CN103102345B - Aminoquinazoline derivative, salts thereof and application method - Google Patents
Aminoquinazoline derivative, salts thereof and application method Download PDFInfo
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- CN103102345B CN103102345B CN201210455471.2A CN201210455471A CN103102345B CN 103102345 B CN103102345 B CN 103102345B CN 201210455471 A CN201210455471 A CN 201210455471A CN 103102345 B CN103102345 B CN 103102345B
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- amino
- heteroaryl
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- 0 CCC(N(C)*)O Chemical compound CCC(N(C)*)O 0.000 description 2
- ULFWNKDACVUZOD-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC1(F)F)=O Chemical compound CC(C)(C)OC(N(CC1)CC1(F)F)=O ULFWNKDACVUZOD-UHFFFAOYSA-N 0.000 description 1
- SMRQLKOQFODOFF-CMJOXMDJSA-N CC(C)([C@H](C1)N(CCCOc2cc3c(Nc(cc4Cl)ccc4F)ncnc3cc2OC)C[C@@H]1F)O Chemical compound CC(C)([C@H](C1)N(CCCOc2cc3c(Nc(cc4Cl)ccc4F)ncnc3cc2OC)C[C@@H]1F)O SMRQLKOQFODOFF-CMJOXMDJSA-N 0.000 description 1
- NLYNXYMMSZJMTH-UHFFFAOYSA-N CC(C)([N](C)(C)C)O Chemical compound CC(C)([N](C)(C)C)O NLYNXYMMSZJMTH-UHFFFAOYSA-N 0.000 description 1
- VWBHHSJRPOSFGG-UHFFFAOYSA-N CC(Oc(c(OC)cc1ncn2)cc1c2Cl)=O Chemical compound CC(Oc(c(OC)cc1ncn2)cc1c2Cl)=O VWBHHSJRPOSFGG-UHFFFAOYSA-N 0.000 description 1
- ANGPUOTYQQFHKN-UHFFFAOYSA-N CC(Oc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OC)=O Chemical compound CC(Oc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OC)=O ANGPUOTYQQFHKN-UHFFFAOYSA-N 0.000 description 1
- YGLIWNMERWBUIL-NHAQELONSA-N CCN(CC)C(/C=C/[C@H](CCC1)N1C(OC(C)(C)C)=O)=O Chemical compound CCN(CC)C(/C=C/[C@H](CCC1)N1C(OC(C)(C)C)=O)=O YGLIWNMERWBUIL-NHAQELONSA-N 0.000 description 1
- SASWORYDCNWZRX-QGZVFWFLSA-N COc1cc2ncnc(Nc(cc3)cc(C#C)c3F)c2cc1OCCCN(CC1)C[C@@H]1F Chemical compound COc1cc2ncnc(Nc(cc3)cc(C#C)c3F)c2cc1OCCCN(CC1)C[C@@H]1F SASWORYDCNWZRX-QGZVFWFLSA-N 0.000 description 1
- ITUKEQZJJKHLKP-UHFFFAOYSA-N COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCCN(CC1)CC1(F)F Chemical compound COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCCN(CC1)CC1(F)F ITUKEQZJJKHLKP-UHFFFAOYSA-N 0.000 description 1
- HPEJWARAOYTWST-CQSZACIVSA-N COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCCN(CC1)C[C@@H]1F Chemical compound COc1cc2ncnc(Nc(cc3Cl)ccc3F)c2cc1OCCCN(CC1)C[C@@H]1F HPEJWARAOYTWST-CQSZACIVSA-N 0.000 description 1
Abstract
The invention relates to the field of medicines and discloses an aminoquinazoline derivative, salts thereof and drug preparations of the aminoquinazoline derivative and salts. The aminoquinazoline derivative and the salts are used for adjusting the activity of protein tyrosine kinase and signal response between cells or in cells. The invention also relates to a pharmaceutically acceptable drug composition comprising the compound and a method for treating high proliferative diseases of mammals, especially human by using the composition.
Description
Invention field
The invention relates to new amino quinazoline derivative and salt thereof, be used for the treatment of the disease of higher proliferation, as the cancer relevant with Mammals.The present invention especially about the compound of arrestin tyrosine kinase activity, thus between T suppression cell or intracellular signal response.The present invention be equally about use compound of the present invention or pharmaceutically comprise the compounds of this invention composition to treat Mammals, the especially method of mankind's hyperproliferative disease.
Background of invention
Protein kinase represents the protein that a large class plays an important role in cellular function retentive control and various cytopathic regulation and control.Protein tyrosine kinase can range growth factor receptors (as: VEGFR, EGFR, PDGFR, FGFR and erbB2) or non-acceptor (as: c-src and bcr-abl) kinases.The Tyrosylprotein kinase of acceptor type can be divided into again 20 kinds of different subfamilies; But not the Tyrosylprotein kinase of acceptor type has a variety of subfamily.Receptor tyrosine kinase is a large fermentoid, and somatomedin can be made to cross over cytolemma and keep extracellular calmodulin binding domain CaM, cross-film district and intracellular portion are as having kinase whose function, and phosphorylation in a concrete protein-tyrosine residue, thus affects cell proliferation.Variant or inappropriate protein kinase activity can cause the deterioration of the state of an illness.
The list of described kinases part comprises abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes and Zap70.Suppress the therapeutic goal that described kinases has become important.
EGF-R ELISA (epidermal growth factor receptor, EGFR) be a kind of receptor type tyrosine kinase, process LAN and (or) undergoing mutation in many tumours, control tumor growth by signal transduction, and generate with new vessel, the Infiltration and metastasis etc. of tumour has close relationship.EGF-R ELISA is the important regulatory factor of Growth of Cells, differentiation and survival, and its member has: erbB-1 (EGFR, HER1), erbB-2 (EGFR, HER2), erbB-3 (EGFR, and erbB-4 (EGFR, HER4) HER3).Their structural similitudies, by the protein tyrosine kinase district composition of the outer ligand binding domain of born of the same parents, single transmembrane district and high conservative.This structure has the function of acceptor, has again the ability that extracellular signal is converted into born of the same parents' internal effect, is a kind of cross-film transfer mode of novelty.Once acceptor is combined with particular ligand, just can by the autophosphorylation of corresponding Tyrosylprotein kinase activated receptor, thus the signal transduction pathway in activating cells.These signal transmission paths comprise: the activation of Ras kinase protein and short cell fission kinase protein MAPK, the multiple protein of activation both this again in activating cells core, comprise the critical loops protein D 1 of cell cycle proliferation, thus cause DNA synthesis, Growth of Cells, differentiation.The excessive activation of growth factor receptors causes the proliferation out of control of cell, thus produces various types of excessively proliferative disease, as nonsmall-cell lung cancer, mammary cancer, the cancer of the brain etc.The suppression of growth factor receptor tyrosine kinase is proved the effect having and regulate cellular replication out of control, therefore becomes the target of new type antineoplastic medicine.
Abstract of invention
The present invention relates to the method for new amino-quinazoline compound and treatment cell proliferation disorders.Compound for protein tyrosine kinase activity of the present invention has restraining effect.More satisfactory, compound of the present invention has multiple inhibitor function, can suppress as EGFR signal response.
Especially, compound involved in the present invention, and pharmaceutically acceptable composition, can be effective as EGFR inhibitor.
On the one hand, the present invention relates to a kind of compound as shown in the formula (I):
Or its racemic mixture, diastereomer, enantiomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, or pharmacy acceptable salt, wherein, R
a, R
b, R
c, R
d, A, X
1, X
2, X
3, X
4shown in being defined as follows with n.
Some of them embodiment is, R
afor aryl, heteroaryl or unsaturated heterocycle;
R
bfor alkyl or hydrogen;
R
cfor hydrogen, alkyl, haloalkyl, ether alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
Each X
1and X
2be S, O, CH independently
2or NH;
A is-(CH
2)
p-X
5-(CH
2)
q-or-(CH
2)
p-;
X
3for CH, or N;
X
4for O, S, CH
2, NH, CHR
eor NR
f; Wherein X
3during for CH, X
4be not CH
2or CHR
e;
X
5for O, NH or S;
R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, ether alkyl, the alkyl that hydroxyl replaces, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, haloalkyl, assorted alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, amino, nitro, carboxyl, cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl, formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group, heterocyclic radical alkylamino, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy,
R
efor-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, ether alkyl, the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, haloalkyl, assorted alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, amino, nitro, carboxyl, cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl, formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group, heterocyclic radical alkylamino, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy;
R
ffor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-, ether alkyl, the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, haloalkyl, assorted alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, carboxyl, cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each R
1and R
2be hydrogen independently, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or haloalkyl;
Each g is 0,1 or 2 independently;
Each n, p, q, i and j are 1,2,3,4 or 5 independently;
Wherein, when A is-(CH
2)
p-time, R
dbe not hydrogen or hydroxyl; With when n is 1, R
dbe not=NOCH
3,
with
Wherein each group-(CH
2)
p-X
7-(CH
2)
q-,-(CH
2)
p-,-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, ether alkyl, unsaturated heterocycle, amino, carboxyl, alkyl, alkylamino, the alkyl that hydroxyl replaces, haloalkyl, assorted alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl, formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group, heterocyclic radical alkylamino, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy can be all substituted or non-substituted groups.Wherein said substituting group is, hydroxyl, hydroxyalkyl, amino, halogen, cyano group, oxo (=O), aryl, heteroaryl, alkoxyl group, alkyl, haloalkyl, aminoalkyl group, alkylamino, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy or arylalkyl.
Some of them embodiment is, A is-(CH
2)
p-X
5-(CH
2)
qor-(CH
2)
p-;
X
5for O, NH or S;
Each p and q is 1,2,3,4 or 5 independently;
structural unit is selected from following minor structure:
Wherein, X
4for O, S, NH or NR
f;
R
3for-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-, R
1-C (=O) O (CH
2)
i-, C
2-10ether alkyl, the C that hydroxyl replaces
4-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
3it is not hydroxyl;
R
4for hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C
2-10ether alkyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10alkoxy aryl, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
4it is not hydroxyl;
R
5for-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-, C
2-10ether alkyl, fluorine, chlorine, bromine, iodine, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkylamino, C
1-6assorted alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group;
Each R
6, R
7, R
8and R
9be-CH=CHC (=O) NR independently
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
inR
1r
2, R
1-C (=O) O-(CH
2)
i-, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkylamino, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group;
R
10for-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-, C
2-10ether alkyl, the C that hydroxyl replaces
4-10alkyl, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, X
5for CH
2time, R
10be not hydrogen; Wherein, A is-(CH
2)
p-time, R
10it is not hydroxyl;
R
ffor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, C
2-10ether alkyl, C
1-10the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroarylalkyl, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each g is 0,1 or 2 independently;
Each i and j is 1,2,3,4 or 5 independently; With
Each R
1and R
2be hydrogen independently, C
1-6alkyl, C
3-8cycloalkyl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl or halo C
1-6alkyl.
Some of them embodiment is, R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, when A is-(CH
2)
p-time, R
dbe not hydrogen or hydroxyl; When n is 1, R
dbe not=NOCH
3,
R
efor-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group;
R
ffor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6thiazolinyl, C
1-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each g is 0,1 or 2 independently;
Each i and j is 1,2,3,4 or 5 independently; With
Each R
1and R
2be hydrogen independently, C
1-6alkyl, C
3-8cycloalkyl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl or halo C
1-6alkyl.
Some of them embodiment is, R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1o (CH
2)
i-O-(CH
2)
j-, R
1-C (=O) O (CH
2)
i-,-(CH
2)
i-NR
1r
2,=NOR
1, methoxymethyl, ethoxyl methyl, methoxvethoxvmethvl, the C that hydroxyl replaces
1-10alkyl, hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, trifluoromethyl, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, amino, nitro, carboxyl, cyano group, phenyl, benzyl, pyrazolyl or pyrazolyl; Wherein, when A is-(CH
2)
p-time, R
dbe not hydrogen or hydroxyl; When n is 1, R
dbe not=NOCH
3,
R
efor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, methoxymethyl, ethoxyl methyl, methoxvethoxvmethvl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, trifluoromethyl, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, amino, nitro, carboxyl, cyano group, phenyl, pyrazolyl imidazolyl or benzyl;
R
ffor R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-, methoxymethyl, ethoxyl methyl, methoxvethoxvmethvl, the C that hydroxyl replaces
1-10alkyl, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclobutyl, carboxyl, cyano group, phenyl or benzyl; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each i and j is 1,2,3,4 or 5 independently; With
Each R
1and R
2be hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, benzyl or trifluoromethyl independently.
Some of them embodiment is,
structural unit is selected from following minor structure:
Some of them embodiment is, R
astructural formula for shown in formula (II):
Wherein, each R
11and R
12be hydrogen independently, fluorine, chlorine, bromine, iodine, thiazolinyl; alkynyl, alkyl, cycloalkyl, haloalkyl, assorted alkyl, alkoxyl group; alkylamino, heterocyclic radical, hydroxyl, amino, nitro, carboxyl; cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl; formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group; heterocyclic radical alkylamino, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy.
Other embodiment is, each R
11and R
12be hydrogen independently, fluorine, chlorine, bromine, iodine, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl, halo C
1-6alkyl, hydroxyl, amino, nitro, carboxyl, cyano group, C
6-10aryl or C
1-9heteroaryl.
Other embodiment is, R
abe selected from substructure formula:
Some of them embodiment is, R
bfor hydrogen or C
1-6alkyl.
Some of them embodiment is, R
cfor hydrogen, C
1-6alkyl, halo C
1-6alkyl, C
2-10ether alkyl, C
1-6assorted alkyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, C
6-10aryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl or C
1-9heteroaryl C
1-6alkyl.
Some of them embodiment is, R
cfor methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, methoxy ethyl, cyclopropyl, cyclopentyl, phenyl or phenyl methyl.
Some of them embodiment is, the present invention has compound as shown in the formula (III):
Wherein, R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, C
1-10the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, C
1-6alkyl, halo C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, C
6-10arylamino, C
1-9heteroaryl amino, aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
2-10heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; With
N is 1 or 2, and when n is 1, R
dbe not=NOCH
3,
One aspect of the present invention relates to pharmaceutical composition, comprises compound of the present invention, or their steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or their prodrug, or optional pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.Some of them embodiment is, these compounds are protein tyrosine kinase inhibitors, and other embodiment is, these compounds are inhibitor of EGFR signal response.
Some of them embodiment is, pharmaceutical composition of the present invention comprises additional treatment agent further, and these additional treatment agent are preferably chemotherapeutic agent, antiproliferative, are used for the treatment of the medicine of nonsmall-cell lung cancer and epidermal carcinoma, or their combination.
Some of them embodiment is, additional treatment agent of the present invention is Zorubicin (Adriamycin), Wyeth-Ayerst Laboratories (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabin), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), Fluracil (Fluorouracil), imatinib mesylate (Imatinib mesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib), Iressa (Iressa), Xarelto (Sorafenib), Sutent (Sunitinib), Interferon, rabbit (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vinealeucoblastine(VLB), vincristine(VCR), Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix (Panitumumab), or their combination.
The present invention relates to protection on the other hand, processes, treats or alleviate the method for patient's proliferative disorders, and the pharmaceutically acceptable effective dose that described method comprises the pharmaceutical composition using compound of the present invention or contain compound of the present invention carries out administration to patient.
The present invention relates to the pharmaceutical composition using a kind of compound of the present invention or comprise compound of the present invention on the other hand and produces for protection, process or treatment patient proliferative disorders, and alleviates the purposes of the medicine of its severity.
Some of them embodiment is, proliferative disorders of the present invention is metastatic carcinoma.Other embodiment is, proliferative disorders of the present invention is epidermal carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, CNS(central nervous system) cancer, glioblastoma, or myeloproliferative disease.Other embodiment is, proliferative disorders of the present invention is atherosclerosis or pulmonary fibrosis.
The present invention relates to a kind of method suppressing in biological sample or adjust protein kinase activity on the other hand, and described method comprises the pharmaceutical composition using compound of the present invention or comprise compound of the present invention and contacts with described biological sample.
Some of them embodiment is, protein kinase of the present invention is receptor tyrosine kinase, and other embodiment is, described receptor tyrosine kinase is EGFR.
The present invention relates to a kind of method of arrestin Tyrosylprotein kinase on the other hand, and the method comprises kinases and contacts with compound of the present invention or composition.Present invention is specifically related to a kind of method suppressing EGFR signal response, the method comprises acceptor and contacts with compound of the present invention or composition.Suppress receptor protein kinase active, particularly EGFR response, can carry out in unicellular or multi-cell organism.If be present in multi-cell organism, method described in the invention comprises use compound of the present invention or composition carries out administration to organism.Some of them embodiment is, described organism is Mammals, and other embodiment is, described organism is the mankind.Other embodiment is, described method further comprises the contact of kinases and additional treatment agent.
The present invention relates on the other hand a kind of method of inhibition of cell proliferation activity, and the method comprises cell and compound of the present invention or composition can the dose of exposure of effective inhibition of cell proliferation.Other embodiment is, described method further comprises the contact of cell and additional treatment agent.
