CN102718745A - Novel amino pyridine compound, its preparation method, pharmaceutical composition containing compound and application thereof - Google Patents
Novel amino pyridine compound, its preparation method, pharmaceutical composition containing compound and application thereof Download PDFInfo
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- CN102718745A CN102718745A CN2011100791339A CN201110079133A CN102718745A CN 102718745 A CN102718745 A CN 102718745A CN 2011100791339 A CN2011100791339 A CN 2011100791339A CN 201110079133 A CN201110079133 A CN 201110079133A CN 102718745 A CN102718745 A CN 102718745A
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- 0 CC**C(C)C(C1C(C)(C)CC1C1CC1)([C@@]1C(C2)C2CC1)[C@]1C=CC=CC=CC=C/C=C1 Chemical compound CC**C(C)C(C1C(C)(C)CC1C1CC1)([C@@]1C(C2)C2CC1)[C@]1C=CC=CC=CC=C/C=C1 0.000 description 2
- VVDCRJGWILREQH-UHFFFAOYSA-N CC(C)(C)OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O Chemical compound CC(C)(C)OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
- JNHQLHUOWISSQS-UHFFFAOYSA-N CC(c(c(Cl)ccc1F)c1Cl)Sc1c(N)ncc(C(CC2)=CCN2C(N(C)C)=O)c1 Chemical compound CC(c(c(Cl)ccc1F)c1Cl)Sc1c(N)ncc(C(CC2)=CCN2C(N(C)C)=O)c1 JNHQLHUOWISSQS-UHFFFAOYSA-N 0.000 description 1
- MXIDXFFVYRISSH-UHFFFAOYSA-N CC(c(c(Cl)ccc1F)c1Cl)Sc1c(N)ncc(C2=CCNCC2)c1 Chemical compound CC(c(c(Cl)ccc1F)c1Cl)Sc1c(N)ncc(C2=CCNCC2)c1 MXIDXFFVYRISSH-UHFFFAOYSA-N 0.000 description 1
- FERXSPCVEYOEDT-LBPRGKRZSA-N C[C@@H](c(c(Cl)ccc1F)c1Cl)Sc1c(N)ncc(-c2c[n](C3CCNCC3)nc2)c1 Chemical compound C[C@@H](c(c(Cl)ccc1F)c1Cl)Sc1c(N)ncc(-c2c[n](C3CCNCC3)nc2)c1 FERXSPCVEYOEDT-LBPRGKRZSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, specifically to a compound which is used as a receptor tyrosine kinase MET inhibitor and is shown in the formula I, its enantiomer, diastereomer, racemate and their mixture or its pharmaceutically acceptable salt, a preparation method thereof, a pharmaceutical composition containing the compound and an application thereof.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to as amido pyridine compounds and their, its preparation method of receptor tyrosine kinase MET suppressor factor, the pharmaceutical composition that contains this compounds and purposes.
Background technology
Targeted therapy has produced great effect to cancer therapy undoubtedly.The generation of tumour, evolution, diffusion and tumor vascular depends on various signal transduction pathways.The purpose that reaches the treatment tumour through these signal paths of target makes remarkable progress, and has many medicines successfully to go on the market.For example, the cancer therapy drug imatinib (imatinib) based on the exploitation of ABL Tyrosylprotein kinase has curative effect preferably to chronic granulocytic leukemia (CML).In recent years, the member of Met proto-oncogene family has received extensive concern.Said Met family comprises Met (also being called c-Met) and Ron acceptor.LCK c-Met is that a kind of cell surface receptor is HGFr (HGFR), is encoded by the Met proto-oncogene.Different with most other receptor tyrosine kinases, sophisticated Met is by the outer α chain (50kDa) of born of the same parents and the structure performance function of β chain (140kDa, born of the same parents' inner segment that will contain the kinases district is anchored on the cytolemma) the composition heterodimer of striding film.HGF is the part of Met, as a multi-functional cytokine, can bring into play short migration, anti-apoptosis and mitogenetic effect.
C-Met has high expression level and is closely related with poor prognosis in the cancer of the overwhelming majority and part sarcoma, like lung cancer, mammary cancer, colorectal carcinoma, prostate cancer, pancreas cancer, cancer of the stomach, liver cancer, ovarian cancer, kidney, neurospongioma, melanoma etc.C-Met perhaps passes through the Tyrosylprotein kinase of other pathway activations born of the same parents inner segment through interacting with its part HGF/SF, inducing cell propagation, invasion and attack, migration, and the inhibition apoptosis, the promotion vasculogenesis plays an important role in the incidence and development process of tumour.
In tumour, the kinase whose abnormal activation mechanism of c-Met mainly contains the autocrine and the paracrine loop of Met gene amplification, Met transgenation, the rise of c-Met transcriptional level, ligand dependent.Met gene amplification and the albumen that thereupon produces cross expression and the composing type activation is present in numerous human primary carcinoma, comprises in the cancer of the stomach and the esophageal carcinoma, the nonsmall-cell lung cancer and medulloblastoma to EGFR suppressor factor acquired resistance.The Met gene also can carry the reactivity sudden change.The sickness rate dependency of various Met kind systems and somatic mutation and tumour is lower.The activation of modal Met composing type is that the Met of non-gene amplification transcribes rise in human tumor, thereby causes protein expression to increase.In addition, HGF self can activate transcribing of Met, and also can promote the dispersion of cancer cells through the mode positive regeeration of paracrine.HGF also can be more common in glioma, mammary cancer, rhabdosarcoma and osteosarcoma with the form abnormal activation Met of autocrine.
Be different from other kinases; Can there be interaction in c-Met with other tumour associated molecules of cell surface; For example integrin family, dead associated receptor, other receptor tyrosine kinases etc., thus the tumour correlation effect is amplified in crosslinked activation, has greatly promoted the incidence and development of tumour; Wherein c-Met has played the effect of hinge, suppresses the effect that it just can suppress a plurality of tumour target spot performances.
Especially EGFR receptor tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance that it should be noted that clinical application causes just because of Met gene activation ERBB3 signal transduction pathway.The in vitro tests of carrying out simultaneously shows that behind blocking-up c-Met signal, Iressa can recover curative effect.Therefore the drug combination of c-Met suppressor factor and EGFR suppressor factor can delay the generation of EGFR-TKIs acquired resistance, prolongs its clinical work-ing life, and it has the important clinical meaning.
As previously mentioned, the signal transduction of blocking-up HGF-c-Met can be used as one of strategy of antineoplaston.This path of selective exclusion not only can suppress tumor growth, can also suppress the transfer of tumour.Mainly be directed against the target c-Met suppressor factor research of HGF-c-Met signal path at present: the biological antagonist of HGF and c-Met, the micromolecular inhibitor of inhibition PTK catalytic activity and the specific antibody that is directed against HGF and c-Met through 3 kinds of strategies.Wherein the overwhelming majority is in the preclinical study stage, and minority gets into the clinical study stage.For example, the injection people source monoclonal antibody Rilotumumab of Amgen company research and development has been in clinical stage second phase, and its indication comprises nonsmall-cell lung cancer, large bowel cancer, prostate cancer, digestive tract cancer etc.The PF-02341066 micromolecular inhibitor of Pfizer company research and development has been in clinical three stages phase.
Because c-Met suppressor factor class, especially micromolecular inhibitor series antineoplastic medicament many places do not come into the market in clinical study as yet, and antibody drug is often relatively more expensive, wide space is provided for the research and development of such medicine.Therefore, the c-Met kinases is a target that is rich in the antitumor drug research of prospect.
Summary of the invention
One object of the present invention is to provide the amido pyridine compounds and their shown in a kind of general formula (I), its pharmaceutically useful salt, enantiomer, diastereomer or racemic modification.
Another object of the present invention is to provide the preparation method of compound shown in a kind of above-mentioned general formula (I).
A further object of the present invention is to provide a kind of pharmaceutical composition that comprises compound shown in one or more above-mentioned general formulas (I) of treating significant quantity or its pharmaceutically useful salt.
Another purpose of the present invention is to provide compound shown in the above-mentioned general formula (I) to be used to treat the relevant cell proliferative diseases of Tyrosylprotein kinase c-Met signal transduction pathway, the for example purposes in the medicine of cancer, hyperplasia, restenosis, immune disorders and inflammation in preparation.
Compound of the present invention can be used for suppressing Tyrosylprotein kinase, particularly receptor tyrosine kinase Met.
The invention provides compound shown in a kind of general formula (I), its pharmaceutically useful salt, enantiomer, diastereomer or racemic modification,
Wherein:
X is-S-,-S (O)
2-,-S (O)-,-SO
2N (R
5)-,-CO-or-CON (R
5)-;
M is 0 or 1;
R
1For replacing or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical, replace or unsubstituted C6-C10 aryl, perhaps
Said heterocyclic radical contains 1～4 heteroatoms that is selected from oxygen, sulphur and the nitrogen;
Said R
1In the aryl of substituted saturated or undersaturated C3-C12 heterocyclic radical or said substituted C6-C10 on comprise 1～5 substituting group, said substituting group be alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR
7R
8,-OR
3COR
6,-CON (R
1) R
3R
6,-CON (R
1) R
3NR
6R
7,-R
3CONR
6R
7,-COR
3OH, phenyl, substituted phenyl, naphthyl, xenyl or replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical; Wherein said substituted phenyl comprises 1～5 substituting group, this substituting group be independently of one another alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, saturated or undersaturated C3-C12 heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR
7R
8Said replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain 1-4 and are selected from the heteroatoms in oxygen, sulphur and the nitrogen, and replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain one or more alkyl that are selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, saturated or undersaturated C3-C12 heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-R
3R
6,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CONR
6R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR/R
8In substituting group;
R
2Be the alkyl of hydrogen, halogen, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C6 straight or branched, the unsaturated alkyl of C2-C6 straight or branched, the alkoxyl group of C1-C6 straight or branched, the alkyloyl of C1-C6 straight or branched or the alkylamino of C1-C6 straight or branched;
R
1, R
2Can be interconnected to ring;
R
3, R
4Be the alkoxyl group, C3-C12 cyclic hydrocarbon radical, the alkyloyl of C1-C6 straight or branched, the alkylamino of C1-C6 straight or branched of unsaturated alkyl, the C1-C6 straight or branched of alkyl, the C2-C6 straight or branched of hydrogen, halogen, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C6 straight or branched independently of one another.
R
3And R
4Can connect into ring;
R
15For the unsaturated alkyl of the alkyl of hydrogen, halogen, C1～C6 straight or branched, C2～C6 straight or branched, itrile group, nitro, amino, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-R
3OH ,-R
3R
4,-R
3NR
1R
2,-R
3R
5,-R
3CONR
1R
2,-CONR
1R
2,-COR
3OH, replacement or unsubstituted at least one heteroatomic 5 yuan or the 6 yuan of heterocyclic radicals that are selected among N, O and the S that contain, said substituting group be halogen, C1～C6 straight or branched alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1Or-CONR
1R
2
for replacing or unsubstituted C6-C10 aryl, replacement or unsubstituted C5-C12 heteroaryl, said heteroaryl contains 1-4 heteroatoms that is selected from oxygen, sulphur and nitrogen;
Said
In substituting group be alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-OR
3R
6,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CONR
6R
7NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR
7R
8, phenyl, substituted phenyl, naphthyl, xenyl, replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical; Wherein said substituted phenyl comprises 1～5 substituting group, this substituting group be independently of one another unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, the C3-C12 of alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched saturated or undersaturated heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, R
6N (R
7) CON (R
8)-,-N (R
6) R
3SO
2R
8, R
7N (R
6) R
3SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR
7R
8Said replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain the heteroatoms that 1-4 is selected from oxygen, sulphur and nitrogen, and substituted saturated or undersaturated C3-C12 heterocyclic radical contain unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, heterocycloalkenyl, the C3-C12 of one or more alkyl that are selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched saturated or undersaturated heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, R
6N (R
7) CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6With-OR
3NR
7R
8In substituting group;
R
5, R
6, R
7, R
8, R
9Be the alkyl of hydrogen, halogen, C1-C12 straight or branched, unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, C1-C6 alkoxyl group, C1-C6 acyl group, C6-C12 aryl, replacement or the unsubstituted saturated or undersaturated C3-C12 heterocyclic radical of C2-C12 straight or branched independently of one another; Said replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain the heteroatoms that 1-4 is selected from oxygen, sulphur and nitrogen, and substituted C3-C12 heterocyclic radical contain one or more alkyl that are selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched unsaturated alkyl, C1-C6 alkoxyl group, C3-C12 cyclic hydrocarbon radical, saturated or undersaturated C3-C12 heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-R
3OH and-SO
2R
1In substituting group; R
5, R
6, R
7, R
8And R
9In any two can form ring with the nitrogen-atoms that links to each other when linking to each other with identical nitrogen-atoms; R
5, R
6, R
7, R
8, R
9In any two form ring with the carbon atom that links to each other when linking to each other with identical carbon atom;
R
1, R
2Be the alkyl of hydrogen or C1～C6 independently of one another respectively; R
3Alkylidene group for C1～C6.
Further, in a preferred embodiment of compound of Formula I of the present invention, wherein m is 0 or 1; X is selected from-S-,-S (O)
2N (R
5)-or-CON (R
5)-; R
1For:
Wherein, U is C, N or O; Z is C or N; Q is N or O;
R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18And R
19Be independently of one another alkyl, the C2～C6 straight or branched of hydrogen, halogen, C1～C6 straight or branched unsaturated alkyl, itrile group, nitro, amino, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-R
3OH ,-R
3R
4,-R
3NR
1R
2,-R
3R
5,-R
3CONR
1R
2,-CONR
1R
2,-COR
3OH, replacement or unsubstituted at least one heteroatomic 5 yuan or the 6 yuan of heterocyclic radicals that are selected among N, O, the S that contain, said substituting group be halogen, C1～C6 straight or branched alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-CONR
1R
2
R
1, R
2Be the alkyl of hydrogen, C1～C6 independently of one another respectively;
R
3Alkylidene group for C1～C6;
R
4Be to replace or unsubstituted at least one heteroatomic 5 yuan or the 6 yuan of heterocyclic radicals that are selected among N, O, the S that contain, said substituting group be halogen, C1～C6 straight or branched alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-CONR
1R
2
R
5For by 1～5 substituted phenyl of halogen atom, said halogen is fluorine, chlorine, bromine or iodine.
In the another preferred embodiment of compound of Formula I of the present invention, wherein m is 0 or 1; X is selected from-S-,-SO
2N (R
5)-or-CON (R
5)-;
For
Wherein, R
20, R
21, R
22, R
23, R
24Respectively be independently of one another alkyl, the C2～C6 straight or branched of hydrogen, halogen, C1～C6 straight or branched unsaturated alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-OR
1,-OR
3R
4Said halogen is fluorine, chlorine, bromine or iodine;
Further be preferably selected from following structure fragment:
R
5, R
1, R
3And R
4Definition identical with aforesaid definition.
In the preferred embodiment of the present invention, the compound of general formula I of the present invention is preferably following particular compound:
Compound of the present invention possibly have asymmetric center, chiral axis and chirality plane and can exist with the form of enantiomer, diastereomer, racemic modification and composition thereof.
