CN103804358A - Biaryl hydantoin derivate and preparation method, medicine composition and application thereof - Google Patents

Biaryl hydantoin derivate and preparation method, medicine composition and application thereof Download PDF

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CN103804358A
CN103804358A CN201310567203.4A CN201310567203A CN103804358A CN 103804358 A CN103804358 A CN 103804358A CN 201310567203 A CN201310567203 A CN 201310567203A CN 103804358 A CN103804358 A CN 103804358A
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alkyl
bolites
tautomer
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solvate
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CN103804358B (en
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段文虎
万惠新
夏广新
梅德盛
林逸鹏
刘学军
沈竞康
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Shanghai Phaarmaceuticals Holding Co ltd
Shanghai Institute of Materia Medica of CAS
Shanghai Pharmaceuticals Holding Co Ltd
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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

The invention provides a compound as shown in a Formula I or salts, solvent compounds, pre-drugs, stereoisomers, tautomers, polymorphic forms or metabolites thereof that are acceptable pharmaceutically, a medicine composition containing the same and an application thereof in preparation of medicines for treating male hormone receptor relevant diseases.

Description

One class Diarylhydantoin derivative, its preparation method, pharmaceutical composition and application
Technical field
The invention belongs to medical chemistry field, relate to particularly a class Diarylhydantoin derivative, its preparation method, pharmaceutical composition and the purposes aspect medical.
Background technology
Androgen receptor (androgen recepror, AR) is a kind of 110,000 dalton's (110KDa) protein, is a member of steroid receptor (steroid receptor).Similar with other steroid receptor, AR contains three structural domains: N-end structure territory, be positioned at central DNA binding site and the structural domain that comprises consideration convey shifting signal, and the C-end structure territory of containing ligand binding site.N-end structure territory is called as Activation Activity 1(activation function1 containing one) functional transcription site, do not need other structural area, this transcription site itself just can activate transcribing of target gene.C-end contains and is called as Activation Activity 2(activation function2) transcription site, under the activation of its part, can activate transcribing of its target gene.AR without ligand binding is mainly distributed in tenuigenin, and heat shock protein(HSP) forms mixture.When with male sex hormone (as testosterone and dihydrotestosterone etc.) in conjunction with after, AR from heat shock protein(HSP) form complex body be released, carry out phosphorylation reaction, form dimer, and transfer in nucleus, be attached on the DNA fragmentation relevant to it, thereby stimulate transcribing of its target gene.The transcriptional activity of the androgen receptor that ligand binding activates is considered to be called as co-activating (coactivators) as the protein coordination of SRC-1, TIF-2 and AIB-1 and completed by a group.Co-activating can be modified nuclear staining body structure, contributes to attraction and stable transcripton to transcribe to target gene.And when in the time that inhibitor is combined, co-suppression (corepressors), as NCoR or SMRT can be attracted, causes transcribing being suppressed.
Having the optionally Main Function of AR antagonist is directly to stop testosterone or dihydrotestosterone to be combined with androgen receptor, and the effect of blocking-up male sex hormone to cell, makes cell produce " hunger " phenomenon, finally impels apoptosis.It can be used for: 1) prevention and treatment prostate cancer (prostate cancer, PC), mammary cancer, ovarian cancer, cervical cancer, bladder cancer etc.; 2) treatment comprises the diseases such as benign prostate enlargement, comedo, bald and hair hyperplasia; 3) male contraception; 4) treating a series of imbalances relevant to male hormones crosses strong and sexual desire as sexual desire and lacks of proper care; 5) prevent from reducing the heating of relevant symptom after as castration to male sex hormone; 6) be specifically designed to prevention or suppress the muscle growth of women in turning property therapeutic process.
Treatment PC is the most important application clinically of AR antagonist.PC is in sickness rate the first mortality ratio the second in male sex's malignant tumour, and only the U.S. in 2008 just has 186320 PC to increase case newly, separately has 26660 patient deaths.Though the sickness rate of China is lower than west, along with improving constantly of rhythm of life, standard of living and diagnostic level, PC is just being the trend of continuous rising.This cancer is a kind of progress malignant tumour more rapidly, if can not get early stage diagnosis and treatment, from finding symptom, average survival time was only has 3-5.Early stage PC can be controlled effectively by operation or chemotherapy.But for PC in late period, its general therapeutic strategy is the anti androgenic therapy based on male sex hormone and acceptor (AR) thereof, the castration of performing the operation (as bilateral orchidectomy etc.) and the treatment of androgen antagonist medicine.But most patients, after this treatment, there will be in 18-24 week that sb.'s illness took a turn for the worse, occur castration tolerance type prostate cancer (Castration-Resistant Prostate Cancer, CRPC).Now, the existing androgen antagonist medicine that used is clinically no longer inhibited to CRPC, and some medicine is as flutamide and bicalutamide have agonism to CRPC on the contrary, has 80% patient finally because CRPC is dead.Further research shows, the part of male sex hormone and its combination is essential to the growth of CRPC, shows that androgen receptor is still the important target spot of this disease.But express the reasons such as increase and AR sudden change due to AR, cause existing antiprostate cancer only to have weak antagonistic activity.Therefore, need development to there is higher antagonistic activity AR antagonist and treat CRPC.
In recent years, the research of Diarylhydantoin class AR antagonist had been obtained to the progress of milestone sample, as MDV3100(IC 50=40nM, LNCaP cell), ARN-509 etc.Wherein, MDV3100, by Medivation company and Astra Pharma Inc.'s joint development, is used for the treatment of CRPC in August, 2012 by U.S. FDA approval.In random a, double blinding, placebo-controlled study, 1199 were once accepted to be divided at random MDV3100 treatment group and placebo take Docetaxel as the CRPC of main chemotherapy scheme.Result shows: compared with placebo, MDV3100 treatment group patient Overall survival median significantly increases (18.4vs13.6 month, P < 0.0001), and mortality risk reduces by 37% compared with placebo.It is clinical in the I phase at present that another MDV3100 is used for the treatment of mammary cancer.ARN-509 is developed by Amgen, is used for the treatment of CRPC existing clinical in the I/II phase.The progress of MDV3100 and ARN-509 shows that Diarylhydantoin class AR antagonist has very good development prospect.
Figure BDA0000413658510000021
Summary of the invention
The invention provides a kind of and the diverse Diarylhydantoin analog derivative of prior art, its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, and preparation method thereof, intermediate, the pharmaceutical composition that comprises them, and their application in the medicine for the preparation for the treatment of androgen-receptor related diseases, particularly prostate cancer.The prepared Diarylhydantoin analog derivative of the present invention has and preferably suppresses active androgen receptor.
On the one hand, the invention provides a kind of suc as formula the compound shown in I or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites,
Figure BDA0000413658510000031
Wherein,
A ring is 6～10 yuan of aromatic rings; Be preferably 6～10 yuan of aromatic rings; More preferably phenyl ring or naphthalene nucleus; More preferably phenyl ring;
B ring is phenyl ring or 6 yuan of hetero-aromatic rings; Be preferably phenyl ring or pyridine ring; More preferably phenyl ring or 2,3,5-, tri-substituted pyridines rings; More preferably phenyl ring;
R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl is not necessarily by one or more C3～C6 cycloalkyl, C1～C6 alkoxyl group ,-NH of being selected from 2, single (C1～C6 alkyl) amino, two (C1～C6 alkyl) amino, D atom, phenyl and-C (O) R 8in group replace, wherein R 8be selected from-NH 2, single (C1～C6 alkyl) amino, two (C1～C6 alkyl) is amino or at least contain 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl; Be preferably H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C4 alkoxyl group, two (C1～C4 alkyl) amino, D atom, phenyl and-C (O) R 8in group replace, wherein R 8be selected from-NH 2or at least containing 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl; Be preferably again H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C4 alkoxyl group, two (C1～C4 alkyl) amino, D atom, phenyl and-C (O) R 8in group replace, wherein R 8be selected from-NH 2or at least containing 6 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 6 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl; More preferably H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from cyclopropyl, cyclobutyl, methoxyl group, D atom, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or N methyl piperazine base; More preferably H, methyl, ethyl, cyclopropyl methyl, cyclobutylmethyl, phenyl, benzyl, 2-(methoxyl group) ethyl ,-CH 2c (O) NH 2or
R 2for H, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms; Be preferably H, F, Cl, Br or C1～C3 alkyl; Be preferably again H or halogen; More preferably H or F;
R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, OH, carboxyl, benzyloxy, C1～C4 alkoxyl group or halo C1～C2 alkyl; Preferably R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, C1～C4 alkoxyl group or halo C1～C2 alkyl; More preferably R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H ,-OCH 3or-CH 2cl;
Or R 3, R 4with common 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals of forming of the carbon atom being connected with them; Preferably R 3, R 4with common 4～6 yuan of heterocyclic radicals that form 3～6 yuan of cycloalkyl or contain 1 Sauerstoffatom of the carbon atom being connected with them; 3～6 yuan of wherein said cycloalkyl are preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclobutyl or cyclopentyl; 4～6 yuan of described heterocyclic radicals are preferably oxa-cyclobutyl, azelidinyl, tetrahydrofuran base, oxa-cyclohexyl, pyrrolidyl, dioxane base, piperidyl or N-methyl piperidine base, more preferably oxa-cyclobutyl, azelidinyl or oxa-cyclohexyl, more preferably oxa-cyclobutyl or oxa-cyclohexyl; More preferably R 3, R 4jointly form cyclobutyl, cyclopentyl or oxa-cyclohexyl with the carbon atom being connected with them;
R 5for cyano group, halogen, C1～C4 alkyl or C1～C4 alkoxyl group, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms; Preferably R 5for halogen, methyl, halogenated methyl or-OCH 3; More preferably R 5for halogen ,-CH 3,-CF 3or-OCH 3;
R 7for H or halogen, be preferably H or F, more preferably H;
X is S or O, is preferably S;
Y is-(CH 2) n-, O or direct key, wherein-(CH 2) n-not necessarily by one or more D atoms or methyl substituted, n is 1 or 2; Preferably Y is-(CH 2) n-or direct key, wherein-(CH2) n-not necessarily by one or more methyl substituted, n is 1 or 2; More preferably Y is-(CH 2) 2-or-CH (CH 3)-.
In one embodiment, in general formula I,
A ring is 6～10 yuan of aromatic rings; Be preferably phenyl ring;
B ring is phenyl ring or 6 yuan of hetero-aromatic rings; Be preferably phenyl ring;
R 1for H or C1～C4 alkyl, described C1～C4 alkyl is not necessarily by one or more C3～C6 cycloalkyl, C1～C6 alkoxyl group ,-NH of being selected from 2, single (C1～C6 alkyl) amino, two (C1～C6 alkyl) is amino ,-CONH 2, group in single (C1～C6 alkyl) formamyl, two (C1～C6 alkyl) formamyl and D atom replaces; Be preferably H or C1～C3 alkyl, described C1～C3 alkyl is not necessarily by one or more C3～C6 cycloalkyl, C1～C4 alkoxyl group, two (C1～C4 alkyl) amino ,-CONH of being selected from 2replace with the group in D atom; More preferably H or C1～C2 alkyl, described C1～C2 alkyl is not necessarily by one or more cyclopropyl, methoxyl group, diethylamino ,-CONH of being selected from 2replace with the group in D atom; Be preferably again H, methyl, ethyl, cyclopropyl methyl, 2-(methoxyl group) ethyl, 2-(diethylamino) ethyl ,-CH 2cONH 2or-CD 3; More preferably H, methyl or ethyl;
R 2for H, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms; Be preferably H, F, Cl, Br or C1～C3 alkyl; Be preferably again H or halogen; More preferably H or F;
R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, OH, carboxyl, benzyloxy or C1～C4 alkoxyl group; Be preferably H, OH or C1～C4 alkoxyl group; Preferably, R 3and R 4in at least 1 be methyl; More preferably, R 3and R 4be methyl;
Or R 3, R 4with common 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals of forming of the carbon atom being connected with them, 3～6 yuan of wherein said cycloalkyl are preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclobutyl; 4～6 yuan of described heterocyclic radicals are preferably oxa-cyclobutyl, azelidinyl, tetrahydrofuran base, pyrrolidyl, dioxane base, piperidyl or N-methyl piperidine base, more preferably oxa-cyclobutyl or azelidinyl, more preferably oxa-cyclobutyl;
R 5for cyano group, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms; Be preferably cyano group, F, Cl, Br or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by the atom in one or more F of being selected from, Cl and Br; More preferably cyano group, F, Cl or C1～C2 alkyl, described C1～C2 alkyl is not necessarily replaced by one or more F atoms; Be preferably again cyano group, F, Cl or-CF 3; More preferably-CF 3;
X is S or O,
Y is-(CH 2) n-, O or direct key, wherein-(CH 2) n-not necessarily being replaced by one or more D atoms, n is 1 or 2; Preferably Y is-CH 2-;
R 7for H.
In another embodiment of the invention, the compound of described general formula I is preferably suc as formula the compound shown in II,
Figure BDA0000413658510000051
Wherein,
R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C6 alkoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from that amino, list (C1～C6 alkyl) are amino, two (C1～C6 alkyl) is amino or at least contain 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl; Preferably R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C6 alkoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or at least contain 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl; Preferred R again 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C6 alkoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or at least contain 6 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 6 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl; Further preferred R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from cyclopropyl, cyclobutyl, methoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or N methyl piperazine base; More preferably R 1for H, methyl, ethyl, phenyl, cyclopropyl methyl, cyclobutylmethyl, 2-(methoxyl group) ethyl, benzyl ,-CH 2c (O) NH 2or
R 2for H, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms; Preferably R 2for H or halogen; More preferably R 2for H or F;
R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, C1～C4 alkoxyl group or halo C1～C2 alkyl; Preferably R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H ,-OCH 3or-CH 2cl;
Or R 3, R 4with common 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals of forming of the carbon atom being connected with them; Preferably R 3, R 4with common 4～6 yuan of heterocyclic radicals that form 3～6 yuan of cycloalkyl or contain 1 Sauerstoffatom of the carbon atom being connected with them; More preferably R 3, R 4jointly form cyclobutyl, cyclopentyl or oxa-cyclohexyl with the carbon atom being connected with them;
R 5for halogen, C1～C4 alkyl or C1～C4 alkoxyl group, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms; Preferably R 5for halogen, methyl, halogenated methyl or-OCH 3; More preferably R 5for halogen ,-CH 3,-CF 3or-OCH 3;
R 7for H or halogen; Be preferably H;
Y is-(CH 2) n-, wherein-(CH 2) n-not necessarily being replaced by one or more C1～C4 alkyl, n is 1 or 2; Preferably Y is-(CH 2) n-, wherein-(CH 2) n-not necessarily by one or more methyl substituted, n is 1 or 2; More preferably Y is-(CH 2) 2-or-CH (CH 3)-.
In a preferred implementation more of the present invention, when Y is-(CH 2) 2-time, R 2for H.
In a preferred embodiment of the present invention, a kind of compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites as shown in above formula I or II is provided, wherein, A ring is phenyl ring or quinoline ring, B ring is phenyl ring, and in formula I or II, other substituting group as defined above and preferably.
In a further preferred embodiment of the present invention, a kind of compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites as shown in above formula I or II is provided, wherein, A ring, for phenyl ring or quinoline ring, encircles with A the cyano group, the R that are connected 5, R 7and
Figure BDA0000413658510000071
all be arranged on the phenyl ring of A ring, and cyano group and
Figure BDA0000413658510000072
be each other para-orientation, B ring is phenyl ring, and in formula I or II, other substituting group as defined above and preferably.
Of the present invention one more preferred embodiment in, a kind of compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites as shown in above formula I or II is provided, wherein, A ring is phenyl ring, with A encircle the cyano group that is connected with
Figure BDA0000413658510000073
on A ring, be each other para-orientation, R 5for trifluoromethyl or halogen, R 7for H or halogen, B ring is phenyl ring, and in formula I or II, other substituting group as defined above and preferably.
At one again in further preferred embodiment of the present invention, a kind of compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites as shown in above formula I or II is provided, wherein, A ring is phenyl ring, with A encircle the cyano group that is connected with
Figure BDA0000413658510000074
on A ring, be each other para-orientation, R 5for trifluoromethyl, R 7for H, B ring is phenyl ring, and in formula I or II, other substituting group as defined above and preferably.
In an embodiment being more preferably of the present invention, a kind of compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites as shown in above formula I or II is provided, wherein, A ring is phenyl ring, R 5for trifluoromethyl, R 7for H, with A encircle the cyano group that is connected with
Figure BDA0000413658510000075
on A ring, be each other para-orientation, encircle with A the cyano group and the R that are connected 5on A ring, be each other ortho position and replace, B ring is phenyl ring, and in formula I or II, other substituting group as defined above and preferably.
In a preferred embodiment of the present invention, work as R 2during for halogen, R 2with
Figure BDA0000413658510000076
on B ring, being each other ortho position replaces.
In a further preferred embodiment of the present invention, work as R 2during for F, R 2with
Figure BDA0000413658510000081
on B ring, being each other ortho position replaces.
In the embodiment of present invention further optimization, the compound shown in formula I of the present invention or II is preferably selected from following compound:
Figure BDA0000413658510000082
Figure BDA0000413658510000091
Figure BDA0000413658510000101
On the other hand, the invention provides the preparation method of described formula I compound.Formula I compound of the present invention can be prepared by the following method:
There is annulation by I-1 and I-2 and make in method 1 target compound I
Figure BDA0000413658510000102
Wherein, each group definition as previously mentioned.
