CN101087761A - Tetracyclic indole derivatives as antiviral agents - Google Patents

Tetracyclic indole derivatives as antiviral agents Download PDF

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CN101087761A
CN101087761A CN 200580044207 CN200580044207A CN101087761A CN 101087761 A CN101087761 A CN 101087761A CN 200580044207 CN200580044207 CN 200580044207 CN 200580044207 A CN200580044207 A CN 200580044207A CN 101087761 A CN101087761 A CN 101087761A
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alkyl
compound
independently
hydrogen
ring
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C·埃尔科拉尼
J·哈伯曼
F·纳耶斯
S·蓬齐
M·劳利
I·斯坦斯费尔德
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Abstract

The present invention relates to tetracyclic indole compounds of formula (I); wherein R<1>, R<2>, A, Ar, W, X, Y and Z are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, and their use for the treatment or prevention of infection by hepatitis C virus.

Description

Tetracyclic indole derivatives as antiviral agent
The present invention relates to the tetracyclic indole compound, comprise they pharmaceutical composition, its in prevention and treatment purposes and this compound and the preparation of compositions method in the hepatitis C infection.
Hepatitis C virus (HCV) is the cause of virus infection.Still can't infect and thoroughly treat, but think in Mammals especially human body, suppress its RNA polymerase and will help treatment HCV.
The International Patent Application WO of announcing 93/00334 (Fidia-Georgetown Institute forthe Neurosciences) discloses and has been used for the treatment of the composition that spirit and sacred disease use and the following indole derivatives of method:
Figure A20058004420700101
Wherein A, Z, R 1, R 2, R 3, R 4With n such as wherein definition.Yet, the document openly tetracyclic indole derivatives in treatment or prevent purposes in the virus infection.
The International Patent Application WO of announcing 2005/080399 (Japan Tobacco Inc.) discloses the assorted tetracyclic compound of following condensed and as the purposes of HCV AG14361:
Figure A20058004420700102
Wherein A, X, Cy, G 1, G 2, G 3, G 4, G 5, G 6, R 1, R 2, R 3, R 4, R 5, R 6With a such as wherein definition.
The invention provides the compound and the acceptable salt of medicine thereof of formula (I):
Figure A20058004420700111
Wherein
A is C 3-8Cycloalkyl, optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Ar is the part that comprises at least one aromatic ring, have 5,6,9 or 10 annular atomses simultaneously, choose wantonly and comprise 1,2 or 3 heteroatoms that independently is selected from N, O and S, for example phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrazolyl and imidazolyl, described ring is optional by group Q 1And Q 2Replace;
Q 1Be halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, (CH 2) 0-3Aryl, heteroaryl, CONR cR d, (CH 2) 0-3NR cR d, O (CH 2) 0-3C 3-8Cycloalkyl, O (CH 2) 1-3NR cR d, O (CH 2) 0-3CONR cR d, O (CH 2) 0-3CO 2H, O (CH 2) 0-3Aryl, O (CH 2) 0-3Heteroaryl, OCHR eR fOr O (CH 2) 0-3S (O) 2(CH 2) 0-3NR cR d
R cAnd R dIndependently be selected from hydrogen, C 1-6Alkyl and C (O) C 1-6Alkyl;
Perhaps R cAnd R dConnected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, optional comprise 1 or 2 other heteroatoms that independently is selected from O and S and/or 1 or 2 and independently is selected from NH and NC 1-4The group of alkyl, wherein said ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R eAnd R fIndependently be selected from hydrogen, C 1-4Alkyl and C 1-4Alkoxyl group;
Perhaps R eAnd R fBe connected to form the heterolipid ring of 4-7 annular atoms by the heteroatoms that is selected from N, O and S, wherein said ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
And wherein said C 1-4Alkyl, C 1-4Alkoxyl group and aryl are optional to be replaced by halogen or hydroxyl;
Q 2Be halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group, wherein said C 1-4Alkyl and C 1-4Alkoxyl group is optional to be replaced by halogen or hydroxyl;
Perhaps Q 1And Q 2Can be connected to form the ring of 4-7 atom, wherein said ring is optional to comprise 1 or 2 heteroatoms that independently is selected from N, O and S, and optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R 1And R 2In one be CO 2H, C (O) NHS (O) 2NR aR b, C (O) NHS (O) 2C 1-6Alkyl, C (O) NHS (O) 2(CH 2) 0-3CO 2R cOr C (O) NHS (O) 2(CH 2) 0-3Aryl,
And R 1And R 2In another be hydrogen;
R aAnd R bIndependently be selected from hydrogen and C 1-6Alkyl,
Perhaps R aAnd R bConnected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms that independently is selected from O and S and/or 1 or 2 and independently be selected from S (O), S (O) 2, NH and NC 1-4The group of alkyl;
Y be C=O or-CR 14aR 15a-;
Z is chemical bond or NR 10
R 10Be hydrogen, hydroxyl, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C (O) C 1-6Alkyl, Het, (CH 2) 0-3NR 16R 17, C (O) (CH 2) 0-3NR 16R 17And NHC (O) (CH 2) 0-3NR 16R 17
R 14, R 14a, R 15And R 15aIndependently be selected from hydrogen, hydroxyl, C separately 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, (CH 2) 0-3C 3-8Cycloalkyl, C 1-6Alkoxyl group, C (O) C 1-6Alkyl, (CH 2) 0-3Aryl, (CH 2) 0-3Het, C (O) (CH 2) 0-3Het, (CH 2) 0-3NR 16R 17, (CH 2) 0-3OR 16, (CH 2) 0-3C (O) (CH 2) 0-3NR 16R 17, NR 18C (O) (CH 2) 0-3NR 16R 17, S (O) 0-2(CH 2) 0-3NR 16R 17, (CH 2) 0-3Heteroaryl or C (O) (CH 2) 0-3Heteroaryl is chosen wantonly and independently is selected from C by one or two 1-6Alkyl, hydroxyl, halogen, C 1-6Alkoxyl group, SH and S (C 1-6Alkyl) group replaces;
R 16And R 17Independently be selected from hydrogen, C 1-6Alkyl, (CH 2) 0-4NR 18R 19, (CH 2) 0-3Het, (CH 2) 0-3Heteroaryl, (CH 2) 0-3C (O) (CH 2) 0-3NR 18R 19Or (CH 2) 0-3C 3-8Cycloalkyl, optional by C 1-6Alkyl, (CH 2) 0-3OH or (CH 2) 0-3C 1-6Alkoxyl group replaces;
Perhaps R 16And R 17Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms that independently is selected from O and S and/or 1 or 2 and independently be selected from S (O), S (O) 2, NH, NC 1-4Alkyl and N (CH 2) 0-3C 1-4The group of alkoxyl group, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R 18And R 19Independently be selected from hydrogen, C 1-6Alkyl and heteroaryl;
Perhaps R 18And R 19Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms that is selected from O and S and/or 1 or 2 and be selected from S (O), S (O) 2, NH and NC 1-4The group of alkyl, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Condition is that the compound of formula (I) is not a 13-cyclohexyl-6, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate or 13-cyclohexyl-6 also, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also.
Another organizes compound and the acceptable salt of medicine thereof that preferred compound is a formula (Ia) the present invention:
Figure A20058004420700131
Wherein
Ar comprises 1,2 or 3 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for choosing wantonly;
Y be C=O or-CR 14aR 15a
Z is chemical bond or NR 10
R 10, R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen, hydroxyl, C separately 1-6Alkyl, C 2-6Thiazolinyl, C 1-6Alkoxyl group, C (O) C 1-6Alkyl, Het, (CH 2) 0-3NR 16R 17, C (O) (CH 2) 0-3NR 16R 17And NHC (O) (CH 2) 0-3NR 16R 17
R 16And R 17Independently be selected from hydrogen, C 1-6Alkyl and (CH 2) 0-4NR 18R 19
Perhaps R 16And R 17Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms or S (O), S (O) that is selected from O and S 2, NH or NC 1-4Alkyl group, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R 18And R 19Independently be selected from hydrogen and C 1-6Alkyl;
Perhaps R 18, R 19Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms or S (O), S (O) that is selected from O and S 2, NH or NC 1-4Alkyl group, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Condition is that the compound of formula (Ia) is not a 13-cyclohexyl-6, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.
In one embodiment, Ar comprises 1 or 2 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for choosing wantonly.Preferred Ar comprises 1 heteroatomic five yuan or hexa-atomic aromatic ring that is selected from N, O and S for choosing wantonly.More preferably Ar is phenyl, pyrimidyl, furyl or thienyl.Most preferably Ar is phenyl or thienyl.
When Z is NR 10The time, preferred R 10Be hydrogen, C 1-6Alkyl or (CH 2) 0-3R 16R 17, R wherein 16And R 17Define suc as formula (Ia).More preferably R 10Be C 1-6Alkyl or (CH 2) 1-3R 16R 17, R wherein 16And R 17Independently be selected from hydrogen and C 1-6Alkyl.R most preferably 10Be C 1-4Alkyl or (CH 2) 1-3R 16R 17, R wherein 16And R 17Independently be selected from hydrogen and C 1-4Alkyl.Suitable R 10Examples of groups comprises methyl and (CH 2) 2N (CH 3) 2
In another embodiment, R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen, C separately 1-6Alkyl or (CH 2) 0-3R 16R 17, R wherein 16And R 17Define suc as formula (Ia).Preferred R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen and (CH separately 2) 0-3NR 16R 17, R wherein 16And R 17Independently be selected from hydrogen, C 1-4Alkyl and (CH 2) 1-3NR 18R 19, R wherein 18And R 19Define suc as formula (Ia).More preferably R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen and NR separately 16R 17, R wherein 16And R 17Independently be selected from hydrogen, methyl and (CH 2) 1-3NR 18R 19, R wherein 18And R 19Independently be selected from hydrogen and C 1-4Alkyl.Suitable R 14, R 15, R 14aAnd R 15aExamples of groups comprises hydrogen, NH (CH 2) 2N (CH 3) 2And N (CH 3) (CH 2) 2N (CH 3) 2
In another embodiment, Y is-CR 14aR 15a-.Preferred Y is-CHR 14a-.
Another organizes compound and the acceptable salt of medicine thereof that preferred compound is a formula (Ib) the present invention:
Figure A20058004420700151
Wherein
R 10Be hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or (CH 2) 1-3NR 16R 17
R 16And R 17Independently be selected from hydrogen and C 1-6Alkyl;
R 14And R 15Independently be selected from hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 3-8Cycloalkyl;
Perhaps R 14aAnd R 15aForm the oxo base together;
Condition is that the compound of formula (Ib) is not 3-chloro-14-cyclohexyl-5-(2-piperidines-1-base ethyl)-5,6,7, and the 8-tetrahydro indole is [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid also.
In one embodiment, R 10Be hydrogen, C 1-6Alkyl or (CH 2) 1-3NR 16R 17, R wherein 16And R 17Define suc as formula (Ib).Preferred R 10Be C 1-6Alkyl or (CH 2) 1-3R 16R 17, R wherein 16And R 17Independently be selected from hydrogen and C 1-4Alkyl.More preferably R 10Be C 1-4Alkyl or (CH 2) 2N (C 1-4Alkyl) 2Suitable R 10Examples of groups comprises methyl and (CH 2) N (CH 3) 2
In another embodiment, R 14aAnd R 15aIndependently be selected from hydrogen or C 1-6Alkyl, perhaps R 14aAnd R 15aForm the oxo base together.Preferred R 14aAnd R 15aIndependently be selected from hydrogen or C 1-4Alkyl, perhaps R 14aAnd R 15aForm the oxo base together.More preferably R 14aAnd R 15aBe all hydrogen, perhaps R 14aAnd R 15aForm the oxo base together.