The present invention relates to the treatment to Patient cells's proliferative disease on the other hand, and the method comprises the dosage that needs of patients effectively treats required compound of the present invention or its composition administration.Other embodiment is, described method further comprises the administration of additional treatment agent.
The present invention relates to a kind of method suppressing patient tumors to grow on the other hand, and the method comprises the dosage that needs of patients effectively treats required compound of the present invention or its composition administration.Other embodiment is, described method further comprises the administration of additional treatment agent.
The present invention relates on the other hand the preparation of compound that formula (I) comprises, the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Accompanying drawing explanation
Fig. 1 is kinase assay process in Embodiment C
Circumstantial letter of the present invention
Definition and general terms
The present invention will list the document corresponding to the content specialized determined in detail, and embodiment is all attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim defines.Those skilled in the art is by many for identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of document distinguish with similar material and the present patent application or conflict, comprising but be never limited to the definition of term, the usage of term, the technology of description, or as the scope that the present patent application controls.
Unless other aspects of the following definition of application show by the present invention.According to object of the present invention, chemical element is according to the periodic table of elements, and CAS version and pharmaceutical chemicals handbook, 75, thEd, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry; " ThomasSorrell, University Science Books, Sausalito:1999, and " March'sAdvanced Organic Chemistry; " by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged reference.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound of the present invention, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " optionally " no matter before whether being positioned at term " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to, hydroxyl, hydroxyalkyl, amino, halogen, cyano group, oxo (=O), aryl, heteroaryl, alkoxyl group, alkyl, haloalkyl, aminoalkyl group, alkylamino, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy or arylalkyl etc.
The term " aliphatic " that the present invention uses or " aliphatic group ", represent straight chain (i.e. non-branched) or side chain, substituted or non-substituted completely saturated or contain the hydrocarbon chain of one or more degree of unsaturation.Unless otherwise detailed instructions, aliphatic group contains 1-20 carbon atom, and some of them embodiment is, aliphatic group contains 1-10 carbon atom, other embodiment is, aliphatic group contains 1-8 carbon atom, and other embodiment is, aliphatic group contains 1-6 carbon atom, other embodiment is, aliphatic group contains 1-4 carbon atom, and other embodiment is, aliphatic group contains 1-3 carbon atom.Suitable aliphatic group comprises, but is not limited to, straight or branched, substituted or non-substituted alkyl, alkylidene group, alkenyl or alkynyl group, as methyl, and ethyl, propyl group, vinyl etc.
The term " alkyl " that the present invention uses comprises the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkyl can independently optionally replace by one or more substituting group described in the invention.Some of them embodiment is, alkyl contains 1-10 carbon atom, other embodiment is, alkyl contains 1-8 carbon atom, and other embodiment is, alkyl contains 1-6 carbon atom, other embodiment is, alkyl contains 1-4 carbon atom, and other embodiment is, alkyl contains 1-3 carbon atom.Alkyl group further example comprises, but is not limited to, methyl (Me ,-CH
3), ethyl (Et ,-CH
2cH
3), n-propyl (n-Pr ,-CH
2cH
2cH
3), sec.-propyl (i-Pr ,-CH (CH
3)
2), normal-butyl (n-Bu ,-CH
2cH
2cH
2cH
3), isobutyl-(i-Bu ,-CH
2cH (CH
3)
2), sec-butyl (s-Bu ,-CH (CH
3) CH
2cH
3), the tertiary butyl (t-Bu ,-C (CH
3)
3), n-pentyl (-CH
2cH
2cH
2cH
2cH
3), 2-amyl group (-CH (CH
3) CH
2cH
2cH
3), 3-amyl group (-CH (CH
2cH
3)
2), 2-methyl-2-butyl (-C (CH
3)
2cH
2cH
3), 3-methyl-2-butyl (-CH (CH
3) CH (CH
3)
2), 3-methyl isophthalic acid-butyl (-CH
2cH
2cH (CH
3)
2), 2-methyl-1-butene base (-CH
2cH (CH
3) CH
2cH
3), n-hexyl (-CH
2cH
2cH
2cH
2cH
2cH
3), 2-hexyl (-CH (CH
3) CH
2cH
2cH
2cH
3), 3-hexyl (-CH (CH
2cH
3) (CH
2cH
2cH
3)), 2-methyl-2-amyl group (-C (CH
3)
2cH
2cH
2cH
3), 3-methyl-2-amyl group (-CH (CH
3) CH (CH
3) CH
2cH
3), 4-methyl-2-amyl group (-CH (CH
3) CH
2cH (CH
3)
2), 3-methyl-3-amyl group (-C (CH
3) (CH
2cH
3)
2), 2-methyl-3-amyl group (-CH (CH
2cH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (-C (CH
3)
2cH (CH
3)
2), 3,3-dimethyl-2-butyl (-CH (CH
3) C (CH
3)
3), n-heptyl, n-octyl, etc.Term " alkyl " and its prefix " alkane " use herein, all comprise the saturated carbon chains of straight chain and side chain.
The present invention use term " haloalkyl " represent alkyl replace by one or more identical or different halogen atom, wherein alkyl has implication as described in the present invention, halogen atom and fluorine, chlorine, bromine or iodine, and such example comprises, but be not limited to trifluoromethyl, trifluoroethyl etc.
The term " alkyl that hydroxyl replaces " that the present invention uses represents that alkyl is optionally substituted with one or more hydroxyl group and replaces, wherein alkyl has implication as described in the present invention, and such example comprises, but is not limited to, methylol, (R)-hydroxyethyl, (S)-hydroxyethyl, (R)-hydroxypropyl, (S)-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyl-2-propyl group, 3-hydroxyl-3-amyl group etc.
The term " ether alkyl " that the present invention uses represents in alkyl containing one or more O or S, and be connected with all the other molecules by carbon atom, wherein alkyl has implication as described in the present invention, such example comprises, but be not limited to, methoxymethyl, ethoxyethyl group, propoxypropyl, ethoxyethoxyethyl etc.
Term " thiazolinyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, and wherein at least one position is undersaturated condition, and namely a C-C is sp
2double bond, the group of its alkenyl groups can independently optionally replace by one or more substituting group described in the invention, comprise the location that group has negation " just " or " E " " Z ", wherein concrete example comprises, but be not limited to, vinyl (-CH=CH
2), allyl group (-CH
2cH=CH
2), propenyl (CH
3cH=CH-) etc.
Term " alkynyl " represents the monovalent hydrocarbon of 2-12 carbon atom straight chain or side chain, wherein at least one position is undersaturated condition, namely a C-C is sp triple bond, wherein alkynyl group can independently optionally replace by one or more substituting group described in the invention, concrete example comprises, but be not limited to, ethynyl (-C three CH), propargyl (-CH
2c tri-CH), etc.
Term " carbocylic radical " or " cycloalkyl " refer to monovalence or multivalence, non-aromatic, the unsaturated ring of saturated or part, comprise the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom.The bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic ring simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable carbocylic radical comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical comprises further, but is never limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.And described " carbocylic radical " or " cycloalkyl " they can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, arylalkyl etc.
Term " cycloalkyl oxy " or " carbocylic radical oxygen base " comprise the optional cycloalkyl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with all the other molecules by Sauerstoffatom, such example comprises, but is not limited to cyclopropyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, the cyclopropyl oxygen base etc. that hydroxyl replaces.
Term " alkoxyl group " comprises the optional alkyl replaced, and as defined herein, be connected on Sauerstoffatom, and be connected with all the other molecules by Sauerstoffatom, such example comprises, but is not limited to methoxyl group, oxyethyl group, propoxy-etc.
Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylamino is one or two C
1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C
1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " assorted alkyl " be expressed as one or more atom on alkyl can independently person replace by heteroatoms, alkyl as defined herein, and be connected with all the other molecules by carbon atom, some of them embodiment is, " assorted alkyl " be the side chain of 1-10 atom or straight chain (1-9 carbon atom be selected from N, O, P, 1-3 the heteroatoms of S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO
2, PO, PO
2group, such example comprises, but is not limited to amino methyl, methoxy ethyl etc.
Term " heterocycle " or " heterocyclic radical " commutative use herein, all refer to monocycle, dicyclo, or three-ring system, wherein on ring one or more atom can independently optionally replace by heteroatoms, ring can be completely saturated or comprise one or more degree of unsaturation, but is never the fragrant same clan, has one or more tie point to be connected to other molecules and gets on.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocycle " or " heterocyclic radical " group be 3-7 ring monocycle (1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO
2, PO, PO
2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO
2, PO, PO
2group).
Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocyclic fused formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indyl quinolizinyl and N-pyridyl urea.The example of heterocyclic group also comprises, 1,1-dioxidothiomorpholinyl, and wherein on ring two carbon atoms replace by Sauerstoffatom as pyrimidine dione base.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
What term " unsaturated heterocycle " represented is that heterocyclic radical comprises one or more degree of unsaturation, but is never the fragrant same clan, has one or more tie point to be connected to other molecules and gets on; Wherein heterocyclic radical has implication as described in the present invention, and such example comprises, but is not limited to, 2H-pyranyl, 4H-pyranyl etc.
Term " heterocyclyloxy base " comprises the optional heterocyclic radical replaced, as defined herein, be connected on Sauerstoffatom, wherein Sauerstoffatom is connected with molecule rest part, and such example comprises, but be not limited to pyrroles-2-oxygen base, pyrroles-3-oxygen base, piperidines-2-oxygen base, piperidines-3-oxygen base, piperazine-2-oxygen base, piperidines-4-oxygen base etc.
Term " heterocyclylamino group " represent amino group replace by one or two heterocyclyl groups, wherein nitrogen-atoms is connected with molecule rest part, and heterocyclic radical has implication as described in the present invention, such example comprises, but is not limited to pyrroles-2-amino, pyrroles-3-is amino, piperidines-2-is amino, and piperidines-3-is amino, and piperidines-4-is amino, piperazine-2-is amino, and two pyrroles-2-are amino.
Term " Heterocyclylalkyl " comprises the alkyl that heterocyclic radical replaces; Term " heterocyclylalkoxy " comprises the alkoxyl group that heterocyclic radical replaces, and wherein Sauerstoffatom is connected with the rest part of molecule; Term " heterocyclic radical alkylamino " comprises the alkylamino that heterocyclic radical replaces, and wherein nitrogen-atoms is connected with the rest part of molecule; Wherein heterocyclic radical, alkyl, alkoxyl group and alkylamino radicals have implication as described in the present invention.Such example comprises, but is not limited to pyrroles-2-methyl, morpholine-4-methyl, pyrroles-2-methoxyl group, piperidines-2-oxyethyl group, piperazine-2-ethylamino, morpholine-4-propoxy-, morpholine-4-ethylamino etc.
Term " heteroatoms " represents one or more O, S, N, P and Si, comprises N, the form of any oxidation state of S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Such as, or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, N(is as the N in 3,4-dihydro-2 h-pyrrole base), NH(is as the NH in pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).
Term " halogen " refers to F, Cl, Br or I.
Term used in the present invention " undersaturated " represents that part is containing one or more degree of unsaturation.
Term " aryl " can be used alone or as most of " aralkyl " " aralkoxy " or " aryloxy alkyl ", represent the monocycle altogether containing 6-14 ring, dicyclo, with the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use, as aromatic nucleus can comprise phenyl, and naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " arylalkyl " represent alkyl replace by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, and such example comprises, but is not limited to phenmethyl, styroyl, to methylphenylethyl, styryl etc.
Term " aryloxy " comprises the optional aryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to phenoxy group, to tolyloxy, to second phenoxy group etc.
Term " arylamino " represent amino group replace by one or two aromatic yl group, wherein aryl has implication as described in the present invention, and such example comprises, but is not limited to phenyl amino, diphenyl amino, and xylyl is amino.
Term " alkoxy aryl " comprise alkoxy base replace by one or more aromatic yl group, wherein aryl, alkoxyl group have implication as described in the present invention, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but be not limited to benzyloxy, to toluene oxyethyl group, to ethylbenzene methoxyl group etc.
Term " aryl alkane amino " represent alkylamino radicals replace by one or more aromatic yl group, wherein aryl, alkylamino have implication as described in the present invention, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but be not limited to phenyl methylamino-, phenylbenzene ethylamino etc.
Term " heteroaryl " can be used alone or as most of " heteroarylalkyl " or " heteroarylalkoxy ", represent the monocycle altogether containing 5-14 ring, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " fragrant heterocycle " or " heteroaromatics " and use.And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) etc.
Term " heteroarylalkyl " represent alkyl group replace by one or more heteroaryl groups, wherein alkyl group and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-ethyl, thiazole-2-methyl, imidazoles-2-ethyl, pyrimidine-2-propyl group etc.
Term " heteroaryl oxygen base " comprises the optional heteroaryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heteroaryl groups has implication as described in the present invention, and such example comprises, but be not limited to pyridine-2-oxygen base, thiazole-2-oxygen base, imidazoles-2-oxygen base, pyrimidine-2-oxygen base etc.
Term " heteroaryl amino " represent amino group replace by one or two heteroaryl groups, wherein heteroaryl has implication as described in the present invention, and such example comprises, but do not limit pyridine-2-amino, thiazole-2-is amino, and imidazoles-2-is amino, and pyrimidine-2-is amino.
The heteroarylalkyl group that term " heteroarylalkoxy " comprises containing Sauerstoffatom is connected with molecule rest part by Sauerstoffatom, and wherein heteroaryl and alkoxy base have implication as described in the present invention.Such example comprises, but is not limited to pyridyl-2-methoxyl group, pyridyl-4-oxyethyl group, thiazolyl-2-oxyethyl group, imidazoles-3-propoxy-etc.
Term " heteroarylalkylamino " represent alkylamino radicals replace by one or more heteroaryl groups, wherein heteroaryl, alkylamino have implication as described in the present invention, and be connected with molecule rest part by Sauerstoffatom, such example comprises, but be not limited to pyridyl-2-methylamino-, pyridyl-4-ethylamino, thiazolyl-2-ethylamino, imidazoles-3-third amino etc.
Term " amino-sulfonyl " represents the amino sulphonyl groups replaced, and forms sulfamyl (-SO
2nH
2).
Term " formamyl " represents the amino formyl group replaced, and forms carbamyl (-CONH
2).
No matter term " carboxyl ", be used alone or be used in conjunction with other terms, as " carboxyalkyl ", and expression-CO
2h.
As described in the invention, substituting group is drawn two keys and is connected to the member ring systems (as shown in a and b) that the ring at center is formed and represents two substituting groups any commutable position on ring and can replace.Such as, a represents any position that may be substituted on A ring, as shown in b1-b12 in b.
As described in the invention, substituting group is drawn a key and is connected to the member ring systems (as shown by c) that the ring at center is formed and represents R
dcan be able to replace any commutable position on ring.Such as, c represent any position that may be substituted on W ring all can by R
dreplace.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug
1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Designand Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates andPhosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., NewYork, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can be transformed mutually by low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-enol and imine-enamine.Valence (valency) tautomer comprises the change reassembling into bonding electron.
Term " tautomer " or " tautomeric form " represent that the isomers of different-energy can be transformed mutually by lower energy barrier.Such example comprises, but is not limited to, and proton tautomer (i.e. prototropy isomer) comprises the change by proton shifting, the isomerization of such as keto-enol and imine-enamine.Valence tautomer comprises the restructuring change of some bonding electronss.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts indetail in J.Pharmaceutical Sciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, oxysuccinic acid, 2 hydroxy propanoic acid, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C
1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH
2cH
2sO
2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
The description of the compounds of this invention
The amino-quinazoline compound that the present invention relates to and pharmaceutical preparation thereof, to tyrosine kinase receptor, especially the disease of EGFR adjustment or the treatment of illness have potential purposes.On the one hand, the present invention relates to a kind of compound as shown in the formula (I):
Or its racemic mixture, diastereomer, enantiomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, or pharmacy acceptable salt, wherein, R
a, R
b, R
c, R
d, A, X
1, X
2, X
3, X
4shown in being defined as follows with n.
Some of them embodiment is, R
afor aryl, heteroaryl or unsaturated heterocycle;
R
bfor alkyl or hydrogen;
R
cfor hydrogen, alkyl, haloalkyl, ether alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
Each X
1and X
2be S, O, CH independently
2or NH;
A is-(CH
2)
p-X
5-(CH
2)
q-or-(CH
2)
p-;
X
3for CH, or N;
X
4for O, S, CH
2, NH, CHR
eor NR
f; Wherein X
3during for CH, X
4be not CH
2or CHR
e;
X
5for O, NH or S;
R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, ether alkyl, the alkyl that hydroxyl replaces, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, haloalkyl, assorted alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, amino, nitro, carboxyl, cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl, formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group, heterocyclic radical alkylamino, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy,
R
efor-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, ether alkyl, the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, haloalkyl, assorted alkyl, alkoxyl group, alkylamino, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, amino, nitro, carboxyl, cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl, formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group, heterocyclic radical alkylamino, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy;
R
ffor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-, ether alkyl, the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, haloalkyl, assorted alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, carboxyl, cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each R
1and R
2be hydrogen independently, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or haloalkyl;
Each g is 0,1 or 2 independently;
Each n, p, q, i and j are 1,2,3,4 or 5 independently;
Wherein, when A is-(CH
2)
p-time, R
dbe not hydrogen or hydroxyl; With when n is 1, R
dbe not=NOCH
3,
with
Wherein each group-(CH
2)
p-X
7-(CH
2)
q-,-(CH
2)
p-,-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, ether alkyl, unsaturated heterocycle, amino, carboxyl, alkyl, alkylamino, the alkyl that hydroxyl replaces, haloalkyl, assorted alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl, formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group, heterocyclic radical alkylamino, aryloxy, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy can be all substituted or non-substituted groups.Wherein said substituting group is, hydroxyl, hydroxyalkyl, amino, halogen, cyano group, oxo (=O), aryl, heteroaryl, alkoxyl group, alkyl, haloalkyl, aminoalkyl group, alkylamino, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy or arylalkyl.
