CN104693211A - Imidazole derivative as antiviral agent and pharmaceutical application thereof - Google Patents

Imidazole derivative as antiviral agent and pharmaceutical application thereof Download PDF

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Publication number
CN104693211A
CN104693211A CN201310661317.5A CN201310661317A CN104693211A CN 104693211 A CN104693211 A CN 104693211A CN 201310661317 A CN201310661317 A CN 201310661317A CN 104693211 A CN104693211 A CN 104693211A
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China
Prior art keywords
base
methyl
imidazoles
benzo
indoline
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CN201310661317.5A
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Chinese (zh)
Inventor
贺海鹰
石卫华
江志赶
韩丽霞
孙继奎
黎健
陈曙辉
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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Priority to CN201310661317.5A priority Critical patent/CN104693211A/en
Priority to ES14870381T priority patent/ES2757570T3/en
Priority to PCT/CN2014/090771 priority patent/WO2015085844A1/en
Priority to CN201480061605.XA priority patent/CN105793265B/en
Priority to PT148703812T priority patent/PT3081569T/en
Priority to US15/103,189 priority patent/US9850251B2/en
Priority to EP14870381.2A priority patent/EP3081569B1/en
Priority to JP2016539200A priority patent/JP6118470B2/en
Priority to TW103142944A priority patent/TWI730936B/en
Publication of CN104693211A publication Critical patent/CN104693211A/en
Priority to HK16110640.5A priority patent/HK1223607A1/en
Priority to US15/708,906 priority patent/US10030029B2/en
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Abstract

The invention discloses an antiviral compound and a composition thereof, relates to application of the antiviral compound and the composition in preparing a medicine for treating virus infection, and in particular to an imidazole derivative for treating respiratory syncytial virus infection.

Description

As imdazole derivatives and the pharmaceutical applications thereof of antiviral agent
Technical field
The present invention relates to a kind of antiviral compound and composition thereof, and relate to its preparation treatment virus infective medicament in application.Particularly, the present invention relates to the imdazole derivatives for the treatment of respiratory syncytial virus infection.
Background technology
Respiratory syncytial virus (RSV) is the major cause causing lower respiratory infection that baby, children, old man and immunizing power sufferer are serious.Serious virus infection can cause to be needed hospital care or causes dead bronchiolitis or pneumonia (JAMA, 1997,277,12).Current approved ribavirin is used for the treatment of this virus infection, and ribavirin is with the nucleoside analog of aerosol form intranasal administration, and this drug toxicity is quite large, and its effect is still disputable.Except ribavirin, RespiGam and Synagis be respectively in and the immunoglobulin (Ig) of RSV and monoclonal antibody.They are preventative two biotechnological formulations for the treatment of rsv infection high risk child of existing approved.RespiGam and Synagis is very expensive and need parenteral administration.
Known a lot of medicine can be used for suppressing respiratory syncytial virus (De Clercq, Int.J.Antiviral Agent, 1996,7,193).The people such as Y.Tao (EP0058146A1,1998) disclose known antihistaminic agent cetirizine and show anti-RSV activity.The J.Med.Chem.1983 of the people such as Tidwell, 26,294 (US4,324,794,1982), the Antimicrobial Agents and Chemotherapy of the people such as Dubovi, 1981,19, all report a series of amidino compounds as RSV inhibitor in 649.The people such as Hsu at US5,256, also disclose a series of 6-aminopyrimidinone with anti-RSV antiviral activity in 668 (1993).In addition, disclose in the people (Antiviral Res.1998,38,31) such as the people such as Y.Gluzman (AU patent, Au-A-14,704,1997) and P.R.Wyde a series of be used for the treatment of and/or prevent rsv infection containing triaizine compounds.The people such as S.Shigeta are at Antiviral Chem. & amp; Chemother.1992,3, [1, the 2-a] benzopyrrole of pyrido disclosed in 171 and Kui Linpyrimido quinoline [1,2a] benzoglyoxaline.Prove that these compounds suppress orthomyxovirus and Paramyxo virus to copy in HeLa cell.It is reported, have ethylene glycol connect base two-benzoglyoxaline is also effective rhinovirus inhibitor people such as (, J.Med.Chem.1972,15,655) Roderick.Other structurally relevant compounds be have anti-mycotic activity two-benzoglyoxaline (B.Cakir etc., Eczacilik Fak Derg.1988,5,71).In the recent period, the people such as Yu has found the benzoglyoxaline (WO 00/04900) of a series for the treatment of and prevention rsv infection.In addition, Theodore Nitz have also discovered a series of formula III compound (WO 99/38508) suppressing RSV in Hep-2 cell tissue culture measures.
At present, BMS discloses BMS433771, and its general structure is such as formula shown in (B-I):
（B-Ⅰ）
The WO2013068769A1 of Viral discloses a compounds, and its general structure is such as formula shown in (B-II):
（B-Ⅱ）
The WO2010103306A1 of AstraZeneca discloses a compounds, and its general structure is such as formula shown in (B-III):
（B-Ⅲ）
Can be used for suppressing respiratory syncytial virus although there is above-claimed cpd in prior art, they have much room for improvement in active and deliquescent etc.
Summary of the invention
The object of the present invention is to provide compound or its pharmacy acceptable salt shown in formula I, (II), (III) or (IV),
（Ⅰ）
（Ⅱ）
（Ⅲ）
（Ⅳ）
Wherein,
A, E, A ', E ', A ' ', E ' ', A ' ' ', the E ' ' ' CH that separately represents N or be optionally substituted;
Y, Y ', Y ' ', Y ' ' ' separately represent (the CH be optionally substituted 2) p, p is the integer of 0-3, Y, Y when p is 0 ', Y ' ', Y ' ' ' representative only plays the singly-bound of ligation;
Represented by dotted arrows singly-bound, double bond or not Cheng Jian, when , , , , , , or when middle dotted line all can not represent key, this structural unit does not exist;
D, D ', D ' ', D ' ' ' separately represent C or N, as D, D ', D ' ' or D ' ' ' be during C its connect represented by dotted arrows singly-bound, as D, D ', D ' ' or D ' ' ' is the represented by dotted arrows not Cheng Jian that during N, it connects;
M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' [OH, SH, NH of separately representing H, halogen, CN or being optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
R 1, R 1', R 1' ' [OH, SH, NH of being separately selected from H, halogen, CN or being optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
R 1' ' ' represent fluorine, chlorine, bromine, iodine, CN, OH, SH, NH 2, halo or hydroxyl generation or unsubstituted [C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl];
M, m ', m ' ' is independently selected from 0,1,2,3 or 4;
M ' ' ' is selected from 1,2,3 or 4;
R 2, R 2', R 2' ', R 2[OH, SH, NH that ' ' ' is separately selected from H, halogen, CN or is optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
Z, Z ' separately represent [the NH, (R that are optionally substituted 5) t(CH 2) qor (CH 2) q(R 5) t], R 5be selected from C=O, C=S, S(=O), S(=O) 2, O or S, t be 0 or 1, q be 0,1,2 or 3, t and q different time be 0;
U or V separately represents (NH) that be optionally substituted r1(R 6) r2(CH 2) r3, (R 6) r2(NH) r1(CH 2) r3, (CH 2) r3(NH) r1(R 6) r2, (NH) r1(CH 2) r3(R 6) r2, (R 6) r2(CH 2) r3(NH) r1or (CH 2) r3(R 6) r2(NH) r1, R 6be selected from C=O, C=S, S(=O), S(=O) 2, O or S, r 1, r 3separately be selected from 0,1,2 or 3, r 2be 0 or 1, r 1, r 2and r 3be the singly-bound that 0 expression U or V representative only plays ligation simultaneously, and be singly-bound when U with V is different;
L represents heteroatoms or heteroatoms group;
[OH, SH, NH that T ', T ' ' separately represent H, halogen, CN or be optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
B represents 3 ~ 8 yuan of alicyclic hydrocarbon be optionally substituted;
Q, Q ', Q ' ', Q ' ' ' separately represent optionally be substituted 5-12 unit cyclic hydrocarbon or 5-12 unit heterocyclic hydrocarbon; With
Optionally, compound or its pharmacy acceptable salt have one or more chiral centre.
In a preferred version of the present invention, represented by dotted arrows singly-bound or double bond, M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent the CH be optionally substituted 2or CH.
In a preferred version of the present invention, , , , do not exist, M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent [the C be optionally substituted 1-12alkyl, C 1-12assorted alkyl, C 1-12hydrocarbon is mixed base, C 1-12hydrocarbon is mixed base C 1-12alkyl ,-C 1-12oH ,-C 0-12cOOH ,-OC 1-12cOOH ,-C 1-12cN ,-C 0-12cONH 2,-C 0-12o C 1-12,-C 0-12cO C 1-12,-C 0-12cOO C 1-12,-C 0-12o(O=) C C 1-12,-C 0-12s (=O) C 1-12or-C 0-12s (=O) 2c 1-12], wherein, above-mentioned group itself optionally exists with the form of aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, and the number of described aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, ring member nitrogen atoms and number, ring and ring or ring and chain or the mode of connection between chain and chain are arbitrary under the prerequisite that chemically Absorbable organic halogens realizes, heteroatoms or heteroatoms are rolled into a ball and are separately selected from O, S, N, S (=O) and/or S (=O) 2, the number of heteroatoms or heteroatoms group is arbitrary under the prerequisite that chemically Absorbable organic halogens realizes.Further preferably, wherein M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent halo or hydroxyl generation or amine generation or unsubstituted [C 6-12aryl or heteroaryl or heterocyclic base, C 3-8cyclic group or heterocyclic radical or ring are mixed base, C 1-6alkyl, C 1-6alkane is mixed base, C 1-6assorted alkyl, C 2-6alkenyl or alkynyl, C 2-6assorted thiazolinyl or assorted alkynyl, C 2-6mix base or alkynes of alkene is mixed base], described heteroatoms or heteroatoms group are separately selected from O, S, N, S (=O) and/or S (=O) 2, the number of heteroatoms or heteroatoms group is arbitrary under the prerequisite that chemically Absorbable organic halogens realizes.Further preferably, wherein M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent halo or hydroxyl generation or amine generation or unsubstituted [phenyl, , xenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidyl, 1,3-oxygen five rings base, pyrazolyl, 2-pyrazolinyl, pyrazolidyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-azoles base, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl group, 4 h-pyranyl, pyridyl, piperidyl, 1,4-dioxane base, morpholinyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,3,5-trithian base, 1,3,5-triazinyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnolines base or quinoxalinyl].
In a preferred version of the present invention, Q, Q in above-claimed cpd or its pharmacy acceptable salt ', Q ' ', Q ' ' ' separately structural unit shown in representative formula (a):
（a）
Wherein, X a, X b, X c, X dthe CH separately representing N or be optionally substituted.
In a preferred version of the present invention, in above-claimed cpd or its pharmacy acceptable salt, B represents the cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or suberyl or ring octyl group that are optionally substituted.
In a preferred version of the present invention, above-claimed cpd or its pharmacy acceptable salt, have structure shown in formula (V), (VI), (VII) or (VIII):
（Ⅴ）
（Ⅵ）
（Ⅶ）
（Ⅷ）
Wherein, X 1, X 2, X 3, X 4, X 1', X 2', X 3', X 4', X 1' ', X 2' ', X 3' ', X 4' ', X 1' ' ', X 2' ' ', X 3' ' ', X 4the CH that ' ' ' separately represents N or be optionally substituted.
