CN1349499A

CN1349499A - Thio-oxindole derivatives

Info

Publication number: CN1349499A
Application number: CN00807133A
Authority: CN
Inventors: A·芬森; 张普文; M·C·科科; J·E·弗罗贝尔; J·P·爱德华兹; T·K·琼斯; C·M·特格利; 智林; E·G·梅伦斯基
Original assignee: Ligand Pharmaceuticals Inc; American Home Products Corp
Current assignee: Wyeth LLC; Ligand Pharmaceuticals Inc
Priority date: 1999-05-04
Filing date: 2000-05-01
Publication date: 2002-05-15
Anticipated expiration: 2020-05-01
Also published as: NO20015380D0; BG106078A; NO320912B1; JP2002543182A; KR20020000636A; NZ515351A; EA200101180A1; MXPA01011285A; HUP0200993A2; PL351407A1; EA005034B1; CA2371633A1; CN1143847C; AU767762B2; EP1181275A1; GEP20043266B; SK15902001A3; CZ20013950A3; AU4681400A; TR200103288T2

Abstract

This invention relates to compounds which are agonists of the progesterone receptor which have the general structure (1) or (2) wherein the substituted groups are as defined herein, or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.

Description

Thio-oxindole derivatives

Invention field

The present invention relates to the compound as the progesterone receptor agonist, their preparation and purposes.

Background of invention

Intracellular receptor (IR) forms the relevant generegulation agent of a class formation, is called " ligand dependent transcription factor " (R.M.Evans, Science, 240,889,1988).Steroid receptor family is a subclass of IR family, comprises progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glycocorticosteroid receptor (GR) and mineralcorticoid receptor (MR).

For PR natural hormone or part is the steroid Progesterone, but has also synthesized compound such as medroxyprogesterone acetate or Levonorgestrel as part.In case have part in the pericellular liquid, part is just by the passive film that diffuses through, and combines with IR and to produce the receptor/ligand mixture.The specific gene promoter that exists in this mixture and the cell DNA combines.In case be incorporated into DNA, mixture is with regard to the proteinic generation of regulating mRNA and this genes encoding.

Compound in conjunction with IR and simulation natural hormone effect is called agonist, and the compound that suppresses this hormonal action is called antagonist.

Known natural in women's health, playing an important role with synthetic PR agonist.The PR agonist can be used for controlling the prescription of fertility, has the ER agonist to exist usually, perhaps they can with the coupling of PR antagonist.The ER agonist can be used to treat symptoms of menopause, but participant causes the dangerous uterus multiplication effect that increases of uterus carcinoma relevant.Reducing/eliminated with the administration of PR agonist should danger.

The compounds of this invention has demonstrated and can be used as Progesterone and work in conjunction with the competitive inhibitor of PR, can be used as agonist.These compounds can be used for contraception and postmenopausal hormone replacement therapy.

People such as Jones are in U.S. Patent No. 5,688, have described PR antagonist dihydroquinoline A in 810.

A

People such as Jones are in U.S. Patent No. 5,693, have described the enol ether B as the PR part in 646.

People such as Jones (U.S. Patent No. 5,696,127) have described the Compound C as the PR part.

People such as Zhi (J.Med.Chem., 41,291,1998) have described lactone D, E and the F as the PR antagonist.

People such as Zhi have described the ether G (J.Med.Chem., 41,291,1998) as the PR antagonist.

People such as Combs disclose the acid amides H (J.Med.Chem., 38,4880,1995) as the PR part.

People such as Perlman have described the vitamins D stand-in I (Tet.Letters, 35,2295,1994) as the PR part.

People such as Hamann have described PR antagonist J (Ann.N.Y.Acad.Sci., 761,383,1995).

People such as Chen have described PR antagonist K (people POI-37 such as Chen, 16 ^ThIht.Cong.Het.Chem., Montana, 1997).

People such as Kurihari have described PR ligand L (J.Antibiotics, 50,360,1997).

People such as Kuhla disclose the oxindole M (WO 86/03749) with cardiac activity.

Weber has proposed to be used for the oxindole N (WO 91/06545) of cardiovascular indications.

People such as Fischer have described the preparation method (U.S. Patent No. 5,453,516) who prepares the compound that comprises formula O.

R=is various

People such as Singh have described PDE III type inhibitor P (J.Med.Chem., 37,248,1994).

People such as Andreani have described cytotoxic agent Q (Acta.Pharn.Nord., 2,407,1990).

People such as Binder have described the structure R (WO 97/13767) as preparation COX II inhibitor intermediate.

Walsh has described the oxindole S (U.S. Patent No. 4,440,785, U.S. Patent No. 4,670,566) as intermediate.

R1=F, Cl, Br, alkyl, NH ₂

The R2=alkyl, alkoxyl group, F, Cl, NH2, CF ₃

The claimed oxindole T of people such as Bohrn (WO 91/06545) as cardiovascular agent.

People such as Bohm have proposed formula U (WO 91/04974).

JP 63112584 A have formula V:

People such as Boar have described the dioxolane W (WO93/12085 A1) as preparation acetylcholinesterase depressant intermediate.

People such as Kende have described the method (this method is used for the present invention) (SynthCommun., 12,1,1982) of the oxindole (as X) of preparation 3,3 replacements.

Detailed Description Of The Invention

The invention provides compound with formula 1 or 2:

Wherein:

R ₁And R ₂Independently be selected from H, alkyl, the alkyl of replacement; OH; O (alkyl); O (alkyl of replacement); OAc; Aryl; The optional aryl that replaces; Heteroaryl; The optional heteroaryl that replaces; Alkaryl; Miscellaneous alkyl aryl; The 1-proyl; Or 3-proyl:

Or R ₁And R ₂Be connected to form and comprise one of following ring:

-CH ₂(CH ₂) _nCH ₂-；-CH ₂CH ₂CMe ₂CH ₂CH ₂-；-O(CH ₂) _mCH ₂-；O(CH ₂) _pO-；

-CH ₂CH ₂OCH ₂CH ₂-; Or-CH ₂CH ₂N (H or alkyl) CH ₂CH ₂-;

M is integer 1-4;

N is integer 1-5;

P is integer 1-4;

Or R ₁And R ₂Form together and one of the following two keys that link to each other:

CMe ₂C (cycloalkyl), O, C (cyclic ethers).

R ₃Be selected from H, OH, NH ₂, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₆Alkenyl, the alkynyl of alkynyl or replacement, or COR ^A

R ^ABe selected from H, C ₁-C ₃Alkyl, the C of replacement ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, the C of replacement ₁-C ₃Alkoxyl group, C ₁-C ₃Aminoalkyl, or the C that replaces ₁-C ₃Aminoalkyl;

R ₄Be selected from H, halogen, CN, NH ₂, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, the C of replacement ₁-C ₆Alkoxyl group, C ₁-C ₆Aminoalkyl, or the C that replaces ₁-C ₆Aminoalkyl;

R ⁵Be selected from a), b) or c):

A) R ⁵Be to contain substituent X, the trisubstituted phenyl ring as follows of Y and Z:

X is selected from halogen, OH, CN, C ₁-C ₃Alkyl, the C of replacement ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, the C of replacement ₁-C ₃Alkoxyl group, C ₁-C ₃Alkylthio, the C of replacement ₁-C ₃Alkylthio, S (O) alkyl, S (O) ₂Alkyl, C ₁-C ₃Aminoalkyl, the C of replacement ₁-C ₃Aminoalkyl, NO ₂, C ₁-C ₃Perfluoroalkyl contains 1-3 heteroatomic 5 or 6 yuan of heterocycles, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, COR ^B, OCOR ^B, NR ^CCOR ^B

R ^BBe selected from H, C ₁-C ₃Alkyl, the C of replacement ₁-C ₃Alkyl, aryl, the aryl of replacement, C ₁-C ₃Alkoxyl group, the C of replacement ₁-C ₃Alkoxyl group, C ₁-C ₃Aminoalkyl, or the C that replaces ₁-C ₃Aminoalkyl;

R ^CBe H, C ₁-C ₃Alkyl, or the C that replaces ₁-C ₃Alkyl;

Y and Z independently are selected from H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl, or C ₁-C ₃Alkylthio;

Or

B) R ⁵Be to contain 1,2 or 3 to be selected from O, S, SO, SO ₂Or NR ⁶Heteroatoms and contain 1 or 2 and be selected from substituent 5 or 6 yuan of heterocycle: the H of following independence, halogen, CN, NO ₂And C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Aminoalkyl, COR ^D, or NR ^ECOR ^D

R ^DBe H, C ₁-C ₃Alkyl, the C of replacement ₁-C ₃Alkyl, aryl, the aryl of replacement, C ₁-C ₃Alkoxyl group, the C of replacement ₁-C ₃Alkoxyl group, C ₁-C ₃Aminoalkyl, or the C that replaces ₁-C ₃Aminoalkyl;

R ^EBe H, C ₁-C ₃Alkyl, or the C that replaces ₁-C ₃Alkyl;

R ⁶Be H, or C ₁-C ₃Alkyl; Or

C) R ⁵Be indoles-4-base, indoles-7-base or benzo-2-thienyl group, this group can be selected from halogen, low alkyl group, CN, NO by 1-3 ₂, lower alkoxy, or CF ₃Substituting group randomly replace;

Q ¹Be S, NR ₇, CR ₈R ₉

R ₇Be selected from CN, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₂-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, acyl group, the acyl group of replacement, aroyl, the aroyl of replacement, SO ₂CF ₃, OR ¹¹Or NR ¹¹R ¹²

R ₈And R ₉Be independently to be selected from following substituting group: H, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, NO ₂, CN, or CO ₂R ₁₀,

R ₁₀Be C ₁-C ₃Alkyl; Or

CR ₈R ₉Be 6 yuan of rings shown in the following structure

Q ²Be selected from following groups:

R ¹¹, R ¹²And R ¹³Independently be selected from H, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, acyl group, the acyl group of replacement, the aroyl of aroyl or replacement or alkylsulfonyl;

Or its pharmacy acceptable salt.

R in the compound of the present invention ¹¹, R ¹²And R ¹³One group of preferable substituting group of expression is H, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl ,-C (O)-(C ₁-C ₆Alkyl) ,-S (O) ₂-(C ₁-C ₆Alkyl), phenyl or benzyl.

Should be appreciated that and the present invention includes compound described herein, chemical formula and substituent all tautomers.

Two groups of preferred compounds of the present invention are represented with structure 2 and 3 respectively:

R wherein ₅Be dibasic phenyl ring, it contains substituent X as follows and Y

X is selected from halogen, CN, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl, NO ₂, C ₁-C ₃Perfluoroalkyl contains 1-3 heteroatomic 5 yuan of heterocycles, or C ₁-C ₃Thio alkoxy;

Y be 4 ' or 5 ' position on be selected from following substituting group: H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl group, C ₁-C ₄Alkyl, or C ₁-C ₃Alkylthio;

Or its pharmacy acceptable salt.

Another preferred group of formula 2 is R wherein ₅For having those compounds that show 5 yuan of rings of structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

X ' is selected from halogen, CN, NO ₂, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, C ₁-C ₃Alkyl, or C ₁-C ₃Alkoxyl group;

Y ' is selected from H, F or C ₁-C ₄Alkyl;

Or its pharmacy acceptable salt.

The preferable subclass of another of above-claimed cpd is R wherein ₅For by the thiophene of above-mentioned X ' and Y ' replacement or those compounds of furan nucleus.

Formula 2 and 3 the preferable compound of another group are R wherein ₅Those compounds for 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

X ²Be halogen, CN, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂Or NO ₂

Q ¹Be S, NR ₇, CR ₈R ₉

R ₇Be selected from CN, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, or SO ₂CF ₃

R ₈And R ₉Independent of being selected from following substituting group: H, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, NO ₂, CNCO ₂R ₁₀,

R ₁₀Be C ₁-C ₃Alkyl;

CR ₈R ₉Under having, show in 6 yuan of rings of structure

Or its pharmacy acceptable salt.

Also have one group of preferable compound to comprise those compounds with following general formula:

Each R wherein ₅It is the dibasic phenyl ring as follows that contains substituent X and Y

Or its pharmacy acceptable salt.

The compound that another group is preferable with following formula

Be R wherein ₅Those compounds for 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

Q ²As mentioned above;

R ₁₀Be C ₁-C ₃Alkyl;

CR ₈R ₉Under having, show in 6 yuan of rings of structure

Or its pharmacy acceptable salt.

Another organizes preferred The compounds of this invention shown in structure 4,

R wherein ₁₄Be selected from H, acyl group, the acyl group of replacement, aroyl, the aroyl of replacement, alkylsulfonyl, the alkylsulfonyl of replacement.

R wherein ₅It is the dibasic phenyl ring as follows that contains substituent X and Y

X is selected from halogen, CN, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, CNHNHOH, CNH ₂NOH, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl, NO ₂, C ₁-C ₃Perfluoroalkyl contains 1-3 heteroatomic 5 yuan of heterocycles, or C ₁-C ₃Thio alkoxy;

Or its pharmacy acceptable salt.

Another preferable group of formula 4 is R wherein ₅For having 5 yuan of rings that show structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

X ＇ is selected from halogen, CN, NO ₂, CONH ₂, CNHNHOH, CNH ₂NOH, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, C ₁-C ₃Alkyl, or C ₁-C ₃Alkoxyl group;

Y ' is selected from H, F or C ₁-C ₄Alkyl;

Or its pharmacy acceptable salt.

Another preferred group is R wherein in the above-claimed cpd ₅By above-mentioned X ' and the thiophene of Y ＇ replacement or those compounds of furan nucleus.

Preferred formula 4 compounds of another group are R wherein ₅Be those compounds with 6 yuan of rings of following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl;

Or its pharmacy acceptable salt.

Another organizes preferred The compounds of this invention shown in structure 5,

X is selected from halogen, CN, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, CNHNOH, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl, NO ₂, C ₁-C ₃Perfluoroalkyl contains 1-3 heteroatomic 5 yuan of heterocycles, or C ₁-C ₃Thio alkoxy;

Or its pharmacy acceptable salt.

Preferable formula 5 compounds of another group are R wherein ₅For having those compounds that show 5 yuan of rings of structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ＇ is selected from H, F or C ₁-C ₄Alkyl;

Or its pharmacy acceptable salt.

Another preferable group is R wherein in the above-claimed cpd ₅For by the thiophene of above-mentioned X ' and Y ' replacement or those compounds of furan nucleus.

Another preferable group of formula 5 compounds is R wherein ₅Those compounds for 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl;

Or its pharmacy acceptable salt.

Another organizes preferable The compounds of this invention shown in structure 6,

R wherein ₁₅Be selected from H, methyl, CO ₂R, acyl group, the acyl group of replacement, aroyl, the aroyl of replacement, alkyl, the alkyl of replacement, CN.

Or its pharmacy acceptable salt.

Another preferred group of formula 6 is R wherein ₅For having those compounds that show 5 yuan of rings of structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ' is selected from H, F or C ₁-C ₄Alkyl;

Or its pharmacy acceptable salt.

The preferred group of another of above-claimed cpd is R wherein ₅For by the thiophene of above-mentioned X ' and Y ' replacement or those compounds of furan nucleus.

Another preferred group of formula 6 compounds is R wherein ₅Those compounds for 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₈And R ₉Independent of being selected from following substituting group: H, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, NO ₂, CN CO ₂R ₁₀,

R ₁₀Be C ₁-C ₃Alkyl;

Or its pharmacy acceptable salt.

Another preferred group of The compounds of this invention shown in structure 7,

Or its pharmacy acceptable salt.

Another preferred group of formula 7 compounds is R wherein ₅For having those compounds that show 5 yuan of rings of structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ＇ is selected from H, F or C ₁-C ₄Alkyl;

Or its pharmacy acceptable salt.

Another preferred group of formula 7 compounds is R wherein ₅Those compounds for 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl;

Or its pharmacy acceptable salt.

Compound of the present invention can contain asymmetric carbon, and compounds more of the present invention can contain one or more asymmetric centers, and therefore optical isomer and diastereomer can be arranged.Though formula 1 and 2 does not show with stereochemistry, the present invention includes these optical isomers and diastereomer; And the R and the S steric isomer of racemization and the enantiomer-pure disassembled; And other mixtures of R and S steric isomer and their pharmacy acceptable salts.

Term used herein " alkyl " refers to contain the straight or branched radical of saturated aliphatic hydro carbons group of 1-8 carbon atom (the preferable 1-6 of a having carbon atom); " alkenyl " comprises straight chain and the branched-chain alkyl that contains 1 or 2 carbon-carbon double bond and 2-8 carbon atom (preferable have 2-6 carbon atom); " alkynyl " comprises straight chain and the branched-chain alkyl that contains at least 1 or 2 carbon carbon triple bonds and 2-8 carbon atom (the preferable 2-6 of a having carbon atom).

Term " acyl group " refers to the carbonyl substituted base, includes the straight chain and the side chain radical of saturated aliphatic hydrocarbyl group of 1-8 carbon atom (the preferable 1-6 of a having carbon atom).Term " acyl group of replacement " refers to be selected from halogen, CN, OH and NO by 1-6 ₂The optional aforesaid acyl group that replaces of substituting group.

Term " aroyl " also refers to carry the carbonyl substituted base of phenyl or heteroaryl group.This type of heteroaryl group comprises 2-, 3-or 4-pyridyl, 2-and 3-furyl, 2-or 3-thienyl or 2-or 4-pyrimidyl.Term " aroyl of replacement " also refers to be selected from halogen, CN, OH and NO by 1-6 ₂The optional aforesaid aroyl that replaces of substituting group.

Term " alkyl of replacement ", " alkenyl of replacement " and " alkynyl of replacement " refer to have one or more following substituent abovementioned alkyls, alkenyl and alkynyl: halogen, CN, OH, NO ₂, amino, aryl, heterocycle, the aryl of replacement, the heterocycle of replacement, alkoxyl group, aryloxy, the alkoxyl group of replacement, alkyl-carbonyl, alkyl carboxyl, alkylamino, arylthio.These substituting groups can be connected on any carbon atom of alkyl, alkenyl or alkynyl, but condition is this stable chemical group that connects and composes.

The term of this paper " aryl " refers to aromatic systems, and it can be monocycle or many aromatic rings of condensing or linking together, condenses or at least a portion of the ring that connects forms conjugated virtue system.Aromatic yl group can comprise (but being not restricted to): phenyl, naphthyl, xenyl, anthryl, tetralyl, phenanthryl.

Term " aryl of replacement " refers to have 1-4 and is selected from following substituent above-mentioned aryl: halogen, CN, OH, NO ₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyl group, aryloxy, replacement alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or arylthio.

Term used herein " heterocycle " refers to stable 4-to 7-unit's monocycle or stable many rings heterocycle, and it can be saturated, fractional saturation or undersaturated, and is made of carbon atom and 1-4 heteroatoms that is selected from N, O and S atom.N and S atom can be oxidized.Heterocycle also can comprise any many rings, and wherein above-mentioned heterocycle can condense in aromatic ring.Heterocycle also can be connected in any heteroatoms or carbon atom, and condition is that the structure that obtains must be chemically stable.These heterocyclic groups comprise, but be not limited to tetrahydrofuran (THF), piperidyl, piperazinyl, 2-oxo-piperidine base, azatropylidene base (azepinyl), pyrrolidyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indyl, quinolyl, thienyl, furyl, benzofuryl, benzothienyl, thio-morpholinyl, thio-morpholinyl sulfoxide and isoquinolyl.

Term used herein " heterocycle of replacement " refers to have 1-4 and is selected from following substituent above-mentioned heterocycle: halogen, CN, OH, NO ₂, amino, alkyl, replacement alkenyl, alkynyl, alkoxyl group, aryloxy, alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or the arylthio of replacement of alkyl, cycloalkyl, alkenyl, replacement.

Term used herein " alkylthio " refers to the SR group, and wherein R contains 1-8 carbon atom, the alkyl of the preferable 1-6 of a having carbon atom or the alkyl of replacement.Term " alkoxyl group " refers to the OR group, and wherein R contains 1-8 carbon atom, the alkyl of the preferable 1-6 of a having carbon atom or the alkyl of replacement.Term " aryloxy " refers to the OR group, and wherein R is the aryl of above-mentioned aryl or replacement.The term of this paper " alkyl-carbonyl " refers to the RCO group, and wherein R contains 1-8 carbon atom, the alkyl of the preferable 1-6 of a having carbon atom or the alkyl of replacement.The term of this paper " alkyl carboxyl " refers to the COOR group, and wherein R contains 1-8 carbon atom, the alkyl of the preferable 1-6 of a having carbon atom or the alkyl of replacement.Term " aminoalkyl " refers to secondary amine and tertiary amine, and wherein the alkyl of alkyl or replacement contains 1-8 carbon atom, and preferable have a 1-6 carbon atom, and they can be identical or different, and tie point is on a nitrogen-atoms.Term " halogen " refers to Cl, Br, F or I.

The compounds of this invention can make with following method.

Scheme 1

According to scheme 1, under nitrogen low temperature (-20 ℃ approximately), at lithium chloride or N, N, N ', N '-methyl ethylenediamine exist down, at inert solvent (as THF, diethyl ether) handles commercially available oxindole 3 (Kende with organo-metallic highly basic (as butyllithium, di-isopropyl lithamide, hexamethyldisilazane potassium (potassium hexamethyldisilazide)) in, Deng the people, Synth.Commun., 12,1,1982).Use excessive electrophilic material (as alkylogen, preferably alkyl iodide) to handle two negatively charged ion things of gained then.If connect R ₁And R ₂, as 3 of product 4 volution arranging, the electrophilic material should be bifunctional so, promptly is diiodide.In acetate (can add organic cosolvent such as methylene dichloride as required), making 4 brominations reposefully in the presence of the sodium acetate, obtain aryl bromide 5 subsequently with bromine.Under inert atmosphere (argon gas, nitrogen), room temperature, bromizate thing 5 and in suitable solvent (for example THF, glycol dimethyl ether, acetone, ethanol or toluene), react with palladium salt (closing palladium (0) or acid chloride) as four (triphenyl phosphines).Then in water with aryl or heteroaryl boric acid or boric acid ester and alkali (yellow soda ash, triethylamine, potassiumphosphate) or under anhydrous condition, handle this mixture with fluorochemical (cesium fluoride).Use the required product 6 of standard method separation and purification then.

Make Indolin-2-one derivative 6 in appropriate organic solvent (pyridine, THF, diox, glycol dimethyl ether, methylene dichloride, benzene,toluene,xylene), reacting under the temperature between room temperature and the solvent refluxing temperature, obtain thiocarbonyl derivative 7 with Lawessen ' reagent or thiophosphoric anhydride.The additive of use such as sodium bicarbonate may help.

If R ₁And R ₂Difference then can make 3 two negatively charged ion and 1 normal electrophilic reagent R ₁-X (X is leavings group such as I) reaction makes intermediate 4.Separable then gained monoalkylation compound is used R under identical conditions ₂-X reacts again, or uses R then and there ₂-X carries out the alkylation second time.Perhaps, if required product 7 will contain R ₂=H passes through the isolating monoalkylation intermediate of step subsequently so.

Scheme 2

Also available other method connects aryl or the heteroaryl (Ar) and oxindole platform (being skeleton) of side joint, for example makes compound 5 and aryl or heteroaryl stannane, aryl or heteroaryl zinc or aryl or heteroaryl magnesium halide reaction (scheme 2) in the presence of palladium or nickel catalyzator.Above-mentioned required aryl or heteroaryl metallics are made by standard technique.

According to scheme 3, also other functional group can be added on 3 of indoline platform.Make undersaturated indoline 8 oxidations (preferable (is for example refluxing with tin anhydride) under neutrality or the acidic conditions) in dried De diox, obtain isatin 9.Compound 9 can be further functionalized, by obtain ketal 11 with pure and mild acid catalyst processing under dehydration conditions.Perhaps, (in toluene, reflux in appropriate condition with piperidines; Or in THF, use TiCl ₄/ Zn refluxes) under, 9 and second kind of reactive ketone obtain alkylene derivative 11.Isatin 9 and Grignard reagent or organolithium reaction obtain the tertiary alcohol 12 (R=H).Then, these alcohol can be further functionalized by alkylation or acylations step.

Scheme 3

In appropriate organic solvent (pyridine, THF, diox, glycol dimethyl ether, methylene dichloride, benzene,toluene,xylene), under the temperature between room temperature and the solvent refluxing temperature, make the reaction of Indolin-2-one derivative 6 and Lawessen reagent or thiophosphoric anhydride, obtain thiocarbonyl derivative 7.Also can adopt additive such as sodium bicarbonate.

Scheme 4

Another kind of preparation mode is, in appropriate organic solvent (pyridine, THF, diox, glycol dimethyl ether, methylene dichloride, benzene,toluene,xylene), under the temperature under the inert atmosphere (nitrogen or argon gas), between room temperature and the solvent refluxing temperature, make the reaction of compound 5 and Lawessen reagent or thiophosphoric anhydride, obtain thiocarbonyl derivative 13.Bromizating thing 13 then reacts with highly basic (being preferably sodium hydride, hexamethyldisilazane sodium, potassium hydride KH) in anhydrous solvent (for example THF, diethyl ether), descend and n-Butyl Lithium and N at low temperature (50 ℃ to-20 ℃) then, N, N ', N '-Tetramethyl Ethylene Diamine reaction, after when appropriate,, obtain boric acid 14 (scheme 4) after the acid treatment with boric acid three alkane esters (trimethyl borate or three isopropyl esters) reaction.Then, compound 14 can (four (triphenyl phosphines) close palladium (0) or acid chloride in the catalytic condition of palladium, alkali (sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, CsF) solvent (toluene/ethanol/water, THF/ water, glycol dimethyl ether/water, anhydrous dimethyl oxygen base ethane)) following and aryl or heteroaryl bromine, aryl or heteroaryl iodine, trifluoromethanesulfonic acid aromatic ester or assorted aromatic ester or fluoro sulfonic acid aromatic ester or the reaction of assorted aromatic ester obtain required compound 7.