Some of them embodiment is, A is-(CH
2)
p-X
5-(CH
2)
qor-(CH
2)
p-;
X
5for O, NH or S;
Each p and q is 1,2,3,4 or 5 independently;
structural unit is selected from following minor structure:
Wherein, X
4for O, S, NH or NR
f;
R
3for-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-, R
1-C (=O) O (CH
2)
i-, C
2-10ether alkyl, the C that hydroxyl replaces
4-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
3it is not hydroxyl;
R
4for hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C
2-10ether alkyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10alkoxy aryl, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
4it is not hydroxyl;
R
5for-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-, C
2-10ether alkyl, fluorine, chlorine, bromine, iodine, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkylamino, C
1-6assorted alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group;
Each R
6, R
7, R
8and R
9be-CH=CHC (=O) NR independently
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
inR
1r
2, R
1-C (=O) O-(CH
2)
i-, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, C
1-6alkyl, C
1-6haloalkyl, C
1-6alkylamino, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group;
R
10for-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-, C
2-10ether alkyl, the C that hydroxyl replaces
4-10alkyl, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, X
5for CH
2time, R
10be not hydrogen; Wherein, A is-(CH
2)
p-time, R
10it is not hydroxyl;
R
ffor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, C
2-10ether alkyl, C
1-10the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroarylalkyl, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each g is 0,1 or 2 independently;
Each i and j is 1,2,3,4 or 5 independently; With
Each R
1and R
2be hydrogen independently, C
1-6alkyl, C
3-8cycloalkyl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl or halo C
1-6alkyl.
Some of them embodiment is, R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, when A is-(CH
2)
p-time, R
dbe not hydrogen or hydroxyl; When n is 1, R
dbe not=NOCH
3,
R
efor-CH=CHC (=O) NR
1r
2, R
1-S (=O)
g-, R
1-S (=O)
go-, R
1-OS (=O)
g-, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, amino-sulfonyl, formamyl, C
6-10arylamino, C
1-9heteroaryl amino, C
6-10aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group;
R
ffor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-, C
2-10ether alkyl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, C
1-6alkyl, C
1-6haloalkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6thiazolinyl, C
1-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
1-9heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each g is 0,1 or 2 independently;
Each i and j is 1,2,3,4 or 5 independently; With
Each R
1and R
2be hydrogen independently, C
1-6alkyl, C
3-8cycloalkyl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl or halo C
1-6alkyl.
Some of them embodiment is, R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1o (CH
2)
i-O-(CH
2)
j-, R
1-C (=O) O (CH
2)
i-,-(CH
2)
i-NR
1r
2,=NOR
1, methoxymethyl, ethoxyl methyl, methoxvethoxvmethvl, the C that hydroxyl replaces
1-10alkyl, hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, trifluoromethyl, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, amino, nitro, carboxyl, cyano group, phenyl, benzyl, pyrazolyl or pyrazolyl; Wherein, when A is-(CH
2)
p-time, R
dbe not hydrogen or hydroxyl; When n is 1, R
dbe not=NOCH
3,
R
efor-CH=CHC (=O) NR
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, methoxymethyl, ethoxyl methyl, methoxvethoxvmethvl, the C that hydroxyl replaces
1-10alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, trifluoromethyl, dimethylamino, diethylamino, vinyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, amino, nitro, carboxyl, cyano group, phenyl, pyrazolyl imidazolyl or benzyl;
R
ffor R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-, methoxymethyl, ethoxyl methyl, methoxvethoxvmethvl, the C that hydroxyl replaces
1-10alkyl, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclobutyl, carboxyl, cyano group, phenyl or benzyl; Wherein, A is-(CH
2)
p-time, R
fit is not methyl;
Each i and j is 1,2,3,4 or 5 independently; With
Each R
1and R
2be hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, benzyl or trifluoromethyl independently.
Some of them embodiment is,
structural unit is selected from following minor structure:
Some of them embodiment is, R
astructural formula for shown in formula (II):
Wherein, each R
11and R
12be hydrogen independently, fluorine, chlorine, bromine, iodine, thiazolinyl; alkynyl, alkyl, cycloalkyl, haloalkyl, assorted alkyl, alkoxyl group; alkylamino, heterocyclic radical, hydroxyl, amino, nitro, carboxyl; cyano group, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino-sulfonyl; formamyl, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heterocyclylamino group; heterocyclic radical alkylamino, heteroaryl oxygen base, alkoxy aryl, heteroarylalkoxy, heterocyclyloxy base or heterocyclylalkoxy.
Other embodiment is, each R
11and R
12be hydrogen independently, fluorine, chlorine, bromine, iodine, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl, halo C
1-6alkyl, hydroxyl, amino, nitro, carboxyl, cyano group, C
6-10aryl or C
1-9heteroaryl.
Other embodiment is, R
abe selected from substructure formula:
Some of them embodiment is, R
bfor hydrogen or C
1-6alkyl.
Some of them embodiment is, R
cfor hydrogen, C
1-6alkyl, halo C
1-6alkyl, C
2-10ether alkyl, C
1-6assorted alkyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, C
6-10aryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl or C
1-9heteroaryl C
1-6alkyl.
Some of them embodiment is, R
cfor methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, methoxy ethyl, cyclopropyl, cyclopentyl, phenyl or phenyl methyl.
Some of them embodiment is, the present invention has compound as shown in the formula (III):
Wherein, R
dcan be identical or different, be-CH=CHC (=O) NR independently of one another
1r
2, R
1-C (=O)-, R
1-C (=S)-, R
1o (CH
2)
i-O-(CH
2)
j-,-(CH
2)
i-NR
1r
2, R
1-C (=O) O (CH
2)
i-,=NOR
1, C
1-10the alkyl that hydroxyl replaces, fluorine, chlorine, bromine, iodine, C
1-6alkyl, halo C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkoxyl group, C
1-6alkylamino, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, C
2-10heterocyclic radical, amino, nitro, carboxyl, cyano group, C
6-10aryl, C
1-9heteroaryl, C
6-10aryl C
1-6alkyl, C
1-9heteroaryl C
1-6alkyl, C
6-10arylamino, C
1-9heteroaryl amino, aryl C
1-6alkylamino, C
1-9heteroaryl C
1-6alkylamino, C
2-10heterocyclylamino group, C
2-10heterocyclic radical C
1-6alkylamino, C
6-10aryloxy, C
1-9heteroaryl oxygen base, C
6-10aryl C
1-6alkoxyl group, C
2-10heteroaryl C
1-6alkoxyl group, C
2-10heterocyclyloxy base or C
2-10heterocyclic radical C
1-6alkoxyl group; With
N is 1 or 2, and when n is 1, R
dbe not=NOCH
3,
In other embodiment, the present invention relates to following one of them compound and pharmacy acceptable salt, solvate, but be never limited to these compounds:
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, and the disease of mediation occurs for the production of pharmaceutical prod treatment acute and chronic blood vessel, comprises that those are described in the invention.Compound of the present invention is producing the application in cancer therapy drug.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treats the illness mediated by EGFR.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and at least one pharmaceutically acceptable carrier, the effective treatment consumption needed for the combination of assistant agent or thinner.
The present invention comprises the disease that treatment patient vessel occurs to mediate equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The composition of compound of the present invention, preparation and administration
According to another aspect, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I), the compound listed by the present invention, or the compound of embodiment 1-79, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound detectably can suppress the protein kinase in biological sample or patient body effectively.There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:TheScience and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia ofPharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, per rectum administration, nose administration, containing taking administration, and vagina administration or by the administration of implantable medicine box.Term as used herein " through injection " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.The injection system of composition sterile of the present invention can be water or oleaginous suspension.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is the nontoxic acceptable thinner of injection or solvent, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil by convention can as solvent or suspension medium.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Lipid acid, as oleic acid and its glyceride derivative can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain alcohol diluents or dispersion agent, and as carboxymethyl cellulose or similar dispersing agents, the pharmaceutical preparation being generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.Other conventional tensio-active agents, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of targeted drug formulation.
The pharmaceutically acceptable composition of the present invention can be carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to, capsule, tablet, water suspension or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
In addition, the pharmaceutically acceptable composition of the present invention can with the form rectal administration of suppository.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum, thus melts in the rectum and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal relating to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable using topical preparations can prepare and be applied to these fields or organ.
Rectal suppository (see above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot also can medication like this.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carrier containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitable carrier comprises, but is not limited to, mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
Preparation can be prepared into for eye, pharmaceutically acceptable composition; as isotonic micronized suspension, the Sterile Saline of pH regulator or other aqueous solution, preferably; the Sterile Saline of isotonic solution and pH regulator or other aqueous solution, can add disinfection preservative as benzalkonium chloride.In addition, for eye, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by the gaseous solvents of nose or inhalation.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, use phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent to improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (particularly cottonseed, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic aseptic parenteral solution, suspension or the emulsion made through acceptable thinner or solvent parenterally, such as, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise list or the DG of synthesis.In addition, lipid acid such as oleic acid can be applied to injection.
Injection can be aseptic, as defended metre filter by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other sterile injectable medium before use.In order to extend the effect of compound of the present invention, usually need the absorption being slowed down compound by subcutaneous injection or intramuscularly.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on and depends on grain size and crystal shape successively by its dissolution rate.In addition, can be dissolved in oil vehicles by compound or disperse to have come the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and the microcapsule matrix as many lactic acid-polyglycolide formation compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and poly-(acid anhydrides).Injection storage form also can embed the liposome compatible with bodily tissue by compound or microemulsion prepares.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can prepare by the auxiliary material of compound of the present invention and suitable non-perfusing or carrier being mixed, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid in room temperature but are then liquid under body temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with the pharmaceutically acceptable inert excipient of at least one or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material used has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can by dressing, add shell such as known coating method on enteric coating and other drug preparation and prepare.They optionally can comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the sole active agent in the method release composition postponed.As implant compositions can comprise multimeric species and wax.
Active compound can form microcapsule formulations together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula by dressing or can add shell, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise substance besides inert diluents as general application, if tableting lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They optionally can comprise tranquilizer, or preferably, in certain part of enteron aisle, with the sole active agent in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but is not limited to, polymer and wax.
Compound of the present invention by local or formulation through percutaneous drug delivery comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any required sanitas or required buffer reagent under sterile conditions.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it is delivered in body at control compound more advantage, and such formulation can by dissolving or preparing in decentralized compound to suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate controls film or compound is scattered in polymer matrix or gelatin to control its speed.
Compound of the present invention is preferably prepared into dosage unit form to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit type " refer to that patient obtains the physical dispersion unit of the required medicine of suitably treatment herein.But, should be appreciated that compound of the present invention or composition every day total usage will judge determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the seriousness of illness and the illness be treated for any one special patient or organism, the activity of particular compound, concrete composition used, age of patient, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
The change that can produce the consumption of the compound of the present invention of single dosage form composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is, composition can be prepared into the inhibitor of dosage in 0.01-200mg/kg body weight/day by formulation method, and the amount being accepted composition by patient carries out administration.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with the agent of one or more other additional treatment (pharmacy), wherein drug combination causes acceptable untoward reaction, and this has special meaning for the treatment of high proliferative disease as cancer.In this case, compound of the present invention can in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, the disease that the normal drug treatment of additional treatment agent is special is exactly known " suitably disease therapy "." additional treatment agent " used in the present invention comprises chemotherapeutic agent or other antiproliferative medicines can in conjunction with compounds for treating proliferative disease of the present invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and those compounds described by following patent: WO 2006/010264, WO 03/024448, WO2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/030705, WO 2005/092899, comprise with demethylating agent, but be not limited to, 5-mixes nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the compound described by Publication about Document: US 6, 268137, US5, 578, 716, US5, 919, 772, US 6, 054, 439, US 6, 184, 211, US 6, 020, 318, US6, 066, 625, US 6, 506, 735, US 6, 221, 849, US 6, 953, 783, US 11/393, 380.
Other embodiment is, chemotherapeutic agent or other anti-proliferative drugs can in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutic agent comprises, but be not limited to, other therapies or carcinostatic agent can be combined carcinostatic agent of the present invention and be comprised surgery, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, biological response modifier (Interferon, rabbit, interleukin, tumour necrosis factor (TNF), the effect of TRAIL receptor target and vehicle), overheated and psychrotherapy, dilute the reagent (as antiemetic) of any untoward reaction, with the chemotherapeutic agent of other accreditations, include, but are not limited to, alkylating drug (mustargen, Chlorambucil, endoxan, melphalan, ifosfamide), metabolic antagonist (methotrexate, pemetrexed (Pemetrexed) etc.), purine antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Dx (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), mineral ion (cis-platinum, carboplatin), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol)), imatinib mesylate (Gleevec), Zorubicin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other), kinase inhibitor (imatinib (Imatinib), Sutent (Sutent), Xarelto (Nexavar), Cetuximab (Erbitux), Trastuzumab (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and other).Drug inhibition or activate the approach of cancer as mTOR, HIF(hypoxia inducible factor) approach and other.Cancer therapy more widely forum is shown in
http:// www.nci.nih.gov/, the oncologic inventory of FAD accreditation is shown in
http:// www.fda.gov/cder/cancer/druglist-rame.htm, and Merck Manual, the 18 edition .2006, all contents are all combine reference.
Other embodiment is, compound of the present invention can in conjunction with cytotoxic anticancer agent.Such carcinostatic agent can find the 13 edition the Merck index (2001) is inner.These carcinostatic agents comprise, but be never limited to, Asparaginase (Asparaginase), bleomycin (Bleomycin), carboplatin, carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytosine arabinoside (Cytarabine), Dacarbazine (Dacarbazine), dactinomycin (Dactinomycin), daunorubicin (Daunorubicin), Zorubicin (Dx), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), methotrexate (Methotrexate), ametycin (Mitomycin C), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), Procarbazine (Procarbazine), raloxifene (Raloxifen), streptozocin (Streptozocin), tamoxifen (Tamoxifen), Tioguanine (Thioguanine), Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), vindesine.
Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but be never limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-azacytidine, CldAdo (Cladribine), busulfan (Busulfan), stilboestrol, 2', 2'-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (Erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (Idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (Melphalan), mitotane (Mitotane), taxol, pentostatin (Pentostatin), N-phosphate base-L-Aspartic acid (PALA), Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide), Uniteston, phosphinothioylidynetrisaziridine (Thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
What other were suitable comprises newfound cytotoxic substance with the cytotoxin class carcinostatic agent of compound combined utilization of the present invention, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and derivative that is natural or synthesis thereof, Temozolomide (Temozolomide) (Quinn et al., J.Clin.Oncology, 2003, 21 (4), 646-651), tositumomab (Bexxar), Trabedectin (Vidal et al., Proceedings ofthe American Society for Clinical Oncology, 2004, 23, abstract 3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001, 1, 370-377).
Other embodiment is, compound of the present invention can in conjunction with other signal transduction inhibitors.What is interesting is signal transduction inhibitor using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) and their respective parts.Such reagent comprises, but is never limited to, antibody therapy as Trastuzumab (trastuzumab), Cetuximab (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but be never limited to, small molecule kinase inhibitors as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004,64,4931-4941).
Other embodiment is, compound of the present invention is in conjunction with the receptor kinase (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) of other signal transduction inhibitor targetings in division kinase domain family, and their respective parts.Such reagent comprises, but is not limited to, and antibody is as rhuMAb-VEGF (Avastin).Such reagent comprises, but be never limited to, micromolecular inhibitor is as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res.2000, 60 (8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequin et al., 92nd AACR Meeting, New Orleans, Mar.24-28, 2001, abstract 3152), KRN-951 (Taguchi et al., 95th AACRMeeting, Orlando, FIa, 2004, abstract 2575), CP-547, 632 (Beebe et al., Cancer Res.2003, 63, 7301-7309), CP-673, 451 (Roberts et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 3989), CHIR-258 (Lee et al., Proceedings of the AmericanAssociation of Cancer Research, 2004, 45, abstract 2130), MLN-518 (Shen et al., Blood, 2003, 102, 11, abstract 476).