In a preferred version of the present invention, above-mentioned R 1, R 1', R 1' ' be selected from fluorine, chlorine, bromine, iodine, CN, the NH that is optionally substituted independently of one another 2, halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl, halo or hydroxyl generation or amine generation or unsubstituted C 2-6alkenyl or alkynyl.Further, R 1, R 1', R 1' ' preferred from fluorine, chlorine, bromine, iodine, CN, CF independently of one another 3, NH 2, CH 3, CH 2nH 2or CH(NH 2) 2.
In a preferred version of the present invention, above-mentioned R 1' ' ' be selected from fluorine, chlorine, bromine, iodine, CH 3, CF 3, CN, OH, SH or NH 2.
In a preferred version of the present invention, above-mentioned R 2, R 2', R 2' ', R 2' ' ' be separately selected from-the C be optionally substituted 1-10r 3, carbochain or carbocyclic ring optionally insert one or more heteroatoms or heteroatoms group, wherein,
R 3be selected from OR 4, H, halogen, CN ,=O or the [NH that is optionally substituted 2, acid amides ,-COOH or-OS(=O) 2cH 3];
R 4be selected from phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester,-sulfinate or H;
Heteroatoms on carbochain or carbocyclic ring or heteroatoms group are selected from O, N, Si and/or Si (OH).
In a preferred version of the present invention, above-mentioned R 2, R 2', R 2' ', R 2' ' ' be selected from , C 1-6r 2b, or C 1-6alkyl, wherein,
H 1-5, f 1-3be selected from 0,1,2,3 independently of one another;
R 2a, R 2bbe selected from CN, OR independently of one another 2x, C(=O) R 2y;
R 2xbe selected from H, phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester or-sulfinate;
R 2ybe selected from optionally by [OH, NH of halogen, methyl, trifluoromethyl or methoxy substitution 2or-OC 1-6];
R 2cbe selected from O, S, C=O, C=S, S(=O), S(=O) 2, CR 2c1r 2c2, NR 2c3;
R 2dbe selected from N, CR 2d1;
R 2c1, R 2c2, R 2c3, R 2d1[OH, SH, NH of being separately selected from H, halogen, CN or being optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl].
In a preferred version of the present invention, above-mentioned R 2, R 2', R 2' ', R 2' ' ' be selected from .
In a preferred version of the present invention, above-mentioned R 4be selected from H ,-P (=O) (O C 2h 5) 2,-P(=O) (ONa) 2or-P(=O) (OK) 2.
In a preferred version of the present invention, above-mentioned Z, Z ' CH that represents C=O, C=S or be optionally substituted 2.
In a preferred version of the present invention, above-mentioned U or V separately represents [the CH be optionally substituted 2, (CH 2) 2, O(CH 2) 2, (CH 2) 2o, NH(C=O), (C=O) NH] or C=O.
In a preferred version of the present invention, above-mentioned L represents O, S, S=O, S(=O) 2or the NH be optionally substituted.
In a preferred version of the present invention, above-mentioned T ', T ' ' be separately selected from halo or hydroxyl generation amine generation or unsubstituted C 1-6alkyl, halo or hydroxyl generation or amine generation or unsubstituted C 2-6alkenyl or alkynyl, halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkoxyl group, the NH be optionally substituted 2, optionally 5-12 unit's cyclic group of being substituted or heterocyclic radical or ring to mix base, described NH 2substituting group be selected from C 1-6alkyl, C 5-8heterocyclic radical, C 5-8heterocyclic radical C 1-6alkyl or C 5-8ring is mixed base C 1-6alkyl, NH 2substituting group number be 1 or 2, described heteroatoms or heteroatoms group are selected from O, S, N, S(=O) or S(=O) 2.Further, above-mentioned T ', T ' ' are separately selected from CF 3, halo or hydroxyl generation or amine generation or unsubstituted [CH 3, CH(CH 3) 2, cyclopropyl, OCH 3, OCH(CH 3) 2, N(CH 3) 2, N(CH 2cH 3) 2, , phenyl, , , or ].
In a preferred version of the present invention, above-mentioned A, A ', A ' ', A ' ' ', E, E ', E ' ', E ' ' ', Y, Y ', Y ' ', Y ' ' ', M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ', R 1, R 1', R 1' ', R 1' ' ', R 2, R 2', R 2' ', R 2' ' ', R 3, Z, Z ', U, V, L, T ', T ' ', Q, Q ', the substituting group of Q ' ' or Q ' ' ' [OH, SH, NH of being selected from halogen, CN ,=O ,=S or being optionally substituted 2, PH 2, mix base and/or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl].
In a preferred version of the present invention, above-mentioned alkyl, assorted alkyl, hydrocarbon base or hydrocarbon base alkyl of mixing of mixing is selected from [the C be optionally substituted 1-12alkyl, C 1-12assorted alkyl, C 1-12hydrocarbon is mixed base, C 1-12hydrocarbon is mixed base C 1-12alkyl ,-C 1-12oH ,-C 0-12cOOH ,-OC 1-12cOOH ,-C 1-12cN ,-C 0-12cONH 2,-C 0-12o C 1-12,-C 0-12cO C 1-12,-C 0-12cOO C 1-12,-C 0-12o(O=) C C 1-12,-C 0-12s (=O) C 1-12or-C 0-12s (=O) 2c 1-12], wherein, above-mentioned group itself optionally exists with the form of aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, and the number of described aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, ring member nitrogen atoms and number, ring and ring or ring and chain or the mode of connection between chain and chain are arbitrary under the prerequisite that chemically Absorbable organic halogens realizes, heteroatoms or heteroatoms are rolled into a ball and are separately selected from O, S, N, S (=O) and/or S (=O) 2, the number of heteroatoms or heteroatoms group is arbitrary under the prerequisite that chemically Absorbable organic halogens realizes.
In a preferred version of the present invention, above-mentioned OH, SH, NH 2, PH 2, alkyl, assorted alkyl, hydrocarbon the mix substituting group of base alkyl of base and/or hydrocarbon of mixing is selected from halogen, OH, SH, NH 2, PH 2, CN ,=O ,=S, CF 3,-OCF 3,-OCH 3, protecting group and/or leavings group.
In a preferred version of the present invention, the substituting group of above-mentioned Z or Z ' is selected from halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl, halo or hydroxyl generation or amine generation or unsubstituted C 2-6alkenyl or alkynyl, the NH be optionally substituted 2, the optional 5-12 unit cyclic group or heterocyclic radical that is substituted, described NH 2substituting group be selected from C 1-6alkyl, C 5-8heterocyclic radical, C 5-8heterocyclic radical C 1-6alkyl or C 5-8ring is mixed base C 1-6alkyl, NH 2substituting group number be 1 or 2, described heteroatoms or heteroatoms group are selected from O, S, N, S(=O) or S(=O) 2.Further, the substituting group of above-mentioned Z or Z ' is selected from CF 3, or , substituent number is 1 or 2.
In a preferred version of the present invention, the substituting group of above-mentioned L is selected from halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl ,-COO C 1-6alkyl ,-COO alkylene phenyl ,-CO C 1-6alkyl ,-S(=O) 2c 1-6alkyl, C 1-6cycloalkyl or C 1-6heterocyclylalkyl, described heteroatoms is selected from O, S or N, and heteroatomic number is 1 or 2.Further, the substituting group of L is selected from methyl ,-COOC(CH 3) 3,-COOCH(CH 3) 2, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) ,-C(=O) CH(CH 3) 2,-S(=O) 2cH 3, or .
Another object of the present invention is to provide compound or its pharmacy acceptable salt shown in formula (Ⅸ),
(Ⅸ)
Wherein,
R 7be selected from-R 8aoR 8bor , wherein structural unit preferably ;
R 8abe selected from-the C of halogen, methyl, trifluoromethyl or the methoxy substitution be optionally substituted 1-10alkyl, preferably ;
R 8bbe selected from phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester or-sulfinate, preferably-P (=O) (O C 2h 5) 2,-P(=O) (ONa) 2or-P(=O) (OK) 2.；
J 1-5be selected from 0,1,2,3 independently of one another;
R 9be selected from CN, OR 9a, C(=O) R 9b;
R 9abe selected from H, phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester or-sulfinate, preferred H ,-P (=O) (O C 2h 5) 2,-P(=O) (ONa) 2or-P(=O) (OK) 2;
R 9bbe selected from [OH, NH of H, the halogen be optionally substituted, methyl, trifluoromethyl or methoxy substitution 2or-OC 1-6].
Further, the present invention includes but be not limited to following preferred version:
1) 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone;
2) 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-spiral shell [indoline-3,4 '-piperidines]-2-ketone;
3) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone;
4) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone;
5) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone;
7) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone-1 ', 1 '-dioxide;
8) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4,5-dihydro-2H-spiral shells [furans-3,3 '-indoline]-2 '-one;
9) tertiary butyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters;
10) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methylspiro [azetidinyl-3,3 '-indoline]-2 '-one;
11) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-methylspiro [azetidinyl-3,3 '-indoline]-2 '-one;
12) sec.-propyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters;
13) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one;
14) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one;
15) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one;
16) tertiary butyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters;
17) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone;
18) sec.-propyl base-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters;
19) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone;
20) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone;
21) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone;
22) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [imidazolidine-4,3 '-indoline]-2,2 ', 5-triketone;
23) 1-((1-(4-hydroxyl fourth collection)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one;
24) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one;
25) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one;
26) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-cyclopropyl quinazoline-2 (1H)-one;
27) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-phenylquinazoline-2 (1H)-one;
28) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-dimethyl) quinazoline-2 (1H)-one;
29) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-diethyl) quinazoline-2 (1H)-one;
30) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-morpholine quinazoline-2 (1H)-one;
31) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one;
32) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methoxyquinazoline hydrochloride-2 (1H)-one;
33) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropoxy quinazoline-2 (1H)-one;
34) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(pyridin-4-yl) quinazoline-2 (1H)-one;
35) 1-((5-(aminomethyl)-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one;
36) 1 '-((1-(4-hydroxybutyl)-4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
37) 1 '-((1-(4-hydroxybutyl)-4-phenyl-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
38) 1 '-((1-(4-hydroxybutyl)-3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one;
39) 1 '-((1-(4-hydroxybutyl)-4-(thiazol-2-yl)-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one;
40) 4-(the bromo-2-of 5-((2-trifluoromethyl)-1H-benzo [d] imidazoles-1-base) methyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol;
41) 1 '-((the bromo-1-of 6-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
42) 1 '-((the bromo-1-of 4-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
43) 1 '-((the chloro-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
44) 1 '-((1-(4-hydroxybutyl)-5-iodo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
45) 1 '-((1-(4-hydroxybutyl)-5-methyl isophthalic acid H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
46) 1 '-((1-(4-hydroxybutyl)-5-Trifluoromethyl-1 H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
47) 1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen;
48) 1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-6-cyanogen;
49) 1'-((1-((3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone;
50) methyl-3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylicesters;
51) 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylic acid;
52) 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-acid amides;
53) 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-nitrile;
54) 1'-((the bromo-1-of 5-(the fluoro-4-hydroxy phenyl of 5,5,5-tri-)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone;
55) 1'-((the bromo-1-of 5-(3,4-dihydroxyl butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone;
56) 4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium salt;
57) 4-(the bromo-2-of 5-((1-(isopropyloxycarbonyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium; With
58) 4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid disodium,
Optionally, above-claimed cpd or its pharmacy acceptable salt have one or more chiral centre,
Above-claimed cpd is named as compound 1 ~ 58 respectively, and its structural formula and preparation method be detailed in Example 1 ~ 58 successively.
