrochloride (235.0mg) and phenol (497.9mg), obtain rose pink buttery title compound (288.2mg).
1H-NMR(CDCl
3)δ：2.45(3H，s)，3.92-4.00(2H，m)，4.04(2H，t，J＝4.4Hz)，4.45-4.55(4H，m)，6.42(1H，s)，6.75-6.85(3H，m)，6.85-6.96(2H，m)，7.19-7.37(3H，m)，7.45-7.53(1H，m)，7.75-7.82(2H，m)，7.85(1H，d，J＝2.8Hz)，8.46(1H，s)，8.73(1H，br?s)。
(ii) 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-6-methyl-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
According to (v) identical method is reacted with embodiment 198, by using 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethylamino benzonitrile acid esters (281.5mg), 1N aqueous sodium hydroxide solution (0.6mL) and methyl alcohol (2mL), obtain the title compound (119.1mg) of white powder.
1H-NMR(DMSO-d
6)δ2.47(3H，s)，3.44-3.56(4H，m)，3.81-3.89(2H，m)，4.56(2H，t，J＝4.5Hz)，4.71-4.79(1H，m)，6.35(1H，s)，6.88-6.95(2H，m)，7.06-7.14(1H，m)，7.26(1H，d，J＝9Hz)，7.50(1H，t，J＝9Hz)，7.66(1H，dd，J＝9Hz，2.5Hz)，8.01(1H，d，J＝2.5Hz)，8.30(1H，s)，8.99(1H，br?s)。
Embodiment 200
4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5-[2-(2-hydroxyl-oxethyl) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-6-nitrile
(i) preparation of 4-(3,3-diethoxy third-1-alkynes-1-yl)-6-phenoxy pyrimidine-5-amine
React according to the method (iv) identical with embodiment 9, by using 4-iodo-6-phenoxy pyrimidine-5-amine (7.0g), 3,3-diethoxy third-1-alkynes (3.8mL), anti--two (triphenylphosphine) palladium chloride (II) (783.3mg), cuprous iodide (I) (255.2mg) and acetonitrile (160mL)/triethylamine (120mL), obtain brown buttery title compound (6.20g).
1H-NMR(CDCl
3)δ：1.29(6H，t，J＝7.2Hz)，3.62-3.77(2H，m)，3.77-3.91(2H，m)，4.48(2H，br?s)，5.56(1H，s)，7.14-7.21(2H，m)，7.27-7.33(1H，m)，7.39-7.50(2H，m)，8.11(1H，s)。
The (ii) preparation of 6-(diethoxymethyl)-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine
4-(3,3-diethoxy third-1-alkynes-1-yl)-6-phenoxy pyrimidine-5-amine (2.30g) is dissolved in the 1-Methyl-2-Pyrrolidone (7.5mL), and mixture is cooled to 0 ℃.The 1.0M tetrahydrofuran solution (7.6mL) of potassium tert.-butoxide is added drop-wise in this solution, and mixture was stirred 30 minutes down at 0 ℃.And at room temperature stirred 1.5 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 50: 50), obtain greenish orange look solid title compound (1.34g).
1H-NMR(CDCl
3)δ：1.29(6H，t，J＝7.1Hz)，3.52-3.75(4H，m)，5.78(1H，s)，6.66(1H，br?d，J＝2.2Hz)，7.26-7.34(3H，m)，7.42-7.52(2H，m)，8.52(1H，s)，8.95(1H，br?s)。
The (iii) preparation of 4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-formaldehyde
6-(diethoxymethyl)-4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidines (3.15g) are dissolved in the tetrahydrofuran (THF) (40mL), add 1N hydrochloric acid (40mL), and mixture was at room temperature stirred 2 hours.With reaction mixture with in and the 1N aqueous sodium hydroxide solution, and organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure with mixed solvent ethyl acetate/tetrahydrofuran (THF)=1/1. that extracts.Filter collecting precipitation thing and dry, obtain the title compound (2.17g) of yellow powder shape.
1H-NMR(DMSO-d
6)δ：7.25-7.40(3H，m)，7.43-7.58(3H，m)，8.44(1H，s)，10.06(1H，s)，13.26(1H，s)。
The (iv) preparation of 4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-carboxylic acid
4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-formaldehyde (carbaldehyde) (2.17g) is dissolved in the methyl-sulphoxide (21mL), and adds water (14mL) solution of SODIUM PHOSPHATE, MONOBASIC (5.45g).Water (14mL) drips of solution of Textone (2.06g) is added in this solution, and mixture was stirred 2 hours.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture gradually, and use the pH regulator of 1N hydrochloric acid to 2-3 solution.Filter and collect the throw out that generates, water and Di Iso Propyl Ether wash, and dry, obtain the title compound (2.40g) of white powder.
1H-NMR(DMSO-d
6)δ：7.09(1H，s)，7.23-7.36(3H，m)，7.41-7.54(2H，m)，8.36(1H，s)，12.82(1H，s)。
(the v) preparation of 4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-methane amide
Thionyl (two) chlorine (7mL) is joined in 4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-carboxylic acid (465.0mg), and mixture was stirred 2 hours down at 75 ℃.The concentrating under reduced pressure reaction mixture, and be suspended in the tetrahydrofuran (THF) (10mL).Above-mentioned suspension is joined in the ammoniacal liquor (20mL) gradually, and filter the collecting precipitation thing.With the mixed extractant solvent of filtrate with ethyl acetate/tetrahydrofuran (THF)=1/1, with the saturated brine washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Filter the collecting precipitation thing, the throw out of collecting with previous filtration merges, and dry, obtains the title compound (427.4mg) of pale yellow powder.
1H-NMR(DMSO-d
6)δ：7.25(1H，s)，7.27-7.35(3H，m)，7.39-7.57(2H，m)，7.75(1H，s)，8.17(1H，s)，8.36(1H，s)，12.58(1H，s)。
(the vi) preparation of 4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-nitrile
4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-methane amide (1.67g) is suspended in the phosphoryl chloride (20mL), and suspension was stirred 3 hours down at 70 ℃.The concentrating under reduced pressure reaction mixture, and resistates is dissolved in the tetrahydrofuran (THF) (25mL).Water and ammoniacal liquor are joined in this solution, and with the mixed extractant solvent of mixture with ethyl acetate/tetrahydrofuran (THF)=1/1.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 67: 33), obtain the title compound (1.07g) of pale yellow powder.
1H-NMR(CDCl
3)δ：7.29-7.39(3H，m)，7.46-7.55(2H，m)，7.59(1H，s)，8.47(1H，s)，13.76(1H，s)。
(vii) 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-6-cyano group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylamino benzonitrile acid esters
4-phenoxy group-5H-pyrrolo-[3,2-d] pyrimidine-6-nitrile (240.4mg) is dissolved in N, in the dinethylformamide (5mL), and adds the 2-{2-[(methylsulfonyl) the oxygen base] oxyethyl group } ethylamino benzonitrile acid esters (354.1mg) and salt of wormwood (354.8mg).React according to the method (iii) identical,, obtain the title compound (266.5mg) of colorless oil by using the as above mixture of preparation with embodiment 198.
1H-NMR(CDCl3)δ：3.73-3.79(2H，m)，3.96(2H，t，J＝4.9Hz)，4.37-4.43(2H，m)，4.83(2H，t，J＝4.9Hz)，7.17(1H，s)，7.18-7.23(2H，m)，7.27-7.35(1H，m)，7.36-7.49(4H，m)，7.51-7.58(1H，m)，7.85-7.92(2H，m)，8.49(1H，s)。
(viii) 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-6-cyano group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } preparation of ethylamino benzonitrile acid esters
React according to the method (iv) identical with embodiment 198, by using 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-6-cyano group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethylamino benzonitrile acid esters (261.5mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (264.4mg), pyridine hydrochloride (221.6mg) and phenol (461.6mg), obtain the title compound (282.6mg) of yellow oil.
1H-NMR(CDCl
3)δ：3.96-4.06(2H，m)，4.16-4.22(2H，m)，4.45-4.54(2H，m)，4.68-4.79(2H，m)，6.80(1H，d，J＝8.8Hz)，7.01-7.09(1H，m)，7.14-7.20(1H，m)，7.24(1H，s)，7.27-7.53(6H，m)，7.68-7.76(2H，m)，7.92(1H，d，J＝2.5Hz)，8.53(1H，s)，8.95(1H，s)。
(ix) 4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5-[2-(2-hydroxyl-oxethyl) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-6-nitrile
According to (v) identical method is reacted with embodiment 198, by using 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-6-cyano group-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethylamino benzonitrile acid esters (282.6mg), 1N aqueous sodium hydroxide solution (0.6mL) and methyl alcohol (3mL), obtain the title compound (143.2mg) of white powder.
1H-NMR(CDCl
3)δ：1.77(1H，t，J＝4.4Hz)，3.74-3.88(4H，m)，4.08-4.16(2H，m)，4.70-4.80(2H，m)，7.05-7.15(2H，m)，7.16-7.21(1H，m)，7.25(1H，s)，7.30-7.36(1H，m)，7.43(1H，t，J＝7.8Hz)，7.67(1H，dd，J＝8.8Hz，2.8Hz)，7.96(1H，d，J＝2.8Hz)，8.58(1H，s)，9.03(1H，s)。
Embodiment 201
2-{3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propoxy-} preparation of ethylate hydrochlorate
(i) 3-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] preparation of propyl group methanesulfonates
(8.05g) is suspended in N with 60% sodium hydride, in the dinethylformamide (80mL), and suspension is cooled to 0 ℃.Drip propane-1, the N of 3-glycol (7.2mL), dinethylformamide (10mL) solution, and mixture stirred 1 hour down at 0 ℃.With the N of 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (4.0mL), dinethylformamide (10mL) drips of solution is added in this reaction soln, and mixture was stirred 2 hours down at 0 ℃.Saturated aqueous ammonium chloride solution is joined in the reaction mixture, and with mixture ether and ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (100mL), and adds triethylamine (9mL) and methylsulfonyl chloride (2.3mL).Mixture was at room temperature stirred 3 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 20: 80), obtain the title compound (3.78g) of colorless oil.
1H-NMR(CDCl
3)δ：1.45-1.66(4H，m)，1.66-1.92(2H，m)，1.96-2.09(2H，m)，3.02(3H，s)，3.45-3.68(6H，m)，3.81-3.94(2H，m)，4.36(2H，t，J＝6.2Hz)，4.62(1H，dd，J＝4.4Hz，2.7Hz)。
(ii) 4-chloro-5-{3-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] propyl group }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (203.6mg), 3-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] propyl group methanesulfonates (559.3mg) is dissolved in N, in the dinethylformamide (4mL), add cesium carbonate (1.30g), and mixture was stirred 4.5 hours down at 40 ℃.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=67: 33 → 20: 80), obtain the title compound (380.2mg) of colorless oil.
1H-NMR(CDCl
3)δ：1.44-1.70(4H，m)，1.70-1.95(2H，m)，1.95-2.24(2H，m)，3.23-3.43(2H，m)，3.45-3.69(2H，m)，3.78-4.02(2H，m)，4.53-4.75(3H，m)，6.69(1H，d，J＝3.3Hz)，7.66(1H，d，J＝3.3Hz)，8.69(1H，s)。
(iii) 2-{3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propoxy-} preparation of ethylate hydrochlorate
With 4-chloro-5-{3-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) oxyethyl group] propyl group }-5H-pyrrolo-[3,2-d] pyrimidine (380.2mg) is dissolved in the Virahol (7mL), add 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (419.2mg), and mixture stirred 18 hours down at 80 ℃.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=50: 50 → 0: 100), and mixture is dissolved in the ethyl acetate (4mL).(0.3mL) joins in this solution with 4N hydrochloric acid-ethyl acetate, and filters the collecting precipitation thing, and dry, obtains the title compound (398.2mg) of white solid.
1H-NMR(CDCl
3)δ：1.86-2.02(2H，m)，3.22(2H，t，J＝5.8Hz)，3.27-3.40(2H，m)，3.41-3.55(2H，m)，4.53-4.69(2H，m)，6.50(1H，d，J＝3.0Hz)，7.16-7.26(2H，m)，7.30(1H，d，J＝8.9Hz)，7.47(1H，d，J＝7.7Hz)，7.56-7.76(2H，m)，7.97(1H，s)，8.35(1H，s)，8.61(1H，s)。
Embodiment 202
2-[4-({ 3-chloro-4-{3-(trifluoromethyl) phenoxy group } phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] preparation of ethanamide
(i) [4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethyl acetate
React according to the method (iii) identical with embodiment 201, by using (4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl acetate (119.3mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (171.3mg) and Virahol (3mL), obtain orange buttery title compound (221.2mg).
1H-NMR(CDCl
3)δ：1.37(3H，t，J＝7Hz)，4.37(2H，q，J＝7Hz)，4.98(2H，s)，6.66(1H，d，J＝3.3Hz)，7.09(1H，d，J＝8.8Hz)，7.09-7.14(1H，m)，7.17-7.22(1H，m)，7.24(1H，d，J＝3.3Hz)，7.32(1H，d，J＝7.8Hz)，7.42(1H，t，J＝7.8Hz)，7.53(1H，dd，J＝8.8Hz，2.8Hz)，7.83(1H，d，J＝2.8Hz)，8.52-8.63(2H，m)。
(ii) [4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of acetate
Will [4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl acetate (221.2mg) is dissolved in the mixed solvent of tetrahydrofuran (THF) (1.5mL)/ethanol (1.5mL), add 1N aqueous sodium hydroxide solution (0.6mL), and mixture was at room temperature stirred 30 minutes.It is 2-3 that reaction mixture is adjusted to pH with 1N hydrochloric acid, and with the mixed extractant solvent of ethyl acetate/tetrahydrofuran (THF)=1/1.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is filtered collection and dry, obtain the title compound (169.8mg) of yellow powder shape.
1H-NMR(DMSO-d
6)δ：5.62(2H，s)，6.70(1H，d，J＝3.0Hz)，7.22-7.31(2H，m)，7.35(1H，d，J＝8.8Hz)，7.51(1H，d，J＝8Hz)，7.59(1H，dd，J＝8.8Hz，2.5Hz)，7.65(1H，t，J＝8Hz)，7.86(1H，d，J＝2.5Hz)，7.95(1H，d，J＝3.0Hz)，8.70(1H，s)，9.99(1H，s)。
(iii) 2-[4-({ 3-chloro-4-{3-(trifluoromethyl) phenoxy group } phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] preparation of ethanamide
Will [4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] acetate (149.3mg) is dissolved in N; in the dinethylformamide (1.6mL); add 2-(methylsulfonyl) ethamine (60.3mg), 1H-1; 2; 3-benzotriazole-1-alcohol (67.8mg), triethylamine (0.15mL) and N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (93.0mg), and mixture at room temperature stirred 17 hours.In addition; add 2-(methylsulfonyl) ethamine (120.6mg), 1H-1; 2,3-benzotriazole-1-alcohol (134.6mg), triethylamine (0.3mL) and N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (181.4mg), and mixture at room temperature stirred 24 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → 90: 10), and by alkaline silica gel column chromatography processing (elutriant, hexane: ethyl acetate=33: 67 → 0: 100 → ethyl acetate: methyl alcohol=90: 10), obtain the title compound (20.3mg) of white powder.
1H-NMR(DMSO-d
6)δ：2.98(3H，s)，3.27(2H，t，J＝6.9Hz)，3.50-3.61(2H，m)，5.12(2H，s)，6.54(1H，d，J＝3.0Hz)，7.15-7.26(2H，m)，7.33(1H，d，J＝8.8Hz)，7.47(1H，d，J＝8.0Hz)，7.56-7.68(3H，m)，8.04(1H，d，J＝2.5Hz)，8.38(1H，s)，9.07(1H，t，J＝5.8Hz)，9.97(1H，s)。
Embodiment 203
4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of fourth-2-alkynes-1-alcohol
(i) the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } preparation of fourth-2-alkynes-1-alcohol
60% sodium hydride (1.39g) is suspended in the tetrahydrofuran (THF) (50mL), and suspension is cooled to 0 ℃, drip fourth-2-alkynes-1, tetrahydrofuran (THF) (20mL) solution of 4-glycol (3.0g), and mixture at room temperature stirred 1 hour.(5.26g) joins in the reaction mixture with tert-butyldimethylsilyl chloride, and mixture was at room temperature stirred 24 hours.Water is joined in the reaction mixture, and with the mixture extracted with diethyl ether.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=100: 0 → 80: 20), obtain the title compound (1.48g) of colorless oil.
1H-NMR(CDCl
3)δ：0.12(6H，s)，0.91(9H，s)，1.60-1.66(1H，m)，4.27-4.33(2H，m)，4.36(2H，t，J＝1.8Hz)。
The (ii) 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } preparation of fourth-2-alkynes-1-base methanesulfonates
With the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } fourth-2-alkynes-1-alcohol (701.4mg) is dissolved in the ethyl acetate (15mL), and this solution is cooled to 0 ℃.Add triethylamine (1.1mL) and methylsulfonyl chloride (0.3mL), and mixture was stirred 3 hours down at 0 ℃.Water is joined in the reaction mixture, and with the mixture extracted with diethyl ether.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → 50: 50), obtain the title compound (469.7mg) of colorless oil.
1H-NMR(CDCl
3)δ：0.12(6H，s)，0.91(9H，s)，3.12(3H，s)，4.37(2H，t，J＝1.9Hz)，4.89(2H，t，J＝1.9Hz)。
The (iii) preparation of 5-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } fourth-2-alkynes-1-yl)-4-chloro-5H-pyrrolo-[3,2-d] pyrimidine
React according to the method (ii) identical with embodiment 201, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (211.9mg), the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } fourth-2-alkynes-1-base methanesulfonates (464.0mg), cesium carbonate (672.7mg) and N, dinethylformamide (5mL) obtains the title compound (431.1mg) of yellow oil.
1H-NMR(CDCl
3)δ：0.07(6H，s)，0.87(9H，s)，4.35(2H，t，J＝2Hz)，5.33(2H，t，J＝2Hz)，6.76(1H，d，J＝3.3Hz)，7.69(1H，d，J＝3.3Hz)，8.72(1H，s)。
(iv) 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of fourth-2-alkynes-1-alcohol
With 5-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } fourth-2-alkynes-1-yl)-4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (408.3mg) is dissolved in the Virahol (7mL), add 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (421.0mg), and mixture stirred 6 hours down at 80 ℃.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.The oily matter that obtains is dissolved in the tetrahydrofuran (THF) (6mL), adds the tetrahydrofuran solution (2mL) of 1.0M tetrabutylammonium fluoride, and mixture was at room temperature stirred 1 hour.In this reaction mixture, add saturated aqueous ammonium chloride solution, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=67: 33 → 20: 80), and by the hexane/ethyl acetate crystallization, obtain the title compound (425mg) of white crystals.
1H-NMR(CDCl
3)δ：4.07-4.13(1H，m)，4.45-4.52(2H，m)，5.01-5.06(2H，m)，6.44(1H，d，J＝3.3Hz)，7.06-7.16(3H，m)，7.18-7.22(1H，m)，7.33(1H，d，J＝8Hz)，7.43(1H，t，J＝8Hz)，7.57(1H，dd，J＝8.8Hz，2.5Hz)，7.82(1H，s)，7.95(1H，d，J＝2.5Hz)，8.40(1H，s)。
Embodiment 204
(2E)-and 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of but-2-ene-1-alcohol
The toluene solution (0.8mL) of 70% pair of (2-methoxy ethoxy) sodium aluminum hydride is dissolved in the tetrahydrofuran (THF) (4mL), and this solution is cooled to 0 ℃.Drip 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] tetrahydrofuran (THF) (10mL) solution of fourth-2-alkynes-1-alcohol (262.4mg), and mixture stirred 2 hours down at 0 ℃.In reaction mixture, add 10% wet chemical, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=33: 67 → 0: 100), and by the hexane/ethyl acetate crystallization, obtain the title compound (195.9mg) of white crystals.
1H-NMR(DMSO-d
6)δ：3.81-3.92(2H，m)，4.75(1H，t，J＝5.5Hz)，5.17(2H，m)，5.56(1H，br?d，J＝15Hz)，5.80(1H，br?d，J＝15Hz)，6.53(1H，d，J＝3.0Hz)，7.16-7.26(2H，m)，7.30(1H，d，J＝8.8Hz)，7.47(1H，d，J＝7.7Hz)，7.57-7.74(3H，m)，7.98(1H，d，J＝2.2Hz)，8.36(1H，s)，8.48(1H，s)。
Embodiment 205
3-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propane-1, the preparation of 2-glycol
(i) 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) propane-1, the preparation of 2-two basic dibenzoates
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (500mg), 3-N-PROPYLE BROMIDE-1,2-two basic dibenzoates (1.77g), cesium carbonate (1.59g) and N, the mixture of dinethylformamide (6.5mL) stirred 4 hours down at 80 ℃.Reaction mixture is diluted with ethyl acetate (100mL), and water (80mL) washing.Separate organic layer, through dried over mgso, and concentrating under reduced pressure.Resistates by silica gel column chromatography purifying (hexane/ethyl acetate=90/10 → 40/60), is obtained the title compound (401mg) of white powder.