Another organizes compound and the acceptable salt of medicine thereof that preferred compound is a formula (Ic) the present invention:
Figure A20058004420700161
Wherein
R 10Be hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl or C2 -6Alkynyl;
R 14And R 15Independently be selected from hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or (CH 2) 0-3NR 16R 17
R 16And R 17Independently be selected from hydrogen and C 1-6Alkyl.
In one embodiment, R 10Be hydrogen or C 1-6Alkyl.Preferred R 10Be hydrogen or C 1-4Alkyl.More preferably R 10Be methyl.
In another embodiment, R 14And R 15Independently be selected from hydrogen, C 1-6Alkyl or (CH 2) 0-3NR 16R 17, R wherein 16And R 17Independently be selected from hydrogen and C 1-4Alkyl.Preferred R 14And R 15Independently be selected from hydrogen, C 1-4Alkyl or NR 16R 17, R wherein 16And R 17Independently be selected from hydrogen and methyl.More preferably R 14And R 15Be hydrogen or N (CH 3) 2
Another organizes compound and the acceptable salt of medicine thereof that preferred compound is a formula (Id) the present invention:
Figure A20058004420700162
Wherein
Ar comprises 1,2 or 3 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for choosing wantonly, and described ring is optional by group Q 1Replace;
R 14, R 15, R 14a, R 15dAnd Q 1Define suc as formula (I), condition is that the compound of formula (Id) is not a 13-cyclohexyl-6,7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-methyl-formiate or 13-cyclohexyl-6,7-dihydro-5H-pyrrolo-[2 ', 1 ': 3,4] [1,4] diazacyclo heptene [1,2-a] indoles-10-formic acid also.
In one embodiment, Ar comprises 1 or 2 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for choosing wantonly, and described ring is optional by halogen, hydroxyl, C 1-6Alkyl or C 1-6Alkoxyl group replaces.Preferred Ar comprises 1 heteroatomic five yuan or hexa-atomic aromatic ring that is selected from N, O and S for choosing wantonly, and described ring is optional by halogen, hydroxyl or C 1-4Alkoxyl group replaces.More preferably Ar is optional five yuan or the hexa-atomic aromatic ring that comprises a S atom, and described ring is optional by C 1-4Alkoxyl group replaces.More preferably Ar is phenyl or thienyl, chooses wantonly to be replaced by methoxyl group.
In another embodiment, R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen, C 1-6Alkyl, (CH 2) 0-3OR 16(CH 2) 0-3NR 16R 17, R wherein 16And R 17Define suc as formula (Id).Preferred R 14And R 14aIn one be hydrogen, C 1-6Alkyl, (CH 2) 0-3OR 16Or (CH 2) 0-3NR 16R 17, R wherein 16And R 17Suc as formula (I) define R 14And R 14aIn another be hydrogen.More preferably R 14And R 14aIn one be (CH 2) 0-3OR 16Or (CH 2) 0-3NR 16R 17, R wherein 16And R 17Suc as formula (Id) define R 14And R 14aIn another be hydrogen.R most preferably 14And R 14aIn one be OR 16Or NR 16R 17, R wherein 16And R 17Suc as formula (I) define R 14And R 14aIn another be hydrogen.
Work as R 14, R 15, R 14aAnd R 15aIn any one or a plurality of be (CH 2) 0-3OR 16Or (CH 2) 0-3NR 16R 17The time, preferred R 16And R 17Independently be selected from hydrogen, C 1-6Alkyl, (CH 2) 0-3NR 18R 19, (CH 2) 0-3Het, (CH 2) 0-3Heteroaryl, (CH 2) 0-3C (O) (CH 2) 0-3NR 18R 19Or (CH 2) 0-3C 3-8Cycloalkyl, wherein R 18And R 19Define suc as formula (I).More preferably R 16And R 17Independently be selected from hydrogen, C 1-6Alkyl and (CH 2) 1-3NR 18R 19, R wherein 18And R 19Define suc as formula (I).R most preferably 16And R 17Independently be selected from hydrogen, C 1-4Alkyl and (CH 2) 1-3NR 18R 19, R wherein 18And R 19Independently be selected from hydrogen and C 1-6Alkyl, perhaps R 18And R 19Connected nitrogen-atoms forms the heterolipid ring of 5 or 6 annular atomses together, and described ring can be chosen wantonly and comprise other 1 O or S atom and/or NH or NC 1-4Alkyl.Particularly, R 16And R 17Independently be selected from hydrogen, methyl and (CH 2) 2NR 18R 19, R wherein 18And R 19Independently be selected from methyl and ethyl, perhaps R 18And R 19Connected nitrogen-atoms forms the tetramethyleneimine basic ring together.Suitable R 14, R 15, R 14aAnd R 15aExamples of groups comprises hydrogen,
Figure A20058004420700181
With
Preferred R 15And R 15aIndependently be selected from hydrogen and C 1-6Alkyl.More preferably R 15And R 15aIndependently be selected from hydrogen and C 1-4Alkyl.R most preferably 15And R 15aIndependently be selected from hydrogen, methyl and ethyl.Particularly, R 15And R 15aBe all hydrogen.
When any variable in formula (I) or any substituting group occurs when once above, the definition the when definition when it occurs at every turn is independent of other each time and occurs.
Term used herein " alkyl " or " alkoxyl group " partly refer to the straight or branched group as group or group.The example of suitable alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl and the tertiary butyl.The example of suitable alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.
The cycloalkyl that this paper mentions can be represented by for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Suitable cycloalkylalkyl can be for example cyclopropyl methyl.
Term used herein " thiazolinyl " partly refers to the straight or branched group as group or group.The example of suitable thiazolinyl comprises vinyl and allyl group.
Term used herein " halogen " refers to fluorine, chlorine, bromine and iodine.
Term used herein " aryl " partly refers to the carbocyclic ring aromatic ring as group or group.The example of suitable aryl comprises phenyl and naphthyl.
Term used herein " heteroaryl " partly refers to comprise 1-4 the first hetero-aromatic ring system of heteroatomic 5-10 that is selected from N, O and S as group or group.The specific examples of this group comprises pyrryl, furyl, thienyl, pyridyl, pyrazolyl, imidazolyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, triazolyl,  di azoly, thiadiazolyl group, triazinyl, tetrazyl, indyl, benzothienyl, benzimidazolyl-and quinolyl.
Term used herein " Het " partly refers to the heterolipid ring of 4-7 atom as group or group, and described ring can comprise 1,2 or 3 heteroatoms or S (O), the S (O) that are selected from N, O and S 2, NH or NC 1-4Alkyl group.
When with " optional by ... replace " when describing compound or group, can there be one or more substituting groups in expression.Optional substituting group can be connected with the compound or the group of its replacement in every way, directly connects or connects by following linking group as an example: amine, acid amides, ester, ether, thioether, sulphonamide, sulphonamide, sulfoxide, urea, thiocarbamide and urethane.The suitable former generation basic body chosen can be replaced by another substituting group, the latter directly or by for example above the linking group of example be connected with the former.
Particular compound in the scope of the invention is included in the compound and the acceptable salt of medicine thereof of name in following examples and the table.
When as medicine, the salt of formula (I) compound should be the nontoxic acceptable salt of medicine.Yet other salt can be used for preparing The compounds of this invention or the acceptable salt of its nontoxic medicine.The acceptable salt of the medicine that The compounds of this invention is suitable comprises acid salt, and it can form by for example the solution of The compounds of this invention being mixed with the solution of the acceptable acid of medicine (for example hydrochloric acid, fumaric acid, tosic acid, toxilic acid, Succinic Acid, acetic acid, citric acid, tartrate, carbonic acid acid, phosphoric acid or sulfuric acid).The salt of amine groups also can comprise quaternary ammonium salt, and wherein said amino nitrogen atom is connected with suitable organic group, for example alkyl, thiazolinyl, alkynyl or aralkyl moiety.In addition, when The compounds of this invention had acidic moiety, the acceptable salt of its suitable medicine can comprise metal-salt, for example an alkali metal salt (for example sodium salt or sylvite) and alkaline earth salt (for example calcium salt or magnesium salts).
Described salt can form by traditional method, for example the described product of free alkali form and monovalent or more appropriate acid are reacted in insoluble solvent of salt or medium, or in the water equal solvent, react, water is removed by vacuum or lyophilize, or changes the negatively charged ion of existing salt into another kind of negatively charged ion on suitable ion exchange resin.
The prodrug that comprises following formula (I) compound in the scope of the present invention.Generally speaking, this prodrug is the functional derivatives of formula (I) compound, and it can be converted to required formula (I) compound in vivo easily.H.Bundgaard " Design of Prodrugs (the prodrug design) " of writing for example, Elsevier, 1985 have described the ordinary method that is used to select and prepare suitable prodrug derivant.
Prodrug can be the derivative of the pharmacology non-activity of biologically active substance (" female medicine " or " parent molecule "), and it need transform in vivo to discharge described active medicine, is improved with respect to female its hereditary property of medicine molecule simultaneously.Transform in the described body and can be for example result of some metabolic process, for example chemistry of carboxylicesters, phosphoric acid ester or sulfuric ester or enzymic hydrolysis, the perhaps reduction of susceptible to functional group or oxidation.
The solvate that comprises formula (I) compound and salt thereof in the scope of the present invention, for example hydrate.
The N-oxide compound that also comprises formula (I) compound in the scope of the present invention.
Any enantiomer, diastereomer, geometrical isomer and the tautomer that also comprise formula (I) compound in the scope of the present invention.Should be understood that all this isomer and composition thereof all within the scope of the present invention.
The present invention also provides formula (I) compound or the acceptable salt of its medicine that is used for the treatment of.
The present invention provides formula defined above (I) compound or the purposes of the acceptable salt of its medicine in the preparation medicine on the other hand, and described medicine is used for the treatment of or prevents the infection of hepatitis C virus in human body or the animal.
The present invention provides a kind of pharmaceutical composition on the other hand, and described composition comprises and drug acceptable carrier bonded formula defined above (I) compound or the acceptable salt of its medicine.Described composition can be any suitable form, depends on the administering mode of imagination.It can be tablet, capsule or the liquid form that for example is used for orally give, or for being used for the solution or the suspension of parenteral admin.
Described pharmaceutical composition is also optional to comprise other material that one or more are used for the treatment of virus infection, for example antiviral agent, or immunomodulator, for example α-, β-or gamma-interferon.
On the other hand, the invention provides a kind of method of the disease that suppresses hepatitis C virus polysaccharase and/or treatment or prevent to be caused by hepatitis C virus, described method comprises human or animal's (preferred mammal) object treatment of suffering from this illness or prevents aforementioned pharmaceutical compositions or formula defined above (I) compound or the acceptable salt of its medicine of significant quantity." significant quantity " refers to be enough to produce for object the amount of benefit, or the amount that causes patient's illness to change at least.
The injection speed that gives described compound depends on multiple factor, the activity that comprises the particular compound of using, the metabolic stability of this compound and action time, patient's age, body weight, general health, sex, diet, mode of administration and time, discharge rate, drug combination, the severity of concrete illness and the host who treats.Proper dosage can be 0.02-5 or 10g/ days, and oral dosage is that 2-5 is doubly high.For example, suitable administration can be the described compound/kg body weight of 10-50mg, 1-3 time/day.Suitable value can be selected by conventionally test.Described compound can be individually dosed or with the other therapies associating, simultaneously or give successively.For example, its can with antiviral agent, immunomodulator, anti-infective or the vaccine Combined Preparation of the known significant quantity of those of ordinary skills.It can be by any suitable way administration, comprises oral, intravenously, skin and subcutaneous administration.It can be administered directly to suitable site, or passes through the mode administration of target specific site (for example certain cell).Suitable targeted approach is known.
The present invention provides a kind of method of pharmaceutical compositions on the other hand, and described method comprises mixes at least a formula defined above (I) compound or the acceptable salt of its medicine with one or more medicine acceptable auxiliary, diluent or carrier and/or one or more other therapeutic activity agent or prophylactic activity agent.