Another object of the present invention is to provide a kind of pharmaceutical composition, comprise treatment significant quantity according to above-claimed cpd or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
Another object of the present invention is to the application providing above-claimed cpd or its pharmacy acceptable salt or its pharmaceutical composition in the medicine of preparation treatment respiratory syncytial virus infection.
Term " pharmacy acceptable salt " refers to the salt of the compounds of this invention, prepared by the have compound of specified substituent and the acid of relative nontoxic or alkali that are found by the present invention.When containing relatively acid functional group in compound of the present invention, can by obtaining base addition salt by the mode that the alkali of q.s contacts with the neutral form of this compounds in pure solution or suitable inert solvent.Pharmaceutically acceptable base addition salt comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.When containing the functional group of alkalescence relatively in compound of the present invention, can by obtaining acid salt by the mode that the acid of q.s contacts with the neutral form of this compounds in pure solution or suitable inert solvent.The example of pharmaceutically acceptable acid salt comprises inorganic acid salt, and described mineral acid comprises such as hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphoric acid one hydrogen root, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid HI, phosphorous acid etc.; And organic acid salt, described organic acid comprises acid as similar in acetic acid, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, FUMARIC ACID TECH GRADE, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, tosic acid, citric acid, tartrate and methylsulfonic acid etc.; Also comprise the salt of amino acid (as arginine etc.), and if the organic acid salt such as glucuronic acid are (see Berge et al., " Pharmaceutical Salts ", Journal of Pharmaceutical Science 66:1-19 (1977)).Some specific compound of the present invention contains alkalescence and acid functional group, thus can be converted into arbitrary alkali or acid salt.
Preferably, make salt and alkali or acid contact in a usual manner, then be separated parent compound, thus the neutral form of raw compounds again.The difference of the form of the parent fo salt various with it of compound is some physical properties, such as, different solubility in polar solvent.
" pharmacy acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein, by modifying described parent compound with sour salify or with the mode of alkali salify.The example of pharmacy acceptable salt includes but not limited to: base ratio is as the basic metal or organic salt etc. of the mineral acid of amine or organic acid salt, acid group such as carboxylic acid.Pharmacy acceptable salt comprises conventional avirulent salt or the quaternary ammonium salt of parent compound, the salt that such as nontoxic mineral acid or organic acid are formed.Conventional avirulent salt includes but not limited to that those are derived from mineral acid and organic acid salt, described mineral acid or organic acid are selected from Aspirin, 2-ethylenehydrinsulfonic acid, acetic acid, xitix, Phenylsulfonic acid, phenylformic acid, bicarbonate radical, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, glyconic acid, L-glutamic acid, oxyacetic acid, Hydrogen bromide, hydrochloric acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, toxilic acid, oxysuccinic acid, amygdalic acid, methanesulfonic, nitric acid, oxalic acid, pamoic acid, pantothenic acid, toluylic acid, phosphoric acid, poly galacturonic, propionic acid, Whitfield's ointment, stearic acid, sub-acetic acid, succsinic acid, thionamic acid, Sulphanilic Acid, sulfuric acid, tannin, tartrate and tosic acid.
Pharmacy acceptable salt of the present invention can be synthesized by conventional chemical processes by the parent compound containing acid group or base.Generally, the preparation method of such salt is: in water or organic solvent or both mixtures, and these compounds via free acid or alkali form are prepared with stoichiometric suitable alkali or acid-respons.Usually, the non-aqueous media such as preferred ether, ethyl acetate, ethanol, Virahol or acetonitrile.
Except the form of salt, also there is prodrug forms in compound provided by the present invention.Easily there is chemical transformation in physiological conditions thus change into compound of the present invention in the prodrug of compound described herein.In addition, prodrug can be switched to compound of the present invention by chemistry or biochemical method in environment in vivo.
Some compound of the present invention can exist with nonsolvated forms or solvation form, comprises hydrate forms.Generally speaking, solvation form is suitable with non-solvated form, is included within scope of the present invention.Some compound of the present invention can exist with polycrystalline or amorphous form.
Some compound of the present invention can have unsymmetrical carbon (optical center) or double bond.Racemic modification, diastereomer, geometrical isomer and single isomer all comprise within the scope of the present invention.
Unless otherwise prescribed, term " is substituted " any one or more hydrogen atoms referred in specific atoms and is substituted with a substituent, and comprises the variant of heavy hydrogen and hydrogen, as long as the valence state of specific atoms is normal and after replacing compound is stable.When substituting group is ketone group (namely=O), mean that two hydrogen atoms are substituted.Ketone replacement can not occur on aromatic base.Term " is optionally substituted " and refers to and can be substituted, and also can not be substituted, and substituent kind and number can be arbitrary on the basis that chemically can realize.
Unless otherwise prescribed, when any variable (such as R) occurs once in the composition or structure of compound, its definition is at each occurrence all independently.Therefore, such as, if group replace by 0-2 R, then described group can optionally at the most replace by two R, and the R in often kind of situation has independently option.In addition, the combination of substituting group and/or its variant to be only only when such combination can produce stable compound and to be allowed to.
Unless otherwise prescribed, can be cross connected to two atomic time on a ring when a substituent key, this substituting group can with the arbitrary atom phase bonding on this ring.When do not indicate in cited substituting group or group its by which atom be connected to chemical structure of general formula comprise but the compound specifically do not mentioned time, this substituting group can pass through its any atom phase bonding.The combination of substituting group and/or its variant is only only when such combination can produce stable compound and is allowed to.
Unless otherwise prescribed, term " alkyl " itself or its subordinate concept (such as alkyl, thiazolinyl, alkynyl, phenyl etc.) or as another substituent part represent straight chain, side chain or the hydrocarbon atomic group of ring-type or its combination, it can be completely saturated, unit or polynary undersaturated, can be monosubstituted, two replacements or polysubstituted, divalence or polyad group can be comprised, there is the carbon atom of specified quantity (as C 1-C 10represent 1 to 10 carbon).Described alkyl comprises aliphatic group and aryl radical, and described aliphatic group comprises chain and ring-type, specifically includes but not limited to alkyl, thiazolinyl, alkynyl, and described aryl radical includes but not limited to the aryl radical of 6-12 unit, such as benzene, naphthalene etc.
Unless otherwise prescribed, described assorted alkyl refers to that heteroatoms or heteroatoms group include but not limited to N, NH, are substituted or protected NH, O, S, S(=O containing heteroatoms or heteroatoms group on hydrocarbyl backbone), S(=O) 2.
Unless otherwise prescribed, term " alkyl " itself or as another substituent part represent straight chain, side chain or the hydrocarbon atomic group of ring-type or its combination, it can be completely saturated, unit or polynary undersaturated, can be monosubstituted, two replacements or polysubstituted, divalence or polyad group can be comprised, there is the carbon atom of specified quantity (as C 1-C 10represent 1 to 10 carbon).In certain embodiments, atomic group that is that term " alkyl " represents straight chain or side chain or their combination, can be completely saturated, unit or polynary undersaturated, can comprise divalence and polyad group.The example of stable hydrocarbon atomic group includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, isobutyl-, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl, and the homologue of the atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl or isomer.Unsaturated alkyl has one or more double bond or triple bond, the example includes but not limited to vinyl, 2-propenyl, butenyl, crot(on)yl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-and 3-proyl, 3-butynyl, and more senior homologue and isomer.
Unless otherwise prescribed, term " alkoxyl group ", " alkylamino " and " alkylthio " (or thio alkoxy) belong to idiomatic expression, refer to those alkyl groups being connected to the rest part of molecule respectively by Sauerstoffatom, amino or a sulphur atom.
Unless otherwise prescribed, term " assorted alkyl " itself or combine with another term the straight chain representing stable, side chain the hydrocarbon atomic group of ring-type or its combine, be made up of the carbon atom of certain number and at least one heteroatoms.In certain embodiments, term " assorted alkyl " itself or combine with another term the straight chain representing stable, the hydrocarbon atomic group of side chain or its composition, be made up of the carbon atom of certain number and at least one heteroatoms.In an exemplary embodiment, heteroatoms is selected from B, O, N and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen heteroatom is optionally quaternized.Heteroatoms B, O, N and S can be positioned at the position that any interior location of assorted alkyl or this alkyl are attached to molecule rest part.Example includes but not limited to-CH 2-CH 2-O-CH 3,-CH 2-CH 2-NH-CH 3,-CH 2-CH 2-N (CH 3)-CH 3,-CH 2-S-CH 2-CH 3,-CH 2-CH 2,-S (O)-CH 3,-CH 2-CH 2-S (O) 2-CH 3,-CH=CH-O-CH 3,-CH 2-CH=N-OCH 3he – CH=CH-N (CH 3)-CH 3.Two heteroatomss can be continuous print, such as-CH at the most 2-NH-OCH 3.
Unless otherwise prescribed, term " cycloalkyl " and " Heterocyclylalkyl " itself or combine with other terms " alkyl " and " alkyl of mixing " that represent cyclisation respectively.In addition, with regard to Heterocyclylalkyl, heteroatoms can occupy the position that this heterocycle is attached to molecule rest part.The example of cycloalkyl includes but not limited to cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, suberyl etc.The limiting examples of heterocyclic radical comprises 1-(1,2,5,6-tetrahydro pyridyl), piperidino, 2-piperidyl, 3-piperidyl, 4-morpholinyl, morpholinyl, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF) indol-3-yl, tetramethylene sulfide-2-base, tetramethylene sulfide-3-Ji, 1-piperazinyl and 2-piperazinyl.
Unless otherwise prescribed, term " halo element " or " halogen " itself or represent fluorine, chlorine, bromine or iodine atom as another substituent part.In addition, term " haloalkyl " is intended to comprise single haloalkyl and multi-haloalkyl.Such as, term " halo (C 1-C 4) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2-trifluoroethyls, 4-chlorobutyl and 3-bromopropyl etc.
Unless otherwise prescribed, term " aryl " represents polyunsaturated aromatic hydrocarbon substituting group, can be monosubstituted, two to replace or polysubstituted, it can be monocycle or many rings (preferably 1 to 3 ring), and they condense together or covalently bound.Term " heteroaryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, heteroatoms is selected from B, N, O and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl is connected to the rest part of molecule by heteroatoms.The non-limiting example of aryl or heteroaryl comprises phenyl, 1-naphthyl, 2-naphthyl, 4-xenyl, 1-pyrryl, 2-pyrryl, 3-pyrryl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purine radicals, 2-benzimidazolyl-, 5-indyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.The substituting group of any one aryl above-mentioned and heteroaryl ring system is selected from acceptable substituting group hereinafter described.
Unless otherwise prescribed, for simplicity, aryl is comprising aryl as defined above and heteroaryl ring with (such as aryloxy, arylthio, aralkyl) during other term conbined usage.Therefore, term " aralkyl " is intended to comprise those atomic groups (such as benzyl, styroyl, pyridylmethyl etc.) that aryl is attached to alkyl, comprise wherein carbon atom (as methylene radical) by those alkyl that such as Sauerstoffatom replaces, such as phenoxymethyl, 2-pyridine oxygen methyl 3-(1-naphthyloxy) propyl group etc.
Unless otherwise prescribed, " ring " represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.So-called ring comprises condensed ring.The number of ring atom is generally defined as first number of ring, and such as, " 5 ~ 7 ring " refers to around arrangement 5 ~ 7 atoms.Unless otherwise prescribed, this ring optionally comprises 1 ~ 3 heteroatoms.Therefore, " 5 ~ 7 ring " comprises such as phenylpyridine and piperidyl; On the other hand, term " 5 ~ 7 yuan of heterocycloalkyl rings " comprises pyridyl and piperidyl, but does not comprise phenyl.Term " ring " also comprises the ring system containing at least one ring, and each " ring " wherein meets above-mentioned definition all independently.