1H-NMR(CDCl3)δ4.58(1H，dd，J＝5Hz，12Hz)，4.73(1H，dd，J＝5Hz，12Hz)，4.84(1H，dd，J＝9Hz，15Hz)，5.11(1H，dd，J＝15Hz，5Hz)，5.84(1H，m)，6.69(1H，d，J＝3Hz)，7.3-7.7(7H，m)，7.91(2H，m)，8.02(2H，m)，8.69(1H，s)。
(ii) 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] propane-1, the preparation of 2-glycol
React according to the method identical with embodiment 183, by using 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) propane-1,2-two basic dibenzoates (250mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (280mg) and 1-Methyl-2-Pyrrolidone (1.14mL), obtain the title compound (180mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.47(2H，m)，3.94(1H，m)，4.50(2H，m)，5.18(1H，br?s)，6.52(2H，d，J＝3Hz)，7.20(2H，m)，7.33(1H，d，J＝9Hz)，7.45(1H，d，J＝8Hz)，7.64(3H，m)，8.04(1H，d，J＝3Hz)，8.35(1H，s)，10.03(1H，br?s)。
Embodiment 206
2-(2-{4-[{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } (methyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (150mg), 3-chloro-N-methyl-4-[3-(trifluoromethyl) phenoxy group] aniline (196mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain title compound (127mg).
1H-NMR(CDCl
3)δ3.38(2H，t，J＝4.5Hz)，3.48(2H，t，J＝4.5Hz)，3.58(3H，s)，3.62(2H，m)，4.00(2H，t，J＝5Hz)，5.08(1H，br?s)，6.64(1H，dd，J＝3Hz，9Hz)，6.70(1H，d，J＝3Hz)，6.72(1H，s)，6.97(2H，m)，7.09(2H，m)，7.40(2H，m)，8.79(1H，s)。
Embodiment 207
N-(2-{4-[{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } (methyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } ethyl)-preparation of 2-(methylsulfonyl) acetamide hydrochloride
With [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (297mg), 3-chloro-N-methyl-4-[3-(trifluoromethyl) phenoxy group] mixture of aniline (453mg) and 1-Methyl-2-Pyrrolidone (1.99mL) stirred 16 hours down at 120 ℃.In this reaction mixture, add 2N hydrochloric acid (1mL), and mixture was stirred 2.5 hours down at 80 ℃.Reaction mixture is diluted with ethyl acetate (80mL), and wash with sodium bicarbonate aqueous solution (30mL).Separate organic layer, through dried over mgso and reduction vaporization.With resistates, 2-(methylsulfonyl) acetate (207mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (429mg), I-hydroxybenzotriazole monohydrate (304mg), triethylamine (0.697mL) and N, dinethylformamide (7.69mL) reacts according to the same procedure of embodiment 155 described in (iv).The compound that obtains is handled with 4N hydrochloric acid/ethyl acetate, obtained the title compound (149mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.02(3H，s)，3.20(2H，s)，3.51(2H，m)，3.71(3H，s)，3.90(2H，s)，6.72(1H，d，J＝3Hz)，7.2-7.4(4H，m)，7.52(1H，d，J＝8Hz)，7.68(2H，m)，7.86(1H，d，J＝2Hz)，8.40(1H，m)，8.94(1H，s)。
Embodiment 208
N-[2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-preparation of 3-hydroxy-3-methyl butyramide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-[3-chloro-4-(3-chlorophenoxy) phenyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg) and 3-hydroxy-3-methyl butyric acid (104mg), obtain crystalline title compound (145mg).
1H-NMR(CDCl
3)δ：1.33(6H，s)，2.49(2H，s)，3.55-3.7(2H，m)，4.4-4.55(2H，m)，6.60(1H，d，J＝3.4Hz)，6.85-7.1(4H，m)，7.1-7.3(2H，m)，7.7-7.8(1H，m)，8.05(1H，d，J＝2.6Hz)，8.52(1H，s)，8.64(1H，s)。
Embodiment 209
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(sec.-propyl alkylsulfonyl) ethanamide
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (300mg) and 4-methylmorpholine (3.0mL) be dissolved in the tetrahydrofuran (THF) (7.0mL), add chloro-acetyl chloride (0.7mL), and mixture was stirred 2 hours down at 0 ℃.In ice-cooled downhill reaction mixture, add saturated sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and resistates is dissolved in N, in the mixed solvent of dinethylformamide (3.5mL) and tetrahydrofuran (THF) (6.0mL).In mixture, add 2-methylpropane-2-sodium mercaptides (180mg), and mixture was at room temperature stirred 1 hour.In this reaction mixture, add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=90: 10), obtain oily matter.React according to the method (ii) identical with embodiment 172, by using oily matter and tetraisopropoxy titanium (0.15mL), methyl alcohol (0.52mL) and the 70% tert-butyl peroxide aqueous solution (12.0mL) that as above obtains, obtain crystalline title compound (165mg).
1H-NMR(DMSO-d
6)δ：1.24(6H，d，J＝6.8Hz)，3.45-3.58(3H，m)，4.03(2H，s)，4.56(2H，m)，6.52(1H，m)，7.20-7.99(8H，m)，8.35(1H，s)，8.72(1H，s)。
Embodiment 210
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-the 2-[(cyclopentyl) alkylsulfonyl] preparation of ethanamide
React according to the method identical with embodiment 209, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (350mg), 4-methylmorpholine (3.50mL), chloro-acetyl chloride (0.9mL), pentamethylene sodium mercaptides (890mg), tetraisopropoxy titanium (0.25mL), methyl alcohol (0.55mL) and the 70% tert-butyl peroxide aqueous solution (15.0mL), obtain crystalline title compound (115mg).
1H-NMR(DMSO-d
6)δ：1.50-1.63(4H，m)，1.89(4H，m)，3.47(2H，m)，3.79(1H，m)，3.99(2H，s)，4.56(2H，m)，6.52(1H，m)，7.20-7.99(8H，m)，8.35(1H，s)，8.72(1H，s)。
Embodiment 211
N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(2,2, the 2-trifluoro ethoxy) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine
React according to the method identical with embodiment 171, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (340mg), salt of wormwood (530mg) and 2-(2,2, the 2-trifluoro ethoxy) ethyl methane sulfonate ester (550mg) obtains crystalline title compound (175mg).
1H-NMR(DMSO-d
6)δ：3.91-4.09(4H，m)，3.73-3.76(2H，m)，6.53(1H，d，J＝3Hz)，7.21-7.92(8H，m)，8.36(1H，s)，8.62(1H，s)。
Embodiment 212
(2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) third-2-alkene-1-yl]-preparation of 4-(dimethylamino) but-2-enamides
(i) N-(4,6-two iodine pyrimidines-5-yl)-2,2, the preparation of 2-three fluoro-N-methylacetamides
With 4,6-two iodine pyrimidines-5-amine (20g) is dissolved in the methylene dichloride (200mL), and drips trifluoroacetic anhydride (47.3mL) and triethylamine (8.04mL) successively.Mixture is at room temperature stirred 1 hour, and the concentrating under reduced pressure reaction mixture.Resistates is dissolved in the methyl alcohol (150mL), and under reduced pressure concentrates once more, obtain colourless solid.The solid that obtains is dissolved in N, in the dinethylformamide (106mL), adds salt of wormwood (15.9g) and methyl iodide (10.8mL), and mixture was at room temperature stirred 16 hours.Reaction mixture is diluted with ether (400mL), and water (400mL) washing.Through dried over mgso, and concentrating under reduced pressure obtains the title compound (25.1g) of colorless solid with organic layer.
1H-NMR(CDCl
3)δ：3.34(2H，s)，3.48(1H，s)，8.44(1H，d，J＝2Hz)。
(ii) N-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-6-iodine pyrimidine-5-yl)-2,2, the preparation of 2-three fluoro-N-methylacetamides
With N-(4,6-two iodine pyrimidines-5-yl)-2,2,2-three fluoro-N-methylacetamides (3g) and 3-(4-amino-2-chlorophenoxy) benzonitrile (1.69g) are dissolved in the 1-Methyl-2-Pyrrolidone (11.4mL), and with mixture in 100 ℃ of following heated and stirred 16 hours.In this reaction mixture, add sodium bicarbonate aqueous solution (80mL), and mixture is extracted with ethyl acetate (100mL * 2).Organic layer is washed with saturated brine (80mL), through dried over mgso, and concentrating under reduced pressure.Resistates is passed through silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=90: 10 → hexane: ethyl acetate=50: 50), and by the Di Iso Propyl Ether crystallization, obtain the title compound (1.67g) of colourless crystallization.
1H-NMR(CDCl
3)δ：3.39(3H，s)，7.1-7.6(6H，m)，7.90(1H，d，J＝3Hz)，8.37(1H，s)。
The (iii) preparation of 3-(2-chloro-4-{[6-iodo-5-(methylamino) pyrimidine-4-yl] amino } phenoxy group) benzonitrile
At room temperature, to N-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-6-iodine pyrimidine-5-yl)-2,2, add sodium borohydride (70mg) in Virahol-tetrahydrofuran (THF) (5.0mL-10mL) solution of 2-three fluoro-N-methylacetamides (1.0g).Mixture was at room temperature stirred 1.5 hours, and add ethyl acetate.With the washing of mixture water and saturated brine, and with organic layer through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=4: 1 → 3: 2), obtain the title compound (755mg) of white amorphous solid.
1H-NMR(CDCl
3)δ：2.72(3H，d，J＝6.3Hz)，2.86-2.98(1H，m)，7.15-7.21(3H，m)，7.31-7.45(2H，m)，7.58(1H，dd，J＝9.0，2.7Hz)，7.73(1H，br?s)，7.99(1H，d，J＝2.7Hz)，8.20(1H，s)。
(iv) { (2E)-5-[6-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5-(methylamino) pyrimidine-4-yl] penta-2-alkene-4-alkynes-1-yl } preparation of t-butyl carbamate
React according to the method (ii) identical with embodiment 81, by use 3-(2-chloro-4-{[6-iodo-5-(methylamino) pyrimidine-4-yl] amino } phenoxy group) benzonitrile (755mg), penta-2-alkene-4-alkynyl t-butyl carbamate (0.43g), two (triphenylphosphine) palladium chloride (II) (55.5mg), cuprous iodide (I) (18mg), acetonitrile (16mL) and triethylamine (12mL), obtain brown powder shape crystalline title compound (366mg).
1H-NMR(CDCl
3)δ：1.47(9H，s)，2.78(3H，d，J＝6.3Hz)，3.15-3.27(1H，m)，3.84-3.95(2H，m)，4.53-4.65(1H，m)，5.84-5.93(1H，m)，6.34-6.43(1H，m)，7.09(1H，d，J＝8.7Hz)，7.10-7.22(2H，m)，7.32-7.44(2H，m)，7.55(1H，br?s)，7.59(1H，dd，J＝8.7，2.7Hz)，7.99(1H，d，J＝2.7Hz)，8.46(1H，s)。
(v) [(2E)-3-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) third-2-alkene-1-yl] preparation of t-butyl carbamate
React according to the method (iii) identical with embodiment 81, by using { (2E)-5-[6-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5-(methylamino) pyrimidine-4-yl] penta-2-alkene-4-alkynes-1-yl } t-butyl carbamate (366mg), cuprous iodide (I) are (13mg) and N, dinethylformamide (4.0mL) obtains faint yellow crystalline title compound (200mg).
1H-NMR(CDCl
3)δ：1.48(9H，s)，3.92-4.03(5H，m)，4.71-4.86(1H，m)，6.31-6.45(1H，m)，6.56(1H，d，J＝15.9Hz)，6.67(1H，s)，6.74(1H，s)，7.06-7.22(3H，m)，7.31-7.46(3H，m)，7.75(1H，d，J＝2.7Hz)，8.49(1H，s)。
(vi) 3-[4-({ 6-[(1E)-3-amino third-1-alkene-1-yl]-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-the 2-chlorophenoxy] preparation of benzonitrile dihydrochloride
React according to the method (iv) identical with embodiment 81, by using [(2E)-3-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) third-2-alkene-1-yl] t-butyl carbamate (190mg), 2N hydrochloric acid (4.5mL) and tetrahydrofuran (THF) (9.0mL), obtain the title compound (170mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：3.75(2H，t，J＝5.3Hz)，4.17(3H，s)，6.62-6.72(1H，m)，6.87(1H，s)，7.13(1H，d，J＝16.5Hz)，7.25-7.34(2H，m)，7.43-7.46(1H，m)，7.55-7.67(3H，m)，7.93(1H，d，J＝2.4Hz)，8.16-8.31(3H，m)，8.64(1H，s)，9.83(1H，br?s)。
(vii) (2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyano-benzene oxygen) phenyl] amino }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl) third-2-alkene-1-yl]-preparation of 4-(dimethylamino) but-2-enamides
React according to the method identical with embodiment 82, by using 3-[4-({ 6-[(1E)-3-amino third-1-alkene-1-yl]-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino)-the 2-chlorophenoxy] benzonitrile dihydrochloride (160mg), (2E)-4-(dimethylamino) but-2-ene acid hydrochloride (182mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (420mg), I-hydroxybenzotriazole monohydrate (340mg), triethylamine (0.80mL) and N, dinethylformamide (5.0mL) obtains faint yellow crystalline title compound (74mg).
1H-NMR(DMSO-d
6)δ：2.15(6H，s)，3.00(2H，dd，J＝6.0，1.2Hz)，3.95-4.08(5H，m)，6.05-6.14(1H，m)，6.42-6.53(1H，m)，6.60(1H，dt，J＝15.6，6.6Hz)，6.72(1H，s)，6.78(1H，d，J＝15.6Hz)，7.20-7.28(2H，m)，7.39-7.43(1H，m)，7.53-7.59(2H，m)，7.60-7.68(1H，m)，7.68-7.92(1H，m)，8.28(1H，s)，8.32(1H，t，J＝5.4Hz)，8.77(1H，s)。
Embodiment 213
(2E)-and N-{[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] methyl }-preparation of 4-(dimethylamino) but-2-enamides
(i) 4, the preparation of 6-two iodo-N-methylpyrimidine-5-amine
Ice-cooled down, to 4, add in tetrahydrofuran (THF) (10mL) solution of 6-two iodine pyrimidines-5-amine (1.0g) sodium hydride (60%, 138mg).Mixture was at room temperature stirred 30 minutes.In reaction system, drip tetrahydrofuran (THF) (4.0mL) solution of methyl mesylate (0.256mL).Mixture was at room temperature stirred 3 hours, and add ethyl acetate.With mixture water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (hexane: ethyl acetate=9: 1 → 3: 1), obtain faint yellow crystalline title compound (600mg).
1H-NMR(CDCl
3)δ：3.02(3H，d，J＝5.7Hz)，3.71-3.83(1H，m)，8.04(1H，s)。
(ii) N4-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-6-iodo-N5-methylpyrimidine-4, the preparation of 5-diamines
React according to the method (ii) identical with embodiment 212, by using 4,6-two iodo-N-methylpyrimidines-5-amine (600mg), 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] aniline (504mg) and 1-Methyl-2-Pyrrolidone (10mL), obtain faint yellow crystalline title compound (552mg).
1H-NMR(DMSO-d
6)δ：2.71(3H，d，J＝5.7Hz)，2.87-2.98(1H，m)，6.76-6.85(2H，m)，6.90-6.96(1H，m)，7.09(1H，d，J＝8.7Hz)，7.29-7.34(1H，m)，7.52-7.56(1H，m)，7.70(1H，br?s)，7.96(1H，d，J＝1.5Hz)，8.19(1H，s)。
(iii) { [4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-and 5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] methyl } preparation of t-butyl carbamate
At room temperature, to N4-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl-6-iodo-N5-methylpyrimidine-4, add in acetonitrile (28mL) solution of 5-diamines (1.53g), Propargyl t-butyl carbamate (0.67g) and triethylamine (1.19mL) two (triphenylphosphine) palladium chlorides (II) (100mg) and cuprous iodide (I) (32.5mg).Under argon atmospher, mixture was at room temperature stirred 4.5 hours, 50 ℃ of heating down, and with mixture stirring 6 hours.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (hexane: ethyl acetate=7: 3 → 3: 7 → alkaline silica gel, hexane: ethyl acetate=1: 1 → ethyl acetate), obtain the title compound (1.05g) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.48(9H，s)，4.04(3H，s)，4.52(2H，d，J＝6.0Hz)，4.83-4.95(1H，m)，6.49(1H，s)，6.76-6.96(4H，m)，7.08(1H，d，J＝8.7Hz)，7.31(1H，t，J＝8.3Hz)，7.43(1H，dd，J＝8.3Hz)，7.78(1H，d，J＝2.4Hz)，8.48(1H，s)。
(iv) 6-(amino methyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-preparation of 5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
React according to the method (iv) identical with embodiment 81, by using { [4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] methyl } t-butyl carbamate (1.05g), 2N hydrochloric acid (20mL) and tetrahydrofuran (THF) (40mL), obtain faint yellow crystalline title compound (1.01g).
1H-NMR(DMSO-d
6)δ：4.18(3H，s)，4,39-4.48(2H，m)，6.89(1H，s)，6.94-6.99(2H，m)，7.15(1H，d，J＝9.0Hz)，7.35(1H，d，J＝8.7Hz)，7.50-7.56(1H，m)，7.67(1H，dd，J＝9.0，2.4Hz)，7.94(1H，d，J＝2.4Hz)，8.72(1H，s)，8.77-8.92(3H，m)，10.04(1H，br?s)。
(v) (2E)-N-{[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-yl] methyl }-preparation of 4-(dimethylamino) but-2-enamides
React according to the method identical with embodiment 82, by using 6-(amino methyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5-methyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), (2E)-4-(dimethylamino) but-2-ene acid hydrochloride (124mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (214mg), I-hydroxybenzotriazole monohydrate (171mg), triethylamine (0.52mL) and N, dinethylformamide (5.0mL) obtains the title compound (105mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：2.14(6H，s)，3.00(2H，d，J＝6.3Hz)，4.00(3H，s)，4.58(2H，d，J＝5.4Hz)，6.11(1H，d，J＝15.3Hz)，6.39(1H，s)，6.58-6.68(1H，m)，6.87-6.95(2H，m)，7.04-7.11(1H，m)，7.25(1H，d，J＝8.7Hz)，7.45-7.51(1H，m)，7.60-7.68(1H，m)，7.91(1H，d，J＝2.7Hz)，8.28(1H，s)，8.54-8.61(1H，m)，8.71(1H，s)。
Embodiment 214
N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl-2, the preparation of 2-dimethyl propylene amide hydrochloride
With 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), 3-hydroxyl-2, the N of 2-neopentanoic acid (68mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (166mg), I-hydroxybenzotriazole monohydrate (132mg) and triethylamine (0.40mL), dinethylformamide (5.0mL) solution at room temperature stirred 20 hours.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → methyl alcohol: ethyl acetate=15: 85).Behind concentrating under reduced pressure, add ethyl acetate (2.0mL) and 4N hydrochloric acid/ethyl acetate (0.5mL), and mixture was at room temperature stirred 15 hours.Behind the concentrating under reduced pressure, filter the crystallization of collecting precipitation.At room temperature, in the solution of crystallization in ethanol (2.0mL) of collecting, add the 1N aqueous sodium hydroxide solution, and mixture was stirred 2 days.The concentrating under reduced pressure mixture, and with the ethyl acetate solution water of resistates and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, 4N hydrochloric acid/ethyl acetate (0.5mL) is joined in ethyl acetate (1.0mL) solution of resistates.Behind the concentrating under reduced pressure, filter the crystallization of collecting precipitation.Crystallization is washed with Di Iso Propyl Ether, obtain the title compound (119mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：0.96(6H，s)，3.23-3.52(4H，m)，4.56-4.68(2H，m)，6.64(1H，d，J＝3.0Hz)，7.23-7.30(2H，m)，7.38(1H，d，J＝8.4Hz)，7.52(1H，d，J＝8.1Hz)，7.61-7.69(1H，m)，7.72-7.80(1H，m)，7.85-7.92(2H，m)，8.00-8.03(1H，m)，8.70(1H，s)，9.95-10.06(1H，m)。
Embodiment 215
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) propionic acid amide
At room temperature, to 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-add 2-chlorpromazine chloride (54 μ L) in the mixture of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), triethylamine (0.39mL) and tetrahydrofuran (THF) (5.0mL).Mixture was at room temperature stirred 3 days, add entry, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, methane-sulfinic acid sodium (85mg) and pyridine (67 μ L) are joined the N of resistates, in dinethylformamide (5.0mL) solution, and mixture stirred 2 days down at 70 ℃.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate → ethyl acetate: methyl alcohol=9: 1), and by ethyl acetate-Di Iso Propyl Ether recrystallization, obtain the title compound (114mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.71(3H，d，J＝7.2Hz)，2.98(3H，s)，3.63-3.75(2H，m)，3.81(1H，q，J＝7.2Hz)，4.44-4.55(2H，m)，6.64(1H，d，J＝3.0Hz)，7.09(1H，d，J＝8.7Hz)，7.11-7.18(2H，m)，7.19-7.25(2H，m)，7.30-7.36(1H，m)，7.40-7.47(1H，m)，7.85(1H，dd，J＝8.7，2.7Hz)，8.01(1H，d，J＝2.7Hz)，8.30(1H，s)，8.54(1H，s)。
Embodiment 216
N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3,3, the preparation of 3-three fluoro-2-hydroxy-2-methyl propionic acid amides
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), 2-hydroxyl-2-(trifluoromethyl) propionic acid (88.2mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (160mg), I-hydroxybenzotriazole monohydrate (128mg), triethylamine (0.39mL) and N, dinethylformamide (5.0mL) obtains the title compound (128mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.68(3H，s)，3.65-3.77(2H，m)，3.80-3.89(1H，m)，4.43-4.57(2H，m)，6.63(1H，d，J＝3.0Hz)，7.08(1H，d，J＝8.7Hz)，7.11-7.16(1H，m)，7.19-7.28(3H，m)，7.30-7.36(1H，m)，7.40-7.43(1H，m)，7.79(1H，dd，J＝8.7，2.4Hz)，8.08(1H，d，J＝2.4Hz)，8.31(1H，s)，8.53(1H，s)。
Embodiment 217
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide 4-toluenesulfonate
At room temperature; to N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-add 4-toluene sulfonic acide monohydrate (55.4mg) in ethyl acetate (10mL) solution of 2-(methylsulfonyl) ethanamide (150mg).Mixture is at room temperature stirred 20 hours, and solvent evaporated under reduced pressure.Filter the crystallization of collecting precipitation, and wash, obtain the title compound (150.3mg) of colourless crystallization with ethyl acetate and Di Iso Propyl Ether.