Other embodiment is, compound of the present invention can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society forClinical Oncology, 2004, 23, abstract 3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the AmericanAssociation of Cancer Research, 2004, 45, abstract 2452), FR-901228 (Piekarz et al., Proceedings of the American Society for ClinicalOncology, 2004, 23, abstract 3028) and MGCDOI 03 (US 6, 897, 220).
Other embodiment is, compound of the present invention can in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but be never limited to, Velcade (Bortezomib) (Mackay et al., Proceedings of the American Society forClinical Oncology, 2004,23, Abstract 3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract 3849).Compound of the present invention in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, can also include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition comprising compound of the present invention, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thus obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption (those compositions comprising an additional treatment agent are as described in the invention) of additional treatment agent in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises the amount of therapeutical agent as the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as sole active therapeutical agent.Comprise in the composition of additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.
The purposes of compound of the present invention and composition
The feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I) or the compound listed by the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention compound amount can effectively detectably arrestin kinases as activity of EGFR.Compound of the present invention using be applied to as antitumor drug treatment or reduce EGFR deleterious effect.
Compound of the present invention will be applied to, but never be limited to, and use the significant quantity of compound of the present invention or composition prevent patient's administration or treat patient's proliferative disease.Such disease comprises cancer, especially metastatic carcinoma, nonsmall-cell lung cancer and epidermal carcinoma.
The treatment being applied to knurl is comprised cancer and metastatic carcinoma by compound of the present invention, includes, but are not limited to further, and cancer is as epidermal carcinoma, bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoetic tumor (comprises leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoetic tumor (comprise acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocitic leukemia); The tumour (comprising fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage) of mesenchymal cell origin; Maincenter peripheral nervous system knurl (comprise astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention also can be used for treatment eye disease such as corneal graft rejection, and the new vessel of eye is formed, and retinal neovascularazation comprises damage or metainfective new vessel is formed; Diabetic retinopathy; Retrolental fibroplasia, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds are equally also used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention may be used for processing the situation relevant to diabetes as diabetic retinopathy and microangiopathy.Compound of the present invention is equally for the situation of cancer patients's volume of blood flow minimizing.Compound of the present invention reduces patient tumors transfer also has beneficial effect.
Compound of the present invention, except useful to human treatment, also can be applicable to veterinary treatment pet, the animal of introduced variety and the animal on farm, comprises Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and when salt etc., it also means single compound, salt etc.
Comprise the methods for the treatment of of compound of the present invention or composition administration, comprise the administration to patient's additional treatment agent (combination therapy) further, wherein additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition are as single formulation, or the compound separated or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or different time administration.
The present invention comprises expressing the cytostatic method of EGFR equally, and this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: epidermal carcinoma cell, breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.
The invention provides the method suppressing EGFR kinase activity in biological sample, this method comprises and compound of the present invention or composition being contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of vitro, include, but not limited to, cell cultures or cell extraction; From the examination of living tissue material that Mammals or its extract obtain; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly EGFR kinase activity in biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to, hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, has been used to overcome restenosis (shrinking again of vessel wall after injury).But patient uses stem or other implantable devices to have the risk of clot formation or platelet activation.These disadvantageous effects can stop by using the pharmaceutically acceptable composition precoating device comprising compound of the present invention or alleviate.
The general preparation method of suitable dressing and the dressing of implantable device at document US6,099,562; US 5,886,026; With US 5,304, described by having in 121, dressing is that biocompatible polymeric material, as hydrogel polymer, gathers methyl two silicon ether, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester typically, and composition thereof.Dressing can optionally further cover by suitable dressing, as fluoro Simethicone, polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, carry out the feature of performance group compound Co ntrolled release.Another aspect of the present invention comprises the implantable device using compound of the present invention coating.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or provide " medicine storage institute " with polymkeric substance or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.
General synthetic method
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1
3, d
6-DMSO, CD
3oD or d
6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet ofdoublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6320 being equipped with G1312A binary pump and aG1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6120 being equipped with G1311A quaternary pump and G1316ATCC (column temperature remains on 30 ° of C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 ° of C.
The use of brief word below runs through the present invention:
Synthetic method 1
Compound 8 can be prepared by synthetic method 1, wherein A, R
aand R
bthere is implication as described in the present invention.Compound 1 by with carboxylic acid ammonium as ammonium formiate and orthoformic acid front three (second) ester in polar solvent at a proper temperature as 50-100 ° of C is obtained by reacting compound 2.Then demethylation obtains compound 3.Compound 4 is obtained again by esterification.Carbonyl on compound 4 by chlorizating agent as SOCl
2under the condition of heating, be converted into chlorine atom obtain chloro quinazoline derivatives compounds 5.Compound 5 and suitable amino derivative generation nucleophilic substitution reaction obtain the compound 6 replaced.Then by being hydrolyzed to obtain compound 7.Compound 7 and haloalkane hydro carbons obtain compound 8 by base catalysis under suitable temperature is as 30-60 ° of C.
Synthetic method 2
Compound 17 can be prepared by synthetic method 2, wherein A, R
a, R
b, Pg and R
dthere is implication as described in the present invention.Compound 9 is by obtaining compound 10 after esterification.Then compound 11 is obtained to protecting group on the N of compound 10.Compound 11 obtains compound 12 after reducing.Then oxidized dose obtains compound 13 as Dess-Martin is oxidized.Compound 13 obtains compound 14 with methyltriphenylphospbromide bromide phosphorus reaction under the catalysis of alkali.Then compound 15 is obtained through reduction.Under base catalysis, chemical combination 17 is obtained by reacting with compound 8 after compound 15 deprotection.
Synthetic method 3
Compound 17 can be prepared by synthetic method 3, wherein Y
1for hydrogen or alkyl; Y
2for alkyl; A, R
a, R
b, Pg and R
dthere is implication as described in the present invention.Compound 11 and alkyl grignard reagent are obtained by reacting compound 18.And then eliminative reaction occurs obtain compound 19.Compound 20 is obtained after compound 19 reduces and after deprotection.Compound 20 and compound 8 are obtained by reacting chemical combination 21 under base catalysis.
Synthetic method 4
Compound 25 can be prepared by synthetic method 4, wherein R
1, R
2, A, R
a, R
b, Pg and R
dthere is implication as described in the present invention.Compound 13 and compound 26 are obtained by reacting compound 22 under base catalysis.After compound 22 deprotection with haloalkane hydro carbons by base catalysis in polar solvent and suitable temperature as obtained compound 24 under 30-90 ° of C.Compound 24 and compound 7 are obtained by reacting chemical combination 25 under base catalysis.
Synthetic method 5
Compound 32 can be prepared by synthetic method 5, wherein A, R
a, R
b, Pg and R
dthere is implication as described in the present invention.On compound 27, latter oxidized dose of protection shouts compound 29 as Dess-Martin is oxidized.Compound 29 is obtained by reacting compound 30 under fluorizating agent is as DAST effect.Compound 30 and haloalkane hydro carbons by base catalysis in polar solvent and suitable temperature as obtained compound 31 under 30-90 ° of C.Compound 31 and compound 7 are obtained by reacting chemical combination 32 under base catalysis.If compound 28 is directly fluoridized without oxidation, obtain single fluorine and replace structure.
Embodiment
Embodiment 1
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(3-hydroxyl-3-amyl group)-Pyrrolidine)-propoxy-)-quinazoline
Step 1) 6,7-dimethoxy-4 's-oxo-3-hydrogen-quinazoline
Suspension liquid 2-amino-4, reflux 4h under 5-dimethoxybenzoic acid (23.40g), trimethyl orthoformate (52mL), ammonium formiate (30.00g) and methyl alcohol (400mL) 70 ° of C conditions, after being cooled to room temperature, add 160mL water, filtration obtains 22.70g yellow solid, yield: 93.00%.
1H NMR(400MHz,d
6-DMSO)δ:3.87(s,3H),3.91(s,3H),7.13(s,1H),7.45(s,1H),7.98(s,1H).
Step 2) 6-hydroxyl-7-methoxyl group-4-oxo-3-H-quinazoline
Suspension liquid 6,7-dimethoxy-4 '-oxo-3-H-quinazoline (6.18g), methionine(Met) (4.70g) and methylsulfonic acid (40mL) heat 3h under 130 ° of C conditions, reaction system is poured in frozen water, adding 40% sodium hydroxide regulates pH to be 7, and suction filtration obtains product (5.10g).
Step 3) 6-acetoxyl group-7-methoxyl group-4-oxo-3-H-quinazoline
Under room temperature, diacetyl oxide (10mL) is added in the mixed solution of suspension liquid 6-hydroxyl-7-methoxyl group-4-oxo-3-H-quinazoline (0.57g) and pyridine (4mL), continue 100 ° of C and heat 3h, reaction system is poured in frozen water, suction filtration obtains 0.40g product, yield 53.00%.
1H NMR(400MHz,d
6-DMSO)δ:2.30(s,3H),3.92(s,3H),7.28(s,1H),7.75(s,1H),8.08(s,1H).
The chloro-7-methoxyl group of step 4) 4--6-acetoxyl group-quinazoline
Suspension liquid 6-acetoxyl group-7-methoxyl group-4-oxo-3-hydrogen-quinazoline (2.00g), DMF (0.20mL) and thionyl chloride (30mL) 70 ° of C heat 3h, are directly used in next step reaction after concentrated.
The chloro-4-fluorophenyl of step 5) 4-((3-) amino)-7-methoxyl group-6-acetoxyl group quinazoline
The chloro-4-fluoroaniline (1.49g) of suspension liquid 4-chloro-7-methoxyl group-6-acetoxyl group-quinazoline (2.50g), 3-and Virahol (60mL) 88 ° of C heat 5h, after being cooled to room temperature, collected by suction product, obtains 2.51g solid, two step yields: 81.00%.
The chloro-4-fluorophenyl of step 6) 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline
Under room temperature, the chloro-4-fluorophenyl of suspension liquid 4-((3-) amino) add 5mol/L NaOH (5.00mL) in-7-methoxyl group-6-acetoxyl group quinazoline (2.51g) and methyl alcohol (50mL), stirring at room temperature 6h, pH is regulated to be 5 with 0.1N HCl (aq), suction filtration, collect filter residue, obtain 1.99g solid, yield: 90.00%.
Step 7) 4-((3-chloro-4-fluorophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline
The chloro-4-fluorophenyl of suspension liquid 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (20.00g), salt of wormwood (10.37g), potassiumiodide (1.04g), chlorobromopropane (7.50mL) and DMF (150mL) 40 DEG C of heated and stirred 6h, reaction system is poured into water, filter, filter residue carries out post separation, (developping agent: 10DCM:1MeOH, eluent: EA) obtain 22.05g light yellow liquid, yield: 89.00%.
MS(ESI,pos.ion)m/z:396.1[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.01(m,2H),3.68(t,J=4.2Hz,2H),4.00(s,3H),4.10(t,J=4.2Hz,2H),6.80(s,1H),7.16(s,1H),7.26(s,1H),7.30(s,1H),7.47(s,1H),8.64(s,1H)ppm.
Step 8) L-PROLINE methyl esters
Under condition of ice bath, be slowly added drop-wise to by thionyl chloride (22mL) in methyl alcohol (300mL) solution of L-PROLINE (23.03g), 70 ° of C continue reaction 5h, be spin-dried for solvent, obtain 33.13g crude product, productive rate: 99.00%, directly carry out next step reaction.
1H NMR(400MHz,CDCl
3)δ:4.67(t,J＝8.0Hz,1H),3.82(s,3H),3.40(m,2H),2.42(m,1H),2.14(m,1H),2.05(m,2H)ppm.
Step 9) N-tertiary butyl oxocarbon group-L-PROLINE methyl esters
Under condition of ice bath, tetrahydrofuran (THF) (50mL) solution of tert-Butyl dicarbonate (60.00mL) is slowly added drop-wise to L-PROLINE methyl esters (33.13g), in the tetrahydrofuran (THF) (100ml) of sodium carbonate (46.65g) and the mixed system of water (150mL), room temperature reaction spends the night, filtering solid, filtrate is extracted with ethyl acetate, and uses anhydrous Na
2sO
4dry 1h, filters, and filtrate concentrates rear pillar separation (10:1 (v/v) petrol ether/ethyl acetate) and obtains 33.90g white solid, yield: 74.00%.
1H NMR(400MHz,CDCl
3)δ:1.42,1.47(s,9H),1.87(m,2H),1.96,2.21(m,2H),3.50(m,2H),3.72(s,3H),4.22(m,1H)ppm.
Step 10) (S)-N-tertiary butyl oxycarbonyl-2-(3-hydroxyl-3-amyl group)-Pyrrolidine
Under condition of ice bath, the diethyl ether solution (24mL) of 3.0M ethylmagnesium bromide is slowly added drop-wise in anhydrous tetrahydro furan (120mL) solution of N-tertiary butyl oxocarbon group-L-PROLINE methyl esters (6.87g), continue room temperature reaction to spend the night, under ice bath, drip saturated NH
4after Cl solution (30mL) cancellation reaction, be extracted with ethyl acetate (30mL × 3), use anhydrous Na
2sO
4dry 1h, filters, and filtrate concentrates rear pillar separation (10:1 (v/v) petrol ether/ethyl acetate) and obtains 6.11g transparent liquid, yield: 80.00%.
MS(ESI,pos.ion)m/z:158.1[M-100+1]
+，202.14[M-56+1]
+.
Step 11) (S)-2-(3-hydroxyl-3-amyl group)-Pyrrolidine
Under room temperature, trifluoroacetic acid (1.80mL) is added drop-wise to (S)-N-tertiary butyl oxycarbonyl-2-(3-hydroxyl-3-amyl group) in methylene dichloride (10mL) solution of-Pyrrolidine (0.63g), continue reaction 1.5h, after being spin-dried for solvent, directly carry out next step reaction.
Step 12) (S)-N-(3-chlorine-propyl)-2-(3-hydroxyl-3-amyl group)-Pyrrolidine
Under room temperature, solid K
2cO
3(1.69g) (S)-2-(3-hydroxyl-3-amyl group is joined) in the acetone (10mL) of-Pyrrolidine, add the bromo-3-chloropropane (0.40mL) of 1-, reflux 7h, water dilutes, and extraction into ethyl acetate, uses anhydrous Na
2sO
4dry 1h, filters, and carries out post separation (10/1 (v/v) methylene chloride/methanol) and obtains 0.40g light yellow liquid, yield: 67.00% after filtrate is concentrated.
The chloro-4-fluorophenyl of step 13) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(3-hydroxyl-3-amyl group)-Pyrrolidine)-propoxy-)-quinazoline
Under room temperature, (S)-N-(3-chlorine-propyl)-2-(3-hydroxyl-3-amyl group)-Pyrrolidine (0.38g) joins the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.78g), K
2cO
3(0.29g), in the system of DMF (12mL), continue 80 ° of C and heat 6h, washing, dichloromethane extraction, uses anhydrous Na
2sO
4dry 1h, except desolventizing, concentrated solution carries out post separation, and (developping agent: 10DCM:1MeOH, eluent: 30DCM:1MeOH), obtains 0.95g white solid, yield: 54.00%, HPLC purity 99.80%.
MS(ESI,pos.ion)m/z:259.1[(M+2)/2]
+,517.2[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:0.90(t,J=6.4Hz,6H),1.58(q,J=6.4Hz,4H),1.50(m,4H),1.80(m,2H),2.30(m,3H),2.40(m,2H),3.98(s,3H),4.10(t,J=4.8Hz,2H),7.16(s,1H),7.26(s,1H),7.45(s,1H),7.57(m,1H),7.91(m,1H),8.64(s,1H)ppm.
Embodiment 2
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-vinyl-Pyrrolidine)-propoxy-)-quinazoline
Step 1) (S)-N-tertiary butyl oxycarbonyl-2-methylol-Pyrrolidine
Under 0 ° of C condition, solid hydride aluminium lithium (1.78g) is slowly added in anhydrous tetrahydro furan (200mL) solution of (S)-N-tertiary butyl oxocarbon group-L-PROLINE methyl esters (8.93g), continue 0 ° of C and react 4h, drip a small amount of shrend go out reaction after, solid diatomite filtration, filtrate anhydrous Na
2sO
4dry 1h, filters, and filtrate concentrates rear pillar and is separated, and (developping agent: 3PE:1EA, eluent: 3PE:1EA) obtains 7.36g transparent liquid, yield: 90.00%.
Step 2) (S)-N-tertiary butyl oxycarbonyl-2-Fonnyl-tetrahydro pyrroles
Under ice bath cooling, solid Dess-Martin (16.00g) is slowly added in methylene dichloride (40mL) solution of (S)-N-tertiary butyl oxycarbonyl-2-methylol-Pyrrolidine (6.30g), continue room temperature reaction 1.5h, after being spin-dried for solvent, direct column chromatography purification obtains 5.00g transparent liquid, yield: 81.00%.