The invention provides the pharmaceutically useful salt of general formula (I) compound, be in particular general formula (I) compound and mineral acid or organic acid reaction and form conventional non-toxic salt.For example; Conventional non-toxic salt can make through general formula (I) compound and mineral acid or organic acid reaction; Said mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and said organic acid comprises Hydrocerol A, tartrate, lactic acid, pyruvic acid, acetate, Phenylsulfonic acid, tosic acid, methylsulfonic acid, naphthene sulfonic acid, ethyl sulfonic acid, naphthalene disulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, fumaric acid, succsinic acid, propionic acid, oxalic acid, trifluoroacetic acid, hard ester acid, pounces on acid, hydroxymaleic acid, toluylic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, xitix, para-anilinesulfonic acid, 2-acetoxy-benzoic acid and isethionic acid etc.; Perhaps general formula (I) compound and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, Hydrocerol A, aspartic acid or L-glutamic acid form behind the ester sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt that forms with mineral alkali again; The perhaps methylamine salt, ethylamine salt or the ethanolamine salt that form of general formula (I) compound and organic bases; Perhaps general formula (I) compound and Methionin, l-arginine, ornithine form behind the ester more corresponding inorganic acid salt that forms with hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid or the corresponding organic acid salt that forms with formic acid, acetate, TNP, methylsulfonic acid and ethyl sulfonic acid.
The invention provides the preparation method of the compound of a kind of general formula (I) expression, this preparation method comprises according to following steps:
Scheme 1
Step a: 2-nitro-3-Tetrahydrothienopyriderivatives derivatives is dissolved in the solvent, and adding alkali stirs, and adds N then, and the N-dimethyl sulphide is for formyl chloride, and stirring at room or heating are stirred down, get compound I
a, said solvent is THF, N, dioxane; Be preferably N; Said alkali is pyridine, triethylamine, triethylene diamine (DABCO), diisopropylethylamine, sodium hydride, potassium hydride KH; Be preferably triethylene diamine.
Step b: with I
aBe dispersed in the phenyl ether, reflux gets compound I
b
Step c: will
Be dissolved in the solvent, add alkali, under ice bath, drip acylating reagent, drip and finish, stirring at room gets compound I
cPerhaps will
Carry out halo with halide reagent, get compound I
c, said solvent is methylene dichloride, acetonitrile, THF, N, glycol dimethyl ether or dioxane; Said acylating reagent is benzene sulfonyl chloride, Tosyl chloride, methane sulfonyl chloride, trifluoromethanesulfonyl chloride or naphthalic sulfonic chloride;
Steps d: with compound I
bBe dispersed in the solvent with suitable alkali, stir for some time down, steam solvent, add I at-10～40 ℃
cSolution, stirring at room, compound I
d, said solvent is the mixed solvent of water, methyl alcohol and THF; Said alkali is preferably Pottasium Hydroxide;
Step e: with compound I
dUse iron powder, under the acid effect, reduce, get compound I
eSaid acid is hydrochloric acid, acetic acid;
Step f: use bromide reagent to compound I
eCarry out bromination, get compound I
f, said bromide reagent is N-bromo-succinimide or bromine;
Step g: with compound I
fWith boric acid ester or boric acid, catalytic coupling under palladium catalyst, get end product;
Scheme 2
Step h: with compound I
cMiddle Y replaces with nitrogenous group W, gets compound I
g, said Y is iodine, bromine, chlorine, alkyl ester, aryl ester, alkyl sulfonyl ester or fragrant sulfonyl ester; Said W is phthalimide-based, nitrine, succimide or phthalic imidine;
Step I: with compound I
gReduce, hydrolysis or hydrogenolysis, compound I
h
Step j: under-10～0 ℃, 2-amido-5-bromopyridine verivate is added in the chlorsulfonic acid in batches,, get compound I 140～180 ℃ of reactions down
i
Step k: with compound I
hAnd I
iBe dissolved in the solvent, under the effect of alkali, get compound I
i, said solvent is but is not limited only to methylene dichloride, acetonitrile, THF, N, glycol dimethyl ether or dioxane; Said alkali is pyridine, triethylamine, triethylene diamine (DABCO) or diisopropylethylamine;
Step l: carry out the reaction identical with step g;
Scheme 3
Step m:2-amido nicotinic acid derivates carries out bromination, gets compound I
kSaid bromide reagent is N-bromo-succinimide or bromine;
Step n: with compound I
kAnd I
hNeutralize, get compound I
1
Step o: carry out the reaction identical with step g;
Scheme 4
Step p: will
Carry out reduction amination or carry out nucleophilic substitution, get compound I
m
Step q: carry out the reaction identical with step k;
Step r: carry out the reaction identical with step g.
Pharmaceutical composition of the present invention contains compound or its pharmaceutically useful salt of the above-mentioned general formula (I) of treating significant quantity, and contains one or more pharmaceutically useful carriers.This medicinal compsns can also further comprise odorant agent, flavouring agent etc.
It is 1～99% active ingredient that pharmaceutical composition provided by the present invention preferably contains weight ratio; Its preferred ratio is; General formula (I) compound accounts for the 65wt%～99wt% of gross weight as activeconstituents, and rest part is pharmaceutically acceptable carrier, diluent or solution or salts solution.
Compound provided by the present invention and pharmaceutical composition can be various ways; Like tablet, capsule, pulvis, syrup, solution shape, suspension-s and aerosol etc., and may reside in the disinfector of injecting or instiling with suitable being used in suitable solid or liquid support or the diluent.
The various formulations of pharmaceutical composition of the present invention can be according to conventional preparing method's preparation of pharmaceutical field.Comprise 0.05～200mg general formula (I) compound in the unit metering of its pharmaceutical formulation, preferably, comprise 0.1mg～100mg general formula (I) compound in the metering of the unit of pharmaceutical formulation.
Compound of the present invention and pharmaceutical composition can comprise humans and animals to the clinical use of Mammals, can through port, the route of administration of nose, skin, lung or gi tract etc.Most preferably be oral.Most preferably per daily dose is 0.01～200mg/kg body weight, disposable taking, or 0.01～100mg/kg body weight part vic.Which kind of instructions of taking that don't work, individual's optimal dose should be decided according to concrete treatment.Generally be to begin, increase dosage gradually until find optimal dosage from low dose.
In addition, the inventor finds that through experiment general formula (I) compound can be used for regulating and control receptor tyrosine kinase activity, especially the member of acceptor junket ammonia kinase Met subfamily.Regulation and control of the present invention are to increase or reduce the kinase whose activity of Met.In one embodiment, The compounds of this invention has suppressed the kinase whose activity of Met.
Compound of the present invention and compsn are used for treatment and preventing cancer, hyperplasia, restenosis, immune disorders and inflammation; Said cancer comprises; But be not limited to histiocytic lymphoma, ovarian cancer, neck phosphor shaped epithelial cell cancer, cancer of the stomach, mammary cancer, children's hepatocellular carcinoma, colorectal carcinoma, cervical cancer, lung cancer, sarcoma, nasopharyngeal carcinoma, carcinoma of the pancreas, spongioblast cancer, prostate cancer, small cell lung cancer, nonsmall-cell lung cancer, multiple myeloma, thyroid carcinoma, carcinoma of testis, cervical cancer, adenocarcinoma of lung, colorectal carcinoma, Papillary Renal Cell Carcinoma, glioblastoma, carcinoma of endometrium, esophagus cancer, white blood disease, renal cell carcinoma, bladder cancer, liver cancer and astrocytoma etc.; Be more preferably used in the following cancer of treatment: neck phosphor shaped epithelial cell cancer, histiocytic lymphoma, adenocarcinoma of lung, small cell lung cancer, nonsmall-cell lung cancer, carcinoma of the pancreas, Papillary Renal Cell Carcinoma, liver cancer, cancer of the stomach, colorectal carcinoma, multiple myeloma and glioblastoma.
Compound of the present invention and compsn are used for treatment, prevention or regulation and control cancer cells and cancer metastasis knurl, especially for the metastatic tumor of prevention or regulation and control ovarian cancer, children's hepatocellular carcinoma, metastatic neck phosphor shaped epithelial cell cancer, cancer of the stomach, mammary cancer, colorectal carcinoma, cervical cancer, lung cancer, nasopharyngeal carcinoma, carcinoma of the pancreas, glioblastoma and sarcoma.
Embodiment
In following embodiment, will further illustrate the present invention.These embodiment only are used to explain the present invention, but do not limit the present invention in any way.
The starting raw material of using among the present invention is commercial the purchase without special instruction.
As used some abbreviation among give a definition schema and the embodiment:
Embodiment 1
Step 1: preparation N, N-dimethyl--1-[(2-nitropyridine-3)-oxygen base] thioformamide
With 2-nitro-3-pyridone (10.00g, 71.38mmol), N; (10.59g 85.66mmol) is dissolved among the 50mL DMF N-dimethyl amido sulfo-formyl chloride, adds DABCO (triethylene diamine) (9.61g; 85.66mmol), behind the stirring at room 24h, in reaction solution, add entry 150mL; With ETHYLE ACETATE 600mL extraction, organic phase is used 3 * 100mL water, saturated common salt water washing, anhydrous Na successively
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets yellow solid.Not purified, directly be used for next step.
1H?NMR(400MHz，CDCl
3)δ8.47(dd，J＝2.4，4.4Hz，1H)，7.77(dd，J＝2.4，8.0Hz，1H)，7.70(dd，J＝4.4，8.0Hz，1H)，3.45(s，3)，3.40(s，3H)。
Step 2: preparation N, N-dimethyl--1-[(2-nitropyridine-3)-sulfenyl] methane amide (1)
To go up step gained N, N-dimethyl--1-[(2-nitropyridine-3)-oxygen base] thioformamide bullion is scattered in 150mL Ph
2Among the O, under argon shield, in 160 ℃ of reaction 3h, cooling, (petrol ether/ethyl acetate 4/1-2/1, v/v) separation and purification get 9.7g yellow solid (two step overall yields: 60%) with the ether recrystallization again through column chromatography.
1H?NMR(300MHz，CDCl
3)δ8.53(dd，J＝1.8，4.8Hz，1H)，8.18(dd，J＝1.8，8.1Hz，1H)，7.60(dd，J＝4.8，8.1Hz，1H)，3.12(s，3H)，3.04(s，3H)。
Schema 2
Embodiment 2
Step 1: preparation 1-(3-fluoro-2,6-dichlorophenyl) ethanol
(20.00g 96.60mmol) is dissolved among the 100mL MeOH, adds NaBH in batches with 1-(3-fluoro-2,6-dichlorophenyl) ethyl ketone
4(7.31g 193.21mmol), behind the stirring at room 2h, adds entry 20mL in reaction solution, organic solvent is removed under reduced pressure, and resistates is with ETHYLE ACETATE 150mL extraction, and organic phase is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets colourless transparent oil liquid.Not purified, directly be used for next step.
Step 2: preparation 1-(3-fluoro-2,6-dichlorophenyl) sulfonyl methane ethyl ester (2)
To go up step gained 1-(3-fluoro-2,6-dichlorophenyl) ethanol bullion and be dissolved in 150mL CH
2Cl
2In, add Et
3N (13.43mL, the 96.60mmol) DMAP of catalytic amount are cooled to 0 ℃, drip MsCl (7.48mL, 96.60mmol), keep 0 ℃ of 1h after, add entry 30mL, organic phase is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 10/1, v/v) separation and purification get white waxy solid 23.40g (two step overall yields: 84.4%) to resistates through the sharp separation column chromatography.
1H?NMR(300MHz，CDCl
3)δ7.34(dd，J＝4.5，9.0Hz，1H)，7.70(dd，J＝7.8，9.0Hz，1H)，6.46(q，J＝6.6Hz，1H)，2.91(s，3H)，1.84(d，J＝6.6Hz，3H)。
Schema 3
Embodiment 3
Step 1: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-the 2-nitropyridine
With N, (10.00g, 44.01mmol), (5.43g 96.81mmol) places the 250mL eggplant type flask to KOH to N-dimethyl--1-[(2-nitropyridine-3)-sulfenyl] methane amide, under argon shield, flask is placed ice-water bath, adds MeOH/THF/H with syringe
2(2/2/1, v/v/v) 100mL finishes O, removes ice-water bath; Stirring at room treats that TLC detects and not had N, during N-dimethyl--1-[(2-nitropyridine-3)-sulfenyl] methane amide, removes organic solvent under reduced pressure; Under argon shield, add 1-(3-fluoro-2,6-dichlorophenyl) sulfonyl methane ethyl ester (12.64g, THF solution 120mL 44.01mmol) with syringe; Behind the stirring at room 24h, organic solvent is removed under reduced pressure, reaction solution extracts with ETHYLE ACETATE 300mL; Organic phase water 3 * 40mL, saturated aqueous common salt washs successively, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure.Not purified, directly be used for next step.
1H?NMR(300MHz，CDCl
3)δ8.36(d，J＝3.9Hz，1H)，7.88(d，J＝7.8Hz，1H)，7.46(m，1H)，7.33-7.26(m，1H)，7.08-7.03(m，1H)，5.33-5.24(m，1H)，1.88-1.85(m，3H)。
Step 2: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine
To go up step gained 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-2-nitropyridine bullion is dissolved among the 150mL EtOH, add reduced iron powder (12.06g, 216.02mmol); 1M HCl 10mL is warming up to 80 ℃, behind the backflow 8h gradually; Filter, remove solvent under reduced pressure, resistates is used CH
2Cl
2Extraction, organic phase is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, the gained bullion with petrol ether/ethyl acetate (4/1, v/v) recrystallization, remainder is through sharp separation column chromatography (petrol ether/ethyl acetate 6/1, v/v) separation and purification, common white solid 6.6g.(two step overall yields: 47.28%).
1H?NMR(400MHz，CDCl
3)δ8.01(d，J＝4.8Hz，1H)，7.42(m，1H)，7.46(m，1H)，7.29-7.26(m，0.5H)，7.17(dd，J＝5.2，8.8Hz，0.5H)，7.01-6.97(m，1H)，6.53-6.49(m，1H)，5.17(br，2H)，5.04-4.97(m，1H)，1.84-1.81(m，3H).
Step 3: preparation 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine (3)
With 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } (4.00g 12.61mmol) is dissolved in 100mL CH to pyridine-2-amine
2Cl
2, be cooled to-10 ℃, drip NBS (2.24g, CH 12.61mmol)
2Cl
2Solution 100mL or CH
3CN 20mL solution drips and finishes, and organic solvent is removed under reduced pressure, at CH
2Cl
2, petrol ether/ethyl acetate (4/1, v/v) in recrystallization, remainder through the sharp separation column chromatography (petrol ether/ethyl acetate 8/1, v/v) separation and purification, altogether white solid 4.89g, productive rate 97.9%.
1H?NMR(300MHz，CDCl
3)δ8.05-8.04(m，1H)，7.52(dd，J＝2.4，5.4Hz，1H)，7.32-7.26(m，0.5H)，7.21(dd，J＝4.8，8.7Hz，0.5H)，7.05-6.99(m，1H)，5.18(br，2H)，5.07-4.98(m，1H)，1.84(dd，J＝2.7，7.2Hz，3H)。
Schema 4
Embodiment 4
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-2-amine (DC295-4)
In microwave reactor with 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl pyridine-2-amine (80mg, 0.20mmol); 1-methyl-4-pyrazoles boric acid pinacol ester (50.43mg; 0.24mmol), two hydration Potassium monofluorides (57.03mg, 0.61mmol); (10.42mg 0.01mmol) is scattered in 3mL DME/H to four triphenyl phosphorus palladiums
2O/EtOH (7/3/2, v/v/v) in, 110 ℃ in microwave, the reaction 50min after, use ethyl acetate extraction, organic phase is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, preparation TLC separation and purification (CH
2Cl
2/ MeOH 50/1, v/v), gets light yellow solid 50mg, productive rate 62.3%.