Unless otherwise prescribed, term used herein " heteroatoms " comprises the atom beyond carbon (C) and hydrogen (H), such as, comprise oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al) and boron (B) etc.
Unless otherwise prescribed, term " leavings group " refer to can by another kind of functional group or atom by substitution reaction (such as nucleophilic substitution reaction) the functional group that replaces or atom.Such as, representational leavings group comprises triflate; Chlorine, bromine, iodine; Sulfonate group, as methanesulfonates, tosylate, brosylate, p-toluenesulfonic esters etc.; Acyloxy, as acetoxyl group, trifluoroacetyl oxygen base etc.
Unless otherwise prescribed, term " protecting group " includes but not limited to " amino protecting group ", " hydroxyl protecting group " or " sulfhydryl protected base ".Term " amino protecting group " refers to the blocking group being suitable for stoping side reaction on amino nitrogen position.Representational amino protecting group includes but not limited to: formyl radical; Acyl group, such as alkanoyl (as ethanoyl, tribromo-acetyl base or trifluoroacetyl group); Alkoxy carbonyl, as tert-butoxycarbonyl (Boc); Arylmethoxycarbonyl groups, as carbobenzoxy-(Cbz) (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); Arylmethyl, as benzyl (Bn), trityl (Tr), 1,1-bis--(4'-p-methoxy-phenyl) methyl; Silyl, as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc.Term " hydroxyl protecting group " refers to the protecting group being suitable for stoping hydroxyl side reaction.Representative hydroxyl protecting group includes but not limited to: alkyl, as methyl, ethyl and the tertiary butyl; Acyl group, such as alkanoyl (as ethanoyl); Arylmethyl, as benzyl (Bn), to methoxy-benzyl (PMB), 9-fluorenyl methyl (Fm) and diphenyl methyl (diphenyl-methyl, DPM); Silyl, as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc.
Unless otherwise prescribed, the example of haloalkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group, and pentachloro-ethyl." alkoxyl group " represents the abovementioned alkyl with given number carbon atom connected by oxo bridge.C 1-6alkoxyl group comprises C 1, C 2, C 3, C 4, C 5and C 6alkoxyl group.The example of alkoxyl group includes but not limited to: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, n-pentyloxy and s-pentyloxy." cycloalkyl " comprises saturated cyclic group, as cyclopropyl, cyclobutyl or cyclopentyl.3-7 cycloalkyl comprises C 3, C 4, C 5, C 6and C 7cycloalkyl." alkenyl " comprises the hydrocarbon chain of straight or branched configuration, wherein any on this chain stable site exists one or more carbon-to-carbon double bond, such as vinyl and propenyl.
Unless otherwise prescribed, term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Unless otherwise prescribed, term " heterocycle " or " heterocyclic radical " mean stable monocycle or dicyclo or bicyclic heterocycle, they can be saturated, part is undersaturated or undersaturated (aromatics), they comprise carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S, and wherein above-mentioned any heterocycle can be fused on a phenyl ring and form dicyclo.
Unless otherwise prescribed, the example of heterogeneous ring compound includes but not limited to: acridyl, azocine base, benzimidazolyl-, benzofuryl, benzo sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazyl, benzisoxa oxazolyl, benzisothiazole base, benzimidazoline base, carbazyl, 4a h-carbazyl, carbolinyl, chromanyl, chromene, cinnolines base decahydroquinolyl, 2 h, 6 h-1,5,2-dithiazine base, dihydrofuran also [2,3- b] tetrahydrofuran base, furyl, furazan base, imidazolidyl, imidazolinyl, imidazolyl, 1 h-indazolyl, indoles thiazolinyl, indolinyl, indolizine base, indyl, 3 h-indyl, isatino base, isobenzofuran-base, pyrans, pseudoindoyl, iso-dihydro-indole-group, pseudoindoyl, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydro isoquinolyl, oxadiazoles base, 1, 2, 3-oxadiazoles base, 1, 2, 4-oxadiazoles base, 1, 2, 5-oxadiazoles base, 1, 3, 4-oxadiazoles base, oxazolidinyl, oxazolyl, isoxazolyl, oxindole base, pyrimidyl, phenanthridinyl, phenanthroline base, azophenlyene, thiodiphenylamine, benzo xanthinyl, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4-piperidone base, piperonyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, 2 h-pyrryl, pyrryl, pyrazolyl, quinazolyl, quinolyl, 4 h-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazyl, 6 h-1,2,5-thiadiazine base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl, thiazolyl, isothiazolyl thienyl, thienyl, thieno-oxazolyl, thieno-thiazolyl, Thienoimidazole base, thienyl, triazinyl, 1,2,3-triazoles base, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.Also comprise condensed ring and spirocyclic compound.
Unless otherwise prescribed, compound of the present invention can be prepared by multiple synthetic method well-known to those skilled in the art, comprise and be equal to substitute mode in embodiment, its embodiment formed with the combination of other chemical synthesis process and the art technology enumerated known by personnel below, preferred embodiment include but not limited to embodiments of the invention.
Unless otherwise prescribed, the structure of compound by nucleus magnetic resonance (NMR) or/and liquid chromatography mass spectrometric (LCMS) is determined.NMR displacement (d) is with 10 -6(ppm) unit provides.The mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-with Bruker AVANCE-400 nuclear magnetic resonance spectrometer d 6 ), deuterochloroform (CDCl 3), deuterated methanol (CD 3oD), tetramethylsilane (TMS) is inside designated as.
Unless otherwise prescribed, mensuration liquid phase part Agilent 1200 (Xtimate C18 2.1*30mm chromatographic column) and the mass spectrum part Agilent 6110 (ion source: ESI) of liquid chromatography mass spectrometric LCMS.
Unless otherwise prescribed, the mensuration of HPLC uses Shimadzu LC10AD high pressure liquid chromatograph (Xtimate C18 2.1*30mm chromatographic column).
Unless otherwise prescribed, tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15 mm ~ 0.2 mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4 mm ~ 0.5 mm.
Unless otherwise prescribed, column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
Unless otherwise prescribed, known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, TCI, Alfa, the splendid chemistry science and technology company such as (Accela ChemBio Inc), Beijing coupling far away.
Unless otherwise prescribed, without specified otherwise in embodiment, reaction can all be carried out under argon atmospher or nitrogen atmosphere.Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas or the nitrogen balloon of an about 1L volume.
Unless otherwise prescribed, nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Unless otherwise prescribed, pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.
Unless otherwise prescribed, microwave reaction uses CEM Discover-S 908860 type or Biotage Initiator 60 microwave reactor.
Unless otherwise prescribed, without specified otherwise in embodiment, solution refers to the aqueous solution.
Unless otherwise prescribed, without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C ~ 30 DEG C.
Unless otherwise prescribed, the monitoring of the reaction process in embodiment adopts tlc (TLC), the system of reacting the developping agent used has: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: sherwood oil and ethyl acetate system, D: acetone, the volume ratio of solvent regulates according to the polarity difference of compound.
Unless otherwise prescribed, the system of eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: sherwood oil and ethyl acetate system, C: methylene dichloride and acetone system, the volume ratio of solvent is different and regulate according to the polarity of compound, also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent regulates.
Can specifically describe the present invention by embodiment below, these embodiments also do not mean that any limitation of the invention.Unless otherwise prescribed, all solvents used in the present invention are commercially available, can use without the need to being further purified.Unless otherwise prescribed, the present invention adopts following initialism: aq represents water; HATU represents O-7-azepine benzotriazole-1-base)-N, N, N', N'-tetramethyl-urea hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride; M-CPBA represents 3-chloroperoxybenzoic acid; Eq represents equivalent, equivalent; CDI represents carbonyl dimidazoles; DCM represents methylene dichloride; PE represents sherwood oil; DIAD represents diisopropyl azo-2-carboxylic acid; DMF represents DMF; DMSO represents methyl-sulphoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methyl alcohol; CBz represents carbobenzoxy-(Cbz), is a kind of amine protecting group group; It is a kind of amine protecting group group that BOC represents tert-butyl carbonyl; HOAc represents acetic acid; NaCNBH 3represent sodium cyanoborohydride; R.t. room temperature is represented; O/ N representative is spent the night; THF represents tetrahydrofuran (THF); Boc 2o represents two-di-tert-butyidicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropyl ethyl amine; SOCl 2represent sulfur oxychloride; CS 2represent dithiocarbonic anhydride; TsOH represents tosic acid; NFSI represents the fluoro-N-(benzenesulfonyl of N-) benzsulfamide; NCS represents 1-chlorine tetramethyleneimine-2,5-diketone; n-Bu 4nF represents tetrabutylammonium; IPrOH represents 2-propyl alcohol; Mp represents fusing point.Unless otherwise prescribed, manually or the name of ChemDraw software, commercial compound adopts supplier directory name to compound.
Compared with prior art, the compounds of this invention is efficient, low toxicity, all achieves significantly even unforeseeable progress, be more suitable for pharmacy in activity, transformation period, solubleness and pharmacokinetics etc.
Embodiment
Describe the present invention below by embodiment, but and do not mean that any unfavorable restriction of the present invention.Describe in detail the present invention herein, wherein also disclose its specific embodiment mode, to those skilled in the art, will be apparent carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention.
Embodiment 1
1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone
The first step
4-((2-nitrophenyl) amido) butyl-1-alcohol
By fluoro-for 1-2-oil of mirbane 1a(6.73 g, 47.75 mmol) are dissolved in 70 mL Isosorbide-5-Nitrae-dioxane, add 4-amido butyl-1-alcohol (5.1 g, 57.3 mmol) and triethylamine (7.23 g, 71.63 mmol), stirring at room temperature 2 hours.By reaction solution concentrating under reduced pressure, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains product 4-((2-nitrophenyl) amido) butyl-1-alcohol 1b(9.31 g, orange oily matter), product is not purified directly carries out next step reaction.
1H NMR (400 MHz, DMSO-d6) δ 8.14 (m, 1H), 8.06 (dd, J=1.3 Hz, 8.6 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.06 (d, J=8.6 Hz, 1H), 6.71 - 6.64 (m, 1H), 4.46 (t, J=5.2 Hz, 1H), 3.48 - 3.35 (m, 4H), 1.70-1.62 (m, 2H), 1.57 - 1.46 (m, 2H)。
Second step
4-((2-aminocarbonyl phenyl) amido) butyl-1-alcohol
By crude product 4-((2-nitrophenyl) amido) butyl-1-alcohol 1b(22.3 g, 106.09 mmol) are dissolved in 250 mL methyl alcohol, add 50% wet palladium carbon (3.0 g). reaction solution, in room temperature, under hydrogen balloon pressure, stirs 12 hours.Reaction solution was considered, and concentrated to obtain product 4-((2-aminocarbonyl phenyl) amido) butyl-1-alcohol 1c(14.7 g, red oil), product is not purified directly carries out next step reaction.
1H NMR (400 MHz, DMSO-d6) δ 6.87 - 6.79 (m, 1H), 6.74 - 6.64 (m, 3H), 3.67 (t, J=5.9 Hz, 2H), 3.47 - 3.26 (m, 2H), 3.13 (t, J=6.4 Hz, 2H), 1.78 - 1.66 (m, 4H)。
3rd step
4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol
By crude product 4-((2-aminocarbonyl phenyl) amido) butyl-1-alcohol 1c(4.2 g, 23.3 mmol) are dissolved in the 4 moles often liter HCl aqueous solution of 40 mL, and add Mono Chloro Acetic Acid (3.3 g, 34.96 mmol), reaction solution is heated to 80 oc reacts 2 hours.Reaction solution is cooled to room temperature, adjust ph to 5 ~ 6 under ice-water bath, be extracted with ethyl acetate (100 mL × 3), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol 1d(3.1 g, faint yellow solid), productive rate: 55.8%.
