CN104829613A - Diaryl-substituted pyrazolo ring derivative and preparation method thereof, and applications of diaryl-substituted pyrazolo ring derivative in medicine field - Google Patents

Diaryl-substituted pyrazolo ring derivative and preparation method thereof, and applications of diaryl-substituted pyrazolo ring derivative in medicine field Download PDF

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CN104829613A
CN104829613A CN201510174036.6A CN201510174036A CN104829613A CN 104829613 A CN104829613 A CN 104829613A CN 201510174036 A CN201510174036 A CN 201510174036A CN 104829613 A CN104829613 A CN 104829613A
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base
phenyl
pyrimidine
amino
pyrazoles
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CN104829613B (en
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安晓霞
别平彦
杨午立
庄戈诗
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Chifeng Mongolia Biotechnology Co., Ltd.
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SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention discloses a diaryl-substituted pyrazolo ring derivative having a structure represented by a formula I, and a preparation method thereof, and applications of the diaryl-substituted pyrazolo ring derivative in the medicine field. The diaryl-substituted pyrazolo ring derivative has significant SK-MEL28 cell inhibition activity, can be adopted as a BRAF inhibitor, can be used for preparation of drugs for prevention or treatment of melanoma and B-RAF V600E mutation associated diseases, and has broad application prospects and values. The formula I is defined in the instruction.

Description

The pyrazolo lopps derivative that diaryl replaces, its preparation method and the application at field of medicaments thereof
Technical field
The present invention relates to pyrazolo lopps derivative of diaryl replacement and its preparation method and application, particularly, a kind of the pyrazolo lopps derivative, its preparation method and in application pharmaceutically that there is the diaryl of SK-MEL28 cell inhibitory activity that B-RAF V600E suddenlys change high expression level and replace is related to.
Background technology
Tumour is one of most serious disease threatening human health, and in recent years along with the development of cytobiology and tumor pharmacology, the chemotherapy of tumour there occurs huge change.Traditional chemotherapeutic agent is owing to non-specifically blocking cell fission thus also causing Normal cell death and abandoned gradually while killing tumour cell, simultaneously, in tumour cell abnormal activation signal path in key node albumen as target spot, find that efficient, low toxicity, high specificity micromolecular inhibitor has become the important directions of current antitumor drug research and development.The receptor tyrosine kinase (RTK) that unconventionality expression activates in tumour has become the focus of antitumor drug research owing to all playing keying action at links such as tumor development, Invasion and Metastasis, chemoresistant.
Mitogen activated protein kinase (MAPKs) is transmitted by a large amount of cell surface receptor mediate intracellular signal.In the path of MAPK mediation, RAF/MEK/ERK signal cascade is subject to extensive concern, because it plays an important role in the formation of a large amount of human cancer, and particularly those effects relevant with RAF protein activation.
Research shows that the activation of RAF mainly comprises and removes suppression to RAF catalysis region by the regulation and control region of N-terminal.RAS calmodulin binding domain CaM and the region of being rich in halfcystine all take part in the interaction of kinase region and self suppressing of RAF.This basic role pattern is applicable to three kinds of all Raf albumen (A-RAF, B-RAF and C-RAF).But for also needing A-RAF and C-RAF some other step to reach maximum activation, as activated the phosphorylation of amino-acid residue and the dephosphorylation of negative regulation amino-acid residue.Therefore, B-RAF is the most easily by albumen that RAS activates in this family.In addition, the kinase whose activity of B-RAF is higher than C-RAF and A-RAF a lot.
According to existing achievement in research, B-RAF is the important isoform proteins relevant to cell proliferation, and is the important target of carcinogenic RAS.Confirm that the abnormal sudden change in body only occurs when B-RAF, it is 30 ~ 60% (Nature that this abnormal sudden change is considered to the incidence occurred in malignant melanoma of skin, 2002,417,949 ~ 954), incidence in thyroid carcinoma is 30 ~ 50%, incidence in colorectal carcinoma is 5 ~ 20%, and the incidence in ovarian cancer is 30% or less (Nature Rev.Mol.Cell Biology, 2004,5,875 ~ 885).Up to now, 45 kinds or more B-RAF sudden changes of planting have been found.The B-RAF albumen of sudden change is at NIH3T3 cell (Nature, 2002,417,949 ~ 954) and melanoma cell (Cancer Res., 2004,64,2338 ~ 2342) changed in, and melanomatous survival and transformation are absolutely necessary (CancerRes., 2003,63,5198 ~ 5202).Therefore, the B-Raf being in the series signals transduction core of Raf/MEK/ERK plays vital effect in the survival of tumour.
RAF kinase inhibitor has been used to stop tumor cell proliferation thus treat following cancer: histocytic lymphoma, small cell lung cancer and carcinoma of the pancreas and mammary cancer.Sorafenib is oral cytostatic Mutiple Targets kinase inhibitor, is used for the treatment of advanced renal cell carcinoma by FDA approval.Sorafenib by inhibition tumor cell hyperplasia and tumor-blood-vessel growth to stop tumor growth (Clark etc., 2005, Clinical Cancer Res 11 (15): 5472-5480; Yu etc., 2005, Oncogene 24 (46): 6861-6869; Wilhelm etc., 2004, Cancer Res.64 (19): 7099-7109).
But the application of above-mentioned targeted therapies is unsatisfactory, there will be such as resistance and population and lack the problems such as tumor response.Therefore, this area needs the new inhibitor of exploitation badly to overcome the problems in oncotherapy.
Summary of the invention
The object of this invention is to provide a kind of BRAF inhibitor of new high-efficiency low-toxicity.
A first aspect of the present invention provides a kind of such as formula the compound shown in I, its pharmacy acceptable salt, its prodrug, its hydrate or solvate:
In formula:
N is 1 or 2;
X is N or CH;
Y is halogen or NR 2r 3;
R 1be selected from lower group: substituted or unsubstituted C 1-C 8alkyl, substituted or unsubstituted C 3-C 8cycloalkyl, substituted or unsubstituted C 6-C 10aryl, containing 1-3 heteroatomic heteroaryl, wherein, described replacement refers to the substituting group having and be selected from lower group: C 1-C 3alkyl, C 1-C 3haloalkyl, C 3-C 8cycloalkyl, C 6-C 10aryl, C 1-C 6alkoxyl group, halogen;
R 2be selected from lower group: H, formyl radical, alkoxy carbonyl ,-L 1nHC (O) OR 1a,-L 1nHC (O) NHR 1a, substituted or unsubstituted C 3-C 6cycloalkyl, substituted or unsubstituted C 1-C 3alkyl, substituted or unsubstituted acyl group;
Wherein, described " replacement " refer to the substituting group having and be selected from lower group: cyano group ,-C (O) NH 2, hydroxyl or C 1-C 6alkyl;
L 1optionally be selected from halogen, C independently of one another by 1-3 1-C 4the C of alkyl or halogen substiuted 1-C 4the C that alkyl replaces 1-C 4alkylidene group;
R 1afor H, C 1-C 4the C of alkyl or halogen substiuted 1-C 4alkyl;
R 3for H or methyl;
R 4for H, halogen or C 1-C 4alkyl;
R 5for H or halogen;
R 6for H, halogen, C 1-C 4alkoxyl group, C 1-C 4alkyl;
R 7for halogen, H or C 1-C 4alkyl.
In another preference, described aryl is optionally selected from halogen, CH independently of one another by 1-3 3or CF 3substituting group replace.
