CN106146474A - Thiocarbamoyl imidazole diketone and Imidazole diketone compound and application thereof - Google Patents
Thiocarbamoyl imidazole diketone and Imidazole diketone compound and application thereof Download PDFInfo
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- CN106146474A CN106146474A CN201510201561.2A CN201510201561A CN106146474A CN 106146474 A CN106146474 A CN 106146474A CN 201510201561 A CN201510201561 A CN 201510201561A CN 106146474 A CN106146474 A CN 106146474A
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- 0 *CC(*I)(C(N(*)C1*)=O)N1C1=CC(*N(*)C2=O)C2=C1 Chemical compound *CC(*I)(C(N(*)C1*)=O)N1C1=CC(*N(*)C2=O)C2=C1 0.000 description 8
- ILHVNGDVXBBWQZ-UHFFFAOYSA-N CC(C)(C(N(C1=S)C(CC(C(F)(F)F)C=C2)=C2OC)=O)N1c1cc(F)c(CC(CC2(C)N=CC=CN2)C2=O)c2c1 Chemical compound CC(C)(C(N(C1=S)C(CC(C(F)(F)F)C=C2)=C2OC)=O)N1c1cc(F)c(CC(CC2(C)N=CC=CN2)C2=O)c2c1 ILHVNGDVXBBWQZ-UHFFFAOYSA-N 0.000 description 1
- AEIQGWTXHVAHHC-UHFFFAOYSA-N CC(C)(C(N(C1=S)c(cc2C(F)(F)F)ccc2C#N)=O)N1c1cc(C(N(C2)c3c(C)[o]nc3C)=O)c2c(F)c1 Chemical compound CC(C)(C(N(C1=S)c(cc2C(F)(F)F)ccc2C#N)=O)N1c1cc(C(N(C2)c3c(C)[o]nc3C)=O)c2c(F)c1 AEIQGWTXHVAHHC-UHFFFAOYSA-N 0.000 description 1
- NZABADQYOAUQQI-UHFFFAOYSA-N CC(C)(C(N(C1=S)c(cc2C)ccc2C#N)=O)N1c1cc(C(NCC2)=O)c2cc1F Chemical compound CC(C)(C(N(C1=S)c(cc2C)ccc2C#N)=O)N1c1cc(C(NCC2)=O)c2cc1F NZABADQYOAUQQI-UHFFFAOYSA-N 0.000 description 1
- OKUGOSHRNWAANB-UHFFFAOYSA-N C[IH]CC1C[IH]CC1 Chemical compound C[IH]CC1C[IH]CC1 OKUGOSHRNWAANB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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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
- C07D413/14—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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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
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
Thiocarbamoyl imidazole diketone and Imidazole diketone compound and application thereof.The invention provides formula (I) compound or pharmaceutically acceptable salt thereof, solvate, prodrug, stereoisomer, tautomer, metabolite, wherein X, Y, Z, R1、R2、R3, A as defined herein.Present invention also offers the method preparing described compound, and described compound is as androgen receptor antagonists, in the disease that treatment androgen receptor is relevant, as bad in carcinoma of prostate, prostate hyperplasia, acne, alopecia, hair hypertrophy, breast carcinoma, male's sexual etc. in purposes.
Description
Technical field
The present invention relates to a class thiocarbamoyl imidazole diketone and imidazole diketone, its synthetic method and be used to treat the disease that androgen receptor is relevant
Or imbalance.
Background technology
Carcinoma of prostate has become the important diseases threatening men's health.In North America and Europe, carcinoma of prostate is the male tumor that sickness rate is the highest, dead
Rate is only second to pulmonary carcinoma.In China, the annual sickness rate of carcinoma of prostate is also increasing with the speed of about 10%.The growth of tumor of prostate is the most complete
Relying on androgen receptor (AR) approach, androgen receptor plays the target spot of biological effect as androgen, it has also become biomedical sector research
Focus.
Androgen receptor (AR) belongs to nuclear receptor family, comprises 918 amino acid residues, thus 3 important domains of composition, is respectively
DNA binding domain, ligand binding domain and nitrogen end binding domain.Between DNA binding domain and ligand binding domain, also have a nuclear localization signal, be positioned at
Between DNA binding domain and hinge, in androgen receptor and DNA cohesive process, play vital effect.Under normal circumstances, non-activated
AR is positioned at Cytoplasm, with heat shock protein 90 and some other protein binding, after AR is combined with endogenous androgens dihydrotestosterone, AR
Ligand binding domain conformation change, separate with the associated proteins such as heat shock protein 90, AR forms the dimer of activation and is situated between by nuclear localization signal
Lead in entrance nucleus, identify the androgen response element on corresponding DNA promoter sequence, and in connection, raise other coactivators altogether
Transcribing of coactivation AR target gene.To the growth of cell, breed, break up the corresponding biological effect of generation.AR carcinoma of prostate, comedo,
The disease that the androgens such as alopecia, benign prostate enlargement are correlated with plays a significant role.
Traditional AR receptor antagonist, such as bicalutamide, Drogenil, nilutamide etc., with dihydrotestosterone competition binding androgen receptor-part
Calmodulin binding domain CaM, but easily undergo mutation in this region, the androgen receptor of sudden change still can be combined with the coactivator of trace after being combined with traditional antagonist,
Not only causing antagonist to lose antagonism, but also make it produce agonist activity, this is the main cause that castration-resistant prostate cancer occurs.Newly
Type competitiveness androgen receptor antagonists, Shandong as miscellaneous in grace amine and ARN-509, androgen receptor is Dimerized makes it cannot shift in nucleus in suppression
And be combined with target gene, cause target gene to transcribe.And novel competitive androgen receptor antagonists generally parent to the androgen receptor of sudden change
Higher with property so that receptor can not be combined with coactivator, so, can be used for the treatment of castration-resistant prostate cancer.Grace miscellaneous Shandong amine is in 2012
Year is by FDA approval treatment carcinoma of prostate.But grace miscellaneous Shandong amine has some neurotoxicityes, such as epilepsy, accordingly, it would be desirable to exploitation is more safe and effective
Androgen receptor antagonists.
Summary of the invention
It is an object of the invention to provide a class thiocarbamoyl imidazole diketone and imidazole cyclohexadione compounds, its pharmaceutically acceptable salt, hydrate,
Solvate or stereoisomer are as novel androgen receptor antagonists.
It is a further object to provide the compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer
Pharmaceutical composition.
A further object of the present invention is to provide the compounds of this invention application in the medicine preparing the disease relevant to estrogen receptor activity.
Further aim of the present invention is to provide the compound of a kind of present invention, its pharmaceutically acceptable salt, hydrate, solvate or vertical
Body isomer, or the method that a combination thereof thing treats the disease relevant to estrogen receptor activity.
Compound, its pharmaceutically acceptable salt, hydrate, solvate or the stereoisomer that a kind of formula (I) of one aspect of the present invention offer represents:
Wherein,
X is for being substituted or unsubstituted aryl, heteroaryl；
R1And R2It is each independently hydrogen, any substituted C1-6Alkyl；
Or R1、R2And form 3-7 unit cycloalkyl, 4-6 unit Heterocyclylalkyl, wherein cycloalkyl and Heterocyclylalkyl together with the carbon atom being connected with them
Can be optionally substituted；
R3For being substituted or unsubstituted heteroaryl；
A is for being substituted or unsubstituted aromatic ring, hetero-aromatic ring；
Y is O or S；
Z is for being substituted or unsubstituted-(CH2)m-、-O-(CH2)n-、-CO-、-S-(CH2)n-、-SO-、-SO2-、-NH-(CH2)n-,-NH-CO-,
Wherein m is 0,1,2,3；N is 0,1,2.