1H NMR (400 MHz, CDCl 3) δ 7.76 (d, J=7.3 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.34 - 7.28 (m, 2H), 4.86 (s, 2H), 4.34 - 4.28 (m, 2H), 3.72 (t, J=6.1 Hz, 2H), 2.06-1.98 (m, 2H), 1.72 - 1.63 (m, 2H)。
4th step
2,2 '-diiodo-ethyl ether
By 2,2 '-dichloroethyl ether 1e(10 g, 70 mmol) and sodium iodide (30 g, 0.2 mol) and 100 mL acetone are heated to 55 oc refluxes 18 hours.By reaction solution concentrating under reduced pressure, add 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtains crude product 2,2 '-diiodo-ethyl ether 1f(16 g, colorless oil), product is not purified directly carries out next step reaction.
1H NMR (400 MHz, CDCl 3) δ 3.80 - 3.71 (m, 5 H) 3.65 - 3.59 (m, 1 H) 3.24 (t, J=6.72 Hz, 4 H)。
5th step
The tertiary butyl-2-oxoindoline-1-carboxylicesters
By Indolin-2-one 1g(20 g, 150 mmol) and DMAP (3.4 g, 28 mmol) are dissolved in 200 mL acetonitriles, add Boc 2o (41.9 g, 192 mmol), stirring at room temperature 16 hours.Reaction solution concentrating under reduced pressure, add 200 mL saturated sodium bicarbonate aqueous solutions, extraction into ethyl acetate (200 mL × 2), merge organic phase, use water (200 mL × 2), saturated nacl aqueous solution to wash (200 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the tertiary butyl-2-oxoindoline-1-carboxylicesters 1h(12 g, white solid), productive rate: 34.2%.
1H NMR (400 MHz, CDCl 3) δ 7.81 (d, J=8.28 Hz, 1 H) 7.37 - 7.30 (m, 1 H) 7.26 (s, 1 H) 7.17 (d, J=7.52Hz, 1 H) 3.68 (s, 2 H) 1.67 (s, 9 H)。
6th step
The tertiary butyl-2-oxo-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-1-carboxylicesters
By the tertiary butyl-2-oxoindoline-1-carboxylicesters 1h(4.40 g, 18.84 mmol), 2,2 '-diiodo-ethyl ether 1f(6.04 g, 18.82 mmol) and cesium carbonate (24.10 g, 73.69 mmol) are dissolved in 50 mL DMF, room temperature reaction 16 hours.Reaction solution adds 200 mL water, extraction into ethyl acetate (200 mL × 2), merges organic phase, water (200 mL × 3), saturated nacl aqueous solution is used to wash (200 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain the tertiary butyl-2-oxo-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-1-carboxylicesters 1i(2.46 g, white solid), productive rate: 43.8%.
1H NMR (400 MHz, CDCl 3) δ 7.83 (d, J=8.08 Hz, 1 H) 7.37 - 7.27 (m, 2 H) 7.20 (d, J=7.32 Hz, 1 H) 4.31 - 4.19 (m, 2 H) 3.91 (dt, J=11.92, 4.20 Hz, 2 H) 1.93 (dd, J=10.03, 4.40 Hz, 2 H) 1.89 - 1.79 (m, 2 H) 1.69 - 1.62 (m, 9 H)。
7th step
2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone
By the tertiary butyl-2-oxo-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-1-carboxylic acid 1i(2.46 g, 8.11 mmol) are dissolved in 14 mL methylene dichloride, add 7 mL trifluoroacetic acids, room temperature reaction half an hour.Adjust ph to 5 ~ 6 under reaction solution ice-water bath, with dichloromethane extraction (50 mL × 2), merge organic phase, water (50 mL × 2), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone 1j(0.9 g, white solid), productive rate: 54.6%.
1H NMR (400 MHz, CDCl 3) δ 7.94 (br. s., 1 H) 7.36 (d, J=7.52 Hz, 1 H) 7.23 (t, J=7.94 Hz, 1 H) 7.12 - 7.00 (m, 1 H) 6.90 (d, J=7.72 Hz, 1 H) 4.24 (ddd, J=11.85, 7.55, 4.40 Hz, 2 H) 3.93 (dt, J=11.58, 4.92 Hz, 2 H) 2.01 – 1.79 (m, 4 H)。
8th step
1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-furans]-2-ketone
By 2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone 1j(0.2 g; 0.98 mmol) be dissolved in 2 mL dry DMF; 60% sodium hydride (0.047 g is added under condition of ice bath; 1.18 mmol); stirred under nitrogen atmosphere half an hour, add 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol 1d(0.235 g, 0.98 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-furans]-2-ketone 1(0.12 g, white solid), productive rate: 30.1%.
MS m/z (ESI): 406.0 [M+1]
1H NMR (400 MHz, CD 3OD) δ 7.65-7.63 (d, J=8.0Hz, 1H), 7.60-7.53 (m, 2H), 7.35-7.28 (m, 3H), 7.16-7.07 (m, 2H), 5.29 (s, 2H), 4.43-4.39 (m, 2H), 4.29-4.26 (m, 2H), 4.00-3.97 (m, 2H), 3.62-3.58 (m, 2H), 1.98-1.86 (m, 6H), 1.66-1.62 (m, 2H)。
Embodiment 2
1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-spiral shell [indoline-3,4 '-piperidines]-2-ketone
The first step
1 '-benzyl spiral shell [indoline-3,4 '-piperidines]-2-ketone
By Indolin-2-one 2a(5 g, 37.55 mmol) are dissolved in 50 mL THF, and-60 oc adds NaHMDS (187.8 mL, 187.8 mmol), and-60 oc stirs 0.5 hour, adds the chloro-N-of N-benzyl-2-(2-chloroethyl) diethylamine, reaction solution stirring at room temperature 18 hours.Reaction solution is poured in 200 mL frozen water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (50 mL × 3), saturated nacl aqueous solution to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 1 '-benzyl spiral shell [indoline-3,4 '-piperidines]-2-ketone 2b(2 g, colorless oil), productive rate: 18.2%.
1H NMR (400MHz, CDCl 3) δ 7.76 (b.r.s, 2H), 7.43-7.39 (m, 3H), 7.37-7.33 (m, 2H), 7.28-7.27 (m, 1H), 7.23-7.21 (m, 1H), 7.05-7.03 (m, 1H), 7.89-7.87 (d, J = 8.0 Hz, 1H), 3.70 (s, 2H), 2.97-2.94 (m, 2H), 2.74-2.72 (m, 2H), 2.03-2.00 (m, 2H), 1.89-1.85 (m, 2H)。
Second step
The tertiary butyl-2-oxo spiral shell [indoline-3,4 '-piperidines]-1 '-carboxylicesters
By 1 '-benzyl spiral shell [indoline-3,4 '-piperidines]-2-ketone 2b(100 mg, 0.34 mmol) is dissolved in 20 mL THF, adds (Boc) 2o (224 mg, 1.03 mmol), 50% wet palladium carbon (10 mg), reaction solution under 50 psi hydrogen pressures, stirring at room temperature 12 hours.Reacting liquid filtering, concentrates to obtain the product tertiary butyl-2-oxo spiral shell [indoline-3,4 '-piperidines]-1 '-carboxylicesters 2c(85 mg, yellow oil), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.72 (s, 1H), 7.29-7.21 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.88-3.79 (m, 4H), 1.90-1.78 (m, 4H), 1.50 (s, 9H)。
3rd step
Tertiary butyl 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,4 '-piperidines]-1 '-carboxylicesters
By the crude product tertiary butyl-2-oxo spiral shell [indoline-3,4 '-piperidines]-1 '-carboxylicesters 2c(80mg; 0.26 mmol) be dissolved in 1 mL dry DMF; 60% sodium hydride (13 mg are added under condition of ice bath; 0.31 mmol); stirred under nitrogen atmosphere half an hour, add 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (80mg, 0.31mmol; 1.2eq.), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains product tertiary butyl 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,4 '-piperidines]-1 '-carboxylicesters 2d(110 mg, white solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.79-7.77 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.34-7.23 (m, 5H), 7.07-7.05 (m, 1H), 5.24 (s, 2H), 4.29 (t, J = 8.0 Hz, 2H), 3.91-3.86 (m, 2H) ,3.75-3.70 (m, 4H), 1.89-1.78 (m, 6H), 1.68 (t, J = 6.8 Hz, 2H), 1.51 (s, 9H)。
4th step
1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,4 '-piperidines]-2-ketone
By crude product tertiary butyl 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,4 '-piperidines]-1 '-carboxylicesters 2d(100mg, 0.198mmol) is dissolved in 2 mL MeOH, and room temperature adds HCl/MeOH (4N, 2 mL), reaction solution stirring at room temperature 1 hour.Concentrating under reduced pressure, purifies with preparative high-performance liquid chromatographic and obtains title product 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,4 '-piperidines]-2-ketone 2(20 mg, white solid), productive rate: 25.0%.
MS m/z (ESI): 405.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.57 (t, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.32-7.25 (m, 3H), 7.15-7.11 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 5.29 (s, 2H), 4.43 (t, J = 7.6 Hz, 2H), 3.88-3.83 (m, 2H), 3.61 (t, J = 6.4 Hz, 2H), 3.43 (d, J = 13.2 Hz, 2H), 2.25-2.16 (m, 4H), 1.95-1.91 (m, 2H), 1.66-1.62 (m, 2H)。
Embodiment 3
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone
The first step
4-((the bromo-2-nitrophenyl of 4-) amido) butyl-1-alcohol
By fluoro-for 4-bromine 1-2-oil of mirbane 3a(10.45 g, 47.75 mmol) are dissolved in 100 mL Isosorbide-5-Nitrae-dioxane, add 4-amido butyl-1-alcohol (5.1 g, 57.3 mmol) and triethylamine (7.23 g, 71.63 mmol), stirring at room temperature 2 hours.By reaction solution concentrating under reduced pressure, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains product 4-((the bromo-2-nitrophenyl of 4-) amido) butyl-1-alcohol 3b(12.8 g, orange oily matter), product is not purified directly carries out next step reaction.
Second step
4-((the bromo-phenyl of 2-amido-4-) amido) butyl-1-alcohol
By crude product 4-((4-bromine 2-nitrophenyl) amido) butyl-1-alcohol 3b(2.89 g, 10.0 mmol) are dissolved in 30 mL methylene dichloride, add six hydration Nickel Chloride (3.57 g, 15.0 mmol). after room temperature reaction half hour, add sodium borohydride (1.14g, 30.0mmol), stirring at room temperature 12 hours.Reacting liquid filtering, concentrated, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains product 4-((2-amido-4-bromophenyl) amido) butyl-1-alcohol 3c(2.4 g, orange oily matter), product is not purified directly carries out next step reaction.
3rd step
4-(the bromo-2-chloromethyl of 5-)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol
By crude product 4-((2-amido-4-bromophenyl) amido) butyl-1-alcohol 3c(6.0 g, 23.3 mmol) are dissolved in the 4 moles often liter HCl aqueous solution of 40 mL, and add 2-Mono Chloro Acetic Acid (3.3 g, 34.96 mmol), reaction solution is heated to 80 oc reacts 2 hours.Reaction solution is cooled to room temperature, adjust ph to 5 ~ 6 under ice-water bath, be extracted with ethyl acetate (100 mL × 3), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 4-(the bromo-2-chloromethyl of 5-)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol 3d(4.1 g, faint yellow solid), productive rate: 55.8%.