In another preference, described compound is selected from lower group:
N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides;
N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin;
N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-Toluidrin;
Propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides;
Propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides;
The fluoro-N-{3-of 2,6-bis-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base] base-phenyl }-benzsulfamide;
N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides;
Propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-acid amides;
N-{3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin;
Propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-acid amides;
Propane-1-sulfonic acid (3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-phenyl)-acid amides;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-bases } base-phenyl)-2,6-bis-fluoro-benzsulfamides;
Propane-1-sulfonic acid { 3-[3-(2-cyano group-ethylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyridine-2-base]-phenyl }-acid amides;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-phenyl base)-2,6-bis-fluoro-benzsulfamides;
N-(3-{3-[PA-4-base]-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyridine-2-base }-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;
N-(5-chlorine 3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2-fluorophenyl base)-2,6-difluorobenzenesulfonamide;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2,4 difluorobenzene base)-2,6-difluorobenzenesulfonamide;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2,6-difluorophenyls)-2,6-difluorobenzenesulfonamide;
Methyl (S)-(1-((4-(2-(3-((2,6-difluorophenyl) sulfonamido)-2-fluorophenyl)-5,6-dihydro-4H-pyrroles [1,2-b] pyrazole-3-yl) pyrimidine-2-base) amino) propane-2-base) carbamate;
2, the fluoro-N-of 6-bis-(the fluoro-3-of 2-(3-(2-((2-(sulfonyloxy methyl) ethyl) is amino) pyrimidine-4-yl) 4H-5,6-pyrrolin is [3,2-b] pyrazoles-2-base also) phenyl) benzsulfamide.
A second aspect of the present invention provides a kind of preparation method of formula I, and described method comprises step:
Two replace alkynes intermediate V and the addition reaction of sydnone III initial ring, obtain pyrazolo lopps derivative I:
In another preference, this step temperature of reaction is 170-180 DEG C, is preferably 175 DEG C.
A third aspect of the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition contains the formula I as described in a first aspect of the present invention for the treatment of significant quantity, or its pharmacy acceptable salt, tautomer, optical isomer, pharmaceutically acceptable solvate.
In another preference, described pharmaceutical composition is used for the treatment of relevant disease of suddenling change to B-RAF V600E, or described pharmaceutical composition is used for the treatment of and suddenlys change relevant disease to B-RAF V600E.
In another preference, described relevant disease of suddenling change to B-RAF V600E is selected from lower group: abnormal cell proliferation, metamorphosis, hypoerkinesia, or its combination.
A fourth aspect of the present invention provides a kind of B-RAF kinase inhibitor, described inhibitor contains the formula I as described in a first aspect of the present invention suppressing significant quantity, or its pharmacy acceptable salt, tautomer, optical isomer, pharmaceutically acceptable solvate.
In another preference, described pharmacy acceptable salt is the salt of group under being selected from of formula I: inorganic acid salt, organic acid salt, alkylsulfonate, arylsulphonate, or its combination; Preferably, described salt is selected from lower group: hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion, metilsulfate, ethyl sulfonate, benzene sulfonate, tosilate, or its combination.
In another preference, described pharmaceutically acceptable solvate, refers to the solvate that formula I and the solvent being selected from lower group are formed: water, ethanol, Virahol, ether, acetone, or its combination.
A fifth aspect of the present invention provides the purposes of formula I, for:
A () prepares B-RAF inhibitor;
B () suppresses the activity of SK-MEL28 cell for external non-therapeutic;
C () is for the inhibition tumor cell growth of external non-therapeutic ground;
D () is for the preparation of the medicine for the treatment of B-RAF V600E inhibition from mutation activity.
A sixth aspect of the present invention provides a kind of kinase whose method of suppression B-RAF of external non-therapeutic, and described method comprises step:
Deposit in case in formula I or its pharmacy acceptable salt, culturing cell, thus suppress B-RAF kinase activity in described cell.
A seventh aspect of the present invention provides a kind of method for the treatment of and BRAF V600E mutation-related diseases, and described method comprises step:
To formula I as described in the first aspect of the invention or its pharmacy acceptable salt, tautomer, optical isomer, the pharmaceutically acceptable solvate for the treatment of target administering therapeutic effective dose.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
The present inventor, through long-term and deep research, has unexpectedly prepared a class and had compound such as formula structure shown in I, and described compound is the effective B-RAF inhibitor of a class, is especially suitable for use as the inhibitor of B-RAF V600E inhibition from mutation activity.Based on above-mentioned discovery, contriver completes the present invention.
Term
In the present invention, described alkyl comprises the alkyl of straight or branched, and described alkenyl comprises the alkenyl of straight or branched, and described alkynyl group comprises the alkynyl of straight or branched, and described halogen is F, Cl, Br or I.
Unless stated otherwise, in the present invention, term " replacement " refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: C1 ~ C4 alkyl, C3 ~ C7 cycloalkyl, C1 ~ C4 alkoxyl group, halogen, hydroxyl, carboxyl (-COOH), C1 ~ C4 aldehyde radical, C2 ~ C4 acyl group, C2 ~ C4 ester group, amino, phenyl; Described phenyl comprises unsubstituted phenyl or has 1-3 substituent substituted-phenyl, and described substituting group is selected from: halogen, C1-C4 alkyl, cyano group, OH, nitro, C3 ~ C7 cycloalkyl, C1 ~ C4 alkoxyl group, amino.
Especially, in this article, unless stated otherwise, the atom mentioned comprises its all isotopic form, such as, when mentioning " hydrogen atom ", refers to hydrogen atom, D atom, tritium atom or its combination.In the present invention, the abundance of the various isotope atom of certain element can be this element in the naturally occurring state of occurring in nature, also can be the state of certain isotopic enrichment.
Term " C1 ~ C6 alkyl " refers to the straight or branched alkyl with 1 ~ 6 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or similar group.
Especially, unless stated otherwise, in the present invention, when not limiting the carbon atom number of group, refer to that there is 1-10 carbon atom, the group of a preferred 1-6 carbon atom.
In another preference, described heterocycle is saturated rings or unsaturated ring.
Term " C1 ~ C4 alkoxyl group " refers to the straight or branched alkoxyl group with 1-4 carbon atom, such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy or similar group.
Term " alkyl acyl " or " alkyl-carbonyl " refer to the group with "-CO-alkyl " structure, such as methylacyl, ethyl acyl group, Acryl, sec.-propyl acyl group, butyl acyl group, isobutyl-acyl group, sec-butyl acyl group, tertiary butyl acyl group or similar group.
Term " pharmaceutically acceptable solvate " refers to the solvate of corresponding compound and water, ethanol, Virahol, ether, acetone.
Formula I
The invention provides a kind of such as formula the compound shown in I:
In formula:
N is 1 or 2;
X is N or CH;
Y is halogen or NR 2r 3;
R 1be selected from lower group: substituted or unsubstituted C 1-C 8alkyl, substituted or unsubstituted C 3-C 8cycloalkyl, substituted or unsubstituted C 6-C 10aryl, containing 1-3 heteroatomic heteroaryl, wherein, described replacement refers to the substituting group having and be selected from lower group: C 1-C 3alkyl, C 1-C 3haloalkyl, C 3-C 8cycloalkyl, C 6-C 10aryl, C 1-C 6alkoxyl group, halogen;
R 2be selected from lower group: H, formyl radical, alkoxy carbonyl ,-L 1nHC (O) OR 1a,-L 1nHC (O) NHR 1a, substituted or unsubstituted C 3-C 6cycloalkyl, substituted or unsubstituted C 1-C 3alkyl, substituted or unsubstituted acyl group;
Wherein, described " replacement " refer to the substituting group having and be selected from lower group: cyano group ,-C (O) NH 2, hydroxyl or C 1-C 6alkyl;
L 1optionally be selected from halogen, C independently of one another by 1-3 1-C 4the C of alkyl or halogen substiuted 1-C 4the C that alkyl replaces 1-C 4alkylidene group;
R 1afor H, C 1-C 4the C of alkyl or halogen substiuted 1-C 4alkyl;
R 3for H or methyl;
R 4for H, halogen or C 1-C 4alkyl;
R 5for H or halogen;
R 6for H, halogen, C 1-C 4alkoxyl group, C 1-C 4alkyl;
R 7for halogen, H or C 1-C 4alkyl.