Perhaps, (four (triphenyl phosphines) close palladium (0) or acid chloride in the catalytic condition of palladium to make compound 13, alkali (sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, CsF) solvent (acetone, toluene/ethanol/water, THF/ water, glycol dimethyl ether/water, anhydrous dimethyl oxygen base ethane)) following and aryl or heteroaryl bromine, aryl or heteroaryl iodine, trifluoromethanesulfonic acid aromatic ester or assorted aromatic ester or fluoro sulfonic acid aromatic ester or the reaction of assorted aromatic ester, obtain required compound 7.

Scheme 5

Bromizating thing 5 reacts with highly basic (being preferably sodium hydride, hexamethyldisilazane sodium, potassium hydride KH) in anhydrous solvent (for example THF, (two) ether), descend and n-Butyl Lithium and N at low temperature (50 ℃ to-20 ℃) then, N, N ', N '-Tetramethyl Ethylene Diamine reaction, behind the appropriate time,, obtain boric acid 15 (scheme 5) after the acid treatment with boric acid three alkane esters (trimethyl borate or three isopropyl esters) reaction.Then, compound 15 can (four (triphenyl phosphines) close palladium (0) or acid chloride in the catalytic condition of palladium, alkali (sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, CsF) solvent (toluene/ethanol/water, THF/ water, glycol dimethyl ether/water, anhydrous dimethyl oxygen base ethane)) following and aryl or heteroaryl bromine, aryl or heteroaryl iodine, trifluoromethanesulfonic acid aromatic ester or assorted aromatic ester or fluoro sulfonic acid aromatic ester or the reaction of assorted aromatic ester obtain required compound 6.

Another kind of strategy is to make organic zinc or azoviolet from compound 5, then under the palladium catalytic condition then and there with aryl or heteroaryl bromine, aryl or heteroaryl iodine, trifluoromethanesulfonic acid aromatic ester or assorted aromatic ester or fluoro sulfonic acid aromatic ester or the reaction of assorted aromatic ester, obtain compound 6.These organic zincs or magnesium material can make like this, at anhydrous solvent (as THF, diethyl ether) uses highly basic (preferred sodium hydride in, hexamethyldisilazane sodium, potassium hydride KH) processing bromide 57, descend and n-Butyl Lithium and N N, N ' then at low temperature (50 to-20 ℃), the inferior reacting ethylenediamine of N '-tetramethyl-, in due course between back and Zinc Chloride Anhydrous or magnesium bromide reaction.

In appropriate organic solvent (pyridine, THF, diox, glycol dimethyl ether, methylene dichloride, benzene,toluene,xylene), under the temperature between room temperature and the solvent refluxing temperature, make the reaction of Indolin-2-one derivative 6 and Lawesson reagent or thiophosphoric anhydride, obtain thiocarbonyl derivative 15.Also can adopt additive such as sodium bicarbonate.

Scheme 6

According to scheme 6, thioamide derivatives 7 can be transformed into enamine derivates 16 (people such as Wrobel, J.Med.Chem., 1989,2493).

Therefore; thioamides 7 (Pg=H; 2-(trimethyl silyl)-ethoxyl methyl; benzyl etc.) with the reaction of Tetrafluoroboric acid triethyl oxygen; react with nucleophile (Nitromethane 99Min., cyanamide, fluoroform sulphonamide, Meldrum acid etc.) then; under conditions suitable (for example the tetrabutyl ammonium fluoride among the THF being used for PG=2-(trimethyl silyl)-ethoxyl methyl), remove blocking group then, obtain enamine derivates 16.The suitable solvent of two steps is selected from methylene dichloride, THF, diox, 1, and the 2-ethylene dichloride is reflected under the inert atmosphere (nitrogen or argon gas)-78 ℃ and carries out to the temperature of solvent boiling point.

Scheme 7

According to scheme 7, in the presence of suitable alkali (as amine alkali such as pyridine, triethylamine or two-different-propyl group ethamine or Quilonum Retard, sodium, potassium or caesium), in appropriate organic solvent (as DMF, THF, DMSO, diox or acetonitrile), at-78 ℃ to the temperature between the solvent boiling point, with alkylating agent (as methyl-iodide, iodoethane, 2,4-dinitrobenzene fluorobenzene or 4-nitro fluorobenzene) handle intermediate 7, obtain sulfo-imido ether 17.Subsequently at-78 ℃ to the temperature between the solvent boiling point, the acid salt (example hydrochloric acid) that makes intermediate 17 and azanol or azanol at suitable solvent (such as, but be not limited to pyridine, methyl alcohol, ethanol, Virahol, DMF, THF or DMSO, randomly have additive such as tertiary amine base or sodium acetate or potassium acetate) middle reaction, obtain N-hydroxyamidines 18.

In the presence of suitable alkali (as amine alkali such as pyridine, triethylamine or diisopropylethylamine or Quilonum Retard, sodium, potassium or caesium) or Lewis acid (for example boron-trifluoride etherate, II valency lead salt, titanium tetrachloride, II valency magnesium salts or silver salt), in the solvent (for example DMF, THF, DMSO, diox or acetonitrile, chloroform, benzene, toluene or methylene dichloride) compatible with selected alkali or Lewis acid, with the carbon nucleophile (as malonate derivative, as propane dinitrile, cyan-acetic ester, nitroacetic acid ester or malonic ester) intermediate 17 is handled similarly, obtain affixture 19.If the radicals R 3 in the affixture 19 is carboxylicesterss, it can be by for example handling direct decarboxylation to obtain enamine derivates 20 with for example sodium iodide in room temperature in DMSO to the temperature between the solvent boiling point so.Perhaps, at first making ester at first be hydrolyzed into carboxylic acid in suitable solvent (for example THF, diox, acetonitrile, methyl alcohol or ethanol) (handles with containing buck, for example use lithium hydroxide, sodium hydroxide or potassium hydroxide), decarboxylation in the presence of acid (example hydrochloric acid or sulfuric acid) in suitable solvent (as acetonitrile, THF, diox) then obtains derivative 20.Perhaps, can make the xanthate of carboxylic acid like this: in THF,, handle with dithiocarbonic anhydride then with alkali (as sodium hydride or potassium hydride KH) reaction.Under the temperature, inert nitrogen or the argon gas atmosphere that raise, in solvent, in the presence of radical initiator (as Benzoyl Peroxide or Diisopropyl azodicarboxylate),, obtain product 20 subsequently with the tributyltin hydride reaction such as benzene or toluene.

Scheme 8

Scheme 8 has been described another strategy of synthetic product 18.Under the temperature between-78 ℃ and the solvent boiling point, at suitable alkali (as amine alkali, as pyridine, triethylamine or diisopropylethylamine or Quilonum Retard, yellow soda ash, salt of wormwood or cesium carbonate) exist down, in appropriate organic solvent (as DMF, THF, DMSO, diox or acetonitrile), with alkylating agent (as methyl-iodide, iodoethane, 2,4-dinitrobenzene fluorobenzene, 4-nitro fluorobenzene) handle bromide 13 (also can adopt corresponding chlorinated thing, iodide or triflate), obtain sulfo-polyurethane 21.Subsequently at-78 ℃ to the temperature between the solvent boiling point, at suitable solvent (such as, but be not limited to piconol, ethanol, Virahol, DMF, THF or DMSO, randomly in the presence of such as additives such as tertiary amine base or sodium acetate or potassium acetates) in, make the reactant salt of intermediate 21 and azanol or azanol and acid (example hydrochloric acid, Hydrogen bromide), obtain N-hydroxyamidines 22.Use compatible group (as benzyl oxide, acyl derivative, tetrahydropyranyl ethers, methoxymethyl ether, silyl ether) protection intermediate 22 then, obtain derivative 23.Perhaps, can make hydroxylamine derivative (be selected from but the be not limited to above-mentioned blocking group) direct reaction of compound 21 and protection, directly obtain derivative 23.Then, under room temperature, inert atmosphere (argon gas, nitrogen), in suitable solvent (as THF, glycol dimethyl ether, acetonitrile, ethanol or toluene), make compound 23 and palladium salt (for example four (triphenyl phosphines) close palladium (0) or acid chloride) reaction.Then, in water, with aryl or heteroaryl boric acid or boric acid ester and alkali (yellow soda ash, triethylamine, potassiumphosphate) or under anhydrous condition, handle this mixture, reactant is heated to solvent boiling point with fluorochemical (cesium fluoride).Separate and the required product 24 of purifying with standard method then.

Then, compound 24 can be in the protection of going down of the definite condition of blocking group characteristic.For example, if blocking group is a benzyl oxide, in suitable solvent (as methylene dichloride), will obtain compound 18 so with boron tribromide or trimethyl silyl iodinate.Other method of removing benzyl oxide is included in palladium catalyst and has hydrogenation (hydrogen or other hydrogen source are as cyclohexadiene or ammonium formiate) down.The solvent that is applicable to this method comprises methyl alcohol, ethanol, THF, ethyl acetate He diox, carries out to the temperature between the solvent boiling point in room temperature.If blocking group is acetal derivant (THP trtrahydropyranyl ether or a methoxymethyl ether), can in solvent (methyl alcohol, ethanol, THF diox or acetonitrile), under acidic conditions (hydrochloric acid, sulfuric acid, tosic acid or acidic ion exchange resin), be hydrolyzed so.If blocking group is acyl derivative (for example acetic ester, a benzoic ether); hydrolysis under acidic conditions as mentioned above so, or in solvent (as alcohol, THF, diox or acetonitrile), under alkaline condition (lithium hydroxide, sodium hydroxide or potassium hydroxide), be hydrolyzed to the temperature between the solvent boiling point in room temperature.If blocking group is a silyl ether; compound 18 can make so so: for example make intermediate 24 hydrolysis under above-mentioned acidic conditions; perhaps in such as alcohol, THF, diox or acetonitrile equal solvent, in room temperature to the temperature between the solvent boiling point, compound 24 is contacted with fluorine example source (for example Potassium monofluoride, cesium fluoride or tertiary butyl Neutral ammonium fluoride).The inert atmosphere that may need nitrogen or argon gas.

The another kind of method of synthetic compound 18 is that the N-hydroxyamidines 23 that will protection be arranged is transformed into boric acid or boric acid ester (exchanges by lithium halogen; use the triisopropyl borate ester cancellation then; or catalytic and tetramethyl ethylene ketone two boron (diboronpinacolate) coupling) by palladium; then in above-mentioned suitable palladium catalytic system, with this boric acid or boric ester derivative and aryl chloride, aryl bromide, aryl iodide or the coupling mutually of trifluoromethanesulfonic acid aromatic ester.As described in scheme 8, go protection subsequently, obtain required compound 18.

Scheme 9

According to scheme 9, (for example iron or the hydrazine-Raney nickel in shortening, the acetate) handles N-hydroxyamidines 18 under reductive condition, obtains intermediate 25.The solvent that is applicable to this method comprises methyl alcohol, ethanol, THF, ethyl acetate He diox, carries out to the temperature between the solvent boiling point in room temperature.Protection secondary nitrogen (as non-limiting example, having shown t-butyl carbamate) obtains compound 26 under standard conditions.Compound 26 is in suitable solvent (THF, acetonitrile or DMF, randomly exist such as alkali such as pyridine, sodium hydride or potassium tert.-butoxides), make compound 26 and Electron Affinities cyanic acid reagent (as cyanogen bromide, N-cyano group benzotriazole or cyanogen bromide/4-dimethylaminopyridine mixture) reaction, obtain required compound 27.In some cases, the cyaniding step be attended by removing of secondary nitrogen-protecting group group, if this goes protection to take place, need further hydrolysis so then and there.

After the scheme 8 of synthetic compound 18, also but synthetic compound 27, this can with shown in the employing scheme 9 reaction similar strategy from N-cyano group bromination amidine 28 and suitable functionalized aryl boric acid or the coupling mutually of boric acid aromatic ester that compound 22 makes, obtain compound 27.In another strategy, intermediate 28 can be transformed into corresponding boric acid or boric acid ester, then in Suzuki or Suzuki type palladium linked reaction with suitable functionalized aryl bromide coupling.

Compound of the present invention can be pharmaceutically or the acceptable acid of physiology or alkali deutero-salt form use.These salt include, but is not limited to the salt with following acid formation: mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, organic acid such as acetate, oxalic acid, succsinic acid and toxilic acid.Other salt comprise the salt that forms with basic metal or alkaline-earth metal, as sodium, potassium, calcium or magnesium, with the form (when giving this form, it can change into active part in vivo) of " prodrug " of ester, carbamate or other routines.

The present invention includes pharmaceutical composition and methods of treatment, this methods of treatment comprises pharmaceutically one or more above-claimed cpds or its pharmacy acceptable salt as the progesterone receptor agonist of significant quantity give Mammals.

Single using or coupling progesterone receptor agonist of the present invention can be used for contraception and treats and/or prevents hemorrhage of functional disorder, leiomyoma of uterus, endometriosis; Polycystic ovarian syndrome, uterine endometrium, ovary, breast, colon, prostate cancer tumor and gland cancer.Other purposes of the present invention comprises stimulating ingests.

When compound is used for such use; they can with one or more pharmaceutically acceptable carrier or mixed with excipients; as solvent, thinner etc.; and can following form oral administration: tablet, capsule, dispersive powder, particle or suspension (for example containing the 0.05-5% suspension agent of having an appointment), syrup (for example containing 10-50% sugar) and elixir (for example containing about 20-50% ethanol) etc., or with form (wait and ooze the suspension agent that contains about 0.05-5% in the medium) administered parenterally of sterile injectable solution or suspension.These pharmaceutical preparations can contain and the about 25-90% activeconstituents of carrier blended, usually approximately between the 5%-60% (weight).

The effective dose of used activeconstituents can be according to the severity of used particular compound, mode of administration and disease to be treated and is different.But when The compounds of this invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.The Mammals big for major part, the total dose of every day is about 1-100mg, preferably is about 2-80mg.Be applicable to that dosage form for oral administration comprises the active compound of about 0.5-500mg, with solid-state or liquid pharmaceutically acceptable carrier thorough mixing.Can regulate this dosage regimen to obtain optimum therapeutic response.For example, but divide the several times administration every day, or dosage is reduced pari passu by the needs of treatment situation.

Can give these active compounds by oral and intravenously, intramuscular or subcutaneous route.Solid-state carrier comprises: starch, lactose, secondary calcium phosphate, Microcrystalline Cellulose, sucrose and kaolin, and liquid carrier comprises: sterilized water, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil), as long as be fit to the characteristic of activeconstituents and required form of medication.Should be included in the pharmaceutical compositions normally used adjuvant for example seasonings, tinting material, sanitas and antioxidant such as vitamin-E, vitamins C, BHT and BHA.

From being easy to preparation and administration, preferred pharmaceutical composition is a solid-state composition, especially the capsule of tablet and hard filling or liquid filling.The oral administration of compound is preferred.

But these active compounds are parenteral or intraperitoneal administration also.The solution or the suspension that also can in the water that suitably is mixed with tensio-active agent (as hydroxypropylcellulose), prepare these active compounds (free alkali or pharmacy acceptable salt).Also can in glycerine, liquid, polyoxyethylene glycol and their mixtures in oil, prepare dispersion liquid.Under common storage and working conditions, contain sanitas in these preparations to prevent microorganism growth.

The medicament forms that is fit to injection comprises aseptic aqueous solution or dispersion liquid and aseptic powder (being used for temporarily preparing aseptic injectable solution or dispersion liquid).In all situations, these forms must be aseptic and must be that fluid is to be easy to the use of syringe.It must be stable under manufacturing and condition of storage, and must be able to resist the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, contains just like water, alcohol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.

Further understand the present invention by following non-restrictive example.

Embodiment 1

5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-thioketones

Spiral shell [hexanaphthene-1.3 '-[3H] indoles]-2 '-(1 ' H) ketone

Anhydrous tetrahydro furan (800cm with oxindole (25 grams, 0.19 mole) ³) be cooled to-20 ℃, slowly add then n-Butyl Lithium (2.5M in hexane, 152cm ³, 0.38 mole), add N then, N, N ＇, N ＇-Tetramethyl Ethylene Diamine (51cm ³, 0.38 mole).After 15 minutes, slowly add 1,5-two iodopentanes (174 grams, 0.54 mole) make the mixture temperature to room temperature.Stir after 16 hours, add saturated aqueous ammonium chloride (1L) and ethyl acetate (1L).After 15 minutes, layering, water ethyl acetate extraction (x2).Merge organic layer,, use salt solution (500cm then with hydrochloric acid (1N) extraction ³) washing, dry (MgSO ₄), and concentrate acquisition oil.With hexane (200cm ³) and benzene (20cm ³) develop this oil.Collecting precipitation, vacuum-drying obtains clear crystal shape subhead compound (26.3 grams, 69.6%): fusing point 110-114 ℃; ¹H NMR (DMSO-d6) δ 1.67 (m, 10H), 6.84 (d, 1H, J=8Hz) 6.94 (t, 1H, J=8Hz), 7.17 (t, 1H, J=8Hz), 7.44 (d, 1H, J=8Hz), 10.3 (S, 1H).

5 '-the bromine spiral shell [hexanaphthene-13 '-[3H] indoles]-2 ' (1 ' H)-ketone

Containing spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (acetate (300cm of 1 ' H)-ketone (17.6 grams, 0.09 mole) ³) add sodium acetate (8.0 grams, 0.1 mole) and bromine (14.6 grams, 0.091 mole) and stirring in the solution.After following 30 minutes of the room temperature, reaction mixture is distributed between water and ethyl acetate.The water ethyl acetate extraction.Merge organic layer, wash with water, dry (MgSO ₄) and evaporation, develop resistates with hexane.Collecting precipitation, and vacuum-drying obtain canescence lenticular subhead compound (16.5 grams, 67%): fusing point 196-199 ℃; ¹H NMR (DMSO-d6) δ 1.62 (m, 10H), 6.8 (d, 1H, J=6.8Hz), 7.36 (d, 1H, J=8.2,1.8Hz), 7.58 (dd, 1H, J=8.2,1.8Hz), 10.44 (S, 1H).

5-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone

Under nitrogen, stir contain 5 '-bromine spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (0.32 gram, 1.14 mmoles) and four (triphenyl phosphines) close the glycol dimethyl ether (6cm of palladium (0) (0.14 restrains 0.12 mmole) ³) solution 20 minutes.In this mixture, add the water (3cm that contains 3-chlorophenylboronic acid (0.21 gram, 1.37 mmoles) and yellow soda ash (0.36 gram, 3.4 mmoles) then ³).Solution was refluxed 6 hours, be cooled to room temperature then, pour in the water, with ethyl acetate extraction (x3).Merge organic extract, water and salt water washing, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 3), obtain yellow solid shape subhead compound (0.28 gram, 0.89 mmole, 80%): fusing point 164-165 ℃, 1H NMR (CDCl ₃) δ 1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J=8.1Hz, 1H), 7.22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H); ¹³C-NMR ((CDCl ₃) 20.17,24.12,31.92 (t), 47.22 (s), 109.21,121.94,124.06,125.50,125.79,125.97,126.38,128.96 (d), 132.88,133.59,135.60,139.14,142.17,182.89 (s); MS (EI) m/z 310,312 (M-H) ⁺Analytical value (C ₁₉H ₁₈ClNO) C, H, N.

Under nitrogen, containing 5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (dry xylene (20cm of 1 ' H)-ketone (0.63 gram, 2.0 mmoles) ³) middle adding 2,4-two (4-p-methoxy-phenyl)-1,3-dithia-2,4-two phosphorus heterocycle butane (diphosphetane)-2,4-disulphide (0.89 gram, 2.2 mmoles) refluxes mixture heating up.After 72 hours, evaporate this mixture, resistates is carried out column chromatography (SiO ₂, ethyl acetate: hexane, gradient elution), obtain a solid, from diisopropyl ether/hexane recrystallization, obtain yellow crystals shape title compound (0.17 gram, 0.51 mmole, 26%): fusing point 223-227C; D (CDCl3) 1.53-1.66 (m, 8H), 1.83-2.05 (m, 4H), 2.07-2.17 (m, 2H), 7.11 (d, 1H, J=8.0Hz) 7.31-7.53 (m, 3H), 7.54 (s, 1H), 7.86 (S, 1H), 9.93 (s, 1H, br): MS ((+APCI) m/z 328 (M+H)+.

Embodiment 2

3-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) benzonitrile

Containing 5 '-the bromine spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (glycol dimethyl ether (20cm of 1 ' H)-ketone (1.00 grams, 3.57 mmoles) ³) add four (triphenyl phosphines) in the solution and close palladium (0.20 gram, 0.17 mmole).After 15 minutes, add 3-formyl radical phenyl-boron dihydroxide (1.00 grams, 6.93 grams), add the water (10cm that contains salt of wormwood (2.90 grams, 21 mmoles) then ³).After refluxing following 20 hours, cooling mixture is poured in the water also with ethyl acetate extraction (x3).Merge organic extract, with the saturated brine washing, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane, gradient elution), obtain white solid title compound (0.66 gram, 2.15 mmoles, 60%), ¹H NMR (CDCl ₃) δ 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8Hz), 7.48 (dd, 1H, J=8,2Hz), 7.61 (t, 1H, J=8Hz), 7.66 (d, 1H, J=2Hz), 7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2Hz), 8.30 (s, 1H, br); MS ((+) ESI) m/z 306 (M+H) ⁺

3-(1 ', 2 '-dihydro-2 '-the oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) benzaldoxime

Contain 3-(1 ', 2 '-dihydro-2 '-oxo volution hexane-1,3 '-[3H] indoles-5 '-yl) ethanol of phenyl aldehyde (0.59 gram, 1.95 mmoles): water (10cm ³, 8: 2) and middle oxammonium hydrochloride (0.17 gram, 2.5 mmoles) and the sodium acetate (0.20 gram, 2.5 mmoles) of adding.After 20 minutes, concentrate this mixture, add entry, with ethyl acetate extraction product (x2).Merge organic layer, with saturated sodium bicarbonate solution, water and saturated brine washing, dry (MgSO ₄) and evaporation, obtaining the oxime shown in the subhead (0.63 gram, 1.95 mmoles, 100%), it can not be further purified and directly use, ¹H NMR (CDCl ₃) δ 1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H), 6.86 (d, 1H, J=8Hz), 7.36 (dd, 1H, J=8,2Hz), 7.43-7.50 (m, 1H), 7.57-7.67 (m, 2H), 7.85 (s, 1H, br), 8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br); MS ((-) ESI) m/z 319 (M-H) ^-

3-(1 ', 2 '-dihydro-2 '-the oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) benzonitrile

With tin anhydride (0.38 gram, 3.50 mmoles) handle contain 3-(1 ', 2 '-dihydro-2 '-the oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) chloroform (10cm of benzaldoxime (0.48 gram, 1.49 mmoles) ³) solution, reflux.After 16 hours, enriched mixture, resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 4), product is recrystallization from ethyl acetate-hexane, obtains white solid subhead compound (0.161 gram, 0.53 mmole, 35%): fusing point 190-191 ℃; ¹H NMR (CDCl ₃) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8Hz), 7.42 (dd, 1H, J=8,2Hz), 7.54 (t, 1H, J=8Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7,2Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H) ⁺

According to the step of embodiment 1 make 3-(1 ', 2 '-dihydro-2 '-the oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) benzonitrile and Lawesson ' s reagent react, obtain title compound: fusing point＞231 ℃ (decomposition); ¹H NMR (DMSO-d ₆) δ 1.38-1.55 (and m, 3H), 1.82-1.99 (m, 7H), 7.16 (d, 1H, J=8.1Hz), 7.63-7.69 (m, 2H), 7.80 (d, 1H, J=7.7Hz), 8.01 (d, 1H, J=8Hz) and 12.76 (s, 1H); MS ((-)-APCI) m/z 317[M-H] ^-

Embodiment 3

4-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-2-thiophene formonitrile HCN

3-(trimethylammonium stannyl)-2-thiophene formonitrile HCN.Make to contain 3-bromo-2-thiophene formonitrile HCN (0.8 gram, 4.3 mmoles), four (triphenyl phosphines) close the glycol dimethyl ether (5cm of palladium (0) (0.25 gram, 0.2 mmole) and hexa methyl ditin (1.4 grams, 4.3 mmoles) ³) reflux 14 hours, be cooled to room temperature then.Reaction mixture is adsorbed on the florisil, and with column chromatography purifying (SiO ₂, methylene dichloride: hexane 1: 9), obtain clarifying thickness oily subhead compound (1.04 grams, 3.8 mmoles, 90%): ¹H NMR (CDCl ₃) δ 0.35 (s, 9H), 7.56 (d, J=0.9Hz, 1H), 7.66 (d, J=0.9Hz, 1H).

4-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-2-thiophene formonitrile HCN

Under nitrogen, stir contain 5 '-bromine spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (0.53 gram, 1.9 mmoles), dichloro two (triphenyl phosphine) palladium (II) (0.1 gram, 0.14 mmole) and the glycol dimethyl ether (8cm of TRIPHENYLARSINE (0.14 gram, 0.47 mmole) ³) solution 20 minutes.Then, in this mixture, add 3-(trimethylammonium stannyl)-2-thiophene formonitrile HCN (0.64 gram, 2.35 mmoles).Solution was refluxed 32 hours.After being cooled to room temperature, reaction mixture is adsorbed on the florisil, and with column chromatography purifying (SiO ₂, ethyl acetate: hexane 2: 3) obtain pale solid shape subhead compound (0.43 gram, 1.39 mmoles, 74%): ¹H NMR (CDCl ₃) δ 1.56-2.1 (m, 10H), 6.97 (d, J=8.0Hz, 1H), 7.39 (dd, J=8.03,1.45Hz, 1H), 7.57 (d, J=1.45Hz, 1H), 7.59 (d, J=1.4Hz, 1H), 7.84 (d, J=1.4Hz, 1H), 8.32 (br s, 1H); ¹³C-NMR (CDCl ₃) δ 22.07,26.56,34.4 (t), 48.13 (s), 110.18 (d), 111.3,114.75 (s), 122.92,126.76 (d), 128.44 (s), 137.55 (d), 138.11,142.71,144.49,182.13 (s); MS (EI) m/z 307 (M-H)+; Analytical value (C ₁₈H ₁₆N ₂OS) C, H, N.