The present invention also provides the preparation method of formula (I) compound.
According to universal method (a), formula (I) but the preparation of the intramolecularly closed loop of compound through type (II) compound:
Figure A20058004420700211
R wherein 1, R 2, A and Ar define suc as formula (I), in the cyclization process or behind the cyclization, X ' is converted to-CR 14R 15-, W ' is-CH 2-or in the cyclization process or behind the cyclization, be converted to-CH 2-, Y ' is converted to Y in the cyclization process or behind the cyclization, and Z ' is for Z or be converted to Z in the cyclization process or behind the cyclization.W ', X ', Y ' and Z ' can be respectively group-CH 2-, the suitable activation precursor of X, Y and Z, they can utilize that drawings and Examples are described in closed loop procedure or after the closed loop or the procedure known to those skilled in the art is converted to-CH 2-, X, Y and Z.For example, when Z was chemical bond, W ', X ', Y ' and Z ' were suitable precursor, and they are for alkene or can be exchanged into alkene to carry out the closed loop replacement(metathesis)reaction.Perhaps, when Z be R 10The time, X ' can be CH 2-halogen, CH 2-ester, CH 2-aldehyde, epoxy group(ing) or ethylenimine group.
According to universal method (b), formula (I) but the preparation of the intramolecularly closed loop of compound through type (III) compound:
Figure A20058004420700221
R wherein 1, R 2, A, Ar, Y and Z define suc as formula (I), X ' is-CR 14R 15-or in the cyclization process or behind the cyclization, be converted to-CR 14R 15-, in the cyclization process or behind the cyclization, W ' is converted to-CH 2-.W ' and X ' can be respectively group-CH 2-and-CR 14R 15-suitable activation precursor, can utilize that drawings and Examples are described in closed loop procedure or after the closed loop or the procedure known to those skilled in the art is converted into-CH 2-and-CR 14R 15-.For example, W ' can be CH 2-halogen, perhaps W ' and X ' can be epoxy group(ing) or ethylenimine group together.When W ' is CH 2-halogen (CH for example 2-Br) time, described reaction is being carried out in suitable solvent (for example DMF) in the presence of the alkali (for example sodium hydroxide) usually.When W ' and X ' were epoxy group(ing), described reaction was being carried out in suitable solvent (for example DMF) in the presence of the alkali (for example sodium hydroxide) usually.
Formula (II) and compound (III) are known to those skilled in the art, perhaps can be by the known ordinary method preparation of those of ordinary skills, and the method for for example utilizing drawings and Examples to describe, or by conspicuous other method.
The more details of appropriate method are seen drawings and Examples.For example, can utilize synthetic method well known to those skilled in the art formula (I) compound to be converted to other formula (I) compound.
General synthetic route
Generally speaking, can use five kinds of synthetic routes to obtain the compound of formula (I).
Method A
Figure A20058004420700231
On indole nitrogen with 2-bromo indole intermediate (as preparation as described in the International Patent Application WO of announcing 2004/087714) functionalization to introduce the precursor W ' of functional group/X ', as the arbitrary of connexon (tether) or two unit-CH 2-/X.The cross-coupling of Pd-mediation (for example Suzuki, Stille etc.) is introduced in the aromatic ring that the C2 position has the Z ' of precursor functional group/Y ' then, as the arbitrary of connexon or two unit Z/Y.Carry out functional group after the closed loop and handle the Fourth Ring system that obtains.Go the ester protection to obtain the target indolecarboxylic acid then, wherein the C2 position of aromatic ring links to each other with indole nitrogen.
Method B
At first introduce the C2 aromatic ring by the cross-coupling method (Suzuki, Stille etc.) of Pd-mediation.Make up connexon then, at last cyclisation closed loop on indole nitrogen.Go the ester protection to obtain the target indolecarboxylic acid then, wherein the C2 position of aromatic ring links to each other with indole nitrogen.
Method C
The fused tetracyclic intermediate that is generated by method A and B carries out functional group's processing on connexon, then go the ester protection to obtain the indolecarboxylic acid that target C2 connects.
Method D
The indolecarboxylic acid that the C2 that is generated by method A-C connects is further handled derivation by carboxylicesters functional group, obtains having the compound of carboxylicesters substituent or carboxylic acid amides.
Any step in above-mentioned synthetic order must and/or need be protected the sensitivity or the active group of any associated molecule.It can utilize traditional protecting group to realize, Protective Groups in Organic Chemistry (vitochemical protecting group) for example, J.F.W.McOmie writes, Plenum Press, 1973 and T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis (protecting group of organic synthesis), John Wiley﹠amp; Sons, the third edition, 1999 protecting groups of describing.Protecting group can utilize methods known in the art to remove easily in step subsequently.
Following examples are to elaboration of the present invention.
Suppress test (embodiment i) at enzyme) and based on the inferior chromosome duplication test of cell (embodiment ii) in, the test The compounds of this invention is to the inhibition activity of HCV RNA RNA-dependent polysaccharase (NS5B).The IC50 of described compound in enzyme test be less than 5 μ M, simultaneously several examples in based on the test of cell EC50 less than 2 μ M.
The title of compound utilizes the software (6.0 editions) of ACDLabs to generate among the embodiment.
I) external HCV NS5B enzyme suppresses test
The insect cell that WO 96/37619 has described by the recombinate shape virus infection of this enzyme of coding prepares recombinant HCV RdRp.The result shows when utilizing RNA to make template, and described purifying enzyme has a rna polymerase activity external.The document has been described the polymerization test that utilizes poIy (A) and oligo (U) to make primer or assorted poly-template.The radioactivity that is insoluble to acid by mensuration is carried out quantitatively the combination that contains tritium UTP or NTP.This test has been used to screen above-mentioned all cpds as HCV RdRp inhibitor.
Radioactivity UMP in conjunction with following mensuration.Standard reaction (50 μ l) is 7.5 tris/HCl, 5mM MgCl comprising 20mM pH 2, 1mM DTT, 50mM NaCl, 0.03%N-octyl glucoside, 1 μ Ci[ 3H]-UTP (40Ci/mmol, NEN), carry out in the damping fluid of 10 μ M UTP, 10 μ g/mlpoly (A) or 5 μ M NTP and the assorted poly-template of 5 μ g/ml.In test, add the Oligo (U) that acts on PoIy (A) template 12(1 μ g/ml is Genset) as primer.Final NS5B enzyme concn is 5nM.Erection sequence is: 1) compound, 2) enzyme, 3) template/primer, 4) NTP.22 ℃ hatch 1 hour after, add the TCA termination reaction of 50 μ l 20%, sample is placed the DE81 strainer.With comprising 1M Na 2HPO 4/ NaH 2PO 4, the thorough washing filter of the 5%TCA of pH 7.0, water and ethanol rinsing successively, dry air is measured and strainer bonded radioactivity with scintillometer.In the presence of above-mentioned each compound of various concentration, carry out this reaction, utilize following formula to determine IC 50Value:
% residual activity=100/ (1+[I]/IC 50) s
Wherein [I] is inhibitor concentration, and " s " is for suppressing slope of a curve.
Ii) the HCV based on cell duplicates test
By using the identical sub-transfection Huh-7 of the rna replicon cell of describing with (1999) (EMBL-genbank No AJ242652) such as Lohmann of I377neo/NS3-3 '/wt, obtain the stable cell clone that keeps inferior karyomit(e) HCV replicon.By utilizing ELISA measurements determination NS3 protein expression that virus replication is monitored, utilize the monoclonal antibody 10E5/24 (as described in disclosed International Patent Application WO 02/59321) of anti-NS3 directly the cell that is grown on the 96 hole microtiter plates to be carried out ELISA test (Cell-ELISA).With 10 4Cells/well (final volume is 0.1ml DMEM/10%FCS) density is gone into the cell kind in 96 orifice plates.Inoculate after two hours, add the 50 μ l DMEM/10%FCS that comprise 3 times of concentration inhibitor, incubated cell 96 hours is fixed 10 minutes with ice-cold Virahol then.Measure each condition of duplicating, and mean absorbance is used for calculating.With PBS washed cell twice, the sealing of PBS+0.1% Triton X100+0.02% SDS (PBSTS) suspension of the skim-milk with 5% is hatched at 4 ℃ with the 10E5/24 monoclonal antibody that is diluted among breast/PBSTS then.After PBSTS washing 5 times, be diluted among breast/PBSTS with the alkaline phosphatase link coupled Fc anti-mouse IgG of specificity (Sigma) incubated at room cell 3 hours.After as above washing once more,, read in the absorbancy of 405/620nm at interval with p-nitrophenyl phosphate disodium substrate (Sigma) reaction solution.We use data set in calculating, and wherein the absorbance of the sample of hatching without inhibitor is 1-1.5.By data substitution Hill equation being calculated the inhibitor concentration (IC that NS3 expresses reduction by 50% 50),
Suppress mark=1-(Ai-b)/(A 0-b)=[I] n/ ([I] n+ IC 50)
Wherein:
Ai=with shown in the absorbance of the inhibitor concentration HBI10 cell of hatching.
The absorbance of the HBI10 cell that A0=is hatched without inhibitor.
The absorption value of the Huh-7 cell that b=is hatched in microtiter plate and without inhibitor with the equal densities plating.
The n=Hill coefficient.
Iii) universal method
All solvents buy from the market all that (Fluka puriss.), directly uses without being further purified.Except that routine is gone protection and coupling step, be reflected in the glassware of oven drying (110 ℃) and under nitrogen atmosphere, carry out.Use the dried over sodium sulfate organic extraction, concentrating under reduced pressure in rotatory evaporator (after filtering the removal siccative).Flash chromatography carries out according to disclosed method (W.C Still etc., J Org Chem 1978,43,2923) or in the commercially available flash chromatography system (Biotage corporation and Jones Flashmaster II) that uses prepacked column on silica gel.
The general direct supplier from the market of reagent obtains (and directly using), but uses a small amount of self-control compound.At latter event, described reagent can utilize that scientific literature is reported or the known conventional synthesis step of those skilled in the art makes easily.
Record on the Bruker AM series nuclear magnetic resonance analyser of moving with 300-600MHz (nominal) frequency 1H NMR spectrogram.With part/1,000,000 (ppm) note, and utilize the solvent peak that exists to do corresponding to the chemical shift (δ) of the signal of not commutative proton (and detectable exchangeable protons) with reference to being measured with respect to tetramethylsilane.According to multiplicity (s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak; And combination), coupling constant (hertz (Hz)) and proton number are listed in signal in the table.Utilize Perkin Elmer API 100 or Waters MicroMass ZQ (with negative (ES -) or (ES just +) the ionization mode operation) obtaining mass spectrum (MS) data, the result is reported to the ratio (m/z) of ion source quality to electric charge.Carrying out preparative scale HPLC on Waters Delta Prep 4000 separation modules of being furnished with Waters 486 absorption detectors or Gilson preparation system separates.At all situations, utilize to comprise the water of 0.1%TFA and the linear gradient elution compound of MeCN, flow velocity is the 15-40ml/ branch.
Abbreviation below in embodiment, accompanying drawing and table, using: Ac: ethanoyl; Ar: aryl; Cat.: catalytic; Dioxane: 1, the 4-dioxane; Dppf:(1,1 '-two diphenylphosphines) ferrocene; 1,2-DCE:1,2-ethylene dichloride; DCM: methylene dichloride; DIPEA: diisopropylethylamine; DMAP:N, N-lutidine-4-amine; DME: glycol dimethyl ether; DMF: dimethyl formamide; DMSO: methyl-sulphoxide; DMP:Dess-Martin Periodinane; EDACHCl:1-ethyl-(3-dimethylaminopropyl) carbodiimide HCl salt; Eq.: equivalent; Et 3N: triethylamine; EtOAc: ethyl acetate; Et 2O: diethyl ether; EtOH: ethanol; H: hour; Et 3SiH: triethyl silicane; HOAc: acetic acid; HATU: phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea ; Me: methyl; MeCN: acetonitrile; MeOH: methyl alcohol; Min: minute; MS: mass spectrum; The NBS:N-bromo-succinimide; PE: sherwood oil; Ph: phenyl; Quant.: quantitatively; RP-HPLC: RPLC; Rt: room temperature; Sec: second; SFC: overcritical liquid chromatography; S.s.: saturated solution; TBTU: Tetrafluoroboric acid O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea salt; TFA: trifluoroacetic acid; THF: tetrahydrofuran (THF); THP: tetrahydropyrans; TMS: three silicomethanes.