In another preference, described aryl is optionally selected from halogen, CH independently of one another by 1-3 3or CF 3substituting group replace.
In another preference, described compound is selected from lower group:
N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides;
N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin;
N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-Toluidrin;
Propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides;
Propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides;
The fluoro-N-{3-of 2,6-bis-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base] base-phenyl }-benzsulfamide;
N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides;
Propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-acid amides;
N-{3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin;
Propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-acid amides;
Propane-1-sulfonic acid (3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-phenyl)-acid amides;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-bases } base-phenyl)-2,6-bis-fluoro-benzsulfamides;
Propane-1-sulfonic acid { 3-[3-(2-cyano group-ethylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyridine-2-base]-phenyl }-acid amides;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-phenyl base)-2,6-bis-fluoro-benzsulfamides;
N-(3-{3-[PA-4-base]-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyridine-2-base }-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;
N-(5-chlorine 3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2-fluorophenyl base)-2,6-difluorobenzenesulfonamide;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2,4 difluorobenzene base)-2,6-difluorobenzenesulfonamide;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2,6-difluorophenyls)-2,6-difluorobenzenesulfonamide;
Methyl (S)-(1-((4-(2-(3-((2,6-difluorophenyl) sulfonamido)-2-fluorophenyl)-5,6-dihydro-4H-pyrroles [1,2-b] pyrazole-3-yl) pyrimidine-2-base) amino) propane-2-base) carbamate;
2, the fluoro-N-of 6-bis-(the fluoro-3-of 2-(3-(2-((2-(sulfonyloxy methyl) ethyl) is amino) pyrimidine-4-yl) 4H-5,6-pyrrolin is [3,2-b] pyrazoles-2-base also) phenyl) benzsulfamide.
More preferably, formula I of the present invention is as shown in table 1.
Table 1
The preparation method of formula I
Present invention also offers a kind of preparation method of formula I, described method comprises step:
Two replace alkynes intermediate V and the addition reaction of sydnone III initial ring, obtain pyrazolo lopps derivative I:
In another preference, this step temperature of reaction is 170-180 DEG C, is preferably 175 DEG C.
Pharmacy acceptable salt
The medicinal forms of the compounds of this invention can comprise compound itself, and other versions pharmaceutically acceptable, as optical isomer, and cis-trans-isomer etc., or pharmacy acceptable salt or solvate.
Preferably, described pharmacy acceptable salt includes, but are not limited to: inorganic acid salt, organic acid salt, alkylsulfonate, arylsulphonate, or its combination; Preferably, described salt is selected from lower group: hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion, metilsulfate, ethyl sulfonate, benzene sulfonate, tosilate, or its combination;
Preferably, described pharmaceutically acceptable solvate includes, but are not limited to: the solvate of described compound and water, ethanol, Virahol, ether, acetone etc.
The purposes of formula I
Formula I of the present invention is used for:
A () prepares B-RAF inhibitor;
B () suppresses the activity of SK-MEL28 cell for external non-therapeutic;
C () is for the inhibition tumor cell growth of external non-therapeutic ground;
D () is for the preparation of the medicine for the treatment of B-RAF V600E inhibition from mutation activity.
Major advantage of the present invention comprises:
Compared with prior art, the human skin malignant melanoma SK-MEL28 cell strain of pyrazolo lopps derivative to B-RAF V600E sudden change high expression level that diaryl provided by the invention replaces has obvious restraining effect; Especially compound 17 and 18, its half-inhibition concentration IC 50value is respectively 137nM and 124nM, better than positive control medicine Wei Luofeini (182nM), has good development and application prospect.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
The structure of compound obtained in following embodiment be by nucleus magnetic resonance ( 1and mass spectrum (MS), adopt NOE (Nuclear Overhauser Effect) to be determined if desired HNMR).
1hNMR displacement (δ) provides with the unit of 1,000,000/(ppm). 1the mensuration of HNMR uses BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and the solvent of mensuration is deuterated dimethyl sulfoxide (DMSO-d 6), deuterochloroform (CDCl 3), be inside designated as tetramethylsilane (TMS), chemical shift is with 10 -6provide as unit.
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
IC 50the mensuration of value is with NovoStar microplate reader (German BMG company).
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate.
Silica gel column chromatography uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
In addition, in following examples if no special instructions, reaction is carried out all in a nitrogen atmosphere.
Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.
In following examples if no special instructions, the solution in reaction all refers to the aqueous solution.
Embodiment 1
The first step:
By two (triphenylphosphine) palladium chloride (47mg under room temperature, 0.067mmol) with triphenylphosphine (35mg, 0.134mmol) be dissolved in THF (10ml), add triethylamine (15ml) and 2 successively, 4-dichloro pyrimidine (2g, 13.4mmol), stirred under nitrogen atmosphere 15 minutes, then cuprous iodide (26mg is added successively, 0.134mmol) with 3-ethynyl-aniline (1.77g, 14.77mmol), outer temperature 90 DEG C stirs 4h, it is anti-complete that TLC detects raw material, cooling, suction filtration, filter cake ethyl acetate is washed, merge organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure.Purify with silica gel column chromatography and obtain 3-(the chloro-pyrimidine of 2--4-ethynyl)-aniline (1.2g, faint yellow solid) yield: 39%. 1MS m/z(ESI):230.6[M+1]
1HNMR(400Hz,DMSO-d 6):8.82(m,1H),7.75(m,1H),7.13(t,1H),6.79(m,2H),6.74(m,1H),5.41(s,2H).
Second step:
By 3-(the chloro-pyrimidine of 2--4-ethynyl)-aniline (1g under room temperature, 4.4mmol) He 2,5-difluoro chloride (1g, 4.84mol) add in methylene dichloride (20ml), then under ice bath, drip pyridine (0.64ml), dropwise rear stirring at room temperature 60h, it is complete that TLC monitors raw material reaction, 1N HCl solution (30ml) washs, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure.Purify with silica gel column chromatography and obtain N-[3-(the chloro-pyrimidine of 2--4-ethynyl)-phenyl]-2,6-bis-fluoro-benzsulfamides (1g, white solid), yield: 56%. 1MS m/z(ESI):406.8[M+1]
1HNMR(400Hz,DMSO-d 6):11.25(s,1H),8.85(m,1H),7.82-7.72(m,2H), 7.44(m,3H),7.32(m,3H).
3rd step:
Under room temperature, N-[3-(the chloro-pyrimidine of 2--4-ethynyl)-phenyl]-2,6-bis-fluoro-benzsulfamides (1.1g, 2.71mmol) are suspended in the sym-trimethylbenzene of 80ml; add 4,5,6; 7-tetrahydrochysene [1,2,3] oxadiazoles also [3; 4-a] pyridine-8--3-phenates (0.42g; 3mmol), nitrogen replacement three times, rises to outer temperature 175 DEG C under nitrogen protection; stir 24h, TLC monitoring raw material reaction complete.Removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains N-{3-[3-(2 chloro-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2, the fluoro-benzsulfamide of 6-bis-(0.33g, yellow solid) yield: 24%. 1MS m/z(ESI):502.9[M+1]
1HNMR(400Hz,DMSO-d 6):10.97(s,1H),8.42(d,1H),7.71(m,1H),7.32-7-13(m,6H),6.82(d,1H),4.15(m,2H),3.01(m,2H),2.00(m,2H),1.83(m,2H).