Step 3) (S)-N-tertiary butyl oxycarbonyl-2-vinyl-Pyrrolidine
Under room temperature; solid potassium tert-butoxide (5.07g) joins in the anhydrous tetrahydrofuran solution (70mL) of methyltriphenylphosphonium bromide (14.34g); continue 60 ° of C and heat 1h; after being down to room temperature; add anhydrous tetrahydro furan (20mL) solution of (S)-N-tertiary butyl oxycarbonyl-2-Fonnyl-tetrahydro pyrroles (5.00g), continue room temperature reaction and spend the night, washing; extraction into ethyl acetate, uses anhydrous Na
2sO
4dry 1h, filters, and carry out post separation after filtrate is concentrated, (developping agent: 15PE:1EA, eluent: 15PE:1EA) obtains 3.73g light yellow liquid, yield: 75.00%.
Step 4) (S)-2-vinyl-Pyrrolidine
Under room temperature, trifluoroacetic acid (14.00mL) is added drop-wise in methylene dichloride (80mL) solution of (S)-N-tertiary butyl oxycarbonyl-2-vinyl-Pyrrolidine (3.73g), continue reaction 1.5h, after being spin-dried for solvent, directly carry out next step reaction.
Step 5) (S)-N-(3-chlorine-propyl)-2-vinyl-Pyrrolidine
Under room temperature, solid K
2cO
3(20.00g) join in the acetone (60mL) of (S)-2-vinyl-Pyrrolidine, add the bromo-3-chloropropane (2.80mL) of 1-, reflux 7h, washing, extraction into ethyl acetate, uses anhydrous Na
2sO
4dry 1h, filters, and carry out post separation after filtrate is concentrated, (developping agent: 20DCM:1MeOH, eluent: 20DCM:1MeOH) obtains 2.05g light yellow liquid, yield: 63.00%.
The chloro-4-fluorophenyl of step 6) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-vinyl-Pyrrolidine)-propoxy-)-quinazoline
Under room temperature, (S)-N-(3-chlorine-propyl)-2-vinyl-Pyrrolidine (1.06g) joins the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (1.50g), K
2cO
3(2.60g), in the system of DMF (25mL), continue 80 ° of C and heat 6h, washing, dichloromethane extraction, uses anhydrous Na
2sO
4dry 1h, filters, and carry out post separation after filtrate is concentrated, (developping agent: 10DCM:1MeOH, eluent: 30DCM:1MeOH), obtains 1.28g white solid, yield: 60.00%, HPLC purity: 95.43%.
MS(ESI,pos.ion)m/z:229[(M+2)/2]
+,457.1[M+1]
+；
1H NMR(400MHz,CDCl
3)δ:1.65(m,1H),1.81(m,2H),1.97(m,1H),2.10(m,2H),2.20(m,1H),2.29(m,1H),2.74(q,J=8.0Hz,1H),2.96(m,1H),3.22(m,1H),4.00(s,3H),4.17(m,1H),4.28(m,1H),5.09(m,2H),5.67(m,1H),7.16(s,1H),7.26(s,1H),7.45(s,1H),7.57(m,1H),7.91(m,1H),8.64(s,1H)ppm.
Embodiment 3
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-ethyl-Pyrrolidine)-propoxy-)-quinazoline
Step 1) (S)-N-tertiary butyl oxycarbonyl-2-ethyl-Pyrrolidine
Under room temperature, (S) ethanol (40mL) solution of-N-tertiary butyl oxycarbonyl-2-vinyl-Pyrrolidine (0.40g) under 10% palladium carbon effect of catalytic amount by hydrogen reducing 2h, filtering palladium carbon, concentrated solution, obtain 0.25g transparent liquid, yield: 62.00%, is directly used in next step reaction.
Step 2) (S)-2-ethyl-Pyrrolidine
Under room temperature, trifluoroacetic acid (7.50mL) is added drop-wise in methylene dichloride (70mL) solution of (S)-N-tertiary butyl oxycarbonyl-2-ethyl-Pyrrolidine (2.02g), continue reaction 2h, after being spin-dried for solvent, directly carry out next step reaction.
Step 3) (S)-N-(3-chlorine-propyl)-2-ethyl-Pyrrolidine
Under room temperature, solid K
2cO
3(14.00g) join in the acetone (30mL) of (S)-2-ethyl-Pyrrolidine, add the bromo-3-chloropropane (1.51mL) of 1-, reflux 7h, water dilutes, and extraction into ethyl acetate, uses anhydrous Na
2sO
4dry 1h, filters, and carry out post separation after filtrate is concentrated, (developping agent: 20DCM:1MeOH, eluent: 20DCM:1MeOH) obtains 1.00g light yellow liquid, yield: 56.00%.
The chloro-4-fluorophenyl of step 4) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-ethyl-Pyrrolidine)-propoxy-)-quinazoline
Under room temperature, (S)-N-(3-chlorine-propyl)-2-ethyl-Pyrrolidine (0.98g) joins the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (1.37g), K
2cO
3(2.96g), in the system of DMF (20mL), continue 80 ° of C and heat 10h, water dilutes, and dichloromethane extraction, uses anhydrous Na
2sO
4dry 1h, filters, and carry out post separation after filtrate is concentrated, (developping agent: 10DCM:1MeOH, eluent: 30DCM:1MeOH), obtains 1.10g white solid, yield: 56.00%, HPLC purity: 99.20%.
MS(ESI,pos.ion)m/z:459.20[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:0.92(t,J=4.8Hz,3H),1.39(m,3H),1.42(m,1H),2.01(m,2H),2.29(m,4H),2.37(m,1H),3.10(m,1H),3.29(m,1H),4.01(s,3H),4.24(m,1H),4.34(m,1H),7.10(s,1H),7.20(t,J=8.8Hz,1H),7.54(m,1H),7.55and 7.70(each m,total 1H),7.89(m,1H),8.65(s,1H)ppm.
Embodiment 4
4-((3-chloro-4-fluorophenyl) amino) the fluoro-tetramethyleneimine of-7-methoxyl group-6-(3-(3-)-propoxy-)-quinazoline
Step 1) N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine
3-hydroxy-pyrrolidine hydrochloride (3.70g) is suspended in tetrahydrofuran (THF) (30mL).Under stirring at room temperature, add the aqueous solution (30mL) of salt of wormwood (6.21g), then slowly add Boc
2o(6.87g) tetrahydrofuran (THF) (20mL) solution, stirring at room temperature reaction 1.5h.Reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, washes five times (100mL × 5), and saturated common salt is washed once, anhydrous sodium sulfate drying.Except desolventizing obtains crude product 3.85g, yield 68.63%, is directly used in the next step.
MS(ESI,pos.ion)m/z:210[M+23]
+;
1H NMR(400MHz,CDCl
3)δ:1.49(s,9H),1.93-1.99(m,2H),3.30-3.46(m,4H),4.43(s,1H)ppm.
Step 2) N-tertiary butyl oxygen acyl group-3-fluoropyrrolidine
N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine (2.00g, 1eq) is dissolved in methylene dichloride (30mL), is cooled to-10 DEG C under nitrogen protection, is slowly added dropwise to DAST(1.8eq), drip off and slowly rise to stirred overnight at room temperature afterwards.In reaction system, drip a small amount of shrend of people to go out reaction, add dchloromethane after washing twice, saturated common salt washing once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleumether/EtOAc=10/1) after filtrate is concentrated and obtain 0.27g colorless oil, yield: 13.37%.
MS(ESI,pos.ion)m/z:212[M+23]
+.
Step 3) 3-fluoropyrrolidine
N-tertiary butyl oxygen acyl group-3-fluoropyrrolidine (0.42g) is dissolved in methylene dichloride (25mL), adds trifluoroacetic acid (2mL), stirring at room temperature 1h; then pressure reducing and steaming solvent; in residue, add toluene (10mL), and then boil off, residue is directly used in the next step.Step 4) N-(3-chlorine-propyl) the fluoro-tetramethyleneimine of-3-
In the crude product of the fluoro-tetramethyleneimine of 3-, add acetone (30mL), salt of wormwood (3.06g), and then add the chloro-3-N-PROPYLE BROMIDE (0.52g) of 1-, then reflux 7h.Filter and pressure reducing and steaming solvent, residue with Ethyl acetate (100mL) dissolves, washing twice, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleum ether/EtOAc=3/1) after filtrate is concentrated and obtain 86mg product, yield: 23.50%.
MS(ESI,pos.ion)m/z:166[M+1]
+.
Step 5) 4-((3-chloro-4-fluorophenyl) amino) the fluoro-tetramethyleneimine of-7-methoxyl group-6-(3-(3-)-propoxy-)-quinazoline
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.14g) is dissolved in DMF (6mL), add salt of wormwood (0.30g), stirring at room temperature 10min, then N-(3-chlorine-propyl is added) DMF(2mL of the fluoro-tetramethyleneimine of-3-(86mg)) solution, be then warmed up to 90 ° of C and react 20h.Methylene dichloride (100mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 100mg is obtained, yield: 42.90%, purity: 93.56%.
MS(ESI,pos.ion)m/z:450[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.07-2.13(m,2H),2.15-2.33(m,2H),2.50-2.55(m,4H),2.58-2.68(m,4H),4.18(m,2H),5.03-5.20(m,1H),7.08(t,J=17.60Hz，1H),7.29(d,J=1.60Hz，1H),7.65-7.69(m,2H),8.51(s,1H),8.89(s,1H)ppm.
Embodiment 5
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-(3,3 difluoro-pyrrolidin)-propoxy-)-quinazoline
Step 1) N-tertiary butyl oxygen acyl group-3-oxo-pyrroli
N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine (3.00g) is dissolved in methylene dichloride (50mL), is cooled to 0 ° of C, then add Dai Si-Martin's oxygenant (8.83g), rise to stirring at room temperature 3h.Add saturated sodium thiosulfate solution (50mL) cancellation reaction, filter and separate organic phase, aqueous phase washes with water, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleum ether/EtOAc=10/1) after filtrate is concentrated and obtain 2.05g product, yield: 69.25%.
MS(ESI,neg.ion)m/z:130[M-55]
-.
Step 2) synthesis of N-tertiary butyl oxygen acyl group-3,3 difluoro-pyrrolidin
N-tertiary butyl oxygen acyl group-3-oxo-pyrroli (2.4g, 1.0eq) is dissolved in methylene dichloride (40mL), under nitrogen protection, is cooled to-40 ° of C, be slowly added dropwise to DAST (1.6eq). drip finish slowly rise to stirred overnight at room temperature.In reaction system, drip a small amount of shrend of people to go out reaction, add dchloromethane after washing twice, saturated common salt washing once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleum ether/EtOAc=20/1) after filtrate is concentrated and obtain the above-mentioned intermediate of 1.11g, yield: 41.34%.
MS(ESI,pos.ion)m/z:230[M+23]
+;
1H NMR(400MHz,CDCl
3)δ:1.49(s,9H),2.28-2.37(m,2H),3.55-3.69(m,4H)ppm.
Step 3) N-(3-chlorine-propyl)-3,3-difluoro-pyrrolidin
The synthesis (1.11g) of N-tertiary butyl oxygen acyl group-3,3 difluoro-pyrrolidin is dissolved in methylene dichloride (30mL), adds trifluoroacetic acid (5mL); stirring at room temperature 1h, then pressure reducing and steaming solvent, add toluene (5mL) in residue; and then boil off, residue is directly used in the next step.
In above-mentioned crude product, add acetone (30mL), salt of wormwood (10eq), and then add the chloro-3-N-PROPYLE BROMIDE (1.5eq) of 1-, then reflux 12h.Filter and pressure reducing and steaming solvent, residue with Ethyl acetate (100mL) dissolves, washing twice, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleum ether/EtOAc=3/1) after filtrate is concentrated and obtain 0.28g product, yield: 28.54%.
MS(ESI,pos.ion)m/z:184[M+1]
+.
The chloro-4-fluorophenyl of step 4) 4-((3-) amino)-7-methoxyl group-6-(3-(3,3-difluoro-pyrrolidin)-propoxy-)-quinazoline
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.40g) is dissolved in DMF (10mL), add salt of wormwood (0.88g), stirring at room temperature 10min, then N-(3-chlorine-propyl is added)-3, the DMF(2mL of 3-difluoro-pyrrolidin (0.28g)) solution, be then warmed up to 80 ° of C and react 12h.Stopped reaction, adds methylene dichloride (100mL), then washes repeatedly in system, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 410mg is obtained, yield: 70.120%, purity: 99.02%.
MS(ESI,pos.ion)m/z:468[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.08(t,J=13.60Hz，2H),2.25-2.32(m,2H),2.68(t,J=13.60Hz，2H),2.76(t,J=14.00Hz，2H),2.94(t,J=13.20Hz，2H),3.97(s,3H),4.18(t,J=13.20Hz，2H),7.14(t,J=17.60Hz，2H),7.25(d,J=8.80Hz，2H),7.44(s,1H),7.52(m,1H),7.89(m,1H),8.65(s,1H)ppm.
Embodiment 6
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
Step 1) (S)-N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine
(S)-3-hydroxy-pyrrolidine hydrochloride (20.00g) is suspended in tetrahydrofuran (THF) (200mL).Under stirring at room temperature, add the aqueous solution (30mL) of salt of wormwood (45.00g), then slowly add Boc
2o(42.36g) tetrahydrofuran (THF) (50mL) solution, stirring at room temperature reaction 20h.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, washes five times (100mL × 5), and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, filtrate is concentrated obtains crude product 21g, and yield 69.24%, is directly used in the next step.
MS(ESI,pos.ion)m/z:210[M+23]
+.
Step 2) (R)-N-tertiary butyl oxygen acyl group-3-fluoropyrrolidine
(S)-N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine (20.88g, 1eq) is dissolved in methylene dichloride (30mL), under nitrogen protection, is cooled to-10 ° of C, be slowly added dropwise to DAST (1.2eq). drip finish slowly rise to stirred overnight at room temperature.In reaction system, drip a small amount of shrend of people to go out reaction, add methylene dichloride (200mL) and dilute after washing twice, saturated common salt washing once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleumether/EtOAc=10/1) after filtrate is concentrated and obtain 8.57g brown oil, yield: 40.58%.
MS(ESI,pos.ion)m/z:212[M+23]
+.
Step 3) (R)-3-fluoropyrrolidine
(R)-N-tertiary butyl oxygen acyl group-3-fluoropyrrolidine (7.00g) is dissolved in methylene dichloride (100mL); add trifluoroacetic acid (16mL); stirring at room temperature 6h; heating reflux reaction 2h; then pressure reducing and steaming solvent; toluene (10mL) is added in residue, and then pressure reducing and steaming, residue is directly used in the next step.
Step 4) (R)-N-(3-chlorine-propyl)-3-fluoropyrrolidine
In the crude product of (R)-3-fluoropyrrolidine, add acetone (200mL), salt of wormwood (10eq), and then add the chloro-3-N-PROPYLE BROMIDE (2.0eq) of 1-, then reflux 12h.Filter and pressure reducing and steaming solvent, residue with Ethyl acetate (200mL) dissolves, washing twice, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleum ether/EtOAc=3/1) after filtrate is concentrated and obtain 3.61g product, yield: 59.08%.
MS(ESI,pos.ion)m/z:166[M+1]
+.
The chloro-4-fluorophenyl of step 5) 4-((3-) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (3.22g) is dissolved in DMF (6mL); add salt of wormwood (6.95g); stirring at room temperature 10min; then (R)-N-(3-chlorine-propyl is added) the DMF solution of-3-fluoropyrrolidine (2.00g), be then warmed up to 80 ° of C under nitrogen protection and react 20h.Methylene dichloride (200mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 1.18g is obtained, yield: 26.10%.Purity: 96.08%.
MS(ESI,pos.ion)m/z:450[M+1]
+；
1H NMR(400MHz,CDCl
3)δ:2.10-2.173(m,4H),2.21-2.36(m,1H),2.70-2.74(m,2H),2.98-3.11(m,2H),4.26-4.35(m,2H),5.13-5.27(m,1H),7.16(m,1H),7.25-7.27(m,2H),7.54-7.58(m,2H),7.92(m,1H),8.62(s,1H)ppm.
Embodiment 7
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-3-fluoropyrrolidine)-propoxy-)-quinazoline
Step 1) (R)-N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine
(R)-3-hydroxy-pyrrolidine hydrochloride (5.00g) is suspended in tetrahydrofuran (THF) (50mL).Under stirring at room temperature, add the aqueous solution (100mL) of salt of wormwood (11.21g), then slowly add Boc
2o(10.64g) tetrahydrofuran (THF) (50mL) solution, stirring at room temperature reaction is spent the night.Reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, washes five times (100mL × 5), and saturated common salt is washed once, anhydrous sodium sulfate drying.Except desolventizing obtains crude product 7.52g, yield 99.60%, is directly used in the next step.
MS(ESI,pos.ion)m/z:210[M+23]
+.
