CN101605794B - Aza-benzofuranyl compounds and methods of use - Google Patents
Aza-benzofuranyl compounds and methods of use Download PDFInfo
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- CN101605794B CN101605794B CN200780039152.0A CN200780039152A CN101605794B CN 101605794 B CN101605794 B CN 101605794B CN 200780039152 A CN200780039152 A CN 200780039152A CN 101605794 B CN101605794 B CN 101605794B
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- 0 *c(cc(c(I)c1)F)c1F Chemical compound *c(cc(c(I)c1)F)c1F 0.000 description 7
- CVDPCPUJBJLLLV-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC1ON(C(C(C)=C1C=C)=O)C1=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC1ON(C(C(C)=C1C=C)=O)C1=O)=O CVDPCPUJBJLLLV-UHFFFAOYSA-N 0.000 description 1
- GIIDZEBNRLNGMS-HTQZYQBOSA-N CC(C)(C)OC(N(CC1)[C@H](CO)[C@@H]1O)=O Chemical compound CC(C)(C)OC(N(CC1)[C@H](CO)[C@@H]1O)=O GIIDZEBNRLNGMS-HTQZYQBOSA-N 0.000 description 1
- SVSSZFBZFUSINI-SFYZADRCSA-N CC(C)(C)OC(N(CC[C@H]1O)[C@@H]1C(OC)=O)=O Chemical compound CC(C)(C)OC(N(CC[C@H]1O)[C@@H]1C(OC)=O)=O SVSSZFBZFUSINI-SFYZADRCSA-N 0.000 description 1
- LPQZERIRKRYGGM-UHFFFAOYSA-N CC(C)(C)OC(N1CCCC1)=O Chemical compound CC(C)(C)OC(N1CCCC1)=O LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 1
- UKQGSVWBONLFAR-UHFFFAOYSA-N CC(C)(CO)ON Chemical compound CC(C)(CO)ON UKQGSVWBONLFAR-UHFFFAOYSA-N 0.000 description 1
- CMZQPQQRGBOLHN-UHFFFAOYSA-N CC(C)(COC)N Chemical compound CC(C)(COC)N CMZQPQQRGBOLHN-UHFFFAOYSA-N 0.000 description 1
- BSGNFEINQPVTSZ-UHFFFAOYSA-N CC(C)COC(N(CC1)CC1OC)=O Chemical compound CC(C)COC(N(CC1)CC1OC)=O BSGNFEINQPVTSZ-UHFFFAOYSA-N 0.000 description 1
- TUWXAMIPZBZJHL-UHFFFAOYSA-N CC(C)[Si+](C(C)C)(C(C)C)OCc(cc1)cc(F)c1Br Chemical compound CC(C)[Si+](C(C)C)(C(C)C)OCc(cc1)cc(F)c1Br TUWXAMIPZBZJHL-UHFFFAOYSA-N 0.000 description 1
- RYANKFVJHKIENT-UHFFFAOYSA-N CCOC(COc(ncnc1)c1C(OCC)=O)=O Chemical compound CCOC(COc(ncnc1)c1C(OCC)=O)=O RYANKFVJHKIENT-UHFFFAOYSA-N 0.000 description 1
- IKTUPXVOIFCUNA-UHFFFAOYSA-N CCOC(c([o]c(C(C)=C)c1C)c1NC)=O Chemical compound CCOC(c([o]c(C(C)=C)c1C)c1NC)=O IKTUPXVOIFCUNA-UHFFFAOYSA-N 0.000 description 1
- QPFRZXRXFXAWDX-UHFFFAOYSA-N CCOC(c([o]c(C)c1C=C)c1Nc(c(Cl)c1)ccc1Br)=O Chemical compound CCOC(c([o]c(C)c1C=C)c1Nc(c(Cl)c1)ccc1Br)=O QPFRZXRXFXAWDX-UHFFFAOYSA-N 0.000 description 1
- FOCFQRFAZVBYIW-UHFFFAOYSA-N CCOC(c([o]c(C=C)c1C(Cl)=[IH])c1OS(C(F)(F)F)(=O)=O)=O Chemical compound CCOC(c([o]c(C=C)c1C(Cl)=[IH])c1OS(C(F)(F)F)(=O)=O)=O FOCFQRFAZVBYIW-UHFFFAOYSA-N 0.000 description 1
- BGMISDJLJICNNV-UHFFFAOYSA-N CCOC(c([o]c1c2cncc1)c2N)=N Chemical compound CCOC(c([o]c1c2cncc1)c2N)=N BGMISDJLJICNNV-UHFFFAOYSA-N 0.000 description 1
- CXQWCZYYSDDCRH-UHFFFAOYSA-N CCOC(c([o]c1c2cncc1F)c2Nc(c(F)c1)ccc1SC)=O Chemical compound CCOC(c([o]c1c2cncc1F)c2Nc(c(F)c1)ccc1SC)=O CXQWCZYYSDDCRH-UHFFFAOYSA-N 0.000 description 1
- JKEOVLLFTXARFH-UHFFFAOYSA-N CN(C)C(c([o]c(C(CN)=C)c1C=C)c1Nc(c(F)c1)ccc1I)=O Chemical compound CN(C)C(c([o]c(C(CN)=C)c1C=C)c1Nc(c(F)c1)ccc1I)=O JKEOVLLFTXARFH-UHFFFAOYSA-N 0.000 description 1
- HMVFITKXZCNKSS-UHFFFAOYSA-N CN(C)CCOC Chemical compound CN(C)CCOC HMVFITKXZCNKSS-UHFFFAOYSA-N 0.000 description 1
- BHNCZRFXNHVDDT-UHFFFAOYSA-N COC1CCOCC1 Chemical compound COC1CCOCC1 BHNCZRFXNHVDDT-UHFFFAOYSA-N 0.000 description 1
- AVPAYFOQPGPSCC-UHFFFAOYSA-N COC1CNC1 Chemical compound COC1CNC1 AVPAYFOQPGPSCC-UHFFFAOYSA-N 0.000 description 1
- BWRWNUQAQPAYCK-UHFFFAOYSA-N COC1CNCC1 Chemical compound COC1CNCC1 BWRWNUQAQPAYCK-UHFFFAOYSA-N 0.000 description 1
- MRWRHHSVHWCISU-UHFFFAOYSA-N COC1CNCCC1 Chemical compound COC1CNCCC1 MRWRHHSVHWCISU-UHFFFAOYSA-N 0.000 description 1
- JFSYLINYOHTYGG-UHFFFAOYSA-N COCCNS(C)(=O)=O Chemical compound COCCNS(C)(=O)=O JFSYLINYOHTYGG-UHFFFAOYSA-N 0.000 description 1
- VIWSRIQZJGQSHL-GFCCVEGCSA-N C[C@H](CONC(c([o]c(C)c1C)c1Nc1ccc(C)cc1)=C)O Chemical compound C[C@H](CONC(c([o]c(C)c1C)c1Nc1ccc(C)cc1)=C)O VIWSRIQZJGQSHL-GFCCVEGCSA-N 0.000 description 1
- JAYCCPWHQQRJLI-UHFFFAOYSA-N O=C(c1ccccc1C1=O)N1OC1COC(c2ccccc2)OC1 Chemical compound O=C(c1ccccc1C1=O)N1OC1COC(c2ccccc2)OC1 JAYCCPWHQQRJLI-UHFFFAOYSA-N 0.000 description 1
- QBHLBOWSRQBAHM-UHFFFAOYSA-N OC(c([o]c(c1cnc2)c2Br)c1Br)=O Chemical compound OC(c([o]c(c1cnc2)c2Br)c1Br)=O QBHLBOWSRQBAHM-UHFFFAOYSA-N 0.000 description 1
- IMRGVWZLCZERSQ-UHFFFAOYSA-N OC(c1cnccc1Cl)=O Chemical compound OC(c1cnccc1Cl)=O IMRGVWZLCZERSQ-UHFFFAOYSA-N 0.000 description 1
- CALDMMCNNFPJSI-RFZPGFLSSA-N OC[C@@H](C1)NC[C@@H]1O Chemical compound OC[C@@H](C1)NC[C@@H]1O CALDMMCNNFPJSI-RFZPGFLSSA-N 0.000 description 1
- OQEBIHBLFRADNM-WISUUJSJSA-N OC[C@H]([C@@H]1O)NC[C@@H]1O Chemical compound OC[C@H]([C@@H]1O)NC[C@@H]1O OQEBIHBLFRADNM-WISUUJSJSA-N 0.000 description 1
Abstract
The invention relates to azabenzofuranyl compounds of Formula (I) with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzofuranyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The inventionalso relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
Description
Related application
The application is international patent application, its requirement is filed in the U.S. Provisional Application 60/839 on August 21st, 2006,161, be filed in the U.S. Provisional Application 60/871 on December 22nd, 2006,591, be filed in the U.S. Provisional Application 60/917 on May 11st, 2007,623 and be filed in the U.S. Provisional Application 60/944 on June 18th, 2007,741 right of priority, the content at this by above-mentioned provisional application is incorporated herein by reference.
Technical field
The present invention relates to have aza-benzofuranyl (azabenzofuranyl) compound of anticancer and/or anti-inflammatory activity, relate more specifically to suppress the aza-benzofuranyl compounds of MEK kinase activity.The invention still further relates to the method for described compound for external, original position and in-vivo diagnostic or treatment mammalian cell or related diseases illness of science of using.
Background technology
How to transmit the extracellular growth signals in order to understand Ras, occurred MAP (mitogen-activated protein(MAP), mitogen-activated protein) kinases (MAPK) approach as film in conjunction with the crucial path between Ras and nucleus.The MAPK approach comprises a succession of phosphorylation event that relates to three kinds of crucial kinases (being Raf, MEK (map kinase kinases) and ERK (map kinase)).The GTP of activation causes the kinase whose activation of Raf and indirect phosphorylation in conjunction with Ras.Then Raf two serine residues (being S218 and S222 for MEK1, is S222 and S226 for MEK2) upper to MEK1 and MEK2 carry out phosphorylation (Ahn et al., Methods in Enzymology 2001,332,417-431).Then the MEK of activation is that map kinase ERK1 and ERK2 carry out phosphorylation to its unique known substrate.For ERK1, ERK appears at Y204 and T202 is upper through the phosphorylation of MEK, and appear at Y185 for ERK2 and T183 upper (Ahn et al., Methods in Enzymology 2001,332,417-431).The ERK of phosphorylation forms dipolymer, and (Khokhlatchevet al., Cell 1998,93,605-615) then to be transferred to its nucleus gathered.In nucleus, relate to ERK in several important cell functions, these functions include but not limited to that nuclear translocation, signal transduction (signal transduction), DNA repair, nucleosome assembles and transposition (nucleosome assembly and translocation) and mRNA processing and translation (Ahn et al., Molecular Cell 2000,6,1343-1354).Generally speaking, process the activation that the cell with somatomedin causes ERK1 and ERK2, this has caused propagation, and caused differentiation in some cases (Lewis et al., Adv.Cancer Res.1998,74,49-139).
Strong evidence demonstration, in the map kinase approach, the genetic mutation of related protein kinase and/or overexpression cause uncontrolled cell proliferation and finally cause tumour to form in proliferative disease.For example, the sudden change that certain cancers comprises the continuous activation that causes the above-mentioned approach that caused by the continuous generation of somatomedin.Other sudden change can cause the inactivation shortage of the GTP of activation in conjunction with the Ras mixture, and this causes again the activation of map kinase approach.The carcinogenic form of the sudden change of Ras is found in the cancer of 50% colorectal carcinoma and>90% carcinoma of the pancreas and multiple other type that (Kohl et al., Science 1993,260,1834-1837).Recently, (Nature 2002,417,949-954) for Davies, H.et al. in surpassing 60% malignant melanoma, to have identified the bRaf sudden change.These sudden changes in bRaf cause the cascade of composition activation map kinase.The research of primary tumor sample and clone also has been presented to constitutive character activation or the overactivity (Hoshino of map kinase approach in carcinoma of the pancreas, colorectal carcinoma, lung cancer, ovarian cancer and kidney (kidney cancer), R.et al., Oncogene 1999,18,813-822).
MEK occurs as attractive treatment target in map kinase cascade approach.The MEK that is in Ras and Raf downstream is high degree of specificity to the phosphorylation of map kinase; In fact, the unique known substrate of MEK phosphorylation is map kinase ERK1 and ERK2.Shown in several researchs MEK has been suppressed to have potential treatment benefit.For example, shown that the small molecules mek inhibitor suppresses people's tumor growth (the Sebolt-Leopold et al. in nude mouse heterograft (nude mouse xenograft), Nature-Medicine 1999, 5 (7), 810-816), Trachet et al., AACR Apr.6-10, 2002, Poster#5426 and Tecle, H.IBC 2.sup.nd InternationalConference of Protein Kinases, Sep.9-10, 2002), Static allodni (static allodynia) (disclosed WO 01/05390 on January 25 calendar year 2001) in the retardance animal and growth (the Milella et al. that suppresses acute myelocytic leukemia (acute myeloid leukemia) cell, J Clin Invest2001, 108 (6), 851-859).
For example in WO02/06213, WO 03/077855 and WO03/077914, several small molecules mek inhibitors are being discussed.Still exist the therapeutical agent as effective with safe is used for the treatment of to various proliferative disease states as the illness relevant to the MEK hyperactivity hyperkinesia and by the needs of the new mek inhibitor of the disease of MEK Cascade control.
Summary of the invention
The present invention relates generally to the azepine benzofuran compound (and/or its solvate and salt) that has anticancer and/or anti-inflammatory activity and more specifically have the formula I of MEK kinase inhibiting activity.Some excess proliferative (hyperproliferative) and inflammatory diseases are characterised in that the adjusting to the MEK kinase function, for example, due to sudden change or the overexpression of described protein (MEK kinases).Therefore, the compounds of this invention and the composition that comprises it can be used for overmedication proliferative disease (as cancer) and/or inflammatory diseases (as rheumatoid arthritis).
Wherein
Z
1for CR
1or N;
Z
2for CR
2or N;
Z
3for CR
3or N;
Z
4for CR
4or N;
Z wherein
1, Z
2, Z
3and Z
4in one or two be N;
R
1, R
2, R
3and R
4independently be selected from H, halogen, CN, CF
3,-OCF
3,-NO
2,-(CR
14r
15)
nc (=Y) R
11,-(CR
14r
15)
nc (=Y) OR
11,-(CR
14r
15)
nc (=Y) NR
11r
12,-(CR
14r
15)
nnR
11r
12,-(CR
14r
15)
noR
11,-(CR
14r
15)
nsR
11,-(CR
14r
15)
nnR
12c (=Y) R
11,-(CR
14r
15)
nnR
12c (=Y) OR
11,-(CR
14r
15)
nnR
13c (=Y) NR
11r
12,-(CR
14r
15)
nnR
12sO
2r
11,-(CR
14r
15)
noC (=Y) R
11,-(CR
14r
15)
noC (=Y) OR
11,-(CR
14r
15)
noC (=Y) NR
11r
12,-(CR
14r
15)
noS (O)
2(OR
11) ,-(CR
14r
15)
noP (=Y) (OR
11) (OR
12) ,-(CR
14r
15)
noP (OR
11) (OR
12) ,-(CR
14r
15)
ns (O) R
11,-(CR
14r
15)
ns (O)
2r
11,-(CR
14r
15)
ns (O)
2nR
11r
12,-(CR
14r
15)
ns (O) (OR
11) ,-(CR
14r
15)
ns (O)
2(OR
11) ,-(CR
14r
15)
nsC (=Y) R
11,-(CR
14r
15)
nsC (=Y) OR
11,-(CR
14r
15)
nsC (=Y) NR
11r
12, C
1-C
12alkyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl;
W is
R
5and R
6independently be selected from H or C
1-C
12alkyl;
X
1be selected from R
11,-OR
11,-NR
11r
12,-S (O) R
11with-S (O)
2r
11; Work as X
1for R
11or-OR
11the time, R
5and X
1in R
11perhaps R
5and X
1in-OR
11the optional nitrogen-atoms be connected with them connects together to form and has 0-2 the saturated or unsaturated ring of extra heteroatomic 4-7 unit that is selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21;
X
2be selected from carbocylic radical, heterocyclic radical, aryl and heteroaryl;
R
11, R
12and R
13independent is H, C
1-C
12alkyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl; Or
R
11and R
12form together with the nitrogen connected with them and have the first saturated rings of 0-2 heteroatomic 3-8 that is selected from O, S and N, unsaturated ring or aromatic ring, wherein said ring optionally is selected from following one or more groups and is replaced: halogen, CN, CF
3,-OCF
3,-NO
2, C
1-C
6alkyl ,-OH ,-SH ,-O (C
1-C
6alkyl) ,-S (C
1-C
6alkyl) ,-NH
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl)
2,-SO
2(C
1-C
6alkyl) ,-CO
2h ,-CO
2(C
1-C
6alkyl) ,-C (O) NH
2,-C (O) NH (C
1-C
6alkyl) ,-C (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-NHC (O) (C
1-C
6alkyl) ,-NHSO
2(C
1-C
6alkyl) ,-N (C
1-C
6alkyl) SO
2(C
1-C
6alkyl) ,-SO
2nH
2,-SO
2nH (C
1-C
6alkyl) ,-SO
2n(C
1-C
6alkyl)
2,-OC (O) NH
2,-OC (O) NH (C
1-C
6alkyl) ,-OC (O) N (C
1-C
6alkyl)
2,-OC (O) O (C
1-C
6alkyl) ,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) N (C
1-C
6alkyl)
2,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-NHC (O) O (C
1-C
6alkyl) and-N (C
1-C
6alkyl) C (O) O (C
1-C
6alkyl);
R
14and R
15independently be selected from H, C
1-C
12alkyl, aryl, carbocylic radical, heterocyclic radical and heteroaryl;
Y is independently O, NR
11or S;
R wherein
1, R
2, R
3, R
4, R
5, R
6, X
1, X
2, R
11, R
12, R
13, R
14and R
15in each described alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl is independent optionally independently is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21;
Each R
16, R
17and R
18independent is H, C
1-C
12alkyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl optionally are selected from following one or more groups and are replaced: halogen, oxo, CN ,-OCF
3, CF
3,-NO
2, C
1-C
6alkyl ,-OH ,-SH ,-O (C
1-C
6alkyl) ,-S (C
1-C
6alkyl) ,-NH
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl)
2,-SO
2(C
1-C
6alkyl) ,-CO
2h ,-CO
2(C
1-C
6alkyl) ,-C (O) NH
2,-C (O) NH (C
1-C
6alkyl) ,-C (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-NHC (O) (C
1-C
6alkyl) ,-NHSO
2(C
1-C
6alkyl) ,-N (C
1-C
6alkyl) SO
2(C
1-C
6alkyl) ,-SO
2nH
2,-SO
2nH (C
1-C
6alkyl) ,-SO
2n(C
1-C
6alkyl)
2,-OC (O) NH
2,-OC (O) NH (C
1-C
6alkyl) ,-OC (O) N (C
1-C
6alkyl)
2,-OC (O) O (C
1-C
6alkyl) ,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) N (C
1-C
6alkyl)
2,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-NHC (O) O (C
1-C
6alkyl) and-N (C
1-C
6alkyl) C (O) O (C
1-C
6alkyl); Or
R
16and R
17form together with the nitrogen connected with them and have the heteroatomic 3-8 of the 0-2 that is selected from O, S and N unit saturated rings, unsaturated ring or aromatic ring, wherein said ring optionally is selected from following one or more groups and is replaced: halogen, CN ,-OCF
3, CF
3,-NO
2, C
1-C
6alkyl ,-OH ,-SH ,-O (C
1-C
6alkyl) ,-S (C
1-C
6alkyl) ,-NH
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl)
2,-SO
2(C
1-C
6alkyl) ,-CO
2h ,-CO
2(C
1-C
6alkyl) ,-C (O) NH
2,-C (O) NH (C
1-C
6alkyl) ,-C (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-NHC (O) (C
1-C
6alkyl) ,-NHSO
2(C
1-C
6alkyl) ,-N (C
1-C
6alkyl) SO
2(C
1-C
6alkyl) ,-SO
2nH
2,-SO
2nH (C
1-C
6alkyl) ,-SO
2n(C
1-C
6alkyl)
2,-OC (O) NH
2,-OC (O) NH (C
1-C
6alkyl) ,-OC (O) N (C
1-C
6alkyl)
2,-OC (O) O (C
1-C
6alkyl) ,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) N (C
1-C
6alkyl)
2,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-NHC (O) O (C
1-C
6alkyl) and-N (C
1-C
6alkyl) C (O) O (C
1-C
6alkyl);
R
19and R
20independently be selected from H, C
1-C
12alkyl, aryl-(CH
2)
n-, carbocylic radical-(CH
2)
n-, heterocyclic radical-(CH
2)
n-and heteroaryl-(CH
2)
n-;
R
21for C
1-C
12alkyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, carbocylic radical, heterocyclic radical, aryl or heteroaryl, wherein R
21in each member optionally be selected from following one or more groups and replaced: halogen, CN ,-OCF
3, CF
3,-NO
2, C
1-C
6alkyl ,-OH ,-SH ,-O (C
1-C
6alkyl) ,-S (C
1-C
6alkyl) ,-NH
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl)
2,-SO
2(C
1-C
6alkyl) ,-CO
2h ,-CO
2(C
1-C
6alkyl) ,-C (O) NH
2,-C (O) NH (C
1-C
6alkyl) ,-C (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-NHC (O) (C
1-C
6alkyl) ,-NHSO
2(C
1-C
6alkyl) ,-N (C
1-C
6alkyl) SO
2(C
1-C
6alkyl) ,-SO
2nH
2,-SO
2nH (C
1-C
6alkyl) ,-SO
2n(C
1-C
6alkyl)
2,-OC (O) NH
2,-OC (O) NH (C
1-C
6alkyl) ,-OC (O) N (C
1-C
6alkyl)
2,-OC (O) O (C
1-C
6alkyl) ,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-N (C
1-C
6alkyl) C (O) NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) N (C
1-C
6alkyl)
2,-NHC (O) NH (C
1-C
6alkyl) ,-NHC (O) N (C
1-C
6alkyl)
2,-NHC (O) O (C
1-C
6alkyl) and-N (C
1-C
6alkyl) C (O) O (C
1-C
6alkyl);
Each Y ' is independent is O, NR
22or S;
R
22for H or C
1-C
12alkyl; And
M and n independently are selected from 0,1,2,3,4,5 or 6.
The present invention includes the composition (as pharmaceutical composition) that contains formula I compound (and/or its solvate, hydrate and/or salt) and carrier (pharmaceutically acceptable carrier).The present invention also comprises the composition (as pharmaceutical composition) that contains formula I compound (and/or its solvate, hydrate and/or salt) and carrier (pharmaceutically acceptable carrier) and another kind of chemotherapeutic agent and/or another kind of anti-inflammatory drug.The present composition for example is used in, in Mammals (people) and suppresses abnormal cell growth or overmedication proliferative disease.The present composition also is used in for example, in Mammals (people) treatment inflammatory diseases.
Present invention resides in the method that for example, suppresses abnormal cell growth or overmedication proliferative disease in Mammals (people), described method comprises that the composition that will treat the formula I compound (and/or its solvate and salt) of significant quantity or comprise it is independent or give described Mammals together with another kind of chemotherapeutic agent.
Present invention resides in the method for for example, in Mammals (people) treatment inflammatory diseases, described method comprises that the composition that will treat the formula I compound (and/or its solvate and salt) of significant quantity or comprise it is independent or give described Mammals together with another kind of anti-inflammatory drug.
The present invention includes the method for the compounds of this invention for external, original position and in-vivo diagnostic or treatment mammalian cell, organ or related diseases illness of science of using.
Embodiment
Now describing certain embodiments of the present invention in detail is the shown embodiment of additional structure and chemical formula.When the present invention describes by cited embodiment, should be appreciated that they not are intended to limit the invention to those embodiments.On the contrary, the present invention is intended to contain all changes, modification and the equivalent form of value that can be included in the scope of the invention as defined as claim.One skilled in the art will realize that those methods of describing with the application and material type like or several different methods and material of equal value, these methods and material can be used in practice of the present invention.The present invention never is limited to described method and material.If the document of one or more introducings, patent and analogous material and the different or contradiction of the application's (including but not limited to the usage of defined term, term, described technology etc.), be as the criterion with the application.
Definition
The defined term of the application " alkyl " refers to by one to 12 saturated straight chain that carbon atom forms or side chain univalence hydrocarbyl.The example of alkyl include but not limited to methyl (Me ,-CH
3), ethyl (Et ,-CH
2cH
3), the 1-propyl group (n-Pr, n-propyl ,-CH
2cH
2cH
3), the 2-propyl group (i-Pr, sec.-propyl ,-CH (CH
3)
2), the 1-butyl (n-Bu, normal-butyl ,-CH
2cH
2cH
2cH
3), 2-methyl isophthalic acid-propyl group (i-Bu, isobutyl-,-CH
2cH (CH
3)
2), the 2-butyl (s-Bu, sec-butyl ,-CH (CH
3) CH
2cH
3), the 2-methyl-2-propyl (t-Bu, the tertiary butyl ,-C (CH
3)
3), the 1-amyl group (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), 1-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, 1-heptyl, 1-octyl group etc.
Term " thiazolinyl " refers to that at least one the unsaturated site that has be comprised of one to 12 carbon atom is carbon carbon sp
2the straight or branched univalence hydrocarbyl of two keys, wherein said thiazolinyl comprises the group with " cis " and " trans " orientation (or " E " and " Z " is orientated).Example includes but not limited to vinyl (ethylenyl or vinyl) (CH=CH
2), allyl group (CH
2cH=CH
2) etc.
Term " alkynyl " refers to the straight or branched univalence hydrocarbyl that at least one unsaturated site is carbon carbon sp triple bond that has be comprised of one to 12 carbon atom.Example include but not limited to ethynyl (C ≡ CH), proyl (propargyl ,-CH
2c ≡ CH) etc.
Term " carbocyclic ring (carbocycle) ", " carbocylic radical (carbocyclyl) ", " carbocyclic ring (carbocyclic ring) " and " cyclic hydrocarbon radical (cycloalkyl) " refer to the ring with 3 to 12 carbon atoms or fractional saturation saturated as the unit price nonaro-maticity of two rings as monocycle or 7 to 12 carbon atoms.The two ring carbocyclic rings with 7 to 12 atoms can be arranged as for example two rings [4,5], [5,5], [5,6] or [6,6] system, the two ring carbocyclic rings with 9 or 12 annular atomses can be arranged as two rings [5,6] or [6,6] system, or be arranged as bridge system (bridged system) as two rings [2.2.1] heptane, two ring [2.2.2] octanes and two ring [3.2.2] nonanes.The example of monocycle carbocyclic ring includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-ring penta-1-thiazolinyl, 1-ring penta-2-thiazolinyl, 1-ring penta-3-thiazolinyl, cyclohexyl, 1-hexamethylene-1-thiazolinyl, 1-hexamethylene-2-thiazolinyl, 1-hexamethylene-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl etc.
" aryl " means to remove by the single carbon atom from parent aromatic ring system the unit price aromatic hydrocarbyl be comprised of 6-18 carbon atom that a hydrogen atom obtains.In example arrangement, some aryl are represented as " Ar ".Aryl comprises the bicyclic groups contained with the ring of saturated, fractional saturation or aromatic carbocyclic or heterocyclic fused aromatic ring.Typical aryl includes but not limited to benzene, naphthalene, anthracene, indenyl (indenyl), the indanyl (indanyl), 1 by benzene (phenyl), replacement, 2-dihydronaphthalene, 1,2,3, the group that 4-tetralyl etc. obtains.
Term " heterocycle (heterocycle) ", " heterocyclic radical (heterocyclyl) " and " heterocycle (heterocyclicring) " commutative use in this application, refer to the carbon ring group of the saturated or fractional saturation (in ring, thering is one or more pairs of keys and/or triple bond) formed by 3 to 18 annular atomses, wherein at least one annular atoms is the heteroatoms that is selected from nitrogen, oxygen and sulphur, all the other annular atomses are C, and wherein one or more annular atomses are optional independently to be replaced by one or more substituting groups as described below.Heterocycle can be two rings that have the monocycle of 3 to 7 ring memberses (2 to 6 carbon atoms and 1 to 4 heteroatoms that is selected from N, O, P and S) or have 7 to 10 ring memberses (4 to 9 carbon atoms and 1 to 6 heteroatoms that is selected from N, O, P and S), for example two encircle [4,5], [5,5], [5,6] or [6,6] system.Heterocycle is described in Paquette, Leo A.; " Principles ofModern Heterocyclic Chemistry " (W.A.Benjamin, New York, 1968) (particularly the 1st, 3,4,6,7 and 9 chapters); " The Chemistryof Heterocyclic Compounds, A series of Monographs " (John Wiley& Sons, NewYork, 1950 to present) (particularly the 13rd, 14,16,19 and 28 volumes); And in J.Am.Chem.Soc. (1960) 82:5566." heterocyclic radical " also comprises ring or aromatic carbocyclic or the heterocyclic fused group of heterocyclic group and saturated, fractional saturation.The example of heterocycle includes but not limited to pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidino-(1-position only) (piperidino), morpholino (morpholino), parathiazan generation (thiomorpholino), thia oxa-cyclohexyl (thioxanyl), piperazinyl, homopiperazine base (homopiperazinyl), azetidinyl, oxetanyl, the Thietane base, homopiperidinyl (homopiperidinyl), oxepane alkyl (oxepanyl), thia suberane base (thiepanyl), oxa-
base (oxazepinyl), diaza
base (diazepinyl), thia
base (thiazepinyl), 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane base, 1,3-dioxane amyl group, pyrazolinyl, dithia cyclohexyl (dithianyl), dithia cyclopentyl (dithiolanyl), dihydro pyranyl, dihydro-thiophene base, dihydrofuran base, pyrazolidyl, imidazolinyl, imidazolidyl, 3-azabicyclic [3.1.0] hexyl, 3-azabicyclic [4.1.0] heptane base and azabicyclic [2.2.2] hexyl.Spiral shell partly is also included within the scope of this definition.The example of the heterocyclic radical that annular atoms is replaced by oxo (=O) part is pyrimidine ketone group (pyrimidinonyl) and 1,1-dioxo-parathiazan base.
Term " heteroaryl " refers to the unit price aromatic group be comprised of 5 or 6 rings, and comprises that it contains the one or more heteroatomss that independently are selected from nitrogen, oxygen and sulphur by 5-18 former molecular carbocyclic fused ring system (wherein at least one ring is aromatics).The example of heteroaryl is pyridyl (comprising for example 2 hydroxy pyrimidine base), imidazolyl, imidazopyridyl, pyrimidyl (comprising for example 4-hydroxy pyrimidine base), pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrryl, quinolyl, isoquinoline 99.9 just, indyl, benzimidazolyl-, benzofuryl, the cinnolines base, indazolyl, the indolizine base, phthalazinyl, pyridazinyl, triazinyl, pseudoindoyl, pteridyl, purine radicals, oxadiazolyl, triazolyl, thiadiazolyl group, the furazan base, the benzofuraxan base, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinoxalinyl, phthalazinyl and furo pyridyl.
Heterocycle or heteroaryl can be carbon (carbon connection) or (nitrogen connection) connection when suitably connecting.By way of example and unrestricted, the heterocycle of bond with carbon or heteroaryl are at following position bonding: 2 of pyridine, 3, 4, 5 or 6, 3 of pyridazine, 4, 5 or 6, 2 of pyrimidine, 4, 5 or 6, 2 of pyrazine, 3, 5 or 6, furans, tetrahydrofuran (THF), thiophene, 2 of pyrroles or Pyrrolidine, 3, 4 or 5, oxazole, 2 of imidazoles or thiazole, 4 or 5, isoxazole, 3 of pyrazoles or isothiazole, 4 or 5, 2 or 3 of aziridine, 2 of azetidine, 3 or 4, 2 of quinoline, 3, 4, 5, 6, 7 or 8, or isoquinoline 99.9 1, 3, 4, 5, 6, 7 or 8.
By way of example and unrestricted, the heterocycle of nitrogen bonding or heteroaryl are at following position bonding: aziridine, azetidine, pyrroles, tetramethyleneimine, 2-pyrroline, 3-pyrroline, imidazoles, imidazolidine, 2-tetrahydroglyoxaline, 3-tetrahydroglyoxaline, pyrazoles, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidines, piperazine, indoles, indoline, 1H-indazole 1, isoindole or isoindoline 2,4 of morpholine, and carbazole or β-carboline 9.
Term " halogen " refers to F, Cl, Br or I.The heteroatoms existed in heteroaryl or heterocyclic radical comprises that oxidised form is as N
+→ O
-, S (O) and S (O)
2.
Term " treatment (treating) " or " treatment (treatment) " refer to that therapeutic disposes and preventive measure, wherein purpose be prevention slow down that physiology that (alleviating) do not expect changes or obstacle as development or the diffusion of cancer.For purposes of the present invention, clinical effectiveness useful or expectation includes but not limited to relief of symptoms, reduces lesion degree, stablizes (not being to worsen) morbid state, postpones or slows down progression of disease, improvement or relaxes morbid state and improvement (part takes a turn for the better or improvement fully), and no matter these results are detectable or undetectable." treatment (treating) " also can mean to compare with the expection survival of not receiving treatment the survival of prolongation.Need the object for the treatment of to comprise the object that the object of suffering from illness or obstacle and the object of easily suffering from described illness or obstacle or described illness or obstacle should be prevented.
Term " treatment significant quantity " means the amount of the compounds of this invention of disease specific, illness or obstacle that (i) treatment or prevention the application describe, (ii) weaken, improve or eliminate the amount of the compounds of this invention of one or more symptoms of disease specific, illness or obstacle that the application describes, or (iii) prevention or postpone the amount of the compounds of this invention of outbreak of one or more symptoms of disease specific, illness or obstacle that the application describes.In the situation of cancer, the medicine for the treatment of significant quantity can reduce the quantity of cancer cells; Reduce tumor size; Suppressing (slow down to a certain extent and preferably stop) cancer cells infiltrates in peripheral organs; Suppress to a certain extent tumor growth; And/or alleviate to a certain extent one or more symptoms relevant to cancer.If medicine can prevent the growth of cancer cells and/or kill existing cancer cells, it may be (cytostatic) of cell growth inhibition and/or Cytotoxic.For cancer therapy, can for example by estimating progression of disease time (TTP) and/or definite response rate (RR), measure effect.
Term " abnormal cell growth " and " excess proliferative disease " commutative use in this application.Except as otherwise noted, " abnormal cell growth " used in this application refers to the Growth of Cells (for example contact inhibition lacks (loss of contact inhibition)) that does not rely on normal regulating mechanism.This comprises for example misgrowth of following cell: the tumour cell (tumour) that the Tyrosylprotein kinase that (1) suddenlys change by expression or overexpression receptor tyrosine kinase are bred; (2) the optimum and malignant cell in other proliferative disease of abnormal tyrosine-kinase enzyme activation appears; (3) any tumour that its propagation is affected by receptor tyrosine kinase; (4) its propagation is subject to any tumour that abnormal serine/threonine kinase activation affects; And the optimum and malignant cell in other proliferative disease of abnormal serine/threonine kinase activation appears in (5).
Term " cancer (cancer) " and " (cancerous) of cancer " refer to or describe the physiological conditions that feature in Mammals is typically unadjusted Growth of Cells." tumour " comprises one or more cancer cells.The example of cancer includes but not limited to cancer knurl (carcinoma), lymphoma, blastoma, sarcoma and lymph or lymph sample malignant tumour.The example more specifically of described cancer comprises squamous cell carcinoma (for example epithelium squamous cell carcinoma), lung cancer, comprise small cell lung cancer, nonsmall-cell lung cancer (" NSCLC "), adenocarcinoma of lung (adenocarcinoma of the lung) and squamous cell lung carcinoma (squamous carcinoma of thelung), peritoneal cancer, hepatocellular carcinoma, cancer of the stomach (gastric or stomach cancer), comprise gastrointestinal cancer, carcinoma of the pancreas, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, hepatoma (hepatoma), breast cancer (breast cancer), colorectal carcinoma, the rectum cancer, colorectal carcinoma, carcinoma of endometrium or uterus carcinoma, salivary-gland carcinoma, kidney or renal cancer, prostate cancer, carcinoma vulvae (vulvalcancer), thyroid carcinoma, liver cancer (hepatic carcinoma), anus cancer, penile cancer, acute leukemia, and head/cancer of the brain and neck cancer.
" chemotherapeutic agent " is the compound that can be used for treating cancer.The example of chemotherapeutic agent comprise Erlotinib (
Genentech/OSI Pharm.), bortezomib (Bortezomib) (
Millennium Pharm.), fulvestrant (
AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (
Novartis), imatinib mesylate (
Novartis), PTK787/ZK 222584 (Novartis), oxaliplatin (
Sanofi), 5-FU (5 FU 5 fluorouracil), formyl tetrahydrofolic acid (Leucovorin), rapamycin (Sirolimus,
Wyeth), Lapatinib (Lapatinib) (
GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (Sorafenib, BAY43-9006, Bayer Labs) and Gefitinib (
AstraZeneca), (SU 5271 for AG1478, AG1571, Sugen), alkylating agent as phosphinothioylidynetrisaziridine (thiotepa) and
endoxan, alkyl sulfonate esters (alkyl sulfonate) is as busulfan, Improsulfan and piposulfan (piposulfan), aziridine is as benzodopa, card ripple quinone, meturedopa and uredopa, Ethylenimine (ethylenimine) and methylaminacrine (methylamelamine), comprise hexamethyl melamine, tretamine (triethylenemelamine), triethylenephosphoramide (triethylenephosphoramide), triethylenethiophosphoramide (triethylenethiophosphoramide) and trimethylomelamine, Annona lactone (acetogenin) (especially its suffering of Bradley (bullatacin) and its octanone of Bradley (bullatacinone)), camptothecine (comprising synthetic analog Hycamtin (topotecan)), bryostatin (bryostatin), callystatin, CC-1065 (comprising its Adozelesin (adozelesin), Carzelesin (carzelesin) and the synthetic analog of Bizelesin (bizelesin)), cryptophycins (particularly cryptophycin 1 and cryptophycin 8), dolastatin (dolastatin), duocarmycin (comprising synthetic analog KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictyin, spongistatin, mustargen is as Chlorambucil, Chlornaphazine, chlorine phosphamide (chlorophosphamide), Estramustine, ifosfamide, chlormethine (mechlorethamine), mustron (mechlorethamine oxide hydrochloride), melphalan, novoembichin (novembichin), phenesterin (phenesterine), prednimustine (prednimustine), Trofosfamide (trofosfamide), uracil mastard (uracil mustard), nitrourea is as BCNU, chlorozotocin (chlorozotocin), Fotemustine, lomustine, Ni Mositing and Ranimustine, antibiotic for example, as enediyne (enediyne) antibiotic (especially calicheamycin γ 1I and calicheamycin ω I1 (Angew Chem.Intl.Ed.Engl. (1994) 33:183-186) of calicheamycin (calicheamicin), anthracycline antibiotic (dynemicin), comprise dynemicin A, diphosphonate (bisphosphonate) is as clodronate (clodronate), Ai Sipeila mycin (esperamicin), and neocarzinostatin chromophore (neocarzinostatin chromophore) and related colour albumen enediyne antibiotic chromophore (enediyne antibiotic chromophore), aclacinomysin, D actinomycin D (actinomycin), authramycin, azaserine (azaserine), bleomycin, act-C (cactinomycin), carabicin, carminomycin (carminomycin), carzinophillin (carzinophilin), chromomycin (chromomycin), actinomycin D (dactinomycin), daunorubicin (daunorubicin), floor mop is than star (detorubicin), 6-diazo-5-oxo-L-nor-leucine (6-diazo-5-oxo-L-norleucine),
(Doxorubicin), morpholino-Doxorubicin, cyano group morpholino-Doxorubicin, 2-pyrrolin subbase-Doxorubicin and deoxidation Doxorubicin, epirubicin (epirubicin), esorubicin, idarubicin, marcellomycin (marcellomycin), mitomycin is as mitomycin C, Mycophenolic Acid (mycophenolic acid), nogalamycin (nogalamycin), olivomycin (olivomycins), Peplomycin (peplomycin), porfiromycin (porfiromycin), Puromycin (puromycin), triferricdoxorubicin (quelamycin), rodorubicin (rodorubicin), broneomycin (streptonigrin), streptozotocin (streptozocin), tubercidin (tubercidin), ubenimex (ubenimex), Zinostatin (zinostatin), zorubicin, antimetabolite is as methopterin and 5 FU 5 fluorouracil (5-FU), folacin is as denopterin, methopterin, sieve purine (pteropterin) of talking endlessly, Trimetrexate (trimetrexate), purine analogue is as fludarabine (fludarabine), 6-MP, ITG (thiamiprine), thioguanine (thioguanine), pyrimidine analogue is as ancitabine (ancitabine), azacitidine (azacitidine), 6-nitrogen guanosine (6-azauridine), Carmofur (carmofur), cytarabine (cytarabine), di-deoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), Yi Nuota shore (enocitabine), floxuridine (floxuridine), androgen is as Calusterone (calusterone), dromostanolone propionate (dromostanolone propionate), epithioandrostanol (epitiostanol), Mepitiostane (mepitiostane), Testolactone (testolactone), antiadrenergic drug (anti-adrenal) is as aminoglutethimide (aminoglutethimide), mitotane (mitotane), Trilostane (trilostane), folic acid supplement (folic acid replenisher) is as folinic acid (frolinic acid), aceglatone (aceglatone), aldophosphamide glucosides (aldophosphamide glycoside), amino-laevulic acid (aminolevulinic acid), eniluracil (eniluracil), amsacrine (amsacrine), bestrabucil, bisantrene (bisantrene), the Yi Da song kills (edatraxate), Defosfamide (defofamine), demecolcine (demecolcine), diaziquone (diaziquone), elfornithine, Elliptinium Acetate (elliptinium acetate), Epothilones (epothilone), ethoglucid (etoglucid), gallium nitrate (gallium nitrate), hydroxycarbamide (hydroxyurea), lentinan (lentinan), Lonidamine (lonidainine), maytansinol (maytansinoid) is as maytansine (maytansine) and ansamitocin (ansamitocin), mitoguazone (mitoguazone), mitoxantrone (mitoxantrone), mopidanmol, nitragin (nitraerine), Pentostatin (pentostatin), Phenamet (phenamet), THP (pirarubicin), Losoxantrone (losoxantrone), podophyllic acid (podophyllinic acid), 2-ethyl hydrazine, procarbazine (procarbazine),
polysaccharide compound (JHS Natural Products, Eugene, OR), razoxane (razoxane), rhizomycin (rhizoxin), sizofiran (sizofiran), Spirogermanium (spirogermanium), tenuazonic acid (tenuazonic acid), triethyleneiminobenzoquinone (triaziquone), 2,2 ', 2 "-RA3, trichothecene (trichothecene) (especially T-2 toxin, verracurin A, Roridine A and anguidine), urethane, eldisine, Dacarbazine (dacarbazine), mannomustine (mannomustine), dibromannitol (mitobronitol), mitolactol (mitolactol), pipobroman (pipobroman), gacytosine, cytarabine (arabinoside) (" Ara-C "), endoxan, phosphinothioylidynetrisaziridine, taxane for example
(taxol, Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE
TM(Cremophor-free), the albumin through engineering approaches Nanoparticulate formulations of taxol (albumin-engineered nanoparticle formulations ofpaclitaxel) (American Pharmaceutical Partners, Schaumberg, Illinois) and
(doxetaxel,
-Poulenc Rorer, Antony, France), chloranmbucil,
(gemcitabine), 6-thioguanine, mercaptopurine, methopterin, platinum analogs is as cis-platinum and carboplatin, vincaleukoblastinum, Etoposide (VP-16), ifosfamide, mitoxantrone, vincristine,
(vinorelbine), Novantrone (novantrone), Teniposide (teniposide), the Yi Da song kills (edatrexate), daunorubicin, aminopterin-induced syndrome, capecitabine
ibandronate (ibandronate), CPT-11, topoisomerase enzyme inhibitor RFS2000, DFMO (difluoromethylornithine) (DMFO), retinoids (retinoid) is as retinoic acid (retinoic acid), and the officinal salt of above-mentioned any material, acid and derivative.