1H-NMR(DMSO-d
6)δ：2.29(3H，s)，3.07(3H，s)，3.44-3.60(2H，m)，4.06(2H，s)，4.61-4.70(2H，m)，6.66(1H，d，J＝3.0Hz)，7.11(2H，d，J＝8.4Hz)，7.22-7.28(2H，m)，7.38(1H，d，J＝8.7Hz)，7.47(2H，d，J＝8.4Hz)，7.50-7.55(1H，m)，7.62-7.72(2H，m)，7.89-7.96(2H，m)，8.65-8.74(2H，m)，9.70-9.80(1H，m)。
Embodiment 218
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) acetamide hydrochloride
According to embodiment 217 in identical method react; by using N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide (150mg), 4N hydrochloric acid/ethyl acetate (0.13mL) and ethyl acetate (10mL), obtain the title compound (147mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：3.06(3H，s)，3.35-3.59(2H，m)，4.07(2H，s)，4.63-4.74(2H，m)，6.67(1H，d，J＝3.0Hz)，7.25-7.30(2H，m)，7.38(1H，d，J＝8.7Hz)，7.51-7.54(1H，m)，7.62-7.72(2H，m)，7.92-7.99(2H，m)，8.70-8.79(2H，m)，9.78-9.89(1H，m)。
Embodiment 219
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide mesylate
According to embodiment 217 in identical method react; by using N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide (1.0g), methylsulfonic acid (0.126mL) and ethyl acetate (50mL), obtain the title compound (1.14g) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：2.30(3H，s)，3.06(3H，s)，3.47-3.61(2H，m)，4.06(2H，s)，4.63-4.72(2H，m)，6.67(1H，d，J＝3.3Hz)，7.23-7.29(2H，m)，7.37-7.40(2H，m)，7.63-7.73(2H，m)，7.91-7.98(2H，m)，8.68-8.78(2H，m)，9.80(1H，brs)。
Embodiment 220
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-the 1-methylethyl }-preparation of 2-(methylsulfonyl) ethanamide
(i) preparation of [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)-1-methylethyl] t-butyl carbamate
At room temperature, in tetrahydrofuran (THF) (50mL) solution of 2-aminopropane-1-alcohol (1.0g), add tert-Butyl dicarbonate (3.1mL).Mixture is at room temperature stirred 3 days, and concentrating under reduced pressure.In tetrahydrofuran (THF) (30mL) solution of resistates and triethylamine (3.7mL), add methylsulfonyl chloride (1.54mL) down ice-cooled, and mixture was stirred 30 minutes.In reaction system, add sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, and through dried over mgso.Behind the concentrating under reduced pressure, with 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (1.02g), cesium carbonate (6.49g) and N, dinethylformamide (10mL) joins in the resistates, and mixture was stirred 3 days down at 40 ℃.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Behind the concentrating under reduced pressure, separate resistates, and by silica gel column chromatography purifying (hexane: ethyl acetate=3: 1 → 2: 3), obtain the title compound (1.16g) of faint yellow oily thing.
1H-NMR(CDCl
3)δ：0.93-1.35(12H，m)，4.02-4.18(1.5H，m)，4.39-4.53(1.5H，m)，4.57-4.70(1H，m)，6.74(1H，d，J＝3.0Hz)，7.50(1H，d，J＝3.0Hz)，8.71(1H，s)。
(ii) 5-(2-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
With [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl)-1-methylethyl] t-butyl carbamate (350mg) and 3-chloro-4-[3-(trifluoromethyl) phenoxy group] 1-Methyl-2-Pyrrolidone (3.5mL) solution of aniline (423mg) stirred 4 hours down at 120 ℃.After being cooled to room temperature, add triethylamine (0.24mL) and tert-Butyl dicarbonate (0.13mL), and mixture was stirred 20 hours.Water is joined in the reaction system, and with the mixture ethyl acetate extraction.With organic layer water and saturated brine washing, and through dried over mgso.Separate resistates, and by silica gel column chromatography purifying (hexane: ethyl acetate=19: 1 → 3: 2 → ethyl acetate), obtain brown solid.At room temperature, in solid tetrahydrofuran (THF) (20mL) solution that obtains, add 2N hydrochloric acid (10mL), and mixture was stirred 20 hours down at 60 ℃.Behind the concentrating under reduced pressure, add ethanol, and mixture is further concentrated.In resistates, add Di Iso Propyl Ether, and filter the crystallization of collecting precipitation.This crystallization is washed with Di Iso Propyl Ether, obtain faint yellow crystalline title compound (225mg).
1H-NMR(DMSO-d
6)δ：1.17(3H，d，J＝6.6Hz)，3.35-3.77(1H，m)，4.75-4.89(1H，m)，4.98-5.09(1H，m)，6.75(1H，d，J＝2.7Hz)，7.23-7.30(2H，m)，7.37(1H，d，J＝8.7Hz)，7.52-7.54(1H，m)，7.64-7.69(2H，m)，7.89-7.97(1H，m)，8.04-8.10(1H，m)，8.24-8.43(3H，m)，8.74(1H，s)，10.04(1H，br?s)。
(iii) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-the 1-methylethyl }-preparation of 2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using 5-(2-aminopropyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (150mg), 2-(methylsulfonyl) acetate (77mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (160mg), I-hydroxybenzotriazole monohydrate (128mg), triethylamine (0.39mL) and N; dinethylformamide (5.0mL) obtains the title compound (34mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.28(3H，d，J＝6.6Hz)，3.14(3H，s)，3.71-3.80(1H，m)，4.00(2H，s)，4.12-4.26(1H，m)，4.98-5.04(1H，m)，6.62(1H，d，J＝3.3Hz)，6.82-6.88(1H，m)，7.07(1H，d，J＝8.7Hz)，7.12-7.24(3H，m)，7.30-7.35(1H，m)，7.41-7.49(1H，m)，7.79(1H，dd，J＝8.7，2.7Hz)，7.95(1H，d，J＝2.7Hz)，8.52(1H，s)，8.54(1H，br?s)。
Embodiment 221
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-hydroxy-3-methyl butyramide mesylate
At room temperature, to N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-add methylsulfonic acid (26 μ L) in ethyl acetate (10mL) solution of 3-hydroxy-3-methyl butyramide (200mg).Mixture is at room temperature stirred 1 hour, and concentrating under reduced pressure.In resistates, add ethanol and ethyl acetate, and filter the crystallization of collecting precipitation, obtain the title compound (223mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ：1.12(6H，s)，2.21(2H，s)，2.29(3H，s)，3.41-3.54(2H，m)，4.56-4.68(2H，m)，6.66(1H，d，J＝3.3Hz)，7.26-7.28(2H，m)，7.37(1H，d，J＝9.0Hz)，7.51-7.54(1H，m)，7.61-7.75(2H，m)，7.95-8.03(2H，m)，8.31-8.40(1H，m)，8.72(1H，s)，10.11-10.19(1H，m)。
Embodiment 222
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-ethyl-2-(methylsulfonyl) ethanamide
(i) preparation of [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] ethyl carbamic acid tert-butyl ester
React according to the method identical with embodiment 163 (i), by using 2-(ethylamino) ethanol (1.00g), tert-Butyl dicarbonate (2.58mL), tetrahydrofuran (THF) (100mL), methylsulfonyl chloride (1.30mL), triethylamine (3.12mL), tetrahydrofuran (THF) (50mL), 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (0.86g), cesium carbonate (7.5g) and N, dinethylformamide (20mL) obtains the title compound (630mg) of faint yellow oily thing.
1H-NMR(CDCl
3)δ：0.84-1.48(12H，m)，2.80-2.93(1H，m)，3.07-3.22(1H，m)，3.51-3.67(2H，m)，4.52-4.72(2H，m)，6.73(1H，d，J＝3.3Hz)，7.29-7.47(1H，m)，8.71(1H，s)。
The (ii) preparation of { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } ethyl carbamic acid tert-butyl ester
React according to the method (ii) identical with embodiment 155, by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] the ethyl carbamic acid tert-butyl ester (630mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (725mg) and Virahol (6.0mL), obtain the title compound (950mg) of colorless solid.
1H-NMR(CDCl
3)δ：1.18(3H，t，J＝7.2Hz)，1.52(9H，s)，3.35(2H，q，J＝7.2Hz)，3.49-3.58(2H，m)，4.41-4.51(2H，m)，6.60(1H，d，J＝3.0Hz)，7.07(1H，d，J＝9.0Hz)，7.09-7.15(1H，m)，7.18-7.22(2H，m)，7.29-7.33(1H，m)，7.39-7.45(1H，m)，7.93(1H，d，J＝9.0，2.4Hz)，8.04(1H，d，J＝2.4Hz)，8.51(1H，s)，8.92(1H，br?s)。
(iii) N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(ethylamino) ethyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
React according to the method (iii) identical with embodiment 155, by using { 2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } the ethyl carbamic acid tert-butyl ester (950mg), 2N hydrochloric acid (5.0mL) and tetrahydrofuran (THF) (10mL), obtain faint yellow crystalline title compound (861mg).
1H-NMR(DMSO-d
6)δ：1.18(3H，t，J＝7.5Hz)，2.89-3.02(2H，m)，3.33-3.47(2H，m)，5.03-5.12(2H，m)，6.72-6.77(1H，m)，7.22-7.29(2H，m)，7.37(1H，d，J＝9.0Hz)，7.51-7.54(1H，m)，7.61-7.71(2H，m)，7.91-7.98(1H，m)，8.04-8.10(1H，m)，8.72(1H，s)，9.05-9.21(2H，m)，9.95-10.05(1H，m)。
(iv) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-ethyl-2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(ethylamino) ethyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (150mg), 2-(methylsulfonyl) acetate (76mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (158mg), I-hydroxybenzotriazole monohydrate (126mg), triethylamine (0.38mL) and N; dinethylformamide (5.0mL) obtains the title compound (94mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.36(3H，t，J＝7.2Hz)，3.20(3H，s)，3.61(2H，q，J＝7.2Hz)，3.71-3.80(2H，m)，4.15(2H，s)，4.45-4.53(2H，m)，6.64(1H，d，J＝3.3Hz)，7.08(1H，d，J＝8.7Hz)，7.10-7.17(1H，m)，7.19-7.23(2H，m)，7.30-7.35(1H，m)，7.40-7.46(1H，m)，7.89(1H，dd，J＝8.7，2.7Hz)，7.96(1H，d，J＝2.7Hz)，8.53(1H，s)，8.60(1H，s)。
Embodiment 223
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N-ethyl-3-hydroxy-3-methyl butyramide
React according to the method (iv) identical with embodiment 155, by using N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5-[2-(ethylamino) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), 3-hydroxy-3-methyl butyric acid (64.6mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (157mg), I-hydroxybenzotriazole monohydrate (125mg), triethylamine (0.38mL) and N, dinethylformamide (5.0mL) obtains the title compound (106mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：1.29(3H，t，J＝7.2Hz)，1.34(6H，s)，2.56(2H，s)，3.47(2H，q，J＝7.2Hz)，3.65-3.75(2H，m)，4.42-4.52(3H，m)，6.62(1H，d，J＝3.0Hz)，7.08(1H，d，J＝8.7Hz)，7.10-7.15(1H，m)，7.20(1H，d，J＝3.0Hz)，7.24-7.33(2H，m)，7.39-7.46(1H，m)，7.72(1H，dd，J＝8.7，2.4Hz)，8.03(1H，d，J＝2.4Hz)，8.50(1H，s)，8.81(1H，s)。
Embodiment 224
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(dimethylamino) ethanamide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), N, N-N-methylsarcosine (59.4mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (166mg), I-hydroxybenzotriazole monohydrate (132mg), triethylamine (0.40mL) and N, dinethylformamide (5.0mL) obtains the title compound (84mg) of colourless crystallization.
1H-NMR(CDCl
3)δ：2.29(6H，s)，3.05(2H，s)，3.58-3.70(2H，m)，4.45-4.54(2H，m)，6.63(1H，d，J＝3.0Hz)，7.08(1H，d，J＝9.0Hz)，7.10-7.15(1H，m)，7.20(1H，d，J＝3.0Hz)，7.23-7.34(2H，m)，7.36-7.45(1H，m)，7.70-7.79(2H，m)，8.10(1H，d，J＝2.7Hz)，8.52(1H，s)，8.63(1H，s)。
Embodiment 225
N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-the 2-methyl isophthalic acid, the preparation of 3-oxazole-4-methane amide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (210mg), 2-methyl isophthalic acid, 3-oxazole-4-carboxylic acid (210mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (560mg), I-hydroxybenzotriazole monohydrate (100mg), triethylamine (2.0mL) and tetrahydrofuran (THF) (10mL) obtain the title compound (112.1mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ2.41(3H，s)，3.56(2H，m)，4.67(2H，m)，6.53(1H，d，J＝3Hz)，7.21-7.91(8H，m)，8.30(1H，s)，8.42(2H，m)，8.87(1H，br?s)。
Embodiment 226
N-(2-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-2,2, the preparation of 2-Halothane sulphonamide
(i) preparation of 2-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-1H-isoindole-1,3 (2H)-diketone
React according to the method identical with embodiment 172 (i), by using 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol (4.00g), tetrahydrofuran (THF) (25mL), triethylamine (13.0mL), methylsulfonyl chloride (7.25mL), Phthalimide potassium (4.51g), tetrahydrofuran (THF) (60mL) and N, dinethylformamide (50mL) obtains title compound (5.20g).
1H-NMR(DMSO-d
6)δ3.69(4H，s)，3.83(2H，m)，4.61(2H，m)，6.33(1H，m)，7.13-7.23(3H，m)，7.42-7.95(9H，m)，8.24(1H，s)，8.75(1H，s)。
(ii) N-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-2,2, the preparation of 2-Halothane sulphonamide
With 2-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-1H-isoindole-1,3 (2H)-diketone (100mg) are dissolved in the ethanol (2.0mL), add hydrazine monohydrate (0.45mL), and mixture was stirred 1 hour.In this reaction mixture, add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=95: 5).The oily matter that obtains is dissolved in the tetrahydrofuran (THF) (5.0mL).Add N-methylmorpholine (2.0mL), drip 2,2 down ice-cooled, 2-trifluoro ethyl sulfonyl chloride (0.10mL), and with mixture stirring 1 hour.Add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=80: 20).By ether/ethyl acetate crystallization, obtain crystalline title compound (36.0mg).
1H-NMR(DMSO-d
6)δ3.10(2H，m)，3.47(2H，m)，3.79(2H，m)，4.30(2H，m)，4.68(2H，m)，6.52(1H，m)，7.20-8.02(9H，m)，8.35(1H，s)，8.79(1H，s)。
Embodiment 227
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (270mg), acetate (0.20mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (500mg), I-hydroxybenzotriazole monohydrate (100mg), triethylamine (2.0mL) and tetrahydrofuran (THF) (10mL), obtain the title compound (62.1mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ1.79(3H，s)，3.37(2H，m)，4.51(2H，m)，6.51(1H，d，J＝3Hz)，7.20-7.81(7H，m)，8.06(1H，m)，8.26(1H，m)，8.34(1H，s)，8.81(1H，s)。
Embodiment 228
The preparation of N-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-2-(methylsulfonyl) acetamide hydrochloride
With 2-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-1H-isoindole-1,3 (2H)-diketone (600mg) are dissolved in the ethanol (30mL), add hydrazine monohydrate (8.0mL), and mixture was stirred 1 hour.In this reaction mixture, add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=95: 5).React according to the method (iv) identical with embodiment 155; by using oily matter, 2-(methylsulfonyl) acetate (500mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.50g), I-hydroxybenzotriazole monohydrate (200mg), triethylamine (2.0mL) and the tetrahydrofuran (THF) (20mL) that obtains, obtain the title compound (312mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.06(3H，s)，3.16-3.47(4H，m)，3.81(2H，m)，3.98(2H，s)，4.86(2H，s)，6.70(1H，m)，7.25-7.68(6H，m)，7.97-8.01(2H，m)，8.44(1H，m)，8.75(1H，s)，9.90(1H，s)。
Embodiment 229
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 1H-pyrazole-3-formamide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (250mg), 1H-pyrazoles-3-carboxylic acid (210mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (500mg), I-hydroxybenzotriazole monohydrate (100mg), triethylamine (2.0mL) and tetrahydrofuran (THF) (15mL), obtain the title compound (67.0mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.58(2H，m)，4.64(2H，m)，6.49(1H，m)，6.57(1H，s)，7.21-7.79(8H，m)，8.01(1H，s)，8.33(1H，s)，8.49(1H，m)，8.77(1H，s)，13.25(1H，s)。
Embodiment 230
(2R)-N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2, the preparation of 3-dihydroxyl propionic acid amide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (350mg), (2R)-2,3-dihydroxypropionic acid (400mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.70g), I-hydroxybenzotriazole monohydrate (1.0g), triethylamine (2.0mL) and tetrahydrofuran (THF) (10mL) obtain the title compound (197.3mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.33-3.58(4H，m)，3.87(1H，m)，4.53(2H，m)，4.69(1H，m)，5.62(1H，d，J＝5Hz)，6.48(1H，d，J＝3Hz)，7.20-7.81(7H，m)，8.05(1H，d，J＝2Hz)，8.14(1H，m)，8.34(1H，s)，8.77(1H，s)。
Embodiment 231
The preparation of N-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl) Toluidrin
React according to the method (ii) identical with embodiment 226, by using 2-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-1H-isoindole-1,3 (2H)-diketone (200mg), hydrazine monohydrate (1.50mL), methylsulfonyl chloride (0.70mL), N-methylmorpholine (1.20mL), ethanol (7.0mL) and tetrahydrofuran (THF) (10mL) obtain the title compound (18.2mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ2.78(3H，s)，3.04(2H，m)，3.48(2H，m)，3.79(2H，m)，4.68(2H，m)，6.52(1H，d，J＝3Hz)，7.03-7.70(8H，m)，8.02(1H，s)，8.35(1H，s)，8.81(1H，s)。
Embodiment 232
The preparation of N-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl) ethanamide
With 2-(2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethyl)-1H-isoindole-1,3 (2H)-diketone (200mg) are dissolved in the ethanol (5.0mL), add hydrazine monohydrate (3.0mL), and mixture was stirred 1 hour.In this reaction mixture, add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture ethyl acetate extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=95: 5).React according to the method identical,, obtain the title compound (146.0mg) of colourless crystallization by using oily matter, diacetyl oxide (1.0mL), N-methylmorpholine (1.0mL) and the tetrahydrofuran (THF) (5.0mL) that obtains with embodiment 180.
1H-NMR(DMSO-d
6)δ1.69(3H，s)，3.12(2H，m)，3.44(2H，m)，3.79(2H，m)，4.66(2H，m)，6.52(1H，d，J＝3Hz)，7.20-7.78(8H，m)，8.00(1H，s)，8.36(1H，s)，8.85(1H，s)。
Embodiment 233
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N2-(methylsulfonyl) G-NH2
Use 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (450mg), N-(tert-butoxycarbonyl) glycine (500mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (960mg), I-hydroxybenzotriazole monohydrate (300mg), triethylamine (4.0mL) and tetrahydrofuran (THF) (25mL), this reaction is carried out according to the same procedure of embodiment 155 described in (iv).The compound that obtains is dissolved in the methyl alcohol (5.0mL), adds 4N hydrochloric acid/ethyl acetate (8mL), and mixture was stirred 5 hours.Add 8N aqueous sodium hydroxide solution (8mL) and water (10mL), and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and resistates is dissolved in the tetrahydrofuran (THF) (5.0mL).Add N-methylmorpholine (1.0mL), drip methylsulfonyl chloride (0.70mL) down ice-cooled, and mixture was stirred 1 hour.Add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and the separation resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=80: 20), and, obtain crystalline title compound (47.9mg) by ether/ethyl acetate crystallization.
1H-NMR(DMSO-d
6)δ2.89(3H，s)，3.46(2H，m)，3.58(2H，m)，4.54(2H，m)，6.51(1H，d，J＝3Hz)，7.20-7.78(8H，m)，8.02(1H，s)，8.27(1H，m)，8.36(1H，s)，8.77(1H，s)。
Embodiment 234
4-(2-chloro-4-{[5-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) preparation of piperidines-1-carboxyl tert-butyl ester
(i) N-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-preparation of 2-(methylsulfonyl) ethanamide
[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (300mg) is dissolved in the trifluoroacetic acid (5.0mL), and mixture was stirred 15 minutes.Add toluene (5mL), evaporating solvent, and separate resistates, and by alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=75: 25).React according to the method (iv) identical with embodiment 155; by oily matter, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.50g), triethylamine (2.0mL), 2-(methylsulfonyl) acetate (180mg) and the tetrahydrofuran (THF) (10mL) that use obtains, obtain the title compound (64.0mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.07(3H，s)，3.57(2H，m)，4.00(2H，s)，4.57(2H，m)，6.74(1H，d，J＝3Hz)，7.92(1H，d，J＝3Hz)，8.49(1H，m)，8.63(1H，s)。
(ii) 4-(2-chloro-4-{[5-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) preparation of piperidines-1-carboxyl tert-butyl ester
React according to the method (ii) identical with embodiment 155; by using N-[2-(4-chloro-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide (60.0mg) and 4-(4-amino-2-chlorophenoxy) piperidines-1-carboxyl tert-butyl ester (160mg), obtain the title compound (24.0mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ1.41(9H，s)，1.50-1.70(2H，m)，1.81-1.95(2H，m)，3.10(3H，s)，3.22-3.60(6H，m)，4.04(2H，s)，4.45-4.65(3H，m)，6.47(1H，d，J＝3Hz)，7.23(1H，d，J＝9Hz)，7.55-7.58(2H，m)，7.75(1H，d，J＝3Hz)，8.27(1H，s)，8.48(1H，s)，8.66(1H，m)。
Embodiment 235
3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] preparation of propionamide hydrochloride
(i) preparation of 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl propionate
4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (303mg) are dissolved in N, in the dinethylformamide (9mL), add ethyl propenoate (0.3mL) and salt of wormwood (538mg) successively, and mixture was at room temperature stirred 7.5 hours.Add ethyl propenoate (0.2mL), and mixture was stirred 16 hours.Further add ethyl propenoate (0.3mL) and salt of wormwood (526mg), and mixture was stirred 6 hours.Reaction mixture is handled with saturated aqueous ammonium chloride solution, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=66: 34 → 20: 80), obtain the title compound (404mg) of colorless oil.
