CN106366078A - Indazole-oxadiazole derivative, medicinal composition containing derivative, and application of derivative in tumor prevention - Google Patents

Indazole-oxadiazole derivative, medicinal composition containing derivative, and application of derivative in tumor prevention Download PDF

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Publication number
CN106366078A
CN106366078A CN201510443488.XA CN201510443488A CN106366078A CN 106366078 A CN106366078 A CN 106366078A CN 201510443488 A CN201510443488 A CN 201510443488A CN 106366078 A CN106366078 A CN 106366078A
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indazole
diazole
base
arh
compound
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盛荣
胡永洲
曹戟
李姗
裘妮
赵梦丹
杨波
何俏军
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Zhejiang University ZJU
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an indazole-oxadiazole derivative with the structure represented by general formula a shown in the description, or a pharmaceutically acceptable salt or solvate thereof. In the formula, X is O or N, Y is N, Z is N or O, and all groups are as defined in the description. The invention also discloses a medicinal composition adopting the derivative as an active component, and a use of the derivative. Compounds synthesized in the invention have an HIF-1 inhibition effect, and most of the compounds have a substantial HIF-1 inhibition effect, have strong in-vivo and in-vitro anti-HIF-1 effect on human colorectal carcinoma cell strains (HCT116) and other tumor cell strains, and can be used for treating tumor diseases.

Description

Indazole-diazole analog derivative, the pharmaceutical composition containing it and its application in antitumor
Technical field
The present invention relates to drug world and in particular to a kind of indazole-diazole analog derivative, containing its pharmaceutical composition and its application in antitumor.
Background technology
Although the early diagnosis and therapy field of tumor makes great progress in recent years, antitumor drug has been able to control or delay the development of Partial tumors, such as leukemia, and the treatment for the solid tumor accounting for malignant tumor more than 90% reaches far away satisfied curative effect.In the evolution of solid tumor, low-oxygen environment is one of environmental condition that it is subjected to, and tumor cell is under low-oxygen environment, a series of biological characteristics can be made sexually revise, produce corresponding antagonism mechanism, as tumor-blood-vessel growth, cell proliferation, apoptosis suppression, cell cycle arrest, energy metabolism and Invasion and Metastasis etc., thus producing the tolerance to radiotherapy, chemotherapy, directly affect reduction therapeutic effect.Hypoxia inducible factor-1 (hif-1) plays the role of a nucleus in each bars pathway of cell adapted low-oxygen environment, hundreds of target gene such as the relevant tumor-blood-vessel growth of controllable, carbohydate metabolism, cell survival, transcriptional regulatory, therefore, the hypoxia antitumor strategy of targeting hif-1 has become as the focus of current antineoplastic medicine research.
The hypoxia inducible factor (hif) having now been found that has tri- kinds of hif-1, hif-2 and hif-3.Hif-1 was found by semenza etc. first in 1992, and it is the cell crucial transcriptional regulatory factor under anoxic conditions, plays the role of a nucleus in each bars pathway of cell adapted low-oxygen environment.The structural homology of hif-2 and hif-3 and hif-1 difference 42% and 37%, but its function is not yet completely bright.The heterodimeric body protein that hif-1 is made up of hif-1 α and hif-1 β subunit, hif-1 α is peculiar for hif-1, it is regulation subunit is also function subunit, secondary structure includes base-helix-loop-helix (bhlh) domain, pas domain, oxygen dependence degraded (odd) domain and transcription activating domain (n-tad and c-tad), and therefore its protein expression level is regulated and controled by intracellular oxygen concentration.Hif-1 β is Structural subunits, without oxygen dependence degraded (odd) domain, stably expresses in the cell.
Due to hif-1, to be related to signal path, oncogene numerous, between the hif-1 inhibitor of prior art report, architectural difference is huge, between medicine, dependency is little, such as pi3k inhibitor ly29400, mtor inhibitor thunder bar mycin, egfr inhibitor gefitinib, topo i inhibitor topotecan, heat shock protein hsp90 inhibitor geldanamycin etc..These inhibitor pass through to intervene the important life links such as transcription, translation and the degraded of intracellular hif-1, the protein level of impact hif-1, but, as the nonspecific inhibitor of hif-1, above-claimed cpd easily causes other uncertain biological effects, and internal toxic and side effects are larger.Therefore, the inhibitor of development of new hif-1 is expected to provide the clinical medicine of brand-new mechanism of action for oncotherapy.
Content of the invention
For the deficiencies in the prior art, the technical problem to be solved is to provide a kind of new indazole-diazole analog derivative, contain its pharmaceutical composition and its application in antitumor as hif-1 inhibitor.
Term illustrates: term used herein " alkyl ", different number of atom unless indicated, refers to the straight or branched hydrocarbon chain comprising 1-6 carbon atom.The example of the present invention " alkyl " used includes but is not limited to methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, isobutyl group, isopropyl and the tert-butyl group." alkyl " also includes replacing alkyl.Described alkyl can optionally be replaced by halogen or hydroxyl one or many.Therefore, term " alkyl " may include, such as trifluoromethyl and trifluoroethyl, and other haloalkyl, and hydroxymethyl and the hydroxylated alkyl of specified other.
Term used herein " alkoxyl " refers to-o- alkyl group, wherein alkyl as defined above.The example of " alkoxyl " used herein includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and tert-butoxy." alkoxyl " also includes substituted alkoxy.Alkoxyl can optionally be optionally substituted by halogen one or many.
Term used herein " aryl " refers to that the full carbon of 5-12 carbon atom is monocyclic or fused polycycle group, has the pi-electron system of total conjugated.The non-limiting examples of aryl have: phenyl ring, naphthalene nucleus, anthracene nucleus.
Term used herein " heterocyclic aryl " refers to the undersaturated carbocyclic ring of 5-12 annular atom, and wherein one or more carbon are by the hetero atom such as displacement such as oxygen, nitrogen, sulfur.Hetero-aromatic ring can be monocyclic or bicyclic, condensed by two rings and form.Specific heterocyclic aryl may is that furyl, thienyl, pyridine radicals, pyrimidine radicals, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl and imidazole radicals etc..
Term used herein " arylamine " refer to the hydrogen atom in amino molecule be substituted with aryl after a class organic amine compound, wherein " aryl " as defined above.
Term used herein " heterocyclic aryl amine " refer to the hydrogen atom in amino molecule replaced by heterocyclic aryl after a class organic amine compound, wherein " heterocyclic aryl " as defined above.
The hydrogen atom that term used herein " fatty amine " refers in amino molecule replaced by fatty alkyl after a class organic amine compound, including alkylamine and Cycloalkyl amine.Wherein, " alkylamine " refers to comprise the straight chain amine of 1-6 carbon atom or branched-chain hydrocarbons streptamine, and example includes but is not limited to methyl amine, ethylamine, n-pro-pyl amine, n-butylamine, n-pentyl amine, isobutylamine, isopropylamine and tert-butylamine etc.." Cycloalkyl amine " refers to the saturation monocycle carbocyclic ring amine with 3-6 carbon atom, different number of atom unless indicated, and specific " cycloalkyl " includes such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and cyclooctyl.
Term used herein " nitrogen heterocyclic ring fatty amine " refers to the class organic amine compound after at least one carbon atom is replaced by nitrogen-atoms in cycloalkyl, and example includes but is not limited to morpholine, piperazine, piperidines, nafoxidine, azetidine." nitrogen heterocyclic ring fatty amine " also includes substituted nitrogen-containing heterocyclic fatty amine, specifically includes n- methyl piperazine, 4- hydroxy piperidine, 4- methanol piperidines etc..
Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine.
The present invention adopts the following technical scheme that:
One class indazole-diazole analog derivative, has a formula a structure:
Or its pharmaceutically acceptable salt or solvate, wherein:
X is o or n, and y is n, and z is n or o；
r1Selected from-(ch2)m-n(r3r4), benzoyl, aniline formoxyl, benzenesulfonyl, r5The benzyl replacing, m represents the integer of 2-8；Wherein, r5Selected from hydrogen, halogen, nitro, c1-6Alkyl, c1-6Alkoxyl, co-nr3r4、o(ch2)n-nr3r4, n represents the integer of 2-6；-nr3r4For amine；
r2Selected from unsubstituted or by r6The aryl of replacement, heterocyclic aryl, benzyl；Wherein r6Selected from halogen, c1-6Alkyl, c1-6Alkoxyl, trifluoromethoxy, trifluoromethyl, dimethylamino；
Further, currently preferred indazole-diazoles compound, the five-membered ring being made up of x, y, zIt preferably is selected from
Further, currently preferred indazole-diazoles compound, r2Selected from unsubstituted or by r6The phenyl of replacement, furyl, thienyl, pyridine radicals, benzyl；
Further, currently preferred indazole-diazoles compound, described-nr3r4Selected from arylamine, heterocyclic aryl amine, fatty amine, nitrogen heterocyclic ring fatty amine；
Further, currently preferred indazole-diazoles compound, described-nr3r4Selected from five yuan or hexa-atomic arylamine, the five-ring heterocycles arylamine comprising o, n or s atom, the hexa-member heterocycle arylamine comprising o, n or s atom, the fatty amine of 1-6 carbon atom length, 3-6 member heterocyclic ring containing nitrogen fatty amine, such as aniline, naphthylamines, imidazoles -2- amine, thiophene -2- amine, thiazole -2- amine, propylamine, 2-aminopropane., piperidines, morpholine, 4- hydroxy piperidine, n- methyl piperazine, piperidines -4- methanol, cyclopropylamine etc..Preferably, described comprise in five yuan of o, n or s atom or hexa-member heterocycle arylamine, the quantity of described o, n or s atom can be 1-4.
Further, currently preferred indazole-diazoles compound, described r1For r5The benzyl replacing, wherein, r5O (the ch replacing for optional position on the phenyl ring of benzyl2)n-nr3r4, r2For r6The phenyl replacing.
It will be appreciated that the present invention includes all combinations of special groups and the subgroup of present invention definition, including the substituent group described in shown in each embodiment defined in summary above, throughout the specification and claims.