Following material is also included within the definition of " chemotherapeutic agent ": (i) for regulate or inhibitory hormone to the hormone antagonist medicine of the effect of tumour, as antiestrogen (anti-estrogen) and selective estrogen receptor modulators (selective estrogen receptor modulator, SERM), comprise that for example tamoxifen (comprises
tamoxifen Citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene (trioxifene), Lei Luoxifen (keoxifene), LY117018, onapristone (onapristone) and
(Citric Acid Toremitene (toremifine citrate)); (ii) suppress the aromatase inhibitor of aromatase enzyme (regulating estrogen production in suprarenal gland), for example 4 (5)-imidazoles, aminoglutethimide,
(Magace (megestrol acetate)),
(Exemestane (exemestane); Pfizer), formestanie, fadrozole (fadrozole),
(vorozole (vorozole)),
(letrozole; Novartis) and
(Anastrozole (anastrozole); AstraZeneca); (iii) androgen antagonist medicine (anti-androgen), as flutamide, Nilutamide (nilutamide), bicalutamide (bicalutamide), leuprorelin acetate (leuprolide) and goserelin (goserelin) and troxacitabine (troxacitabine) (1,3-dioxolane nucleosides cytosine(Cyt) analogue); (iv) kinases inhibitor; (v) lipid kinase inhibitors; (vi) antisense oligonucleotide, particularly suppress those antisense oligonucleotides of the genetic expression in signal transduction pathway related in abnormal cell proliferation, for example PKC-α, Ralf and H-Ras; (vii) ribozyme as the vegf expression inhibitor (for example
) and the HER2 expression inhibitor; (viii) vaccine is as gene therapeutic vaccine, for example
with
rIL-2; Topoisomerase 1 inhibitor as
rmRH; (ix) anti-angiogenic medicaments as rhuMAb-VEGF (
genentech); And (x) pharmacologically acceptable salt, acid and the derivative of above-mentioned any material.Other anti-angiogenic medicaments comprises MMP-2 (MMP2) inhibitor, MMP-9 (GELB) inhibitor, COX-II (cyclooxygenase II) inhibitor and vegf receptor tyrosine kinase inhibitor.Can be described in WO 96/33172 with the example of the above-mentioned useful matrix metallo-proteinase inhibitor of the compounds of this invention/composition coupling, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606, 046, EP 931, 788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, United States Patent (USP) 5, 863, 949, United States Patent (USP) 5, 861, 510 and EP 780, in 386, all these documents are introduced to the application as a reference in full.The example of vegf receptor tyrosine kinase inhibitor comprises 4-(the bromo-2-fluoroanilino of 4-)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline (ZD6474; Embodiment 2 in WO 01/32651), 4-(the fluoro-2 methyl indole of 4--5-base oxygen base)-6-methoxyl group-7-(3-pyrrolidin-1-yl propoxy-)-quinazoline (AZD2171; Embodiment 240 in WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 ((Sutent (sunitinib); WO01/60814) and compound disclosed compound in PCT publication number WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354 for example.
Can comprise with other example of the chemotherapeutic agent of the compounds of this invention coupling the inhibitor of PI3K (phosphoinositide-3 kinases), as the compound to report in Publication about Document: Yaguchi et al (2006) Jour.ofthe Nat.Cancer Inst.98 (8): 545-556; US 7173029; US 7037915; US 6608056; US 6608053; US 6838457; US 6770641; US 6653320; US 6403588; WO2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070; US 6703414; With WO 97/15658, all these documents are introduced to the application as a reference in full.The specific examples of described PI3K inhibitor comprise SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (the PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.).
The term used in the application " inflammatory diseases " includes but not limited to rheumatoid arthritis, atherosclerosis, congestive heart failure, inflammatory bowel (including but not limited to Crohn's disease (Crohn ' sdisease) and ulcerative colitis), chronic obstructive pulmonary disease (chronic obstructive pulmonarydisease in the lung), liver renal fibrosis disease (fibrotic disease in the liver and kidney), Crohn's disease, tetter is (as psoriasis, eczema and scleroderma (scleroderma)), osteoarthritis, multiple sclerosis, asthma, the disease relevant to diabetic complication and obstacle, organ is as lung, liver, the struvite complication of the fibrosis organ failure of kidney (fibrotic organ failure) and cardiovascular systems is as acute coronary syndrome (acute coronary syndrome).
" anti-inflammatory drug " is for can be used for treating the compound of inflammation.The example of anti-inflammatory drug comprise the agent of injectable protein for treatment as
with
other example of anti-inflammatory drug comprises nonsteroidal anti-inflammatory agent (NSAID), as Ibuprofen BP/EP or acetylsalicylic acid (it reduces swelling alleviating pain); Alleviate the antirheumatic (DMARD) of disease, as Rheumatrex; 5-aminosalicylic acid ester (medicine of sulfasalazine (sulfasalazine) and non-sulfanilamide (SN)); Cortin; Immunomodulator as 6-MP (" 6-MP "), azathioprine (" AZA "), S-Neoral and biological response modifier (biological responsemodifier) as Remicade.RTM. (infliximab (infliximab)) and Enbrel.RTM. (etanercept (etanercept)); Fibroblast growth factor (fibroblast growth factor); Platelet-derived somatomedin (platelet derived growth factor); The enzyme retarding agent is as Arava.RTM. (leflunomide); And/or the cartilage protection medicine is as hyaluronic acid, glycosamine and chrondroitin.
Term used in this application " prodrug " refers to can be through enzyme or hydrolytic activation or be converted into precursor or the derivative form of the compounds of this invention that has more active parent form.Referring to for example Wilman, " Prodrugs in Cancer Chemotherapy " Biochemical Society Transactions, 14, pp.375-382,615th Meeting Belfast (1986) and Stella et al., " Prodrugs:A ChemicalApproach to Targeted Drug Delivery; " Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985).Prodrug of the present invention include but not limited to containing the prodrug of the prodrug of ester, phosphate ester-containing, containing the prodrug of the prodrug of thiophosphatephosphorothioate, sulfur-bearing acid esters, containing prodrug, the D-of peptide amino acid modified prodrug, glycosylated prodrug, containing the prodrug of beta-lactam, containing the prodrug of the optional phenoxy-acetamide replaced, containing prodrug, 5-flurocytosine and other 5 FU 5 fluorouracil prodrug of the optional phenyl-acetamides replaced, these prodrugs can be converted into the medicine that has more active no cytotoxicity.The example that can derive as the cytotoxic drug for prodrug forms of the present invention includes but not limited to the compounds of this invention and chemotherapeutic agent as above.
" metabolite " is the product produced by particular compound or the metabolism in vivo of its salt.Can use the metabolite of routine techniques authenticating compound known in the art, and their activity is determined in use test as described in the present application.Described product can result from such as the oxidation of the compound of institute's administration, hydroxylation, reduction, hydrolysis, amidation, desamidization, esterification, take off esterification, enzymatic cleavage etc.Therefore, the present invention includes the metabolite of the compounds of this invention, comprise the compound produced by following methods, described method comprises makes the compounds of this invention contact the time that is enough to produce its meta-bolites with Mammals.
The vesicles that " liposome " is comprised of various types of lipid, phosphatide and/or tensio-active agent, it can be used for medicine (MEK kinase inhibitor as disclosed as the application and optional chemotherapeutic agent) is delivered to Mammals.With biomembranous fat homotaxis, the component of liposome is arranged with double-deck form usually.
Term " package insert (package insert) " refers to the specification sheets in the commercially available back that is usually included in the treatment product, it is containing the information relevant for indication, usage, dosage, administration, contraindication and/or warning item, and these information relate to the use of above-mentioned treatment product.
Term " chirality " refer to there is the mirror image mating partner (mirror image partner) can not overlapping character molecule, and term " achirality " refer to can be overlapping with its mirror image mating partner molecule.
Therefore term " steric isomer " refers to have identical chemical constitution with the link situation but the orientation of their atoms spatially Bu Tong can not be by the compound mutually transformed around the singly-bound rotation.
" diastereomer " refers to have the not steric isomer of mirror image each other of two or more chiral centres and its molecule.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.The mixture of diastereomer can split analysis operation by height to be separated as crystallization, electrophoresis and chromatogram.
" enantiomer " refers to each other two kinds of steric isomers of compound that can not overlapping mirror image.
Stereochemistry definition used in this application and routine are usually according to 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.The compounds of this invention can contain asymmetric or chiral centre, therefore with different stereoisomeric forms in any ratio, exists.Be contemplated that all stereoisomeric forms in any ratio of the compounds of this invention, include but not limited to that diastereomer, enantiomer and atropisomer (atropisomers) and their mixture, as racemic mixture, have formed part of the present invention.Multiple organic compound exists with the optical activity form, and they have the ability on the plane of Plane of rotation polarized light.When description has optically active compound, with prefix D and L or R and S, mean the absolute configuration of molecule around one or mulitiple chiral centers.Prefix d and l or (+) and (-) are used to specify the symbol of the rotation that plane polarized light causes by compound, and wherein (-) or l mean that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.For given chemical structure, except these steric isomers, each other mirror image, these steric isomers are identical.Concrete steric isomer also can be described as enantiomer, the so-called enantiomerism mixture of the mixture of described isomer.50: 50 mixtures of enantiomer are called racemic mixture or racemic modification, while there is no stereoselectivity or stereospecificity in chemical reaction or method, this situation can not occur.Term " racemic mixture " and " racemic modification " refer to the molar mixture that waits of two kinds of enantiomer materials, and it does not have optical activity.
Term " tautomer " or " tautomeric form " refer to the constitutional isomer of the different-energy that can transform mutually by low energy barrier (low energybarrier).For example, proton tautomerism body (protontautomer) (also referred to as proton shifting tautomer (prototropic tautomer)) comprises the mutual conversion of being undertaken by proton shifting, as keto-enol isomerization and imines-enamine isomerization.Valence tautomerism body (valence tautomer) comprises the mutual conversion of being undertaken by the restructuring of some bonding electronss.
Phrase used in this application " pharmacologically acceptable salt " refers to the pharmaceutically acceptable organic or inorganic salt of the compounds of this invention.Exemplary salt includes but not limited to vitriol, citrate, acetate, oxalate, muriate, bromide, iodide, nitrate, hydrosulfate, phosphoric acid salt, acid phosphate, γ-picolinic acid salt, lactic acid salt, salicylate, the acid citrate, tartrate, oleate, tannate (tannate), pantothenate (pantothenate), bitartrate, ascorbate salt, succinate, maleate, gentisate (gentisinate), fumarate, gluconate, glucuronate, saccharate (saccharate), formate, benzoate, glutaminate, mesylate (mesylate (mesylate)), esilate, benzene sulfonate, tosilate, pamoate (1, 1 '-methylene radical-bis--(2-hydroxyl-3-naphthoate)), basic metal (for example sodium and potassium) salt, alkaline-earth metal (for example magnesium) salt and ammonium salt.Pharmacologically acceptable salt can relate to the inclusion compound (inclusion) of another kind of molecule as acetate ion, succinate ion or other counter ion.Counter ion can be any organic or inorganic parts of stable matrix compound electric charge.In addition, pharmacologically acceptable salt can have more than a charge atom in its structure.The situation of the part that a plurality of charge atoms are pharmacologically acceptable salt can have a plurality of counter ion.Therefore, pharmacologically acceptable salt can have one or more charge atoms and/or one or more counter ion.
If the compounds of this invention is alkali, can prepare by the available any appropriate method in this area by the pharmacologically acceptable salt of expectation, for example use mineral acid (example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, methylsulfonic acid, phosphoric acid etc.) or with organic acid (as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid, Whitfield's ointment, pyrans glycosyl acid (pyranosidyl acid) is as glucuronic acid or galacturonic acid, alpha hydroxy acid is as Citric Acid or tartrate, amino acid is as aspartic acid or L-glutamic acid, aromatic acid is as phenylformic acid or styracin, sulfonic acid is as tosic acid or ethyl sulfonic acid etc.) the processing free alkali.
If the compounds of this invention is acid, can prepare by any appropriate method by the pharmacologically acceptable salt of expectation, such as using inorganic or organic bases (as amine (primary amine, secondary amine or tertiary amine), alkali metal hydroxide or alkaline earth metal hydroxides etc.) processing free acid.The illustrative examples of acceptable acid addition salts includes but not limited to the organic salt obtained from following material: amino acid as glycine and arginine, ammonia, primary amine, secondary amine and tertiary amine and cyclic amine as piperidines, morpholine and piperazine; And the inorganic salt that obtain from following material: sodium, calcium, potassium, magnesium, iron, copper, zinc, aluminium and lithium.
Phrase " pharmaceutically useful " mean other composition that described material or composition must comprise with preparation and/or with the Mammals of its treatment chemically and/or be compatible on toxicology.
" solvate " refers to combination or the complexing of one or more solvent molecules and the compounds of this invention.The example that forms the solvent of solvate includes but not limited to water, Virahol, ethanol, methyl alcohol, DMSO, ethyl acetate, acetic acid and thanomin.Term " hydrate " refers to the complex compound when solvent molecule is water.
Term " protecting group " refers to the substituting group that stops or protect concrete functional group when other functional group be often used on compound reacts.For example, " amino protecting group " is the prevention be connected with amino or the substituting group of protecting amino functionality in compound.Suitable amino protecting group comprises ethanoyl, trifluoroacetyl group, tert-butoxycarbonyl (BOC), benzyl oxygen base carbonyl (CBZ) and 9-fluorenyl methoxy carbonyl (Fmoc).Similarly, " hydroxyl protecting group " refers to the substituting group that stops or protect the hydroxyl of hydroxy functionality.Suitable protecting group comprises ethanoyl and silyl." carboxyl-protecting group " refers to the substituting group that stops or protect carboxyl functionality's carboxyl.Common carboxyl-protecting group comprises phenyl sulfonyl ethyl, cyano ethyl, 2-(trimethyl silyl) ethyl, 2-(trimethyl silyl) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino)-ethyl, nitro-ethyl etc.For general description of protecting group and uses thereof, referring to T.W.Greene, Protective Groups inOrganic Synthesis, John Wiley& Sons, New York, 1991.
Except as otherwise noted, term " the compounds of this invention (compound of this invention) " and " the compounds of this invention (compounds of the present invention) " and " formula I compound " comprise formula I compound and steric isomer, geometrical isomer, tautomer, solvate, metabolite, salt (for example pharmacologically acceptable salt) and prodrug.
The invention provides the aza-benzofuranyl compounds that useful as kinase inhibitors particularly can be used as the formula I as above of MEK kinase inhibitor.The present invention includes the compound of formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h and III-i, and all other variablees are suc as formula defining in I.
In one embodiment of the invention, the compound that compound is formula I-b, I-f, I-g, I-h, II-b, II-f, II-g, II-h, III-b, III-f, III-g and III-h, and all other variablees are suc as formula defining in I.
In one embodiment of the invention, the compound that compound is formula III-c, and all other variablees are suc as formula defining in I.
In one embodiment of the invention, R
1for H, halogen, CN, CF
3,-NR
11r
12,-OR
11,-SR
11,-C (=O) NR
11r
12or C
1-C
6alkyl, and all other variablees are suc as formula defining in I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In another embodiment of the present invention, R
1for H, halogen, CN, CF
3, C
1-C
6alkyl ,-NR
11r
12(R wherein
11and R
12independent is H or C
1-C
6alkyl) ,-OR
11(R wherein
11for H or C
1-C
6alkyl) or-SR
11(R wherein
11for H or C
1-C
6alkyl); And all other variablees are suc as formula defining in I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In another embodiment of the present invention, R
1for H, Cl, CN, CF
3, methyl ,-NH
2,-NH (CH
3) ,-N (CH
3)
2,-OH or-OCH
3; And all other variablees are suc as formula defining in I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In another embodiment of the present invention, R
1for H; And all other variablees are suc as formula defining in I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f or III-g.
In one embodiment of the invention, R
2for H, halogen, CN, CF
3,-NR
11r
12,-OR
11,-SR
11,-C (=O) NR
11r
12or C
1-C
6alkyl, and all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
2for H, halogen, CN, CF
3, C
1-C
6alkyl ,-NR
11r
12(R wherein
11and R
12independent is H or C
1-C
6alkyl) ,-OR
11(R wherein
11for H or C
1-C
6alkyl) or-SR
11(R wherein
11for H or C
1-C
6alkyl); And all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
2for H, Cl, CN, CF
3, methyl ,-NH
2,-NH (CH
3) ,-N (CH
3)
2,-OH or-OCH
3; And all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In one embodiment of the invention, R
3for H, halogen, CN, CF
3,-NR
11r
12,-OR
11,-SR
11,-C (=O) NR
11r
12or C
1-C
6alkyl, and all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
3for H, halogen, CF
3or C
1-C
6alkyl; And all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
3for H, F, CF
3or methyl; And all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
3for H, F, Cl, CF
3, methyl or CN; And all other variablees suc as formula in I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e or III-i the definition or as hereinbefore defined.
In one embodiment of the invention, R
4for H, halogen, CN, CF
3,-NR
11r
12,-OR
11,-SR
11,-C (=O) NR
11r
12or C
1-C
6alkyl, and all other variablees suc as formula in I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h the definition or as hereinbefore defined.
In another embodiment of the present invention, R
4for H, halogen, CN, CF
3,-NR
11r
12,-C (=O) NR
11r
12(R wherein
11and R
12independent is H or C
1-C
6alkyl) ,-OR
11(R wherein
11for H or C
1-C
6alkyl) or-SR
11(R wherein
11for H or C
1-C
6alkyl); And all other variablees suc as formula in I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h the definition or as hereinbefore defined.
In another embodiment of the present invention, R
4for H, Br, Cl, CN, CF
3,-NH
2,-NH (CH
3) ,-N (CH
3)
2,-C (O) NH
2,-C (O) NHCH
3,-C (O) N (CH
3)
2,-OH or-OCH
3; And all other variablees suc as formula in I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h the definition or as hereinbefore defined.
In another embodiment of the present invention, R
4for H, Br, Cl, CN, CF
3,-NH
2,-NH (CH
3) ,-N (CH
3)
2,-C (O) NH
2,-C (O) NHCH
3,-C (O) N (CH
3)
2,-OH or-OCH
3; And all other variablees suc as formula in I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h the definition or as hereinbefore defined.
In another embodiment of the present invention, R
4for halogen ,-OH or the C that optionally replaced by halogen
1-C
6alkyl; And all other variablees suc as formula in I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h the definition or as hereinbefore defined.
In another embodiment of the present invention, R
4independent is Cl, Br, Me (methyl), Et (ethyl), F, CHF
2, CF
3or-OH; And all other variablees suc as formula in I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g or III-h the definition or as hereinbefore defined.
In one embodiment of the invention, R
5for H or C
1-C
6alkyl; And all other variablees suc as formula in I, I-a to I-i or II-a to II-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
5for H or methyl; And all other variablees suc as formula in I, I-a to I-i or II-a to II-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
5for H; And all other variablees suc as formula in I, I-a to I-i or II-a to II-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
5for methyl; And all other variablees suc as formula in I, I-a to I-i or II-a to II-i the definition or as hereinbefore defined.
In one embodiment of the invention, R
6for H or C
1-C
6alkyl; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
6for H or methyl; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
6for H; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, R
6for methyl; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In one embodiment of the invention, X
1for OR
11(being formula II-a to II-i); And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In one embodiment of the invention, X
1for OR
11, R wherein
11for H; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for OR
11, R wherein
11the C replaced for independently being selected from following one or more groups
1-C
12alkyl (C for example
1-C
6alkyl): halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
and all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for OR
11, R wherein
11the heterocyclic radical (for example 4 to 6 yuan of heterocyclic radicals) replaced for optionally independently being selected from following one or more groups: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for OR
11, R wherein
11for having 4 to 6 yuan of heterocyclic radicals of 1 azo-cycle atom, wherein said heterocyclic radical optionally independently is selected from following one or more groups and is replaced: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
and all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In one embodiment of the invention, X
1for R
11, and X
1and R
5the nitrogen-atoms be connected with them connects together to form and has 0-2 the saturated or unsaturated ring of extra heteroatomic 5-7 unit that is selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for R
11, and X
1and R
5the nitrogen-atoms be connected with them connects together to form and has 0-2 the first saturated rings of extra heteroatomic 5-6 that is selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, W is
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, W is
And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, W is
and all other variablees
Suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In one embodiment of the invention, X
1for R
11, and X
1and R
5the nitrogen-atoms be connected with them connects together to form and has 0-1 extra heteroatomic 4 yuan of saturated or unsaturated rings that are selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, W is
and all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In one embodiment of the invention, X
1for-OR
11, and X
1-OR
11and R
5the nitrogen-atoms be connected with them connects together to form and has 0-2 the saturated or unsaturated ring of extra heteroatomic 4-7 unit that is selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for-OR
11, and X
1-OR
11and R
5the nitrogen-atoms be connected with them connects together to form and has 0-2 the saturated or unsaturated ring of extra heteroatomic 5-7 unit that is selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined
In another embodiment of the present invention, X
1for-OR
11, and X
1-OR
11and R
5the nitrogen-atoms be connected with them connects together to form and has 0-2 the first saturated rings of extra heteroatomic 5-6 that is selected from O, S and N, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, W is
and all other variablees suc as formula in I or I-a to I-i the definition or as hereinbefore defined.
In one embodiment of the invention, X
1for R
11; And all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for R
11, R wherein
11for H; And all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for R
11, R wherein
11the C replaced for independently being selected from following one or more groups
1-C
12alkyl (C for example
1-C
6alkyl): halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for
And all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for-S (O)
2r
11, and all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
1for-S (O)
2r
11, R wherein
11for H or methyl; And all other variablees suc as formula in I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or I-i the definition or as hereinbefore defined.
In one embodiment of the invention, W is-OR
11(being formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i), the wherein R of W
11for H or C
1-C
12alkyl; And all other variablees as hereinbefore defined.
In another embodiment of the present invention, W is-OR
11(being formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i), the wherein R of W
11for H; And all other variablees as hereinbefore defined.
In another embodiment of the present invention, W is-OR
11(being formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h or III-i), the wherein R of W
11for C
1-C
6alkyl; And all other variablees as hereinbefore defined.
In one embodiment of the invention, X
2for example, for aryl (phenyl), wherein said aryl optionally independently is selected from following one or more groups and is replaced: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
and all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
and all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for by C
1-C
4the C that alkyl replaces
6-C
10aryl, and all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for example, for carbocylic radical (C
4-C
6carbocylic radical) or heterocyclic radical (for example 4 to 6 yuan of heterocyclic radicals), wherein said carbocylic radical or heterocyclic radical optionally independently are selected from following one or more groups and are replaced: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
nc (=Y ') R
16,-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nc (=Y ') NR
16r
17,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
nnR
18c (=Y ') NR
16r
17,-(CR
19r
20)
nnR
17sO
2r
16,-(CR
19r
20)
noC (=Y ') R
16,-(CR
19r
20)
noC (=Y ') OR
16,-(CR
19r
20)
noC (=Y ') NR
16r
17,-(CR
19r
20)
noS (O)
2(OR
16) ,-(CR
19r
20)
noP (=Y ') (OR
16) (OR
17) ,-(CR
19r
20)
noP (OR
16) (OR
17) ,-(CR
19r
20)
ns (O) R
16,-(CR
19r
20)
ns (O)
2r
16,-(CR
19r
20)
ns (O)
2nR
16r
17,-(CR
19r
20)
ns (O) (OR
16) ,-(CR
19r
20)
ns (O)
2(OR
16) ,-(CR
19r
20)
nsC (=Y ') R
16,-(CR
19r
20)
nsC (=Y ') OR
16,-(CR
19r
20)
nsC (=Y ') NR
16r
17and R
21; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for C
4-C
6carbocylic radical, and wherein said carbocylic radical quilt-C (=Y ') R
16replace; And all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
In another embodiment of the present invention, X
2for
and all other variablees suc as formula in I, I-a to I-i, II-a to II-i or III-a to III-i the definition or as hereinbefore defined.
Another embodiment of the present invention comprises compound and the following compounds of describing in embodiment 5-159:
The compounds of this invention is according to the operation of describing in following scheme and embodiment or prepares by methods known in the art.Starting raw material and various intermediate can obtain from commercial source, from the commercial compound preparation, or use synthetic method (those methods of for example describing in WO02/06213, WO 03/077855 and the WO03/077914) preparation of knowing.
For example, formula (I-b), (II-b) but or the route of synthesis of general introduction in 5-azepine cumarone operational version 1,2 and 3 (III-b) preparation.
scheme 1
Formula (IV) compound can be used the disclosed method preparation of describing in document.Can make formula (IV) compound and hydroxyethanoic acid methyl esters or hydroxyethanoic acid ethyl ester, under the existence at alkali as sodium hydride, at suitable solvent as N, dinethylformamide or 1, in the 2-glycol dimethyl ether, at-50 ℃ to room temperature reaction, acquisition formula (VI) compound.
Can in the following manner formula (VI) compound be converted into to formula (VII) compound: make formula (VI) compound and halogenating agent as pure phosphoryl bromide (phosphorus oxybromide) or its at suitable solvent as the solution in toluene, in room temperature to 140 ℃ reaction.Alternatively, can make formula (VI) compound and nine fluorine butyl sulfonic acid fluoride (nonafluorobutane sulphonyl fluoride), at alkali as diisopropylethylamine and catalyzer as N, under the existence of N-dimethyl-4-aminopyridine, solvent as methylene dichloride in, at room temperature reaction; Or with N-phenyl trifluoromethanesulfonate methylsulfonyl imines (N-phenyltrifluoromethanesulfonimide, Tf2NPh), under the existence at alkali as diisopropylethylamine, at suitable solvent as 1, in the 2-glycol dimethyl ether, the reflux temperature reaction in room temperature to solvent.In addition, can be with trifluoromethanesulfanhydride anhydride at alkali under the existence as pyridine, solvent as methylene dichloride in, process formula (VI) compound at-20 ℃ to envrionment temperature.
Formula (VIII) compound can obtain from formula (VII) compound as follows: make formula (VII) compound and aniline (introducing suitable substituent R 1), at catalyzer as three (dibenzalacetone) two palladiums (0) or palladium, alkali is as potassiumphosphate, sodium tert-butoxide, 1, 8-diazabicylo [5.4.1] 11 carbon-7-alkene or cesium carbonate, part is as 9, 9 '-dimethyl-4, 5-bis-(diphenylphosphino) xanthene, 2, 2 '-bis-(diphenylphosphino)-1, 1 '-dinaphthalene, 2-(dicyclohexyl phosphino-)-2 '-(N, the N-dimethylamino) biphenyl, 2-(dicyclohexyl phosphino-)-2 ', under 6 '-dimethoxy-biphenyl or tributylphosphine exist, at suitable solvent as toluene, 1, the 2-glycol dimethyl ether, in tetrahydrofuran (THF) or dioxane, reflux temperature reaction in room temperature to solvent, or under microwave irradiation, 70 ℃ to 150 ℃ reactions.
Alternatively, formula (VIII) compound can obtain from formula (VI) compound as follows: make formula (VI) compound and formula (IX) compound (using the disclosed method preparation of describing document), at suitable solvent as toluene or 1, in the 2-glycol dimethyl ether, reflux temperature reaction in room temperature to solvent, or under microwave irradiation, 100 ℃ to 180 ℃ reactions.
Formula (X) compound can obtain from formula (VIII) compound as follows: make formula (VIII) compound and alkali as sodium hydroxide, protonic solvent as ethanol or methyl alcohol in, at room temperature to reflux temperature, react.
Can make functionalized azanol (commercially available or according to scheme 8 preparation) or the amine of formula (X) compound and formula (XII), and suitable coupling agent is as O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-
hexafluorophosphate, N-(3-(dimethylamino) propyl group)-N '-ethyl-carbodiimide hydrochloride or N, N '-dicyclohexylcarbodiimide, in N-hydroxyl-1, under the existence of 2,3-benzotriazole, under suitable alkali exists as diisopropylethylamine or triethylamine, at inert solvent as tetrahydrofuran (THF), N, in dinethylformamide or methylene dichloride, at about room temperature reaction, acquisition formula (XI) compound.Alternatively, formula (XI) compound can directly obtain from formula (VIII) compound as follows: make formula (VIII) compound and amine or azanol DNHR, under Lewis acid (Lewis acid) exists as trimethyl aluminium, solvent as DCM (methylene dichloride) in, at room temperature to reflux temperature, react.
Alternatively, can prepare from formula (XIII) compound according to scheme 2 by formula (VIII) compound.
scheme 2
Formula (XIII) compound can be used the disclosed method preparation of describing in document.The compound of general formula (XIV) can be used the method for above just describing from formula (IV) compound preparation formula (VI) compound, from formula (XIII) compound, prepares.
Can prepare from formula (XIV) compound as follows by formula (VIII) compound: use the method for above just describing from formula (VI) compound preparation formula (VIII) compound, formula (XIV) compound is reacted with formula (XV) compound (introducing suitable substituent R 1).Alternatively, prepared from formula (XIV) compound by formula (VIII) compound: make formula (XIV) compound and formula (XVI) compound (introducing suitable substituent R 1) as follows, under existence at alkali as sodium hydride or hexamethl disilamine base lithium (lithium hexamethyldisilazane), at suitable solvent as tetrahydrofuran (THF) or N, in dinethylformamide, in room temperature to 150 ℃ reaction.
Alternatively, also can prepare from formula (VII) compound according to scheme 3 by formula (X) compound.
scheme 3
Can use the method for above just describing from formula (VIII) compound preparation formula (X) compound, formula (VII) compound is converted into to formula (XVII) compound.
Can use the method for above just describing from formula (X) compound preparation formula (XI) compound, by formula (XVII) compound and amine as the 2-amino-2-methyl-1-propanol coupling, then with reagent as pure thionyl chloride or its suitable solvent as the solution in methylene dichloride, chloroform or ether or pure phosphoryl chloride or its at suitable solvent as the solution in methylene dichloride, chloroform or ether, reflux temperature reaction in room temperature to solvent, obtain formula (XVIII) compound.
Formula (XIX) compound can obtain from formula (XVIII) compound as follows: make formula (XVIII) compound and aniline (introducing suitable substituent R 1), at catalyzer as three (dibenzalacetone) two palladiums (0) or palladium, alkali is as potassiumphosphate, sodium tert-butoxide, 1, 8-diazabicylo [5.4.1] 11 carbon-7-alkene or cesium carbonate, part is as 9, 9 '-dimethyl-4, 5-bis-(diphenylphosphino) xanthene, 2, 2 '-bis-(diphenylphosphino)-1, 1 '-dinaphthalene, 2-(dicyclohexyl phosphino-)-2 '-(N, the N-dimethylamino) biphenyl, 2-(dicyclohexyl phosphino-)-2 ', under 6 '-dimethoxy-biphenyl or tributylphosphine exist, at suitable solvent as toluene, 1, the 2-glycol dimethyl ether, in tetrahydrofuran (THF) or dioxane, reflux temperature reaction in room temperature to solvent, or under microwave irradiation, 70 ℃ to 150 ℃ reactions.
Alternatively, formula (XIX) compound can obtain from formula (XVIII) compound as follows: make formula (XVIII) compound and aniline (introducing suitable substituent R 1), under alkali exists as sodium hydride or hexamethl disilamine base lithium, at suitable solvent as tetrahydrofuran (THF) or N, in dinethylformamide, in room temperature to 150 ℃ reaction.Formula (X) compound can obtain from formula (XIX) compound as follows: make formula (XIX) compound and sour example hydrochloric acid or acetic acid, suitable solvent as water in, in room temperature to the reaction of the reflux temperature of solvent.
But the route of synthesis of general introduction preparation in the 6-azepine cumarone operational version 4 of formula I-c, II-c or III-c.
scheme 4
Formula (XX) compound can be used the disclosed method preparation of describing in document.Can make formula (XX) compound and hydroxyethanoic acid methyl esters or hydroxyethanoic acid ethyl ester, at phosphine as triphenylphosphine, under the existence of azodicarboxy acid alkyl ester as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid, aprotic solvent as tetrahydrofuran (THF) or ether in, reflux temperature reaction in room temperature to solvent, acquisition formula (XXI) compound.
Can make formula (XXI) compound at alkali under the existence as sodium hydride, suitable solvent as DMF or 1,2-glycol dimethyl ether in, at-50 ℃ to room temperature reaction, acquisition formula (XXII) compound.
Can in the following manner formula (XXII) compound be converted into to formula (XXIII) compound: make formula (XXIII) compound and halogenating agent as pure phosphoryl bromide or its at suitable solvent as the solution in toluene, in room temperature to 140 ℃ reaction.Alternatively, can make formula (XXII) compound and nine fluorine butyl sulfonic acid fluoride at alkali as diisopropylethylamine and catalyzer as N, under the existence of N-dimethyl-4-aminopyridine, solvent as methylene dichloride in, at room temperature reaction; Or with N-phenyl trifluoromethanesulfonate methylsulfonyl imines at alkali under the existence as diisopropylethylamine, suitable solvent as 1,2-glycol dimethyl ether in, the reflux temperature reaction in room temperature to solvent.In addition, can be with trifluoromethanesulfanhydride anhydride at alkali under the existence as pyridine, solvent as methylene dichloride in, process formula (XXII) compound at-20 ℃ to envrionment temperature.
Formula (XXIV) compound can obtain from formula (XXIII) compound as follows: make formula (XXIII) compound and aniline (introducing suitable substituent R 1), at catalyzer as three (dibenzalacetone) two palladiums (0) or palladium, alkali is as potassiumphosphate, sodium tert-butoxide, 1, 8-diazabicylo [5.4.1] 11 carbon-7-alkene or cesium carbonate, part is as 9, 9 '-dimethyl-4, 5-bis-(diphenylphosphino) xanthene, 2, 2 '-bis-(diphenylphosphino)-1, 1 '-dinaphthalene, 2-(dicyclohexyl phosphino-)-2 '-(N, the N-dimethylamino) biphenyl, 2-(dicyclohexyl phosphino-)-2 ', under 6 '-dimethoxy-biphenyl or tributylphosphine exist, at suitable solvent as toluene, 1, the 2-glycol dimethyl ether, in tetrahydrofuran (THF) or dioxane, reflux temperature reaction in room temperature to solvent, or under microwave irradiation, 70 ℃ to 150 ℃ reactions.
Alternatively, formula (XXIV) compound can obtain from formula (XXII) compound as follows: make formula (XXII) compound and formula (IX) compound (using the disclosed method preparation of describing document), at suitable solvent as toluene or 1, in the 2-glycol dimethyl ether, reflux temperature reaction in room temperature to solvent, or under microwave irradiation, 100 ℃ to 180 ℃ reactions.
Formula (XXVI) compound can obtain from formula (XXIV) compound as follows: make formula (XXIV) compound and alkali as sodium hydroxide, protonic solvent as ethanol or methyl alcohol in, at room temperature to reflux temperature, react.
Can make functionalized azanol (commercially available or according to scheme 8 preparation) or the amine of formula (XXVI) compound and formula (XII), and suitable coupling agent is as O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-
hexafluorophosphate, N-(3-(dimethylamino) propyl group)-N '-ethyl-carbodiimide hydrochloride or N, N '-dicyclohexylcarbodiimide, in N-hydroxyl-1, under 2,3-benzotriazole exists, under suitable alkali exists as diisopropylethylamine or triethylamine, at inert solvent as tetrahydrofuran (THF), N, in dinethylformamide or methylene dichloride, at about room temperature reaction, acquisition formula (XXVII) compound.Alternatively, formula (XXVII) compound can directly obtain from formula (XXIV) compound as follows: make formula (XXIV) compound and amine or azanol DNHR Lewis acid exists as trimethyl aluminium, solvent as DCM in, at room temperature to reflux temperature, react.
The furo of formula I-f, II-f or III-f [2,3-d] but the route of synthesis preparation of general introduction in pyrimidine operational version 5.
scheme 5
Formula (XXVIII) compound can be according to the method preparation of describing in document.Can make formula (XXVIII) compound and halogenating agent as pure phosphoryl chloride or its at suitable solvent as the solution in toluene, at room temperature to reflux temperature, react, obtain formula (XXIX) compound.
Formula (XXXVI) compound can use with as shown in scheme 1 from the similar method of method of formula (IV) compound preparation formula (XI) compound, from formula (XXIX) compound, obtain.
The furo [3,2-c] of the furo of formula I-h, II-h and II-h [2,3-d] pyridazine and formula I-g, II-g and III-g but the route of synthesis preparation of general introduction in pyridazine operational version 6.
scheme 6
Formula (L) compound can be according to the method preparation of describing in document.Formula (LVI) compound can use with as shown in scheme 1 from the similar method of method of formula (IV) compound preparation formula (XI) compound, from formula (L) compound, obtain.Alternatively, formula (LIV) compound can be according to scheme 7 preparations.
scheme 7
Formula (LVIII) compound can be used the disclosed method preparation of describing in document.The compound of general formula (LIV) can be used the method for above just describing from formula (XIII) compound preparation formula (VIII) compound, from formula (LIX) compound, prepares.
The azanol of formula (XII) can be used the route of synthesis preparation of general introduction in the method described in document or scheme 8.
scheme 8
The primary alconol of general formula (XXXVII) or secondary alcohol can be used the method preparation of describing in document.Can use phosphine and coupling agent as the diethylazodicarboxylate, make the primary alconol of general formula (XXXVII) or secondary alcohol react the compound that obtains general formula (XXXVIII) with HP.The compound of general formula (XXXVIII) can carry out deprotection with hydrazine or methyl hydrazine, obtains the azanol of general formula (XII-a).Formula (XII-a) compound can further be modified as follows: use reductive agent as sodium triacetoxy borohydride, sodium cyanoborohydride or borine-pyridine, solvent as ethylene dichloride in, carry out the reductibility ammonification at envrionment temperature to reflux temperature and aldehydes or ketones.In addition, formula (XII-a) compound can further be modified as follows: under the existence at alkali as triethylamine, at solvent, carry out alkylation with haloalkane (alkyl halide) in as methylene dichloride, obtain the azanol of general formula (XII-b).
The method that the aniline of the general formula used in above-described cross-coupling reaction (XXXIX) is described in can be by document or according to scheme 9 preparations.
scheme 9
Can use catalyzer as tetrakis triphenylphosphine palladium, make the chloro-oil of mirbane of 4-that replaces and hexamethyldisilane (hexamethyldisilane) solvent as dimethylbenzene in, at room temperature to reflux temperature, react.Nitro can be used the method reduction of describing in document, under at hydrogen atmosphere, under 1 to 5 atmospheric pressure, under catalyzer exists as palladium/carbon, solvent as ethanol or ethyl acetate in, at room temperature reaction.
The method that the triflate of the general formula used in above-described cross-coupling reaction (XL) is described in can using document or according to scheme 10 preparation.
scheme 10
The halogenated phenol that can make formula (XLI) and two equivalent alkyl lithium reagents react in as THF (tetrahydrofuran (THF)) at solvent as n-Butyl Lithium, then use trialkylsilkl halogenide (trialkylsilyl halide) as the trimethylsilyl chloride cancellation, obtain trialkylsilkl phenol (XLII).Can use the document operation further to make trialkylsilkl phenol react, obtain triflate or the nine fluorine fourth sulphonates (nonaflate) of formula (XL).
Should be appreciated that, when suitable functional group exists, the compound of formula (I), (II), (III) or any intermediate of using in their preparation can adopt replacement, oxidation, reduction or scission reaction to carry out further derivatize by one or more standard synthetic methods.Concrete substitution technique comprises conventional alkylation, arylation, heteroaryl, acidylate, sulfonylation, halogenation, nitrated, formylation and coupling operation.
For example, aryl bromide or aryl chloride group can be converted into aryl iodide as follows: use Finkelstein reaction (Finkelstein reaction) at solvent as 1, in the 4-dioxane, adopt propiodal as sodium iodide, catalyzer is as cuprous iodide, and part is as trans-N, N '-dimethyl-1, the 2-cyclohexanediamine, then heat reaction mixture at reflux temperature.Aryl trialkyl silicomethane can be converted into aryl iodide as follows: with propiodal as iodine monochloride, contain or containing Lewis acid as the solvent of silver tetrafluoroborate as methylene dichloride in, process described silicomethane at-40 ℃ to reflux temperature.
In another embodiment, primary amine (NH
2) group can carry out alkylation as follows: use reductive alkylation process on glycopeptides at solvent as halohydrocarbon as 1, the 2-ethylene dichloride, or alcohol is as in ethanol, in case of necessity under acid exists as acetic acid, in the envrionment temperature left and right, use aldehydes or ketones, and hydroborate for example sodium triacetoxy borohydride or sodium cyanoborohydride.Secondary amine (NH-) group can be used like aldehydes and carry out alkylation.