Reagent: Zhan catalyst I (dichloride [1,3-two (2,4, the 6-trimethylphenyl)-4,5-dihydro-imidazol--2-subunit]-[4-chloro-1-isopropoxy-benzylidene] ruthenium: available from ZannanPharma Ltd (www.zannanpharma.com); According to preparing (aminosulfonyl) methyl acetate with the similar method of the related esters of aminosulfonyl acetate, for example Tetrahedron Lett 1989,30 (22), and 2869; Bull Soc Chim France 1975,3,807.
Embodiment 1:13-cyclohexyl-5-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-formic acid and 13-cyclohexyl-6-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles is the preparation of [2,1-a] [2] benzo-aza suberene-10-formic acid also
Step 1:3-cyclohexyl-2-(2-ethenylphenyl)-1H-indoles-6-methyl-formiate
2-bromo-3-cyclohexyl-1H-indoles-6-methyl-formiate (as preparation as described in the WO 2004/087714) and (2-ethenylphenyl) boric acid (1.5 equivalent) are dissolved in the dioxane (0.07M), and add the Na of 2M 2CO 3The aqueous solution (6 equivalent).Make the solution degassing with the argon gas bubbling, add Pd (PPh 3) 2Cl 2(0.2 equivalent), reaction mixture refluxed 1 hour; After the cooling, add EtOAc, water and salt solution washing soln, Na 2SO 4Drying, vacuum concentration.(PE/EtOAc9: 1) separate title compound, productive rate is 91% to utilize chromatography; MS (ES +) m/z 360 (M+H) +
Step 2:1-allyl group-3-cyclohexyl-2-(2-ethenylphenyl)-1H-indoles-6-methyl-formiate
At 0 ℃ of NaH (in mineral oil) (1.5 equivalent), add allyl bromide 98 (1.5 equivalent) after 1 hour, stirring at room suspension 2 hours to the anhydrous DMF solution adding 60% of the 3-of 0.3M cyclohexyl-2-(2-ethenylphenyl)-1H-indoles-6-methyl-formiate.Dilute described mixture with EtOAc, with 1N HCl, water and salt water washing, Na 2SO 4Drying, vacuum concentration get title compound (100%, be crude product); MS (ES +) m/z 400 (M+H) +
Step 3:13-cyclohexyl-7H-indoles is [2.1-a] [2] benzo-aza suberene-10-methyl-formiate also
Thick 1-allyl group-3-cyclohexyl-2-(2-ethenylphenyl)-1H-indoles-6-methyl-formiate is dissolved in (0.02M) among the DCM, and handled 1 hour at 35 ℃ with zhan catalyst I (0.3 equivalent).Add NEt 3(7 equivalent), vacuum is removed solvent.Utilize chromatography (PE/EtOAc 95: 5) purifying residue to get title compound (84%); MS (ES +) m/z 372 (M+H) +
Step 4:13-cyclohexyl-5-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles also [2,1- A] [2] benzo-aza suberene-10-formic acid and 13-cyclohexyl-6 (2-tetramethyleneimine-1-base oxethyl)- 6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also
With BH 3Me 213-cyclohexyl-7H-indoles of S (1.6 equivalents, the THF solution of 2M) adding 0.2M is the THF solution of [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also, stirring at room mixture 2 hours; Add the NaOH aqueous solution (3 equivalent) of 3M and 35% H at 0 ℃ 2O 2(3 equivalent), room temperature continue stirring and spend the night.Use saturated NaHCO 3After the aqueous solution dilution, water extracts with EtOAc, water and salt water washing organic phase, Na 2SO 4Dry, vacuum concentration obtains 13-cyclohexyl-5-hydroxyl-6, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate and 13-cyclohexyl-6-hydroxyl-6 also, 7-dihydro-5H-indoles is 4: 1 mixtures of [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.The aforementioned crude product is dissolved in (20ml/mmol) in the toluene, adds 40% the NaOH aqueous solution (15 equivalent) and Tetrabutylammonium bromide (0.25 equivalent), stirred the mixture 30 minutes.Add hydrochloric acid 1-(2-chloroethyl) tetramethyleneimine (3 equivalent) then, heated the gained mixtures 1 day at 70 ℃; Evaporate to dryness gets residue, separates to such an extent that isomer (overall yield is 32%) (condition: post: Waters X-TERRA MS C18,10 microns, 19 * 150mm is selected in two kinds of zones by this residue through RP-HPLC; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; 75%A isocratic elution 3 minutes, internal linear changed to 20%A in 12 minutes).
13-cyclohexyl-5-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid (mainly) also:
1H NMR(400MHz，DMSO，300K)δ1.16-1.51(4H，m)，1.58-2.06(12H，m)，2.82-2.90(2H，m)，3.00-3.21(3H，m)，3.45-3.75(5H，m)，4.23-4.73(2H，m)，7.46-7.64(5H，m)，7.83-7.87(1H，m)，8.13(1H，s)，12.30(1H，bs)；MS(ES +)m/z 473(M+H) +.
13-cyclohexyl-6-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid (less important) also:
1H NMR(400MHz，DMSO，330K)δ1.16-1.56(4H，m)，1.68-2.26(12H，m)，2.80-2.93(1H，m)， 2.98-3.18(3H，m)，3.46-3.68(4H，m)，3.78-3.83(1H，m)，4.04-4.07(1H，m)，4.18-4.37(1H，m)，4.75-4.90(1H，m)，7.43-7.49(4H，m)，7.65(1H，dd，J 8.6，1.1)，7.88(1H，d，J 8.6)，8.13-8.22(1H，m)，11.44(1H，bs)；MS(ES +)m/z 473(M+H) +.
Embodiment 2:13-cyclohexyl-5-[[2-(dimethylamino) ethyl]-(methyl) amino]-6,7-dihydro-5H-indoles is the preparation of [2,1-a] [2] benzo-aza suberene-10-formic acid also
Select isomer 13-cyclohexyl-5-hydroxyl-6 in 0 ℃ of two kinds of zone to 0.2M, 7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-methyl-formiate and 13-cyclohexyl-6-hydroxyl-6,7-dihydro-5H-indoles also [2,1-a] the DCM solution of mixture (as embodiment 1, the described preparation of step 4) of [2] benzo-aza suberene-10-methyl-formiate adds PBr 3(0.5 equivalent), stirring at room mixture 2 hours.Use the EtOAc diluted reaction mixture, water and salt water washing, Na 2SO 4Dry, vacuum concentration, obtain being dissolved in the 5-bromo-13-cyclohexyl-6 among the MeCN, 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate and 6-bromo-13-cyclohexyl-6 also, 7-dihydro-5H-indoles also [2,1-a] mixture of [2] benzo-aza suberene-10-methyl-formiate, use N, N, N-trimethylammonium ethane-1,2-diamines (8 equivalent) was handled 3 hours at 55 ℃; Evaporated in vacuo gets 13-cyclohexyl-5-[methyl (2-tetramethyleneimine-1-base ethyl) amino]-6,7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-methyl-formiate crude product and unreacted 6-bromo-13-cyclohexyl-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.Utilize the 1M KOH aqueous solution (6 equivalent) in dioxane (0.1M), aforementioned mixtures of methyl esters to be hydrolyzed at 60 ℃; Described reaction was finished in 2 hours, and RP-HPLC purifying and lyophilize get title compound, and productive rate is 49% (condition: post: X-TERRA MS C18,10 microns, 19 * 150mm; Flow velocity: 20ml/ branch; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; 75%A isocratic elution 3 minutes, internal linear changed to 20%A in 12 minutes).
1H NMR(400MHz，DMSO，300K)δ1.15-1.78(6H，m)，1.82-2.09(5H，m)，2.19-2.30(3H，m)，2.55-2.7(2H，m)，2.78(6H，s)，2.80-2.96(1H，m)，3.13-3.40(4H，m)，4.60-4.66(1H，m)，7.40(1H，d，J 7.2)，7.47-7.56(2H，m)，7.62(1H，d，J 8.3)，7.75(1H，d，J 7.2)，7.87(1H，d，J 8.3)，8.14(1H，s)；MS(ES +)m/z 460(M+H) +.
Embodiment 3:13-cyclohexyl-5-[(2-tetramethyleneimine-1-base ethyl) amino]-6,7-dihydro-5H-indoles is the preparation of [2,1-a] [2] benzo-aza suberene-10-formic acid also
Handle the 5-bromo-13-cyclohexyl-6 of 0.03M at 55 ℃ of utilizations (2-tetramethyleneimine-1-base ethyl) amine (5 equivalent), 7-dihydro-5H-indoles is the MeCN solution 4 hours of [2,1-a] [2] benzo-aza suberene-10-manthanoate (as embodiment 2 preparations) also; Evaporated in vacuo gets 13-cyclohexyl-5-[(2-tetramethyleneimine-1-base ethyl) amino]-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate crude product also.Utilize the 1M KOH aqueous solution (6 equivalent) in dioxane (0.1M), aforementioned methyl esters to be hydrolyzed at 60 ℃; Described reaction was finished in 2 hours, and RP-HPLC purifying and lyophilize get title compound, and productive rate is 24% (condition: post: X-TERRA MSC18,10 microns, 19 * 150mm; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; 75%A isocratic elution 3 minutes, internal linear changed to 20%A in 12 minutes).
1H NMR(400MHz，DMSO，300K)δ1.15-1.77(7H，m)，1.90-2.17(10H，m)，2.78-2.91(2H，m)，3.40-3.59(7H，m)，4.11-4.16(1H，m)，4.75-4.81(1H，m)，7.51-7.66(5H，m)，7.92(1H，d，J 8.5)，8.20(1H，s)；MS(ES +)m/z 472(M+H) +
Embodiment 4:13-cyclohexyl-5-[methyl (2-tetramethyleneimine-1-base ethyl) amino]-6,7-dihydro-5H-indoles is the preparation of [2,1-a] [2] benzo-aza suberene-10-formic acid also
With 13-cyclohexyl-5-[(2-tetramethyleneimine-1-base ethyl) amino]-6,7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-methyl-formiate (as embodiment 3 preparations) is dissolved among the DCM, with AcOH with its pH regulator to 6; The HCHO aqueous solution of adding 37% added NaCNBH after 30 minutes 3(3 equivalent), the stirring at room mixture overnight.Use the EtOAc diluted reaction mixture, with 1N NaOH and salt water washing, drying, evaporation obtains 13-cyclohexyl-5-[methyl (2-tetramethyleneimine-1-base ethyl) amino]-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.Utilize the 1M KOH aqueous solution (6 equivalent) in dioxane (0.1M), aforementioned methyl esters to be hydrolyzed at 60 ℃; Described reaction was finished in 2 hours, and RP-HPLC purifying and lyophilize get title compound, and productive rate is 29% (condition: post: X-TERRA MSC18,10 microns, 19 * 150mm; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; 75%A isocratic elution 3 minutes, internal linear changed to 20%A in 12 minutes).