Particularly, I-1 and I-2 are joined in the first polar solvent, (type of heating adopts microwave or oil bath heating to heat this mixture, 30～150 ℃ of temperature) to TLC detection reaction completely after, to adding the aqueous solution of sour A and the second polar solvent (itself and the first solvent identical or different) in reaction mixture, this mixture of reflux is until TLC detection reaction is complete, and from this mixture, separation and purification obtains target compound I.Wherein, the first polar solvent comprises DMF, DMA, DMSO, NMP etc., preferably DMF; The second polar solvent comprises methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, DMF etc., particular methanol; Acid A comprises hydrochloric acid, sulfuric acid, phosphoric acid etc., preferably hydrochloric acid and sulfuric acid.
Wherein, intermediate compound I-2 can be made by intermediate compound I-5 and raw material I-6 reaction, or are made by intermediate compound I-5, raw material I-7 and metal cyanides (NaCN, KCN etc.) or trialkyl cyanogen silane reaction.
Figure BDA0000413658510000103
Reaction conditions and operation steps can be according to International Patent Application WO 2006/124118 and periodical literature J.Med.Chem.2010, and in 53,2779-2796., disclosed content is carried out.
Method 2 target compound I are made by intermediate compound I-3 and I-4 reaction
Figure BDA0000413658510000111
Wherein, in I-3, X is O or S; R in I-4 1with in formula I, define identically, be not just H; In the target compound I generating in this reaction, X is O, and other each group definition as previously mentioned.
At temperature-80～0 ℃, I-3 is dissolved in to (preferably DMF and DMSO) in polar aprotic solvent, add alkalimetal hydride (preferably sodium hydride), continue at this temperature and stir 10～100 minutes, then be warmed up to 20～30 ℃, add halogenated alkane I-4, TLC detection reaction completes, and from reaction mixture, separation and purification obtains target compound I.
Wherein, intermediate compound I-3 can be by I-1 and wherein R of I-2( 1for H) reaction make.Reaction conditions and operation steps are with the reaction of I-1 and I-2 in method 1.
Method 3 target compound I are transformed and make under strong alkaline condition by I-8
Figure BDA0000413658510000112
Wherein, each group definition as previously mentioned.At temperature-80～0 ℃, I-8 is dissolved in to (preferably DMF and DMSO) in polar aprotic solvent, adds alkalimetal hydride (preferably sodium hydride), continue at this temperature and stir, TLC detection reaction completes, and from reaction mixture, separation and purification obtains target compound I.
Should be understood that, for formula I of the present invention or II compound, those skilled in the art are under the instruction of aforesaid method, can prepare with the combination of the several different methods known by the technical staff in organic synthesis or pharmaceutical chemistry field, can be by described method above, combine with synthetic method known in the art or variation thereon understood by one of ordinary skill in the art, synthesize the compounds of this invention, and be not limited to aforesaid method.
Formula I of the present invention or II compound can be prepared from the starting raw material following general approach and process that are easy to obtain.Should be understood that, what the present invention provided is typical case or preferred process conditions are (, mol ratio, solvent, pressure, charging process or order of temperature of reaction, time, reactant etc.), can also use other process conditionss, except as otherwise noted.Optimum reaction condition can change with concrete raw material, intermediate, reagent, catalyzer or solvent used, but these conditions can be determined by conventional optimization procedures by those skilled in the art.
Formula I of the present invention or II compound can be monitored preparation process or chemical structure is identified by any suitable method known in the art.For example, thin-layer chromatography, liquid chromatography, gas-chromatography, mass spectrum, LC-MS, nucleus magnetic resonance, infrared spectra, UV spectrum etc.
The preparation of compound can relate to protection and the deprotection of multiple chemical groups.For the needs of protection and deprotection; and can be easy to be determined by those skilled in the art to the selection of suitable protecting group; the Protective Groups in Organic Synthesis(second edition that the chemical process of protecting group is write people such as such as Greene; Wiley & Sons; 1991) in, find, it is incorporated herein by reference with overall form at this.
On the other hand, the present invention also provides a kind of pharmaceutical composition, it comprises the compound shown in formula I or the II that treats significant quantity or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, and at least one pharmaceutical excipient.Described pharmaceutical composition comprises oral dosage form, parenteral dosage forms, exterior-applied formulation and rectal administration formulation.In some embodiments, the oral dosage form of described pharmaceutical composition comprises tablet, capsule, pill, pulvis, sustained-release preparation, solution and suspension etc., parenteral dosage forms comprises sterile solution, suspension or emulsion, exterior-applied formulation comprises ointment, finish, emulsion, gel, suspension, solution, lotion or emulsifiable paste, and rectal administration formulation comprises suppository, drops.The selection of pharmaceutical excipient because of route of administration and effect feature different, conventionally can be weighting agent, thinner, tackiness agent, wetting agent, disintegrating agent, lubricant, emulsifying agent or suspending agent etc.In other embodiments, described pharmaceutical composition also comprises at least one other treatment agent.Preferably, pharmaceutical composition provided by the invention is oral dosage form.
On the other hand, the invention provides a kind of method that regulates estrogen receptor activity, comprise described formula I or II compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, or the pharmaceutical composition that comprises above-mentioned substance contacts with androgen receptor.Preferably, adjusting estrogen receptor activity of the present invention is for suppressing estrogen receptor activity.
Another aspect, the present invention also provides described formula I or II compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, or the pharmaceutical composition that comprises above-mentioned substance is in the application of preparing in medicine, and described medicine is used for the treatment of androgen-receptor related diseases.According to an embodiment of the invention, described androgen-receptor related diseases comprises that prostate cancer, mammary cancer, hyperplasia of prostate, hirsutism, acne, bald head, muscle exhaustion, gonad function are weak, osteoporosis, cholesterol are too high, male sterility, male's sexual is bad, anaemia is fat, sexual desire is hoped low and melancholia.According to the present invention one preferred embodiment, described androgen-receptor related diseases is castration tolerance type prostate cancer.
Again on the one hand, the present invention also provides described formula I or II compound or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, or the pharmaceutical composition that comprises above-mentioned substance is used for the treatment of the method for androgen-receptor related diseases, described methods for the treatment of comprises above-mentioned active substance is contacted with Mammals.According to an embodiment of the invention, described androgen-receptor related diseases comprises that prostate cancer, mammary cancer, hyperplasia of prostate, hirsutism, acne, bald head, muscle exhaustion, gonad function are weak, osteoporosis, cholesterol are too high, male sterility, male's sexual is bad, anaemia is fat, sexual desire is hoped low and melancholia.According to the present invention one preferred embodiment, described androgen-receptor related diseases is castration tolerance type prostate cancer.
some chemistry or technical term of pharmacology
Unless otherwise specified, the technical term of chemistry and the technical term of pharmacology in the application's claims and specification sheets has implication as described below.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" cyano group " refer to-CN.
" isocyano-" refer to-N=C=O.
" isothiocyano " refer to-N=C=S.
" hydroxyl " refer to-OH.
" carboxyl " refer to-COOH.
" benzyloxy " refer to-OCH 2c 6h 5.
Abbreviation " DMA " refers to N,N-dimethylacetamide.
Abbreviation " NMP " refers to N-Methyl pyrrolidone.
" C1～C4 " refers to that in its defined group (as alkyl, alkoxyl group, cycloalkyl etc.), carbon atom number is 1,2,3 or 4.Can know thus the implication of other terms of describing in a similar manner by inference, as " C1～C6 ", " C3～C6 " etc.
" 6～10 yuan " refer to that the atom number that surrounds this closed hoop skeleton itself in its defined closed ring system group (as aryl, heteroaryl, heterocyclic radical etc.) is 6,7,8,9 or 10, can get different numbers according to the number of rings of closed ring system group, saturation ratio and the atomic property that forms this ring etc.Can know thus the implication of other terms of describing in a similar manner by inference, as " 3～6 yuan ", " 4～6 yuan " etc.
" alkyl " only refer to by carbon atom form with hydrogen atom, containing unsaturated link(age), there is for example 1 to 12 carbon atom and the hydrocarbon chain group of the straight or branched that is connected with the rest part of molecule by singly-bound.Conventionally, the example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-methyl butyl, 2,2-dimethyl propyl, n-hexyl, heptyl, 2-methyl hexyl, 3-methyl hexyl, octyl group, nonyl and decyl etc.
" alkoxyl group " refers to formula-OR group, and wherein R is alkyl as hereinbefore defined.Conventionally, the example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy etc.
" single (C1～C6 alkyl) amino " refers to formula-NHR group, and wherein R is the alkyl with 1～6 carbon atom as hereinbefore defined.
" two (C1～C6 alkyl) amino " refers to formula-NR ar bgroup, wherein R a, R bbe the alkyl with 1～6 carbon atom as hereinbefore defined independently of one another.
" single (C1～C6 alkyl) formamyl " refers to formula-CONHR group, and wherein R is the alkyl with 1～6 carbon atom as hereinbefore defined.
" two (C1～C6 alkyl) formamyl " refers to formula-CONR ar bgroup, wherein R a, R bbe the alkyl with 1～6 carbon atom as hereinbefore defined independently of one another.
" cycloalkyl " refers to stable non-aromatic monocycle or the multi-ring alkyl that are only made up of carbon atom and hydrogen atom, can comprise fused rings system, bridged-ring system or volution system, conventionally has 3 to 15 carbon atoms.It can be connected with the rest part of molecule by singly-bound via the upper any suitable carbon atom of ring.Conventionally, the example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.With regard to object of the present invention, preferably there is the cycloalkyl of the monocycle system of 3 to 6 carbon atoms, more preferably there is the cycloalkyl of the monocycle system of 3 to 5 carbon atoms.
" heterocyclic radical " refers to by 2 to 14 carbon atoms and 1 to 6 and is selected from 3 yuan to the 20 yuan stable non-aromatic cyclic groups that the heteroatoms of nitrogen, oxygen and sulphur forms jointly, it can be the member ring systems of monocycle, dicyclo, three rings or more rings, also can comprise fused rings system, bridged-ring system or volution system.It can be connected with the rest part of molecule by singly-bound via carbon atom or the heteroatoms of the upper any suitable of ring.Nitrogen-atoms wherein can optionally further be replaced to form tertiary amine or quaternary ammonium structure by other groups.Conventionally, the example of heterocyclic radical includes but not limited to that nitrogen heterocyclic propyl group, azelidinyl, oxa-cyclobutyl, pyrrolidyl, imidazolinyl, pyrazolidyl, imidazolidyl, thiazolidyl, isothiazole alkyl, isoxazole alkyl, tetrahydrofuran base, dioxolanyl, oxa-cyclohexyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazine base, N-replace homopiperazine base, piperidyl, N-substituted piperidine base, dioxane base, indolinyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base etc.With regard to object of the present invention, preferably 3 yuan to 7 yuan and at least contain 1 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen, oxygen or sulphur, further preferably 4 yuan to 6 yuan and at least contain 1 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen or oxygen, more preferably 4 yuan to 6 yuan and at least contain 1～2 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen or oxygen.
" aryl " or " aromatic ring " refers to the conjugation aromaticity hydrocarbon member ring systems group with 6 to 18 carbon atoms, can be monocycle, dicyclo, three rings or polycyclic system more.It can be connected with the rest part of molecule by singly-bound via the atom on aromatic nucleus.Conventionally, the example of aryl includes but not limited to phenyl, naphthyl, anthryl, phenanthryl, fluorenyl etc.With regard to object of the present invention, preferably there is 6 to 10 monocycles of carbon atom or the aryl of bicyclic system or aromatic ring.
" heteroaryl " or " hetero-aromatic ring " refers to by 1 to 15 carbon atom and 1 to 6 and is selected from 5 yuan to the 16 yuan conjugation aromaticity ring system groups that the heteroatoms of nitrogen, oxygen and sulphur forms jointly, can be monocycle, dicyclo, three rings or polycyclic system more, it can be connected with the rest part of molecule by singly-bound via the atom on aromatic nucleus.Conventionally, the example of heteroaryl includes but not limited to pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazol radical, tetrazole base, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indazolyl, benzimidazolyl-, benzotriazole base, quinolyl, isoquinolyl, benzothiazolyl, benzo pyridazinyl, quinazolyl, quinoxalinyl etc.With regard to object of the present invention, preferably 6 to 10 yuan and at least contain 1 and be selected from the heteroatomic monocycle of nitrogen, oxygen or sulphur or heteroaryl or the hetero-aromatic ring of bicyclic system, more preferably by the heteroaryl or the hetero-aromatic ring that at least condense the bicyclic system forming containing 5 to 6 yuan of hetero-aromatic rings of 1 nitrogen-atoms and phenyl ring.
" pharmaceutically acceptable acid salt " refer to can retain free alkali biological effectiveness and without other side effect, the salt forming with mineral acid or organic acid.Inorganic acid salt includes but not limited to hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt etc., organic acid salt includes but not limited to formate, acetate, 2, 2-dichloroacetate, trifluoroacetate, propionic salt, hexanoate, octylate, caprate, undecylenate, glycollate, gluconate, lactic acid salt, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, Citrate trianion, palmitate, stearate, oleate, cinnamate, lauroleate, malate, glutaminate, pyroglutamate, aspartate, benzoate, mesylate, benzene sulfonate, tosilate, alginates, ascorbate salt, salicylate, 4-ASA salt, napadisilate etc." pharmaceutically acceptable base addition salt " refer to can keep free acid biological effectiveness and without salt other side effect, that form with mineral alkali or organic bases.Include but not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc. derived from the salt of mineral alkali.Preferred inorganic salt are ammonium salt, sodium salt, sylvite, calcium salt and magnesium salts.Include but not limited to following salt derived from the salt of organic bases: primary amine class, secondary amine class and tertiary amines, substituted amine, comprise natural amine, cyclic amine and deacidite, such as ammonia, Isopropylamine, Trimethylamine 99, diethylamine, quadrol, triethylamine, tripropyl amine, thanomin, diethanolamine, trolamine, dimethylethanolamine, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, the glucosamine etc. of being substituted.These salt can be by the known method preparation of this specialty.
" solvate " refers to that some compound molecule of the present invention is in crystallisation process, associates and the aggregate of formation with one or more solvent molecules.Solvent molecule can be water or other organic solvents (as methyl alcohol, ethanol, acetone etc.).
" prodrug " refers to pharmaceutically acceptable metabolic precursor thereof of some compound of the present invention, and it does not have activity conventionally, but changes under physiological condition and have bioactive parent compound of the present invention in vivo.Conventionally can improve the character of parent compound at aspects such as solubleness, histocompatibility or pharmacokinetics.
" steric isomer " refer to by same atoms and form, and by identical key bonding, but has the compound of different three-dimensional structures.Formula I of the present invention or II compound are contained various possible optically active isomers, cis-trans-isomer and composition thereof.
" tautomer " refers to another atom from an atom transfer of molecule to same molecular of proton and the isomer that forms.Formula I of the present invention or II compound are contained various possible tautomers and composition thereof.
" polymorphic form " refer to some compound of the present invention under solid state due to exist two or more differing molecular arrange the different solid crystal phases that produce.Formula I of the present invention or II compound are contained various possible crystal formations and composition thereof.
After " meta-bolites " refers to that some compound of the present invention is absorbed by body, the compound producing through the bio-transformation such as functionalization reaction (I phase bioconversion reaction, comprises oxidation, reduction, hydrolysis etc.) and association reaction (II phase bioconversion reaction) in body under the effect of enzyme.
" pharmaceutical composition " refers to the pharmaceutical preparation for example, forming for bioactive compounds being delivered to the medium of Mammals (people) of conventionally being accepted by compound of the present invention and optional this area.This medium comprises pharmaceutically acceptable carrier.The object of pharmaceutical composition is the administration that promotes organism, is beneficial to absorption and then the performance biological activity of activeconstituents.Wherein, " pharmaceutically acceptable carrier " includes but not limited to that any government administration section license of being correlated with is for can be for the mankind or domestic animal, relatively nontoxic and the mankind or domestic animal are not caused to adjuvant, carrier, vehicle, glidant, sweetener, thinner, sanitas, dyestuff/tinting material, correctives, tensio-active agent, wetting agent, dispersion agent, suspending agent, stablizer, isotonic agent, solvent or the emulsifying agent etc. of bad physiological response.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but do not limit the present invention.
In following preparation example, 1h-NMR measures with Varian Mercury AMX300 type instrument.VG ZAB-HS or VG-7070 type and Esquire3000plus-01005 mensuration for MS.
compound Preparation Example
Embodiment 14-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 2)
Figure BDA0000413658510000161
4-amido-2-trifluoromethyl benzonitrile (10.0g, 53.8mmoL) joins in normal hexane (22.5mL) and water (25.0mL), in reinforced complete this mixed system, under room temperature, stirs 8 minutes.Under ice bath, thiophosgene (4.5mL, 58.5mmoL) is added drop-wise in above-mentioned mixed system to the reinforced complete stirred overnight at room temperature that is placed in.Filter, normal hexane for solid (2 × 25.0mL) washing, discards solid, and filtrate decompression is steamed to 1/5th of original volume, is positioned over 4 ℃ of refrigerator overnight.Filter, solid high vacuum dry, obtains white solid 11.0g, and productive rate is 81%. 1H?NMR(CDCl 3,300MHz)δ(ppm)7.84(d,J=8.4Hz,1H),7.59(d,J=1.8Hz,1H),7.49(dd,J 1=8.4Hz,J 2=1.8Hz,1H).