In another embodiment, primary amine or secondary amine group can be converted into amide group (NHCOR ' or-NRCOR ') by acidylate.Acidylate can realize as follows: with suitable acyl chlorides, at alkali under the existence as triethylamine, at suitable solvent, react in as methylene dichloride; Or with suitable carboxylic acid at suitable coupling agent as HATU (O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-
hexafluorophosphate), under existing, at suitable solvent, react in as methylene dichloride.Similarly, amine groups can be converted into sulfuryl amine group (NHSO as follows
2r ' or-NR " SO
2r '): make amine groups and suitable SULPHURYL CHLORIDE under suitable alkali exists as triethylamine, react in as methylene dichloride at suitable solvent.Primary amine or secondary amine group can be converted into as follows urea groups (NHCONR ' R " or-NRCONR ' R "): make primary amine or secondary amine group and suitable isocyanic ester under suitable alkali exists as triethylamine, react in as methylene dichloride at suitable solvent.
Amine (NH
2) can obtain as follows: reduction nitro (NO
2), for example by catalytic hydrogenation for example, under metal catalyst (palladium/carrier (as carbon)) exists, solvent as ethyl acetate or alcohol as methyl alcohol in, use for example hydrogen.Alternatively, can by chemical reduction for example under sour example hydrochloric acid exists, use metal (as tin or iron) carry out as described in conversion.
In another embodiment, amine (CH
2nH
2) group can obtain as follows: nitrile (CN) is reduced, for example by catalytic hydrogenation for example, under metal catalyst (palladium/carrier (as carbon) or Raney Ni (Raneynickel)) exists, solvent for example, as ether (cyclic ethers is as tetrahydrofuran (THF)) in, use for example hydrogen at-78 ℃ of reflux temperatures to solvent.
In another embodiment, amine (NH
2) group can be as follows from hydroxy-acid group (CO
2h) obtain: by hydroxy-acid group (CO
2h) be converted into corresponding acid azide (CON
3), carry out Ku Ertisi rearrangement (Curtiusrearrangement), then the isocyanic ester (N=C=O) formed is hydrolyzed.
Aldehyde radical (CHO) can be converted into amine groups (CH as follows
2nR ' R "): the reductibility ammonification solvent as halohydrocarbon (as methylene dichloride) or alcohol (as ethanol) in; in case of necessity under the existence of acid as acetic acid, at envrionment temperature left and right use amine and hydroborate (as sodium triacetoxy borohydride or sodium cyanoborohydride).
In another embodiment, aldehyde radical can be converted into thiazolinyl (CH=CHR ') as follows: under standard conditions well known by persons skilled in the art, use suitable phosphine alkane (phosphorane) or phosphonic acid ester (phosphonate) to carry out witig reaction (Wittig reaction) or Wadsworth-Emmons reaction.
Aldehyde radical can obtain as follows: at suitable solvent, use in as toluene diisobutyl aluminium hydride to ester group (as-CO
2et) or nitrile (CN) reduced.Alternatively, aldehyde radical can obtain as follows: use any suitable oxidizers well known by persons skilled in the art to carry out oxidation to alcohol radical (alcohol group).
The character that depends on R, ester group (CO
2r ') can be converted into corresponding acid groups (CO by acid-catalyzed hydrolysis or alkali catalyzed hydrolysis
2h).If R is the tertiary butyl, can realize as follows acid-catalyzed hydrolysis: for example with organic acid, as trifluoroacetic acid, in water-containing solvent, processed, or processed in water-containing solvent with the mineral acid example hydrochloric acid.
Hydroxy-acid group (CO
2h) can be by the amine with suitable under suitable coupling agent exists as HATU, suitable solvent as methylene dichloride in reaction and be converted into acid amides (CONHR ' or-CONR ' R ").
In another embodiment, carboxylic acid can add a carbon atom (be homologated by onecarbon) (-CO as follows
2become-CH of H
2cO
2h): carboxylic acid is converted into to corresponding acyl chlorides (COCl), then carries out Arndt-Eistert synthesis (Arndt-Eistert synthesis).
In another embodiment ,-OH group can be as follows from corresponding ester (as-CO
2r ') or aldehyde (CHO) generate: for example use complex metal hydride (solution as lithium aluminum hydride in ether or tetrahydrofuran (THF) or sodium borohydride at solvent as the solution in methyl alcohol) to be reduced.Alternatively, alcohol can by for example use lithium aluminum hydride in solvent as the solution in tetrahydrofuran (THF) or use borine in solvent as the corresponding acid of the solution reduction in tetrahydrofuran (THF) (CO
2h) prepare.
Alcohol radical can be used condition well known by persons skilled in the art to be converted into leaving group as halogen atom or alkylsulfonyl oxygen base (for example, for example, as alkyl sulphonyl oxygen base (trifluoromethyl sulfonyl oxygen base) or aryl sulfonyl oxygen base (p-toluenesulfonyl oxygen base)).For example, can make alcohol for example, react and obtain corresponding muriate in halohydrocarbon (methylene dichloride) with thionyl chloride.Also can use alkali (for example triethylamine) in described reaction.
In another embodiment, alcohol, phenol or amide group can carry out alkylation as follows: make phenol or acid amides with pure solvent as tetrahydrofuran (THF) in, phosphine for example triphenylphosphine and activator as the existence of diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid or azodicarboxy dimethyl phthalate under coupling.Alternatively, alkylation can realize as follows: use suitable alkali to carry out deprotonation as sodium hydride, then add alkylating reagent as haloalkane.
Aromatic halogen substituting group in compound can carry out halogen-metal exchange as follows: the alkali for substituting group of the aromatic halogen in compound (as lithium alkali for example n-Butyl Lithium or tert-butyl lithium), optionally at low temperature as-78 ℃ of left and right, at solvent, process in as tetrahydrofuran (THF), then with the electrophilic reagent cancellation to introduce the substituting group of expectation.Thus, for example formyl radical can be by introducing as electrophilic reagent with DMF.Alternatively, the aromatic halogen substituting group can carry out the reaction of metal (for example palladium or copper) catalysis to introduce for example acid groups, ester group, cyano group, amide group, aryl, heteroaryl, thiazolinyl, alkynyl, sulfo-or amino substituting group.Spendable proper operation comprises those operations of being described by Heck, Suzuki, Stille, Buchwald or Hartwig.
The aromatic halogen substituting group also can carry out nucleophilic displacement after the nucleophilic reagent with suitable is as amine or pure the reaction.Advantageously, above-mentioned reaction can be carried out in the temperature raise under the existence of microwave irradiation.
As described below, test the compounds of this invention and suppressed MEK activity and the ability (elementary mensuration) activated and they biological action (secondary mensuration) to grown cell.Following compound can be used as mek inhibitor, and described compound has the IC that is less than 10 μ M (be more preferably less than 5 μ M, even be more preferably less than 1 μ M, be more preferably less than 0.5 μ M most) in the MEK of embodiment 1a or 1b determination of activity
50, there is the IC that is less than 5 μ M (be more preferably less than 0.1 μ M, most preferably be less than 0.01 μ M) in the MEK of embodiment 2 activation determination
50, there is the IC that is less than 10 μ M (be more preferably less than 5 μ M, most preferably be less than 0.5 μ M) in the cell proliferating determining of embodiment 3
50, and/or there is the IC that is less than 10 μ M (be more preferably less than 1 μ M, most preferably be less than 0.1 μ M) in the ERK of embodiment 4 phosphorylation assay
50.
The present invention includes the composition (as pharmaceutical composition) that contains formula I compound (and/or its solvate and salt) and carrier (pharmaceutically acceptable carrier).The present invention also comprises and contains formula I compound (and/or its solvate and salt) and carrier (pharmaceutically acceptable carrier) and also contain just like the another kind of chemotherapeutic agent of the application's description and/or the composition (as pharmaceutical composition) of another kind of anti-inflammatory drug.The present composition for example is used in, in Mammals (people) and suppresses abnormal cell growth or overmedication proliferative disease.The present composition also is used in for example, in Mammals (people) treatment inflammatory diseases.
The compounds of this invention and composition also are used in for example, in Mammals (people) treatment autoimmune disorder, destructive osteopathia (destructive bone disorder), proliferative disease, infectious diseases (infectious disease), virus disease, fibrotic disease or neurodegenerative disease.The example of above-mentioned diseases/disorders includes but not limited to diabetes and diabetic complication, diabetic retinopathy (diabeticretinopathy), retinopathy of prematurity (retinopathy of prematurity), age related macular degeneration (age-related macular degeneration), vascular tumor, idiopathic pulmonary fibrosis (idiopathicpulmonary fibrosis), rhinitis and atopic dermatitis (atopic dermatitis), ephrosis and renal failure, POLYCYSTIC KIDNEY DISEASE (polycystic kidney disease), congestive heart failure, neurofibromatosis (neurofibromatosis), the organ-graft refection, emaciation, apoplexy, septic shock, in heart failure, the organ-graft refection, alzheimer disease, chronic pain or neuropathic pain, and virus infection is as HIV, hepatitis B virus (HBV), human papillomavirus (human papilloma virus, HPV), cytomegalovirus (CMV) and Epstein-Barr virus (Epstein-Barr virus, EBV).For purposes of the present invention, chronic pain include but not limited to primary pain (idiopathic pain) with to chronic alcoholism, vitamin deficiency, uremia, hypothyroidism (hypothyroidism), inflammation, pain that sacroiliitis is relevant, and postoperative pain (post-operative pain).Neuropathic pain is relevant to various disease conditions, these illnesss include but not limited to inflammation, postoperative pain, phantom limb pain (phantom limb pain), burn pain (burnpain), gout, trigeminal neuralgia (trigeminal neuralgia), pain after acute herpes pain and bleb (acute herpetic and postherpetic pain), cusalgia (causalgia), diabetic neuropathy, reticulattion avulsion (plexus avulsion), neuroma, vasculitis (vasculitis), virus infection, crush injury (crush injury), constriction injury (constriction injury), tissue injury (tissue injury), amputation (limb amputation), the nerve injury between central nervous system of unifying of arthritis ache and peripheral nervous system.
The compounds of this invention and composition also are used in for example, in Mammals (people) treatment pancreatitis or kidney disease (ephrosis that comprises proliferative glomerulonephritis (proliferative glomerulonephritis) and diabetes-induced).
The compounds of this invention and composition for example also are used in, in Mammals (people) and prevent protoblast implantation (blastocyte implantation).
Present invention resides in the method that for example, suppresses abnormal cell growth or overmedication proliferative disease in Mammals (people), described method comprises the formula I compound (and/or its solvate and salt) that gives described Mammals treatment significant quantity or the composition that contains it.The present invention also is included in the method for for example, in Mammals (people) treatment inflammatory diseases, and described method comprises the formula I compound (and/or its solvate and/or salt) that gives described Mammals treatment significant quantity or the composition that contains it.
Present invention resides in the method that for example, suppresses abnormal cell growth or overmedication proliferative disease in Mammals (people), described method comprises the formula I compound (and/or its solvate and salt) that gives described Mammals treatment significant quantity or the composition that contains it, and the another kind of chemotherapeutic agent as described in the application.The present invention also is included in the method for for example, in Mammals (people) treatment inflammatory diseases, described method comprises the formula I compound (and/or its solvate and/or salt) that gives described Mammals treatment significant quantity or the composition that contains it, and the another kind of anti-inflammatory drug as described in the application.
Present invention resides in the method for for example, in Mammals (people) treatment autoimmune disorder, destructive osteopathia, proliferative disease, infectious diseases, virus disease, fibrotic disease or neurodegenerative disease, described method comprises the formula I compound (and/or its solvate and salt) that gives described Mammals treatment significant quantity or the composition that contains it, and optionally also gives another kind of medicine.The example of above-mentioned diseases/disorders includes but not limited to diabetes and diabetic complication, diabetic retinopathy, retinopathy of prematurity, age related macular degeneration, vascular tumor, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, ephrosis and renal failure, POLYCYSTIC KIDNEY DISEASE, congestive heart failure, neurofibromatosis, the organ-graft refection, emaciation, apoplexy, septic shock, in heart failure, the organ-graft refection, alzheimer disease, chronic pain or neuropathic pain, and virus infection, as HIV, hepatitis B virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
Present invention resides in the method for for example, treating pancreatitis or kidney disease (ephrosis that comprises proliferative glomerulonephritis and diabetes-induced) in Mammals (people), described method comprises the formula I compound (and/or its solvate and salt) that gives described Mammals treatment significant quantity or the composition that contains it, and optionally also gives another kind of medicine.
For example present invention resides in, in Mammals (people) method that prevents that protoblast from implanting, described method comprises the formula I compound (and/or its solvate and salt) that gives described Mammals treatment significant quantity or the composition that contains it, and optionally also gives another kind of medicine.
The present invention includes the method for the compounds of this invention for external, original position and in-vivo diagnostic or treatment mammalian cell, organ or related diseases illness of science of using.
Also believe, the compounds of this invention can make abnormal cells to for killing and/or suppressing the purpose of these Growth of Cells and the radiotherapy that carries out is more responsive.Therefore, the invention still further relates to the abnormal cells for example made, in Mammals (people) and be sensitive to radiocurable method, described method comprises the composition that gives a certain amount of formula I compound of described Mammals (and/or its solvate and salt) or contain it, and described amount is effective for making abnormal cells be sensitive to radiotherapy.
The administration of the compounds of this invention (hereinafter referred to as " active compound ") can be undertaken by sending described compound to any method of action site.These methods comprise oral route, intraduodenal route, parenteral injection (comprising in intravenously, subcutaneous, intramuscular, blood vessel or infusion), local, suction and rectal administration.
The amount of the active compound of institute's administration can be depending on severity, medicine-feeding rate, the disposition (disposition) of compound and the doctor's that prescribes the judgement of treated experimenter, disease or illness.Yet the scope of effective dose is approximately 0.001 to about 100mg/ kg body weight/sky, preferably, approximately 1 to about 35mg/kg/ days, it is single dose or broken dose.For the people of 70kg, effective dose can add up to approximately 0.05 to 7g/ days, preferably approximately 0.05 to about 2.5g/ days.In some cases, dosage level lower than the lower limit of above-mentioned scope can be enough far away, and in other cases, can use larger dosage and not cause any harmful side effect, condition is at first described larger dosage to be divided into to some low doses for administration in a day.
Active compound can be used as independent treatment, or with those chemotherapeutic agent couplings that for example the application describes of one or more chemotherapeutic agents.Described combination therapy can or separately give each treatment group by while, priority and assign to realize.
Pharmaceutical composition can for example be the form that is suitable for oral administration, and it is tablet, capsule, pill, powder agent, extended release preparation, solution, suspensoid; Be suitable for the form of parenteral injection, it is sterile solution agent, suspensoid or emulsion; Be suitable for the form of topical, it is ointment or ointment; Or being suitable for the form of rectal administration, it is suppository.Pharmaceutical composition can be the unit dosage form that is suitable for the single-dose exact dosage desired.Pharmaceutical composition can comprise conventional pharmaceutical carrier or vehicle, and as the compounds of this invention of activeconstituents.In addition, it can comprise other pharmaceutical reagent, carrier, auxiliary material etc.
Exemplary administered parenterally form comprises for example, solution or suspensoid in aseptic aqueous solution (aqueous solution of propylene glycol or the dextrose aqueous solution) of active compound.If expectation, can carry out suitable buffering to above-mentioned formulation.
Suitable pharmaceutical carrier comprises inert diluent or filling agent, water and various organic solvent.If expectation, pharmaceutical composition can contain extra composition, as correctives, tackiness agent, vehicle etc.Thus, for oral administration, contain various vehicle and can use together with various disintegrating agents (as starch, Lalgine and some composition silicate (complex silicate)) and tackiness agent (as sucrose, gelatin and gum arabic) as the tablet of Citric Acid.In addition, lubricant (as Magnesium Stearate, sodium lauryl sulphate and talcum) can be used for the tablet purpose usually.The solids composition of similar type also can be used by the form of soft-filled gelatin capsule agent and hard-filled gelatin capsule agent.Therefore, preferred material comprises lactose (lactose or milksugar) and high molecular weight polyethylene glycol.When aqueous suspensions or elixir are expected to be useful in oral administration, active compound wherein can be mixed with following material: various sweeting agents or correctives, tinting material or dyestuff, with emulsifying agent or suspending agent (if expectation), and thinner is as water, ethanol, propylene glycol, glycerine or their combination.
The method of the various pharmaceutical compositions of the active compound that to those skilled in the art, preparation contains concrete amount is known or apparent.For example, referring to Remington ' sPharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.thEdition (1975).
Embodiment
Abbreviation
DBU 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene
The DCM methylene dichloride
The DIAD diisopropyl azo-2-carboxylic acid
The DIPEA diisopropylethylamine
The DMAP DMAP
The DMF dimethyl formamide
EDCI 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-
hexafluorophosphate
HCl hydrochloric acid
HM-N
the diatomite that can effectively absorb aqueous sample that HM-N is improved form
The HOBt I-hydroxybenzotriazole
The industrial methylated spirit of IMS (industrial methylated spirit)
The ICl iodine monochloride
The LDA lithium diisopropylamine
MeOH methyl alcohol
NaHCO
3sodium bicarbonate
NaOH sodium hydroxide
Pd (PPh
3)
4tetrakis triphenylphosphine palladium (0)
Pd
2dba
3three (dibenzalacetone) two palladiums (0)
Si-SPE is pre-filled
the flash chromatography on silica gel post
Si-ISCO is pre-filled
the flash chromatography on silica gel post
The THF tetrahydrofuran (THF)
Xantphos 9,9-dimethyl-4,5-bis-(diphenylphosphino) xanthene
Common experimental conditions
Use Varian Unity Inova (400MHz) the spectrograph record with triple resonant 5mm probe in envrionment temperature
1h NMR spectrum.Chemical shift is expressed as the ppm with respect to the tetramethyl-silicomethane.Use following abbreviation: the br=bandwidth signals, s=is unimodal, d=doublet, dd=double doublet, t=triplet, q=quartet, m=multiplet.
Use one of following method to carry out high pressure liquid chromatography-mass spectrum (LCMS) experiment to determine retention time (R
t) and correlated quality ion (mass ion).
Method A: tested on the Waters Micromass ZQ quadrupole mass spectrometer be connected in the Hewlett Packard HP1100 LC system with diode-array detector.This system is used the flow velocity of 5 microns C18100 of Higgins Clipeus * 3.0mm post and 1ml/ minute.Initial solvent systems was 95% water that contains 0.1% formic acid (solvent orange 2 A) and 5% acetonitrile that contains 0.1% formic acid (solvent B) in first minute, then lasted 14 minutes gradients again and rose to 5% solvent orange 2 A and 95% solvent B.Final solvent systems keeps constant and continues 5 minutes again.
Method B: tested on the Waters Platform LC quadrupole mass spectrometer be connected in the HewlettPackard HP1100 LC system with diode-array detector and 100 automatic samplers, use the flow velocity of Phenomenex Luna C18 (2) 30 * 4.6mm posts and 2ml/ minute.Solvent systems was 95% water that contains 0.1% formic acid (solvent orange 2 A) and 5% acetonitrile that contains 0.1% formic acid (solvent B) in 0.50 minute that starts, and then lasted 4 minutes gradients again and rose to 5% solvent orange 2 A and 95% solvent B.Final solvent systems keeps constant and continues 0.50 minute again.
Method C: tested on the PE SciexAPI 150EX quadrupole mass spectrometer be connected in the ShimadzuLC-10AD LC system with diode-array detector and 225 automatic samplers, use the flow velocity of Kromasil C1850 * 4.6mm post and 3ml/ minute.Solvent systems is following gradient: originate in 100% water that contains 0.05%TFA (trifluoroacetic acid) (solvent orange 2 A) and 0% acetonitrile that contains 0.0375%TFA (solvent B), last 4 minutes and rise to 10% solvent orange 2 A and 90% solvent B.Final solvent systems keeps constant and continues 0.50 minute again.
Method D: tested on the Shimadzu LCMS-2010A liquid chromatography mass instrument be connected in the Shimadzu LC-10AD VP LC system with diode-array detector.Use the flow velocity of Kromasil1005 micron C1850 * 4.6mm post and 2.5ml/ minute.Initial solvent systems is 100% water that contains 0.05% trifluoroacetic acid (solvent orange 2 A) and 0% acetonitrile that contains 0.05% trifluoroacetic acid (solvent B), then lasts 8 minutes gradients and rises to 10% solvent orange 2 A and 90% solvent B.Final solvent systems keeps constant and continues 2 minutes again.
Method E: tested on the Agilent Technologies liquid chromatography mass instrument be connected in the Agilent Technologies Series 1100LC system with diode-array detector.Use the flow velocity of 3.5 microns SB-C18 30 * 2.6mm posts of Zorbax and 0.5ml/ minute.Initial solvent systems is 95% water that contains 0.05% trifluoroacetic acid (solvent orange 2 A) and 5% acetonitrile that contains 0.0375% trifluoroacetic acid (solvent B), then lasts 9 minutes gradients and rises to 5% solvent orange 2 A and 95% solvent B.Final solvent systems keeps constant and continues 1 minute again.
Use Personal Chemistry Emrys Iniatiator
tMor Optimizer
tMcarry out microwave experiment, described device is used single mode syntonizer and aerodynamic field tuning (dynamic field tuning), both can be reappeared and control.The temperature of 40-250 ℃ can be realized, and the high pressure to 20 bar can be reached.
Embodiment 1a:MEK measures (MEK determination of activity)
Use the people of the composition activation of expressed in insect cells to suddenly change MEK1 as the source of enzymic activity, its ultimate density in kinase assays is 62.5nM.
Described being determined under 50 μ M ATP existence carried out 30 minutes, uses the restructuring GST-ERK1 produced in intestinal bacteria (E.Coli) as substrate.The phosphorylation of the HTRF reagent detection substrate that use is provided by Cisbio is also quantitative.Above-mentioned HTRF reagent by with allophycocyanin (allophycocyanin) (XL665) combination anti-GST antibody and with anti-phosphoric acid (Thr202/Tyr204) the ERK antibody of europium kryptofix 222 (europium-cryptate) combination, form.Antiphosphotyrosine antibody is identified in the ERK1 of Thr202 and the upper dual phosphorylation of Tyr204.When these two kinds of antibody all when ERK1 is combined (when substrate is phosphorylated), after 340nm excites, the transfer of energy from kryptofix 222 to allophycocyanin occurred, cause launching and the proportional fluorescence of the amount of produced phosphorylated substrate.Use porous photofluorometer (multiwellfluorimeter) to detect fluorescence.
Compound is diluted in DMSO, then add to and measure in damping fluid, the final DMSO concentration in mensuration is 1%.
IC
50be defined as given compound and realize the concentration in 50% inhibition when contrast.Use XLfit software package (2.0.5 version) to calculate IC
50value.
Embodiment 1b:MEK measures (MEK determination of activity)
Use the people of the composition activation of expressed in insect cells to suddenly change MEK1 as the source of enzymic activity, its ultimate density in kinase assays is 15nM.
Described being determined under 50 μ M ATP existence carried out 30 minutes, uses the restructuring GST-ERK1 produced in intestinal bacteria (E.Coli) as substrate.The phosphorylation of the HTRF reagent detection substrate that use is provided by Cisbio is also quantitative.Above-mentioned HTRF reagent is comprised of the anti-GST antibody with allophycocyanin (XL665) combination and anti-phosphoric acid (Thr202/Tyr204) the ERK antibody of being combined with the europium kryptofix 222.Above-mentioned antibody is used in the ultimate density of 4 μ g/ml and 0.84 μ g/ml respectively.Antiphosphotyrosine antibody is identified in the ERK1 of Thr202 and the upper dual phosphorylation of Tyr204.When these two kinds of antibody all when ERK1 is combined (when substrate is phosphorylated), after 340nm excites, the transfer of energy from kryptofix 222 to allophycocyanin occurred, cause launching and the proportional fluorescence of the amount of produced phosphorylated substrate.Use the porous photofluorometer to detect fluorescence.
Compound is diluted in DMSO, then add to and measure in damping fluid, the final DMSO concentration in mensuration is 1%.
IC
50be defined as given compound and realize the concentration in 50% inhibition when contrast.Use XLfit software package (2.0.5 version) to calculate IC
50value.
In embodiment 1a or the described mensuration of 1b, the compound of embodiment 5-18,20-102,105-109,111-118,120-133,136-149 and 151-160 demonstrates the IC that is less than 10 μ M
50, the great majority in these compounds demonstrate the IC that is less than 5 μ M
50.
Embodiment 2:bRaf measures (MEK activation determination)
The bRaf mutant of the composition activation of use expressed in insect cells is as the source of enzymic activity.
Described being determined under 200 μ M ATP existence carried out 30 minutes, uses the restructuring GST-ERK1 produced in intestinal bacteria (E.Coli) as substrate.Use the phosphorylation of HTRF detection substrate also quantitatively, these reagent are provided by Cisbio.Above-mentioned HTRF reagent is comprised of the anti-GST antibody with allophycocyanin (XL665) combination and anti-phosphoric acid (Ser217/Ser221) the MEK antibody of being combined with the europium kryptofix 222.Antiphosphotyrosine antibody is identified in the upper dual phosphorylation of Ser217 and Ser221 or the MEK of phosphorylation separately on Ser217.When these two kinds of antibody all when MEK is combined (when substrate is phosphorylated), after 340nm excites, the transfer of energy from kryptofix 222 to allophycocyanin occurred, cause launching and the proportional fluorescence of the amount of produced phosphorylated substrate.Use the porous photofluorometer to detect fluorescence.
Compound is diluted in DMSO, then add to and measure in damping fluid, the final DMSO concentration in mensuration is 1%.
IC
50be defined as given compound and realize the concentration in 50% inhibition when contrast.Use XLfit software package (2.0.5 version) to calculate IC
50value.
In this measures, the compound of embodiment 5-19 demonstrates the IC that is less than 5 μ M
50.
Embodiment 3: cell proliferating determining
In cell proliferating determining, use following clone to be tested compound:
HCT116 human colorectal cancer (ATCC)
A375 people's malignant melanoma (ATCC)
At 37 ℃ at 5%CO
2in the humidification incubator, these two kinds of clones are all maintained in DMEM/F12 (1: the 1) substratum (Gibco) that is supplemented with 10%FCS.
Cell is inoculated in 96 orifice plates with 2,000 cells/well, makes the solution of its compound that is exposed to different concns in 0.83%DMSO after 24 hours.Make the long 72h of cell regeneration, then isopyknic CellTiter-Glo reagent (Promega) is added in every hole.This make cytolysis and produce with the amount of the ATP discharged proportional (therefore with hole in cell number proportional) luminous signal, described luminous signal can be used porous luminometer (multiwell luminometer) to detect.
EC
50be defined as given compound and realize the concentration in 50% inhibition when contrast.Use XLfit software package (2.0.5 version) to calculate EC
50value.
In this measures, embodiment 5-13,15-16,18,20-22,24-25,28,31,35,38-39,41,109,133-134,138,140-141 and 160 compound all demonstrate the EC that is less than 10 μ M in arbitrary clone
50.
Embodiment 4: the phosphoric acid based on cell-ERK measures
In the phosphoric acid based on cell-ERK ELISA, use following clone to be tested compound:
HCT116 human colorectal cancer (ATCC)
A375 people's malignant melanoma (ATCC)
At 37 ℃ at 5%CO
2in the humidification incubator, these two kinds of clones are all maintained in DMEM/F12 (1: the 1) substratum (Gibco) that is supplemented with 10%FCS.
Cell is inoculated in 96 orifice plates with 2,000 cells/well, makes the solution of its compound that is exposed to different concns in 0.83%DMSO after 24 hours.Make the long 2h of cell regeneration or 24h, fixing with formaldehyde (2% ultimate density), then use methanol crossover.With after TBST-3%BSA sealing, at 4 ℃ by fixing cell overnight incubation together with first antibody (from the anti-phosphoric acid ERK of rabbit).Cell is hatched together with iodate the third ingot (Propidium Iodide) (DNA fluorescence dye), then use with the anti-rabbit second antibody of fluorescence AlexaFluor 488 dyestuffs (molecular probe) combination cell p-ERK is detected.Using Acumen Explorer (TTP Labtech) laser scanning micro plate cell counter (laser-scanningmicroplate cytometer) to be analyzed fluorescence, is then PI signal (proportional with cell number) by Alexa Fluor 488 signal normalizations.
EC
50be defined as given compound and realize the concentration of half signal between baseline and peak response.Use XLfit software package (2.0.5 version) to calculate EC
50value.
In this measures, embodiment 5-13,15-16,18,20-26,28-29,31,35,38-39,41-48,50,55,59-61,68,70,73-74,76,79,81-84,87,91,95,99,109,111,113,117,118,120,122-124,126-127,131,133,134,138-141,144,147,152 and the compound of 155-160 all demonstrate the EC that is less than 10 μ M in arbitrary clone
50.
Synthesizing of aza-benzofuranyl core
3-(the fluoro-phenyl amino of the bromo-2-of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
the chloro-pyridine-3-carboxylic acid of step 1:4-
According to the people such as Guillier (1995) J.Org.Chem.60 (2): the operation in 292-6, under argon gas atmosphere to cold (78 ℃) LDA (21ml, 1.6M hexane solution, 33.3mmol) add 4-chloropyridine (5.0g, 33.3mmol) in solution in anhydrous THF (70ml).After 1 hour, solution is poured on fast to the solid CO in the 250ml Erlenmeyer flask-78 ℃ of reactions
2on bed.After making it be warmed to envrionment temperature, by solution with water (30ml) cancellation.Vacuum is removed volatile organic solvent, then by remaining ether (3 * 100ml) extraction for aqueous suspension.Water is cooled to 0 ℃, by adding concentrated hydrochloric acid to be adjusted to pH, is then 4.Make the throw out ageing (age) that forms 30 minutes, then collect after filtration.By cold ether (10ml) washing for solid, obtain title compound, it is white solid (3.2g, 61%).
the chloro-pyridine-3-carboxylic acid ethyl ester of step 2:4-
Suspension reflux by the chloro-pyridine-3-carboxylic acid of 4-(3.0g, 19.0mmol) in thionyl chloride (50ml) 90 minutes.After being cooled to envrionment temperature, solution is concentrated into dry, then uses toluene (2 * 50ml) azeotropic, obtain solid.The solid of formation is added in cooling (0 ℃) ethanol (25ml) and DIPEA (15ml) solution in batches.By reaction mixture, stirring at room 4 hours, then vacuum concentration, then added water (75ml).Ethyl acetate for solution (2 * 75ml) extraction, right latter incorporated organic phase is through dried over sodium sulfate, then concentrated, obtains title compound, and it is brown oil (3.3g, 94%).
1HNMR(CDCl
3，400MHz)9.03(s，1H)，7.58(d，J＝5.4Hz，1H)，7.41(dd，J＝5.4Hz，0.5Hz，1H)，4.45(q，J＝7.3Hz，2H)，1.43(t，J＝7.3Hz，3H)。
step 3:3-hydroxyl-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Under nitrogen atmosphere to the cooling chloro-pyridine-3-carboxylic acid ethyl ester of (0 ℃) 4-(910mg, 4.9mmol) and hydroxyethanoic acid ethyl ester (0.48ml, 5.1mmol) add in solution in dry DMF (17ml) sodium hydride (9.8mmol, 60%, 392mg).Reaction mixture is stirred to 16 hours (0 ℃ to room temperature), then by adding acetic acid (1.2ml) acidifying, then concentrate and obtain resistates.Add water (23ml), then mixture is stirred 5 minutes, now collect after filtration the brown precipitate thing formed, then water (3 * 30ml) washing obtains title compound, and it is light brown solid (875mg, 86%).
1H?NMR(DMSO-D
6，400MHz)9.18(d，J＝1.2Hz，lH)，8.60(d，J＝6.0Hz，1H)，7.66(dd，J＝6.0Hz，0.8Hz，1H)，4.32(q，J＝7.2Hz，2H)，1.32(t，J＝7.2Hz，3H)。LCMS (method B): R
t=1.42 minutes, M+H
+=208.
step 4:3-(trifyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By the 3-hydroxyl-furo [3 stirred; 2-c] pyridine-2-carboxylic acids ethyl ester (3.15g; 15.204mmol), N; N-bis-(trifluoromethyl sulfonyl) aniline (10.08g; 28.24mmol) and N; the solution of N-diisopropylethylamine (11.35ml, 65.16mmol) in glycol dimethyl ether (50ml) was 95 ℃ of heating 35 minutes.Then reaction mixture is cooled to room temperature, concentrating under reduced pressure.Then through flash chromatography (ISCO, 45ml/min, last 20 minutes 0-60% ethyl acetate/hexane for silica gel, 120g post), resistates is carried out to purifying, obtain title compound, it is light yellow oil/white waxy solid (4.11g, 79.7%).
1HNMR(CDCl
3，400MHz)9.07(s，1H)，8.75(d，1H)，7.59(d，1H)，4.54(q，2H)，1.47(t，3H)。LCMS (5 minutes, method 2): R
t=2.93 minutes, M+H
+=339.6.
step 5:3-(the fluoro-phenyl amino of the bromo-2-of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By 3-(trifyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (4.11g, 12.11mmol), the bromo-2-fluoroaniline of 4-(3.76g, 19.38mmol), Pd
2dba
3(925mg, 1.01mmol), Xantphos (591mg, 1.02mmol) and K
3pO
4(4.95g, 22.61mmol) suspension in toluene (60ml) is by degassed 10 minutes of bubbling nitrogen (bubbling nitrogen), then is heated to 105 ℃ and keep 24 hours.Then reaction mixture is cooled to room temperature, and dilutes by ethyl acetate (100ml).Then the mixture formed is filtered through diatomite 545, diatomite washs by extra 50ml ethyl acetate.Then concentrated filtrate, and, through flash chromatography (ISCO, 45ml/min, last 40 minutes 0-70% ethyl acetate/hexane for silica gel, 120g post) purifying, obtain title compound, it is white solid (2.96g, 64.5%).
1H?NMR(CDCl
3，400MHz)8.60(m，2H)，7.66(s，1H)，7.50(d，m?1H)，7.39(d，d，1H)，7.30(d，m，1H)，7.16(t，1H)，4.49(q，2H)，1.47(t，3H)。LCMS (5 minutes, method 2): R
t=2.47 minutes, M+H
+=378.9.
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-amino-pyridine-4-carboxylic acid
According to the people such as Zhou (2001) Bioorg.Med.Chem.Lett.9 (8): the operation of 2061-2071, by bromine (1.22ml, 23.9mmol) slowly be added to cooling (5 ℃) 2.5N NaOH solution (60ml, 150mmol), stir after 5 minutes, add pyrrolo-[3,4-c] pyridine-1,3-diketone (3.5g, 23.6mmol).Temperature is risen to 80 ℃, mixture is stirred 1 hour, then be cooled to envrionment temperature.Carefully add acetic acid (5.9ml, 98.3mmol) (note: emit gas), then, by solution stirring 10 minutes, form thus throw out, it is collected after filtration.Solid water (20ml) and MeOH (20ml) washing, then drying obtains title compound, and it is yellow solid (2.1g, 64%).
step 2:3-hydroxyl-Pyridine-4-carboxylic acid
Add the vitriol oil (1.5ml) in suspension to 3-amino-pyridine-4-carboxylic acid (2.1g, 15.2mmol) in water (35ml).Solution is cooled to 5 ℃ and vigorous stirring, then adds the solution of Sodium Nitrite (1.05g, 15.2mmol) in water (10ml).Suspension slowly is heated to 80 ℃, then keeps 15 minutes in this temperature, then be cooled to 65 ℃ and add acetic acid (1.5ml).By add liquor ammoniae fortis (about 3.5ml) by the pH regulator of solution to pH be 4.5, then mixture is placed in to refrigerator overnight.Collect after filtration the throw out formed, water (20ml) washing, then vacuum-drying, obtain title compound, and it is yellow solid (1.85g, 88%).
1H?NMR(d
4-MeOH，400MHz)8.37(s，1H)，8.09(d，J＝5.5Hz，1H)，7.81(d，J＝5.5Hz，1H)。
step 3:3-hydroxyl-Pyridine-4-carboxylic acid ethyl ester
By 3-hydroxyl-Pyridine-4-carboxylic acid (1.83g, 13.2mmol) reflux 48 hours in the mixture of ethanol (40ml) and the vitriol oil (1.0ml).Mixture is cooled to the then concentrated resistates that obtains of room temperature.By in resistates water-soluble (10ml), then by adding NaHCO
3(about 2g) neutralization.DCM for organic constituent (3 * 20ml) extraction, the organic extract liquid of merging, through dried over mgso concentrated, obtains title compound, and it is yellow oil, and described oily matter solidifies (1.87g, 85%) when standing.
1HNMR(d
4-MeOH，400MHz)10.40(s，1H)，8.49(s，1H)，8.21(d，J＝5.20Hz，1H)，7.62(d，J＝5.20Hz，1H)，4.47(q，J＝6.44Hz，2H)，1.45(t，J＝6.44Hz，3H)。
step 4:3-(ethoxycarbonyl methoxy)-Pyridine-4-carboxylic acid ethyl ester
To cold (5 ℃) 3-hydroxyl-Pyridine-4-carboxylic acid ethyl ester (1.67g, 1.0mmol), hydroxyethanoic acid ethyl ester (1.15ml, 12.0mmol) and triphenylphosphine (3.93g, 15.0mmol) drip diisopropyl azo-2-carboxylic acid (2.94ml, 15.0mmol) in solution in anhydrous THF (50ml).Reaction mixture is warmed to envrionment temperature gradually, and then stirs 1 hour.Solution is concentrated, then, through flash chromatography (Si-SPE, pentane: ether, gradient is 50: 50 to 0: 100) purifying, obtain title compound, it is yellow oil (2.15g, 85%).LCMS (method B): R
t=2.69 minutes, M+H
+=254.
step 5:3-hydroxyl-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester
By 3-(ethoxycarbonyl methoxy)-Pyridine-4-carboxylic acid ethyl ester (2.1g, 8.3mmol) solution in THF (50ml) carefully is added in the cold solution of (0 ℃) potassium tert.-butoxide (966mg, 8.6mmol) in THF (20ml).After 30 minutes, reaction mixture is by adding acetic acid (10ml) cancellation.Evaporating solvent, obtain jelly, it is dissolved in ethyl acetate (50ml) to then water (2 * 10ml) washing.Separate organic layer, then through anhydrous sodium sulfate drying.Solution is concentrated and obtains title compound, and it is yellow solid (1.60g, 94%).LCMS (method B): R
t=1.89 minutes, M+H
+=208.
step 6:3-(nine fluorine fourths-1-alkylsulfonyl oxygen base)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ of 3-hydroxyl-furo [2 to stirring, 3-c] pyridine-2-carboxylic acids ethyl ester (1.16g, 5.60mmol) successively add DIPEA (1.32ml, 7.5mmol) and nine fluorine butyl sulfonic acid fluoride (1.25ml, 6.9mmol) in suspension in DCM (15ml).After 10 minutes, reaction mixture is warmed to room temperature, and then stirs 20 hours.Reaction mixture is concentrated, resistates is dissolved in DCM (100ml), successively water (50ml) and 1N NaOH solution (20ml) washing.Separate the organic layer merged, then through dried over sodium sulfate vacuum concentration.Through flash chromatography (Si-SPE, pentane: ether, gradient is 80: 20 to 50: 50) purifying, obtain title compound, it is white solid (895mg, 33%).LCMS (method B): R
t=4.34 minutes, M+H
+=490.
step 7:3-(the fluoro-phenyl amino of the bromo-2-of 4-)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester
Make degassed 3-(nine fluorine fourths-1-alkylsulfonyl oxygen base)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester (838mg, 1.71mmol), the bromo-2-fluoroaniline of 4-(423mg, 2.23mmol), Pd
2dba
3(78mg, 0.09mmol), Xantphos (99mg, 0.17mmol) and DBU (651 μ l, the 4.28mmol) solution in toluene (3.3ml) is accepted microwave irradiation 20 minutes at 150 ℃.Reaction mixture is concentrated, the resistates of formation is adsorbed on to HM-N upper, then, through flash chromatography (Si-SPE, pentane: ether, gradient is 80: 20 to 0: 100) purifying, obtain title compound, it is white solid (369mg, 57%).LCMS (method B): R
t=3.77 minutes, M+H
+=380/382.
step 8:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester
By 3-(the fluoro-phenyl amino of the bromo-2-of 4-)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester (311mg, 0.82mmol), cuprous iodide (I) (8mg, 0.04mmol), sodium iodide (246mg, 1.64mmol) and trans-N, N '-dimethyl-1,2-cyclohexanediamine (13 μ l, 0.08mmol) mixture in Isosorbide-5-Nitrae-dioxane (0.8ml) is 115 ℃ of heating 26 hours under argon gas atmosphere.Once reaction mixture is cooled to room temperature, mixture is concentrated, then, through flash chromatography (Si-SPE, EtOAc) purifying, obtain title compound, it is yellow oil (220mg, 63%).LCMS (method B): R
t=3.91 minutes, M+H
+=427.
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
the fluoro-4-of step 1:2-(trimethyl silyl)-phenyl amine
The chloro-2-fluoronitrobenzene of 4-(6.0g, 34.2mmol) is added in the 100ml round-bottomed flask, then adds hexamethyldisilane (18.9g, 129.0mmol, 26.4ml) and dimethylbenzene (13ml).Mixture is carried out to magnetic agitation, pass into nitrogen 10 minutes by glass pipette in solution simultaneously, or until all solids dissolving.
Add tetrakis triphenylphosphine palladium (0) (1.0g, 0.9mmol), flask is equipped with reflux exchanger, then reaction mixture refluxed is heated to 24-48 hour, has stream of nitrogen gas slowly to pass through the rubber septum (rubber septum) that is placed in condenser overhead simultaneously.After being cooled to room temperature, ether for reaction mixture (40ml) dilution, then pass through silica filler and (be filled to the 30ml SiO in 60ml sintered glass funnel
2/ ether slurry) filter.Ether for filter cake (60ml) washing, the organic liquor vacuum concentration by merging, obtain orange, by it through flash chromatography (250ml silica gel, 98: 1: 1 hexane-CH
2cl
2-ether) purifying, obtain the fluoro-4-of 2-(trimethyl silyl) oil of mirbane (5.45g, 75%), and it is yellowish-orange oily matter.
