CN1820012A

CN1820012A - Organosilicon compounds and their use

Info

Publication number: CN1820012A
Application number: CN 200480019528
Authority: CN
Inventors: D·J·米勒; G·A·肖维尔; R·康罗伊; J·黛斯; R·塔克; D·特伯
Original assignee: Paradigm Therapeutics Ltd
Current assignee: Paradigm Therapeutics Ltd
Priority date: 2003-07-09
Filing date: 2004-06-18
Publication date: 2006-08-16
Also published as: GB0316090D0; ZA200510283B

Abstract

A compound of formula (I) or formula (II): wherein the variables are as defined in the claims.

Description

Silicoorganic compound and their purposes

Invention field

The present invention relates to compound and their purposes in treatment.

Background of invention

Gonadotropin releasing hormone (GnRH) plays a crucial role in the biology of reproduction.GnRH also is called luteinizing hormone-releasing hormone (LRH) (LH-RH).

GnRH decapeptide (pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Art-Pro-Gly-NH ₂Or p-EHWSYGLRPG-NH ₂) be in the neurone of MBH by bigger precursor through enzyme urge processing and form.Described peptide is to be released in the hypophyseal portal vessel recycle system with pulse mode, and wherein GnRH interacts with the high-affinity receptor (7-strides the film g protein coupled receptor) that is arranged in the prepituitary gland gland of brain base portion.Here, GnRH causes the release of prolan B (LH) and follicle stimulating hormone (FSH), and the both is gonad-stimulating hormone (gonad-stimulating hormone).LH stimulates testis and ovary to produce testosterone and estradiol respectively, and FSH stimulates women's hair follicle growth and the male sex's seminal fluid to form.When correctly playing a role, the pulsation release of GnRH is crucial with concentration level to the steroid generation of maintenance sexual gland and to the normal reproductive function relevant with growth and sexual development.

Hypophysis is altering a great deal in life to the response of GnRH.GnRH and gonad-stimulating hormone at first appear in the fetus in about pregnant ten weeks.Susceptibility to GnRH reduces, till pubarche.Yet during the later junior three of birth month, there is of short duration rising in it.Before pubescence, FSH to the response of GnRH greater than the response of LH to GnRH.In case pubarche, to the susceptibility raising of GnRH, and the LH that then takes place to pulse secretes.In postpuberty and whole reproductive age, the pulsation of GnRH discharges and to take place all day, simultaneously to the response of LH greater than response to FSH.The GnRH of pulsation discharges and causes the LH and the FSH of pulsing to discharge, and discharges testosterone and estradiol thus from sexual gland.After climacteric, the concentration of FSH and LH raises, and postclimacteric FSH level is than the level height of LH.

Give the cyclical level reduction that GnRH agonist and antagonist can cause LH and FSH for a long time.The GnRH agonist is the acceptor on the originality GnRH stimulation pituitary gland in the simulation, the compound that causes LH and FSH to discharge.Sexual hormoue produces after the of short duration rising (" outburst " replys), gives the downward modulation that the GnRH agonist can cause the GnRH acceptor for a long time.This desensitization that is in harmonious proportion down causes the cyclical level of LH and FSH to reduce.Although experienced the outburst of sx sexual hormoue, the GnRH agonist is the preferred therapeutic of property steroid dependency physiopathology always.The GnRH agonist has been used to reduce testosterone and has produced, thereby reduced the prostate volume in the benign prostatic hyperplasia (BPH) and in prostate cancer, make tumor growth slow.This compounds also is used to treat breast and ovarian cancer.

In recent years, it is feasible that the clinical assessment of GnRH antagonist has become, and shown that hypophysis is had acute effect, yet do not observe the outburst relevant with agonist.Reported that the GnRH antagonist is used for the treatment of the purposes of ovary, breast and prostate cancer.

Other purposes of antagonist comprises endometriosis (comprising the endometriosis that is accompanied by pain), hysteromyoma, ovary and cystic disease of breast (comprising the polycystic ovary disease), prostatomegaly, through closing (for example secondary amenorrhea) and precocious puberty.These compounds also go for the sx of premenstrual tension syndrome (PMS).Antagonist also is applicable to the secretion of regulating the gonad-stimulating hormone in the boar, with retardation spermatogenesis (for example male contraception articles for use), and is used for the treatment of man's sexual crime.GnRH antagonist and agonist have shown to have practicality in treatment, but wherein retroactive inhibition hypophysis-gonad axis is desired.

The existence of GnRH acceptor on prepituitary gland cell and some tumor cell types provides the chance of developing drugs, and this medicine works to acceptor, with treatment hormone-dependency cancer and hormonal independent cancer.

Usually, the male sex hormone forfeiture is the most effective systemic treatment of the prostatic metastatic carcinoma of treatment.Prostatic normal growth, maintenance and function need male sex hormone.Yet, prostate cancer and benign prostatic hyperplasia, very common in the male sex, and in continuing the androgenic environment of contact, develop.Utilize the GnRH antagonist to block hypophysis-gonad axis, reduced the male sex hormone generation, and cause tumor growth to be regulated.

The GnRH antagonist has direct effect by the acceptor on the blocking-up tumour cell to tumor growth.As for those to the two direct cancer type of response all of sexual hormoue and GnRH, antagonist by two kinds of mechanism in that slow down should be effective aspect the tumor growth.Owing on many prostate glands and breast cancer cell, there is the GnRH acceptor, think that recently the GnRH antagonist also may be effective in treatment non-hormone dependence tumour.Nearest document example shows, have the GnRH acceptor on many cancerous cell line.Especially, prostate cancer, ovarian cancer and mammary cancer (are seen for example people such as Montagnani, Arch.Ital, Urol.Androl.1997,69 (4), 257-263; People such as Jungwirth, Prostate 1997,32 (3), 164-172; People such as Srkalovic, Int.J.Oncol.1998,12 (3), 489-498; People such as Kottler, Int.J.Cancer1997,71 (4), 595-599.