The o-Xylol (20 milliliters) that contains 4-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-5-yl)-2-thiophene formonitrile HCN (1.0 grams, 3.2 mmoles) and Lawesson ' s reagent (1.3 grams, 3.2 mmoles) was heated 2.5 hours.With distilled water wash reaction mixture (5 * 100 milliliters), use dried over mgso, and evaporation.Product column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 5), obtain light yellow solid shape title compound (0.2 gram, 20%): fusing point 230-232 ℃; ¹H-NMR (DMSO-d ₆) δ 12.72 (s, 1H), 8.52 (d, 1H, J=1.5Hz), 8.36 (d, 1H, J=1.5Hz), 8.00 (d, 1H, J=1.5Hz), 7.69 (dd, 1H, J=6.4,1.8Hz), 7.10 (d, 1H, J=8.3Hz), 1.98-1.77 (m, 7H), 1.43-1.33 (m, 3H); MS (EI) M ⁺@m/z 324.

Embodiment 4

3-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-5-fluorine benzonitrile

Containing 5 '-the bromine spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(dry tetrahydrofuran (200cm of 1 ' H)-ketone (11 grams, 0.04 mole) ³) add sodium hydride (60% dispersion liquid, in mineral oil, 1.6 grams, 0.04 mole) in the solution.Stir under the room temperature after 30 minutes, mixture be cooled to-78 ℃, slowly add butyllithium (1.7M in hexane, 23.2cm ³, 0.04 mole).After 30 minutes, add boric acid diisopropyl ester (25cm ³, 0.11 mole), make the mixture temperature to room temperature.After 2 hours, add hydrochloric acid (1N, 500cm ³) and ethyl acetate (500cm ³).The water ethyl acetate extraction merges organic layer then, water and salt water washing, dry (MgSO ₄) and evaporation.Develop resistates with hexane, vacuum-drying precipitation, obtain (2 '-oxo-2,3-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid (8.3 grams, 86%) pale solid, it can not be further purified and uses.Do further to develop the sample that obtains with ethyl acetate and have following character: fusing point 255-260 ℃ dec.; ¹H NMR (DMSO-d6) δ 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J=7.72Hz) 7.66 (d, 1H, J=7.72Hz) 7.91 (s, 3H, br), 10.36 (s, 1H); MS ((-) ESI) m/z244[M-H].

3-(1,2-dioxy-2-oxo spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-5-fluorine benzonitrile

-78 ℃, contain 3, the diethyl ether (100cm of 5-two bromofluoro benzenes ³) in be added dropwise to n-Butyl Lithium (2.5M, 8cm ³, 20 mmoles).After 30 minutes, with containing DMF (20cm ³) diethyl ether (10cm ³) handle this mixture, and continue down to stir at-78 ℃.After 30 minutes, with diluted hydrochloric acid aqueous solution cancellation mixture, the ethyl acetate extraction water layer is used in layering.Merge organic layer, water and salt water washing, dry (MgSO ₄) and evaporation, obtain oily 3-fluoro-5-bromobenzaldehyde (4.0 grams, 19.7 mmoles, 100%): ¹H NMR (CDCl ₃) δ wherein 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS (EI) m/z 202,204[M ⁺].

At the ethanol that contains the compound of last description (4.0 gram, 19.7 mmoles): water (8: 2,50cm ³) in the solution, add sodium acetate (1.72 grams, 21 mmoles) and oxammonium hydrochloride (1.45 grams, 21 mmoles), make the mixture heating up backflow.After 30 minutes, cooling mixture, evaporation distributes resistates between water and ethyl acetate.With ethyl acetate aqueous layer extracted again, merge organic layer, water, saturated sodium bicarbonate solution and salt water washing, dry (MgSO ₄) and evaporation, obtaining 3-fluoro-5-bromobenzaldehyde oxime (3.76 grams, 17.24 mmoles, 87%), it can not be further purified and directly use: ¹H NMR (CDCl ₃) δ 7.24-7.27 (and m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s, 1H); MS (EI) m/z 217[M ⁺].

Under nitrogen, above-mentioned oxime (3.76 gram, 17.24 mmoles) and venus crystals (II) (370mg) are dissolved in acetonitrile (100cm ³) in, and reflux.After 5 hours, evaporating mixture is used the up in ethyl acetate resistates, with sulfuric acid (1N), water and salt water washing, and dry (MgSO ₄) and evaporation, obtaining 3-fluoro-5-bromobenzyl nitrile (3.08 grams, 15.39 mmoles, 89%), it can not be further purified and directly use.

Under nitrogen, above-mentioned bromide (3.0 gram, 15 mmoles) and four (triphenyl phosphines) are closed palladium (0) (0.86 restrains 0.75 mmole) be dissolved in glycol dimethyl ether (130cm ³) in.After 15 minutes, adding is dissolved in water (40cm ³) in (2 '-oxo-2,3-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid (2.82 grams, 11.5 mmoles) and yellow soda ash (3.1 grams, 29.3 mmoles), make the mixture heating up backflow.After 8 hours, cool off this mixture, pour in the water also with ethyl acetate extraction (x3).Merge organic layer, wash with water then, dry (MgSO ₄) and evaporation.Use column chromatography purifying resistates (ethyl acetate: hexane, gradient elution) then, recrystallized product from methyl alcohol, obtain 3-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-5-yl)-5-fluorine benzonitrile (1.78 grams, 5.55 mmole, 48%): fusing point 199-205 ℃; ¹H NMR (CDCl ₃) δ 1.64-2.03 (m, 10H), 7.03 (d, 1H, J=8Hz), 7.31 (dt, 1H, J=7.7 and 1.6Hz), 7.41 (dd, 1H, J=8,1.7Hz), 7.49 (dt, 1H, J=9.6,2Hz), 7.58 (d, 1H, J=2Hz), 7.64 (s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320[M ⁺].

Under nitrogen, at the dimethylbenzene (10cm that contains 3-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-5-yl)-5-fluorine benzonitrile (0.32 gram, 1.0 mmoles) ³) add Lawesson ' s reagent (0.89 gram, 2.22 mmoles) in the solution, make the reactant reflux.After 4 hours, cool off this mixture, evaporation is carried out column chromatography (SiO to resistates ₂, ethyl acetate: hexane, gradient elution) and obtain (0.143 gram, 0.42 mmole, 42%) white solid: fusing point 236-250 ℃; ¹H NMR (CDCl ₃) δ 1.54-1.66 (m, 3H), 1.86-2,18 (m, 7H), 7.16 (d, 1H, J=8.1Hz), 7.33-7.36 (m, 1H), 7.46-7.52 (m, 2H), 7.65 (s, 1H), 7.85 (d, 1H, J=1Hz), 10.05 (s, 1H); MS ((+)-APCI) m/z 337[M+H] ⁺

Embodiment 5

4-methyl-5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H]-indoles]-the 5-yl)-2-thiophene thioamides

With 2 '-oxo-2 ', 3 ＇-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid (2.45 the gram, 10 mmoles), 2-bromo-5-cyano group-3 methyl thiophene (2.4 grams, 12 mmoles), potassium (4 grams, 29 mmoles) and four (triphenyl phosphines) close the glycol dimethyl ether of palladium (0) (0.6 gram, 0.5 mmole): water: ethanol (130cm ³, 10: 2: 1) in be heated to 80 ℃, heated 16 hours, pour into then in 1 premium on currency, and use ethyl acetate extraction.With salt water washing organic layer, dry (MgSO ₄) and concentrate.Crude product is carried out column chromatography (SiO ₂, ethyl acetate: hexane, 1: 1), obtain title compound (0.9 gram, 28%): fusing point 200-203 ℃; ¹H NMR (DMSO-d ₆) δ 1.63 (m, 8H), 1.87 (m, 2H), 2.27 (s, 3H), 6.95 (d, 1H, J=8.13Hz), 7.34 (dd, 1H, J=8.13,1.98Hz) 7.54 (d, 1H, J=1.98Hz), 7.82 (S, and 1H) 10.50 (S, 1H); MS ((+) APC1) m/z 323[M+H] ⁺

To contain 4-methyl-5-[2 '-oxo-2 ' 3 '-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-2-thiophene formonitrile HCN (0.61 gram, 1.9 mmole) and thiophosphoric anhydride (0.92 the gram, 2.1 mmole) De diox (17 milliliters) solution are heated to 85 ℃, heat 30 minutes.Reaction mixture is poured in the distilled water,, used dried over mgso, and be evaporated to dried with sodium bicarbonate aqueous solution and distilled water wash.Resistates column chromatography purifying (2.5%MeOH/CH ₂Cl ₂) obtain orange-brown solid shape title compound (0.05 gram, 8%): fusing point 244-249 ℃; ¹H-NMR (DMSO-d ₆) δ 12.75 (s, 1H), 9.54 (s, 1H), 9.34 (s, 1H), 7.76 (d, 1H, J=1.5Hz), 7.58 (s, 1H), 7.45 (dd, 1H, J=6.4,1.8Hz), 7.14 (d, 1H, J=7.9Hz), 2.26 (s, 3H), 1.98-1.89 (m, 7H), 1.83-1.81 (m, 3H); MS ((+) APCI) [M+H] ⁺@m/z 373.

Embodiment 6-pharmacology

In following external and in vivo test, estimate the progestogenic activity of The compounds of this invention.Vitro efficacy, is renderd a service in 1 microgram/kilogram-30 mg/kg scope in the body in the 000nM scope at 0.01nM-10.

A. extracorporeal biology

By following test determination extracorporeal biology: (1) competitive radioligand combination: with having the A type people progesterone receptor of Progesterone as radioligand; (2) cotransfection test provides with agonist EC ₅₀With antagonist IC ₅₀The functional vigor of value representation; (3) T47D cell proliferation, this provides another functional trial of agonist and antagonist data; (4) T47D cell alkaline phosphatase enzyme test, it also provides the functional trial of agonist and antagonist data.

1.hPR in conjunction with testing: with reference to Pathirana, C.; Stein, R.B.; Berger, T.S.; Fenical, W.; Ianiro, T.; Mais, D.E.; Torres, A.; Glodman, M.E., " non-steroid class people progesterone receptor is regulated marine alga cymopliabarbata ", and J.Steroid Biochem.Mol.Biol., 1992,41,733-738 carries out.

2. the test of the PRE-luciferase in the CV-1 cell

The purpose of this test is PRE-luciferase reporter molecule to be determined the progestogenic or the anti-pregnant effect of compound according to compound in the activity in the CV-1 cell of people PR and PRE-luciferase plasmids cotransfection.Material and method used in this test are as follows:

A. growth medium: DMEM (BioWhittaker), it contain 10% (v/v) foetal calf serum (heat inactivation), 0.1mMMEM non-essential amino acid, 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mMGlutaMax (GIBCO, BRL).Test medium: DMEM (BioWhittaker), no phenol red, contain 10% (v/v) active carbon desorption foetal calf serum (heat inactivation), 0.1mM non-essential amino acid, 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, BRL).

B. the cultivation of cell, transfection, processing and luciferase test

CV-1 cell stoste is maintained in the growth medium.With 1.2 * 10 ⁷There is (250ml) cotransfection of the pGL3 plasmid of two PRE and calf thymus DNA (as carrier DNA) that the 50mg supersound process is crossed individual cell, 5mg pLEM plasmid (inserting hPR-B at Sph1 and BamH1 site), 10mg luciferase sequence upstream.In 260V and 1, carry out electroporation with BioradGene Pulser II under the 000mF.Behind the electroporation, cell is resuspended to growth medium, and on the flat board of 96-hole, cultivates with 40,000 cells/well (200 μ l).After the overnight incubation, change substratum into test medium.In test medium, handle these cells then with contrast or test compounds.In the presence of the 3nM Progesterone, measure the contraception activity of compound.Handle after 24 hours, discard substratum, (GIBCO BRL) washs these cells 3 times with D-PBS.Each hole adds 50 μ l cell lysis buffer solution, and (WI), dull and stereotyped (Lab line Instrument Inc.) goes up jolting 15 minutes at titer plate jolting instrument for Promega, Madison.Luciferase reagent with Promega is measured uciferase activity.

C. interpretation of result

Various processing repeat 4 times at least.With the data analysis agonist of logarithm conversion and the variance and the non-linear dose response curve match of antagonist pattern.Reduce the influence of outlier (outlier) with the Huber weighted method.With the numerical evaluation EC that converts again ₅₀Or IC ₅₀In the one-way analysis of variance and non-linear response analysis with JMP software (SAS Institute, Inc.).

D. control compound

Contrast progestogen is Progesterone and trimegestone (trimegestone), and the contrast antiprogestin is RU486.All compounds are all carried out full dose response curve measure, and calculate EC ₅₀Or IC ₅₀Value.

The EC of contrast progestogen in three independent studies of table 1 ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

EC50 95％CI

Compound embodiment. (nM) the SE lower limit upper limit

Progesterone 1 0.616 0.026 0.509 0.746

2 0.402 0.019 0.323 0.501

3 0.486 0.028 0.371 0.637

Trimegestone 1 0.0075 0.0002 0.0066 0.0085

2 0.0081 0.0003 0.0070 0.0094

The EC of antiprogestin RU486 in three independent studies of 3 0.0067 0.0003 0.0055 0.0082 tables 2. ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

IC50 95％CI

Compound embodiment (nM) the SE lower limit upper limit

RU486 1 0.028 0.002 0.019 0.042

2 0.037 0.002 0.029 0.048

3 0.019 0.001 0.013 0.027

Progestogenic activity: compare with control vector, the compound that makes the PRE-uciferase activity significantly increase (p＜0.05) is thought activated.

Anti-pregnant activity: compound has significantly reduced 3nM Progesterone inductive PRE-uciferase activity (p＜0.05).

EC ₅₀: produce the PRE-uciferase activity and (be defaulted as-nM) compound concentration and the standard deviation of half maximum increased value.

IC ₅₀: produce 3nM Progesterone inductive PRE-uciferase activity and (be defaulted as-nM) compound concentration and the standard deviation of half maximum minimizing value.

3.T47D cell proliferation experiment

The purpose of this experiment is to measure progestogenic and anti-pregnant effectiveness with the cell proliferation experiment of T47D cell.Measure compound to DNA synthetic influence in the T47D cell.Below be this experiment used material and method:

A. growth medium: be supplemented with 10% (v/v) foetal calf serum (not heated and inactivated), 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, DEME BRL): F12 (1: 1) (GIBCO, BRL).

B. handle substratum: be supplemented with 0.5% active carbon desorption foetal calf serum, 100U/ml penicillin, 200mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, no phenol red minimum essential medium (MEM) BRL) (#51200-038 GIBCO, BRL).

C. cell cultures

T47D cell stoste is maintained in the growth medium.BrdU is mixed experiment, the amount of cell with 10,000 cells/well placed in the growth medium of 96-orifice plate (Falcon, Becton Dickinson Labware).After the overnight incubation, change substratum into the processing substratum, before processing, cultivated these cells again 24 hours.Compound stoste is dissolved in appropriate carriers (in 100% ethanol or 50% ethanol/50%DMSO), with handling the substratum dilution, adds to cell then.Gestagen and antiprogestin control compound all are marked in full dosage-response curve.The carrier final concentration is 0.1%.In control wells, cell is only accepted carrier.In the presence of 0.03nM trimegestone (progestogen agonist in contrast), measure antiprogestin.Handle after 24 hours, discard substratum, with 10mM BrdU (Amersham Life Science, Arlington Heights, IL) these cells of mark 4 hours in handling substratum.

D. cell proliferation experiment

When the BrdU mark finishes, discard substratum, by supplier's explanation, ((#RPN 250, Amersham Life Science) measure mixing of BrdU with cell proliferation ELISA test kit.Briefly, make cell in containing the ethanol of fixing agent, fix 30 minutes, in the damping fluid of blockading, cultivate 30 minutes then to reduce background.The anti-BrdU antibody that is marked with peroxidase labelling is added in the hole, cultivated 60 minutes.With PBS rinsing cell 3 times, with 3,3 ', 5,5 '-tetramethyl benzidine (TMB) substrate cultivation 10-20 minute (effectiveness that depends on the compound of being tested).In each hole, add 25 μ l 1M sulfuric acid then and react, read the 450nm optical density(OD) with plate reader in 5 minutes with color development stopping.

E. interpretation of result

Mate the variance and the non-linear dose response curve of agonist and antagonist pattern with the data analysis that square root converts.Reduce the weights influence (downweight) of outlier effect with Huber weighting method.Calculate EC by the value that converts again ₅₀Or IC ₅₀In single dose that variance one-way analysis and non-linear dose response are analyzed and dose response are analyzed, adopt JMP software (SAS Institute, Inc.).

F. control compound

Trimegestone and Veramix (MPA) be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are all measured in full dose response curve mode, and calculated EC ₅₀Or IC ₅₀Value.EC in table 3. independent studies ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

EC ₅₀ 95％CI

Compound embodiment (nM) the SE lower limit upper limit

Trimegestone 1 0.017 0.003 0.007 0.040

2 0.014 0.001 0.011 0.017

3 0.019 0.001 0.016 0.024

MPA 1 0.019 0.001 0.013 0.027

The EC of 2 0.017 0.001 0.011 0.024 table 4. antiprogestin RU486 ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

IC ₅₀ 95％CI

Compound embodiment (nM) the SE lower limit upper limit

RU486 1 0.011 0.001 0.008 0.014

2 0.016 0.001 0.014 0.020

3 0.018 0.001 0.014 0.022

EC ₅₀: compound concentration and standard deviation when BrdU being mixed reach half maximum increased value; IC ₅₀: make 0.1 trimegestone inductive BrdU mix compound concentration and the standard deviation that reaches half maximum minimizing value.

4.T47D cell alkaline phosphatase experiment

The purpose of this experiment is by measuring compound progestogen or antiprogestin to be identified in the influence of T47D cell alkaline phosphatase activities.Below be this experiment used processing and method.

A. substratum: be supplemented with 5% (v/v) active carbon desorption foetal calf serum (not heated and inactivated), 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates and 2mM GlutaMax (GIBCO, DMEM BRL): F12 (1: 1) (GIBCO, BRL).

B. alkaline phosphatase is tested damping fluid:

I.0.1M Tris-HCl, pH 9.8, contain 0.2%Triton X-100; II.0.1M Tris-HCl, pH9.8 contains 4mM p-nitrophenyl phosphate (Sigma)

C. cell cultures and processing:

Refrigerated T47D cell is thawed in 37 ℃ of water-baths, and be diluted to 280,000 cells/ml with substratum.The cell suspending liquid that in each hole of 96-hole flat board (Falcon, Becton Dickinson Labware), adds the dilution of 180 microlitres.In each hole, add contrast or the test compounds of 20 microlitres then with the substratum dilution.When the test progesterone antagonist is active, in the presence of the 1mM Progesterone, add contrast antiprogestin or test compounds.37 ℃ of 5%CO ₂Cultivated these cells 24 hours in the/moistening atmosphere.

D. alkaline phosphatase experiment

When processing finishes, discard the substratum in the flat board, in each hole, add 50 μ l experiment damping fluid I.With the jolting 15 minutes on titer plate jolting instrument of these flat boards.Then 150 microlitres experiment damping fluid II is added in each hole.Under 405nM test wavelength, be measuring space optical density(OD) totally 30 minutes with 5 minutes.

E. interpretation of result: analyze the dosage reply data

To contrast and test compounds, enzyme reaction rate (slope) (Y-axle) is drawn dose response curve with dosage (X-axle).The data of square root conversion are used for the variance analysis and the non-linear dose response curve match of agonist and antagonist pattern.Reduce the influence of outlier with the Huber weighted method.By the numerical evaluation EC that converts again ₅₀Or IC ₅₀In the single dose of the one-way analysis of variance and non-linear response analysis and dose response study, use JMP software (SASInstitute, Inc.).

F. control compound

Progesterone and trimegestone be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are all measured with full dose response curve, calculated EC ₅₀Or IC ₅₀Value.The EC of contrast progestogen in three independent experiments of table 5. ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

EC50 95％CI

Compound embodiment (nM) the SE lower limit upper limit

Progesterone 1 0.839 0.030 0.706 0.996

2 0.639 0.006 0.611 0.669

3 1.286 0.029 1.158 1.429

Trimegestone 1 0.084 0.002 0.076 0.091

2 0.076 0.001 0.072 0.080

The EC of contrast progestogen in three independent experiments of 3 0.160 0.004 0.141 0.181 tables 6. ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

IC50 95％CI

Compound embodiment (nM) the SE lower limit upper limit

RU486 1 0.103 0.002 0.092 0.115

2 0.120 0.001 0.115 0.126

3 0.094 0.007 0.066 0.134

B. biology in the body

Initial in vivo test is a rat decidua model, and it can be used for measuring the gestagenic action of agonist and antagonist.Experiment is to suppress model with the rat ovulation in second individuality, and this model still also is in the development phase so flow process is not provided.

1. rat decidua experiment: to be assessment progestogen and antiprogestin compare to the effect of rat uterus deciduaization and with the relative effectivenes of various test compounds the purpose of this flow process.Below be used material and method:

A. method: test compounds is dissolved in 100% ethanol, and mixes with Semen Maydis oil (carrier).Prepare at oil (Mazola by heating (～80 ℃) this mixture ethanol evaporation then ^TM) in test compounds stoste.Subsequently before handling animal, with 100% Semen Maydis oil or contain 10% alcoholic acid Semen Maydis oil and dilute test compounds.When these two kinds of carriers are compared, do not find that decidua is variant between replying.

B. animal (RACUC flow process #5002)

(Taconic Farms NY) obtains ovariectomized female Sprague-Dawley rat (～60 day age and 230g) from Taconic.At least 10 days spays before processing are to reduce the round-robin sex steroid.These animals are closed support in the room of light/dark cycle was arranged in 12 hours, and feed with standard rat feed and feedwater arbitrarily.

C. handle

Before processing, rat is weighed, be divided into 4 or 5 groups at random.0.2 ml of carrier that will contain test compounds by subcutaneous injection gives nape, or fills out with 0.5 milliliter and to feed.Handle animal every day once, continue 7 days.For the antiprogestin of test, gave animal testing compound and EC at three days that handle ₅₀The Progesterone of dosage (5.6 mg/kg).After decidua stimulated, animal continued to accept Progesterone necrotomy after four days.

D. dosage

Prepare dosage according to mg/kg group mean body weight.In all researchs, the control group of accepting carrier is arranged.The half value that increases with logarithm determine dose response curve (as 0.1,0.3,1.0,3.0mg/kg ...).

E. decidua is induced

The injection back is about 24 hours for the third time, by with 21G pin scraping myometrium (antimesometrial) chamber epithelium, makes a horn of uterus generation decidua.Do not swipe in the diagonal angle, as unprovoked contrast.After about 24 hours, pass through CO in final processing ₂Suffocate and put to death rat, measure body weight.Take out the uterus, clean out fat.Weigh respectively decidua horn of uterus (D-angle) and the contrast horn of uterus (C-angle).

F. interpretation of result

Increase by decidua horn of uterus weight is calculated at D-angle/C-angle transforms normality and the homogeneity maximization that makes variance with logarithm.Reduce the influence of viewed improper conversion value in (downweight) dose response curve match and the variance one-way analysis with Huber M-algorithm for estimating.Use JMP software in unidirectional ANOVA and non-linear response analysis (SAS Institute, Inc.).

G. control compound

All progestogen control compounds are all tested in full dose response curve mode, calculated the EC of uterus weight in wet base ₅₀The EC of table 7. independent experiment ₅₀, standard deviation (SE) and 95% fiducial interval (CI) estimated value

EC ₅₀ 95％CI

Compound embodiment (mg/kg, s.c.) the SE lower limit upper limit

Progesterone 1 5.50 0.77 4.21 7.20

2 6.21 1.12 4.41 8.763-ketone desogestrels, 1 0.11 0.02 0.07 0.16 (3-Ketodesogestrel) 2 0.10 0.05 0.11 0.25

3 0.06 0.03 0.03 0.14 Levonorgestrels 1 0.08 0.03 0.04 0.16

2 0.12 0.02 0.09?0.17

3 0.09 0.02 0.06?0.13

4 0.09 0.02 0.06?0.14

MPA 1 0.42 0.03 0.29?0.60

2 0.39 0.05 0.22?0.67

Average EC in the dose response curve of three kinds of control compounds of 3 0.39 0.04 0.25 0.61 tables 8. ₅₀, standard deviation and 95% confidence interval estimate

EC50 95％CI

Compound (mg/kg, s.c.) the SE lower limit upper limit

Progesterone 5.62 0.62 4.55 7.00

3-ketone desogestrel 0.10 0.02 0.07 0.14

The EC of Levonorgestrel 0.10 0.01 0.08 0.12 table 9. antiprogestin RU486 ₅₀, standard deviation and 95% confidence interval estimate

IC ₅₀ 95％CI

Compound embodiment (mg/kg, p.o.) the SE lower limit upper limit

RU486 1 0.21 0.07 0.05 0.96

2 0.14 0.02 0.08 0.27

Concentration: compound concentrations in the experiment (being defaulted as the mg/kg body weight)

Route of administration: the approach that gives the animalizing compound.

Body weight: the average overall of animal heavy (being defaulted as kg).

D-angle: the weight in wet base of decidua horn of uterus (being defaulted as mg).

C-angle: the weight in wet base (being defaulted as mg) of contrast horn of uterus.

Decidua is replied: [(D-C)/C] * 100%

Progestogenic activity: compare with control vector and significantly to induce the compound of deciduaization (p＜0.05) to think activated.

Anti-pregnant activity: make EC ₅₀(p＜0.05) compound that Progesterone inductive deciduaization significantly reduces.

The EC of uterus weight ₅₀: the compound concentration (being defaulted as mg/kg) that decidua is replied reach half maximum increased value.