Then by the fluoro-4-of 2-(trimethyl silyl) oil of mirbane (5.45g, 25.6mmol) be dissolved in ethanol (100ml), be transferred in Parr shaker bottle (Parr shaker bottle), use nitrogen wash, the 10%Pd-C that then packs into (0.4g).By reaction mixture hydrogenation (45psiH on Pa Er device (Parr apparatus)
2) 1h, then through diatomaceous earth filler, filter.The filter cake washing with alcohol, then that the filtrate merged is concentrated.The resistates formed, through flash chromatography (250ml silica gel, 95: 5 hexane-ether) purifying, obtains title compound, and it is brown oily matter (4.31g, 92%).
step 2:3-(4-(trimethyl silyl)-fluoro-phenyl amino of 2-)-furo [3,2-c] pyridine-2-carboxylic
acetoacetic ester
By 3-(trifyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (17.5g, 51.58mmol), the fluoro-4-of 2-(trimethyl silyl)-phenyl amine (10g, 54.26mmol), Pd
2dba
3(2.98g, 3.26mmol), Xantphos (1.94mg, 3.26mmol) and K
3pO
4(15.83g, 72.34mmol) suspension in toluene (100ml) by degassed 10 minutes of bubbling nitrogen, then is heated to 105 ℃ and keep 24 hours in the 300ml pressure bottle.Then reaction mixture is cooled to room temperature, and dilutes by ethyl acetate (200ml).Then make the mixture formed filter through diatomite 545, diatomite washs by extra 100ml ethyl acetate.Then concentrated filtrate, and, through flash column chromatography (silica gel, 0-55% ethyl acetate/hexane) purifying, obtain title compound, it is yellow solid (17.9g, 93.2%).LCMS (method C): R
t=2.47 minutes, M+H
+=373.
1H?NMR(CDCl
3，400MHz)8.66(d，1H)，8.57(d，1H)，7.52(s，1H)，7.45(d，d，1H)，7.30(m，2H)，4.50(q，2H)，1.49(t，3H)。
step 3:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Weigh up fast 16.0g (72.49mmol) AgBF
4, add in the 1000mL round-bottomed flask, then with rubber septum, cover.Then flask is used to anhydrous N
2clean 10 minutes, afterwards flask is cooled to-50 ℃, maintain inert atmosphere simultaneously.Add wherein the 300ml anhydrous methylene chloride, then the mixture formed is stirred 15 minutes under nitrogen at-50 ℃.Then add 9.0g (24.16mmol) 3-(4-(trimethyl silyl)-fluoro-phenyl amino of 2-)-furo [3 in reaction mixture, 2-c] solution of pyridine-2-carboxylic acids ethyl ester in the 75ml anhydrous methylene chloride, stir mixture 30 minutes under nitrogen at-50 ℃.The color of reaction mixture is clear and bright yellow.Then following reaction mixture: last 30 minutes and under agitation drip the 25ml ICl (CH of 1.0M
2cl
2solution, 25mmol).Add ICl to cause sedimentary formation (white/brown) (when ICl contacts with reaction mixture, the color of reaction mixture is yellow-local red, and it becomes yellow (containing white depositions)).Reaction mixture is stirred 30 minutes under nitrogen at-50 ℃.LC/MS shows that reaction finishes.Then add the saturated Na of 200ml at-50 ℃ by priority
2s
2o
3solution and 100ml water will react cancellation.Then mixture is transferred in separating funnel and jolting.Then make mixture through filter paper filtering.Then black solid on filter paper further discards by dichloromethane rinse.Then filtrate is transferred in separating funnel.It is extracted with methylene dichloride (3 * 100ml) fast.Then the dichloromethane layer merged is used to 170ml4M NH in separating funnel
4the OH solution washing.Then separate dichloromethane layer, and pass into nitrogen with except deammoniation.Then it used to dried over mgso, filter and concentrating under reduced pressure, obtain yellow solid.Then make solid powder and use ether (2 * 30ml) to grind, then vacuum-drying obtains 8.90g title product (yellow solid, 86.4%).LCMS (method C): R
t=2.47 minutes, M+H
+=427.
1H?NMR(CDCl
3，400MHz)8.64(d，1H)，8.9(d，1H)，7.66(s，1H)，7.54(d，d，1H)，7.46(d，d，m，2H)，7.13(t，1H)，4.49(q，2H)，1.49(t，3H)。
3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-amino-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Last under nitrogen atmosphere at-10 ℃ in the mixture of the sodium hydride that 5 minutes clockwise stirs (60% suspension in mineral oil, 6.0g, 150mmol) in DMF (160ml) and add hydroxyethanoic acid ethyl ester (14.5ml, 150mmol).After 35 minutes, reaction mixture further is cooled to-35 ℃, then lasts and within 5 minutes, add the 4-chloropyridine-solution of 3-formonitrile HCN (4-chloronicotinonitrile) (6.9g, 50mmol) in DMF (40ml).Then last 1.5 hours and make reaction mixture be warmed to gradually-5 ℃, use afterwards acetic acid: water (45ml: 400ml) solution cancellation, then use ethyl acetate (2 * 200ml) extraction.The water separated, by adding the solid sodium bicarbonate alkalization, is then used ethyl acetate (3 * 200ml) extraction.The sodium hydrogen carbonate solution for organic extract liquid (100ml) merged and water (2 * 100ml) washing, then separate organic phase, dry (MgSO
4), filter and vacuum-evaporation.Through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient be 60: 40 to 0: 100 then for ethyl acetate: methyl alcohol, 90: 10) resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (6.25g, 61%).LCMS (method B): R
t=1.45 minutes, M+H
+=207.
step 2:3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
To degassed 3-amino-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (206mg, 1.0mmol), Isosorbide-5-Nitrae-diiodo-benzene (3.3g, 10.0mmol), Pd
2dba
3(24mg, 26 μ mol), Xantphos (30mg, 52 μ mol) and the solution of potassiumphosphate (424mg, 2.0mmol) in toluene (10ml) are stirred, and then under argon gas atmosphere, are heated to 105 ℃ and keep 42 hours.Cooling reaction mixture is poured in aqueous ammonium chloride solution, then used ethyl acetate (3 * 70ml) extraction.The extraction liquid merged is water (2 * 100ml) and salt solution (50ml) washing successively, then separates organic phase, dry (MgSO
4), filter and vacuum-evaporation.Through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 60: 40), the resistates formed is carried out to purifying, obtain title compound, it is pale solid (100mg, 24%).LCMS (method B): R
t=3.16 minutes, M+H
+=409.
3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-(the chloro-phenyl amino of the bromo-2-of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Make degassed 3-(nine fluorine fourths-1-alkylsulfonyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (500mg, 1.02mmol), the bromo-2-chloroaniline of 4-(275mg, 1.33mmol), Pd
2dba
3(47mg, 0.05mmol), Xantphos (59mg, 0.10mmol) and DBU (388 μ l, the 2.56mmol) solution in toluene (2.0ml) is accepted microwave irradiation 10 minutes at 150 ℃.Reaction mixture is concentrated, then make the resistates formed be adsorbed on HM-N above, afterwards through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 0: 100) purifying, obtain title compound, it is white solid (183mg, 47%).LCMS (method B): R
t=3.54 minutes, M+H
+=395/397.
step 2:3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By 3-(the chloro-phenyl amino of the bromo-2-of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (183mg, 0.46mmol), cuprous iodide (I) (4mg, 0.02mmol), sodium iodide (139mg, 0.93mmol) and trans-N, N '-dimethyl-1,2-cyclohexanediamine (7 μ l, 0.04mmol) mixture in Isosorbide-5-Nitrae-dioxane (0.5ml) is 115 ℃ of heating 44 hours under argon gas atmosphere.Reaction mixture is cooled to room temperature, then adds extra cuprous iodide (I) (4mg, 0.02mmol) and trans-N, N '-dimethyl-1,2-cyclohexanediamine (7 μ l, 0.04mmol) then continues heating 18 hours under argon gas atmosphere at 115 ℃.Then reaction mixture is cooled to room temperature, with methylene dichloride dilution, the then aqueous solution, water and the salt water washing of 10% ammonia for priority.Organic extract liquid, through dried over sodium sulfate, filters and vacuum concentration, obtains resistates, it is carried out to purifying through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 0: 100), obtain title compound, it is pale solid (115mg, 57%).LCMS (method B): R
t=3.97 minutes, M+H
+=443.
3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-(4-bromo-2, the fluoro-phenyl amino of 6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Make degassed 3-(nine fluorine fourths-1-alkylsulfonyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (500mg, 1.02mmol), 4-bromo-2,6-difluoroaniline (277mg, 1.33mmol), Pd
2dba
3(47mg, 0.05mmol), Xantphos (59mg, 0.10mmol) and DBU (388 μ l, the 2.56mmol) solution in toluene (2.0ml) is accepted microwave irradiation 10 minutes at 150 ℃.Reaction mixture is concentrated, then the resistates of formation is adsorbed on to HM-N upper, afterwards through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 0: 100) purifying, obtain title compound, it is white solid (89mg, 22%).LCMS (method B): R
t=3.38 minutes, M+H
+=397/399.
step 2:3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
(4-bromo-2 to make 3-, the fluoro-phenyl amino of 6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (165mg, 0.42mmol), cuprous iodide (I) (4mg, 0.02mmol), sodium iodide (125mg, 0.83mmol) and trans-N, N '-dimethyl-1, the mixture of 2-cyclohexanediamine (7 μ l, 0.04mmol) in Isosorbide-5-Nitrae-dioxane (0.5ml) accepted microwave irradiation 15 minutes at 180 ℃.By extra cuprous iodide (I) (4mg, 0.02mmol), sodium iodide (60mg, 0.40mmol) and trans-N, N '-dimethyl-1,2-cyclohexanediamine (7 μ l, 0.04mmol) is added in reaction mixture, makes it again at 180 ℃, accept microwave irradiation 15 minutes.Reaction mixture is diluted with methylene dichloride, then the aqueous solution, water and the salt water washing of 10% ammonia for priority.Organic extract liquid is through dried over sodium sulfate, filter and concentrate to obtain resistates, by it through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 0: 100) purifying, obtain title compound, it is pale solid (137mg, 74%).LCMS (method B): R
t=3.48 minutes, M+H
+=445.
3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-(4-bromo-2, the fluoro-phenyl amino of 5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Make degassed 3-(nine fluorine fourths-1-alkylsulfonyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (500mg, 1.02mmol), 4-bromo-2,5-difluoroaniline (277mg, 1.33mmol), Pd
2dba
3(47mg, 0.05mmol), Xantphos (59mg, 0.10mmol) and DBU (388 μ l, the 2.56mmol) solution in toluene (2.0ml) is accepted microwave irradiation 10 minutes at 150 ℃.Reaction mixture is concentrated, then the resistates of formation is adsorbed on to HM-N upper, afterwards through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 0: 100) purifying, obtain title compound, it is white solid (231mg, 57%).LCMS (method B): R
t=3.22 minutes, M+H
+=397/399.
step 2:3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By 3-, (4-bromo-2, the fluoro-phenyl amino of 5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (222mg, 0.56mmol), cuprous iodide (I) (5mg, 0.03mmol), sodium iodide (168mg, 1.12mmol) and trans-N, N '-dimethyl-1, the mixture of 2-cyclohexanediamine (10 μ l, 0.06mmol) in Isosorbide-5-Nitrae-dioxane (0.5ml) was 110 ℃ of heating 18 hours.By extra cuprous iodide (I) (5mg, 0.03mmol) and trans-N, N '-dimethyl-1,2-cyclohexanediamine (10 μ l, 0.06mmol) is added in reaction mixture, and then 110 ℃ of heating 6 hours.Reaction mixture is cooling, with methylene dichloride dilution, the then aqueous solution, water and the salt water washing of 10% ammonia for priority.Organic extract liquid, through dried over sodium sulfate, filters and concentrates, and obtains resistates, by it through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 0: 100) purifying, obtain title compound, it is white solid (170mg, 68%).LCMS (method B): R
t=3.30 minutes, M+H
+=445.
the bromo-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids
the bromo-3-hydroxyl-furo of step 1:7-[3,2-c] pyridine-2-carboxylic acids ethyl ester
0 ℃ (ice/water) to 4, add sodium hydride (1.04g in 5-dibromo pyridine-3-carboxylic acid, ethyl ester (2.68g, 8.67mmol) and hydroxyethanoic acid ethyl ester (0.90g, the 8.67mmol) solution in DMF (25ml), 26mmol, 60% oily dispersion liquid).Reaction mixture is stirred 15 minutes at 0 ℃, then make it be warmed to room temperature and keep 2h.Reaction mixture is cooled to 0 ℃, then adds 1M HCl (18ml, 18mmol).Throw out is filtered, then wash with water, obtain title compound, it is pale solid (2.35g, 95%).LCMS (method B): R
t=2.96 minutes, M+H
+=285/287.
step 2:3, the bromo-furo of 7-bis-[3,2-c] pyridine-2-carboxylic acids
The mixture of bromo-3-hydroxyl-furo [3,2-c] the pyridine-2-carboxylic acids ethyl ester of 7-(1.14g, 4.0mmol) and phosphoryl bromide (5.6g, 19.5mmol) is heated 2 hours at 140 ℃.Reaction mixture is cooled to room temperature, then adds trash ice (about 30ml).Mixture, by adding solid NaOH neutralization, is then 3.0 by carefully adding 1M HCl to be adjusted to pH.The throw out formed is filtered, and then priority water and washed with dichloromethane, obtain title compound, and it is white solid (1.2g, 90%).LCMS (method B): R
t=2.62 minutes, M+H
+=320/322/324.
step 3:3, the bromo-furo of 7-bis-[3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-1,1-dimethyl-ethyl)-
acid amides
By 3,7-bis-bromo-furo [3,2-c] pyridine-2-carboxylic acids (1.2g, 3.74mmol) and carbonyl dimidazoles (0.85g, 5.24mmol), the mixture in acetonitrile (18ml) was 50 ℃ of heating 2 hours.Another batch of carbonyl dimidazoles (0.035g, 0.5mmol) is added in reaction mixture, then at 50 ℃, continues heating 1 hour.After being cooled to envrionment temperature, 2-amino-2-methyl-propyl-1-alcohol (0.30ml, 3.13mmol) is added in solution.Make reaction mixture in room temperature standing 19 hours, then be heated to 50 ℃ and keep 1 hour, afterwards vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 80: 20 to 0: 100), the resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (0.53g, 72%).LCMS (method B): R
t=2.57 minutes, M+H
+=391/393/395.
step 4:3, the bromo-2-of 7-bis-(4,4-dimethyl-4,5-dihydro-oxazole-2-yl)-furo [3,2-c] pyridine
Add thionyl chloride (0.25ml, 3.43mmol) in the bromo-furo of 3,7-bis-[3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-1,1-dimethyl-ethyl)-solution of acid amides (0.53g, 1.35mmol) in methylene dichloride (10ml).Mixture, at stirring at room 1h, then is heated to reflux and keep 2h, is cooled to afterwards 0 ℃.By 1M NaOH (15ml) neutralization for mixture, methylene dichloride for water layer (2 * 15ml) extraction.Collected organic layer, then through dried over mgso, vacuum concentration obtains resistates.Through flash chromatography (Si-SPE, methylene dichloride is ethyl acetate then), the resistates formed is carried out to purifying, obtain title compound, it is light yellow gluey thing (250mg, 50%).LCMS (method B): R
t=3.11 minutes, M+H
+=373/375/377.
the bromo-2-of step 5:[7-(4,4-dimethyl-4,5-dihydro-oxazoles-2-yl)-furo [3,2-c] pyridine-3-
base]-(the iodo-phenyl of the fluoro-4-of 2-)-amine
To 3, the bromo-2-(4 of 7-bis-, 4-dimethyl-4,5-dihydro-oxazoles-2-yl)-furo [3,2-c] pyridine (250mg, 0.67mmol) and the solution of the iodo-2-fluoroaniline of 4-(474mg, 2mmol) in THF (2ml) in add the solution (2ml, 1M solution) of hexamethl disilamine base lithium (lithium hexamethyldisilazide) in THF.Reaction mixture, 50 ℃ of heating 4 hours, then is cooled to room temperature water (15ml) dilution.Methylene dichloride for water layer (2 * 10ml) extraction, the organic extract liquid of merging is through MgSO
4drying, then vacuum concentration obtains resistates.Through flash chromatography (Si-SPE, hexanaphthene: t-butyl methyl ether, gradient is 1: 1 to 1: 2), the resistates formed is carried out to purifying, obtain title compound, it is light brown solid (150mg, 42%).LCMS (method A): R
t=13.97 minutes, M+H
+=530/532.
the bromo-3-of step 6:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids
By [the bromo-2-of 7-(4,4-dimethyl-4,5-dihydro-oxazoles-2-yl)-furo [3,2-c] pyridin-3-yl]-(the iodo-phenyl of the fluoro-4-of 2-)-amine (110mg, 0.2mmol) and 1M HCl (2ml, mixture 2mmol) is at 100 ℃ of heating 4 hours, then cooling and vacuum concentration.The resistates of formation is dissolved in methyl alcohol (3ml), then successively adds methanol solution (0.4ml, 1mmol) and the water (1ml) of 2.5M NaOH.Then mixture is heated 1 hour at 75 ℃, add afterwards the 1M NaOH aqueous solution (1ml, 1mmol), then continue heating 2 hours.By the reaction mixture vacuum concentration, residue is ethyl acetate (2 * 2ml) washing for water layer.Then for water layer 1M HCl (about 1.5ml) to be acidified to pH be 4, then vacuum concentration, to about half volume, then makes it standing in room temperature.Collect after filtration the throw out formed, then successively water (1ml) and ethyl acetate (1ml) washing, obtain title compound, and it is yellow/brown solid (66mg, 69%).LCMS (method B): R
t=3.34 minutes, M+H
+=477/479.
5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
step 1:4-hydroxyl-pyrimidine-5-carboxylic acid's ethyl ester
Add 1,3,5-triazines (6.0g, 74.1mmol) and diethyl malonate (11.3ml, 74.1mmol) in solution to preformed sodium (1.70g, 73.9mmol) in dehydrated alcohol in (300ml).Reaction mixture is heated to reflux.After heating 3h, reaction mixture is cooled to room temperature concentrating under reduced pressure, obtains resistates.By in resistates water-soluble (300ml), then be cooled to 5 ℃, and by adding hydrochloric acid (6ml) acidifying.Mixture, 5 ℃ of ageings 48 hours, is then filtered.The solid formed washes with water, and then drying under reduced pressure, obtain title compound, and it is beige solid (3.0g, 24%).
1H?NMR(d
6-DMSO，400MHz)8.47(s，1H)，8.37(d，s，1H)，4.22(q，J＝7.2Hz，2H)，1.26(t，J＝7.2Hz，3H)。
the chloro-pyrimidine-5-carboxylic acid's ethyl ester of step 2:4-
Drip diisopropylethylamine (3.4ml, 19.6mmol) and phosphoryl chloride (1.8ml, 19.6mmol) in suspension in toluene (35ml) to 4-hydroxyl-pyrimidine-5-carboxylic acid's ethyl ester (3.0g, 17.6mmol) under nitrogen atmosphere.Reaction mixture is heated to 70 ℃, stirs 2 hours, then be cooled to 5 ℃.Add 1M aqueous sodium hydroxide solution (26ml), then by the mixture dilute with water, and be extracted with ethyl acetate.Organic layer water, saturated sodium bicarbonate solution washing, then through dried over sodium sulfate, filter and concentrate, and obtains title compound, and it is brown oil (2.56g, 77%).
1H?NMR(CDCl
3，400MHz)9.13(s，1H)，9.08(s，1H)，4.47(q，J＝6.9Hz，2H)，1.44(t，J＝6.9Hz，3H)。
step 3:4-(ethoxycarbonyl methoxy)-pyrimidine-5-carboxylic acid's ethyl ester
Add hydroxyethanoic acid ethyl ester (1.6ml, 16.5mmol) at 5 ℃ in the suspension of sodium hydride (60% dispersion liquid in mineral oil, 602mg, 15.1mmol) in anhydrous THF (55ml) under nitrogen atmosphere.Reaction mixture is stirred 30 minutes at 5 ℃, then drip the solution of the chloro-pyrimidine-5-carboxylic acid's ethyl ester of 4-(2.56g, 13.8mmol) in anhydrous THF (20ml).Reaction mixture is stirred 30 minutes at 5 ℃.Acetic acid (3ml) is added in reaction mixture, then vacuum concentration.The resistates of formation is dissolved in ethyl acetate, and successively water and salt water washing, then, through dried over sodium sulfate concentrating under reduced pressure, obtain resistates.Make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 00 to 40: 60) purifying, obtain title compound, it is yellow oil (2.67g, 76%).
1H?NMR(CDCl
3，400MHz)9.05(s，1H)，8.82(s，1H)，5.05(s，2H)，4.41(q，J＝7.1Hz，2H)，4.24(q，J＝7.1Hz，2H)，1.40(t，J＝7.1Hz，3H)，1.28(t，J＝7.1Hz，3H)。
step 4:5-hydroxyl-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
Add sodium tert-butoxide (1.40g) in solution in anhydrous THF (80ml) to 4-(ethoxycarbonyl methoxy)-pyrimidine-5-carboxylic acid's ethyl ester (2.12g, 8.3mmol) under inert atmosphere at 5 ℃.Reaction mixture is stirred 30 minutes at 5 ℃, then add the 1M hydrochloric acid soln.By the mixture dilute with water, then be extracted with ethyl acetate.Separate organic layer, and successively water and salt water washing, through dried over sodium sulfate, filter and concentrating under reduced pressure, obtain title compound, it is white solid (934mg, 54%).
1HNMR(CDCl
3，400MHz)9.22(s，1H)，9.14(s，1H)，4.51(q，J＝7.3Hz，2H)，1.47(t，J＝7.3Hz，3H)。
step 5:5-(trifyl oxygen base)-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
To 5-hydroxyl-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester (1.2g, 5.8mmol) and the solution of diisopropylethylamine (1.5ml, 8.7mmol) in glycol dimethyl ether (25ml) in add N-phenyl trifluoromethanesulfonate methylsulfonyl imines (2.3g, 6.4mmol).Reaction mixture be heated to reflux and stir 1 hour, then being cooled to room temperature, concentrating under reduced pressure.Resistates is dissolved in ethyl acetate, then water, saturated sodium bicarbonate aqueous solution and salt water washing.Organic layer is through dried over sodium sulfate, filters, and is adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 100: 0 to 50: 50) purifying, obtains title compound, and it is colorless oil (1.5g, 77%).
1H?NMR(CDCl
3，400MHz)9.23(s，2H)，4.54(q，J＝7.2Hz，2H)，1.47(t，J＝7.2Hz，3H)。
step 6:5-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [2,3-d] pyrimidine-6-carboxylic
acetoacetic ester
Under nitrogen atmosphere by degassed 5-(trifyl oxygen base)-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester (1.5g, 4.4mmol), the fluoro-4-of 2-(trimethyl silyl)-phenyl amine (888mg, 4.8mmol), Pd
2dba
3(202mg, 0.22mmol), Xantphos (127mg, 0.22mmol) and K
3pO
4(1.9g, 8.8mmol) solution in toluene (20ml) is heated to reflux and stirs 4 hours.Reaction mixture is cooled to room temperature, then passes through diatomite filtration, filter cake is washed by ethyl acetate.Organic layer is water and salt water washing successively, through dried over sodium sulfate, filters and concentrating under reduced pressure.The resistates of formation is dissolved in methylene dichloride, is adsorbed on HM-N upper, then through flash chromatography (Si-SPE, ethyl acetate: hexanaphthene, gradient is 0: 100 to 40: 60) purifying, obtain title compound, it is oily matter, described oily matter crystallization when standing (1.2g, 75%).LCMS (method B): R
t=4.39 minutes, M+H
+=374.
step 7:5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester
At 5 ℃ to 5-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester (1.2g, 3.2mmol) add the solution of iodine monochloride (674mg, 4.2mmol) in methylene dichloride (5ml) in solution in methylene dichloride (10ml).Reaction mixture is stirred 1 hour at 5 ℃, then add the thiosulfuric acid saturated aqueous solution of sodium.Separate organic layer, then successively water and salt water washing, through dried over sodium sulfate, filter and concentrating under reduced pressure.The resistates of formation is ground with hot ethanol, spend the night in the room temperature ageing.Collect after filtration the throw out formed, then use cold washing with alcohol, vacuum-drying afterwards obtains title compound, and it is white solid (864mg, 63%).
1H?NMR(CDCl
3，400MHz)9.08(s，1H)，8.70(s，1H)，7.78(s，1H)，7.57(dd，J＝9.6Hz，1.9Hz，1H)，7.51(ddd，J＝8.4Hz，1.7Hz，1.7Hz，1H)，7.03(dd，J＝8.2Hz，8.2Hz，1H)，4.49(q，J＝7.4Hz，2H)，1.46(t，J＝7.4Hz，3H)。
3-((the fluoro-4-iodophenyl of 2-) methylamino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Under inert atmosphere by sodium hydride (60% dispersion liquid in mineral oil, 45mg, 1.12mmol) be added to the 3-(the iodo-phenyl amino of the fluoro-4-of 2-) of stirring-furo [3 by part, 2-c] pyridine-2-carboxylic acids ethyl ester (430mg, 1.0mmol) and the solution of methyl iodide (310 μ l, 4.98mmol) in DMF (3ml) in.This mixture is stirred 3 hours, then use the salt solution cancellation, and extract by ethyl acetate (3 * 40ml).The organic extract liquid salt water washing merged, dry (MgSO
4), filter and vacuum concentration.Use flash chromatography (Si-SPE, gradient is 40: 100 to 100: 100 ether) to carry out purifying to the resistates formed, obtain title compound, it is yellow solid (57mg, 13%).LCMS (method B): R
t=3.26 minutes, M+H
+=440.
3-(the chloro-phenyl amino of the bromo-2-of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Under argon gas atmosphere by degassed 3-(trifyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (300mg, 0.88mmol), the bromo-2-chloroaniline of 4-(201mg, 0.97mmol), Pd
2dba
3(40mg, 0.044mmol), Xantphos (59mg, 0.044mmol) and Tripotassium phosphate (373mg, 1.76mmol) the solution reflux in toluene (5ml) 16 hours.Reaction mixture is filtered and vacuum concentration.Through flash chromatography (Si-SPE, pentane: ether, gradient is 80: 20 to 50: 50), the resistates formed is carried out to purifying, obtain title compound, it is yellow solid (177mg, 51%).LCMS (method B): R
t=3.76 minutes, M+H
+=395/397.
3-(the fluoro-phenyl amino of 4-methyl-2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Under argon gas atmosphere by degassed 3-amino-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (300mg, 1.46mmol), 4-bromine-3-fluorine methylbenzene (277 μ l, 2.19mmol), Pd
2dba
3(67mg, 0.073mmol), Xantphos (84mg, 0.15mmol) and Tripotassium phosphate (620mg, 2.92mmol) the solution reflux in toluene (10ml) 16 hours.By the reaction mixture vacuum concentration, through flash chromatography (Si-SPE, pentane: ether, gradient is 100: 0 to 75: 25), resistates is carried out to purifying, obtain title compound, it is yellow solid (252mg, 55%).LCMS (method B): R
t=3.14 minutes, M+H
+=315.
3-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
the fluoro-thiophenol of the bromo-3-of step 1:4-
The fluoro-benzene sulfonyl chloride of the bromo-3-of 4-(324 μ l, 2.19mmol) is added drop-wise in the solution of triphenylphosphine (1.73g, 6.58mmol) in the mixture of dimethyl formamide (125 μ l) and methylene dichloride (5ml).Solution, stirring at room 16 hours, is then added to 1M aqueous hydrochloric acid (5ml), separate each layer.By the organic layer vacuum concentration, then the resistates of formation is absorbed in 1M aqueous sodium hydroxide solution (10ml).The suspension formed is through diatomite filtration, and filtrate is with ether (10ml * 3) washing, then by adding 1M aqueous hydrochloric acid (10ml) neutralization.Ether for solution (10ml * 3) extraction, by the dry (Na of the organic extract liquid merged
2sO
4), then vacuum concentration, obtain title compound, and it is colorless oil (225mg, 50%).
1H?NMR(CDCl
3，300MHz)7.47(1H，dd，J＝8.4，7.5Hz)，7.06(1H，dd，J＝8.9，2.2Hz)，6.93(1H，ddd，J＝8.4，2.1，0.7Hz)，3.54(1H，br?s)。
the fluoro-4-of the bromo-2-of step 2:1-(methyl sulfenyl)-benzene
Solution by the 4-fluoro-thiophenol of bromo-3-(225mg, 1.09mmol) in tetrahydrofuran (THF) (3ml) is cooled to 0 ℃.Add sodium hydride (60% dispersion liquid in mineral oil, 52mg, 1.31mmol), then mixture is stirred 5 minutes.Then add methyl iodide (78 μ l, 1.25mmol), last 20 minutes and under agitation make mixture get back to room temperature.Add methylene dichloride (10ml), 1M aqueous hydrochloric acid cancellation for reaction.Separate each layer, organic layer washes with water, dry (MgSO
4), vacuum concentration then.Through flash chromatography (Si-SPE, pentane: ether, gradient is 100: 0 to 90: 10), resistates is carried out to purifying, obtain title compound, it is glassy yellow oily matter (208mg, 86%).
1H?NMR(CDCl
3，400MHz)7.43(1H，dd，J＝8.4，7.2)，7.00(1H，dd，J＝9.4，2.3)，6.91(1H，ddd，J＝8.4，2.1，0.7)，2.48(3H，s)。
step 3:3-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Under argon gas atmosphere by the degassed fluoro-4-of the bromo-2-of 3-amino-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (121mg, 0.59mmol), 1-(methyl sulfenyl)-benzene (195mg, 0.88mmol), Pd
2dba
3(27mg, 0.030mmol), Xantphos (34mg, 0.059mmol) and Tripotassium phosphate (250mg, 1.18mmol) the solution reflux in toluene (3ml) 60 hours.Reaction mixture is filtered, by the filtrate vacuum concentration.Through flash chromatography (Si-SPE, pentane: ether, gradient is 100: 0 to 50: 50), the resistates formed is carried out to purifying, obtain title compound, it is yellow solid (128mg, 63%).LCMS (method B): R
t=3.24 minutes, M+H
+=347.
the chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:4,5-dichloropyridine-3-formaldehyde
Add n-Butyl Lithium (47.45ml, 75.9mmol, the hexane solution of 1.6M) at-40 ℃ to Diisopropylamine (10.73ml, 75.9mmol) in THF in solution in (60ml), at-40 ℃, by solution stirring 15 minutes, then be cooled to-70 ℃.Drip the solution of 3,4-dichloropyridine (10.7g, 72.3mmol) in THF (30ml), holding temperature is below-65 ℃.Reaction mixture is stirred to 2h at-70 ℃, then add DMF (6.74ml, 86.8mmol).Then reaction mixture is stirred to 1h at-40 ℃, then make it be warmed to-5 ℃, last 3 minutes afterwards under rapid stirring and carefully add saturated ammonium chloride solution (50ml).Then mixture is distributed between saturated ammonium chloride solution (150ml) and methylene dichloride (150ml), and separate each layer.Methylene dichloride for water layer (2 * 100ml) extraction, the organic layer of merging is through dried over mgso, then vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: ethyl acetate, gradient is 100: 0 to 94: 6) purifying, obtain title compound, it is white waxy solid (8.01g, 63%).
step 2:4,5-dichloropyridine-3-formoxime
Solution by 4,5-dichloropyridine-3-formaldehyde (8.01g, 45.51mmol) in ethanol (50ml) is added in the solution of hydroxylamine hydrochloride (3.48g, 50.06mmol) in water (50ml) of rapid stirring.Reaction mixture, stirring at room 45 minutes, is then distributed between ethyl acetate (100ml) and water (100ml).Ethyl acetate for water layer (2 * 50ml) extraction, the organic layer of merging is through dried over mgso, and then vacuum concentration obtains title compound, and it is white solid (8.3g, 96%).
step 3:4,5-dichloropyridine-3-formonitrile HCN
Add carbonyl dimidazoles (7.99g, 49.26mmol) in suspension to 4,5-dichloropyridine-3-formoxime (7.84g, 41.05mmol) in methylene dichloride (150ml).Then mixture is heated to reflux and keep 1.5h, cooling afterwards, then use saturated sodium bicarbonate aqueous solution (70ml) and water (70ml) washing.Organic layer is through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: methylene dichloride, gradient is 20: 80 to 0: 100), the resistates formed is carried out to purifying, obtain title compound, it is white solid (0.53g, 72%).LCMS (method B): R
t=2.86 minutes, there do not is any ion.
the chloro-furo of step 4:3-amino-7-[3,2-c] pyridine-2-carboxylic acids ethyl ester
Add sodium hydride (0.63g, 15.7mmol, 60% oily dispersion liquid) in solution in (15ml) to hydroxyethanoic acid ethyl ester (1.48ml, 15.7mmol) in DMF at-10 ℃.Mixture is stirred 35 minutes in this temperature, then be cooled to-40 ℃.Drip 4, the 5-dichloropyridine-solution of 3-formonitrile HCN (0.906g, 5.24mmol) in DMF (5ml), then make reaction mixture be warmed to-15 ℃ and keep 30 minutes, then be warmed to-5 ℃ and keep 1h.Mixture is poured in 10: 1 water/acetic acid (25ml), and water (25ml) dilution, then use ethyl acetate (2 * 30ml) extraction.It is 8 that water is adjusted to pH with saturated sodium bicarbonate aqueous solution, then uses ethyl acetate (2 * 25ml) extraction.The organic layer merged is through dried over mgso, then vacuum concentration.Through flash chromatography, (Si-SPE, ethyl acetate: triethylamine 98: 2) resistates formed is carried out to purifying, obtain title compound, it is yellow solid (0.60g, 48%).LCMS (method B): R
t=2.79 minutes, M+H
+=241,243.
the chloro-3-of step 5:7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine
-2-carboxylic acid, ethyl ester
To the chloro-furo [3 of 3-amino-7-, 2-c] pyridine-2-carboxylic acids ethyl ester (4.16g, 17.3mmol) add cesium carbonate (11.27g, 34.6mmol) in solution in toluene (100ml), then mixture is carried out to degassed (argon gas/vacuum).Add wherein the fluoro-4-of trifluoromethanesulfonic acid 2-(trimethyl silyl)-phenyl ester (7.1g, 22.5mmol), Pd
2dba
3(395mg, 0.432mmol) and Xantphos (0.5g, 0.865mmol), then by the container argon cleaning.Reaction mixture is heated to reflux and keep 19h, cooling, then pour in saturated ammonium chloride solution (150ml).Ethyl acetate for water layer (3 * 60ml) extraction, the organic layer of merging is through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: methylene dichloride, gradient is 1: 0 to 0: 1) purifying, obtain title compound, it is light yellow solid (5.13g, 73%).LCMS (method B): R
t=4.80 minutes, M+H
+=407,409.
the chloro-3-of step 6:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to the chloro-3-of 7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (250mg, 0.615mmol) add iodine monochloride (1.23ml in solution in methylene dichloride (25ml), 1.23mmol, the dichloromethane solution of 1M), then solution is stirred 1 hour in this temperature.Add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate (25ml).Methylene dichloride for water layer (2 * 25ml) extraction, the salt water washing of the organic layer of merging, through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: methylene dichloride, gradient is 1: 0 to 0: 1), the resistates formed is carried out to purifying, obtain title compound, it is yellow waxy solid (0.22g, 78%).LCMS (method B): R
t=4.30 minutes, M+H
+=461,463.
7-cyano group-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:7-cyano group-3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyrrole
pyridine-2-carboxylic acid, ethyl ester
To the chloro-3-of 7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (0.64g, 1.57mmol) add zinc cyanide (II) (0.22g in solution in DMF (15ml), 12.63mmol), then mixture is carried out to degassed (argon gas/vacuum).Then add Pd
2dba
3(72mg, 0.079mmol) and 2-(dicyclohexyl phosphino-)-2 ', 6 '-dimethoxy-1,1 '-biphenyl (S-Phos, 65mg, 0.158mmol), the container argon cleaning, sealing then is heated to 150 ℃ and keep 30 minutes under microwave irradiation.Reaction mixture is cooling, remove volatile matter, resistates and toluene (3 * 15ml) azeotropic.Through flash chromatography (Si-SPE, hexanaphthene: dichloromethane gradient is 1: 0 to 0: 1 to be then 10% ethyl acetate/dichloromethane), the resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (0.46g, 74%).LCMS (method B): R
t=4.52 minutes, M+H
+=398.
step 2:7-cyano group-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to 7-cyano group-3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (0.46g, 1.16mmol) add iodine monochloride (2.32ml in solution in methylene dichloride (40ml), 2.32mmol, the dichloromethane solution of 1M), then the mixture formed is stirred 30 minutes in this temperature.Add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate solution (35ml).Methylene dichloride for water layer (2 * 25ml) extraction, the salt water washing of the organic layer of merging, through dried over mgso vacuum concentration then.Through flash chromatography (Si-SPE, methylene dichloride: ethyl acetate, gradient is 10: 0 to 10: 1), the resistates formed is carried out to purifying, obtain title compound, it is yellow waxy solid (0.36g, 69%).LCMS (method B): R
t=4.10 minutes, M+H
+=452.
3-(the fluoro-4-triisopropyl of 2-silyl oxygen ylmethyl-phenyl amino)-furo [3,2-c] pyridine-2-
carboxylic acid, ethyl ester
the fluoro-benzyl oxygen of the bromo-3-of step 1:(4-base)-triisopropyl-silicomethane
Add triisopropyl silyl chloride (0.472ml, 2.2mmol) in (the fluoro-phenyl of the bromo-3-of 4-)-methyl alcohol (410mg, 2.0mmol) and the solution of imidazoles (163mg, 2.4mmol) in DMF (10ml).Reaction mixture, stirring at room 18 hours, is then distributed between ethyl acetate and water.Separate organic layer, use the salt water washing, dry (Na
2sO
4), filter and and vacuum concentration.Through flash chromatography (Si-SPE, pentane), the resistates formed is carried out to purifying, obtain title compound, it is colorless oil (643mg, 89%).
1H?NMR(CDCl
3，400MHz)7.48(dd，J＝8.1，7.0Hz，1H)，7.16(d，J＝9.7Hz，1H)，6.99(d，J＝8.7Hz，1H)，4.78(s，2H)，1.04-1.24(m，21H)。
step 2:3-(the fluoro-4-triisopropyl of 2-silyl oxygen ylmethyl-phenyl amino)-furo [3,2-c]
the pyridine-2-carboxylic acids ethyl ester
By degassed 3-amino-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (206g, 1.0mmol), (the fluoro-benzyl oxygen of the bromo-3-of 4-base)-triisopropyl-silicomethane (433mg, 1.2mmol), Pd
2dba
3(36mg, 0.039mmol), Xantphos (46mg, 0.08mmol) and K
3pO
4(297mg, 1.4mmol) solution in toluene (1ml) is heated to 110 ℃, then stirs 4 hours.Reaction mixture is cooled to envrionment temperature, then uses EtOAc (ethyl acetate) dilution, filter through Celite pad.The filtrate vacuum concentration is obtained to the dark oil thing.Through flash chromatography (gradient is 0: 100 to 5: 95 for Si-SPE, MeOH: DCM), described oily matter is carried out to purifying, obtain title compound, it is yellow oil (166mg, 34%).LCMS (method B): R
t=5.39 minutes, M+H
+=487.
3-(the fluoro-4-methoxyl group-phenyl amino of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
the fluoro-4-methoxyl group-benzene of the bromo-2-of step 1:1-
Add sodium hydride (60% dispersion liquid in mineral oil, 115mg, 2.88mmol) by part in solution to the 4-fluoro-phenol of bromo-3-(500mg, 2.62mmol) in anhydrous THF (10ml).Reaction mixture is stirred 20 minutes, then add methyl iodide (0.500ml, 8.0mmol).The mixture that forms, stirring at room 16 hours, is then distributed between EtOAc and water.Separate organic layer, successively use saturated sodium bicarbonate solution and salt water washing, dry (Na
2sO
4), filter and concentrate, obtain title compound, it is light yellow oil (518mg, 96%).
1H?NMR(CDCl
3，400MHz)7.41(dd，J＝8.8，8.0Hz，1H)，6.69(dd，J＝10.3，2.8Hz，1H)，6.61(ddd，J＝8.8，2.8，1.0Hz，1H)，3.79(s，3H)。
step 2:3-(the fluoro-4-methoxyl group-phenyl amino of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By degassed 3-amino-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (206g, 1.0mmol), the 1-fluoro-4-methoxyl group-benzene of bromo-2-(246mg, 1.2mmol), Pd
2dba
3(46mg, 0.050mmol), Xantphos (58mg, 0.10mmol) and K
3pO
4(254mg, 1.2mmol) solution in toluene (5ml) is heated to 110 ℃, then stirs 18 hours.Reaction mixture is cooled to envrionment temperature, then, with the EtOAc dilution, filters through Celite pad.The filtrate vacuum concentration is obtained to the dark oil thing.Through flash chromatography (gradient is 0: 100 to 10: 90 for Si-SPE, MeOH: DCM), this oily matter is carried out to purifying, obtain title compound, it is yellow oil (130mg, 39%).LCMS (method B): R
t=2.93 minutes, M+H
+=331.
3-(4-bromo-2,5-difluorophenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Degassed 3-(trifyl oxygen base) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (678mg, 2.00mmol), 4-is bromo-2,5-difluoroaniline (670mg, 3.22mmol), Pd
2dba
3the K of (147mg, 0.160mmol), Xantphos (97.0mg, 0.168mmol) and fine pulverizing
3pO
4(793mg, 3.74mmol) solution in toluene (7.5ml) in sealed tube 105 ℃ of heated overnight.Reaction mixture is cooled to envrionment temperature, then uses ethyl acetate (15ml) dilution, filter through silica filler (15ml is filled in ether).By filter cake, with after more polyacetic acid ethyl ester (20ml) washs, filtrate is through dried over mgso, and then vacuum concentration obtains brown oil.Through flash chromatography (silica gel is used 5: 3: 2 hexane-methylene dichloride-ether), resistates is carried out to purifying, obtain title compound, it is brown solid (329mg, 41%).
3-(the iodo-phenoxy group of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-(the fluoro-4-nitro-phenoxy group of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
In room temperature by 3-hydroxyl-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (2.70g, 13.0mmol), 3,4-difluoro nitrobenzene (2.89ml, 26.1mmol) and hexaoxacyclooctadecane-6-6 (3.45g, 13.0mmol) successively be added in the suspension of potassium hydride KH (1.10g, 27.4mmol) in DMF (30ml).Reaction mixture is heated to 100 ℃ and keep 2h, then is cooled to room temperature, pour in water/saline mixture.EtOAc extraction 3 times for water layer, right salt water washing 1 time for latter incorporated organic liquor, through Na
2sO
4dry and concentrated.Through silica gel chromatography (30-80%EtOAc: Hex (hexane)), resistates is carried out to purifying, obtain title compound (442mg, 10% yield), it is yellow soup compound.LCMS (method C): R
t=2.07 minutes, M+H
+=347.