The GnRH antagonist that is suitable for mainly be GnRH peptide analogs (see, for example, WO93/03058).The peptide antagonists of peptide hormone has some tires, but is to use existing peptide antagonists usually with problem, because peptide is by the physiology enzyme liberating, and it is bad usually to distribute in the organism of being treated.They have limited effect as medicine thus.

WO00/20358 discloses the non-peptide analogs of GnRH.

Sila-the replacement of medicine (C/Si-exchange) is a new relatively method of seeking the silicoorganic compound with useful biological characteristics.This method comprises with the particular carbon atom in the silicon substitution compound, and how the biological characteristics of monitoring compound changes.The summary of this method is provided in Tacke and Zilch, Endeavour, and New Series, 10, among the 191-197 (1986).

Summary of the invention

First aspect of the present invention is the compound of formula (I) or formula (II):

Wherein

A and C are identical or different, and each is key ,-(CH ₂) _n-,-C (R ^b) ₂-,-Si (R ^c) ₂-,-O-,-S (O) _m-,-N=,-N (R ^b)-,-N (R ^e) C (=X)-or-C (=X)-;

B is-(CH ₂) _n-,-O-,-C (R ^b) ₂-,-Si (R ^c) ₂-,-C (R ^b)=(R ^b)-,-C (R ^b)=,-(CH ₂) _nC (R ^g) ₂-,-C (R ^g) ₂(CH ₂) _n-or-CH (R ^b) CH (R ^b)-;

Wherein any of A, B and C is optional quilt-Si (R ^c) ₃Replace;

D is-(CH ₂) _n-,-C (=X)-,-O-,-S (O) _m-,-C (=X) N (R ^e)-,-C (R ^b) ₂-,-C (R ^b)=C (R ^b)-,-CH (R ^b) CH (R ^b)-;

E chooses existence wantonly and is-(CH ₂) _n-,-N (R ^d)-,-(CH ₂) _nN (R ^d)-or-N (R ^d) (CH ₂) _n-;

F is-C (=X)-or-N (R ^d)-;

G is-(CH ₂) _n-,-N (R ^d)-,-(CH ₂) _nN (R ^d)-or-N (R ^d) (CH ₂) _n

J chooses existence wantonly and is-O--N (R ^c) C (=X)-,-C (=X) N (R ^c)-,-S (O) _m-,-N (R ^C) S (O) _m-,-S (O) _mN (R ^c)-or-N (R ^e)-;

K chooses existence wantonly and is optional by R ^bThe alkylidene group that replaces; Or K is cycloalkenyl group, inferior cycloalkenyl group, arylidene, inferior Heterocyclylalkyl, inferior Heterocyclylalkyl or inferior heteroaryl, and wherein any one is optional by R ^aReplace;

L be hydrogen, halogen ,-N (R ^f) ₂, cycloalkyl, cycloalkenyl group, aryl, Heterocyclylalkyl, heterocycloalkenyl or heteroaryl, wherein any one is optional by R ^a,-C (=X) OR ^d,-OH ,-OR ^c,-C (=X) N (R ^b) (R ^c) ,-S (O) _mN (R ^b) (R ^c) or-the CN replacement;

Each R ^aIdentical or different, and be hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group ,-alkoxyl group-(CH ₂) _nC (O) ₂R ^b,-O-aryl ,-C (=X) R ^c,-NO ₂,-CN ,-N (R ^c) C (=X) R ^c,-C (=X) N (R ^c) ₂,-S (O) ₂N (R ^c) ₂Or-N (R ^e) ₂

Each R ^bIdentical or different, and be hydrogen or alkyl;

Each R ^cIdentical or different, and be alkyl, cycloalkyl ,-alkyl-aryl ,-alkyl-cycloalkyl or aryl, it is optional by R ^aReplace;

Each R ^dIdentical or different, and be hydrogen, alkyl or aryl, it is optional by R ^aReplace;

Each R ^eIdentical or different, and be hydrogen or alkyl; Or R ^eBe aryl or heteroaryl, any in two is optional by R ^aReplace;

Each R ^fIdentical or different, and be hydrogen or alkyl; Or R ^f-N-R ^fForm Heterocyclylalkyl together, heterocycloalkenyl or heteroaryl;

R ^g-C-R ^gForm heterocyclic radical together;

Each X is identical or different, and is oxygen or sulphur;

Ring is 1 and 2 identical or different, and each is arylidene or inferior heteroaryl, and any in two is optional by R ^aReplace;

Each m is identical or different, and is 0,1 or 2; With

Each n is identical or different, and is 0,1,2 or 3;

Condition is that among A, B and the C at least one comprises Siliciumatom; Each is not a key for A and C; This compound does not comprise Si-Si key, N-N singly-bound, Si-O key, Si-N key or N-O-N key;

Or its pharmacy acceptable salt,

Therefore compound of the present invention can be used as the GnRH antagonist and works, and has the treatment practicality in can lack of proper care in oncotherapy or at treatment or prevention endometriosis, hysteromyoma, disease of ovary, cystic disease of breast, prostatomegaly, amenorrhoea, precocious puberty, premenstrual tension syndrome, property-steroid-dependency physiopathology, benign prostatic hyperplasia, Alzheimer, HIV infection, AIDS or by thyroid function caused disease or the retardation spermatogenesis.

Therefore, another aspect of the present invention is that compound of the present invention is used for preparing and is used for cancer therapy or is used for the treatment of or prevents endometriosis, hysteromyoma, disease of ovary, cystic disease of breast, prostatomegaly, amenorrhoea, precocious puberty, premenstrual tension syndrome, property-steroid-dependency physiopathology, benign prostatic hyperplasia, Alzheimer, HIV infection, AIDS or by the lack of proper care purposes of medicine of caused disease or retardation spermatogenesis of thyroid function.

Another aspect of the present invention is a pharmaceutical composition, and it comprises compound of the present invention and pharmaceutically acceptable diluent or carrier.

Invention is described

Preferred some compound and substituent composition; Specifically see dependent claims.

Term used herein " alkyl " is meant to have an optional substituted straight or branched moieties to six carbon atom.This term comprises, for example, and methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl or the like.Substituting group can be identical or different in each the generation, and be selected from halogen or the like." C _1-6Alkyl " have an identical implication." alkylidene group " is meant similar divalent group.