1H?NMR(300MHz，CDCl
3)δ8.14(d，J＝1.8Hz，1H)，7.55(s，1H)，?7.51(dd，J＝2.4，3.6Hz，1H)，7.45(s，1H)，7.32-7.27(m，0.5H)，7.17(dd，J＝4.8，8.7Hz，0.5H)，7.01-6.96(m，1H)，5.23(s，2H)，5.09-5.00(m，1H)，3.93(s，3H)，1.86-1.83(m，3H)。
Schema 5
Embodiment 5
Step 1: preparation 4-(methanesulfonyloxy group) piperazine-1-t-butyl formate
Except 4-hydroxyl piperazine-1-t-butyl formate being replaced to outside 1-(3-fluoro-2, the 6-dichlorophenyl) ethanol, to prepare 4-(methanesulfonyloxy group) piperazine-1-t-butyl formate with embodiment 1 identical mode.
Step 2: preparation 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate
(2.63g 17.90mmol) is dissolved among the 40mL DMF, places under the ice bath, and add massfraction is 60% sodium hydride (787.49mg in batches with 4-bromo-1H-pyrazoles; 19.69mmol), after finishing, behind the stirring 1h; Piperazine-(5.00g 17.90mmol), is warming up to 100 ℃ to the 1-t-butyl formate to add 4-(methanesulfonyloxy group); Stirred overnight is cooled to room temperature, in reaction solution, adds 100mL H
2O, and the EA extraction (3 * 200mL), merge organic layer, use H more successively
2O (3 * 50mL), saturated NaCl solution 100mL washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 10/1-5/1, v/v) separation and purification gets white solid 4.3g, productive rate 72.77% through column chromatography.
1H?NMR(300MHz，CDCl
3)δ7.46(s，1H)，7.43(s，1H)，4.28-4.18(m，3H)，2.92-2.83(m，2H)，2.12-2.08(m，2H)，1.94-1.80(m，2H)，1.47(s，9H)。
Step 3: preparation N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester
With 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate (2.00g, 6.06mmol), duplex tetramethyl ethylene ketone base diboron hexahydride (1.85g, 7.27mmol), Potassium ethanoate (1.78g, 17.17mmol), Pd (dppf) Cl
2(247mg 0.303mmol), is scattered among the 15mL DMF, under argon shield, places 80 ℃ of oil baths, and reaction is spent the night, and is cooled to room temperature, in reaction solution, adds 45mL H
2O, and the EA extraction (3 * 100mL), merge organic layer, use H more successively
2O (3 * 50mL), saturated NaCl solution 100mL washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 4/1, v/v) separation and purification gets white solid 1.49g, productive rate 65.21% through column chromatography.
1H?NMR(300MHz，CDCl
3)δ7.79(s，1H)，7.73(s，1H)，4.32-4.23(m，3H)，2.92-2.84(m，2H)，2.15-2.10(m，2H)，1.96-1.82(m，2H)，1.47(s，9H)，1.32(s，12H)。
Step 4: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine
Except N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester is replaced to 1-methyl-4-pyrazoles boric acid pinacol ester, to react with embodiment 4 identical modes, product separates through preparation HPLC.
1H?NMR(300MHz，CDCl
3)δ8.14-8.12(m，1H)，7.56(s，1H)，7.51-7.49(m，2H)，7.32-7.26(m，0.5H)，7.17(dd，J＝4.8，9.0Hz，0.5H)，7.02-6.96(m，1H)，5.19(s，2H)，5.09-5.01(m，1H)，4.31-4.23(m，3H)，2.93-2.86(m，2H)，2.12-2.18(m，2H)，1.90-1.99(m，2H)，1.86-1.83(m，3H)，1.48(s，9H)。
Step 5: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-5)
With 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-(20.00mg 0.035mmol) is dissolved in 2mL CH to pyridine-2-amine to 5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl]
2Cl
2, drip TFA 0.5mL stirring at room 1h, with the reaction solution evaporate to dryness, resistates is used CH
2Cl
2/ MeOH (10/1, v/v) dissolving, with the saturated sodium bicarbonate solution washing, water is again through CH
2Cl
2Extraction merges organic layer, through anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets white solid, productive rate 80%.
1H?NMR(400MHz，CDCl
3)δ8.15-8.14(m，1H)，7.57(s，1H)，7.52(s，1H)，7.50-7.49(m，1H)，7.30(dd，J＝4.8，8.8Hz，0.5H)，7.18(dd，J＝4.8，8.8Hz，0.5H)，7.03-6.98(m，1H)，5.13(s，2H)，5.08-5.02(m，1H)，4.31-4.24(m，1H)，3.36-3.32(m，2H)，2.90-2.83(m，2H)，2.25-2.22(m，2H)，2.06-1.97(m，2H)，1.86-1.83(m，3H)。
Embodiment 6
Preparation (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-5-A)
Schema 6
Step 1: preparation (S)-1-(3-fluoro-2,6-dichlorophenyl) ethanol
With 1-(3-fluoro-2,6-dichlorophenyl) ethanol (24g, 114.81mmol), (16.06g 74.63mmol) is scattered in 300mL 1 to the Boc-L-proline(Pro); In the 2-ethylene dichloride, be cooled to 0 ℃, add in succession EDCI (17.61g, 91.85mmol); (1.68g 13.78mmol), keeps 0 ℃ to DMAP, and reaction is spent the night; In reaction solution, add 100m water, collected organic layer, organic layer is through saturated NaCl solution washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 100/1-50/1, v/v) separation and purification gets white solid 7g, productive rate 58%, ee%＞99% through column chromatography.
Step 2: preparation (S)-1-(3-fluoro-2,6-dichlorophenyl) sulfonyl methane ethyl ester
Except replacing outside 1-(3-fluoro-2, the 6-dichlorophenyl) ethanol, to react with embodiment 2 identical modes with (S)-1-(3-fluoro-2,6-dichlorophenyl) ethanol.
Step 3: preparation (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-the 2-nitropyridine
Except replacing outside 1-(3-fluoro-2,6-dichlorophenyl) the sulfonyl methane ethyl ester, to react with embodiment 3 identical modes with (S)-1-(3-fluoro-2,6-dichlorophenyl) sulfonyl methane ethyl ester.
Step 4: preparation (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine
Except with (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-2-nitropyridine replacement 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl-the 2-nitropyridine outside, to react with embodiment 3 identical modes.
Step 5: preparation (R)-5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine
Except with (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replacement 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to react with embodiment 3 identical modes.
Step 6: preparation (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine
Except with (R)-5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replacement 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to react with embodiment 5 identical modes.
Step 7: preparation (R)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine
Except using (R)-3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine replacement 3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine outside, to react with embodiment 5 identical modes.
1H?NMR(400MHz，CDCl
3)δ8.15-8.14(m，1H)，7.57(s，1H)，7.52(s，1H)，7.51-7.50(m，1H)，7.30(dd，J＝4.8，8.8Hz，0.5H)，7.18(dd，J＝4.8，8.8Hz，0.5H)，7.02-6.98(m，1H)，5.16(s，2H)，5.09-5.02(m，1H)，4.26-4.19(m，1H)，3.29-3.26(m，2H)，2.83-2.76(m，2H)，2.19-2.14(m，2H)，1.98-1.88(m，2H)，1.86-1.83(m，3H)。
Embodiment 7
Preparation (S)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-5-B)
Embodiment 5 gained Compound D C295-5 are separating obtained through preparation HPLC.Separation condition: Chiralpak I A chiral column (10 * 250mm); Flow velocity: 6mL/min; Eluent: ethanol/normal hexane=87/13.
1H?NMR(400MHz，CDCl
3)δ8.15-8.14(m，1H)，7.57(s，1H)，7.52(s，1H)，7.51-7.50(m，1H)，7.30(dd，J＝4.8，8.8Hz，0.5H)，7.18(dd，J＝4.8，8.8Hz，0.5H)，7.02-6.98(m，1H)，5.15(s，2H)，5.09-5.02(m，1H)，4.26-4.20(m，1H)，3.29-3.26(m，2H)，2.83-2.76(m，2H)，2.20-2.17(m，2H)，1.98-1.88(m，2H)，1.86-1.83(m，3H)。
Embodiment 8
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazole-3-yl] pyridine-2-amine (DC295-6)
Except replacing N-tertbutyloxycarbonyl-3-pyrazoles boric acid pinacol ester, to prepare Compound D C295-6 with embodiment 5 identical modes with N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester.MS(ESI，m/z)：466.1[M+H]
+.
Embodiment 9
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-imidazo-3-yl] pyridine-2-amine (DC295-7)
Except replacing N-tertbutyloxycarbonyl-4-imidazoles boric acid pinacol ester, to prepare Compound D C295-7 with embodiment 5 identical modes with N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester.MS(ESI，m/z)：466.0[M+H]
+.
Embodiment 10
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-8)
Except with 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replaces to 5-bromo-3-{ [1-(2,3-two fluoro-6-chloro-phenyl-s) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-8 with embodiment 5 identical modes.MS(ESI，m/z)：450.1[M+H]
+.
Embodiment 11
Preparation 3-{ [1-(3,5-two fluoro-2-chloro-phenyl-s) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-9)
Except with 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replaces to 5-bromo-3-{ [1-(3,5-two fluoro-2-chloro-phenyl-s) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-9 with embodiment 5 identical modes.MS(ESI，m/z)：450.1[M+H]
+.
Embodiment 12
Preparation 3-{ [1-(3,5-two fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-10)
Except with 5-bromo-3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replaces to 5-bromo-3-{ [1-(3; 5-two fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-10 with embodiment 5 identical modes.MS(ESI，m/z)：484.0[M+H]
+.
Embodiment 13
Preparation 3-{ [1-(2, the 3-difluorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-11)
Except with 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replaces to 5-bromo-3-{ [1-(2, the 3-difluorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-11 with embodiment 5 identical modes.MS(ESI，m/z)：416.1[M+H]
+.
Embodiment 14
Preparation 3-(1-{2,3-two fluoro-4-[(2-morpholine-4-yl) oxyethyl group] phenyl } ethylmercapto group)-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-12)
Except with 5-bromo-3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine replaces to 5-bromo-3-(1-{2; 3-two fluoro-4-[(2-morpholine-4-yl) oxyethyl group] phenyl } outside ethylmercapto group pyridine-2-amine, to prepare Compound D C295-12 with embodiment 5 identical modes.MS(ESI，m/z)：545.2[M+H]
+.
Schema 6
Embodiment 15
Step 1: preparation 2-(4-bromo-1H-pyrazol-1-yl) ethanol
With 4-bromo-1H-pyrazoles (1.00g, 6.80mmol), bromoethanol (0.53mL, 7.48mmol); Cesium carbonate (2.66g, 8.16mmol), TBAI (tetrabutylammonium iodide) (502.63mg; 1.36mmol), be scattered among the 20mL DMF, place 90 ℃ of oil baths; Behind the reaction 2h, be cooled to room temperature, in reaction solution, add 60mL H
2O, and the EA extraction (3 * 100mL), merge organic layer, use H more successively
2O (3 * 50mL), saturated NaCl solution 60mL washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 7/3, v/v) separation and purification gets light yellow oily liquid 850mg, productive rate 65.38% through the sharp separation column chromatography.
1H?NMR(300MHz，CDCl
3)δ7.49(s，1H)，7.48(s，1H)，4.23(t，J＝4.8Hz，2H)，3.99(t，J＝4.8Hz，2H)，2.73(br，1H)。
Step 2: preparation N-2-hydroxyethyl-4-pyrazoles boric acid pinacol ester
Except 2-(4-bromo-1H-pyrazol-1-yl) ethanol is replaced to 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate, to react with embodiment 5 identical modes, product is through column chromatography (PE/EA1/1 → CH
2Cl
2/ MeOH 50/1) separation and purification, productive rate 11.03%.
1H?NMR(300MHz，CDCl
3)δ7.81(s，1H)，7.74(s，1H)，4.27(t，J＝4.8Hz，2H)，3.99(t，J＝4.8Hz，2H)，1.32(s，12H)。
Step 3: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(hydroxyethyl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-13)
Except N-2-hydroxyethyl-4-pyrazoles boric acid pinacol ester is replaced to 1-methyl-4-pyrazoles boric acid pinacol ester, to react with embodiment 4 identical modes, product separates productive rate 18.5% through preparation HPLC.
1H?NMR(300MHz，CDCl
3)δ：8.09(s，1H，7.59(s，1H)，7.53(s，1H)，7.51-7.49(m，1H)，7.30(dd，J＝4.8，8.7Hz，0.5H)，7.17(dd，J＝4.8，8.7Hz，0.5H)，7.03-6.97(m，1H)，5.19(s，2H)，5.07-5.02(m，1H)，4.26(t，J＝4.8Hz，2H)，4.04(t，J＝4.8Hz，2H)，1.86-1.83(m，3H)。
Schema 7
Embodiment 16
Step 1: preparation 2-(4-bromo-1H-pyrazol-1-yl) ETHYLE ACETATE
(1.00g 6.80mmol) is dissolved among the 10mL DMF, places under the ice bath, and add massfraction is 60% sodium hydride (326.56mg in batches with 4-bromo-1H-pyrazoles; 19.69mmol), after finishing, behind the stirring 1h, add METHYL BROMOACETATE (0.83mL; 7.48mmol), (225.90mg 1.36mmol), is warming up to 80 ℃ to KI; Reaction 8h is cooled to room temperature, in reaction solution, adds 20mL H
2O, and the EA extraction (2 * 75mL), merge organic layer, use H more successively
2O (3 * 15mL), saturated NaCl solution 40mL washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 10/1, v/v) separation and purification gets transparent liquid 1.327g, productive rate 83.46% through the sharp separation column chromatography.
1H?NMR(300MHz，CDCl
3)δ7.51(s，2H)，4.87(s，2H)，4.24(q，J＝6.9Hz，2H)，1.29(t，J＝6.9Hz，3H)。
Step 2: preparation 2-[4-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-1H-pyrazol-1-yl] ETHYLE ACETATE
Except 2-(4-bromo-1H-pyrazol-1-yl) ETHYLE ACETATE is replaced to 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate, to react with embodiment 5 identical modes, product is through column chromatography (CH
2Cl
2/ MeOH, 50/1) separation and purification, productive rate 7.51%.
Step 3: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-{1-[(2-oxyethyl group-2-oxo) ethyl]-1H-pyrazoles-4-yl } pyridine-2-amine
Except [4-(4,4,5 with 2-; 5-tetramethyl--1,3,2-dioxy borine-2-yl)-and the 1H-pyrazol-1-yl] ETHYLE ACETATE replaces to outside 1-methyl-4-pyrazoles boric acid pinacol ester; To react with embodiment 4 identical modes; Product is through column chromatography (petrol ether/ethyl acetate 1/1, v/v) separation and purification, productive rate 33.5%.
Step 4: preparation 2-[4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl)-the 1H-pyrazol-1-yl] acetate
With 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-{1-[(2-oxyethyl group-2-oxo) ethyl]-1H-pyrazoles-4-yl } pyridine-2-amine 46mg is dissolved among the 2mL THF, adds 1mL 2N NaOH solution; Reflux; Reaction 5h removes the organic solvent steaming, and the pH that regulates water layer is 2-3; The EA extraction, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets the 43mg bullion.