1H?NMR(CDCl
3，400MHz)8.83(d，J＝1.2Hz，1H)，8.72(d，J＝6.0Hz，1H)，8.17(dd，J＝10.0，2.4Hz，1H)，8.03(ddd，J＝9.2，2.8，1.6Hz，1H)，7.59(dd，J＝5.6，0.8Hz，1H)，7.08(dd，J＝9.2，8.0Hz，1H)，4.36(q，J＝7.2Hz，2H)，1.28(t，J＝7.2Hz，3H)。
step 2:3-(the fluoro-phenoxy group of 4-amino-2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
Iron powder (299mg, 5.36mmol) is added in 3-(the fluoro-4-nitro-phenoxy group of the 2-)-solution of furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (460mg, 1.3mmol) in ethanol (8ml) and the 2N HCl aqueous solution (8ml).Reaction mixture is heated to 50 ℃, then is cooled to room temperature.Remove unreacted iron with magnet, then by the reaction mixture vacuum concentration.The water and the ethanol that add each 10ml, then add solid sodium bicarbonate (1.5g).Add 3.2g silica gel, then vacuum is removed volatile matter.Through silica gel chromatography, (40-80%EtOAc: Hex) resistates is carried out to purifying, obtain title compound (130mg, 31% yield), it is the canescence foam.LCMS (method C): R
t=1.35 minutes, M+H
+=317.
1HNMR(CDCl
3，400MHz)8.54(d，J＝3.6Hz，1H)，8.16(d，J＝0.8Hz，1H)，7.45(dd，J＝5.6，0.8Hz，1H)，7.09(t，J＝8.8Hz，1H)，6.53(dd，J＝12.4，2.8Hz，1H)，6.44(ddd，J＝8.8，2.8，1.6Hz，1H)，4.47(q，J＝7.2Hz，2H)，3.81(br，2H)，1.42(t，J＝7.2Hz，3H)。
step 3:3-(the iodo-phenoxy group of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃, Sodium Nitrite (aqueous solution of 1.18ml 0.382M) is added drop-wise to 3-(the fluoro-phenoxy group of 4-amino-2-)-furo [3,2-c] in the suspension of pyridine-2-carboxylic acids ethyl ester (130mg, 0.41mmol) in the 2M HCl aqueous solution (3.5ml).Reaction mixture is stirred 45 minutes at 0 ℃, then add sodium iodide (aqueous solution of 1.18ml 1.39M, 1.64mmol).By reaction mixture at 0 ℃ to stirred overnight at room temperature.Add sodium hydroxide (aqueous solution of 7ml 1N) and Na
2s
2o
3(5ml saturated aqueous solution), water layer CH
2cl
2extract 3 times.The organic liquor merged is through Na
2sO
4drying, filter and concentrate.Through silica gel chromatography, (30-70%EtOAc: Hex) resistates is carried out to purifying, obtain title compound (60mg, 30% yield), it is white solid.LCMS (method C): R
t=2.29 minutes, M+H
+=428.
1H?NMR(CDCl
3，400MHz)8.63(d，J＝6.4Hz，1H)，8.53(d，J＝1.2Hz，1H)，7.58(dd，J＝9.6，2.0Hz，1H)，7.52(dd，J＝6.0，1.2Hz，1H)，7.37(dt，J＝8.8，1.6Hz，1H)，6.86(t，J＝8.4Hz，1H)，4.41(q，J＝7.2Hz，2H)，1.34(t，J＝7.2Hz，3H)。
3-(the fluoro-4-iodophenyl of 2-amino)-7-benzofurane is [3,2-c] pyridine-2-carboxylic acids ethyl ester also
step 1:4,5-dibromo pyridine-3-carboxylic acid
Under nitrogen, to 5-bromopyridine-3-carboxylic acid (25.25g, 125mmol), the solution in anhydrous tetrahydro furan (500ml) is stirred and is cooled to-70 ℃.The mixture formed lasts 1 hour dropwise to be processed with lithium diisopropylamine (1.8M, 144ml, 260mmol).After adding end, solution is stirred 2.5 hours at-55 ℃, then be cooled to-70 ℃, then last 30 minutes and dropwise process with 1,2-dibromo tetrachloroethane (50g, 154.5mmol).Stir after 30 minutes, last 2 hours and make mixture be warmed to-20 ℃, then carefully add water (150ml).Then vacuum is removed organic solvent, resistates water (500ml) dilution, and then, with the ethyl acetate washing, with concentrated hydrochloric acid, water layer being acidified to pH afterwards is 3.00.The product of collecting precipitation, then obtain title compound (14.2g) 60 ℃ of vacuum-dryings after filtration.Filtrate is extracted with ethyl acetate, and extraction liquid washes with water, dry (MgSO
4), filter and vacuum concentration the title compound of getting back (18.6g, ultimate production 32.8g, 93%).
1H?NMR(DMSO-d
6，400MHz)8.92(s，1H)，8.73(s，1H)。
step 2:4,5-dibromo pyridine-3-carboxylic acid, ethyl ester
Suspension by 4,5-dibromo pyridine-3-carboxylic acid (32.8g, 116.7mmol) in acetonitrile (550ml), in stirring at room, then lasts 10 minutes with 1, and 1 '-carbonyl dimidazoles (29.87g, 180mmol) is dropwise processed.By the mixture that forms stirring at room 3 hours.Now add ethanol (78ml), and then continue to stir 48 hours.Then solution is filtered, vacuum-evaporation filtrate obtains light brown oily thing.This oily matter is dissolved in ethyl acetate, and solution is water and salt water washing successively, then through dried over mgso, filters and vacuum-evaporation, obtains brown oil.Through flash chromatography (SiO
2, methylene dichloride is eluent) and this oily matter is carried out to purifying, obtain title compound (20.6g, 57%).
1H?NMR(CDCl
3，400MHz)8.80(s，1H)，8.75(s，1H)，4.45(q，2H?J＝7.0Hz)，1.39(t，3H?J＝7.0Hz)。
the bromo-3-hydroxyl of step 3:7-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By hydroxyethanoic acid ethyl ester (6.30ml, 66.5mmol) solution in dry DMF (50ml) is added drop-wise to the sodium hydride (8.00g of stirring, 60% dispersion liquid, 200mmol) in the suspension in dry DMF (80ml), cooling holding temperature is below 10 ℃ simultaneously.After adding, mixture is stirred 30 minutes, then drips the solution of 4,5-dibromo pyridine-3-carboxylic acid, ethyl ester (20.60g, 66.5mmol) in dry DMF (50ml), simultaneously again holding temperature below 10 ℃.Last and within 1.5 hours, make the garnet/brown solution formed slowly be warmed to room temperature, then cancellation, and with 1M HCl acidified aqueous solution to pH be 3.00.Collect after filtration the solid sediment formed, resistates is water and cold washing with acetone successively, then 45 ℃ of vacuum-dryings, obtains title compound (11.98g, 63%).
1H?NMR(DMSO-d
6，400MHz)9.13(s，1H)，8.76(s，1H)，4.35(q，2H?J＝7.3Hz)，1.33(t，3H?J＝7.3Hz)。LCMS (method B): R
t=2.82 minutes, M+H
+=286,288.
the bromo-3-trifyl of step 4:7-oxygen base furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 5-10 ℃ by trifluoromethanesulfanhydride anhydride (8.32ml, 49.66mmol) solution in anhydrous DCM (70ml) is added drop-wise to the bromo-3-hydroxyl of the 7-furo [3 of stirring, 2-c] pyridine-2-carboxylic acids ethyl ester (12.80g, 44.7mmol) and the solution of pyridine (10.88ml, 128mmol) in anhydrous DCM (400ml) in.The mixture formed is stirred 1.5 hours at 5-10 ℃, then last 3 hours and make it slowly be warmed to room temperature, make afterwards its standing 16 hours.Mixture is diluted with DCM, with the 1M HCl aqueous solution, water, saturated NaHCO
3the aqueous solution and salt water washing, then through dried over mgso, filter also vacuum concentration and obtain light brown oily thing.Through flash chromatography (SiO
2, methylene dichloride) and this oily matter is carried out to purifying, obtain title compound, it is yellow solid (11.84g, 63%).
1H?NMR(CDCl
3，400MHz)8.96(s，1H)，8.83(s，1H)，4.55(q，2H?J＝7.2Hz)，1.47(t，3H?J＝7.2Hz)。
the bromo-3-of step 5:7-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino) furo [3,2-c] pyridine-2-
carboxylic acid, ethyl ester
By 7-bromo-3-trifyl oxygen base furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (11.84g, 28.3mmol) in dry toluene (160ml) with Pd
2(dba)
3(1.0g, 1.20mmol), Xantphos (0.572g, 1.0mmol) and Tripotassium phosphate (11.25g, 53.75mmol) stir together.Mixture is carried out degassed, then add the solution of 2-fluoro-4-(trimethyl silyl) phenyl amine (5.38g, 29.54mmol) in dry toluene (10ml).Again mixture is carried out degassed, then 115 ℃ the heating 4 hours.Reaction mixture is distributed between ethyl acetate and water, then filter, separate each layer.Organic layer is water and salt water washing successively, through dried over mgso, filters also vacuum-evaporation and obtains brown solid.Through flash chromatography (SiO
2, 30% hexanaphthene/DCM) and this solid is carried out to purifying, obtain title compound, it is light yellow solid (7.1g, 55%).
1H?NMR(CDCl
3，400MHz)8.66(s，1H)，8.50(s，1H)，7.73(s，1H)，7.27(m，3H)，4.50(q，2H?J＝7.0Hz)，1.47(t，3H?J＝7.0Hz)，0.29(s，9H)。LCMS (method B): R
t=4.81 minutes, M+H
+=451,453.
step 6:3-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino)-7-benzofurane is [3,2-c] pyridine also
-2-carboxylic acid, ethyl ester
Room temperature under argon gas by the bromo-3-of 7-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (100mg, 0.22mmol) suspension and phenyl-boron dihydroxide (30mg, 0.242mmol) in ethanol (2ml) stir together.Stir after 20 minutes, add Pd (OAc)
2(2mg, 0.66 μ mol), triphenylphosphine (0.5mg, 0.002mmol) and 2M Na
2cO
3the aqueous solution (130 μ l, 0.264mmol), reaction mixture is carried out degassed, reflux 3 hours under argon gas then.Reaction mixture is cooled to room temperature, and dilute with water, then be extracted with ethyl acetate.Organic layer is water and salt water washing successively, then through dried over mgso, filters and vacuum-evaporation, obtains yellow solid.Through flash chromatography (SiO
2, 30% hexanaphthene/DCM) and this solid is carried out to purifying, obtain title compound, it is light yellow solid (31mg, 31%).
1H?NMR(CDCl
3，400MHz)8.73(s，1H)，8.61(s，1H)，7.87(d，2H?J＝7.80Hz)，7.72(s，1H)，7.59-7.44(m，3H)，7.35-7.25(m，3H)，4.33(q，2H?J＝7.0Hz)，1.43(t，3H?J＝7.0Hz)，0.30(s，9H)。LCMS (method B): R
t=4.91 minutes, M+H
+=449.
step 7:3-(the fluoro-4-iodophenyl of 2-amino)-7-benzofurane is [3,2-c] pyridine-2-carboxylic acids ethyl ester also
At 0-5 ℃ to 3-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino)-7-benzofurane also [3,2-c] pyridine-2-carboxylic acids ethyl ester (30mg, 0.067mmol) solution in DCM (2ml) stirred and use the solution (130 μ l, 0.13mmol) of 1MICl in DCM dropwise to process.The mixture formed is stirred 2 hours at 0-5 ℃, then add 1M Na
2s
2o
3the aqueous solution (1ml).Separate each layer, organic layer is water and salt water washing successively, through dried over mgso, filters and vacuum-evaporation, obtains title compound (quantitatively).
1H?NMR(CDCl
3，400MHz)8.75(s，lH)，8.58(s，1H)，7.87(d，2H?J＝7.80Hz)，7.67(s，1H)，7.59-7.44(m，5H)，7.05(t，1H?J＝8.50Hz)，4.47(q，2H?J＝7.10Hz)，1.43(t，3H?J＝7.10Hz)。LCMS (method B): R
t=4.40 minutes, M+H
+=503.
3-(the fluoro-4-iodophenyl of 2-amino)-7-methyl furan is [3,2-c] pyridine-2-carboxylic acids ethyl ester also
step 1:3-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino)-7-methyl furan is [3,2-c] pyridine also
-2-carboxylic acid, ethyl ester
By the bromo-3-of 7-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (1.0g, 2.2mmol) and salt of wormwood (456.5mg, 3.3mmol), tetrakis triphenylphosphine palladium (0) (255mg, 0.22mmol) and trimethylboroxin (trimethylboroxine) (305 μ l, 2.2mmol) in anhydrous Isosorbide-5-Nitrae-dioxane (5ml), stir together.Reaction mixture is carried out degassed, then stir under argon gas 6 hours at 110 ℃, then be cooled to room temperature, standing 16 hours.Methylene dichloride and water dilution for reaction mixture.Separate organic layer, successively water and salt water washing, through dried over mgso, then filter and vacuum-evaporation, obtains resistates.Through flash chromatography (SiO
2, 30% hexanaphthene/DCM is 1% methyl alcohol/DCM then) and thick resistates is carried out to purifying, obtain title compound, it is light yellow solid (710mg, 83%).
1H?NMR(CDCl
3，400MHz)8.50(s，1H)，8.38(s，1H)，7.70(s，1H)，7.32-7.22(m，3H)，4.48(q，2H?J＝7.0Hz)，2.54(s，3H)，1.46(t，3H?J＝7.0Hz)，0.29(s9H)。LCMS (method B): R
t=4.12 minutes, M+H
+=387.
step 2:3-(the fluoro-4-iodophenyl of 2-amino)-7-methyl furan is [3,2-c] pyridine-2-carboxylic acids ethyl ester also
At 0-5 ℃ to 3-(the fluoro-4-of 2-(trimethyl silyl) phenyl amino)-7-methyl furan also [3,2-c] pyridine-2-carboxylic acids ethyl ester (710mg, 1.84mmol) solution in DCM (25ml) stirred and use the solution (3.5ml, 3.5mmol) of 1M ICl in DCM dropwise to process.The mixture formed is stirred 2 hours at 0-5 ℃, then add 1M Na
2s
2o
3the aqueous solution (12ml).Separate each layer, organic layer water, salt water washing, then through dried over mgso, filter also vacuum-evaporation and obtain resistates.Through flash chromatography (SiO
2, gradient is 0-1%MeOH/DCM) and thick resistates is carried out to purifying, obtain title compound, it is light yellow solid (448mg, 55%).
1H?NMR(CDCl
3，400MHz)8.47(s，1H)，8.39(s，1H)，7.65(s，1H)，7.52(dd，1H?J＝9.8，1.9Hz)，7.44(dt，1H?J＝8.4，1.3Hz)，7.00(t，1H?J＝8.5Hz)，4.48(q，2H?J＝7.0Hz)，2.53(s，3H)，1.46(t，3H?J＝7.0Hz)。LCMS (method B): R
t=3.39 minutes, M+H
+=441.
2-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group carbamyl)-3-(fluoro-4-of 2-
iodo-phenyl amino)-furo [3,2-c] pyridine-7-carboxylic acid ethyl ester
step 1:3-hydroxyl-furo [3,2-c] pyridine-2,7-dicarboxylic acid 2-benzyl ester 7-ethyl ester
At 0 ℃ to 4-chloro-pyridine-3, add sodium hydride (97mg in 5-diethyl dicarboxylate (250mg, 0.971mmol) and hydroxyethanoic acid benzyl ester (145 μ l, the 1.019mmol) solution in DMF (5ml), 2.43mmol, 60% dispersion liquid in mineral oil).Make mixture be warmed to room temperature, stir 3 hours, then by adding acetic acid (1ml) cancellation.Then by the mixture vacuum concentration, the resistates water of formation grinds and filters.The solid recrystallization from methanol/water formed, obtain title compound, and it is light yellow solid (120mg, 36%).LCMS (method B): R
t=3.29 minutes, M+H
+=342.
step 2:3-(trifyl oxygen base)-furo [3,2-c] pyridine-2,7-dicarboxylic acid 2-benzyl ester 7-
ethyl ester
At 0 ℃ to 3-hydroxyl-furo [3,2-c] pyridine-2,7-dicarboxylic acid 2-benzyl ester 7-ethyl ester (120mg, 0.352mmol) and pyridine (85 μ l, 1.056mmol) drip trifluoromethanesulfanhydride anhydride (63 μ l, 0.37mmol) in solution in methylene dichloride (1.5ml).Reaction mixture, stirring at room 90 minutes, is then distributed between methylene dichloride (30ml) and 0.1M HCl (10ml).Separate organic layer, successively use saturated sodium bicarbonate solution (10ml) and salt solution (10ml) washing.The organic layer separated is through dried over mgso, and then vacuum concentration obtains title compound, and it is colorless oil (88mg, 53%).
1H?NMR(CDCl
3，400MHz)9.27(1H，s)，9.17(1H，s)，7.48(2H，m)，7.38(3H，m)，5.48(2H，s)，4.52(2H，q，J＝7.2Hz)，1.43(3H，t，J＝7.2Hz)。
step 3:3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine-2,7-
dicarboxylic acid 2-benzyl ester 7-ethyl ester
To 3-(trifyl oxygen base)-furo [3; 2-c] pyridine-2; 7-dicarboxylic acid 2-benzyl ester 7-ethyl ester (88mg; 0.186mmol) and the solution of the fluoro-4-of 2-(trimethyl silyl)-phenyl amine (41mg 0.223mmol) in toluene (1.5ml) in add potassiumphosphate (55mg; 0.26mmol), then to mixture, carry out degassed.By Pd
2dba
3(8.5mg, 0.0093mmol) and Xantphos (11mg, 0.0186mmol) are added in this mixture, the container argon cleaning.Reaction mixture is heated to reflux and keeps 1.5 hours, cooling, then pass through diatomite (washing by ethyl acetate) and filter.Filtrate is with saturated sodium bicarbonate solution (10ml) washing, then through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: t-butyl methyl ether, gradient is 1: 0 to 3: 1), the resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (48mg, 51%).LCMS (method B): R
t=4.89 minutes, M+H
+=507.
step 4:3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine-2,7-
dicarboxylic acid 7-ethyl ester
Under nitrogen to 3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine-2,7-dicarboxylic acid 2-benzyl ester 7-ethyl ester (48mg, 0.0949mmol) add palladium/carbon (12mg, 10% palladium/gac) in solution in ethyl acetate (2ml).Suspension is stirred 2 hours under hydrogen atmosphere in room temperature.Reaction mixture, through diatomite filtration, with the ethyl acetate washing, obtains title product by the filtrate vacuum concentration, and it is colorless oil (34mg, 86%).LCMS (method B): R
t=4.31 minutes, M+H
+=417, [M-H]
-=415.
step 5:2-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group carboxamide
base)-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-7-carboxylic acid ethyl ester
At-5 ℃ to 2-(((R)-2; 2-dimethyl-[1; 3] dioxolane-4-yl) methoxyl group carbamyl)-3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3; 2-c] pyridine-7-carboxylic acid ethyl ester (37mg; 0.068mmol) add iodine monochloride (136 μ l in solution in methylene dichloride (2ml); 0.136mmol; the dichloromethane solution of 1M); then solution is stirred 1 hour in this temperature; add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate solution (15ml).Separate water layer, then use methylene dichloride (2 * 25ml) extraction, afterwards by the organic layer salt water washing merged, through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: ethyl acetate, gradient is 1: 0 to 0: 1 to be then 15% ethanol/methylene), the resistates formed is carried out to purifying, obtain title compound, it is yellow waxy solid (29mg, 71%).LCMS (method B): R
t=3.92 minutes, M+H
+=600.
2-(dimethylamino formyl radical)-3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo
[3,2-c] pyridine-7-carboxylic acid ethyl ester
step 1:2-(dimethylamino formyl radical)-3-hydroxyl-furo [3,2-c] pyridine-7-carboxylic acid ethyl ester
At 0 ℃ to 4-chloro-pyridine-3,5-diethyl dicarboxylate (430mg, 1.67mmol) and the 2-hydroxy-n, N-dimethyl-ethanamide (189mg, 1.84mmol) add sodium hydride (200mg in solution in DMF (7ml), 5.01mmol, 60% dispersion liquid in mineral oil).The mixture of formation is warmed to room temperature, then stirs 2.5 hours.Reaction is by adding acetic acid (1ml) cancellation.Then by the mixture vacuum concentration, the resistates of formation grinds and filters in water, obtains title compound, and it is light yellow solid (200mg, 43%).LCMS (method B): R
t=2.73 minutes, M+H
+=279.
step 2:2-(dimethylamino formyl radical)-3-(trifyl oxygen base)-furo [3,2-c] pyridine
-7-carboxylic acid, ethyl ester
At 0 ℃ to 2-(dimethylamino formyl radical)-3-hydroxyl-furo [3; 2-c] pyridine-7-carboxylic acid ethyl ester (440mg; 1.58mmol) and pyridine (0.38ml; 4.74mmol) drip trifluoromethanesulfanhydride anhydride (0.29ml, 1.74mmol) in solution in methylene dichloride (7ml).Reaction mixture, stirring at room 120 minutes, is then distributed between methylene dichloride (50ml) and 0.1M HCl (20ml).Organic layer is successively used saturated sodium bicarbonate solution (20ml) and salt solution (20ml) washing.The organic layer merged is through dried over mgso, and vacuum concentration obtains title compound afterwards, and it is colorless oil (144mg, 22%).LCMS (method B): R
t=3.39 minutes, M+H
+=411.
step 3:2-(dimethylamino formyl radical)-3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furan
also [3,2-c] pyridine-7-carboxylic acid ethyl ester of muttering
To 2-(dimethylamino formyl radical)-3-(trifyl oxygen base)-furo [3; 2-c] pyridine-7-carboxylic acid ethyl ester (144mg; 0.351mmol) and the fluoro-4-of 2-(trimethyl silyl)-phenyl amine (90mg; 0.492mmol) add potassiumphosphate (149mg in solution in toluene (3ml); 0.70mmol), then to mixture, carry out degassed.By Pd
2dba
3(16.1mg, 0.0176mmol) and Xantphos (20mg, 0.035mmol) are added in reaction mixture, the container argon cleaning.Then reaction mixture be heated to reflux and keep 3 hours, cooling, then through Hyflo, filter, by ethyl acetate, wash.Filtrate is washed with saturated sodium bicarbonate solution (30ml), and organic layer is through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: t-butyl methyl ether, gradient is 3: 1 to 1: 1), the resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (84mg, 54%).LCMS (method B): R
t=4.58 minutes, M+H
+=444.
the fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
the fluoro-pyridine-3-carboxylic acid ethyl ester of the chloro-5-of step 1:4-
Suspension by the 4-fluoro-pyridine-3-carboxylic acid of chloro-5-(0.36g, 2.06mmol) in thionyl chloride (3ml) was 80 ℃ of heating 2 hours, until most solid is dissolved.By the reaction mixture vacuum concentration, toluene for resistates (2 * 20ml) azeotropic.The resistates of formation is dissolved in ethanol (5ml) and diisopropylethylamine (1.76ml, 10.31mmol), then by reaction mixture stirring at room 18 hours.By the reaction mixture vacuum concentration, with the ethyl acetate dilution, successively use 0.1M HCl, saturated sodium bicarbonate solution and salt water washing.Organic layer, through dried over mgso, filters and vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: ethyl acetate, gradient is 1: 0 to 92: 8), the resistates formed is carried out to purifying, obtain title compound, it is colorless oil (415mg, 99%).
1H?NMR(CDCl
3，400MHz)1.43(3H，t，J＝7.1Hz)，4.46(2H，q，J＝7.1Hz)，8.60(1H，d，J＝0.8Hz)，8.86(1H，s)。
the fluoro-3-hydroxyl-furo of step 2:7-[3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to the fluoro-pyridine-3-carboxylic acid ethyl ester of the chloro-5-of 4-(400mg, 1.975mmol) and hydroxyethanoic acid ethyl ester (196 μ l, 2.074mmol) add sodium hydride (158mg in solution in DMF (10ml), 3.95mmol, 60% dispersion liquid in mineral oil), make mixture be warmed to room temperature, then stir 2 hours.Reaction is by adding acetic acid (1.5ml) cancellation.Then by the mixture vacuum concentration, the resistates of formation grinds in water, obtains title compound, and it is light yellow solid (460mg, quantitative).LCMS (method B): R
t=2.59 minutes, M+H
+=226.
the fluoro-3-of step 3:7-(trifyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to the fluoro-3-hydroxyl-furo [3 of 7-, 2-c] pyridine-2-carboxylic acids ethyl ester (460mg, 1.97mmol) and the solution of pyridine (0.48ml, 5.91mmol) in methylene dichloride (10ml) in drip trifluoromethanesulfanhydride anhydride (612mg, 2.17mmol).Reaction mixture, stirring at room 90 minutes, is then distributed between methylene dichloride (50ml) and 0.1M HCl (20ml).Separate organic layer, then successively with saturated sodium bicarbonate solution (20ml) and salt solution (20ml) washing.The organic layer merged is through dried over mgso, then vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride), the resistates formed is carried out to purifying, obtain title compound, it is colorless oil (470mg, 67%).LCMS (method B): R
t=3.76 minutes, M+H
+=358.
the fluoro-3-of step 4:7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine
-2-carboxylic acid, ethyl ester
To the fluoro-3-of 7-(trifyl oxygen base)-furo [3; 2-c] pyridine-2-carboxylic acids ethyl ester (470mg; 1.32mmol) and the fluoro-4-of 2-(trimethyl silyl)-phenyl amine (337mg; 1.84mmol) add potassiumphosphate (558mg in solution in toluene (15ml); 2.63mmol), then to mixture, carry out degassed.By Pd
2dba
3(60.5mg, 0.066mmol) and Xantphos (76.5mg, 0.132mmol) are added in reaction mixture, the container argon cleaning.Reaction mixture is heated to reflux and keeps 4 hours, cooling, then through Hyflo, filter, by ethyl acetate, wash.Filtrate is washed with saturated sodium bicarbonate solution, and organic layer is through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: ethyl acetate, gradient is 1: 0 to 9: 1), the resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (490mg, 95%).LCMS (method B): R
t=4.70 minutes, M+H
+=391.
the fluoro-3-of step 5:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At-10 ℃ to the fluoro-3-of 7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (490mg, 1.256mmol) add iodine monochloride (2.51ml in solution in methylene dichloride (8ml), 2.51mmol, the dichloromethane solution of 1M), then solution is stirred to 2h between-10 ℃ and 0 ℃.Add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate solution (15ml).Separate water layer, then use methylene dichloride (3 * 25ml) extraction, afterwards by the organic layer salt water washing merged, through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient be 1: 0 to 3: 1 then for methylene dichloride) resistates formed is carried out to purifying, obtain thick material.Thick material is ground in hexanaphthene, obtain title compound, it is yellow waxy solid (250mg, 45%).LCMS (method B): R
t=4.13 minutes, M+H
+=445.
the fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
the fluoro-pyridine of the chloro-5-of step 1:4--3-formoxime
Under nitrogen to the cooling chloro-pyridine (11.0g of (78 ℃) fluoro-4-of 3-, 84mmol) drip lithium diisopropylamine (1.8M solution in the solution in THF, 47ml, 84mmol), then the solution formed is stirred 18 hours at-70 to-80 ℃.Drip DMF (7.68g, 1.25 equivalents), then continue to stir 30 minutes at-78 ℃, reaction mixture is added in ice/2M HCl afterwards.By the solution extracted with diethyl ether, organic layer is stripped with 2M HCl, and two kinds of aqueous solution separately retain.Each personal hydroxylamine hydrochloride (8.76g, 126mmol) of water extract is processed, and then with salt of wormwood, being adjusted to pH is 5.Stir after 1 hour, mixture is extracted with ethyl acetate (* 2), the organic extract liquid be combined carries out drying (Na
2sO
4), filter and vacuum concentration, obtain title compound, it is brown solid (11.07g, 76%).LCMS (method B): R
t=2.49 minutes, M+H
+175.
the chloro-5-fluorine pyridine of step 2:4--3-formonitrile HCN
Add carbonyl dimidazoles (9.5g, 58.5mmol) in the fluoro-pyridine of the chloro-5-of the 4--suspension of 3-formoxime (6.8g, 39.0mmol) in methylene dichloride (150ml).Then by mixture reflux 30 minutes, then be cooled to room temperature, afterwards successively with saturated sodium bicarbonate aqueous solution and water washing.Organic layer, through dried over sodium sulfate vacuum concentration, then grinds the resistates of formation in ether/hexanaphthene, obtains title compound, and it is light yellow solid (4.05g, 79%).
1H?NMR(CDCl
3400MHz)8.71(1H，d，J＝0.4Hz)，8.70(1H，s)。
the fluoro-furo of step 3:3-amino-7-[3,2-c] pyridine-2-carboxylic acids ethyl ester
The chloro-5-fluorine pyridine of 4--3-formonitrile HCN (4.0g, 25.6mmol) is dissolved in DMF (50ml), successively uses salt of wormwood (17.8g, 128mmol) and hydroxyethanoic acid ethyl ester (3.64ml, 38.4mmol) to process.The reaction mixture formed is heated 50 minutes at 80 ℃, then be cooled to room temperature, dilute by ethyl acetate.Solution with water washing (* 2), dry (Na
2sO
4), filter and vacuum concentration.The solid of formation is ground in ether, obtain title compound, it is pale solid (3.58g, 63%).LCMS (method B): R
t=2.65 minutes, M+H
+225.
the fluoro-3-of step 4:7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine
-2-carboxylic acid, ethyl ester
By degassed 3-amino-7-fluoro-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (2.5g, 11.1mmol), the fluoro-4-of trifluoromethanesulfonic acid 2-(trimethyl silyl)-phenyl ester (4.2g, 13.3mmol), Pd
2dba
3(508mg, 0.56mmol), Xantphos (642mg, 1.12mmol) and Cs
2cO
3(7.2g, 22.2mmol) solution reflux in toluene (25ml) 1 hour.Reaction mixture is cooled to envrionment temperature, then filters through Celite pad, wash by ethyl acetate.By the filtrate vacuum concentration, the resistates formed is carried out to flash chromatography (Si-SPE, gradient is 0-30% ethyl acetate/hexanaphthene) and obtain the red/orange resistates.Resistates is ground in methyl alcohol, obtain title compound, it is yellow solid (2.5g, 58%).LCMS (method B): R
t=4.71 minutes, M+H
+391.
the fluoro-3-of step 5:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to the fluoro-3-of 7-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino) furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (2.5g, 6.4mmol) add iodine monochloride (2.08g in solution in methylene dichloride (60ml), 12.8mmol, dichloromethane solution), solution is stirred to and is made its warm 45 minutes.Leach the solid of precipitation, retain residues, wash filtrate by saturated aqueous sodium thiosulfate, dry (Na
2sO
4), filter and vacuum concentration, obtain resistates.By filtering and the concentrated resistates merging obtained, then in ether, grind, obtain filbert solid (2.58g, 91%).LCMS (method B): R
t=4.14 minutes, M+H
+=445.
the chloro-3-of 4-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:2, the chloro-pyridine-3-carboxylic acid ethyl ester of 4-bis-
Add n-Butyl Lithium (10.6ml, 16.9mmol, the hexane solution of 1.6M) at-78 ℃ to Diisopropylamine (2.4ml, 16.9mmol) in THF in solution in (40ml) under inert atmosphere, then solution is stirred 15 minutes at-78 ℃.Drip 2,4-dichloropyridine (1.8ml, 16.9mmol), then reaction mixture is stirred 2 hours at-78 ℃, then add ethyl cyanoformate (4.0ml, 40.4mmol).Then reaction mixture is stirred 1 hour at-78 ℃, then make it be warmed to room temperature.Then mixture is distributed and separates between water and ethyl acetate each layer.Organic layer is successively used saturated sodium bicarbonate solution and salt water washing, through dried over mgso, and vacuum concentration then.Through flash chromatography (Si-SPE, pentane: ether, gradient is 1: 0 to 4: 1), the resistates formed is carried out to purifying, obtain title compound, it is colorless oil (1.6g, 43%).
1H?NMR(CDCl
3，400MHz)8.34(1H，d，J＝5.4Hz)，7.33(1H，d，J＝5.4Hz)，4.49(2H，q，J＝7.1Hz)，1.43(3H，t，J＝7.1Hz)。
step 2:4-chloro-3-hydroxyl-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
0 ℃ under inert atmosphere to 2, add sodium hydride (60% dispersion liquid in mineral oil by part in the chloro-pyridine-3-carboxylic acid ethyl ester of 4-bis-(1.6g, 7.3mmol) and the solution of hydroxyethanoic acid ethyl ester (0.72ml, 7.6mmol) in DMF, 584mg, 14.6mmol).Then reaction mixture is stirred 3 hours at 0 ℃, by carefully adding acetic acid (about 5ml) cancellation, dilute with water, then be extracted with ethyl acetate.Separate organic layer, successively water and salt water washing, through dried over sodium sulfate concentrated, obtain title compound, and it is yellow solid (1.75g, 100%).LCMS (method B): R
t=2.99 minutes, M+H
+=242.
the chloro-3-of step 3:4-(trifyl oxygen base)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By 4-chloro-3-hydroxyl-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (1.8g, 7.5mmol), N-phenyl-fluoroform sulfimide (5.0g, 14.0mmol) and diisopropylethylamine (5.5ml, 32.3mmol) mixture in glycol dimethyl ether (30ml) stirs 48 hours at 90 ℃, be cooled to room temperature, then concentrating under reduced pressure.Through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 1: 0 to 1: 1), the resistates formed is carried out to purifying, obtain title compound, it is light yellow solid (1.06g, 38%).LCMS (method B): R
t=3.94 minutes, M+H
+=374.
the chloro-3-of step 4:4-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine
-2-carboxylic acid, ethyl ester
Under argon gas atmosphere by the chloro-3-of degassed 4-(trifyl oxygen base)-furo [3; 2-c] pyridine-2-carboxylic acids ethyl ester (810mg; 2.17mmol), the fluoro-4-of 2-(trimethyl silyl)-phenyl amine (306mg, 1.67mmol), Pd
2dba
3(31mg, 0.03mmol), Xantphos (58mg, 0.10mmol) and cesium carbonate (817mg, 2.50mmol) the solution reflux in toluene (17ml) 16 hours.Reaction mixture is through diatomite filtration vacuum concentration.Through flash chromatography (Si-SPE, pentane: ether, gradient is 1: 0 to 0: 1), the resistates formed is carried out to purifying, obtain title compound, it is white solid (558mg, 82%).LCMS (method B): R
t=4.64 minutes, M+H
+=407.
the chloro-3-of step 5:4-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to the chloro-3-of 4-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (265mg, 0.65mmol) add iodine monochloride (1.3ml in solution in methylene dichloride (6.5ml), 1.3mmol, the dichloromethane solution of 1M), then solution is stirred 1 hour in this temperature.Add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate solution (25ml).Methylene dichloride for water layer (2 * 25ml) extraction, the salt water washing of the organic layer of merging, through dried over mgso vacuum concentration, obtain title compound, and it is yellow solid (239mg, 80%).
LCMS (method B): R
t=4.22 minutes, M+H
+=461.
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-4-methyl-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
step 1:3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-4-methyl-furo [3,2-c] pyrrole
pyridine-2-carboxylic acid, ethyl ester
To the chloro-3-of 4-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (406mg, 1.0mmol) add trimethylboroxin (0.14ml in solution in dioxane (5ml), 1.0mmol), tetrakis triphenylphosphine palladium (115mg, 0.1mmol) and salt of wormwood (207mg, 1.5mmol), then mixture is carried out degassedly, then reflux is 6 hours.Reaction mixture is cooled to room temperature, then filters through Celite pad, it is washed by ethyl acetate.Merging filtrate vacuum concentration obtain resistates, by it through flash chromatography (Si-SPE, pentane: ether, gradient is 1: 0 to 0: 1) purifying.Obtain title compound, it is light yellow oil (221mg, 57%).LCMS (method B): R
t=3.53 minutes, M+H
+=387.
step 2:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-4-methyl-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
At 0 ℃ to 3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino)-4-methyl-furo [3,2] pyridine-2-carboxylic acids ethyl ester (215mg, 0.56mmol) add iodine monochloride (1.1ml in solution in methylene dichloride (5ml), 1.1mmol, the dichloromethane solution of 1M), then solution is stirred 1 hour in this temperature.Add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate solution (25ml).Methylene dichloride for water layer (2 * 25ml) extraction, the salt water washing of the organic layer of merging, through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, hexanaphthene: methylene dichloride, gradient is 1: 0 to 0: 1), the resistates formed is carried out to purifying, obtain title compound, it is yellow solid (241mg, 98%).LCMS (method B): R
t=2.99 minutes, M+H
+=441.
3-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By 3-(trifyl oxygen base)-furo [3; 2-c] pyridine-2-carboxylic acids ethyl ester (1.26g; 3.71mmol) and the fluoro-4-of 2-(methyl sulfenyl)-phenyl amine (816mg, 5.20mmol) be dissolved in toluene (25ml), successively add Pd
2(dba)
3(170mg, 0.19mmol), Xantphos (214mg, 0.37mmol) and Tripotassium phosphate (1.57g, 7.42mmol).Mixture is carried out fully degassed, then clean with argon gas, then stir 16 hours at 120 ℃ under argon gas.After cooling, mixture is through diatomite filtration, then concentrated.Through flash chromatography (Si-SPE, ether: pentane, gradient is 1: 4 to 1: 0), the resistates formed is carried out to purifying, obtain title compound, it is brown solid (770mg, 60%).LCMS (method B): R
t=3.29, M+H
+347.
the fluoro-3-of 7-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By the degassed fluoro-4-of the bromo-2-of 3-amino-7-fluoro-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (0.2g, 0.89mmol), 1-(methyl sulfenyl)-benzene (0.34g, 1.5mmol), Pd
2dba
3(0.041g, 0.045mmol), Xantphos (0.052g, 0.089mmol) and K
3pO
4(0.38g, 1.8mmol) solution reflux in toluene (5ml) 18 hours.Reaction mixture is cooled to envrionment temperature, then filters through Hyflo pad (washing by ethyl acetate).By the filtrate vacuum concentration, the resistates formed is carried out to flash chromatography (Si-SPE, gradient is the 0-10% ethyl acetate/dichloromethane), obtain title compound, it is yellow solid (0.18g, 55%).LCMS (method B): R
t=3.95 minutes, M+H
+365.
the chloro-3-of 7-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester
By the degassed fluoro-4-of the bromo-2-of 3-amino-7-chloro-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (0.1g, 0.42mmol), 1-(methyl sulfenyl)-benzene (0.16g, 0.71mmol), Pd
2dba
3(0.019g, 0.021mmol), Xantphos (0.024g, 0.042mmol) and K
3pO
4(0.18g, 0.83mmol) solution reflux in toluene (2.5ml) 18 hours.Reaction mixture is cooled to envrionment temperature, then filters through Hyflo pad (washing by ethyl acetate).By the filtrate vacuum concentration, then the resistates formed is carried out to flash chromatography (Si-SPE, gradient is the 0-10% ethyl acetate/dichloromethane), obtain title compound, it is light yellow solid (0.087g, 54%).LCMS (method B): R
t=4.14 minutes, M+H
+379.
Synthesizing of representational amine and azanol
o-cyclopropyl methyl hydroxylamine hydrochloride
According to the people such as Marquez (2005) Synth.Comm.35 (17): 2265-2269, prepare.
o-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol
According to the people such as Bailey (1991) J.Med.Chem.34 (1): 57-65, prepare.
o-(2-(vinyl oxygen base)-ethyl)-azanol
According to WO 0206213 preparation.
n-methyl-O-(2-(vinyl oxygen base)-ethyl)-azanol
Formaldehyde (aqueous solution of 37%w/w, 80 μ l, 1.0mmol) is added in cooling (0 ℃) O-(2-(vinyl oxygen base)-ethyl)-solution of azanol (105mg, 1.0mmol) in ethanol (1ml).Mixture is stirred 30 minutes, then add tosic acid pyridine (pyridinium para-toluenesulfonate) (250mg, 1.0mmol) and sodium cyanoborohydride (70mg, 1.1mmol).Make the suspension formed be warmed to envrionment temperature, then stir 20 hours.Evaporating solvent, by ethyl acetate for resistates (25ml) dilution, with salt solution (20ml) washing, dry (MgSO
4), to filter, then evaporation, obtain the product of expecting, and it is oily matter (84mg, 71%).
1H?NMR(CDCl
3，400MHz)6.44-6.55(m，1H)，4.98(s，1H)，4.16-4.24(m，1H)，3.98-4.06(m，1H)，3.82-3.96(m，4H)，2.59(s，3H)。
4-(tertiary butyl-dimethyl-silyl oxygen base)-isoxazole alkyls
The tertiary butyl-dimethyl-chloromethane silane (0.5g, 3.21mmol) is added to and stirs in the isoxazole alkyl-solution of 4-alcohol hydrochloride (0.40g, 3.18mmol) in DMF (3ml), then mixture is stirred 2.5 hours in envrionment temperature.Evaporating solvent then distributes resistates between ethyl acetate (50ml) and water (20ml).Separate organic phase, successively water (3 * 20ml) and salt solution (20ml) washing, dry (MgSO
4), filter and evaporate the product that obtains expectation, it is colorless oil (0.62g, 96%).
1H?NMR(CDCl
3，400MHz)5.52(s，1H)，4.60-4.65(m，1H)，3.45-3.62(m，1H)，3.80-4.05(m，1H)，2.80-3.05(m，2H)，0.80(s，9H)，0.08(s，6H)。
(S)-3-(amino oxygen base)-tetramethyleneimine-1-carboxylic acid tert-butyl ester
step 1:(S)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-base oxygen base)-tetramethyleneimine-1-carboxylic acid uncle
butyl ester
By (R)-3-hydroxyl-tetramethyleneimine-1-carboxylic acid tert-butyl ester (1.37g, 7.31mmol) be dissolved in THF (20ml), then add 2-hydroxyl-isoindole-1,3-diketone (1.19g, 7.31mmol) and triphenylphosphine (1.92g, 7.31mmol), then last 10 minutes and drip diisopropyl azo-2-carboxylic acid (1.33ml, 8.04mmol).Reaction mixture is stirred 18 hours in envrionment temperature, then evaporating solvent.Through flash column chromatography (gradient is 100: 0 to 80: 20 for Si-SPE, DCM: EtOAc), resistates is carried out to purifying, obtain title compound, it is colorless oil (1.43g, 59%).