1H NMR(400MHz，DMSO，300K)δ1.16-1.77(8H，m)，1.80-2.11(8H，m)，2.19-2.31(2H，m)，2.61-2.87(5H，m)，2.98-3.41(7H，m)，4.54-4.66(1H，m)，7.42(1H，d，J 8.1)，7.47-7.54(2H，m)，7.63(1H，d，J8.3)，7.69-7.75(1H，m)，7.86(1H，d，J 8.3)，8.12(1H，s)；MS(ES +) m/z 486(M+H) +
Embodiment 5:13-cyclohexyl-6-{[2-(dimethylamino) ethyl] amino }-6,7-dihydro-5H-indoles is the preparation of [2,1-a] [2] benzo-aza suberene-10-formic acid also
Step 1:13-cyclohexyl-5,6-dihydroxyl-6,7-dihydro-7H-indoles be [2,1-a] [2] benzo-aza also Suberene-10-methyl-formiate
Handle the also acetone/THF/H of [2,1-a] [2] benzo-aza suberene-10-methyl-formiate (as embodiment 1, step 3 preparation) of 13-cyclohexyl-7H-indoles with N-methylmorpholine-N-oxide compound (1.2 equivalent) 2O (1/1/1) solution (0.11M) is then used OsO 4(H 2Among the O, 4% weight) (0.1 equivalent) processing, stirred overnight at room temperature.Use the Na of 10% weight then 2SO 3Handle the gained clear solution, stirred 30 minutes, then use H 2The O dilution is extracted with EtOAc.With salt water washing organic phase, Na 2SO 4Drying, vacuum-evaporation get the emulsus solid of pure title compound; MS (ES +) m/z 406 (M+H) +
Step 2:10-cyclohexyl-2-oxo-3a, 14b-dihydro-4H-[1,3] dioxole also [4,5-d] Indoles is [2,1-a] [2] benzo-aza suberene-7-methyl-formiate also
Use Et 3N (4 equivalent) handles 13-cyclohexyl-5, and 6-dihydroxyl-6,7-dihydro-5H-indoles be the DCM solution (0.05M) of [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also, is cooled to-50 ℃.Add triphosgene (0.4 equivalent), make described solution be warming up to room temperature in 30 minutes.After the room temperature 2 hours, add saturated NaHCO 3, extract solution with EtOAc.Use H 2O and salt water washing organic phase, dry (Na 2SO 4), vacuum-evaporation obtains purified title compound; MS (ES +) m/z 432.3 (M+H) +
Step 3:13-cyclohexyl-6-hydroxyl-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza ring heptan also Alkene-10-methyl-formiate
Handle 10-cyclohexyl-2-oxo-3a with Raney-Ni (aqueous slurry), 14b-dihydro-4H-[1,3] dioxole [4,5-d] indoles also [2 also, 1-a] acetone/MeO (3/1) solution (0.02M) of [2] benzo-aza suberene-7-methyl-formiate, at 1 atmospheric H 2The reaction mixture of following hydrogenation vigorous stirring.After 48 hours, cross filter solid, vacuum-evaporation filtrate gets purified title compound; MS (ES +) m/z 390.3 (M+H) +
Step 4:13-cyclohexyl-6-([2-(dimethylamino) ethyl] amino)-6, the 7-dihydro-the 5H-indoles also [2,1-a] [2] benzo-aza suberene-10-formic acid
Handle 13-cyclohexyl-6-hydroxyl-6 at 0 ℃ with DMP (1.3 equivalent), 7-dihydro-5H-indoles is the DCM solution (0.05M) of [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also, rises to room temperature, stirred 2 hours in nitrogen atmosphere then.Use the EtOAc diluting soln then, use saturated NaHCO 3, water and salt water washing, Na 2SO 4Drying, vacuum-evaporation get 13-cyclohexyl-6-oxo-6, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.Head product is dissolved in 1, among the 2-DCE (0.05M), adds 2-dimethylamino ethamine, regulate pH to 6, stirred solution 30 minutes with AcOH.Add NaBH (OAc) 3, stirring at room solution spends the night.After the EtOAc dilution, with NaOH (1N), water and salt water washing organic phase, Na 2SO 4Drying, vacuum-evaporation get 13-cyclohexyl-6-{[2-(dimethylamino) ethyl] amino }-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.Utilize the 1M KOH aqueous solution (6 equivalent) in dioxane (0.1M), aforementioned methyl esters to be hydrolyzed at 60 ℃; Described reaction was finished in 2 hours, and RP-HPLC purifying and lyophilize get title compound, and productive rate is 31% (condition: post: X-TERRA MS C18,10 microns, 19 * 150mm; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; 75%A isocratic elution 3 minutes, internal linear changed to 20%A in 12 minutes).
1H NMR(400MHz，DMSO，300K)δ1.16-1.59(4H，m)，1.61-2.12(6H，m)，2.74-2-98(8H，m)，3.12-3.43(7H，m)，4.69-4.73(1H，m)，7.49-7.58(4H，m)，7.67-7.73(1H，m)，7.90-7.93(1H，m)，8.24(1H，bs)；MS(ES +) m/z 446.4(M+H) +
Embodiment 6:13-cyclohexyl-6-{[2-(dimethylamino) ethyl] [(methyl) amino] }-6,7-dihydro-5H-indoles is the preparation of [2,1-a] [2] benzo-aza suberene-10-formic acid also
With 13-cyclohexyl-6-{[2-(dimethylamino) ethyl] amino }-6,7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-methyl-formiate (as embodiment 5, step 4 preparation) is dissolved among the DCM (0.07M), regulates pH to 6 with AcOH; The HCHO aqueous solution of adding 37% adds NaCNBH after half an hour 3(3 equivalent), the stirring at room mixture overnight.Use the EtOAc diluted reaction mixture, with 1N NaOH and salt water washing, drying, evaporate 13-cyclohexyl-6-{[2-(dimethylamino) ethyl] [(methyl) amino]-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.Utilize the 1M KOH aqueous solution (6 equivalent) in dioxane (0.1M), aforementioned methyl esters to be hydrolyzed at 60 ℃; Described reaction was finished in 2 hours, and RP-HPLC purifying and lyophilize get title compound, and productive rate is 20% (condition: post: X-TERRA MS C18,10 microns, 19 * 150mm; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; 75%A isocratic elution 3 minutes, internal linear changed to 20%A in 12 minutes).
1H NMR(400MHz，DMSO，300K)δ 1.16-1.59(4H，m)，1.61-2.12(6H，m)，2.74-2-98(11H，m)，3.18-3.30(1H，m)，3.50-3.69(4H，m)，3.91-3.99(1H，m)，4.21-4.30(1H，m)，4.89-5.01(1H，m)，7.39-7.58(4H，m)，7.64-7.71(1H，m)，7.92-7.99(1H，m)，8.23-8.32(1H，bs)；MS(ES +) m/z 460.5(M+H) +
Embodiment 7:12-cyclohexyl-4-(2-tetramethyleneimine-1-base oxethyl)-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] azepine also [1,2-a] indoles-9-formic acid and 12-cyclohexyl-5-(2-tetramethyleneimine-1-base oxethyl)-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] the also preparation of [1,2-a] indoles-9-formic acid of azepine
Step 1:3-cyclohexyl-2-(3-formyl-1-thienyl)-1H-indoles-6-methyl-formiate
With 2-bromo-3-cyclohexyl-1H-indoles-6-methyl-formiate (as disclosed International Patent Application WO 2004/087714 preparation), (3-formyl-2-thienyl) boric acid (1.2 equivalent), spray-dired KF (5 equivalent) and Pd (tBu 3P) 2(0.2 equivalent) is dissolved in (0.15M) in the dioxane; At N 2The stirring at room reaction mixture is 4 hours in the atmosphere, and then adds KF, boric acid and catalyzer, continues to stir and spends the night.All volatile matters of vacuum-evaporation, by flash chromatography (PE/EtOAc 8: 2) separate title compound.Productive rate is 99%; MS (ES +) m/z 368 (M+H) +
Step 2:3-cyclohexyl-2-(3-vinyl-2-thienyl)-1H-indoles-6-methyl-formiate
Drip Tebbe reagent (in toluene, 0.5M) at 0 ℃ of anhydrous THF solution to the 3-of 0.2M cyclohexyl-2-(3-formyl-2-thienyl)-1H-indoles-6-methyl-formiate; After 30 minutes, use Et 2O diluted mixture thing, and with the NaOH aqueous solution quencher of 0.1M.Add Na after 5 minutes 2SO 4And Celite TM, filtering mixt; Vacuum concentrated filtrate is with flash chromatography (PE/EtOAc 10: 1) purifying residue.Productive rate is 34%; MS (ES +) m/z 366 (M+H) +
Step 3:1-allyl group-3-cyclohexyl-2-(3-vinyl-2-thienyl)-1H-indoles-6-formic acid first Ester
Add 60% NaH (in mineral oil) (1.2 equivalent) to the anhydrous DMF solution of the 3-of 0.1M cyclohexyl-2-(3-vinyl-2-thienyl)-1H-indoles-6-methyl-formiate; When no longer including gas evolution, add allyl bromide 98 (1.4 equivalent), stirring at room suspension 30 minutes.Evaporate all volatile matters, with flash chromatography (PE/EtOAc 10: 1) separate title compound.Productive rate is 77%.
1H NMR(400MHz，CDCl 3，300K)δ1.28-1.90(m，10H)，2.60-2.69(m，1H)，3.97(s，3H)，4.52(d b，J16.6，1H)，4.63(d b，J 16.6，1H)，4.89(d，J 17.2，1H)，5.08(d，J 10.1，1H)，5.19(d，J 11.1，1H)，5.59(d，J17.4，1H)，5.76 5.84(m，1H)，6.35(dd，J 17.4，11.1，1H)，7.39-7.46(m，2H)，7.80(d，J 8.6，1H)，7.84(d，J8.6，1H)，8.08(s，1H)
Step 4:12-cyclohexyl-6H-thieno-[2 ', 3 ': 3,4] azepine [1,2-a] indoles-9-first also The acid methyl esters
1-allyl group-3-cyclohexyl-2-(3-vinyl-2-thienyl)-1H-indoles-6-methyl-formiate is dissolved in (0.03M) among the DCM, handled 2 hours with Zhan catalyst I (5mg/100mg substrate) at 35 ℃.After removing solvent, get title compound (90%) with flash chromatography (PE/EtOAc 12: 1) purifying residue; MS (ES +) m/z 378 (M+H) +
Step 5:12-cyclohexyl-4-(2-tetramethyleneimine-1-base oxethyl)-5,6-dihydro-4H-thieno- [2 ', 3 ': 3,4] azepine also [1,2-a] indoles-9-formic acid and 12-cyclohexyl-5-(2-tetramethyleneimine-1- Base oxethyl)-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] azepine [1,2-a] indoles-9-first also Acid
To the 12-of 0.1M cyclohexyl-6H-thieno-[2 ', 3 ': 3,4] azepine also the anhydrous THF solution of [1,2-a] indoles-9-methyl-formiate add BH 3Me 2S (1.6 equivalents, the THF solution of 2M), stirring at room mixture 3 hours; Add the NaOH aqueous solution (3 equivalent) of 3M and 35% H at 0 ℃ 2O 2(3.5 equivalent), room temperature continue to stir 2 hours.After the EtOAc dilution, use saturated NaHCO 3The aqueous solution and saline water extraction mixture.Na 2SO 4Dry organic phase, vacuum-evaporation gets 12-cyclohexyl-4-hydroxyl-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] azepine also [1,2-a] indoles-9-methyl-formiate and 12-cyclohexyl-5-hydroxyl-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] azepine 4: 1 mixtures of [1,2-a] indoles-9-methyl-formiate also.This crude mixture is dissolved in (0.07M) in the toluene, adds the NaOH aqueous solution (15 equivalent) of Tetrabutylammonium bromide (0.25 equivalent) and 40%, mixture is warming up to 70 ℃.After this temperature stirs half an hour, add hydrochloric acid 1-(2-chloroethyl) tetramethyleneimine (3 equivalent), continue heating 2 days at 70 ℃.Vacuum is steamed all volatile matters, with RP-HPLC separate product (overall yield is 27%).(condition: post: Waters X-TERRA MS C18,7 microns, 19 * 150mm; Gradient: A:H 2O+0.1%TFA; B:MeCN+0.1%TFA; Become 1%A by 99%A in 15 minutes).