Embodiment 22-methyl-4-nitrobenzene methyl
Figure BDA0000413658510000162
Under ice bath, by SOCl 2(4.8mL, 66.2mmoL) is added drop-wise in anhydrous methanol (100mL).After drip again anhydrous methanol (70mL) solution of 2-methyl-4-nitrobenzoic acid (10.0g, 55.2mmoL), within 1 hour, dropwise.This mixed system is placed in 70 ℃ of reactions of oil bath 7 hours, and TLC detection reaction is complete.Cooling, pressure reducing and steaming solvent.Residue is dissolved in ethyl acetate (100mL), adds saturated sodium bicarbonate (100mL), separatory, and ethyl acetate for water (50mL) is extracted once.Merge organic phase, anhydrous magnesium sulfate drying, filters, pressure reducing and steaming solvent, and high vacuum dry, obtains white solid 10.5g, and productive rate is 98%. 1H?NMR(CDCl 3,300MHz)δ(ppm)8.10-8.01(m,3H),3.95(s,3H),2.69(s,3H).
Embodiment 32-(brooethyl)-4-nitrobenzene methyl
Figure BDA0000413658510000171
By 2-methyl-4-nitrobenzene methyl (200mg, 1.0mmoL), benzoyl peroxide (48.5mg, 0.2mmoL), N-bromo-succinimide (213mg, 1.2mmoL) joins CCl 4(15mL) in; under the protection of Ar gas; heating reflux reaction 7 hours; cooling, use successively saturated sodium bicarbonate (3 × 20mL), saturated aqueous common salt (20mL) washing, pressure reducing and steaming solvent; residue separates with rapid column chromatography; eluent is PE:EA=20:1, obtains white solid 124mg, and productive rate is 44%. 1H?NMR(CDCl 3,300MHz)δ(ppm)8.34-8.01（m,3H),4.97(s,2H),4.00(s,3H).
Embodiment 45-nitro-1-iso-dihydro-indole
Figure BDA0000413658510000172
2-(brooethyl)-4-nitrobenzene methyl (250mg, 0.92mmoL) is joined to ammonia (NH 3) saturated methanol solution (5mL) in, under room temperature, stir 2 hours, TLC detection reaction is complete.Pressure reducing and steaming solvent, residue joins in ethyl acetate (7mL), and ultrasonic 3 minutes, be placed in-20 ℃ of refrigerators 3 minutes, there are a large amount of solids, to filter, high vacuum dry, obtains faint yellow solid 150mg, and productive rate is 92%. 1H?NMR(CDCl 3,300MHz)δ(ppm)9.01(s,1H),8.47(d,J=0.9Hz,1H),8.30(dd,J 1=8.1Hz,J 2=0.9Hz,1H),7.89(d,J=8.1,1H).
Embodiment 55-amino-1-iso-dihydro-indole (intermediate 8a)
By 5-nitro-1-isoindolone (100mg, 0.56mmoL), reduced iron powder (314mg, 5.6mmoL) joins in ethanol (2.0mL) and concentrated hydrochloric acid (0.5mL), reflux 2 hours, and TLC detection reaction is complete.Cooling, with ammonia (NH 3) saturated methanol solution neutralizing acid, diatomite filtration, methanol wash, pressure reducing and steaming solvent, obtains white solid 70.0mg, productive rate is 84%. 1H?NMR(CD 3OD,300MHz)δ(ppm)7.48-7.46(d,J=6.6Hz,1H),6.73-6.71(m,2H),4.30(s,2H).
Embodiment 62-methyl-2-(1-oxoisoindoline diindyl-5-base amido) propionitrile (intermediate 9a)
Figure BDA0000413658510000181
By 5-amino-1-iso-dihydro-indole (intermediate 8a, 2.1g, 14.2mmoL), acetone (3.5mL, 47.6mmoL) and sodium cyanide (2.1g, 46.8mmoL) join in 90% acetic acid (45mL).Reinforced complete, stirring at room temperature 48 hours.In reaction solution, add water (50mL) and ethyl acetate (100mL), separatory, organic phase successively water (3 × 50mL), saturated sodium bicarbonate (50mL), water (50mL) is washed, anhydrous magnesium sulfate drying, filters pressure reducing and steaming solvent, residue separates with rapid column chromatography, eluent is PE:EA=1:1, obtains white solid 2.7g, and productive rate is 88%. 1H?NMR(CDCl 3,300MHz)δ(ppm)8.10(s,1H),7.48-7.44(d,J=8.4Hz,1H),6.92-6.89(m,2H),6.68(s,1H),4.28(s,1H),1.68(s,6H).
Embodiment 74-[4,4-dimethyl-5-oxo-3-(1-oxoisoindoline diindyl-5-yl)-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 1)
Figure BDA0000413658510000182
By 4-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 9a, 209mg, 0.92mmoL), 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido) propionitrile (100mg, 0.46mmoL) join in dry DMF (5.0mL), 50 ℃ of reactions of microwave 6 hours, TLC detection reaction is complete.Join 2N HCl(4.0mL) and methyl alcohol (4.0mL) in, reflux 1 hour.Cooling, pressure reducing and steaming solvent.Residue joins in ethyl acetate, pH value is adjusted to neutrality, separatory with saturated sodium bicarbonate.Organic phase pressure reducing and steaming solvent, residue separates with rapid column chromatography, and eluent is methylene dichloride: acetone=20:1, obtains white solid 55mg, and productive rate is 30%. 1H?NMR(DMDO-d6,300MHz)δ(ppm)8.05(t,1H),8.01-7.97(m,2H),7.86-7.84(m,1H),7.44-7.42(m,1H),6.45(s,1H),4.56(s,2H),1.63(s,6H).
The fluoro-3-nitrobenzoic acid of the bromo-6-of embodiment 82-(intermediate 4b)
Under ice bath, nitrosonitric acid (1.0mL, 11.4mmoL) is added drop-wise in the mixing solutions of the bromo-6-fluorobenzoic acid of 2-(2.5g, 11.4mmoL) and the vitriol oil (7.5mL).After dropwising, this system is placed in stirring at room temperature 2 hours.Pour in frozen water (40.0mL), occur a large amount of solids, filter, solid washes with water, and high vacuum dry obtains white solid 2.5g, and productive rate is 83%.Be directly used in the next step.
The fluoro-3-nitrobenzene methyl of the bromo-6-of embodiment 92-(intermediate 5b)
Figure BDA0000413658510000192
Fluoro-bromo-2-6-3-nitrobenzoic acid (intermediate 4b, 2.5g, 9.5mmoL) is joined in thionyl chloride (11.0mL) to reflux 1 hour.Pressure reducing and steaming volatizable material, residue joins in anhydrous methanol (30mL), reflux 1 hour.Pressure reducing and steaming solvent, high vacuum dry, obtains white solid 2.5g, and productive rate is 96%.Be directly used in the next step.
The fluoro-3-amido of the bromo-6-of embodiment 102-methyl benzoate (intermediate 6b)
Figure BDA0000413658510000193
By fluoro-bromo-2-6-3-nitrobenzene methyl (intermediate 5b, 2.5g, 9.0mmoL), reduced iron powder (1.0g, 17.8mmoL) joins in Glacial acetic acid (13.0mL), reflux 2 hours, and TLC detection reaction completes.Diatomite filtration, ethyl acetate washing, pressure reducing and steaming solvent.Residue joins in ethyl acetate (30mL) and water (10mL), separatory, and pressure reducing and steaming solvent, residue separates with rapid column chromatography, and eluent is petrol ether/ethyl acetate=10/1, obtains colourless liquid 1.7g, and productive rate is 70%. 1H?NMR(DMDO-d6,300MHz)δ(ppm)8.05(t,1H),7.05(t,1H),6.92-6.90(m,1H),5.44(s,2H),3.86.(s,3H).
Embodiment 113-amine-2-itrile group-6-fluorophenyl carbamate (intermediate 7b)
By the fluoro-3-amido of bromo-2-6-methyl benzoate (intermediate 6b, 1.7g, 6.9mmoL), nitrilation cuprous (6.5g, 73.1mmoL) joins in dry DMF (50mL), and in 160 ℃ of reactions of oil bath 15 minutes, TLC detection reaction completed.Cooling, diatomite filtration, ethyl acetate washing, pressure reducing and steaming solvent.Residue joins in ethyl acetate, washes with water.Pressure reducing and steaming solvent, residue rapid column chromatography separates, and eluent is petrol ether/ethyl acetate=3/1, obtains white solid 530mg, and productive rate is 40%. 1H?NMR(CDCl 3,300MHz)δ(ppm)7.16(t,1H),6.90-6.85(dd,J 1=9.0Hz,J 2=3.9Hz,1H),4.53(br,2H),3.99(s,3H).
Embodiment 124-amido-7-fluorine isoindoline-1-ketone (intermediate 8b)
Figure BDA0000413658510000202
By 3-amine-2-itrile group-6-fluorophenyl carbamate (intermediate 7b, 275mg, 1.4mmoL) and Raney's nickel (30mg) join in the mixing solutions of methyl alcohol (19mL) and water (6mL), in 50 ℃, 3 kilograms of exert pressure hydrogenation 7 hours, diatomite filtration, pressure reducing and steaming solvent, high vacuum dry, obtains white solid 210mg, and productive rate is 89%.Be directly used in the next step. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.45 (br, 1H), 6.92-6.82 (m, 2H), 4.78 (br, 2H), 4.29 (s, 2H) .MS (ESI): m/z=189.0 (M+Na) +.
Embodiment 132-(the fluoro-1-oxoisoindoline diindyl-4-of 7-base amido)-2-methyl propionitrile (intermediate 9b)
Except replacing intermediate 8a with intermediate 8b, the preparation of intermediate 9b is with intermediate 9a, white solid, and productive rate is 51%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.55 (br, 1H), 7.29 (dd, J 1=6.6Hz, J 2=2.7Hz, 1H), 7.13 (t, 1H), 5.03 (s, 1H), 4.37 (s, 2H), 1.78 (s, 6H).
Embodiment 144-[3-(the fluoro-1-oxoisoindoline diindyl-4-of 7-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 2)
Figure BDA0000413658510000211
Except replacing intermediate 9a with intermediate 9b, the preparation of compound 2 is with compound 1, white solid, and productive rate is 35%. 1HNMR(CDCl 3，300MHz)δ(ppm)7.98(dd，J 1=19.2Hz，J 2=2.4Hz，1H)，7.84(dd，J 1=8.4Hz,J 2=2.1Hz,1H),7.46(dd,J 1=8.7Hz,J 2=3.9Hz,1H),7.31(t,1H),7.10(s,1H),4.50(q,2H),1.75(s,3H),1.53(s,3H).
The bromo-3-fluoride-6-nitrobenzoic acid of embodiment 152-(intermediate 4c) and the bromo-3-fluorine-5-nitro benzoic acid of 2-(intermediate 4e)
Figure BDA0000413658510000212
Under ice bath, nitrosonitric acid (2mL, 22.83mmoL) is added drop-wise in the mixing solutions of the 2-fluoro-phenylformic acid of bromo-3-(5g, 22.8mmoL) and the vitriol oil (15mL).After dropwising, be placed in stirring at room temperature 2 hours.Be poured onto in frozen water, occur a large amount of solids, filter, solid washes with water, high vacuum dry, and white solid 5.3g, is the mixture (4c/4e=2/1) of intermediate 4c and 4e, productive rate is 88%.The major part of this mixture is directly used in next step reaction, on a small quantity through column chromatography for separation, identifies as follows:
Intermediate 4c, 1h NMR (CDCl 3, 300MHz) and δ (ppm) 8.26 (dd, J 1=6.9, J 2=3.3Hz, 1H), 7.48 (dd, J 1=6.9Hz, J 2=5.7Hz, 1H).
Intermediate 4e, 1h NMR (CD 3oD, 400MHz) δ (ppm) 8.39 (dd, J 1=1.8Hz, J 2=1.2Hz, 1H), 8.18 (dd, J 1=6.0Hz, J 2=1.8Hz, 1H).
The bromo-3-fluoride-6-nitrobenzoic acid of embodiment 162-methyl esters (intermediate 5c) and the bromo-3-fluorine-5-nitro benzoic acid of 2-methyl esters (intermediate 5e).
Figure BDA0000413658510000213
Except replacing intermediate 4b with intermediate 4c and intermediate 4e mixture, the preparation of intermediate 5c and intermediate 5e mixture, with intermediate 5b, obtains reddish-brown target product, and productive rate is 100%, is directly used in next step.
The bromo-3-fluorophenyl carbamate of embodiment 176-amino-2-(intermediate 6c) and the bromo-3-fluorophenyl carbamate of 5-amido 2-(intermediate 6e)
Figure BDA0000413658510000221
Except replacing intermediate 5b with intermediate 5c and intermediate 5e mixture, the preparation of intermediate 6c and intermediate 6e mixture is with intermediate 6b.Product, through column chromatography for separation, obtains intermediate 6c and intermediate 6e sterling.
Intermediate 6c, white solid, productive rate is 53%.TLC:Rf=0.66(developping agent: petrol ether/ethyl acetate=6:1). 1H?NMR(CDCl 3，300MHz)δ(ppm)6.99（dd,J 1=9.0Hz,J 2=7.8Hz,1H)，6.60(dd,J 1=9.0Hz,J 2=4.2Hz,1H),4.58(br,2H),3.94(s,3H).
Intermediate 6e, white solid, productive rate is 27%.TLC:Rf=0.33(developping agent: petrol ether/ethyl acetate=6:1). 1H?NMR(CDCl 3，300MHz)δ(ppm)6.88（dd,J 1=2.7Hz,J 2=1.2Hz,1H)，6.56(dd,J 1=9.9Hz,J 2=2.7Hz,1H),3.97(s,5H).
Embodiment 186-amino-2-itrile group-3-fluorophenyl carbamate (intermediate 7c)
Figure BDA0000413658510000222
Except replacing intermediate 6b with intermediate 6c, the preparation of intermediate 7c is with intermediate 7b, white solid, and productive rate is 30%.Be directly used in the next step.
Embodiment 197-amido-4-fluorine isoindoline-1-ketone (intermediate 8c)
Figure BDA0000413658510000223
Except replacing intermediate 7b with intermediate 7c, the preparation of intermediate 8c is with intermediate 8b, white solid, and productive rate is 58%. 1hNMR (acetone-d6,300MHz) δ (ppm) 7.41 (br, 1H), 7.00 (t, 3H), 6.30 (dd, J 1=9.0Hz, J 2=3.6Hz, 1H), 5.72 (br, 2H), 4.39 (s, 3H).
Embodiment 202-(the fluoro-3-oxoisoindoline diindyl-4-of 7-base amido)-2-methyl propionitrile (intermediate 9c)
Figure BDA0000413658510000231
Except replacing intermediate 8a with intermediate 8c, the preparation of intermediate 9c is with intermediate 9a, white solid, and productive rate is 62%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.66 (br, 1H), 7.23 (dd, J 1=17.7Hz, J 2=8.7Hz, 1H), 7.02 (br, 1H), 6.98 (dd, J 1=8.4Hz, J 2=5.7Hz, 1H), 4.46 (s, 2H), 1.78 (s, 6H).
Embodiment 214-[3-(the fluoro-3-oxoisoindoline diindyl-4-of 7-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 3)
Figure BDA0000413658510000232
Except replacing intermediate 9a with intermediate 9c, the preparation of compound 3 is with compound 1, white solid, and productive rate is 36%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.98-7.95（m,1H),7.90-7.87(m,1H),7.45-7.36(m,1H),7.35-7.26(m,1H),6.42(br,1H),4.52(s,2H),1.73(s,3H),1.51(s,3H).
The fluoro-5-phenylformic acid of the bromo-4-of embodiment 222-(intermediate 4d)
Figure BDA0000413658510000233
Except replacing the bromo-6-fluorobenzoic acid of 2-with the bromo-4-fluorobenzoic acid of 2-, intermediate 4d's is synthetic with intermediate 4b, white solid, and productive rate is 91%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.59(d,J=7.8Hz,1H),7.88(d,J=5.7Hz,1H).
The fluoro-5-methyl benzoate of the bromo-4-of embodiment 232-(intermediate 5d)
Figure BDA0000413658510000234
Under ice bath, sulfur oxychloride (4.1mL, 56.0mmoL) is added drop-wise in anhydrous methanol (244mL), after dropwising, continue with this understanding to stir 30 minutes.Add the 2-fluoro-5-phenylformic acid of bromo-4-(13.4g, 50.8mmoL), in 60 ℃ of reacting by heating 18 hours.Pressure reducing and steaming solvent, adds ethyl acetate, and with saturated sodium carbonate washing, pressure reducing and steaming solvent, high vacuum dry, obtains faint yellow solid 14g, and productive rate is 99%.Be directly used in the next step. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.62(d,J=7.8Hz,1H),7.69(d,J=9.3Hz,1H)，3.99(s,3H).
The bromo-4-fluorophenyl carbamate of embodiment 245-amino-2-(intermediate 6d)
Figure BDA0000413658510000241
By the fluoro-5-methyl benzoate of bromo-2-4-(14.0g, 50.3mmoL) and reduced iron powder (14.1g, 252.0mmoL) join ethanol (396.0mL), in the mixing solutions of water (96.0mL) and Glacial acetic acid (19.3mL), in 110 ℃ of reacting by heating 1 hour, TLC detection reaction was complete.Cooling, pressure reducing and steaming solvent, adds ethyl acetate and saturated sodium bicarbonate in residue.Separatory, organic phase anhydrous magnesium sulfate drying, filters, pressure reducing and steaming solvent, high vacuum dry, obtains yellow solid 10.0g, and productive rate is 80%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.30-7.18(m,2H),3.92(s,3H).