4th step:
By N-{3-[3-(2 chloro-pyrimidine-4-yl)-4 under room temperature, 5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2, fluoro-benzsulfamide (the 0.1g of 6-bis-, 0.2mmol) add in the ammonia/methanol solution of the 7mol/L of 15ml, it is complete that 90 DEG C of tube sealing reaction 60h, TLC monitor raw material reaction, 50ml methylene dichloride is added, concentrating under reduced pressure after being cooled to room temperature.Purify with silica gel column chromatography and obtain N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides (0.01g, white solid) yield: 10.4%. 1MS m/z(ESI):483.5[M+1]
1HNMR(400Hz,DMSO-d 6):10.93(s,1H),7.92(d,1H),7.71(m,1H),7.28-7.09(m,6H),6.43(s,2H),5.97(d,1H),4.11(m,2H),2.97(m,2H),2.00(m,2H),1.80(m.2H).
Embodiment 2
The first step:
By 3-(the chloro-pyrimidine of 2--4-ethynyl)-aniline (1.5g under room temperature, 6.6mmol) with methylsulfonyl chloride (0.83g, 7.26mol) add in methylene dichloride (30ml), then under ice bath, pyridine (0.6ml) is dripped, dropwise rear stirring at room temperature 60h, TLC and monitor raw material reaction completely, 1N HCl solution (30ml) washs, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure.Purify with silica gel column chromatography and obtain N-[3-(the chloro-pyrimidine of 2--4-ethynyl)-phenyl]-Toluidrin (1.4g, yellow solid), yield: 69%. 1MS m/z(ESI):308.7[M+1]
1HNMR(400Hz,DMSO-d 6):10.06(s,1H),8.86(d,1H),7.83(d,1H),7.52-7.35(m,4H),3.06(s,3H).
Second step:
By N-[3-(the chloro-pyrimidine of 2--4-ethynyl)-phenyl]-Toluidrin (0.8g under room temperature, 2.6mmol) be suspended in the sym-trimethylbenzene of 25ml, add 4, 5, 6, 7-tetrahydrochysene [1, 2, 3] oxadiazoles also [3, 4-a] pyridine-8--3-phenates (0.37g, 2.6mmol), nitrogen replacement three times, outer temperature 175 DEG C is risen under nitrogen protection, stir 24h.TLC monitoring raw material reaction complete. removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-4, 5, 6, 7-tetrahydrochysene-pyrazolo [1, 5-a] pyridine-2-base]-phenyl }-Toluidrin (120mg, yellow solid) yield: 11.4%. 1MS m/z(ESI):404.8[M+1]
3rd step:
By N-{3-[3-(the chloro-pyrimidine of 2--4-yl)-4 under room temperature, 5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin (0.12g, 0.3mmol) adds in the ammonia/methanol solution of the 7mol/L of 15ml, 90 DEG C of tube sealing reaction 60h, it is complete that TLC monitors raw material reaction, adds 50ml methylene dichloride, concentrating under reduced pressure after being cooled to room temperature.Purify with silica gel column chromatography and obtain N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl-Toluidrin (20mg, white solid) yield: 17.4%. 1MS m/z(ESI):385.5[M+1]
1HNMR(400Hz,DMSO-d 6):9.75(s,1H),8.03(d,1H),7.36(m,2H),7.21(m,2H),6.45(d,2H),6.20(d,1H),4.14(m,2H),2.98(m,5H),2.00(m,2H),1.80(m,2H).
Embodiment 3
The first step:
By N-[3-(the chloro-pyrimidine of 2--4-ethynyl)-phenyl]-Toluidrin (0.8g, 2.6mmol) be suspended in the sym-trimethylbenzene of 25ml, add 5, 6-dihydro-4H-pyrrolo-[1, 2-C] [1, 2, 3] oxadiazoles-7--3-phenates (0.33g, 6mmol), nitrogen replacement three times, outer temperature 175 DEG C is risen under nitrogen protection, stir 24h.TLC monitoring raw material reaction complete. removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-5, 6-dihydro-4H-pyrrolo-[1, 2-b] pyrazoles-2-base]-phenyl }-Toluidrin (80mg, yellow solid) yield: 7.9%. 1MS m/z(ESI):390.8[M+1]
3rd step:
By N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-5 under room temperature, 6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-Toluidrin (80mg, 0.2mmol) add in the ammonia/methanol solution of the 7mol/L of 15ml, 90 DEG C of tube sealing reaction 60h, it is complete that TLC monitors raw material reaction, adds 50ml methylene dichloride, concentrating under reduced pressure after being cooled to room temperature.Purify with silica gel column chromatography and obtain N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl-Toluidrin (15mg, white solid) yield: 20.2%. 1MS m/z(ESI):371.4[M+1]
1HNMR(400Hz,DMSO-d 6):9.78(s,1H),8.03(d,1H),7.39-7.20(m,4H),6.39(m,2H),6.26(d,1H),4.14(m,2H),3.12(m,2H),2.96(s,3H),2.58(m,2H).
Embodiment 4
The first step:
By 3-(the chloro-pyrimidine of 2--4-ethynyl)-aniline (1.5g under room temperature, 6.6mmol) with sulfonyl propyl chlorine (1g, 7.26mol) add in methylene dichloride (30ml), then under ice bath, pyridine (0.6ml) is dripped, dropwise rear stirring at room temperature 60h, TLC and monitor raw material reaction completely, 1N HCl solution (10ml) washs, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure.Purify with silica gel column chromatography and obtain propane-1-sulfonic acid [3-(2-chloropyrimide-4-ethynyl)-phenyl]-amine (1.5g, yellow solid), yield: 68%. 1MS m/z(ESI):336.8[M+1]
1HNMR(400Hz,DMSO-d 6):10.10(s,1H),8.85(d,1H),7.83(d,1H),7.49-7.35(m,4H),3.17(m,2H),1.74(m,2H),0.97(t,3H).
Second step:
By propane-1-sulfonic acid [3-(2-chloropyrimide-4-ethynyl)-phenyl]-amine (0.8g under room temperature, 1.85mmol) be suspended in the sym-trimethylbenzene of 25ml, add 4, 5, 6, 7-tetrahydrochysene [1, 2, 3] oxadiazoles also [3, 4-a] pyridine-8--3-phenates (0.26g, 1.85mmol), nitrogen replacement three times, outer temperature 175 DEG C is risen under nitrogen protection, stir 24h, it is complete that TLC monitors raw material reaction, removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains propane-1-sulfonic acid { 3-[3-(the chloro-pyrimidine-4-yl of 2-)-4, 5, 6, 7-tetrahydrochysene-pyrazolo [1, 5-a] pyridine-2-base]-phenyl }-amine (0.1g, yellow solid) yield: 12.5%. 1MS m/z(ESI):432.9[M+1]
3rd step:
By propane-1-sulfonic acid { 3-[3-(the chloro-pyrimidine-4-yl of 2-)-4 under room temperature, 5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-amine (0.1g, 0.23mmol) adds in the ammonia/methanol solution of the 7mol/L of 15ml, 90 DEG C of tube sealing reaction 60h, it is complete that TLC monitors raw material reaction, adds 50ml methylene dichloride, concentrating under reduced pressure after being cooled to room temperature.Purify with silica gel column chromatography and obtain propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides (60mg, white solid) yield: 63.8%. 1MS m/z(ESI):413.5[M+1]
1HNMR(400Hz,DMSO-d 6):9.80(s,1H),8.02(d,1H),7.33-7.14(m,4H),6.46(s,2H),6.16(d,1H),4.13(m,2H),3.02(m,4H),2.00(m,2H),1.81(m,2H),1.68(m,2H),0.92(t,3H).