More specifically, the preferred compound of the indazole-diazole analog derivative of formula a structure of the present invention is selected from:
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- methoxyphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- trifluoromethyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- chlorphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (pyridin-4-yl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- phenyl -1,2,4- diazole；
3- (4- chlorobenzyl) -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole；
3- benzyl -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole；
3- (4- tert-butyl-phenyl) -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole；
2- (5- (1- (4- chlorobenzyl) -1h-3- indazolyl) -3-1,2,4- di azoly) ethyl acetate；
5- (1- (4- chlorobenzyl) -1h-3- indazolyl) -3- (2- methoxyphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (2- chlorphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- dimethylamino phenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (thiophene -2- base) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (furan -2- base) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3- methoxyphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3- chlorphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3,4,5- trimethoxyphenyl) -1,2,4- diazole；
2- (5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole -3- base) ethanol；
5- (1- (4- luorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (4- nitrobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- luorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (4- methoxy-benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (2,6- difluorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (pyridine -2 ylmethyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (pyridin-4-yl methyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole
5- (1- (4- methyl-benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
N- (4- chlorphenyl) -3- (3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- carboxylic acid amides；
(3- (3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- base) (4- chlorphenyl) ketone；
5- (1- p-toluenesulfonyl -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (1-4- methyl piperazine-propyl group) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (1- morpholine propyl group) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (1-4- hydroxy piperidine-propyl group) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
Morpholine -3- (3- (5- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole) -1h- indazole methyl) benzophenone；
(4- methylpiperazine-1-yl) (3- (3- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole -5- base) -1h- indazole -1- base) methyl) benzophenone；
5- (1- (3- (2 (4- methylpiperazine-1-yl) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (2 (morpholine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (2 (4- hydroxy piperidine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
N- (Cvclopropvlmethvl) -2- (3- ((3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- base) methyl) phenoxy group) ethamine；
5- (1- (4- (2 (4- hydroxy piperidine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
2- (1- (4- chlorobenzyl) -1h- indazole -3- base) -5- (pyridin-4-yl) -1,3,4- diazole
Or its above-claimed cpd pharmaceutically acceptable salt or solvate.
The indazole of formula a structure-diazole analog derivative can be synthesized by following steps:
The synthetic method of compound i series:
Indazole 1- position substituted benzyl can first be introduced, then prepare 3- again and replace -5- indazole -1,2,4- oxadiazole derivatives:
Specific course of reaction may is that indazole -3 carboxylic acid (compound 3) can directly be bought with replacing nitrile (compound 1).Compound 1 and oxammonium hydrochloride. generate n- hydroxyl benzamidine derivative (compound 2) in the basic conditions, alkali used can be organic base or inorganic base, organic base can select pyridine, triethylamine, n, n- diisopropylethylamine, inorganic base can select potassium carbonate, sodium carbonate, solvent used is alcohol-water, and between 20-90 DEG C, concrete condition is shown in embodiment to reaction temperature.Under the effect of thionyl chloride and low mass molecule alcohol (as methanol), room temperature reaction obtains indazole -3 carboxylate (as compound 4) to compound 3, then with r5There is substitution reaction in the benzyl bromide a-bromotoluene replacing or benzyl chloride, obtain 1- (r in the basic conditions5Substituted benzyl) -1h- indazole -3 carboxylate methyl ester (compound 5), solvent for use is generally n, n- dimethylformamide (dmf) or oxolane (thf), alkali used is mainly sodium hydride or potassium tert-butoxide, and reaction temperature is between 20-60 DEG C.Compound 5 hydrolyzes in the basic conditions and obtains 1- (r5Substituted benzyl) -1h- indazole -3 carboxylic acid (compound 6), mainly from alcohol-water, dioxane-water etc., alkali used is mainly Lithium hydrate, sodium hydroxide, potassium hydroxide etc. to solvent, and reaction temperature is between 20-60 DEG C.Finally, compound 6 obtains target compound i series with n- hydroxyl benzamidine derivative 2 reaction under edci (1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride) and hobt (I-hydroxybenzotriazole) effect, solvent used is n, n- dimethylformamide (dmf), first room temperature reaction two hours, it is then heated to 140 DEG C of reaction half an hour, sterling can be obtained through column chromatography purification.
Can also first prepare 3- aryl -5- indazole -1,2,4- diazole (compound 7), then with r5The benzyl bromide a-bromotoluene replacing or benzyl chloride generation substitution reaction:
Specific course of reaction may is that the reaction under edci and hobt effect of compound 3 and compound 2 obtains 3- aryl -5- indazole -1,2,4- diazole (compound 7), solvent used is n, n- dimethylformamide (dmf) or acetonitrile, room temperature reaction is again heated to 140 DEG C of reaction half an hour after two hours, product is through column chromatography purification.Compound 7 and r5There is substitution reaction in the basic conditions in the benzyl bromide a-bromotoluene replacing or benzyl chloride, obtain target compound i through column chromatography purification, solvent for use is generally n, n- dimethylformamide (dmf), oxolane (thf), acetonitrile etc., alkali used is mainly potassium carbonate, sodium hydride or potassium tert-butoxide, typically reacts at room temperature.
The synthetic method of compound ii-v series compound:
Synthesize 3- aryl -5- indazole -1,2,4- diazole (compound 7) first, then introduce corresponding indazole n-1 bit substituent, prepare series compound ii, iii, iv and v:
Specific course of reaction may is that compound 7 and r5There is substitution reaction in the phenylisocyanate derivant replacing, obtain series compound ii through column chromatography purification, and solvent for use is generally oxolane (thf), acetonitrile, dichloromethane, chloroform etc., typically reacts at room temperature.
Compound 7 and r5There is substitution reaction in the basic conditions in substituted benzene formyl chlorine derivative, obtain series compound iii through column chromatography purification, solvent for use is generally n, n- dimethylformamide (dmf), oxolane (thf), acetonitrile, dioxane etc., alkali used is sodium hydride, potassium tert-butoxide, sodium hydroxide etc., typically reacts at room temperature.
Compound 7 and r5There is substitution reaction in the basic conditions in substituted phenylsulfonyl chloride derivant, obtain series compound iv through column chromatography purification, solvent for use is generally n, n- dimethylformamide (dmf), oxolane (thf), acetonitrile, dioxane etc., alkali used is sodium hydride, potassium tert-butoxide, sodium hydroxide etc., typically reacts at room temperature.
There is substitution reaction in compound 7 and 1,3- bromo-chloropropane, obtain compound 8 in the basic conditions, and through column chromatography purification, solvent for use is generally dmf or thf, and alkali used is mainly sodium hydride or potassium tert-butoxide, typically reacts at room temperature.Compound 8 is reacted with various amine in the basic conditions and obtains series compound v, and solvent used is generally acetonitrile or oxolane, and alkali used is mainly triethylamine or potassium carbonate etc., and reaction temperature is typically at 80-100 DEG C.
The synthetic method of vi series compound:
Specific course of reaction may is that compound 5 and hydrazine hydrate are substituted reaction and obtain compound 9, in diisopropyl ethyl amine (dipea) and o- BTA-n, with substituted carboxylic acid r under the catalysis of n, n', n'- tetramethylurea Tetrafluoroboric acid ester (tbtu)2Cooh reacts, and cyclization under dipea and paratoluensulfonyl chloride (tscl) catalysis further, obtains target product compound vi through column chromatography purification, solvent for use is generally acetonitrile, dioxane, oxolane etc., carries out at 20-100 DEG C.
The present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition comprises at least one active component and at least one pharmaceutically acceptable carrier, described active component can optionally the compound of self-drifting a structure and its preferred compound, described compound pharmaceutically acceptable salt, in the solvate of described compound any one or arbitrarily multiple.
Described " pharmaceutically acceptable carrier " refers to the conventional pharmaceutical carrier of pharmaceutical field, including the conventional thinner of pharmaceutical field, excipient such as water etc., filler such as starch etc., binding agent such as cellulose derivative, gelatin etc., wetting agent such as glycerol, disintegrating agent such as agar, Calcium Carbonate etc., absorption enhancer such as quaternary ammonium compound, surfactant such as hexadecanol, absorption carrier such as Kaolin and soap clay, lubricant such as Pulvis Talci etc. is it may also be necessary to add flavouring agent, sweeting agent etc..
Pharmaceutical preparation is applied to by any suitable administration, such as oral (including buccal or sublingual administration), rectally, nose administration, local administration (including buccal, sublingual administration or percutaneous dosing), vagina administration or parenteral (including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection) approach.These preparations can be by any method preparation known in art of pharmacy.Method for example by active component is mixed with carrier or excipient.
The present invention provides the described compound of formula a structure and its preferred compound, described compound, and pharmaceutically acceptable salt, the solvate of described compound and other drugs are used in combination the purposes in preparing cancer therapy drug.Further, described cancer is selected from breast carcinoma, sarcoma, pulmonary carcinoma, carcinoma of prostate, colon and rectum carcinoma, renal carcinoma, cancer of pancreas, leukemia, neuroblastoma, glioma, head cancer, neck cancer, thyroid carcinoma, hepatocarcinoma, ovarian cancer, carcinoma vulvae, cervical cancer, carcinoma of endometrium, carcinoma of testis, bladder cancer, the esophageal carcinoma, gastric cancer, nasopharyngeal carcinoma, carcinoma of buccal mucosa, oral cancer, gastrointestinal stromal tumor, skin carcinoma, multiple myeloma.
Can and the antineoplastic agent that be used in combination of compound or pharmaceutically acceptable salt thereof provided by the present invention include but and non-limiting at least one following species: mitotic inhibitor (as vinblastine, vindesine and vinorelbine)；Tubulin decomposing inhibitor (as Taxol)；Alkylating reagent (as cisplatin, carboplatin and cyclophosphamide)；Antimetabolite (as 5-fluorouracil, ftorafur, methotrexate, cytosine arabinoside and hydroxyurea)；Pluggable antibiotic (as A Leisu, mitomycin and bleomycin A5)；Enzyme (as asparagine enzyme)；Topoisomerase inhibitors (as relied on primary glycosides and camptothecine)；Biological response modifier (as interferon)；Proteasome inhibitor (as bortezomib).
Inventor is confirmed by many experiments, compound synthesized by the present invention is respectively provided with the inhibitory action of hif-1, wherein most compound has significant inhibitory action to hif-1, and the tumor cell lines such as human colon cancer cell strain (hct116) are shown with the effect of the anti-hif-1 in potent inside and outside.Therefore, the compounds of this invention can be applied in the medicine treat the related solid tumor of human or animal's cell proliferative as hif-1 inhibitor.
Brief description
Fig. 1 is compound i-30, i-32 inhibitory action figure to internal hif-1 transcriptional activity.Wherein, a figure is the operational flowchart that compound suppresses hif-1 transcriptional activity experiment in mice body；After b figure is medication three days, show matched group and medication group (compound i-30, i-32 and yc-1 using xenogen imaging system[1]) inhibition figure to internal hif-1；C figure is the cold light intensity rate of medication group and matched group, ± standard deviation of averaging (n>=3, *, p<0.05, * * *, p<0.001).
Specific embodiment
Specific embodiment included below is to illustrate, being understood not to limitation of the scope of the invention.In addition, it is to be understood that after having read the content of present invention instruction, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims limited range.