Term used herein " alkoxyl group " is meant and comprises an optional substituted straight or branched alkoxyl group to six carbon atom.This term comprises, for example, and methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy, hexyloxy or the like.Substituting group can be identical or different in each the generation, and be selected from halogen or the like." C _1-6Alkoxyl group " have an identical implication.

Term used herein " halogen " is meant F, Cl, Br or I.

Term used herein " aryl " is meant optional substituted aromatic nucleus system that comprises six to ten annular atomses and the optional substituted multi-loop system with two or more rings (wherein at least one is an aromatic series).This term comprises, for example, and phenyl and naphthyl.Group can be chosen wantonly and be substituted the base replacement, and substituting group can be identical or different in each the generation, and be selected from R ^aOr the like." arylidene " is meant similar divalent group.

Term used herein " cycloalkyl " is meant to have three saturated alicyclic parts to six carbon atom.This term comprises, for example, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.This group can be chosen any substituting group of being described wantonly herein and replace." cycloalkylidene " is meant similar divalent group.

Term used herein " cycloalkenyl group " is meant to have three to six carbon atom and have the alicyclic part of at least one two key.This term comprises, for example, and cyclopentenyl, cyclohexenyl or the like.This group can be chosen any substituting group of being described wantonly herein and replace." inferior cycloalkenyl group " is meant similar divalent group.

Term used herein " Heterocyclylalkyl " is meant the heteroatomic saturated heterocyclic part with three to seven carbon atoms and one or more N of being selected from, O, S, P and Si.This term comprises, for example, and azetidinyl, pyrrolidyl, tetrahydrofuran base, piperidyl or the like.This group can be chosen any substituting group of being described wantonly herein and replace." inferior Heterocyclylalkyl " is meant similar divalent group.

Term used herein " heteroaryl " is meant the aromatic nucleus system of five to ten atoms (wherein at least one atom is selected from O, N and S).This term comprises, for example, and furyl, thienyl (thiophenyl), pyridyl, indyl, quinolyl or the like.This group can be chosen wantonly by R ^aDeng replacement." inferior heteroaryl " is meant similar divalent group.

Term used herein " heterocyclic radical " is meant the heteroatomic saturated or undersaturated heterocyclic moiety with three to seven carbon atoms and one or more N of being selected from, O, S, P and Si.This term comprises, for example, and piperidyl, pyrrolidyl, morpholinyl or the like.Group can be polycyclic (a for example condensed ring system), and group comprises two or more rings, and wherein at least one comprises heteroatoms.

Preferred compound of the present invention comprises:

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,7-trimethylammonium-1-sila-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-trimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(8-methoxyl group-1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,4,4,5,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-methoxyl group-1,1,4,4,8-pentamethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(6-chloro-1,1-dimethyl-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(4,4,7-trimethylammonium-4-sila-chroman-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[(pyridine-2-yl) methylamino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,5-trimethylammonium-1-sila-1H-indenes-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-1H-indenes-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[1,1,6-trimethylammonium-3-(2-propyl group)-1-sila-2,3-dihydro-1H-indenes-5-base oxygen base]-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-chloro-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-chloro-1,1,7-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-4-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(5-methoxyl group-1,1-dimethyl-1-sila-2,3-dihydro-1H-indenes-6-base oxygen base)-N-{2-[(pyridine-2-yl) methylamino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-yl) methyl]-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-yl) methyl]-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-yl) methyl]-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-(2-methylamino-4,6-dimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-{2-[(pyridine-2-yl) methylamino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro indenes-6-yl) methyl]-N-(4-chloro-2,6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,3,4,4,6-vegolysen-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[2-(morpholine-4-yl)-ethylamino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,4,4,6-pentamethyl--1,4-two silas-1,2,3,4-naphthane-5-oxygen base)-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(7 '-hydroxyl-1,1,1 ', 1 ', 6,6 '-hexamethyl-3,3 '-spiral shell-1,1 '-two silas-4,4 '-dioxo-1,1 ', 2,2 ', 3,3 ', 4,4 '-octahydro dinaphthyl-7-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-[1,1,2,6-tetramethyl--3-(2-propyl group)-1-sila-2,3-dihydro indenes-5-base oxygen base]-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide;

5-(1,1,3,4,4-pentamethyl--1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide.

5-(1,1,5-trimethylammonium-1-sila-2,3-dihydro indenes-6-base oxygen base)-N-(4-chloro-2,6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,3,3,5-pentamethyl--1-sila-2,3-dihydro indenes-6-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(1,1,3,3,6-pentamethyl--1-sila-2,3-dihydro indenes-5-base oxygen base)-N-(2, the 6-Dimethoxyphenyl) furans-2-methane amide;

5-(8-methoxyl group-1,1,4,4,6-pentamethyl--1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(morpholine-4-yl)-N-third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4-dimethoxy-pyridine-3-yl) furans-2-methane amide.

5-(1,1,3,4,4,6-vegolysen-sila-1,2,3,4-naphthane-7-base oxygen base)-N-(2,4,6-trimethoxy-1,3-pyrimidine-5-yl) furans-2-methane amide and

5-(1,1,3,4,4,6-vegolysen-sila-1,2,3,4-naphthane-7-base oxygen base)-N-[2-(2-N, N-dimethyl aminoethyl)-4,6-trimethoxy-1,3-pyrimidine-5-yl] furans-2-methane amide;

Its corresponding structure is (left-to-right order) as follows respectively:

Compound of the present invention can be a chirality.They can be the forms of single enantiomer or diastereomer or racemic modification.

Compound of the present invention can prepare with racemic form by the concrete synthetic or Split Method that this area will be understood, or with independent enantiomeric form preparation.By standard technique, for example to form diastereomer right by forming salt with optically active acid, then carries out the regeneration of fractional crystallization and free alkali, for example compound can be split as their enantiomorph.Perhaps, the enantiomorph of compounds can use chiral column, separate by HPLC.