Embodiment 5
By propane-1-sulfonic acid { 3-[3-(the chloro-pyrimidine-4-yl of 2-)-4 under room temperature, 5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-amine (0.1g, 0.23mmol), 5ml isobutylamine adds in single port bottle, stirred overnight at room temperature, and it is complete that TLC monitors raw material reaction, add 50ml methylene dichloride, wash with 10ml 1N hydrochloric acid soln.Purify with silica gel column chromatography and obtain propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides (30mg, faint yellow solid) yield: 28.0%. 1MS m/z(ESI):467.6[M+1]
1HNMR(400Hz,DMSO-d 6):9.82(s,1H),8.03(d,1H),7.32-7.12(m,5H),6.16(d,1H),4.14(m,2H),3.00(m,5H),2.00(m,2H),1.75(m,2H),1.66(m,2H),1.25(m,2H),0.89(m,9H).
Embodiment 6
By N-{3-[3-(2 chloro-pyrimidine-4-yl)-4 under room temperature, 5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2, the fluoro-benzsulfamide (0.1g, 0.2mmol) of 6-bis-, 5ml isobutylamine adds in single port bottle, stirred overnight at room temperature, it is complete that TLC monitors raw material reaction, adds 50ml methylene dichloride, wash with 10ml 1N hydrochloric acid soln.Purify with silica gel column chromatography and obtain the fluoro-N-{3-of 2,6-bis-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base] base-phenyl }-benzsulfamide (30mg, faint yellow solid) yield: 28.0%. 1MS m/z(ESI):555.6[M+1]
1HNMR(400Hz,DMSO-d 6):10.93(s,1H),7.95(d,1H),7.67(m,1H),7.28-7.07(m,6H),5.97(m,1H),4.15(m,2H),3.01(m,4H),2.00(m,2H),1.83(m,2H),1.25(m,1H),0.86(m,6H).
Embodiment 7
The first step:
By N-[3-(the chloro-pyrimidine of 2--4-ethynyl)-phenyl]-2 under room temperature, fluoro-benzsulfamide (the 1.1g of 6-bis-, 2.71mmol) be suspended in the sym-trimethylbenzene of 25ml, add 5, 6-dihydro-4H-pyrrolo-[1, 2-C] [1, 2, 3] oxadiazoles-7--3-phenates (0.34g, 2.71mmol), nitrogen replacement three times, outer temperature 175 DEG C is risen under nitrogen protection, stir 24h.TLC monitoring raw material reaction complete. removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-5, 6-dihydro-4H-pyrrolo-[1, 2-b] pyrazoles-2-base]-phenyl }-2, 6-bis-fluoro-sulphonamide (0.22g, yellow solid) yield: 16.6%. 1MS m/z(ESI):488.9[M+1]
1HNMR(400Hz,DMSO-d 6):10.99(s,1H),8.42(d,1H),7.74(m,1H),7.32-7.18(m,6H),6.88(d,1H),4.20(m,2H),3.14(m,2H),2.61(m,2H).
Second step:
By N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-5 under room temperature, 6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-2,6-bis-fluoro-sulphonamide (0.1g, 0.2mmol) add in the ammonia/methanol solution of the 7mol/L of 15ml, it is complete that 90 DEG C of tube sealing reaction 60h, TLC monitor raw material reaction, 50ml methylene dichloride is added, concentrating under reduced pressure after being cooled to room temperature.Purify with silica gel column chromatography and obtain N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides (0.04g, faint yellow solid) yield: 43.0%. 1MS m/z(ESI):467.5[M+1]
1HNMR(400Hz,DMSO-d 6):10.96(s,1H),7.91(d,1H),7.69(m,1H),7.32-7.13(m,6H),6.39(s,2H),6.04(d,1H),4.14(m,2H),3.09(m,2H),2.57(m,2H).
Embodiment 8
The first step:
By propane-1-sulfonic acid [3-(2-chloropyrimide-4-ethynyl)-phenyl]-amine (0.8g under room temperature; 1.85mmol) be suspended in the sym-trimethylbenzene of 25ml; add 5,6-dihydro-4H-pyrrolo-[1,2-C] [1; 2; 3] oxadiazoles-7--3-phenates (0.24g, 1.85mmol), nitrogen replacement three times; rise to outer temperature 175 DEG C under nitrogen protection, stir 24h.It is complete that TLC monitors raw material reaction, removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains propane-1-sulfonic acid-{ 3-[3-(the chloro-pyrimidine-4-yl of 2-)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-amine (0.08g, yellow solid) yield: 10.8%. 1MS m/z(ESI):418.9[M+1]
Second step:
By propane-1-sulfonic acid-{ 3-[3-(the chloro-pyrimidine-4-yl of 2-)-5 under room temperature, 6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-amine (0.08g, 0.19mmol) add in the ammonia/methanol solution of the 7mol/L of 15ml, 90 DEG C of tube sealing reaction 60h, it is complete that TLC monitors raw material reaction, adds 50ml methylene dichloride, concentrating under reduced pressure after being cooled to room temperature.Purify with silica gel column chromatography and obtain propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-acid amides (0.06g, faint yellow solid) yield: 79.6%. 1MS m/z(ESI):399.5[M+1]
1HNMR(400Hz,DMSO-d 6):9.84(s,1H),8.01(d,1H),7.37(m,2H),7.22(m,2H),6.34(s,2H),6.22(d,1H),4.15(m,2H),3.17-3.01(m,4H),2.58(m,2H),1.70(m,2H),0.94(t,3H).
Embodiment 9
By N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-4 under room temperature, 5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin (0.1g, 0.24mmol), 5ml isobutylamine adds in single port bottle, stirred overnight at room temperature, and it is complete that TLC monitors raw material reaction, add 50ml methylene dichloride, wash with 10ml 1N hydrochloric acid soln.Purify with silica gel column chromatography and obtain N-{3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin (0.04g, faint yellow solid) yield: 38.1%. 1MS m/z(ESI):441.5[M+1]
1HNMR(400Hz,DMSO-d 6):9.75(s,1H),8.02(d,1H),7.32-7.14(m,5H),6.17(d,1H),4.12(m,2H),2.99-2.89(m,7H),2.01(m,2H),1.81(m,2H),1.22(m,1H),0.83(d,6H).
Embodiment 10
By propane-1-sulfonic acid-{ 3-[3-(the chloro-pyrimidine-4-yl of 2-)-5 under room temperature, 6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-amine (0.1g, 0.24mmol), 5ml isobutylamine adds in single port bottle, stirred overnight at room temperature, and it is complete that TLC monitors raw material reaction, add 50ml methylene dichloride, wash with 10ml 1N hydrochloric acid soln.Purify with silica gel column chromatography and obtain propane-1-sulfonic acid-{ 3-[3-(2-isobutyl amine-pyrimidine-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-amine (20mg, faint yellow solid) yield: 18.3%. 1MS m/z(ESI):455.6[M+1]
1HNMR(400Hz,DMSO-d 6):9.80(s,1H),8.03(d,1H),7.31-7.14(m,4H),6.16(d,1H),4.14(m,2H),3.02(m,5H),2.01(m,2H),1.82(m,2H),1.24(m,1H),0.92-0.83(m,9H).