Embodiment 1: the preparation of compound 2 (replacing n- hydroxyl benzenecarboximidamide)
The preparation of 4- trifluoromethoxy-n- hydroxyl benzenecarboximidamide (compound 2a)
By oxammonium hydrochloride. (2.8g, 40mmol), sodium carbonate (2.7g, 26mmol) is dissolved in water (33ml), adds 4- trifluoromethoxy benzonitrile (3.0g, 16mmol) with ethanol (17ml), temperature rising reflux reacts 6 hours.Extracted with ethyl acetate (2 × 100ml) after being cooled to room temperature, merge organic layer, saturation nacl is washed, anhydrous na2so4It is dried, recycling design obtains white powder 3.1g, yield 89%；Fusing point: 107-109 DEG C；1h-nmr(δ,dmso-d6): 9.76 (s, 1h, oh), 7.79 (d, 2h, j=8.5hz, arh), 7.38 (d, 2h, j=8.5hz, arh), 5.90 (s, 2h, nh).
The preparation of 4- methoxyl group-n- hydroxyl benzenecarboximidamide (compound 2b)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 4 methoxy benzonitrile, obtains white solid, yield 65%；Fusing point: 119-120 DEG C.
The preparation of 4- trifluoromethyl-n- hydroxyl benzenecarboximidamide (compound 2c)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 4- trifluoromethylbenzonitrile, obtains white solid, yield 92%；Fusing point: 113-114 DEG C；1h-nmr(δ,dmso-d6): 9.92 (s, 1h, oh), 7.90 (d, 2h, j=8.5hz, arh), 7.75 (d, 2h, j=8.0hz, arh), 5.98 (s, 2h, nh).
The preparation of 4- chloro- n- hydroxyl benzenecarboximidamide (compound 2d)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 4 chlorobenzonitriles, obtains white solid, yield 81%；Fusing point: 133-134 DEG C.
The preparation of 4- pyridine radicals amidoxim (compound 2e)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 4 cyanopyridines, obtains white solid, yield 90%；Fusing point: 197-198 DEG C.
The preparation of n- hydroxyl benzenecarboximidamide (compound 2f)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with benzonitrile, obtains white solid, yield 73%；Fusing point: 73-75 DEG C.
The preparation of n- hydroxyl -2- (4- chlorphenyl) ethanamidine (compound 2g)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 2- (4- chlorphenyl) acetonitrile, obtains white solid, yield 67%；Fusing point: 94-96 DEG C.
The preparation of n- hydroxyl 2- phenylacetamidino (compound 2h)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 2- phenylacetonitrile, obtains white solid, yield 70%；Fusing point: 65-66 DEG C.
The preparation of the 4- tert-butyl group-n- hydroxyl benzenecarboximidamide (compound 2i)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 4 tert-butyl benzene formonitrile HCNs, obtains white solid, yield 73%；Fusing point: 147-149 DEG C；1h-nmr(δ,cdcl3): 7.57 (d, 2h, j=8.5hz, arh), 7.43 (d, 2h, j=8.5hz, arh), 4.90 (brs, 2h, nh), 1.33 (s, 9h, 3 × ch3).
The preparation of 3- hydroxylamino -3- amidino groups ethyl propionate (compound 2j)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with ethyl cyanoacetate, obtains faint yellow solid, yield 66%；Fusing point: 58-59 DEG C.
The preparation of 2- methoxyl group-n- hydroxyl benzenecarboximidamide (compound 2k)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 2 methoxy benzonitrile, obtains white solid, yield 94%；Fusing point: 104-105 DEG C.
The preparation of 2- chloro- n- hydroxyl benzenecarboximidamide (compound 2l)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 2 chlorobenzonitriles, obtains white solid, yield 84%；Fusing point: 116-118 DEG C.
The preparation of 4- dimethylamino-n- hydroxyl benzenecarboximidamide (compound 2m)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 4 dimethylamino benzonitriles, obtains white solid, yield 94%；Fusing point: 179-180 DEG C.
The preparation of n- hydroxyl -2- thiophene carbonamidine (compound 2n)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with thiophene -2- nitrile, obtains white solid, yield 73%；Fusing point: 86-88 DEG C.
The preparation of n- hydroxyl -2- furan carbonamidine (compound 2o)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with furan -2- nitrile, obtains white solid, yield 44%；Fusing point: 52-53 DEG C.
The preparation of 3- methoxyl group-n- hydroxyl benzenecarboximidamide (compound 2p)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 3 methoxy benzonitrile, obtains white solid, yield 94%；Fusing point: 100-102 DEG C.
The preparation of 3- chloro- n- hydroxyl benzenecarboximidamide (compound 2q)
Operating process, with the synthesis of compound 2a, simply replaces 4- trifluoromethoxy benzonitrile with 3 chlorobenzonitriles, obtains white solid, yield 95.7%；Fusing point: 111-112 DEG C.
The preparation of 3,4,5- trimethoxy-n- hydroxyl benzenecarboximidamide (compound 2r)
With the synthesis of compound 2a, simply with 3,4,5- trimethoxy-benzonitriles replace 4- trifluoromethoxy benzonitrile, obtain white solid, yield 83.87% for operating process；Fusing point: 155-157 DEG C；1h-nmr(δ,dmso-d6): 9.56 (s, 1h, oh), 6.99 (s, 2h, arh), 5.82 (s, 2h, nh), 3.80 (s, 6h, 2 × och3),3.67(s,3h,och3).
Embodiment 2:5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3-r2The preparation of -1,2,4- diazole (compound i-1～i-19)
The preparation of step 1. 1h- indazole -3- carboxylate methyl ester (compound 4 ')
1h- indazole -3- carboxylic acid (1.50g, 9.3mmol) is dissolved in methanol (50ml), is slowly added to thionyl chloride (2.20g, 18.6mmol) under ice bath, room temperature reaction is overnight.Decompression and solvent recovery, adds water (30ml) in residue, and with ethyl acetate (2 × 100ml) extraction, merges organic layer, and saturation nacl is washed, anhydrous na2so4It is dried, recycling design obtains white powder 1.51g, yield 93.0%；Fusing point: 163-165 DEG C.
The preparation of step 2. 1- (4- chlorobenzyl) -1h- indazole -3- carboxylate methyl ester (compound 5 ')
By 1h- indazole -3- carboxylate methyl ester (compound 4 ') (0.30g, 1.7mmol) it is dissolved in anhydrous dmf (5ml), add sodium hydride (0.08g, 1.8mmol) under ice bath and 30min is stirred at room temperature, add p-chlorobenzylchloride (0.30g, 1.8mmol), continue reaction 4h after add water (20ml) be quenched, be extracted twice with ethyl acetate (40ml), merge organic layer, washed with water, saturation nacl successively, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: dichloromethane (3:5) eluting, obtain white solid 0.29g, yield 57%；156-157 DEG C of fusing point；1h-nmr(δ,cdcl3): 8.28 (d, 1h, j=8.0hz, arh), 7.43 (t, 1h, j=7.5hz, arh), 7.36 (m, 2h, arh), 7.30 (d, 2h, j=8.0hz, arh), 7.18 (d, 2h, j=8.0hz, arh), 5.69 (s, 2h, benzylic-ch2),4.07(s,3h,och3).
The preparation of step 3. 1- (4- chlorobenzyl) -1h- indazole -3- carboxylic acid (compound 6 ')
By 1- (4- chlorobenzyl) -1h- indazole -3- carboxylate methyl ester (compound 5 ') (0.17g, 0.58mmol) it is dissolved in oxolane (5ml), add 0.25n sodium hydrate aqueous solution (5ml) under room temperature and react overnight.Add ethyl acetate (20ml) and water (15ml), separate organic layer, discard；Water layer adjusts ph to 1 with 1n hydrochloric acid, separates out a large amount of white solids, sucking filtration, filter cake is washed with a small amount of, drying under reduced pressure obtains white solid 0.11g, yield 69%；Fusing point: 196-197 DEG C.
The preparation of step 4. 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-1)
By 1- (4- chlorobenzyl) -1h- indazole -3- carboxylic acid (compound 6 ') (80mg, 0.28mmol) it is dissolved in anhydrous dmf (2.0ml), add edci (64mg, 0.33mmol) with hobt (45mg, 0.33mmol), 4- trifluoromethoxy-n- hydroxyl benzenecarboximidamide (compound 2a) (74mg is added after 30min is stirred at room temperature, 0.33mmol) continue reaction 1h, it is warming up to 140 DEG C of reaction 1h again, add water after being cooled to room temperature (8ml) be quenched, ethyl acetate (25ml) is extracted twice, and is washed with water, saturation nacl successively, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether/dichloromethane (1:1) eluting, obtain white solid 97mg, yield 74%；133-135℃；1h-nmr(δ,cdcl3): 8.37 (d, 1h, j=8.0hz, arh), 8.32 (d, 2h, j=7.5hz, arh), 8.00 (d, 1h, j=8.5hz, arh), 7.60-7.64 (m, 3h, arh), 7.51 (t, 1h, j=7.5hz, arh), 7.43 (d, 2h, j=8.5hz, arh), 7.38 (d, 2h, j=8.5hz, arh), 5.92 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- methoxyphenyl) -1,2,4- diazole (compound i-2)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2b, obtains white solid, yield 57%；Fusing point: 157-159 DEG C；1h-nmr(δ,cdcl3): 8.35 (d, 1h, j=8.5hz, arh), 8.12 (d, 2h, j=9.0hz, arh), 7.98 (d, 1h, j=8.5hz, arh), 7.62 (t, 1h, j=7.5hz, arh), 7.49 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=8.5hz, arh), 7.36 (d, 2h, j=8.5hz, arh), 7.17 (d, 2h, j=9.0hz, arh), 5.90 (s, 2h, benzylic-ch2),3.86(s,3h,och3).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- trifluoromethyl) -1,2,4- diazole (compound i-3)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2c, obtains white solid, yield 62%；Fusing point: 185-186 DEG C；1h-nmr(δ,cdcl3): 8.40 (d, 2h, j=8.0hz, arh), 8.37 (d, 1h, j=8.5hz, arh), 7.98-8.01 (m, 3h,), arh 7.63 (t, 1h, j=7.5hz, arh), 7.51 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=8.5hz, arh), 7.38 (d, 2h, j=8.5hz, arh), 5.91 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- chlorphenyl) -1,2,4- diazole (compound i-4)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2d, obtains white solid, yield 71%；Fusing point: 175-176 DEG C；1h-nmr(δ,cdcl3): 8.34 (d, 1h, j=8.0hz, arh), 8.19 (d, 2h, j=8.5hz, arh), 7.99 (d, 1h, j=8.5hz, arh), 7.70 (d, 2h, j=8.5hz, arh), 7.62 (t, 1h, j=7.5hz, arh), 7.50 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=8.5hz, arh), 7.37 (d, 2h, j=8.5hz, arh), 5.91 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (pyridin-4-yl) -1,2,4- diazole (compound i-5)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2e, obtains white solid, yield 66%；Fusing point: 182-184 DEG C；1h-nmr(δ,cdcl3): 8.86 (d, 2h, j=6.0hz, arh), 8.37 (d, 2h, j=8.5hz, arh), 8.11 (d, 2h, j=6.0hz, arh), 8.00 (d, 1h, j=8.5hz, arh), 7.63 (t, 1h, j=7.5hz, arh), 7.51 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=8.5hz, arh), 7.37 (d, 2h, j=9.0hz, arh), 5.92 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- phenyl -1,2,4- diazole (compound i-6)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2f, obtains white solid, yield 77%；Fusing point: 144-145 DEG C；1h-nmr(δ,cdcl3): 8.37 (d, 1h, j=8.0hz, arh), 8.19 (dd, 2h, j1=8.0hz, j1=2.0hz, arh), 7.99 (d, 1h, j=8.5hz, arh), 7.59-7.65 (m, 4h, arh), 7.50 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=9.0hz, arh), 7.37 (d, 2h, j=9.0hz, arh), 5.91 (s, 2h, benzylic-ch2).