Can there be different tautomeric forms in some compounds of described formula, and it also belongs to this

Invention scope.

Compound of the present invention can be amino or the hydroxyl of protection or the carboxy form of protection of protection.Term used herein " amino of protection ", " hydroxyl of protection " and " carboxyl of protection " are meant amino, hydroxyl and the carboxyl of protecting in mode well-known to those skilled in the art.For example, amino can pass through carbobenzoxy-(Cbz), tertbutyloxycarbonyl, ethanoyl or similar radical protection, or with phthalimido or similar group form.Carboxyl can be with for example form protection of methyl, ethyl, benzyl or tertiary butyl ester of ester of easy disconnection.

Some compounds of described formula can be with solvate forms, and for example hydrate exists, and it also belongs to the scope of the invention.

Compound of the present invention can be the form of pharmacy acceptable salt, for example inorganic or organic acid additive salt.This inorganic acid addition salt comprises for example Hydrogen bromide, hydrochloric acid, nitric acid, phosphoric acid and vitriolic salt.Organic acid addition salt comprises; acetate for example; Phenylsulfonic acid; phenylformic acid; camphorsulfonic acid; citric acid; 2-(4-chlorophenoxy)-2 Methylpropionic acid; 1, the 2-ethionic acid; ethyl sulfonic acid; ethylenediamine tetraacetic acid (EDTA) (EDTA); fumaric acid; glucoheptonic acid; glyconic acid; L-glutamic acid; the N-bismuth glycolyl arsanilate; the 4-Sucrets; urobenzoic acid; 2-(4-hydroxy benzoyl) phenylformic acid; 1-hydroxyl-2-naphthoic acid; 3-hydroxyl-2-naphthoic acid; the 2-ethylenehydrinsulfonic acid; lactobionic acid; just-dodecyl sulphate; toxilic acid; oxysuccinic acid; amygdalic acid; methylsulfonic acid; methylsulfuric acid; glactaric acid; the 2-naphthene sulfonic acid; pamoic acid; pantothenic acid; phosphenylic acid (phosphanilic acid) ((4-aminophenyl) phosphonic acids); picric acid; Whitfield's ointment; stearic acid; succsinic acid; tannic acid; tartrate; terephthalic acid; right-toluenesulphonic acids; the salt of 10-undecylenic acid or the like.

To understand during this class salt can be used for the treatment of, as long as they are pharmaceutically acceptable.This class salt can be with traditional mode, prepares by making compound and suitable acid-respons.Compound of the present invention can prepare by any appropriate method known in the art and/or by following method:

Scheme 1

SEM=2-trimethyl silyl-ethyl wherein

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme?7

To understand, the method that describes in detail above in order to illustrate purpose of the present invention, should not be seen as restriction fully.Utilize method similar or similar reagents and/or condition well known by persons skilled in the art also can be used for obtaining compound of the present invention.

Any mixture of the finished product that obtained or intermediate, can be based on the physical chemistry difference of component, be separated into pure the finished product or intermediate in a known manner, for example by chromatography, distillation, fractional crystallization, if or be suitable or if possible in the case at this, can separate by forming salt.

The activity of compound and selectivity can be measured by any suitable test known in the art.

Compound of the present invention can be used for the treatment of many slight illness, illness and disease, including, but not limited to cancer, endometriosis, hysteromyoma, disease of ovary, cystic disease of breast, prostatomegaly, amenorrhoea, precocious puberty, premenstrual tension syndrome, property-steroid dependency physiopathology, benign prostatic hyperplasia, Alzheimer, HIV infection, AIDS with by lack of proper care caused disease or be used for the retardation spermatogenesis of thyroid function.

Term used herein " cancer " is meant with the uncontrolled misgrowth of cell to be any disease or the illness of feature, the cancer that comprises all known types, for example bladder cancer, mastocarcinoma, colorectal carcinoma, the cancer of the brain, osteocarcinoma, a cancer, blood cancer, cancer eye, neck cancer, skin carcinoma, lung cancer, ovarian cancer, prostate cancer and the rectum cancer; Digestive tract cancer, gastrointestinal cancer, carcinoma of endometrium, hematology cancer, relevant cancer, flesh bone cancer, neuroscience and the gynecology cancer of AIDS; Lymphoma, melanoma and leukemia.

In therepic use, active compound can give by oral, rectum, intravaginal, parenteral, suction (lung is sent), part, eye, nose or cheek chamber.The preferred oral administration.Therapeutic composition of the present invention thus can be taked this any known drug composition forms that gives method.Can be with mode compositions formulated well known by persons skilled in the art, so that obtain controllable release, snap-out release or continue to discharge compound of the present invention for example.The pharmaceutically acceptable carrier that is suitable in this composition is well known in this area.Composition of the present invention can comprise the active compound of 0.1-99% weight.Composition of the present invention generally prepares with unit dosage.Preferably, unitary dose comprises the amount of active ingredient 1-500mg.The vehicle that is used for preparation of compositions is a vehicle known in the art.

Can measure the proper dosage level by any appropriate method well known by persons skilled in the art.Yet also will understand, concrete dosage level for arbitrary concrete patient will depend on multiple factor, comprise the severity of activity, age, body weight, general health state, sex, diet, time of administration, route of administration, drainage rate, drug regimen and the disease for the treatment of of the particular compound that is adopted.

Being used for oral composition is preferred composition of the present invention, and has the known pharmaceutical forms that is used for this administration, for example tablet, capsule, granule, syrup and moisture or oily suspension.The pharmaceutical composition that comprises active ingredient can be the form that is suitable for orally using, for example, and tablet, lozenge, lozenge, water or oily suspension, dispersible powder or granule, milk sap, hard or soft capsule, or syrup or elixir.For orally using the composition that designs, can prepare according to any known method in preparation of pharmaceutical compositions field, and for the medicine fineness and agreeable to the taste preparation are provided, this composition can comprise one or more and be selected from following reagent: sweeting agent, flavouring agent, tinting material and sanitas.Tablet contain with nontoxic, pharmaceutically acceptable, be suitable for preparing tablet excipient blended active ingredient.These vehicle can be, for example, and inert thinner, lime carbonate for example, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example, W-Gum or Lalgine; Tackiness agent, starch gelatin for example, gum arabic, Microcrystalline Cellulose or Polyvinylpyrolidone (PVP); With lubricant for example Magnesium Stearate, stearic acid or talcum powder.Tablet can be no dressing, maybe can carry out dressing by known technology, with delay disintegration and absorption in gi tract, thereby provides continuous action in the long time.For example, can postpone material for example glyceryl monostearate or distearin duration of service.