1H NMR (400 MHz, CDCl 3) δ 7.90 (d, J=1.6 Hz, 1H), 7.44 - 7.41 (m, 1H), 7.29 - 7.27 (d, J=8.4 Hz, 1H), 4.86 (s, 2H), 4.32- 4.28 (t, J=8 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H), 2.06-1.98 (m, 2H), 1.72 - 1.63 (m, 2H)。
4th step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone
By 2 '; 3 '; 5 '; 6 '-tetrahydrochysene spiral shell dihydro [indoles-3,4 '-pyrans]-2-ketone (0.2 g, 0.98 mmol) is dissolved in 2 mL dry DMF; 60% sodium hydride (0.047 g is added under condition of ice bath; 1.18 mmol), stirred under nitrogen atmosphere half an hour, add 4-(the bromo-2-chloromethyl of 5-)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol 3d(0.310 g, 0.98 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone 3(0.14 g, white solid), productive rate: 30.1%.
MS m/z (ESI): 484.0 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.94 (d, J=1.0 Hz, 1 H), 7.52 (d, J=7.8 Hz, 1 H), 7.40 (d, J=7.5 Hz, 2 H), 7.30 - 7.23 (m, 2 H), 7.14 - 7.06 (m, 1 H), 5.24 (s, 2 H), 4.41-4.16 (m, 4 H), 4.05-3.90 (m, 2 H), 3.72 (t, J=5.9 Hz, 2 H), 1.94 - 1.88 (m, 4 H), 1.76 - 1.65 (m, 4 H)。
Embodiment 4
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone
The first step
Spiral shell [indoline-3,4 '-piperidines]-2-ketone
By 1 '-benzyl spiral shell [indoline-3,4 '-piperidines]-2-ketone 4a(1.3 g, 4.45 mmol) are dissolved in 50 mL MeOH, add 50% wet palladium carbon (0.4 g), reaction solution under 55psi hydrogen pressure, 60 oc stirs 2 days.Reacting liquid filtering, filtrate concentrates to obtain product spiral shell [indoline-3,4 '-piperidines]-2-ketone 4b(0.9 g, yellow oil), product is not purified directly carries out next step reaction.
1H NMR (400MHz, DMSO-d6) δ 10.52 (brs, 1H), 7.34-7.33 (m, 1H), 7.22-7.19 (m, 1H), 7.01-6.98 (m, 1H), 6.88-6.86 (m, 1H), 3.38-3.33 (m, 2H), 3.16-3.12 (m, 2H), 1.95-1.88 (m, 2H), 1.83-1.79 (m, 2H)。
Second step
1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone
By spiral shell [indoline-3,4 '-piperidines]-2-ketone 4b(0.2 g, 0.99 mmol) be dissolved in 15 mL MeOH, add 1 mL TFA, regulate pH to 3, add paraformaldehyde (0.148 g, 4.94 mmol), reaction solution stirring at room temperature 20 minutes, add sodium cyanoborohydride (0.37 g, 5.93 mmol), reaction solution is in 40 oc stirs 12 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3), saturated nacl aqueous solution to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain 1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone 4c(0.2 g, colorless oil), productive rate: 95.0%.
3rd step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone
By 1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone 4c(150 mg; 0.69 mmol) be dissolved in 3 mL dry DMF; 60% sodium hydride (18 mg are added under condition of ice bath; 0.76 mmol); stirred under nitrogen atmosphere half an hour; add 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (200mg, 0.63mmol), reaction solution stirring at room temperature 16 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone 4(7 mg, white solid), productive rate: 2.2%.
MS m/z (ESI): 497.2 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.81 (s, 1H), 7.70-7.68 (m, 1H), 7.59-7.57 (m, 1H), 7.41-7.39 (m, 1H), 7.35-7.33 (m, 1H), 7.21-7.19 (m, 1H), 7.12-7.10 (m, 1H), 5.418 (s, 2H), 4.54-4.50 (m, 2H), 3.87-3.80 (m, 2H), 3.64-3.61 (m, 2H), 3.56-3.53 (m, 2H), 3.00 (s, 3H), 2.49-2.43 (m, 2H), 2.24-2.20 (m, 2H), 2.02-1.96 (m, 2H), 1.66-1.64 (m, 2H)。
Embodiment 5
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3,4 '-piperidines]-2-ketone
The first step
1 '-(oxa-ring fourth-3-base) spiral shell [dihydro-3,4 '-piperidines]-2-ketone
By spiral shell [indoline-3,4 '-piperidines]-2-ketone 5a(0.2 g, 0.99 mmol), be dissolved in 15 mL MeOH, add 1 mL TFA, regulate pH to 3, add oxa-ring fourth-3-ketone (0.36 g, 4.94 mmol), reaction solution stirring at room temperature 20 minutes, add sodium cyanoborohydride (0.37 g, 5.93 mmol), reaction solution stirring at room temperature 12 hours, add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain 1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3, 4 '-piperidines]-2-ketone 5b(0.15 g, white solid), productive rate: 59.0%.
1H NMR (400MHz, CDCl 3) δ 7.53 (brs, 1H), 7.34-7.32 (d, J= 7.6 Hz, 1H), 7.23-7.20 (m, 1H), 7.07-7.05 (m, 1H), 6.88-6.87 (d, J= 7.6 Hz, 1H), 4.75-4.69 (m, 4H), 3.75-3.68 (m, 1H), 2.84-2.78 (m, 2H), 2.63-2.59 (m, 2H), 2.01-1.96 (m, 4H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3,4 '-piperidines]-2-ketone
By 1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3,4 '-piperidines]-2-ketone 5b(80 mg; 0.31 mmol) be dissolved in 4 mL dry DMF; 60% sodium hydride (8 mg are added under condition of ice bath; 0.34 mmol); stirred under nitrogen atmosphere half an hour; add 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (89 mg, 0.28mmol), reaction solution stirring at room temperature 16 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3,4 '-piperidines]-2-ketone 5(40 mg, white solid), productive rate: 26.0%.
MS m/z (ESI): 539.1 [M+1]
1H NMR (400MHz, DMSO-d6) δ 7.77 (s, 1H), 7.57-7.50 (m, 2H), 7.38-7.36 (m, 1H), 7.21-7.198 (m, 1H), 7.15-7.13 (m, 1H), 7.09-7.03 (m, 1H), 5.19 (s, 2H), 4.58-4.56 (m, 3H), 4.50-4.48 (m, 2H), 4.30 (m, 2H), 3.35-3.32 (m, 4H), 2.68 (m, 2H), 1.83 (m, 4H), 1.69 (m, 2H), 1.45 (m, 2H)。
Embodiment 6
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone
The first step
The tertiary butyl-3,3-bis-(hydroxymethyl)-2-oxoindoline-1-carboxylicesters
By the tertiary butyl-2-oxoindoline-1-carboxylicesters 6a(12 g, 51.5 mmol) are dissolved in 100 mL1, in 4-dioxane, add formaldehyde solution (11.3 mL, 37 %) and sodium carbonate (1.0 g, 9.43 mmol), stirring at room temperature 2 hours.Reaction solution is concentrated, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate concentrates, and purifies gained resistates with silica gel column chromatography with eluent system B, obtain the tertiary butyl-3,3-bis-(hydroxymethyl)-2-oxoindoline-1-carboxylicesters 6b(10 g, white solid), productive rate: 66 %.
1H NMR (400 MHz, CDCl 3) δ 7.92-7.67 (m, 1 H), 7.41-7.36 (m, 2 H), 7.24-7.22 (m, 1 H), 4.79-4.71 (m, 1 H), 4.07-3.98 (m, 4 H), 1.67 (s, 9 H)。
Second step
The tertiary butyl-3,3-bis-(((methyl sulphonyl) oxygen) methyl)-2-oxoindoline-1-carboxylicesters
By the tertiary butyl-3,3-bis-(hydroxymethyl)-2-oxoindoline-1-carboxylicesters 6b(12 g, 10.9 mmol) are dissolved in 100 mL methylene dichloride.Reaction is cooled to 0 oc, adds triethylamine (37.5 mL, 21.8 mmol) and methylsulfonyl chloride (11.7 g, 21.8 mmol) successively by syringe.0 oc reacts 3 hours; reaction solution is concentrated; obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions; with dichloromethane extraction (100 mL × 2); merge organic phase; water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate concentrates; purify gained resistates with silica gel column chromatography with eluent system B, obtain the tertiary butyl-3,3-bis-(((methyl sulphonyl) oxygen) methyl)-2-oxoindoline-1-carboxylicesters 6c(7 g, colourless liquid), productive rate: 38 %.
1H NMR (400 MHz, CDCl 3) δ 7.90-7.88 (d, J = 8.0 Hz, 1H), 7.45-7.41 (m, 2 H), 7.28-7.24 (m, 1 H), 4.60-4.57 (d, J = 10.0 Hz, 2 H), 4.48-4.46 (d, J = 10.0 Hz, 2 H), 2.92 (s, 6 H), 1.65 (s, 9 H)。
3rd step
Spiral shell [indoline-3,3 '-Thietane base]-2 ketone
By the tertiary butyl-3,3-bis-(((methyl sulphonyl) oxygen) methyl)-2-oxoindoline-1-carboxylicesters 6c(8 g, 17.8 mmol) are dissolved in 100 mL DMF, add sodium sulphite (2.12 g, 27.2 mmol).Reaction is heated to 105 oc maintains 6 hours, room temperature is cooled to after reaction terminates, reaction solution is poured in frozen water-saturated ammonium chloride solution, reaction solution is concentrated, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate concentrates, purify gained resistates with silica gel column chromatography with eluent system B, obtain spiral shell [indoline-3,3 '-thietanyl]-2 ketone 6d(1.4 g, white solid), productive rate: 41 %.
1H NMR (400 MHz, CDCl 3) δ 7.98-7.96(d, J=7.2 Hz, 1 H), 7.81 (brs, 1 H), 7.23-7.19(m, 1H), 7.11-7.08 (m, 1H), 6.82-6.81 (d, J = 7.6 Hz, 1H), 3.82-3.79 (d, J = 9.6 Hz, 2H), 3.13-3.10 (d, J = 9.6 Hz, 2H)。
4th step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone
By spiral shell [indoline-3,3 '-thietanyl]-2 ketone 6d(80 mg; 0.42 mmol) be dissolved in 4 mL dry DMF; 60% sodium hydride (11 mg are added under condition of ice bath; 0.50 mmol); stirred under nitrogen atmosphere half an hour; add 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (120 mg, 0.42 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone 6(85 mg, white solid), productive rate: 47 %.
MS m/z (ESI): 472.0 [M+1]
1H NMR (400 MHz, CD 3OD) δ 8.22-8.20 (d, J = 7.2 Hz, 1H), 7.89-7.87 (m, 2H), 7.76-7.74 (d, J = 8.8 Hz, 1H), 7.40-7.38 (m, 1H), 7.32-7.28 (m, 1H), 7.10-7.08 (d, J = 7.6 Hz, 1H), 5.53 (s, 2H), 4.63-4.59 (t, J = 7.6 Hz, 2H), 3.90-3.88 (d, J = 9.6 Hz, 2H), 3.66-3.63 (t, J = 6.4 Hz, 2H), 3.27-3.24 (d, J = 9.6 Hz, 2H), 2.03-2.00 (m, 2H), 1.72-1.66 (m, 2H)。
Embodiment 7
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone-1 ', 1 '-dioxide
The first step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone-1 ', 1 '-dioxide
By 1-((the bromo-1-of 5-(4-hydroxybutane base)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-thietanyl]-2-ketone 7a(100 mg, 0.21mmol) be dissolved in the mixed solvent of 7.8 mL water-methanol-acetone (0.8:5.4:1.6), add Potassium Monopersulfate (320 mg, 0.42 mmol), stirring at room temperature 12 hours, reaction solution pours saturated ammonium chloride solution into, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate concentrates, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 1-((the bromo-1-of 5-(4-hydroxybutane base)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3, 3 '-thietanyl]-2-ketone-1 ', 1 '-dioxide 7(30 mg, white solid), productive rate: 25.7 %.