Step 2) (S)-N-tertiary butyl oxygen acyl group-3-fluoropyrrolidine
(R)-N-tertiary butyl oxygen acyl group-3-hydroxyl pyrrolidine (3.00g, 1eq) is dissolved in methylene dichloride (30mL), under nitrogen protection, is cooled to-10 ° of C, be slowly added dropwise to DAST (1.8eq).Drip and slowly rise to stirred overnight at room temperature afterwards.In reaction system, drip a small amount of shrend of people to go out reaction, add methylene dichloride (100mL) and dilute after washing twice, saturated common salt washing once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleumether/EtOAc=10/1) after filtrate is concentrated and obtain 0.97g brown oil, yield: 32.00%.
MS(ESI,pos.ion)m/z:212[M+23]
+.
Step 3) (S)-3-fluoropyrrolidine
(S)-N-tertiary butyl oxygen acyl group-3-fluoropyrrolidine (0.97g) is dissolved in methylene dichloride (30mL); add trifluoroacetic acid (5mL); stirring at room temperature 1h; then pressure reducing and steaming solvent; toluene (10mL) is added in residue; and then boil off, residue is directly used in the next step.
Step 4) (S)-N-(3-chlorine-propyl)-3-fluoropyrrolidine
In the crude product of (S)-3-fluoropyrrolidine, add acetone (30mL), salt of wormwood (7.08g, 10eq), and then add the chloro-3-N-PROPYLE BROMIDE (2.0eq) of 1-, then reflux 20h.Filter and pressure reducing and steaming solvent, residue with Ethyl acetate (100mL) dissolves, washing twice, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, carry out column chromatography for separation (eluent: Petroleum ether/EtOAc=3/1) after filtrate is concentrated and obtain 3.61g product, yield: 59.08%.
MS(ESI,pos.ion)m/z:166[M+1]
+.
The chloro-4-fluorophenyl of step 5) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-3-fluoropyrrolidine)-propoxy-)-quinazoline
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.80g) is dissolved in DMF (15mL); add salt of wormwood (1.74g); stirring at room temperature 10min; then (S)-N-(3-chlorine-propyl is added) DMF (5mL) solution of-3-fluoropyrrolidine (0.50g), be then warmed up to 80 ° of C under nitrogen protection and react 20h.Methylene dichloride (100mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 0.28g is obtained, yield: 25.00%, purity: 98.00%.
MS(ESI,pos.ion)m/z:449[M+1]
+；
1H NMR(400MHz,CDCl
3)δ:2.20-2.23(m,4H),2.21-2.36(m,1H),2.70-2.77(m,3H),2.99-3.06(m,2H),3.97(s,3H),4.24(t,2H),5.14-5.30(m,1H),7.11-7.16(m,1H),7.16-7.23(m,1H),7.58(s,1H),7.59-7.63(m,1H),7.93(m,1H),8.19(s,1H),8.65(s,1H)ppm.
Embodiment 8
4-((4-fluorophenyl) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
Step 1) 4-((4-fluorophenyl) amino)-7-methoxyl group-6-acetoxyl group quinazoline
Under suspension liquid 4-chloro-7-methoxyl group-6-acetoxyl group-quinazoline (2.17g), para-fluoroaniline (1.00mL) and Virahol (40mL) 83 ° of C conditions, reflux is overnight, after being down to room temperature, solid product Virahol (100mL) washs, obtain 2.42g white solid, yield 85.90%.
Step 2) 4-((4-fluorophenyl) amino)-7-methoxyl group-6-hydroxyl-quinazoline
Under room temperature, 5mol/L NaOH (5.00mL) joins compound 4-((4-fluorophenyl) amino) in the mixed system of-7-methoxyl group-6-acetoxyl group quinazoline (2.42g) and methyl alcohol (30mL), after 4h, pH=7 is regulated with 1N HCl, collecting by filtration obtains 1.83g white solid, yield 86.90%.
Step 3) 4-((4-fluorophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline
Under room temperature, chlorobromopropane (1.90mL) joins compound 4-((4-fluorophenyl) amino)-7-methoxyl group-6-hydroxyl-quinazoline (1.83g), K
2cO
3(2.21g), in the system of DMF (20mL), continue 40 ° of C heating overnight, reaction system has been poured into water a large amount of solid and has separated out, carry out post separation, (developping agent: 3PE:1EA, eluent: 3PE:1EA), obtain 2.11g white solid, yield: 91.02%.
Step 4) 4-((4-fluorophenyl) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
(3R)-N-Boc-3-fluoropyrrolidine (0.40g) is dissolved in methyl alcohol/hydrogenchloride (10mL), stirring at room temperature reaction 1h.Pressure reducing and steaming solvent, obtains residue.Residue is dissolved in DMF(10mL) in, add salt of wormwood (0.73g), 4-((4-fluorophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline (0.40g), tetrabutylammonium iodide (20mg), is heated to 90 ° of C and reacts 20h.Methylene dichloride (50mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 132mg is obtained, yield: 28.82%.Purity: 93.49%.
MS(ESI,pos.ion)m/z:415[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.13-2.20(m,10H),2.49-2.50(m,1H),2.76-2.77(m,2H),2.97-3.02(m,2H),4.00(s,3H),4.25(t,J=6.88Hz，2H),5.12-5.30(m,1H),7.09(m,2H),7.24-7.26(t,1H),7.32(s,1H),7.64-7.68(m,2H),8.61(s,1H)ppm.
Embodiment 9
4-((4-fluorophenyl) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
Step 1) 4-((3-ethynyl phenyl) amino)-7-methoxyl group-6-acetoxyl group quinazoline
Under suspension liquid 4-chloro-7-methoxyl group-6-acetoxyl group-quinazoline (4.31g), 3-aminophenylacetylene (3.00g) and Virahol (65.00mL) 83 ° of C conditions, reflux is overnight, after being down to room temperature, solid product Virahol (100mL) washs, collecting by filtration obtains 4.89g solid product, yield 85.90%.
Step 2) 4-((3-ethynyl phenyl) amino)-7-methoxyl group-6-hydroxyl-quinazoline
Under room temperature, 5mol/L NaOH (10.00mL) aqueous solution is added drop-wise to compound 4-((3-ethynyl phenyl) amino) in methyl alcohol (30mL) system of-7-methoxyl group-6-acetoxyl group quinazoline (4.54g), continue to stir 5h, pH=7 is regulated with the 1mol/L HCl aqueous solution, collecting by filtration obtains 3.30g white solid, yield 86.90%.
Step 3) 4-((3-ethynyl phenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline
Under room temperature, chlorobromopropane (6.06mL) joins compound 4-((3-ethynyl phenyl) amino)-7-methoxyl group-6-hydroxyl-quinazoline (5.95g), K
2cO
3(7.06g) in the system of DMF (60mL), continue 40 ° of C and heat 6h, reaction system has been poured into water a large amount of solid and has separated out, carry out post separation, (developping agent: 3PE:1EA, eluent: 3PE:1EA), obtain 5.80g white solid, yield: 77.00%.
Step 4) 4-((3-ethynyl phenyl) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
(3R)-N-Boc-3-fluoropyrrolidine (0.40g) dissolves in methyl alcohol/hydrogenchloride (10mL), stirring at room temperature reaction 3h.Pressure reducing and steaming solvent, obtains residue.Residue is dissolved in DMF(10mL) in, add salt of wormwood (0.73g), 4-((3-ethynyl phenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline (0.40g), tetrabutylammonium iodide (20mg), is heated to 80 ° of C and reacts 18h.Methylene dichloride (50mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 250mg is obtained, yield: 55.56%, purity: 95.62%.
MS(ESI,pos.ion)m/z:421[M+1]
+；
1H NMR(400MHz,CDCl
3)δ:1.71(s,1H),2.01-2.05(m,2H),2.12-2.16(m,1H),2.71(d,J=3.04Hz，2H),2.94(s,3H),3.10(s,1H),4.00(s,3H),4.25(t,J=2.16Hz，2H),5.12-5.30(m,1H),7.21(s,1H),7.25-7.29(m,1H),7.30-7.36(m,1H),7.36(t,1H),7.41(s,1H),7.75-7.76(m,1H),7.88(t,J=3.52Hz，1H),8.67(s,1H)ppm.
Embodiment 10
4-((3-ethynyl-4-fluorophenyl) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
Step 1) 4-((3-ethynyl-4-fluorophenyl) amino)-7-methoxyl group-6-acetoxyl group quinazoline
Under suspension liquid 4-chloro-7-methoxyl group-6-acetoxyl group-quinazoline (4.31g), 4-fluoro-3-acetylene aniline (2.77g) and Virahol (65.00mL) 83 ° of C conditions, reflux is overnight, after being down to room temperature, solid product Virahol (100mL) washs, filtration obtains 5.29g solid product, productive rate 88.30%.
Step 2) 4-((3-ethynyl-4-fluorophenyl) amino)-7-methoxyl group-6-hydroxyl-quinazoline
Under room temperature, 5mol/L NaOH (10.00mL) joins compound 4-((3-ethynyl-4-fluorophenyl) amino) in the mixed system of-7-methoxyl group-6-acetoxyl group quinazoline (5.29g) and methyl alcohol (30mL), after 4h, pH=7 is regulated with 1N HCl, collecting by filtration obtains 3.90g white solid, yield 83.69%.
Step 3) 4-((3-ethynyl-4-fluorophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline
Under room temperature, chlorobromopropane (3.80mL) joins compound 4-((3-ethynyl-4-fluorophenyl) amino)-7-methoxyl group-6-hydroxyl-quinazoline (3.90g), K
2cO
3(4.36g) in the system of DMF (30mL), continue 40 ° of C heating overnight, fall reaction system and be poured into water the precipitation of a large amount of solid, carry out post separation, (developping agent: 3PE:1EA, eluent: 3PE:1EA), obtain 3.30g white solid, yield: 68.00%.
Step 4) 4-((3-ethynyl-4-fluorophenyl) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
(3R)-N-Boc-3-fluoropyrrolidine (0.50g) dissolves in methyl alcohol/hydrogenchloride (10mL), stirring at room temperature reaction 1h.Pressure reducing and steaming solvent, obtains residue.Residue is dissolved in DMF(12mL) in, add salt of wormwood (0.73g), 4-((3-ethynyl-4-fluorophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline (0.33g), tetrabutylammonium iodide (20mg), is heated to 80 ° of C and reacts 16h.Methylene dichloride (50mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 112mg is obtained, yield: 29.86%.Purity: 95.17%.
MS(ESI,pos.ion)m/z:439[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.10-2.12(m,1H),2.13-2.26(m,3H),2.43(d,1H),2.68-2.74(m,3H),2.94(m,3H),3.00-3.13(m,2H),4.00(s,3H),4.28(t,J=6.80Hz，2H),5.12-5.30(m,1H),7.19(s,1H),7.22-7,26(m,1H),7.37(s,1H),7.89(s,1H),8.00-8,04(m,1H),8.18(m，1H),8.65(s,1H)ppm.
Embodiment 11
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((2S, 4S)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-)-propoxy-)-quinazoline
Step 1) (2S, 4R)-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine
Ice-water bath, to the hydrochloride (5.00g of (2S, 4R)-2-carboxylic acid-4-hydroxy-pyrrolidine, thionyl chloride (2.6mL is slowly dripped in anhydrous methanol (60mL) solution 1.0eq), 1.2eq), add in 15 minutes, then heat 4 hours under 65 ° of C.It is white solid (5.40g, 100.00%) that concentrating under reduced pressure obtains target compound.
Step 2) (2S, 4R)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine
Under ice-water bath condition, to the hydrochloride (5.40g, 1eq) of (2S, 4R)-2-methyl oxygen acyl group-4 hydroxy-pyrrolidine, in methylene dichloride (120mL) solution of triethylamine (14.5mL, 3.5eq), slowly drip (Boc)
2methylene dichloride (20mL) solution of O (8.2mL, 1.2eq), room temperature for overnight subsequently.Add methylene dichloride (50mL × 3) extraction, after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.Filter, it is white solid (6.30g, 86.10%) that filtrate reduced in volume residue obtains target product through column chromatography for separation (ethyl acetate) purifying.
The fluoro-tetramethyleneimine of step 3) (2S, 4S)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-
Ice-water bath; under nitrogen protection; to (2S; 4R)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine (2.94g; 12.0mmol, 1.0eq) methylene dichloride (60mL) solution in slowly drip DAST (2.63mL, 21.6mmol; 1.8eq), more at room temperature stir 5 hours.Add 10mL saturated sodium bicarbonate solution, dichloromethane extraction (50mL × 3), after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.Filter, it is colorless oil (1.85g, 63.00%) that filtrate reduced in volume residue obtains target product through column chromatography for separation (10:1 (v/v) petrol ether/ethyl acetate) purifying.
MS (ESI, pos.ion) m/z:270.5 [M+23]
+; C
11h
18fNO
4calculating accurate mass: 247.12.
Step 4) (2S, 4S)-N-tertiary butyl oxygen acyl group-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-
Ice-water bath; under nitrogen protection; to (2S, 4S)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-fluoro-tetramethyleneimine (1.85g, 7.48mmol; methyl-magnesium-bromide diethyl ether solution (3.0M is slowly dripped in anhydrous tetrahydro furan (100mL) solution 1.0eq); 7.5mL, 22.5mmol, 3.0eq); 40min adds, more at room temperature stirring is spent the night.10mLH is added under ice-water bath
2o, extraction into ethyl acetate (50mL × 3), after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.It is colorless oil (1.85g, 99.00%) that concentrating under reduced pressure residue obtains target product through column chromatography for separation (10:1 (v/v) petrol ether/ethyl acetate) purifying.
Step 5) (2S, 4S)-N-(3-chlorine-propyl)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-
Under room temperature; under nitrogen protection, to (2S, 4S)-N-tertiary butyl oxygen acyl group-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine (1.85g of-4-; 7.5mmol; trifluoroacetic acid (5.3mL, 75.0mmol, 10.0eq) is added in methylene dichloride (30mL) solution 1.0eq); after stirring 2 hours; add 20mL toluene, the residue after pressure reducing and steaming solvent need not purifying, directly carries out next step reaction.
Under room temperature, add acetone (30mL) in above-mentioned residue, then add Anhydrous potassium carbonate (5.20g, 37.5mmol, 5.0eq) successively, the bromo-3-chloropropane (1.10mL, 11.2mmol, 1.5eq) of 1-, then reaction system heats 6 hours under 65 ° of C.After above-mentioned system cooling, add 10mLH
2o, extraction into ethyl acetate (50mL × 3), after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.Filter, it is yellow oil (0.81g, 48%) that filtrate reduced in volume residue obtains target product through column chromatography for separation (30:1 (v/v) methylene chloride/methanol) purifying.
The chloro-4-fluorophenyl of step 6) 4-((3-) amino)-7-methoxyl group-6-(3-((2S, 4S)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-)-propoxy-)-quinazoline
Under room temperature, to the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (1.05g, 3.3mmol, 1.0eq), Anhydrous potassium carbonate (2.27g, 16.4mmol, 5.0eq), tetrabutylammonium iodide (61mg, 0.16mmol, 0.05eq) is at DMF(15mL) mixed system in add (2S, 4S)-N-(3-chlorine-propyl)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine (0.81g of-4-, 3.6mmol, 1.1eq) DMF(12mL) solution, be then heated to 60 ° of C.After 10 hours, reaction system is cooled to room temperature, adds 10mL H
2o cancellation is reacted, add 20mL diluted ethyl acetate, isolate organic phase, aqueous phase ethyl acetate (20mL × 3) extraction, after merging organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume residue obtains crude product through column chromatography for separation (20:1 (v/v) methylene chloride/methanol) purifying, then in methylene dichloride/petroleum ether system, recrystallization obtains target product is faint yellow solid (1.32g, 79.00%), purity is 91.67%.
MS (ESI, pos.ion) m/z:508.1 (M+1); C
25h
29clF
2n
4o
3calculating accurate mass: 506.19.
1H NMR(CDCl
3,400MHz)δ:1.11(3H,s),1.21(3H,s),1.60-1.83(3H,m),2.02(1H,m),2.16(2H,m),2.95-3.17(5H,m),3.99(3H,s),4.26(2H,m),5.16(1H,d,J=88.6Hz),7.16(1H,t,J=8.8Hz),7.27(2H,m),7.62(2H,m),7.90(1H,m),8.63(1H,s)ppm.
Embodiment 12
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((2S, 4R)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-)-propoxy-)-quinazoline
Step 1) (2S, 4S)-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine
Ice-water bath, to the hydrochloride (5.00g of (2S, 4S)-2-carboxylic acid-4-hydroxy-pyrrolidine, thionyl chloride (2.6mL is slowly dripped in anhydrous methanol (60mL) solution 1.0eq), 1.2eq), add in 15 minutes, then heat 4 hours under 65 ° of C.It is white solid (5.40g, 100.00%) that concentrating under reduced pressure obtains target compound.
Step 2) (2S, 4S)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine
Under ice-water bath condition, to the hydrochloride (5.40g, 1eq) of (2S, 4S)-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine, in methylene dichloride (120mL) solution of triethylamine (14.5mL, 3.5eq), slowly drip (Boc)
2methylene dichloride (20mL) solution of O (8.2mL, 1.2eq), room temperature for overnight subsequently.Add methylene dichloride (50mL × 3) extraction, after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.Filter, it is white solid (6.30g, 86.1%) that filtrate reduced in volume residue obtains target product through column chromatography for separation (ethyl acetate) purifying.