1H-NMR(CDCl
3)δ：1.22(3H，t，J＝7.1Hz)，2.92(2H，t，J＝6.3Hz)，4.13(2H，q，J＝7.1Hz)，4.80(2H，t，J＝6.3Hz)，6.70(1H，d，J＝3.3Hz)，7.61(1H，d，J＝3.3Hz)，8.71(1H，s)。
(ii) 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethyl propionate
React according to the method (iii) identical with embodiment 201, by using 3-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl propionate (404mg), Virahol (10mL) and 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (555mg), obtain the title compound (687mg) of faint yellow oily thing.
1H-NMR(CDCl
3)δ：1.26(3H，t，J＝7Hz)，2.99-3.10(2H，m)，4.24(2H，q，J＝7Hz)，4.53-4.65(2H，m)，6.69(1H，d，J＝3.3Hz)，7.06-7.17(2H，m)，7.18-7.24(1H，m)，7.27-7.35(2H，m)，7.43(1H，t，J＝7.9Hz)，7.65(1H，dd，J＝8.8Hz，2.6Hz)，7.92(1H，d，J＝2.6Hz)，8.54(1H，s)，9.14(1H，s)。
(iii) 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of propionic acid
React according to the method (ii) identical with embodiment 202, by using 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] mixed solvent of ethyl propionate (683mg), 1N aqueous sodium hydroxide solution (2mL) and tetrahydrofuran (THF) (6mL)/ethanol (6mL), obtain the title compound (595mg) of pale yellow powder.
1H-NMR(DMSO-d
6)δ：2.84(2H，t，J＝6.4Hz)，4.69(2H，t，J＝6.4Hz)，6.52(1H，d，J＝3.0Hz)，7.14-7.29(2H，m)，7.32(1H，d，J＝8.9Hz)，7.47(1H，d，J＝7.7Hz)，7.56-7.80(3H，m)，7.94(1H，s)，8.35(1H，s)，9.10(1H，s)，12.72(1H，s)。
(iv) 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] preparation of propionamide hydrochloride
React according to the method (iii) identical with embodiment 202; by using 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] propionic acid (199mg); 2-(methylsulfonyl) ethamine (106mg); I-hydroxybenzotriazole monohydrate (84.7mg); N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (128.6mg); triethylamine (0.1mL) and N; dinethylformamide (2mL); obtain 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] propionic acid amide (140mg).With the 3-[4-that obtains ({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] propionic acid amide is dissolved in the ethyl acetate (2mL); add 4N hydrochloric acid-ethyl acetate (0.1mL); and filter collecting precipitation thing and dry, obtain the title compound (119mg) of white powder.
1H-NMR(DMSO-d
6)δ：2.82-2.90(2H，m)，2.91(3H，s)，3.18(2H，t，J＝6.6Hz)，3.40-3.51(2H，m)，4.72-4.83(2H，m)，6.70(1H，d，J＝3.0Hz)，7.23-7.32(2H，m)，7.41(1H，d，J＝8.8Hz)，7.52(1H，d，J＝7.7Hz)，7.66(1H，t，J＝7.7Hz)，7.74(1H，dd，J＝8.8Hz，2.5Hz)，8.01-8.08(2H，m)，8.67(1H，t，J＝5.6Hz)，8.76(1H，s)，10.80(1H，s)。
Embodiment 236
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-hydroxyl propionamide hydrochloride
React according to the method (iii) identical with embodiment 202, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (303mg), 3.6M the 3-hydroxy-propionic acid aqueous solution (0.25mL), I-hydroxybenzotriazole monohydrate (231mg), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (322mg), triethylamine (0.8mL) and N, dinethylformamide (3mL), obtain N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl propionic acid amide.With the N-{2-[4-that obtains ({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl propionic acid amide is dissolved in the ethyl acetate (2mL), add 4N hydrochloric acid-ethyl acetate (0.1mL), and with the product that obtains by the ethyl acetate crystallization, obtain the title compound (80.9mg) of white crystals.
1H-NMR(DMSO-d
6)δ：2.21(2H，t，J＝6.5Hz)，3.39-3.51(2H，m)，3.54(2H，t，J＝6.5Hz)，4.67(2H，t，J＝7.0Hz)，6.68(1H，t，J＝3.0Hz)，6.94-7.04(2H，m)，7.16(1H，d，J＝8.3Hz)，7.36(1H，d，J＝8.8Hz)，7.54(1H，t，J＝8.3Hz)，7.72(1H，dd，J＝8.8Hz，2.6Hz)，7.93-8.04(2H，m)，8.36(1H，t，J＝5.8Hz)，8.74(1H，s)，10.23(1H，s)。
Embodiment 237
5-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] pentane-1, the preparation of 2-glycol
(i) preparation of 3-(2,2-dimethyl-1,3-dioxane penta-4-yl) propane-1-alcohol
With pentane-1,2,5-triol (5.00g) is dissolved in the acetone (150mL), adds 2,2-Propanal dimethyl acetal (10.5mL) and 4-toluene sulfonic acide (794mg), and mixture at room temperature stirred 1.5 hours.The concentrating under reduced pressure reaction mixture, and separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 50: 50), obtain the title compound (3.79g) of colorless oil.
1H-NMR(CDCl
3)δ：1.37(3H，s)，1.42(3H，s)，1.57-1.77(4H，m)，2.05(1H，br?s)，3.53(1H，t，J＝7.3Hz)，3.60-3.77(2H，m)，4.00-4.21(2H，m)。
The (ii) preparation of 3-(2,2-dimethyl-1,3-dioxane penta-4-yl) propyl group methanesulfonates
React according to the method (ii) identical with embodiment 203, by using 3-(2,2-dimethyl-1,3-dioxane penta-4-yl) propane-1-alcohol (2.30g), methylsulfonyl chloride (0.8mL), triethylamine (3.0mL) and ethyl acetate (50mL) obtain the title compound (2.13g) of colorless oil.
1H-NMR(CDCl
3)δ：1.35(3H，s)，1.41(3H，s)，1.62-1.73(2H，m)，1.75-2.02(2H，m)，3.02(3H，m)，3.50-3.57(1H，m)，4.02-4.17(2H，m)，4.21-4.36(2H，m)。
(iii) 4-chloro-5-[3-(2,2-dimethyl-1,3-dioxane penta-4-yl) propyl group]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine
React according to the method (ii) identical with embodiment 201, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (151mg), 3-(2,2-dimethyl-1,3-dioxane penta-4-yl) propyl group methanesulfonates (319mg), cesium carbonate (574mg) and N, dinethylformamide (1.5mL) obtains the title compound (176mg) of white powder.
1H-NMR(CDCl
3)δ：1.34(3H，s)，1.40(3H，s)，1.53-1.73(2H，m)，1.80-2.13(2H，m)，3.47-3.53(1H，m)，3.97-4.18(2H，m)，4.41-4.70(2H，m)，6.72(1H，d，J＝3.3Hz)，7.51(1H，d，J＝3.3Hz)，8.70(1H，s)。
(iv) 5-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] pentane-1, the preparation of 2-glycol
React according to the method (iii) identical with embodiment 201, by using 4-chloro-5-[3-(2,2-dimethyl-1,3-dioxane penta-4-yl) propyl group]-5H-pyrrolo-[3,2-d] pyrimidine (171mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (195mg) and Virahol (3.5mL), obtain crude product.This crude product is dissolved in the methyl alcohol (1mL), adds 1N hydrochloric acid (0.5mL), and mixture was at room temperature stirred 3.5 hours.Reaction mixture is handled with the 1N aqueous sodium hydroxide solution, used ethyl acetate extraction, with the saturated brine washing, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → 95: 5), obtain the title compound (179mg) of white crystals.
1H-NMR(DMSO-d
6)δ：1.03-1.41(2H，m)，1.61-1.93(2H，m)，3.08-3.28(2H，m)，3.28-3.43(1H，m)，4.44(1H，t，J＝5.5Hz)，4.47-4.59(3H，m)，6.49(1H，d，J＝3.0Hz)，7.17-7.27(2H，m)，7.30(1H，d，J＝9.1Hz)，7.47(1H，d，J＝8.5Hz)，7.57-7.74(3H，m)，7.97(1H，d，J＝2.4Hz)，8.34(1H，s)，8.61(1H，s)。
Embodiment 238
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-hydroxyl propionamide hydrochloride
React according to the method (iii) identical with embodiment 202, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (300mg), 3.6M the 3-hydroxy-propionic acid aqueous solution (0.25mL), I-hydroxybenzotriazole monohydrate (231mg), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (330mg), triethylamine (0.8mL) and N, dinethylformamide (3mL), obtain N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl propionic acid amide.With the N-{2-[4-that obtains ({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl propionic acid amide is dissolved in the ethyl acetate (2mL), and adds 4N hydrochloric acid-ethyl acetate (0.1mL).The product that obtains by re-crystallizing in ethyl acetate, is obtained the title compound (63.1mg) of white powder.
1H-NMR(DMSO-d
6)δ：2.22(2H，t，J＝6.5Hz)，3.39-3.52(2H，m)，3.55(2H，t，J＝6.5Hz)，4.65(2H，t，J＝6.7Hz)，6.67(1H，d，J＝3.0Hz)，7.24-7.32(2H，m)，7.37(1H，d，J＝8.8Hz)，7.53(1H，d，J＝8.0Hz)，7.66(1H，t，J＝8.0Hz)，7.72(1H，dd，J＝8.8Hz，2.5Hz)，7.96-8.01(2H，m)，8.34(1H，t，J＝5.8Hz)，8.74(1H，s)，10.17(1H，s)。
Embodiment 239
N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3,3, the preparation of 3-trifluoropropyl acid amides
React according to the method (iii) identical with embodiment 202, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (150mg), 3,3,3-trifluoroacetic acid (0.06mL), I-hydroxybenzotriazole monohydrate (142mg), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (200mg), triethylamine (0.4mL) and N, dinethylformamide (1.5mL), and, obtain the title compound (64.0mg) of yellow crystal by the Di Iso Propyl Ether crystallization.
1H-NMR(DMSO-d
6)δ：3.19(2H，q，J＝11.2Hz)3.43(2H，m)，4.58(2H，t，J＝6.4Hz)，6.52(1H，d，J＝3.0Hz)，7.18-7.26(2H，m)，7.30(1H，d，J＝9Hz)，7.47(1H，d，J＝7.5Hz)，7.57-7.67(2H，m)，7.76(1H，dd，J＝9Hz，2.5Hz)，8.00(1H，d，J＝2.5Hz)，8.36(1H，s)，8.50(1H，t，J＝5.3Hz)，8.72(1H，s)。
Embodiment 240
3-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } propane-1, the preparation of 2-diol hydrochloride
(i) preparation of the tertiary butyl { 2-[(2,2-dimethyl-1,3-dioxane penta-4-yl) methoxyl group] oxyethyl group } dimethylsilane
(890mg) is suspended in N with 60% sodium hydride, in the dinethylformamide (60mL), and suspension is cooled to 0 ℃.Drip (2,2-dimethyl-1,3-dioxane penta-4-yl) methyl alcohol (2.3mL), and mixture was stirred 1 hour down at 0 ℃.In this reaction mixture, add (2-bromine oxethyl) (tertiary butyl) dimethylsilane (3mL), and mixture was stirred 2 hours down at 0 ℃.In reaction mixture, add saturated aqueous ammonium chloride solution, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=100: 0 → 90: 10), obtain the title compound (1.04g) of yellow oil.
1H-NMR(CDCl
3)δ：0.06(6H，s)，0.89(9H，s)，1.36(3H，s)，1.42(3H，s)，3.47-3.63(4H，m)3.71-3.79(3H，m)，4.06(1H，dd，J＝8.2Hz，6.3Hz)，4.20-4.35(1H，m)。
(ii) 2-[(2,2-dimethyl-1,3-dioxane penta-4-yl) methoxyl group] preparation of ethyl methane sulfonate ester
With the tertiary butyl { 2-[(2,2-dimethyl-1,3-dioxane penta-4-yl) methoxyl group] oxyethyl group } dimethylsilane (1.03g) is dissolved in the tetrahydrofuran (THF) (20mL), adds the tetrahydrofuran solution (4mL) of 1.0M tetrabutylammonium fluoride, and mixture was at room temperature stirred 1 hour.In this reaction mixture, add saturated aqueous ammonium chloride solution, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (20mL), and, uses methylsulfonyl chloride (0.3mL) and triethylamine (2mL), obtain the title compound (857mg) of yellow oil according to similar embodiment 203 this reaction of carrying out described in (ii).
1H-NMR(CDCl
3)δ：1.36(3H，s)，1.42(3H，s)，3.07(3H，s)，3.56(1H，d，J＝1.4Hz)，3.58(1H，d，J＝1.9Hz)，3.73(1H，dd，J＝8.3Hz，6.3Hz)，3.77-3.82(2H，m)，4.06(1H，dd，J＝8.3Hz，6.3Hz)，4.24-4.33(1H，m)，4.35-4.41(2H，m)。
(iii) 4-chloro-5-{2-[(2,2-dimethyl-1,3-dioxane penta-4-yl) methoxyl group] ethyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine
React according to the method (ii) identical with embodiment 201, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (152mg), 2-[(2,2-dimethyl-1,3-dioxane penta-4-yl) methoxyl group] ethyl methane sulfonate ester (327mg), cesium carbonate (576mg) and N, dinethylformamide (1.5mL) obtains the title compound (298mg) of colorless oil.
1H-NMR(CDCl
3)δ：1.33(3H，s)，1.38(3H，s)，3.37-3.50(2H，m)，3.59(1H，dd，J＝8.3Hz，6.6Hz)，3.87(2H，dt，J＝5.1Hz，2.2Hz)，3.96(1H，dd，J＝8.3Hz，6.6Hz)，4.11-4.22(1H，m)，4.66-4.72(2H，m)，6.71(1H，d，J＝3Hz)，7.57(1H，d，J＝3Hz)，8.70(1H，s)。
(iv) 3-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } propane-1, the preparation of 2-diol hydrochloride
React according to the method (iv) identical with embodiment 237, by using 4-chloro-5-{2-[(2,2-dimethyl-1,3-dioxane penta-4-yl) methoxyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine (295mg), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (359mg) and Virahol (6mL), obtain 3-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } propane-1, the 2-glycol.With the 3-{2-[4-that obtains ({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } propane-1, the 2-glycol is dissolved in the ethyl acetate (6mL), adds 4N hydrochloric acid-ethyl acetate (0.2mL), and the concentrating under reduced pressure mixture.Resistates by the ethyl acetate crystallization, is obtained the title compound (360mg) of white powder.
1H-NMR(DMSO-d
6)δ：3.10-3.26(2H，m)，3.31-3.42(1H，m)，3.42-3.56(2H，m)，3.78-3.89(2H，m)，4.77-4.89(2H，m)，6.71(1H，d，J＝3.0Hz)，7.22-7.31(2H，m)，7.36(1H，d，J＝8.8Hz)，7.52(1H，d，J＝7.7Hz)，7.60-7.73(2H，m)，7.96-8.06(2H，m)，8.75(1H，s)，9.96(1H，s)。
Embodiment 241
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-malonamide nitrile
React according to the method (iii) identical with embodiment 202, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (201mg), cyanoacetic acid (65.9mg), I-hydroxybenzotriazole monohydrate (215mg), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (300mg), triethylamine (0.55mL) and N, dinethylformamide (2.0mL), and, obtain the title compound (104mg) of yellow powder shape by the Di Iso Propyl Ether crystallization.
1H-NMR(DMSO-d
6)δ：3.36-3.47(2H，m)，3.56(2H，s)，4.58(2H，t，J＝6.3Hz)，6.52(1H，d，J＝3.3Hz)，7.18-7.28(2H，m)，7.31(1H，d，J＝8.8Hz)，7.47(1H，d，J＝7.7Hz)，7.56-7.68(2H，m)，7.73(1H，dd，J＝8.8Hz，2.5Hz)，7.99(1H，d，J＝2.5Hz)，8.36(1H，s)，8.44(1H，t，J＝5.8Hz)，8.67(1H，s)。
Embodiment 242
N-{4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] fourth-2-alkynes-1-yl }-preparation of 2-(methylsulfonyl) ethanamide
(i) preparation of (4-neoprene-2-alkynes-1-yl) t-butyl carbamate
In the mixed solvent with 4-neoprene-2-alkynes-water-soluble (200mL)/methyl alcohol of 1-amine hydrochlorate (10.5g) (40mL), add tert-Butyl dicarbonate (19mL), and mixture was at room temperature stirred 2 hours.In the case, making reaction soln remain on pH with the 4N aqueous sodium hydroxide solution is 10-11.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=100: 0 → 80: 20), obtain the title compound (14.5g) of faint yellow oily thing.
1H-NMR(CDCl
3)δ：1.45(9H，s)，3.89-4.06(2H，m)，4.14(2H，t，J＝2.1Hz)，4.71(1H，br?s)。
The (ii) preparation of [4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) fourth-2-alkynes-1-yl] t-butyl carbamate
With 4-chloro-5H-pyrrolo-[3,2-d] pyrimidines (1.51g), (4-neoprene-2-alkynes-1-yl) t-butyl carbamate (2.60g), cesium carbonate (4.80g) and N, the mixture of dinethylformamide (15mL) at room temperature stirred 2 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, through anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Separate resistates, and by silica gel column chromatography purifying (elutriant, hexane: ethyl acetate=80: 20 → 33: 67), obtain orange buttery title compound (2.61g).
1H-NMR(CDCl
3)δ：1.44(9H，s)，3.87-4.05(2H，m)，4.71(1H，s)，5.29(2H，t，J＝2.1Hz)，6.76(1H，d，J＝3.3Hz)，7.70(1H，d，J＝3.3Hz)，8.72(1H，s)。
The (iii) preparation of { 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] fourth-2-alkynes-1-yl } t-butyl carbamate
React according to the method (iii) identical with embodiment 201, by using [4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) fourth-2-alkynes-1-yl] t-butyl carbamate (1.32g), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (1.43g) and Virahol (25mL), and, obtain the title compound (1.86g) of colourless powder shape by hexane/Di Iso Propyl Ether crystallization.
1H-NMR(CDCl
3)δ：1.39(9H，s)，4.03-4.08(2H，m)，4.80(1H，br?s)，5.08(2H，t，J＝2.1Hz)，6.60(1H，d，J＝3.3Hz)，7.09(1H，d，J＝8.8Hz)，7.10-7.15(1H，m)，7.18-7.23(2H，m)，7.33(1H，d，J＝7.8Hz)，7.43(1H，t，J＝7.8Hz)，7.51(1H，dd，J＝8.8Hz，2.5Hz)，7.68(1H，s)，7.97(1H，d，J＝2.5Hz)，8.56(1H，s)。
(iv) 5-(4-amino fourth-2-alkynes-1-yl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
Will 4-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] fourth-2-alkynes-1-yl } t-butyl carbamate (1.90g) is dissolved in the tetrahydrofuran (THF) (35mL), add 2N hydrochloric acid (18mL), and mixture was stirred 16 hours down at 60 ℃.In this reaction mixture, add ethanol, and the concentrating under reduced pressure mixture.Resistates by the ethyl acetate crystallization, is obtained the title compound (802mg) of white powder.
1H-NMR(DMSO-d
6)δ：3.71-3.84(2H，m)，5.97(2H，s)，6.74(1H，d，J＝3Hz)，7.23-7.32(2H，m)，7.36(1H，d，J＝8.8Hz)，7.52(1H，d，J＝8.0Hz)，7.66(1H，t，J＝8.0Hz)，7.76(1H，dd，J＝8.8Hz，2.5Hz)，8.05(1H，d，J＝2.5Hz)，8.21(1H，d，J＝3Hz)，8.42-8.60(3H，m)，8.76(1H，s)，10.49(1H，s)。
(v) N-{4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] fourth-2-alkynes-1-yl }-preparation of 2-(methylsulfonyl) ethanamide
React according to the method (iii) identical with embodiment 202; by using 5-(the amino fourth of 4--2-alkynes-1-yl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine dihydrochloride (204mg); methylsulfonyl acetate (102mg); I-hydroxybenzotriazole monohydrate (204mg); N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (287mg); triethylamine (0.5mL) and N; dinethylformamide (2mL); and, obtain the title compound (55.8mg) of pale yellow powder by Di Iso Propyl Ether/ethyl acetate crystallization.