Embodiment 255-amino-2-itrile group-4-fluorophenyl carbamate (intermediate 7d)
Except replacing intermediate 6b with intermediate 6d, the preparation of intermediate 7d is with intermediate 7b, white solid, and productive rate is 18%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.62(d,J=8.7Hz,1H),7.69(d,J=10.5Hz,1H)，3.95(s,3H).
Embodiment 266-amido-5-fluorine isoindoline-1-ketone (intermediate 8d)
Except replacing intermediate 7b with intermediate 7d, the preparation of intermediate 8d is with intermediate 8b, white solid, and productive rate is 85%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.34(s,1H),7.19(d,J=10.8Hz,1H),7.01(d,J=8.1Hz,1H),5.32(s,2H),4.17(s,2H).
Embodiment 272-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido)-2-methyl propionitrile (intermediate 9d)
Figure BDA0000413658510000251
Except replacing intermediate 8a with intermediate 8d, the preparation of intermediate 9d is with intermediate 9a, white solid, and productive rate is 73%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.51(s,1H),7.39(d,J=11.1Hz,1H),7.26(d,J=7.8Hz,1H),5.92(s,1H),4.25(s,2H),1.67(s,6H).
Embodiment 284-[3-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 4);
Figure BDA0000413658510000252
Except replacing intermediate 9a with intermediate 9d, the preparation of compound 4 is with compound 1, white solid, and productive rate is 18%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.00-7.98(m,2H),7.89-7.82(m,2H),7.46-7.43(d,J=9.0Hz,1H),6.78(s,1H),4.55(s,2H),1.70(s,3H),1.54(s,3H).MS(ESI):m/z=461.0(M-H) -.
Embodiment 295-amido-2-itrile group-3-fluorophenyl carbamate (intermediate 7e)
Figure BDA0000413658510000253
Except replacing intermediate 6b with intermediate 6e, the preparation of intermediate 7e is with intermediate 7b, white solid, and productive rate is 38%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)7.09(d,J=2.4Hz,1H),6.81(s,2H),6.63(dd,J 1=12.6Hz,J 2=2.4Hz,1H),3.84(s,3H).
Embodiment 306-amido-4-fluorine isoindoline-1-ketone (intermediate 8e)
Figure BDA0000413658510000254
Except replacing intermediate 7b with intermediate 7e, the preparation of intermediate 8e is with intermediate 8b, white solid, and productive rate is 68%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.47(s,1H),6.66(d,J=1.5Hz,1H),6.52(dd,J 1=11.4Hz,J 2=1.8Hz,1H),5.58(s,2H),4.21(s,2H).
Embodiment 312-(the fluoro-3-oxoisoindoline diindyl-5-of 7-base amido)-2-methyl propionitrile (intermediate 9e)
Except replacing intermediate 8a with intermediate 8e, the preparation of intermediate 9e is with intermediate 7a, white solid, and productive rate is 61%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.65(s,1H),6.92(s,1H),6.79(d,J=12.3Hz,1H),6.62(s,1H),4.30(s,2H),1.65(s,6H).
Embodiment 324-[3-(the fluoro-3-oxoisoindoline diindyl-5-of 7-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 5)
Figure BDA0000413658510000262
Except replacing intermediate 9a with intermediate 9e, the preparation of compound 5 is with compound 1, white solid, and productive rate is 37%. 1H?NMR(CD 3OD，300MHz)δ(ppm)8.20-8.15(m,2H),8.03-7.99(m,2H),7.67(d,J=1.2Hz,1H),7.51(dd,J 1=9.0Hz,J 2=1.2Hz,1H),4.61(s,2H),1.61(s,6H).
The fluoro-4-nitrobenzoic acid of the bromo-6-of embodiment 332-(intermediate 4f)
Figure BDA0000413658510000263
By fluoro-2-1-methyl-4-oil of mirbane (20.0g, 129mmoL), iron powder (0.87g, 15.5mmoL) joins in bromine (45.6g, 284mmoL), 100 ℃ of reacting by heating of oil bath 100 hours in tube sealing.Cooling, be poured onto in frozen water, with the excessive bromine of sodium sulfite treatment.Ether extraction, merges organic phase, uses saturated common salt water washing, separatory.Pressure reducing and steaming solvent, residue separates with rapid column chromatography, and eluent is sherwood oil, obtains the fluoro-2-methyl-5-nitro of the bromo-3-of 1-benzene, white solid 7.5g, productive rate is 25%. 1H?NMR(CDCl 3，300MHz)δ(ppm)2.41(d,J=3.0Hz,1H),8.26(s,1H),7.86(d,J=8.4Hz,1H).MS(ESI):m/z=232.0(M-H) -.
By bromo-1-3-fluoro-2-methyl-5-nitro benzene (6.0g, 25.8mmoL), potassium permanganate (16.3g, 103.0mmoL), potassium hydroxide (11.5g, 206mmoL) joins in water (60.0mL), 70 ℃ of reacting by heating of oil bath 8 hours, TLC detection reaction is complete.Diatomite filtered while hot, hot wash.Cooling, pH value is adjusted to neutrality with concentrated hydrochloric acid, ether extraction, pressure reducing and steaming solvent, residue separates with rapid column chromatography, and eluent is ethyl acetate/methanol=9/1, obtains white solid 1.7g, and productive rate is 25%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.10(dd,J 1=2.4Hz,J 2=1.2Hz,1H),7.96(dd,J 1=8.1Hz,J 2=2.4Hz,1H).MS(ESI):m/z=262.0(M-H) -.
The fluoro-4-nitrobenzene methyl of the bromo-6-of embodiment 342-(intermediate 5f)
Figure BDA0000413658510000271
Except replacing intermediate 4b with intermediate 4f, the preparation of intermediate 5f is with intermediate 5b, white solid, and productive rate is 93%.Be directly used in the next step.
Embodiment 354-amido-2-itrile group-6-fluorophenyl carbamate (intermediate 6f)
Except replacing intermediate 5b with intermediate 5f, the preparation of intermediate 6f is with intermediate 6b, white solid, and productive rate is 93%.Be directly used in the next step.
Figure BDA0000413658510000272
The fluoro-4-nitrobenzene methyl of embodiment 362-itrile group-6-(intermediate 7f)
Figure BDA0000413658510000273
Except replacing intermediate 6b with intermediate 6f, the preparation of intermediate 7f is with intermediate 7b, white solid, and productive rate is 43%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)6.84(d,J=2.1Hz,1H),6.69(s,2H),6.57(d,J=14.1Hz,1H),3.78(s,3H).MS(ESI):m/z=193.0(M-H) -.
Embodiment 375-amido-7-fluorine isoindoline-1-ketone (intermediate 8f)
Figure BDA0000413658510000274
Except replacing intermediate 7b with intermediate 7f, the preparation of intermediate 8f is with intermediate 8b, white solid, and productive rate is 58%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)7.88(s,1H),6.41(d,J=1.2Hz,1H),6.27(dd,J 1=12.3Hz,J 2=1.5Hz,1H),6.02(s,2H),4.18(s,2H).MS(ESI):m/z=189.0(M+Na) +.
Embodiment 382-(the fluoro-1-oxoisoindoline diindyl-5-of 7-base amido)-2-methyl propionitrile (intermediate 9f)
Figure BDA0000413658510000281
Except replacing intermediate 8a with intermediate 8f, the preparation of intermediate 9f is with intermediate 9a, white solid, and productive rate is 56%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.10(s,1H),6.97(s,1H),6.73(s,1H),6.53(d,J=12.3Hz,1H),4.29(d,2H),1.68(s,6H).MS(ESI):m/z=256.0(M+Na) +.
Embodiment 394-[3-(the fluoro-1-oxoisoindoline diindyl-5-of 7-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 6)
Figure BDA0000413658510000282
Except replacing intermediate 9a with intermediate 9f, the preparation of compound 6 is with compound 1, white solid, and productive rate is 37%. 1H?NMR(CD 3OD，300MHz)δ(ppm)8.18-8.16(m,2H),8.01-7.99(m,1H),7.48(s,1H),7.33(d,J=7.2Hz,1H),4.56(s,2H),1.61(s,6H).MS(ESI):m/z=463.0(M+H) +.
Embodiment 404-[3-(the fluoro-2-methyl-3-of 6-oxoisoindoline diindyl-5-yl)-4,4-dimethyl-2,, 5-dioxo alkyl imidazole-1-yl] and-2-(trifluoromethyl) cyanobenzene (compound 7)
Figure BDA0000413658510000283
Under ice bath, 60% sodium hydride (3.5mg, 0.087mmoL) is joined in the dry DMF (3.0mL) of compound 4 (30.0mg, 0.067mmoL).After reinforced, continue under ice bath, to stir 30 minutes.Remove ice bath, at room temperature add methyl iodide (21 μ L, 0.33mmoL).Continue at room temperature to stir 3 hours, TLC detection reaction completes.Add ethyl acetate, wash with water.Pressure reducing and steaming solvent, rapid column chromatography separates, and eluent is petrol ether/ethyl acetate=1/2, obtains white solid 25.0mg, and productive rate is 81%. 1H?NMR(CD 3OD，300MHz)δ(ppm)8.19(s,1H),8.05(d,J=8.4Hz,1H),7.94(d,J=8.4Hz,1H),7.80(d,J=6.6Hz,1H),7.38(d,J=8.7Hz,1H),4.45(s,2H),3.22(s,3H),1.58(s,6H).MS(ESI):m/z=461.0(M+H) +.
Embodiment 414-[3-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-4,4-dimethyl-2,, 5-dioxo alkyl imidazole-1-yl] and-2-(trifluoromethyl) cyanobenzene (compound 8)
Under ice bath, 60% sodium hydride (3.5mg, 0.087mmoL) is joined to compound 4(30.0mg, 0.067mmoL) dry DMF (3.0mL) in.After reinforced, continue under ice bath, to stir 30 minutes.Remove ice bath, at room temperature stir 3 hours, TLC detection reaction completes.Add ethyl acetate, water (3 ×) washing.Pressure reducing and steaming solvent, rapid column chromatography separates, and eluent is petrol ether/ethyl acetate=1/2, obtains white solid 21.0mg, and productive rate is 70%. 1H?NMR(CD 3OD，300MHz)δ(ppm)8.19(s,1H),8.07(d,J=12.0Hz,1H),7.96(d,J=8.4Hz,1H),7.84(d,J=6.6Hz,1H),7.42(d,J=8.7Hz,1H),6.50(s,1H),4.54(s,2H),1.59(s,6H).MS(ESI):m/z=447.0(M+H) +.
Embodiment 424-[3-(the fluoro-3-oxoisoindoline diindyl-5-of 2-ethyl 6-yl)-4,4-dimethyl-2,, 5-dioxo alkyl imidazole-1-yl] and-2-(trifluoromethyl) cyanobenzene (compound 9)
Figure BDA0000413658510000292
Except replacing methyl iodide with iodoethane, the preparation of compound 9 is with compound 7, white solid, and productive rate is 62%. 1H?NMR(CD 3OD，300MHz)δ(ppm)8.22(s,1H),8.08(dd,J 1=8.7Hz,J 2=1.8Hz,1H),8.00(d,J=8.4Hz,1H),7.83(d,J=6.6Hz,1H),7.43(d,J=8.7Hz,1H),4.49(s,2H),3.73(q,2H),1.61(s,6H),1.33(t,J=7.2Hz,3H).MS(ESI):m/z=475.0(M+H) +.
Embodiment 431-(the fluoro-3-oxoisoindoline diindyl-5-of 7-base amido) cyclobutyl formonitrile HCN (intermediate 9g)
Figure BDA0000413658510000301
By intermediate 8e(180mg, 0.92mmoL) and trimethylammonium nitrile silane (2.0mL) join in cyclobutanone (7.0mL), 70 ℃ of reacting by heating of oil bath are spent the night hour, TLC detection reaction is complete.Add saturated potassium carbonate (2.0mL), ethyl acetate is extracted, pressure reducing and steaming solvent, and residue separates with rapid column chromatography, and eluent is ethanol/methylene=1/20, obtains faint yellow solid 220.0mg, and productive rate is 98%.Be directly used in the next step.
Embodiment 444-[[5-(the fluoro-3-oxoisoindoline diindyl-5-of 7-yl)-8-oxo-6-sulphur oxo-5,7-diaza spiro [3.4] octane-7-yl]]-2-(trifluoromethyl) cyanobenzene (compound 10)
Figure BDA0000413658510000302
Except replacing intermediate 9a with intermediate 9g, the preparation of compound 10 is with compound 1, white solid, and productive rate is 41%. 1h NMR (acetone-d6,300MHz) δ (ppm) 8.27 (d, J=7.2Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=6.3Hz, 1H), 8.00-7.90 (m1H), (7.65 d, J=1.5Hz, 1H), 7.53 (dd, J 1=9.3Hz, J 2=1.5Hz, 1H), 4.66 (s, 2H), 2.76-2.62 (m, 4H), 2.14-2.07 (m, 1H), 1.68-1.64 (m, 1H) .MS (ESI): m/z=475.0 (M+H) +.
Two (tertbutyloxycarbonyl) amino of embodiment 455-[]-2-itrile group-4-fluorophenyl carbamate (intermediate 10a)
Under ice bath, by intermediate 8d(1.9g, 9.9mmoL), Boc acid anhydrides (5.7g, 21.7mmoL), N, N-dimethyl amine yl pyridines (122mg, 1.0mmoL) joins in anhydrous THF, naturally heats up, and stirring is spent the night.Pressure reducing and steaming solvent, residue separates with rapid column chromatography, and eluent is sherwood oil, obtains white solid 2.2g, and productive rate is 56%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.01(d,J=7.5Hz,1H),7.54(d,J=9.0Hz,1H),3.99(s,3H),1.44(s,18H).MS(ESI):m/z=417.0(M+Na) +.
Two (tertbutyloxycarbonyl) amino of embodiment 466-[]-5-fluorine isoindoline-1-ketone (intermediate 11a)
Figure BDA0000413658510000311
Except replacing intermediate 7b with intermediate 10a, the preparation of intermediate 11a is with intermediate 8b, white solid, and productive rate is 63%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.65 (d, J=6.9Hz, 1H), 7.49 (d, J=9.6Hz, 1H), 4.51 (s, 2H), 1.44 (s, 18H) .MS (ESI): m/z=389.0 (M+Na) +.
Two (tertbutyloxycarbonyl) amino of embodiment 476-[]-5-fluorine isoindoline-1-ketone (intermediate 12a)
Figure BDA0000413658510000312
By intermediate 11a(1.2g, 3.28mmoL), cesium carbonate (3.24g, 10.0mmoL) and methyl iodide (1.1mL, 16.0mmoL) join in dry DMF (10.0mL), stirred overnight at room temperature.Mixed system joins in ethyl acetate, washes with water, and pressure reducing and steaming solvent, residue separates with rapid column chromatography, and eluent is petrol ether/ethyl acetate=5/1, obtains white solid 720.0mg, and productive rate is 58%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.61 (d, J=6.9Hz, 1H), 7.48 (d, J=9.6Hz, 1H), 4.50 (s, 2H), 3.11 (s, 3H), 1.43 (s, 18H) .MS (ESI): m/z=403.0 (M+Na) +.
Embodiment 486-amino-5-fluorine-2-methyl isoindoline-1-ketone (intermediate 13a)
Figure BDA0000413658510000313
Under ice bath, trifluoroacetic acid (14.4mL) is added drop-wise to intermediate 12a(720mg, 1.9mmoL) methylene dichloride (28.8mL) in.Naturally rise to room temperature, stirring is spent the night.Pressure reducing and steaming solvent, residue joins in ethyl acetate, uses successively saturated sodium bicarbonate and water washing, pressure reducing and steaming solvent, high vacuum dry, obtains white solid 310mg, and productive rate is 91%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.21(d,J=6.3Hz,1H),7.03(d,J=7.8Hz,1H),4.24(s,2H),3.90(br,2H),3.15(s,3H).MS(ESI):m/z=203.0(M+Na) +.
Embodiment 492-(the fluoro-2-methyl-3-of 6-oxoisoindoline diindyl-5-base amino)-2-methyl propionitrile (intermediate 14a)
Figure BDA0000413658510000321
Except replacing intermediate 8a with intermediate 13a, the preparation of intermediate 14a is with intermediate 9a, white solid, and productive rate is 62%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.45 (d, J=6.0Hz, 1H), 7.30 (d, J=8.6Hz, 1H), 5.25 (s, 1H), 4.34 (s, 2H), 3.08 (s, 3H), 1.79 (s, 6H) .MS (ESI): m/z=270.0 (M+Na) +.
Embodiment 504-[3-(the fluoro-2-methyl-3-of 6-oxoisoindoline diindyl-5-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 11)
Figure BDA0000413658510000322
Except replacing intermediate 9a with intermediate 14a, the preparation of compound 11, with compound 1, obtains white solid, and productive rate is 32%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.00-7.96(m,2H),7.86(dd,J 1=8.4Hz,J 2=2.4Hz,1H),7.79(d,J=6.6Hz,1H),7.40(d,J=8.4Hz,1H),4.47(s,2H),3.22(s,3H),1.69(s,3H),1.53(s,3H).MS-EI:m/z=476.0(M) +.