The IC of uterus weight ₅₀: make EC ₅₀The compound concentration (being defaulted as mg/kg) that reaches half maximum reduction value is replied in the decidua of Progesterone inductive.

The data of table 10. representative compounds

Embodiment # Ki/nM CV-1 IC50/nM ovulation suppresses IC100mg/kg

5 0.3

3 0.1 0.2

1 0.2 0.8

4 0.06 0.1 0.1

Embodiment 7

5-(1,2-dihydro-2-sulfo-spiral shell [pentamethylene-1,3-[3H] indoles]-5 '-yl)-1H-pyrroles-2-formonitrile HCN

5-(2 '-oxo-2 ', 3 '-dihydro spiral shell [pentamethylene-1,3 '-[3H] indoles]-5 '-Ji-2-cyanopyrrole: under nitrogen gas stream, stir contain 5 '-bromine spiral shell [pentamethylene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (2.0 grams, 7.5 mmole) and four (triphenyl phosphines) close glycol dimethyl ether (50 milliliters) solution 15 minutes of palladium (0) (430 milligrams, 0.3 mmole).In this solution, add 1-tertbutyloxycarbonyl pyrroles-2-boric acid (2.1 gram, 9.7 mmoles) successively and contain the water (10 milliliters) of salt of wormwood (2.4 restrain 17 mmoles).With mixture heating up to 80 ℃ and heated 3 hours, make its cooling then.Reaction mixture is poured in the water (50 milliliters), with ethyl acetate extraction (3 * 50 milliliters).Merge organic layer,, and use dried over mgso with salt solution (30 milliliters) washing.Filtering solution and vacuum concentration.From 20% ethyl acetate/hexane crystallization obtain 2-(1 ', 2 '-dihydro-2 '-oxo spiral shell [pentamethylene-1,3 '-[3H] indoles]-5 '-yl)-1H-pyrroles-1-carboxylic acid tert-butyl ester (2.2 grams, 83%) white powder, fusing point 179-180.5 ℃. ¹H?NMR(DMSO-d ₆，400MHz)δ1.30(s，9H)，1.75-1.98(m，8H)，6.16(dd，1H，J＝1.8，3.3Hz)，6.22(‘t’，1H，J＝3.3，3.3Hz)，6.79(d，1H，J＝7.9Hz)，7.08(dd，1H，J＝1.8，7.9Hz)，7.14(‘d’，1H，J＝1.5Hz)，7.28(dd，J＝1.9，3.3Hz)，10.30(s，1H)。MS(EI)m/z?352[M ⁺]。C ₂₁H ₂₄N ₂O ₃The analytical calculation value: C, 71.57; H, 6.86; N, 7.95.Measured value: C, 71.08; H, 6.83; N, 7.74.

Under-78 ℃, contain 2-(1 ', 2 '-dihydro-2 '-oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-1H-pyrroles-1-carboxylic acid tert-butyl ester (2.2 grams, 6.0 add isocyanic acid chlorine sulfonyl ester (0.63 milliliter, 7.0 mmoles) among THF mmole) (anhydrous, 25 milliliters).After 90 minutes, add dimethyl formamide (11 milliliters, 140 mmoles), make the reactant temperature to room temperature.Reaction mixture is poured in the water (50 milliliters), with ethyl acetate extraction (2 * 50 milliliters).Merge organic layer,, use dried over mgso, filter and vacuum concentration with salt solution (50 milliliters) washing.On silica gel through flash column chromatography purifying (30% ethyl acetate/hexane) obtain white crystal shape 5-(2 '-oxo-2 ', 3 '-dihydro spiral shell [pentamethylene-1,3 '-[3H] indoles]-5 '-Ji-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (1.7 grams, 75%), fusing point 167-9 ℃. ¹H?NMR(DMSO-d ₆，400MHz)δ1.34(s，9H)，1.75-1.98(m，8H)，6.39(d，1H，J＝3.7Hz)，6.84(d，1H，J＝7.9Hz)，7.17(dd，1H，J＝1.8，7.9Hz)，7.28(‘t’，2H)，10.41(s，1H)。MS(ESI)m/z?376[M-H] ^-。C ₂₂H ₂₃N ₃O ₃The analytical calculation value: C, 70.01; H, 6.14; N, 11.13.Measured value: C, 69.67; H, 6.38; N, 11.04.

With 5-(2 ＇-oxo-2 ', 3 '-dihydro spiral shell [pentamethylene-1,3 '-[3H] indoles]-5 '-Ji-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (1 gram, 2.7 mmoles) adds and is plugged with rubber septum and nitrogen inlet is housed and makes in 25 milliliters of round-bottomed flasks of the pinprick that gas discharges.When flask places oil bath and be heated to 165 ℃, keep violent nitrogen gas stream.After following 20 minutes of this temperature, from oil bath, take out flask and make its cooling.Crystallization obtains yellow powder shape title compound (600 milligrams, 79%), fusing point 285-286 ℃ from ether. ¹H?NMR(DMSO-d ₆，400MHz)δ1.75-2.03(m，8H)，6.60(dd，1H，J＝2.4，3.7Hz)，6.84(d，1H，J＝8.1Hz)，6.94(dd，1H，J＝2.4，3.7Hz)，7.52(dd，1H，J＝1.8，8.1Hz)，7.60(d，1H，J＝1.8Hz)，10.38(s，1H)，12.45(s，1H)。MS(ESI)m/z?276[M-H] ^-。C ₁₇H ₁₅N ₃The analytical calculation value of O: C, 73.63; H, 5.45; N, 15.15.Measured value: C, 73.24; H, 5.34; N, 14.96.

At 5-(1,2-dihydro-2-oxo-spiral shell [pentamethylene-1,3-[3H] indoles]-5 '-yl)-1H-pyrroles-2-formonitrile HCN (0.18 gram, 0.7 mmole, 1 equivalent) adds Lawesson ' s reagent (0.14 gram in the p-Xylol (20 milliliters), 0.36 mmole, 0.5 equivalent), made the reactant reflux 1 hour.Reactant is cooled to room temperature, and is adsorbed on the silica gel.On silica gel,, obtain orange powder shape product with flash column chromatography purifying (20% ethyl acetate/hexane).Be further purified with HPLC, obtain green solid shape title compound (0.144 gram, 70%), fusing point 275-276 ℃ (decomposition). ¹HNMR(d ₆-DMSO，300MHz)δ1.81-2.16(m，8H)，6.69(dd，1H，J＝2.3，3.7Hz)，6.98(dd，1H，J＝1.8，3.7Hz)，7.04(d，1H，J＝8.2Hz)，7.63(dd，1H，J＝1.6，8.2Hz)，7.72(d，1H，J＝1.3Hz)，12.57(s，1H)，12.65(s，1H)。MS(ESI)[M-H] ^-＝292。C ₁₇H ₁₅N ₃The computational analysis value of S: C, 69.6; H, 5.15; N, 14.32.Measured value: C, 69; H, 5.31; N, 13.81.

Embodiment 8

5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-1-(tertbutyloxycarbonyl)-pyrroles-2-formonitrile HCN

Under nitrogen, containing 5 '-bromo-spiral shell [hexanaphthene-1,3 '-indoline]-2 '-ketone (3.4 grams, 12 mmoles) 1, add four (triphenyl phosphines) in 2-DME (100 milliliters) solution and close palladium (O) (70 milligrams, 5 moles of %).After 15 minutes, add 2-boron (borono)-1H-pyrroles-1-carboxylic acid 1-tert-butyl ester (1.3eq, 3.31 grams, 15.6 mmoles) successively and contain K ₂CO ₃Water (5 milliliters) solution of (2.3 equivalents, 3.83 grams, 27.6 mmoles).Solution is heated to 80 ℃ of heating 3 hours, makes its cooling then.Reaction mixture is poured in the water (200 milliliters), with ethyl acetate extraction (2 * 100 milliliters).Merge organic layer,, and use dried over mgso with salt solution (150 milliliters) washing.Filtering solution, vacuum concentration, resistates carries out flash column chromatography purifying (with 30% ethyl acetate/hexane wash-out) on silica gel, obtain 2-(1 ', 2 '-dihydro-2 '-oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-and 1H-pyrroles-1-carboxylic acid tert-butyl ester (3.4 grams, 76%) white powder, 177 ℃ of fusing points. ¹H?NMR(CDCl ₃；300MHz)δ1.38(s，9H)，1.59-1.93(m，10H)，6.18(m，1H)，6.23(＇t＇，1H，3Hz)，6.91(d，1H，J＝8Hz)，7.21(d，1H，J＝8Hz)，7.34(m，1H)，7.44(s，1H)，8.33(br?s，1H，D ₂Oex)。MS((+)-APCI)m/z?367[(M+H) ⁺]。C ₂₂H ₂₆N ₂O ₃The analytical calculation value: C, 72.11; H, 7.15; N, 7.64.Measured value: C, 71.7; H, 7.16; N, 7.5.

Under-78 ℃, contain 2-(1 ', 2 '-dihydro-2 '-oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-1H-pyrroles-1-carboxylic acid tert-butyl ester (0.75 gram, 2 mmoles) THF is (anhydrous, 20 milliliters) add isocyanic acid chlorine sulfonyl ester (1.15 equivalents, 0.23 milliliter, 2.3 mmoles) in the solution.After 90 minutes, add DMF (20 equivalents, 3.6 milliliters, 46 mmoles), make the reactant temperature to room temperature.Reaction mixture is poured in the water (50 milliliters), with ethyl acetate extraction (2 * 50 milliliters).Merge organic layer,, use dried over mgso, filter and vacuum concentration with salt solution (50 milliliters) washing.On silica gel through flash column chromatography purifying (30% ethyl acetate/hexane) obtain oily 5-(2 '-oxo-2 ', 3 '-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-Ji-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (0.5 gram, 63%), the crystallization from acetone of this oil, obtain white crystal, 156 ℃ of fusing points. ¹H?NMR(d ₆-DMSO，400MHz)δ1.32(s，9H)，1.50(m，3H)，1.60-1.70(m，5H)，1.75-1.85(m，2H)，6.38(d，1H，J＝3.7Hz)，6.87(d，1H，J＝7.9Hz)，7.18(dd，1H，J＝1.5，7.9Hz)，7.27(d，1H，J＝3.7Hz)，7.48(d，1H，J＝1.8Hz)，10.42(bs，1H)。MS(EI)m/z?391(M ⁺)。C ₂₃H ₂₅N ₃O ₃The analytical calculation value: C, 70.57; H, 6.44; N, 10.73.Measured value: C, 69.82; H, 6.46; N, 10.43.

Containing 2-cyano group-5-(1,2-dihydro 2-oxo spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-1H-pyrroles-1-carboxylic acid tert-butyl ester (0.7 gram, 1.8 mmole, 1 equivalent) adds Lawesson ' s reagent (0.47 gram in the toluene (70 milliliters), 1.1 mmole, 0.65 equivalent), made the reactant reflux 1 hour.Reactant is cooled to room temperature, pours in the water (100 milliliters), with ethyl acetate extraction (2 * 100 milliliters).Merge organic layer,, use dried over mgso, filter and vacuum concentration with salt solution (50 milliliters) washing.On silica gel,, obtain yellow solid shape title compound (0.7 gram, 96%) with flash column chromatography purifying (20-30% ethyl acetate/hexane). ¹H?NMR(d ₆-DMSO，500MHz)δ1.30-1.98(m，19H)，6.45(d，1H，J＝3.7Hz)，7.09(d，1H，J＝7.9Hz)，7.31-7.34(m，2H)，7.81(d，1H，J＝1.4Hz)，12.74(s，1H)。MS(ESI)[M-H] ^-＝406。C ₂₃H ₂₅N ₃O ₂The analytical calculation value of S: C, 67.79; H, 6.18; N, 10.31.Measured value: C, 67.86; H, 5.99; N, 10.25.

Embodiment 9

5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-1-H-pyrroles-2-formonitrile HCN

Containing 5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-1-(tertbutyloxycarbonyl)-pyrroles-2-formonitrile HCN (0.5 gram, 1.2 mmole, 1 equivalent) adds in THF (5 milliliters) solution and contain sodium ethylate (0.25 gram, 3.6 mmole, 3 equivalents) ethanol (5 milliliters) makes reactant in 80 ℃ of heating 24 hours.Solvent removed in vacuo is distributed resistates between ethyl acetate (50 milliliters) and water (50 milliliters).Layering is with ethyl acetate extraction (50 milliliters) water layer.Merge organic layer,, use dried over mgso, filter and vacuum concentration with salt solution (50 milliliters) washing.On silica gel,, obtain yellow powder shape title compound (0.27 gram, 68%) with flash column chromatography purifying (30% ethyl acetate/hexane). ¹HNMR(d ₆-DMSO，500MHz)δ1.32-1.99(m，10H)，6.71(d，1H，J＝3.7Hz)，7.00(d，1H，J＝3.7Hz)，7.09(d，1H，J＝8.4Hz)，7.70(dd，1H，J＝1.6，8.4Hz)，8.05(d，1H，J＝1.1Hz)，12.67(s，1H)，12.73(s，1H)。MS(ESI)[M-H] ^-＝306。C ₁₈H ₁₇N ₃The analytical calculation value of S: C, 70.33; H, 5.57; N, 13.67.Measured value: C, 69.64; H, 5.79; N, 13.04.

Embodiment 10

5-(2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-1-methyl-pyrroles-2-formonitrile HCN

Contain 5-(2 '-oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-1-methyl-pyrroles-2-formonitrile HCN (0.55 gram, 1.8 mmole, 1 equivalent) adds Lawesson ' s reagent (0.47 gram in toluene (50 milliliters) solution, 1.1 mmole, 0.65 equivalent), make reactant in 80 heating 1 hour.Reactant is cooled to room temperature, pours in the water (100 milliliters), with ethyl acetate extraction (2 * 100 milliliters).Merge organic layer,, use dried over mgso, filter and vacuum concentration with salt solution (50 milliliters) washing.On silica gel, use the flash column chromatography purifying, obtain yellow solid shape product (0.32 gram, 55%). ¹H?NMR(d ₆-DMSO，500MHz)δ1.36-1.99(m，10H)，3.7(s，3H)，6.35(d，1H，J＝4.2Hz)，7.05(d，1H，J＝4.2Hz)，7.16(d，1H，J＝7.9Hz)，7.44(dd，1H，J＝1.6，8.1Hz)，7.83(d，1H，J＝1.6Hz)，12.75(s，1H)。MS(ESI)[M-H] ^-＝320。C ₁₉H ₁₉N ₃The analytical calculation value of S: C, 70.99; H, 5.96; N, 13.07.Measured value: C, 68.69; H, 5.36; N, 12.27.

Embodiment 11

5-(1,2-dihydro-2-sulfo-spiral shell [pentamethylene-1,3-[3H] indoles]-the 5-yl)-3-thiophene formonitrile HCN

5-bromo-2-thiophene formonitrile HCN: under nitrogen, the mixture heating up of 5-bromo-2 thiophene carboxaldehyde (96.0 grams, 500 mmoles), oxammonium hydrochloride (111.9 grams, 500 mmoles), pyridine (500 milliliters) and ethanol (500 milliliters) was refluxed 2 hours.Reaction mixture is cooled to room temperature, and vacuum concentration obtains oil.Develop this crude product with frozen water, on filter membrane, collect the gained solid.Make a part of above-mentioned solid (44.31 grams, 215 mmoles), the mixture of the acetonitrile (1.4L) of single hydrated copper acetate (II) (4.2 grams, 21 mmoles), reflux 3 hours.Solvent removed in vacuo is dissolved in resistates in the ethyl acetate.With 5% aqueous sulfuric acid (2 * 30 milliliters), water (2 * 30 milliliters), salt solution (20 milliliters) washs this solution, dry then (MgSO ₄).Solvent removed in vacuo is dissolved in resistates in the minimum chloroform (1L), makes its crystallization.Collect the gained crystal on filter membrane, concentrated filtrate and chromatogram purification (silica gel, chloroform) obtain pale solid shape subhead compound (31.5 grams merge thing, 58%).IR(film)cm ^-1?2200。 ¹H-NMR(CDCl ₃)δ7.39-7.38(d，1H，J＝4。1Hz)，7.10(d，1H，J＝4.0Hz)；MS(EI)m/z?187(M ⁺，98％)189(M ⁺，100％)。

Step according to embodiment 5, with 5-bromo-2-thiophene formonitrile HCN and (2 '-oxo-2 ', 3 '-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid makes 5-(1,2-dihydro-2-oxo-spiral shell [pentamethylene-1,3-[3H] indoles]-the 5-yl)-3-thiophene formonitrile HCN: fusing point 225-228 ℃; ¹H NMR (DMSO-d ₆) δ 1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J=8.13Hz), 7.55 (dd, 1H, J=8.13,1.76Hz), 7.60 (d, 1H, J=4.17Hz), 7.75 (d, 1H, J=1.76Hz), 7.93 (d, 1H, J=4.17Hz), 10.51 (s, 1H); MS ((+) APC1) m/z 309[M+H] ⁺

Under 80 ℃, stir and contain 5-(1,2-dihydro-2-oxo-spiral shell [pentamethylene-1,3-[3H] indoles]-the 5-yl)-3-thiophene formonitrile HCN (0.66 gram, 2.4 mmole) and 2,4-two (4-p-methoxy-phenyl)-1,3-two thiophenes-2,4-two phosphorus heterocycle butane-2, toluene (250 milliliters) solution of 4-disulphide (0.97 gram, 2.4 mmoles) 2 hours.This solution of vacuum concentration.Use the ethyl acetate extraction resistates, wash ethyl acetate solution with water, use dried over mgso, and concentrate.Resistates obtains title compound with column chromatography purifying (silica gel, ethyl acetate, hexane 20/80), fusing point 269-272 ℃ (0.24 gram, 32%). ¹H-NMR(DMSO-d ₆)δ2.09(m，8H)，7.05(d，J＝8.1Hz，1H)，7.55(dd，J＝8.1，1.7Hz，1H)，7.7(d，J＝1.7Hz，1H)，7.95(d，J＝1.3Hz，1H)，8.49(d，J＝1.3Hz，1H)，8.49(d，J＝1.3Hz，1H)，12.68(s，1H)；MS(EI?NEG)m/z?309(M-H) ^-。

Embodiment 12

5-(1,2-dihydro-sulfo-spiral shell (pentamethylene-1,3-[3H] indoles)-the 5-yl)-2-thiophene formonitrile HCN

(1,2-dihydro-oxo spiral shell (pentamethylene-1,3-[3H] indoles)-5yl)-2-thiophene formonitrile HCN (2g, 6.8 mmoles) and Lawesson ' s reagent (3.32g, 8.2 mmoles) make title compound from 3 hours 5-of reflux toluene (150 milliliters).Yield is 1.5 grams (48.3%). fusing point 250-253 ℃. ¹H NMR (DMSO-d ₆) δ 12.75 (S, 1H), 7.98-7.97 (d, 1H, J=3.9Hz), 7.71-7.70 (d, 1H, J=5.2Hz), 7.65-7.62 (d, 1 hour J=8.1Hz), 7.09-7.07 (d, 1 hour, J=8.1 Hz) 2.13 2.08 (m, 6H), 1.99-1.85 (m, 2H); MS.[M-H] ^-=309.IR (SP ATR) 1430,1620,2220cm ^-1.C ₁₇H ₁₄N ₂S ₂Computational analysis value C, 65.77; H, 4.55 N, 9.02.obs′d?C65.27；H，4.41；N，8.84。

Embodiment 13

5-(3-fluoro-4-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5-(3-fluoro-4-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone: according to the step of embodiment 5, from 4-bromo-2-fluoroanisole and (2 '-oxo-2 ', 3 '-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid makes white solid subhead compound, and fusing point 178-180 ℃; ¹H-NMR (DMSO-d ₆) δ 10.4 (and s, 1H), 7.65 (d, 1H, J=1.1Hz), 7.5-7.4 (m, 3H), 7.2 (t, 1H, J=d J=8.8Hz), 3.9 (s, 3H), 1.9 (m, 2H) 1.7-1.6 (m, 8H); MS (APCI (-)) m/z 324[M-H] ^-C ₂₀H ₂₀FNO ₂The analytical calculation value.：C，73.83，H，6.20，N，4.30。Measured value: C, 73.55, H, 6.23, N, 4.40.

Making 5-(3-fluoro-4-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone and the mixture of pyridine that contains the thiophosphoric anhydride of identical weight reflux and to spend the night and make title compound.Vacuum is removed pyridine, handles resistates with the 5N hydrochloric acid soln then, and recrystallization in ethanol obtains gray solid subsequently, fusing point 228-229 ℃; ¹H-NMR (DMSO-d6) δ 12.7 (s, 1H), 7.9 (s, 1H), 7.6-7.5 (m, 2H), 7.5-7.4 (m, 1H), 7.2 (t, 1H, J=8.8Hz), 7.1 (d, 1H, J=8.1Hz), 3.9 (s, 3H), 1.9-1.8 (m, 7H), 1.4-1.3 (m, 3H); MS (APCI (-)) [M-H] ^-M/z 324.C ₂₀H ₂₀The analytical calculation value of FNOS.0.25 water C, 69.44; H, 5.97; N, 4.05.Measured value: C, 69.43; H, 5.75; N, 4.32.

Embodiment 14

5-(2-amino-5-pyrimidyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

By 5-(2-amino-5-pyrimidyl) spiral shell [hexanaphthene-1,3-[3H]-indoles]-2 (1H)-ketone and the mixture that contains the pyridine of identical weight thiophosphoric anhydride reflux to spend the night and make.Vacuum is removed pyridine, handles resistates with the 5N hydrochloric acid soln then, and recrystallization in ethanol obtains gray solid subsequently; Fusing point 274-277 ℃ (decomposition); ¹H-NMR (DMSO-d ₆) δ 12.7 (s, 1H), 8.6 (s, 2H), 7.9 (s, 1H), 7.5 (d, 1H, J=8.1Hz), 7.1 (d, 1H, J=8.1Hz), 6.8 (s, 2H), 1.9-1.8 (m, 7H), 1.4-1.3 (m, 3H).MS(APCI(-))[M-H] ^-m/z?309。

Embodiment 15

3-(1,2-dihydro-2-sulfo-spiral shell [pentamethylene-1,3-[3H] indoles]-the 5-yl)-5-fluorine benzonitrile

Spiral shell [pentamethylene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone

Under nitrogen, at 40 (cm of-25 ℃ oxindoles (2.0 grams, 15.0 mmoles) ³) be added dropwise in the anhydrous THF solution n-Butyl Lithium (1.6M in hexane, 19.7cm ³, 31.5 mmoles).In the gained milky solution, add N, N, N ＇, N ＇-Tetramethyl Ethylene Diamine (4.75cm ³, 31.5 mmoles).After 30 minutes, add and contain 1, the THF (3cm of 4-two butyl iodides (21.9 grams, 70.6 mmoles) ³) solution, make the reaction mixture temperature to room temperature, stirred 14 hours.Reaction mixture is poured in the water,, merged organic layer, with dilute hydrochloric acid (pH1) and water (x2) washing, dry (MgSO with ethyl acetate extraction (x2) ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 4) obtain brown solid shape subhead compound (1.4 grams, 7.5 mmoles, 50%): ¹H NMR (CDCl ₃) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5,1.0Hz, 1H), 7.01 (dd, J7.5,1.0Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (brs, 1H).

5-bromo-spiral shell [pentamethylene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone

Acetate (2cm with brominated (0.24 gram, 1.51 mmoles) ³) handle and to contain spiral shell [pentamethylene-1,3 '-[3H] indoles]-2 ' (acetate (10cm of 1 ' H)-ketone (0.27 gram, 1.4 mmoles) and sodium acetate (0.12 restrains 1.46 mmoles) ³) solution.After 30 minutes, mixture is poured in the saturated sodium bicarbonate solution,, merged organic layer, water, saturated sodium bicarbonate solution and water washing, dry (MgSO with ethyl acetate extraction (x2) ₄) and evaporation, obtaining pale solid shape subhead compound (0.37 gram, 1.47 mmoles, 96%), it can not be further purified and directly use: ¹H NMR (CDCl ₃) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8Hz, 1H), 7.30-7.39 (m, 2H), 8.63 (br s, 1H).

5 '-(3-cyano group-5-fluorophenyl)-spiral shell [pentamethylene-1,3 ＇-[3H] indoles]-2 ' (1 ' H)-ketone:

Under nitrogen, stirring contains the glycol dimethyl ether (20cm that 3-cyano group-5-fluoro-bromobenzene (0.5 gram, 2.6 mmoles) four (triphenyl phosphines) close palladium (0) (0.2 gram) ³) solution 20 minutes.Then, in this mixture, add (spiral shell [pentamethylene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone-5-yl) boric acid (0.9 gram, 3.9 mmoles) and contain the water (5cm of yellow soda ash (0.8 restrains 7.8 mmoles) ³).Solution was refluxed 18 hours, be cooled to room temperature then, pour among the 2N NaOH, with ethyl acetate extraction (x3).Merge extract, water and salt water washing, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate, hexane) and obtain white needles subhead compound (0.35 gram, 44%).Fusing point: 235-237 ℃; ¹HNMR (DMSO-d ₆) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7,2.0,7.0Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8,6.4Hz), 6.9 (d, 1H, J=8.1Hz), 2.0-1.9 (m, 8H); MS (EI) M ⁺@m/z 306.