Embodiment 11
By propane-1-sulfonic acid-{ 3-[3-(the chloro-pyrimidine-4-yl of 2-)-5 under room temperature, 6-dihydro-4H-pyrrolo-[1, 2-b] pyrazoles-2-base]-phenyl }-amine (0.1g, 0.24mmol), N, N-diisopropylethylamine (0.062g, 0.48mmol), 3-aminopropionitrile (0.05g, 0.72mmol), N-Methyl pyrrolidone (2.5ml) adds in single port bottle, add sodium carbonate (0.051g again, 0.48mmol), the 90 DEG C of stirrings of outer temperature are spent the night, it is complete that TLC monitors raw material reaction, add 50ml ethyl acetate, use 10ml saturated sodium bicarbonate solution successively, 10ml water, the water washing of 10ml saturated common salt.Anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue over silica gel is column chromatography eluting obtains propane-1-sulfonic acid (3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base }-phenyl)-acid amides (0.03g, faint yellow solid) yield: 27.8%. 1MS m/z(ESI):452.5[M+1]
1HNMR(400Hz,DMSO-d 6):9.81(s,1H),8.11(d,1H),7.53-7.11(m,4H),6.28(d,1H),4.14(m,2H),3.40(m,2H),3.03(m,3H),2.55(m,2H),2.02(m, 2H),1.83(m,2H),1.66(m,2H),0.92(t,3H).
Embodiment 12
By N-{3-[3-(2 chloro-pyrimidine-4-yl)-4 under room temperature, 5, 6, 7-tetrahydrochysene-pyrazolo [1, 5-a] pyridine-2-base]-phenyl }-2, fluoro-benzsulfamide (the 0.1g of 6-bis-, 0.2mmol), N, N-diisopropylethylamine (0.052g, 0.4mmol), 3-aminopropionitrile (0.043g, 0.6mmol), N-Methyl pyrrolidone (2.5ml) adds in single port bottle, add sodium carbonate (0.043g again, 0.4mmol), the 90 DEG C of stirrings of outer temperature are spent the night, it is complete that TLC monitors raw material reaction, add 50ml ethyl acetate, use 10ml saturated sodium bicarbonate solution successively, 10ml water, the water washing of 10ml saturated common salt.Anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue over silica gel is column chromatography eluting obtains N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base } base-phenyl)-2, the fluoro-benzsulfamide of 6-bis-(0.03g, faint yellow solid) yield: 27.8%. 1MS m/z(ESI):536.6.[M+1]
1HNMR(400Hz,DMSO-d 6):10.69(s,1H),8.01(d,1H),7.33-6.98(m,6H),6.67(m,1H),6.45(m,1H),6.04(m,1H),4.13(m,2H),3.53(m,2H),3.02(m,2H),2.67(m,2H),1.99(m,2H),1.82(m,2H).
Embodiment 13
By propane-1-sulfonic acid { 3-[3-(the chloro-pyrimidine-4-yl of 2-)-4 under room temperature, 5, 6, 7-tetrahydrochysene-pyrazolo [1, 5-a] pyridine-2-base]-phenyl }-amine (0.1g, 0.23mmol), N, N-diisopropylethylamine (0.059g, 0.46mmol), 3-aminopropionitrile (0.048g, 0.69mmol), N-Methyl pyrrolidone (2.5ml) adds in single port bottle, add sodium carbonate (0.049g again, 0.46mmol), the 90 DEG C of stirrings of outer temperature are spent the night, it is complete that TLC monitors raw material reaction, add 50ml ethyl acetate, use 10ml saturated sodium bicarbonate solution successively, 10ml water, the water washing of 10ml saturated common salt.Anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue over silica gel is column chromatography eluting obtains propane-1-sulfonic acid { 3-[3-(2-cyano group-ethylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyridine-2-base]-phenyl }-acid amides (0.03g, faint yellow solid) yield: 28.0%. 1MS m/z(ESI):466.6.[M+1]
1HNMR(400Hz,DMSO-d 6):9.81(s,1H),8.11(d,1H),7.35-7.13(m,4H),6.27(d,1H),4.16(m,2H),3.53(m,2H),3.02(m,4H),2.62(m,2H),2.02(m,2H),1.83(m,2H),1.64(m,2H),0.92(t,3H).
Embodiment 14
By N-{3-[3-(the chloro-pyrimidine-4-yl of 2-)-5 under room temperature, 6-dihydro-4H-pyrrolo-[1, 2-b] pyrazoles-2-base]-phenyl }-2, 6-bis-fluoro-sulphonamide (0.1g, 0.2mmol), N, N-diisopropylethylamine (0.052g, 0.4mmol), 3-aminopropionitrile (0.043g, 0.6mmol), N-Methyl pyrrolidone (2.5ml) adds in single port bottle, add sodium carbonate (0.043g again, 0.4mmol), the 90 DEG C of stirrings of outer temperature are spent the night, it is complete that TLC monitors raw material reaction, add 50ml ethyl acetate, use 10ml saturated sodium bicarbonate solution successively, 10ml water, the water washing of 10ml saturated common salt.Anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Residue over silica gel is column chromatography eluting obtains N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base }-phenyl base)-2, the fluoro-benzsulfamide of 6-bis-(0.03g, faint yellow solid) yield: 28.7%. 1MS m/z(ESI):522.5.[M+1]
1HNMR(400Hz,DMSO-d 6):10.72(s,1H),8.02(d,1H),7.26-7.14(m,6H),6.66(d,1H),6.46(m,1H),6.10(m,1H),4.17(m,2H),3.52(m,2H),3.14(m,2H),2.69-2.57(m,4H).
Embodiment 15
The first step
By 3-(2 under room temperature, the fluoro-benzsulfamide of 6-bis-) the fluoro-methyl benzoate (2.95g of-2-, 8.54mmol) add in toluene (200ml), drip the di-isopropyl aluminum hydride toluene solution that concentration is 1.5 moles often liter under ice bath, add nature and rise to stirred overnight at room temperature.It is complete that TLC monitors raw material reaction, methyl alcohol (10ml) is dripped under ice bath, stir 0.5h, add ethyl acetate (100ml) again, organic phase is successively with saturated aqueous tartaric acid solution (100ml), water (100ml), saturated aqueous common salt (100ml) washs, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains 2, the fluoro-N-of 6-bis-(the fluoro-3-methylol-phenyl of 2-)-benzsulfamide (2.7g, faint yellow solid) yield: 99%. 1MS m/z(ESI):318.3.[M+1]
1HNMR(400Hz,CDCl 3):7.59-7.46(m,2H),7.30(m,1H),7.22-6.97(m,4H),4.70(s,2H).
Second step
By 2 under room temperature, the fluoro-N-of 6-bis-(the fluoro-3-methylol-phenyl of 2-)-benzsulfamide (3.1g, 10.00mmol) adds in methylene dichloride (30ml), adds pyridinium chlorochromate drone salt (3.2g under ice bath, 15.00mmol), stirred overnight at room temperature.It is complete that TLC monitors raw material reaction; suction filtration; filter cake use water (500ml) dissolves; dichloromethane extraction (100ml*3); merge organic phase anhydrous sodium sulfate drying, removal of solvent under reduced pressure, resistates TLC monitors raw material reaction complete 2; the fluoro-N-of 6-bis-(the fluoro-3-formyl-phenyl of 2-)-benzsulfamide (2.74g, white solid) yield 86%. 1MS m/z(ESI):316.2.[M+1]
1HNMR(400Hz,CDCl 3):10.25(s,1H),7.92(m,1H),7.65-7.52(m,2H),7.41(s,1H),7.27(m,1H),7.03(m,2H).