Embodiment 511-(the fluoro-2-methyl-3-of 6-oxoisoindoline diindyl-5-amino) cyclobutyronitrile (intermediate 14b)
Figure BDA0000413658510000323
Except replacing acetone with cyclobutanone, and with outside 6-amino-5-fluorine-2-methyl isoindoline-1-ketone (intermediate 13a) replacement 5-amino-1-iso-dihydro-indole (intermediate 8a), the same 9a of preparation of intermediate 14b, obtains white solid, and productive rate is 55%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.31 (d, J=10.8Hz, 1H), 6.99 (d, J=7.8Hz, 1H), (5.97 s, 1H), 4.34 (s, 2H), 3.09 (s, 3H), (2.83-2.81 m, 2H), 2.63-2.54 (m, 2H), 2.23-2.18 (m, 2H) .MS (ESI): m/z=260.0 (M+H) +.
Embodiment 524-[[5-(the fluoro-2-methyl-3-of 6-oxoisoindoline diindyl-5-yl)-8-oxo-6-sulphur oxo-5,7-diaza spiro [3.4] octane-7-yl]]-2-(trifluoromethyl) cyanobenzene (compound 12)
Figure BDA0000413658510000331
Except replace 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido with 1-(the fluoro-2-methyl-3-of 6-oxoisoindoline diindyl-5-amino) cyclobutyronitrile (intermediate 14b)) propionitrile (intermediate 9a), the preparation of compound 12 is with compound 1, obtain white solid, productive rate is 26%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.00-7.97(m,2H),7.89-7.83（m,2H),7.44(d,J=8.1Hz,1H),4.49(s,2H),3.22(s,3H),2.75-2.57(m,2H),2.43-2.22(m,2H),1.69-1.59(m,2H).MS(ESI):m/z=489.0(M+H) +.
Embodiment 531-(the fluoro-1-oxoisoindoline diindyl-5-of 7-base amido) cyclobutyronitrile
Figure BDA0000413658510000332
Except replacing acetone with cyclobutanone, the preparation of intermediate 1-(the fluoro-1-oxoisoindoline diindyl-5-of 7-base amido) cyclobutyronitrile is with 2-methyl-2-(1 oxoisoindoline diindyl-5-base amido) propionitrile (intermediate 9a), white solid, productive rate is 78%. 1H?NMR(CDCl 3，400MHz)δ(ppm)6.84(s,1H),6.42(s,1H),6.34(dd,J=10.9,1.4Hz,1H),4.72(s,1H),4.38(s,2H),2.85(ddd,J=12.3,8.8,5.6Hz,2H),2.42(dd,J=12.1,8.3Hz,2H),2.35–2.12(m,2H).
Embodiment 544-[5-(the fluoro-1-oxoisoindoline diindyl-5-of 7-yl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-(trifluoromethyl) cyanobenzene (compound 13)
Figure BDA0000413658510000333
Except substituting 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido with intermediate 1-(the fluoro-1-oxoisoindoline diindyl-5-of 7-amino) cyclobutyronitrile) propionitrile (intermediate 9a), the preparation of compound 13 is with compound 1, light yellow solid, productive rate is 75%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.99(d,J=8.4Hz,1H),7.97(s,1H),7.89(s,1H),7.85(dd,J=8.2,1.9Hz,1H),7.28(s,1H),7.14(d,J=8.9Hz,1H),4.60(s,2H),2.73(m,2H),2.65–2.47(m,2H),2.28(m,1H),1.72(m,1H).EI-MS474.08[M] +.
The bromo-5-fluorine isoindoline-1-of embodiment 556-ketone
Figure BDA0000413658510000341
6-amido-5-fluorine isoindoline-1-ketone (intermediate 8d) (3.0g, 18.1mmoL) is joined in the mixing solutions of water (110mL) and the vitriol oil (40mL), be cooled to 0 ℃, slowly drip NaNO 2(1.9g) water (30mL) solution.Dropwise rear continuation stirs 1 hour at this temperature.By CuBr(3.9g) 48% hydrobromic acid solution (300mL) be added drop-wise in above-mentioned system, dropwise, 60 ℃ of oil bath reacting by heating, the completing of TLC detection reaction.Thin up, extracts by ethyl acetate.Organic phase concentrating under reduced pressure, residue separates with rapid column chromatography, and eluent is methylene dichloride: methyl alcohol=50:1, obtains gray solid 3.6g, and productive rate is 88%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.73(brs,1H),7.92(d,J=6.3Hz,1H),7.64(d,J=8.4Hz,1H),4.35(s,2H).EI-MS229.0[M] +.
The bromo-2-of embodiment 566-(cyclopropyl methyl)-5-fluorine isoindoline-1-ketone
Figure BDA0000413658510000342
Under ice bath, NaH (60%, 5.1mg, 0.127mmoL) is joined in dry DMF (0.87mL) solution of the bromo-5-fluorine isoindoline-1-ketone of 6-(20.0mg, 0.087mmoL).Reinforced complete, stir 5 minutes.Add brooethyl cyclopropane (13.0 μ L, 0.127mmoL) and tetrabutylammonium iodide (9.5mg, 0.024mmoL).Continue under ice bath, to stir 2 hours the completing of TLC detection reaction.Water extracts the reaction of going out, and ethyl acetate is extracted.Organic phase concentrating under reduced pressure, residue Preparative TLC chromatographic separation, developping agent is sherwood oil: ethyl acetate=2:1, obtains white solid 8.0mg, productive rate is 32%. 1h NMR (acetone-d6,300MHz) δ (ppm) 7.91 (d, J=4.8Hz, 1H), 7.56 (d, J=6.6Hz, 1H), 4.60 (s, 2H), 3.42 (d, J=8.1Hz, 2H), 1.07 (m, 1H), 0.56 (m, 2H), 0.33 (m, 1H).
The fluoro-3-isoindoline-5-of embodiment 572-[2-(cyclopropyl methyl)-6-amido]-2 Methylpropionic acid
Figure BDA0000413658510000351
By bromo-6-2-(cyclobutylmethyl)-5-5-fluorine isoindoline-1-ketone (95.0mg, 0.33mmoL), aminoisobutyric acid (52.0mg, 0.50mmoL), K 2cO 3(117.0mg; 0.84mmoL), CuCl (6.24mg, 0.063mmoL); 2-acetyl cyclohexanone (9.0 μ L) and water (14.0 μ L) join in DMF (0.45mL), under argon shield, spend the night in 105 ℃ of oil bath reactions.Pressure reducing and steaming solvent, residue adds water, pH value is adjusted to neutrality with 1N hydrochloric acid.Decompression is except anhydrating, and residue separates with rapid column chromatography, and eluent is methylene dichloride: methyl alcohol=10:1, obtains incarnadine oily matter 40mg, and productive rate is 40%. 1H?NMR(CD 3OD，300MHz)δ(ppm)7.22(brs,1H),7.04(br,1H),4.47(brs,2H),3.42(d,J=6.9Hz,1H),1.98(s,1H),1.59(s,6H),1.06(m,1H),0.56(m,2H),0.32(m,1H).
The fluoro-3-isoindoline-5-of embodiment 582-[2-(cyclopropyl methyl)-6-amido]-2 Methylpropionic acid methyl esters
By the fluoro-3-isoindoline-5-of 2-[2-(cyclopropyl methyl)-6-amido]-2 Methylpropionic acid (40.0mg, 0.13mmoL), K 2cO 3(22.0mg), methyl iodide (10 μ L) joins in dry DMF (0.23mL), stirred overnight at room temperature.Pressure reducing and steaming solvent.Residue Preparative TLC chromatographic separation, developping agent is sherwood oil: ethyl acetate=1:1, obtains yellow oil 21mg, productive rate is 50%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.06(d,J=10.5Hz,1H),6.97(d,J=7.8Hz,1H),4.48(brs,1H),4.34(s,2H),3.74(s,3H),3.41(d,J=7.2Hz,2H),1.61(s,6H),1.00(m,1H),0.56(m,2H),0.29(m,1H).
The fluoro-3-isoindoline-5-of embodiment 594-[[3-[2-(cyclopropyl methyl)-6-amido]-4,4-dimethyl-5-oxo-2--thiocarbamoyl imidazole alkane-1-yl]]-2-(trifluoromethyl) cyanobenzene (compound 14)
Figure BDA0000413658510000353
By 4-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 2) (34mg, 0.15mmoL) and the fluoro-3-isoindoline-5-of 2-[2-(cyclopropyl methyl)-6-amido]-2 Methylpropionic acid methyl esters (21mg, 0.066mmoL) join in dry DMF (0.40mL), in 50 ℃ of reactions of microwave 6 hours.Pressure reducing and steaming solvent, residue Preparative TLC chromatographic separation, developping agent is methylene dichloride: acetone=20:1, obtains white solid 17mg, productive rate is 50%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.00（m,2H),7.87(dd,J=8.4,1.5Hz,1H),7.79(d,J=6.9Hz,1H),7.42(d,J=8.7Hz,1H),4.59(s,2H),3.50(m,2H),1.69(s,3H),1.53(s,3H),1.07(m,1H),0.62(m,2H),0.30(m,1H).
Embodiment 604-[3-(the fluoro-2-acetylaminohydroxyphenylarsonic acid of 6-3-oxoisoindoline diindyl-5-yl)-4,4-dimethyl-2-sulfo--5-oxo-imidazole alkane-1 base]-2-(trifluoromethyl) cyanobenzene (compound 15)
By compound 4(46.0mg, 0.10mmoL), 2-bromoacetamide (68.6mg, 0.50mmoL) and Anhydrous potassium carbonate (137.5mg, 1.0mmol) joined in dry DMF (1.0mL), in 50 ℃ of reactions 24 hours.Pressure reducing and steaming solvent, residue Preparative TLC chromatographic separation, developping agent is DCM:MeOH=20:1, obtains white solid 6.0mg, productive rate is 18%. 1H?NMR(CD 3OD,400MHz)δ(ppm)8.22-8.10(m,2H),8.01(dd,J=8.3,1.3Hz,1H),7.86(d,J=6.6Hz,1H),7.61(d,J=9.1Hz,1H),4.66(s,2H),4.40-4.24(m,2H),1.66(s,3H),1.52(s,3H).EI-MS519.10[M] +.
The fluoro-2-of embodiment 614-{3-[6-(2-(4-methylpiperazine-1-yl)-2-oxoethyl)-3-oxoisoindoline diindyl-5-yl]-4,4-dimethyl-2-sulfo--5-oxo-imidazole alkane-1 base }-2-(trifluoromethyl) cyanobenzene (compound 16)
Figure BDA0000413658510000362
By compound 4(30.0mg, 0.06mmoL), cesium carbonate (105.7mg, 0.32mmoL) joins in dry DMF (1.0mL), then adds N-methyl chloride acetylpiperazine (27.7mg, 0.13mmol), and 50 ℃ are reacted 24 hours.Pressure reducing and steaming solvent, residue Preparative TLC chromatographic separation, developping agent is DCM:MeOH=10:1, obtains white solid 2.33mg, yield is 12%. 1H?NMR(CDCl 3,300MHz)δ(ppm)8.01(d,J=8.1Hz,2H),7.88(d,J=8.3Hz,1H),7.82(d,J=6.5Hz,1H),7.43(d,J=8.7Hz,1H),4.71(dd,J=28.1,15.3Hz,2H),4.41(dd,J=74.3,22.4Hz,2H),3.66(d,J=18.8Hz,4H),2.52(d,J=18.9Hz,4H),2.38(s,3H),1.71(s,3H),1.55(s,3H).EI-MS602.17[M] +.
Embodiment 624-[3-(the fluoro-2-tertbutyloxycarbonyl-3-of 6-oxoisoindoline diindyl-5-yl)-4,4-dimethyl-2-sulfo--5-oxo-imidazole alkane-1 base]-2-(trifluoromethyl) cyanobenzene
By compound 4(150.0mg, 0.32mmoL), DMAP(7.93mg, 0.06mmoL) and (Boc) 2o(106.2mg, 0.49mmol) join anhydrous THF(5.0mL) in, room temperature reaction 2 hours.Pressure reducing and steaming solvent, residue Preparative TLC chromatographic separation, developping agent is methylene dichloride: acetone=20:1, obtains white solid 146.0mg, productive rate is 80.0%. 1H?NMR(CDCl 3，400MHz)δ(ppm)7.98(dd,J=10.0,5.0Hz,2H),7.91-7.81(m,2H),7.43(d,J=8.5Hz,1H),4.84(d,J=2.6Hz,2H),1.68(s,3H),1.59(s,9H),1.52(s,3H).
Embodiment 634-[3-(6-fluoro-1,2-dimethyl-3-oxoisoindoline diindyl-5-yl)-4,4-dimethyl-2-sulfo--5-oxo-imidazole alkane-1 base]-2-(trifluoromethyl) cyanobenzene (compound 17) and 4-[3-(the fluoro-1-methyl-3-of 6-oxoisoindoline diindyl-5-yl)-4,4-dimethyl-2-sulfo--5-oxo-imidazole alkane-1 base]-2-(trifluoromethyl) cyanobenzene (compound 18)
Figure BDA0000413658510000372
By compound 4(146.0mg, 0.26mmoL), cesium carbonate (169.1mg, 0.52mmoL) joins in dry DMF (5.0mL), then adds methyl iodide (184.2mg, 1.30mmol), and room temperature reaction spends the night.Add saturated ammonium chloride dilution, be extracted with ethyl acetate 3 times, merge organic phase, add DCM(3.0ml), trifluoracetic acid (2.0ml), room temperature reaction spends the night.Pressure reducing and steaming solvent, residue Preparative TLC chromatographic separation, developping agent is methylene dichloride: acetone=20:1.
Compound 17 is white solid, 4.0mg, and productive rate is 3%. 1H?NMR(CDCl 3，400MHz)δ(ppm)7.98(dd,J=15.2,5.0Hz,2H),7.86(dd,J=8.3,1.9Hz,1H),7.83-7.75(m,2H),3.95(d,J=15.8Hz,1H),3.23(s,3H),1.71(s,3H),1.56(s,6H).EI-MS490.11[M] +.
Compound 18 is white solid, 15.0mg, and productive rate is 13%. 1H?NMR(CD 3OD，400MHz)δ(ppm)8.22-8.11(m,2H),8.02(dd,J=8.3,1.7Hz,1H),7.82(d,J=6.6Hz,1H),7.62(d,J=9.0Hz,1H),4.80(m,1H),1.67(d,J=3.8Hz,3H),1.52(t,J=6.2Hz,6H).EI-MS476.09[M] +.
Embodiment 641-(the fluoro-3-oxoisoindoline diindyl-5-of 6-amido) cyclopentyl formonitrile HCN
Figure BDA0000413658510000381
Except replacing acetone with cyclopentanone, the preparation of compound 1-(the fluoro-3-oxoisoindoline diindyl-5-of 6-amino) ring valeronitrile is with 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido) propionitrile (intermediate 9a), obtain white solid, productive rate is 26%.1H?NMR(CDCl 3，300MHz)δ(ppm)8.00-7.97(m,2H),7.89-7.83（m,2H),7.44(d,J=8.1Hz,1H),4.49(s,2H),3.22(s,3H),2.75-2.57(m,2H),2.43-2.22(m,2H),1.69-1.59(m,2H).MS-ESI:489.0[M+H]+.
Embodiment 654-[1-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-4-oxo-2-sulfo--1,3-diaza [4.4] spiral shell-3-in ninth of the ten Heavenly Stems yl]-2-(trifluoromethyl) cyanobenzene (compound 19)
Figure BDA0000413658510000382
Except substituting intermediate 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido with intermediate 1-(the fluoro-3-oxoisoindoline diindyl-5-of 6-amido) cyclopentyl formonitrile HCN) propionitrile (intermediate 9a), the preparation of compound 19 is with compound 1, white solid 41mg, productive rate is 27%. 1H?NMR（CDCl 3，400MHz）δ(ppm)8.00-7.99(m,2H),7.90-7.86(m,2H),7.46(d,J=8.8Hz,1H),7.09(s,1H),4.57(s,2H),2.42-2.29(m,4H),2.04-1.89(m,4H).MS-ESI489[M+H] +.
Embodiment 662-(the fluoro-3-oxoisoindoline diindyl-5-of 6-amido)-3-methoxyl group-2-methyl propionitrile
Figure BDA0000413658510000383
Except replacing acetone with 1-methoxy acetone, the same 2-of preparation (the fluoro-3-oxoisoindoline diindyl-5-of 6-base the amido)-2-methyl propionitrile (intermediate 9d) of 2-(the fluoro-3-oxoisoindoline diindyl-5-of 6-amido)-3-methoxyl group-2-methyl propionitrile, white solid 325mg, productive rate is 51%. 1H?NMR（CDCl 3，400MHz）δ(ppm)7.57（d,J=8.0Hz,1H）,7.51（brs，1H），7.19（d，J=10.0Hz,1H），4.77（d,J=3.6Hz,1H），4.39（s,2H），3.73(d,J=9.2Hz,1H),3.67(d,J=9.2Hz,1H),3.53(s,3H),1.73(s,3H).
Embodiment 674-[3-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-4-methoxymethyl-4-methyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 20)
Figure BDA0000413658510000391
Except replace 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido with 2-(the fluoro-3-oxoisoindoline diindyl-5-of 6-amido)-3-methoxyl group-2-methyl propionitrile) propionitrile (intermediate 9a), the preparation of compound 20 is with compound 1, white solid, productive rate is 20%. 1H?NMR（CDCl 3，300MHz）δ(ppm)8.00-7.82(m,4H),7.45(d,J=8.7Hz,1H),7.11(brs,1H),4.55(s,2H),3.76(d,J=9.9Hz,1H),3.52(d,J=9.9Hz,1H),3.50(s,3H),1.45(m,3H).LRMS(ESI)m/z[M+H] +493.