1H-NMR(DMSO-d
6)δ：3.07(3H，s)，3.92-4.00(2H，m)，4.02(2H，s)，5.50(2H，s)，6.55(1H，d，J＝3Hz)，7.18-7.28(2H，m)，7.32(1H，d，J＝9.1Hz)，7.48(1H，d，J＝7.1Hz)，7.57-7.70(2H，m)，7.76(1H，d，J＝3Hz)，8.02(1H，d，J＝2.5Hz)，8.39(1H，s)，8.62(1H，s)，8.77(1H，t，J＝5.5Hz)。
Embodiment 243
N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-4,4, the preparation of 4-three fluoro-3-hydroxy-3-methyl butyramides
React according to the method (iii) identical with embodiment 202, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (201mg), 4,4,4-three fluoro-3-hydroxy-3-methyl butyric acid (131mg), I-hydroxybenzotriazole monohydrate (159mg), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (372mg), triethylamine (0.55mL) and tetrahydrofuran (THF) (2mL), and, obtain the title compound (104mg) of white crystals by Di Iso Propyl Ether/ethyl acetate crystallization.
1H-NMR(DMSO-d
6)δ：1.36(3H，s)，2.26-2.48(2H，m)，3.36-3.56(2H，m)，4.53(2H，t，J＝6.7Hz)，6.18(1H，s)，6.51(1H，d，J＝3.0Hz)，7.15-7.26(2H，m)，7.30(1H，d，J＝8.8Hz)，7.47(1H，d，J＝8.0Hz)，7.56-7.72(2H，m)，7.81(1H，dd，J＝8.8Hz，2.5Hz)，8.04(1H，d，J＝2.5Hz)，8.35(1H，s)，8.42(1H，t，J＝5.9Hz)，8.83(1H，s)。
Embodiment 244
4-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] butyro-preparation
(i) preparation of 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl butyrate
React according to the method (ii) identical with embodiment 201, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (1.01g), 4-bromo-butyric acid ethyl ester (1.2mL), cesium carbonate (3.23g) and N, dinethylformamide (10mL) obtains the title compound (1.70g) of yellow oil.
1H-NMR(CDCl
3)δ：1.25(3H，t，J＝7Hz)，2.09-2.44(4H，m)，4.13(2H，q，J＝7Hz)，4.56(2H，t，J＝7.0Hz)，6.73(1H，d，J＝3Hz)，7.50(1H，d，J＝3Hz)，8.71(1H，s)。
(ii) 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of ethyl butyrate
React according to the method (iii) identical with embodiment 201, by using 4-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl butyrate (1.70g), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (2.19g) and Virahol (35mL), obtain the title compound (2.69g) of yellow solid.
1H-NMR(CDCl
3)δ：1.31(3H，t，J＝7.2Hz)，2.12-2.27(2H，m)，2.50-2.61(2H，m)，4.24(2H，q，J＝7.2Hz)，4.34-4.48(2H，m)，6.60(1H，d，J＝3.3Hz)，7.08(1H，d，J＝8.0Hz)，7.11-7.17(1H，m)，7.19-7.25(2H，m)，7.32(1H，d，J＝8.0Hz)，7.43(1H，t，J＝8.0Hz)，7.82(1H，dd，J＝8.8Hz，2.6Hz)，8.00(1H，d，J＝2.6Hz)，8.16(1H，s)，8.52(1H，s)。
(iii) 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] butyro-preparation
React according to the method (ii) identical with embodiment 202, by using 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] mixed solvent of ethyl butyrate (2.69g), 1N aqueous sodium hydroxide solution (7mL) and tetrahydrofuran (THF) (20mL)/ethanol (20mL), obtain the title compound (2.02g) of white solid.
1H-NMR(DMSO-d
6)δ：1.87-2.00(2H，m)，2.20(2H，t，J＝6.9Hz)，4.52(2H，t，J＝7.6Hz)，6.50(1H，d，J＝3.0Hz)，7.17-7.28(2H，m)，7.30(1H，d，J＝8.8Hz)，7.47(1H，d，J＝7.7Hz)，7.57-7.76(3H，m)，7.99(1H，d，J＝2.5Hz)，8.34(1H，s)，8.61(1H，s)，12.33(1H，s)。
Embodiment 245
4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-N-[2-(methylsulfonyl) ethyl] preparation of butyramide
React according to the method (iii) identical with embodiment 202; by using 4-[4-((3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] butyric acid (250mg); 2-(methylsulfonyl) ethamine (128mg); I-hydroxybenzotriazole monohydrate (114mg); N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (492mg); triethylamine (0.15mL) and tetrahydrofuran (THF) (1.5mL)/N; the mixed solvent of dinethylformamide (1.5mL); and, obtain the title compound (142mg) of white crystals by the ethyl acetate crystallization.
1H-NMR(DMSO-d
6)δ：1.90-2.03(2H，m)，2.08-2.19(2H，m)，2.97(3H，s)，3.20-3.30(2H，m)，3.40-3.52(2H，m)，4.49(2H，t，J＝7.2Hz)，6.50(1H，d，J＝3Hz)，7.17-7.24(1H，m)，7.24-7.27(1H，m)，7.30(1H，d，J＝9Hz)，7.47(1H，d，J＝8Hz)，7.62(1H，t，J＝8Hz)，7.67(1H，d，J＝3Hz)，7.82(1H，dd，J＝9Hz，2.5Hz)，8.09(1H，d，J＝2.5Hz)，8.29(1H，t，J＝5.6Hz)，8.34(1H，s)，8.79(1H，s)。
Embodiment 246
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 3-hydroxyl propionic acid amide mesylate
React according to the method (iii) identical with embodiment 202, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (3.50g), 3.6M the 3-hydroxy-propionic acid aqueous solution (5.6mL), I-hydroxybenzotriazole monohydrate (4.56g), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (10.1g), triethylamine (10mL) and tetrahydrofuran (THF) (17mL)/N, the mixed solvent of dinethylformamide (17mL), obtain N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl propionic acid amide.With the N-{2-[4-that obtains ({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxyl propionic acid amide is dissolved in the ethyl acetate (50mL), add methylsulfonic acid (0.155mL), and mixture was stirred 2 hours.The concentrating under reduced pressure reaction mixture, and, obtain the title compound (1.04g) of white crystals by re-crystallizing in ethyl acetate.
1H-NMR(DMSO-d
6)δ：2.22(2H，t，J＝6.3Hz)，2.31(3H，s)，3.41-3.51(4H，m)，3.56(2H，t，J＝6.5Hz)，6.67(1H，d，J＝3.0Hz)，7.25-7.32(2H，m)，7.37(1H，d，J＝8.8Hz)，7.50-7.56(1H，m)，7.62-7.74(2H，m)，7.98(1H，d，J＝2.8Hz)，8.33(1H，t，J＝5.5Hz)，8.75(1H，s)，10.11(1H，s)。
Embodiment 247
4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl]-preparation of N-methoxybutyramide
React according to the method (iii) identical with embodiment 202, by using 4-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] butyric acid (252mg), O-methyl hydroxy amine hydrochloric acid salt (85mg), I-hydroxybenzotriazole monohydrate (105mg), N-[3-(dimethylamino) propyl group]-N-ethyl-carbodiimide hydrochloride (484mg), triethylamine (0.7mL) and tetrahydrofuran (THF) (1mL)/N, the mixed solvent of dinethylformamide (1mL) obtains the title compound (98.1mg) of white crystals.
1H-NMR(DMSO-d
6)δ：1.92-1.99(4H，m)，3.55(3H，s)，4.46-4.56(2H，m)，6.51(1H，d，J＝2.8Hz)，7.18-7.27(2H，m)，7.30(1H，d，J＝8.8Hz)，7.47(1H，d，J＝7.7Hz)，7.58-7.69(2H，m)，7.74-7.81(1H，m)，8.03(1H，s)，8.34(1H，s)，8.75(1H，br?s)，11.02(1H，br?s)。
Embodiment 248
3-hydroxy-3-methyl-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of butyramide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine (238mg), 3-hydroxy-3-methyl butyric acid (0.0865mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (154mg), I-hydroxybenzotriazole monohydrate (109mg), triethylamine (0.374mL) and N, dinethylformamide (10.5mL) obtains colourless powder shape crystalline title compound (203mg).
1H-NMR(DMSO-d
6)δ1.13(6H，s)，2.12(3H，s)，2.21(2H，s)，3.41(2H，m)，4.51(2H，t，J＝6Hz)，4.70(1H，s)，6.47(1H，d，J＝3Hz)，6.88(2H，m)，7.04(2H，m)，7.47(1H，t，J＝8Hz)，7.61(1H，d，J＝3Hz)，7.65(2H，m)，8.28(2H，m)，8.73(1H，br?s)。
Embodiment 249
3-hydroxy-3-methyl-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of butyramide
(i) 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride
With { the 2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3 that obtains among the embodiment 188 (i), 2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (2.9g) is dissolved in tetrahydrofuran (THF) (80mL)/2N hydrochloric acid (40mL), and mixture was stirred 16 hours down at 60 ℃.The concentrating under reduced pressure reaction mixture, (80mL) joins in the resistates with ethanol, and mixture is under reduced pressure concentrated once more.Ethyl acetate is joined in the resistates, and solid filtering is collected and drying under reduced pressure, obtain the title compound (2.58g) of solid powdery.
1H-NMR(DMSO-d
6)δ2.20(3H，s)，3.29(2H，m)，5.06(2H，m)，6.73(1H，d，J＝3Hz)，7.11(1H，d，J＝9Hz)，7.22(2H，m)，7.48(2H，m)，7.61(2H，m)，8.08(1H，d，J＝3Hz)，8.42(3H，br?s)，8.70(1H，s)，10.04(1H，br?s)。
(ii) 3-hydroxy-3-methyl-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of butyramide
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), 3-hydroxy-3-methyl butyric acid (0.0644mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (115mg), I-hydroxybenzotriazole monohydrate (81mg), triethylamine (0.279mL) and N, dinethylformamide (7.82mL) obtains colourless powder shape crystalline title compound (203mg).
1H-NMR(DMSO-d
6)δ1.13(6H，s)，2.13(3H，s)，2.21(2H，s)，3.42(2H，m)，4.52(2H，t，J＝7Hz)，4.69(1H，s)，6.47(1H，d，J＝3Hz)，7.03(1H，m)，7.18(2H，m)，7.42(1H，d，J＝8Hz)，7.5-7.7(4H，m)，8.26(2H，m)，8.73(1H，br?s)。
Embodiment 250
2-{2-[4-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (150mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (139mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain colourless crystallization title compound (132mg).
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.43(3H，s)，3.51(4H，br?s)，3.84(2H，t，J＝4.5Hz)，4.63(2H，t，J＝4.5Hz)，4.73(1H，t，J＝4.5Hz)，6.49(1H，d，J＝3Hz)，6.93(1H，d，J＝8Hz)，7.16(1H，dd，J＝9Hz，3Hz)，7.23(1H，d，J＝8Hz)，7.56(2H，m)，7.65(1H，d，J＝3Hz)，8.17(1H，d，J＝3Hz)，8.28(1H，s)，8.78(1H，br?s)。
Embodiment 251
N-{2-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
(i) { 2-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-and 5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of t-butyl carbamate
According to the same procedure described in the embodiment 188 (i), by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (500mg), 3-methyl-4-[(6-picoline-3-yl) the oxygen base] aniline (542mg) and Virahol (5mL), obtain the title compound (799mg) of white powder.
1H-NMR(CDCl
3)δ1.47(9H，s)，2.24(3H，s)，2.52(3H，s)，3.49(2H，m)，4.46(2H，m)，5.18(1H，m)，6.58(1H，d，J＝3Hz)，6.89(1H，d，J＝9Hz)，7.0-7.2(3H，m)，7.65(2H，m)，8.27(1H，d，J＝2Hz)，8.41(1H，br?s)，8.48(1H，s)。
(ii) 5-(2-amino-ethyl)-N-{3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride
Will 2-[4-(3-methyl-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (790mg) is dissolved in tetrahydrofuran (THF) (24mL)/2N hydrochloric acid (12mL), and mixture was stirred 16 hours down at 60 ℃.The concentrating under reduced pressure reaction mixture, (30mL) joins in the resistates with ethanol, and mixture is under reduced pressure concentrated once more.Ethyl acetate is joined in the resistates, and solid filtering is collected and drying under reduced pressure, obtain the title compound (701mg) of solid powdery.
1H-NMR(DMSO-d
6)δ2.23(3H，s)，2.68(3H，s)，3.29(2H，m)，5.11(2H，m)，6.74(1H，d，J＝3Hz)，7.16(1H，d，J＝8Hz)，7.52(1H，d，J＝9Hz)，7.62(1H，s)，7.80(1H，m)，7.96(1H，m)，8.10(1H，m)，8.37(1H，d，J＝3Hz)，8.51(3H，brs)，8.71(1H，s)。
(iii) N-{2-[4-({ 3-methyl-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using 5-(2-amino-ethyl)-N-{3-methyl-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (250mg), 2-(methylsulfonyl) acetate (107mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149mg), I-hydroxybenzotriazole monohydrate (105mg), triethylamine (0.360mL) and N; dinethylformamide (10mL) obtains colourless powder shape crystalline title compound (205mg).
1H-NMR(DMSO-d
6)δ2.17(3H，s)，2.44(3H，s)，3.34(3H，s)，3.45(2H，q，J＝6Hz)，4.05(2H，s)，4.55(2H，t，J＝6Hz)，6.47(1H，d，J＝3Hz)，6.94(1H，d，J＝9Hz)，7.1-7.3(2H，m)，7.55(3H，m)，8.18(1H，d，J＝3Hz)，8.28(1H，s)，8.51(1H，br?s)，8.67(1H，t，J＝5Hz)。
Embodiment 252
2-[2-(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (150mg), 3-chloro-4-(pyridine-2-ylmethoxy) aniline (152mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (149mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.47(4H，m)，3.81(2H，t，J＝4.5Hz)，4.61(2H，t，J＝4.5Hz)，4.70(1H，t，J＝4.5Hz)，5.27(2H，s)，6.48(1H，d，J＝3Hz)，7.20(1H，d，J＝9Hz)，7.37(1H，dd，J＝7Hz，4.5Hz)，7.49(1H，dd，J＝9Hz，3Hz)，7.58(1H，d，J＝8Hz)，7.64(1H，d，J＝3Hz)，7.84(1H，d，J＝3Hz)，7.88(1H，m)，8.27(1H，s)，8.59(1H，dd，J＝3Hz，1Hz)，8.70(1H，br?s)。
Embodiment 253
N-[2-(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-preparation of 2-(methylsulfonyl) ethanamide
(i) [2-(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] preparation of t-butyl carbamate
According to the same procedure described in the embodiment 188 (i), by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (500mg), 3-chloro-4-(pyridine-2-ylmethoxy) aniline (594mg) and Virahol (5mL), obtain the title compound (812mg) of white powder.
1H-NMR(CDCl
3)δ1.48(9H，s)，3.46(2H，m)，4.43(2H，m)，5.19(1H，t，J＝5Hz)，5.29(2H，s)，6.56(1H，d，J＝3Hz)，6.98(1H，d，J＝9Hz)，7.14(1H，d，J＝3Hz)，7.2-7.3(2H，m)，7.6-7.8(3H，m)，7.87(1H，d，J＝3Hz)，8.46(1H，s)，8.51(1H，br?s)，8.59(1H，m)。
(ii) 5-(2-amino-ethyl)-N-[3-chloro-4-(pyridine-2-ylmethoxy) phenyl]-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride
Will [2-(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (790mg) is dissolved in tetrahydrofuran (THF) (24mL)/2N hydrochloric acid (12mL), and mixture was stirred 16 hours down at 60 ℃.The concentrating under reduced pressure reaction mixture, (30mL) joins in the resistates with ethanol, and mixture is under reduced pressure concentrated once more.Ethyl acetate is joined in the resistates, and solid filtering is collected and drying under reduced pressure, obtain the title compound (826mg) of solid powdery.
1H-NMR(DMSO-d
6)δ3.29(2H，m)，5.07(2H，m)，5.49(2H，s)，6.73(1H，dd，J＝3Hz，1Hz)，7.34(1H，d，J＝9Hz)，7.52(1H，dd，J＝9Hz，3Hz)，7.68(1H，m)，7.74(1H，d，J＝2Hz)，7.85(1H，m)，8.09(1H，d，J＝3Hz)，8.24(1H，m)，8.47(3H，br?s)，8.69(1H，s)，8.77(1H，m)，10.19(1H，br?s)。
(iii) N-[2-(4-{[3-chloro-4-(pyridine-2-ylmethoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-preparation of 2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using 5-(2-amino-ethyl)-N-[3-chloro-4-(pyridine-2-ylmethoxy) phenyl]-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (261mg), 2-(methylsulfonyl) acetate (107mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149mg), I-hydroxybenzotriazole monohydrate (105mg), triethylamine (0.360mL) and N; dinethylformamide (10mL) obtains colourless powder shape crystalline title compound (182mg).
1H-NMR(DMSO-d
6)δ3.10(3H，s)，3.44(2H，q，J＝6Hz)，4.06(2H，s)，4.53(2H，t，J＝6Hz)，5.28(2H，s)，6.46(1H，d，J＝3Hz)，7.22(1H，d，J＝9Hz)，7.37(1H，dd，J＝8Hz，6Hz)，7.57(3H，m)，7.78(1H，d，J＝2Hz)，7.89(1H，dt，J＝2Hz，8Hz)，8.26(1H，s)，8.49(1H，br?s)，8.60(1H，d，J＝5Hz)，8.67(1H，t，J＝6Hz)。
Embodiment 254
(2S, 4R)-4-hydroxyl-2-[({2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } amino) carbonyl] preparation of tetramethyleneimine-1-carboxyl tert-butyl ester
React according to the method (iv) identical with embodiment 155, by using 5-(2-amino-ethyl)-N-{3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (300mg), (4R)-1-(tert-butoxycarbonyl)-4-hydroxyl-L-proline(Pro) (118mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (172mg), I-hydroxybenzotriazole monohydrate (122mg), triethylamine (0.418mL) and N, dinethylformamide (11.73mL) obtains the title compound (310mg) of colourless powder shape.
1H-NMR(CDCl
3)δ1.43(9H，s)，1.9-2.1(2H，m)，2.22(3H，s)，2.50(1H，brs)，3.44(2H，m)，3.61(2H，m)，4.44(4H，m)，6.58(1H，d，J＝3Hz)，6.94(1H，d，J＝9Hz)，7.10(1H，m)，7.18(2H，m)，7.27(2H，m)，7.39(1H，d，J＝8Hz)，7.65(1H，d，J＝9Hz)，7.73(1H，m)，8.39(1H，br?s)，8.48(1H，s)。
Embodiment 255
(4R)-preparation of 4-hydroxy-n-{ 2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-L-prolyl ammonia dihydrochloride
With (2S, 4R)-4-hydroxyl-2-[({2-[4-(3-methyl-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } amino) carbonyl] tetramethyleneimine-1-carboxyl tert-butyl ester (230mg) is dissolved in the methylene dichloride (2.39mL), add trifluoroacetic acid (1.79mL), and mixture was at room temperature stirred 2 hours.The concentrating under reduced pressure reaction mixture, and with resistates be dissolved in ethyl acetate/tetrahydrofuran (THF) (1: 1,50mL) in.Organic layer is washed with saturated sodium bicarbonate aqueous solution (30mL), through dried over mgso, and concentrating under reduced pressure.Resistates is carried out the alkaline silica gel chromatography handle (ethyl acetate/methanol=100/0 → 80/20).Collection contains the fraction and the concentrating under reduced pressure of title compound.Resistates is dissolved in the ethyl acetate, adds 4N hydrochloric acid (0.252mL), and, obtain title compound (136mg) crystalline mixture.
1H-NMR(DMSO-d
6)δ1.66(1H，m)，2.14(1H，m)，2.21(3H，s)，3.04(1H，m)，3.23(1H，m)，3.49(3H，m)，3.67(1H，m)，4.16(2H，m)，4.36(1H，m)，4.83(2H，m)，5.55(1H，br?s)，6.66(1H，d，J＝3Hz)，7.13(1H，d，J＝9Hz)，7.23(2H，m)，7.49(2H，m)，7.61(2H，m)，7.94(1H，m)，8.56(1H，m)，8.68(1H，s)，8.95(1H，m)，10.02(2H，m)。
Embodiment 256
2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide mesylate
With 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] ethyl } ethanamide (680mg) is dissolved in the ethyl acetate (3.4mL); add methylsulfonic acid (0.0887mL) down at 50 ℃, and mixture was stirred 10 minutes.And at room temperature further stirred 2 hours.Filter the crystallization of collecting precipitation, and wash, obtain the title compound (797mg) of colourless crystallization with Di Iso Propyl Ether.
1H-NMR(DMSO-d
6)δ2.20(3H，s)，2.31(3H，s)，3.05(3H，s)，3.55(2H，q，J＝6Hz)，4.06(2H，s)，4.68(2H，t，J＝6Hz)，6.65(1H，d，J＝3Hz)，7.13(1H，d，J＝9Hz)，7.23(2H，m)，7.49(2H，m)，7.62(2H，m)，7.91(1H，d，J＝3Hz)，8.70(2H，m)，9.84(1H，br?s)。
Embodiment 257
2-{2-[4-(3-chloro-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (150mg), 3-chloro-4-[(6-picoline-3-yl) the oxygen base] aniline (152mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (133mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ2.44(3H，s)，3.48(4H，m)，3.83(2H，t，J＝4.5Hz)，4.64(2H，t，J＝4.5Hz)，4.71(1H，t，J＝4.5Hz)，6.52(1H，d，J＝3Hz)，7.18(1H，d，J＝9Hz)，7.24(2H，m)，7.62(1H，dd，J＝9Hz，2Hz)，7.69(1H，d，J＝3Hz)，8.00(1H，d，J＝2Hz)，8.20(1H，d，J＝1Hz)，8.34(1H，s)，8.96(1H，br?s)。
Embodiment 258
N-{2-[4-({ 3-chloro-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
(i) { 2-[4-({ 3-chloro-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-and 5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of t-butyl carbamate
According to embodiment 188 (i) in identical method, by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (500mg), 3-chloro-4-[(6-picoline-3-yl) the oxygen base] aniline (594mg) and Virahol (5mL), obtain the title compound (673mg) of white powder.