Step 5: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(N, N-dimethyl-carbonyl ethyl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-14)
(43mg 0.097mmol) is dissolved in 2mL DMF to acetate, places ice bath with 2-[4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-1H-pyrazol-1-yl]; Add in succession HATU (39mg, 0.102mmol), DIPEA (0.036mL, 0.205mmol); (9.53mg 0.117mmol), finishes the dimethylamine hydrochloride solid, removes ice bath; Stirring at room behind the reaction 1h, adds the saturated NaHCO of 1mL in reaction solution
3Solution, H is used in 50mL EA extraction successively
2O (2 * 10mL), saturated NaCl solution 10mL washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (EA/MeOH 100/3, and v/v) separation and purification gets the 22mg white solid, productive rate 48.21% through the sharp separation column chromatography.
Schema 8
Embodiment 17
Step 1: preparation 4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl) oil of Niobe
With 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } and pyridine-2-amine (1.2g, 3.03mmol); 4-methoxycarbonyl phenylo boric acid (0.65g, 3.64mmol), yellow soda ash (0.96g; 9.09mmol), (0.21g 0.30mmol) is scattered in 10mL DME/H to bi triphenyl phosphorus palladium chloride
2O (4/1, v/v) in, under argon shield, be heated to 80 ℃, the reaction 17h after, with the reaction solution evaporate to dryness, use ethyl acetate extraction, organic phase is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 3/2, v/v) separation and purification get bullion 1.22g to product through column chromatography.
Step 2: preparation 4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl) phenylformic acid
To go up step gained bullion and be dissolved among the 15mL THF, add 10mL 2N NaOH solution, reflux reaction 5h; Be cooled to room temperature, use ethyl acetate extraction, regulate water layer pH to 3, suction filtration; Filter cake is water successively, and the ETHYLE ACETATE washing with the filter cake oven dry, gets 0.71g (two step overall yields: 53.59%).
1H?NMR(400MHz，DMSO-d
6)δ12.94(br，1H)，δ8.35(t，J＝2.4Hz?1H)，7.92(d，J＝8.4Hz，2H)，7.54(dd，J＝5.2，8.8Hz，0.5H)，7.52-7.46(m，3H)，7.40-7.35(m，1.5H)，6.54(d，J＝6.8Hz，2H)，5.07(q，J＝7.2Hz，1H)，1.82-1.80(m，3H)。
Step 3: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-{4-[(woods-4-yl) carbonyl] phenyl } pyridine-2-amine (DC295-15)
Except the morpholine ring is replaced to the dimethylamine hydrochloride solid, 4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-3 base) phenylformic acid replaces to 2-[4-(6-amido-5-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-the 1H-pyrazol-1-yl] outside the acetate; To react with embodiment 16 identical modes, (EA/MeOH 100/1, v/v) separation and purification through the sharp separation column chromatography for product; Get white solid, productive rate 72.3%.
1H?NMR(300MHz，CDCl
3)δ8.26(d，J＝2.1Hz，1H)，7.66(d，J＝2.1Hz，1H)，7.47-7.41(m，4H)，7.30(dd，J＝5.1，8.4Hz，0.5H)，7.17(dd，J＝5.1，8.4Hz，0.5H)，7.03-6.97(m，1H)，5.31(br，2H)，5.12-5.04(m，1H)，3.80-3.46(m，8H)，1.87-1.84(m，3H)。
Embodiment 18
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(4-{ [4-(pyrroline-1-yl) piperidines-1-yl] carbonyl } phenyl) pyridine-2-amine (DC295-16)
Except replacing the morpholine ring, to prepare Compound D C295-16, productive rate 76.3% with embodiment 17 identical modes with 4-(pyrroline-1-yl) piperidines.
1H?NMR(300MHz，CDCl
3)δ8.26(d，J＝2.4Hz，1H)，7.65(d，J＝2.4Hz，1H)，7.43-7.38(m，4H)，7.29(dd，J＝5.1，8.7Hz，0.5H)，7.17(dd，J＝5.1，8.7Hz，0.5H)，7.02-6.97(m，1H)，5.24(s，2H)，5.10-5.03(m，1H)，4.67-4.60(m，1H)，3.83-3.77(m，1H)，3.07-2.86(m，2H)，2.68-2.55(m，4H)，2.30-2.66(m，1H)，2.15-1.55(m，11H)。
Embodiment 19
Preparation 4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-N-[2-(diethylammonium amido) ethyl] BM (DC295-17)
Except with N ', outside N '-diethyl ethylenediamine replacement morpholine ring, to prepare Compound D C295-17, productive rate 73.5% with embodiment 17 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.26(d，J＝1.8Hz，1H)，7.80(d，J＝8.4Hz，2H)，7.65(d，J＝2.4Hz，1H)，7.42(d，J＝8.4Hz，2H)，7.30-7.26(m，0.5H)，7.17-7.11(m，1.5H)，7.02-6.96(m，1H)，5.36(s，2H)，5.09-5.02(m，1H)，3.52-3.45(m，2H)，2.65(t，J＝5.7Hz，2H)，2.57(q，J＝7.2Hz，4H)，1.83(dd，J＝2.4，7.2Hz，3H)，1.04(t，J＝7.2Hz，6H)。
Embodiment 20
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-{4-[(4-N-METHYL PIPERAZINE-1-yl) carbonyl] phenyl } pyridine-2-amine (DC295-18)
Except replacing the morpholine ring, to prepare Compound D C295-18, productive rate 73.7% with embodiment 17 identical modes with the 4-N-METHYL PIPERAZINE.
1H?NMR(300MHz，CDCl
3)δ8.26(d，J＝2.8Hz，?1H)，7.65-7.64(m，1H)，7.45-7.40(m，4H)，7.29(dd，J＝4.8，8.8Hz，0.5H)，7.16(dd，J＝4.8，8.8Hz，0.5H)，7.02-6.98(m，1H)，5.25(s，2H)，5.08-5.03(m，1H)，3.85-3.76(m，2H)，3.55-3.44(m，2H)，2.55-2.31(m，7H)，1.87-1.84(m，3H)。
Embodiment 21
Preparation (2 ' S)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(4-{ [2 '-(pyrroline-1-ylmethyl) pyrroline-1-yl] carbonyl } phenyl) pyridine-2-amine (DC295-19)
Except replacing the morpholine ring, to prepare Compound D C295-19, productive rate 66.7% with embodiment 17 identical modes with (S)-(pyrroles-2-ylmethyl) pyrroles.
1H?NMR(400MHz，CDCl
3)δ8.26(d，J＝2.0Hz，1H)，7.65(d，J＝2.0Hz，1H)，7.56-7.52(m，2H)，7.42-7.39(m，2H)，7.27-7.31(m，0.5H)，7.18-7.14(m，0.5H)，7.02-6.97(m，1H)，5.39(s，2H)，5.10-5.03(m，1H)，4.45(br，1H)，3.73-3.45(m，2H)，3.08-2.92(m，2H)，2.75-2.2.60(m，4H)，2.42-2.15(m，2H)，2.04-1.91(m，3H)，1.87-1.80(m，6H)。
Embodiment 22
Preparation 4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl)-N, N-dimethyl benzamide (DC295-20)
Except replacing the morpholine ring, to prepare Compound D C295-20, productive rate 47.1% with embodiment 17 identical modes with dimethylin.
1H?NMR(300MHz，CDCl
3)δ8.27(d，J＝2.4Hz，1H)，7.66(d，J＝2.4Hz，1H)，7.47(d，J＝8.1Hz，2H)，7.41(d，J＝8.1Hz，2H)，7.32-7.27(m，0.5H)，7.17(dd，J＝5.1，8.7Hz，0.5H)，7.03-6.97(m，1H)，5.36(s，2H)，5.11-5.03(m，1H)，3.13(s，3H)，3.03(s，3H)，1.87-1.84(m，3H)。
Embodiment 23
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(4-{ [4-(propane-2-yl) piperazine-1-yl)] carbonyl } phenyl) pyridine-2-amine (DC295-21)
Except replacing the morpholine ring, to prepare Compound D C295-21, productive rate 90.5% with embodiment 17 identical modes with 1-sec.-propyl piperazine.
1H?NMR(300MHz，CDCl
3)δ8.24(d，J＝2.4Hz，1H)，7.64(d，J＝2.4Hz，1H)，7.45-7.38(m，4H)，7.30-7.26(m，0.5H)，7.15(dd，J＝5.1，8.7Hz，0.5H)，7.03-6.97(m，1H)，5.08-5.03(m，1H)，3.88-3.77(m，2H)，3.55-3.37(m，2H)，2.86-2.54(m，5H)，1.87-1.84(m，3H)，1.09(d，J＝6.3Hz，6H)。
Embodiment 24
Preparation (3 ' S)-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(4-[(3 '-hydroxyl) pyrroline-1-yl] carbonyl } phenyl) pyridine-2-amine (DC295-22)
Except replacing the morpholine ring, to prepare Compound D C295-22, productive rate 54.0% with embodiment 17 identical modes with (S)-3-hydroxyl pyrroles.
1H?NMR(300MHz，CDCl
3)δ8.25(s，1H)，7.66(s，1H)，7.60-7.54(m，2H)，7.40(d，J＝4.5Hz，2H)，7.32-7.26(m，0.5H)，7.17(dd，J＝5.1，9.0Hz，0.5H)，7.02-6.97(m，1H)，5.32(s，2H)，5.11-5.03(m，1H)，4.60(s，0.5H)，4.48(s，0.5H)，3.84-3.46(m，4H)，2.14-1.99(m，3H)，1.87-1.84(m，3H)。
Embodiment 25
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-{4-[(4-methane sulfonyl piperazine-1-yl) carbonyl] phenyl } pyridine-2-amine (DC295-23)
Except replacing the morpholine ring, to prepare Compound D C295-23, productive rate 55.3% with embodiment 17 identical modes with 4-methane sulfonyl piperazine.
1H?NMR(300MHz，CDCl
3)δ8.27(d，J＝2.4Hz，1H)，7.67(d，J＝2.4Hz，1H)，7.45(s，4H)，7.30(dd，J＝4.8，8.7Hz，0.5H)，7.17(dd，J＝4.8，8.7Hz，0.5H)，7.03-6.97(m，1H)，5.33(s，2H)，5.12-5.05(m，1H)，3.89-3.67(m，4H)，3.28(br，4H)，2.82(s，3H)，1.87-1.84(m，3H)。
Embodiment 26
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(4-{ [(3-hydroxyl) piperidines-1-yl] carbonyl } phenyl) pyridine-2-amine (DC295-24)
Except replacing the morpholine ring, to prepare Compound D C295-24, productive rate 42.0% with embodiment 17 identical modes with the 3-hydroxy piperidine.
1H?NMR(300MHz，CDCl
3)δ8.25(d，J＝2.4Hz，1H)，7.66(d，J＝2.4Hz，1H)，7.46(d，J＝8.7Hz，2H)，7.40(d，J＝8.7Hz，2H)，7.32-7.26(m，0.5H)，7.17(dd，J＝5.1，8.7Hz，0.5H)，7.02-6.97(m，1H)，5.33(s，2H)，5.11-5.03(m，1H)，3.95-3.28(m，5H)，2.07-1.48(m，7H)。
Embodiment 27
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(4-{ [4-(2-hydroxyethyl) piperazine-1-yl] carbonyl } phenyl) pyridine-2-amine (DC295-25)
Except replacing the morpholine ring, to prepare Compound D C295-25, productive rate 68.6% with embodiment 17 identical modes with 2-(piperazine-1-yl) ethanol.
1H?NMR(400MHz，CDCl
3)δ8.24(d，J＝2.0Hz，1H)，7.65(d，J＝2.0Hz，1H)，7.44-7.39(m，4H)，7.29(dd，J＝4.8，8.8Hz，?0.5H)，7.16(dd，J＝4.8，8.8Hz，0.5H)，7.01-6.96(m，1H)，5.39(s，2H)，5.07-5.04(m，1H)，3.81-3.46(m，6H)，2.70-2.51(m，6H)，1.85-1.83(m，3H)。
Embodiment 28
Preparation 4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl)-N-[(4-fluorophenyl) methyl] BM (DC295-26)
Except replacing the morpholine ring, to prepare Compound D C295-26, productive rate 66.3% with embodiment 17 identical modes with 4-fluorophenyl methylamine.
1H?NMR(400MHz，CDCl
3)δ8.23(d，J＝2.4Hz，1H)，7.83(d，J＝8.0Hz，2H)，7.64(d，J＝2.4Hz，1H)，7.40(d，J＝8.0Hz，2H)，7.34-7.26(m，2.5H)，7.14(dd，J＝4.8，8.8Hz，0.5H)，7.04-6.95(m，3H)，6.85(t，J＝5.6Hz，1H)，5.41(s，2H)，5.09-5.04(m，1H)，4.60(d，J＝5.6Hz，2H)，1.86-1.83(m，3H)。
Embodiment 29
Preparation 4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl)-N-[(3, the 5-difluorophenyl) methyl] BM (DC295-27)
Except with 3, outside the 5-difluorophenyl methylamine replacement morpholine ring, to prepare Compound D C295-27, productive rate 68.4% with embodiment 17 identical modes.
1H?NMR(400MHz，CDCl
3)δ8.25(d，J＝2.0Hz，1H)，7.85(d，J＝8.4Hz，2H)，7.65(d，J＝2.0Hz，1H)，7.42(d，J＝8.4Hz，2H)，7.31-7.26(m，0.5H)，7.15(dd，J＝4.8，8.8Hz，0.5H)，7.03(t，J＝6.0Hz，1H)，7.00-6.96(m，1H)，6.88-6.84(m，2H)，6.73-6.67(m，1H)，5.41(s，2H)，5.08-5.04(m，1H)，4.62(d，J＝6.0Hz，2H)，1.86-1.84(m，3H)。
Embodiment 30
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[2-(4-N-METHYL PIPERAZINE-1-yl) pyridine-5-yl] pyridine-2-amine (DC295-28)
Except replacing N-tertbutyloxycarbonyl-3-pyrazoles boric acid pinacol ester, to prepare Compound D C295-28, productive rate 32% with embodiment 5 identical modes with 2-(4-N-METHYL PIPERAZINE-1-yl)-5-pyridine boric acid pinacol ester.
1H?NMR(400MHz，CDCl
3)δ8.22(br，1H)，8.17(d，J＝2.0Hz，1H)，7.56(t，J＝3.2Hz，1H)，7.52-7.48(m，1H)，7.30-7.26(m，0.5H)，7.17(dd，J＝4.8，8.8Hz，0.5H)，7.01-6.97(m，1H)，6.69(d，J＝8.8Hz，1H)，5.21(s，2H)，5.10-5.03(m，1H)，3.62-3.59(m，4H)，2.57-2.55(m，4H)，2.87(s，3H)，1.86-1.83(m，3H)。
Embodiment 31
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(pyrimidine-5-yl) pyridine-2-amine (DC295-29)
Except replacing N-tertbutyloxycarbonyl-3-pyrazoles boric acid pinacol ester, to prepare Compound D C295-29, productive rate 28.73% with embodiment 5 identical modes with 5-pyrimidine boric acid pinacol ester.
1H?NMR(300MHz，CDCl
3)δ9.16(s，1H)，8.74(s，2H)，8.24-8.22(m，2H)，7.61-7.60(m，1H)，7.31(dd，J＝4.8，8.7Hz，0.5H)，7.18(dd，J＝4.8，8.7Hz，0.5H)，7.05-6.98(m，1H)，5.62(br，2H)，5.12-5.03(m，1H)，1.88-1.84(m，3H)。
Schema 9
Embodiment 32
Step 1: preparation 2-(4-bromine phenoxy)-1-morpholine ethyl ketone
(2.00g, 8.66mmol), (0.83mL 9.52mmol) is dissolved in 40mL CH to morpholine with 2-(4-bromine phenoxy) acetate
2Cl
2, adding DCC (1.88g, 9.09mmol), stirring at room, behind the reaction 3h, suction filtration, the evaporate to dryness of will filtrating, (petrol ether/ethyl acetate 1/1, v/v) separation and purification get 2.30g, productive rate 88.5% to resistates through column chromatography through product.