The chloro-4-[5-of embodiment 682-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-8-oxo-6-sulphur oxo-5,7-diaza spiro [3.4]-2-octane-7-yl]-2-(trifluoromethyl) cyanobenzene (compound 21)
Figure BDA0000413658510000392
Except replacing 4-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 2) with 4-isothiocyano-2-chlorobenzonitrile, the preparation of compound 21 is with compound 13, white solid, and productive rate is 29%. 1H?NMR(DMSO-d6，300MHz,)δ(ppm)8.83(s,1H),8.19(d,J=8.2Hz,1H),8.02(s,1H),7.78(dd,J=21.5,9.7Hz,2H),4.50(s,2H),2.63(m,2H),2.30(m,2H),2.00-1.59(m,2H).MS-EI440.05[M] +.
Embodiment 694-[5-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-bromobenzylcyanide (compound 22)
Figure BDA0000413658510000393
Except replacing 4-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 2) with 4-isothiocyano-2-bromobenzylcyanide, the preparation of compound 22 is with compound 13, white solid, and productive rate is 33%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)8.83(s,1H),8.15(d,J=8.4Hz,2H),7.84-7.74(m,2H),4.49(s,2H),2.63(m,2H),2.33(m,2H),1.97-1.59(m,2H).MS-EI485.0[M+H] +.
Embodiment 704-[5-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methyl benzonitrile (compound 23)
Figure BDA0000413658510000401
Except replacing 4-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 2) with 4-isothiocyano-2-methyl benzonitrile, the preparation of compound 23 is with compound 13, yellow solid, and productive rate is 38%. 1H?NMR(CDCl 3，300MHz,)δ(ppm)7.89(d,J=6.7Hz,1H),7.75(d,J=8.2Hz,1H),7.43(dd,J=14.1,8.2Hz,3H),6.33(s,1H),4.57(s,2H),2.67(m,2H),2.43–2.16(m,2H),1.67–1.51(m,2H).MS-EI420.11[M] +.
Embodiment 714-[5-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-3-anisole formonitrile HCN (compound 24)
Figure BDA0000413658510000402
Except replacing 4-isothiocyano-2-trifluoromethyl cyanobenzene (intermediate 2) with 4-isothiocyano-3-anisole formonitrile HCN, the preparation of compound 24 is with compound 13, yellow solid, yield 42%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.89(d,J=6.7Hz,1H),7.70(d,J=8.1Hz,1H),7.46(d,J=8.5Hz,1H),7.17-7.07(m,2H),6.34(s,1H),4.57(s,2H),3.98(s,3H),2.80-2.57(m,2H),2.44-2.19(m,2H),1.66(m,2H).MS-EI436.10[M] +.
The bromo-2-of embodiment 726-(cyclobutylmethyl)-5-fluorine isoindoline-1-ketone
Figure BDA0000413658510000403
Except replacing brooethyl cyclopropane with Bromomethylcyclobutane, the preparation of the bromo-2-of 6-(cyclobutylmethyl)-5-5-fluorine isoindoline-1-ketone is with the bromo-2-of 6-(cyclopropyl methyl)-5-5-fluorine isoindoline-1-ketone, yellow solid, productive rate is 30%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.02(d,J=6.3Hz,1H),7.19(d,J=7.8Hz,1H),4.29(s,2H),3.62(d,J=7.8Hz,2H),2.70-2.60(m,1H),2.13-1.80(m,6H).
The fluoro-3-isoindoline-5-of embodiment 732-[2-(cyclobutylmethyl)-6-amido]-2 Methylpropionic acid
Figure BDA0000413658510000411
Except replacing the bromo-2-of 6-(cyclopropyl methyl)-5-fluorine isoindoline-1-ketone with the bromo-2-of 6-(cyclobutylmethyl)-5-fluorine isoindoline-1-ketone, the fluoro-3-isoindoline-5-of 2-[2-(cyclobutylmethyl)-6-amido] the fluoro-3-isoindoline-5-of the same 2-[2-of preparation (cyclopropyl the methyl)-6-amido of-2 Methylpropionic acid]-2 Methylpropionic acid, yellow oil, productive rate is 42%.Be directly used in the next step.
The fluoro-3-isoindoline-5-of embodiment 742-[2-(cyclobutylmethyl)-6-amido]-2 Methylpropionic acid methyl esters
Figure BDA0000413658510000412
Except with 2-[2-(cyclobutylmethyl)-the fluoro-3-isoindoline-5-of 6-amido]-2 Methylpropionic acid replaces the fluoro-3-isoindoline-5-of 2-[2-(cyclopropyl methyl)-6-amido]-2 Methylpropionic acid, the fluoro-3-isoindoline-5-of 2-[2-(cyclobutylmethyl)-6-amido] the fluoro-3-isoindoline-5-of the same 2-[2-of preparation (cyclopropyl the methyl)-6-amido of-2 Methylpropionic acid methyl esters]-2 Methylpropionic acid methyl esters, yellow oil, productive rate is 38%. 1H?NMR(CDCl 3，300MHz)δ(ppm)7.04(d,J=10.8Hz,1H),6.95(d,J=7.8Hz,1H),4.48(brs,1H),4.18(s,2H),3.75(s,3H),3.58(d,J=7.8Hz,2H),2.66-2.61(m,1H),2.66-1.67(m,6H),1.62(s,6H).
The fluoro-3-isoindoline-5-of embodiment 754-[[3-[2-(cyclobutylmethyl)-6-amido]-4,4-dimethyl-5-oxo-2--thiocarbamoyl imidazole alkane-1-yl]]-2-(trifluoromethyl) cyanobenzene (compound 25)
Figure BDA0000413658510000413
Except with 2-[2-(cyclobutylmethyl)-the fluoro-3-isoindoline-5-of 6-amido]-2 Methylpropionic acid methyl esters replaces the fluoro-3-isoindoline-5-of 2-[2-(cyclopropyl methyl)-6-amido]-2 Methylpropionic acid methyl esters, the preparation of compound 25 is with compound 14, white solid, productive rate is 54%. 1h NMR (acetone-d6,300MHz) δ (ppm) 8.31-8.26 (m, 2H), 8.15-8.04 (m, 1H), 7.75 (d, J=6.6Hz, 1H), 7.62 (d, J=9.3Hz, 1H), 4.58 (s, 2H), (3.63 d, J=7.5Hz, 2H), 2.82-2.75 (m, 1H), 2.12-2.04 (m, 6H), 1.85 (s, 3H), 1.75 (s, 3H) .MS-ESI531.0[M+H] +.
Embodiment 764-[3-(the fluoro-3-oxo-2-of 6-phenyl isoindoline-5-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl]-2-(trifluoromethyl) cyanobenzene (compound 26)
Figure BDA0000413658510000421
By compound 4(50.0mg, 0.108mmoL), iodobenzene (14 μ L, 0.13mmoL), CuI (2.1mg, 0.0108moL), K 3pO 4(41.0mg, 0.216mmoL) and N, N'-dimethyl-ethylenediamine (3.0 μ L, 0.216mmoL) is added in dry toluene (1.0mL), under argon shield, spends the night in 120 ℃ of reactions of oil bath.Add water, be extracted with ethyl acetate.Organic phase concentrating under reduced pressure, residue separates with rapid column chromatography, and eluent is sherwood oil: ethyl acetate=2:1, obtains white solid 24.0mg, and productive rate is 42%. 1h NMR (acetone-d6,300MHz) δ (ppm) 8.32-8.28 (m, 2H), 8.14 (dd, J=6.0,1.5Hz, 1H), 7.98 (dd, J=6.6,0.9Hz, 2H), 7.88 (d, J=5.1Hz, 1H), 7.75 (d, J=6.9Hz, 1H), 7.48-7.44 (m, 2H), 7.23-7.19 (m, 1H), (5.15 d, J=4.8Hz, 2H), 1.78 (s, 3H), 1.61 (s, 3H) .MS-ESI539.0[M+H] +.
Embodiment 774-[3-(the fluoro-3-oxoisoindoline diindyl-5-of 2-benzyl-6-yl)-4,4-dimethyl-2-sulfo--5-oxo-imidazole alkane-1 base]-2-trifluoromethyl cyanobenzene (compound 27)
Figure BDA0000413658510000422
By compound 4(46.2mg, 0.1mmoL), cylite (17.1mg, 0.1mmoL) and cesium carbonate join in anhydrous dimethyl sulfoxide (5.0mL), under argon shield, react 6 hours in 50 ℃ of oil baths.Add ethyl acetate, methyl-sulphoxide is removed in washing.Organic phase is concentrated, and residue separates with rapid column chromatography, and eluent, for for sherwood oil: ethyl acetate=2:1, obtains white solid 3.0mg, and productive rate is 5.5%. 1h NMR (acetone-d6,300MHz) δ (ppm) 8.31-8.26 (m, 2H), 8.11 (d, J=9.1Hz, 1H), 7.80 (d, J=6.5Hz1H), 7.65 (d, J=3.2Hz, 1H), 7.38 (m, 5H), 4.78 (d, J=14.2Hz, 2H), 4.50 (d, J=3.2Hz, 2H), 1.75 (s, 3H), 1.58 (s, 1H) .MS-ESI551.0[M-H] -.
Embodiment 784-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido) tetrahydrochysene-2H-pyrans-4-formonitrile HCN
Figure BDA0000413658510000431
Except replacing acetone with 4-oxo pimelinketone, the same 2-of preparation (the fluoro-3-oxoisoindoline diindyl-5-of 6-base the amido)-2-methyl propionitrile (intermediate 9d) of 4-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido) tetrahydrochysene-2H-pyrans-4-formonitrile HCN, white solid, productive rate is 91.0%.Be directly used in the next step.
Embodiment 794-[1-(the fluoro-3-oxoisoindoline diindyl-5-of 6-yl)-4-oxo-2-sulfo--1,3-phenodiazine spiral shell [4,5] certain herbaceous plants with big flowers alkane-3-yl]-2-trifluoromethyl cyanobenzene (compound 28)
Figure BDA0000413658510000432
Except substituting 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido with intermediate 4-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido) tetrahydrochysene-2H-pyrans-4-formonitrile HCN) propionitrile (intermediate 9a), the preparation of compound 28 is with compound 1, yellow solid, productive rate is 60%. 1H?NMR(CD 3OD,300MHz)δ(ppm)8.18(m,2H),8.04(d,J=6.2Hz,2H),7.81(d,J=6.6Hz,1H),7.62(d,J=9.0Hz,1H),4.58(s,2H),4.12(q,2H),3.86(m,2H),2.33(m,2H),2.15(m,1H),1.88(m,1H).MS-EI504.0[M] +.
The chloro-2-of embodiment 804-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido)-2-methylbutyronitrile
Figure BDA0000413658510000433
Except replacing acetone with the chloro-2-butanone ketone of 4-, the same 2-of preparation (the fluoro-3-oxoisoindoline diindyl-5-of 6-base the amido)-2-methyl propionitrile (intermediate 9d) of the chloro-2-of 4-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido)-2-methylbutyronitrile, productive rate is 76%.Be directly used in the next step.
Embodiment 814-[4-(2-chloromethyl)-3-(the fluoro-2-acetylaminohydroxyphenylarsonic acid of 6-3-oxoisoindoline diindyl-5-yl)-4-methyl-2-sulfo--5-oxo-imidazole alkane-1-yl]-2-trifluoromethyl cyanobenzene (compound 29)
Figure BDA0000413658510000441
Except replace intermediate 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido with the chloro-2-of intermediate 4-(the fluoro-3-oxoisoindoline diindyl-5-of 6-base amido)-2-methylbutyronitrile) propionitrile (intermediate 9a), the preparation of compound 29 is with compound 1, light yellow solid, yield 19%. 1h NMR (acetone-d6,300MHz) δ (ppm) 8.40-8.33 (m, 2H), 8.25-8.22 (d, J=8.9Hz, 1H), 7.88 (s, 1H), 7.5 (brs, 1H), 7.38 (s, 1H), 4.67 (t, J=7.8Hz, 2H), 4.46 (s, 2H), 3.18 (t, J=6.9Hz, 2H), 2.15 (s, 3H) .MS-EI510.0[M] +.
Embodiment 822-methyl-2-(6-methyl-5-oxo-6,7-dihydro-5H-pyrroles [3,4-b] pyridin-3-yl amido) propionitrile
Figure BDA0000413658510000442
Except using 3-amido-6-methyl-6,7-dihydro-5H-pyrroles [3,4-b] and pyridine-5-ketone substitute outside intermediate 5-amino-1-iso-dihydro-indole (intermediate 8a), intermediate 2-methyl-2-(6-methyl-5-oxo-6,7-dihydro-5H-pyrroles [3,4-b] pyridin-3-yl amido) preparation of propionitrile is with 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido) propionitrile (intermediate 9a).White solid, productive rate is 60%.Be directly used in the next step.
Embodiment 834-(3-(6-methyl-5-oxo-6,7-dihydro-5H-pyrroles [3,4-b] pyridin-3-yl)-4,4-dimethyl-5-oxo-2-thiocarbamoyl imidazole alkane-1-yl)-2-trifluoromethyl cyanobenzene (compound 30)
Figure BDA0000413658510000443
Except using intermediate 2-methyl-2-(6-methyl-5-oxo-6,7-dihydro-5H-pyrroles [3,4-b] and pyridine 3-base amido) propionitrile substitutes intermediate 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido) outside propionitrile (intermediate 9a), the preparation of compound 30 is with compound 1.Light yellow solid, productive rate is 7%. 1H?NMR(CD 3OD,300MHz)δ(ppm)8.77(d,J=5.4Hz,1H),8.20(m,3H),8.05(d,J=8.4Hz,1H),4.65(s,2H),3.25(s,3H),1.61(s,6H).MS-EI459.1[M] +.
Embodiment 842-methyl-4-nitrobenzene methyl
Figure BDA0000413658510000451
2-methyl-4-nitrobenzoic acid (5.0g, 27.60mmol) is dissolved in methyl alcohol (60mL), stirs the lower vitriol oil (1.5mL) that drips.Reinforced complete, reflux 22 hours.Cooling, concentrated, add water, with dichloromethane extraction, merge organic phase, saturated common salt water washing.Organic phase anhydrous sodium sulfate drying, filters, and pressure reducing and steaming solvent, obtains yellow solid 5.26g, and productive rate is 98%.Be directly used in the next step. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.11-8.05(m,3H),3.95(s,3H),2.69(s,3H).
Embodiment 852-(brooethyl)-4-nitrobenzene methyl
Figure BDA0000413658510000452
2-methyl-4-nitrobenzene methyl (5.0g, 25.62mmoL) is joined to CCl 4(30mL), in, under agitation add N-bromo-succinimide (6.84g, 38.43mmoL) and Diisopropyl azodicarboxylate (421mg, 2.56mmoL).Under argon shield, be heated to 70 ℃, stir 2 hours.Cooling, pressure reducing and steaming solvent, residue separates with rapid column chromatography, obtains white solid 3.49g, and productive rate is 50%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.34(d,J=2.1Hz,1H),8.21(d,J=8.7,2.1Hz,1H),8.12(d,J=8.4Hz,1H),4.98(s,2H),4.01(s,3H).
Embodiment 862-(nitrile methyl)-4-nitrobenzene methyl
Figure BDA0000413658510000453
By 2-(brooethyl)-4-nitrobenzene methyl (3.4g, 12.41mmoL), sodium cyanide (608mg, 12.41mmoL) is added in dioxane (15mL) and water (20mL) mixed system, be heated to 80 ℃, stir 4 hours.Cooling, add water, be extracted with ethyl acetate.Pressure reducing and steaming solvent, residue separates with rapid column chromatography, obtains white solid 1.11g, and productive rate is 41%. 1H?NMR(CDCl 3，300MHz)δ(ppm)8.44(m,1H),8.28-8.27(m,2H),4.31(s,2H),4.01(s,3H).
Embodiment 874-amido-2-(nitrile methyl) methyl benzoate
Figure BDA0000413658510000461
2-(nitrile methyl)-4-nitrobenzene methyl (1.13g, 5.06mmoL), methyl alcohol (10mL), tetrahydrofuran (THF) (10mL) and ammonium chloride (2.7g, 50.55mmoL) join water (20mL) and iron powder (1.42g, in mixed system 25.28mmoL), be heated to 80 ℃, stir 3 hours.Cooling, add water, be extracted with ethyl acetate, merge organic phase, saturated sodium-chloride washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, obtains yellow solid 962mg, and productive rate is 100%.Be directly used in the next step. 1H?NMR(DMSO-d6，300MHz)δ(ppm)7.72(d,J=8.7Hz,1H),6.66(d,J=2.4Hz,1H),6.53(dd,J=8.7,2.1Hz,1H),6.19(s,2H),4.16(s,2H),3.74(s,3H).
Embodiment 886-amido-3,4-dihydro-isoquinoline-1 (2H)-one
Figure BDA0000413658510000462
Except replacing 3-amine-2-itrile group-6-fluorophenyl carbamate with 4-amido-2-(nitrile methyl) methyl benzoate, 6-amido-3, the preparation of 4-dihydro-isoquinoline-1 (2H)-one is with 4-amido-7-fluorine isoindoline-1-ketone (intermediate 8b).White solid, productive rate is 85%. 1H?NMR(DMSO-d6，300MHz)δ(ppm)7.50(d,J=8.4Hz,1H),7.36(s,1H),6.44(dd,J=8.4,1.6Hz,1H),6.33(s,1H),5.69(s,2H),3.29-3.25(m,2H),2.70(t,J=6.4Hz,2H).