The preparation of 3- (4- chlorobenzyl) -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole (compound i-7)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2g, obtains white solid, yield 20%；Fusing point: 126-128 DEG C；1h-nmr(δ,cdcl3): 8.17 (d, 1h, j=8.5hz, arh), 7.95 (d, 1h, j=8.5hz, arh), 7.58 (t, 1h, j=7.5hz, arh), 7.40-7.44 (m, 5h,), arh 7.40 (d, 2h, j=8.5hz,), arh 7.32 (d, 2h, j=8.5hz,), arh 5.86 (s, 2h, benzylic-ch2),4.24(s,2h,benzylic-ch2).
The preparation of 3- benzyl -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole (compound i-8)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2h, obtains white solid, yield 23%；Fusing point: 120-121 DEG C；1h-nmr(δ,cdcl3): 8.17 (d, 1h, j=8.5hz, arh), 7.95 (d, 1h, j=8.5hz, arh), 7.58 (t, 1h, j=7.5hz, arh), 7.44 (d, 1h, j=7.5hz,), arh 7.37-7.41 (m, 6h, arh), 7.32 (d, 2h, j=8.5hz, arh), 7.28 (t, 1h, j=7.5hz, arh), 5.86 (s, 2h, benzylic-ch2),4.23(s,2h,benzylic-ch2).
The preparation of 3- (4- tert-butyl-phenyl) -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole (compound i-9)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2i, obtains white solid, yield 61%；Fusing point: 162-163 DEG C；1h-nmr(δ,cdcl3): 8.35 (d, 1h, j=8.0hz, arh), 8.10 (d, 2h, j=8.5hz, arh), 7.98 (d, 1h, j=8.5hz, arh), 7.65 (d, 2h, j=8.5hz, arh), 7.62 (t, 1h, j=7.5hz, arh), 7.50 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=8.5hz, arh), 7.36 (d, 2h, j=8.5hz, arh), 5.91 (s, 2h, benzylic-ch2),1.34(s,9h,3×ch3).
The preparation of 2- (5- (1- (4- chlorobenzyl) -1h-3- indazolyl) -3-1,2,4- di azoly) ethyl acetate (compound i-10)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2j, obtains white solid, yield 12.46%；Fusing point: 147-148 DEG C；1h-nmr(δ,cdcl3): 8.12 (d, 1h, j=8.0hz, arh), 7.97 (d, 1h, j=8.5hz, arh), 7.60 (t, 1h, j=7.5hz,), arh 7.46 (t, 1h, j=7.5hz, arh), 7.41 (d, 2h, j=8.5hz, arh), 7.35 (d, 2h, j=8.5hz, arh), 5.88 (s, 2h,), benzylic-ch2 4.18 (q, 2h, j=7.0hz, ch2ch3), 4.05 (s, 2h, ch2), 1.29 (t, 3h, j=7.0hz, ch2ch3).
The preparation of 5- (1- (4- chlorobenzyl) -1h-3- indazolyl) -3- (2- methoxyphenyl) -1,2,4- diazole (compound i-11)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2k, obtains white solid, yield 70%；Fusing point: 154-155 DEG C；1h-nmr(δ,cdcl3): 8.43-8.45 (m, 1h, arh), 8.35 (dd, 1h, j1=7.5hz, j2=1.5hz, arh), 7.52-7.55 (m, 1h, arh), 7.47-7.50 (m, 1h, arh), 7.40-7.43 (m, 2h,), arh 7.32 (d, 2h, j=8.5hz, arh), 7.24 (d, 2h, j=9.0hz, arh), (7.13-7.16 m, 1h, arh), (7.12 d, 1h, arh), 5.77 (s, 2h, benzylic-ch2),4.05(s,3h,ch3).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (2- chlorphenyl) -1,2,4- diazole (compound i-12)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2l, obtains white solid, yield 67%；Fusing point: 132-133 DEG C；1h-nmr(δ,cdcl3): 8.44 (d, 1h, j=8.0hz, arh), 8.17 (dd, 1h, j1=8.0hz, j2=2.0hz, arh), 7.61 (dd, 1h, j1=8.0hz, j2=1.5hz, arh), 7.41-7.51 (m, 5h, arh), 7.33 (d, 2h, j=8.5hz, arh), 7.25 (d, 2h, j=9.0hz, arh), 5.77 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- dimethylamino phenyl) -1,2,4- diazole (compound i-13)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2m, obtains white solid, yield 55%；Fusing point: 205-207 DEG C；1h-nmr(δ,cdcl3): 8.44 (d, 1h, j=8.5hz, arh), 8.16 (d, 2h, j=9.9hz, arh), 7.46-7.48 (m, 1h,), arh 7.39-7.42 (m, 2h, arh), 7.30 (d, 2h, j=8.5hz, arh), 7.22 (d, 2h, j=7.5hz, arh), 6.84 (d, 2h, j=6.5hz,), arh 5.75 (s, 2h, benzylic-ch2),3.01(s,6h,2×ch3).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (thiophene -2- base) -1,2,4- diazole (compound i-14)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2n, obtains white solid, yield 72%；Fusing point: 173-174 DEG C；1h-nmr(δ,cdcl3): 8.43 (d, 1h, j=8.5hz, arh), 8.01 (dd, 1h, j1=4.0hz, j2=1.5hz, arh), 7.58 (dd, 1h, j1=5.0hz, j2=1.0hz, arh), 7.44-7.51 (m, 1h, arh), 7.42-7.45 (m, 2h, arh), 7.32 (d, 2h, j=8.5hz, arh), 7.21-7.24 (m, 3h, arh), 5.77 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (furan -2- base) -1,2,4- diazole (compound i-15)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2o, obtains white solid, yield 67%；Fusing point: 191-192 DEG C；1h-nmr(δ,cdcl3): 8.41 (d, 1h, j=9.0hz, arh), 7.67 (d, 1h, j=1.0hz, arh), 7.46-7.50 (m, 1h,), arh 7.40-7.43 (m, 2h, arh), 7.34 (d, 2h, j=3.0hz, arh), 7.31 (d, 2h, j=8.5hz, arh), 7.23 (d, 2h, j=8.5hz,), arh 6.62 (dd, 1h, j1=3.5hz, j2=2.0hz, arh), 5.74 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3- methoxyphenyl) -1,2,4- diazole (compound i-16)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2p, obtains white solid, yield 73%；Fusing point: 156-157 DEG C；1h-nmr(δ,cdcl3): 8.46 (d, 1h, j=8.5hz, arh), 7.91 (d, 1h, j=6.0hz, arh), 7.82 (s, 1h, arh), 7.42-7.52 (m, 4h,), arh 7.33 (d, 2h, j=8.5hz,), arh 7.25 (d, 2h, j=8.5hz,), arh 7.12 (dd, 1h, j1=8.5hz, j2=3.0hz, arh), 5.77 (s, 2h, benzylic-ch2),3.94(s,3h,ch3).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3- chlorphenyl) -1,2,4- diazole (compound i-17)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2q, obtains white solid, yield 67%；Fusing point: 136-137 DEG C；1h-nmr(δ,cdcl3): 8.44 (d, 1h, j=8.0hz, arh), 8.30 (t, 1h, j=2.0hz, arh), 8.16-8.18 (m, 1h, arh), 7.50-7.53 (m, 1h, arh), 7.46-7.49 (m, 2h,), arh 7.41-7.45 (m, 2h, arh), 7.31 (d, 2h, j=8.5hz, arh), 7.23 (d, 2h, j=8.5hz, arh), 5.76 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3,4,5- trimethoxyphenyl) -1,2,4- diazole (compound i-18)
Operating process, with the preparation of compound i-1, simply replaces compound 2a with compound 2r, obtains white solid, yield 76%；Fusing point: 125-126 DEG C；1h-nmr(δ,cdcl3): 8.44 (d, 1h, j=8.5hz, arh), 7.54 (s, 2h, arh), 7.51 (d, 1h, j=8.0hz, arh), 7.43-7.46 (m, 2h,), arh 7.33 (d, 2h, j=8.5hz,), arh 7.26 (d, 2h, j=8.5hz,), arh 5.78 (s, 2h, benzylic-ch2),4.01(s,6h,2×och3),3.96(s,3h,och3).
The preparation of 2- (5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole -3- base) ethanol (compound i-19)
Lithium aluminium hydride reduction (52mg, 1.38mmol) is added in absolute ether (1ml) in 0 DEG C, is slowly dropped into absolute ether (5ml) solution of compound i-10 (39mg, 0.98mmol), 0 DEG C of reaction 1h.Slowly add water (2ml) and ammonium chloride saturated aqueous solution (2ml) that reaction is quenched in system, filter.Filtrate is extracted with ethyl acetate (15ml), washes successively, and saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: ethyl acetate (1:1) eluting, obtain white solid 21mg, yield 60%；Fusing point: 118-119 DEG C；1h-nmr(δ,cdcl3): 8.33 (d, 1h, j=8.0hz, arh), 7.47-7.50 (m, 1h, arh), 7.39-7.44 (m, 2h, arh), 7.32 (d, 2h, j=8.5hz, arh), 7.23 (d, 2h, j=8.5hz, arh), 5.73 (s, 2h, benzylic-ch2), 4.17 (t, 2h, j=5.5hz, ch2), 3.19 (t, 2h, j=6.0hz, ch2).