In a kind of embodiment of the compounds of this invention, X is 6-10 unit aryl, 5-6 unit heteroaryl, described aryl and heteroaryl optionally by 1 to
5 R4Replace, wherein, each R4Separately selected from hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, carboxyl, sulfydryl, fluoroform
Base, difluoromethyl, trifluoromethoxy, difluoro-methoxy ,-NR5R6；Or
Each R4Separately selected from substituted or unsubstituted alkyl, acyl group, Thioacyl, amide groups, ester group, sulfonyl, sulfinyl,
Cycloalkyl, Heterocyclylalkyl, thiazolinyl, alkynyl, alkoxyl, alkenyloxy group；
Each R5And R6Separately selected from hydrogen, C1-6Alkyl, 3-8 unit cycloalkyl, 3-6 unit Heterocyclylalkyl, phenyl, 5-6 unit heteroaryl；Wherein
Alkyl, cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl can by one or more selected from halogen, amino, hydroxyl, nitro, cyano group, trifluoromethyl,
C1-4Alkyl, C1-4Alkoxyl, C1-4The substituent group of alkyl amino replaces.
In a such embodiment of class, X is phenyl, 5-6 unit heteroaryl, described phenyl and heteroaryl optionally by 1 to 5 independently selected from
Hydrogen, halogen, cyano group, trifluoromethyl, nitro, acetyl group ,-NR5R6、C1-6Alkyl, amide groups, mesyl, C1-6The replacement of alkoxyl
Base replaces, wherein, and R5And R6As defined in claim 2；
In another kind of such embodiment, X is can be by 1-3 R7Substituted phenyl, wherein, each R7Separately selected from hydrogen, halogen,
Nitro, cyano group, trifluoromethyl, acetyl group, C1-4Alkyl, C1-4Alkoxyl, dimethyl amido, sulfonyl, amide groups.
In the second embodiment of the present invention, R1And R2It is each independently hydrogen, C1-4Alkyl；Wherein alkyl optionally by 1 to 5 selected from hydrogen,
Fluorine, chlorine, bromine, iodine, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, the substituent group of difluoro-methoxy replace；
Or R1、R2And form 3-6 unit cycloalkyl, 5-6 unit Heterocyclylalkyl together with the carbon atom being connected with them.
In a such embodiment of class, R1And R2It is each independently hydrogen, methyl ,-CH2F；
Or R1、R2And form cyclopropane, Tetramethylene., Pentamethylene., hexamethylene, oxetanes, oxa-together with the carbon atom being connected with them
Pentamethylene., oxinane, azetidine, aza-cyclopentane, piperidine.
In another kind of such embodiment, R1And R2For methyl；
Or R1、R2And form Tetramethylene. together with the carbon atom being connected with them.
In the third embodiment of the present invention, A is phenyl ring, hetero-aromatic ring, and described phenyl ring and hetero-aromatic ring are not necessarily by 1 to 3 R8Replace,
The most each R8Separately selected from hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, carboxyl, sulfydryl, trifluoromethyl ,-NR5R6, or
Person
Each R8Separately selected from substituted or unsubstituted alkyl, amide groups, ester group, sulfonyl, sulfinyl, thiazolinyl, alkynyl, alcoxyl
Base；
R5And R6As defined in claim 2.
In a such embodiment of class, A is phenyl ring, R8As defined in claim 8.
In another kind of such embodiment, R8Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, fluoromethylene, trifluoromethyl, first
Epoxide, nitro.
In the 4th kind of embodiment of the present invention, Z is for being substituted or unsubstituted-(CH2) m-,-CO-,-NH-CO-, wherein m is 0,1,2.
In a such embodiment of class, Z is-(CH2)m-, the most each-CH2-can optionally be selected from hydrogen, halogen, hydroxyl, nitro, trifluoro
Methyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy ,-NR5R6, cyano group, carboxyl, C1-6Alkyl, C1-6Alkoxyl, C1-6Thiazolinyl, C1-6
Alkynyl, acyl group, ester group, amide groups, the substituent group of sulfonyl replace, wherein alkyl, thiazolinyl, alkynyl, acyl group, ester group, amide groups, sulphonyl
Base can be selected from hydrogen, halogen, C1-4The substituent group of alkyl replaces；Wherein, R5And R6As defined in claim 2；
M is 1,2.
In another kind of such embodiment, Z is selected from-CH2-、-CH2-CH2-、-CH(CH3The most each-the CH of)-,2-or-CH-can be selected
Replace from the substituent group of hydrogen, nitro, methyl, methoxyl group, trifluoromethyl, dimethylamino, cyano group.
In the 5th kind of embodiment of the present invention, R3For heteroaryl, described heteroaryl can be by 1 to 4 R9Replace, wherein, each R9Independently
Selected from hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, carboxyl, sulfydryl, trifluoromethyl ,-NR5R6, wherein, R5And R6As right is wanted
Ask defined in 2；Or
Each R9Independently selected from substituted or unsubstituted alkyl, acyl group, amide groups, ester group, sulfonyl, sulfinyl, thiazolinyl, alkynyl, alkane
Epoxide, alkenyloxy group.
In a such embodiment of class, R3Selected from furan, pyrroles, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazoles, triazole, four
Azoles, imidazoles, azoles, isoxazole, diazole, triazole, diazole, pyrazine, pyridazine, triazine, thiadiazoles, indole, quinoline, isoquinolin
And benzothiophene, and R3The substituent group being optionally independently selected from R9 by 1 to 4 replaces；Wherein
R9Selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, cyano group, nitro, carboxyl, trifluoromethyl ,-NR5R6、C1-6Alkyl, C1-6Alkoxyl,
Acyl group, ester group and amide groups, wherein said alkyl, alkoxyl, acyl group, ester group and amide groups optionally by one or more be independently selected from fluorine, chlorine,
Bromine, iodine, C1-4Alkyl and C6-8The substituent group of aryl is replaced；
R5And R6As defined in claim 2.
The typical compound of the present invention includes, but are not limited to:
The invention provides a kind of medicine, wherein contain compound, its pharmaceutically useful salt, its prodrug or its solvate described herein
As effective ingredient.
The invention provides a kind of pharmaceutical composition, wherein contain compound described herein, its pharmaceutically useful salt, its prodrug or it is molten
Agent compound is as effective ingredient.
The invention provides compound, its pharmaceutically useful salt, its prodrug, its solvate or a combination thereof thing described herein treatment with
Application in estrogen receptor activity relevant disease.
The disease that present invention androgen receptor described herein is relevant is carcinoma of prostate, prostate hyperplasia, acne, alopecia, hair hypertrophy, breast
Adenocarcinoma, male's sexual are bad.
Summary of the invention
The present invention includes isotope-labeled compound, and they are equal to those described by formula (I), but one or more atom by atomic mass or
Mass number is different from the atom of the common atomic mass of nature or mass number and is replaced.The isotopic example bag in the compounds of this invention can be introduced
Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O,
31P, 32P, 35S, 18F and 36Cl.Other isotopic the compounds of this invention containing above-mentioned isotope and/or other atom, its prodrug
The scope of the present invention is broadly fallen into the pharmaceutically acceptable salt of described compound or described prodrug.Some isotope-labeled chemical combination of the present invention
Thing, such as introduce radiosiotope (such as 3H and 14C) can be used for medicine and/or substrate tissue measure of spread.Tritium, i.e. 3H and carbon
-14, i.e., 14C isotope is particularly preferred, because they easily preparation and detections.And then, replaced by heavier isotope, such as deuterium, i.e.
2H, due to the higher benefit that can provide in treatment of metabolic stability, such as, extends Half-life in vivo or reduces volume requirements, thus in some situation
Under be probably preferably.Isotope-labeled formula (I) compound of the present invention and prodrug thereof typically can be prepared, carry out following flow process and
/ or embodiment with technique disclosed in preparation example time, replace nonisotopically labelled reagent with the isotope-labeled reagent being readily obtained.