12-cyclohexyl-4-(2-tetramethyleneimine-1-base oxethyl)-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] azepine [1,2-a] indoles-9-formic acid (mainly) also:
1H NMR(400MHz，DMSO，300K)δ1.35-1.43(m，3H)，1.59-1.85(m，9H)，1.97-2.05(m，2H)，2.25-2.32(m，1H)，2.60-2.68(m，1H)，2.79-2.90(m，2H)，3.17-3.26(m，4H)，3.30-3.36(m，1H)，3.51-3.64(m，2H)，4.09-4.22(m，2H)，4.75(t，J 6.14，1H)，7.31(d，J 5.26，1H)，7.60(dd，J8.55，1H)，7.77(d，J 5.26，1H)，7.85(d，J 8.55，1H)，8.14(s，1H)，9.44(s b，1H)；MS(ES +)m/z 479.4(M+H) +
12-cyclohexyl-5-(2-tetramethyleneimine-1-base oxethyl)-5,6-dihydro-4H-thieno-[2 ', 3 ': 3,4] azepine [1,2-a] indoles-9-formic acid (less important) also:
1H NMR(400MHz，DMSO，330K)δ 1.27-1.38(m，3H)，1.69-2.32(m，11H)，2.57-2.62(m，1H)，3.03-3.18(m，4H)，3.38-3.56(m，4H)，3.85-3.90(m，1H)，3.94-4.00(m，1H)，4.03-4.08(m，1H)，4.31-4.35(m，2H)，7.20(d，J 5.04，1H)，7.63(dd，J 8.55，1H)，7.70(d，J 5.05，1H)，7.86(d，J 8.55，1H)，8.16(s.1H)，9.53(s b，1H)；MS(ES +)m/z 479.4(M+H) +
Embodiment 8:14-cyclohexyl-5-[2-(dimethylamino) ethyl]-6-oxo-5,6,7, the 8-tetrahydro indole is [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid also
Step 1:3-[2-bromo-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl] propionic acid
DMF solution (0.2M) to 2-bromo-3-cyclohexyl-1H-indoles-6-methyl-formiate (being prepared by commercially available indoles-6-methyl-formiate as described in disclosed International Patent Application WO 2004/087714) adds 3.5 normal NaH (60%, in the mineral oil), stirring at room gained solution 1 hour.Add 1.1 normal 3-bromo-propionic acids then, stirring at room mixture 2 hours.Vacuum concentration DMF, residue dissolves with EtOAc.With 1N HCl washing organic phase, then use salt water washing, Na then 2SO 4Drying is filtered vacuum evaporating solvent.Next step uses the crude product of title compound; MS (ES +) m/z 408 (M+H) +, m/z 410 (M+H) +
Step 2:2-bromo-3-cyclohexyl-1-(3-methoxyl group-3-oxopropyl)-1H-indoles-6-methyl-formiate
To 3-[2-bromo-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl] toluene of propionic acid: MeOH (7: 3; 0.2M) mixture solution drips 1.6 equivalents (trimethyl silyl) diazomethane (hexane solution of 2M), stirring at room solution 1 hour.With excessive (trimethyl silyl) diazomethane of acetic acid quencher, vacuum concentrated solution then.Get title compound with flash chromatography (Biotagecartridge Si40S, 1: 9 EtOAc/PE) purifying crude product, productive rate (two steps) is 63%.MS(ES +)m/z 422(M+H) +，m/z 424(M+H) +
Step 3:2-{2-[(tertbutyloxycarbonyl) amino] phenyl }-3-cyclohexyl-1-(3-methoxyl group-3-oxo Propyl group)-1H-indoles-6-methyl-formiate
Dioxane solution (0.15M) to 2-bromo-3-cyclohexyl-1-(3-methoxyl group-3-oxopropyl)-1H-indoles-6-methyl-formiate adds Na 2CO 3(4 equivalents, the aqueous solution of 2M), [2-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl] t-butyl carbamate (1.5 equivalent) and dichloride two (triphenylphosphine) are closed palladium (II) (0.2 equivalent).Reflux mixture 45 minutes.Filter reaction mixture dilutes filtrate with EtOAc then.Use H 2O and salt water washing organic phase, Na 2SO 4Drying is filtered vacuum concentration.With flash chromatography (Biotagecartridge Si65i, 1: 9 EtOAc/PE) purifying crude product, get the white solid (60%) of title compound; MS (ES +) m/z 535 (M+H) +
Step 4:3-[2-{2-[(tertbutyloxycarbonyl) amino] phenyl }-3-cyclohexyl-6-(methoxycarbonyl)-1H- Indoles-1-yl] propionic acid
To the 2-{2-[(tertbutyloxycarbonyl) amino] phenyl }-THF of 3-cyclohexyl-1-(3-methoxyl group-3-oxopropyl)-1H-indoles-6-methyl-formiate: H 2O (4: 1; 0.1M) mixture solution adds 1.1 normal lithium hydroxide monohydrates.Stirring at room mixture 1.5 hours.With 1 N HCl quencher reaction, vacuum evaporating solvent.With minimum Et 2O wash residual thing, filter gained precipitate the white solid (81%) of title compound; MS (ES +) m/z 521 (M+H) +
Step 5:3-[2-(2-aminophenyl)-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl] propionic acid
To uncle 3-[2-{2-[(-butoxy carbonyl) amino] phenyl }-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl] the DCM solution (0.05M) of propionic acid adds the TFA of excessive greatly (＞100 equivalent), stirring at room solution 1 hour.Vacuum is removed volatile matter and is got title compound (quantitatively); MS (ES +) m/z 421 (M+H) +
Step 6:14-cyclohexyl-6-hydrogen is for-5,6,7, and the 8-tetrahydro indole is [1,2-e] [1,5] benzodiazepine also Cyclooctene-11-methyl-formiate
To 3-[2-(2-aminophenyl)-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl] the DCM solution (0.01M) of propionic acid adds 3.5 equivalent DIPEA and 1.2 equivalent HATU, stirring at room mixture 15 minutes.Vacuum is removed DCM, and the residue acetone solution adds 1 N HCl until pH=2.Filtration gained precipitation, the dry product that gets, productive rate is 75%; MS (ES +) m/z403 (M+H) +
Step 7:14-cyclohexyl-5-[2-(dimethylamino) ethyl]-6-oxo-5,6,7, the 8-tetrahydro indole And [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate
To 14-cyclohexyl-6-oxo-5,6,7, the 8-tetrahydro indole also DMF solution (0.1M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate adds NaH (1.4 equivalents, 60%, be dispersed in the mineral oil), stirring at room solution 1 hour.Simultaneously, the DMF solution (0.5M) of 1: 1 molar mixture such as grade of preparation hydrochloric acid (2-chloroethyl) dimethylamine and NaH (60%, be dispersed in the mineral oil).After 30 minutes, slowly add this mixture (2.5 normal (2-chloroethyl) dimethylamine), stirring at room mixture overnight to the indoles anion solutions.Vacuum is removed DMF, and residue dissolves with EtOAc.Use H 2O (twice) washs organic phase, uses the salt water washing then, then Na 2SO 4Drying is filtered vacuum evaporating solvent.Crude compound need not to be further purified and is used for next step; MS (ES +) m/z 474 (M+H) +
Step 8:14-cyclohexyl-5-[2-(dimethylamino) ethyl]-6-oxo-5,6,7, the 8-tetrahydro indole And [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid
To 14-cyclohexyl-5-[2-(dimethylamino) ethyl]-6-oxo-5,6,7, the 8-tetrahydro indole also solution (0.1M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate DCM adds 7 equivalent BBr 3(the DCM solution of 1M).Stirring at room solution 20 minutes.The vacuum-evaporation volatile matter.Then with preparation RP-HPLC (stationary phase: post Waters XTERRA prep C 18,5 μ m, 19 * 150mm.Moving phase: TFA buffered MeCN/H with 0.1% 2O) purifying crude product.Merge the component that comprises pure compound, lyophilize gets title compound (two step productive rates are 40%).
1H NMR(400MHz， DMSO-d 6，300K)δ1.10-1.35(m， 3H)，1.50-1.60(m，1H)，1.60-1.75(m，2H)，1.80-2.00(m，4H)，2.40-2.45(m，1H partially obscured by DMSO peak)，2.70(s，6H)，2.72-2.80(m， 2H)，2.90-3.15(m，2H)，3.20-3.40(m，1H obscured by H 2O peak)，3.61-3.75(m，1H)，3.80-3.90(m，1H)，4.75-4.85(m，1H)，7.53-7.58(m，1H)，7.60-7.68(m，3H)，7.69-7.75(m，1H)，7.86(d，J 8.4，1H)，8.14(s，1H)，9.27(br s，1H)；MS(ES +)m/z460(M+H) +
Embodiment 9:14-cyclohexyl-5-[2-(dimethylamino) ethyl]-5,6,7, the 8-tetrahydro indole is [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid also
To 14-cyclohexyl-5-[2-(dimethylamino) ethyl]-6-oxo-5,6,7, the 8-tetrahydro indole also THF solution (0.1M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate (as embodiment 8, step 7 preparation) adds BH 3Me 2S (20 equivalents, the THF solution of 2 M).Stirring at room solution spends the night.Carefully add MeOH to mixture and react, then add the NaOH (＞10 equivalent) of excessive 1 N with quencher.60 ℃ of heated mixt 12 hours.Vacuum evaporating solvent.Then with preparation RP-HPLC (stationary phase: post Waters XTERRA prepC18,5 μ m, 19 * 100mm.Moving phase: TFA buffered MeCN/H with 0.1% 2O) purifying crude product.Merge the component that comprises pure compound, lyophilize obtains title compound (three step productive rates are 24%).
1HNMR(300MHz，DMSO-d 6+TFA，300K)δ1.15-1.40(m，3H)，1.50-1.58(m，1H)，1.60-1.75(m，3H)，1.80-2.00(m，5H)，2.55-2.65(m，1H)，2.74(s，3H)，2.78(s，3H)，2.90-3.10(m，2H)，3.10-3.30(m，4H)，3.55-3.65(m，1H)，4.50-4.65(m，1H)，6.95-7.01(m，1H)，7.10-7.20(m，2H)，7.35-7.45(m，1H)，7.64(d，J 8.2，1H)，7.84(d，J 8.2，1H)，8.09(s，1H)；MS(ES +)m/z 446(M+H) +
Embodiment 10:14-cyclohexyl-5-methyl-5,6,7,8-tetrahydro indole be [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid also
Step 1:14-cyclohexyl-5,6,7,8-tetrahydro indole also [1,2-e] [1,5] benzodiazepine cyclooctene- The 11-methyl-formiate
To 14-cyclohexyl-6-oxo-5,6,7, the 8-tetrahydro indole also THF solution (0.15M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate (as embodiment 8, step 6 preparation) adds 20 equivalent BH 3Me 2S (the THF solution of 2M), stirring at room mixture 6 hours.Add the careful quencher solution of MeOH until no longer bubbling.Vacuum-evaporation volatile matter then.Thick residue is directly used in next step; MS (ES +) m/z 389 (M+H) +
Step 2:14-cyclohexyl-5-methyl-5,6,7,8-tetrahydro indole be [1,2-e] [1,5] benzodiazepine also Cyclooctene-11-methyl-formiate
To 14-cyclohexyl-5,6,7, the 8-tetrahydro indole also DCE solution (0.05M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate adds the 1 equivalent formaldehyde (H of 37% weight 2O solution) and 2 equivalent NaBH (OAc) 3, stirring at room solution 1 hour.Use the EtOAc diluted reaction mixture.Use NaHCO 3(saturated solution) and salt water washing organic phase.Na 2SO 4Dry organic phase is filtered and vacuum concentration.Title compound is directly used in next step; MS (ES +) m/z403 (M+H) +
Step 3:14-cyclohexyl-5-methyl-5,6,7,8-tetrahydro indole be [1,2-e] [1,5] benzodiazepine also Cyclooctene-11-formic acid
To 14-cyclohexyl-5-methyl-5,6,7, the 8-tetrahydro indole also DCM solution (0.1M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate adds 5 equivalent BBr 3(the DCM solution of 1M).Stirring at room solution 20 minutes.Vacuum evaporating solvent.Then with preparing RP-HPLC (stationary phase: post Waters XTERRA prep C18,5um, 19 * 100mm automatically.Moving phase: TFA buffered MeCN/H with 0.1% 2O) purifying crude product.Merge the component that comprises pure compound, lyophilize gets title compound (two step productive rates are 60%).