Embodiment 3:5- (1- (r5Substituted benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-20～i-27) preparation
The preparation of step 1. 5- (1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 7 ')
By 1h- indazole -3- carboxylic acid (702mg, 4.3mmol) it is dissolved in anhydrous dmf (24ml), add edci (905mg, 4.7mmol) with hobt (638mg, 4.7mmol), 4- trifluoromethoxy-n- hydroxyl benzenecarboximidamide (compound 2a) (867mg is added after 30min is stirred at room temperature, 3.9mmol) and continue react 1h, it is warming up to 140 DEG C of reaction 1h again, add water after being cooled to room temperature (60ml) be quenched, crude product with ethyl acetate (150ml) extract, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: dichloromethane (1:1) eluting, obtain white solid 704mg, yield 52%；Fusing point: 209-210 DEG C；1h-nmr(δ,dmso-d6): δ 14.31 (s, 1h, n-h), 8.36-8.32 (m, 3h, arh), 7.79 (d, j=8.5hz, arh), 7.65 (d, j=8.6hz, arh), 7.59 (t, j=8.0hz, arh), 7.47 (t, j=8.0hz, arh).
The preparation of step 2. 5- (1- (4- luorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-20)
By compound 7 ' (80mg, 0.23mmol) it is dissolved in anhydrous dmf (2ml), add sodium hydride (11mg, 0.27mmol) under ice bath, add after 30min is stirred at room temperature to fluorobenzyl chloride (40mg, 0.27mmol) and continue react 4h, add water (5ml) be quenched, crude product with ethyl acetate (15ml) extract, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: dichloromethane (1:1) eluting, obtain white solid 63mg, yield 60%；Fusing point: 128-130 DEG C；1h-nmr(δ,cdcl3): 8.36 (d, 1h, j=8.5hz, arh), 8.32 (d, 2h, j=9.0hz, arh), 8.02 (d, 1h, j=8.5hz, arh), 7.60-7.63 (m, 3h, arh), 7.50 (t, 1h, j=7.5hz, arh), 7.40-7.43 (m, 2h, arh), 7.20 (t, 2h, j=89.0hz,), arh 5.90 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- nitrobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-21)
Operating process, with the preparation of compound i-20, simply with replacing nitrobenzyl bromo to fluorobenzyl chloride, obtains white solid, yield 17%；Fusing point: 175-176 DEG C；1h-nmr(δ,cdcl3): 8.40 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=9.0hz, arh), 8.24 (d, 2h, j=8.5hz, arh), 8.02 (d, 1h, j=8.5hz,), arh 7.63-7.65 (m, 3h, arh), 7.57 (d, 2h, j=8.5hz, arh), 7.54 (t, 1h, j=7.5hz, arh), 6.11 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (3- luorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-22)
Operating process with the preparation of compound i-20, simply between fluorine benzyl chloride replace to fluorobenzyl chloride, obtain white solid, yield 46%；Fusing point: 128-129 DEG C；1h-nmr(δ,cdcl3): 8.39 (d, 1h, j=8.0hz, arh), 8.34 (d, 2h, j=8.5hz, arh), 8.02 (d, 1h, j=8.5hz, arh), 7.62-7.65 (m, 3h, arh), 7.53 (t, 1h, j=7.5hz, arh), 7.39-7.43 (m, 1h, arh), 7.22 (d, 1h, j=9.5hz, arh), 7.14-7.18 (m, 2h, arh), 5.96 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- methoxy-benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-23)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with p-methoxybenzyl chloride, obtains white solid, yield 33%；Fusing point: 144-145 DEG C；1h-nmr(δ,cdcl3): 8.34 (d, 1h, j=8.0hz, arh), 8.31 (d, 2h, j=9.0hz, arh), 8.00 (d, 1h, j=8.5hz, arh), 7.63 (d, 2h, j=8.5hz, arh), 7.59 (d, 1h, j=8.0hz, arh), 7.48 (t, 1h, j=7.5hz, arh), 7.34 (d, 2h, j=8.5hz, arh), 6.91 (d, 2h, j=9.0hz, arh), 5.81 (s, 2h, benzylic-ch2),3.70(s,3h,och3).
The preparation of 5- (1- (2,6- difluorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-24)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with 2,6- difluoro benzyl chloride, obtains white solid, yield 37%；Fusing point: 183-184 DEG C；1h-nmr(δ,cdcl3): 8.36 (d, 1h, j=8.5hz, arh), 8.31 (d, 2h, j=9.0hz, arh), 8.04 (d, 1h, j=8.5hz, arh), 7.70 (t, 1h, j=7.5hz,), arh 7.63 (d, 2h, j=8.5hz, arh), 7.48-7.54 (m, 2h, arh), 7.21 (t, 2h, j=8.0hz, arh), 5.95 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (pyridine -2 ylmethyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-25)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with 2- chloromethylpyridine, obtains white solid, yield 42%；Fusing point: 168-169 DEG C；1h-nmr(δ,cdcl3): 8.51 (d, 1h, j=4.0hz, arh), 8.38 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=8.5hz, arh), 7.95 (d, 1h, j=8.5hz, arh), 7.82 (t, 1h, j=7.5hz, arh), 7.60-7.64 (m, 3h, arh), 7.52 (t, 1h, j=7.5hz, arh), 7.30-7.34 (m, 2h, arh), 6.02 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (pyridin-4-yl methyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-26)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with 4- chloromethylpyridine, obtains white solid, yield 50%；Fusing point: 163-164 DEG C；1h-nmr(δ,cdcl3): 8.55 (d, 2h, j=6.0hz, arh), 8.40 (d, 1h, j=8.5hz, arh), 8.33 (d, 2h, j=8.5hz, arh), 7.97 (d, 1h, j=8.5hz,), arh 7.62-7.65 (m, 3h, arh), 7.54 (t, 1h, j=7.5hz, arh), 7.23 (d, 2h, j=5.5hz, arh), 6.01 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- methyl-benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-27)
Operating process, with the preparation of compound i-20, simply with replacing methyl benzyl chloride to fluorobenzyl chloride, obtains white solid, yield 37%；Fusing point: 129-130 DEG C；1h-nmr(δ,cdcl3): 8.35 (d, 1h, j=8.5hz, arh), 8.31 (d, 2h, j=8.5hz, arh), 7.97 (d, 1h, j=8.5hz, arh), 7.63 (d, 2h, j=8.0hz, arh), 7.61 (t, 1h, j=7.5hz, arh), 7.25 (d, 2h, j=8.0hz, arh), 7.21 (t, 1h, j=8.0hz, arh), 7.15 (d, 2h, j=8.0hz, arh), 5.84 (s, 2h, benzylic-ch2),2.24(s,3h,ch3).
Embodiment 4:r2r1The preparation of n-3- (3- (5- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole) -1h- indazole methyl) benzophenone (compound i-28～i-29)
The preparation of step 1. 3- bromo methyl acid (compound 10)
By m-methyl benzoic acid (2.0g, 14.7mmol) it is dissolved in dichloromethane (6ml) and is heated to reflux with benzoyl peroxide (bpo, 0.036g, 0.15mmol), it is dividedly in some parts nbs (2.6g, 14.7mmol), continue to be heated to reflux 2h, add water after being cooled to room temperature (10ml) reaction is quenched, with dichloromethane (50ml) extraction, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, after concentration, obtain faint yellow solid 2.7g, yield 86%；149-151 DEG C of fusing point.
The preparation of step 2. (3- 2-bromomethylphenyl) (morpholine) ketone (compound 11)
3- bromo methyl acid (1.3g, 5.9mmol) and thionyl chloride (0.8ml, 10.8mmol) are added in anhydrous response bottle, after being heated to reflux 1.5h, thionyl chloride is removed under reduced pressure.Anhydrous methylene chloride (10ml) dissolving residue is added in reaction bulb, it is cooled to 0 DEG C, it is slowly added to diisopropyl ethyl amine (1.40g, 10.8mmol) with morpholine (0.51g, 5.9mmol), after 0 DEG C of continuation reaction 20min, add saturated sodium bicarbonate aqueous solution (10ml) that reaction is quenched, with dichloromethane (50ml) extraction, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, after concentration, obtain pale yellow oil 1.55g, yield 93%；Esi-ms:m/z=248 [m+1]+.
The preparation of (3- 2-bromomethylphenyl) (4- methyl piperidine -1- base) ketone (compound 12)
Operating process, with the preparation of compound 11, simply replaces morpholine with n- methyl piperazine, obtains pale yellow oil, yield 90%；Esi-ms:m/z=297 [m+1]+.
The preparation of step 3. morpholine -3- (3- (5- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole) -1h- indazole methyl) benzophenone (compound i-28)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with compound 11, obtains white solid, yield 15%；Fusing point: 124-126 DEG C；1h-nmr(δ,cdcl3): 8.35 (d, 1h, j=8.5hz, arh), 8.30 (d, 2h, j=9.0hz, arh), 8.88 (d, 1h, j=8.5hz,), arh 7.59-7.62 (m, 3h, arh), 7.50 (t, 1h, j=7.5hz, arh), 7.42-7.43 (m, 2h,), arh 7.38 (s, 1h, arh), 7.33-7.35 (m, 1h, arh), 5.95 (s, 2h, benzylic-ch2),3.26-3.56(m,8h,morpholine).
(4- methylpiperazine-1-yl) (3- (3- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole -5- base) -1h- indazole -1- base) methyl) and benzophenone (compound i-29) preparation
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with compound 12, obtains white solid, yield 19%；Fusing point: 129-130 DEG C；1h-nmr(δ,cdcl3): 8.48 (d, 1h, j=8.5hz, arh), 8.31-8.27 (m3h, arh), 7.85 (d, 1h, j=8.5hz, arh), (7.60-7.50 m, 2h, arh), (7.46-7.37 m, 5h, arh), 5.97 (s, 2h, benzylic-ch2),3.71(brs,4h,piperazine),3.15(s,3h,ch3),2.36(brs,4h,piperazine).Embodiment 5: the preparation of compound i-30～compound i-34
The preparation of step 1. 3- tertiary butyl dimethyl Si yl benzoic acid methyl ester (compound 13)
By NSC 40536 (3.3g, 21.7mmol), dimethylamino naphthyridine (dmap) (0.13g, 1.1mmol) with triethylamine (6.0ml, 43.4mmol) it is dissolved in dichloromethane (30ml), it is slowly added to tert-butyl chloro-silicane (6.6g under ice bath, dichloromethane (10ml) solution 43.4mmol), is stirred overnight at room temperature.Use saturation nh successively4Cl, the washing of saturation nacl, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether/dichloromethane (10:1) eluting, obtain colorless oil 4.6g, yield 79%；1h-nmr(δ,cdcl3): 7.64 (d, 1h, j=8.0hz, arh), 7.49 (d, 1h, j=2.0hz, arh), 7.31 (t, 1h, j=8.0hz, arh), 7.04 (dd, 1h, j1=8.0hz, j2=2.0hz, arh), 3.90 (s, 3h, och3),0.99(s,9h,3×ch3),0.22(s,6h,2×ch3).