The preparation that orally uses can also provide with the form of hard capsule, wherein for example lime carbonate, calcium phosphate or kaolin mix with inert solid diluent with active ingredient, or provide with the form of soft capsule, wherein with active ingredient and water or oily medium for example peanut oil, whiteruss or mixed with olive oil.

Aqeous suspension contains the active substance with the mixed with excipients that is suitable for preparing aqeous suspension.This vehicle is a suspension agent, Xylo-Mucine for example, methylcellulose gum, Vltra tears, sodium alginate, Polyvinylpyrolidone (PVP), Tragacanth and Sudan Gum-arabic; Dispersion or wetting agent can be naturally occurring phosphatide, Yelkin TTS for example, or the condensation product of alkylene oxide and lipid acid, polyoxyethylene stearic acid ester for example, or the condensation product of oxyethane and long chain aliphatic, for example heptadecane vinyloxy group hexadecanol, or oxyethane and derived from the condensation product of the partial ester of lipid acid, for example polyoxyethylene sorbitan monooleate.Aqeous suspension can also contain one or more sanitass, for example, and P-hydroxybenzoic acid ethyl ester or n-propyl ester, one or more tinting materials, one or more flavouring agents and one or more sweeting agent, for example sucrose or asccharin.

Oily suspension can be by being suspended in vegetables oil such as peanut oil with active ingredient, sweet oil, and sesame oil or Oleum Cocois or mineral oil are such as being prepared in the whiteruss.Butyrous suspension can contain thickening material such as beeswax, paraffinum durum, or hexadecanol.Can add sweeting agent, for example those that list above and flavouring agent are to provide agreeable to the taste oral preparations.These compositions can by add antioxidant for example xitix preserve.

Be adapted to pass through and add dispersible powder and the granula that entry prepares aqeous suspension, provide and dispersion agent or wetting agent, suspension agent and one or more sanitas blended active ingredient.Also can there be suitable sweeting agent, flavouring agent and tinting material.

Pharmaceutical composition of the present invention can also be the form of oil-in-water emulsion.Oil phase can be a vegetables oil, for example sweet oil or peanut oil, or mineral oil, and such as whiteruss, or these mixture.Examples of suitable emulsifiers can be that naturally occurring natural gum is such as Sudan Gum-arabic or Tragacanth, naturally occurring phospholipid is such as soybean, Yelkin TTS, with ester or partial ester derived from lipid acid and hexitol acid anhydrides, for example, sorbitan monooleate, with the condensation product of described partial ester and oxyethane, for example, the polyoxyethylene sorbitan monooleate.Emulsion can also contain sweeting agent and flavouring agent.

Syrup and elixir can be with sweeting agent such as, glycerine, propylene glycol, Sorbitol Powder or sucrose preparation.Such preparation can also contain negative catalyst, sanitas, seasonings and tinting material.Pharmaceutical composition can be with the aseptic injectable water or the form of oleaginous suspension.This suspension can use the preparation of aforesaid suitable dispersion agent or wetting agent and suspension agent according to known technology.Aseptic injection preparation can also be at nontoxic parenteral acceptable diluent or aseptic injectable solution or the suspension in the solvent, for example solution in 1,3 butylene glycol.Acceptable vehicle that can adopt and solvent are water, ringer's solution and isotonic sodium chlorrde solution.In addition, use aseptic fixed oil as solvent or suspension medium usually.For this purpose, can use the fixed oil of any brand to comprise synthetic list-or Diglyceride.In addition, lipid acid is being applied aspect the preparation injection such as oleic acid.

Compound of the present invention can also give with the form of the suppository of rectal administration.These compositions can be by preparing medicine and the non-irritating mixed with excipients that suits, and this vehicle is a solid under normal temperature, but is liquid under rectal temperature, therefore melts to discharge medicine in rectum.This class material is theobroma oil and polyoxyethylene glycol.

Be used for topical drug delivery composition and also be suitable for the present invention.Pharmaceutically active compound can be dispersed in pharmaceutically acceptable creme, ointment or the gelifying agent.Suitable creme can for example prepare in the light liquid paraffin by active compound being incorporated into topical vehicle, and topical vehicle uses surfactant-dispersed in water-bearing media.Ointment can be by for example mineral oil or paraffin mix and prepares with active compound and topical vehicle.Gelifying agent can prepare by active compound is mixed with the topical vehicle that comprises jelling agent.For the transdermal administration compound, but the composition of topical administration also can comprise matrix, and pharmaceutically active compound of the present invention is dispersed in the matrix, so that compound and skin contact.

The following example is for example understood the present invention.

In an embodiment, all syntheticly under the drying nitrogen protection, carry out.Dry and purifying tetrahydrofuran (THF) (THF), diethyl ether, methylene dichloride, toluene and m-xylene according to standard method, and under condition of nitrogen gas, store.Sherwood oil is meant the fraction with boiling point 40-60 ℃.Tlc (TLC) is at silicon-dioxide (SiO ₂) carry out on the plate. ¹H NMR spectrum is at CDCl at 400MHz ₃Middle generation, except as otherwise noted.

1: two (Chlorodimethyl silyl) methane of intermediate

This compound is according to people such as Greber, Makromol.Chem., 1962,52,174-183 synthetic.

2: two (ethynyl dimetylsilyl) methane of intermediate

This compound is according to people such as Kusumoto, Chem.Lett., 1988,1149-1152 synthetic.

Intermediate 3: methyl 5-(fourth-2-alkynyl)-2-furoate

This compound is according to WO-A-04/045625 disclosed method synthetic.