Embodiment 892-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-base amido) propionitrile
Figure BDA0000413658510000463
Except using 6-amido-3,4-dihydro-isoquinoline-1 (2H)-one replaces outside 5-amino-1-iso-dihydro-indole (intermediate 8a), intermediate 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-y base amido) preparation of propionitrile is with 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido) propionitrile (intermediate 9a).White solid 191mg, productive rate is 67%. 1H?NM(DMSO-d6，300MHz)δ(ppm)7.66(d,J=8.4Hz,1H),7.56(s,1H),6.74(dd,J=8.4,2.4Hz,1H),6.69(s,1H),6.63(d,J=2.0Hz,1H),3.30-3.34(m,2H),2.81(t,J=6.4Hz,2H),1.67(s,6H).
Embodiment 904-[4,4-dimethyl-5-oxo-3-(1-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-2-t thiocarbamoyl imidazole alkane-1-yl)-2-trifluoromethyl cyanobenzene (compound 31)
Figure BDA0000413658510000471
Except using intermediate 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-base amido) propionitrile replaces 2-methyl-2-(1-oxoisoindoline diindyl-5-base amido) outside propionitrile (intermediate 9a), the preparation of compound 31 is with compound 1.White solid, productive rate is 30%. 1h NMR (acetone-d6,300MHz) δ (ppm) 8.29 (d, J=8.7Hz, 1H), 8.22 (m, 1H), 8.12-8.09 (m, 2H), 7.42-7.40 (m, 2H), 7.18 (brs, 1H), 3.57-3.63 (m, 2H), 3.09 (t, J=6.6Hz, 2H), 1.64 (s, 6H) .MS-EI m/z458M +.
Embodiment 917-nitro-3,4-dihydro-2H-isoquinoline-1-ketone preparation (intermediate 15)
By raw material 3, sulfuric acid for 4-dihydro-2H-isoquinoline-1-ketone (1.47g, 9.99mmoL) (20ml) dissolves, and drips nitrosonitric acid (2ml) under ice bath cooling conditions.Stirring at room temperature 45 minutes, reaction solution is poured in a large amount of frozen water.The aqueous solution is extracted with ethyl acetate, ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter and be concentrated into the dry yellow oil that obtains, rapid column chromatography separates (sherwood oil: ethyl acetate=3:1) and obtains intermediate 15(800mg).LC-MS:C 9h 8n 2o 3[M+H] +calculated value 193.05, measured value 192.9.
Embodiment 927-amino-3,4-dihydro-2H-isoquinoline-1-ketone preparation (intermediate 16)
Figure BDA0000413658510000473
Get the dissolve with methanol of intermediate 15 (500mg) 30ml, add the Raney-Ni catalyzer of 1g, under hydrogen condition, stir and spend the night. reacting liquid filtering, the methanol wash of 200ml for filter cake, merging filtrate, is concentrated into the dry white solid that obtains.This solid rapid column chromatography separates (sherwood oil: ethyl acetate=1:1) and obtains intermediate 16 (400mg). 1h NMR (DMSO-d6,400MHz) δ (ppm) 8.55 (d, 1H, J=2Hz), 8.32 (dd, 1H, J=2,8.4Hz), 7.64 (d, 1H, J=8.4Hz), 3.44 (m, 2H), 3.07 (m, 2H) .LC-MS:C 9h 10n 2o[M+H] +calculated value 163.08, measured value 164.0.
Embodiment 932-methyl-2-[(1-oxygen-3,4-dihydro-2H-isoquinoline 99.9-7-yl) amido] propionitrile preparation (intermediate 17)
Figure BDA0000413658510000481
By intermediate 16(400mg) use 10ml acetone solution, add trimethyl silicane cyanogen (2ml) and 2ml acetic acid, tube sealing, is heated to 60 ℃ and spends the night.Reaction solution cool to room temperature, after concentrating under reduced pressure, add water, ethyl acetate for the aqueous solution (100ml × 3) extraction, ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filters and is concentrated into the dry yellow oil that obtains, and rapid column chromatography separates (sherwood oil: ethyl acetate=2:1) and obtains intermediate 17 (460mg).(DMSO-d6,400MHz) δ (ppm) 7.40 (d, 1H, J=3.2Hz), 7.13 (d, 1H, J=8.0Hz), 6.95 (dd, 1H, J=2.8,8.0Hz), 6.15 (s, 1H), 3.33 (t, 2H, J=), 2.77 (t, 2H), 1.63 (s, 6H) .LC-MS:C 13h 15n 3o[M+H] +calculated value 230.1, measured value 230.0.
Embodiment 944-(4,4-dimethyl-5-oxygen-3-(1-oxygen-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-thiocarbamoyl imidazole alkane-1-yl)-2-(trifluoromethyl) cyanobenzene preparation (compound 32)
Figure BDA0000413658510000482
Intermediate 17 (460mg, 2.006mmoL), 4-isothiocyanic acid base-2-(trifluoromethyl) cyanobenzene (480mg, 2.1mmoL) be dissolved in anhydrous tetrahydro furan with catalytic amount triethylamine, tube sealing, is heated to 50 ℃, and stirring is spent the night.Reaction solution cool to room temperature, is evaporated to dry.Gained dissolving crude product is in the methyl alcohol of 10ml, add the hydrochloric acid soln of the 2N of 3ml, reflux and be cooled to room temperature after 1 hour, the concentrated methyl alcohol that boils off, ethyl acetate extraction. organic layer anhydrous magnesium sulfate drying, filter, be concentrated into dryly, gained oily matter rapid column chromatography (methylene dichloride: acetone=10:1) obtains target compound.(CD 3oD, 400MHz) δ (ppm) 8.11-8.21 (m, 2H), 8.03 (d, 1H, J=8.0Hz), 7.95 (d, 1H, J=2.0Hz), 7.53-7.55 (m, 2H), 3.59 (t, 2H, J=6.8Hz), 3.11 (t, 2H, J=6.4Hz), 1.60 (s, 6H) .LC-MS:C 22h 17f 3n 4o 2s[M+H] +calculated value 459.1, measured value 458.8.
Embodiment 955-fluorine 1-isoindolinone preparation (intermediate 18)
Figure BDA0000413658510000491
The dissolve with methanol of 30ml for 2-cyano group-4-fluorophenyl carbamate (1.5g, 8.4mmoL), adds the Raney-Ni catalyzer of 1g, under hydrogen condition, stirs and spends the night.Reacting liquid filtering, ethyl acetate for filter cake (200ml) washing, merging filtrate, is concentrated into the dry crude product that obtains.Rapid column chromatography separates (sherwood oil: ethyl acetate=5:1) and obtains intermediate 18(1.2g, white solid) .LC-MS:C 8h 6fNO[M+H] +calculated value 152.0, measured value 152.0.
The fluoro-2-of embodiment 965-(2-methoxyethyl) 1-isoindolinone preparation (intermediate 19)
Figure BDA0000413658510000492
Raw material midbody 18 (700mg, 4.6315mmoL) is dissolved with 10ml DMF, under ice bath is cooling, add sodium hydrogen (65%, 342mg) in batches.Gained mixture stirs after 30 minutes and adds the bromo-2-methyl ethyl ether of 1-(800mg), and gained dark solution is heated to 60 ℃, stirs 5 hours.Reaction solution is cooled to room temperature, and LC-MS detection display reacts completely, and reaction solution is poured in frozen water.Ethyl acetate for the aqueous solution (100ml × 3) extraction, ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter and be concentrated into the dry yellow oil that obtains, rapid column chromatography separates (sherwood oil: ethyl acetate=1:1) and obtains intermediate 19 (800mg). 1h NMR (CDCl 3, 400MHz) and δ (ppm) 7.83-7.80 (m, 1H), 7.16-7.12 (m, 1H), 4.52 (s, 2H), 3.79 (t, 2H, J=4.8Hz), (3.64 t, 2H, J=4.8Hz), 3.33 (s, 3H) .LC-MS:C 11h 12fNO 2[M+H] +calculated value 210.1, measured value 210.0.
The fluoro-2-of embodiment 975-(2-methoxyethyl)-6-nitro-1-isoindolinone preparation (intermediate 20)
Figure BDA0000413658510000493
To get intermediate 19 (800mg), with sulfuric acid (20ml) dissolving, under ice bath cooling conditions, drip nitrosonitric acid (2ml). stirring at room temperature 3 hours, reaction solution is poured in a large amount of frozen water.The aqueous solution is extracted with ethyl acetate, and ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filter and be concentrated into the dry yellow oil that obtains, rapid column chromatography separates (sherwood oil: ethyl acetate=10:1) and obtains intermediate 20(yellow solid, 800mg).LC-MS:C 11h 11fN 2o 4calculated value [M+H] +255.1, measured value 254.9.
Embodiment 986-amino-5-fluorine-2-(2-methoxyethyl) 1-isoindolinone preparation (intermediate 21)
Figure BDA0000413658510000494
The dissolve with methanol of 30ml for intermediate 20 (800mg), adds the Raney-Ni catalyzer of 1g, under hydrogen condition, stirs and spends the night.Reacting liquid filtering, ethyl acetate for filter cake (200ml) washing, merging filtrate, is concentrated into the dry intermediate 21(700mg that obtains). 1h NMR (CD 3oD, 400MHz) δ (ppm) 7.20-7.17 (m, 2H), 4.44 (s, 2H), 3.76 (t, 2H, J=5.2Hz), 3.64 (t, 2H, J=5.2Hz), 3.37 (s, 3H) .LC-MS:C 11h 13fN 2o 2[M+H] +calculated value 225.1, measured value 225.0.
The fluoro-2-of embodiment 992-[[6-(2-methoxyl group)-3-oxygen-isoindoline-5-yl] amino]-2-methyl propionitrile preparation (intermediate 22)
Figure BDA0000413658510000501
Get intermediate 21 (400mg) and use 30ml acetone solution, add trimethyl silicane cyanogen (1ml) and several acetic acid, tube sealing, is heated to 50 ℃ and constant temperature and continues to stir 48 hours.Reaction solution cool to room temperature, after concentrating under reduced pressure, add water, ethyl acetate for the aqueous solution (100ml × 3) extraction, ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filters and is concentrated into the dry yellow oil that obtains, and rapid column chromatography separates (sherwood oil: ethyl acetate=1:2) and obtains intermediate 22 (400mg). 1h NMR (CD 3oD, 400MHz) δ (ppm) 7.55 (d, 1H, J=8.0Hz), 7.30 (d, 1H, J=6.8Hz), 4.88 (s, 3H), 4.50 (s, 2H), 3.79 (t, 2H, J=4.8Hz), 3.65 (t, 2H, J=4.8Hz), 1.78 (s, 6H) .LC-MS:C 15h 18fN 3o 2[M+H] +calculated value 292.1, measured value 291.9.
Embodiment 1004-(3-(the fluoro-2-of 6-(2-methoxyethyl)-3-oxindole quinoline-5-yl)-4,4-dimethyl-5-oxygen-2-thiocarbamoyl imidazole alkane-1-yl)-2-(trifluoromethyl) cyanobenzene preparation (compound 33)
Figure BDA0000413658510000502
4-isothiocyanate group-2-(trifluoromethyl) cyanobenzene (160mg) and intermediate 22 (200mg) are dissolved in dry DMF, and tube sealing, is heated to 80 ℃, and stirring is spent the night.Reaction solution cool to room temperature, gained crude product adds in the methyl alcohol of 10ml, adds subsequently the hydrochloric acid soln of the 2N of 3ml, stirring at room temperature 3 hours, the concentrated methyl alcohol that boils off, ethyl acetate extraction.Organic layer anhydrous magnesium sulfate drying, filters, and is concentrated into dryly, and gained oily matter Preparative TLC chromatography (methylene dichloride: acetone=10:1) obtains compound 33. 1h NMR (DMSO-d6,400MHz) δ (ppm) 8.42-8.40 (m, 1H), 8.34 (s, 1H), 8.14-8.11 (m, 1H), 7.80-7.77 (m, 1H), 4.62 (s, 2H), 3.73-3.64 (m, 4H), 3.28 (s, 3H), 1.60 (s, 3H), 1.51 (s, 3H) .LC-MS:C 24h 20f 4n 4o 3s[M+H] +calculated value 521.1, measured value 520.8.
Embodiment 1012-methyl-3,4-dihydro-isoquinoline-1 (2H) ketone preparation (intermediate 23)
Figure BDA0000413658510000511
By raw material 3, DMF(100ml for 4-dihydro-isoquinoline-1 (2H) ketone (8g, 54.36mmoL)) dissolve, ice bath is cooling, adds sodium hydrogen (60%, 3.0g) in batches, gained mixture continues to stir after 30 minutes, adds methyl iodide (15g, 105.68mmoL).Reaction solution stirred overnight at room temperature, pour in frozen water, ethyl acetate (500ml × 3) extraction, ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filters and is concentrated into the dry yellow oil that obtains, rapid column chromatography separates (sherwood oil: ethyl acetate=1:1) and obtains intermediate 23(7.5g, yellow oil). 1h NMR (CDCl 3, 400MHz) and δ (ppm) 8.10 (dd, 1H, J=1.6,7.6Hz), 7.42 (t, 1H, J=5.6Hz), 7.35 (t, 1H, J=7.6Hz), 7.17 (dd, 1H, J=0.4,7.6Hz), 3.58 (t, 2H, J=6.8Hz), 3.17 (s, 3H), 3.02 (t, 2H, J=6.8Hz) .LC-MS:C 10h 11nO calculated value [M+H] +162.1, measured value 162.0.
Embodiment 1022-methyl-7-nitro-3,4-dihydro-isoquinoline-1 (2H) ketone preparation (intermediate 24)
Figure BDA0000413658510000512
By intermediate 23(7.5g) with sulfuric acid (100ml) dissolving, under ice bath cooling conditions, drip nitrosonitric acid (20ml). stirred overnight at room temperature, reaction solution is poured in a large amount of frozen water..The aqueous solution is extracted with ethyl acetate, and ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filters and is concentrated into the dry yellow solid that obtains, sherwood oil: ethyl acetate=10:1 washing, filter and obtain intermediate 24 yellow solids, 8.5g. 1H?NMR(CDCl 3，400MHz)δ(ppm)8.93(dd,1H,J=2.4Hz),8.28(dd,1H,J=2.4,8.0Hz),7.39(d,1H,J=8.4Hz),3.66(t,2H,J=6.8Hz),3.22(s,3H),3.15(t,2H,J=6.4Hz).
Embodiment 1037-amino-2-methyl-3,4-dihydro-isoquinoline-1 (2H) ketone preparation (intermediate 25)
By intermediate 24(8.5g) with the dissolve with methanol of 250ml, add the Raney-Ni catalyzer of 1g, under hydrogen condition, stir and spend the night. reacting liquid filtering, methyl alcohol filter cake for (200ml) washs, and merging filtrate, is concentrated into the dry intermediate 25 that obtains. 1H?NMR(CD 3OD，400MHz)δ(ppm)7.30(dd,1H,J=2.4Hz),7.00(d,1H,J=8.0Hz),6.84(dd,1H,J=2.4,8.0Hz),3.57(t,2H,J=6.8Hz),3.13(s,3H),2.89(t,2H,J=6.8Hz).
Embodiment 1042-methyl-2-(2-methyl isophthalic acid-oxo-1,2,3,4-tetrahydroisoquinoline-7-amino) propionitrile preparation (intermediate 26)
Figure BDA0000413658510000521
By intermediate 25(3.3g) use 10ml acetone solution, add trimethyl silicane cyanogen (5ml) and several acetic acid, tube sealing, is heated to 90 ℃ and constant temperature and continues to stir 48 hours.Reaction solution cool to room temperature, after concentrating under reduced pressure, add water, ethyl acetate for the aqueous solution (100ml × 3) extraction, ethyl acetate layer washes with water, saturated common salt water washing, anhydrous sodium sulfate drying, filters and is concentrated into the dry yellow oil that obtains, and rapid column chromatography separates (methylene dichloride: methyl alcohol=5:1) and obtains intermediate 26 (3.0g). 1H?NMR(CDCl 3，400MHz)δ(ppm)7.58(s,1H),7.13-7.09(m,2H),3.75(brs,1H),3.55(t,2H,9.6Hz),3.17(s,1H),2.93(t,2H,J=9.6Hz),1.73(s,6H).
Embodiment 1054-(4,4-dimethyl-3-(2-methyl isophthalic acid-oxygen-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-oxygen-2-thiocarbamoyl imidazole alkane-1-yl)-2-(trifluoromethyl) cyanobenzene preparation (compound 34)
Figure BDA0000413658510000522
By intermediate 26(160mg) and 4-isothiocyanate group-2-(trifluoromethyl) cyanobenzene (160mg) be dissolved in dry DMF, tube sealing, is heated to 80 ℃, stirring is spent the night.Reaction solution cool to room temperature, gained crude product adds in the methyl alcohol of 10ml, adds subsequently the hydrochloric acid soln of the 2N of 3ml, stirred overnight at room temperature, the concentrated methyl alcohol that boils off, ethyl acetate extraction.Organic layer anhydrous sodium sulfate drying, filters, and is concentrated into dryly, and gained oily matter Preparative TLC chromatography (sherwood oil: ethyl acetate=1:2) obtains compound 34(180mg, yellow solid). 1h NMR (CDCl 3, 400MHz) and δ (ppm) 8.05-7.99 (m, 3H), 7.88-7.86 (m, 1H), 7.9 (s, 1H), 3.67 (t, 2H, J=6.8Hz), 3.21 (s, 3H), (3.13 t, 2H, J=6.8Hz), 1.59 (s, 6H) .LC-MS:C 23h 19f 3n 4o 2s[M+H] +calculated value 473.1, measured value 473.1.