3rd step
By iodomethyl triphenyl phosphonium iodide phosphorus (6.9g under room temperature, 13mmol) add and newly steam in tetrahydrofuran (THF) (90ml), the tetrahydrofuran solution (13ml) that concentration is two (trimethyl silicon based) Lithamide of 1 mole often liter is added under ice bath, add stirring at room temperature 1h, solution becomes clarification, be cooled to-60 DEG C and add HMPA (2.7ml, 15mmol), add and be cooled to-78 DEG C of droppings 2, new steaming tetrahydrofuran (THF) (60ml) solution of the fluoro-N-of 6-bis-(2-fluoro-3-formyl-phenyl)-benzsulfamide, 0.5h is stirred at adding-78 DEG C, then naturally stirring at room temperature 2h is risen to.It is complete that TLC monitors raw material reaction, under ice bath, system is slowly added in saturated ammonium chloride solution (300ml), extract with methyl tertiary butyl ether (100ml*3), merge organic phase anhydrous sodium sulfate drying, removal of solvent under reduced pressure, resistates adds in tetrahydrofuran (THF) (5ml), add the tetrahydrofuran solution that concentration is the tetrabutyl ammonium fluoride of 1 mole often liter again, 85 DEG C of glass tube sealing reaction 18h, it is complete that TLC monitors raw material reaction, cool to room temperature, system is added in water (100ml), ethyl acetate (50ml*3) extracts, merge organic phase anhydrous sodium sulfate drying, removal of solvent under reduced pressure, residue over silica gel chromatography purification obtains N-(the fluoro-phenyl of 3-ethynyl-2-)-2, fluoro-benzsulfamide (the 1g of 6-bis-, faint yellow solid) yield: 37.0%. 1MS m/z(ESI):312.2.[M+1]。
1HNMR(400Hz,CDCl 3):7.65(m,1H),7.55(m,1H),7.23(m,2H),7.08-6.98(m,3H),3.30(s,1H).
4th step
Under room temperature, 4-bromopyridine-2-t-butyl carbamate (0.055g is added successively in there-necked flask, 0.2mmol), two (triphenylphosphine) palladium chloride (0.003g, 0.004mmol), cuprous iodide (0.0004g, 0.002mmol), system nitrogen ball (nitrogen: hydrogen volume ratio is about 4:1) replaces three times, adds triethylamine (0.1ml).Be warming up to interior temperature 80 degrees Celsius, drip acetonitrile (2.5ml) solution of the fluoro-benzsulfamide (0.062g, 0.2mmol) of N-(the fluoro-phenyl of 3-ethynyl-2-)-2,6-bis-while hot, add return stirring 1h.It is complete that TLC monitors raw material reaction, be cooled to room temperature, add water (10ml), ethyl acetate (5ml*3) extracts, and merges organic phase anhydrous sodium sulfate drying, removal of solvent under reduced pressure, residue over silica gel chromatography purification obtains { 4-[3-(2, the fluoro-benzsulfamide of 6-bis-) the fluoro-phenylacetylene of-2-]-pyridine-2-base }-t-butyl carbamate (40mg, faint yellow solid), yield: 39.7%. 1MS m/z(ESI):504.5.[M+1]。
1HNMR(400Hz,DMSO-d 6):11.04(s,1H),10.03(s,1H),8.31(d,1H),7.91(s,1H),7.75(m,1H),7.55(m,1H),7.41-7.13(m,4H),7.15(d,1H),1.49(s,9H).
5th step
By { 4-[3-(2 under room temperature, the fluoro-benzsulfamide of 6-bis-) the fluoro-phenylacetylene of-2-]-pyridine-2-base }-t-butyl carbamate (0.22g, 0.44mmol) be suspended in the sym-trimethylbenzene of 25ml, add 4, 5, 6, 7-tetrahydrochysene [1, 2, 3] oxadiazoles also [3, 4-a] pyridine-8--3-phenates (0.062g, 0.44mmol), nitrogen replacement three times, outer temperature 175 DEG C is risen under nitrogen protection, stir 24h.TLC monitoring raw material reaction complete. removal of solvent under reduced pressure, crude product silica gel column chromatography purifying obtains N-(3-{3-[PA-4-base]-4, 5, 6, 7-tetrahydro-pyrazole also [1, 5-a] pyridine-2-base }-2-fluorophenyl)-2, 6-difluorobenzenesulfonamide (0.014g, faint yellow solid) yield: 13.2%. 1MS m/z(ESI):500.5.[M+1]
1HNMR(400Hz,DMSO-d 6):7.65(m,2H),7.30-7.14(m,4H),6.26(s,1H),6.02-5.94(m,2H),4.14(m,2H),2.82(m,2H),2.01(m,2H),1.81(m,2H).
Embodiment 16
Except compound disclosed in above embodiment, also synthesize the compound with following test result, the synthetic method of described compound and the equal reference example 15 of step.
1MS m/z(ESI):573.2[M+1]；
1MS m/z(ESI):557.63[M+1]；
1MS m/z(ESI):557.63[M+1]；
1MS m/z(ESI):616.63[M+1]；
1MS m/z(ESI):593.61[M+1]。
Embodiment 17 biological experiment
By the propagation half-inhibition concentration IC of CCK-8 detection kit detection compound to human skin malignant melanoma cell strain SK-MEL28 50
(1) materials and methods
Cell strain:
SK-MEL28 human skin malignant melanoma cell strain (cell biological institute of the Chinese Academy of Sciences)
Reagent and consumptive material:
Cell Counting Kit-8(Cat#CK04-13，Dojindo)
96 well culture plates (Cat#3599, Corning Costar)
Foetal calf serum (Cat#10099-141, GIBCO)
Substratum (Invitrogen)
Desk-top microplate reader SpectraMax M5Microplate Reader (Molecular Devices)
(2) preparation of reagents
The preparation of substratum:
Clone Substratum
SK-MEL28 EMEM+10％FBS
The preparation of compound:
Final concentration is made to be 1mM by DMSO diluted compounds.
(3) cell cultures
I () collects logarithmic phase cell, counting, with perfect medium Eddy diffusion cell;
(ii) adjust cell concn to suitable concn, inoculate 96 orifice plates, 100 μ l cell suspensions are inoculated in every hole;
(iii) cell is at 37 DEG C, 100% relative humidity, 5%CO 224 hours are hatched in incubator.
(4) IC 50experiment
I () collects logarithmic phase cell, counting, and with perfect medium Eddy diffusion cell, adjustment cell concn inoculates 96 orifice plates to suitable concn (SK-MEL28 cell, 6k cells/well), and every hole adds 100 μ l cell suspensions.Cell at 37 DEG C, 100% relative humidity, 5%CO 2after hatching 24 hours in incubator.
(ii) with DMSO by after testing compound 3 times of gradient dilutions 8 times, add in 95 corresponding μ l perfect mediums by the 5 every holes of μ l, obtain the compounds of 20 times of dilutions.Above-claimed cpd is added cell by 25 μ l/ holes.Final compound concentration from 10 μMs to 0 μM, 3 times of dilutions, totally 10 concentration point.
(iii) cell is placed in 37 DEG C, 100% relative humidity, 5%CO 272 hours are hatched in incubator.Substratum is abandoned in suction, and the perfect medium added containing 10%CCK-8 is placed in 37 DEG C of incubators and hatches 2 ~ 4 hours.On SpectraMax M5Microplate Reader, measure the absorbancy at 450nm wavelength place gently after concussion, using 650nm place absorbancy as reference, calculate inhibiting rate.