1H-NMR(CDCl
3)δ1.49(9H，s)，2.53(3H，s)，3.48(2H，m)，4.46(2H，m)，5.26(1H，t，J＝6Hz)，6.59(1H，d，J＝3Hz)，7.01(1H，d，J＝9Hz)，7.09(1H，d，J＝8Hz)，7.18(2H，m)，7.85(1H，dd，J＝9Hz，3Hz)，8.00(1H，d，J＝3Hz)，8.30(1H，d，J＝3Hz)，8.50(1H，s)，8.63(1H，br?s)。
(ii) 5-(2-amino-ethyl)-N-{3-chloro-4-[(6-picoline-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride
Will 2-[4-(3-chloro-4-[(6-picoline-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (643mg) is dissolved in tetrahydrofuran (THF) (19.5mL)/2N hydrochloric acid (9.75mL), and mixture was stirred 16 hours down at 60 ℃.The concentrating under reduced pressure reaction mixture, (50mL) joins in the resistates with ethanol, and mixture is under reduced pressure concentrated once more.Ethyl acetate is joined in the resistates, and solid filtering is collected, and drying under reduced pressure, obtain the title compound (646mg) of solid powdery.
1H-NMR(DMSO-d
6)δ2.68(3H，d，J＝6Hz)，3.30(2H，m)，5.14(2H，m)，6.77(1H，d，J＝3Hz)，7.40(1H，m)，7.6-7.9(2H，m)，8.00(2H，m)，8.12(1H，m)，8.52(4H，m)，8.77(1H，s)，10.50(1H，m)。
(iii) N-{2-[4-({ 3-chloro-4-[(6-picoline-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using 5-(2-amino-ethyl)-N-{3-chloro-4-[(6-picoline-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (261mg), 2-(methylsulfonyl) acetate (107mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149mg), I-hydroxybenzotriazole monohydrate (105mg), triethylamine (0.360mL) and N; dinethylformamide (10mL) obtains colourless powder shape crystalline title compound (230mg).
1H-NMR(DMSO-d
6)δ2.45(3H，s)，3.10(3H，s)，3.45(2H，q，J＝6Hz)，4.04(2H，s)，4.56(2H，t，J＝6Hz)，6.50(1H，d，J＝3Hz)，7.18(1H，d，J＝9Hz)，7.25(1H，d，J＝2Hz)，7.62(1H，d，J＝3Hz)，7.70(1H，dd，J＝9Hz，3Hz)，7.95(1H，d，J＝2Hz)，8.22(1H，m)，8.34(1H，s)，8.67(2H，m)。
Embodiment 259
2-{2-[4-(3-chloro-4-[(5-chloropyridine-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } the alcoholic acid preparation
React according to the method identical with embodiment 183, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (150mg), 3-chloro-4-[(5-chloropyridine-3-yl) the oxygen base] aniline (165mg) and 1-Methyl-2-Pyrrolidone (0.863mL), obtain the title compound (145mg) of colourless crystallization.
1H-NMR(DMSO-d
6)δ3.49(4H，m)，3.84(2H，t，J＝4.5Hz)，4.65(2H，t，J＝4.5Hz)，4.72(1H，t，J＝4.5Hz)，6.53(1H，d，J＝3Hz)，7.33(1H，d，J＝9Hz)，7.49(1H，m)，7.69(2H，m)，8.04(1H，d，J＝2Hz)，8.32(1H，d，J＝2Hz)，8.36(1H，s)，8.40(1H，d，J＝2Hz)，9.02(1H，br?s)。
Embodiment 260
N-{2-[4-({ 3-chloro-4-[(5-chloropyridine-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
(i) { 2-[4-({ 3-chloro-4-[(5-chloropyridine-3-yl) oxygen base] phenyl } amino)-and 5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of t-butyl carbamate
React according to the method identical with embodiment 188 (i), by using [2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl] t-butyl carbamate (500mg), 3-chloro-4-[(5-chloropyridine-3-yl) the oxygen base] aniline (643mg) and Virahol (5mL), obtain the title compound (769mg) of white powder.
1H-NMR(CDCl
3)δ1.50(9H，s)，3.49(2H，m)，4.48(2H，m)，5.21(1H，t，J＝6Hz)，6.60(1H，d，J＝3Hz)，7.11(1H，d，J＝9Hz)，7.21(2H，m)，7.94(1H，dd，J＝9Hz，3Hz)，8.06(1H，d，J＝3Hz)，8.29(2H，m)，8.53(1H，s)，8.69(1H，br?s)。
(ii) 5-(2-amino-ethyl)-N-{3-chloro-4-[(5-chloropyridine-3-yl) oxygen base] phenyl }-preparation of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine tri hydrochloride
Will 2-[4-(3-chloro-4-[(5-chloropyridine-3-yl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } t-butyl carbamate (700mg) is dissolved in tetrahydrofuran (THF) (19.5mL)/2N hydrochloric acid (9.75mL), and mixture was stirred 16 hours down at 60 ℃.The concentrating under reduced pressure reaction mixture, (50mL) joins in the resistates with ethanol, and mixture is under reduced pressure concentrated once more.Ethyl acetate is joined in the resistates, and solid filtering is collected and drying under reduced pressure, obtain the title compound (663mg) of solid powdery.
1H-NMR(DMSO-d
6)δ3.30(2H，m)，5.09(2H，m)，6.77(1H，d，J＝3Hz)，7.40(1H，d，J＝9Hz)，7.61(1H，m)，7.69(1H，dd，J＝9Hz，2Hz)，7.96(1H，d，J＝2Hz)，8.12(1H，d，J＝3Hz)，8.35(1H，d，J＝2Hz)，8.40(3H，s)，8.46(1H，d，J＝2Hz)，8.77(1H，s)，10.36(1H，m)。
(iii) N-{2-[4-({ 3-chloro-4-[(5-chloropyridine-3-yl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of 2-(methylsulfonyl) ethanamide
React according to the method (iv) identical with embodiment 155; by using 5-(2-amino-ethyl)-N-{3-chloro-4-[(5-chloropyridine-3-yl) the oxygen base] phenyl }-5H-pyrrolo-[3; 2-d] pyrimidine-4-amine tri hydrochloride (271mg), 2-(methylsulfonyl) acetate (107mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (149mg), I-hydroxybenzotriazole monohydrate (105mg), triethylamine (0.360mL) and N; dinethylformamide (10mL) obtains colourless powder shape crystalline title compound (255mg).
1H-NMR(DMSO-d
6)δ3.09(3H，s)，3.45(2H，m)，4.04(2H，s)，4.56(2H，t，J＝6Hz)，6.50(1H，d，J＝3Hz)，7.34(1H，d，J＝9Hz)，7.50(1H，m)，7.63(1H，d，J＝3Hz)，7.76(1H，dd，J＝9Hz，2Hz)，7.99(1H，d，J＝3Hz)，8.32(1H，d，J＝2Hz)，8.35(1H，s)，8.40(1H，d，J＝2Hz)，8.66(1H，m)，8.73(1H，br?s)。
Embodiment 261
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of piperidines-1-carboxyl tert-butyl ester
(i) 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } preparation of piperidines-1-carboxyl tert-butyl ester
With 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethylamino benzonitrile acid esters (3.46g), 4-(4-amino-2-chlorophenoxy) piperidines-1-carboxyl tert-butyl ester (3.27g) and Virahol (50mL) stirs down at 80 ℃ and spends the night.The concentrating under reduced pressure reaction mixture adds entry and saturated sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 10: 90).Concentrating under reduced pressure target fraction.Resistates by ethyl acetate-Di Iso Propyl Ether crystallization, is obtained the title compound (4.70g) of white powder.
1H-NMR(CDCl
3)δ1.48(9H，s)，1.71-1.92(4H，m)，3.33-3.45(2H，m)，3.62-3.73(2H，m)，3.90-3.97(2H，m)，4.05(2H，t，J＝4.4Hz)，4.29-4.39(1H，m)，4.46-4.52(2H，m)，4.56(2H，t，J＝4.4Hz)，6.61(1H，d，J＝3.3Hz)，6.72(1H，d，J＝8.7Hz)，7.19(1H，d，J＝3.3Hz)，7.29(1H，dd，J＝8.7，2.7Hz)，7.33-7.40(2H，m)，7.50-7.57(1H，m)，7.69(1H，d，J＝2.7Hz)，7.78-7.83(2H，m)，8.47(1H，s)，8.55(1H，br?s)。
(ii) 4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of piperidines-1-carboxyl tert-butyl ester
With 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } piperidines-1-carboxyl tert-butyl ester (636mg) is dissolved in the mixed solvent of methyl alcohol (10mL) and tetrahydrofuran (THF) (10mL), add 1N aqueous sodium hydroxide solution (2mL), and mixture at room temperature stirred spend the night.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 10: 90).Concentrating under reduced pressure target fraction.Solvent evaporated under reduced pressure, and with the resistates that obtains by ethyl acetate-ether crystallization, obtain the title compound (498mg) of white powder.
1H-NMR(CDCl
3)δ1.47(9H，s)，1.75-1.96(4H，m)，2.27(1H，br?s)，3.33-3.45(2H，m)，3.63-3.82(6H，m)，4.00(2H，t，J＝4.5Hz)，4.39-4.47(1H，m)，4.54(2H，t，J＝4.5Hz)，6.58(1H，d，J＝3.3Hz)，6.95(1H，d，J＝8.8Hz)，7.17(1H，d，J＝3.3Hz)，7.52(1H，dd，J＝8.8，2.7Hz)，7.70(1H，d，J＝2.7Hz)，8.46(1H，s)，8.60(1H，br?s)。
Embodiment 262
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-(2, the 6-difluorophenyl) piperidines-1-carboxamide hydrochloride
(i) 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] preparation of ethylamino benzonitrile acid esters dihydrochloride
4N hydrochloric acid/ethyl acetate solution (20mL) and ethanol (10mL) are joined 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } in piperidines-1-carboxyl tert-butyl ester (3.82g), and mixture at room temperature stirred 5 hours.The concentrating under reduced pressure reaction mixture, and with the resistates that obtains by ethanol-ethyl acetate crystallization, obtain the title compound (3.68g) of white powder.
1H-NMR(DMSO-d
6)δ1.85-2.00(2H，m)，2.07-2.21(2H，m)，3.02-3.28(4H，m)，3.77(2H，m)，3.88(2H，m)，4.29(2H，m)，4.70-4.79(1H，m)，4.89(2H，m)，6.60(1H，d，J＝3.0Hz)，7.25(1H，d，J＝8.7Hz)，7.42-7.51(3H，m)，7.61-7.73(4H，m)，7.98(1H，d，J＝3.0Hz)，8.57(1H，s)，9.20-9.50(2H，m)，9.85(1H，brs)。
(ii) 4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-(2, the 6-difluorophenyl) piperidines-1-carboxamide hydrochloride
Under vigorous stirring, to 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] add 2,6-difluorophenyl isocyanate (93mg) in the mixture of ethylamino benzonitrile acid esters dihydrochloride (305mg), 10% aqueous sodium carbonate (10mL), ethyl acetate (15mL) and tetrahydrofuran (THF) (5mL).Mixture was at room temperature stirred 2 hours, add entry, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is dissolved in methyl alcohol (8mL) and the tetrahydrofuran (THF) (2mL).Add 1N aqueous sodium hydroxide solution (1mL), and mixture was at room temperature stirred 3 hours.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 15: 85).Concentrating under reduced pressure target fraction.Resistates is dissolved in the ethyl acetate-ethanol, and adds 1N hydrochloric acid/ethyl acetate solution (0.5mL).Solvent evaporated under reduced pressure, and with the resistates that obtains by ethanol-ethyl acetate crystallization, obtain the title compound (202mg) of white powder.
1H-NMR(DMSO-d
6)δ1.60-1.75(2H，m)，1.91-2.04(2H，m)，3.20-3.55(6H，m)，3.68-3.81(2H，m)，3.84(2H，m)，4.72-4.85(3H，m)，6.67(1H，d，J＝3.0Hz)，7.06-7.17(2H，m)，7.23-7.32(1H，m)，7.35(1H，d，J＝8.9Hz)，7.51(1H，dd，J＝8.9，2.5Hz)，7.77(1H，d，J＝2.5Hz)，7.99(1H，d，J＝3.0Hz)，8.34(1H，s)，8.68(1H，s)，9.79(1H，br?s)。
Embodiment 263
2-(2-{4-[(3-chloro-4-{[1-(cyclopentylcarbonyl) piperidin-4-yl] oxygen base } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethylate hydrochlorate
React according to the method (ii) identical with embodiment 262, by use 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethyl benzoate dihydrochloride (305mg), 10% aqueous sodium carbonate (10mL), ethyl acetate (15mL), tetrahydrofuran (THF) (5mL) and pentamethylene carbonyl chloride (80mg), obtain the title compound (207mg) of white powder.
1H-NMR(DMSO-d
6)δ1.45-2.06(12H，m)，2.95-3.08(1H，m)，3.30-3.55(6H，m)，3.69-3.80(2H，m)，3.83(2H，t，J＝4.4Hz)，4.70-4.85(3H，m)，6.67(1H，d，J＝3.0Hz)，7.34(1H，d，J＝9.0Hz)，7.50(1H，dd，J＝9.0，2.7Hz)，7.76(1H，d，J＝2.7Hz)，7.99(1H，d，J＝3.0Hz)，8.68(1H，s)，9.82(1H，br?s)。
Embodiment 264
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-cyclopentyl piperidines-1-carboxamide hydrochloride
To 1, add tetrahydrofuran (THF) (1mL) solution of cyclopentamine (85mg) in two (1H-imidazoles) tetrahydrofuran (THF) (5mL) solution (162mg) of 1 '-carbonyl, and mixture was at room temperature stirred 1 hour.Adding 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] tetrahydrofuran (THF) (1mL) solution of ethylamino benzonitrile acid esters dihydrochloride (305mg) and triethylamine (0.153mL), and mixture at room temperature stirred spend the night.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is dissolved in methyl alcohol (8mL) and the tetrahydrofuran (THF) (2mL).Add 1N aqueous sodium hydroxide solution (1mL), and mixture at room temperature stirred spend the night.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 10: 90).Concentrating under reduced pressure target fraction.Resistates is dissolved in the ethyl acetate-ethanol, and adds 1N hydrochloric acid/ethyl acetate solution (0.5mL).Solvent evaporated under reduced pressure, and with the resistates that obtains by ethanol-ethyl acetate crystallization, obtain the title compound (188mg) of white powder.
1H-NMR(DMSO-d
6)δ1.30-1.95(12H，m)，3.15-3.27(2H，m)，3.40-3.50(4H，m)，3.55-3.67(2H，m)，3.83(2H，t，J＝4.6Hz)，3.82-3.98(1H，m)，4.62-4.72(1H，m)，4.80(2H，m)，6.30(1H，d，J＝6.4Hz)，6.67(1H，d，J＝3.0Hz)，7.32(1H，d，J＝9.0Hz)，7.50(1H，dd，J＝9.0，2.6Hz)，7.75(1H，d，J＝2.6Hz)，7.99(1H，d，J＝3.0Hz)，8.68(1H，s)，9.82(1H，br?s)。
Embodiment 265
4-[2-chloro-4-((5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-(4-p-methoxy-phenyl) piperidines-1-carboxamide hydrochloride
React according to the method (ii) identical with embodiment 262, by use 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters dihydrochloride (305mg), 10% aqueous sodium carbonate (10mL), ethyl acetate (15mL), tetrahydrofuran (THF) (5mL) and 4-anisole based isocyanate (75mg), obtain the title compound (209mg) of white powder.
1H-NMR(DMSO-d
6)δ1.60-1.75(2H，m)，1.90-2.03(2H，m)，3.34-3.51(6H，m)，3.68-3.80(2H，m)，3.70(3H，s)，3.84(2H，t，J＝4.5Hz)，4.70-4.85(3H，m)，6.68(1H，d，J＝3.2Hz)，6.82(2H，d，J＝9.1Hz)，7.31-7.40(3H，m)，7.51(1H，dd，J＝8.9，2.6Hz)，7.77(1H，d，J＝2.6Hz)，7.99(1H，d，J＝3.2Hz)，8.44(1H，br?s)，8.68(1H，s)，9.81(1H，br?s)。
Embodiment 266
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-(4-aminomethyl phenyl) piperidines-1-carboxamide hydrochloride
React according to the method (ii) identical with embodiment 262, by use 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters dihydrochloride (305mg), 10% aqueous sodium carbonate (10mL), ethyl acetate (15mL), tetrahydrofuran (THF) (5mL) and 4-aminomethyl phenyl isocyanic ester (67mg), obtain the title compound (190mg) of white powder.
1H-NMR(DMSO-d
6)δ1.60-1.75(2H，m)，1.90-2.03(2H，m)，2.23(3H，s)，3.34-3.51(6H，m)，3.69-3.80(2H，m)，3.84(2H，t，J＝4.5Hz)，4.69-4.84(3H，m)，6.67(1H，d，J＝3.0Hz)，7.03(2H，d，J＝8.5Hz)，7.31-7.39(3H，m)，7.51(1H，dd，J＝8.9，2.7Hz)，7.76(1H，d，J＝2.7Hz)，7.99(1H，d，J＝3.0Hz)，8.50(1H，br?s)，8.68(1H，s)，9.82(1H，br?s)。
Embodiment 267
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of t-butyl perbenzoate hydrochloride
(i) 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } preparation of t-butyl perbenzoate
With 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] mixture of ethylamino benzonitrile acid esters (1.46g), 4-(4-amino-2-chlorophenoxy) t-butyl perbenzoate (1.35g) and Virahol (30mL) stirs down at 80 ℃ and spends the night.The concentrating under reduced pressure reaction mixture adds entry and saturated sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, ethyl acetate).Concentrating under reduced pressure target fraction, and with resistates by ethyl acetate-ether crystallization, obtain the title compound (1.54g) of white powder.
1H-NMR(CDCl
3)δ1.59(9H，s)，3.93-3.99(2H，m)，4.05-4.11(2H，m)，4.46-4.52(2H，m)，4.55-4.61(2H，m)，6.64(1H，d，J＝3.2Hz)，6.82-6.90(3H，m)，7.22(1H，d，J＝3.2Hz)，7.30-7.40(3H，m)，7.47-7.54(1H，m)，7.76-7.81(2H，m)，7.90(1H，d，J＝2.6Hz)，7.94(2H，d，J＝9.1Hz)，8.51(1H，s)，8.78(1H，br?s)。
(ii) 4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of t-butyl perbenzoate hydrochloride
With 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } t-butyl perbenzoate (189mg) is dissolved in the mixed solvent of methyl alcohol (5mL) and tetrahydrofuran (THF) (1mL), add 1N aqueous sodium hydroxide solution (0.6mL), and mixture at room temperature stirred spend the night.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 10: 90).Concentrating under reduced pressure target fraction.Resistates is dissolved in the ethyl acetate-ethanol, and adds 1N hydrochloric acid/ethyl acetate solution (0.3mL).Solvent evaporated under reduced pressure, and with the resistates that obtains by ethanol-ethyl acetate crystallization, obtain the title compound (163mg) of white powder.
1H-NMR(DMSO-d
6)δ1.54(9H，s)，3.41-3.52(4H，m)，3.85(2H，m)，4.84(2H，m)，6.71(1H，d，J＝3.2Hz)，7.02(2H，d，J＝8.9Hz)，7.36(1H，d，J＝8.9Hz)，7.69(1H，dd，J＝8.9，2.4Hz)，7.93(2H，d，J＝8.9Hz)，8.00(1H，d，J＝2.4Hz)，8.04(1H，d，J＝3.2Hz)，8.75(1H，s)，10.00(1H，br?s)。
Embodiment 268
N-(tertiary butyl)-4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide hydrochloride salt
(i) 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } preparation of benzoate hydrochlorate
Trifluoroacetic acid (10mL) is joined 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } in the t-butyl perbenzoate (1.26g), and mixture at room temperature stirred 3 hours.The concentrating under reduced pressure reaction mixture adds 4N hydrochloric acid/ethyl acetate solution, and mixture is under reduced pressure concentrated once more.The resistates that obtains by the ethyl acetate crystallization, is obtained the title compound (1.16g) of white powder.
1H-NMR(DMSO-d
6)δ3.76-3.83(2H，m)，3.92(2H，t，J＝4.4Hz)，4.26-4.34(2H，m)，4.89(2H，m)，6.63(1H，d，J＝3.4Hz)，6.98(2H，d，J＝8.8Hz)，7.27(1H，d，J＝8.8Hz)，7.41-7.50(2H，m)，7.55-7.73(4H，m)，7.92-8.03(4H，m)，8.66(1H，s)，9.91(1H，br)。
(ii) N-(tertiary butyl)-4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] preparation of benzamide hydrochloride salt
With 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } benzoate hydrochlorate (183mg), 2-methylpropane-2-amine (0.038mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole monohydrate (55mg), triethylamine (0.050mL) and N, the mixture of dinethylformamide (3mL) at room temperature stirs and spends the night.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 10: 90).Concentrating under reduced pressure target fraction.Resistates is dissolved in the mixed solvent of methyl alcohol (5mL) and tetrahydrofuran (THF) (1mL), adds 1N aqueous sodium hydroxide solution (0.6mL), and mixture was at room temperature stirred 3 days.Water is joined in the reaction mixture, and with the mixture ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and the resistates that obtains is carried out the alkaline silica gel column chromatography handle (elutriant, methyl alcohol: ethyl acetate=0: 100 → 10: 90).Concentrating under reduced pressure target fraction.Resistates is dissolved in the ethyl acetate-ethanol, and adds 1N hydrochloric acid/ethyl acetate solution (0.3mL).Solvent evaporated under reduced pressure, and with the resistates that obtains by ethanol-ethyl acetate crystallization, obtain the title compound (118mg) of white powder.