The chloro-4-of embodiment 1062-(4,4-dimethyl-3-(2-methyl isophthalic acid-oxygen-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-oxygen-2-thiocarbamoyl imidazole alkane-1-yl) cyanobenzene preparation (compound 35)
Figure BDA0000413658510000531
By intermediate 26(120mg) and the chloro-4-isothiocyanate group of 2-cyanobenzene (110mg) be dissolved in dry DMF, tube sealing, is heated to 80 ℃, stirring is spent the night.Reaction solution cool to room temperature, gained crude product adds in the methyl alcohol of 10ml, adds subsequently the hydrochloric acid soln of the 2N of 3ml, stirred overnight at room temperature, the concentrated methyl alcohol that boils off, ethyl acetate extraction.Organic layer anhydrous sodium sulfate drying, filters, and is concentrated into dryly, and gained oily matter Preparative TLC chromatography (sherwood oil: ethyl acetate=1:2) obtains target compound (34mg, yellow solid). 1h NMR (DMSO-d6,400MHz) δ (ppm) 8.19 (d, 1H, J=8.4Hz), 8.04 (d, 1H, J=1.6Hz), 7.86 (s, 1H), 7.75 (m, 1H), 7.49-7.46 (m, 2H), 3.61 (t, 2H, J=6.4Hz), 3.09 (t, 2H, J=6.4Hz), 3.05 (s, 3H), 1.50 (s, 6H) .LC-MS:C 22h 19clN 4o 2s[M+H] +calculated value 439.1, measured value 439.1.
Embodiment 1074-amino-2, the fluoro-benzyl cyanide preparation of 6-bis-(intermediate 27)
By bromo-4-3,5-difluoroaniline (1.0g) and zinc cyanide (5.6g), Pd (PPh 3) 4(320mg) be blended in NMP (5ml) solvent, system stirs and spends the night with ℃ reaction of argon exchange post-heating to 100.TLC monitoring reaction finishes.With ethyl acetate and water dilute and filter after layering, organic phase washes with water, saturated common salt water washing, the dry rear evaporate to dryness that filters obtains thick product, separates (sherwood oil: ethyl acetate=15:1) obtain intermediate 27 yellow solids (320mg) through rapid column chromatography. 1h NMR (CDCl 3, 400MHz) and δ (ppm) 6.23 (d, 2H), 4.62 (brs, 2H) .LC-MS:C 7h 4f 2n 2[M+H] +calculated value 155.0, measured value 155.0.
Embodiment 1082, the fluoro-4-isothiocyanic acid of 6-bis-base cyanobenzene preparation (intermediate 28)
Intermediate 27 (300mg) is suspended in to methylene dichloride and water (20ml:20ml), adds 1g solid sodium bicarbonate.Gained reaction solution drips the dichloromethane solution of thiophosgene (400mg), stirred overnight at room temperature.TLC demonstration has been reacted, and dichloromethane layer separates, and anhydrous sodium sulfate drying filters, and concentrates and obtains intermediate 28, is directly used in the next step.
Embodiment 1094-(4,4-dimethyl-3-(2-methyl isophthalic acid-oxygen-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-oxygen-2-thiocarbamoyl imidazole alkane-1-yl)-2,6-difluorobenzonitrile preparation (compound 36)
Figure BDA0000413658510000541
By intermediate 26(120mg) and intermediate 28 (120mg) be dissolved in dry DMF, tube sealing, is heated to 80 ℃, stirring is spent the night.Reaction solution cool to room temperature, gained crude product adds in the methyl alcohol of 10ml, adds subsequently the hydrochloric acid soln of the 2N of 3ml, stirred overnight at room temperature, the concentrated methyl alcohol that boils off, ethyl acetate extraction.Organic layer anhydrous sodium sulfate drying, filters, and is concentrated into dryly, and gained oily matter Preparative TLC chromatography (sherwood oil: ethyl acetate=1:1) obtains compound 36(18mg, yellow solid). 1h NMR (CDCl 3, 400MHz) and δ (ppm) 8.03 (d, 1H, J=2.0Hz), 7.38-7.30 (m, 4H), 3.67 (t, 2H, J=6.8Hz), 3.20 (s, 3H), 3.12 (t, 2H, J=6.8Hz), 1.60 (s, 6H) .LC-MS:C 22h 18F 2n 4o 2s[M+H] +calculated value 441.0, measured value 441.1.
biological activity test example 1compound suppresses male sex hormone DHT androgen receptor activation is detected
Object: investigate the restraining effect of test-compound cell levels to the androgen receptor activation being caused by DHT.
Subject cell: androgen receptor positive cell LNCaP, and mistake is expressed androgen receptor, is surely proceeded to luciferase (luciferase) plasmid that is subject to androgen receptor regulating and expressing simultaneously; Hereinafter to be referred as L1AR cell.
Experimental technique: use Luciferase assay system test kit (PROMEGA; E1501), detect Luciferase enzymic activity in cell.
Experimental procedure:
1, normally cultivate L1AR cell (containing the RPMI-1640 substratum of 10%FBS), after digestion, nutrient solution is changed into containing 10%Charcoal Stripped FBS(activated carbon treatment foetal calf serum) RPMI-1640 nutrient solution, by 2000, every hole cell density kind plate in 96 orifice plates;
2, plant plate after 3 days, dosing: cell control group is set, DHT control group (adding final concentration 1nM DHT), compound test group is (containing final concentration 1nM DHT, compound initial concentration is 1800nM, successively 3 times of dilutions be 1800,600,200,66.67,22.22,7.41,2.47,0.82nM)
3, compound treatment, after 3 days, is abandoned supernatant, and every hole adds the cell pyrolysis liquid 20 μ l of equilibrium at room temperature, and shaking table concussion makes the abundant cracking of cell.
4, liquid after lysis is moved in the 96 opaque blanks in hole, every hole adds 100 μ l Luciferase assay detection reagent, uses immediately PerkinEmlerEnvision after mixing tMinstrument is measured fluorescence intensity (Relative Light Unit, RLU) in full wavelength period.
5, compound calculates AR activation inhibiting rate:
Inhibiting rate (%)=(drug study hole-DHT control group)/(cell control group-DHT control group) × 100
6, adopt Graphpad Prism5.0 to carry out Log (inhibitor) vs.response-Variable slope (four parameters) fitting of a curve to data, calculate corresponding IC 50.
Test result:
Compound IC 50（nM）
1 24.2
2 120
3 92.3
4 41.6
5 50.9
7 21.6
14 24.1
15 86.2
19 60.0
21 12.8
22 6.0
23 38.8
24 23.7
25 31.2
26 27.2
27 74.9
28 153
32 66.7
34 36.7
35 30.2
36 68.4
biological activity test example 2the restraining effect of compound to DHT induction prostate cancer cell line LNCaP PSA protein excretion
Experimental technique: PSA (Total) the EIA detection kit that uses ALPCO company to produce, the content of detection cell conditioned medium PSA.
Experimental procedure:
1, normally cultivate LNCaP cell (containing the RPMI1640 substratum of 10%FBS), after digestion, nutrient solution changed into containing 10%CS-FBS(charcoal adsorption treatment serum) RPMI1640 nutrient solution, plant plate in 96 orifice plates, cell density is 2 × 10 4/ ml, approximately 2000/hole;
2, plant plate after 3 days, upgrade containing 1nM DHT containing 10%CS-FBS(charcoal adsorption treatment serum) RPMI1640 nutrient solution.Dosing: the 1 negative control wells in hole (add 1nM DHT, do not add compound) is set, and positive compound MDV3100 and embodiment compound initial concentration are 10000nM, successively 5 times of dilutions be 2000,400,80,16,3.2,0.64,0.128nM.
3,, after compound treatment 3d, get the PSA(Total that supernatant 50 μ l use ALPCO company to produce) EIA detection kit, the content of detection cell conditioned medium PSA.FlexStation3 measures optical density value (Optical Density, OD) at wavelength 450nm place.
Data processing and result:
1, experiment end time point, micro-Microscopic observation, compound cell growth is without obvious restraining effect, and the inhibitory rate of cell growth of each compound, lower than 30%, is got rid of cytotoxicity tentatively certainly.
2, the inhibiting rate of PSA protein excretion calculates: inhibiting rate (%)=[1-(medicine is subject to prospect hole-negative control hole)/negative control hole] × 100
3, according to the inhibiting rate of each concentration, with GraphPad Prism calculating IC 50, result is as shown in the table:
Compound IC 50（nM）
1 31.6
4 19.8
5 17.5
6 168
7 56.0
9 26.5
10 33.0
11 15.7
12 24.1

Claims (38)

1. suc as formula the compound shown in I or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or a meta-bolites,
Figure FDA0000413658500000011
Wherein,
A ring is 6～10 yuan of aromatic rings;
B ring is phenyl ring or 6 yuan of hetero-aromatic rings;
R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl is not necessarily by one or more C3～C6 cycloalkyl, C1～C6 alkoxyl group ,-NH of being selected from 2, single (C1～C6 alkyl) amino, two (C1～C6 alkyl) amino, D atom, phenyl and-C (O) R 8in group replace, wherein R 8be selected from-NH 2, single (C1～C6 alkyl) amino, two (C1～C6 alkyl) is amino or at least contain 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl;
R 2for H, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms;
R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, OH, carboxyl, benzyloxy, C1～C4 alkoxyl group or halo C1～C2 alkyl;
Or R 3, R 4with common 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals of forming of the carbon atom being connected with them;
R 5for cyano group, halogen, C1～C4 alkyl or C1～C4 alkoxyl group, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms;
R 7for H or halogen;
X is S or O;
Y is-(CH 2) n-, O or direct key, wherein-(CH 2) n-not necessarily by one or more D atoms or methyl substituted, n is 1 or 2.
2. compound according to claim 1 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein:
A ring is 6～10 yuan of aromatic rings;
B ring is phenyl ring or 6 yuan of hetero-aromatic rings;
R 1for H or C1～C4 alkyl, described C1～C4 alkyl is not necessarily by one or more C3～C6 cycloalkyl, C1～C6 alkoxyl group ,-NH of being selected from 2, single (C1～C6 alkyl) amino, two (C1～C6 alkyl) is amino ,-CONH 2, group in single (C1～C6 alkyl) formamyl, two (C1～C6 alkyl) formamyl and D atom replaces;
R 2for H, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms;
R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, OH, carboxyl, benzyloxy or C1～C4 alkoxyl group;
Or R 3, R 4with common 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals of forming of the carbon atom being connected with them;
R 5for cyano group, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms;
X is S or O;
Y is-(CH 2) n-, O or direct key, wherein-(CH 2) n-not necessarily being replaced by one or more D atoms, n is 1 or 2;
R 7for H.
3. compound as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, A ring is phenyl ring, B ring is phenyl ring.
4. compound as claimed in claim 3 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, the cyano group on A ring with
Figure FDA0000413658500000021
be each other para-orientation.
5. compound as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H or C1～C3 alkyl, described C1～C3 alkyl is not necessarily by one or more C3～C6 cycloalkyl, C1～C4 alkoxyl group, two (C1～C4 alkyl) amino ,-CONH of being selected from 2replace with the group in D atom.
6. compound as claimed in claim 5 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H or C1～C2 alkyl, described C1～C2 alkyl is not necessarily by one or more cyclopropyl, methoxyl group, diethylamino ,-CONH of being selected from 2replace with the group in D atom.
7. compound as claimed in claim 6 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H, methyl, ethyl, cyclopropyl methyl, 2-(methoxyl group) ethyl, 2-(diethylamino) ethyl ,-CH 2cONH 2or-CD 3.
8. compound as claimed in claim 7 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H, methyl or ethyl.
9. compound as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 2for H or halogen.
10. compound as claimed in claim 9 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 2for H or F.
11. compounds as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, work as R 3and R 4be independently of one another-CH 2-R 6time, R 6for H.
12. compounds as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, work as R 3, R 4while forming 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals with the carbon atom being connected with them is common, 3～6 yuan of described cycloalkyl are cyclopropyl, cyclobutyl or cyclopentyl, and 4～6 yuan of heterocyclic radicals are oxa-cyclobutyl or azelidinyl.
13. compounds as claimed in claim 12 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, 3～6 yuan of cycloalkyl are cyclobutyl, and 4～6 yuan of heterocyclic radicals are oxa-cyclobutyl.
14. compounds as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 5for cyano group or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by the atom in one or more F of being selected from, Cl and Br.
15. compounds as claimed in claim 14 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 5for C1～C2 alkyl, described C1～C2 alkyl is not necessarily replaced by one or more F atoms.
16. compounds as claimed in claim 15 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 5for-CF 3.
17. compounds as claimed in claim 2 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, Y is-CH 2-.
18. compounds as claimed in claim 1 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, the compound of formula I is the compound shown in formula II below:
Figure FDA0000413658500000041
Wherein,
R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C6 alkoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from that amino, list (C1～C6 alkyl) are amino, two (C1～C6 alkyl) is amino or at least contain 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl;
R 2for H, halogen or C1～C4 alkyl, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms;
R 3and R 4be independently of one another-CH 2-R 6, wherein R 6for H, C1～C4 alkoxyl group or halo C1～C2 alkyl;
Or R 3, R 4with common 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals of forming of the carbon atom being connected with them;
R 5for halogen, C1～C4 alkyl or C1～C4 alkoxyl group, described C1～C4 alkyl is not necessarily replaced by one or more halogen atoms;
R 7for H or halogen;
Y is-(CH 2) n-, wherein-(CH 2) n-not necessarily being replaced by one or more C1～C4 alkyl, n is 1 or 2.
19. compounds as claimed in claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C6 alkoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or at least contain 5～7 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 5～7 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl;
20. compounds as claimed in claim 19 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from C3～C6 cycloalkyl, C1～C4 alkoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or at least contain 6 yuan of heterocyclic radicals of 1 nitrogen-atoms, described 6 yuan of heterocyclic radicals that at least contain 1 nitrogen-atoms are not necessarily replaced by C1～C4 alkyl.
21. compounds as claimed in claim 20 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H, C1～C4 alkyl or phenyl, described C1～C4 alkyl not necessarily by one or more be selected from cyclopropyl, cyclobutyl, methoxyl group, phenyl and-C (O) R 8in group replace, wherein R 8be selected from amino or N methyl piperazine base.
22. compounds as claimed in claim 21 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 1for H, methyl, ethyl, phenyl, cyclopropyl methyl, cyclobutylmethyl, 2-(methoxyl group) ethyl, benzyl ,-CH 2c (O) NH 2or
23. compounds as claimed in claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 2for H or halogen.
24. compounds as claimed in claim 23 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 2for H or F.
25. compounds as claimed in claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, work as R 3and R 4be independently of one another-CH 2-R 6time, R 6for H ,-OCH 3or-CH 2cl.
26. compounds as claimed in claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, work as R 3, R 4while forming 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals with the carbon atom being connected with them is common, 4～6 yuan of described heterocyclic radicals are 4～6 yuan of heterocyclic radicals that contain 1 Sauerstoffatom.
27. compounds as claimed in claim 26 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, work as R 3, R 4while forming 3～6 yuan of cycloalkyl or 4～6 yuan of heterocyclic radicals with the carbon atom being connected with them is common, 3～6 yuan of cycloalkyl are cyclobutyl or cyclopentyl, and 4～6 yuan of heterocyclic radicals are oxa-cyclohexyl.
28. compounds as claimed in claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 5for halogen, methyl, halogenated methyl or-OCH 3.
29. compounds as claimed in claim 28 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, R 5for halogen, methyl ,-CF 3or-OCH 3.
30. as the compound of claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, and R 7for H or fluorine.
31. as the compound of claim 18 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, and wherein, Y is-(CH 2) n-, wherein-(CH 2) n-not necessarily by one or more methyl substituted, n is 1 or 2.
32. as the compound of claim 31 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, and wherein, Y is-(CH 2) 2-or-CH (CH 3)-.
33. as the compound of claim 32 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, and when Y is-(CH 2) 2-time, R 2for H.
34. compounds as claimed in claim 1 or its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites, wherein, described compound is selected from following compound:
Figure FDA0000413658500000061
Figure FDA0000413658500000071
Figure FDA0000413658500000081
35. 1 kinds of pharmaceutical compositions, it comprises being selected from according to one or more in the compound described in any one in claim 1～34, its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form and meta-bolites for the treatment of significant quantity, and one or more optional pharmaceutical excipients.
Compound, its pharmacy acceptable salt, solvate, prodrug, steric isomer, tautomer, polymorphic form or meta-bolites described in 36. claim 1～34 any one, or the application in the medicine for the preparation for the treatment of androgen receptor relative disease of pharmaceutical composition described in claim 35.
37. application according to claim 36, wherein, described androgen-receptor related diseases is that prostate cancer, mammary cancer, hyperplasia of prostate, hirsutism, acne, bald head, muscle exhaustion, gonad function are weak, osteoporosis, cholesterol are too high, male sterility, male's sexual is bad, anaemia is fat, sexual desire is hoped low or melancholia.
38. application according to claim 36, wherein, described androgen-receptor related diseases is castration tolerance type prostate cancer.
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