Intermediate 4: methyl 5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5- Base) methyl]-the 2-furoate

Within 14 hours, with cyclopentadienyl dicarbapentaborane cobalt [CpCo (CO) ₂328 milligrams, 1.82mmol] m-xylene (90 milliliters) drips of solution add to two (ethynyl dimetylsilyl) methane (intermediate 2 of stirring, 2.02 gram, 11.2mmol) and methyl 5-(fourth-2-alkynyl)-2-furoate (intermediate 3,2.00 gram is 11.2mmol) in the boiling mixture in m-xylene (20 milliliters).(for fear of adding CpCo (CO) ₂Be heated before the solution, the dropping funnel that will contain this catalyzer separates by Glass tubing (length 20cm) and reaction mixture refluxed, makes CpCo (CO) by Glass tubing ₂Solution freely splashes in the backflow mixture.) removal of solvent under reduced pressure, and with resistates on silica gel by column chromatography purifying [column dimension: 60 * 3.5cm; Silica gel: 300g (32-63 μ m, ICN 02826); Elutriant: n-hexane/ethyl acetate (95: 5)].Relevant fraction (GC control) is merged, removal of solvent under reduced pressure, dried residue (15mbar, 20 ℃, 30 minutes) obtains 2.62 light yellow oils in a vacuum, and it is used ebullient normal hexane (17mL was-20 ℃ of crystallizations 3 days) crystallization.With product recrystallization under the same conditions, by the solid of decant resulting separation, with cold (20 ℃) normal hexanes (8mL) washing, dry (0.001mbar, 20 ℃, 2 hours) obtain title compound colourless crystallization solid (1.78g, 44%) in a vacuum; 111 ℃ of fusing points.C ₁₉H ₂₆O ₃Si ₂Ultimate analysis calculated value: C, 63.64; H, 7.31.Measured value: C, 63.7; H, 7.2.

Intermediate 5:2,4,6-trimethoxy-benzene amine hydrochlorate

This compound is according to WO-A-04/045625 disclosed method synthetic.

Intermediate 6: suffering-2-alkynes-4-alcohol

At room temperature be accompanied by stirring, the valeral among the anhydrous THF (100 milliliters) (5.84 milliliters, 1.1 molar equivalents) joined in 1-proyl magnesium bromide (0.5M, in THF, the 100 milliliters) solution in during 30 minutes.With ice and the mixture of saturated aqueous ammonium chloride (1: 1,120mL) before the cancellation, at room temperature further stirring reaction 3 hours.Separate organic phase, and before the organic moiety drying (sal epsom) and vacuum concentration that will merge, (3 * 100mL) extractions contain water section with sherwood oil.The light yellow oil that obtains (7.28g) is uniformly basically, and without being further purified just in next step use.R _f(0.19 10% diethyl ether-sherwood oil). ¹HNMR δ _H0.92 (3H, t, J=7.1Hz), 1.31-1.49 (4H, m), 1.65-1.79 (2H, m), 1.86 (3H, s) and 4.34 (1H, br, s).

Intermediate 7: suffering-2-alkynes-4-ketone

During 3 hours, in acetone (30 milliliters) solution of suffering-2-alkynes-4-alcohol (intermediate 6,2.41 grams), be added dropwise to the mixture of chromium trioxide (1.91 gram), the vitriol oil (1.62 milliliters) and water (20 milliliters).After at room temperature further stirring 30 minutes, the further water of reaction solution (50mL) is diluted, and (separate drying (sal epsom) and concentrated in 3 * 30mL) by product being extracted into ether.With vacuum distilling purifying desired material (boiling point 61-63 ℃, 8mbar, 1.54g). ¹H NMR (CDCl ₃) δ _H0.96 (3H, t, J=7.3Hz), 1.27-1.41 (2H, m), 1.61-1.69 (2H, m), 2.05 (3H, s) and 2.56 (2H, t, J=7.3Hz).

Intermediate 8:1-(1,3,6-trimethylammonium-1,3-two silas-2,3-dihydro-1H-indenes-5-yl)-pentanone

During about 3 hours, under refluxad, to two (ethynyl dimetylsilyl) methane (intermediate 2,1.40 gram, 7.78mmol), (intermediate 7,0.96 gram 7.78mmol) He in anhydrous dimethyl benzene (100 milliliters) mixture is added dropwise to CpCo (CO) to suffering-2-alkynes-4-ketone ₂Anhydrous dimethyl benzene (40 milliliters) solution of (0.25 molar equivalent, 0.241 milliliter).Further adding foregoing CpCo (CO) ₂(0.25 molar equivalent, before anhydrous dimethyl benzene (40mL) solution 0.241mL), heated mixt spends the night to refluxing.Under refluxad heated mixt spends the night once more.After cooling, remove volatile matter in a vacuum, with resistates column chromatography (SiO ₂, 10% methylene dichloride is in sherwood oil) and purifying, obtain needed compound (748mgs, 32%).LC-MS：m/z＝305(M+H ⁺)。 ¹H NMR δ _H0.03 (2H, s), 0.32 (6H, s), 0.33 (6H, s), 0.97 (3H, t, J=7.3), 1.38-1.47 (2H, m), 1.68-1.75 (2H, m) 2.48 (3H, s), 2.93 (2H, t, J=7.32), 7.42 (1H, S) and 7.72 (1H, s).

Intermediate 9:1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-alcohol

(8,250 milligrams in intermediate adds 3-chloro-peroxy benzoic acid (mCPBA, 190mg in methylene dichloride 0.82mmol) (5 milliliters) solution to 1-(1,3,6-trimethylammonium-1,3-two silas-2,3-dihydro-1H-indenes-5-yl)-pentanone; 0.82mmol, about 71%mCPBA).Further in reaction mixture, added part mCPBA (190mg in second day; 0.82mmol), be heated backflow then, spend the night.The 3rd day, reduce in a vacuum before the mother liquor, remove by filter colourless precipitation, be dissolved in the methyl alcohol (10mL) and handle with sodium methylate (25% weight, in methyl alcohol, 0.822 mole).After at room temperature stirring 2.5 hours, mixture is concentrated, be dissolved in the water (10mL) also with hydrochloric acid (1M) acidifying.The mixture that obtains is extracted into ethyl acetate (in 3 * 25mL), and with the extract drying (sal epsom) that merges and concentrated.By column chromatography (SiO ₂, 10% to 25% diethyl ether is in sherwood oil) and obtain needed homogeneous state phenol, it is off-white color solid (10mg).R _f=0.43 (25% diethyl ether is in sherwood oil). ¹H NMR (CDCl ₃) δ-0.05 (and 2H, s), 0.29 (12H, s), 2.29 (3H, s), 4.75 (1H, s, br), 6.96 (1H, S) and 7.35 (1H, s).