The preparation of 4- tertiary butyl dimethyl Si yl benzoic acid methyl ester (compound 14)
Operating process, with the preparation of compound 13, simply replaces NSC 40536 with methyl parahydroxybenzoate, obtains colorless oil, yield 73%；1h-nmr(δ,cdcl3): 7.95 (d, 2h, j=8.0hz, arh), 6.86 (d, 2h, j=8.0hz, arh), 4.36 (q, 2h, och2ch3),1.38(t,3h,och2ch3),0.98(s,9h,3×ch3),0.22(s,6h,2×ch3).
The preparation of step 2. 3- bromomethylphenoxv t-butyldimethyl silane (compound 15)
By lithium aluminium hydride reduction (1.4g, 37.5mmol) it is added in anhydrous tetrahydro furan (30ml), it is cooled to 0 DEG C after 10min is stirred at room temperature, it is slowly added to compound 13 (4.0g, anhydrous tetrahydro furan (20ml) solution 15.0mmol), continue reaction 30min., 0 DEG C is slowly added to water (20ml) and reaction is quenched, and adds saturation nh4Cl solution (50ml), filters, filtrate is extracted twice with ethyl acetate (40ml), is washed with water, saturation nacl successively, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: dichloromethane (1:2) eluting, obtain colorless oil 2.4g.By triphenylphosphine (1.7g, 6.6mmol), imidazoles (0.5g, 7.4mmol) it is dissolved in anhydrous methylene chloride (20ml) and be slowly added to bromine (0.32ml in 0 DEG C, 6.4mmol), above-mentioned grease (1.2g is added after stirring 15min, dichloromethane (4ml) solution 4.9mmol), keeps 0 DEG C to continue reaction 1h.Dchloromethane, washes successively, and saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: dichloromethane (1.5:1) eluting, obtain colorless oil 0.65g, yield 44%；1h-nmr(δ,cdcl3): 7.21 (t, 1h, j=8.0hz, arh), 6.99 (d, 1h, j=8.0hz, arh), 6.88 (d, 1h, j=2.0hz, arh), 6.78 (dd, 1h, j1=8.0hz, j2=2.0hz, arh), 4.44 (s, 2h, benzylic-ch2),0.99(s,9h,3×ch3),0.21(s,6h,2×ch3).
The preparation of 4- bromomethylphenoxv t-butyldimethyl silane (compound 16)
Operating process, with the preparation of compound 15, is simply used compound 14 to replace compound 13, is obtained colorless oil, yield 55%；1h-nmr(δ,cdcl3): 7.27 (d, 2h, j=8.5hz, arh), 6.80 (d, 2h, j=8.5hz, arh), 4.49 (s, 2h, benzylic-ch2),0.98(s,9h,3×ch3),0.20(s,6h,2×ch3).
Step 3. 5- (1- (3- ((t-Butyldimethylsilyl) epoxide) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1, the preparation of 2,4- diazole (compound 17)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with compound 15, obtains white solid, yield 31%；Fusing point: 139-140 DEG C；1h-nmr(δ,cdcl3): 8.42 (d, 1h, j=8.0hz, arh), 8.35 (d, 2h, j=9.0hz, arh), 7.46-7.41 (m, 2h, arh), 7.39 (d, 2h, j=8.5hz, arh), 7.19 (t, 1h, j=8.0hz,), arh 6.89 (d, 1h, j=8.0hz, arh), 6.76 (d, 1h, j=8.0hz, arh), 6.72 (s, 1h, arh), 5.74 (s, 2h, benzylic-ch2),0.91(s,9h,3×ch3),0.09(s,6h,2×ch3).
The preparation of 5- (1- (4- ((t-Butyldimethylsilyl) epoxide) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 18)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with compound 16, obtains white solid, yield 38%；Fusing point: 142-143 DEG C；1h-nmr(δ,cdcl3): 8.41 (d, 1h, j=8.0hz, arh), 8.34 (d, 2h, j=9.0hz, arh), 7.46 (d, 2h, j=8.0hz, arh), 7.42-7.39 (m, 1h, arh), 7.38 (d, 2h, j=9.0hz, arh), 7.19 (d, 2h, j=8.5hz, arh), 6.79 (d, 2h, j=8.5hz, arh), 5.72 (s, 2h, benzylic-ch2),0.95(s,9h,3×ch3),0.16(s,6h,2×ch3).
The preparation of step 4. 5- (1- (3- hydroxybenzyl) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 19)
By compound 17 (49mg, 0.086mmol) it is dissolved in anhydrous tetrahydro furan (3ml), 0 DEG C is slowly added to tetrabutyl ammonium fluoride (45mg, oxolane (2ml) solution 0.17mmol), room temperature reaction 30min, with diluted ethyl acetate, washes successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: ethyl acetate (1.5:1) eluting, obtain white solid 37mg, yield 97%, fusing point: 173-174 DEG C；1h-nmr(δ,cdcl3): 8.39 (d, 1h, j=8.0hz, arh), 8.28 (d, 2h, j=9.0hz, arh), 7.43 (d, 2h, j=8.5hz, arh), (7.40-7.37 m, 1h, arh), 7.36 (d, 2h, j=8.5hz, arh), 7.23 (t, 1h, j=7.5hz, arh), 6.89 (d, 1h, j=8.0hz, arh), (6.78-6.76 m, 1h, arh), (6.69 s, 1h, arh), 5.73 (s, 2h, benzylic-ch2).
The preparation of 5- (1- (4- hydroxybenzyl) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 20)
Operating process, with the preparation of compound 19, is simply used compound 18 to replace compound 17, is obtained white solid, yield 92%；Fusing point: 220-221 DEG C；1h-nmr(δ,cdcl3): 8.41 (d, 1h, j=8.5hz, arh), 8.34 (d, 2h, j=9.0hz, arh), 7.47 (d, 2h, j=2.5hz, arh), 7.43-7.41 (m, 1h, arh), 7.39 (d, 2h, j=8.5hz, arh), 7.28 (d, 2h, j=8.5hz, arh), 6.88 (d, 2h, j=9.0hz, arh), 5.73 (s, 2h, benzylic-ch2).
The preparation of step 5. 5- (1- (3- (2- bromine oxethyl) benzyl) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 21)
By compound 19 (150mg, 0.33mmol) He 1,2- Bromofume (0.3ml, 3.3mmol) it is dissolved in anhydrous propanone (20ml), add Anhydrous potassium carbonate (275mg, 2.0mmol), diluted ethyl acetate is used after back flow reaction 24h, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: ethyl acetate (5:1) eluting, obtain white solid 75mg, yield 52%, fusing point: 164-165 DEG C；1h-nmr(δ,cdcl3): 8.43 (d, 1h, j=8.5hz, arh), 8.34 (d, 2h, j=9.0hz, arh), 7.48-7.45 (m, 2h, arh), 7.43-7.40 (m, 1h, arh), 7.39 (d, 2h, j=8.0hz, arh), 7.26-7.24 (m, 1h, arh), 6.92 (d, 1h, j=7.5hz, arh), 6.85-6.83 (m, 2h, arh), 5.76 (s, 2h, benzylic-ch2), 4.24 (t, 2h, j=7.5hz, ch2), 3.60 (t, 2h, j=7.5hz, ch2).
The preparation of 5- (1- (4- (2- bromine oxethyl) benzyl) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 22)
Operating process, with the preparation of compound 21, is simply used compound 20 to replace compound 19, is obtained white solid, yield 46%；Fusing point: 133-134 DEG C；1h-nmr(δ,cdcl3): 8.42 (d, 1h, j=8.0hz, arh), 8.34 (d, 2h, j=8.5hz, arh), 7.49-7.45 (m, 2h,), arh 7.43-7.41 (m, 1h, arh), 7.39 (d, 2h, j=8.5hz, arh), 7.28 (d, 2h, j=8.5hz, arh), 6.88 (d, 2h, j=9.0hz,), arh 5.73 (s, 2h, benzylic-ch2), 4.27 (t, 2h, j=6.0hz, ch2), 3.62 (t, 2h, j=7.5hz, ch2).
Step 6. 5- (1- (3- (2 (4- methylpiperazine-1-yl) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1, the preparation of 2,4- diazole (compound i-30)
By compound 21 (40mg, 0.072mmol) it is dissolved in anhydrous acetonitrile (4ml), add Anhydrous potassium carbonate (59mg, 0.42mmol) and n- methyl piperazine (43mg, 0.42mmol), it is cooled to room temperature after being heated to reflux 24h, add water (5ml) reaction is quenched, crude product with ethyl acetate (50ml) extract, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with ethyl acetate: methanol: triethylamine (50:5:1) eluting, obtain faint yellow solid 21mg, yield 52%；Fusing point: 62-63 DEG C；1h-nmr(δ,cdcl3): 8.41 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=8.5hz, arh), 7.47-7.43 (m, 2h, arh), 7.42-7.40 (m, 1h, arh), 7.38 (d, 2h, j=8.5hz,), arh 7.24 (t, 1h, j=7.5hz, arh), 6.91-6.84 (m, 2h, arh), 6.83 (d, 1h, j=8.0hz, arh), 5.74 (s, 2h, benzylic-ch2), 4.03 (t, 2h, j=6.0hz, ch2), 2.76 (t, 2h, j=6.0hz, ch2),2.57-2.46(brd,8h,piperazine),2.70(s,3h,ch3)；13c-nmr(δ,cdcl3): 171.25,167.75,159.21,151.33,140.56,136.91,130.04,130.00,129.49,127.70,125.43,123.74,123.20,121.73,121.06,119.76,114.20,113.78,110.39,65.89,57.03,55.01,54.97,54.25,53.53,45.99.
The preparation of 5- (1- (3- (2 (morpholine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-31)
Operating process, with the preparation of compound i-30, is simply replaced n- methyl piperazine with morpholino, is obtained white solid, yield 61%；Fusing point: 62-63 DEG C；1h-nmr(δ,cdcl3): 8.41 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=9.0hz, arh), 7.49-7.41 (m, 2h,), arh 7.42-7.39 (m, 1h, arh), 7.38 (d, 2h, j=8.0hz, arh), 6.89 (d, 1h, j=7.5hz, arh), 6.84-6.82 (m, 2h,), arh 5.74 (s, 2h, benzylic-ch2), 4.05 (t, 2h, j=5.5hz, ch2), 3.71 (t, 4h, j=4.5hz, morpholine), 2.75 (t, 2h, j=5.5hz, ch2), 2.54 (t, 4h, j=4.5hz, morpholine)；13c-nmr(δ,cdcl3): 171.24,167.76,159.14,151.33,140.56,136.95,130.06,130.02,129.48,127.71,125.40,123.75,123.20,121.74,121.07,119.84,114.20,113.76,110.37,66.83,65.68,57.50,54.23,54.03..