1H?NMR(300MHz，CDCl
3)δ7.39(d，J＝9.0Hz，2H)，6.84(d，J＝9.0Hz，2H)，4.67(s，2H)，3.66-3.58(m，8H)。
Step 2: preparation 1-(morpholine-4-yl)-2-[4-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl) phenoxy] ethyl ketone
Except 2-(4-bromine phenoxy)-1-morpholine ethyl ketone being replaced to 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate, to react with embodiment 5 identical modes, product is through column chromatography (PE/EA, 3/2) separation and purification, productive rate 71.3%.
1H?NMR(300MHz，CDCl
3)δ7.76(d，J＝8.7Hz，2H)，6.94(d，J＝8.7Hz，2H)，4.72(s，2H)，3.66-3.61(m，8H)，1.33(s，12H)。
Step 3: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-{4-[(woods-4-yl) carbonyl methoxyl group] phenyl } pyridine-2-amine (DC295-30)
Except with 1-(morpholine-4-yl)-[4-(4,4,5 for 2-; 5-tetramethyl--1,3,2-dioxy borine-2-yl) phenoxy] ethyl ketone replaces to outside 1-methyl-4-pyrazoles boric acid pinacol ester; To react with embodiment 4 identical modes, product is through preparation HPLC separation and purification, productive rate 25.84%.
1H?NMR(400MHz，CDCl
3)δ8.19(d，J＝1.6Hz?1H)，7.60(t，J＝2.0Hz，1H)，7.32-7.27(m，2.5H)，7.17(dd，J＝4.8，8.8Hz，0.5H)，7.02-6.97(m，3H)，5.23(s，2H)，5.07-5.04(m，1H)，4.73(s，2H)，3.70-3.61(m，8H)，1.86-1.83(m，3H)。
Flow process Figure 10
Embodiment 33
Step 1: preparation 4-(5-bromopyridine-2-yl) morpholine
With 2g 2, the 5-dibromo pyridine is scattered in the 10mL morpholine, 120 ℃ in microwave, and reaction 100min adds 150mL EA in reaction solution, use 0.1N HCl 30mL successively, H
2O 30mL, 0.1NNaOH solution, the saturated common salt water washing, organic layer is used anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and product is enough pure, directly carries out next step reaction.
Step 2: preparation 4-[5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl) pyridine-2-yl] morpholine
Except 4-(5-bromopyridine-2-yl) morpholine being replaced to 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate; To react with embodiment 5 identical modes; (PE/EA 4/1, v/v) separation and purification, productive rate 62.83% through the sharp separation column chromatography for product.
1H?NMR(300MHz，CDCl
3)δ8.55-8.54(m，1H)，7.84(dd，J＝1.8，8.7Hz，1H)，6.58(d，J＝8.7Hz，1H)，3.80(t，J＝4.8Hz，4H)，3.57(t，J＝4.8Hz，4H)，1.32(s，12H)。
Step 3: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[6-(morpholine-4-yl) pyridin-3-yl] pyridine-2-amine (DC295-31)
Except [5-(4,4,5 with 4-; 5-tetramethyl--1,3,2-dioxy borine-2-yl) pyridine-2-yl] morpholine replaces to outside 1-methyl-4-pyrazoles boric acid pinacol ester; To react with embodiment 4 identical modes, product is through preparation HPLC separation and purification, productive rate 22.03%.
1H?NMR(300MHz，CDCl
3)δ8.21(d，J＝2.4Hz?1H)，8.14(d，J＝2.4Hz，1H)，7.55(t，J＝2.7Hz，1H)，7.52-7.48(m，1H)，7.29-7.24(m，0.5H)，7.15(dd，J＝4.8，8.7Hz，0.5H)，7.02-6.97(t，J＝8.7Hz，1H)，6.65(d，J＝8.7Hz，1H)，5.38(s，2H)，5.09-4.99(m，1H)，3.84-3.80(m，4H)，3.52-3.49(m，4H)，1.86-1.83(m，3H)。
Flow process Figure 11
Embodiment 34
Step 1: preparation tetrahydropyrans-4-alcohol
Except Tetrahydro-pyran-4-one being replaced to outside 1-(3-fluoro-2, the 6-dichlorophenyl) ethyl ketone, to react with embodiment 2 identical modes.
Step 2: preparation tetrahydropyran-4-base methane sulfonate
Except tetrahydropyrans-4-alcohol being replaced to outside 1-(3-fluoro-2, the 6-dichlorophenyl) ethanol, to react with embodiment 2 identical modes.
Step 3: preparation 1-(tetrahydropyran-4-base)-4-bromo-1H-pyrazoles
Except the tetrahydropyran-4-base methane sulfonate being replaced to 4-(methanesulfonyloxy group) piperazine-1-t-butyl formate, to react with embodiment 5 identical modes.
1H?NMR(300MHz，DMSO-d
6)δ8.06(s，1H)，7.55(s，1H)，4.41-4.35(m，1H)，3.95-3.92(m，2H)，3.47-3.40(m，2H)，1.95-1.87(m，4H)。
Step 4: preparation 1-(tetrahydropyran-4-base)-4-pyrazoles boric acid pinacol ester
Except 1-(tetrahydropyran-4-base)-4-bromo-1H-pyrazoles being replaced to 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate, to react with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ7.80(s，1H)，7.75(s，1H)，4.42-4.31(m，1H)，4.12-4.07(m，2H)，3.57-3.49(m，2H)，2.13-1.99(m，4H)，1.32(s，12H)。
Step 5: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(pyrans-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-32)
Except 1-(tetrahydropyran-4-base)-4-pyrazoles boric acid pinacol ester is replaced to 1-methyl-4-pyrazoles boric acid pinacol ester, reacting with embodiment 4 identical modes, product is through reversed phase chromatography column separating purification or recrystallizing methanol, productive rate 29.66%.
1H?NMR(300MHz，CDCl
3)δ8.12-8.11(m，1H)，7.56(s，1H)，7.51-7.489(m，2H)，7.30-7.26(m，0.5H)，7.16(dd，J＝5.1，9.0Hz，0.5H)，7.01-6.95(m，1H)，5.25(s，2H)，5.08-5.00(m，1H)，4.37-4.28(m，1H)，4.13-4.08(m，2H)，3.58-3.46(m，2H)，2.12-2.00(m，4H)，1.87-1.83(m，3H)。
Flow process Figure 12
Embodiment 35
Step 1: preparation 5-bromo indole-2-ketone
(1g 7.51mmol) is dissolved in 30mL CH with the 2-indolone
2Cl
2/ CH
3CN (1: 1, v/v), be cooled to-10 ℃, dropping contains NBS (N-bromo-succinimide) (1.34g, CH 7.51mmol)
3CN solution 10mL, after drip finishing, reaction 5h moves to room temperature reaction 2h, and suction filtration gets the 1.255g brown solid, productive rate 78.8%.
Step 2: preparation indol-2-one-5-boric acid pinacol ester
Except 5-bromo indole-2-ketone being replaced to 4-(4-bromo-1H-pyrazol-1-yl) piperazine-1-t-butyl formate, to react with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.57(br，1H)，7.71-7.67(m，2H)，6.89(d，J＝7.5Hz，1H)，3.52(s，2H)，1.34(s，12H).
Step 3: preparation 5-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-2,3-dihydro-1H-indol-2-one (DC295-33)
Except indol-2-one-5-boric acid pinacol ester being replaced to 1-methyl-4-pyrazoles boric acid pinacol ester, to react with embodiment 4 identical modes, product is through column chromatographic isolation and purification (CH
2Cl
2/ MeOH 50/1, and v/v), productive rate 32.69%, products therefrom are again through acetone recrystallization.
1H?NMR(300MHz，CDCl
3)δ8.20(d，J＝1.8Hz，1H)，7.99(s，1H)，7.62-7.61(m，1H)，7.32-7.15(m，3H)，7.02-6.96(m，1H)，6.90(d，J＝8.1Hz，1H)，5.22(s，2H)，5.10-5.03(m，1H)，3.59(s，2H)，1.86(d，J＝7.2Hz，3H)。
Flow process Figure 13
Embodiment 36
Step 1: preparation N, N-dimethyl--1H-4-pyrazoles boric acid pinacol ester
With 1H-4-pyrazoles boric acid pinacol ester (150mg, 0.77mmol), triethylamine (0.27mL, 1.93mmol); The DMAP catalytic amount is dissolved in the 5mL anhydrous methylene chloride, under ice bath, adds N, and N-dimethyl methyl acyl chlorides (0.18mL, 1.93mmol); Finish, move to room temperature reaction 34h, in reaction solution, add 5mL water; Use the 40mL dichloromethane extraction, organic layer is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and (petrol ether/ethyl acetate 4/1, v/v) separation and purification get the 145mg white solid, productive rate 70.75% to product through the rapid separator column column chromatography.
1H?NMR(300MHz，CDCl
3)δ8.40(s，1H)，7.87(s，1H)，3.21(s，6H)，1.33(s，12H).
Step 2: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(1-N, N-dimethyl-carbonyl-1H-pyrazoles-4-yl) pyridine-2-amine (DC295-34)
Except with N, N-dimethyl--1H-4-pyrazoles boric acid pinacol ester replaces to outside 1-methyl-4-pyrazoles boric acid pinacol ester, and to react with embodiment 4 identical modes, product is through preparation TLC separation and purification, productive rate 41.26%.
1H?NMR(300MHz，CDCl
3)δ8.20-8.19(m，1H)，8.17-8.16(m，1H)，7.72(d，J＝1.5Hz，1H)，7.53(d，J＝1.5Hz，1H)，7.31(dd，J＝5.1，8.7Hz，0.5H)，7.18(dd，J＝5.1，8.7Hz，0.5H)，7.03-6.98(m，1H)，5.22(s，2H)，5.10-5.01(m，1H)，3.26(s，6H)，1.86-1.83(m，3H)。
Flow process Figure 14
Embodiment 37
Step 1: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(2-acetoxyl group acetyl carbonyl piperidines-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine
With 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (120mg, 0.26mmol), triethylamine (0.039mL; 0.28mmol), be dissolved in the 5mL anhydrous methylene chloride, under ice bath, drip 2-alpha-Acetoxyacetyl chloride (0.029mL; 0.27mmol), keep ice bath 15min, in reaction solution, add 10mL water; Use the 50mL dichloromethane extraction, organic layer is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, and product is through rapid separator column column chromatography (CH
2Cl
2/ MeOH 50/1, v/v) separation and purification, productive rate 48.03%.
1H?NMR(300MHz，CDCl
3)δ8.07(s，1H)，7.56-7.52(m，3H)，7.34-7.26(m，0.5H)，7.17(dd，J＝5.1，8.7Hz，0.5H)，7.04-6.99(m，1H)，5.78(s，2H)，5.07-5.03(m，1H)，4.78(s，2H)，4.70-4.66(m，1H)，4.41-4.34(m，1H)，3.86-3.82(m，1H)，3.26(t，J＝2.4Hz，1H)，2.87(t，J＝2.4Hz，1H)，2.29-2.20(m，5H)，2.04-1.97(m，2H)，1.86-1.83(m，3H)。
Step 2: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(2-glycoloyl carbonyl piperidines-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-35)
With 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(2-acetoxyl group acetyl carbonyl piperidines-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine 70mg be dissolved in 5mL MeOH/H2O (3/2, v/v) in; Add 25mg one hydronium(ion) oxidation lithium, stirring at room, reaction 2h; With the reaction solution evaporate to dryness; (CH2Cl2/MeOH 20/1, v/v) separation and purification, productive rate 58.64% through the rapid separator column column chromatography for the resistates product.
1H?NMR(300MHz，CDCl
3)δ8.12(d，J＝1.8Hz，1H)，7.57(s，1H)，7.53(d，J＝1.8Hz，1H)，7.51(s，1H)，7.31(dd，J＝5.1，8.7Hz，0.5H)，7.18(dd，J＝5.1，8.7Hz，0.5H)，7.03-6.96(m，1H)，5.32(s，2H)，5.09-5.02(m，1H)，4.73-4.69(m，1H)，4.43-4.33(m，1H)，4.22(s，2H)，3.76-3.66(m，1H)，3.23-3.13(m，1H)，3.00-2.91(m，1H)，2.27-2.23(m，2H)，2.07-1.95(m，2H)，1.86-1.83(m，3H)。
Embodiment 38
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(1-methylsulfonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-36)
Except replacing the 2-alpha-Acetoxyacetyl chloride, to prepare Compound D C295-36, productive rate 68.53% with embodiment 37 identical modes with methane sulfonyl chloride.
1H?NMR(300MHz，CDCl
3)δ8.12(d，J＝2.1Hz，1H)，7.58(s，1H)，7.52-7.50(m，2H)，7.31(dd，J＝5.1，9.0Hz，0.5H)，7.17(dd，J＝5.1，9.0Hz，0.5H)，7.04-6.98(m，1H)，5.26(s，2H)，5.10-5.02(m，1H)，4.33-4.23(m，1H)，3.96-3.92(m，2H)，2.99-2.89(m，2H)，2.86(s，3H)，2.31-2.26(m，2H)，2.22-2.09(m，2H)，1.86-1.83(m，3H)。
Embodiment 39
Preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(N, N-dimethyl-carbonyl piperidines-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine (DC295-37)
Except using N, N-dimethyl methyl acyl chlorides is replaced outside the 2-alpha-Acetoxyacetyl chloride, to prepare Compound D C295-37, productive rate 48% with embodiment 37 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.11(s，1H)，7.55(s，1H)，7.51-7.49(m，2H)，7.31-7.26(m，0.5H)，7.17(dd，J＝4.8，8.7Hz，0.5H)，7.04-6.98(m，1H)，5.25(s，2H)，5.08-5.00(m，1H)，4.31-4.21(m，1H)，3.82-3.77(m，2H)，2.96-2.85(m，8H)，2.18-2.13(m，2H)，2.08-1.94(m，2H)，1.86-1.83(m，3H)。
Flow process Figure 15
Embodiment 40
Step 1: preparation 4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-N, N-dimethyl--1,2,3,6-tetrahydropyridine-1-t-butyl formate
Except with 4-(4,4,5; 5-tetramethyl--1,3,2-dioxy borine-2-yl)-5; 6-dihydropyridine-1 (2H)-t-butyl formate replaces to outside 1-methyl-4-pyrazoles boric acid pinacol ester, reacting with embodiment 4 identical modes, product through the resistates product through rapid separator column column chromatography (CH
2Cl
2/ MeOH 50/1, v/v) separation and purification, productive rate 71.52%;
Step 2: preparation 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-(1,2,3,6-tetrahydropyridine-4-yl) pyridine-2-amine
Except with 4-(6-amido-5-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-N, N-dimethyl--1,2; 3; 6-tetrahydropyridine-1-t-butyl formate replacement 3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl }-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine outside, to prepare this compound with embodiment 5 identical modes;
Step 3: preparation 4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridin-3-yl)-N, N-dimethyl--1,2,3,6-tetrahydropyridine-1-methane amide (DC295-38)
Except with 3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl }-5-(1,2,3; 6-tetrahydropyridine-4-yl) pyridine-2-amine replacement 3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine outside, to prepare Compound D C295-38, productive rate 36.37% with embodiment 39 identical modes.