MS m/z (ESI): 504.0 [M+1]
1H NMR (400 MHz, CD 3OD) δ: 7.94-7.92 (d, J = 7.6 Hz, 1H), 7.82-7.76 (m, 2H), 7.66-7.64 (m, 1H), 7.39 (m, 1H), 7.29-7.27 (m, 1H), 7.12-7.10 (d, J = 8.0 Hz, 1H), 5.51 (s, 2H), 4.79-4.75 (m, 2H), 4.58-4.54 (m, 2H), 4.43-4.39 (m, 2H), 3.66-3.63 (m, 2H), 2.04-1.96 (m, 2H), 1.72-1.65 (m, 2H)。
Embodiment 8
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4,5-dihydro-2H-spiral shells [furans-3,3 '-indoline]-2 '-one
The first step
N-(2-bromophenyl) tetrahydrofuran (THF)-3-methane amide
By tetrahydrofuran (THF)-3-formic acid 8a(8.02 g, 70 mmol) are dissolved in 100 mL methylene dichloride, add oxalyl chloride (10 mL), stirring at room temperature 2 hours under ice bath.Reaction solution is concentrated, obtains dissolving crude product in 100 mL methylene dichloride, add o-bromoaniline (12.0 g, 70 mmol) and triethylamine (20 g, 210 mmol) under ice bath successively, stirring at room temperature 2 hours.Reaction solution concentrates, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate concentrates, and purifies gained resistates, obtain N-(2-bromophenyl) tetrahydrofuran (THF)-3-methane amide with silica gel column chromatography with eluent system B 8b(14 g, white solid), productive rate: 74 %.
1H NMR (400 MHz, CDCl 3) δ 8.31 (d, J=8.0 Hz, 1H), 7.96 (br. s., 1H), 7.61 - 7.46 (m, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.98 (t, J=7.3 Hz, 1H), 4.18 - 4.03 (m, 2H), 3.99 - 3.91 (m, 1H), 3.87 (q, J=7.7 Hz, 1H), 3.12 (td, J=6.5, 12.5 Hz, 1H), 2.37 - 2.23 (m, 2H)。
Second step
N-(2-bromophenyl)-N-(4-methoxy-benzyl) tetrahydrofuran (THF)-3-methane amide
By N-(2-bromophenyl) tetrahydrofuran (THF)-3-methane amide 8b(5.4 g, 20 mmol) are dissolved in 40 mL DMF, add 60% sodium hydride (1.6 g under condition of ice bath; 40 mmol), stirred under nitrogen atmosphere half an hour, then add p-methoxybenzyl chloride (4.68 g; 30 mmol), stirring at room temperature 12 hours.Reaction is poured in frozen water, with dichloromethane extraction (100 mL × 2), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate concentrates, purify gained resistates with silica gel column chromatography with eluent system B, obtain N-(2-bromophenyl)-N-(4-methoxy-benzyl) tetrahydrofuran (THF)-3-methane amide 8c(8.0 g, white solid), productive rate: 100 %.
1H NMR (400 MHz, CDCl 3) δ 7.73 - 7.66 (m, 1H), 7.25 - 7.16 (m, 2H), 7.08 (dd, J=6.4, 8.4 Hz, 2H), 6.78 (dd, J=1.6, 8.4 Hz, 2H), 6.76 - 6.65 (m, 1H), 5.56 (d, J=14.1 Hz, 1H), 4.01 - 3.83 (m, 3H), 3.79 - 3.76 (m, 3H), 3.67 (d, J=7.8 Hz, 2H), 2.76 - 2.63 (m, 1H), 2.44 - 2.32 (m, 1H), 2.16 - 2.02 (m, 1H), 1.97 - 1.85 (m, 1H), 1.84 - 1.72 (m, 1H)。
3rd step
1 '-(4-methoxy-benzyl)-4,5-dihydro-2H-spiral shell [furans-3,3 '-indoline]-2 '-one
By N-(2-bromophenyl)-N-(4-methoxy-benzyl) tetrahydrofuran (THF)-3-methane amide 8c(2.5 g, 6.4 mmol) be dissolved in 6 mL dioxane, add thricyclohexyl phosphorus (700 mg successively, 2.5 mmol and sodium tert-butoxide (1.75 g, 12.5 mmol), palladium (275 mg are added under nitrogen protection, 1.22 mmol). lower reaction 40 minutes are spent in microwave heating to 75, reacting liquid filtering, reaction solution concentrates, obtain crude product and add 100 mL saturated sodium bicarbonate aqueous solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate concentrates, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1 '-(4-methoxy-benzyl)-4, 5-dihydro-2H-spiral shell [furans-3, 3 '-indoline]-2 '-one 8d(1.2 g, white solid), productive rate: 61 %.
1H NMR (400 MHz, CDCl 3) δ 7.34 - 7.27 (m, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.20 - 7.10 (m, 1H), 7.09 - 6.99 (m, 1H), 6.84 (d, J=8.5 Hz, 2H), 6.80 - 6.73 (m, 1H), 4.86 (s, 2H), 4.30 - 4.18 (m, 2H), 4.14 - 4.04 (m, 1H), 3.97 (d, J=8.5 Hz, 1H), 3.77 (s, 3H), 2.66 - 2.46 (m, 1H), 2.26 - 2.12 (m, 1H)。
4th step
4,5-dihydro-2H-spiral shell [furans-3,3 '-indoline]-2 '-one
By 1 '-(4-methoxy-benzyl)-4,5-dihydro-2H-spiral shell [furans-3,3 '-indoline]-2 '-one 8d(2.0 g, 6.5 mmol) be dissolved in 10 mL trifluoromethanesulfonic acids, react 2 hours under room temperature, reaction solution is poured in frozen water, with dichloromethane extraction (100 mL × 2), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate concentrates, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 4,5-dihydro-2H-spiral shell [furans-3,3 '-indoline]-2 '-one 8e(0.96 g, white solid), productive rate: 80 %.
1H NMR (400 MHz, CDCl 3) δ 8.29 (br. s., 1H), 7.29 (d, J=7.3 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.11 - 7.01 (m, 1H), 6.92 (d, J=7.5 Hz, 1H), 4.28 - 4.19 (m, 2H), 4.07 (d, J=8.5 Hz, 1H), 3.97 (d, J=8.5 Hz, 1H), 2.54 (s, 1H), 2.19 (td, J=6.7, 12.9 Hz, 1H)。
5th step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4,5-dihydro-2H-spiral shells [furans-3,3 '-indoline]-2 '-one
By 4,5-dihydro-2H-spiral shell [furans-3,3 '-indoline]-2 '-one 8e(378 mg; 2.0 mmol) be dissolved in 10 mL dry DMF; 60% sodium hydride (96 mg are added under condition of ice bath; 2.4 mmol); stirred under nitrogen atmosphere half an hour; add 4-(2-chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (761 mg, 2.4 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4,5-dihydro-2H-spiral shell [furans-3,3 '-indoline]-2 '-one 8(340 mg, white solid), productive rate: 36.2%.
MS m/z (ESI): 470.0 [M+1]
1H NMR (400 MHz, CD 3OD) δ 7.97 - 7.89 (m, 2H), 7.81 (dd, J=1.6, 8.9 Hz, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.25 - 7.19 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 5.60 (d, J=1.8 Hz, 2H), 4.68 - 4.59 (m, 2H), 4.30 - 4.22 (m, 1H), 4.22 - 4.14 (m, 1H), 4.10 - 4.08 (d, J=8.8 Hz, 1H), 4.04-4.02 (d, J=8.8 Hz, 1H), 3.67 - 3.64 (t, J=6.0Hz, 2H), 2.58 - 2.54 (m, 1H), 2.34 - 2.31 (m, 1H), 2.08 – 2.04 (m, 2H), 1.72 - 1.68 (m, 2H)。
Embodiment 9
The tertiary butyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters
The first step
The tertiary butyl-3-((2-bromophenyl) amido formacyl) azetidinyl-1-carboxylicesters
By 1-(tertiary butyl oxycarbonyl) azetidinyl-3-carboxylic acid 9a(5.85 g, 29.07 mmol) are dissolved in 50 mL THF, and room temperature adds carbonyl dimidazoles (4.95 g, 30.52 mmol), return stirring 90 minutes.Room temperature adds 2-bromaniline (5.0 g; 29.07 mmol); return stirring 12 hours; by reaction solution concentrating under reduced pressure; obtain crude product and add 300 mL water; be extracted with ethyl acetate (200 mL × 2); merge organic phase; water (200 mL × 2), saturated nacl aqueous solution is used to wash (200 mL × 2) successively; with anhydrous sodium sulfate drying, filter, filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain the tertiary butyl-3-((2-bromophenyl) formamyl) azetidinyl-1-carboxylicesters 9b(5 g, colorless oil), productive rate: 48.4%.
1H NMR (400MHz, CDCl 3), δ 8.35 (d, J= 7.9 Hz, 1H), 7.66 (br. s., 1H), 7.55 (d, J= 7.9 Hz, 1H), 7.34 (t, J= 7.7 Hz, 1H), 7.02 (t, J= 7.5 Hz, 1H), 4.29 - 4.14 (m, 4H), 3.46 - 3.34 (m, 1H), 1.46 (s, 9H)。
Second step
The tertiary butyl-3-((2-bromophenyl) (4-methoxy-benzyl) formamyl) azetidinyl-1-carboxylicesters
By the tertiary butyl-3-((2-bromophenyl) formamyl) azetidinyl-1-carboxylicesters 9b(5.0 g; 14.08 mmol) be dissolved in 50 mL dry DMF; 60% sodium hydride (0.676 g is added under condition of ice bath; 16.89 mmol); stirred under nitrogen atmosphere half an hour; add p-methoxybenzyl chloride (2.42 g, 15.48 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 300 mL water; extraction into ethyl acetate (200 mL × 2); merge organic phase; water (200 mL × 3), saturated nacl aqueous solution is used to wash (200 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain the tertiary butyl-3-((2-bromophenyl) (4-methoxy-benzyl) formamyl) azetidinyl-1-carboxylicesters 9c(6.5 g, colorless oil), productive rate: 97.2%.
1H NMR (400MHz, CDCl 3) δ 7.69 (dd, J = 1.9, 7.7 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.65 (dd, J = 2.0, 7.3 Hz, 1H), 5.56 (d, J = 14.1 Hz, 1H), 4.29 (br. s., 1H), 4.00 (d, J = 14.3 Hz, 2H), 3.79 (s, 3H), 3.72 (br. s., 1H), 3.56 (br. s., 1H), 3.10 - 3.01 (m, 1H), 1.41 (s, 9H)。
3rd step
The tertiary butyl-1 '-(4-methoxy-benzyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters
By the tertiary butyl-3-((2-bromophenyl) (4-methoxy-benzyl) formamyl) azetidinyl-1-carboxylicesters 9c(1.63 g, 3.42 mmol) are dissolved in 5 mL dry toluenes, add palladium catalyst i-Pr-PEPPSI9 (163 mg, CAS:905459-27-0), sodium tert-butoxide (493 mg, 5.13 mmol), 110 oc microwave stirs 30 minutes.Add reaction solution 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 3), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain the tertiary butyl-1 '-(4-methoxy-benzyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 9d(3.7 g, colorless oil), productive rate: 68.6%.