General step A

In vitro reflux in sealing contain 5 '-(3-cyano group-5-fluorophenyl)-spiral shell [pentamethylene-1,3 '-[3H] indoles]-2 ' (toluene (10 milliliters) of 1 ' H)-ketone (40 milligrams) and Lawesson ' s reagent (50 milligrams) made title compound in 16 hours.Concentrate this mixture, resistates is dissolved among the minimum THF, use HPLC (SiO then ₂, 30cm * 2.5cm, ethyl acetate-hexane 2: 8,20 ml/min) and purifying, obtain pale solid shape title compound (0.022 gram): fusing point 236-238 ℃; ¹H NMR (DMSO-d ₆) δ 12.66 (br s, 1H), 8.11 (s, 1H), 7.97 (dt, 1H, J=10.1 and 2.2Hz), and 7.79-7.76 (m, 2H), 7.68 (dd, 1H, J=8.1 and 1.7Hz), 7.07 (d, 1H, J=8.1Hz), 2.10-2.05 (m, 6H) and 1.97-1.88 (m, 2H); MS (EI) m/z 322[M] ⁺

Embodiment 16

5-(3-chloro-phenyl-)-3,3-dimethyl-1,3-dihydro-2H-indoles-2-thioketones

5-(3-chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one.Under nitrogen, stirring contains 5-bromo-1,3-dihydro-3, and 3-dimethyl-2H-indol-2-one (0.98 gram, 4.07 moles) and four (triphenyl phosphines) close the glycol dimethyl ether (35cm of palladium (0) (0.239 gram) ³) solution.After 15 minutes, add 3-chlorophenylboronic acid (1.27 grams, 8.13 moles), add the water (15cm that contains salt of wormwood (3.40 grams, 45 mmoles) then ³).Made the reactant reflux 2 hours, and at room temperature stirred then and spend the night.With saturated ammonium chloride diluted mixture thing, with ethyl acetate extraction (x3).Merge organic layer, dry (MgSO ₄), filter and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane, 1: 3), obtain subhead compound (0.284 gram, 25%): fusing point 188-189 ℃; ¹H NMR (DMSO-d ₆) δ 3.34 (s, 6H), 6.93 (d, 1H, J=8.04Hz), 7.38-7.35 (m, 1H), 7.53-7.43 (m, 2H), 7.61 (d, 1H, J=7.68Hz), 7.70 (s, 2H), 10.40 (s, 1H); IR (KBr) 3420,3150,3050,1700cm ^-1MS (EI) m/z 270 (M-H) ^-The CHN calculated value is C ₁₆H ₁₄ClNO+0.1C ₄H ₈O ₂: C, 70.21; H, 5.32; N, 4.99; Measured value: C, 70.3; H, 5.44; N, 4.93.

According to general step A, backflow 5-in toluene (10 milliliters) (3-chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (100 milligrams) and Lawesson ＇ s reagent (120 milligrams) preparation title compound obtain pale solid shape title compound (0.031 gram): fusing point 158-160 ℃; ¹H NMR (CDCl ₃) δ 9.67 (and br s, 1H), 7.55 (s, 1H), 7.47-7.43 (m, 3H), 7.40-7.30 (m, 2H), 7.08 (d, 1H, J=8.7Hz) and 1.50 (s, 6H); MS (EI) m/z 287/289[M] ⁺

Embodiment 17

3-benzyl-5-(3-chloro-phenyl-)-3-methyl isophthalic acid, 3-dihydro-2H-indoles-2-thioketones

According to general step A, backflow 3-benzyl-5-in toluene (10 milliliters) (3-chloro-phenyl)-3-methyl isophthalic acid, 3-dihydro-indol-2-one (100 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound obtain pale solid shape title compound (0.022 gram): fusing point 168-170 ℃; ¹H NMR (CDCl ₃) δ 9.23 (br s, 1H), 7.49 (s, 1H), 7.49-7.30 (m, 4H), 7.21 (s, 1H), 7.15-7.09 (m, 3H), 6.96-6.94 (m, 2H), 6.89 (d, 1H, J=8.0Hz), 3.19 (dd, 2H, J=40.5 and 13Hz) and 1.57 (s, 3H); MS (EI) m/z 363/365[M] ⁺

Embodiment 18

4-(3,3-dimethyl-2-sulfo--2,3-dihydro-1H-indoles-5-yl)-2-furyl formonitrile HCN

4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indoles-5-yl)-furans-2-formonitrile HCN.

Step according to embodiment 5, with (2 '-oxo-[2,3-dihydro-3,3-dimethyl-1,3 '-[3H] indoles]-5 '-yl) (200 milligrams in boric acid (354 milligrams, 1.7 mmoles) and 4-bromo-furans-2-formonitrile HCN, 1.2 mmole) make (76 milligrams of white solid subhead compounds, 0.3 mmole, 26%): fusing point .199.6-201.4 ℃ ¹H NMR (DMSO-d ₆) δ 1.28 (s, 6H), 6.89 (d, J=8.0Hz, 1H), 7.48 (dd, J=8.0,1.8Hz, 1H), 7.65 (d, J=1.5Hz, 1H), 8.1 (s, 1H), 8.5 (s, 1H), 10.46 (s, 1H); MS (ESI) m/z 251 (M-H) ^-Anal.C ₁₅H ₁₂N ₂O ₂.0.6H ₂O

According to general step A, backflow 4-(3 in toluene (10 milliliters), 3-dimethyl-2-oxo-2,3-dihydro-1H-indoles-5-yl)-and furans-2-formonitrile HCN (73 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound, make pale solid shape title compound (0.003 gram): fusing point 188-191 ℃; ¹H NMR (CDCl3) δ 9.63 (br s, 1H), 7.83 (s, 1H), 7.36-7.33 (m, 3H), 7.06 (d, 1H, J=7.9Hz) and 1.48 (s, 6H); MS (EI) m/z268[M] ⁺

Embodiment 19

5-(3-p-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-2H-indoles-2-thioketones

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one: stirring contains 3,3-dimethyl-indol-2-one (0.65 gram, 4.03 mmoles) and sodium acetate (0.33 gram, 4.07 mmoles) acetate (5cm ³), in reaction mixture, be added dropwise to the acetate (5cm of brominated (0.66 gram, 4.13 mmoles) then ³).Reaction stirred 50 minutes is poured in the water then.Make the mixture alkalization with yellow soda ash, with ethyl acetate extraction (x3), dry (MgSO ₄), filter and evaporation, obtain subhead compound (0.89 gram, 92%) ¹H NMR (DMSO-d ₆) δ 1.21 (s, 6H), 6.76 (d, 1H, J=8.22Hz), 7.29 (dd, 1H, J=2.12Hz, 8.23Hz), 7.49 (d, 1H, J=2.03Hz), 10.4 (s, 1H).

Under nitrogen, stirring contains 5-bromo-1,3-dihydro-3, and 3-dimethyl-2H-indol-2-one (0.33 gram, 1.38 mmoles) and four (triphenyl phosphines) close the glycol dimethyl ether (12cm of palladium (0) (0.094 gram) ³).After 15 minutes, add 3-anisole ylboronic acid (0.42 gram, 2.76 mmoles), add the water (5cm that contains salt of wormwood (1.15 grams, 8.34 mmoles) then ³).Make the reactant reflux 5 hours, and be cooled to room temperature then.Add saturated aqueous ammonium chloride and ethyl acetate, filtering mixt.With ethyl acetate extraction (x2) water layer, merge organic layer, dry (MgSO ₄), filter and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 3), obtain 5-(3-methoxyl group-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (0.11 gram, 31%), fusing point=157-158 ℃; ¹H NMR (DMSO-d ₆) δ 3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m, 2H), 7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14Hz), 10.4 (s, 1H); MS (EI) m/z 266 (M-H) ^-C ₁₇H ₁₇NO ₂The CHN analytical value: C, 76.38; H, 6.41; N, 5.24; Measured value: C, 76.02; H, 6.49; N, 5.02.

According to general step A, backflow 5-(3-methoxyl group-phenyl)-3 in toluene (10 milliliters), 3-dimethyl-1,3-dihydro-indol-2-one (100 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound make pale solid shape title compound (0.022 gram): fusing point 149-150 ℃; ¹H NMR (CDCl ₃) δ 9.69 (and br s, 1H), 7.49-7.46 (m, 2H), 7.37 (t, 1H, J=8.0Hz), 7.16 (d, 1H, J=7.7Hz), 7.09-7.06 (m, 2H), 6.90 (dd, 1H, J=8.2 and 2.3Hz) 3.88 (s, 3H) and 1.50 (s, 6H); MS (EI) m/z 283[M] ⁺

Embodiment 20

3-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-4-fluorine benzonitrile

3-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-4-fluorine benzonitrile

Step preparation according to embodiment 5: fusing point 205-206 ℃. ¹H?NMR(DMSO-d ₆)δ10.47(s，1H)，8.08-8.06(dd，1H)，7.89-7.85(m，1H)，7.65(s，1H)，7.54-7.49(m，1H)，7.43-7.40(tt，1H)，6.95-6.93(d，1HJ＝7.9Hz)，1.97-1.83(m，2H)，1.69-1.55(m，8H)；MS(EI)m/z320(M ⁺)。

According to general step A, backflow 3-(1 in toluene (10 milliliters), 2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-4-fluorine benzonitrile (100 milligrams) and Lawesson ＇ s reagent (120 milligrams) preparation title compound, make pale solid shape title compound (0.037 gram): fusing point 230-233 ℃; ¹H NMR (CDCl ₃) δ 9.82 (br s, 1H), 7.86 (s, 1H), 7.77 (dd, 1H, J=7.0 and 1.8Hz), 7.68-7.63 (m, 1H), 7.45 (d, 1H, J=8.0Hz), 7.31 (d, 1H, J=9.0Hz), 7.15 (d, 1H, J=8.1Hz), 2.17-1.84 (m, 7H) and 1.60-1.54 (m, 3H); MS (EI) m/z 336[M] ⁺

Embodiment 21

5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-the 3-pyridine carbonitrile

Make to contain 3-bromopyridine-5-formonitrile HCN (2.79 grams, 15.26 mmoles), hexa methyl ditin (5.00 grams, 15.26 mmoles) and four (triphenyl phosphines) close the anhydrous dimethyl oxygen base ethane (30cm of palladium (O) (0.20 gram, 0.17 mmole) ³) solution reflux under nitrogen.After 16 hours, concentrate this mixture, and with column chromatography purifying (SiO ₂, ethyl acetate: hexane 5: 95), obtain 3-cyanopyridine-5-trimethylammonium stannane (2.82 grams, 10.55 mmoles, 69%): ¹H NMR (CDCl ₃) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); MS ((+) APCI) m/z 269 (M+H) ⁺

Make to contain 5 '-bromine spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (1.97 grams, 7.05 mmole), 3-cyanopyridine-5-trimethylammonium stannane (2.26 grams, 8.46 mmole), dry toluene (the 30cm of palladium (II) (0.33 gram, 0.47 mmole) and lithium chloride (1.48 grams, 35 mmoles) is closed in chlorination two (triphenyl phosphine) ³) vlil.After 16 hours, cool off this mixture, it is distributed between ethyl acetate and water.With ethyl acetate aqueous layer extracted again (x2), merge organic extract, wash dry (MgSO with water ₄) and evaporation.Resistates is carried out column chromatography (SiO ₂, ethyl acetate: hexane, 1: 2), then further with preparation property LC purifying (Primesphere C18,10micron, 50 * 250mm, MeCN: water 1: 1,100cm ³/ minute, room temperature 7.92 minutes), obtain 3-(1 ', 2 '-dihydro-2 '-the oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) pyridine carbonitrile white crystal (0.56 gram, 1.84 mmoles, 26%): fusing point 232-234 ℃, ¹HNMR (CDCl ₃) δ 1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, J=8Hz), 7.49 (dd, 1H, J=8,2Hz), 7.66 (d, 1H, 2Hz), 8.15 (t, 1H, J=2Hz), 8.39 (s, 1H, br), 8.89 (d, 1H, J=2Hz), 9.06 (d, 1H, J=2Hz); MS ((+)-ESI) m/z 304 (M+H) ⁺Analytical value C ₁₉H ₁₇N ₃OCHN.

According to general step A, backflow 3-in toluene (10 milliliters) (1 ', 2 '-dihydro-2 '-oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) pyridine carbonitrile (100 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound, make yellow solid shape title compound (0.004 gram): fusing point 237-238 ℃; ¹H NMR (CDCl ₃) δ 9.56 (br s, 1H), 9.03 (d, 1H, J=1.9Hz), 8.87 (d, 1H, J=1.4Hz), 8.12 (s, 1H), 7.87 (s, 1H), 7.50 (d, 1H, J=8.1Hz), 7.17 (d, 1H, J=8.1Hz), 2.19-1.85 (m, 7H) and 1.59-1.54 (m, 3H); MS ((-)-APCI) m/z 318[M-H] ^-

Embodiment 22

5-(3, the 4-difluorophenyl) spiral shells [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5 '-(3, the 5-difluorophenyl) spiral shell [hexanaphthene-1.3 '-[3H] indoles]-2 ' (1 ' H)-ketone: the step according to embodiment 5 makes: fusing point 180-183 ℃; ¹H-NMR (CDCl ₃) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=6.2,2.0Hz), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J=8.1Hz), 7.76 (tt, 1H, J=4.3,2.3Hz), 2.05-1.62 (m, 10H); MS ((+) APCI) m/z 314[M+H] ⁺

According to general step A, in toluene (10 milliliters), reflux 5 '-(3, the 5-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (100 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound make yellow solid shape product (0.020 gram): fusing point 232-233 ℃; ¹H NMR (CDCl ₃) δ 10.05 (and br s, 1H), 7.83 (s, 1H), 7.44 (dd, 1H, J=8.1 and 1.4Hz), 7.38-7.30 (m, 1H), 7.26-7.19 (m, 3H), 7.11 (d, 1H, J=8.1Hz), 2.17-1.82 (m, 7H) and 1.66-1.53 (m, 3H); MS ((-)-APCI) m/z 328[M-H] ^-

Embodiment 23

5-(5-chloro-2-thienyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5-(5-chloro-2-thienyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone: the step according to embodiment 5 makes: fusing point 191-192 ℃, ¹H NMR (CDCl ₃) δ 1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, J=4.0Hz, 1H), 7.36 (dd, J=7.5,1.6Hz, 1H), 7.53 (d, J=0.9Hz, 1H), 7.80 (brs, 1H); ¹³C-NMR (THF-d ₈) δ 21.35,25.33,33.12 (t), 48.32 (s), 110.40,121.66,121.96,125.44,127.25 (d), 128.17,128.43,136.92,140.20,143.43,183.72 (s); MS (EI) m/z 318 (M+H) ⁺Analytical value (C ₁₇H ₁₆ClNOS) C, H, N.

According to general step A, backflow 5-in toluene (10 milliliters) (5-chloro-2-thienyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone (100 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound, make yellow solid shape product (0.041 gram): fusing point 231-232 ℃; ¹H NMR (CDCl ₃) δ 9.75 (and br s, 1H), 7.82 (d, 1H, J=1.2Hz), 7.43 (dd, 1H, J=8.1 and 1.6Hz), 7.04-7.02 (m, 2H), 6.89 (d, 1H, J=3.8), 2.15-1.84 (m, 7H) and 1.59-1.52 (m, 3H); MS ((-)-APCI) m/z 332/334[M-H] ^-

Embodiment 24

5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-3-furans formonitrile HCN

5-(1 ', 2 '-dihydro-2 '-the oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-3-furans formonitrile HCN:

Step according to embodiment 5 makes: fusing point 243-245 ℃. ¹H-NMR(DMSO-d ₆)δ10.48(s，1H)，8.62(d，1H?J＝0.7Hz)，7.76(d，1H?J＝1.5Hz)，7.58-7.55(dd，1H)，7.33(d，1H?J＝0.7Hz)，6.92-6.90(d，1H?J＝8.1Hz)，1.87-1.83(m，2H)，1.73-1.53(m，8H)。MS((+)EI)m/z292(M+)。

According to general step A, backflow 5-in toluene (10 milliliters) (1 ', 2 '-dihydro-2 '-oxo spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 ＇-yl)-and 3-furans formonitrile HCN (100 milligrams) and Lawesson ' s reagent (120 milligrams) preparation title compound, make yellow solid shape product (0.020 gram): fusing point 264-268 ℃; ¹H NMR (CDCl ₃) δ 9.66 (and br s, 1H), 7.98 (s, 2H), 7.59 (dd, 1H, J=8.2 and 1.5Hz), 7.08 (d, 1H, J=8.2Hz), 6.78 (s, 1H), 2.16-1.85 (m, 7H) and 1.56-1.52 (m, 2H): MS ((-)-APCI) m/z 307[M-H] ^-

Embodiment 25

5-(3-chlorine 4-fluorophenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5 '-(3-chloro-4-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone.Step according to embodiment 5 makes: fusing point 188-189 ℃; ¹H-NMR (CDCl ₃) δ 7.97 (s, 1H), 7.57-7.54 (m, 2H), 7.41-7.34 (m, 2H), 7.20 (t, 1H, J=8.7Hz), 9.96 (d, 1H, J=8.1Hz), 2.04-1.65 (m, 10H); MS ((+) APCI) m/z 330[M+H] ⁺

According to general step A, backflow 5 in toluene (10 milliliters) '-(3-chlorine 4-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (100 milligrams) and Lawesson ' s reagent (100 milligrams) preparation title compound make pale solid shape product (0.036 gram): ¹H NMR (DMSO-d ₆) δ 12.74 (br s, 1H), 7.92 (d, 1H, J=1.4Hz), 7.87 (dd, 1H, J=7.1 and 2.3Hz), 7.70-7.65 (m, 1H), 7.61 (dd, 1H, J=7.1 and 1.5Hz), 7.49 (t, 1H, J=8.9Hz), 7.14 (d, 1H, J=8.1Hz), 1.99-1.82 (m, 7H) and 1.40-1.37 (m, 3H): MS ((-)-APCI) m/z 344/346[M-H] ^-

Embodiment 26

5-(3-chloro-5-fluorophenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5 '-(3-chloro-5-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone:

Step according to embodiment 5 makes: fusing point 178-180 ℃; ¹H-NMR (CDCl ₃) δ 8.50 (s, 1H), 7.57 (d, 1H, J=1.8Hz), 7.39 (dd, 1H, J=6.2,1.9Hz), 7.33-7.32 (m, 1H), 7.15 (dq, 1H, J=5.7,1.7,0.7Hz), 7.06 (dq, 1H, J=4.2,1.9,0.4Hz), 7.00 (d, 1H, J=8.1Hz), 2.05-1.64 (m, 10H); MS ((-) ESI) [M-H] ^-@m/z 328.

According to general step A, backflow 5 in toluene (10 milliliters) '-(3-chloro-5-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (100 milligrams) and Lawesson ' s reagent (100 milligrams) preparation title compound make pale solid shape product (0.039 gram): ¹H NMR (DMSO-d ₆) δ 12.76 (br s, 1H), 7.97 (d, 1H, J=1.1Hz), 7.67 (dd, 1H, J=8.1 and 1.4Hz), and 7.60-7.54 (m, 2H), (7.40 dt, 1H, J=8.65 and 2.0Hz), 7.14 (d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m, 3H): MS ((-)-APCI) m/z344/346[M-H] ^-

Embodiment 27

5-(3, the 5-difluorophenyl) spiral shells [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5 '-(3, the 5-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone:

Step according to embodiment 5 makes: fusing point 180-183 ℃; ¹H-NMR (CDCl ₃) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=6.2,2.0Hz), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J=8.1Hz), 7.76 (tt, 1H, J=4.3,2.3Hz), 2.05-1.62 (m, 10H); MS ((+) APCI) m/z314[M+H] ⁺

According to general step A, in toluene (10 milliliters), reflux 5 '-(3, the 5-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (100 milligrams) and Lawesson ' s reagent (100 milligrams) preparation title compound make pale solid shape title compound (0.029 gram): ¹H NMR (DMSO-d ₆) δ 12.76 (and br s, 1H), 7.84 (s, 1H), 7.64-7.56 (m, 1H), 7.46 (d, 1H, J=8.1Hz), 7.40-7.32 (m, 1H), 7.22-7.15 (m, 2H), 1.99-1.80 (m, 7H) and 1.38-1.35 (m, 3H); MS ((-)-APCI) m/z 328[M-H] ^-

Embodiment 28

5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-4-propyl group-2-thiophene formonitrile HCN

5-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-4-propyl group-2-thiophene formonitrile HCN.Make title compound with the mode that is similar to embodiment 5, make 5-bromo-4-n-propyl group thiophene-2-formonitrile HCN (1.17 grams, 5 mmoles), (1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles)-5-boric acid (1.24 gram, 5 mmoles), four (triphenyl phosphines) closes palladium, salt of wormwood (2.75 grams, 21 mmoles), water (10 milliliters) and glycol dimethyl ether (50 milliliters) reflux are spent the night, and obtain product (0.7 gram, 40%): fusing point 168-171 ℃; ¹H NMR (DMSO-d ₆) δ 10.56 (and s, 1H), 7.93 (s, 1H) 7.52-7.51 (d, 1H, J=1.5Hz), 7.33-7.29 (dd, 1H, J=1.6Hz), 7.00-6.96 (d, 1H, J=8.0Hz), 2.62-2.57 (t, 2H), 1.86 (m, 2H), 1.70-1.56 (m, 11H), 0.88-0.84 (t, H); MSm/z (APCI (+)) 351[M+H] ⁺IR (KBr) 1620,1700,2200cm ^-1C ₂₁H ₂₂N ₂OS1/2H ₂The calculated value C of O, 70.2; H, 6.39; N, 7.79.Measured value: C, 70.67; H, 6.34; N, 7.62.

According to general step A, backflow 5-(1 in toluene (10 milliliters), 2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl) 4-propyl group-2-thiophene formonitrile HCN (90 milligrams) and Lawesson ' s reagent (90 milligrams) preparation title compound, make orange solids shape title compound (0.037 gram): ¹H NMR (DMSO-d ₆) δ 12.83 (br s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, J=7.7Hz), 7.19 (d, 1H, J=8.0Hz), 2.60 (t, 2H, J=8.0Hz), 1.98-1.79 (m, 7H), and 1.64-1.56 (m, 2H), 1.39-1.35 (m, 2H) and 0.87 (t, 3H, J=7.3Hz): MS ((-)-APCI) m/z 365[M-H] ^-

Embodiment 29

5-(3-fluorine 4-nitrophenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5-(3-fluoro-4-nitrophenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone: as described in embodiment 5, from (2 '-oxo-2,3-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid (3.2 the gram, 12.5 mmole) and 4-bromo-2-fluoro-oil of mirbane (3 gram, 13.6 mmoles) obtain yellow solid shape title compound (0.7 gram, 16%): fusing point 213-215 ℃; ¹H NMR (DMSO-d ₆) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H, J=8.13Hz), 7.68 (dd, 1H, J=8.13,1.76Hz), 7.74 (dd, 1H, J=8.68,1.76Hz), 7.86 (d, 1H, J=1.98Hz), 7.92 (dd, 1H, J=13.4,1.76Hz), 8.18 (t, 1H, J=8.46Hz) and 10.52 (s, 1H); MS (EI) m/z=340 (M ⁺).

According to general step A, backflow 5-in toluene (10 milliliters) (3-fluoro-4-nitrophenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone (90 milligrams) and Lawesson ' s reagent (90 milligrams) preparation title compound, obtain yellow solid shape product (0.021 gram): ¹H NMR (DMSO-d ₆) δ 12.82 (br s, 1H), 8.21 (t, 1H, J=8.4Hz), 8.07 (d, 1H, J=1Hz), 7.98 (dd, 1H, J=13.1Hz), 7.79 (dt, 1H, J=8.1 and 2.6Hz), 7.19 (1H, J=8.2Hz), 1.99-1.83 (m, 7H) and 1.42-1.39 (m, 3H): MS ((-)-APCI) m/z 355[M-H] ^-

Embodiment 30

4-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-2-furans formonitrile HCN

4-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-5-yl)-2-furans formonitrile HCN: under nitrogen, stir and contain 3-bromo-5-cyano group-furans (0.75 gram, 4.4 mmoles) and four (triphenyl phosphines) close the glycol dimethyl ether (20cm of palladium (0) (0.4 restrains) ³) solution 20 minutes.Then, in this mixture, add (spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone-5-yl) boric acid (1.6 grams, 6.5 mmoles) and contain the water (5cm of sodium acetate (1.4 restrain 13.1 mmoles) ³).Solution was refluxed 18 hours, be cooled to room temperature then, pour among the 2N NaOH, with ethyl acetate extraction (x3).Merge extract, water and salt water washing, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate, hexane), obtain pale solid shape product (0.45 gram, 36%).Fusing point: 240-242 ℃; ¹H NMR (DMSO-d ₆) δ 10.4 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd, 1H, J=1.5 6.5Hz), 6.9 (d, 1H, J=8.0Hz), 2.0-1.6 (m, 10H); MS (EI) M ⁺@m/z292.

According to general step A, backflow 4-(1 in toluene (10 milliliters), 2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-2-furans formonitrile HCN (67 milligrams) and Lawesson ' s reagent (67 milligrams) preparation title compound, make yellow solid shape title compound (0.018 gram): ¹H NMR (DMSO-d ₆) δ 12.74 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.62 (dd, 1H, J=8.0 and 1.0Hz), 7.10 (s, 1H, J=8.1Hz), 1.94-1.78 (m, 7H) and 1.35-1.32 (m, 3H): MS ((-)-APCI) m/z 307[M-H] ^-

Embodiment 31

5 ＂-(3-chloro-phenyl-) spiral shell [tetramethylene-1,3 ＂-[3H] indoles]-2 ＂ (1 ＂ H)-thioketones

5-bromine spiral shell [tetramethylene-1.3-[3H] indoles]-2 (1H)-ketone: containing spiral shell [tetramethylene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (J.Med.Chem.1987,824-9) (1.0 grams, 6 mmoles) in Glacial acetic acid (10 milliliters) stirred solution, at room temperature be added dropwise to Glacial acetic acid (6 milliliters) solution of brominated (0.30 milliliter, 6 mmoles).Stir after 10 minutes, add anhydrous sodium acetate (0.47 gram, 6 mmoles), make solution for vacuum concentration.Resistates is dissolved in the ether (50 milliliters), successively water (50 milliliters), saturated sodium bicarbonate aqueous solution (50 milliliters), water (50 milliliters) and salt solution (30 milliliters) washing.Use the dried over mgso organic layer, filter and vacuum concentration.Crystallization obtains white fine hair shape solid product (1.1 grams, 73%), fusing point 235-7 ℃ from ether. ¹H?NMR(DMSO-d ₆，300MHz)2.15-2.41(m，6H)，6.74(d，1H，J＝8.2Hz)，7.33(dd，1H，J＝2，8.2Hz)，7.75(d，1H，J＝2Hz)，10.36(bs，1H)。MS(EI)m/z?251[M ⁺]。C ₁₁H ₁₀The analytical calculation value of BrNO: C, 52.41; H, 4.00; N, 5.56.Measured value: C, 51.98; H, 4.24; N, 5.42.