1H?NMR(400MHz，CDCl
3)δ8.05(s，1H)，7.44(dd，J＝2.1，4.5Hz，1H)，7.31-7.26(m，0.5H)，7.18(dd，J＝5.1，8.7Hz，0.5H)，7.03-6.97(m，1H)，5.83-5.80(m，1H)，5.15(s，2H)，5.0-4.97(m，1H)，3.89-3.87(m，2H)，3.42(t，J＝5.7Hz，2H)，2.86(s，6H)，2.42-2.40(m，2H)，1.84-1.81(m，3H)。
Flow process Figure 16
Embodiment 41
Step 1: preparation 2-(1-azidoethyl)-4-fluoro-1,3-dichlorobenzene
With 1-(3-fluoro-2,6-dichlorophenyl) sulfonyl methane ethyl ester (1g, 3.48mmol), sodiumazide (0.45g; 6.97mmol) be dissolved among the 10mL DMF, under nitrogen protection, being heated to 50 ℃, reaction is spent the night; Reaction solution is cooled to room temperature, adds 20mL water, with ETHYLE ACETATE (2 * 10mL) extractions; Organic layer is water successively, saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets product, and is enough pure, directly is used for next step.
Step 2: preparation 1-(3-fluoro-2,6-dichlorophenyl) ethamine
With 2-(1-azidoethyl)-4-fluoro-1, (815mg, 3.48mmol), (296.1mg, 4.53mmol), (428.4mg 8.61mmol) is scattered in 8mL EtOH/H to ammonium chloride to zinc powder to the 3-dichlorobenzene
2O (3/1, v/v) in, stirring at room 3h, if reaction not exclusively, but reflux adds 10mL CH in reaction solution
2Cl
2, suction filtration, filter cake is used CH
2Cl
2Washing, the evaporate to dryness of will filtrating, resistates is with ETHYLE ACETATE 60mL extraction, and organic layer is used saturated common salt water washing, anhydrous Na
2SO
4Drying is filtered, and removes solvent under reduced pressure, gets product, and enough pure, productive rate 70.67% directly is used for next step.
Step 3: preparation 5-bromo-2-amido nicotinic acid
(10g 72.40mmol) is scattered among the 40mL HAc, drips to contain bromine (4.82mL, HAc solution 20mL 94.12mmol) with diamino-nicotinic acid; Vigorous stirring 30min, suction filtration, filter cake washs with HAc; Behind thick product drying, get white solid 14.5g with recrystallizing methanol, productive rate 92.29%.MS(ESI，m/z)：216.8[M+H]
+。
Step 4: preparation 5-bromo-2-amido-N-(1-(3-fluoro-2,6-dichlorophenyl) ethyl) niacin hydroxyacyl amine
Except with 5-bromo-2-amido nicotinic acid; 1-(3-fluoro-2; The 6-dichlorophenyl) ethamine replacement 2-[4-(2-amido-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } pyridine-5-yl)-1H-pyrazol-1-yl] acetate is outside the dimethylamine hydrochloride solid; To prepare this compound, productive rate 69.5% with embodiment 19 identical modes.
1HNMR(300MHz，DMSO-d
6)δ9.12(d，J＝5.1Hz，1H)，δ8.27(d，J＝2.1Hz，1H)，8.15(d，J＝2.1Hz，1H)，7.50-7.45(m，1H)，7.39-7.34(m，1H)，7.12(s，2H)，5.62-5.53(m，1H)，1.56(t，J＝8.7Hz，3H)。
Step 5: preparation 4-[4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] amine formyl } pyridin-3-yl)-the 1H-pyrazol-1-yl] piperidines-1-t-butyl formate
Except with 5-bromo-2-amido-N-(1-(3-fluoro-2; The 6-dichlorophenyl) ethyl) niacin hydroxyacyl amine replaces to 5-bromo-3-{ [1-(2; 6-two chloro-3-fluorophenyls) ethyl] sulfenyl } outside pyridine-2-amine, to react with embodiment 4 identical modes, (MeOH/H2O 3/1 through reversed phase column chromatography for product; V/v) separate productive rate 37.59%.
Step 6:2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-carboxamide (DC295-39)
Except with 4-[4-(6-amido-5-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] amine formyl } pyridin-3-yl)-the 1H-pyrazol-1-yl] piperidines-1-t-butyl formate replacement 3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine outside, to prepare Compound D C295-39 with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.29(d，J＝2.1Hz，1H)，7.72(d，J＝2.1Hz，1H)，7.69(s，1H)，7.61(s，1H)，7.33-7.27(m，1H)，7.17(d，J＝8.4Hz，1H)，7.08-7.03(m，1H)，6.24(s，2H)，6.19-6.08(m，1H)，4.31-4.23(m，1H)，3.31-3.27(m，2H)，2.86-2.77(m，2H)，2.23-2.19(m，2H)，2.03-1.94(m，2H)，1.68(d，J＝6.9Hz，3H)。
Embodiment 42
Preparation 2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-[1-(morpholine-4-yl)-pyridin-3-yl] pyridine-3-carboxamide (DC295-40)
Except replacing outside N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester, to prepare Compound D C295-40, productive rate 40.32% with embodiment 41 identical modes with 4-[5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl) pyridine-2-yl] morpholine.
1H?NMR(400MHz，CDCl
3)δ8.34(dd，J＝0.8，2.4Hz，1H)，8.26(d，J＝2.4Hz，1H)，7.83(d，J＝2.4Hz，1H)，7.65(dd，J＝2.8，8.8Hz，1H)7.32-7.28(m，1H)，7.23(d，J＝9.6Hz，1H)，7.07-7.03(m，1H)，6.74(dd，J＝0.4，8.8Hz，1H)，6.60(s，2H)，6.19-6.09(m，1H)，3.86(t，J＝8.8Hz，4H)，3.57(t，J＝8.8Hz，4H)，1.69(d，J＝7.2Hz，3H)。
Embodiment 43
Preparation 2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-[1-(pyrans-4-yl)-1H-pyrazoles-4-yl] pyridine-3-carboxamide (DC295-41)
Except replacing N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester, to prepare Compound D C295-41, productive rate 59.06% with embodiment 41 identical modes with 1-(tetrahydropyran-4-base)-4-pyrazoles boric acid pinacol ester.
1H?NMR(300MHz，CDCl
3)δ8.28(d，J＝1.8Hz，1H)，7.75(d，J＝1.8Hz，1H)，7.69(s，1H)，7.60(s，1H)，7.32-7.25(m，1H)，7.17(d，J＝8.4Hz，1H)，7.08-7.02(m，1H)，6.32(s，2H)，6.16-6.07(m，1H)，4.42-4.32(m，1H)，4.14-4.09(m，2H)，3.59-3.51(m，2H)，2.14-2.07(m，4H)，1.68(d，J＝6.9Hz，3H)。
Embodiment 44
Preparation 2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-(2-oxo-2,3-dihydro-1H-indoles-5-yl) pyridine-3-carboxamide (DC295-42)
Except replacing N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester, to prepare Compound D C295-42, productive rate 19.50% with embodiment 41 identical modes with indol-2-one-5-boric acid pinacol ester.
1HNMR(300MHz，DMSO-d
6)δ12.94(br，1H)，δ10.45(s，1H)，9.15(d，J＝5.1Hz，1H)，8.35(d，J＝2.1Hz，1H)，8.27(d，J＝2.1Hz，1H)，7.55(s，1H)，7.50-7.45(m，1H)，7.36(t，J＝8.7Hz，1H)，6.96(s，2H)，6.90(d，J＝8.1Hz，1H)，5.68-5.59(m，1H)，3.56(s，2H)，1.60(d，J＝7.2Hz，3H)。
Embodiment 45
Preparation 2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-{4-[2-(morpholine-4-yl)-2-oxo oxyethyl group] phenyl } pyridine-3-carboxamide (DC295-43)
Except with 1-(morpholine-4-yl)-[4-(4,4,5 for 2-; 5-tetramethyl--1,3,2-dioxy borine-2-yl) phenoxy] outside ethyl ketone replacement N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester; To prepare Compound D C295-43, productive rate 46.06% with embodiment 41 identical modes.
1H?NMR(400MHz，CDCl
3)δ8.34(d，J＝2.4Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.41(d，J＝8.4Hz，2H)，7.31-7.28(m，1H)，7.19(d，J＝8.8Hz，1H)，7.06-7.01(m，3H)，6.32(s，2H)，6.15-6.08(m，1H)，4.73(s，2H)，3.70-3.66(m，4H)，3.63-3.61(m，4H)，1.66(d，J＝6.8Hz，3H)。
Embodiment 46
Preparation 2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-(pyrimidine-5-yl) pyridine-3-carboxamide (DC295-44)
Except replacing N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester, to prepare Compound D C295-44, productive rate 37.22% with embodiment 41 identical modes with pyrimidine-5-boric acid tetramethyl ethylene ketone.
1H?NMR(400MHz，CDCl
3)δ9.21(s，1H)，8.90(s，2H)，8.40(d，J＝2.4Hz，1H)，7.84(d，J＝2.4Hz，1H)，7.32-7.29(m，1H)，7.17(d，J＝8.4Hz，1H)，7.08-7.04(m，1H)，6.57(s，2H)，6.18-6.10(m，1H)，1.69(d，J＝6.8Hz，3H)。
Flow process Figure 17
Embodiment 47
Step 1: preparation 5-bromo-2-amido pyridine-3-SULPHURYL CHLORIDE
Under-15 ℃, 700mg adds in the 5mL chlorsulfonic acid in batches with 5-bromo-2-amido pyridine, and question response liquid is homogeneous phase; Be warming up to 160 ℃ gradually, reaction 3h is cooled to room temperature; Under agitation, slowly pour in the ice cube, wash rice goes out white solid; Suction filtration is collected filter cake, gets 400mg 5-bromo-2-amido pyridine-3-SULPHURYL CHLORIDE bullion.
Step 2: preparation 5-bromo-2-amido-N-(1-(3-fluoro-2,6-dichlorophenyl) ethyl) pyridine-3-sulphonamide
With 1-(3-fluoro-2,6-dichlorophenyl) ethamine (306.51mg, 1.47mmol), triethylamine (205 μ L; 1.47mmol) be dissolved in the 10mL anhydrous methylene chloride, under ice bath, add 400mg 5-bromo-2-amido pyridine-3-SULPHURYL CHLORIDE bullion, finish; Move to react under the room temperature and spend the night, in reaction solution, add entry 10mL, the 60mL dichloromethane extraction; Organic layer is used dried over sodium sulfate, filters, and removes solvent under reduced pressure; (PE/EA 3/2, v/v) separation and purification, two step overall yields 20.86% through the rapid separator column column chromatography for product.
1H?NMR(300MHz，DMSO-d
6)δ8.78(br，1H)，δ8.11(d，J＝2.4Hz，1H)，7.48-7.24(m，3H)，6.77(s，2H)，5.19-5.12(m，1H)，1.50(d，J＝7.2Hz，3H)。
Step 3: preparation 4-[4-(6-amido-5-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfamic } pyridin-3-yl)-the 1H-pyrazol-1-yl] piperidines-1-t-butyl formate
Except with 5-bromo-2-amido-N-(1-(3-fluoro-2; The 6-dichlorophenyl) ethyl) pyridine-3-sulphonamide replaces to 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to react with embodiment 4 identical modes; Product is through column chromatography (MeOH/CH2Cl250/1; V/v) separate, productive rate 40.08% gets white solid through recrystallizing methanol again.
1H?NMR(300MHz，CDCl
3)δ：8.11(d，J＝1.5Hz，1H)，7.79-7.76(m，1H)，7.63(s，1H)，7.57-7.54(m，1H)，7.02-6.91(m，1H)，6.77-6.72(m，1H)，6.28-6.17(m，1H)，5.51(s，2H)，5.47-5.37(m，1H)，4.35-4.25(m，3H)，2.96-2.85(m，2H)，2.19-2.16(m，2H)，2.01-1.89(m，2H)，1.60(d，J＝7.2Hz，3H)，1.49(s，9H)。
Step 4: preparation 2-amido-N-[1-(3-fluoro-2,6-dichlorophenyl) ethyl]-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-sulphonamide (DC295-45)
Except with 4-[4-(6-amido-5-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfamic } pyridin-3-yl)-the 1H-pyrazol-1-yl] piperidines-1-t-butyl formate replacement 3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine outside, to prepare Compound D C295-45 with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.13(d，J＝2.4Hz，1H)，7.79-7.76(m，1H)，7.63(s，1H)，7.58-7.56(m，1H)，7.03-6.95(m，1H)，6.78-6.73(m，1H)，6.32(br，1H)，5.52(s，2H)，5.44-5.37(m，1H)，4.31-4.22?(m，1H)，3.30-3.26(m，2H)，2.83-2.76(m，2H)，2.23-2.18(m，2H)，1.99-1.86(m，2H)，1.60(d，J＝7.5Hz，3H)。
Flow process Figure 18
Embodiment 48
Step 1: preparation 4-fluoro-3-chloro-methylphenylamine
(1.86g 34.35mmol) is dissolved in 50mL methyl alcohol, and (1g, 6.87mmol), (1.03g, 34.35mmol), backflow 3h postcooling to 0 ℃ adds NaBH to Paraformaldehyde 96 in reaction solution to add 3-fluoro-4-chloroaniline in succession with sodium methylate
4(1.30g, 34.35mmol), after finishing, 2h again refluxes; Be cooled to room temperature, add 10mL water to reaction solution, remove organic solvent under reduced pressure, water layer is used ethyl acetate extraction; Organic layer is with saturated NaCl solution washing, and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure; Get product 960mg light yellow liquid, enough pure, productive rate 87.56%.
1H?NMR(300MHz，CDCl
3)δ6.96(t，J＝9.0Hz，1H)，δ6.60-6.57(dd，J＝2.4，6.0Hz，1H)，6.45-6.40(m，1H)，3.64(br，1H)，2.80(s，3H)。
Step 2: preparation 5-bromo-2-amido-N-methyl-N-(4-fluoro-3-chloro-phenyl-)-pyridine-3-sulphonamide
(294mg 1.84mmol) is dissolved in the 8mL triethylamine, under nitrogen protection, adds 5-bromo-2-amido pyridine-3-SULPHURYL CHLORIDE (500mg with 4-fluoro-3-chloro-methylphenylamine; 1.84mmol), being heated to 60 ℃, reaction 3h is with the reaction solution evaporate to dryness; Resistates is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying, filters, and removes solvent under reduced pressure; (PE/EA 8/1, and v/v) separation and purification gets the 200mg end product, productive rate 27.5% through column chromatography.