Formula (I) compound can generate pharmaceutically acceptable preparation further, comprises the salt of formula (I) compound, solvate, salt include but
It is not limited to acid-addition salts and/or alkali salt.
The present invention also comprises formula (I) compound of therapeutically effective amount or its most acceptable salt and its pharmaceutically acceptable carrier, diluent
Or excipient.All these forms broadly falls into the present invention.
Following definition used herein is applicable.
" alkyl " refers to a group and the alkyl of other groups such as halogen substiuted and the construction unit of alkoxyl in the present invention, it is possible to make straight
Chain or side chain.Including straight chained alkyl such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, 11
Alkyl, dodecyl etc..This term also includes the branched chain isomer of straight chained alkyl, includes but not limited to group such as below :-CH (CH3)2、
-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、
-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)-CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、
-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、
-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3) etc..Therefore,
Term alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.Preferably alkyl includes C1-12Straight chained alkyl and C3-10Branched alkyl.
Term " thiazolinyl " refers to that two of which adjacent carbon atom is by doubly linked alkyl as defined above.
Term " alkynyl " refers to that two of which adjacent carbon atom is by three bonded alkyl as defined above.
Term " halogen " refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine.
Term " alkoxyl " refers to (alkyl) O-group, and wherein alkyl is defined herein.
Term " alkenyloxy group " refers to (thiazolinyl) O-group, and wherein thiazolinyl is defined herein.
Term " aryl " refers to that the wherein looped each atom of shape is the aromatic ring of carbon atom.Aryl rings can by five, six, seven, eight
Individual, nine or the carbon atoms formation more than nine.Aromatic yl group can be optionally substituted.The example of aromatic yl group include but not limited to phenyl, naphthyl,
Phenanthryl, anthryl, fluorenyl and indenyl.
Term " heteroaryl " refers to comprise 1 to 5 hetero atom, the heteroaromatic system of 5 to 14 annular atomses, wherein hetero atom include O, S and
N.In some instances, the monocycle that heteroaryl can include with one or more aromatic carbocyclic, non-aromatic carbocycle or non-aromatic cycloheteroalkyl condense is miscellaneous
Aryl.Heteroaryl can be covalently bound with defined chemical constitution in any heteroatom producing rock-steady structure or carbon atom.In heteroaryl one
Individual or multiple N or S atom can oxidized (such as pyridine N-oxides, thiophene S-oxide, thiophene S, S-dioxide).The reality of this heteroaryl
Example include furyl, pyrrole radicals, pyridine radicals, thienyl, pyrimidine radicals, pyridazinyl, triazolyl, pyrazinyl, tetrazole radical, pyrazolyl, imidazole radicals,
Thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, di azoly, indyl, isoindolyl, benzothienyl, benzo furan
Mutter base, 2,3-dihydro benzo furyl, 1,4-benzodioxane base, quinolyl, isoquinolyl, 2-methylquinoline base, quinazolyl, quinoxalinyl,
Benzotriazole base, benzothiazolyl, benzimidazolyl, benzisothia oxazolyl, benzisoxa oxazolyl, benzisoxa oxazolyl, benzodiazole base,
Cinnolines base, 1H-indyl, 2H-indyl, indolizine base, isobenzofuran-base, naphthyridinyl, phthalazinyl, pteridyl, purine radicals, azoles pyrrole
Piperidinyl, thiazolopyridinyl, imidazopyridyl, furopyridyl, thienopyridine base, Pyridopyrimidine base, pyrido-pyrazine base, pyrrole
Pyridine pyridazinyl, thieno thiazolyl, thieno oxazolyl, Thienoimidazole base, tetrahydric quinoline group, benzothiophene pyridine radicals, benzofuran
And pyridine radicals, 4,5,6,7-tetrahydro indole base etc..According to structure, heteroaryl groups can be single free radical or diradical (that is, heteroarylidene base
Group).
Term " cycloalkyl " refers to monocycle or multi-ring free radical, and it contains only carbon and hydrogen, and is optionally saturated, and part is undersaturated
Or it is the most undersaturated.Group of naphthene base includes the group with 3 to 10 annular atomses.The illustrative example of group of naphthene base includes following portion
Point:
According to structure, group of naphthene base is single free radical or diradical (such as, ring alkylidene group).
Term " Heterocyclylalkyl " refers to an at least hetero atom selected from O, N and S and optionally the most non-aromatic containing one or more double or triple bonds
Cycloalkyl.Cycloheteroalkyl can have 3-14 annular atoms as entirety and (such as have for monocyclic heterocycloalkyl containing 1-5 hetero atom
3-6 annular atoms, has 7-14 annular atoms for multi-ring Heterocyclylalkyl).Heterocyclylalkyl can produce rock-steady structure any heteroatom or
On carbon atom covalently bound with defined chemical constitution.One or more N or S atom on Heterocyclylalkyl can oxidized (such as morpholine N-
Oxide, tetrahydro-1,4-thiazine S-oxide, tetrahydro-1,4-thiazine S, S-dioxide).Heterocyclylalkyl can also contain one or more oxo groups, such as adjacent benzene
Two acyliminos, piperidone base, oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidine radicals, pyridine-2 (1H)-one base etc..The reality of Heterocyclylalkyl
Example also include morpholinyl, tetrahydro-1,4-thiazine base, pyranose, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,
Pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-thiazoles base, hexahydroisoindoline base, piperidyl, azetidine, piperazinyl etc..
Term " acyl group " represents Alkyl-CO-group, and wherein this alkyl is as described herein.Exemplary acyl includes acetyl group, benzoyl etc..
Term " Thioacyl " represents alkyl-CS-group, and wherein this alkyl is as described herein.
Term " aryl alkyl " expression aryl-alkyl-, wherein aryl and moieties are described above.Exemplary arylalkyl groups includes benzyl, benzene second
Base, menaphthyl etc..
Term " hydroxyl " refers to group-OH.Term " sulfydryl " refers to group-SH.
Term " amino " refers to group-NH2。
Term " cyano group " refers to group-CN.
Term " nitro " refers to group-NO2.Term " nitroso-group " refers to group-NO.
Term " trifluoromethyl " refers to group-CF3.Term " difluoromethyl " refers to group-CHF2.Term " trifluoromethoxy " refers to group-O-CF3。
Term " difluoro-methoxy " refers to group-O-CHF2。
Term " carboxyl " refers to-C (=O)-OH.
Term " ester group " refer to R-O-C (O)-, wherein R be selected from alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, Heterocyclylalkyl.
The groups such as wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, Heterocyclylalkyl are as defined herein.
Term " amide groups " refers to group-C (O)-NRR ', wherein R and R ' be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl,
Aryl, heteroaryl, Heterocyclylalkyl.The groups such as wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl, Heterocyclylalkyl are as herein
Defined in.
Term " sulfonyl " refers to group-S (O)2-R, wherein R selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl,
Heterocyclylalkyl ,-NR ' R ", wherein said R ' and R " separately selected from hydrogen, hydroxyl, amino, substituted or unsubstituted alkyl, miscellaneous
Cycloalkyl, aryl, heteroaryl, thiazolinyl, alkynyl or cycloalkyl.Wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl,
The groups such as Heterocyclylalkyl are as defined herein.
Term " sulfinyl " refers to group-S (O)-R, and wherein R is selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl
Base, Heterocyclylalkyl ,-NR ' R ", wherein said R ' and R " separately selected from hydrogen, hydroxyl, amino, substituted or unsubstituted alkyl,
Heterocyclylalkyl, aryl, heteroaryl, thiazolinyl, alkynyl or cycloalkyl.Wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl,
The groups such as Heterocyclylalkyl are as defined herein.