Under nitrogen, containing 5-bromine spiral shell [tetramethylene-1,3-[3H] indoles] add four (triphenyl phosphines) in glycol dimethyl ether (50 milliliters) solution of-2 (1H)-ketone (0.6 gram, 2 mmoles) and close palladium (0) (140 milligrams, 0.1 mmole).Add 3-chlorophenylboronic acid (0.48 gram, 3 mmoles) successively and contain the water (5 milliliters) of salt of wormwood (0.76 restrains 5 mmoles) at this solution.Mixture makes its cooling then in 80 ℃ of heating 3 hours.Reaction mixture is poured in the water (100 milliliters), with ethyl acetate extraction (3 * 100 milliliters).Merge organic layer,, use dried over mgso with salt solution (50 milliliters) washing.Filtering solution, vacuum concentration, resistates HPLC purifying (Zorbax PRO, C18,10u, 15A, 50 * 250mm; 35%H ₂O/65%AcCN; 254NM; Room temperature), obtain white powder 5-(3-chloro-phenyl-) spiral shell [tetramethylene-1,3-[3H] indoles]-2 (1H)-ketone (200 milligrams, 35%), fusing point 199.5-201 ℃. ¹H?NMR(DMSO-d ₆，300MHz)2.21-2.28m，2H)，2.40-2.45(m，4H)，6.87(d，1H，J＝8.1Hz)，7.37(‘d′，1H)，7.44-7.52(m，2H)，7.65(bd，1H，J＝7.8Hz)，7.76(bs，1H)，7.92(bs，1H)，10.35(s，1H)。MS(EI)m/z?283[M ⁺]。C ₁₇H ₁₄The analytical calculation value of CINO: C, 71.96; H, 4.97; N, 4.94.Measured value: C, 70.75; H, 5.07; N, 4.68.

According to general step A, backflow 5-(3-chloro-phenyl-) spiral shell [tetramethylene-1 in toluene (10 milliliters), 3-[3H] indoles]-2 (1H)-ketone (55 milligrams) and Lawesson ' s reagent (55 milligrams) preparation title compound, make orange solids shape title compound (0.016 gram): ¹H NMR (DMSO-d ₆) δ 12.58 (br s, 1H), 8.07 (d, 1H, J=1.5Hz), 7.82 (t, 1H, J=1.7Hz), 7.70 (d, 1H, J=7.74Hz), 7.60 (dd, 1H, J=8.12 and 1.71Hz), 7.49 (t, 1H, 7.9Hz), 7.41 (d, 1H, J=8.32Hz), 7.05 (d, 1H, J=8.14Hz) and 2.57-2.27 (m, 6H); MS ((-)-APCI) m/z298/300[M-H] ^-

Embodiment 32

5 ＂-(2-chloro-phenyl-) spiral shell [hexanaphthene-1,3 ＂-[3H] indoles]-2 ＂ (1 ＂ H)-thioketones

According to general step A, reflux in toluene (10 milliliters) 5 ＂-(2-chloro-phenyl-) spiral shell [hexanaphthene-1,3 ＂-[3H] indoles]-2 ＂ (1 ＂ H)-thioketones (90 milligrams) and Lawesson ' s reagent (90 milligrams) make 0.042 gram pale solid shape product: ¹H NMR (DMSO-d ₆) δ 12.75 (and br s, 1H), 7.80 (d, 1H, J=1.1Hz) 7.58-7.55 (m, 1H), 7.48-7.36 (m, 4H), 7.16 (d, 1H, J=8.0Hz); MS ((-)-APCI) m/z 326/328[M-H] ^-

Embodiment 33

5 ＂-(4-chloro-phenyl-) spiral shell [hexanaphthene-1,3 ＂-[3H] indoles-2 ＂ (1 ＂ H)-thioketones

According to general step A, backflow 5-(4-chloro-phenyl-) spiral shell [hexanaphthene-1,3-[3H] indoles in toluene (10 milliliters)]-2 (1H)-ketone (90 milligrams) and Lawesson ' s reagent (90 milligrams) makes 0.035 gram pale solid shape product: ¹H NMR (DMSO-d ₆) δ 12.74 (br s, 1H), 7.91 (d, 1H, J=1.3Hz), 7.69 (d, 2H, J=5.5Hz), 7.60 (dd, 1H, J=8.1 and 1.4Hz), 7.50 (d, 2H, J=8.5Hz), 7.15 (d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and 1.50-1.36 (m, 3H); MS ((-)-APCI) m/z 326/328[M-H] ^-

Embodiment 34

5-(1 ＂, 2 ＂-dihydro-2 ＂-sulfo-spiral shell [hexanaphthene-1,3 ＂-[3H] indoles]-5 ＂-yl)-4-methyl-2-thiophene formonitrile HCN

5-bromo-4-methyl-2 thiophene carboxaldehyde: under-40 ℃, nitrogen, in anhydrous THF (400 milliliters) solution that contains diethylamine (28 grams, 0.383 mole), add the hexane solution that contains n-Butyl Lithium (2.5M, 153 milliliters, 0.383 mole).After adding, under-40 ℃, nitrogen, stirred this solution 30 minutes, be cooled to-78 ℃, be added dropwise to anhydrous THF (450 milliliters) solution that contains 2-bromo-3 methyl thiophene (45 grams, 0.254 mole) and handle.Stirred this reaction soln 30 minutes down at-78 ℃, handle with dry DMF (100 milliliters).Make the mixture temperature to room temperature, with 1N aqueous hydrochloric acid (1 liter) cancellation.With this solution of ethyl acetate extraction (3 * 450 milliliters), water and salt water washing, dry (MgSO ₄).After the solvent removed in vacuo, obtain white solid title compound (46 grams, 88.3%).Matter sample is produced in crystallization from hexane: fusing point 63-65 ℃; IR (KBr) 1654cm ^-1 ¹H-NMR(CDCl ₃)δ9.75(S，1H)，7.45(S，1H)，2.26(S，3H)；MS(EI)m/z?204/206(M ⁺)。C ₆H ₅The analytical calculation value of BrOS: C, 35.14; H, 2.46.Measured value: C, 35.00; H, 2.44.

5-bromo-4-methyl-2-thiophene formonitrile HCN: the step with embodiment 5 makes from 5-bromo-4-methyl-2 thiophene carboxaldehyde.White solid: fusing point 40-42 ℃; IR (KBr) 2200cm ^-1 ¹H-NMR (CDCl ₃) δ 7.29 (S, 1H), 2.21 (S, 3H).MS (EI) m/z 201/203 (M ⁺, 98%/100%); C ₆H ₄The analytical calculation value of BrNS: C, 35.66; H, 1.99; N, 6.93.Measured value: C, 36.00; H, 2.14; N, 6.76.

Step according to embodiment 5, with (2 '-oxo-[2,3-dihydro-3,3-dimethyl-1,3 '-[3H] indoles]-5 '-yl) (357 milligrams of boric acid, 1.7 mmole) and 5-bromo-4-thiotolene-2-formonitrile HCN (295 milligrams, 1.5 mmoles) obtain 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indoles-5-yl)-(227 milligrams of 4-thiotolenes-2-formonitrile HCN, 0.8 mmole, 55%) white solid: fusing point 192.3-193 ℃ ¹H NMR (DMSO-d ₆) δ 1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d, J=8.0Hz, 1H), 7.34 (dd, J=8.0,1.8Hz, 1H), 7.49 (d, J=1.7Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); MS (EI) m/z 282 (m) ⁺Analytical value C ₁₆H ₁₄N ₂OS.

Backflow 5-in toluene (20 milliliters) (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indoles-5-yl)-4-thiotolene-2-formonitrile HCN (0.77 gram, 2.39 mmoles) and thiophosphoric anhydride (0.42 restrains 0.96 mmole) make title compound.After 3 hours, the cooling reactant distributes between water and ethyl acetate, separates organic layer, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate-hexane gradient wash-out), obtain orange solids shape product (0.25 gram, 0.73 mmole, 30%): ¹H NMR (DMSO-d ₆) δ 12.82 (and br s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, 2Hz), 7.49 (dd, 1H, J=8.1,1.6Hz), 7.18 (d, 1H, J=8.1Hz), 1.99-1.80 (m, 7H) and 1.40-1.36 (m, 3H); MS ((-)-APCI) m/z 321[M-H] ^-

Embodiment 35

5-(1 ＂, 2 ＂-dihydro-2 ＂-sulfo-spiral shell [hexanaphthene-1,3 ＂-[3H] indoles]-5 ＂-yl)-2-thiophene formonitrile HCN

5-bromo-2-thiophene formonitrile HCN: under nitrogen, make 5-bromo-2 thiophene carboxaldehyde (96.0 grams, 500 mmoles), oxammonium hydrochloride (111.9 grams, 500 mmoles), pyridine (500 milliliters), and the mixture heating up of ethanol (500 milliliters) refluxed 2 hours.Reaction mixture is cooled to room temperature, and vacuum concentration obtains oil.Crude product filters and collects the gained solid with frozen water development twice.Make an above-mentioned solid part (44.31 grams, 215 mmoles), the mixture heating up of venus crystals (II) monohydrate (4.2 grams, 21 mmoles) in acetonitrile (1.4L) refluxed 3 hours.Solvent removed in vacuo is dissolved in resistates in the ethyl acetate.With 5% aqueous sulfuric acid (2 * 30 milliliters), water (2 * 30 milliliters), salt solution (20 milliliters) washs this solution, and dry (MgSO ₄).Solvent removed in vacuo is dissolved in resistates in the minimum chloroform (1L), makes its crystallization.Collect the gained crystal on filter membrane, concentrated filtrate with chromatogram purification (silica gel, chloroform), obtains pale solid shape subhead compound (31.5 grams merge thing, 58%).IR(film)cm ^-1?2200。 ¹H-NMR(CDCl ₃)δ7.39-7.38(d，1H，J＝4。1Hz)，7.10(d，1H，J＝4.0Hz)；MS(EI)m/z?187(M ⁺，98％)189(M ⁺，100％)。

Step according to embodiment 5, with 5-bromine 2-thiophene formonitrile HCN and (2 '-oxo-2 ', 3 '-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid make 5-(2 '-oxo-2 ', 3 '-the dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 ' base-2-thiophene formonitrile HCN: fusing point 225-228 ℃; ¹H NMR (DMSO-d ₆) δ 1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J=8.13Hz), 7.55 (dd, 1H, J=8.13,1.76Hz), 7.60 (d, 1H, J=4.17Hz), 7.75 (d, 1H, J=1.76Hz), 7.93 (d, 1H, J=4.17Hz), 10.51 (s, 1H); MS ((+) APC1) m/z 309[M+H] ⁺

Backflow 5-in toluene (20 milliliters) (2 '-oxo-2 ', 3 '-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 ' base-2-thiophene formonitrile HCN (0.69 gram) and thiophosphoric anhydride (0.4 restrains) make title compound.After 3 hours, the cooling reactant is poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Separate organic layer, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate-hexane gradient wash-out), obtain orange solids shape title compound (0.215 gram): ¹H NMR (DMSO-d ₆) δ 12.82 (and br s, 1H), 8.00-7.98 (m, 2H), 7.74 (d, 1H, J=4.1Hz), 7.69 (dd, 1H, J=8.2 and 1.6Hz), 7.14 (d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H); MS ((-)-APCI) m/z 323[M-H] ^-

Embodiment 36

5 ＂-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 ＂-[3H] indoles]-2 ＂ (1 ＂ H)-thioketones

5 '-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone: the step according to embodiment 5 makes: fusing point 171-172 ℃; ¹H-NMR (CDCl ₃) δ 8.43 (s, 1H), 7.62 (d, 1H, J=1.8Hz), 7.42 (dt, 1H, J=6.2,2.0Hz), 7.39-7.37 (m, 1H), 7.33 (dt, 1H, J=5.1,1.3Hz), 7.26 (dq, 1H, J=5.9,2.1Hz), 7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H); MS ((+) APCI) m/z 296[M+H] ⁺.

Backflow 5 in toluene (20 milliliters) '-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (0.70 gram) and thiophosphoric anhydride (0.4 gram) make title compound.After 3 hours, the cooling reactant is poured in the saturated sodium bicarbonate aqueous solution, and is used ethyl acetate extraction, separates organic layer, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate-hexane gradient wash-out), obtain pale solid shape product (0.42 gram): ¹HNMR (DMSO-d ₆) δ 12.75 (and br s, 1H), 7.95 (d, 1H, J=1.5Hz), 7.64 (dd, 1H, J=8.13 and 1.5Hz), 7.53-7.48 (m, 3H), 7.21-7.14 (m, 2H), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H); MS ((-)-APCI) m/z 310[M-H] ^-

Embodiment 37

5-(3-hydroxy phenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

5 '-(3-hydroxy phenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone: the step according to embodiment 5 makes: fusing point 213-216 ℃; ¹H NMR (CDCl ₃) δ 1.60-1.96 (and m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J=8Hz), 7.01-7.04 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 7.38 (d, 1H, J=8Hz), 7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (s, 1H, br); MS ((+)-APCI) m/z 294[M+H] ⁺

According to general step A, in toluene (10 milliliters), reflux down from contain 5 '-(3-hydroxy phenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-ketone (100 milligrams) and Lawesson ' s reagent (110 milligrams) make pale solid shape title compound (0.0045 restrains): ¹H NMR (CDCl ₃) δ 9.59 (br s, 1H), 7.89 (s, 1H), (7.49 dd, 1H, J=8.1 and 1.5Hz), 7.33 (t, 1H, J=7.9Hz), 7.15-7.10 (m, 3H), 6.84 (dd, 1H, J=8.0 and 2.2Hz), and 2.17-2.05 (m, 2H), 1.98-1.88 (m, 5H) and 1.57-1.53 (m, 3H): MS ((-)-APCI) m/z 308[M-H] ^-

Embodiment 38

5-(3-chloro-phenyl-)-3,3-diethyl-1,3-dihydro-2H-indoles-2-thioketones

Under nitrogen, dried THF (400 milliliters) solution of oxindole (40 gram, 0.3 mole) is cooled to-25 ℃, be added dropwise to n-Butyl Lithium (2.5M in hexane, 240 milliliters, 0.6 mole) and handle.In gained solution, add N,N,N (90.4 milliliters, 0.6 mole).After 30 minutes, add iodoethane (48 milliliters, 0.6 mole), make the reaction mixture temperature to room temperature, stirring is spent the night.Pour reaction mixture into NH ₄In the Cl aqueous solution,, merge organic layer with ethyl acetate extraction (2x), with dilute hydrochloric acid, water and salt water washing, dry (MgSO ₄) and concentrate.With hexane development oily resistates, obtain crude product (24.5 grams, 51%).3 gram samples are carried out the ethyl acetate/hexane recrystallization, obtain 3-ethyl-indol-2-one (1.4 gram), fusing point 100-101 ℃; ¹H-NMR (DMSO-d ₆) δ 0.76 (t, 3H, J=7.5Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J=5.7Hz), 6.8 (dt, 1H, J=7.69,0.45Hz), 6.93 (dt, 1H, J=7.45,1.10Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270[M+H].

Under nitrogen, the dried THF (200 milliliters) of 3-ethyl-indol-2-one (16 gram, 0.1 mole) is cooled to-25 ℃, be added dropwise to n-Butyl Lithium (2.5M in hexane, 80 milliliters, 0.2 mole) and handle.In gained solution, add N,N,N (30 milliliters, 0.2 mole).After 30 minutes, add iodoethane (8 milliliters, 0.1 mole), reaction mixture temperature to room temperature and stirring spent the night.Pour reaction mixture into NH ₄In the Cl aqueous solution,, merge organic layer with ethyl acetate extraction (2x), with dilute hydrochloric acid, water and salt water washing, dry (MgSO ₄) and concentrate.With hexane development oily resistates, obtain 3,3-diethyl indol-2-one (9 grams, 45%), fusing point 156-159 ℃; ¹HNMR (DMSO-d ₆) δ 10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H), 7.58 (d, 1HJ=1.7Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 6.91-6.89 (d, 1HJ=8.2Hz), 1.87-1.80 (m, 2H), 1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z190 (M+H).

Contain 3 with bromine (6.4 grams, 40 mmoles) processing, acetate (100 milliliters) solution of 3-diethyl indol-2-one (8 grams, 40 mmoles) and sodium acetate (4 grams, 48 mmoles).After 30 minutes, this mixture of dilute with water is with ethyl acetate extraction (2x); Merge organic layer, water, saturated sodium bicarbonate solution and salt water washing, dry (MgSO ₄) and evaporation obtain crude product (7.6 gram, 75%).Sample is carried out the ethyl acetate/hexane recrystallization, obtain 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one, fusing point 164-165 ℃; ¹H-NMR (DMSO-d ₆) δ 10.45 (s, 1H), 7.41-7.40 (d, 1H, J=2.2Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J=8.2Hz), 1.78-1.65 (m, 4H), 0.50-0.46 (m, 6H); MS (ESI) m/z 266/268 (M-H).

Make and contain 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 grams, 10 mmoles), 3-chlorophenylboronic acid (1.6 grams, 10 mmoles), salt of wormwood (4 grams, 30 mmoles) and four (triphenyl phosphines) close the glycol dimethyl ether (100 milliliters) of palladium (O) (0.5 gram, 0.4 mmole), ethanol (25 milliliters), and water (25 milliliters) vlil 6 hours.After being cooled to room temperature, this mixture of dilute with water, and with acetoacetic ester extraction (2x).Merge organic extract, water and salt water washing, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 3), obtain 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (0.8 gram, 27%), fusing point 195-197 ℃; ¹H-NMR (DMSO-d ₆) δ 7.70 (t, 1H, J=2Hz), 7.62-7.60 (m, 1H), 7.58 (d, 1H, J=1.7Hz), 7.52, (dd, 1H, J=8.1,2Hz), 7.43 (t, 1H, 7.9Hz), 7.36-7.33 (m, 1H), 6.90 (d, 1H, J=8.1Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, J=7.4Hz); MS (+APCI) m/z 300/302 (M-H).

According to general step A, backflow 5-in toluene (10 milliliters) (3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100 milligrams) and Lawesson ' s reagent (100 milligrams) make yellow solid shape product (0.023 gram): ¹H NMR (DMSO-d ₆) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8Hz), 7.75 (d, 1H, J=1.6Hz), 7.68-7.62 (m, 2H), 7.48 (t, 1H, J=7.9Hz), 7.40 (d, 1H, J=8.3Hz), 7.09 (d, 1H, J=8.1Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H, J=7.3Hz): MS ((-)-APCI) m/z 314/316[M-H] ^-

Embodiment 39

5-[4-fluoro-3-(trifluoromethyl) phenyl] spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

As described in embodiment 5, from (2 '-oxo-2,3-dihydro spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl) boric acid (2.5 the gram, 10 mmoles) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 gram, 8 mmoles) make 5-[4-fluoro-3-(trifluoromethyl) phenyl] spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone, obtain solid state title compound (0.87 gram, 30%): 222 ℃ of fusing points; ¹H NMR (DMSO-d ₆) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.92 (d, 1H, J=8.13Hz), 7.51 (dd, 1H, J=8.13,1.76Hz), 7.55 (dd, 1H, J=10.54,9.01Hz) 7.72 (d, 1H, J=1.76Hz), 7.90 (dd, 1H, J=7.03,2.20Hz), 7.98 (m, 1H) and 10.39 (s, 1H); MS (EI) m/z 363 (M ⁺).

According to general step A, backflow 5-[4-fluoro-3-(trifluoromethyl) phenyl in toluene (10 milliliters)] spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-ketone (90 milligrams) and Lawesson ' s reagent (90 milligrams) obtain yellow solid shape product (0.016 gram): ¹H NMR (DMSO-d ⁶) δ 12.75 (and br s, 1H), 8.06-8.00 (m, 1H), 7.96-7.92 (m, 2H), 7.66-7.56 (m, 2H), 7.16 (d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m, 3H): MS ((-)-APCI) m/z 378[M-H] ^-

Embodiment 40

4-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-2-fluorine benzonitrile

According to general step A, backflow 4-(1 in toluene (10 milliliters), 2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl)-2-fluorine benzonitrile (90 milligrams) and Lawesson ' s reagent (90 milligrams) obtains orange solids shape title compound (0.050 gram): ¹H NMR (DMSO-d ₆) δ 12.80 (br s, 1H), 8.04 (d, 1H, J=1.3Hz), 7.98 (t, 1H, J=7.5Hz), 7.92 (dd, 1H, J=11.3 and 1.3Hz), 7.76 (d, 2H, J=8.0Hz), 7.18 (d, 1H, J=8.2Hz), 1.99-1.82 (m, 7H) and 1.40-1.38 (m, 3H); MS ((-)-APCI) m/z 335[M-H] ^-

Embodiment 41

5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl) 4-normal-butyl-2-thiophene formonitrile HCN

Make title compound with the mode that is similar to embodiment 5, make 5-bromo-4-normal-butyl nitrilthiophene (1.24 grams, 5.1 mmole), (1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles)-5-boric acid (1.24 grams, 5.05 mmoles), four (triphenyl phosphines) close palladium (0.25 gram), salt of wormwood (2.75 grams, 21 mmoles), water (10 milliliters) and glycol dimethyl ether (50 milliliters) reflux 5 hours obtain 5-(1,2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl) 4-normal-butyl-2-thiophene formonitrile HCN (1 gram, 54%), fusing point 130-132 ℃. ¹H NMR (DMSO-d ₆) δ 10.56 (s, 1H), 7.92 (s, 1H), 7.52-7.51 (d, 1H, J=1.2Hz), 7.32-7.29 (dd, 1H, J=1.5Hz), 6.98-6.96 (d, 1H, J=8.0Hz), and 2.64-2.59 (t, 2H), 1.99-1.86 (m, 2H), and 1.70-1.50 (m, 11H), 1.32-1.22 (m, 2H), and 0.86-0.82 (t, 3H); MS (APCI (+)) m/z 365[M+H] ⁺IR (KBr) 1620,1700; 2200cm ^-1Analyze and be C ₂₂H ₂₄N ₂OS1/4H ₂O.Calculated value C, 71.61; H, 6.69; N7.59.Measured value C, 71.13; H, 6.61; N, 6.91.

According to general step A, backflow 5-(1 in toluene (10 milliliters), 2-dihydro-2-oxo-spiral shell [hexanaphthene-1,3-[3H] indoles]-the 5-yl) 4-normal-butyl-2-thiophene formonitrile HCN (90 milligrams) and Lawesson ' s reagent (90 milligrams) makes title compound, obtains orange solids shape product (0.050 gram): ¹H NMR (DMSO-d ₆) δ 12.83 (br s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, J=8.1Hz), 7.18 (d, 1H, J=8.1Hz), 2.63 (t, 1H, J.79=8.0Hz), 1.99-1.77 (m, 7H), 1.60-1.50 (m, 2H), 1.39-1.35 (m, 3H), 1.29-1.22 (m, 2H) and 0.81 (t, 3H, 7.3Hz): MS ((-)-APCI) m/z 379[M-H] ^-

Embodiment 42

5-(3-fluoro-5-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 (1H)-thioketones

According to general step A, backflow 5-in toluene (10 milliliters) (3-fluoro-5-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3-[3H] indoles] the preparation title compound of-2 (1H)-ketone (90 milligrams) and Lawesson ' s reagent (90 milligrams), obtain pale solid shape product (0.043 gram): ¹H NMR (DMSO-d6) δ 12.74 (br s, 1H), 7.90 (s, 1H), (7.63 dd, 1H, J=8.1 and 1.2Hz), 7.13 (d, 1H, J=8.1Hz), 7.08 (d, 1H, J=10Hz), 7.01 (s, 1H), (6.83 dt, 1H, J=11 and 2.0Hz), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H): MS ((-)-APCI) m/z 340[M-H] ^-

Embodiment 43

5-(3-chloro-phenyl-)-N-hydroxyl spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2-amine

At room temperature, containing 5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (add sodium hydride (60%, in oil, 0.1 gram, 2.5 mmoles) among the dried THF (15 milliliters) of 1 ' H)-thioketones (0.74 gram, 2.25 mmoles).After 15 minutes, add methyl-iodide (0.18 milliliter, 2.88 mmoles).After 1 hour, reaction mixture is distributed between water and ethyl acetate, with salt water washing organic layer, dry (MgSO ₄) and evaporation, obtaining 5-(3-chloro-phenyl-)-2-(methylthio group) spiral shell [hexanaphthene-1,3 '-[3H] indoles] (0.80 gram, 100%), it can not be further purified and directly use:

In DMSO (20 milliliters) solution that contains the compound of last description (1.96 grams, 5.73 mmoles), add azanol (60% H ₂O, 5 milliliters), with mixture heating up to 120 ℃.After 1 hour, the cooling reactant distributes between diethyl ether and saturated aqueous ammonium chloride.Water and salt water washing organic layer, dry then (MgSO ₄) and evaporation.Make crude product crystallization in methyl alcohol then, obtain white solid title compound (1.67 grams, 5.08 mmoles, 89%): ¹HNMR (CDCl3) δ 7.52 (t, 1H, J=1.7Hz), 7.43-7.28 (m, 7H), 6.83 (d, 1H, J=8Hz) and 1.98-1.51 (m, 10H); MS (ESI (+)) m/z 327/329[M+H] ⁺

Embodiment 43

N-(acetoxyl group)-5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2-amine

Under nitrogen, contain 5-(3-chloro-phenyl-) N-hydroxyl spiral shell [hexanaphthene-1,3 '-[ ³H] indoles]-add diacetyl oxide (0.08 milliliter, 0.8 mmole) and 4-dimethylaminopyridine (catalytic amount) in methylene chloride-methanol (9: 1, the 10 milliliters) solution of 2-amine (0.23 gram, 0.71 mmole).After 20 minutes, the evaporation reaction thing is with column chromatography (SiO ₂, methyl alcohol: purified product methylene dichloride 5: 95).Then, develop product, obtain title compound (0.12 gram, 0.32 mmole, 45%) with diisopropyl ether: ¹H NMR (CDCl3) δ 7.52-7.51 (m, 2H), 7.43-7.27 (m, 5H), 6.88 (d, 1H, J=8Hz), 2.27 (s, 3H), 2.04-1.92 (m, 4H), 1.84-1.74 (m, 4H) and 1.72-1.57 (m, 2H); MS (ESI (+)) m/z 369/371[M+H] ⁺C ₂₁H ₂₁ClN ₂O ₂0.5H ₂O?requires?C?66.98：H，5.64：N?7.34。FoundC?66.74：H，5.86：N?7.41。

Embodiment 45

5 '-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

According to the method for embodiment 43, from 5 '-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-thioketones (0.59 gram, 1.90 mmoles) makes title compound (0.053 gram, 0.17 mmole, 10%): ¹H NMR (DMSO-d6) δ 9.59 (s, 1H), 9.40 (s, 1H), 7.57 (d, 1H, J=1.5Hz), 7.46-7.39 (m, 4H), 7.11-7.05 (m, 1H), 6.80 (d, 1H, J=8.1Hz), and 2.04-1.97 (m, 2H), 1.82-1.74 (m, 2H) and 1.66-1.42 (m, 6H): MS (ESI (-)) m/z 309[M-H] ^-, C19H19FN2O needs C:73.53, H:6.17, N:9.03.Measured value C:73.33, H:6.07, N:8.83.