The fluoro-tetramethyleneimine of step 3) (2S, 4R)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-
Ice-water bath; under nitrogen protection; to (2S; 4S)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-hydroxy-pyrrolidine (2.94g; 12.0mmol, 1.0eq) methylene dichloride (60mL) solution in slowly drip DAST (2.63mL, 21.6mmol; 1.8eq), more at room temperature stir 5 hours.Add 10mL saturated sodium bicarbonate solution, dichloromethane extraction (50mL × 3), after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.Filter, it is colorless oil (1.85g, 63%) that filtrate reduced in volume residue obtains target product through column chromatography for separation (10:1 (v/v) petrol ether/ethyl acetate) purifying.
MS (ESI, pos.ion) m/z:270.5 (M+23); C
11h
18fNO
4calculating accurate mass: 247.12.
Step 4) (2S, 4R)-N-tertiary butyl oxygen acyl group-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-
Ice-water bath; under nitrogen protection; to (2S, 4R)-N-tertiary butyl oxygen acyl group-2-methyl oxygen acyl group-4-fluoro-tetramethyleneimine (1.85g, 7.48mmol; methyl-magnesium-bromide diethyl ether solution (3.0M is slowly dripped in anhydrous tetrahydro furan (100mL) solution 1.0eq); 7.5mL, 22.5mmol, 3.0eq); 40min adds, more at room temperature stirring is spent the night.10mLH is added under ice-water bath
2o, extraction into ethyl acetate (50mL × 3), after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.It is colorless oil (1.85g, 99%) that concentrating under reduced pressure residue obtains target product through column chromatography for separation (10:1 (v/v) petrol ether/ethyl acetate) purifying.
Step 5) (2S, 4R)-N-(3-chlorine-propyl)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-
Under room temperature; under nitrogen protection, to (2S, 4R)-N-tertiary butyl oxygen acyl group-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine (1.85g of-4-; 7.5mmol; trifluoroacetic acid (5.3mL, 75.0mmol, 10.0eq) is added in methylene dichloride (30mL) solution 1.0eq); after stirring 2 hours; add 20mL toluene, the residue after pressure reducing and steaming solvent need not purifying, directly carries out next step reaction.
Under room temperature, add acetone (30mL) in above-mentioned residue, then add Anhydrous potassium carbonate (5.20g, 37.5mmol, 5.0eq) successively, the bromo-3-chloropropane (1.10mL, 11.2mmol, 1.5eq) of 1-, then reaction system heats 6 hours under 65 ° of C.After above-mentioned system cooling, add 10mLH
2o, extraction into ethyl acetate (50mL × 3), after merging organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying.Filter, it is yellow oil (0.81g, 48.00%) that filtrate reduced in volume residue obtains target product through column chromatography for separation (30:1 (v/v) methylene chloride/methanol) purifying.
The chloro-4-fluorophenyl of step 6) 4-((3-) amino)-7-methoxyl group-6-(3-((2S, 4R)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine of-4-)-propoxy-)-quinazoline
Under room temperature, to the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (1.05g, 3.3mmol, 1.0eq), Anhydrous potassium carbonate (2.27g, 16.4mmol, 5.0eq), tetrabutylammonium iodide (61mg, 0.16mmol, 0.05eq) is at DMF(15mL) mixed system in add (2S, 4R)-N-(3-chlorine-propyl)-2-(2-hydroxyl-2-propyl group) the fluoro-tetramethyleneimine (0.81g of-4-, 3.6mmol, 1.1eq) DMF(12mL) solution, be then heated to 60 ° of C.After 10 hours, reaction system is cooled to room temperature, adds 10mL H
2o cancellation is reacted, add 20mL diluted ethyl acetate, isolate organic phase, aqueous phase ethyl acetate (20mL × 3) extraction, after merging organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure residue obtains crude product through column chromatography for separation (20:1 (v/v) methylene chloride/methanol) purifying, in methylene dichloride/petroleum ether system, recrystallization obtains target product is again faint yellow solid (1.32g, 79.00%), and purity is 91.67%.
MS (ESI, pos.ion) m/z:508.1 (M+1); C
25h
29clF
2n
4o
3calculating accurate mass: 506.19.
1H NMR(CDCl
3,400MHz)δ:1.16(3H,s),1.29(3H,s),1.95-2.35(5H,m),2.45-2.60(2H,m),2.73(1H,m),3.50(3H,m),4.01(3H,s),4.27(1H,m),4.35(1H,m),5.14(1H,d,J=54.8Hz),7.17(1H,t,J=8.8Hz),7.18(1H,m),7.62(2H,m),7.90(1H,m),8.63(1H,s)ppm.
Embodiment 13
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine)-propoxy-)-quinazoline
Step 1) diethyl-(2-diethylamino-2-oxo-ethyl)-phosphoric acid ester
Triethyl-phosphite (5.50mL) and the chloro-N of 2-, N-diethyl acetamide (6.80mL) is heated to 180 ° of C in 100mL round-bottomed flask, stirring reaction 8.0h, reaction solution is directly carried out post separation (developping agent: DCME/MeOH=7/1, eluent: DCME/MeOH=20/1) obtain 4.50g light yellow oil, yield: 60.00%, purity: 92.00%.
MS(ESI,pos.ion)m/z:252.3[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:4.14(m,4H),3.42(m,4H),2.99(d,J＝8.6Hz,2H),1.34(t,J=4.6Hz,6H),1.20(t,J=10.6Hz,3H),1.11(t,J=4.6Hz,3H)ppm.
Step 2) (S)-N-tertiary butyl oxygen acyl group-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine
Diethyl-(2-diethylamino-2-oxo-ethyl)-phosphoric acid ester (2.80g) is dissolved in THF; be cooled to-78 ° of C; 60% sodium hydride (0.50g) slowly adds; after this thermotonus 15min; the THF solution of (S)-N-tertiary butyl oxygen acyl group-2-Formyl-pyrrol alkane (2.00g) is instilled; at this thermotonus 12.0h; add methyl alcohol cancellation reaction; reaction solution is poured into water; use dichloromethane extraction (50mL × 3) again; after merging organic phase, use anhydrous Na
2sO
4drying, except desolventizing, concentrated solution carries out post separation (developping agent: DCME/MeOH=15/1, eluent: DCME/MeOH=30/1) and obtains 1.18g yellow oil, yield: 40.00%.
MS(ESI,pos.ion)m/z:297[M+H]
+;
1H NMR(400MHz,CDCl
3):δ:6.74(m,1H),6.20(m,1H),4.44(m,1H),3.37(m,6H),1.81-2.05(m,4H),1.43(s,9H),1.14-1.19(m,6H)ppm.
Step 3) (S)-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine
By (S)-N-tertiary butyl oxygen acyl group-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine (1.00g) is dissolved in ethyl acetate; under room temperature, 3M Hydrochloride/ethyl acetate is added; room temperature reaction 2.0h; concentrate and obtain 0.77g light yellow oil; yield: 90.00%, directly drops into next step without being further purified.
MS(ESI,pos.ion)m/z:m/z 196.3[M+H]
+.
Step 4) (S)-N-(3-chlorine-propyl)-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine
(S)-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine (0.77g), the bromo-3-chloropropane (0.98mL) of 1-and salt of wormwood (3.20g) reflux 10.0h in acetone, cooling, filter, post separation (developping agent: DCM/MeOH=10/1 is carried out after mother liquor concentrations, eluent: DCM/MeOH=20/1) obtain the oily matter of 0.18g yellow, yield: 20.00%.
MS(ESI,pos.ion)m/z:273.2[M+H]
+.
The chloro-4-fluorophenyl of step 5) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine)-propoxy-)-quinazoline
Respectively by (S)-N-(3-chlorine-propyl)-2-(3-diethylamino-3-oxo-propenyl)-tetramethyleneimine (0.47g), salt of wormwood (0.45g) and the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.47g) joins in the round-bottomed flask containing the 50mL of 30mLDMF, the frozen water of 50mL is added after 80 ° of C react 7.0h, use dichloromethane extraction (50mL × 3) again, after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: DCM/MeOH=10/1, eluent: DCM/MeOH=20/1) and obtain the lurid solid of 0.16g, yield: 20.00%, purity: 93.00% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:557.1[M+H]
+;
1H NMR(400MHz,d
6-DMSO)δ:9.34(s,1H),8.59(s,1H),7.98(t,J=8.6Hz,1H),7.70(t,J=4.6Hz,1H),7.64(s,2H),7.24(d,J=10.6Hz,1H),7.09(t,1H),6.83(m,1H),6.27(d,J=12.6Hz,1H),4.25(m,1H),3.96(s,5H),3.37(m,6H),2.02-2.05(m,4H),1.81-1.95(m,4H),1.17-1.19(m,6H)ppm.
Embodiment 14
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(2-propyl group)-tetramethyleneimine)-propoxy-)-quinazoline
Step 1) N-benzyl base oxocarbon group-L-PROLINE methyl esters
L-PROLINE methyl esters (6.45g) and salt of wormwood (10.35g) stirring at room temperature 30min in acetonitrile, be cooled to 0 ° of C, benzyloxy dicarbonyl chloride (8.55mL) is slowly added, continue at this thermotonus 3.0h, reaction solution is poured in frozen water, use dichloromethane extraction (50mL × 3) again, after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: PE/EA=3/1, eluent: PE/EA=7/1) and obtains 12.20g colorless oil, yield: 92.80%, purity: 95.00% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:264.2[M+H]
+;
1H NMR(400MHz,CDCl
3)δ:2.04(m,2H),2.24(m,1H),2.42(m,1H),3.44(m,2H),3.82(s,3H),4.77(t,J=8.6Hz,1H),5.02(s,2H),7.33(m,5H)ppm.
Step 2) (S)-N-benzyl oxygen acyl group-2-(2-hydroxyl-2-propyl group)-tetramethyleneimine
N-benzyl base oxocarbon group-L-PROLINE methyl esters (6.88g) is dissolved in anhydrous THF, under ice bath, slowly the ether grignard reagent of methyl-magnesium-bromide (52mL) is slowly instilled, continue at this thermotonus 12.0h, saturated ammonium chloride solution cancellation is reacted, be extracted with ethyl acetate again (100mL × 3), after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: PE/EA=3/1, eluent: PE/EA=8/1) and obtains 3.22g colorless oil, yield: 94.00%, purity: 95.00% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:264.3[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:1.10(s,3),1.18(s,3H),1.25(m,1H),1.71(m,1H),2.04(m,2H),3.27(m,1H),3.78(m,1H),3.94(t,J=8.2Hz,1H),5.16(s,2H),5.61(s,1H),7.34(m,5H)ppm.
Step 3) (S)-N-benzyl oxygen acyl group-2-(2-propenyl)-tetramethyleneimine
Under-50 ° of C by thionyl chloride (2mL) and triethylamine (28mL) add respectively; (S)-N-benzyl oxygen acyl group-2-(2-hydroxyl-2-propyl group) the THF solution of-tetramethyleneimine (2.64g); continue at this thermotonus 2.0h; be warming up to room temperature reaction 1.0h; reaction solution is poured in frozen water; be extracted with ethyl acetate again (50mL × 3), after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: PE/EA=5/1, eluent: PE/EA=10/1) and obtains 1.46g yellow oil, yield: 60.00% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:112.3[M+H]
+.
Step 4) (S)-2-(2-propyl group)-tetramethyleneimine
By (S)-N-benzyl oxygen acyl group-2-(2-propenyl)-tetramethyleneimine (1.40g) is dissolved in ethyl acetate; add 10% palladium carbon of catalytic amount; room temperature reaction 2.0h in hydrogen system; Filtration of catalyst; 0.48g yellow oil is obtained after filtrate is concentrated; not purified direct input next step, yield: 80.00%.
MS(ESI,pos.ion)m/z:114.2[M+H]
+;
1H NMR(400MHz,CDCl
3)δ:0.91(d,J=4.8Hz,6H),1.43-1.64(m,4H),2.06(m,1H),2.70-2.80(m,3H)ppm.
The chloro-4-fluorophenyl of step 5) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(2-propyl group)-tetramethyleneimine)-propoxy-)-quinazoline
Respectively by chloro-for 4-((3-4-fluorophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline (0.85g), salt of wormwood (1.50g) and (S)-2-(2-propyl group)-tetramethyleneimine (0.17g) joins in the round-bottomed flask containing the 50mL of 35mLDMF, 80 ° of C react 7.0h, pour into after cooling in the frozen water of 50mL, use dichloromethane extraction (50mL × 3) again, after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: DCM/MeOH=10/1, eluent: DCM/MeOH=20/1) and obtain the lurid solid of 0.22g, yield: 47.00%, purity: 92.12% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:486.5[M+H]
+；
1H NMR(400MHz,d
6-DMSO)δ:0.97(d,J=4.6Hz,6H),1.45-1.64(m,2H),2.08(m,1H),2.87(m,3H),3.40(m,2H),4.07(m,2H),4.19(s,3H),4.39(m,2H),7.45(s,1H),7.60(t,J=8.4Hz,1H),7.89(s,2H),8.68(t,J=4.8Hz,1H),8.89(s,1H)ppm.
Embodiment 15
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine)-propoxy-)-quinazoline
Step 1) diethyl-(2-dimethylamino-2-oxo-ethyl)-phosphoric acid ester
Triethyl-phosphite (8.50mL) and the chloro-N of 2-, N-N,N-DIMETHYLACETAMIDE (5.00mL) is heated to 160 ° of C in 100mL round-bottomed flask, after stirring reaction 8h, concentration of reaction solution carries out post separation (developping agent: DCM/MeOH=7/1, eluent: DCME/MeOH=20/1) obtain 5.50g light yellow oil, yield: 60.00%, purity: 92.00%.
MS(ESI,pos.ion)m/z:224[M+H]
+；
1H NMR(400MHz,CDCl
3)δ:4.19(m,J=8.4Hz,4H),3.47(s,6H),2.66(d,J=7.8Hz,2H),1.34(t,J=4.2Hz,6H)ppm.
Step 2) (S)-N-tertiary butyl oxygen acyl group-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine
Diethyl-(2-dimethylamino-2-oxo-ethyl)-phosphoric acid ester (2.80g) is dissolved in THF; be cooled to-78 ° of C; 60% sodium hydride (0.50g) slowly adds; after this thermotonus 15min; the THF solution of (S)-N-tertiary butyl oxygen acyl group-2-Formyl-pyrrol alkane (3.00g) is instilled; at this thermotonus 12h; add methyl alcohol cancellation reaction; reaction solution is poured into water; use dichloromethane extraction (70mL × 3) again; after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: DCME/MeOH=15/1, eluent: DCME/MeOH=30/1) and obtains 1.60g yellow oil, yield: 40.00%, purity: 90.00% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:269.3[M+H]
+;
1H NMR(400MHz,CDCl
3)δ:6.74(m,1H),6.20(m,1H),4.45(m,1H),3.39(m,6H),1.45(s,9H),1.14-1.19(m,6H)ppm.
Step 3) (S)-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine
By (S)-N-tertiary butyl oxygen acyl group-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine (1.70g) is dissolved in ethyl acetate; under room temperature, 3M Hydrochloride/ethyl acetate is added; room temperature reaction 2.0h; concentrate and obtain 1.16g light yellow oil; yield: 90.00%, directly drops into next step without being further purified.
MS(ESI,pos.ion)m/z:169.1[M+H]
+.
Step 4) (S)-N-(3-chlorine-propyl)-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine
(S)-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine (1.16g), the bromo-3-chloropropane (2.90mL) of 1-and salt of wormwood (3.10g) reflux 10.0h in acetone, cooling, filter, post separation (developping agent: DCM/MeOH=10/1 is carried out after mother liquor concentrations, eluent: DCM/MeOH=20/1) obtain the oily matter of 0.39g yellow, yield: 20.00%, purity: 80.00%.
MS(ESI,pos.ion)m/z:273.7[M+H]
+；
The chloro-4-fluorophenyl of step 5) 4-((3-) amino)-7-methoxyl group-6-(3-((S)-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine)-propoxy-)-quinazoline
Respectively by (S)-N-(3-chlorine-propyl)-2-(3-dimethylamino-3-oxo-propenyl)-tetramethyleneimine (0.46g), salt of wormwood (0.45g) and the chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.50g) joins in the round-bottomed flask containing the 50mL of 30mLDMF, the frozen water of 50mL is added after 80 ° of C react 7.0h, use dichloromethane extraction (50mL × 3) again, after merging organic phase, use anhydrous Na
2sO
4drying, filters, and carries out post separation (developping agent: DCM/MeOH=10/1, eluent: DCM/MeOH=20/1) and obtain the lurid solid of 0.20g, yield: 25.00%, purity: 93.60% after filtrate is concentrated.