The compounds of this invention can also be administered with the form of pharmaceutically acceptable salt.Term " pharmaceutically acceptable salt " refers to by pharmaceutically acceptable nothing
Poison alkali or the standby salt of processed with acid, described alkali or acid include inorganic or organic base and inorganic or organic acid.It is included in term " pharmaceutically acceptable salt "
Alkali compounds refers to the nontoxic salts of the usual the compounds of this invention by making free alkali be prepared with the most organic or inorganic acid reaction.
Detailed description of the invention
Formula (I) compound can be prepared according to reaction scheme 1, and wherein each substituent group is as defined in summary of the invention, and X1 is halogen, as chlorine, bromine,
Iodine.
Scheme 1:
Formula (II) compound and the reaction of formula (III) compound can obtain formula (I) compound.This reaction is generally under the catalysis of copper or palladium catalyst
Carry out, such as CuI, CuCl, CuSCN, Cu2O、CuCl2、CuSO4·5H2O、CuO、Cu(OAc)2、Cu(acac)2、Pd2(dba)3、Pd(PPh3)4、
Pd(OAc)2、Pd(dppf)Cl2、Pd(PPh3)2Cl2、PdCl2Deng.Operational alkali has potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, uncle
Butanol potassium, sodium tert-butoxide, sodium phenate, sodium hydride, butyl lithium, tert-butyl lithium etc..Operational part have ethylenediamine, N-methyl ethylenediamine,
N, N '-dimethyl ethylenediamine, N, N-dimethyl-ethylenediamine, N, N, N', N'-tetramethylethylenediamine, cis-1,2-cyclohexanediamine, anti-form-1,2-cyclohexanediamine,
Trans-N, N'-dimethyl-1,2-cyclohexane diamine etc..Reaction is at suitable solvent, such as toluene, Isosorbide-5-Nitrae-dioxane, oxolane, N, N-dimethyl methyl
Amide, ethanol, isopropanol etc. are carried out.Reaction is about carried out at room temperature to 210 DEG C, preferably 80-110 DEG C.
Formula (II) compound can be prepared according to reaction scheme 2, and wherein each substituent group is as defined in summary of the invention.
Scheme 2:
Formula (II) compound can pass through formula (IV) compound and formula (V) compound in the presence of acid (example hydrochloric acid, acetic acid etc.), suitable molten
Agent (such as methanol, toluene, ethanol, N,N-dimethylformamide etc.) is reacted and synthesizes.Reaction about temperature at 50 DEG C to 180 DEG C is carried out,
Response speed and productivity can be improved in tube sealing.
Embodiment 1:
4-[3-(6-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene
Formonitrile HCN
Step 1: preparation 4-isothiocyano-2-trifluoromethylbenzonitrile
Thiophosgene (1.37ml, 17.97mmol) is joined in water (22ml), stir 8 minutes, then by 4-amino-2-trifluoromethylbenzonitrile
(2.23g, 11.98mmol) is slowly added in above-mentioned mixed liquor, and after finishing, room temperature continues stirring 1.5h.Thin layer chromatography monitoring reaction is complete,
Extract with dichloromethane, merge organic facies, wash with saturated common salt, filter, be concentrated under reduced pressure to give pale yellowish oil liquid 2.73g, yield 99%.1H NMR(400MHz,CDCl3): δ=7.86 (d, J=8.3Hz, 1H), 7.61 (d, J=1.4Hz, 1H), 7.51 (dd, J=8.3,1.7Hz,
1H)。
Step 2: preparation 2-bromo-4-fluorine-5-nitro benzoic acid
Under ice bath, fuming nitric aicd (4ml, 45.60mmol) is added drop-wise to 2-bromo-4-fluobenzoic acid (10g, 45.66mmol) and concentrated sulphuric acid (34ml)
Mixed solution in.Dripping after finishing, a large amount of white solid occur, move to room temperature and continue stirring 1h, thin layer chromatography monitors reaction completely, by reaction system
It is added dropwise in frozen water, quickly stirs 1h, solid is collected by filtration, wash with frozen water, be dried to obtain 10.40g white solid, yield 86%.
Step 3: preparation 2-bromo-4-fluorine-5-nitro benzoic acid methyl ester
Under ice bath, thionyl chloride (7.09ml, 97.62mmol) is added dropwise in absolute methanol (150ml), stirs 10 minutes, add 2-
Bromo-4-fluorine-5-nitro benzoic acid (10.40g, 39.39mmol), moves to react overnight in oil bath (70 DEG C).Thin layer chromatography monitoring reaction completely, will
Reactant liquor concentrating under reduced pressure, adds saturated sodium bicarbonate aqueous solution, extracts with dichloromethane, collects organic facies, washes with saturated common salt, anhydrous slufuric acid
Sodium is dried, and filters, is concentrated under reduced pressure to give white solid 9.90g, yield 90%.
Step 4: the preparation bromo-4-of 2-fluoro-5-Methyl anthranilate
By bromo-for 2-4-fluorine-5-nitro benzoic acid methyl ester (9.90g, 35.61mmol), reduced iron powder (9.97g, 178.05mmol) joins ethanol
(240ml), in the mixed solution of water (60ml) and glacial acetic acid (15ml), nitrogen is protected, and moves to reaction 1h, thin layer in oil bath (110 DEG C)
Chromatography monitoring reaction is completely.Cooling, adds saturated sodium bicarbonate aqueous solution and adjusts pH to alkalescence, and kieselguhr filters, washes with ethanol, and filtrate is dense
Contracting, adds saturated sodium bicarbonate aqueous solution, is extracted with ethyl acetate, and organic facies anhydrous sodium sulfate is dried, and filters, overstriking silica gel concentrating under reduced pressure,
Column chromatography (petroleum ether: ethyl acetate=5:1), collects and is concentrated to give white solid 7.70g, yield 87%.1H NMR(400MHz,CDCl3):δ
=7.33-7.28 (m, 2H), 3.91 (s, 3H), 3.88 (s, 2H).
Step 5: preparation 5-amino-2-cyano group-4-fluorophenyl carbamate
Bromo-for 2-4-fluoro-5-Methyl anthranilate (7.70g, 31.04mmol) and Cupricin. (4.17g, 46.56mmol) are joined anhydrous
In DMF, moving to reaction 15 minutes in oil bath (160 DEG C), thin layer chromatography monitoring reaction is completely.Cooling, adds ammonia (8ml) and acetic acid second
Ester stir, kieselguhr filter, ethyl acetate washing in filtrate without product, add water extraction, collect organic facies, wash with water to water without indigo plant
Till color, washing organic facies with saturated common salt, anhydrous sodium sulfate is dried, and filters, overstriking silica gel concentrating under reduced pressure, column chromatography (petroleum ether: acetic acid second
Ester=3:1), collect and be concentrated to give white solid 5.20g, yield 86%.1H NMR(400MHz,CDCl3): δ=7.51 (d, J=8.6Hz, 1H),
7.39 (d, J=10.5Hz, 1H), 4.40 (s, 2H), 3.99 (s, 3H).
Step 6: preparation 6-amino-5-fluorine-isoindoline-1-ketone
5-amino-2-cyano group-4-fluorophenyl carbamate (5.20g, 26.78mmol) and Raney's nickel (600mg) are joined methanol (100ml) and
In the mixed solution of water (30ml), under hydrogen balloon, move to reaction 8h in oil bath (50 DEG C).Thin layer chromatography monitoring reaction completely, cools down, diatom
Soil filters, and washes with methanol, concentrating under reduced pressure filtrate, and oil pump is drained, and obtains white solid 4.10g, yield 92%.1H NMR(400MHz,CD3COCD3):
δ=7.23 (d, J=8.0Hz, 1H), 7.02 (d, J=1.9Hz, 1H), 6.92 (dd, J=8.1,2.1Hz, 1H), 4.85 (s, 2H), 4.28 (s, 2H).