Embodiment 46

5 '-(2-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime).With 5 '-bromo-2 '-(methylthio group) spiral shell [hexanaphthene-1,3 '-[3H] indoles] (9.0 grams, 28.98 mmoles) and hydrochloric acid O-benzyl hydroxylamine (13.8 grams, 86.9 mmoles) integrate with in the methyl alcohol (150 milliliters), and 45 ℃ were heated 6 hours.Vacuum-evaporation methyl alcohol.In resistates, add ethyl acetate, use the ammonium chloride solution purging compound.Use the dried over mgso ethyl acetate, collect ethyl acetate, vacuum-evaporation is made flash chromatography (9: 1 hexane/ethyl acetate) to resistates on aluminum oxide 90, obtains required product (6.5 grams, 60%).

¹H?NMR(DMSO-d ₆，300MHz)δ1.38-1.70(m，8H)，1.92-2.06(m，2H)，5.06(s，2H)，6.71(d，1H，J＝8.26Hz)，7.22-7.43(m，7H)，9.62(s，1H)。

Steps A

5 '-(2-fluorophenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-2 ' (1H)-ketone 2 (O-benzyl oxime).Stirring 5 in glycol dimethyl ether (23 milliliters) under nitrogen '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.0 grams, 2.6 mmoles) and four (triphenyl phosphines) close palladium (0) (0.14 gram, 0.12 mmole).After 15 minutes, add 2-fluorophenyl boric acid (0.72 milligram, 5.2 mmoles), add the water (6.0 milliliters) that contains yellow soda ash (1.6 grams, 15.6 mmoles) then.The reactant reflux is spent the night, be cooled to room temperature, filter by Celite pad.Add saturated ammonium chloride, water layer ethyl acetate extraction (3 * 100 milliliters).Merge organic layer, dry (MgSO ₄), filter solvent removed in vacuo.Product fast silica gel chromatogram purifying (eluent: 10: 0.5 hexanes: ethyl acetate), obtain required target compound (0.75 gram, 1.8 mmoles, 72%), be the heavy-gravity oily. ¹H?NMR(500MHz，DMSO-d ₆)δ1.44-1.73(8H，m)1.93-2.06(2H，q)5.00(2H，s)6.88(1H，d，J＝8.1Hz)7.24-7.38(6H，m)7.44-7.56(5H，m)9.64(1H，s)；MS(ESI(+ve))m/z?399(M-H) ^-。

Step B

To contain 5 '-(2-fluorophenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-ethanol (15 milliliters) solution of 2 ' (1H)-ketone 2 (O-benzyl oxime) (0.55 gram, 1.37 mmoles) adds carbon containing and carries in the ethanol (10 milliliters) of palladium (10%, 0.11 gram).At room temperature, under hydrogen (balloon bottle) atmosphere, stirred the mixture 24 hours.Reaction mixture is filtered, vacuum concentrated filtrate by Celite pad.Product obtains title compound (0.45 gram, 1.12 mmoles, 82%), fusing point 200-203 ℃ with fast silica gel chromatogram purifying (hexane: ethyl acetate, gradient elution); ¹H NMR (500MHz, DMSO-d ₆) δ 1.45-1.73 (and 8H, m) 1.96-2.00 (2H, q) 6.83 (1H, d, J=7.9) 7.23-7.50 (6H, m) 9.42 (1H, s) 9.58 (1H, s); MS (ESI (+ve)) m/z 311 (M+H) ⁺

Embodiment 47

5 ' (4-fluorophenyl) spiral shells [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

5 '-(4-fluorophenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime).According to the steps A of embodiment 46, from 5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.0 grams, 2.6 mmoles) and 4-fluorophenyl boric acid (0.72 restrains 5.2 mmoles) make.Product fast silica gel chromatogram purifying (eluent: 10: 0.5 hexanes: ethyl acetate), obtain required thickness oily product (0.70 gram, 1.7 mmoles, 67%). ¹H?NMR(500MHz，DMSO-d ₆)δ1.42-1.77(8H，m)1.95-1.99(2H，q)5.00(2H，s)6.84(1H，d，J＝8.1Hz)7.21-7.63(1H，m)9.58(1H，s)；MS(ESI(-ve))m/z?399(M-H) ^-。

According to the step B of embodiment 45, with 5 '-(4-fluorophenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (0.70 gram, 1.74 mmoles) synthetic product.Product obtains title compound (0.44 gram, 1.4 mmoles, 81%), fusing point 205-208 ℃ with fast silica gel chromatogram purifying (hexane: ethyl acetate, gradient elution); ¹HNMR (500MHz, DMSO-d ₆) δ 1.43-1.77 (and 8H, m) 2.00-2.05 (2H, q) 6.80 (1H, d, J=8.2Hz) 7.21-7.24 (2H, m) 7.33-7.35 (1H, dd, J=1.9Hz) 7.49 (1H, s) 7.60-7.63 (2H, m) 9.35 (1H, s) 9.56 (1H, s); MS (ESI (+ve)) m/z 311 (M+H) ⁺

Embodiment 48

5 '-(3, the 4-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

5 '-(3, the 4-difluorophenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime).According to the steps A of embodiment 46, from 5 '-bromine spiral shell { hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.0 grams, 2.6 mmoles) and 3, (1.6 restrain 4-difluorophenyl boric acid, and 5.2 mmoles contain the THF/H of 50% acid ₂O solution).Product fast silica gel chromatogram purifying (eluent: 10: 0.5 hexanes: ethyl acetate), obtain required thickness oily product (0.75 gram, 1.7 mmoles, 69%). ¹H?NMR(500MHz，DMSO-d ₆)δ1.41-1.78(8H，m)1.95-1.99(2H，q)5.00(2H，s)6.82(1H，d)7.28-7.46(8H，m)7.58(1H，q)7.67-7.71(1H，m)9.61(1H，s)；MS(ESI(-ve))m/z?417(M-H) ^-。

According to the step B of embodiment 46, make last described compound (0.70 gram, 1.6 mmoles) reaction, obtain title compound (0.44 gram, 1.3 mmoles, 80%), ¹H NMR (500MHz, DMSO-d ₆) δ 1.42-1.79 (and 8H, m) 2.01-2.05 (2H, q) 6.78-6.80 (1H, d) 7.39-7.46 (3H, m) 7.55 (1H, s) 7.70 (1H, m) 9.10 (1H, s) 9.59 (1H, s); MS (ESI (+ve)) m/z 329 (M+H) ⁺

Embodiment 49

5 '-(3-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

5 '-(3-p-methoxy-phenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime).According to the steps A of embodiment 45, from 5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.0 grams, 2.6 mmoles) and 3-anisole ylboronic acid (0.79 restrains 5.2 mmoles) make.Product fast silica gel chromatogram purifying (eluent: 10: 0.5 hexanes: ethyl acetate), obtain required thickness oily product (0.80 gram, 1.9 mmoles, 75%). ¹H?NMR(500MHz，DMSO-d ₆)δ1.43-1.78(8H，m)1.95-2.00(2H，q)3.80(3H，s)5.00(2H，s)6.82-6.86(2H，m)7.10-7.16(2H，m)7.28-7.53(10H，m)9.57(1H，s)；MS(ESI(-ve))m/z411(M-H) ^-。

According to the method for embodiment 46 step B, make compound (0.80 gram, the 1.9 mmoles) reaction of last description, obtain white solid title compound (0.48 gram, 1.4 mmoles, 77%).Fusing point 101-104 ℃; ¹HNMR (500MHz, DMSO-d ₆) δ 1.44-1.78 (and 8H, m) 1.99-2.03 (2H, q) 3.81 (3H, s) 6.78 (1H, d) 6.85 (1H, d) 7.10-7.16 (2H, m) 7.30-7.38 (2H, m) 7.50 (1H, d) 9.35 (1H, s) 9.56 (1H, s); MS (ESI (+ve)) m/z 323 (M+H) ⁺

Embodiment 50

5 '-(3-nitrophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

5 '-(3-nitrophenyl)-spiral shell [hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime).According to the steps A of embodiment 45, from 5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.0 grams, 2.6 mmoles) and 3-nitrophenyl boric acid (0.86 restrains 5.2 mmoles) make.With fast silica gel chromatogram purifying (eluent: 10: 0.5 hexanes: ethyl acetate), obtain required thickness oily compound (0.60 gram, 1.4 mmoles, 55%). ¹H?NMR(500MHz，DMSO-d ₆)δ1.42-1.82(8H，m)2.02-2.04(2H，q)5.01(2H，s)6.88(1H，d)7.28-7.71(8H，m)8.08-8.13(2H，m)8.38(1H，d)9.69(1H，s)；MS(ESI(-ve))m/z?426(M-H)-。

Step C

The compound of describing for the last time (0.54 gram, 1.26 mmoles) is dissolved in the dry dichloromethane (25 milliliters), is cooled to-78 ℃ under the nitrogen.In 5 minutes, be added dropwise to boron tribromide (3.8 milliliters, 3.8 mmoles, 1.0M is in methylene dichloride).After 30 minutes, with saturated sodium bicarbonate (5 milliliters) cancellation reaction.Make the reaction mixture temperature to room temperature, the dichloromethane extraction water layer is used in layering.Merge organic layer, dry (Na ₂SO ₄), filter and solvent removed in vacuo.Product fast silica gel chromatogram purifying (eluent: 8: 1 hexanes: ethyl acetate), obtain title compound (0.33 gram, 0.9 mmole, 78%).Fusing point 221-224 ℃; ¹H NMR (500 MHz, DMSO-d ₆) δ 1.42-1.83 (and 8H, m) 1.99-2.07 (2H, q) 6.84-6.85 (1H, dd) 7.50-7.52 (1H, m) 7.67-7.71 (2H, m) 8.08-8.12 (2H, m) 8.37-8.38 (1H, d) 9.48 (1H, s) 9.64 (1H, s); MS (ESI (+ve)) m/z 338 (M+H) ⁺

Embodiment 51

5 '-(3-cyano-phenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles-2 ' (1 ' H)-ketoxime

The 3-[spiral shell [hexanaphthene-1,3 '-[3H] indoles]-(1 ' H)-ketone-2 '-(O-benzyl oxime)] benzonitrile [3H] indoles]-the 5-yl] benzonitrile.According to the steps A of embodiment 46, from 5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.0 grams, 2.6 mmoles) and 3-cyano-phenyl boric acid (0.76 restrains 5.2 mmoles) make.Product fast silica gel chromatogram purifying (eluent: 10: 0.5 hexanes: ethyl acetate), obtain required thickness oily product (0.75 gram, 1.8 mmoles, 71%). ¹H?NMR(500MHz，DMSO-d ₆)δ1.41-1.81(8H，m)1.96-2.03(2H，q)5.01(2H，s)6.86(1H，d)7.28-7.33(9H，m)7.95-7.97(1H，d)8.12(1H，s)9.65(1H，s)；MS(ESI(-ve))m/z?406(M-H) ^-。

According to embodiment 50 step C, make the compound (0.17 gram, 0.43 mmole) and boron tribromide (1.2 milliliters, the 1.2 mmoles) reaction of last description, obtain white solid title compound (0.06 gram, 0.2 mmole, 47%), fusing point 198-200 ℃; ¹H NMR (500MHz, DMSO-d ₆) δ 1.41-1.80 (and 8H, m) 1.97-2.04 (2H, q) 6.80 (1H, q) 7.45-7.69 (4H, m) 7.93-7.95 (1H, dd) 8.10 (1H, s) 9.42 (1H, s) 9.59 (1H, s); (ESI (+ve)) m/z 318 (M+H) ⁺

Embodiment 52

3-[1 ', 2 '-dihydro-2 '-(oxyimino) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 ' yl]-5-fluorine benzonitrile

In dried DMF (10 milliliters) solution that contains 3-fluoro-5-cyano group-bromobenzene (0.4 gram, 2.0 mmoles), add two boron quite any alcohol ester (diboron pinacolate ester) (0.63 gram, 2.5 mmoles), potassium acetate (0.65 gram, 6.7 mmoles) and PdCl ₂(dppf) (0.2 gram) is heated to 80 ℃ with reactant under nitrogen.After 8 hours, adding 5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (0.2 gram, 0.5 mmole), PdCl ₂(dppf) (0.05 gram) and yellow soda ash (1.30 grams, 12.5 mmoles) continue 80 ℃ of heating down.After 8 hours, the cooling reactant distributes between water and ethyl acetate, with salt water washing organic layer, and dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane 1: 20), obtain required product (0.14 gram, 0.33 mmole, 66%).

According to the step C of embodiment 59, make the compound (0.14 gram, 0.33 mmole) and boron tribromide (1.0 milliliters, the 1.0 mmoles) reaction of last description, obtain title compound (0.019 gram, 0.05 mmole, 17%): ¹HNMR (300MHz, DMSO-d ₆) δ 9.65 (s, 1H), 9.49 (s, 1H), 8.04 (m, 1H), 7.89 (dt, 1H, J=10.5 and 2Hz), and 7.72-7.68 (m, 2H), 7.54 (d, 1H, J=8.1Hz), 6.80 (d, 1H, J=8.1Hz), and 2.05-1.99 (m, 2H), 1.84-1.76 (m, 2H) and 1.65-1.44 (m, 6H): MS (ESI (+ve)) m/z336 (M+H) ⁺

Embodiment 53

5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(oxyimino)-5 '-yl)-4-methyl-2-thiophene formonitrile HCN

4-methyl-5-trimethylammonium stannyl-thiophene-2-formonitrile HCN.Under nitrogen, from 5-bromine 4-methyl-thiophene-2-formonitrile HCN (3.08 grams, 15.2 mmoles), four (triphenyl phosphines) close palladium (0) (0.82 gram, 0.71 mmole), and hexa methyl ditin (5.0 grams, 15.2 mmoles) and glycol dimethyl ether (20 milliliters) make.Mixture heating up was refluxed 14 hours.The vacuum concentration reaction mixture is with fast silica gel chromatogram purifying (eluent: 2%MeOH: methylene dichloride), reclaim and obtain required runny oily product (2.8 grams, 0.01 mmole, 67%).1H?NMR(300MHz，DMSO-d ₆)δ0.41(9H，s)，2.28(3H，s)，7.83(1H，s)。

Under nitrogen, in DME (8.0 milliliters), stir the last compound of describing (0.20 gram, 0.50 mmole), dichloro two (triphenyl phosphine) closed palladium (II) (0.02 gram, 0.03 mmole) and TRIPHENYLARSINE (0.03 restrains 0.13 mmole) 20 minutes.Add and to contain 5 '-the bromine spiral shell hexanaphthene-1,3 '-[3H] indoles }-2 ' (DME (2.0 milliliters) solution of 1 ' H)-ketone 2 ' (O-benzyl oxime) (0.18 gram, 0.64 mmole).Solution is heated to refluxes and spend the night.The vacuum concentration reaction soln, (12: 1 hexanes of eluent: ethyl acetate), obtain crude product (0.10 gram, 0.25 mmole, 50%), it can not be further purified and directly use with the fast silica gel chromatogram purifying.

Under-78 ℃, boron tribromide (2.6 milliliters, 2.6 mmoles, 1.0M solution is in methylene dichloride) is added in dry dichloromethane (1.7 milliliters) solution of the product (0.37 gram, 0.86 mmole) that contains last description.Stirred this solution 30 minutes, with saturated sodium bicarbonate (10 milliliters) cancellation.With the mixture temperature to room temperature and layering.Use the dried over sodium sulfate organic layer, filter and vacuum concentration, obtain rough product, (eluent: 6: 1 hexanes: ethyl acetate) this product obtains title compound (0.02 gram, 24%): fusing point 173-176 ℃ with the fast silica gel chromatogram purifying; ¹H NMR (500MHz, DMSO-d ₆) δ 1.44-1.73 (8H, m), 1.96-2.00 (2H, m), 2.28 (3H, s), 6.82-6.84 (1H, m), 7.24-7.26 (1H, dd, J=1.7Hz), 7.38 (1H, m) 7.82 (1H, m) 9.51 (1H, and m) 9.66 (1H, m); MS (ESI (+ve)) m/z 338 (M+H) ⁺

Embodiment 54

5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (oxyimino)-5 '-yl)-2-thiophene formonitrile HCN

Under-78 ℃, nitrogen, in dried THF (30 milliliters) solution that contains 2-cyano thiophene (1.0 grams, 9.16 mmoles) and triisopropyl borate ester (2.3 milliliters, 10 mmoles), be added dropwise to hexamethyldisilazane lithium (1M in THF, 10 milliliters, 10 mmoles).After 30 minutes, with 1N HCl cancellation reaction, use ethyl acetate extraction then, wash organic layer with water, dry (Na2SO4) and evaporation obtain product (1.25 grams, 8.17 mmoles, 89%), and it can not be further purified and directly use: ¹H NMR (500MHz, DMSO-d ₆) δ 8.75 (and br s, 2H), 7.97 (d, 1H, J=8Hz) and 7.73 (d, 1H, J=8Hz): MS (ESI (ve)) m/z 152 (M-H) ^-

According to embodiment 46 steps A, from the product of last description (0.91 gram, 5.95 mmoles) and 5 '-bromine spiral shell { hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.53 restrain 3.97 mmoles) makes.(eluent: 5: 1 hexanes: THF) purifying obtains required product (0.66 gram, 1.59 mmoles), and it can not be further purified and directly use: MS (ESI (ve)) m/z 412 (M-H) with fast silica gel chromatogram ^-

According to embodiment 50 step C, make the compound (0.60 gram, 1.45 mmoles) of last description and boron tribromide (1M in methylene dichloride, 5 milliliters, 5 mmoles) reaction, obtain title compound (0.036 restrains 0.11 mmole, 8%): ¹H NMR (300MHz, DMSO-d ₆) δ 9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, J=3.9Hz), 7.63 (d, 1H, J=1.5Hz), 7.54 (d, 1H, J=3.9Hz), 7.47 (dd, 1H, J=8.1 and 1.6Hz), 6.78 (d, 1H, J=8.1Hz), 2.13-1.90 (m, 2H) and 1.78-1.60 (m, 6H): MS (ESI (+ve)) m/z 324 (M+H) ⁺

Embodiment 55

4-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (oxyimino)-5 '-yl)-2-thiophene formonitrile HCN

4-(trimethylammonium stannyl)-2-thiophene formonitrile HCN makes and contains 3-bromo-2-thiophene formonitrile HCN (0.8 gram, 4.3 mmoles), and four (triphenyl phosphines) close the glycol dimethyl ether (5cm of palladium (0) (0.25 gram, 0.2 mmole) and hexa methyl ditin (1.4 grams, 4.3 mmoles) ³) vlil 14 hours, be cooled to room temperature then.Reaction mixture is adsorbed on the florisil, with column chromatography purifying (SiO ₂, methylene dichloride: hexane 1: 9), obtain clarifying thickness oily subhead compound (1.04 grams, 3.8 mmoles, 90%): 1H NMR (CDCl ₃) δ 0.35 (s, 9H), 7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9Hz, 1H).

Under nitrogen, containing 5 '-bromine spiral shell { hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (1.65 grams, 4.28 mmole), 4-(trimethylammonium stannyl)-2-thiophene formonitrile HCN (1.48 grams, 5.44 mmoles) is in dry dimethoxyethane ethane (20 milliliters) solution of TRIPHENYLARSINE (330 milligrams), add chlorination two (triphenyl phosphine) and close palladium (II), mixture heating up was refluxed 16 hours.After being cooled to room temperature, evaporating mixture, resistates column chromatography purifying (SiO ₂, ethyl acetate: hexane, gradient elution), obtain required product (0.61 gram, 1.47 mmoles, 56%).

According to embodiment 50 step C, make the compound (0.61 gram, 1.47 mmoles) and boron tribromide (methylene dichloride of 1M, 4.5 milliliters, the 4.5 mmoles) reaction of last description, obtain title compound (0.084 gram, 0.26 mmole, 18%): ¹H NMR (300MHz, DMSO-d ₆) δ 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.48 (dd, 1H, J=8.1 and 0.9Hz), 6.76 (d, 1H, J=8.1Hz), 2.03-1.96 (m, 2H) and 1.78-1.42 (m, 6H): MS (ESI (+ve)) m/z 324 (M+H) ⁺

Embodiment 56

5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (the inferior oxygen base of hydroxyl)-5 '-yl)-1H-pyrroles-1-methyl-2-formonitrile HCN

2-{5 ' [spiral shell [hexanaphthene-1,3 '-[3H] indoles]-(1 ' H)-ketone-2 ' (O-benzyl oxime)] }-1H-pyrroles-1-carboxylic acid tert-butyl ester.Make 5 '-bromine spiral shell { hexanaphthene-1,3 '-[3H] indoles }-2 ' (1 ' H)-ketone 2 ' (O-benzyl oxime) (7.4 grams, 19.17 mmole) and four (triphenyl phosphines) close palladium (0) (2.5 gram, 2.00 mmoles) and in DME (100 milliliters) solution, under nitrogen, stirred 15 minutes.In this solution, add 1-tertbutyloxycarbonyl pyrroles boric acid (5.5 grams, 26 mmoles) and 1M yellow soda ash (50 milliliters).Make mixture in 80 ℃ of heating 6 hours, make its cooling then.Reaction mixture is poured in the water, with ethyl acetate extraction (3 * 100 milliliters).Merge organic layer and use dried over mgso.Filtering solution, vacuum concentration, resistates carry out purification by flash chromatography (4.5: 1 hexane/ethyl acetate) on silica gel, obtain white solid product (7.7 grams, 88%). ¹H?NMR(DMSO-d6，300MHz)δ1.28(s，9H)，1.55-1.66(m，8H)，1.83-1.98(m，2H)，4.99(s，2H)，6.12-6.14(m，1H)，6.22(t，1H，J＝3.26Hz)，6.76(d，1H，J＝7.9Hz)，7.02(dd，1H，J＝7.98，1.4Hz)，7.19(s，1H)7.27-7.31(m，2H)，7.35(t，1H，J＝6.8Hz)，7.43(d，1H，J＝8Hz)，9.55(s，1H)。

5 '-(1-tertbutyloxycarbonyl-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(1 ' H) ketone-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester.Containing 2-{5 ' [spiral shell [hexanaphthene-1,3 '-[3H] indoles]-(1 ' H)-ketone-2 ' (O-benzyl oxime)] }-1H-pyrroles-1-carboxylic acid tert-butyl ester (7.7 grams, 16.38 THF mmole) is (anhydrous, 100 milliliters) add sodium hydride (0.665 gram in the solution, 17 mmoles), hydrogen emit stop after, add tert-Butyl dicarbonate (10.9 grams, 50 mmoles) and DMAP (0.20 gram), 65 ℃ of following reaction stirred are 18 hours.Reaction mixture is poured in the water, used ethyl acetate extraction.Merge organic layer, use dried over mgso.Filter this solution, vacuum concentration obtains product (9.0 grams, 15.76 mmoles), and this product is directly used in next step.