Intermediate 10:1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-alcohol

This compound is according to preparing about intermediate 9 described methods.R _f(0.36 10% diethyl ether is in sherwood oil). ¹H NMR δ _H0.200 (6H, s), 0.203 (6H, s), 0.97 (4H, s), 2.25 (3H, s), 4.70 (1H, s), 6.89 (1H, s) and 7.25 (1H, s).

Embodiment 1:5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) first Base]-N-(2,4, the 6-trimethoxyphenyl) furans-2-methane amide

Under-30 ℃, within 10 minutes with (115 milligrams of trimethyl aluminiums, 1.60mmol) toluene (5 milliliters) drips of solution be added to 2,4,6-trimethoxy-benzene amine hydrochlorate (351 milligrams, (dissolving 2,4 in toluene 1.60mmol) (5 milliliters) stirred suspension, 6-trimethoxy-benzene amine hydrochlorate then forms precipitation).Within an hour, to stir the mixture is warming up to 0 ℃, additionally is being warming up to 20 ℃ (resolution of precipitates) within an hour then, then under 0 ℃, within 10 minutes the gained drips of solution is added to 5-[(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-yl) methyl]-(intermediate 4,359mg is in methylene dichloride 1.00mmol) (10mL) stirred solution for 2-furancarboxylic acid methyl ester.The mixture that obtains was stirred 30 minutes down at 0 ℃, stir 3 days [almost Quantitative yield rate (HPLC control), color is from the colourless black that changes to] down at 20 ℃ then, then add semi-saturation ammonium acetate solution (20mL) (precipitation formation).By the filtering separation precipitation, with ethyl acetate (10mL) washing, filtrate and washing lotion are merged, separate the washing of organic layer and water (20mL).With water lotion (A and B) ethyl acetate (2 * 20mL) extractions as follows: first water lotion (A) is extracted with ethyl acetate (20mL) that obtain, then the extract that obtains is used to extract second water lotion (B), separate organic extraction, then use and the described same approach of the order of extraction for the first time, carry out the extraction second time of washing lotion A and B with the fresh portion of ethyl acetate (20mL).All organic extractions are merged, and use anhydrous sodium sulfate drying, removal of solvent under reduced pressure is passed through column chromatography [column dimension: 60 * 3.5cm on silica gel; Silica gel: 300g (32-63 μ m, ICN 02826); Elutriant: ethyl acetate/normal hexane (55: 45)] purifying.Relevant fraction (TLC control) is merged removal of solvent under reduced pressure.Under 20 ℃, during 7 days in, by Skellysolve A (200mL) vapor diffusion in diethyl ether (10mL) solution of crude product, and with residue crystallized.With product recrystallization under the same conditions, by the solid of decant resulting separation, with Skellysolve A (5mL) washing, dry (0.001mbar, 20 ℃, 2 hours) in a vacuum, obtain title compound colourless crystallization solid (357mg, 0.700mmol), productive rate 70%; 105 ℃ of fusing points.C ₂₇H ₃₅NO ₅Si ₂Ultimate analysis calculated value: C, 63.62; H, 6.92; N, 2.75.Measured value: C, 63.6; H, 6.9; N, 2.8.

Embodiment 2:5-(1,1,3,3,6-pentamethyl--1,3-two silas-2,3-dihydro-1H-indenes-5-base oxygen Base)-and N-{2-[3-(morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-first Acid amides

Use illustrational method in this paper scheme 5, by 4,6-dimethoxy-N ²-(3-morpholine and propyl group) pyrimidine-2,5-diamines (it can synthesize according to the method for describing among the WO-A-02/098363) and intermediate 9 can obtain this compound.

Embodiment 3:5-(1,1,4,4,7-pentamethyl--1,4-two silas-1,2,3,4-naphthane-6-base oxygen base -N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans -2-methane amide

Use illustrational method in this paper scheme 6, by 4,6-dimethoxy-N ²-[3-(4-methylpiperazine-1-yl) propyl group] pyrimidine-2,5-diamines (it can synthesize according to the method for describing among the WO-A-02/098363) and intermediate 10 can obtain this compound.

Claims

1. compound or its pharmacy acceptable salt of formula (I) or formula (II)

Wherein

B is-(CH ₂) _n-,-O-,-C (R ^b) ₂-,-Si (R ^c) ₂-,-C (R ^b)=C (R ^b)-,-C (R ^b)=,-(CH ₂) _nC (R ^g) ₂-,-C (R ^g) ₂(CH ₂) _n-or-CH (R ^b) CH (R ^b)-;

Wherein any of A, B and C chosen quilt-Si (R wantonly ^c) ₃Replace;

E chooses existence wantonly and is-(CH ₂) _n-,-N (R ^d)-,-(CH ₂) _nN (R ^d)-or-N (R ^a) (CH ₂) _n-;

F is-C (=X)-or-N (R ^d)-;

G is-(CH ₂) _n-,-N (R ^d)-,-(CH ₂) _nN (R ^d)-or-N (R ^d) (CH ₂) _n

K chooses existence wantonly and is optional by R ^bThe alkylidene group that replaces; Or K is cycloalkylidene, inferior cycloalkenyl group, arylidene, inferior Heterocyclylalkyl, inferior Heterocyclylalkyl or inferior heteroaryl, and wherein any one is optional by R ^aReplace;