Step 7: preparation 2-(6-fluoro-3-oxoisoindoline diindyl-5-base amino)-2-methyl propionitrile
By 6-amino-5-fluorine-isoindoline-1-ketone (4.10g, 24.68mmol), third level natural division (10.81ml, 86.38mmol), acetone (30ml)
Join in tube sealing with glacial acetic acid (5ml), move to oil bath (90 DEG C) is reacted overnight.Thin layer chromatography monitoring reaction completely, cools down, concentrates,
Add ethyl acetate, cross filter solid, and be washed till white by ethyl acetate, drain and obtain white solid 5.10g, yield 89%.1H NMR(400MHz,
DMSO): δ=8.52 (s, 1H), 7.41 (d, J=10.9Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 5.92 (s, 1H), 4.27 (s, 2H), 1.69 (s,
6H)。
Step 8: preparation 4-[3-(6-fluoro-3-oxoisoindoline diindyl-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
By 2-(6-fluoro-3-oxoisoindoline diindyl-5-base amino)-2-methyl propionitrile (3g, 12.86mmol), 4-isothiocyano-2-trifluoromethylbenzene
Formonitrile HCN (5.87g, 25.72mmol), dry DMF (25ml) joins in tube sealing, moves to reaction 16h in oil bath (90 DEG C).Thin layer chromatography
Monitoring reaction completely, adds 2N hydrochloric acid (25ml) and methanol (25ml), is heated to reflux 1.5h.Thin layer chromatography monitoring reaction completely, cools down,
Adding saturated sodium bicarbonate aqueous solution the most neutral, extract with dichloromethane, merge organic facies, wash with water twice, saturated common salt is washed once, anhydrous
Sodium sulfate is dried, and filters, and adds thick silica gel concentrating under reduced pressure, column chromatography (dichloromethane: methanol=20:1), collects and be concentrated to give white solid 3.7g,
Yield 62%.1H NMR (400MHz, CDCl3) δ 8.02 (s, 1H), 8.01 (br s, 1H), 7.90 (dd, J=8.5,1.7Hz, 1H), 7.85 (d, J=
6.6Hz, 1H), 7.46 (d, J=8.7Hz, 1H), 7.36 (s, 1H), 4.58 (s, 2H), 1.72 (s, 3H), 1.56 (s, 3H).
Step 9: preparation 4-[3-(6-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-
Trifluoromethylbenzonitrile
By compound 4-[3-(6-fluoro-3-oxoisoindoline diindyl-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
(200mg, 0.43mmol), Hydro-Giene (Water Science). (82mg, 0.43mmol), tripotassium phosphate (183mg, 0.86mmol), N, N '-dimethyl second two
Amine (94 μ l, 0.86mmol), 2-Bromopyrimidine (48 μ l, 0.52mmol) is added in dry toluene (5ml), and nitrogen is protected, dislocation oil bath 120 DEG C
Stirring 6h.Thin layer chromatography monitoring reaction completely, cools down, adds water, be extracted with ethyl acetate, merge organic facies, wash with saturated common salt, anhydrous
Sodium sulfate is dried, and filters, concentrating under reduced pressure.Column chromatography (dichloromethane: acetone=50:3), collects and is concentrated to give white solid 85mg, yield 37%.1H NMR(400MHz,CDCl3): δ=8.78 (d, J=4.8Hz, 2H), 8.03 7.97 (m, 3H), 7.89 (dd, J=1.9,8.3Hz, 1H),
7.53 (d, J=8.6Hz, 1H), 7.16 (t, J=4.8Hz, 1H), 5.21 (s, 2H), 1.75 (s, 3H), 1.58 (s, 3H) .ESI-MS m/z:540.7
(M+H)+。
Embodiment 2:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 2.ESI-MS m/z:524.8(M+H)+。
Embodiment 3:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 3.ESI-MS m/z:540.7(M+H)+。
Embodiment 4:
4-[3-(6-fluoro-3-oxo-2-(pyridine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 4.1H NMR(400MHz,CDCl3): δ=8.61 (d, J
=8.5Hz, 1H), 8.44 8.42 (m, 1H), 8.03 8.01 (m, 2H), 7.91 7.89 (m, 2H), 7.83 7.78 (m, 1H), 7.53 (d, J=8.6
Hz, 1H), 7.14 (ddd, J=0.9,4.9,7.3Hz, 1H), 5.21 (s, 2H), 1.73 (s, 3H), 1.58 (s, 3H) .ESI-MS m/z:539.8 (M+H)+。
Embodiment 5:
4-[3-(6-fluoro-3-oxo-2-(thiazol-2-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 5.1H NMR(400MHz,CDCl3): δ=8.03 8.00
(m, 2H), 7.94 (d, J=6.6Hz, 1H), 7.89 (dd, J=1.9,8.3Hz, 1H), 7.58 7.56 (m, 2H), 7.13 (d, J=3.6Hz, 1H),
5.25(s,1H),1.73(s,1H),1.58(s,1H).ESI-MS m/z:545.7(M+H)+。
Embodiment 6:
4-[3-(the fluoro-2-of 6-(4-nitropyridine-2-base)-3-oxoisoindoline diindyl-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-fluoroform
Base benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 6.1H NMR(400MHz,CDCl3): δ=9.41 9.40
(m, 1H), 8.70 8.69 (m, 1H), 8.04 8.01 (m, 2H), 7.95 (d, J=6.6Hz, 1H), 7.90 (dd, J=2.0,8.3Hz, 1H), 7.86
(dd, J=2.0,5.4Hz, 1H), 7.57 (d, J=8.5Hz, 1H), 5.25 (s, 2H), 1.76 (s, 3H), 1.60 (s, 3H) .ESI-MS m/z:582.6
(M-H)-。
Embodiment 7:
4-[3-(the fluoro-2-of 6-(4-picoline-2-base)-3-oxoisoindoline diindyl-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-fluoroform
Base benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 7.1H NMR(400MHz,CDCl3): δ=8.44 (s, 1H),
8.27 8.26 (m, 1H), 8.03 8.01 (m, 2H), 7.91 7.88 (m, 2H), 7.52 (d, J=8.4Hz, 1H), 6.96 (d, J=5.0Hz, 1H),
5.19(s,2H),2.44(s,3H),1.74(s,3H),1.58(s,3H).ESI-MS m/z:553.7(M+H)+。
Embodiment 8:
4-[3-(6-fluoro-3-oxo-2-(pyrazine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 8.1H NMR(400MHz,CDCl3): δ=9.93 (s, 1H),
8.43–8.38(m,2H),8.03–7.99(m,2H),7.93–7.91(m,2H),7.56–7.53(m,1H),5.17(s,2H),1.74(s,3H),
1.58(s,3H).ESI-MS m/z:538.7(M-H)-。
Embodiment 9:
4-[3-(6-fluoro-3-oxo-2-(thiophene-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 9.1H NMR(400MHz,CDCl3): δ=8.03 8.01
(m, 2H), 7.91 7.89 (m, 2H), 7.52 (d, J=8.5Hz, 1H), 7.06 (dd, J=1.2,5.4Hz, 1H), 7.01 6.98 (m, 1H), 6.82
(dd, J=1.2,3.8Hz, 1H), 4.98 (d, J=3.9Hz, 2H), 1.74 (s, 3H), 1.58 (s, 3H) .ESI-MS m/z:542.7 (M-H)-。
Embodiment 10:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-chlorobenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 10.ESI-MS m/z:507.1(M+H)+。
Embodiment 11:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-methoxy benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 11.ESI-MS m/z:503.1(M+H)+。
Embodiment 12:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-3-methyl-2-fluoroform
Base benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 12.ESI-MS m/z:555.6(M+H)+。
Embodiment 13:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-methyl benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 13.ESI-MS m/z:487.4(M+H)+。
Embodiment 14:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-bromobenzylcyanide
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 14.ESI-MS m/z:551.4(M+H)+。
Embodiment 15:
4-[5-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-8-oxo-6-sulfur generation-5,7-diaza spiro [3.4] octane-7-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 15.ESI-MS m/z:553.1(M+H)+。
Embodiment 16:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-two (fluoromethyl)-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 16.ESI-MS m/z:575.7(M-H)-。
Embodiment 17:
4-[3-(7-fluoro-1-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 17.ESI-MS m/z:537.8(M-H)-。
Embodiment 18:
4-[3-(4-fluoro-1-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 18.ESI-MS m/z:541.3(M+H)+。
Embodiment 19:
4-[(4-oxo-2-sulfur generation-1-(7-fluoro-3-oxo-2-(pyrimidine-2-base)) isoindoline-5-base)-1,3-diaza spiro [4,4] nonyl-3-yl]-2-trifluoromethylbenzene
Formonitrile HCN
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 19.ESI-MS m/z:567.7(M+H)+。
Embodiment 20:
4-[(4-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-7-oxo-5-sulfur generation-4,6-diaza spiro [2.4] heptane-6-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 20.ESI-MS m/z:539.0(M+H)+。
Embodiment 21:
4-[1-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4-oxo-2-sulfur generation-8-oxygen-1,3-diaza spiro [4.5] decyl-3-yl]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 21.ESI-MS m/z:583.3(M+H)+。
Embodiment 22:
4-[1-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-8-methyl-4-oxo-2-sulfur generation-1,3,8-three azepine [4.5] decyl-3-yl]-2-fluoroform
Base benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 22.ESI-MS m/z:594.5(M-H)-。
Embodiment 23:
4-[3-(6-fluoro-1-methyl-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-fluoroform
Base benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 23.ESI-MS m/z:553.2(M-H)-。
Embodiment 24:
4-[3-(3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 24.ESI-MS m/z:523.5(M+H)+。
Embodiment 25:
4-[3-(7-fluoro-3-oxo-2-(pyridine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 25.ESI-MS m/z:539.9(M+H)+。
Embodiment 26:
4-[3-(7-fluoro-3-oxo-2-(thiazol-2-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 26.ESI-MS m/z:546.6(M+H)+。
Embodiment 27:
4-[3-(7-fluoro-3-oxo-2-(4-nitropyridine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 27.ESI-MS m/z:583.9(M-H)-。
Embodiment 28:
4-[3-(7-fluoro-3-oxo-2-(4-picoline-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 28.ESI-MS m/z:552.2(M-H)-。
Embodiment 29:
4-[3-(7-fluoro-3-oxo-2-(pyrazine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 29.ESI-MS m/z:541.5(M+H)+。
Embodiment 30:
4-[3-(7-fluoro-3-oxo-2-(thiophene-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 30.ESI-MS m/z:545.3(M+H)+。
Embodiment 31:
4-[3-(7-fluoro-3-oxo-2-(2-dimethylamino pyrimidine-5-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoro
Methyl benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 31.ESI-MS m/z:582.0(M-H)-。
Embodiment 32:
4-[3-(7-fluoro-3-oxo-2-(3,5-dimethyl azoles-4-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoro
Methyl benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 32.ESI-MS m/z:555.9(M-H)-。
Embodiment 33:
4-[3-(7-fluoro-3-oxo-2-(furan-3-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 33.ESI-MS m/z:529.4(M+H)+。
Embodiment 34:
4-[3-(7-fluoro-3-oxo-2-(1H-imidazol-4 yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene
Formonitrile HCN
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 34.ESI-MS m/z:527.4(M-H)-。
Embodiment 35:
4-[3-(7-fluoro-3-oxo-2-(isoxazole-4-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 35.ESI-MS m/z:528.3(M-H)-。
Embodiment 36:
4-[3-(7-fluoro-3-oxo-2-(2-methoxy pyrimidine-5-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-fluoroform
Base benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 36.ESI-MS m/z:571.1(M+H)+。
Embodiment 37:
4-[3-(7-fluoro-3-oxo-2-(1-methyl isophthalic acid H-imidazoles-5-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoro
Methyl benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 37.ESI-MS m/z:543.2(M+H)+。
Embodiment 38:
4-[3-(7-fluoro-3-oxo-2-(3-methyl isophthalic acid H-pyrazoles-4-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoro
Methyl benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 38.ESI-MS m/z:541.1(M-H)-。
Embodiment 39:
4-[3-(7-fluoro-3-oxo-2-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-
Trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 39.ESI-MS m/z:561.2(M+H)+。
Embodiment 40:
4-[3-(7-fluoro-3-oxo-2-(pyridin-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 40.ESI-MS m/z:540.3(M+H)+。
Embodiment 41:
4-[3-(7-fluoro-3-oxo-2-(pyridin-4-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 41.ESI-MS m/z:537.8(M-H)-。
Embodiment 42:
4-[3-(7-fluoro-3-oxo-2-(pyrimidine-5-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 42.ESI-MS m/z:541.5(M+H)+。
Embodiment 43:
4-[3-(7-fluoro-3-oxo-2-(thiazole-4-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 43.ESI-MS m/z:546.0(M+H)+。
Embodiment 44:
4-[3-(7-fluoro-3-oxo-2-(thiazole-5-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 44.ESI-MS m/z:546.2(M+H)+。
Embodiment 45:
4-[3-(7-fluoro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 45.ESI-MS m/z:545.6(M+H)+。
Embodiment 46:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-1,2,3,4-tetrahydroisoquinoline-6-base)-2-sulfur oxoimidazolinium-1-base)-2-(trifluoromethyl)
Benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 46.ESI-MS m/z:537.6(M+H)+。
Embodiment 47:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(trifluoromethyl)
Benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 47.ESI-MS m/z:537.1(M+H)+。
Embodiment 48:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(trifluoro
Methyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 48.ESI-MS m/z:555.4(M+H)+。
Embodiment 49:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-6-methoxyl group-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-
Base)-2-(trifluoromethyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 49.ESI-MS m/z:567.2(M+H)+。
Embodiment 50:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-7-fluoro-1,2,3,4-tetrahydroisoquinoline-5-base)-2-sulfur oxoimidazolinium-1-base)-2-(trifluoro
Methyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 50.ESI-MS m/z:555.2(M+H)+。
Embodiment 51:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(three
Methyl fluoride) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 51.ESI-MS m/z:551.5(M+H)+。
Embodiment 52:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-fluoro-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(trifluoro
Methyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 52.ESI-MS m/z:555.1(M+H)+。
Embodiment 53:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-cyano group-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(three
Methyl fluoride) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 53.ESI-MS m/z:560.2(M-H)-。
Embodiment 54:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-methoxyl group-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-
Base)-2-(trifluoromethyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 54.ESI-MS m/z:567.3(M+H)+。
Embodiment 55:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-
Base)-2-(trifluoromethyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 55.ESI-MS m/z:605.5(M+H)+。
Embodiment 56:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-3-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(three
Methyl fluoride) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 56.ESI-MS m/z:551.2(M+H)+。
Embodiment 57:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-3-nitro-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-base)-2-(three
Methyl fluoride) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 57.ESI-MS m/z:582.5(M+H)+。
Embodiment 58:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-3-dimethylamino-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-
Base)-2-(trifluoromethyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 58.ESI-MS m/z:580.1(M+H)+。
Embodiment 59:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-methyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-
Base)-2-(trifluoromethyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 59.ESI-MS m/z:569.2(M+H)+。
Embodiment 60:
4-(4,4-dimethyl-5-oxo-3-(1-oxo-2-(pyrimidine-2-base)-4-trifluoromethyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-base)-2-sulfur oxoimidazolinium-1-