1H-NMR(DMSO-d
6)δ1.37(9H，s)，3.41-3.52(4H，m)，3.85(2H，m)，4.84(2H，m)，6.71(1H，d，J＝3.2Hz)，6.97(2H，d，J＝8.8Hz)，7.29(1H，d，J＝8.8Hz)，7.67(1H，dd，J＝8.8，2.5Hz)，7.72(1H，s)，7.85(2H，d，J＝8.8Hz)，7.99(1H，d，J＝2.5Hz)，8.04(1H，d，J＝3.2Hz)，8.75(1H，s)，10.00(1H，br?s)。
Embodiment 269
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-(2, the 2-dimethyl propyl) benzamide
According to the same procedure of embodiment 268 described in (ii), by using 4-{4-[(5-{2-[2-(benzoyloxy) oxyethyl group] ethyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-yl) amino]-the 2-chlorophenoxy } benzoate hydrochlorate (183mg), neopentyl amine (0.042mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (69mg), I-hydroxybenzotriazole monohydrate (55mg), triethylamine (0.050mL), N, dinethylformamide (3mL), methyl alcohol (5mL), tetrahydrofuran (THF) (1mL) and 1N aqueous sodium hydroxide solution (0.6mL) obtain the title compound (140mg) of white powder.
1H-NMR(DMSO-d
6)δ0.90(9H，s)，3.10(2H，d，J＝6.4Hz)，3.42-3.52(4H，m)，3.86(2H，t，J＝4.6Hz)，4.83(2H，t，J＝4.6Hz)，6.71(1H，d，J＝2.9Hz)，7，01(2H，d，J＝8.5Hz)，7.32(1H，d，J＝8.8Hz)，7.66(1H，dd，J＝8.8，2.2Hz)，7.91(2H，d，J＝8.5Hz)，7.99(1H，d，J＝2.2Hz)，8.03(1H，d，J＝2.9Hz)，8.32(1H，t，J＝6.4Hz)，8.75(1H，s)，9.95(1H，br?s)。
Embodiment 270
4-[2-chloro-4-({ 5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group]-preparation of N-(2,2, the 2-trifluoroethyl) piperidines-1-carboxamide hydrochloride
According to the same procedure described in the embodiment 264, by using 1,1 '-carbonyl two (1H-imidazoles) (97mg), 2,2,2-trifluoro ethamine (0.048mL), 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters dihydrochloride (244mg), triethylamine (0.123mL) and 1N aqueous sodium hydroxide solution (0.6mL), obtain the title compound (101mg) of white powder.
1H-NMR(DMSO-d
6)δ1.53-1.68(2H，m)，1.84-1.98(2H，m)，3.25-3.70(8H，m)，3.77-3.92(4H，m)，4.66-4.77(1H，m)，4.79(2H，t，J＝4.8Hz)，6.67(1H，d，J＝3.1Hz)，7.23(1H，t，J＝6.2Hz)，7.33(1H，d，J＝9.0Hz)，7.50(1H，dd，J＝9.0，2.6Hz)，7.76(1H，d，J＝2.6Hz)，7.99(1H，d，J＝3.1Hz)，8.68(1H，s)，9.78(1H，brs)。
Embodiment 271
4-[2-chloro-4-(5-[2-(2-hydroxyl-oxethyl) ethyl]-5H-pyrrolo-[3,2-d] pyrimidine-4-yl } amino) phenoxy group] piperidines-1-carboxylic acid 2,2, the preparation of 2-trifluoro ethyl ester hydrochloride
According to the same procedure described in the embodiment 264, by using 1,1 '-carbonyl two (1H-imidazoles) (97mg), 2,2,2-trifluoroethanol (0.044mL), 2-[2-(4-{[3-chloro-4-(piperidin-4-yl oxygen base) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters dihydrochloride (244mg), triethylamine (0.123mL) and 1N aqueous sodium hydroxide solution (0.6mL), obtain the title compound (135mg) of white powder.
1H-NMR(DMSO-d
6)δ1.62-1.77(2H，m)，1.89-2.02(2H，m)，3.38-3.52(6H，m)，3.58-3.73(2H，m)，3.83(2H，t，J＝4.7Hz)，4.67-4.85(5H，m)，6.68(1H，d，J＝2.9Hz)，7.34(1H，d，J＝9.0Hz)，7.51(1H，dd，J＝9.0，2.5Hz)，7.76(1H，d，J＝2.5Hz)，7.99(1H，d，J＝2.9Hz)，8.68(1H，s)，9.82(1H，br?s)。
Embodiment 272
N-(tertiary butyl)-4-(2-chloro-4-{[5-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3,2-d] pyrimidine-4-yl] amino } phenoxy group) preparation of piperidines-1-methane amide
With 4-(2-chloro-4-{[5-(2-{[(methylsulfonyl) ethanoyl] amino } ethyl)-5H-pyrrolo-[3; 2-d] pyrimidine-4-yl] amino } phenoxy group) piperidines-1-carboxyl tert-butyl ester (120.0mg) is dissolved in the methyl alcohol (4.0mL); add 4N hydrochloric acid/ethyl acetate (5mL), and mixture was stirred 5 hours.Add 8N aqueous sodium hydroxide solution (5mL) and water (10mL), and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso.Resistates is joined in the reaction system, and with 1,1 '-carbonyl two (1H-imidazoles) (48.5mg) is dissolved in the tetrahydrofuran (THF) (5.0mL) with 2-methylpropane-2-amine (22.0mg), and mixture was stirred 1 hour.Further drip triethylamine (1.0mL), and mixture was stirred 1 hour.Add saturated sodium bicarbonate aqueous solution down ice-cooled, and with the mixture dichloromethane extraction.Extraction liquid is also concentrated through dried over mgso, and separate resistates, and by silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → ethyl acetate: methyl alcohol=80: 20).By ether/ethyl acetate crystallization, obtain crystalline title compound (17.9mg).
1H-NMR(DMSO-d
6)δ1.26(9H，s)，1.50-1.70(2H，m)，1.81-1.95(2H，m)，3.10(3H，s)，3.11-3.65(6H，m)，4.05(2H，s)，4.45-4.65(3H，m)，5.82(1H，s)，6.47(1H，d，J＝3Hz)，7.22(1H，d，J＝9Hz)，7.55-7.58(2H，m)，7.75(1H，d，J＝3Hz)，8.27(1H，s)，8.48(1H，s)，8.66(1H，m)。
Embodiment 273
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N '-methoxyl group urea
Under ice-cooled, to N, the N of N '-carbonyl dimidazoles (187mg) adds O-methyl hydroxy amine hydrochloric acid salt (96mg) and triethylamine (0.27mL) in dinethylformamide (2mL) solution, and mixture was at room temperature stirred 30 minutes.Add 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-N of 5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), dinethylformamide (5mL) solution.At room temperature reaction mixture was stirred 22 hours, at ice-cooled sodium bicarbonate aqueous solution and the salt solution of adding down, and with twice of ethyl acetate extraction of mixture.Collected organic layer is through anhydrous magnesium sulfate drying and concentrated.Resistates is passed through silica gel column chromatography purifying (elutriant, ethyl acetate: methyl alcohol=100: 0 → 80: 20), and further by ethyl acetate/Di Iso Propyl Ether recrystallization, obtain crystalline title compound (116mg).
1H-NMR(CDCl
3)δ：3.6-3.7(2H，m)，3.70(3H，s)，4.5-4.6(2H，m)，6.14(1H，br?s)，6.63(1H，d，J＝3.0Hz)，7.05(1H，d，J＝9.0Hz)，7.1-7.5(5H，m)，7.65-7.75(1H，m)，8.02(1H，d，J＝2.7Hz)，8.46(1H，s)，8.52(1H，s)。
Embodiment 274
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N '-(2-methoxy ethyl) urea
React according to the method identical with embodiment 273, by using 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), 2-methoxy ethyl amine (87mg) and N, dinethylformamide (3mL) obtains pulverous title compound (147mg).
1H-NMR(DMSO-d
6)δ：3.05-3.15(2H，m)，3.12(3H，s)，3.2-3.5(4H，m)，4.55-4.65(2H，m)，6.42(1H，br?s)，6.56(1H，br?s)，6.68(1H，d，J＝1.8Hz)，7.25-7.35(2H，m)，7.36(1H，d，J＝8.7Hz)，7.52(1H，d，J＝8.1Hz)，7.64(1H，d，J＝9.0Hz)，7.76(1H，d，J＝9.0Hz)，7.95-8.05(2H，m)，8.75(1H，s)，9.12(1H，s)。
Embodiment 275
3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] preparation of propionitrile
React according to the method identical with embodiment 171, by using 4-chloro-5H-pyrrolo-[3,2-d] pyrimidine (3.07g), N, dinethylformamide (30mL), salt of wormwood (4.15g), 3-bromopropionitrile (3.48g), 3-chloro-4-[3-(trifluoromethyl) phenoxy group] aniline (2.26g) and Virahol (20mL), obtain pulverous title compound (2.02g).
1H-NMR(DMSO-d
6)δ：3.01(2H，t，J＝6.4Hz)，4.83(2H，t，J＝6.4Hz)，6.58(1H，s)，7.2-7.3(2H，m)，7.31(1H，d，J＝8.4Hz)，7.47(1H，d，J＝7.5Hz)，7.55-7.7(2H，m)，7.7-7.8(1H，m)，7.87(1H，s)，8.37(1H，s)，8.76(1H，s)。
Embodiment 276
6-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-8,9-dihydro-3,5,6, the 9a-tetrazine be the preparation of [cd] Azulene-7 (6H)-imines dihydrochloride also
Ice-cooled down, 12N hydrogenchloride/ethanol (3mL) is joined 3-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] in the propionitrile (200mg), and mixture stirred 2 hours down at 0 ℃.Concentrated reaction mixture, and, obtain pulverous title compound (161mg) with resistates ethyl acetate and Di Iso Propyl Ether washing.
1H-NMR(DMSO-d
6)δ：3.55-3.65(2H，m)，4.7-4.8(2H，m)，6.75-6.8(1H，m)，7.4-7.5(2H，m)，7.5-7.6(2H，m)，7.65-7.75(1H，m)，7.94(1H，s)，8.05-8.1(1H，m)，8.59(1H，s)，9.37(1H，s)，11.29(1H，s)。
Embodiment 277
N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-preparation of N '-methylguanidine dihydrochloride
To N-methyl-N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (carboxamidine) (138mg) and add 5-(2-amino-ethyl)-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group in acetonitrile (4mL) solution of ethyl diisopropyl amine (0.16mL)] phenyl-5H-pyrrolo-[3,2-d] pyrimidine-4-amine dihydrochloride (200mg), and mixture at room temperature stirred 4 days.Add entry down ice-cooled, and with the mixture ethyl acetate extraction.With extraction liquid salt water washing, through anhydrous magnesium sulfate drying and concentrated.Resistates is passed through silica gel column chromatography purifying (elutriant, ethyl acetate: hexane=80: 20 → 100: 0).The product that obtains is dissolved in the ethyl acetate, adds 4N hydrochloric acid/ethyl acetate, and mixture was at room temperature stirred 22 hours.Filter the collecting precipitation thing, and, obtain pulverous title compound (98mg) with ethyl acetate and Di Iso Propyl Ether washing.
1H-NMR(DMSO-d
6)δ：2.57(3H，d，J＝3.3Hz)，3.5-3.7(2H，m)，4.8-4.9(2H，m)，6.72(1H，s)，7.25-7.3(2H，m)，7.38(1H，d，J＝9.0Hz)，7.4-7.6(3H，m)，7.6-7.75(3H，m)，8.01(2H，d，J＝8.1Hz)，8.75(1H，s)，10.15(1H，s)。
Embodiment 278
2-(2-{4-[(3-chloro-4-{4-[3-(1H-imidazoles-1-yl) propyl group] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol dihydrochloride
(i) 3-chloro-4-{4-[3-(1H-imidazoles-1-yl) propyl group] phenoxy group } preparation of oil of mirbane
To 4-[3-(1H-imidazoles-1-yl) propyl group] N of phenol (405mg) and 3-chloro-4-fluoronitrobenzene (370mg), add salt of wormwood (415mg) in dinethylformamide (4mL) solution, and mixture was at room temperature stirred 16 hours.Add entry down ice-cooled, and with the mixture ethyl acetate extraction.With extraction liquid salt water washing, through anhydrous magnesium sulfate drying and concentrated.Resistates is passed through alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: hexane=80: 20 → 100: 0), obtain buttery title compound (669mg).
1H-NMR(CDCl
3)δ：2.1-2.25(2H，m)，2.65(2H，t，J＝7.6Hz)，3.98(2H，t，J＝6.9Hz)，6.86(1H，d，J＝9.0Hz)，6.93(1H，s)，7.02(1H，d，J＝8.6Hz)，7.09(1H，s)，7.21(1H，d，J＝8.6Hz)，7.47(1H，s)，8.04(1H，dd，J＝9.0，2.7Hz)，8.38(1H，d，J＝2.7Hz)。
(ii) 3-chloro-4-{4-[3-(1H-imidazoles-1-yl) propyl group] phenoxy group } preparation of aniline
To 3-chloro-4-{4-[3-(1H-imidazoles-1-yl) propyl group] phenoxy group } add 5%Pt/C (140mg) in methyl alcohol (7mL) solution of oil of mirbane (669mg), and mixture was at room temperature stirred under nitrogen atmosphere 16 hours.Leach 5%Pt/C, and concentrated filtrate.Resistates is passed through alkaline silica gel column chromatography purifying (elutriant, ethyl acetate: hexane=80: 20 → 100: 0), and further use ether and hexane wash, obtain pulverous title compound (277mg).
1H-NMR (CDCl
3) δ: 2.09 (2H, quintet, J=7.2Hz), 2.56 (2H, t, J=7.2Hz), 3.67 (2H, br s), 3.93 (2H, t, J=7.2Hz), 6.56 (1H, dd, J=8.4,2.7Hz), 6.75-6.95 (5H, m), 7.0-7.1 (3H, m), 7.45 (1H, s).
(iii) 2-(2-{4-[(3-chloro-4-{4-[3-(1H-imidazoles-1-yl) propyl group] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) preparation of ethanol dihydrochloride
According to embodiment 138 (ii) and (iii) identical method react, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (207mg), 3-chloro-4-{4-[3-(1H-imidazoles-1-yl) propyl group] phenoxy group } aniline (197mg) and tetrahydrofuran (THF) (4mL), obtain pulverous title compound (99mg).
1H-NMR(DMSO-d
6)δ：2.1-2.3(2H，m)，2.5-2.7(2H，m)，3.4-3.6(2H，m)，3.8-3.9(2H，m)，4.23(2H，t，J＝6.8Hz)，4.87(2H，s)，6.71(1H，d，J＝2.4Hz)，6.92(2H，d，J＝8.1Hz)，7.14(1H，d，J＝8.1Hz)，7.25(2H，d，J＝8.4Hz)，7.6-7.7(1H，m)，7.70(1H，s)，7.83(1H，s)，7.94(1H，s)，8.04(1H，d，J＝3.0Hz)，8.73(1H，s)，9.22(1H，s)。
Embodiment 279
2-(2-{4-[(3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl) butyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) the alcoholic acid preparation
(i) 3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl) butyl] phenoxy group } preparation of oil of mirbane
React according to the method identical with embodiment 278 (i), by using 4-[4-(1H-1,2,3-triazol-1-yl) butyl] phenol (435mg), 3-chloro-4-fluoronitrobenzene (370mg) and N, dinethylformamide (4mL) obtains buttery title compound (721mg).
1H-NMR(CDCl
3)δ：1.6-1.75(2H，m)，1.9-2.05(2H，m)，2.68(2H，t，J＝7.4Hz)，4.43(2H，t，J＝7.2Hz)，6.85(1H，d，J＝9.2Hz)，7.00(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.8Hz)，7.53(1H，s)，7.72(1H，s)，8.04(1H，dd，J＝2.6，9.2Hz)，8.37(1H，d，J＝2.6Hz)。
(ii) 3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl) butyl] phenoxy group } preparation of aniline
React according to the method (ii) identical, by using 3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl) butyl with embodiment 278] phenoxy group } oil of mirbane (711mg) and ethyl acetate (10mL), obtain buttery title compound (626mg).
1H-NMR(CDCl
3)δ：1.55-1.7(2H，m)，1.8-2.0(2H，m)，2.60(2H，t，J＝7.5Hz)，3.65(2H，br?s)，4.39(2H，t，J＝7.2Hz)，6.55(1H，dd，J＝8.7，2.7Hz)，6.75-6.85(3H，m)，6.87(1H，d，J＝8.4Hz)，7.04(2H，d，J＝8.4Hz)，7.49(1H，d，J＝1.0Hz)，7.69(1H，d，J＝1.0Hz)。
(iii) 2-(2-{4-[(3-chloro-4-{4-[4-(1H-1,2,3-triazol-1-yl) butyl] phenoxy group } phenyl) amino]-5H-pyrrolo-[3,2-d] pyrimidine-5-yl } oxyethyl group) the alcoholic acid preparation
According to embodiment 139 (ii) and (iii) identical method react, by using 2-[2-(4-chloro-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) oxyethyl group] ethylamino benzonitrile acid esters (346mg), 3-chloro-4-{4-[4-(1H-1,2, the 3-triazol-1-yl) butyl] phenoxy group } aniline (405mg) and Virahol (5mL), obtain pulverous title compound (293mg).
1H-NMR(DMSO-d
6)δ：1.55-1.7(2II，m)，1.85-2.0(2H，m)，2.62(2H，t，J＝7.2Hz)，3.7-3.75(2H，m)，3.75-3.8(2H，m)，4.02(2H，t，J＝4.2Hz)，4.39(2H，t，J＝6.9Hz)，4.56(2H，t，J＝4.2Hz)，6.63(1H，d，J＝3.0Hz)，6.88(2H，d，J＝8.7Hz)，6.98(1H，d，J＝8.4Hz)，7.08(2H，d，J＝8.7Hz)，7.21(1H，d，J＝3.3Hz)，7.50(1H，s)，7.54(1H，dd，J＝8.7，2.7Hz)，7.87(1H，d，J＝2.7Hz)，7.69(1H，s)，8.51(1H，s)，8.73(1H，s)。
Embodiment 280
2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } preparation of ethanamide methanesulfonates
React according to the method identical with embodiment 256; by using 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3; 2-d] pyrimidine-5-yl] ethyl } ethanamide (900mg), ethyl acetate (4.5mL) and methylsulfonic acid (0.114mL), obtain the title compound (1.0g) of colourless crystallization.
1H-NMR(DMSO-d
6)δ2.19(3H，s)，2.32(3H，s)，3.05(3H，s)，3.55(2H，q，J＝6Hz)，4.06(2H，s)，4.68(2H，t，J＝6Hz)，6.65(1H，d，J＝3Hz)，6.93(2H，m)，7.12(2H，m)，7.4-7.6(3H，m)，7.92(1H，d，J＝3Hz)，8.70(2H，m)，9.84(1H，brs)。
Formulation example 1 (amount of each tablet)
(1) the compound 10.0mg that obtains among the embodiment 39
(2) lactose 60.0mg
(3) W-Gum 35.0mg
(4) gelatin 3.0mg
(5) Magnesium Stearate 2.0mg
The mixture of the compound, 60.0mg lactose and the 35.0mg W-Gum that obtain among the 10.0mg embodiment 39 is utilized the 10 weight % aqueous gelatin solutions (3.0mg gelatin) of 0.03ml, by the granulation of 1mm-mesh screen, subsequently particle drying under 40 ℃ is also sieved once more.The particle that obtains is thus mixed with the 2.0mg Magnesium Stearate and suppress.Use the sugar-coat of the suspension that contains sucrose, titanium dioxide, talcum powder and gum arabic to carry out dressing the gained label, and polish, obtain the tablet of sugar-coat with beeswax.
Formulation example 2 (dosage of each tablet)
(1) the compound 10.0mg that obtains among the embodiment 39
(2) lactose 70.0mg
(3) W-Gum 50.0mg
(4) Zulkovsky starch 7.0mg
(5) Magnesium Stearate 3.0mg
With the aqueous solution (7.0mg Zulkovsky starch) granulation of the compound that obtains among the 10.0mg embodiment 39 and 3.0mg Magnesium Stearate,, and mix with 70.0mg lactose and 50.0mg W-Gum subsequently with these particle dryings with the 0.07ml Zulkovsky starch.Suppress this mixture, obtain tablet.
The clone of experimental example 1A people HER2 gene and the preparation of recombinant baculovirus
Use by total RNA of MCF7 cell preparation as template, by RT-PCR human cloning HER2 gene.The primer that is used for RT-PCR is preparation like this: by nucleotide sequence (the Genbank Accession M11730) information of HER2 gene, nucleotide sequence by the nucleotide sequence of coded markings peptide and restriction enzyme recognition sequence being added to coding HER2 cell intracellular domain district (Genbank AccessionM11730 (2176-3918) makes described protein contain the terminal Flag sign of N-.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 kit (TOYOBO) to carry out this PCR reaction.Make the PCR product that obtains go up electrophoresis at sepharose (1%), dna fragmentation that will be by pcr amplification is by reclaiming on the gel, then with restriction enzyme Sal I and Sph I digestion.Make the DNA of restriction enzyme treatment go up electrophoresis, and the dna fragmentation that obtains is reclaimed, and be connected to the plasmid pFASTBACl (Invitrogen) that digests with restriction enzyme Sal I and SphI, obtain expression plasmid pFB-HER2 at sepharose (1%).Confirm to insert segmental nucleotide sequence, and find that its nucleotide sequence (2176-3918 of GenbankAccession M11730) with HER2 cell intracellular domain is consistent.In addition, use BAC-TO-BAC BaculovirusExpression System (Invitrogen), preparation recombinant baculovirus BAC-HER2.