1H?NMR(300MHz，CDCl
3)δ8.27(d，J＝2.4Hz，1H)，δ7.78(d，J＝2.4Hz，1H)，7.31-7.28(m，1H)，7.12-7.08(m，1H)，5.53(s，2H)，3.22(s，3H)。
Step 3: preparation N-methyl-N-(3-chloro-4-fluorophenyl)-2-amido-5-[1-(1-tertbutyloxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-sulphonamide
Except 5-bromo-2-amido-N-methyl-N-(3-chloro-4-phenyl)-pyridine-3-sulphonamide being replaced to 5-bromo-3-{ [1-(2,6-two chloro-3-fluorophenyls) ethyl] sulfenyl } outside pyridine-2-amine, to react with embodiment 4 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.38(d，J＝2.4Hz，1H)，7.68(d，J＝2.4Hz，1H)，7.64(s，1H)，7.54(s，1H)，7.32-7.29(m，1H)，7.13-7.10(m，2H)，5.52(s，2H)，4.33-4.23(m，3H)，3.23(s，3H)，2.95-2.86(m，2H)，2.18-2.13(m，2H)，2.00-1.91(m，2H)，1.49(s，9H)。
Step 4: preparation N-methyl-N-(3-chloro-4-fluorophenyl)-2-amido-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-sulphonamide (DC295-46)
Except replacing 3-{ [1-(3-fluoro-2 with N-methyl-N-(3-chloro-4-fluorophenyl)-2-amido-5-[1-(1-tertbutyloxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-sulphonamide; The 6-dichlorophenyl) ethyl] sulfenyl-5-[1-(N-tert-butoxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-2-amine outside, to prepare Compound D C295-46 with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.39(d，J＝2.1Hz?1H)，7.68(d，J＝2.1Hz，1H)，7.64(d，J＝0.6Hz，1H)，7.56(d，J＝0.6Hz，1H)，7.32-7.29(m，1H)，7.13-7.10(m，2H)，5.52(s，2H)，4.31-4.21(m，1H)，3.32-3.26(m，2H)，3.23(s，3H)，2.85-2.77(m，2H)，2.22-2.17(m，2H)，2.06-1.91(m，3H)。
Embodiment 49
Preparation 2-amido-N-methyl-N-(3-chloro-phenyl-)-5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridine-3-sulphonamide (DC295-47)
Except with 5-bromo-2-amido-N-methyl-N-(3-chloro-phenyl-)-pyridine-3-sulphonamide replacement 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-47 with embodiment 4 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.36(d，J＝2.4Hz?1H)，7.65(d，J＝2.4Hz，1H)，7.58(s，1H)，7.48(s，1H)，7.28-7.24(m，3H)，7.15-7.12(m，1H)，5.55(s，2H)，3.94(s，3H)，3.25(s，3H)。
Embodiment 50
Preparation N-methyl-N-(3-chloro-phenyl-)-2-amido-5-{ [1-(piperidin-4-yl)-1H-pyrazoles-4-yl] phenyl } pyridine-3-sulphonamide (DC295-48)
Except with 5-bromo-2-amido-N-methyl-N-(3-chloro-phenyl-)-pyridine-3-sulphonamide replacement 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-48 with embodiment 5 identical modes.
1H?NMR(300MHz，DMSO-d
6)δ8.53(d，J＝2.1Hz1H)，8.18(s，1H)，7.75(s，1H)，7.71(d，J＝2.1Hz，1H)，7.41-7.38(m，2H)，7.34(s，1H)，7.28-7.23(m，1H)，6.36(s，2H)，4.22-4.11(m，1H)，3.22(s，3H)，3.06-3.02(m，2H)，2.63-2.55(m，2H)，1.98-1.94(m，2H)，1.84-1.71(m，2H)。
Embodiment 51
Preparation N-methyl-N-(3-chloro-phenyl-)-2-amido-5-{4-[2-oxo-2-(piperazine-4-yl) oxyethyl group] phenyl } pyridine-3-sulphonamide (DC295-49)
Except with 5-bromo-2-amido-N-methyl-N-(3-chloro-phenyl-)-pyridine-3-sulphonamide, ((4-(4,4 for 2-for 4-; 5; 5-tetramethyl--1,3,2-dioxy borine-2-yl) ethanoyl phenoxy)) piperazine-1-t-butyl formate is replaced 5-bromo-3-{ [1-(3-fluoro-2 respectively; The 6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, N-tertbutyloxycarbonyl-4-pyrazoles boric acid pinacol ester is to prepare Compound D C295-49 with embodiment 5 identical modes.
1HNMR(300MHz，CDCl
3)δ8.41(d，J＝2.4Hz?1H)，7.75(d，J＝2.4Hz，1H)，7.32-7.24(m，5H)，7.15-7.11(m，1H)，7.00(d，J＝8.7Hz，2H)，5.61(s，2H)，4.73(s，2H)，3.63-3.55(m，4H)，3.26(s，3H)，2.89-2.83(m，4H)。
Embodiment 52
Preparation N-methyl-N-(3-chloro-phenyl-)-2-amido-5-(pyridin-4-yl) pyridine-3-sulphonamide (DC295-50)
Except with 5-bromo-2-amido-N-methyl-N-(3-chloro-phenyl-)-pyridine-3-sulphonamide; Pyridine-4-boric acid replacement 5-bromo-3-{ [1-(3-fluoro-2; The 6-dichlorophenyl) ethyl] sulfenyl } pyridine-2-amine; Outside 1-methyl-4-pyrazoles boric acid pinacol ester, to prepare Compound D C295-50 with embodiment 4 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.66-8.64(m，2H)，8.57(d，J＝2.1Hz?1H)，7.86(d，J＝2.1Hz，1H)，7.34-7.29(m，4H)，7.17-7.13(m，1H)，5.82(s，2H)，3.27(s，3H)。
Embodiment 53
Preparation N-methyl-N-[3-(trifluoromethyl) phenyl]-2-amido-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-sulphonamide (DC295-51)
Except with 5-bromo-2-amido-N-methyl-N-(3-trifluoromethyl)-pyridine-3-sulphonamide replacement 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-51 with embodiment 5 identical modes.
1H?NMR(300MHz，DMSO-d
6)δ8.54(d，J＝2.7Hz1H)，8.19(s，1H)，7.83(s，1H)，7.73(d，J＝1.8Hz，1H)，7.45-7.37(m，1H)，7.21-7.12(m，3H)，6.38(s，2H)，5.52(s，2H)，4.48-4.39(m，1H)，3.39-3.32(m，2H)，3.22(s，3H)，3.08-2.99(m，2H)，2.27-2.16(m，2H)，2.11-1.97(m，2H)。
Embodiment 54
Preparation N-methyl-N-(pyridin-3-yl)-2-amido-5-[1-(piperidin-4-yl)-1H-pyrazoles-4-yl] pyridine-3-sulphonamide (DC295-52)
Except with 5-bromo-2-amido-N-methyl-N-(pyridin-3-yl)-pyridine-3-sulphonamide replacement 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-52 with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.56-8.52(m，2H)，8.38(d，J＝2.4Hz?1H)，7.67(d，J＝2.4Hz，1H)，7.61-7.58(m，2H)，7.55(s，1H)，7.32-7.26(m，2H)，5.50(s，2H)，4.26-4.18(m，1H)，3.31-3.24(m，5H)，2.82-2.74(m，2H)，2.20-2.14(m，2H)，1.96-1.83(m，2H)，1.74-1.67(m，2H)。
Embodiment 55
Preparation N-methyl-N-(3-chloro-phenyl-)-2-amido-5-{4-[(piperazine-4-yl) carbonyl] phenyl } pyridine-3-sulphonamide (DC295-53)
Except with 5-bromo-2-amido-N-methyl-N-(3-chloro-phenyl-)-pyridine-3-sulphonamide replacement 5-bromo-3-{ [1-(3-fluoro-2,6-dichlorophenyl) ethyl] sulfenyl } outside pyridine-2-amine, to prepare Compound D C295-53 with embodiment 5 identical modes.
1H?NMR(300MHz，CDCl
3)δ8.48(d，J＝2.4Hz?1H)，7.81(d，J＝2.4Hz，1H)，7.51-7.41(m，4H)，7.32-7.25(m，3H)，7.17-7.13(m，1H)，5.72(s，2H)，3.79-3.74(m，2H)，3.49-3.43(m，2H)，3.27(s，3H)，2.97-2.82(m，4H)。
Test example
Embodiment 56
The kinase molecule level suppresses experiment
With enzyme reaction substrate Poly (Glu, Tyr)
4: 1(10mM sodium phosphate buffer, 150mM NaCl pH7.2-7.4) are diluted to 20 μ g/ml to the PBS of the no potassium ion of usefulness, and 125 μ l/ hole coated elisa plates are put 37 ℃ of reactions 12-16 hour.Discard and wash plate in the hole behind the liquid, wash plate three times, each 5 minutes with the T-PBS (PBS that contains 0.1%Tween-20) in 200 μ l/ holes.In 37 ℃ of baking ovens dry enzyme plate 1-2 hour.
Every hole adds with reaction buffer (50mM HEPES pH 7.4,50mM MgCl
2, 0.5mMMnCl
2, 0.2mM Na
3VO
4, 1mM DTT) dilution ATP solution 50 μ L, final concentration 5 μ M.Medicine is diluted to suitable concentration with 1%DMSO, and 10 μ l/ holes add each the tyrosine-kinase zymoprotein with the dilution of 40 μ l reaction buffers more respectively.Put 37 ℃ of shaking tables (100rpm) reaction 1 hour.T-PBS washes plate three times.(each experiment need be established the control wells of no enzyme control wells three holes and corresponding DMSO concentration) adds an anti-PY99100 μ l/ hole (p-Tyr (PY99); Cell Sinaling Technology; Antibody is used the T-PBS1 that contains BSA 5mg/ml: 1000 dilutions), 37 ℃ of shaking tables reacted 0.5 hour.T-PBS washes plate three times.Add the IgG 100 μ l/ holes (antibody is used the T-PBS1 that contains BSA 5mg/ml: 2000 dilute) of two anti-horseradish peroxidase-labeled sheep anti mouses, 37 ℃ of shaking tables reacted 0.5 hour.T-PBS washes plate three times.The OPD colour developing liquid 100 μ l/ holes that add 2mg/ml are (with containing 0.03%H
2O
20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution), 25 ℃ of lucifuges reactions 1-10 minute.(OPD need use ultrasonic when dissolving, colour developing liquid need be joined existing usefulness at present).Add 2M H
2SO
450 μ l/ hole stopped reactions, with wavelengthtunable orifice plate ELIASA SPECTRAMAX 190 readings that decline, wavelength is 492nm.
The inhibiting rate of sample is tried to achieve through formula:
C
50Value is calculated with four parameter fittings through suppressing curve.
Embodiment 57
Western blot hybridization (Western Blot)
The NIH3T3-TPR-Met cell inoculation in 12 orifice plates, after degrees of fusion reaches 80%, is added medicine and the SU11274 effect 6 hours of different concns.Collecting cell is washed once with cold PBS (containing the 1mM vanadic acid sodium), adds 1 * sds gel sample-loading buffer (50mM Tris-HCl (pH 6.8), 100mMDTT, 2%SDS, 10% glycerine, 1mM vanadic acid sodium, 0.1% tetrabromophenol sulfonphthalein) lysing cell.Cell lysate heats 10 minutes in boiling water bath after, in centrifugal 10 minutes of 4 ℃ of 12000rpm.
Get supernatant and carry out the SDS-PAGE electrophoresis; After electrophoresis finishes; With half-dried electrotransfer system albumen is transferred to nitrocellulose filter (Amersham Life Sciences, Arlington Heights, IL; USA); Nitrocellulose filter is placed confining liquid (5% skim-milk is diluted in the TBS/T that contains the 1mM vanadic acid sodium) room temperature sealing 1 hour, then film was placed in the antibody of (1: 1000) or anti-actin (Cell Sinaling Technology) in the antibody of anti-phosphorylation c-Met (Y1234/1235, Cell SinalingTechnology) sealing of (1: 6000) room temperature 2 hours.With the TBS/T washing that contains the 1mM vanadic acid sodium three times, each 15min.Film was placed two anti-(1: 2000) solution room temperature reactions 1-2 hour.The same wash film three times after, with ECL reagent color development, compressing tablet develops.
With above-mentioned nitrocellulose filter with Chemicon (Temecula; CA; USA) after the ReblotTM solution of company is peeled off and is removed the antibody that has combined; Again sealing (5% skim-milk is diluted in TBS/T) detects according to above-mentioned steps with antibody (1: 500) and two anti-(1: 2000) of anti-c-Met (C12, Santa Cruz Biotechnology) again.
Table 1 has shown the selected compound bioassay of this invention result, with IC
50(μ M) expression.
Table 1
| Numbering | c-Met(IC50) | Numbering | c-Met(IC50) |
| DC295-4 | 0.042 | DC295-24 | 0.178 |
| DC295-5 | 0.016 | DC295-28 | 0.027 |
| DC295-5-A | 0.007 | DC295-30 | 0.051 |
| DC295-5-B | 0.376 | DC295-31 | 0.066 |
| DC295-6 | 0.019 | DC295-32 | 0.021 |
| DC295-7 | 0.020 | DC295-33 | 0.130 |
| DC295-8 | 0.045 | DC295-34 | 0.586 |
| DC295-9 | 0.080 | DC295-35 | 0.038 |
| DC295-10 | 0.035 | DC295-36 | 0.033 |
| DC295-11 | 0.100 | DC295-37 | 0.048 |
| DC295-12 | 0.024 | DC295-38 | 0.300 |
| DC295-13 | 0.039 | DC295-39 | 0.319 |
| DC295-14 | 0.062 | DC295-45 | ＞10 |
| DC295-15 | 0.045 | DC295-46 | 7.00 |
| DC295-16 | 0.022 | DC295-47 | 7.3 |
| DC295-17 | 0.101 | DC295-48 | 2.3 |
| DC295-18 | 0.152 | DC295-49 | 4.6 |
| DC295-19 | 0.017 | DC295-50 | ＞10 |
| DC295-20 | 0.045 | DC295-51 | ＞10 |
| DC295-21 | 0.087 | DC295-52 | ＞10 |
| DC295-22 | 0.107 | DC295-53 | ＞10 |
| DC295-23 | 0.077 | ? | ? |
Table 2 has shown that this invention chooses compound to optionally bioassay result of kinases.
Table 2
Embodiment 58
The cell inhibitory effect test
The cell inoculation that the inoculation some amount is in logarithmic phase is in 96 well culture plates, and every hole 90 μ l add the compound of 10 μ l different concns respectively after the overnight cultures, 3 concentration are set, each concentration 3 multiple hole.After the compound effects 72 hours, discard nutrient solution, with the 10%TCA of precooling 4 ℃ fixing 1 hour, distilled water wash 5 times, seasoning in the air.Every then hole adds that (room temperature dyeing 15 minutes discards staining fluid for sulforodamine B, SRB) solution 100 μ l, 1% Glacial acetic acid min. 99.5 washing 5 times, seasoning in the air by the bright B of sulphonyl Luo Dan of the 4mg/ml of 1% Glacial acetic acid min. 99.5 preparation.Add 150 μ l Tris-HCL solution (10mM Tris, pH 10.0) in last every hole, ELIASA 515nm wavelength is measured absorbancy OD value down.
Table 3 has shown that this invention chooses the influence of compound to the ability of cell proliferation of Met mediation, with compound the difference of NIH3T3-TPR-Met cell and NIH3T3 background control cells proliferation inhibition rate (%) is represented.