Base)-2-(trifluoromethyl) benzonitrile
The compounds of this invention, with reference to scheme 1 and the synthetic method of scheme 2, obtains compound 59.ESI-MS m/z:623.2(M+H)+。
Embodiment 61:
6-(5,5-dimethyl-4-oxo-2-sulfur oxo-3-(o-tolyl) imidazoline-1-base)-4-fluoro-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 61.ESI-MS m/z:462.5(M+H)+。
Embodiment 62:
2-(3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-sulfur oxoimidazolinium-1-base) benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 62.ESI-MS m/z:473.5(M+H)+。
Embodiment 63:
The fluoro-6-of 4-(3-(2-fluorophenyl)-5,5-dimethyl-4-oxo-2-sulfur oxoimidazolinium-1-base)-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 63.ESI-MS m/z:466.7(M+H)+。
Embodiment 64:
6-(3-(2-(dimethylamino) phenyl)-5,5-dimethyl-4-oxo-2-sulfur oxoimidazolinium-1-base)-4-fluoro-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 64.ESI-MS m/z:491.2(M+H)+。
Embodiment 65:
6-(5,5-dimethyl-4-oxo-2-sulfur oxo-3-(aminomethyl phenyl) imidazoline-1-base)-4-fluoro-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 65.ESI-MS m/z:462.6(M+H)+。
Embodiment 66:
6-(5,5-dimethyl-3-(3-nitrobenzophenone)-4-oxo-2-sulfur oxoimidazolinium-1-base)-4-fluoro-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 66.ESI-MS m/z:493.4(M+H)+。
Embodiment 67:
6-(5,5-dimethyl-4-oxo-2-sulfur oxo-3-(3-(trifluoromethyl) phenyl) imidazoline-1-base)-4-fluoro-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 67.ESI-MS m/z:516.8(M+H)+。
Embodiment 68:
The fluoro-6-of 4-(3-(3-anisyl)-5,5-dimethyl-4-oxo-2-sulfur oxoimidazolinium-1-base)-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 68.ESI-MS m/z:478.3(M+H)+。
Embodiment 69:
6-(5,5-dimethyl-3-(4-methyl-3-(trifluoromethyl) phenyl)-4-oxo-2-sulfur oxoimidazolinium-1-base)-4-fluoro-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 69.ESI-MS m/z:530.2(M+H)+。
Embodiment 70:
The fluoro-6-of 4-(3-(3-fluoro-4-anisyl)-5,5-dimethyl-4-oxo-2-sulfur oxoimidazolinium-1-base)-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 70.ESI-MS m/z:496.3(M+H)+。
Embodiment 71:
The fluoro-6-of 4-(3-(4-fluoro-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-sulfur oxoimidazolinium-1-base)-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 71.ESI-MS m/z:534.8(M+H)+。
Embodiment 72:
The fluoro-5-of 2-(3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) different imidazoline-5-base)-4,4-dimethyl-5-oxo-2-sulfur oxoimidazolinium-1-base) benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 72.ESI-MS m/z:491.3(M+H)+。
Embodiment 73:
2-(3-(7-fluoro-3-oxo-2-(pyrimidine-2-base) different imidazoline-5-base)-4,4-dimethyl-5-oxo-2-sulfur oxoimidazolinium-1-base)-4-(trifluoromethyl) benzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 73.ESI-MS m/z:541.5(M+H)+。
Embodiment 74:
The fluoro-6-of 4-(3-(2-methoxyl group-5-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-sulfur oxoimidazolinium-1-base)-2-(pyrimidine-2-base) isoindoline-1-
Ketone
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 74.ESI-MS m/z:546.2(M+H)+。
Embodiment 75:
2-[3-(7-fluoro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-1,3-dimethyl benzene
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 75.ESI-MS m/z:476.1(M+H)+。
Embodiment 76:
2-[3-(7-fluoro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-1-fluoro-4-methylbenzene
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 76.ESI-MS m/z:480.2(M+H)+。
Embodiment 77:
2-[3-(7-fluoro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-1-fluoro-4-Nitrobenzol
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 77.ESI-MS m/z:511.2(M+H)+。
Embodiment 78:
4-[3-(7-methyl-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 78.ESI-MS m/z:535.0(M-H)-。
Embodiment 79:
4-[3-(7-methoxyl group-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene
Formonitrile HCN
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 79.ESI-MS m/z:553.2(M+H)+。
Embodiment 80:
4-[3-(7-trifluoromethyl-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 80.ESI-MS m/z:591.2(M+H)+。
Embodiment 81:
4-[3-(7-nitro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 81.ESI-MS m/z:568.1(M+H)+。
Embodiment 82:
4-[3-(4-fluoro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 82.ESI-MS m/z:538.9(M-H)-。
Embodiment 83:
4-[3-(4-methyl-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 83.ESI-MS m/z:537.3(M+H)+。
Embodiment 84:
4-[3-(4-methoxyl group-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene
Formonitrile HCN
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 84.ESI-MS m/z:553.4(M+H)+。
Embodiment 85:
4-[3-(6-trifluoromethyl-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethyl
Benzonitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 85.ESI-MS m/z:591.3(M+H)+。
Embodiment 86:
4-[3-(6-nitro-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 86.ESI-MS m/z:567.9(M+H)+。
Embodiment 87:
4-[3-(6-methyl-3-oxo-2-(thiene-3-yl) isoindoline-5-base)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-base]-2-trifluoromethylbenzene first
Nitrile
The compounds of this invention, with reference to the synthetic method synthesis of embodiment 1, obtains compound 87.ESI-MS m/z:537.2(M+H)+。
Biological assessment
Embodiment 1:
Using the PC-3 LNCaP/AR of high expressed AR, the cell collecting exponential phase is inoculated into 96 orifice plates.Cell was cultivated
Medicine working solution is added, in 37 DEG C of 5%CO after mixing after night2Incubator is cultivated.According to cell growth status 5～7 days upon administration, add CCK-8
Reagent, 37 DEG C of 5%CO2Incubator is hatched.Microplate reader is vibrated, measures absorbance, it is thus achieved that OD value.Corresponding half is calculated according to OD value
Inhibition concentration (IC50)。
Suppression ratio=[(matched group OD value-administration group OD value)/(matched group OD value-blank group OD value)] × 100%, uses GraphPad Prism5
Computed in software IC50(half-inhibition concentration).
Table 1: the androgen receptor antagonist activity of compound
| Compound number | AR antagonistic activity IC50(nM) |
| 1 | 14 |
| 3 | 7 |
| 4 | 38 |
| 5 | 19 |
| 7 | 42 |
| 9 | 47 |
| 15 | 18 |
| 25 | 26 |
| 26 | 11 |
| 28 | 27 |
| 29 | 44 |
| 30 | 21 |
| 32 | 10 |
| 33 | 28 |
| 34 | 33 |
| 35 | 12 |
| 37 | 9 |
| 38 | 16 |
| 39 | 19 |
| 40 | 15 |
| 41 | 15 |
| 42 | 8 |
| 43 | 11 |
| 44 | 15 |
| 45 | 9 |
| Enzalutamide | 72 |
Note: positive control Enzalutamide is purchased from Selleck company.
Part of compounds of the present invention has the antagonism being significantly better than Enzalutamide to androgen receptor.
On the other hand, Enzalutamide, owing to having bigger lipid (LgP=3.2) and poor water solublity, readily penetrates through blood brain screen
Barrier, this is probably and causes it to have neurotoxicity, such as the major reason of epilepsy.The compounds of this invention 29,35,37,38,42 etc. and Enzalutamide
Comparing and have less LgP (lipid) and more preferable water solublity, prompting the compounds of this invention is difficult to, through blood brain barrier, to be had in vivo
Having less neurotoxicity, row adenocarcinoma aspect has preferable prospect before the treatment.