MS(ESI,pos.ion)m/z:529.3[M+H]
+；
1H NMR(400MHz,d
6-DMSO)δ:9.24(s,1H),8.52(s,1H),7.78(t,J=4.6Hz,1H),7.70(t,J=8.4Hz,1H),7.64(s,2H),7.24(d,J=4.2Hz,1H),7.09(t,J=8.0Hz,1H),6.83(m,1H),6.27(m,1H),4.25(m,1H),3.96(m,5H),3.47(m,6H),1.85-1.95(m,4H),1.15-1.17(m,6H)ppm.
Embodiment 16
The fluoro-4-bromophenyl of 4-((2-) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
Step 1) the fluoro-4-bromophenyl of 4-((2-) amino)-7-methoxyl group-6-acetoxyl group quinazoline
Suspension liquid 4-chloro-7-methoxyl group-6-acetoxyl group-quinazoline (2.05g), the fluoro-4-bromaniline of 2-(2.11g, 1.30eq) overnight with reflux under Virahol (40mL) 83 ° of C conditions, after being down to room temperature, solid product Virahol (100mL) washs, obtain 2.78g white solid, yield 84.50%.
Step 2) the fluoro-4-bromophenyl of 4-((2-) amino)-7-methoxyl group-6-hydroxyl-quinazoline
Under room temperature, 5mol/L NaOH (5.00mL) joins the fluoro-4-bromophenyl of compound 4-((2-) amino) in the mixed system of-7-methoxyl group-6-acetoxyl group quinazoline (2.78g) and methyl alcohol (30mL), after 4h, pH=7 is regulated with 1N HCl, collecting by filtration obtains 2.17g white solid, yield 87.15%.
Step 3) 4-((2-fluoro-4-bromophenyl) amino) the chloro-propoxy-of-7-methoxyl group-6-(3-)-quinazoline
Under room temperature, chlorobromopropane (0.71mL) joins the fluoro-4-bromophenyl of compound 4-((2-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (2.17g), K
2cO
3(0.99g), in the system of DMF (20mL), continue 40 ° of C heating overnight, reaction system has been poured into water a large amount of solid and has separated out, carry out post separation, (developping agent: 3PE:1EA, eluent: 3PE:1EA), obtain 2.18g white solid, yield: 82.89%.
Step 4) the fluoro-4-bromophenyl of 4-((2-) amino)-7-methoxyl group-6-(3-((R)-3-fluoropyrrolidine)-propoxy-)-quinazoline
The fluoro-4-bromophenyl of 4-((2-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (1.12g; 3.08mmol) be dissolved in DMF (6mL); add salt of wormwood (0.64g; 4.61mmol); stirring at room temperature 10min; then (R)-N-(3-chlorine-propyl is added) the DMF solution of-3-fluoropyrrolidine (0.61g, 3.69mmol), be then warmed up to 80 ° of C under nitrogen protection and react 10h.Methylene dichloride (200mL) joins in system, then washes repeatedly, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, after filtrate is concentrated, carry out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 0.61g is obtained, yield: 40.50%.Purity: 98.20%.
MS(ESI,pos.ion)m/z:493[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.10-2.30(m,10H),2.45-2.50(m,1H),2.73-2.77(m,2H),2.90-3.02(m,2H),4.04(s,3H),4.28(t,J=6.88Hz，2H),5.15-5.30(m,1H),7.09(m,2H),7.24-7.26(t,1H),7.32(s,1H),7.64-7.68(m,1H),8.61(s,1H)ppm.
Embodiment 17
The chloro-4-fluorophenyl of 4-((3-) amino)-7-methoxyl group-6-(3-(3-pyrazoles-Pyrrolidine)-propoxy-)-quinazoline
Step 1) N-tertiary butyl oxycarbonyl-3-hydroxyl methanesulfonates-Pyrrolidine
N-tertiary butyl oxycarbonyl-3-hydroxyl pyrrolidine (2.0g, 10.68mmol) is dissolved in methylene dichloride (20mL), is cooled to 0 DEG C, be added dropwise to methylsulfonyl chloride (1.29mL, 16.67mmol), then add triethylamine (2.22mL, 16.02mmol), stirring at room temperature 24h is risen to.In reaction solution, add methylene dichloride (100mL) extraction once, then wash, saturated common salt is washed once, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, concentrated solution carries out column chromatography for separation and obtains 2.84g product, yield: 100%.
LC-MS：288(M+23),210(M-55).
Step 2) N-tertiary butyl oxycarbonyl-3-(1-pyrazoles)-Pyrrolidine
Pyrazoles (0.62g; 9.04mmol; 1.2eq) be dissolved in dry DMF(10mL) in; sodium hydride (0.45g, 23.75mmol, 2.5eq) is slowly added under room temperature; then N-tertiary butyl oxycarbonyl-3-hydroxyl methanesulfonates-Pyrrolidine (2.0g is added; 7.54mmol, 1.0eq) DMF(2mL) solution, stirred overnight at room temperature under nitrogen protection.In reaction system, drip ethyl acetate (200mL) dilution, repeatedly, saturated common salt is washed once, anhydrous sodium sulfate drying in washing.Except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleum ether/EtOAc=3/1) and obtains 1.23g product, yield: 68.72%.
LC-MS:238(M+1),182(M-55).
Step 3) N-(3-chloropropyl)-3-(1-pyrazoles)-Pyrrolidine
By N-tertiary butyl oxycarbonyl-3-(1-pyrazoles)-Pyrrolidine (0.6g, 2.53mmol) be dissolved in methylene dichloride (30mL), add trifluoroacetic acid (2mL, 27.01mmol), stirring at room temperature 1h, then pressure reducing and steaming solvent, add toluene (5mL) in residue, and then boil off, residue is directly used in the next step.
In above-mentioned crude product, add acetone (30mL), salt of wormwood (3.49g, 25.25mmol), and then add the chloro-3-N-PROPYLE BROMIDE (0.38mL, 3.84mmol) of 1-, then reflux 12h.Filter and pressure reducing and steaming solvent, residue with Ethyl acetate (100mL) dissolves, washing twice, and saturated common salt is washed once, anhydrous sodium sulfate drying.Except desolventizing, concentrated solution carries out column chromatography for separation and obtains 0.20g product, yield: 37.04%.
LC-MS:214(M+1),237(M+23).
The chloro-4-fluorophenyl of step 4) 4-((3-) amino)-7-methoxyl group-6-(3-(3-pyrazoles-Pyrrolidine)-propoxy-)-quinazoline
The chloro-4-fluorophenyl of compound 4-((3-) amino)-7-methoxyl group-6-hydroxyl-quinazoline (0.25g, 0.78mmol) be dissolved in DMF (8mL), add salt of wormwood (0.54g, 3.90mmol), stirring at room temperature 10min, then the DMF(2mL of N-(3-chloropropyl)-3-(1-pyrazoles)-Pyrrolidine (0.20g, 0.94mmol) is added) solution, be then warmed up to 80 DEG C of reaction 24h.Stopped reaction, adds methylene dichloride (100mL), then washes repeatedly in system, and saturated common salt is washed once, anhydrous sodium sulfate drying.Except desolventizing, concentrated solution carries out column chromatography for separation (eluent: CH
2cl
2/ CH
3oH=20/1) product 330mg is obtained, yield: 80.27%.Purity: 98.28%.
MS(ESI,pos.ion)m/z:497[M+1]
+;
1H NMR(400MHz,CDCl
3)δ:2.10(m,2H),2.24-2.29(m,4H),2.30-2.31(m,1H),2.39-2.42(m,1H),2.48-2.50(m,1H),2.52-2.62(m,1H),2.75-2.81(m,2H),3.04-3.10(m,2H),3.49(s,1H),3.99(s,3H),4.18-4.21(m,1H),4.28-4.30(m,1H),4.88(t,J=7.60Hz,1H),6.23(t,J=10.00Hz,1H),7.11(t,J=17.20Hz,3H),7.24-7.26(m,2H),7.48(d,J=2.40Hz,1H),7.51-7.78(m,3H),7.80(t,J=6.40Hz,1H),8.35(s,1H),8.62(s,1H).
Embodiment A
people's hepatomicrosome stability test
LC/MS/MS general analysis method
The serial LC/MS/MS mass spectrograph of Agilent 6430 is equipped with G4220A binary syringe pump, G1367D automatic sampler and G1315C UV detector; Adopt ESI source, positive ion MRM mode detection analysans.XBradge is used during analyzing
tM-C18 post, specification is: 2.1 × 50mm I.D., 3.5 μMs (Waters, USA).Moving phase is 2mM ammonium formiate, 0.1% aqueous formic acid (A); 2mM ammonium formiate, 0.1% formic acid methanol solution (B); Gradient elution, flow velocity is 0.4mL/min; Column temperature remains on 40 ° of C; Sample size is 5 μ L.Its gradient condition is as shown in table 1:
Table 1 compound hepatomicrosome sample analysis moving phase condition
| Time (min) | A phase (5) | B phase (%) |
| 0.5 | 90 | 10 |
| 1.2 | 10 | 90 |
| 2.5 | 10 | 90 |
| 2.6 | 90 | 10 |
| 4 | 90 | 10 |
People's hepatomicrosome stability test method
People's hepatomicrosome is placed in polypropylen tubes hatch, and guides it to copy.Typical hatching mixed solution comprises people's hepatomicrosome (0.75mg/mL, protein concentration), target compound (1.5 μMs) and cumulative volume are NADPH (6.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution in DMSO, and use PBS to be diluted, the concentration of the DMSO solution making it final is 0.05%.And hatch in the water-bath communicated with air under 37 ° of C, in mixed solution, add albumen after preincubate 10min and start reaction.In different time point (0,15 and 30min), add same volume ice-cold acetonitrile termination reaction.Sample is preserved until carry out LC/MS/MS analysis under-80 ° of C.
The concentration of compound in people's hepatomicrosome incubation mixture is measured by the method for LC/MS/MS.
By using the microsome of sex change to carry out hatching as negative control, hatching under 37 ° of C, reacting and stopping at different time point (0,15 and 30min).
Ketanserin(Sufrexal, 1.5 μ Μ) as positive control, hatch under 37 ° of C, react and stop at different time point (0,15 and 30min).The positive and negative control sample is all comprised, to ensure stability and the integrity of microsome hatching system in each measuring method.
Data analysis
By measuring the sample concentration of different incubation time, with " Log [drug level] ", rate constant is obtained to " incubation time " mapping, ask and calculate drug half-life and inherent clearance rate, the stability CLint of medicine in hepatomicrosome (ref.:Naritomi Y is evaluated with drug half-life and inherent clearance rate value, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experimentsand in vitro metabolic studies with liver microsomes from animals andhumans.Drug Metabolism and Disposition 2001, 29:1316-1324.) compound of the present invention shows as higher hepatic clearance value (CLint>58.95mL/min/kg) in people's hepatomicrosome.
Embodiment B
preclinical pharmacokinetic is evaluated
The present invention assesses the pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body.The compounds of this invention carries out administration with the aqueous solution form of 5%DMSO+5%solutol-15.For intravenous administration: rat, dog, monkey give the dosage of 2mg/kg, and mouse gives the dosage of 10mg/kg.For oral dosage (p.o.): mouse is 40mg/kg, rat, dog and monkey are 5mg/kg.Be within 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour, get blood (0.3mL) at time point, and under 3,000rpm centrifugal 10 minutes.Collect plasma solutions, and preserve under-20 ° of C until carry out above-mentioned LC/MS/MS analysis.
After oral administration, the compounds of this invention goes out higher bioavailability at Mouse and rat common manifestation, and in dog and monkey body, bioavailability is medium.
Biological activity
Following representational measuring method, but be not limited to these methods, will the biological activity evaluating the compounds of this invention be used for.
Embodiment C
eGFR inhibit activities is tested
Preliminary study shows, the compound that the present invention filters out can suppress the activity of EGFR.Cisbio studies the generation that product HTRF kinEASE STK S1 kinase assays/inhibitor screening Kit can detect phosphorylated substrate.In certain buffered soln, add kinases, biotinylated substrate, ATP, zymetology reaction generates the biotinylated substrate of phosphorylation.Then, the specific antibody of anti-phosphorylation site of europium mark and the avidin of XL665 mark is added.Antibody is combined with antigen-specific, vitamin H and avidin specific binding, make europium and XL665 mutually further, and resonance energy transfer occurs, the signal of 620nm and 665nm two wavelength can be detected, reacted the height of kinase activity by the ratio size of these two signals.Concrete testing sequence as shown in Figure 1.
All samples and standard substance all adopt multiple hole to detect, and the majority of compounds detected all has inhibit activities to EGFR.(concrete data are in table 2)
Table 2, embodiment is to the kinase whose inhibit activities of EGFR
| Embodiment | IC 50(nM) | Embodiment | IC 50(nM) | Embodiment | IC 50(nM) | Embodiment | IC 50(nM) |
| 1 | C | 6 | C | 11 | C | 16 | C |
| 2 | C | 7 | C | 12 | C | 17 | C |
| 3 | D | 8 | B | 13 | B | ||
| 4 | D | 9 | A | 14 | A | ||
| 5 | D | 10 | A | 15 | B |
IC
50scope is as follows: A=0.101 nM-1.000 nM; B=1.001 nM-10.000 nM; C=10-100 nM; D>100nM.
Embodiment D
people's cancer xenograft tumor test of pesticide effectiveness
People A431 epidermal carcinoma Xenograft Tumor Models
Xenotransplantation equally can by people's epidermal carcinoma cell (A431 cell, ATCC) produce, as Subcutaneous Tumor Growth (BALB/cA nu/nu in the female nude mice body in 6-7 age in week, Shanghai Slac Experimental Animal Co., Ltd.) (for group of solvents n=8, for each dosage group n=6).When gross tumor volume reaches 100-200mm
3, animal can be divided into solvent control group (0.362g citric acid+30ml propylene glycol+70ml water+6.6ml Emulsifier EL-35 solution) and compound group randomly.Follow-up employing comprises the compounds of this invention and carries out gastric infusion (2.5,5 and 10mg/kg, be dissolved in 0.362g citric acid+30ml propylene glycol+70ml water+6.6ml Emulsifier EL-35 solution) to animal, successive administration 3 weeks, survey 2-3 knurl volume weekly, claim mouse heavy, record data.
tumor growth inhibition (TGI) is analyzed
The crystallization growth of tumour is undertaken evaluating by gross tumor volume size and the relation of time.Major axis (L) and the minor axis (S) of Subcutaneous tumor measure twice weekly by calipers, and the volume (TV) of tumour is by formula (L × W
2)/2) calculate.TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume-median, represents, calculated by following formula with the per-cent of solvent control group gross tumor volume intermediate value:
Adopt Student ' st to carry out statistical study, P value refers to and Vehicle controls group ratio.
Xenograft tumor clinical trial result shows, embodiments of the invention compound can suppress the growth of various human cancer cells nude mouse Subcutaneous Xenograft knurl model person epidermal carcinoma A431, effective dose scope is 5mg/kg ~ 40mg/kg, animal well-tolerated in administration process; In certain dosage range, 65% is greater than to the tumour inhibiting rate of the human epidermal cell cancer A431 of mouse, has good inhibit activities, the general survival state of mouse can be improved in addition, improve its life quality.
Record is finally needed to realize two kinds of modes of the present invention.Correspondingly, embodiments of the invention to be illustratively described, but be not limited to content described in the invention, may be also amendment done within the scope of the present invention or equivalents added in the claims.All publications that the present invention quotes or patent are all as reference of the present invention.
Claims (10)
1. a compound, comprises one of them structure following:
Or its steric isomer, tautomer.
2. compound according to claim 1, is characterized in that, described steric isomer is geometrical isomer.
3. pharmaceutical composition comprises the compound according to any one of claim 1 or claim 2, and pharmaceutically acceptable assistant agent, vehicle or their combination.
4. pharmaceutical composition according to claim 3, described assistant agent is carrier and/or vehicle.
5. pharmaceutical composition according to claim 4, described vehicle is thinner.
6. pharmaceutical composition according to claim 3, it further comprises therapeutical agent, and these therapeutical agents are selected from chemotherapeutic agent, antiproliferative or their combination.
7. pharmaceutical composition according to claim 6, is characterized in that, described antiproliferative is the medicine being used for the treatment of nonsmall-cell lung cancer and epidermal carcinoma.
8. pharmaceutical composition according to claim 6, wherein said therapeutical agent is Zorubicin (Adriamycin), rapamycin (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabin), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), Fluracil (Fluorouracil), imatinib mesylate (Imatinibmesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib), Iressa (Iressa), Xarelto (Sorafenib), Sutent (Sunitinib), Interferon, rabbit (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vinealeucoblastine(VLB), vincristine(VCR), Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix (Panitumumab), or their combination.
9. use claim 1 or the compound described in any one of claim 2 or the pharmaceutical composition described in claim 3 ~ 8 any one to produce for protection, process or a treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.
10. purposes according to claim 9, wherein said proliferative disease is metastatic carcinoma, epidermal carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
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| US9073960B2 (en) | 2011-12-22 | 2015-07-07 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
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| US10336767B2 (en) | 2016-09-08 | 2019-07-02 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
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