(5) data processing
Be calculated as follows the inhibiting rate of drug on tumor Growth of Cells: growth of tumour cell inhibiting rate %=[(Ac-As)/(Ac-Ab)] × 100%
As: the OA (cell+CCK-8+ testing compound) of sample
Ac: the OA (cell+CCK-8+DMSO) of negative control
Ab: the OA (substratum+CCK-8+DMSO) of positive control
(6) experimental result
This experiment test cytotoxicity of above candidate compound to the strain of SK-MEL28 human skin malignant melanoma cell.Final compound concentration from 10 μMs to 0 μM, three times of gradient dilutions, totally 10 concentration point.
IC 50value refers to table 2:
Table 2
Compound number Half-inhibition concentration (uM) Compound number Half-inhibition concentration (uM)
Contrast Wei Luofeini 0.1826 11 0.5112
1 >10 12 1.181
2 >10 13 1.373
3 >10 14 0.2096
4 >10 15 Do not survey
5 8.042 16 Do not survey
6 0.7802 17 0.1376
7 5.572 18 0.1245
8 >10 19 0.4506
9 >10 20 0.6345
10 5.572 / /
As seen from the above table: the human skin malignant melanoma SK-MEL28 cell strain of the pyrazolo lopps derivative that diaryl provided by the invention replaces to B-RAF V600E sudden change high expression level has obvious restraining effect, demonstrates good development and application prospect.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. such as formula the compound shown in I, its pharmacy acceptable salt, its prodrug, its hydrate or solvate:
In formula:
N is 1 or 2;
X is N or CH;
Y is halogen or NR 2r 3;
R 1be selected from lower group: substituted or unsubstituted C 1-C 8alkyl, substituted or unsubstituted C 3-C 8cycloalkyl, substituted or unsubstituted C 6-C 10aryl, containing 1-3 heteroatomic heteroaryl, wherein, described replacement refers to the substituting group having and be selected from lower group: C 1-C 3alkyl, C 1-C 3haloalkyl, C 3-C 8cycloalkyl, C 6-C 10aryl, C 1-C 6alkoxyl group, halogen;
R 2be selected from lower group: H, formyl radical, alkoxy carbonyl ,-L 1nHC (O) OR 1a,-L 1nHC (O) NHR 1a, substituted or unsubstituted C 3-C 6cycloalkyl, substituted or unsubstituted C 1-C 3alkyl, substituted or unsubstituted acyl group;
Wherein, described " replacement " refer to the substituting group having and be selected from lower group: cyano group ,-C (O) NH 2, hydroxyl or C 1-C 6alkyl;
L 1optionally be selected from halogen, C independently of one another by 1-3 1-C 4the C of alkyl or halogen substiuted 1-C 4the C that alkyl replaces 1-C 4alkylidene group;
R 1abe selected from H, C 1-C 4the C of alkyl or halogen substiuted 1-C 4alkyl;
R 3for H or methyl;
R 4for H, halogen or C 1-C 4alkyl;
R 5for H or halogen;
R 6for H, halogen, C 1-C 4alkoxyl group, C 1-C 4alkyl;
R 7for halogen, H or C 1-C 4alkyl.
2. formula I as claimed in claim 1, it is characterized in that, described compound is selected from lower group:
N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides;
N-{3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin;
N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-Toluidrin;
Propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides;
Propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-acid amides;
The fluoro-N-{3-of 2,6-bis-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base] base-phenyl }-benzsulfamide;
N-{3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-2,6-bis-fluoro-benzsulfamides;
Propane-1-sulfonic acid { 3-[3-(2-amino-pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-B] pyrazoles-2-base]-phenyl }-acid amides;
N-{3-[3-(2-isobutylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-base]-phenyl }-Toluidrin;
Propane-1-sulfonic acid { 3-[3-(2-isobutylamino-pyrimidine-4-yl)-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-base]-phenyl }-acid amides;
Propane-1-sulfonic acid (3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-phenyl)-acid amides;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-4,5,6,7-tetrahydrochysene-pyrazolo [1,5-a] pyridine-2-bases } base-phenyl)-2,6-bis-fluoro-benzsulfamides;
Propane-1-sulfonic acid { 3-[3-(2-cyano group-ethylamino-pyrimidine-4-yl)-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyridine-2-base]-phenyl }-acid amides;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-phenyl base)-2,6-bis-fluoro-benzsulfamides;
N-(3-{3-[PA-4-base]-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyridine-2-base }-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;
N-(5-chlorine 3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2-fluorophenyl base)-2,6-difluorobenzenesulfonamide;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2,4 difluorobenzene base)-2,6-difluorobenzenesulfonamide;
N-(3-{3-[2-(2-cyano ethyl is amino)-pyrimidine-4-yl]-5,6-dihydro-4H-pyrrolo-[1,2-b] pyrazoles-2-bases }-2,6-difluorophenyls)-2,6-difluorobenzenesulfonamide;
Methyl (S)-(1-((4-(2-(3-((2,6-difluorophenyl) sulfonamido)-2-fluorophenyl)-5,6-dihydro-4H-pyrroles [1,2-b] pyrazole-3-yl) pyrimidine-2-base) amino) propane-2-base) carbamate;
2, the fluoro-N-of 6-bis-(the fluoro-3-of 2-(3-(2-((2-(sulfonyloxy methyl) ethyl) is amino) pyrimidine-4-yl) 4H-5,6-pyrrolin is [3,2-b] pyrazoles-2-base also) phenyl) benzsulfamide.
3. the preparation method of formula I, is characterized in that, described method comprises step:
Two replace alkynes intermediate V and the addition reaction of sydnone I II initial ring, obtain pyrazolo lopps derivative I:
4. a pharmaceutical composition, is characterized in that, described pharmaceutical composition contains the formula I as claimed in claim 1 for the treatment of significant quantity, or its pharmacy acceptable salt, tautomer, optical isomer, pharmaceutically acceptable solvate.
5. pharmaceutical composition as claimed in claim 4, is characterized in that, described pharmaceutical composition is used for the treatment of relevant disease of suddenling change to B-RAF V600E, or described pharmaceutical composition is used for the treatment of and suddenlys change relevant disease to B-RAF V600E.
6. a B-RAF kinase inhibitor, is characterized in that, described inhibitor contains the formula I as claimed in claim 1 suppressing significant quantity, or its pharmacy acceptable salt, tautomer, optical isomer, pharmaceutically acceptable solvate.
7. pharmaceutical composition as claimed in claim 4 or inhibitor as claimed in claim 6, is characterized in that:
Described pharmacy acceptable salt is the salt of group under being selected from of formula I: inorganic acid salt, organic acid salt, alkylsulfonate, arylsulphonate, or its combination; Preferably, described salt is selected from lower group: hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, formate, acetate, propionic salt, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion, metilsulfate, ethyl sulfonate, benzene sulfonate, tosilate, or its combination;
Described pharmaceutically acceptable solvate, refers to the solvate that formula I and the solvent being selected from lower group are formed: water, ethanol, Virahol, ether, acetone, or its combination.
8. the purposes of formula I as claimed in claim 1, is characterized in that, for:
A () prepares B-RAF inhibitor;
B () suppresses the activity of SK-MEL28 cell for external non-therapeutic;
C () is for the inhibition tumor cell growth of external non-therapeutic ground;
D () is for the preparation of the medicine for the treatment of B-RAF V600E inhibition from mutation activity.
9. the kinase whose method of suppression B-RAF of external non-therapeutic, it is characterized in that, described method comprises step:
Deposit in case in formula I or its pharmacy acceptable salt, culturing cell, thus suppress B-RAF kinase activity in described cell.
10. a method for treatment and BRAF V600E mutation-related diseases, it is characterized in that, described method comprises step:
To formula I as claimed in claim 1 or its pharmacy acceptable salt, tautomer, optical isomer, the pharmaceutically acceptable solvate for the treatment of target administering therapeutic effective dose.
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