Claims (20)
1. a compound shown in formula I and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite:
Wherein:
X is for being substituted or unsubstituted aryl, heteroaryl；
R1And R2It is each independently hydrogen, any substituted C1-6Alkyl；
Or R1、R2And form 3-7 unit cycloalkyl, 4-6 unit Heterocyclylalkyl together with the carbon atom being connected with them, wherein cycloalkyl and Heterocyclylalkyl can be optionally substituted；
R3For being substituted or unsubstituted heteroaryl；
A is for being substituted or unsubstituted aromatic ring, hetero-aromatic ring；
Y is O or S；
Z is for being substituted or unsubstituted-(CH2)m-、-O-(CH2)n-、-CO-、-S-(CH2)n-、-SO-、-SO2-、-NH-(CH2)n-,-NH-CO-, wherein m is 0,1,2,3；N is 0,1,2.
2. compound as claimed in claim 1 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
X is 6-10 unit aryl, 5-6 unit heteroaryl, and described aryl and heteroaryl are optionally by 1 to 5 R4Replace, wherein, each R4Separately selected from hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, carboxyl, sulfydryl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy ,-NR5R6；Or
Each R4Separately selected from substituted or unsubstituted alkyl, acyl group, Thioacyl, amide groups, ester group, sulfonyl, sulfinyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, alkynyl, alkoxyl, alkenyloxy group；
Each R5And R6Separately selected from hydrogen, C1-6Alkyl, 3-8 unit cycloalkyl, 3-6 unit Heterocyclylalkyl, phenyl, 5-6 unit heteroaryl；Wherein alkyl, cycloalkyl, Heterocyclylalkyl, phenyl, heteroaryl can be selected from halogen, amino, hydroxyl, nitro, cyano group, trifluoromethyl, C by one or more1-4Alkyl, C1-4Alkoxyl, C1-4The substituent group of alkyl amino replaces.
3. compound as claimed in claim 2 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
X is phenyl, 5-6 unit heteroaryl, described phenyl and heteroaryl optionally by 1 to 5 independently selected from hydrogen, halogen, cyano group, trifluoromethyl, nitro, acetyl group ,-NR5R6、C1-6Alkyl, amide groups, mesyl, C1-6The substituent group of alkoxyl replaces, wherein, and R5And R6As defined in claim 2.
4. compound as claimed in claim 3 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
X is can be by 1-3 R7Substituted phenyl, wherein, each R7Separately selected from hydrogen, halogen, nitro, cyano group, trifluoromethyl, acetyl group, C1-4Alkyl, C1-4Alkoxyl, dimethyl amido, sulfonyl, amide groups.
5. compound as claimed in claim 1 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
R1And R2It is each independently hydrogen, C1-4Alkyl；Wherein alkyl is optionally replaced selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, the substituent group of difluoro-methoxy by 1 to 5；
Or R1、R2And form 3-6 unit cycloalkyl, 5-6 unit Heterocyclylalkyl together with the carbon atom being connected with them.
6. compound as claimed in claim 5, wherein:
R1And R2It is each independently hydrogen, methyl ,-CH2F；
Or R1、R2And form cyclopropane, Tetramethylene., Pentamethylene., hexamethylene, oxetanes, tetrahydrofuran, oxinane, azetidine, aza-cyclopentane, piperidine together with the carbon atom being connected with them.
7. compound as claimed in claim 6 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
R1And R2For methyl；
Or R1、R2And form Tetramethylene. together with the carbon atom being connected with them.
8. compound as claimed in claim 1 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
A is phenyl ring, hetero-aromatic ring, and described phenyl ring and hetero-aromatic ring are not necessarily by 1 to 3 R8Replace, the most each R8Separately selected from hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, carboxyl, sulfydryl, trifluoromethyl ,-NR5R6, or
Each R8Separately selected from substituted or unsubstituted alkyl, amide groups, ester group, sulfonyl, sulfinyl, thiazolinyl, alkynyl, alkoxyl；
R5And R6As defined in claim 2.
9. compound as claimed in claim 8 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
A is phenyl ring, R8As defined in claim 8.
10. compound as claimed in claim 9 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein:
R8Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, fluoromethylene, trifluoromethyl, methoxyl group, nitro.
11. compound as claimed in claim 1 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolites, wherein:
Z is for being substituted or unsubstituted-(CH2)m-,-CO-,-NH-CO-, wherein m is 0,1,2.
12. compound as claimed in claim 11 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolites, wherein:
Z is-(CH2)m-, the most each-CH2-can optionally be selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy ,-NR5R6, cyano group, carboxyl, C1-6Alkyl, C1-6Alkoxyl, C1-6Thiazolinyl, C1-6Alkynyl, acyl group, ester group, amide groups, the substituent group of sulfonyl replace, and wherein alkyl, thiazolinyl, alkynyl, acyl group, ester group, amide groups, sulfonyl can be selected from hydrogen, halogen, C1-4The substituent group of alkyl replaces；Wherein, R5And R6As defined in claim 2；
M is 1,2.
13. compound as claimed in claim 12 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolites, wherein:
Z is selected from-CH2-、-CH2-CH2-、-CH(CH3The most each-the CH of)-,2-or-CH-can be selected from hydrogen, nitro, methyl, methoxyl group, trifluoromethyl, dimethylamino, cyano group substituent group replace.
14. compound as claimed in claim 1 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolites, wherein:
R3For heteroaryl, described heteroaryl can be by 1 to 4 R9Replace, wherein, each R9Independently selected from hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, carboxyl, sulfydryl, trifluoromethyl ,-NR5R6, wherein, R5And R6As defined in claim 2；Or
Each R9Independently selected from substituted or unsubstituted alkyl, acyl group, amide groups, ester group, sulfonyl, sulfinyl, thiazolinyl, alkynyl, alkoxyl, alkenyloxy group.
15. compound as claimed in claim 14 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolites, wherein:
R3Selected from furan, pyrroles, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazoles, triazole, tetrazolium, imidazoles, azoles, isoxazole, diazole, triazole, diazole, pyrazine, pyridazine, triazine, thiadiazoles, indole, quinoline, isoquinolin and benzothiophene, and R3Optionally it is independently selected from R by 1 to 49Substituent group replaced；Wherein
R9Selected from hydrogen, fluorine, chlorine, bromine, iodine, amino, cyano group, nitro, carboxyl, trifluoromethyl ,-NR5R6、C1-6Alkyl, C1-6Alkoxyl, acyl group, ester group and amide groups, wherein said alkyl, alkoxyl, acyl group, ester group and amide groups are optionally independently selected from fluorine, chlorine, bromine, iodine, C by one or more1-4Alkyl and C6-8The substituent group of aryl is replaced；
R5And R6As defined in claim 2.
Compound described in 16. any one of claim 1-15 and officinal salt, solvate, prodrug, stereoisomer, tautomer, its metabolite, wherein, described compound is selected from following compounds:
17. 1 kinds of medicines, wherein contain the compound described in any one of claim 1-16, its pharmaceutically useful salt, its prodrug or its solvate as effective ingredient.
18. 1 kinds of pharmaceutical compositions, wherein contain the compound described in any one of claim 1-16, its pharmaceutically useful salt, its prodrug or its solvate as effective ingredient.
The application in treatment with estrogen receptor activity relevant disease of compound described in 19. any one of claim 1-16, its pharmaceutically useful salt, its prodrug, its solvate or a combination thereof thing.
20. such as claim 19, the disease that wherein said androgen receptor is relevant is that carcinoma of prostate, prostate hyperplasia, acne, alopecia, hair hypertrophy, breast carcinoma, male's sexual are bad.
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