1H?NMR(CDCl
3，400MHz)7.86(m，2H)，7.77(m，2H)，4.94-5.02(m，1H)，3.66-3.84(m，2H)，3.50-3.65(m，2H)，2.24-2.32(m，1H)，1.93-2.05(m，1H)，1.49(s，9H)。
step 2:(S)-3-(amino oxygen base)-tetramethyleneimine-1-carboxylic acid tert-butyl ester
Last 5 minutes by methyl hydrazine (0.23ml, 4.40mmol) be added drop-wise to (S)-3-(1,3-dioxo-1,3-dihydro-isoindole-2-base oxygen base) in-solution of tetramethyleneimine-1-carboxylic acid tert-butyl ester (1.43g, 4.3mmol) in DCM (12ml).Mixture is stirred 1 hour in envrionment temperature, then evaporation.Resistates is suspended in ether (10ml), then by solid filtering.Filtrate is concentrated, obtain title compound, it is colorless oil (0.86g, 99%).
1H?NMR(CDCl
3，400MHz)4.24-4.26(m，1H)，3.60-3.66(m，1H)，3.44-3.54(m，1H)，3.30-3.42(m，2H)，2.03-2.12(m，1H)，1.84-1.96(m，1H)，1.46(s，9H)。
2-(amino oxygen base)-2-methyl-propyl-1-alcohol hydrochloride
step 1:2-(N-tertbutyloxycarbonyl-amino oxygen base) ethyl isobutyrate
Add potassium hydroxide (2.6294g, 46.86mmol) in solution to N-tertbutyloxycarbonyl-azanol (5.2g, 39.05mmol) in ethanol in (100ml), then in stirring at room until during potassium hydroxide is dissolved in solution.Add wherein 2-isobutyl ethyl bromide (6.87ml, 46.86mmol), then reflux and spend the night.Observe white depositions after 1 hour.Reaction mixture is cooled to room temperature, then filters.White solid is discarded, then concentrated filtrate.The oily resistates is distributed between water (75ml) and ether (3 * 100ml).The ether layer merged, through dried over sodium sulfate, filters and concentrated filtrate, obtains title compound, and it is clarification oily matter (9.543g, 99%).LCMS (method C): R
t=2.55 minutes, M+H
+=247.9.
1HNMR(CDCl
3，400MHz)4.20(q，2H)，1.50(s，6H)，1.498(s，9H)，1.30(t，3H)。
step 2:2-(N-tertbutyloxycarbonyl-amino oxygen base)-2-methyl-prop-1-alcohol
0 ℃ under nitrogen to 2-(N-tertbutyloxycarbonyl-amino oxygen base) ethyl isobutyrate (2.35g, 9.5mmol) add 1.0M tetra lithium aluminium hydride (Lithiumtetrahydroaluminate) in tetrahydrofuran (THF) (17.106ml in solution in anhydrous diethyl ether (100ml), solution 17mmol), then stir 5 hours under nitrogen at 0 ℃.Successively add wherein some CO at 0 ℃
2bead (dry ice) and water (25ml).Then its stirring is spent the night, and be warmed to room temperature in this process.Decant goes out ether layer and puts aside.White solid is ground with ether, then this ether and the previous ether layer obtained are merged.Then discard white solid.The ether layer merged, through dried over sodium sulfate, filters and concentrates, and obtains title compound, and it is white solid (1.94g, 99.5%).
1H?NMR(CDCl
3，400MHz)3.40(s，2H)，1.50(s，9H)，1.20(s，6H)。
step 3:2-(amino oxygen base)-2-methyl-propyl-1-alcohol hydrochloride
In room temperature to 2-(N-tertbutyloxycarbonyl-amino oxygen base)-2-methyl-prop-1-alcohol (1.94g, 9.45mmol) add 4M HCl in dioxane (47.26ml in solution in anhydrous methylene chloride (10ml), solution 200mmol), then stir 1 hour.By the reaction mixture concentrating under reduced pressure, ether for resistates (3 * 30ml) grinds, and obtains title compound, and it is oily matter/white solid (HCl salt).By oily matter/white solid vacuum-drying, be directly used in coupling step (1.10g, 82.2%).
1HNMR(DMSO-d
6，400MHz)3.58(s，2H)，3.48(s，2H)，1.34(s，6H)。
1-(amino oxygen base)-2-methyl propan-2-ol
step 1:2-(2-hydroxy-2-methyl-propoxy-)-isoindole-1, the 3-diketone
Add triethylamine (16.1ml, 115mmol) in room temperature in HP (18.3g, 112mmol) and 1, the 2-epoxy group(ing)-solution of 3-methylpropane (9.50ml, 107mmol) in dry DMF under nitrogen.Reaction mixture becomes scarlet from yellow.Then reaction mixture is heated to 85 ℃ and spend the night.Reaction mixture is cooled to room temperature, then concentrating under reduced pressure.The resistates obtained is distributed between water (100ml) and ether (3 * 75ml).Ether layer water (2 * 50ml) washing merged, through anhydrous magnesium sulfate drying, filter and concentrate and obtain yellow oil (26.8g).Then it is processed with methylene dichloride (35ml), this makes unreacted HP suddenly separate out (crash out) for white depositions.It is leached and discards.Filtrate, through flash column chromatography (ISCO, 45ml/min, last 50 minutes 0-10% ethanol/methylene for 120g, silica gel) purifying, obtains title compound, and it is white solid (13.4g, 53.3%).LCMS (method C): R
t=1.70 minutes, M+H
+=236.1.
1H?NMR(CDCl
3，400MHz)7.84(m，2H)，7.78(m，2H)，4.15(s，2H)，1.39(s，6H)。
step 2:1-(amino oxygen base)-2-methyl propan-2-ol
Under nitrogen at 0 ℃ to 2-(2-hydroxy-2-methyl-propoxy-)-isoindole-1,3-diketone (3.70g, 15.7mmol) add methyl hydrazine (0.879ml, 16.50mmol) in solution in anhydrous methylene chloride (25ml), then at 0 ℃, stir 2 hours.Add methyl hydrazine to form light yellow be then white throw out.After 2 hours by reaction mixture 0 ℃ of filtration, and discard solid.Filtrate decompression is concentrated, obtain title compound, it is light yellow oil (1.65g, 100%).LCMS (method C): R
t=0.34 minute, M+H
+=106.1.
1H?NMR(DMSO-d
6，400MHz)3.60(s，2H)，1.22(s，6H)。
3-(amino oxygen base)-3-methyl fourth-1-alcohol
step 1:2-(3-hydroxy-3-methyl-butoxy)-isoindole-1, the 3-diketone
Under nitrogen in room temperature to HP (3.13g, 19.2mmol) and 3-hydroxy-3-methyl butane (2.00g, 19.2mmol) add boron trifluoride diethyl etherate compound (2.43ml, 19.2mmol) and stir and spend the night in solution in anhydrous methylene chloride.After 18h, reaction mixture becomes black, wherein contains white depositions (HP).Add saturated sodium bicarbonate solution solution (3ml) in reaction mixture, then stirring at room 5 minutes.Then reaction mixture is filtered and is discarded white solid.Concentrated filtrate, then be dissolved in the resistates of the black of acquisition again in the 25ml methylene dichloride and filter.White solid is discarded, and then concentrated filtrate obtains the resistates of black.It is dissolved in methylene dichloride (5ml), then through flash column chromatography (silica gel, 80g, ISCO, 30ml/min, last 45 minutes 0-100% ethyl acetate/hexane) purifying, obtain title compound, it is yellow oil (228mg, 4.75%).LCMS (method C): R
t=1.77 minutes, M+H
+=250.2.
1H?NMR(CDCl
3，400MHz)7.83(m，2H)，7.78(m，2H)，3.95(t，2H)，2.00(t，2H)，1.45(s，6H)。
step 2:3-(amino oxygen base)-3-methyl fourth-1-alcohol
Under nitrogen at 0 ℃ to 2-(3-hydroxy-3-methyl-butoxy)-isoindole-1,3-diketone (228mg, 0.91mmol) add methyl hydrazine (0.05ml in solution in anhydrous methylene chloride (2ml), 0.96mmol), then stir 1 hour, and be warmed to room temperature in this process.Add methyl hydrazine to form light yellow be then white throw out.After 2 hours by reaction mixture 0 ℃ of filtration, and discard solid.Filtrate decompression is concentrated, obtain title compound, it is light yellow solid (95mg, 87%).LCMS (method C): R
t=0.34 minute, M+H
+=120.
1H?NMR(DMSO-d
6，400MHz)3.75(t，2H)，1.83(t，2H)，1.24(s，6H)。
o-(pyridine-2-ylmethyl)-hydroxylamine hydrochloride
step 1:2-(N-tertbutyloxycarbonyl-amino oxygen ylmethyl) pyridine
Add potassium hydroxide (4.63g, 82.61mmol) in solution to N-tertbutyloxycarbonyl-azanol (5.0g, 37.6mmol) in ethanol in (100ml), then in stirring at room until during potassium hydroxide is dissolved in solution.Add wherein 2-(brooethyl) pyridine hydrobromide salt (11.398g, 45.06mmol) and reflux and spend the night.Observe white depositions after 1 hour.Reaction mixture is cooled to room temperature, then filters.White solid is discarded, then concentrated filtrate.The oily resistates is distributed between water (75ml) and ether (3 * 100ml).The ether layer merged, through dried over sodium sulfate, filters and concentrated filtrate, obtains product, and it is yellow oil (6.0g).Oily matter is dissolved in methylene dichloride (10ml), then through flash column chromatography (silica gel, 120g, ISCO, 45ml/min, last 40 minutes 0-100% ethyl acetate/hexane) purifying, obtain title compound, it is white solid (1.78g, 21.2%).LCMS (method C): R
t=1.13 minutes, M+H
+=225.2.
1H?NMR(CDCl
3，400MHz)8.61(d，m，1H)，7.73(t，d，1H)，7.52(s，1H)，7.46(d，t，1H)，5.01(s，2H)，1.50(s，9H)。
step 2:O-(pyridine-2-ylmethyl)-hydroxylamine hydrochloride
In room temperature to N-tertbutyloxycarbonyl-amino oxygen ylmethyl (pyridine-2-yl) (860mg, 3.8mmol) add the solution (5.06ml of 4M HCl in dioxane in solution in anhydrous methylene chloride (2ml), 20mmol), then stir 2 hours.Add ether (25ml) in reaction mixture, then stir 5 minutes.Decant goes out solvent, and ether for resistates (25ml) is processed, then stirred, and then decant.Repeat aforesaid operations one time again, then resistates (white solid) vacuum-drying is obtained to title compound, it is white solid (688mg, 91%).LCMS (method C): R
t=0.36 minute, M+H
+=125.0.
1H?NMR(DMSO-d
6，400MHz)8.70(m，1H)，8.05(m，1H)，7.60(m，2H)，5.20(s，2H)。
o-(1-phenyl-ethyl)-hydroxylamine hydrochloride
Like the class of operation with for the synthesis of O-(pyridine-2-ylmethyl)-hydroxylamine hydrochloride, operate, synthetic from 1-(bromotrifluoromethane) benzene.LCMS (method C): R
t=0.92 minute, M+H
+=138.2.
1HNMR(DMSO-d
6，400MHz)10.90(s，2H)，7.45(m，5H)，5.25(q，1H)，1.50(d，3H)。
o-[2-(tertiary butyl-dimethyl-silyl oxygen base)-propyl group]-azanol
step 1:(2-benzyl Oxy-1-methyl-oxyethyl group)-the tertiary butyl-dimethyl-silicomethane
Tert-butyldimethylsilyl chloride (517mg, 3.43mmol) is added to 1-benzyl oxygen base-propyl-2-alcohol (518mg, 3.12mmol), imidazoles (318mg, 4.66mmol) and 4-DMAP (95mg, 0.78mmol) in CH
2cl
2(3ml) in the solution in.Reaction mixture, at stirring at room 16h, is then added to 2g silica gel, and vacuum is removed volatile matter.Through silica gel chromatography, (0-5%EtOAc: Hex) resistates is carried out to purifying, obtain title compound (713mg, 82% yield), it is clarification oily matter.
step 2:2-(tertiary butyl-dimethyl-silyl oxygen base)-propyl-1-alcohol
Add 20% palladium/carbon (64mg) in the solution of (2-benzyl Oxy-1-methyl-oxyethyl group)-tertiary butyl-dimethyl-silicomethane (640mg, 2.3mmol) in ethyl acetate (10ml).Reaction mixture is vacuumized, use H
2rinse, then at H
2stir 3h under atmosphere.Then make reaction mixture through diatomite filtration, and the concentrated title compound (430mg, 99% yield) that obtains, it is clarification oily matter, it is without being further purified just for next step.
step 3:2-[2-(tertiary butyl-dimethyl-silyl oxygen base)-propoxy-]-isoindole-1, the 3-diketone
At 0 ℃ by DEAD (0.46ml, 2.94mmol) be added drop-wise to 2-(tertiary butyl-dimethyl-silyl oxygen base)-propyl-1-alcohol (430mg, 2.26mmol), triphenylphosphine (593mg, 2.26mmol) and the solution of HP (369mg, 2.26mmol) in THF (10ml) in.0 ℃ of stirring, after 10 minutes, make reaction mixture rise to room temperature, and then continue to stir 48h.Reaction mixture filters and vacuum concentration through coarse glass funnel.Through silica gel chromatography, (0-40%EtOAc: Hex) resistates is carried out to purifying, obtain title compound (139mg, 18% yield), it is white solid.
step 4:O-[2-(tertiary butyl-dimethyl-silyl oxygen base)-propyl group]-azanol
N-methyl hydrazine (23 μ l, 0.43mmol) is added to 2-[2-(tertiary butyl-dimethyl-silyl oxygen base)-propoxy-]-isoindole-1,3-diketone (135mg, 0.40mmol) is in CH
2cl
2(3ml) in the solution in.After stirring at room 1h, leach white depositions, then by the reaction mixture vacuum concentration, obtain title compound (76mg, 92% yield), it is yellow oil.
1H?NMR(CDCl
3，400MHz)5.48(br，2H)，4.04(m，1H)，3.58(dd，1H)，3.52(dd，1H)，1.13(d，3H)，0.89(s，9H)，0.09(s，6H)。
o-[2-(tertiary butyl-dimethyl-silyl oxygen base)-1-methyl-ethyl]-azanol
step 1:1-(tertiary butyl-dimethyl-silyl oxygen base)-propyl-2-alcohol
Tert-butyldimethylsilyl chloride (4.1g, 27mmol) is added to the third-1,2-glycol (2.0ml, 27mmol) and triethylamine (4.93ml, 35.4mmol) in CH
2cl
2in solution in.After stirred overnight at room temperature, reaction mixture is used respectively to the saturated NaHCO of the 1N HCl aqueous solution, water and 1: 1
3solution and salt water washing 1 time.Organic layer is through Na
2sO
4drying, then filter and concentrate.Thick title compound is without being further purified just for next step.
step 2:2-[2-(tertiary butyl-dimethyl-silyl oxygen base)-1-methyl-oxyethyl group]-isoindole-1,
the 3-diketone
At 0 ℃ by DEAD (1.86ml, 11.8mmol) be added drop-wise to 1-(tertiary butyl-dimethyl-silyl oxygen base)-propyl-2-alcohol (1.73g, 9.09mmol), triphenylphosphine (2.38g, 9.09mmol) and the solution of HP (1.48g, 9.09mmol) in THF (45ml) in.After 10 minutes, reaction mixture is risen to room temperature 0 ℃ of stirring, and then continue to stir 48h.Reaction mixture filters and vacuum concentration through coarse glass funnel.Through silica gel chromatography, (0-40%EtOAc: Hex) resistates is carried out to purifying, obtain title compound (1.80g, 59% yield), it is clarification oily matter.
step 3:O-[2-(tertiary butyl-dimethyl-silyl oxygen base)-1-methyl-ethyl]-azanol
N-methyl hydrazine (310 μ l, 5.74mmol) is added to 2-[2-(tertiary butyl-dimethyl-silyl oxygen base)-1-methyl-oxyethyl group]-isoindole-1,3-diketone (1.80g, 5.36mmol) is in CH
2cl
2(20ml) in the solution in.After 1 hour, leach white depositions in stirring at room, then by the reaction mixture vacuum concentration, obtain title compound (682mg, 62% yield), it is yellow oil.
1H?NMR(CDCl
3，400MHz)5.39(br，2H)，3.77-3.68(m，1H)，3.67(dd，1H)，3.61(dd，1H)，1.13(d，3H)，0.90(s，9H)，0.08(s，6H)。
o-(2-phenyl-1,3-dioxane-5-yl)-azanol
step 1:2-(2-phenyl-1,3-dioxane-5-base oxygen base)-isoindole-1, the 3-diketone
At 0 ℃ by diethylazodicarboxylate (0.85ml, 5.41mmol) be added drop-wise to 2-phenyl-1,3-dioxane-5-alcohol (750mg, 4.16mmol), triphenylphosphine (1.09g, 4.16mmol) and the solution of HP (0.679g, 4.16mmol) in THF (20ml) in.At 0 ℃ to stirred overnight at room temperature, vacuum concentration then.Use CH
2cl
2dilution, then filter through Whatman syringe type strainer.Add 4g silica gel vacuum concentration.Through silica gel chromatography (30-70%EtOAc: Hex, rinse with 100%EtOAc), resistates is carried out to purifying, obtain title compound (495mg, 37% yield), it is white solid.
step 2:O-(2-phenyl-1,3-dioxane-5-yl)-azanol
N-methyl hydrazine (87 μ l, 5.74mmol) is added to 2-(2-phenyl-1,3-dioxane-5-base oxygen base)-isoindole-1, and 3-diketone (495mg, 1.52mmol) is in CH
2cl
2(10ml) in the solution in.After stirring at room 3h, leach white depositions, then by the reaction mixture vacuum concentration, obtain title compound (272mg, 92% yield), it is yellow oil.
1H?NMR(CDCl
3，400MHz)7.50-7.46(m，2H)，7.40-7.35(m，3H)，5.44(br，2H)，5.41(s，1H)，4.48-4.42(m，2H)，4.01-3.93(m，1H)，3.66-3.60(m，2H)。
n-(2-(amino oxygen base)-ethyl)-Toluidrin
step 1:[2-(1,3-dioxo-1,3-dihydro-isoindole-2-base oxygen base)-ethyl]-the carboxylamine uncle
butyl ester
At 0 ℃ to N-(tert-butoxycarbonyl) thanomin (5.0g, 31.0mmol), HP (5.1g, 31.0mmol) and triphenylphosphine (8.5g, 32.6mmol) drip diisopropyl azo-2-carboxylic acid (6.3ml, 32.6mmol) in suspension in tetrahydrofuran (THF) (30ml).Reaction mixture is stirred, then last 16 hours and make it be warmed to room temperature.By the reaction mixture vacuum concentration, through flash chromatography (SiO
2, ethyl acetate: hexanaphthene, gradient is 20: 80 to 30: 70) and product is carried out to purifying, obtain title compound, it is oily matter (14.2g).
1H?NMR(CDCl
3，400MHz)7.87-7.85(2H，m)，7.79-7.77(2H，m)，4.26(2H，t，J＝5.5Hz)，3.47-3.43(2H，m)，1.47(9H，s)。
step 2:2-(2-amino-oxyethyl group)-isoindole-1, the 3-diketone
[2-(1,3-dioxo-1,3-dihydro-isoindole-2-base oxygen base)-ethyl]-t-butyl carbamate (4.4g, about 8.6mmol) is dissolved in the solution (4N, 20ml) of hydrochloric acid in dioxane, then stirring at room 3 hours.By the reaction mixture vacuum concentration.The resistates of formation is dissolved in ethyl acetate (20ml) to sodium hydroxide solution for solution (20ml, 1N) washing.Separate water layer, then use ethyl acetate (2 * 10ml) extraction.The organic layer salt water washing merged, then obtain title compound through dried over mgso vacuum concentration, and it is colorless oil (1.96g).
1H?NMR(CDCl
3，400MHz)7.85(2H，dd，J＝5.4，2.9Hz)，7.72(2H，dd，J＝5.4，3.0Hz)，3.99-3.97(2H，m)，3.86-3.83(2H，m)。
step 3:N-[2-(1,3-dioxo-1,3-dihydro-isoindole-2-base oxygen base)-ethyl]-Toluidrin
At 0 ℃ to 2-(2-amino-oxyethyl group)-isoindole-1,3-diketone (1.96g, 8.1mmol) add methylsulfonyl chloride (0.63ml, 8.1mmol) and triethylamine (2.3ml, 16.2mmol) in solution in acetonitrile (20ml) simultaneously.Reaction mixture is stirred 1 hour at 0 ℃, then stirring at room 1 hour.Reaction mixture is filtered, then by the filtrate vacuum concentration.The resistates of formation is dissolved in ethyl acetate (20ml) to then water (20ml) washing.Separate water layer, then use ethyl acetate (2 * 10ml) extraction.The organic layer salt water washing merged, through dried over mgso vacuum concentration, obtain title compound, and it is white solid (1.2g, 44%).
1H?NMR(CDCl
3，400MHz)7.87(2H，dd，J＝5.5，3.1Hz)，7.79(2H，dd，J＝5.5，3.2Hz)，4.36(2H，dd，J＝4.82，4.62Hz)，3.43-3.47(2H，m)，3.05(3H，s)。
step 4:N-(2-(amino oxygen base)-ethyl)-Toluidrin
To N-[2-(1,3-dioxo-1,3-dihydro-isoindole-2-base oxygen base)-ethyl]-add methyl hydrazine (0.1ml, 1.92mmol) in the suspension of Toluidrin (0.55g, 1.92mmol) in methylene dichloride (15ml).Reaction mixture, stirring at room 30 minutes, is formed to white depositions in this process.Reaction mixture is filtered, the filtrate vacuum concentration is obtained to resistates.Through flash chromatography (SiO
2, gradient is the 1-5% ethanol/methylene) and resistates is carried out to purifying, obtain title compound, it is white solid (204mg, 68%).
1H?NMR(CDCl
3，400MHz)3.80(2H，t，J＝4.9Hz)，3.39(2H，t，J＝4.8Hz)，3.00(3H，s)。
n-(cyclopropyl methyl)-O-(2-(vinyl oxygen base)-ethyl)-azanol
Under nitrogen atmosphere by O-(2-(vinyl oxygen base)-ethyl)-azanol (210mg, 2.0mmol) and cyclopropyl formaldehyde (140mg, 2.0mmol) solution in ethanol (2.0ml) is cooled to 0 ℃, then add tosic acid pyridine (pyridinium p-toluenesulfonic acid) (0.5g, 2.0mmol) and sodium cyanoborohydride (0.15g, 2.2mmol).The mixture formed is stirred 24 hours in envrionment temperature.Reaction mixture dilutes by ethyl acetate, successively water and salt water washing, dry (Na
2sO
4), filter and vacuum concentration, obtain colorless oil, it is directly used in next step.
o-[1-(toluene-4-alkylsulfonyl)-1H-imidazoles-2-ylmethyl]-azanol
step 1:2-[1-(toluene-4-alkylsulfonyl)-1H-imidazoles-2-ylmethoxy]-isoindole-1, the 3-diketone
The diisopropyl azo-2-carboxylic acid is added drop-wise to cooling (0 ℃) 2-(hydroxymethyl)-1-(p-methylphenyl alkylsulfonyl) imidazoles (0.60g; 2.4mmol), triphenylphosphine (0.65g; 2.5mmol) and the solution of HP (0.39g, 2.4mmol) in THF (20ml) in.Reaction mixture is stirred and lasts 40 hours makes it be warmed to room temperature.By the reaction mixture vacuum concentration, then resistates is dissolved in methylene dichloride (20ml), this makes product be precipitated as white solid.Collect after filtration product, then use methylene dichloride (5ml) washing, obtain title compound, it is white solid (580mg, 61%).LCMS (method B): R
t=3.46 minutes, M+H
+=398.
step 2:O-[1-(toluene-4-alkylsulfonyl)-1H-imidazoles-2-ylmethyl]-azanol
By methyl hydrazine (40 μ l; 0.75mmol) be added to 2-[1-(toluene-4-alkylsulfonyl)-1H-imidazoles-2-ylmethoxy]-isoindole-1; 3-diketone (300mg; 0.75mmol) in solution in methylene dichloride (3ml), then by reaction mixture stirring at room 20 minutes.Approximately, after 10 minutes, form white depositions.Reaction mixture is filtered, then by the filtrate vacuum concentration to about half volume.Add ether (5ml), this causes white depositions to form.Reaction mixture is filtered, then the filtrate vacuum concentration is obtained to title compound, it is colorless oil (230mg, 114%).Product is used without just being further purified.LCMS (method B): R
t=2.46 minutes, M+H
+=268.
(3S, 4S)-tetramethyleneimine-3, the 4-diol hydrochloride
step 1:(3R, 4R)-1-benzyl-3,4-dihydroxy pyrrolidine-2,5-diketone
The reflux in m-xylene (50ml) by L-(+)-tartrate (1.51g, 10.06mmol) and benzylamine (1.08g, 10.06mmol) is collected water simultaneously in Dean-Stark trap (Dean-Stark trap).After stirring is spent the night, that reaction mixture is concentrated.Resistates is absorbed in the THF/EtOH of minimum, then through flash chromatography on silica gel, (gradient elution, used 3: 1 hexane-ethyl acetate, ethyl acetate and 9: 1 ethyl acetate-ethanols) purifying, obtain title compound, it is brown solid (0.99g, 44%).
step 2:(3S, 4S)-1-benzyl-pyrrole alkane-3, the 4-glycol
By (3R, 4R)-1-benzyl-3,4-dihydroxy pyrrolidine-2, the solution of 5-diketone (0.98g, 4.4mmol) in THF (20ml) slowly is added to the LiAlH of the stirring that is cooled to-5 ℃
4in solution in THF (4.75ml, 11.87mmol, the THF solution of 2.5M).After adding end, reaction mixture is warmed to room temperature, then reflux spends the night.Reaction mixture is cooled to room temperature, then uses saturated NH
4the cancellation of the Cl aqueous solution, until add fashionable any bubble that no longer produces again.By ethyl acetate for reaction mixture (20ml) dilution, filter, solid washs by ethyl acetate.The filtrate merged is concentrated, and then through flash chromatography on silica gel, (gradient elution, use EtOAc and 9: 1EtOAc-EtOH) resistates is carried out to purifying, obtain title compound, it is brown solid (0.52g, 61%).
step 3:(3S, 4S)-tetramethyleneimine-3, the 4-diol hydrochloride
By (3S, 4S)-1-benzyl-pyrrole alkane-3,4-glycol (0.52g, 2.7mmol) is dissolved in ethanol (15ml) and acetic acid (10ml), then on the Pa Er device, uses 10%Pd-C (100mg) hydrogenation (50psi H
2) 6 hours.After diatomite filtration, filter cake is washed by ethyl acetate, the filtrate and the washings that merge is concentrated.Successively use 4N HCl/ dioxane (2ml), methyl alcohol (5ml) and toluene (40ml) dilute and concentrate resistates.Resistates is ground with ether, obtain the hydrochloride of title compound, it is brown solid (0.37g, 97%).
1H?NMR(D
2O，400MHz)4.35(d，J＝3.4Hz，2H)，3.54(dd，J＝12.8Hz，3.4Hz，2H)，3.30(d，J＝12.8Hz，2H)。
3-methylpyrrolidin-3-alcohol hydrochloride
step 1:3-hydroxy-3-methyl tetramethyleneimine-1-carboxylic acid tert-butyl ester
Solution by 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.070g, 0.38mmol) in anhydrous THF (2ml) is cooled to-78 ℃.Then drip the solution of 1M methyl-magnesium-bromide in butyl ether.Reaction mixture is stirred to h, then water (2ml) cancellation at-78 ℃.By after the reaction mixture vacuum concentration, resistates is distributed between ethyl acetate and water.Water layer extracts 1 time by ethyl acetate again, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography on silica gel (gradient elution is used 1: 1 hexane-ethyl acetate and ethyl acetate), resistates is carried out to purifying, obtain title compound (0.054g, 70%).
step 2:3-methylpyrrolidin-3-alcohol hydrochloride
Add 4NHCl/ dioxane solution (1ml) in 3-hydroxy-3-methyl tetramethyleneimine-1-carboxylic acid tert-butyl ester (0.027g, 0.13mmol), then mixture is stirred 2 hours.By solution for vacuum concentration.Toluene for resistates (1ml) dilution, and then concentrated, obtain title compound, it is colorless oil (0.018g, 100%).
(3R, 4R)-4-hydroxyl pyrrolidine-3-aminocarbamic acid (9H-fluorenes-9-yl) methyl ester hydrochloride
step 1:(3R, 4R)-1-(tert-butoxycarbonyl)-4-hydroxyl pyrrolidine-3-aminocarbamic acid (9H-fluorenes
-9-yl) methyl esters
(3R, 4R)-3-amino-4-hydroxy tetramethyleneimine-1-carboxylic acid tert-butyl ester (0.05g, 0.25mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (1ml), water (1ml) and toluene (0.3ml).Then slowly add chloroformic acid fluorenes-9-base methyl esters (0.077g, 0.30mmol), then add sodium bicarbonate (0.083g, 0.99mmol).By reaction mixture in stirred overnight at room temperature.By after the reaction mixture vacuum concentration, resistates is distributed between ethyl acetate and water.Water layer extracts once by ethyl acetate again, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography on silica gel (gradient elution is used 1: 1 hexane-ethyl acetate and ethyl acetate), resistates is carried out to purifying, obtain title compound (0.090g, 90%).
step 2:(3R, 4R)-4-hydroxyl pyrrolidine-3-aminocarbamic acid (9H-fluorenes-9-yl) methyl ester hydrochloride
4N HCl/ dioxane solution (1ml) is added in (3R, 4R)-1-(tert-butoxycarbonyl)-4-hydroxyl pyrrolidine-3-aminocarbamic acid (9H-fluorenes-9-yl) methyl esters, then mixture is stirred 2 hours.By solution for vacuum concentration.Toluene for resistates (1ml) dilution, and then concentrated, obtain title compound, it is colorless oil (0.076g, 100%).
(2R, 3R)-2-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
step 1:(2S, 3R)-1-(tert-butoxycarbonyl)-3-hydroxyl pyrrolidine-2-carboxylate methyl ester
By (2S, 3R)-1-(tert-butoxycarbonyl)-3-hydroxyl pyrrolidine-2-carboxylic acid (1.76g, 7.63mmol) and NaHCO
3(1.28g, 15.3mmol) is suspended in DMF (10ml).Methyl iodide (2.37ml, 5.41g, 38.13mmol) is added in mixture, then by it 50 ℃ of heated overnight.By after the reaction mixture vacuum concentration, resistates is distributed between ethyl acetate and water.Water layer extracts once by ethyl acetate again, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography on silica gel (gradient elution is used 1: 1 hexane-ethyl acetate and ethyl acetate), resistates is carried out to purifying, obtain title compound, it is colorless oil (1.66g, 89%).
step 2:(2R, 3R)-3-hydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Successively add LiCl (0.19g, 4.4mmol) and NaBH in (2S, the 3R)-1-(tert-butoxycarbonyl) stirred-solution of 3-hydroxyl pyrrolidine-2-carboxylate methyl ester (0.36g, 1.47mmol) in THF (5ml)
4(0.17g, 4.4mmol).After adding ethanol (10ml), by the mixture that forms in stirred overnight at room temperature.Reaction flask is placed in to ice bath, and then cooling milky white solution being acidified to pH with 37%HCl is 2-3.Solution is concentrated, resistates is distributed between ethyl acetate and water.Water layer is extracted with ethyl acetate, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography (silica gel is used ethyl acetate), the oily matter formed is carried out to purifying, obtain 0.30g (95%) title compound, it is colorless oil.
step 3:(2R, 3R)-2-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
4N HCl/ dioxane solution (5ml) is added in (2R, 3R)-3-hydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid tert-butyl ester, then mixture is stirred 2 hours.By solution for vacuum concentration.Toluene for resistates (5ml) dilution, and then concentrated, obtain title compound, it is colorless oil (0.21g, 100%).
(3R, 5R)-5-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
step 1:(2R, 4R)-1-((benzyl oxygen base) carbonyl)-4-hydroxyl pyrrolidine-2-carboxylic acid
By cis-4-hydroxy-d-proline (1.0g, 7.63mmol) and NaHCO
3(1.6g, 19.05mmol) is dissolved in H
2in O (16ml), then last 15 minutes and drip the solution of chloroformic acid benzyl ester (1.25ml, 1.49g, 8.76mmol) in toluene (4ml).After 16 hours, separate two-phase in stirring at room.By with ether (4 * 5ml) washing, from water, removing excessive chloroformic acid benzyl ester.With concentrated hydrochloric acid, by aqueous phase as acidified, to pH, be 2, this causes oily product precipitation, by with ethyl acetate (3 * 5ml) repetitive scrubbing water layer, above-mentioned oily product is extracted in ethyl acetate.By the dry (MgSO of the organic layer merged
4) and concentrated, obtain title compound, its oily matter that is thickness (2.02g, 100%).
step 2:(2R, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl esters
By (2R, 4R)-1-((benzyl oxygen base) carbonyl)-4-hydroxyl pyrrolidine-2-carboxylic acid (2.02g, 7.63mmol) and NaHCO
3(1.28g, 15.3mmol) is suspended in DMF (10ml).Methyl iodide (2.37ml, 5.41g, 38.13mmol) is added in mixture, then by its stirring and 50 ℃ of heated overnight.By after the reaction mixture concentrating under reduced pressure, resistates is distributed between ethyl acetate and water.Water layer extracts once by ethyl acetate again, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography on silica gel (gradient elution is used 1: 1 hexane-ethyl acetate and ethyl acetate), resistates is carried out to purifying, obtain title compound, it is colorless oil (1.9g, 89%).
step 3:(2R, 4R)-4-hydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-benzyl carboxylate
To (2R, the 4R)-4-hydroxyl pyrrolidine-1 stirred, successively add LiCl (0.19g, 4.4mmol) and NaBH in the solution of 2-dicarboxylic acid 1-benzyl ester 2-methyl esters (0.41g, 1.47mmol) in THF (5ml)
4(0.17g, 4.4mmol).After adding ethanol (10ml), by the mixture that forms in stirred overnight at room temperature.Reaction flask is placed in to ice bath, and then cooling milky white solution being acidified to pH with 37%HCl is 2-3.Solution is concentrated, and resistates distributes between ethyl acetate and water.Water layer is extracted with ethyl acetate, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography (silica gel is used ethyl acetate), the oily matter formed is carried out to purifying, obtain title compound (0.35g, 95%), it is colorless oil.
step 4:(3R, 5R)-5-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
(2R, 4R)-4-hydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-benzyl carboxylate (0.35g, 1.4mmol) is dissolved in ethanol (30ml), then transfers them in the Parr shaker bottle.After adding 10%Pd-C (0.07g), by mixture under the 50psi hydrogen atmosphere on the Pa Er device jolting 0.5h.Catalyzer is removed through diatomite filtration.The filter cake washing with alcohol, filtrate and washings vacuum concentration by merging, obtain colorless oil.For the ease of processing, this amine is converted into to hydrochloride.4N HCl/ dioxane solution (1ml) is added in resistates with together with enough methyl alcohol (about 1ml), to dissolve resistates fully.After mixing fully, solvent evaporated under reduced pressure.By toluene for solid (20ml) dilution, and then concentrated.Finally, solid is ground with ether, ether is discarded, then by solid vacuum-drying, obtain 0.186g (87%) title compound, it is pink solid.
(3R, 5S)-5-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
To N-tertbutyloxycarbonyl-trans-4-hydroxyl-L-dried meat ammonia alcohol
(N-Boc-trans-4-hydroxy-L-prolinol) add 4N HCl/ dioxane solution (5ml) in (0.422g, 1.94mmol), then by mixture whirling motion 1 hour.By solution for vacuum concentration.Toluene for resistates (10ml) dilution and then concentrated.The white solid formed grinds with ether, and ether is discarded, and then solid vacuum-drying is obtained to 0.29g (97%) title compound, and it is white solid.
1HNMR(D
2O?400MHz)4.65-4.67(m，1H)，3.99-4.06(m，1H)，3.93(dd，J＝12.5Hz，3.6Hz，1H)，3.71(dd，J＝12.5Hz，6.9Hz，1H)，3.44(dd，J＝12.7Hz，3.8Hz，1H)，3.32(d，J＝12.7Hz，1H)，2.11-2.17(m，1H)，1.92-1.98(m，1H)。
(3R, 5R)-5-(hydroxymethyl) pyrrolidin-3-yl t-butyl carbamate
step 1:(2R, 4S)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl esters
(2R in from room temperature to stirring, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl esters (1.45g, 5.2mmol), triphenylphosphine (4.59g, 17.5mmol) and p-nitrobenzoic acid (2.6g, 15.6mmol) drip diethylazodicarboxylate (2.57ml, 17.5mmol) in solution in dry-out benzene (10ml).Then by solution at stirring at room 6h, now vacuum is removed volatile constituent, through flash chromatography (silica gel, hexane-ether 1: 1 and hexane-ether-methylene dichloride 2: 1: 1), resistates is carried out to purifying.This resistates is dissolved in methyl alcohol (10ml), adds K
2cO
3(0.02g, 0.14mmol), then by mixture at stirring at room 1h.After vacuum is removed volatile constituent, through flash chromatography (silica gel, gradient elution are used ether to ethyl acetate), resistates is carried out to purifying, obtain title compound, it is colorless oil (0.33g, 23%).
step 2:4-toluene sulfonic acide (3S, 5R)-1-((benzyl oxygen base) carbonyl)-5-(methoxycarbonyl) pyrroles
alkane-3-base ester
By (2R, 4S)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl esters (0.33g, 1.18mmol) and DMAP (0.43g, 3.55mmol) are dissolved in chloroform, then mixture are cooled in ice-ethanol bath to-5 ℃.Add Tosyl chloride (0.45g, 2.24mmol), then reaction mixture is stirred, it be warmed to room temperature simultaneously and keep 2 hours.Water (0.6ml) cancellation vigorous stirring, after 10 minutes, are separated each layer, and methylene dichloride for water layer (2 *) is extracted.By the dry (MgSO of organic layer
4), through silica filler (7ml is filled in ether), filter, with ether wash-out concentrated.Through flash chromatography (gradient elution is used hexane-ether 1: 1 to ether), resistates is carried out to purifying, obtain title compound, it is colorless oil (0.49g, 95%).
step 3:(2R, 4R)-4-azido-tetramethyleneimine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl esters
By sodiumazide (0.33g, 5.07mmol) be added to 4-toluene sulfonic acide (3S, 5R)-1-((benzyl oxygen base) carbonyl)-5-(methoxycarbonyl) pyrrolidin-3-yl ester (0.49g, 1.13mmol) in solution in DMF (8ml), then by mixture 50 ℃ of heated overnight.After vacuum concentration, resistates is distributed between ether and water.The water layer extracted with diethyl ether, by the dry (MgSO of the organic layer merged
4) and concentrated.Through flash chromatography (silica gel is used ether), the oily matter formed is carried out to purifying, obtain 0.33g (97%) title compound, it is colorless oil.
step 4:(3R, 5R)-the amino first of 1-((benzyl oxygen base) carbonyl)-5-(methoxycarbonyl) pyrrolidin-3-yl
tert-butyl acrylate
Triphenylphosphine (0.33g, 1.15mmol) is added to (2R, 4R)-4-azido-tetramethyleneimine-1, in the solution of 2-dicarboxylic acid 1-benzyl ester 2-methyl esters (0.33g, 1.08mmol) in THF (4ml) and water (2ml).After 50 ℃ of stirrings are spent the night, successively add sodium bicarbonate (0.23g, 2.71mmol) and a contracting tert-Butyl dicarbonate (di-tert-butyl dicarbonate) (0.47g, 2.17mmol), then at 50 ℃, continue again to stir 4h.Volatile matter is removed in decompression, then resistates is distributed between ether and water.The water layer extracted with diethyl ether, then by the dry (MgSO of the organic layer merged
4) and concentrated.Through flash chromatography on silica gel (gradient elution is used hexane-ether 1: 1 to 3: 7), the oily matter formed is carried out to purifying, obtain 0.258g (64%) title compound, it is colorless oil.
step 5:(3R, 5R)-1-((benzyl oxygen base) carbonyl)-5-(hydroxymethyl] the pyrrolidin-3-yl carboxylamine
the tert-butyl ester
To (the 3R stirred, 5R)-1-((benzyl oxygen base) carbonyl)-5-(methoxycarbonyl) pyrrolidin-3-yl t-butyl carbamate (0.16g, 0.42mmol) add LiCl (0.054g, 1.27mmol) and NaBH in solution in THF (1.5ml)
4(0.048g, 1.27mmol).After adding ethanol (3ml), by the mixture that forms in stirred overnight at room temperature, then water (1ml) cancellation.Solution is concentrated, resistates is distributed between ethyl acetate (20ml) and water (3ml).Ethyl acetate for water layer (2 * 2ml) extraction, the salt water washing of the organic layer of merging, dry (MgSO
4) and concentrated.Through flash chromatography (silica gel is used ether), the oily matter formed is carried out to purifying, obtain 0.11g (74%) title compound, it is colorless oil.
step 6:(3R, 5R)-5-(hydroxymethyl) pyrrolidin-3-yl t-butyl carbamate
(3R, 5R)-1-((benzyl oxygen base) carbonyl)-5-(hydroxymethyl) pyrrolidin-3-yl t-butyl carbamate (0.11g, 0.31mmol) is dissolved in ethanol (20ml), then transfers them in the Parr shaker bottle.After adding 10%Pd-C (0.030g), by mixture on the Pa Er device under the 50psi hydrogen atmosphere jolting 0.5h.Catalyzer is removed through diatomite filtration.The filter cake washing with alcohol, then, by the filtrate and the washings vacuum concentration that merge, obtain title compound, and it is colorless oil (0.07g, 100%).