L be hydrogen, halogen ,-N (R ^f) ₂, cycloalkyl, cycloalkenyl group, aryl, Heterocyclylalkyl, heterocycloalkenyl or heteroaryl, wherein any one is optional by R ^a,-C (=X) OR ^d,-OH ,-ORc ,-C (=X) N (R ^b) (R ^c) ,-S (O) _mN (R ^b) (R ^c) or-the CN replacement;

Each R ^bIdentical or different, and be hydrogen or alkyl;

Each R ^dIdentical or different, and be hydrogen, alkyl or aryl, it is chosen wantonly and is replaced by Ra;

R ^g-C-R ^gForm heterocyclic radical together;

Each X is identical or different, and is oxygen or sulphur;

Each m is identical or different, and is 0,1 or 2; With

Each n is identical or different, and is 0,1,2 or 3;

Condition is that among A, B and the C at least one comprises Siliciumatom; Each is not a key for A and C; This compound does not comprise Si-Si key, N-N singly-bound, Si-O key, Si-N key or N-O-N key.

2. according to the compound of claim 1, it is the compound of formula (I).

3. according to the compound of claim 1 or claim 2, wherein A and/or C are-Si (R ^c) ₂-.

4. according to the compound of claim 3, each R wherein ^cIdentical or different and be alkyl.

5. according to the compound of claim 1 or claim 2, wherein A and/or C are-C (R ^b) ₂-,-(CH ₂) _n-,-N (R ^b)-or-O-.

6. according to the compound of claim 5, each R wherein ^bIdentical or different, and be hydrogen or alkyl.

7. according to each compound of aforementioned claim, wherein B is-(CH ₂) _n-,-C (R ^b) ₂-,-CH (R ^b) CH (R ^b)-,-C (R ^b)=C (R ^b)-, or-CH ₂-C (R ^g) ₂-.

8. according to the compound of claim 7, each R wherein ^bIdentical or different, and be hydrogen or alkyl.

9. according to each compound of aforementioned claim, wherein D is-O-,-S-or-CH ₂-.

10. according to each compound of aforementioned claim, wherein E does not exist.

11. according to each compound of aforementioned claim, wherein F be-C (O)-.

12. according to each compound of aforementioned claim, wherein G is-N (R ^d)-.

13. according to the compound of claim 12, wherein R ^dBe hydrogen.

14. according to each compound of aforementioned claim, wherein J and K do not exist, L be hydrogen or-N (R ^f) ₂

15. according to each compound of claim 1 to 13, wherein J is-NH-, K is an alkylidene group, and L is a Heterocyclylalkyl.

16. according to each compound of aforementioned claim, wherein encircling 1 is inferior heteroaryl.

17. according to the compound of claim 16, wherein encircling 1 is furylidene.

18. according to each compound of aforementioned claim, wherein encircling 2 is phenyl, pyrimidyl or pyridyl, wherein any one optional being substituted.

19. according to the compound of claim 18, wherein: encircle 2 substituted 11s, 2 or 3 times, substituting group is identical or different in each the generation, and is selected from alkoxyl group and halogen.

20. the compound according to claim 1 is selected from:

5-(1,1,6-trimethylammonium-1-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{2-[3-(third amino of morpholine-4-)]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,1,2,4,4,7-vegolysen, 4-two silas-1,2,3,4-naphthane-6-base oxygen base)-N-{2-[3-(4-methylpiperazine-1-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furan-2-methane amide;

5-(6-chloro-1,1,4,4-tetramethyl--1,4-two silas-1,2,3,4-naphthane-7-base oxygen base)-N-{2-(3-morpholine-4-yl) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-(1,2,3,4-tetrahydrochysene-4,4,7-trimethylammonium-4-sila-quinoline-6-base oxygen base)-N-{2-[3-(N, N-dimethylamino) third amino]-4,6-dimethoxy-1,3-pyrimidine-5-yl } furans-2-methane amide;

5-[(1,1,5-trimethylammonium-1-sila-2,3-dihydro-1H-indenes-6-yl) methyl]-N-[2-(3-morpholino third amino)-4,6-dimethoxy-1,3-pyrimidine-5-yl] furans-2-methane amide;

5-(1,1,3,4,4,6-vegolysen-sila-1,2,3,4-naphthane-7-base oxygen base)-N-{[2-(2-(morpholine-4-yl)-ethylamino)-4,6-dimethoxy-1,3-pyrimidine-5-yl] furans-2-methane amide;

5-(1,1,3,4,4,6-vegolysen-sila-1,2,3,4-naphthane-7-base oxygen base)-N-[2-(2-N, N-dimethyl aminoethyl)-4,6-trimethoxy-1,3-pyrimidine-5-yl] furans-2-methane amide.

21. according to each compound of aforementioned claim, it is the form of single enantiomer or diastereomer or tautomer.

22. according to each compound of aforementioned claim, the purposes that is used for the treatment of.

23. a pharmaceutical composition comprises each compound and pharmacy acceptable diluent or carrier of claim 1 to 21.

24. the purposes of each compound of claim 1 to 21 is used to prepare the medicine of oncotherapy.

25. the purposes of each compound of claim 1 to 21 is used for the treatment of or prevents the preparation of the medicine of endometriosis, hysteromyoma, disease of ovary, cystic disease of breast, prostatomegaly, amenorrhoea, precocious puberty, premenstrual tension syndrome, property-steroid dependency physiopathology or benign prostatic hyperplasia or retardation spermatogenesis.

26., be used for the treatment of or prevent endometriosis, polycystic ovary disease or secondary amenorrhea with pain according to the purposes of claim 25.

27., be used to prepare the medicine of treatment or prevention Alzheimer according to the purposes of each compound in the claim 1 to 21.

28., be used to prepare the medicine of treatment or prevention HIV infection or AIDS according to the purposes of each compound in the claim 1 to 21.

29., be used to prepare treatment or prevention medicine by thymus gland disease that dysfunction causes according to the purposes of each compound in the claim 1 to 21.

30., be used for the treatment of or prevent multiple cerebral sclerosis, rheumatoid arthritis or type 1 diabetes according to the purposes of claim 29.