1HNMR(400MHz，DMSO-d 6+TFA，300K)δ1.10-1.60(m，5H)，1.60-1.80(m，2H)，1.80-2.10(m，5H)，2.65-2.75(m，2H)，2.85-2.95(m，1H)，2.98(s，3H)，3.55-3.68(m，1H)，4.55-4.65(m，1H)，6.65-6.75(m，1H)，6.84(d，J 8.4，1H)，7.03(d，J 7.6，1H)，7.27-7.32(m，1H)，7.63(d，J 8.4，1H)，7.81(d，J 8.4，1H)，8.08(s，1H)，MS(ES +) m/z 389(M+H) +
Embodiment 11:14-cyclohexyl-7-(dimethylamino)-5-methyl-5,6,7,8-tetrahydro indole be [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid also
Step 1:2-[two (tertbutyloxycarbonyl) amino] methyl acrylate
MeCN solution (0.9M) to N-(tertbutyloxycarbonyl) serine methylester adds 2.5 equivalent tert-Butyl dicarbonates and 0.1 equivalent DMAP.Stirring at room solution 48 hours is then used saturated NaHCO 3Aqueous solution quencher is extracted (twice) with EtOAc.Use saturated aqueous solution NH 4The organic layer that Cl and salt water washing merge, then Na 2SO 4Drying is filtered, and concentrated vacuum gets the butteriness solid (quantitatively) of title compound; MS (ES +) m/z 324 (M+Na) +
Step 2:1-{2-[two (tertbutyloxycarbonyl) amino]-3-methoxyl group-3-oxopropyl }-2-bromo-3-ring Hexyl-1H-indoles-6-methyl-formiate
MeCN solution (0.08M) to 2-bromo-3-cyclohexyl-1H-indoles-6-methyl-formiate (being prepared by commercially available indoles-6-methyl-formiate as described in WO 2004087714) adds 6 equivalent K 2CO 3With 1.2 normal 2-[two (tertbutyloxycarbonyl) amino] methyl acrylate.Stirring at room mixture 16 hours then filters, and vacuum concentration gets the thickness oily matter of title compound, leaves standstill curing (quantitatively); MS (ES +) m/z 659 (M+Na) +, 661 (M+Na) +
Step 3:2-bromo-uncle 1-{2-[(Ding Qing carbonyl) amino]-3-methoxyl group-3-hydrogen is for propyl group)-the 3-hexamethylene Base-1H-indoles-6-methyl-formiate
To 1-{2-[two (tertbutyloxycarbonyl) amino]-3-methoxyl group-3-oxopropyl }-CH of 2-bromo-3-cyclohexyl-1H-indoles-6-methyl-formiate 2Cl 2Solution (0.15M) adds 2 equivalent TFA.Stirring at room solution 10 minutes, then vacuum concentration.The RP-HPLC analytical results of reaction mixture shows that Boc amine goes to protect about 50%.Residue is dissolved in CH once more 2Cl 2In, add 2 equivalent TFA again.After the stirring at room 10 minutes, vacuum is removed volatile matter once more.Current RP-HPLC result show realize amine fully singly go the protection (quantitatively); MS (ES +) m/z559 (M+Na) +, 561 (M+Na) +
Step 4:3-[2-(2-aminophenyl)-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl]-N-(uncle Butoxy carbonyl) L-Ala
To 2-bromo-1-{2-[(tertbutyloxycarbonyl) amino]-3-methoxyl group-3-oxopropyl }-BuOH of 3-cyclohexyl-1H-indoles-6-methyl-formiate: H 2(9: 1,0.08M) solution added 1.5 equivalent 2-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) aniline, 6 equivalent K to O 3PO 4, 5% mole dicyclohexyl (2 ', 6 '-dimethoxy-biphenyl-2-yl) acid chloride of phosphine and 2.5% mole.90 ℃ of heated mixt 4 hours.After being cooled to room temperature,, extract (twice) with EtOAc with HCl (1N) acidifying mixture.With the organic layer that the salt water washing merges, Na 2SO 4Drying is then filtered vacuum concentration.The mixture of crude product is dissolved in THF: H once more 2O (1: 1,0.08M) in, add 2 equivalent LiOH.Stir after 1 hour, go ester protection (shown in RP-HPLC analyzes) fully.Vacuum is removed volatile matter, makes residue at EtOAc and H 2Distribute between the O.With salt water washing organic layer, Na 2SO 4Drying is then filtered vacuum concentration.Thick residue is directly used in next step; MS (ES +) m/z 536 (M+H) +, 558 (M+Na) +
Step 5:7-[(tertbutyloxycarbonyl) amino]-14-cyclohexyl-6-oxo-5,6,7, the 8-tetrahydro indole is also [1,2-e] [1,5]-benzodiazepine cyclooctene-11-methyl-formiate
To 3-[2-(2-aminophenyl)-3-cyclohexyl-6-(methoxycarbonyl)-1H-indoles-1-yl]-CH of N-(tertbutyloxycarbonyl) L-Ala 2Cl 2Solution (0.02M) adds 3 equivalent iPr 2NEt and 1.2 equivalent HATU, stirring at room mixture 16 hours.Use saturated NaHCO 3Aqueous solution quencher reaction is extracted (twice) with EtOAc.With the organic layer that HCl (1N) and salt water washing merge, follow Na 2SO 4Drying is filtered, and concentrates vacuum.With flash chromatography (5-20%EtOAc/1%Et 3N/PE) the purifying crude product gets the oily matter of title compound, and productive rate was 12% (3 step); MS (ES +) m/z 518 (M+H) +, 540 (M+Na) +
Step 6:7-[(tertbutyloxycarbonyl) amino]-14-cyclohexyl-5,6,7, the 8-tetrahydro indole also [1,2- E] [1,5]-benzodiazepine cyclooctene-11-methyl-formiate
To the 7-[(tertbutyloxycarbonyl) amino]-14-cyclohexyl-6-oxo-5,6,7, the 8-tetrahydro indole also THF solution (0.02M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate adds 10 equivalent BH 3THF (the THF solution of 2M), stirring at room mixture 4 hours.All volatile matters are removed in decompression, and thick residue is directly used in next step; MS (ES +) m/z 504 (M+H) +, 526 (M+Na) +
Step 7:7-amino-14-cyclohexyl-5,6,7,8-tetrahydro indole is [1,2-e] [1,5] benzodiazepine also Cyclooctene-11-methyl-formiate
To the 7-[(tertbutyloxycarbonyl) amino]-14-cyclohexyl-5,6,7, the 8-tetrahydro indole is the CH of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate also 2Cl 2Solution (0.02M) adds 100 equivalent TFA.Stirring at room solution 45 minutes, then vacuum concentration gets the thickness oily matter (quantitatively) of product; MS (ES +) m/z 404 (M+H) +
Step 8:14-cyclohexyl-7-(dimethylamino)-5-methyl-5,6,7,8-tetrahydro indole also [1,2- E] [1,5] benzodiazepine cyclooctene-11-methyl-formiate
To 7-amino-14-cyclohexyl-5,6,7, the 8-tetrahydro indole is the CH of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate also 2Cl 2Solution (0.02M) adds 5 equivalent formaldehyde (37% H 2O solution), regulate pH to pH 4 with triethylamine.Stirring at room solution 30 minutes then adds 3 equivalent NaBH 3CN, stirring at room mixture 16 hours.Use saturated NaHCO 3Aqueous solution quencher reaction is extracted (twice) with EtOAc.With the organic layer that the salt water washing merges, follow Na 2SO 4Drying is filtered, and vacuum concentration gets the thickness oily matter (quantitatively) of title compound; MS (ES +) m/z 446 (M+H) +
Step 9:14-cyclohexyl-7-(dimethylamino)-5-methyl-5,6,7,8-tetrahydro indole also [1,2- E] [1,5] benzodiazepine cyclooctene-11-formic acid
To 14-cyclohexyl-7-(dimethylamino)-5-methyl-5,6,7, the 8-tetrahydro indole also MeOH solution (0.05M) of [1,2-e] [1,5] benzodiazepine cyclooctene-11-methyl-formiate added the NaOH of 40 equivalents, 2 N, 65 ℃ of stirring reactions 3 hours.With the HCl acidification reaction to pH 2, vacuum evaporating solvent.Then with preparation RP-HPLC (stationary phase: post Waters XTERRAprep C18,5 μ m, 19 * 150mm.Moving phase: TFA buffered acetonitrile/H with 0.1% 2O) purifying crude product.Merge the component that comprises pure compound, lyophilize gets the brown powder of title compound, and productive rate was 8% (four step).