(2R, 3S)-2-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
step 1:(2S, 3S)-1-(tert-butoxycarbonyl)-3-hydroxyl pyrrolidine-2-carboxylic acid
By in trans-3-hydroxyl-L-PROLINE (2.62g, 20.0mmol) and sodium bicarbonate (5.04g, 60mmol) water-soluble (20ml).Successively add dioxane (20ml) and a contracting tert-Butyl dicarbonate (8.72g, 40mmol).Continue to stir in room temperature and spend the night.Reaction mixture is concentrated, then resistates is distributed between ether (10ml) and water (30ml).Water layer washs once with ether again, then discards organic layer.Make gradually aqueous phase as acidified with dense HCl, this causes oily product precipitation, by with ethyl acetate (3 * 10ml) repetitive scrubbing water layer, above-mentioned oily product being extracted in ethyl acetate.The organic layer salt water washing merged, dry (MgSO
4) and concentrated, obtain title compound, its oily matter that is thickness (4.17g, 90%).
step 2:(2S, 3S)-3-hydroxyl pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esters
By (2S, 3S)-1-(tert-butoxycarbonyl)-3-hydroxyl pyrrolidine-2-carboxylic acid (4.2g, 18.2mmol) and NaHCO
3(3.1g, 36.3mmol) is suspended in DMF (20ml).Methyl iodide (5.7ml, 12.9g, 91.0mmol) is added in mixture, then by it 50 ℃ of heated overnight.By after the reaction mixture vacuum concentration, resistates is distributed between ethyl acetate and water.Water layer extracts once by ethyl acetate again, by the organic layer salt water washing merged, and dry (MgSO
4) and concentrated.Through flash chromatography on silica gel (gradient elution is used 1: 1 hexane-ether to ether), resistates is carried out to purifying, obtain title compound, it is colorless oil (3.7g, 82%).
step 3:(2R, 3S)-3-hydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid tert-butyl ester
By (2S, 3S)-3-hydroxyl pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esters (0.54g, 2.20mmol) is dissolved in THF (8.0ml).Successively add lithium chloride (0.28g, 6.60mmol) and sodium borohydride (0.25g, 6.60mmol) and ethanol (16.0ml).Reaction mixture is stirred and spends the night, then water (4ml) cancellation concentrated.Resistates is distributed between ethyl acetate and water.Water layer is extracted with ethyl acetate.Merge organic layer, use the salt water washing, then dry (MgSO
4).(use ethyl acetate to 9: 1 ethyl acetate-ethanol), obtain 0.5 gram (100%) title compound, it is colorless solid for 50ml silica gel, gradient elution to carry out flash chromatography.
step 4:(2R, 3S)-2-(hydroxymethyl) tetramethyleneimine-3-alcohol hydrochloride
Add 4N HCl/ dioxane solution (6ml) in (2R, 3S)-3-hydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid tert-butyl ester (0.50g, 2.30mmol), then by mixture whirling motion 2 hours.By solution for vacuum concentration.Toluene for resistates (20ml) dilution, and then concentrated, obtain title compound, it is colorless oil (0.36g, 100%).
(2R, 3R, 4S)-2-(hydroxymethyl) tetramethyleneimine-3, the 4-diol hydrochloride
step 1:(S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrroles-2-carboxylic acid
3,4-dehydrogenation-L-PROLINE (1.0g, 8.8mmol) is dissolved in to H
2in O (9.0ml), then add sodium bicarbonate (2.23g, 26.5mmol).Successively add dioxane (9.0ml) and a contracting tert-Butyl dicarbonate (3.86g, 17.7mmol).Reaction mixture is stirred and spends the night, then concentrated.To remain between ether (20ml) and water (25ml) and distribute, then separate each layer.Ethyl acetate for water layer (20ml) dilution, then by the slow acidifying of dense HCl for mixture, the vigorous stirring mixture, be extracted into throw out in organic layer simultaneously.After being acidified to about pH 2 and further being extracted with ethyl acetate, the water layer salt loading, then extract once by ethyl acetate again.The organic layer salt water washing merged, dry (MgSO
4) and concentrated title compound (2.0g, 100%), its colorless oil that is thickness of obtaining.
step 2:(S)-2H-pyrroles-1,2 (5H)-dicarboxylic acid 1-tert-butyl ester 2-methyl esters
By (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrroles-2-carboxylic acid (0.85g, 4.0mmol) is dissolved in ether (10ml) and methyl alcohol (10ml), then in ice/ethanol bath, is cooled to-5 ℃.Dropping trimethyl silyl diazomethane (hexane solution of 4.4ml 2.0M, 8.8mmol).After stirring is spent the night, volatile matter is removed in decompression.Resistates is distributed between ether (20ml) and water (5ml), then separate each layer.The saturated NaHCO of organic layer
3solution and salt water washing, then dry (MgSO
4), through silica filler (7ml), filter, with the ether washing, then concentrated, obtain title compound, it is colorless oil (0.821g, 91%).
step 3:(2S, 3R, 4S)-3,4-dihydroxy pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esters
(S)-2H-pyrroles-1,2 (5H)-dicarboxylic acid 1-tert-butyl ester 2-methyl esters (0.83g, 3.65mmol) is dissolved in the trimethyl carbinol (15ml), tetrahydrofuran (THF) (4ml) and water (1.3ml).(t-butanol solution of 0.37ml100mg/ml, 0.15mmol) with N-methylmorpholine N-oxide compound (0.51g, 4.4mmol) successively to add perosmic anhydride.Reaction mixture, stirring at room 5 hours, is then used to saturated sodium thiosulfate solution (5ml), ethyl acetate (15ml) and water (5ml) dilution.After separating each layer, organic layer washs 1 time with Sulfothiorine again, then uses the salt water washing, dry (MgSO
4), then pass through silica filler (7ml) and filter, with ethyl acetate (75ml) washing, then concentrated.Oily matter is absorbed in the ether/methylene dichloride of minimum, then, through flash chromatography (gradient elution is used hexane-ethyl acetate 3: 7 to ethyl acetate) purifying, obtains title compound, it is colorless oil (0.83g, 87%).
step 4:(3aR, 4S, 6aS)-tetrahydrochysene-2,2-dimethyl-[1,3] dioxole [4,5-c] pyrroles
-4,5-dicarboxylic acid 5-tert-butyl ester 4-methyl esters
By (2S, 3R, 4S)-3,4-dihydroxy pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esters (0.426g, 1.63mmol) is dissolved in 2,2-dimethoxypropane (10ml).Add tosic acid pyridine (0.02g, 0.08mmol), then by reaction mixture in stirred overnight at room temperature.TLC shows the basic end of reaction.Add more 2,2-dimethoxypropane (5ml), then heating gun for mixture (heat gun) is heated until the mixture boiling reduces approximately 1/4 (the approximately 5 minutes used time) by cumulative volume.By ether for reaction mixture (10ml) dilution, by the saturated NaHCO of solution
3solution and salt solution extraction, then be dried (MgSO
4), filter and concentrate, obtain light yellow oil.Carry out flash chromatography (70ml silica gel, gradient elution are used hexane-ether 25: 15 to hexane-ether 1: 1), obtain title compound (0.402g, 82%), it is colorless oil.
step 5:(3aR, 4R, 6aS)-tetrahydrochysene-4-(hydroxymethyl)-2,2-dimethyl-[1,3] dioxane penta
alkene [4,5-c] pyrroles-5-carboxylic acid tert-butyl ester
By (3aR, 4S, 6aS)-tetrahydrochysene-2,2-dimethyl-[1,3] dioxole [4,5-c] pyrroles-4,5-dicarboxylic acid 5-tert-butyl ester 4-methyl esters (0.40g, 1.3mmol) is dissolved in THF (5.0ml), then uses successively lithium chloride (0.17g, 4.0mmol), sodium borohydride (0.15g, 4.0mmol) and ethanol (10ml) processes.Reaction mixture is stirred and spends the night, then water (3ml) cancellation concentrated.Resistates is distributed between ethyl acetate and water.After water layer is extracted to 1 time again by ethyl acetate, salt water washing dry (MgSO for the organic layer of merging
4).Carry out flash chromatography (50ml silica gel, gradient elution are used hexane-ether 6: 4 to ether), obtain 0.36 gram (99%) title compound, it is colorless oil.
step 6:(2R, 3R, 4S)-2-(hydroxymethyl) tetramethyleneimine-3, the 4-diol hydrochloride
By (3aR, 4R, 6aS)-tetrahydrochysene-4-(hydroxymethyl)-2,2-dimethyl-[1,3] dioxole [4,5-c] pyrroles-5-carboxylic acid tert-butyl ester (0.36g, 1.3mmol) is dissolved in 4N HCl/ dioxane (5ml) and water (0.5ml), then by reaction mixture room temperature whirling motion 2 hours.Then volatile matter is removed in decompression, obtains pink oily matter.By this toluene (20ml) dilution for resistates, and then the simmer down to solid, it is ground with ether.Ether is discarded, then by solid vacuum-drying.Obtain 200mg (90%) title compound, it is pink solid.
1H?NMR(D
2O?400MHz)4.37-4.39(m，1H)，4.21(dd，J＝8.6Hz，4.1Hz，1H)，3.98(dd，J＝12.7Hz，3.5Hz，1H)，3.83(dd，J＝12.5Hz，6.0Hz，1H)，3.62(ddd，J＝8.6Hz，6.0Hz，3.5Hz，1H)，3.50(dd，J＝13.0Hz，4.1Hz，1H)，3.37(dd，J＝13.0Hz，2.0Hz，1H)。
(2R, 3S, 4S)-2-(hydroxymethyl) tetramethyleneimine-3, the 4-diol hydrochloride
step 1:
In in heating, 2,3,5-, tri--O-benzyl-β-L-arabinose (0.5g, 1.19mmol) being dissolved in to ethanol (5ml).Add the solution of sodium bicarbonate (249mg, 2.96mmol) in water (2.5ml), then add hydroxylamine hydrochloride (247mg, 3.55mmol).By the nonuniformity mixture stirring at room 5 hours.Then add more hydroxylamine hydrochloride (100mg, 1.44mmol) and sodium bicarbonate (100mg, 1.19mmol), reaction mixture is stirred and spends the night.Add more sodium bicarbonate (0.084g, 1mmol), then mixture be heated to seethe with excitement and keep 5 minutes.After being cooled to room temperature, that reaction mixture is concentrated.The THF for oily matter (20ml) formed grinds, until solid becomes fines.Leach solid, then that filtrate is concentrated.Through flash chromatography, (hexane: ethyl acetate 3: 1) resistates is carried out to purifying, obtain 0.45 gram (87%) product, it is colorless oil.
step 2:
Solution by the oxime (0.45g, 1.0mmol) of 2,3,5-, tri--O-benzyl-β-L-arabinose in anhydrous diethyl ether (5ml) is added drop-wise to LiAlH
4solution (the THF solution of 0.75ml 2.5M, 1.85mmol) in.After adding, mixture is stirred 2 hours in room temperature again.Slowly add the LiAlH of ethyl acetate (1.7ml) with decomposing excessive
4, then add 0.75ml 4N NaOH solution.The muddy suspension formed filters through bed of diatomaceous earth, then the diatomite cake is fully washed by ether and ethyl acetate.Filtrate and washings are concentrated, obtain the oily matter of thickness.Oily matter is absorbed in ethyl acetate (20ml), then uses saturated NaHCO
3solution and salt water washing, then dry (MgSO
4) also concentrate and obtain rough amine, it is light yellow oil (0.44g, 100%).This amine (0.44g, 1.0mmol) is dissolved in THF (3ml) and water (1.5ml).Successively add sodium bicarbonate (0.22g, 2.6mmol) and a contracting tert-Butyl dicarbonate (0.46g, 2.1mmol).Reaction mixture is stirred and spends the night, then concentrated.Resistates distributes between ether (20ml) and water (10ml), then separates each layer.Water layer extracts once with ether again, by the organic layer salt water washing merged, and dry (MgSO
4) and concentrated.Carry out flash chromatography (silica gel, hexane-ether 1: 1), obtain 0.29g (52%) tertbutyloxycarbonyl amine, it is colorless oil.
step 3:
Be that above-mentioned tertbutyloxycarbonyl amine (0.29g, 0.55mmol) and triethylamine (0.13ml, 0.96mmol) are dissolved in methylene dichloride (2.0ml) by alcohol, then in ice-ethanol bath, be cooled to-5 ℃.Add methylsulfonyl chloride (64 μ l, 0.83mmol), then reaction mixture is stirred 2 hours.After water (0.2ml) cancellation, mixture is stirred 30 minutes.Separate each layer, the water layer washed with dichloromethane, by the dry (MgSO of the organic layer merged
4) and concentrated.Through flash chromatography (hexane-ether-methylene dichloride 2: 1: 1), resistates is carried out to purifying, obtain title compound (0.30g, 91%).
step 4:
By above-mentioned N-tertbutyloxycarbonyl-O-methanesulfonates compound (0.247g, 0.412mmol) be dissolved in DMF (2.0ml), then sodium hydride (0.023 gram, 60% oily dispersion liquid) directly is added in solution, then by muddy mixture stirring at room 2.5 hours.TLC shows that reaction finishes.By ether for reaction mixture (8ml) dilution, then directly pass through silica filler (7ml is filled in ether) and filter, filter cake is washed with ether.After volatile matter is removed in decompression, through flash chromatography on silica gel (hexane-ether-methylene dichloride 3: 1: 1), the resistates formed is carried out to purifying, obtain 0.196g (95%) tetramethyleneimine product, it is colorless oil.
step 5:(2R, 3S, 4S)-3,4-dihydroxyl-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Above-mentioned three-O-benzyl-pyrrole alkane (0.24g, 0.47mmol) is dissolved in methyl alcohol (50ml), then is added in the Parr shaker bottle.With after nitrogen wash, add 10%Pd-C (150mg), then by mixture on the Pa Er device with 50psi H
2hydrogenation 4 hours.Reaction mixture filters through Celite pad, by the filter cake methanol wash, then that solution is concentrated.Through flash chromatography (silica gel, gradient elution are used ethyl acetate to ethyl acetate-ethanol 9: 1), the resistates formed is carried out to purifying, obtain triol product (0.103g, 95%), it is colorless oil.
step 6:(2R, 3S, 4S)-2-(hydroxymethyl) tetramethyleneimine-3, the 4-diol hydrochloride
Above-mentioned N-tertbutyloxycarbonyl-tetramethyleneimine (0.103g, 0.442mmol) is dissolved in to 4N HCl/ dioxane (3ml) 2, then room temperature whirling motion 1.5 hours.The reaction mixture vacuum concentration is obtained to colorless oil.By toluene for resistates (20ml) dilution, again concentrated, then with ether, grind, manage to cause crystallization.Resistates solidifies, and ether is discarded, and then by solid vacuum-drying, obtains thick title compound, and it is white solid (75mg, 100%).
1h NMR (D
2o 400MHz) 4.39 (d, J=4.3Hz, 1H), 4.32 (obviously unimodal, 1H), 3.99-4.05 (m, 1H), 3.87-3.93 (m, 2H), 3.66 (dd, J=13.0Hz, 4.3Hz, 1H), 3.30 (d, J=13.0Hz, 1H).
(the iodo-phenyl amino of the fluoro-4-of 2-)-((R)-2,3-bis-for furo [3,2-c] pyridine-2-carboxylic acids for embodiment 5:3-
hydroxyl-propoxy-)-acid amides
step 1:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-diformazan
base-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (60mg, 0.15mmol), the mixture of 1N aqueous sodium hydroxide solution (0.18ml, 0.18mmol) and methyl alcohol (2ml) is 65 ℃ of heating 30 minutes.Reaction mixture is concentrated, then, with toluene (3 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (2ml), then add O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (35mg, 0.23mmol), EDCI (28mg, 0.15mmol), HOBt (22mg, 0.16mmol) and DIPEA (61 μ l, 0.35mmol).After 40 ℃ of stirrings are spent the night, make resistates be adsorbed on HM-N upper, then, through flash chromatography (gradient is 100: 0 to 90: 10 for Si-SPE, ether: MeOH) purifying, obtain title compound, it is yellow foam (30mg, 48%).LCMS (method B): R
t=3.10 minutes, M+H
+=528.
step 2:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxy
base-propoxy-)-acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (30mg, 0.06mmol) be dissolved in methyl alcohol (0.5ml), then be loaded into
on SCX-2 post (5g).Then by methyl alcohol for post (15ml) washing, subsequently by the product 2M NH of expectation
3the MeOH eluant solution, collect elutriant the concentrated resistates that obtains.Make resistates be adsorbed on HM-N upper, then, through flash chromatography (gradient is 100: 0 to 80: 20 for Si-SPE, ether: MeOH) purifying, obtain title compound, it is white solid (18mg, 64%).LCMS (method A): R
t=5.80 minutes, M+H
+=488.
1H?NMR(d
4-MeOH，400MHz)8.53(d，J＝5.9Hz，1H)，8.49(d，J＝1.0Hz，1H)，7.62(dd，J＝5.9Hz，1.0Hz，1H)，7.60(dd，J＝10.3Hz，2.0Hz，1H)，7.51(dd，J＝8.5Hz，2.0Hz，1H)，7.06(t，J＝8.5Hz，1.0Hz，1H)，4.10(m，1H)，3.96(m，2H)，3.63(m，2H)。
(the bromo-phenyl amino of the fluoro-4-of 2-)-((R)-2,3-bis-for furo [3,2-c] pyridine-2-carboxylic acids for embodiment 6:3-
hydroxyl-propoxy-)-acid amides
step 1:3-(the bromo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-diformazan
base-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By 3-(the bromo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (400mg, 1.06mmol), the mixture of 1N aqueous sodium hydroxide solution (1.11ml, 1.11mmol) and methyl alcohol (10ml) is 65 ℃ of heating 30 minutes.By the reaction mixture vacuum concentration, then, with toluene (3 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (10ml), then add O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (255mg, 2.12mmol), EDCI (254mg, 1.32mmol), HOBt (200mg, 1.48mmol) and DIPEA (556 μ l, 3.18mmol).After the envrionment temperature stirring is spent the night, the reaction mixture vacuum concentration is obtained to yellow residue.The resistates of formation is dissolved in ethyl acetate (30ml), and successively water (30ml) and salt solution (30ml) washing, then separate organic layer, then, through dried over sodium sulfate vacuum concentration, obtains yellow oil.Through flash chromatography (Si-SPE, pentane: ethyl acetate, gradient is 50: 50 to 0: 100), oily matter is carried out to purifying, obtain title compound, it is canescence foam (370mg, 73%).
1H?NMR(CDCl
3，400MHz)9.22(s，1H)，7.95(s，1H)，7.67(m，1H)，7.51(m，1H)，7.45-7.31(m，3H)，7.13(t，J＝8.4Hz，1H)，4.49(m，1H)，4.08-4.26(m，3H)，3.89(m，1H)，1.49(s，3H)，1.40(s，3H)。
step 2:3-(the bromo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxy
base-propoxy-)-acid amides
To 3-(the bromo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (50mg, 0.10mmol) in add the solution of 4N HCl in methyl alcohol (1ml), then reaction mixture is stirred 30 minutes in envrionment temperature.Water (10ml) and ethyl acetate (10ml) are added in reaction mixture, then separate organic layer.The saturated NaHCO of organic phase formed
3solution (10ml) washing, then through dried over sodium sulfate, vacuum concentration, obtain resistates afterwards.Resistates is loaded into
on SCX-2 post (5g).Then by methyl alcohol for post (15ml) washing, the MeOH eluant solution with 2M ammonia by the product of expectation, collect elutriant afterwards, then the concentrated resistates that obtains.Through flash chromatography (gradient is 100: 0 to 93: 7 for Si-SPE, DCM: MeOH), resistates is carried out to purifying, obtain title compound, it is white solid (27mg, 59%).LCMS (method A): R
t=5.55 minutes, M+H
+=440/442.
1H?NMR(d
4-MeOH，400MHz)8.52(s，1H)，8.44(s，1H)，7.60(d，J＝5.9Hz，1H)，7.44(dd，J＝8.8Hz，2.2Hz，1H)，7.32(m，1H)，7.19(m，1H)，4.06(m，1H)，3.91(m，2H)，3.59(m，2H)。
embodiment 7:3-(the fluoro-phenyl amino of 4-ethynyl-2-)-furo [3,2-c] pyridine-2-carboxylic acids
((R)-2,3-dihydroxyl-propoxy-)-acid amides
Make 3-(the bromo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (100mg, 0.21mmol), trimethyl silyl acetylene (288 μ l, 2.08mmol) and PdCl
2(PPh
3)
2(7.3mg, 0.01mmol) mixture in triethylamine (3.0ml) is accepted microwave irradiation 10 minutes at 150 ℃.Then by ethyl acetate for reaction mixture (5ml) dilution, by successively water (10ml) and salt solution (5ml) washing of solution formed, organic layer, through dried over sodium sulfate vacuum concentration, obtains resistates.Resistates is dissolved in methyl alcohol (3ml), adds salt of wormwood (58mg, 0.42mmol), then reaction mixture is stirred 1 hour in envrionment temperature.Then reaction mixture is evaporated to dryly, the resistates of formation is dissolved in ethyl acetate (20ml).Organic phase is water (10ml) and salt solution (10ml) washing successively, and through dried over sodium sulfate, then vacuum concentration, obtain resistates.The resistates of formation is dissolved in methyl alcohol (0.5ml), then is loaded into
on SCX-2 post (5g).By methyl alcohol for post (15ml) washing, then the MeOH eluant solution with the 2M triethylamine by the product of expectation, collect elutriant, then concentrates and obtain title compound, and it is white solid (19mg, 24%).LCMS (method A): R
t=5.78 minutes, M+H
+=386.
1H?NMR(d
4-MeOH，400MHz)8.51(m，2H)，7.60(d，J＝5.9Hz，1H)，7.31(dd，J＝11.3Hz，1.8Hz，1H)，7.23(dd，J＝8.4Hz，1.6Hz，1H)，7.06(t，J＝8.5Hz，1H)，4.07(m，1H)，3.92(m，2H)，3.55(m，2H)，3.49(s，1H)。
embodiment 8:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids cyclopropyl methoxy
base-acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (87mg, 0.20mmol), the mixture of 1N aqueous sodium hydroxide solution (0.21ml, 0.21mmol) and methyl alcohol (2ml) is 65 ℃ of heating 60 minutes.By the reaction mixture vacuum concentration, then, with toluene (3 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (5ml), then add cyclopropyl methyl hydroxylamine hydrochloride (49mg, 0.40mmol), EDCI (48mg, 0.25mmol), HOBt (36mg, 0.27mmol) and DIPEA (140 μ l, 0.80mmol).After 40 ℃ of stirrings are spent the night, make resistates be adsorbed on HM-N upper, then, through flash chromatography (gradient is 98: 2 to 95: 5 for Si-SPE, ether: MeOH) purifying, obtain title compound, it is pale solid (31mg, 33%).
1H?NMR(CDCl
3，400MHz)8.84(s，1H)，8.62(s，1H)，8.59(d，J＝5.9Hz，1H)，7.99(s，1H)，7.51(dd，J＝9.7Hz，1.5Hz，1H)，7.43(d，J＝8.6Hz，1H)，7.38(d，J＝5.9Hz，1H)，6.98(t，J＝8.4Hz，1H)，3.90(d，J＝7.5Hz，2H)，1.20(m，1H)，0.66(m，2H)，0.37(m，2H)。
embodiment 9:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids ((R)-2,3-
dihydroxyl-propoxy-)-acid amides
(the iodo-phenyl amino of the fluoro-4-of 2-)-(((R)-2,2-bis-for furo [2,3-c] pyridine-2-carboxylic acids for step 1:3-
methyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By the mixture reflux of 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids ethyl ester (220mg, 0.52mmol), 1N aqueous sodium hydroxide solution (2.0ml) and methyl alcohol (2.0ml) 15 minutes.Reaction mixture is concentrated, then, with toluene (3 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (8ml), then add O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (149mg, 1.04mmol), EDCI (123mg, 0.64mmol), HOBt (98mg, 0.73mmol) and DIPEA (274 μ l, 1.54mmol).After envrionment temperature stirs 16 hours, make resistates be adsorbed on HM-N upper, then, through flash chromatography (gradient is 100: 0 to 90: 10 for Si-SPE, ether: MeOH) purifying, obtain title compound, it is brown oil (124mg, 45%).LCMS (method B): R
t=3.39 minutes, M+H
+=528.
step 2; 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxy
base-propoxy-)-acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (25mg, 0.05mmol) be dissolved in methyl alcohol (0.5ml), then carry out chromatogram (
sCX-2, MeOH: 2M NH
3meOH solution, gradient is 100: 0 to 50: 50) purifying.Then make resistates be adsorbed on HM-N upper, through flash chromatography (gradient is 95: 5 to 80: 20 for Si-SPE, DCM: MeOH) purifying, obtain title compound, it is white solid (19mg, 78%).LCMS (method A): R
t=6.99 minutes, M+H
+=488.
1H?NMR(d
4-MeOH，400MHz)8.88(s，1H)，8.32(d，J＝5.5Hz，1H)，7.55(dd，J＝10.3Hz，2.0Hz，1H)，7.45(ddd，J＝8.5Hz，2.0Hz，1.0Hz，1H)，7.32(dd，J＝5.5Hz，1.0Hz，1H)，6.89(t，J＝8.5Hz，1H)，4.11(dd，J＝9.9Hz，3.5Hz，1H)，3.97(m，2H)，3.63(m，2H)。
embodiment 10:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (the 2-hydroxyl-
oxyethyl group)-acid amides
step 1:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(vinyl oxygen
base)-oxyethyl group)-acid amides
To 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (6.50g, 15.2mmol) add 1.0M aqueous sodium hydroxide solution (31ml, 31mmol) in solution in THF (92ml) and methyl alcohol (31ml).Reaction mixture is heated to 65 ℃ and keep 1.5h, then is cooled to room temperature vacuum concentration.Resistates and toluene (3 * 75ml) azeotropic by forming, then be suspended in THF (75ml).Then add successively O-(2-(vinyl oxygen base)-ethyl)-azanol (1.86g, 18.0mmol), N, N-diisopropylethylamine (10.4ml, 60.0mmol), EDCI (5.75g, 30.0mmol) and HOBt (4.46g, 33.0mmol), by reaction mixture stirring at room 18 hours.Then add 18.9g silica gel, by the mixture vacuum concentration.Through silica gel chromatography (0-7% methyl alcohol: CH
2cl
2) resistates is carried out to purifying, obtain title compound, it is light yellow solid: 4.40g, 60%.LCMS (method C): R
t=2.11 minutes, M+H
+=484.
1H?NMR(CDCl
3，400MHz)8.97(s，1H)，8.63(s，1H)，8.60(d，J＝5.6Hz，1H)，7.98(s，1H)，7.52(dd，J＝9.6，2.0Hz，1H)，7.44(m，1H)，7.39(dd，J＝6.0，1.2Hz，1H)，7.00(t，J＝8.8Hz，1H)，6.56(dd，J＝14.4，6.8Hz，1H)，4.34(m，2H)，4.28(dd，J＝14.0，2.0Hz，1H)，4.12(dd，J＝6.4，2.0Hz，1H)，4.03(m，2H)。
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides
At 0 ℃ to 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(vinyl oxygen base)-oxyethyl group)-acid amides (4.40g, 9.10mmol) add 1.0M aqueous hydrochloric acid (18.2ml, 18.2mmol) in suspension in the mixture of methyl alcohol (14.3ml) and ethanol (51.9ml).After adding end, make reaction mixture rise to room temperature, then stir 1.5h.Then add sodium bicarbonate (4.75g, 56.5mmol) in batches, continue to stir 15 minutes.Add silica gel (14g), then by the mixture vacuum concentration.Through silica gel column chromatography (0-10% methyl alcohol: CH
2cl
2) residual solid is carried out to purifying, obtain title compound, it is light yellow solid: 4.12g, 91%.LCMS (method C): R
t=1.61 minutes, M+H
+=458.
1H?NMR(CDCl
3，400MHz)8.84(s，1H)，8.61(s，1H)，8.60(s，1H)，7.94(s，1H)，7.53(dd，J＝9.6，2.0Hz，1H)，7.43(m，1H)，7.38(dd，J＝6.0，1.2Hz，1H)，7.00(t，J＝8.4Hz，1H)，4.30(b，1H)，4.11(m，2H)，3.83(b，2H)。
embodiment 11:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(vinyl
the oxygen base)-oxyethyl group)-acid amides
embodiment 12:3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl
-propoxy-)-acid amides
step 1:3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl
-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
The mixture of 3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (100mg, 0.24mmol), 1N aqueous sodium hydroxide solution (260 μ l) and ethanol (4ml) is heated 3 hours at 65 ℃.Reaction mixture is concentrated, then, with toluene (3 * 20ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (7ml), add wherein EDCI (57mg, 0.30mmol) and HOBt (45mg, 0.33mmol), mixture is stirred 30 minutes, finally add O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (71mg, 0.48mmol) and DIPEA (125 μ l, 0.72mmol).After envrionment temperature stirs 16 hours, make resistates be adsorbed on HM-N upper, then through flash chromatography (Si-SPE, hexanaphthene: ethyl acetate, gradient is 50: 50 to 0: 100) purifying, obtain title compound, it is pale solid (103mg, 84%).LCMS (method B): R
t=2.86 minutes, M+H
+=510.
step 2:3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-third
the oxygen base)-acid amides
By 3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (100mg, 0.19mmol) be dissolved in methyl alcohol, then carry out chromatogram (
sCX-2, EtOAc is EtOAc then: MeOH: Et
3n, 89: 10: 1) purifying.Make the resistates formed be adsorbed on HM-N above, then, through flash chromatography (gradient is 100: 0 to 90: 10 for Si-SPE, methylene dichloride: MeOH) purifying, obtain title compound, it is light yellow solid (38mg, 42%).LCMS (method A): R
t=6.16 minutes, M+H
+=470.
1H?NMR(d
4-MeOH，400MHz)8.52(d，J＝5.9Hz，1H)，8.48(s，1H)，7.67(d，J＝8.8Hz，2H)，7.60(dd，J＝6.0Hz，0.8Hz，1H)，7.00(d，J＝8.7Hz，2H)，4.09(dd，J＝9.9Hz，3.4Hz，1H)，3.93-4.00(m，2H)，3.61-3.64(m，2H)。
embodiment 13:3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-
dihydroxyl-propoxy-)-acid amides
step 1:3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-diformazan
base-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By 3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (115mg, 0.26mmol), the mixture of 1N aqueous sodium hydroxide solution (0.27ml, 0.27mmol) and industrial methylated spirit (3.0ml) is 65 ℃ of heating 60 minutes.Reaction mixture is concentrated, then, with toluene (3 * 10ml) azeotropic, obtain solid residue.The solid residue of formation is dissolved in anhydrous THF (5ml), add wherein O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (75mg, 0.51mmol), EDCI (65mg, 0.34mmol), HOBt (49mg, 0.36mmol) and DIPEA (175 μ l, 1.02mmol).Reaction mixture is stirred to 48h, then concentrating under reduced pressure.Make to form to make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 95: 5) purifying, obtain title compound, it is yellow oil (119mg, 84%).LCMS (method B): R
t=3.14 minutes, M+H
+=544.
step 2:3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxy
base-propoxy-)-acid amides
By 3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (119mg, 0.22mmol) be dissolved in methyl alcohol (5.0ml), then be loaded into
on SCX-2 post (5g).Then by methyl alcohol for post (15ml) washing, subsequently by the product 2M NH of expectation
3the MeOH eluant solution.Collect elutriant the concentrated resistates that obtains.Make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 90: 10) purifying, obtain title compound, it is white solid (20mg, 18%).LCMS (method A): R
t=7.02 minutes, M+H
+=504.
1H?NMR(d
4-MeOH，400MHz)8.52(d，J＝6.2Hz，1H)，8.52(d，J＝0.9Hz，1H)，7.81(d，J＝2.0Hz，1H)，7.61(dd，J＝6.2Hz，0.9Hz，1H)，7.58(dd，J＝8.5Hz，2.0Hz，1H)，7.01(d，J＝8.5Hz，1H)，4.09-4.05(m，1H)，3.98-3.88(m，2H)，3.60-3.58(m，2H)。
embodiment 14:3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids
((R)-2,3-dihydroxyl-propoxy-)-acid amides
step 1:3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-
dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By 3-(2, the iodo-phenyl amino of the fluoro-4-of 6-bis-)-furo [3,2-c] mixture of pyridine-2-carboxylic acids ethyl ester (137mg, 0.31mmol), 1N aqueous sodium hydroxide solution (0.32ml, 0.32mmol) and industrial methylated spirit (5.0ml) is 65 ℃ of heating 60 minutes.Reaction mixture is concentrated, then, with toluene (2 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (5ml), then add O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (89mg, 0.61mmol), EDCI (77mg, 0.40mmol), HOBt (58mg, 0.43mmol) and DIPEA (213 μ l, 1.22mmol).Reaction mixture is stirred 16 hours, then concentrating under reduced pressure.Make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 95: 5) purifying, obtain title compound, it is yellow oil (63mg, 37%).LCMS (method B): R
t=2.87 minutes, M+H
+=546.
step 2:3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-
dihydroxyl-propoxy-)-acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (63mg, 0.11mmol) is dissolved in methyl alcohol (4.0ml), then is loaded into
on SCX-2 post (5g).Then by methyl alcohol for post (15ml) washing, subsequently by the product 2M NH of expectation
3the MeOH eluant solution.Collect elutriant the concentrated resistates that obtains.Make to form to make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 90: 10) purifying, obtain title compound, it is white solid (17mg, 31%).LCMS (method A): R
t=5.97 minutes, M+H
+=506.
1H?NMR(d
4-MeOH，400MHz)8.48(d，J＝6.0Hz，1H)，8.26(s，1H)，7.55(d，J＝6.0Hz，1H)，7.54-7.49(m，2H)，4.08-4.05(m，1H)，3.96-3.87(m，2H)，3.60-3.58(m，2H)。
embodiment 15:3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids
((R)-2,3-dihydroxyl-propoxy-)-acid amides
step 1:3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-
dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By 3-(2, the iodo-phenyl amino of the fluoro-4-of 5-bis-)-furo [3,2-c] mixture of pyridine-2-carboxylic acids ethyl ester (163mg, 0.37mmol), 1N aqueous sodium hydroxide solution (0.38ml, 0.38mmol) and industrial methylated spirit (4.0ml) is 65 ℃ of heating 30 minutes.By the reaction mixture vacuum concentration, then, with toluene (2 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (5ml), add afterwards O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (106mg, 0.72mmol), EDCI (91mg, 0.470mmol), HOBt (69mg, 0.51mmol) and DIPEA (250 μ l, 1.45mmol).Reaction mixture is stirred to 16 hours then concentrating under reduced pressure.Make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 95: 5) purifying, obtain title compound, it is yellow oil (152mg, 76%).LCMS (method B): R
t=3.01 minutes, M+H
+=546.
step 2:3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-
dihydroxyl-propoxy-)-acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (145mg, 0.27mmol) is dissolved in methyl alcohol (5.0ml), then is loaded into
on SCX-2 post (5g).Then by methyl alcohol for post (15ml) washing, subsequently by the product 2M NH of expectation
3the MeOH eluant solution.Collect elutriant the concentrated resistates that obtains.Make resistates be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 90: 10) purifying, obtain title compound, it is white solid (75mg, 56%).LCMS (method A): R
t=6.49 minutes, M+H
+=506.
1H?NMR(d
4-MeOH，400MHz)8.61(d，J＝0.9Hz，1H)，8.52(d，J＝6.1Hz，1H)，7.61(dd，J＝6.1Hz，0.9Hz，1H)，7.59(dd，J＝10.1Hz，5.7Hz，2H)，6.94(dd，J＝8.4Hz，7.5Hz，1H)，4.07-4.03(m，1H)，3.96-3.87(m，2H)，3.63-3.55(m，2H)。
embodiment 16:4-{[3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carbonyl] amino
the oxygen base }-piperidines-1-carboxylic acid tert-butyl ester
Mixture by 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (398mg, 1mmol), HOBT (190mg, 1.4mmol) and EDCI (240mg, 1.25mmol) in THF (5ml) stirs 1h.Add DIPEA (530 μ l, 3.0mmol) and 4-(amino oxygen base)-piperidines-1-carboxylic acid tert-butyl ester (432mg, 2.0mmol) in this mixture.After stirring is spent the night, by the reaction mixture vacuum concentration, with ethyl acetate (30ml) dilution, then use saturated NaHCO
3solution (10ml) washing.Separate organic layer, through dried over sodium sulfate vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100% to 95: 5), the resistates formed is carried out to purifying, obtain title compound, it is light yellow foam (285mg, 47%).LCMS (method A): R
t=10.43 minutes, M+H
+=597.
1H?NMR(CDCl
3，400MHz)11.86(s，1H)，8.15(s，1H)，7.66(dd，J＝10.8Hz，2.0Hz，1H)，7.61(d，J＝8.6Hz，1H)，7.51(m，1H)，7.43(dd，J＝8.8Hz，1H)，7.32(d，J＝7.7Hz，1H)，7.27(m，1H)，6.86(t，J＝8.8Hz，1H)，4.88(d(br)，J＝3.4Hz，1H)，4.60(t(br)，J＝5.5Hz，1H)，3.17(ddd，J＝13.6，8.8，3.7Hz，2H)，1.97-2.03(m，2H)，1.7-1.81(m，2H)，1.63(s，9H)。
embodiment 17:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(morpholine-4-
base)-oxyethyl group)-acid amides
Mixture by 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (199mg, 0.5mmol), HOBt (95mg, 0.7mmol) and EDCI (125mg, 0.65mmol) in THF (2ml) stirs 1h.Add DIPEA (270 μ l, 1.5mmol) and O-(2-(morpholine-4-yl) ethyl) azanol (146mg, 1.0mmol) in this mixture.After stirring is spent the night, by solution for vacuum concentration, with ethyl acetate (30ml) dilution, then use saturated NaHCO
3solution (10ml) washing.Separate organic layer, through dried over sodium sulfate vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 95: 5), the resistates formed is carried out to purifying, obtain title compound, it is foam, makes its crystallization from ether/methylene dichloride (75mg, 28%).LCMS (method A): R
t=5.67 minutes, M+H
+=527.
1HNMR(CDCl
3，400MHz)8.77(s，1H)，8.63(d，J＝0.7Hz，1H)，8.59(d，J＝5.8Hz，1H)，7.99(s，1H)，7.51(dd，J＝9.7Hz，2.0Hz，1H)，7.42-7.46(m，1H)，7.37(dd，J＝6.0，1.2Hz，1H)，6.99(t，J＝8.5Hz，1H)，4.20-4.12(m，2H)，3.92-3.80(m，2H)，3.17(ddd，J＝13.6，8.8，3.7Hz，2H)，2.03-1.97(m，2H)，1.81-1.7(m，2H)，1.68-1.61(m，2H)。
the bromo-3-of embodiment 18:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids
((R)-2,3-dihydroxyl-propoxy-) acid amides
the bromo-3-of step 1:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-
dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
The bromo-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (50mg, 0.21mmol) and the mixture of carbonyl dimidazoles (35mg, 0.21mmol) in acetonitrile (2ml) are heated 4 hours at 50 ℃.Then by (((R)-2 of O-for reaction mixture, 2-dimethyl-[1,3] dioxolane-4-yl) methyl)-azanol (46mg, 0.36mmol) solution-treated in acetonitrile (1ml), 80 ℃ of heating 3.5 hours, then cooling, then make it standing in room temperature.Reaction mixture is filtered, with the ethyl acetate washing, then collect filtrate vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: ethyl acetate, gradient is 1: 0 to 4: 1 to 0: 1 to be then methyl alcohol), the resistates formed is carried out to purifying, obtain title compound, it is brown solid (11mg, 20%).LCMS (method B): R
t=3.55 minutes, M+H
+=606/608.
the bromo-3-of step 2:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-
dihydroxyl-propoxy-) acid amides
By the bromo-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (40mg, 0.066mmol) be dissolved in the methanol solution (2.79ml of 0.067MHCl, 0.198mmol) in, then stirring at room 40 minutes.By the reaction mixture vacuum concentration, then with toluene (2 * 15ml) azeotropic.The resistates of formation is dissolved in IMS (4ml), then adds salt of wormwood, then stirring at room 4 minutes.Reaction mixture is filtered, then, with the IMS washing, then filtrate vacuum-evaporation is obtained to solid.The solid of formation is ground with acetonitrile, obtain the product of expectation, it is emulsifiable paste shape solid (29mg, 77%).LCMS (method A): R
t=9.06 minutes, M+H
+=566/568.
1H?NMR(CD
3OD)8.68(1H，s，br)，8.42(1H，s，br)，7.61(1H，dd，J＝10.2，1.9Hz)，7.52(1H，m)，7.07(1H，t，J＝8.6Hz)，4.12(1H，dd，J＝10.0，3.4Hz)，3.99(1H，dd，J＝10.0，6.8Hz)，3.96(1H，m)，3.63(2H，m)。
embodiment 19:5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid ((R)-2,3-
dihydroxyl-propoxy-)-acid amides
step 1:5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid (((R)-2,2-diformazan
base-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
By 5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid, ethyl ester (300mg, 0.70mmol), the mixture of 1N aqueous sodium hydroxide solution (0.75ml, 0.75mmol) and industrial methylated spirit (8.0ml) is 65 ℃ of heating 30 minutes.Reaction mixture is concentrated, then, with toluene (3 * 10ml) azeotropic, obtain solid residue.Solid residue is dissolved in anhydrous THF (5ml), then add O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl) azanol (106mg, 0.72mmol), EDCI (91mg, 0.47mmol), HOBt (69mg, 0.51mmol) and DIPEA (250 μ l, 1.45mmol).Reaction mixture is stirred to 18h, then concentrating under reduced pressure.It is upper that the resistates that makes to form is adsorbed on HM-N, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 95: 5) purifying, obtains title compound (124mg, 67%).LCMS (method B): R
t=3.46 minutes, M+H
+=529.
step 2:5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid ((R)-2,3-dihydroxy
base-propoxy-)-acid amides
To 5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (124mg, 0.23mmol) add concentrated hydrochloric acid (10) in suspension in methyl alcohol (5.0ml), then mixture is stirred 1 hour.Then by the reaction mixture concentrating under reduced pressure, be dissolved in methyl alcohol (5ml), then add sodium potassium carbonate (about 200mg).This mixture is stirred 5 minutes, be adsorbed on HM-N upper, then, through flash chromatography (Si-SPE, methylene dichloride: methyl alcohol, gradient is 100: 0 to 0: 100) purifying, obtain title compound, it is white solid (60mg, 54%).LCMS (method A): R
t=7.85 minutes, M+H
+=489.
1H?NMR(d
6-DMSO，400MHz)8.96(s，1H)，8.77(s，1H)，7.64(dd，J＝10.7Hz，1.9Hz，1H)，7.43(ddd，J＝8.5Hz，1.9Hz，0.9Hz，1H)，6.91(dd，J＝8.5Hz，8.5Hz，1H)，3.86-3.71(m，3H)，3.40-3.30(m，4H)。
embodiment 97:3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-carboxylic acids (1-methyl piperidine
-4-base oxygen base) acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (piperidin-4-yl oxygen base)-acid amides (80mg, 0.16mmol), tosic acid pyridine (40mg, 0.16mmol) and formaldehyde (0.05ml, the 10M aqueous solution, 0.48mmol) mixture be suspended in methyl alcohol (0.5ml), then under argon gas, stir 16 hours.Add sodium cyanoborohydride (30mg, 0.47mmol), then by the solution stirring 1h formed.Evaporating solvent then distributes the resistates of formation between ethyl acetate and sodium bicarbonate, separates organic layer, uses the salt water washing, dry (Na
2sO
4) and evaporation.Through flash chromatography (gradient is 0: 100 to 10: 100 for Si-SPE, the methanol solution of 2M ammonia: DCM), the product formed is carried out to purifying, obtain product, it is light yellow solid (50mg, 61% yield).LCMS (method A): R
t=5.49 minutes; M+H
+511.