Table 3
Claims (15)
1. the compound of a general formula (I) expression, its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt,
Wherein,
X is-S-,-S (O)
2-,-S (O)-,-SO
2N (R
5)-,-CO-or-CON (R
5)-;
M is 0 or 1;
R
1For replacing or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical, replace or unsubstituted C6-C10 aryl, perhaps
Said heterocyclic radical contains 1～4 heteroatoms that is selected from oxygen, sulphur and the nitrogen;
Said R
1In the aryl of substituted saturated or undersaturated C3-C12 heterocyclic radical or substituted C6-C10 on comprise 1～5 substituting group, said substituting group be alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR
7R
8,-OR
3COR
6,-CON (R
1) R
3R
6,-CON (R
1) R
3NR
6R
7,-R
3CONR
6R
7,-COR
3OH, phenyl, substituted phenyl, naphthyl, xenyl, or replace or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical; Wherein said substituted phenyl comprises 1～5 substituting group, this substituting group be independently of one another alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, saturated or undersaturated C3-C12 heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6Or-OR
3NR
7R
8Said replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain the heteroatoms that 1-4 is selected from oxygen, sulphur and nitrogen, and substituted saturated or undersaturated C3-C12 heterocyclic radical contain one or more alkyl that are selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, saturated or undersaturated C3-C12 heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-R
3R
6,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CONR
6R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6With-OR
3NR
7R
8In substituting group;
R
2Be the alkyl of hydrogen, halogen, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C6 straight or branched, the unsaturated alkyl of C2-C6 straight or branched, the alkoxyl group of C1-C6 straight or branched, the alkyloyl of C1-C6 straight or branched or the alkylamino of C1-C6 straight or branched;
R
1, R
2Can be interconnected to ring;
R
3, R
4Be the alkyl of hydrogen, halogen, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C6 straight or branched, the unsaturated alkyl of C2-C6 straight or branched, alkoxyl group, C3-C12 cyclic hydrocarbon radical, the alkyloyl of C1-C6 straight or branched or the alkylamino of C1-C6 straight or branched of C1-C6 straight or branched independently of one another;
R
3And R
4Can connect into ring;
R
15For the unsaturated alkyl of the alkyl of hydrogen, halogen, C1～C6 straight or branched, C2～C6 straight or branched, itrile group, nitro, amino, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-R
3OH ,-R
3R
4,-R
3NR
1R
2,-R
3R
5,-R
3CONR
1R
2,-CONR
1R
2,-COR
3OH, replacement or unsubstituted at least one heteroatomic 5 yuan or the 6 yuan of heterocyclic radicals that are selected among N, O and the S that contain, said substituting group be halogen, C1～C6 straight or branched alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1Or-CONR
1R
2 
For replacing or unsubstituted C6-C10 aryl, or replacing or unsubstituted C5-C12 heteroaryl, said heteroaryl contains 1-4 heteroatoms that is selected from oxygen, sulphur and nitrogen;
Said
In substituting group be alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-OR
3R
6,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CONR
6R
7NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
3SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6,-OR
3NR
7R
8, phenyl, substituted phenyl, naphthyl, xenyl, or replace or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical; Wherein said substituted phenyl comprises 1～5 substituting group, this substituting group be independently of one another unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, the C3-C12 of alkyl, the C2-C12 straight or branched of halogen, C1-C12 straight or branched saturated or undersaturated heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCON (R
6) R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, R
7N (R
6) CON (R
8)-,-N (R
6) R
3SO
2R
8, R
7N (R
6) R
3SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6Perhaps-OR
3NR
7R
8Said replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain the heteroatoms that 1-4 is selected from oxygen, sulphur and nitrogen, and substituted saturated or undersaturated C3-C12 heterocyclic radical contain unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, heterocycloalkenyl, the C3-C12 of one or more alkyl that are selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched saturated or undersaturated heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-SOR
6,-SO
2R
6, R
6CO-,-COOR
6,-SO
3R
6,-CONR
6R
7,-CON (R
6) R
3NR
8R
9,-SO
2NR
6R
7,-OCONR
6R
7,-OR
3CONR
7R
8,-N (R
6) R
3COR
8, NR
6R
7CON (R
8)-,-N (R
6) R
7SO
2R
8, NR
6R
7SO
2N (R
8)-,-NR
6R
7,-SR
6,-OR
6With-OR
3NR
7R
8In substituting group;
R
5, R
6, R
7, R
8, R
9Be independently of one another alkyl, the C2-C12 straight or branched of hydrogen, halogen, C1-C12 straight or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon radical, C1-C6 alkoxyl group, C1-C6 acyl group, C6-C12 aryl, or replace or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical; Said replacement or unsubstituted saturated or undersaturated C3-C12 heterocyclic radical contain the heteroatoms that 1-4 is selected from oxygen, sulphur and nitrogen, and substituted C3-C12 heterocyclic radical contain one or more alkyl that are selected from halogen, C1-C12 straight or branched, C2-C12 straight or branched unsaturated alkyl, C1-C6 alkoxyl group, C3-C12 cyclic hydrocarbon radical, saturated or undersaturated C3-C12 heterocyclic radical, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-R
3OH and-SO
2R
1In substituting group; R
5, R
6, R
7, R
8, R
9In any two can form ring with the nitrogen-atoms that links to each other when linking to each other with identical nitrogen-atoms; R
5, R
6, R
7, R
8, R
9In any two form ring with the carbon atom that links to each other when linking to each other with identical carbon atom;
R
1, R
2Be the alkyl of hydrogen or C1～C6 independently of one another respectively; R
3Alkylidene group for C1～C6.
2. general formula according to claim 1 (I) compound, its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt, wherein, m is 0 or 1; X is selected from-S-,-SO
2N (R
5)-with-CON (R
5)-in; R
1For being selected from following group:
Wherein, U is C, N or O; Z is C or N; Q is N or O;
R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18And R
19Respectively be independently of one another alkyl, the C2～C6 straight or branched of hydrogen, halogen, C1～C6 straight or branched unsaturated alkyl, itrile group, nitro, amino, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-R
3OH ,-R
3R
4,-R
3NR
1R
2,-R
3R
5,-R
3CONR
1R
2,-CONR
1R
2,-COR
3OH, replacement or unsubstituted at least one heteroatomic 5 yuan or the 6 yuan of heterocyclic radicals that are selected among N, O and the S that contain, said substituting group be halogen, C1～C6 straight or branched alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1Or-CONR
1R
2
R
1, R
2Be the alkyl of hydrogen or C1～C6 independently of one another respectively;
R
3Alkylidene group for C1～C6;
R
4Be to replace or unsubstituted at least one heteroatomic 5 yuan or the 6 yuan of heterocyclic radicals that are selected among N, O and the S that contain, said substituting group be halogen, C1～C6 straight or branched alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-S (O)
2R
1,-CONR
1R
2
R
5For by 1～5 substituted phenyl of halogen atom, said halogen is fluorine, chlorine, bromine or iodine.
3. general formula according to claim 1 and 2 (I) compound; Its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt; Wherein,
does
Wherein, R
20, R
21, R
22, R
23, R
24Respectively be independently of one another alkyl, the C2～C6 straight or branched of hydrogen, halogen, C1～C6 straight or branched unsaturated alkyl, itrile group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, sulfydryl ,-OR
1Or-OR
3R
4Said halogen is fluorine, chlorine, bromine or iodine;
Said R
1, R
3And R
4Definition identical with the definition in the claim 2.
4. general formula according to claim 3 (I) compound; Its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt; Wherein,
is selected from following structure fragment:
5. general formula according to claim 1 (I) compound, its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt, wherein, said compound is selected from the following compound:
6. general formula according to claim 1 (I) compound; Its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt; Wherein, said pharmaceutically useful salt is the compound of general formula (I) and the non-toxic salt of mineral acid or organic acid reaction formation;
Perhaps general formula (I) compound and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, Hydrocerol A, aspartic acid or L-glutamic acid form behind the ester sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt that forms with mineral alkali again;
The perhaps methylamine salt, ethylamine salt or the ethanolamine salt that form of general formula (I) compound and organic bases;
Perhaps general formula (I) compound and Methionin, l-arginine, ornithine form behind the ester more corresponding inorganic acid salt that forms with hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid or the corresponding organic acid salt that forms with formic acid, acetate, TNP, methylsulfonic acid and ethyl sulfonic acid.
7. described general formula according to claim 6 (I) compound; Its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt; Wherein, Said mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid, and said organic acid comprises Hydrocerol A, tartrate, lactic acid, pyruvic acid, acetate, Phenylsulfonic acid, tosic acid, methylsulfonic acid, naphthene sulfonic acid, ethyl sulfonic acid, naphthalene disulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, fumaric acid, succsinic acid, propionic acid, oxalic acid, trifluoroacetic acid, hard ester acid, pounces on acid, hydroxymaleic acid, toluylic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, xitix, para-anilinesulfonic acid, 2-acetoxy-benzoic acid and isethionic acid.
8. according to the preparation method of each described general formula (I) compound in the claim 1～7, this method is selected from the following scheme:
Scheme 1
Step a: 2-nitro-3-Tetrahydrothienopyriderivatives derivatives is dissolved in the solvent, and adding alkali stirs, and adds N then, and the N-dimethyl sulphide is for formyl chloride, and stirring at room or heating are stirred down, get compound I
a, said solvent is THF, N or dioxane; Said alkali is pyridine, triethylamine, triethylene diamine, diisopropylethylamine, sodium hydride or potassium hydride KH;
Step b: with I
aBe dispersed in the phenyl ether, reflux gets compound I
b
Step c: will
Be dissolved in the solvent, add alkali, under ice bath, drip acylating reagent, drip and finish, stirring at room gets compound I
cPerhaps will
Carry out halo with halide reagent, get compound I
c, said solvent is methylene dichloride, acetonitrile, THF, N, glycol dimethyl ether or dioxane; Said acylating reagent is benzene sulfonyl chloride, Tosyl chloride, methane sulfonyl chloride, trifluoromethanesulfonyl chloride or naphthalic sulfonic chloride;
Steps d: with compound I
bBe dispersed in the solvent with alkali, stir down, steam solvent, add I at-10～40 ℃
cSolution, stirring at room, compound I
d, said solvent is the mixed solvent of water, methyl alcohol and THF; Said alkali is Pottasium Hydroxide;
Step e: with compound I
dUse iron powder, under the acid effect, reduce, get compound I
eSaid hydrochlorate acid or acetic acid;
Step f: use bromizating agent to compound I
eCarry out bromination, get compound I
f, said bromide reagent is N-bromo-succinimide or bromine;
Step g: with compound I
fWith boric acid ester or boric acid, catalytic coupling under palladium catalyst, get end product;
Scheme 2
Step h: with compound I
cMiddle Y replaces with nitrogenous group W, gets compound I
g, said Y is iodine, bromine, chlorine, alkyl ester, aryl ester, alkyl sulfonyl ester or fragrant sulfonyl ester; Said W is phthalimide-based, nitrine, succimide base or phthalic imidine;
Step I: with compound I
gReduce, hydrolysis or hydrogenolysis, compound I
h
Step j: under-10～0 ℃, 2-amido-5-bromopyridine verivate is added in the chlorsulfonic acid in batches,, get compound I 140～180 ℃ of reactions down
i
Step k: with compound I
hAnd I
iBe dissolved in the solvent, under the effect of alkali, get compound I
j, said solvent is methylene dichloride, acetonitrile, THF, N, glycol dimethyl ether or dioxane; Said alkali is pyridine, triethylamine, triethylene diamine or diisopropylethylamine;
Step l: carry out the reaction identical with step g;
Scheme 3
Step m:2-amido nicotinic acid derivates carries out bromination, gets compound I
kSaid bromide reagent is N-bromo-succinimide or bromine;
Step n: with compound I
kAnd I
hNeutralize, get compound I
1
Step o: carry out the reaction identical with step g;
Scheme 4
Step p: will
Carry out reduction amination or carry out nucleophilic substitution, get compound I
m
Step q: carry out the reaction identical with step k;
Step r: carry out the reaction identical with step g;
R
1, R
2, R
3, R
4, R
5Identical with the definition in the claim 1.
9. pharmaceutical composition that is used to treat the cancer relevant with LCK c-Met with prevention; It comprises any described general formula (I) compound in the claim 1～7; Its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt; Pharmaceutically useful carrier, thinner or vehicle.
10. pharmaceutical composition according to claim 9, wherein, described general formula (I) compound, its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt account for 1～99wt% of composition total weight.
11. according to claim 9 or 10 described pharmaceutical compositions, it further comprises odorant agent or flavouring agent.
12. according to any described general formula (I) compound in the claim 1～7, its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt are used for treating the purposes of the medicine of the disease relevant with preventing Tyrosylprotein kinase c-Met signal transduction pathway in preparation.
13. purposes according to claim 12; Wherein, described disease comprises hyperplasia, restenosis, immune disorders, inflammation, histiocytic lymphoma, ovarian cancer, neck phosphor shaped epithelial cell cancer, cancer of the stomach, mammary cancer, children's hepatocellular carcinoma, colorectal carcinoma, cervical cancer, lung cancer, sarcoma, nasopharyngeal carcinoma, carcinoma of the pancreas, spongioblast cancer, prostate cancer, small cell lung cancer, nonsmall-cell lung cancer, multiple myeloma, thyroid carcinoma, carcinoma of testis, cervical cancer, adenocarcinoma of lung, colorectal carcinoma, Papillary Renal Cell Carcinoma, glioblastoma, carcinoma of endometrium, esophagus cancer, white blood disease, renal cell carcinoma, bladder cancer, liver cancer and astrocytoma.
14. purposes according to claim 12; Wherein, described disease is following illness: neck phosphor shaped epithelial cell cancer, histiocytic lymphoma, adenocarcinoma of lung, small cell lung cancer, nonsmall-cell lung cancer, carcinoma of the pancreas, Papillary Renal Cell Carcinoma, liver cancer, cancer of the stomach, colorectal carcinoma, multiple myeloma and glioblastoma, hyperplasia, restenosis, immune disorders and inflammation.
15. according to any described general formula (I) compound in the claim 1～7, its enantiomer, diastereomer, racemic modification and composition thereof or its pharmaceutically useful salt purposes in the treatment disease relevant with prevention Tyrosylprotein kinase c-Met signal transduction pathway.
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|---|---|---|---|
| CN2011100791339A CN102718745A (en) | 2011-03-30 | 2011-03-30 | Novel amino pyridine compound, its preparation method, pharmaceutical composition containing compound and application thereof |
| PCT/CN2012/000412 WO2012129967A1 (en) | 2011-03-30 | 2012-03-29 | New aminopyridine compounds, the preparation method, the pharmaceutical compositions comprising these compounds and the uses thereof |
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| CN2011100791339A CN102718745A (en) | 2011-03-30 | 2011-03-30 | Novel amino pyridine compound, its preparation method, pharmaceutical composition containing compound and application thereof |
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| CN2011100791339A Pending CN102718745A (en) | 2011-03-30 | 2011-03-30 | Novel amino pyridine compound, its preparation method, pharmaceutical composition containing compound and application thereof |
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| CN103087050A (en) * | 2011-10-28 | 2013-05-08 | 山东轩竹医药科技有限公司 | Aryl kinase inhibitor |
| WO2014117718A1 (en) * | 2013-02-02 | 2014-08-07 | 正大天晴药业集团股份有限公司 | Substituted 2-aminopyridine protein kinase inhibitor |
| CN106083708A (en) * | 2016-06-30 | 2016-11-09 | 浙江大学 | 2 aminopyrazole derivatives containing 2 pyridone ring side chains and preparation and application |
| CN107540604A (en) * | 2017-09-19 | 2018-01-05 | 济南大学 | A kind of preparation method of the bromopyridine of 2 amino 5 |
| US9981946B2 (en) | 2014-07-31 | 2018-05-29 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Pyridine-substituted 2-aminopyridine protein kinase inhibitors |
| WO2018214980A1 (en) * | 2017-05-26 | 2018-11-29 | 中国医学科学院药物研究所 | Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof |
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| RU2644769C2 (en) * | 2013-01-23 | 2018-02-14 | Астразенека Аб | Chemical compounds |
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| WO2018214980A1 (en) * | 2017-05-26 | 2018-11-29 | 中国医学科学院药物研究所 | Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof |
| CN108929263A (en) * | 2017-05-26 | 2018-12-04 | 中国医学科学院药物研究所 | Aryl amide Kv2.1 inhibitor and preparation method thereof, pharmaceutical composition and purposes |
| CN107540604A (en) * | 2017-09-19 | 2018-01-05 | 济南大学 | A kind of preparation method of the bromopyridine of 2 amino 5 |
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| WO2012129967A1 (en) | 2012-10-04 |
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