The preparation of 5- (1- (3- (2 (4- hydroxy piperidine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-32)
Operating process, with the preparation of compound i-30, simply replaces n- methyl piperazine with 4- hydroxy piperidine, obtains white solid, yield 86%；Fusing point: 60-61 DEG C；1h-nmr(δ,dmso-d6): 8.37 (d, 1h, j=8.5hz, arh), 8.33 (d, 2h, j=8.5hz, arh), 8.00 (d, 1h, j=8.5hz, arh), 7.65-7.60 (m, 3h, arh), 7.50 (t, 1h, j=7.5hz,), arh 7.26 (t, 1h, j=8.0hz, arh), 6.94 (t, 1h, j=1.5hz, arh), 6.88-6.86 (m, 2h, arh), 5.87 (s, 2h, benzylic-ch2), 4.53 (d, 1h, j=4.0hz, oh), 4.02 (t, 2h, j=5.5hz, ch2),3.44-3.39(m,1h,piperidine),2.74-2.72(m,2h,ch2),2.61-2.59(m,2h,piperidine),2.09-2.05(m,2h,piperidine),1.68-1.65(m,2h,piperidine),1.37-1.32(m,2h,piperidine)；13c-nmr(δ,cdcl3): δ 171.23,167.75,158.93,151.33,140.56,136.98,130.06,129.48,127.74,125.38,123.76,123.18,121.73,121.07,119.92,114.13,113.81,110.38,65.39,56.58,54.19,50.94,50.91,33.50.
N- (Cvclopropvlmethvl) -2- (3- ((3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- base) methyl) phenoxy group) ethamine (compound i-33) preparation
Operating process, with the preparation of compound i-30, simply replaces n- methyl piperazine with cyclopropylamine, obtains white solid, yield 59%；Fusing point: 65-66 DEG C；1H-nmr (δ, dmso): 8.36 (d, 1h, j=8.5hz,), arh 8.32 (d, 2h, j=9.0hz,), arh 7.98 (d, 1h, j=8.5hz,), arh 7.64-7.59 (m, 3h, arh), 7.50 (t, 1h, j=7.5hz,), arh 7.26 (t, 1h, j=8.0hz, arh), 6.91 (d, 1h, j=2.0hz, arh), (6.89-6.86 m, 2h, arh), 5.86 (s, 2h, benzylic-ch2), 3.96 (t, 2h, j=6.0hz, ch2), 2.88 (t, 2h, j=6.0hz, ch2),2.10-2.06(m,1h,cyclopropyl),0.33-0.30(m,2h,cyclopropyl),0.19-0.16(m,2h,cyclopropyl).
The preparation of 5- (1- (4- (2 (4- hydroxy piperidine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound i-34)
Operating process, with the preparation of compound i-30, simply replaces n- methyl piperazine with 4- hydroxy piperidine, replaces 21 with compound 22, obtains white solid, yield 62%；Fusing point: 103-104 DEG C；1h-nmr(δ,cdcl3): 8.41 (d, 1h, j=8.0hz, arh), 8.34 (d, 2h, j=9.0hz, arh), 7.47 (d, 2h, j=8.5hz, arh), 7.42-7.39 (m, 1h, arh), (7.39 d, 2h, j=8.5hz, arh), 7.26 (d, 2h, j=8.5hz, arh), 6.86 (d, 2h, j=9.0hz, arh), 5.72 (s, 2h, benzylic-ch2),4.07(s,2h,ch2),2.87(s,2h,ch2),2.80(s,2h,piperidine),2.30(s,2h,piperidine),1.62(s,4h,piperidine),1.39(s,1h,piperidine).
The preparation of embodiment 6:n- (4- chlorphenyl) -3- (3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- carboxylic acid amides (compound ii-1)
70mg (0.20mmol) compound 7 ' is dissolved in anhydrous tetrahydro furan (2ml), add 31mg (0.20mmol) parachlorobenzyl isocyanic ester, heating reflux reaction 10h, add water (5ml) be quenched, crude product is extracted with ethyl acetate (15ml), wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether/dichloromethane (4:1) eluting, obtain white solid 25mg, yield 25%；Fusing point: 118-119 DEG C；1h-nmr(δ,dmso-d6): 14.32 (s, 1h, conh), 8.35-8.31 (m, 3h, arh), 7.79 (d, 1h, j=8.0hz, arh), 7.65 (d, 2h, j=8.0hz, arh), 7.58 (t, 1h, j=8.0hz, arh), (7.48 t, 1h, j=8.0hz, arh), 7.01 (d, 2h, j=9.0hz, arh), 6.54 (d, 2h, j=9.0hz, arh), 5.23 (s, 2h, benzylic-ch2).
Embodiment 7:(3- (3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- base) (4- chlorphenyl) ketone (compound iii-1) preparation
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with 4- chlorobenzoyl chloride, obtains white solid, yield 40%；Fusing point: 160-161 DEG C；1h-nmr(δ,cdcl3): 8.66 (d, 1h, j=8.5hz, arh), 8.55 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=9.0hz, arh), (8.21 d, 2h, j=9.0hz, arh), 7.79 (t, 1h, j=7.0hz, arh), 7.66 (t, 1h, j=8.0hz, arh), 7.59 (d, 2h, j=8.5hz,), arh 7.41 (d, 2h, j=8.0hz, arh).
The preparation of embodiment 8:5- (1- p-toluenesulfonyl -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound iv-1)
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with paratoluensulfonyl chloride, obtains white solid, yield 52%；Fusing point: 188-189 DEG C；1h-nmr(δ,cdcl3): 8.44 (d, 1h, j=8.0hz, arh), 8.34 (d, 1h, j=8.5hz, arh), 8.30 (d, 2h, j=8.5hz, arh), 8.02 (d, 1h, j=8.5hz, arh), 7.70 (t, 1h, j=8.0hz, arh), 7.56 (t, 1h, j=7.5hz, arh), 7.39 (d, 2h, j=8.0hz, arh), 7.32 (d, 2h, j=8.5hz, arh), 2.38 (s, 3h, ch3).
Embodiment 9:5- (1- (3-nr1r2- 1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound v-1～v-3) preparation
The preparation of step 1. 5- (1- (3- chloropropyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound 8 ')
Operating process, with the preparation of compound i-20, is simply replaced to fluorobenzyl chloride with 1,3- bromo-chloropropane, obtains white solid, yield 54%；Fusing point: 106-107 DEG C；1h-nmr(δ,cdcl3): 8.42 (d, 1h, j=8.5hz, arh), 8.34 (d, 2h, j=8.5hz, arh), 7.67 (d, 1h, j=8.5hz, arh), 7.58 (t, 1h, j=7.5hz,), arh 7.46 (t, 1h, j=7.5hz, arh), 7.39 (d, 2h, j=8.5hz, arh), 4.77 (t, 2h, j=7.0hz, ch2), 3.57 (t, 2h, j=6.0hz, ch2),2.57-2.52(m,2h,ch2).
The step 2. 5- (preparation of 1- (3- (1-4- methyl piperazine-propyl group) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound v-1)
By compound 8 ' (80mg, 0.19mmol) it is dissolved in anhydrous acetonitrile (6ml), add triethylamine (96mg, 0.95mmol) and n- methyl piperazine (76mg, 0.76mmol), heating reflux reaction 24h, add water after being cooled to room temperature (10ml) reaction is quenched, crude product with ethyl acetate (50ml) extract, wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with dichloromethane: ethyl acetate: methanol (3:3:1) eluting, obtain faint yellow solid 48mg, yield 52%；Fusing point: 89-90 DEG C；1h-nmr(δ,cdcl3): 8.30 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=8.5hz, arh), 7.65 (d, 1h, j=8.5hz, arh), 7.53 (t, 1h, j=8.0hz,), arh 7.43 (t, 1h, j=7.5hz, arh), 7.38 (d, 2h, j=8.0hz, arh), 4.66 (t, 2h, j=7.0hz, ch2), 2.36 (t, 2h, j=7.0hz, ch2),2.31(s,3h,ch3),2.24(m,2h,ch2),2.28-2.53(m,8h,4×ch2).
5- (the preparation of 1- (3- (1- morpholine propyl group) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound v-2)
Operating process, with the preparation of compound v-1, is simply replaced n- methyl piperazine with morpholino, is obtained pale yellow oil, yield 49%；1h-nmr(δ,cdcl3): 8.35 (d, 1h, j=8.5hz, arh), 8.33 (d, 2h, j=9.0hz, arh), 7.97 (d, 1h, j=8.5hz, arh), (7.59-7.64 m, 3h, arh), 7.49 (t, 1h, j=7.5hz, arh), 4.68 (t, 2h, j=6.5hz, ch2), 3.50 (t, 4h, j=4.0hz, 2 × ch2),2.24-2.27(m,6h,3×ch2),2.08-2.13(m,2h,ch2).
5- (the preparation of 1- (3- (1-4- hydroxy piperidine-propyl group) -1h-3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole (compound v-3)
Operating process, with the preparation of compound v-1, simply replaces n- methyl piperazine with 4- hydroxy piperidine, obtains white solid, yield 58%；Fusing point: 73-74 DEG C；1h-nmr(δ,cdcl3): 8.39 (d, 1h, j=8.0hz, arh), 8.33 (d, 2h, j=9.0hz, arh), 7.66 (d, 1h, j=8.5hz, arh), 7.53 (t, 1h, j=7.5hz,), arh 7.42 (t, 1h, j=7.0hz, arh), 7.37 (d, 2h, j=8.0hz, arh), 4.65 (t, 2h, j=6.5hz, ch2),3.70(m,1h,och),2.71-2.69(m,2h,ch2),2.33-2.30(m,2h,piperidine),2.22-2.20(m,2h,ch2),2.09(brs,2h,piperidine),1.91-(m,2h,piperidine),1.61-1.55(m,2h,piperidine).
The preparation of embodiment 10:2- (1- (4- chlorobenzyl) -1h- indazole -3- base) -5- (pyridin-4-yl) -1,3,4- diazole (compound vi-1)
The preparation of step 1. 1- (4- chlorobenzyl) -1h- indazole -3- formylhydrazine (compound 9 ')
By 1- (4- chlorobenzyl) -1h- indazole -3- carboxylic acid (compound 6 ') (0.30g, 1.1mmol) and hydrazine hydrate (80%) (5ml) be added in reaction bulb, it is heated to reflux 2h, white crystal is separated out after being cooled to room temperature, sucking filtration, washing obtains white solid 0.24g, yield 75.0%；Fusing point: 160-161 DEG C；1h-nmr(δ,dmso-d6): 9.92 (s, 1h, conh), 7.73 (d, 1h, j=8.5hz, arh), 7.69 (d, 1h, j=8.5hz, arh), 7.39 (d, 1h, j=8.5hz, arh), 7.33-7.28 (m, 3h,), arh 7.21 (t, 1h, j=8.5hz,), arh 5.89 (s, 2h, benzylic-ch2),4.72(s,2h,nhnh2).