1H NMR(400MHz，DMSO-d 6+TFA，300K)δ1.15-1.34(m，3H)，1.54-1.94(m，7H)，2.62-2.68(m，1H)，2.86(s，3H)，2.96(s，6H)，3.13-3.17(m，1H)，3.36-3.41(m，1H)，3.59-3.62(m，1H)，3.88-3.94(m，1H)，4.93-4.98(m，1H)，7.00-7.03(m，1H)，7.13-7.15(m，2H)，7.42-7.46(m，1H)，7.72(d，J 8.3，1H)，7.86(d，J 8.3，1H)，8.29(s，1H)；MS(ES +)m/z 432(M+H) +
Following table comprises more example:
Table 1
Embodiment number Title m/z(ES +)
101 13-cyclohexyl-5-[2-(dimethylamino) oxyethyl group]-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also 447
102 13-cyclohexyl-5-[2-(diethylamino) oxyethyl group]-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also 475
103 13-cyclohexyl-6-[2-(diethylamino) oxyethyl group]-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also 475
104 13-cyclohexyl-3-methoxyl group-6-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also 503
105 13-cyclohexyl-3-methoxyl group-5-(2-tetramethyleneimine-1-base oxethyl)-6,7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also 503

Claims (19)

1. the compound of a formula (I) and the acceptable salt of medicine thereof:
Wherein
A is C 3-8Cycloalkyl, optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Ar is the part that comprises at least one aromatic ring, have 5,6,9 or 10 annular atomses, choose wantonly and comprise 1,2 or 3 heteroatoms that independently is selected from N, O and S, for example phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrazolyl and imidazolyl, described ring is optional by group Q 1And Q 2Replace;
Q 1Be halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, (CH 2) 0-3Aryl, heteroaryl, CONR cR d, (CH 2) 0-3NR cR d, O (CH 2) 0-3C 3-8Cycloalkyl, O (CH 2) 1-3NR cR d, O (CH 2) 0-3CONR cR d, O (CH 2) 0-3CO 2H, O (CH 2) 0-3Aryl, O (CH 2) 0-3Heteroaryl, OCHR eR fOr O (CH 2) 0-3S (O) 2(CH 2) 0-3NR cR d
R cAnd R dIndependently be selected from hydrogen, C 1-6Alkyl and C (O) C 1-6Alkyl;
Perhaps R cAnd R dConnected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, optional comprise 1 or 2 other heteroatoms that independently is selected from O and S and/or 1 or 2 and independently is selected from NH and NC 1-4The group of alkyl, wherein said ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R eAnd R fIndependently be selected from hydrogen, C 1-4Alkyl and C 1-4Alkoxyl group;
Perhaps R eAnd R fBe connected to form the heterolipid ring of 4-7 annular atoms by the heteroatoms that is selected from N, O and S, wherein said ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Wherein said C 1-4Alkyl, C 1-4Alkoxyl group and aryl are optional to be replaced by halogen or hydroxyl;
Q 2Be halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group, wherein said C 1-4Alkyl and C 1-4Alkoxyl group is optional to be replaced by halogen or hydroxyl;
Perhaps Q 1And Q 2Can be connected to form the ring of 4-7 atom, wherein said ring is optional to comprise 1 or 2 heteroatoms that independently is selected from N, O and S, and optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R 1And R 2In one be CO 2H, C (O) NHS (O) 2NR aR b, C (O) NHS (O) 2C 1-6Alkyl, C (O) NHS (O) 2(CH 2) 0-3CO 2R cOr C (O) NHS (O) 2(CH 2) 0-3Aryl,
R 1And R 2In another be hydrogen;
R aAnd R bIndependently be selected from hydrogen and C 1-6Alkyl,
Perhaps R aAnd R bConnected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms that independently is selected from O and S and/or 1 or 2 and independently be selected from S (O), S (O) 2, NH and NC 1-4The group of alkyl;
Y be C=O or-CR 14aR 15a-;
Z is chemical bond or NR 10
R 10Be hydrogen, hydroxyl, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C (O) C 1-6Alkyl, Het, (CH 2) 0-3NR 16R 17, C (O) (CH 2) 0-3NR 16R 17And NHC (O) (CH 2) 0-3NR 16R 17
R 14, R 14a, R 15And R 15aIndependently be selected from hydrogen, hydroxyl, C separately 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, (CH 2) 0-3C 3-8Cycloalkyl, C 1-6Alkoxyl group, C (O) C 1-6Alkyl, (CH 2) 0-3Aryl, (CH 2) 0-3Het, C (O) (CH 2) 0-3Het, (CH 2) 0-3NR 16R 17, (CH 2) 0-3OR 16, (CH 2) 0-3C (O) (CH 2) 0-3NR 16R 17, NR 18C (O) (CH 2) 0-3NR 16R 17, S (O) 0-2(CH 2) 0-3NR 16R 17, (CH 2) 0-3Heteroaryl or C (O) (CH 2) 0-3Heteroaryl is chosen wantonly and independently is selected from C by one or two 1-6Alkyl, hydroxyl, halogen, C 1-6Alkoxyl group, SH and S (C 1-6Alkyl) group replaces;
R 16And R 17Independently be selected from hydrogen, C 1-6Alkyl, (CH 2) 0-4NR 18R 19, (CH 2) 0-3Het, (CH 2) 0-3Heteroaryl, (CH 2) 0-3C (O) (CH 2) 0-3NR 18R 19Or (CH 2) 0-3C 3-8Cycloalkyl, optional by C 1-6Alkyl, (CH 2) 0-3OH or (CH 2) 0-3C 1-6Alkoxyl group replaces;
Perhaps R 16And R 17Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms that is selected from O and S and/or 1 or 2 and independently be selected from S (O), S (O) 2, NH, NC 1-4Alkyl and N (CH 2) 0-3C 1-4The group of alkoxyl group, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R 18And R 19Independently be selected from hydrogen, C 1-6Alkyl and heteroaryl;
Perhaps R 18And R 19Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms that is selected from O and S and/or 1 or 2 and be selected from S (O), S (O) 2, NH and NC 1-4The group of alkyl, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Condition is that the compound of formula (I) is not a 13-cyclohexyl-6, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate or 13-cyclohexyl-6 also, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-formic acid also.
2. the acceptable salt of the compound of claim 1 and medicine thereof, its structure is suc as formula shown in (Ia):
Figure A2005800442070004C1
Wherein
Ar comprises 1,2 or 3 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for choosing wantonly;
Y be C=O or-CR 14aR 15a
Z is chemical bond or NR 10
R 10, R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen, hydroxyl, C separately 1-6Alkyl, C 2-6Thiazolinyl, C 1-6Alkoxyl group, C (O) C 1-6Alkyl, Het, (CH 2) 0-3NR 16R 17, C (O) (CH 2) 0-3NR 16R 17And NHC (O) (CH 2) 0-3NR 16R 17
R 16And R 17Independently be selected from hydrogen, C 1-6Alkyl and (CH 2) 0-4NR 18R 19
Perhaps R 16And R 17Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms or S (O), S (O) that is selected from O and S 2, NH or NC 1-4Alkyl group, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
R 18And R 19Independently be selected from hydrogen and C 1-6Alkyl;
Perhaps R 18, R 19Connected nitrogen-atoms forms the heterolipid ring of 4-7 annular atoms together, and described ring can be chosen wantonly and comprise 1 or 2 other heteroatoms or S (O), S (O) that is selected from O and S 2, NH or NC 1-4Alkyl group, described ring is optional by halogen, hydroxyl, C 1-4Alkyl or C 1-4Alkoxyl group replaces;
Condition is that the compound of formula (Ia) is not a 13-cyclohexyl-6, and 7-dihydro-5H-indoles is [2,1-a] [2] benzo-aza suberene-10-methyl-formiate also.
3. the acceptable salt of the compound of claim 1 and medicine thereof, its structure is suc as formula shown in (Ib):
Wherein
R 10Be hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or (CH 2) 1-3NR 16R 17
R 16And R 17Independently be selected from hydrogen and C 1-6Alkyl;
R 14aAnd R 15aIndependently be selected from hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or C 3-8Cycloalkyl;
Perhaps R 14aAnd R 15aForm the oxo base together;
Condition is that the compound of formula (Ib) is not 3-chloro-14-cyclohexyl-5-(2-piperidines-1-base ethyl)-5,6,7, and the 8-tetrahydro indole is [1,2-e] [1,5] benzodiazepine cyclooctene-11-formic acid also.
4. the compound of claim 3, wherein R 10Be hydrogen, C 1-6Alkyl or (CH 2) 1-3NR 16R 17, R wherein 16And R 17Such as claim 3 definition.
5. the compound of claim 3 or claim 4, wherein R 14aAnd R 15aIndependently be selected from hydrogen or R 14aAnd R 15aForm the oxo base together.
6. the acceptable salt of the compound of claim 1 and medicine thereof, its structure is suc as formula shown in (Ic):
Figure A2005800442070006C1
Wherein
R 10Be hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl;
R 14And R 15Independently be selected from hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or (CH 2) 0-3NR 16R 17
R 16And R 17Independently be selected from hydrogen and C 1-6Alkyl.
7. the compound of claim 6, wherein R 10Be hydrogen or C 1-6Alkyl.
8. the compound of claim 6 or claim 7, wherein R 14And R 15Independently be selected from hydrogen, C 1-6Alkyl or (CH 2) 0-3NR 16R 17, R wherein 16And R 17Independently be selected from hydrogen and C 1-4Alkyl.
9. the acceptable salt of the compound of claim 1 and medicine thereof, its structure is suc as formula shown in (Id):
Figure A2005800442070007C1
Wherein
Ar comprises 1,2 or 3 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for choosing wantonly, and described ring is optional by group Q 1Replace;
R 14, R 15, R 14a, R 15dAnd Q 1Define suc as formula (I), condition is that the compound of formula (Id) is not a 13-cyclohexyl-6,7-dihydro-5H-indoles also [2,1-a] [2] benzo-aza suberene-10-methyl-formiate or 13-cyclohexyl-6,7-dihydro-5H-pyrrolo-[2 ', 1 ': 3,4] [1,4] diazacyclo heptene [1,2-a] indoles-10-formic acid also.
10. the compound of claim 9, wherein Ar comprises 1 or 2 heteroatomic five yuan or hexa-atomic aromatic ring that independently is selected from N, O and S for optional, and described ring is optional by halogen, hydroxyl, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
11. the compound of claim 9 or claim 10, wherein R 14, R 15, R 14aAnd R 15aIndependently be selected from hydrogen, C 1-6Alkyl, (CH 2) 0-3OR 16(CH 2) 0-3NR 16R 17, R wherein 16And R 17Such as claim 9 definition.
12. the acceptable salt of the compound of claim 1 and medicine thereof, described compound is selected from the compound of naming among embodiment and the Biao.
13. each compound or the acceptable salt of its medicine among the claim 1-12, described compound is used for the treatment of.
14. each compound or the acceptable salt of its medicine among the claim 1-12, described compound are used for preparing the medicine of treatment or prevention human or animal infection with hepatitis C virus.
15. a pharmaceutical composition, described composition comprise among the claim 1-12 each compound or the acceptable salt of its medicine, it combines with the medicine acceptable carrier.
16. the pharmaceutical composition of claim 15, described composition also comprise one or more other materials that is used for the treatment of virus infection, for example antiviral agent or immunomodulator, for example α-, β-or gamma-interferon.
17. a method that suppresses the disease that hepatitis C virus polysaccharase and/or treatment or prevention cause by hepatitis C virus, described method comprise among the pharmaceutical composition of the claim 15 of the human or animal's object treatment of suffering from described illness or prevention significant quantity or claim 16 or the claim 1-12 each compound or the acceptable salt of its medicine.
18. the method for a pharmaceutical compositions, described method comprise with among at least a claim 1-12 each compound or the acceptable salt of its medicine and one or more medicine acceptable auxiliary, diluent or carrier and/or one or more other have treatment or a prophylactic activity material mix.
19. a method for preparing each compound among the claim 1-12, described method comprises:
(a) the intramolecularly closed loop of formula (II) compound:
Figure A2005800442070008C1
R wherein 1, R 2, A and Ar such as claim 1 definition, in the cyclization process or behind the cyclization, X ' is converted to-CR 14R 15-, W ' is-CH 2-or in the cyclization process or behind the cyclization, be converted to-CH 2-, Y ' is converted to Y in the cyclization process or behind the cyclization, and Z ' is for Z or be converted to Z in the cyclization process or behind the cyclization; Or
(b) the intramolecularly closed loop of formula (III) compound:
Figure A2005800442070008C2
R wherein 1, R 2, A, Ar, Y and Z such as claim 1 definition, X ' is-CR 14R 15-or in the cyclization process or behind the cyclization, be converted to-CR 14R 15-, W ' is converted to W ' in the cyclization process or behind the cyclization-CH 2-.
CN 200580044207 2004-10-26 2005-10-25 Tetracyclic indole derivatives as antiviral agents Pending CN101087761A (en)

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Publication number Priority date Publication date Assignee Title
CN101981038A (en) * 2008-03-27 2011-02-23 百时美施贵宝公司 Dioxolane and dioxolanone fused indolobenzadiazepine HCV NS5B inhibitors
CN113365985A (en) * 2019-02-02 2021-09-07 博诺康源(北京)药业科技有限公司 Compound with benzo seven-membered ring structure, preparation method and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101981038A (en) * 2008-03-27 2011-02-23 百时美施贵宝公司 Dioxolane and dioxolanone fused indolobenzadiazepine HCV NS5B inhibitors
CN101981038B (en) * 2008-03-27 2013-07-10 百时美施贵宝公司 Dioxolane and dioxolanone fused indolobenzadiazepine HCV NS5B inhibitors
CN113365985A (en) * 2019-02-02 2021-09-07 博诺康源(北京)药业科技有限公司 Compound with benzo seven-membered ring structure, preparation method and application thereof
CN113365985B (en) * 2019-02-02 2022-08-12 博诺康源(北京)药业科技有限公司 Compound with benzo-seven-membered ring structure, preparation method and application thereof

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