1H?NMR(CDCl
3)1.88(2H，m)，2.08(2H，m)，2.22(2H，m)，2.31(3H，s)，2.78(2H，m)，4.08(1H，m)，6.98(1H，t，J＝8.5Hz)，7.37(1H，dd，J＝5.9，1.0Hz)，7.44(1H，m)，7.51(1H，dd，J＝9.8，1.9Hz)，7.99(1H，s)，8.59(1H，d，J＝5.9Hz)，8.63(1H，d，J＝1.0Hz)。
embodiment 98:3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxylic acids (2-(dimethyl
amino) oxyethyl group) acid amides
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(methylamino)-oxyethyl group)-acid amides (45mg, 99mmol), formaldehyde (8 μ l, 107mmol), the mixture of tosic acid pyridine (25mg, 97mmol) in ethanol (1ml) stirs 30 minutes at 0-5 ℃.Add sodium cyanoborohydride (7mg, 106mmol), then by solution stirring at room 30 minutes.Add HCl (1M, 200 μ l), then solution is loaded into
sCX-2 post (2g) is upper, with the methanol solution wash-out of ammonia.Merge suitable cut and also concentrate and obtain resistates, it,, further through flash chromatography (Si-SPE, the methanol solution that gradient is 2M ammonia: DCM 0: 100 to 10: 100) purifying, is obtained to product, it is white foam shape thing (23mg).LCMS (method A): R
t=5.12min, M+H
+484.
1H?NMR(CD
3OD)2.70(6H，s)，3.11(2H，m)，4.15(2H，m)，6.80(1H，t，J＝8.7Hz)，7.42(1H，m)，7.53(1H，dd，J＝10.6，1.9Hz)，7.61(1H，dd，J＝5.9，0.9Hz)，8.47(1H，d，J＝5.9Hz)，8.56(1H，d，J＝0.9Hz)。
the iodo-phenyl amino of the fluoro-4-of embodiment 99:(2-)-N-tert.-butoxy furo [3,2-c] pyridine-2-formyl
amine
By 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (251mg, 0.59mmol), the mixture of the 1N NaOH aqueous solution (1.77ml, 1.77mmol), methyl alcohol (15ml) and tetrahydrofuran (THF) (15ml) refluxes 2 hours.By the reaction mixture vacuum concentration, then, by toluene for resistates (3 * 15ml) azeotropic formed, obtain solid residue.Ether for solid residue (3 * 10ml) grinds, and then discards ether layer.By the solid residue vacuum-drying formed.Then solid residue is dissolved in dry DMF (5ml), then adds O-tertiary butyl hydroxylamine hydrochloride (58mg, 0.56mmol), HATU (270mg, 0.71mmol) and DIPEA (470 μ l, 2.36mmol).After envrionment temperature stirs 18 hours, evaporating solvent, then carry out purifying through preparation property HPLC to the resistates formed, and obtains title compound, and it is white solid (80mg, 23%).LCMS (method E): R
t=2.30 minutes, M+H
+=470.
1H?NMR(CDCl
3，400MHz)8.82(d，1H)，8.69(s，1H)，8.39(s，1H)，8.15(s，1H)，7.73(d，1H)，7.59(dd，1H)，7.51(d，m，1H)，6.85(t，1H)，1.4(2，1H)。
embodiment 100:(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (1-oxo thiophene
azoles alkane-3-yl) ketone
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (thiazolidine-3-yl) ketone is dissolved in methyl alcohol (1ml) and THF (1ml), then is cooled to-5 ℃.Add the solution of ozone (21mg, 0.035mmol) in water (0.5ml), then reaction mixture is stirred, last 1 hour and make it be warmed to room temperature.By ethyl acetate for reaction mixture (3ml) and water (1ml) dilution, then solid is carried out to decant.Separate each layer, water layer is extracted with ethyl acetate, then by the saturated NaHCO of organic layer merged
3the aqueous solution and salt water washing, dry (MgSO
4) and concentrated.Through reversed-phase HPLC, the oily matter formed is carried out to purifying, obtain the tfa salt of title compound, it is yellow solid (6.8mg).LCMS (method D): R
t=2.45 minutes, M+H
+=486.
embodiment 101:(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (1,1-dioxo
parathiazan-4-yl) ketone
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (parathiazan-4-yl) ketone (19mg, 0.039mmol) is dissolved in methyl alcohol (1ml) and THF (1ml), then is cooled to-5 ℃.Add the solution of ozone (30mg, 0.049mmol) in water (0.5ml), then reaction mixture is stirred, last 1 hour simultaneously and make it be warmed to room temperature.By ethyl acetate for reaction mixture (3ml) and water (1ml) dilution, then solid is carried out to decant.Separate each layer, water layer is extracted with ethyl acetate, then by the saturated NaHCO of organic layer merged
3the aqueous solution and salt water washing, dry (MgSO
4) and concentrated.Through reversed-phase HPLC, the oily matter formed is carried out to purifying, obtain the tfa salt of title compound, it is yellow solid (1.5mg).LCMS (method E): R
t=4.17 minutes, M+H
+=516.
embodiment 102:(3-(the fluoro-4-of 2,5-bis-(4-pyrazolyl) phenyl amino) furo [3,2-c] pyridine-2-
base) ((R)-3-hydroxyl pyrrolidine-1-yl) ketone
By degassed, ((4-bromo-2 for 3-, 5-difluorophenyl amino) furo [3,2-c] pyridine-2-yl) ((R)-3-hydroxyl pyrrolidine-1-yl) ketone (53mg, 0.12mmol), 1-tertbutyloxycarbonyl-pyrazoles-4-pinacol borate (53mg, 0.18mmol), Pd (PPh
3)
4(7.0mg, 0.0061mmol) and Na
2cO
3(29mg, 0.27mmol) solution reflux in glycol dimethyl ether (2.0ml), ethanol (0.7ml) and water (0.7ml) spends the night.Reaction mixture is cooled to envrionment temperature, filters, ethyl acetate washing dry for solid, obtain crude product, and it is brown solid (41mg, 80%).LCMS (method D): R
t=1.44 minutes, M+H
+=426.
1h NMR (DMSO-d
6, 400MHz) 8.77-8.82 (m, 2H), 8.66-8.68 (m, 1H), 8.07 (obviously unimodal, 2H), 7.91-7.93 (m, 1H), 7.73-7.78 (m, 1H), 7.10-7.15 (m, 1H), 4.32-4.41 (m, 1H), 3.89-4.04 (m, 2H), 3.76-3.80 (m, 1H), 3.45-3.62 (m, 2H), 1.80-2.02 (m, 2H).
embodiment 104:2-(dimethylamino formyl radical)-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c]
the pyridine-7-carboxylic acid ethyl ester
At-10 ℃ to 2-(dimethylamino formyl radical)-3-(the fluoro-4-of 2-(trimethyl silyl)-phenyl amino) furo [3; 2-c] pyridine-7-carboxylic acid ethyl ester (84mg; 0.19mmol) add iodine monochloride (0.38ml in solution in methylene dichloride (3ml); 0.38mmol; the dichloromethane solution of 1M), then solution is stirred 1 hour in this temperature.Add saturated sodium thiosulfate solution (5ml), then mixture is poured in saturated sodium thiosulfate solution (15ml).Separate water layer, then use methylene dichloride (2 * 25ml) extraction, then by the organic layer salt water washing merged, through dried over mgso vacuum concentration.Through flash chromatography (Si-SPE, methylene dichloride: t-butyl methyl ether, gradient is 1: 0 to 1: 3), the resistates formed is carried out to purifying, obtain title compound, it is yellow waxy solid (87mg, 92%).LCMS (method B): R
t=3.97 minutes, M+H
+=498.
embodiment 105:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-(hydroxymethyl)-furo [3,2-c] pyridine-2-
the carboxylic acid dimethylformamide
At-40 ℃ to 2-(dimethylamino formyl radical)-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3; 2-c] pyridine-7-carboxylic acid ethyl ester (96mg; 0.193mmol) drip lithium triethylborohydride (0.41ml in solution in THF (4ml); 0.41mmol, the THF solution of 1M).The mixture formed is stirred 30 minutes at-40 ℃, then by adding saturated ammonium chloride solution (20ml) will react cancellation.Separate water layer, then use methylene dichloride (3 * 20ml) washing, the organic layer then merged is through dried over mgso vacuum concentration.Through flash chromatography, (Si-SPE, methylene dichloride: ethyl acetate, gradient is within 1: 0 to 0: 1, to be then ethyl acetate: methyl alcohol 85: 15) resistates formed is carried out to purifying, obtain thick material.Thick material is ground in methyl alcohol, obtain title compound, it is white solid (34mg, 39%).
1H?NMR(DMSO-D
6，400MHz)3.07(6H，s，br)，4.83(2H，d，J＝5.6Hz)，5.47(1H，t，J＝5.6Hz)，6.87(1H，t，J＝8.7Hz)，7.43(1H，m)，7.66(1H，dd，J＝10.8，2.0Hz)，8.54(2H，m)，8.56(1H，s)。LCMS (method A): R
t=6.74 minutes, M+H
+=456.
embodiment 106:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-(phenoxymethyl)-furo [3,2-c] pyridine
-2-carboxylic acid dimethylformamide
To 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-(hydroxymethyl)-furo [3,2-c] pyridine-2-carboxylic acids dimethylformamide (34mg, 0.075mmol) and triphenylphosphine (20mg, 0.075mmol) add phenol (7.75mg in solution in THF (3ml), 0.083mmol) and DIAD (18.5 μ l, 0.094mmol), then by mixture stirring at room 21 hours.By ethyl acetate for reaction mixture (40ml) dilution, with 1MNaOH (15ml) and salt solution (15ml) washing.Separate organic layer, through dried over mgso vacuum concentration.Through flash chromatography, (Si-SPE, methylene dichloride: ethyl acetate, gradient is within 1: 0 to 0: 1, to be then ethyl acetate: methyl alcohol 85: 15) resistates formed is carried out to purifying, obtain thick material.Through flash chromatography, (Si-SPE, ethyl acetate: methylene dichloride: hexanaphthene 1: 4: 1) again carry out purifying, obtain title compound, it is white solid (12mg, 30%).
1h NMR (CDCl
3, 400MHz) 3.26 (6H, s, br), (5.37 2H, s), 6.94 (1H, t, J=8.6Hz), 7.02 (3H, m), 7.33 (2H, m), 7.41 (1H, m), 7.49 (1H, dd, J=9.9,1.9Hz), 8.55 (1H, s), 8.66 (2H, obviously unimodal).LCMS (method A): R
t=12.30 minutes, M+H
+=532.
the chloro-3-of embodiment 107:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids sodium
To the chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (100mg, 0.277mmol) add 1M NaOH (0.32ml, 0.32mmol) in suspension in methyl alcohol (7ml), then mixture is stirred 3 hours at 55 ℃.Make the suspension formed be cooled to room temperature, stir 17 hours, then 55 ℃ of heating 2.5 hours.By the reaction mixture vacuum concentration, toluene for resistates (2 * 20ml) azeotropic.Then the resistates water formed is ground, then filter, obtain title compound, it is white solid (74mg, 75%).
1H?NMR(CD
3OD，400MHz)6.95(1H，t，J＝8.6Hz)，7.44(1H，ddd，J＝8.4，1.8，1.2Hz)，7.54(1H，dd，J＝10.4，1.9Hz)，8.48(1H，s)，8.49(1H，s)。LCMS (method A): R
t=10.57 minutes, M+H
+=433.
the chloro-3-of embodiment 108:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxamide
To the chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids sodium (60mg, 0.110mmol) and ammonium chloride (17.5mg, 0.33mmol) add HATU (84mg in solution in DMF (1.5ml), 0.22mmol) and diisopropylethylamine (75 μ l, 0.44mmol), then by the solution that forms stirring at room 3 hours.Reaction mixture is diluted by ethyl acetate, then successively water, saturated sodium bicarbonate solution and salt water washing.Organic layer, through dried over mgso, filters and vacuum concentration.The resistates of formation is ground in acetonitrile, obtain title compound, it is yellow solid (14mg, 30%).
1H?NMR(CDCl
3，400MHz)5.69(1H，s，br)，6.30(1H，s，br)，6.98(1H，t，J＝8.4Hz)，7.46(1H，m)，7.53(1H，dd，J＝9.7，1.9Hz)，8.03(1H，s)，8.46(1H，s)，8.56(1H，s)。LCMS (method A): R
t=10.46 minutes, M+H
+=432.
embodiment 109:3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(first sulphur
acyl amino)-oxyethyl group)-acid amides
By N-(2-(amino oxygen base)-ethyl)-Toluidrin (116mg, 0.75mmol), 3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (300mg, 0.75mmol), EDC (159mg, 0.83mmol), HOBT (112mg, 0.83mmol) and DIPEA (0.13ml, 0.75mmol) be suspended in THF (5ml), then add DMF (5).By reaction mixture stirring at room 16 hours.By the reaction mixture vacuum concentration, resistates is dissolved in ethyl acetate (20ml), then use saturated sodium bicarbonate aqueous solution (20ml) washing.Ethyl acetate for water layer (2 * 10ml) washing, the salt water washing of the organic extract liquid of merging, through dried over mgso vacuum concentration.Make the resistates formed carry out flash chromatography (SiO
2, gradient is the 0-10% ethanol/methylene), obtain title compound, it is faint yellow solid (120mg, 49%).
1H?NMR(CDCl
3，400MHz)8.95(1H，s)，8.61-8.59(2H，m)，7.91(1H，s)，7.54(1H，dd，J＝9.6，1.9Hz)，7.48(1H，dt，J＝8.4，1.3Hz)，7.37(1H，dd，J＝5.9，0.8Hz)，7.03(1H，t，J＝8.4Hz)，6.09-6.06(1H，m)，4.17-4.15(2H，m)，3.47-3.43(2H，m)，3.04(3H，s)。LCMS (method A): R
t=7.34 minutes, M+H
+=535.
the chloro-3-of embodiment 138:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids
((R)-2,3-dihydroxyl-propoxy-)-acid amides
the chloro-3-of step 1:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids
By the chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ethyl ester (150mg, 0.33mmol) (the aqueous solution of 1M of sodium hydroxide for suspension in IMS (10ml), 0.832ml) process, and reaction mixture is heated 3 hours at 60 ℃.Make the mixture that forms cooling, vacuum concentration then, by thick resistates water treatment, then with acetic acid, mixture being adjusted to pH is 5.The suspension formed is filtered, collect resistates vacuum-drying, obtain title compound, it is yellow solid (105mg, 74%).
1H?NMR(DMSO-d
6400MHz)8.63(1H，s)，8.45(1H，s)，7.69(1H，d，J＝10.28Hz)，7.49(1H，d，J＝8.22Hz)，7.03(1H，s)。
the chloro-3-of step 2:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-
dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides
Under nitrogen atmosphere by the chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (177mg, 0.41mmol) suspension in anhydrous methylene chloride (6ml) is cooled to 0 ℃, then use DMF (1) and oxalyl chloride (0.102ml, 1.16mmol) to process.Reaction mixture is stirred 1 hour, then solvent removed in vacuo.By the resistates of formation, again be suspended in methylene dichloride, then use O-(((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methyl)-azanol (101mg, 0.69mmol) and DIPEA (0.172ml, 1.21mmol) solution in methylene dichloride (4ml) dropwise processes, then stir 3 hours.Reaction mixture is washed to (water, salt solution), dry (Na
2sO
4), filter and vacuum concentration, obtain title compound, it is yellow foam (207mg, 90%).Described foam without further analyze or purifying just for next step.
the chloro-3-of step 3:7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-
dihydroxyl-propoxy-)-acid amides
By the chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (((R)-2,2-dimethyl-[1,3] dioxolane-4-yl) methoxyl group)-acid amides (280mg, 0.49mmol) solution in methyl alcohol/dense HCl (the dense HCl of 0.14ml (aqueous solution) is in 25ml methyl alcohol) is in stirring at room, until showing, TLC remains without any starting raw material.By the reaction mixture vacuum concentration, methylene dichloride for resistates (11ml) and triethylamine (0.210ml) are processed, and stir 20 minutes, and then vacuum concentration.Make the solid residue formed carry out reversed-phase HPLC (Phenomenex Luna 5C18,0.1%HCO
2the gradient of H/ water based on acetonitrile), obtain title compound, it is light yellow solid (168mg, 66%).LCMS (method A): R
t=8.87 minutes, M+H
+=522.
1H?NMR(CD
3OD?400MHz)3.61(1H，dd，J＝11.4，5.3Hz)，3.65(1H，dd，J＝11.4，5.1Hz)，3.94(1H，m)，3.99(1H，dd，J＝10.0，6.8Hz)，4.11(1H，dd，J＝10.0，3.5Hz)，7.07(1H，t，J＝8.6Hz)，7.52(1H，m)，7.61(1H，dd，J＝10.2，1.9Hz)，8.38(1H，s)，8.56(1H，s)。
the fluoro-3-of embodiment 139:7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-
hydroxyl-oxethyl) acid amides
the fluoro-3-of step 1:7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids
The fluoro-3-of 7-(the fluoro-4-iodophenyl of 2-the amino)-suspension of furo [3,2-c] pyridine-2 carboxylic acid, ethyl ester (4.00g, 9.0mmol) in ethanol (150ml), in stirring at room, then processed with 1M NaOH, and 60 ℃ of heating 2 hours.Solvent removed in vacuo, then, by resistates water (50ml) dilution, being acidified to pH with glacial acetic acid is 4.Collect after filtration the solid sediment formed, wash with water, then at 40C vacuum-drying (P
2o
5), obtain title compound (3.75g, quantitative).LCMS (method B): R
t3.51 minute, M+H
+417.
the fluoro-3-of step 2:7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-(ethene
base oxygen base) oxyethyl group) acid amides
By the fluoro-3-of 7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids (3.75g, 9.0mmol) suspension in anhydrous DCM (100ml) stirs and use oxalyl chloride (2.24ml at 0 ℃ under argon gas, 25.7mmol) dropwise process, holding temperature is below 5 ℃.The mixture of formation is stirred 1 hour again, then vacuum concentration.At 0 ℃, resistates is suspended in to anhydrous DCM (100ml) again under argon gas in, then use O-(2-(vinyl oxygen base) ethyl) azanol (1.40g, 14.3mmol) and diisopropylethylamine (4.70ml, 3.48g 27mmol) solution in DCM (20ml) is dropwise processed.The solution formed is stirred and lasted 3 hours make it be warmed to room temperature, then successively water and saturated brine washing, dry (MgSO
4), filter and vacuum-evaporation, obtain resistates, make it carry out flash chromatography (SiO
2, gradient is the 0-10% ethyl acetate/dichloromethane) and purifying, obtain title compound, it is yellow solid (2.41g, 53%).LCMS (method B): R
t=3.82 minutes, M+H
+502.
the fluoro-3-of step 3:7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl second
the oxygen base) acid amides
By the fluoro-3-of 7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-(vinyl oxygen base) oxyethyl group) acid amides (2.41g, 4.80mmol) be suspended in ethanol (100ml), then add concentrated hydrochloric acid (2.0ml).By mixture stirring at room 1 hour, then by adding the saturated sodium bicarbonate aqueous solution neutralization.Then solvent removed in vacuo, be dissolved in the resistates of formation in DCM, washes with water, dry (MgSO
4), filter, then vacuum-evaporation obtains thick resistates, makes it carry out flash chromatography (SiO
2, gradient is 0 to 2% ethanol/methylene) and purifying, then recrystallization (methanol aqueous solution), obtain title compound, and it is yellow spicule (0.837g, 36%).LCMS (method A): R
t9.15 minute, M+H
+476.
1H?NMR(DMSO-d
6，400MHz)3.60(2H，m)，3.88-3.93(2H，m)，4.70(1H，br?s)，7.02(1H，t，J＝8.68Hz)，7.46-7.49(1H，m)，7.68(1H，dd，J＝10.55，1.92Hz)，8.36(1H，s)，8.40(1H，s)，8.64(1H，d，J＝2.58Hz)，11.95(1H，s)。
embodiment 20-96 and 111-159
compound in table 2,3 and 4 is to be prepared by the general method of hereinafter summarizing:
Acid amides and hydroxamic acid ester (hydroxamate) are to use coupling general method described below, from suitable acid, prepare.In some instances, do not separate intermediate acid, the thick carboxylate salt produced according to the saponification general method is carried out to linked reaction.
the saponification general method
The mixture of carboxylicesters, the 1N NaOH aqueous solution (1-2 equivalent) and EtOH is heated 1 hour at 70 ℃.By the reaction mixture vacuum concentration, then with methylbenzene azeotropic, obtain thick carboxylate salt.
the coupling general method
Suitable carboxylic acid or carboxylate salt are suspended in anhydrous THF, then add suitable azanol or amine (1-4 equivalent), EDCI (1-2 equivalent) or HATU (1-2 equivalent), HOBt (1-2 equivalent) and DIPEA (2-4 equivalent).In some instances, add DMF as cosolvent to improve solvability.In envrionment temperature, stir until after reaction end (LCMS/TLC), by the reaction mixture vacuum concentration.The resistates of formation is dissolved in ethyl acetate, washes with water, then separate organic layer, through dried over sodium sulfate, vacuum concentration then, a kind of purifying that carries out in general purification process described below.Then if necessary, use a kind of in deprotection condition described below to remove any protecting group.
the deprotection general method
Method A: in envrionment temperature is added to the mixture of substrate in appropriate solvent of protection by the HCl aqueous solution (1N or 2N).Mixture is stirred until analyze (TLC/LCMS) and shown that starting raw material exhausts.By the reaction mixture neutralization, vacuum concentration, then carry out purifying.
Method B: the solution by substrate in methyl alcohol is loaded into
on the SCX-2 post.Then by the post methanol wash, then use the product of 2M ammonia/MeOH wash-out expectation, and collect elutriant, then the concentrated resistates that obtains.Resistates is carried out to purifying.
Method C: the solution by TBAF in THF is added in the solution of silyl ether (silyl ether), and mixture is stirred in envrionment temperature, until analyze (TLC/LCMS), shows that starting raw material exhausts.Then the reaction mixture vacuum concentration is carried out to purifying.
Method D: TFA is added in pure substrate or the solution of substrate in DCM.Reaction mixture is stirred in envrionment temperature, until analyze (TLC/LCMS), show that starting raw material exhausts.By the reaction mixture vacuum concentration, then carry out purifying.
Method E: the solution by 20% piperidines in DME is added in substrate.Reaction mixture is stirred in envrionment temperature, until analyze (TLC/LCMS), show that starting raw material exhausts.Then reaction mixture is concentrated.
Method F: the solution by 4N HCl in dioxane is added in substrate.Reaction mixture is stirred in envrionment temperature, until analyze (TLC/LCMS), show that starting raw material exhausts.Then reaction mixture is concentrated.
Method G: during the separatory such as grade (3 molar equivalent) of the solution [dense HCl (0.14ml) is in methyl alcohol (25ml)] of the HCl that will newly prepare in envrionment temperature in methyl alcohol is added to the substrate of coupling.Mixture is stirred until analyze (TLC/LCMS) and shown that starting raw material exhausts.Inclusion is evaporated to dry, then resistates is dissolved in methylene dichloride, process 10 minutes at triethylamine for room temperature (3 molar equivalent).Then by the mixture vacuum concentration, resistates is carried out to purifying.
the purifying general method
Method A:Si-SPE or Si-ISCO, ethyl acetate/hexanaphthene gradient.
Method B:Si-SPE or Si-ISCO, ethyl acetate/DCM gradient.
Method C:Si-SPE or Si-ISCO, methyl alcohol/DCM gradient.
Method D:Si-SPE or Si-ISCO, the methanol/ethyl acetate gradient.
Method E: reversed-phase HPLC Phenomenex Luna 5 phenyl/hexyl, the gradient of 0.1%TFA/ water based on methyl alcohol.
Method F: reversed-phase HPLC Phenomenex Luna 5 phenyl/hexyl, the gradient of 0.1%TFA/ water based on acetonitrile.
Method G: reversed-phase HPLC Phenomenex Luna 5 phenyl/hexyl, 0.1%HCO
2h/ water is based on the methyl alcohol gradient.
Method H: reversed-phase HPLC Phenomenex Luna 5 phenyl/hexyl, 0.1%HCO
2the gradient of H/ water based on acetonitrile.
Method I: the solution by substrate in methyl alcohol is loaded into
on the SCX-2 post.Then by the post methanol wash, use afterwards the product of 2M ammonia/MeOH wash-out expectation.
Method J:Si-SPE or Si-ISCO, the ethyl acetate/hexane gradient.
Method K: reversed-phase HPLC Sunfire C18, the gradient of 0.05%TFA/ water based on acetonitrile.
Method L:Si-SPE or Si-ISCO, ethanol/ethyl acetate gradient.
Method M:Si-SPE, then ether/pentane gradient is the methanol/ether gradient.
The deviation of general method:
1in hot methanol, grind;
2recrystallization from ethyl acetate;
3in ether, grind;
4recrystallization from ether;
5from 5%MeOH/CHCl
3middle recrystallization;
6si-SPE, eluent is that then ether/pentane is methanol/ether;
7in ethyl acetate, grind;
8carry out the ester saponification with lithium hydroxide;
9use the C18 post;
10reaction is carried out in DMF;
11recrystallization from chloroform/methanol;
12in acetonitrile, grind;
13use DMF as the reaction cosolvent;
14recrystallization from methyl alcohol;
15carry out final wash-out by 10% methanol/ethyl acetate;
16at 55 ℃ of reacting by heating mixtures;
17in ether/DCM, grind.
table 2
table 3
table 4
Claims (19)
1. the compound or its salt of formula I:
Wherein
Z
1for CR
1or N;
Z
2for N;
Z
3for CR
3;
Z
4for CR
4or N;
Z wherein
1, Z
2, Z
3and Z
4in one or two be N;
R
1, R
3and R
4independently be selected from H, halogen, CN, CF
3,-(CR
14r
15)
noR
11, C
1-C
12alkyl and phenyl;
W is
R
5and R
6independently be selected from H or C
1-C
12alkyl;
X
1be selected from R
11,-OR
11or-S (O)
2r
11, work as X
1for R
11or-OR
11the time ,-R
5and X
1in R
11perhaps-R
5and X
1in-OR
11the optional nitrogen-atoms be connected with them connects together to form and has 0-2 the first saturated rings of extra heteroatomic 4-7 that is selected from O and S, and wherein said ring optionally is selected from following one or more groups and replaces: halogen, CN, CF
3,-OCF
3,-NO
2, oxo ,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
ns (O)
2r
16and R
21;
X
2for phenyl, described phenyl optionally independently is selected from following one or more groups and is replaced: halogen, CN, CF
3,-OCF
3,-NO
2,-Si (C
1-C
6alkyl)
3,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16and R
21;
R
11for H, C
1-C
12alkyl, heterocyclic radical, phenyl or heteroaryl, wherein said heterocyclic radical is selected from piperidino-(1-position only), THP trtrahydropyranyl, tetrahydrofuran base, azetidinyl and pyrrolidyl, and described heteroaryl is selected from pyrazolyl, imidazolyl, thiazolyl, different
the azoles base,
azoles base and isothiazolyl; R
11in each described alkyl, heterocyclic radical, phenyl and heteroaryl is independent optionally independently is selected from following one or more groups and replaces :-(CR
19r
20)
nc (=Y ') OR
16,-(CR
19r
20)
nnR
16r
17,-(CR
19r
20)
noR
16,-(CR
19r
20)
n-SR
16,-(CR
19r
20)
nnR
16c (=Y ') R
17,-(CR
19r
20)
nnR
16c (=Y ') OR
17,-(CR
19r
20)
ns (O)
2r
16and R
21;
R
14and R
15independent is H or C
1-C
12alkyl;
Each R
16and R
17independent is H, C
1-C
12alkyl, C
2-C
8thiazolinyl, phenyl, pyridyl, wherein said alkyl optionally is selected from following one or more groups and is replaced :-OH ,-SH;
R
19and R
20independently be selected from H, C
1-C
12alkyl;
R
21for C
1-C
12alkyl, C
2-C
8thiazolinyl, C
2-C
8alkynyl, cyclopropyl, heterocyclic radical, phenyl or heteroaryl, described heterocyclic radical is selected from morpholino, pyrrolidyl, piperidino-(1-position only) and 1,3-dioxane amyl group, and described heteroaryl is selected from pyrazolyl, imidazolyl, thiazolyl, different
the azoles base,
azoles base, isothiazolyl and pyridyl, wherein R
21in each member optionally by one or more C
1-C
6alkyl replaces;
Each Y ' is independent is O or S; And
N is 0 or 1.
2. the compound of claim 1, it is selected from formula I-b, I-f:
3. the compound of claim 2, wherein X
1be selected from:
4. the compound of claim 2, wherein X
1be selected from:
5. the compound of claim 2, wherein X
1for R
11, and R
11and R
5the nitrogen-atoms be connected with them formation that connects together:
6. the compound of claim 2, wherein X
2for
7. the compound of claim 2, wherein R
1be selected from H, CH
3, CF
3, CN ,-OR
11and Cl.
8. the compound of claim 2, wherein R
3be selected from H, CH
3, F or CF
3.
9. the compound of claim 2, wherein R
4be selected from CF
3, Br, Cl or CN.
10. the compound of claim 2, wherein R
4be selected from Cl, Br, Me, Et, F, CF
3or-OH.
11. the compound of claim 2, wherein R
5for H or methyl.
12. the compound of claim 2, wherein R
6for H or methyl.
13. a compound, it is selected from:
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the bromo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the fluoro-phenyl amino of 4-ethynyl-2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids cyclo propyl methoxy-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(vinyl oxygen base)-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of 4-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(2-chlorine-4-iodine-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2,6-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2,5-bis-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
4-{[3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carbonyl] the amino oxygen base }-piperidines-1-carboxylic acid tert-butyl ester,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(morpholine-4-yl)-oxyethyl group)-acid amides,
The bromo-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-) acid amides,
5-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [2,3-d] pyrimidine-6-carboxylic acid ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-carboxylic acids (1-methyl piperidine-4-base oxygen base) acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxylic acids (2-(dimethylamino) oxyethyl group) acid amides,
(the iodo-phenyl amino of the fluoro-4-of 2-)-N-tert.-butoxy furo [3,2-c] pyridine-2-carboxamide,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (1-oxo thiazolidine-3-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (1,1-dioxo parathiazan-4-yl) ketone,
(3-(the fluoro-4-of 2,5-bis-(4-pyrazolyl) phenyl amino) furo [3,2-c] pyridine-2-yl) ((R)-3-hydroxyl pyrrolidine-1-yl) ketone,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-(hydroxymethyl)-furo [3,2-c] pyridine-2-carboxylic acids dimethylformamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-(phenoxymethyl)-furo [3,2-c] pyridine-2-carboxylic acids dimethylformamide,
The chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids sodium,
The chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(methylsulfonyl amino)-oxyethyl group)-acid amides,
The chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
The fluoro-3-of 7-(the fluoro-4-iodophenyl of 2-amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxethyl) acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (piperidin-4-yl oxygen base)-acid amides one formate,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxamide,
The iodo-phenyl of the fluoro-4-of 3-[(2-)-methyl-amino]-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-methyl-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids oxyamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (tetrahydropyran-4-base oxygen base) acid amides,
3-(the chloro-phenyl amino of the bromo-2-of 4-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-{[3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carbonyl]-the amino oxygen base }-azetidine-1-carboxylic acid tert-butyl ester,
[3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-yl]-(4-hydroxyl-different
azoles alkane-2-yl)-ketone,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids methoxyl group-acid amides,
3-(the fluoro-4-methoxyl group-phenyl amino of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-amino-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids [2-(2-oxo-pyrrolidin-1-yl)-oxyethyl group]-acid amides,
3-(the fluoro-4-of 2-(hydroxymethyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the fluoro-4-methyl-phenyl amino of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
(2-{[3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carbonyl]-the amino oxygen base }-ethyl)-methyl-t-butyl carbamate,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(methylamino)-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((S)-pyrrolidin-3-yl oxygen base)-acid amides one formate,
The chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
7-cyano group-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (azetidine-3-base oxygen base)-acid amides one formate,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-isobutoxy furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-isopropoxy furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-(benzyl oxygen base) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-(3-hydroxyl propoxy-) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-[3-(pyridine-2-formamido group) propoxy-] furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-[3-(pyridine-3-formamido group) propoxy-] furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-[3-(pyridine-4-formamido group) propoxy-] furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-propoxy-furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-oxyethyl group furo [3,2-c] pyridine-2-carboxamide,
N-(2-(benzyl oxygen base)-2-methyl propoxy-)-3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxylic acids 2-hydroxy-2-methyl propyl ester,
N-(2-hydroxyl-oxethyl)-3-(the bromo-2-fluorophenyl of 4-amino) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-1-methyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-propoxy-)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-1-(hydroxymethyl)-oxyethyl group)-acid amides,
N-[3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carbonyl]-Toluidrin,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-(piperidin-1-yl)-oxyethyl group)-acid amides,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((R)-3-hydroxyl pyrrolidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((3S, 4S)-3,4-dihydroxy pyrrolidine-1-yl) ketone,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(3-hydroxypropyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-methoxy ethyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-sec.-propyl furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-cyclopropyl ethyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(3-(dimethylamino) propyl group) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-(2-hydroxyl-oxethyl) ethyl) furo [3,2-c] pyridine-2-carboxamide,
N-(3-(1H-imidazoles-1-yl) propyl group)-3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(1,3-dihydroxyl, third-2-yl) furo [3,2-c] pyridine-2-carboxamide,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (thiazolidine-3-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((S)-3-hydroxyl pyrrolidine-1-yl) ketone,
(3-(4-bromo-2,5-difluorophenyl amino) furo [3,2-c] pyridine-2-yl) ((R)-3-hydroxyl pyrrolidine-1-yl) ketone,
(3-(the bromo-2-fluorophenyl of 4-amino) furo [3,2-c] pyridine-2-yl) ((R)-3-hydroxyl pyrrolidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((3S, 4R)-3,4-dihydroxy pyrrolidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((R)-3-amino-pyrrolidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((S)-3-hydroxy piperidine-1-yl) ketone,
3-(the fluoro-4-iodophenyl of 2-amino)-N-((S)-1-hydroxyl third-2-yl) furo [3,2-c] pyridine-2-carboxamide,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (2-(thiazol-2-yl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (3-(methyl sulphonyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((S)-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (2-(hydroxymethyl) piperidin-1-yl) ketone,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-hydroxyethyl)-N-methyl furan is [3,2-c] pyridine-2-carboxamide also,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-hydroxyethyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N, the N-dimethyl furan is [3,2-c] pyridine-2-carboxamide also,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2,3-dihydroxypropyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-((R)-1-hydroxyl third-2-yl) furo [3,2-c] pyridine-2-carboxamide,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (3-(hydroxymethyl) piperidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((R)-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (4-hydroxy piperidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((R)-3-hydroxy piperidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (morpholino) ketone,
3-(the fluoro-4-iodophenyl of 2-amino)-N-methyl furan is [3,2-c] pyridine-2-carboxamide also,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-(2,2-dimethyl-1,3-dioxolane-4-yl) ethyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(3,4-dihydroxyl butyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(2-((S)-2,2-dimethyl-1,3-dioxolane-4-yl) ethyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-((S)-3,4-dihydroxyl butyl) furo [3,2-c] pyridine-2-carboxamide,
3-(the fluoro-4-iodophenyl of 2-amino)-N-isopentyl furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-(phenyl oxygen base) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-(2-hydroxy-2-methyl propoxy-) furo [3,2-c] pyridine-2-carboxamide,
N-(1-hydroxy-2-methyl third-2-base oxygen base)-3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-N-(4-hydroxy-2-methyl fourth-2-base oxygen base) furo [3,2-c] pyridine-2-carboxamide,
N-((pyridine-2-yl) methoxyl group)-3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxamide,
N-(1-phenyl ethoxy)-3-(the iodo-phenyl amino of the fluoro-4-of 2-) furo [3,2-c] pyridine-2-carboxamide,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2-hydroxyl-propoxy-)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((S)-2-hydroxyl-propoxy-)-acid amides,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (3-hydroxy-3-methyl pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((3R, 4R)-3-amino-4-hydroxy pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (3-hydroxy azetidine-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 3R)-3-hydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 3R, 4R)-3,4-dihydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 4R)-4-hydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2S, 4R)-4-hydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 4R)-4-amino-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(3-hydroxypropyl)-N-methyl furan is [3,2-c] pyridine-2-carboxamide also,
3-(the fluoro-4-iodophenyl of 2-amino)-N-(1H-pyrazole-3-yl) furo [3,2-c] pyridine-2-carboxamide,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 3S)-3-hydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 3R, 4S)-3,4-dihydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-phenyl-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-methyl-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
2-((R)-2,3-dihydroxyl-propoxy-carbamyl)-3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-7-carboxylic acid ethyl ester
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (1H-imidazoles-2-ylmethyl)-acid amides,
The chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides,
The fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (piperidines-3-base oxygen base)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((S)-1-(pyrrolidin-2-yl) methoxyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((1H-imidazol-4 yl) methoxyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids [2-(1H-imidazol-4 yl)-ethyl]-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-4-methyl-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
3-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (cyclopropyl methyl)-(2-(vinyl oxygen base)-oxyethyl group)-acid amides one formate,
3-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino-furo [3,2-c] pyridine-2-carboxamide,
The chloro-3-of 4-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
(azetidine-1-yl) (3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ketone,
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) (3-(hydroxymethyl) azetidine-1-yl) ketone,
The chloro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((S)-pyrrolidin-3-yl oxygen base)-acid amides,
The chloro-3-of 7-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
The fluoro-3-of 7-(the fluoro-4-of 2-(methyl sulfenyl)-phenyl amino)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-oxyethyl group)-acid amides,
[(3-(the iodo-phenyl amino of the fluoro-4-of 2-)-7-methyl-furo [3,2-c] pyridine-2-yl]-((2S, 4R)-4-hydroxyl-2-(hydroxymethyl)-pyrrolidin-1-yl) ketone,
The fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((S)-2-hydroxyl-propoxy-)-acid amides,
The fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids (2-hydroxyl-1,1-dimethyl-oxyethyl group)-acid amides,
[the fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-yl]-((R)-3-hydroxyl-pyrrolidin-1-yl)-ketone,
((3S, 4S)-3,4-dihydroxyl-pyrrolidin-1-yl)-[the fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-yl]-ketone,
The fluoro-3-of 7-(the iodo-phenyl amino of the fluoro-4-of 2-)-furo [3,2-c] pyridine-2-carboxylic acids ((R)-2,3-dihydroxyl-propoxy-)-acid amides, and
(3-(the fluoro-4-iodophenyl of 2-amino) furo [3,2-c] pyridine-2-yl) ((2R, 3S, 4S)-3,4-dihydroxyl-2-(hydroxymethyl) pyrrolidin-1-yl) ketone.
14. a pharmaceutical composition, compound and pharmaceutically acceptable carrier that it comprises any one in claim 1,3,5-12 and 13.
15. the purposes of the compound of any one in the medicine for the preparation of suppress abnormal cell growth or overmedication proliferative disease in Mammals in claim 1-13.
16. the purposes of the compound of any one in the medicine for the preparation for the treatment of diseases associated with inflammation in Mammals in claim 1-13.
17. the purposes of the pharmaceutical composition of claim 14 in the medicine for the preparation of suppress abnormal cell growth or overmedication proliferative disease in Mammals.
18. the purposes of the pharmaceutical composition of claim 14 in the medicine for the preparation for the treatment of diseases associated with inflammation in Mammals.
19. the purposes of the pharmaceutical composition of claim 14 in the medicine for the preparation of treat autoimmune disorder, destructive osteopathia, proliferative disease, infectious diseases, virus disease, fibrotic disease, neurodegenerative disease, pancreatitis or kidney disease in Mammals.
Applications Claiming Priority (9)
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| US83916106P | 2006-08-21 | 2006-08-21 | |
| US60/839,161 | 2006-08-21 | ||
| US87159106P | 2006-12-22 | 2006-12-22 | |
| US60/871,591 | 2006-12-22 | ||
| US91762307P | 2007-05-11 | 2007-05-11 | |
| US60/917,623 | 2007-05-11 | ||
| US94474107P | 2007-06-18 | 2007-06-18 | |
| US60/944,741 | 2007-06-18 | ||
| PCT/US2007/076344 WO2008024725A1 (en) | 2006-08-21 | 2007-08-20 | Aza-benzofuranyl compounds and methods of use |
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| CN105384754B (en) * | 2014-09-02 | 2018-04-20 | 上海科州药物研发有限公司 | Heterocycle compound as kinases inhibitor and its preparation method and application |
| CN104610075B (en) * | 2015-02-11 | 2017-08-08 | 安徽省科学技术研究院 | A kind of synthetic method of the butanol of 4 amino 1 |
| CN113979909A (en) * | 2021-10-21 | 2022-01-28 | 上海吉奉生物科技有限公司 | Synthesis method of (3S,5R) -5- (hydroxymethyl) pyrrolidine-3-alkoxide |
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| US6653346B1 (en) * | 2002-02-07 | 2003-11-25 | Galileo Pharmaceuticals, Inc. | Cytoprotective benzofuran derivatives |
| WO2005061476A2 (en) * | 2003-12-22 | 2005-07-07 | Basilea Pharmaceutica Ag | Aroylfuranes and aroylthiophenes |
| WO2007027855A2 (en) * | 2005-09-01 | 2007-03-08 | Array Biopharma Inc. | Raf inhibitor compounds and methods of use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6653346B1 (en) * | 2002-02-07 | 2003-11-25 | Galileo Pharmaceuticals, Inc. | Cytoprotective benzofuran derivatives |
| WO2005061476A2 (en) * | 2003-12-22 | 2005-07-07 | Basilea Pharmaceutica Ag | Aroylfuranes and aroylthiophenes |
| WO2007027855A2 (en) * | 2005-09-01 | 2007-03-08 | Array Biopharma Inc. | Raf inhibitor compounds and methods of use thereof |
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