The preparation of step 2. 2- (1- (4- chlorobenzyl) -1h- indazole -3- base) -5- (pyridin-4-yl) -1,3,4- diazole (compound vi-1)
By 1- (4- chlorobenzyl) -1h- indazole -3- formylhydrazine (compound 9 ') (110mg, 0.37mmol) .gamma.-pyridinecarboxylic acid (45mg, 0.37mmol), diisopropyl ethylenediamine (0.19ml, 1.10mmol) with o- BTA-n, n, n', n'- tetramethylurea Tetrafluoroboric acid (tbtu) (130mg, 0.40mmol) it is dissolved in anhydrous acetonitrile (5ml), 3h is stirred at room temperature.Diisopropyl ethylenediamine (0.13ml is added in reaction system, 0.73mmol) with paratoluensulfonyl chloride (210mg, 1.20mmol) continue 2h is stirred at room temperature, removal of solvent under reduced pressure, crude product is extracted with ethyl acetate (50ml), wash successively, saturation nacl is washed, anhydrous na2so4It is dried, through silica gel column chromatography purification after concentration, with petroleum ether: ethyl acetate (1:1) eluting, obtain pale white solid 82mg, yield 57%；Fusing point: 232-233 DEG C；1h-nmr(δ,cdcl3): 8.87 (d, 2h, j=5.5hz, arh), 8.32 (d, 1h, j=8.0hz, arh), 8.01 (d, 2h, j=5.0hz, arh), 7.96 (d, 1h, j=8.5hz, arh), 7.61 (t, 1h, j=8.0hz, arh), 7.47 (t, 1h, j=7.5hz, arh), 7.42 (d, 2h, j=8.0hz, arh), 7.34 (d, 2h, j=8.5hz, arh), 5.90 (s, 2h, benzylic-ch2).
Embodiment 11: the inhibitory action to external hif-1 transcriptional activity for the indazole-diazole analog derivative
1. experimental technique
Using the hif-1 transcriptional activity inhibitory action to human colon cancer cell hct116 for the luciferase reporter gene measuring compound.The human colon cancer cell hct116 of trophophase of taking the logarithm is inoculated in 60mm plastic culture dish, after cell attachment, using lipo2000 transfection reagent, to hct116 cell transfecting pcdna3.1-hre-luciferase plasmid.After continuing culture 48 hours, give the nutrient chemical (the final concentration of 400ug/ml of g418) containing g418 and screen 14 days, obtain the hct116 cell strain stably expressing hre-luciferase.The hct116 cell taking this stable transfection is inoculated in 96 orifice plates, and every hole cell number controls at 6000 about, after cell attachment, gives the testing compound of gradient concentration.After 96 orifice plates are cultivated 1 hour in normal oxygen environment, put into rapidly in the cell culture incubator containing 1% oxygen, normal oxygen matched group is then still positioned in normal oxygen cell culture incubator.After continuation acts on 24 hours, method according to reagent description detects the data of each hole luciferase, and calculates suppression ratio and corresponding ic according to computing formula (suppression ratio %=(values of control groups-experimental group numerical value)/values of control groups * 100%)50Value.
2. experimental result
Concrete outcome is shown in Table 1.
The hif-1 transcriptional activity inhibitory action to human colon cancer cell hct116 for table 1 part of compounds
3. experimental result and analysis
Through test of many times checking, compound synthesized by the present invention all has the inhibitory action of hif-1, wherein most compound shows the external hif-1 Transcription inhibition effect similar or more excellent to positive control yc-1, especially compound i-30 and i-32, half suppression ratio is respectively less than 1.00 μm, activity improves 8 times about than yc-1, is effective hif-1 inhibitor (referring to table 1).
Embodiment 12: indazole-diazole analog derivative i-30, i-32 inhibitory action to internal hif-1 transcriptional activity
1. experimental technique
The hct116 colon cancer cell line surely having been turned luciferase reporter gene (hre-luciferase) is injected in 20 nude mices, when tumor size reaches 200mm3Afterwards, mice is divided into four groups, respectively matched group, i-30 medication group, i-32 medication group and yc-1 medication group, continuous medication for three days, once a day, dosage is 50mg/kg.After medication three days, show the matched group and medication group inhibition to internal hif-1 using xenogen imaging system.Using the release strength of computed in software cold light, and matched group and the intensity rate of experimental group, average and mapped.(zoopery is ratified through zooscopy committee of Zhejiang University, numbering zju2013101032)
2. experimental result and analysis
The b chart of Fig. 1 is bright, and compound i-30, i-32 and yc-1 all can significantly reduce the luminescent intensity of fluorescein in mice body, illustrates that test-compound also can suppress the activity of hif-1 in transplanted tumor；The c chart of Fig. 1 is bright, and the inhibition of compound i-30, i-32 is better than positive control yc-1, illustrates that test-compound can effectively suppress the hif-1 transcriptional activity in mice body, is potent hif-1 inhibitor.

Claims (10)

1. a kind of indazole-diazole analog derivative, has a formula a structure:
Or its pharmaceutically acceptable salt or solvate, in formula:
X is o or n, and y is n, and z is n or o；
r1Selected from-(ch2)m-n(r3r4), benzoyl, aniline formoxyl, benzenesulfonyl, r5The benzyl replacing, m represents the integer of 2-8；Wherein, r5Selected from hydrogen, halogen, nitro, c1-6Alkyl, c1-6Alkoxyl, co-nr3r4、o(ch2)n-nr3r4, n represents the integer of 2-6；-nr3r4For amine；
r2Selected from unsubstituted or by r6The aryl of replacement, heterocyclic aryl, benzyl；Wherein r6Selected from halogen, c1-6Alkyl, c1-6Alkoxyl, trifluoromethoxy, trifluoromethyl, dimethylamino；
Halogen represents fluorine, chlorine, bromine or iodine.
2. indazole according to claim 1-diazoles compound it is characterised in that: described r2Selected from unsubstituted or by r6The phenyl of replacement, furyl, thienyl, pyridine radicals, benzyl.
3. indazole according to claim 1-diazoles compound it is characterised in that: described-nr3r4Selected from arylamine, heterocyclic aryl amine, fatty amine, nitrogen heterocyclic ring fatty amine.
4. indazole according to claim 3-diazoles compound it is characterised in that: described-nr3r4Selected from five yuan or hexa-atomic arylamine, the five-ring heterocycles arylamine comprising o, n or s atom, the hexa-member heterocycle arylamine comprising o, n or s atom, the fatty amine of 1-6 carbon atom length, 3-6 member heterocyclic ring containing nitrogen fatty amine.
5. the indazole according to any one of claim 1-4-diazoles compound it is characterised in that: described r1For r5The benzyl replacing, wherein, r5O (the ch replacing for optional position on the phenyl ring of benzyl2)n-nr3r4, r2For r6The phenyl replacing.
6. compound according to claim 1 is it is characterised in that described compound is selected from:
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- methoxyphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- trifluoromethyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- chlorphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (pyridin-4-yl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- phenyl -1,2,4- diazole；
3- (4- chlorobenzyl) -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole；
3- benzyl -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole；
3- (4- tert-butyl-phenyl) -5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole；
2- (5- (1- (4- chlorobenzyl)-1h- 3- indazolyl) -3-1,2,4- di azoly) ethyl acetate；
5- (1- (4- chlorobenzyl) -1h- 3- indazolyl) -3- (2- methoxyphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl)-1h- indazole -3- base) -3- (2- chlorphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (4- dimethylamino phenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (thiophene -2- base) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (furan -2- base) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3- methoxyphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3- chlorphenyl) -1,2,4- diazole；
5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -3- (3,4,5- trimethoxyphenyl) -1,2,4- diazole；
2- (5- (1- (4- chlorobenzyl) -1h- indazole -3- base) -1,2,4- diazole -3- base) ethanol；
5- (1- (4- luorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (4- nitrobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- luorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (4- methoxy-benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (2,6- difluorobenzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (pyridine -2 ylmethyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (pyridin-4-yl methyl)-1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole
5- (1- (4- methyl-benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
N- (4- chlorphenyl) -3- (3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- carboxylic acid amides；
(3- (3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- base) (4- chlorphenyl) ketone；
5- (1- p-toluenesulfonyl -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (1-4- methyl piperazine-propyl group) -1h- 3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (1- morpholine propyl group) -1h- 3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (1-4- hydroxy piperidine-propyl group) -1h- 3- indazolyl) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
Morpholine -3- (3- (5- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole) -1h-Indazole methyl) benzophenone；
(4- methylpiperazine-1-yl) (3- (3- (3- (4- Trifluoromethoxyphen-l)) -1,2,4- diazole -5- base) -1h-Indazole -1- base) methyl) benzophenone；
5- (1- (3- (2 (4- methylpiperazine-1-yl) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (2 (morpholine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
5- (1- (3- (2 (4- hydroxy piperidine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
N- (Cvclopropvlmethvl) -2-(3-((3-(4- Trifluoromethoxyphen-l) -1,2,4- diazole -5- base) -1h- indazole -1- base) methyl) phenoxy group) ethamine；
5- (1- (4- (2 (4- hydroxy piperidine -1- base) ethyoxyl) benzyl) -1h- indazole -3- base) -3- (4- Trifluoromethoxyphen-l) -1,2,4- diazole；
2- (1- (4- chlorobenzyl) -1h- indazole -3- base) -5- (pyridin-4-yl) -1,3,4- diazole
Or its above-claimed cpd pharmaceutically acceptable salt or solvate.
7. a kind of pharmaceutical composition, it is characterized in that, described pharmaceutical composition comprises at least one active component and at least one pharmaceutically acceptable carrier or excipient, described active component be selected from compound described in any one of claim 1-6, described compound pharmaceutically acceptable salt, in the solvate of described compound any one or arbitrarily multiple.
8. pharmaceutically acceptable salt, the solvate of described compound and other drugs are used in combination the purposes in preparing antitumor drug for the compound described in any one of claim 1-6, described compound.
9. purposes in preparing antitumor drug for the pharmaceutical composition described in claim 7.
10. purposes according to claim 8 or claim 9 is it is characterised in that described tumor is selected from breast carcinoma, sarcoma, pulmonary carcinoma, carcinoma of prostate, colon and rectum carcinoma, renal carcinoma, cancer of pancreas, neuroblastoma, glioma, head cancer, neck cancer, thyroid carcinoma, hepatocarcinoma, ovarian cancer, carcinoma vulvae, cervical cancer, carcinoma of endometrium, carcinoma of testis, bladder cancer, the esophageal carcinoma, gastric cancer, nasopharyngeal carcinoma, carcinoma of buccal mucosa, oral cancer, gastrointestinal stromal tumor, skin carcinoma, multiple myeloma.
CN201510443488.XA 2015-07-24 2015-07-24 Indazole-oxadiazole derivative, medicinal composition containing derivative, and application of derivative in tumor prevention Pending CN106366078A (en)

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