Under-78 ℃, containing 5 '-(1-tertbutyloxycarbonyl-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(1 ' H) ketone-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester (9.0 grams, 15.76 THF mmole) is (anhydrous, 75 milliliters) the middle isocyanic acid chlorine sulfonyl ester (1.55 milliliters, 17.54 mmoles) that adds.After 90 minutes, add DMF (21 milliliters, 275 mmoles), make the reactant temperature to room temperature.Reactant is poured in the water (200 milliliters), with ethyl acetate extraction (2 * 100 milliliters).Merge organic layer, use dried over mgso, filter and vacuum concentration.On silica gel, use flash column chromatography purifying (10% ethyl acetate/hexane), obtain 5 '-(5-cyano group-1-tertbutyloxycarbonyl-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H) ketone-2 ' (O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester (7.6 grams, 82%) white powder. ¹H?NMR(DMSO-dy，300MHz)δ1.30(s，9H)，1.38(s，9H)，1.58-1.83(m，8H)，1.72-1.73(m，2H)，5.0(s，2H)，6.44-6.45(d，1H，J＝3.76)，7.25-1.46(m，10H)。

5 '-(5-cyano group-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H) ketone-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester.Containing 5 '-(5-cyano group-1-tertbutyloxycarbonyl-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H) ketone-2 ' (O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester (7.6 grams, 3.25 gram, 48 mmoles) THF is (anhydrous, 30 milliliters) in the solution, add ethanol (120 milliliters) solution that contains sodium ethylate.Reaction mixture is heated to 80 ℃ and stir and to spend the night.Mixture is cooled to room temperature and vacuum concentration.Resistates is dissolved in the ethyl acetate water and salt water washing, dried over mgso.Vacuum evaporating solvent obtains product (6.1 grams, 95%). ¹H?NMR(DMSO，500MHz)δ1.38(s，9H)，1.63-1.74(m，8H)，1.88-1.97(m，2H)，5.08(s，2H)6.69-6.7(d，1H，J＝.8Hz)，6.98-6.99(d，1H，J＝.7Hz)，7.29-7.37(m，1H)，7.35(m，2H)，7.42(m，3H)，7.63(dd，1H，J＝1.8，.3Hz)，7.76(d，1H，J＝.4Hz)。

5 '-(5-cyano group-1-methyl isophthalic acid H-pyrroles 2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester.Containing 5 '-(5-cyano group-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H) ketone-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester (6.1 grams, 12.29 add salt of wormwood (6.5 grams in DMF mmole) (75 milliliters) solution, 47 mmoles) and (1 milliliter of methyl-iodide, 15.4 mmole), reaction mixture was at room temperature stirred 2.5 hours.Reaction mixture is poured in the water, used ethyl acetate extraction.With salt water washing organic layer, vacuum concentration solvent.Obtain required product (6.1 grams, 12.29 mmoles), this product can not be further purified and is directly used in next step. ¹HNMR(DMSO，300MHz)δ1.38(s，9H)，1.62-1.98(m，10H)，3.71(s，3H)，5.08(s，2H)，6.34(d，1H，J＝4.1)，7.03(d，1H，J＝3.99)，7.30-7.53(m，8H)。

5-{5 '-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-(1 ' H)-ketone-2 '-(O-benzyl oxime)]-1H-pyrroles-1-methyl-2-formonitrile HCN.With 5 '-(5-cyano group-1-methyl isophthalic acid H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester (6.1g, 12.29 mmole) be dissolved in the diox (5 milliliters), add and contain 4M HCl De diox (10 milliliters), make reactant in 45 ℃ of heating 3.5 hours.The careful saturated sodium bicarbonate neutralise mixt of using.Reaction mixture is poured in the water, used ethyl acetate extraction.With salt water washing organic layer, dried over mgso.Vacuum evaporating solvent.On silica gel,, obtain product (4.36 grams, 94%) with column chromatography purifying (5% ethyl acetate/hexane). ¹H?NMR(DMSO-d6，300MHz)δ1.57-1.7(m，8H)，1.9-2.05(m，2H)，3.68(s，3H)，5.00(s，2H)，6.25(d，1H，J＝3.92)，6.85(d，1H，J＝8.03)，7.00(d，1H，J＝4.08)，7.2-7.44(m，7H)，9.7(s，1H)。

Under-78 ℃, containing 5-{5 '-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-(1 ' H)-ketone-2 '-(O-benzyl oxime)]-add 1M boron tribromide (35 milliliters, in methylene dichloride) in the methylene dichloride (50 milliliters) of 1H-pyrroles-1-methyl-2-formonitrile HCN (4.36 gram, 10.6 mmoles).Make the reaction mixture temperature to room temperature.After 4 hours, with saturated sodium bicarbonate (100 milliliters) cancellation reaction mixture.Collected organic layer with ethyl acetate extraction (2 * 100 milliliters) water layer, merges organic layer, uses the salt water washing, dried over mgso, vacuum evaporating solvent.On silica gel,, obtain white solid title compound (1.35 grams, 40%) with purification by flash chromatography resistates (7: 3 hexane/ethyl acetate). ¹H?NMR(DMSO-d6，300MHz)δ1.58-1.71(m，8H)，1.99-2.00(m，2H)，3.69(s，3H)6.24(d，1H，J＝4.07Hz)，6.8(d，1H，J＝8.05Hz)，6.99(d，1H，J＝4.01Hz)，7.20(dd，1H，J＝8.04，1.57Hz)，7.36(d，1H，J＝1.12Hz)，9.48(s，1H)，9.62(s，1H)。

Embodiment 57

5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(oxyimino-5 '-yl)-1H-pyrroles-2-formonitrile HCN

5-(spiral shell [hexanaphthene-1,3 '-[3] indoles]-2 ' (1H)-(O-benzyl (benyl) oxime))-1H-pyrroles-2-formonitrile HCN.With preparation 5-{5 '-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-(1 ' H)-ketone-2 '-(O-benzyl oxime)]-step of 1H-pyrroles-1-methyl-2-formonitrile HCN, from be dissolved in 2 milliliters of THF and 4M HCl diox/water (10 milliliters) 5 '-(5-cyano group-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H) ketone-2 '-(O-benzyl oxime)-1 '-carboxylic acid tert-butyl ester (0.395 gram, 0.796 mmole), obtain required product (0.220 gram, 0.745 mmole, 95%). ¹H，NMR(DMSO-d6，500MHz)δ1.44-1.50(m，1H)，1.61-1.70(m，7H)，1.94-1.99(m，2H)，5.0(s，2H)，6.55(d，1H，J＝4Hz)，6.79(d，1H，J＝8.0Hz)，6.95(d，1H，J＝4Hz)，7.27-7.31(m，1H)，7.34-7.37(m，2H)，7.42-7.43(m，2H)，7.47(dd，1H，J＝8.0，1.4Hz)，7.65(d，1H，J＝1.5Hz)，9.65(s，1H)，12.4(s，1H)。

According to 5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(oxyimino)-5 '-yl)-step of 1H-pyrroles-1-methyl-2-formonitrile HCN, from 5-(spiral shell [hexanaphthene-1,3 '-[3] indoles]-2 ' (1H)-(O-benzyl oxime))-1H-pyrroles-2-formonitrile HCN (0.325 gram, 0.82 mmole) and 1M boron tribromide (6 milliliters, in methylene dichloride) make title compound, products therefrom be pale solid (0.110 the gram, 0.326 mmole, 44%). ¹H，NMR(DMSO-d6，500MHz)δ1.46-1.5(m，1H)，1.62-1.71(m，7H)，1.95-2.05(m，2H)，6.55(d，1H，J＝4.0Hz)，6.75(d，1H，J＝8.0Hz)，6.94(d，1H，J＝3.47Hz)，7.45(dd，1H，J＝8.1，1.73Hz)，7.63(d，1H，J＝1.73)，9.42(s，1H)，9.59(s，1H)，12.39(s，1H)。

Embodiment 58

4-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (acetoxyl group imino-)-5 '-yl)-2-thiophene formonitrile HCN

At room temperature, containing 4-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (oxyimino)-5 '-yl)-2-thiophene formonitrile HCN (2.21 grams, 6.83 mmole) and in methylene dichloride-pyridine (30 milliliters, 9: 1) solution of diacetyl oxide (1 milliliter) add 4-dimethylaminopyridine (250 milligrams).After 3 hours, with methylene dichloride diluted mixture thing, water, dilute hydrochloric acid and water washing, dry (MgSO ₄) and evaporation.Resistates obtains white solid title compound (0.84 gram, 2.29 mmoles, 33%): MS (ESI (+ve)) m/z 366[M+H with column chromatography purifying (ethyl acetate: hexane, gradient elution)] ⁺

Embodiment 59

3-fluoro-N '-hydroxyl-5-[2 '-(hydroxyl amino) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl] the benzenecarboximidic acid acid amides

(carboximidamide)

5 '-(3-cyano group-5-fluorophenyl)-2-(methylthio group) spiral shell [hexanaphthene-1,3 '-[3H] indoles].The step of describing according to embodiment 43, from 3-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-5-fluorine benzonitrile (0.451 gram, 1.34 mmoles) makes required product (0.316 gram, 0.90 mmole, 67%): ¹H NMR (DMSO, 300MHz) δ 7.74 (d, 1H, J=1.7Hz), 7.68 (t, 1H, J=1.4Hz), 7.58 (d, 1H, J=8.0Hz), 7.54 (t, 1H, J=2.3Hz), 7.50 (dd, 1H, J=8.0 and 1.9Hz), 7.33-7.29 (m, 1H), 2.67 (s, 3H), 2.04-1.78 (m, 7H) and 1.58-1.50 (m, 3H); MS (ESI (+ve)) m/z 351 (M+H) ⁺

In DMSO (10 milliliters) solution that contains last described product (0.30 gram, 0.88 mmole), add azanol (50% aqueous solution, 1 milliliter), reactant is heated to 120 ℃.After 1 hour, cool off this mixture, between saturated aqueous ammonium chloride and ethyl acetate, distribute.Water and salt water washing organic layer, dry (MgSO ₄) and evaporation.Resistates column chromatography purifying (SiO ₂, 5%MeOH is in methylene dichloride), obtain white foam shape title compound (0.079 gram, 0.23 mmole, 26%): ¹H NMR (DMSO, 300MHz) δ 9.79 (s, 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.73 (s, 1H), 7.61 (d, 1H, J=1.3Hz), 7.46 (dd, 1H, J=8.3 and 1.5Hz), 7.34 (d, 1H, J=10Hz), 6.81 (d, 1H, J=8.0Hz), 6.01 (s, 2H), 2.11-2.02 (m, 2H) and 1.81-1.56 (m, 8H): MS (ESI (+ve)) m/z 369 (M+H) ⁺

Embodiment 60

N '-hydroxyl-5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (oxyimino)-5 '-yl)-4-methyl-2-thiophene azomethine

The acid acid amides

4-methyl-5-(spiral shell [hexanaphthene-1,3 ' [3H] indoles] 2 '-(methylthio group)-5 '-yl]-2-thiophene formonitrile HCN.The THF that contains potassium tert.-butoxide (0.32 gram, 2.6 mmoles) add 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-4-methyl-2-thiophene formonitrile HCN (0.84 gram, 2.5 mmoles).After 15 minutes, add methyl-iodide (0.50 gram, 3.48 mmoles).After 3 hours, reactant is poured in the saturated ammonium chloride, used ethyl acetate extraction.Merge organic layer, use dried over mgso.Filtering solution, vacuum concentration, resistates carry out purification by flash chromatography (4: 1 hexane/ethyl acetate) on silica gel, obtain required product (0.530 gram, 85%).(DMSO，300MHz)δ1.48(m，3H)，1.70(m，2H)，1.81(m，5H)，2.32(s，3H)，2.62(s，3H)，7.48(dd，1H，J＝7.87Hz，1.46Hz)，7.5(d，1H，J＝8.05Hz)，7.77(d，1H，J＝1.46Hz)，7.88(s，1H)。

Containing 4-methyl-5-(spiral shell [hexanaphthene-1,3 ' [3H] indoles] 2 '-(methylthio group)-5 '-yl]-add among the DMSO (1 milliliter) of 2-thiophene formonitrile HCN (0.450 gram, 1.3 mmoles) oxammonium hydrochloride (2 milliliters, 50% solution, in water), 100 ℃ were heated 2.5 hours down.Add entry and get muddiness slightly, this mixture is cooled to room temperature until solution becomes.Filter out white solid, collect and be dissolved in the ethyl acetate, use dried over mgso.Filtering solution, vacuum concentration obtains (0.320 gram, 69%).(DMSO-d6，500MHz)δ1.4-1.74(m，8H)，1.94-2.49m，2H)，2.54(s，3H)，5.8(s，1H)，6.79(d，1H，J＝8.0)，7.16(dd，1H，J＝8.12，1.83)，7.39(m，2H)，9.42(s，1H)，9.56(s，1H)，9.58(s，1H)。

Embodiment 61 N '-hydroxyl-4-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(oxyimino)-5 '-Ji-2-thiophene azomethine acid acid amides

According to the step of embodiment 60, make 4-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(methylthio group)-5 '-yl]-2-thiophene formonitrile HCN (0.077 gram, .237 mmole) with 50% azanol (1 milliliter) solution reaction, obtain title compound (0.016 gram, 0.044 mmole, 20%).MS(ESI，(+VE))m/z?357[M+H] ⁺。

Embodiment 62 N '-hydroxyl-5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-(oxyimino)-5 '-yl)-2-thiophene azomethine acid acid amides

Step according to embodiment 60, from 5-(spiral shell [hexanaphthene-1,3 '-[3H] indoles] 2 '-(methylthio group)-5 '-yl]-2-thiophene formonitrile HCN (0.500 gram, 1.5 mmole) and (2 milliliters of 50% hydroxylamine solutions, excessive) the preparation title compound, obtain product (0.200 gram, 0.56 mmole, 56%). ¹H?NMR(DMSO-d6，500MHz)δ1.45-1.75(m，8H)，1.97-2.06(m，2H)，5.89(s，1H)，6.74(d，1H，J＝8Hz)，7.3(d，1H，J＝3.9Hz)，7.34(dd，1H，J＝8.06，1.46Hz)，7.4(d，1H，J＝8.0Hz)，7.5(d，1H，1.95Hz)，9.44(s，1H)，9.58(s，1H)，9.6(s，1H)。

Embodiment 63

5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-cyanamide

5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-amine.Containing 5 '-(3-chloro-phenyl-)-N-hydroxyl spiral shell [hexanaphthene-1,3-[3H] indoles]-2-amine (0.500 gram; 1.53 add (0.600 milliliter of hydrazine hydrate in 25 milliliters of ethanol turbid solutions mmole); 12.24 mmole).Make this solution temperature to 55 ℃, add Raney nickel (50%, in water) this moment in reactant, keep the constant gas release.After 45 minutes, the reaction mixture of heat is filtered by Celite pad, clean with a large amount of hot methanols.Vacuum concentrated filtrate obtains the opaque solid of 0.890 gram.Product comes purifying (eluent, 2%-8% methyl alcohol-methylene dichloride contain 0.1% ammonium hydroxide) with fast silica gel chromatogram, obtains the required product of 0.310 gram (65%) white solid.Fusing point 118-120 ℃. ¹H?NMR?δ(300MHz，DMSO-d ₆)1.31-1.46(m，2H)，1.70-1.93(m，8H)，7.0(d，1H)，7.1(br，2H，2NH)，7.31-7.34(dt，1H，J＝8Hz)，7.41-7.46(t，2H)，7.55-7.58(d，1H)，7.62(s，1H)，7.72(s，1H)；MS(ECI(+ve))m/z?311(M+H) ⁺。

1-tertbutyloxycarbonyl-5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-amine.Under 0 ℃, containing 5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3-[3H] indoles]-2 '-amine (0.310 gram; 0.96 add tert-Butyl dicarbonate (0.252 gram in dry dichloromethane mmole); 1.15 mmole) and 4-dimethylaminopyridine (0.117 the gram; 0.96 mmole).This solution temperature to room temperature, was stirred 24 hours.Water (50 milliliters) diluting reaction thing solution and layering.Use the dried over sodium sulfate organic layer, filter and vacuum concentration, obtain 0.355 gram yellow oil.Product obtains required white solid product (0.081 gram, 20%) with fast silica gel chromatogram purifying (eluent, 1%-3% methyl alcohol-methylene dichloride). ¹H?NMRδ(300MHz，DMSO-d ₆)1.58(m，2H)，1.63(s，9H，Boc)，1.77-1.79(m，8H)，7.42-7.48(m，2H)，7.64-7.68(m，3H)，7.70-7.80(m，2H)，9.72(s，1H，NH)。MS(ECI(+ve))m/z411(M+H) ⁺。

Under 0 ℃, will contain 1 '-tertbutyloxycarbonyl-5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-amine (0.120 gram; 0.29 adding, 2.0 milliliters of dried DMF solution mmole) contain 4-dimethylaminopyridine (0.089 gram; 0.73 mmole) and cyanogen bromide (0.077 the gram; 0.73 in 4.0 milliliters of dried DMF solution mmole).Yellow solution is heated to 40 ℃, heated 16 hours.Processing comprises pours reaction soln into 0.1N NaHCO ₃Extract in (50 milliliters) and with ethyl acetate (3 * 50 milliliters).Merge organic layer, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain 0.091 gram yellow residue.Product fast silica gel chromatogram purifying (5: 1-3: 1 hexane: the substep gradient of ethyl acetate), obtain 0.031 gram (32%) glassy yellow solid state product.225 ℃ of fusing points (decomposition). ¹H?NMRδ(500MHz，DMSO-d ₆)1.46-1.73(m，8H)，1.89-1.90(m，2H)，7.13-7.16(d，1H)，7.38-7.41(dt，1H，J＝8Hz)，7.45-7.50(m，1H)，7.60-7.63(dd，2H，J＝6.4Hz)，7.71(s，1H)，7.85(s，1H)，12.1(s，1H，NH)；MS(ECI(-ve))m/z?336(M-H) ^-。

Can comprise according to other required compound that method described herein makes: 5 '-(3-cyano group-5-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-cyanamide, 5 '-(5-cyano group-1H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-the 2-cyanamide, 5 '-(5-cyano group-1-methyl isophthalic acid H-pyrroles-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-cyanamide, 5 '-(5-cyano group-thiophene-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-cyanamide, 5 '-(5-cyano group-3-methyl-thiophene-2-yl) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-cyanamide, 5 '-(5-cyano group-thiene-3-yl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 '-cyanamide, 3-(2 '-cyano group methylene radical-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl])-5-fluoro-benzonitrile, 5-(2 '-cyano group methylene radical-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl])-1H-pyrroles-2-formonitrile HCN, 5-(2 '-cyano group methylene radical-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl])-1-methyl isophthalic acid H-pyrroles-2-formonitrile HCN, 5-(2 '-cyano group methylene radical-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl])-thiophene-2-formonitrile HCN, 5-(2 '-cyano group methylene radical-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl])-4-methyl-thiophene-2-formonitrile HCN, 4-(2 '-cyano group methylene radical-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl])-thiophene-2-formonitrile HCN.

The publication of this specification sheets all references is all included this paper in as a reference.Though the present invention is described with preferred embodiment, be appreciated that not breaking away from spirit of the present invention can also do some improvement.These improvement are in the appended claim scope of the present invention.

Claims

1. compound with formula 1 or 2, or its pharmacy acceptable salt:

Wherein:

R ₁And R ₂Independently be selected from the alkyl of H, alkyl, replacement; OH; O (alkyl); O (alkyl of replacement); OAc; Aryl; The optional aryl that replaces; Heteroaryl; The optional heteroaryl that replaces; Alkaryl; Miscellaneous alkyl aryl; The 1-proyl; Or 3-proyl:

Or R ₁And R ₂Be connected to form and comprise one of following ring:

-CH ₂CH ₂OCH ₂CH ₂-; Or-CH ₂CH ₂N (H or alkyl) CH ₂CH ₂-;

M is integer 1-4;

N is integer 1-5;

P is integer 1-4;

CMe ₂C (cycloalkyl), O, C (cyclic ethers);

R ⁵Be selected from a), b) or c):

R ^CBe H, C ₁-C ₃Alkyl, or the C that replaces ₁-C ₃Alkyl;

Or

R ^EBe H, C ₁-C ₃Alkyl, or the C that replaces ₁-C ₃Alkyl;

R ⁶Be H, or C ₁-C ₃Alkyl; Or

Q ¹Be S, NR ₇, CR ₈R ₉

R ₇Be selected from CN, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, acyl group, the acyl group of replacement, aroyl, the aroyl of replacement, SO ₂CF ₃, OR ¹¹Or NR ¹¹R ¹²

R ₁₀Be C ₁-C ₃Alkyl; Or

CR ₈R ₉Be 6 yuan of rings shown in the following structure

Q ²Be selected from following groups:

R ¹¹, R ¹²And R ¹³Independently be selected from H, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, acyl group, the acyl group of replacement, the aroyl of aroyl or replacement or alkylsulfonyl.

2. compound according to claim 1 or its pharmacy acceptable salt, it has following formula:

R wherein ₅Be dibasic phenyl ring with following formula:

X is selected from halogen, CN, CONH ₂, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl, NO ₂, C ₁-C ₃Perfluoroalkyl contains 1-3 heteroatomic 5 yuan of heterocycles, or C ₁-C ₃Thio alkoxy; With

Y be 4 ' or 5 ' position on be selected from following substituting group: H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl group, C ₁-C ₄Alkyl, or C ₁-C ₃Alkylthio; With

Q ¹Be S, NR ₇, CR ₈R ₉

3. compound according to claim 1 or its pharmacy acceptable salt, it has following formula:

R wherein ₅Be to have 5 yuan of rings that show structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ' is selected from H, F or C ₁-C ₄Alkyl; With

Q ¹Be S, NR ₇, CR ₈R ₉

4. compound according to claim 1 or its pharmacy acceptable salt, it has following formula:

R wherein ₅Be to have 6 yuan of rings that show structure down

X wherein ¹Be N or CX ²,

Q ¹Be S, NR ₇, CR ₈R ₉

R ₁₀Be C ₁-C ₃Alkyl;

CR ₈R ₉Under having, show in 6 yuan of rings of structure

6. compound according to claim 1, it is 5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3H] indoles]-2 ' (1 ' H)-thioketones or its pharmacy acceptable salt.

7. compound according to claim 1, it be 3-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles-5 '-yl) benzonitrile or its pharmacy acceptable salt.

8. compound according to claim 1, it be 4-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3H] indoles]-5 '-yl)-2-thiophene formonitrile HCN or its pharmacy acceptable salt.

9. compound according to claim 1, it is 3-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H] indoles]-5-yl)-5-fluorine benzonitrile or its pharmacy acceptable salt.

10. compound according to claim 1, it is 4-methyl-5-(1,2-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3-[3H]-indoles]-5-yl)-2-thiophene thioamides or its pharmacy acceptable salt.

11. compound or its pharmacy acceptable salt with following formula:

Each R wherein ₅Be the dibasic phenyl ring that contains substituent X and Y:

Y be 4 ' or 5 ' position on be selected from following substituting group: H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl group, C ₁-C ₄Alkyl, or C ₁-C ₃Alkylthio.

12. compound according to claim 11 or its pharmacy acceptable salt, it has following formula: It is following those compounds, wherein R ₅For having 6 yuan of rings of following structure:

X wherein ¹Be N or CX ²,

Q ²Be selected from following groups:

R ⁷Be selected from CN, C ₁-C ₆Alkyl, the C of replacement ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, the C of replacement ₃-C ₈Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, or SO ₂CF ₃

R ₁₀Be C ₁-C ₃Alkyl;

CR ₈R ₉Under having, show in 6 yuan of rings shown in the structure

13. compound or its pharmacy acceptable salt with following formula:

R wherein ₁₄Be selected from H, acyl group, the acyl group of replacement, aroyl, the aroyl of replacement, alkylsulfonyl, the alkylsulfonyl of replacement,

14. compound according to claim 13 or its pharmacy acceptable salt, wherein R ₅Be to have 5 yuan of rings that show structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

X ' is selected from halogen, CN, NO ₂, CONH ₂, CNHNHOH, CNH ₂NOH, CSNH ₂, CONH alkyl, CSNH alkyl, CON (alkyl) ₂, CSN (alkyl) ₂, C ₁-C ₃Alkyl, or C ₁-C ₃Alkoxyl group;

Y ' is selected from H, F or C ₁-C ₄Alkyl.

15. compound according to claim 13, wherein R ₅By the thiophene or the furan nucleus of X ' and Y ' replacement.

16. compound according to claim 13 or its pharmacy acceptable salt, wherein R ₅Be 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl.

17. compound or its pharmacy acceptable salt with following formula,

18. compound according to claim 17 or its pharmacy acceptable salt, wherein R ₅Be to have 5 yuan of rings that show structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ' is selected from H, F or C ₁-C ₄Alkyl.

19. compound according to claim 17, wherein R ₅By the thiophene or the furan nucleus of above-mentioned X ' and Y ' replacement.

20. compound according to claim 17 or its pharmacy acceptable salt, wherein R ₅Be 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl.

21. compound or its pharmacy acceptable salt with following formula:

R wherein ₁₅Be selected from H, methyl, CO ₂R, acyl group, the acyl group of replacement, aroyl, the aroyl of replacement, alkyl, the alkyl of replacement, CN;

22. compound according to claim 21 or its pharmacy acceptable salt, wherein R ₅Be to have 5 yuan of rings that show structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ' is selected from H, F or C ₁-C ₄Alkyl.

23. compound according to claim 21, wherein R ₅By the thiophene or the furan nucleus of X ' and Y ' replacement.

24. compound according to claim 21 or its pharmacy acceptable salt, wherein R ₅Be 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl.

25. compound or its pharmacy acceptable salt with following formula:

26. compound according to claim 25 or its pharmacy acceptable salt, wherein R ₅Be to have 5 yuan of rings that show structure down

Wherein:

U is O, S, or NR ₆

R ₆Be H, or C ₁-C ₃Alkyl, or C ₁-C ₄CO ₂Alkyl;

Y ' is selected from H, F or C ₁-C ₄Alkyl.

27. compound according to claim 26, wherein R ₅By the thiophene or the furan nucleus of X ' and Y ' replacement.

28. compound according to claim 26 or its pharmacy acceptable salt, wherein R ₅Be 6 yuan of rings with following structure:

X wherein ¹Be N or CX ²,

R ₁₀Be C ₁-C ₃Alkyl.

29. a pharmaceutical composition, it comprises each described compound of claim 1-28 or its pharmacy acceptable salt and pharmaceutically acceptable carrier or vehicle.

30. induce the Mammals method of contraception for one kind, this method comprises each described compound of claim 1-28 or its pharmacy acceptable salt that the Mammals of these needs medicine effective quantity is arranged.

31. a method for the treatment of the Mammals hemorrhage of functional disorder, this method comprise each described compound of claim 1-28 or its pharmacy acceptable salt that the Mammals of these needs medicine effective quantity is arranged.

32. a method for the treatment of Mammals uterine endometrium, ovary, breast, colon or prostatic cancer and gland cancer, this method comprise each described compound of claim 1-28 or its pharmacy acceptable salt that the Mammals of these needs medicine effective quantity is arranged.