The proteinic preparation of experimental example 1B HER2 cell intracellular domain
With the SF-21 cell with 1 * 10
6Cell/mL is inoculated in the Sf-900II SFM substratum (1L that contains 10% foetal calf serum (trace), 50mg/L gentamicin (Invitrogen) and 0.1%Pluronic F-68 (Invitrogen), Invitrogen) in, and use the Erlenmeyer flask of 2L volume under 27 ℃, to carry out wave and culture with 100rpm.After cultivating 24 hours, add recombinant baculovirus BAC-HER2 (13.4mL), and mixture was further cultivated 3 days.With 2, centrifugal 5 minutes of 000rpm obtains the cell of virus infection with this substratum.The cell of this infection is washed with phosphate buffered saline(PBS) (Invitrogen), centrifugal under the same conditions, and with the preservation under-80 ℃ of this cell.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 20,000rpm, broke under the condition 3 times in 30 seconds.The disruptive medium is passed through with 40, and 000rpm made its clarification in centrifugal 30 minutes, and filtered with the filter of 0.45 μ m.With filtrate with about 0.5mL/ minute flow velocity by with Anti-FLAG M2 Affinity Gel (4mL, Sigma) post of Tian Chonging.This post is washed with buffer A, and with the buffer A wash-out that contains 100 μ g/mL mark peptides.Elutriant is concentrated with the Vivaspin 20 (Vivascience) that the molecular weight with 30K blocks (cut off).Concentrated solution is carried out purifying by the gel-filtration of using buffer A equilibrated Hi Load Superdex 200pg 16/60 (AmershamBioscience).Collection contains the fraction of HER2 cell intracellular domain, adds the final concentration of glycerine to 50%, and-80 ℃ of following stored refrigerated.
Determining of experimental example 1C HER2 kinase inhibiting activity
To be dissolved in damping fluid (50mMTris-HCl (pH7.5), the 5mM MgCl of the test compound usefulness kinase reaction in the methyl-sulphoxide (DMSO)
2, 5mM MnCl
2, 2mM dithiothreitol (DTT), 0.01%Tween-20) dilution.The damping fluid (20 μ L) that adds kinase reaction in this compound solution (10 μ L), contain the HER2 cell intracellular domain that obtains among the 5 μ g/mL experimental example 1B and the peptide substrate poly-Glu of 12.5 μ g/mL in this damping fluid: Tyr (4: 1) (Sigma).The ATP solution of adding 20 μ L in the mixture that this obtains (1.25 μ M ATP, 0.05 μ Ci[γ-
32P] ATP), mixture was reacted 10 minutes down at 25 ℃, and the 20%TC solution that will react with 50 μ L stops.This reaction soln was left standstill under 4 ℃ 20 minutes, and use cell capture device (PerkinElmer) that the insoluble part of acid is transferred to GF/C strainer (PerkinElmer), and wash with the 250mM phosphoric acid solution.After the washing, this plate is descended dry 60 minutes at 45 ℃, and add the MicroScinti 0 (PerkinElmer) of 35 μ L.Use TopCount (PerkinElmer) to measure radioactivity.Calculate the HER2 kinase inhibition rate (%) of test compound according to following formula:
Inhibiting rate (%)=(1-(counting-blank of test compound) ÷ (contrast-blank)) * 100
The counting that uses the solution that does not add the compound reaction is as " contrast ", and use does not have the counting conduct " blank " of the solution of compound and HER2 cell intracellular domain.The results are shown in the table 1 of the inhibiting rate of this compound.
Show that by above-mentioned compound of the present invention can suppress the kinase whose activity of HER2 consumingly.
Table 1
The clone of experimental example 2A people EGF acceptor gene and the preparation of recombinant baculovirus
Use by total RNA of A431 cell preparation as template, by RT-PCR human cloning EGF acceptor gene.The primer that is used for RT-PCR is preparation like this: by nucleotide sequence (the Genbank Accession XM_167493) information of EGF acceptor gene, nucleotide sequence (2182-3810 of GenbankAccession XM_167493) by nucleotide sequence and restriction enzyme recognition sequence with the coded markings peptide add to coding EGF recipient cell intracellular domain district makes described protein contain the terminal Flag sign of N-.Described primer nucleotide sequence is as follows.
EGFR-U：
5 '-AATTAAGTCGACATGGACTACAAAGACGATGACGACCGAAGGCGCCACATCGTTCG GAAGCGCACG-3 ' (recognition sequence number: 3) and
EGFR-L：
5 '-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCTTTGTGG-3 ' (recognition sequence number: 4)
Use SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen) to carry out this RT reaction, and use KOD-plus kit (TOYOBO) to carry out this PCR reaction.Make the PCR product that obtains go up electrophoresis at sepharose (1%), dna fragmentation that will be by pcr amplification is by reclaiming on the gel, then with restriction enzyme Sal I and Sph I digestion.To go up electrophoresis at sepharose (1%) with the DNA of restriction enzyme treatment, and the dna fragmentation that obtains will be reclaimed, and be connected to the plasmid pFASTBAC1 (Invitrogen) that digests with restriction enzyme Sal I and Sph I, obtain expression plasmid pFB-EGFR.Confirm to insert segmental nucleotide sequence, and find that its nucleotide sequence (2182-3810 of Genbank Accession XM_167493) with EGFR cell intracellular domain is consistent.In addition, use BAC-TO-BACBaculovirus Expression System (Invitrogen), the viral stock BAC-EGFR of preparation recombinant baculovirus.
The proteinic preparation of experimental example 2B EGF recipient cell intracellular domain
With the SF-21 cell with 1 * 10
6Cell/mL is inoculated in the Sf-900II SFM substratum (1L that contains 10% foetal calf serum (trace), 50mg/L gentamicin (Invitrogen) and 0.1%Pluronic F-68 (Invitrogen), Invitrogen) in, and the Erlenmeyer flask that uses the 2L volume shakes with 100rpm under 27 ℃ and closes cultivation.After cultivating 24 hours, add recombinant baculovirus BAC-EGFR (13.4mL), and mixture was further cultivated 3 days.With 2, centrifugal 5 minutes of 000rpm obtains the cell of virus infection with this substratum.The cell of this infection is washed with phosphate buffered saline(PBS) (Invitrogen), centrifugal under the same conditions, and with the preservation under-80 ℃ of this cell.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 20,000rpm, broke under the condition 3 times in 30 seconds.The disruptive medium is passed through with 40, and 000rpm made its clarification in centrifugal 30 minutes, and filtered with the filter of 0.45 μ m.With filtrate with about 0.5mL/ minute flow velocity by with Anti-FLAG M2 Affinity Gel (4mL, Sigma) post of Tian Chonging.This post is washed with buffer A, and with the buffer A wash-out that contains 100 μ g/mL FLAG peptides.Elutriant is concentrated with the Vivaspin 20 (Vivascience) that the molecular weight with 30K blocks.The damping fluid of this concentrated solution is passed through to use buffer A equilibrated NAP
TM25 posts (Amersham Bioscience) exchange.Collection contains the proteinic fraction of EGF recipient cell intracellular domain, adds the final concentration of glycerine to 50%, and-80 ℃ of following stored refrigerated.
Experimental example 2C EGF receptor kinase suppresses active and determines
To be dissolved in test compound damping fluid (50mM Tris-HCl (pH7.5), 5mM MgCl in the methyl-sulphoxide (DMSO)
2, 5mM MnCl
2, 2mM dithiothreitol (DTT), 0.01%Tween-20) dilution.In this compound solution (5 μ L), add damping fluid (10 μ L), contain the EGF recipient cell intracellular domain protein of 250ng/mL and the biotin labeled polypeptide biotinyl-poly-Glu of 250ng/mL: Tyr (4: 1) (CIS bio International) in this damping fluid.In the mixture that this obtains, add the damping fluid (10 μ L) that contains ATP (5 μ M), mixture was reacted 10 minutes down at 25 ℃, and should react with 25 μ L stop bath (100mM EDTA disodium salts, 62.5mM HEPES damping fluid (pH7.4), 250mM NaCl, 0.1% bovine serum albumin, 10 μ g/mL AlphaScreen test streptoavidin donor bead (Streptavidin Donor beads:PerkinElmer), and 10 μ g/mLAlphaScreen test resists-Tyrosine O-phosphate identification antibody PY-100 bind receptor pearl (Anti-phosphotyrosine (P-Tyr-100) Acceptor beads:PerkinElmer)) stop.This reaction soln was left standstill under 25 ℃ 16 hours, and use plate reader Fusion
TM(PerkinElmer) counting cells.Calculate the kinase inhibition rate (%) of test compound according to following formula:
Inhibiting rate (%)=(1-(counting-blank of test compound) ÷ (contrast-blank)) * 100
The counting that uses the solution that does not add the compound reaction is as " contrast ", and use does not have the counting conduct " blank " of the solution of compound and ATP.The results are shown in the table 2 of the inhibiting rate of this compound.
Show that by above-mentioned compound of the present invention can suppress the activity of EGF receptor kinase consumingly.
Table 2
The vitro inhibition effect of 3 pairs of breast cancer cell BT-474 propagation of experimental example
The suspension of human breast cancer cell BT-474 (100 μ l (6,000 cell)) is inoculated on the microtest plate of 96-hole, and in insulation can (37 ℃, 5% carbonic acid gas), cultivates.Second day, add the solution that 100 μ l dilute 2-each test compound doubly in advance, and with cell cultures 5 days.After removing the substratum that contains test compound, with cell with 50% trichoroacetic acid(TCA) washing and fixing, add 0.4% (w/v) SRB solution (being dissolved in 1% acetate) subsequently with fixing and staining cell albumen (Skehan etc., Journal of theNational Cancer Institute, Vol.82, pp.1107-1112,1990).With after the 1% acetic acid solution washing, add 100 μ l extraction liquids (10mM Tris solution) with extraction pigment, and measure at the absorbing wavelength place of 550nm optical density with the amount of quantitative cell as protein content.Protein content in the control group of reception test compound solution not is decided to be 100%, measures the ratio of the residual protein content of each treatment group, and calculate the content that suppresses residual cell and reach with respect to 50% of contrast required compound concentration (IC
50Value).The results are shown in the table 3.
Table 3
The industry practicality
According to the present invention, provide the pyrroles also [3,2-d] pyrimidine and pyrazoles [4,3-d] pyrimidine compound also, their preparation method and their purposes. These pyrimidine compounds that condense have excellent tyrosine kinase inhibitory activity, for hypotoxic and be very gratifying as drug products.
The application is based on the number of patent application of submitting in Japan 165050/2004 and 58231/2005, and its content is incorporated herein by reference.
Claims (17)
1. the compound or its salt of following formula representative:
R wherein
1aBe hydrogen atom,
R
2aBe C
1-8Alkyl, C
2-8Alkenyl or C
2-8Alkynyl, its each optionally be selected from following substituting group and replaced:
(a) hydroxyl,
(b) optional halogenated C
1-4Alkoxyl group,
(c)-O-(CH
2)
n-OH，
(d)-O-(CH
2)
n-O-CO-NH
2，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-O-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(g)-O-(CH
2)
n-SO
2-phenyl,
(h)-O-(CH
2)
n-SO
2-(CH
2)
n-OH，
(i)-O-(CH
2)
n-NR
8-SO
2-(optional halogenated C
1-4Alkyl),
(j)-CO-NR
8-(CH
2)
n-OH，
(k)-CO-NR
8-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(l)-NR
6R
7，
(m)-NR
8-(CH
2)
n-OH，
(n)-NR
8-(CH
2)
n-SO
2-C
1-4Alkyl,
(o)-NR
8-CO-(CH
2)
n-OH，
(p)-NR
8-CO-(CH
2)
n-O-C
1-4Alkyl,
(q)-NR
8-CO-(CH
2)
n-SO-(optional halogenated C
1-4Alkyl),
(r)-NR
8-CO-(CH
2)
n-SO
2-(optional halogenated C
1-4Alkyl),
(s)-NR
8-CO-(CH
2)
n-SO
2-C
3-8Cycloalkyl,
(t)-NR
8-CO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(u)-NR
8-CO-NH-(CH
2)
n-SO
2-C
1-4Alkyl,
(v)-NR
8-SO
2-(CH
2)
n-SO
2-C
1-4Alkyl,
(w)-S-(CH
2)
n-OH，
(x)-SO-(CH
2)
n-OH，
(y)-SO
2-(CH
2)
n-OH and
(z)-NR
8-CO-(optional substituted heterocyclic radical), described heterocyclic radical choosing is from oxazolyl, pyrazolyl and pyrrolidyl, and this heterocyclic radical is optional to be selected from following substituting group and to be replaced: hydroxyl, C
1-4Alkyl and-CO-O-C
1-4Alkyl,
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, R
8Be hydrogen atom or C
1-4Alkyl, and (CH
2)
nOptional by C
1-4Alkyl or hydroxyl replace;
R
3aBe hydrogen atom or C
1-6Alkyl; Or
R
1aAnd R
2aOptional combination is to form
Or
R
2aAnd R
3aOptional combination is to form C
2-4Alkylidene group,
B
aBe selected from halogen and optional halogenated C for optional by 1-4
1-4The phenyl ring that substituting group replaced of alkyl;
C
aFor being selected from the following phenyl that substituting group replaced: (i) halogen, (ii) optional halogenated C by 1-5
1-4Alkyl, (iii) hydroxyl-C
1-4Alkyl, (iv) heterocycle-C
1-4Alkyl, described heterocycle is selected from imidazolyl and triazolyl, (v) optional halogenated C
1-4Alkoxyl group, (vi) cyano group and (vii) optional by C
1-8The formamyl that alkyl replaces.
2. the compound or its salt of following formula representative:
R wherein
1bBe hydrogen atom, or the optional C that is replaced by hydroxyl
2-4Alkenyl;
R
2bFor
(i) optionally be selected from the following C that substituting group replaced
1-8Alkyl:
(a) halogen,
(b) hydroxyl,
(c) C
1-4Alkoxyl group,
(d)-O-(CH
2)
n-OH，
(e)-O-(CH
2)
n-O-C
1-4Alkyl,
(f)-CO-NR
8-(CH
2)
n-OH，
(g)-NR
6R
7And
(h)-NR
8-(CH
2)
n-OH，
Wherein n is 1 to 4 integer, R
6And R
7Identical or different, and each is hydrogen atom or C
1-4Alkyl, and R
8Be hydrogen atom or C
1-4Alkyl,
(ii) choose wantonly and be selected from following phenyl-C that substituting group replaced
1-4Alkyl:
(a) optional C with hydroxyl
1-4Alkyl,
(b) carboxyl,
(c) C
1-4Alkoxyl group-carbonyl,
(d) be selected from the heterocycle-carbonyl of piperidines-1-base carbonyl and piperazine-1-base carbonyl, it is optional to have the hydroxyl of being selected from and C
1-4The substituting group of alkyl and
(e) optional have a substituent C that is selected from hydroxyl and formamyl
1-4Alkyl-formamyl,
(iii) optional by C
1-4Phenyl-carbonyl that alkoxyl group replaces,
(iv) optional by C
1-4Phenyl-alkylsulfonyl that alkoxyl group replaces, or
(v) heterocycle-C
1-4Alkyl, wherein heterocycle is selected from furyl and tetrahydrofuran base, described heterocycle-C
1-4Alkyl is optional to be selected from following substituting group and to be replaced:
(a) carboxyl and
(b) C
1-4Alkoxyl group-carbonyl;
R
3bBe hydrogen atom or C
1-6Alkyl; Or
R
2bAnd R
3bOptional combination is to form C
2-4Alkylidene group,
B
bBe the optional phenyl ring that is replaced by halogen;
C
bBe selected from halogen, optional halogenated C for optional by 1-5
1-4The phenyl that substituting group replaced of alkyl and cyano group and
Z
bBe C
1-3Alkylidene group.
3. (i) 2-{2-[4-({ 3-chloro-4-[(3-luorobenzyl) oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol,
(ii) 2-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol,
(iii) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxy-3-methyl butyramide,
(iv) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,
(v) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-methyl-2-(methylsulfonyl) propionic acid amide,
(vi) 5-{2-[2-(tertiary butyl alkylsulfonyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine,
(vii) 2-(methylsulfonyl)-N-{2-[4-({ 3-methyl-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } ethanamide,
(viii) N-[2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide, or
(ix) N-{2-[4-({ 3-chloro-4-[3-(trifluoromethoxy) phenoxy group] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide,
Or any salt in them.
4.2-{2-[4-(3-chloro-4-[(3-luorobenzyl) and the oxygen base] phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol, or its salt.
5.2-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] oxyethyl group } ethanol, or its salt.
6.N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-3-hydroxy-3-methyl butyramide, or its salt.
7.N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide, or its salt.
8.N-{2-[4-(3-chloro-4-[3-(trifluoromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-methyl-2-(methylsulfonyl) propionic acid amide, or its salt.
(9.5-{2-[2-tertiary butyl alkylsulfonyl) oxyethyl group] ethyl }-N-{3-chloro-4-[3-(trifluoromethyl) phenoxy group] phenyl }-5H-pyrrolo-[3,2-d] pyrimidine-4-amine, or its salt.
(10.2-methylsulfonyl)-N-{2-[4-(3-methyl-4-[3-(trifluoromethoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl } ethanamide, or its salt.
11.N-[2-(4-{[3-chloro-4-(3-chlorophenoxy) phenyl] amino }-5H-pyrrolo-[3,2-d] pyrimidine-5-yl) ethyl]-2-(methylsulfonyl) ethanamide, or its salt.
12.N-{2-[4-(3-chloro-4-[3-(trifluoromethoxy) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3,2-d] pyrimidine-5-yl] ethyl }-2-(methylsulfonyl) ethanamide, or its salt.
13. pharmaceutical preparation, it comprises among the claim 1-12 each compound or its salt.
14. the pharmaceutical preparation of claim 13, it is a tyrosine kinase inhibitor.
15. the pharmaceutical preparation of claim 13, it is the medicament of prevention or treatment cancer.
16. the pharmaceutical preparation of claim 15, wherein said cancer are mammary cancer, prostate cancer, lung cancer, carcinoma of the pancreas or kidney.
17. each compound or its salt is used for preventing or treating the purposes of the medicine of cancer among the claim 1-12 in preparation.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004165050 | 2004-06-02 | ||
| JP165050/2004 | 2004-06-02 | ||
| JP058231/2005 | 2005-03-02 | ||
| JP2005058231 | 2005-03-02 | ||
| PCT/JP2005/010451 WO2005118588A1 (en) | 2004-06-02 | 2005-06-01 | Fused heterocyclic compound |
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| CN1993362B true CN1993362B (en) | 2010-12-15 |
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| CN2005800261871A Expired - Fee Related CN1993362B (en) | 2004-06-02 | 2005-06-01 | Fused heterocyclic compound |
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|---|---|
| CN (1) | CN1993362B (en) |
| UA (1) | UA91508C2 (en) |
| ZA (1) | ZA200610669B (en) |
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| PL3137470T3 (en) * | 2014-05-01 | 2021-10-11 | Novartis Ag | Compounds and compositions as toll-like receptor 7 agonists |
| SG11201608299TA (en) * | 2014-05-01 | 2016-11-29 | Novartis Ag | Compounds and compositions as toll-like receptor 7 agonists |
| CN105732635A (en) * | 2014-12-29 | 2016-07-06 | 南京明德新药研发股份有限公司 | Toll-like receptor 7 agonist |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1141298A (en) * | 1995-06-07 | 1997-01-29 | 美国辉瑞有限公司 | Pyrimidine-fused heterocyclic compound anti-cancer agents |
| CN1237177A (en) * | 1996-11-27 | 1999-12-01 | 辉瑞大药厂 | Fused bicyclic pyrimidine derivatives |
| US6583154B1 (en) * | 1998-02-06 | 2003-06-24 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
-
2005
- 2005-06-01 ZA ZA200610669A patent/ZA200610669B/en unknown
- 2005-06-01 CN CN2005800261871A patent/CN1993362B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1141298A (en) * | 1995-06-07 | 1997-01-29 | 美国辉瑞有限公司 | Pyrimidine-fused heterocyclic compound anti-cancer agents |
| CN1237177A (en) * | 1996-11-27 | 1999-12-01 | 辉瑞大药厂 | Fused bicyclic pyrimidine derivatives |
| US6583154B1 (en) * | 1998-02-06 | 2003-06-24 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
Non-Patent Citations (3)
| Title |
|---|
| O. S. Sizova. et al..PYRROLO[3,2-d]PYRIMIDINES. IV. SYNTHESIS ANDANTIBACTERIAL AND ANTITUMOR ACTIVITY OF2,4,7-SUBSTITUTED PYRROLO[3,2-d]PYRIMIDINES.Khimiko-farmatsevticheskii Zhurnal16 11.1982,16(11),第1338-1343页. * |
| O.S.Sizova.etal..PYRROLO[3 2-d]PYRIMIDINES. IV. SYNTHESIS ANDANTIBACTERIAL AND ANTITUMOR ACTIVITY OF2 |
| 说明书第21栏第49-56行,实施例191,215. |
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| CN1993362A (en) | 2007-07-04 |
| UA91508C2 (en) | 2010-08-10 |
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