1H NMR (400MHz, CDCl3) δ 7.59 (d, J = 7.3 Hz, 1H), 7.32 - 7.26 (m, 3H), 7.15 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 7.8 Hz, 1H), 4.89 (s, 2H), 4.47 (d, J = 8.3 Hz, 2H), 4.13 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 1.55 (s, 9H)。
4th step
The tertiary butyl-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters
By the tertiary butyl-1 '-(4-methoxy-benzyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 9d(3.68 g, 9.34 mmol) be dissolved in 108 mL acetonitriles and 36 mL water, add ceric ammonium nitrate (20.47 g, 37.36 mmol), stirring at room temperature 2 hours, add reaction solution 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 3) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain the tertiary butyl-2 '-oxo spiral shell [azetidinyl-3, 3 '-indoline]-1-carboxylicesters 9e(500 mg, yellow oily), productive rate: 19.5%.
1H NMR (400MHz, CDCl 3) δ 7.96 (br. s., 1H), 7.54 (d, J =7.3 Hz, 1H), 7.31 - 7.27 (t, J = 8.0 Hz, 1H), 7.18 - 7.09 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 8.3 Hz, 2H), 4.11 - 4.06 (m, 2H), 1.50 (s, 9H)。
5th step
The tertiary butyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters
By the tertiary butyl-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 9e(500 mg; 2.69 mmol) be dissolved in 5 mL dry DMF; 60% sodium hydride (129 mg are added under condition of ice bath; 3.22 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (939 mg, 2.955 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain the tertiary butyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 9(350 mg, white solid), productive rate: 23.5%.
MS m/z (ESI): 555.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.69 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.55 - 7.49 (d, J = 8.0 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 5.29 (s, 2H), 4.44 - 4.33 (m, 4H), 4.16 (d, J = 8.0 Hz, 2H), 3.60 (t, J = 6.1 Hz, 2H), 1.92 - 1.84 (m, 2H), 1.67 - 1.59 (m, 2H), 1.51 (s, 9H)。
Embodiment 10
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methylspiro [azetidinyl-3,3 '-indoline]-2 '-one
The first step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methylspiro [azetidinyl-3,3 '-indoline]-2 '-one
By the tertiary butyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 10a(330 mg, 0.59 mmol) is dissolved in 2 mL MeOH, and room temperature adds HCl/MeOH (4N, 2 mL), reaction solution stirring at room temperature 1 hour.Concentrating under reduced pressure, lyophilize obtain title product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methylspiro [azetidinyl-3,3 '-indoline]-2 '-one 10(200 mg, white solid), productive rate: 74.1%.
MS m/z (ESI): 455.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.93 (d, J = 7.3 Hz, 1H), 7.90 - 7.84 (m, 2H), 7.74 (d, J = 10.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 5.57 (s, 2H), 4.62 (t, J = 7.8 Hz, 2H), 4.56 - 4.49 (m, 2H), 4.47 - 4.39 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.06 (m, 2H), 1.74 - 1.67 (m, 2H)。
Embodiment 11
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-methylspiro [azetidinyl-3,3 '-indoline]-2 '-one
The first step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-methylspiro [azetidinyl-3,3 '-indoline]-2 '-one
By 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methylspiro [azetidinyl-3,3 '-indoline]-2 '-one 11a(180 mg, 0.40 mmol) be dissolved in 2 mL MeOH, add 3 acetic acid, paraformaldehyde (36 mg, 1.186 mmol), reaction solution stirring at room temperature 20 minutes, adds sodium cyanoborohydride (75 mg, 1.186 mmol), reaction solution was in stirring at room temperature 12 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, with preparative high-performance liquid chromatographic purify obtain title product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-methylspiro [azetidinyl-3,3 '-indoline]-2 '-one 11(60 mg, white solid), productive rate: 32.4%.
MS m/z (ESI): 469.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.99 - 7.84 (m, 3H), 7.75 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 5.59 (s, 2H), 4.77 - 4.70 (m, 2H), 4.63 (t, J = 7.7 Hz, 2H), 4.51 (d, J = 11.3 Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 3.66 (t, J = 5.9 Hz, 2H), 3.24 - 3.11 (m, 3H), 2.11 - 2.03 (m, 2H), 1.77 - 1.64 (m, 2H)。
Embodiment 12
Sec.-propyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters
The first step
1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By the tertiary butyl-1 '-(4-methoxy-benzyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 12a(500 mg, 1.27 mmol) are dissolved in 2 mL MeOH, and room temperature adds HCl/MeOH (4N, 2 mL), reaction solution stirring at room temperature 1 hour.Add reaction solution 100 mL saturated sodium carbonate solution, regulate pH to 9, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (50 mL × 3), saturated nacl aqueous solution to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains product 1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 12b(360 mg, yellow oily), product is not purified directly carries out next step reaction.
1H NMR (400MHz, DMSO-d6), δ 7.73 (d, J = 7.3 Hz, 1H), 7.28 - 7.17 (m, 3H), 7.09 (t, J = 8.0 Hz, 1H), 6.94 - 6.81 (m, 3H), 4.79 (s, 2H), 4.00 (d, J = 7.3 Hz, 2H), 3.69 (s, 3H), 3.55 (d, J = 7.3 Hz, 2H)。
Second step
Sec.-propyl-1 '-(4-methoxy-benzyl)-2 '-oxo [azetidinyl-3,3 '-indoline]-1-carboxylicesters
By 1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 12b(360 mg, 1.22 mmol) are dissolved in 4 mL methylene dichloride, and room temperature adds triethylamine (371 mg, 3.67 mmol), drip sec.-propyl oxygen base acyl chlorides (164 mg, 1.34 mmol), stirring at room temperature 1 hour under condition of ice bath.Add reaction solution 100 mL water, dichloromethane extraction (100 mL × 2), merge organic phase, use 1N hydrochloric acid (100 mL × 3), saturated sodium carbonate solution (100 mL × 2), water washing (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains product sec.-propyl-1 '-(4-methoxy-benzyl)-2 '-oxo [azetidinyl-3,3 '-indoline]-1-carboxylicesters 12c(460 mg, yellow oily), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.55 (d, J = 7.3 Hz, 1H), 7.26 - 7.19 (m, 3H), 7.11 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 5.01 – 4.95 (m, 1H), 4.84 (s, 2H), 4.46 (d, J = 8.0 Hz, 2H), 4.13 (d, J = 8.0 Hz, 2H), 3.78 (s, 3H), 1.29 (d, J = 6.3 Hz, 6H)。
3rd step
2,6-pyridine dicarboxylic acid-1-oxide compound
By pyridine-2,6-dicarboxylic acid 12e(15 g, 89.7 mmol) add in 50 mL hydrogen peroxide and form suspension liquid, and add the sodium wolframate (975 mg) of catalytic amount under room temperature condition, suspension liquid is heated to 100 oc stirs 2 hours.Be cooled to room temperature, again add 103mL hydrogen peroxide, be heated to 100 oc stirs 18 hours.Reaction solution is cooled to 0 oc, separates out white crystal, and suction filtration also uses frozen water washing leaching cake, obtains 2,6-pyridine dicarboxylic acid-1-oxide compound 12f(10 g, white solid), productive rate: 61%.
1H NMR (400 MHz, CDCl 3) δ8.73 (d, J=8.0 Hz, 2H), 7.98 (t, J=8.0 Hz, 1H)。
4th step
Sec.-propyl-2 '-oxo [azetidinyl-3,3 '-indoline]-1-carboxylicesters
By sec.-propyl-1 '-(4-methoxy-benzyl)-2 '-oxo [azetidinyl-3,3 '-indoline]-1-carboxylicesters 12c(350 mg, 0.92 mmol) is dissolved in 10.5 mL acetonitriles and 3.5 mL water, adds ceric ammonium nitrate (3.03 g, 5.52 mmol), 2,6-pyridine dicarboxylic acid-1-oxide compounds 12f(1.01 g, 5.52 mmol) stirring at room temperature 2 hours, add saturated sodium carbonate solution 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, water (100 mL × 3), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain sec.-propyl-2 '-oxo [azetidinyl-3,3 '-indoline]-1-carboxylicesters 12d(70 mg, yellow oily), productive rate: 29.3%.
1H NMR (400MHz, CDCl 3) δ 7.67 (br. s., 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.18 - 7.11 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.03 - 4.94 (m, 1H), 4.43 (d, J = 8.0 Hz, 2H), 4.15 - 4.09 (m, 2H), 1.31 - 1.26 (d, J = 4.0 Hz, 6H)。
5th step
Sec.-propyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters
By sec.-propyl-2 '-oxo [azetidinyl-3,3 '-indoline]-1-carboxylicesters 12d(70 mg; 0.269 mmol) be dissolved in 2 mL dry DMF; 60% sodium hydride (13 mg are added under condition of ice bath; 0.323 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (94 mg, 0.296 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product sec.-propyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 12(37 mg, white solid), productive rate: 25.3%.
MS m/z (ESI): 541.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.72-7.62 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.45-7.40 (m, 1H), 7.31-7.24 (m, 1H), 7.22-7.15 (m, 1H), 6.97 (d, J = 7.78 Hz, 1H), 5.29 (s, 2H), 4.98-4.93 (m, 1H), 4.45-4.32 (m, 4H), 4.20 (d, J = 7.78 Hz, 2H), 3.60 (t, J = 6.27 Hz, 2H), 1.93-1.85 (m, 2H), 1.67-1.56 (m, 2H), 1.29 (d, J = 6.27 Hz, 6H)。
Embodiment 13
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
The first step
1-isobutyryl-1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 13a(800 mg, 2.72 mmol) are dissolved in 8 mL methylene dichloride, and room temperature adds triethylamine (400 mg, 3.95 mmol), drip isobutyryl chloride (400 mg, 3.77 mmol), stirring at room temperature 18 hours under condition of ice bath.100 mL water are added to reaction solution; dichloromethane extraction (100 mL × 2); merge organic phase; use 1N hydrochloric acid (100 mL × 3), saturated sodium carbonate solution (100 mL × 2), water washing (100 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates 1-isobutyryl-1 is purified with eluent system B with silica gel column chromatography '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 13b(930 mg, yellow oily), productive rate: 93.9 %.
1H NMR (400 MHz, CDCl 3) δ7.48 (d, J=7.03 Hz, 1H), 7.21-7.26 (m, 3H), 7.08-7.14 (m, 1H), 6.85 (d, J=8.53 Hz, 2H), 6.79 (d, J=7.53 Hz, 1H), 4.84 (d, J=2.01 Hz, 2H), 4.62 (d, J=8.03 Hz, 1H), 4.46 (d, J=9.03 Hz, 1H), 4.29 (d, J=8.03 Hz, 1H), 4.19 (d, J=9.54 Hz, 1H), 3.75-3.79 (m, 3H), 2.53 (td, J=6.96, 13.68 Hz, 1H), 1.19 (d, J=7.03 Hz, 6H)。
Second step
1-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1-isobutyryl-1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 13b(830 mg, 2.277 mmol) be dissolved in 24 mL acetonitriles and 8 mL water, add ceric ammonium nitrate (7.5 g, 13.641 mmol), 2, 6-pyridine dicarboxylic acid-1-oxynitride (1.6 g, 9.1mmol) stirring at room temperature 2 hours, add saturated sodium carbonate solution 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 3) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1-isobutyryl spiral shell [azetidinyl-3, 3 '-indoline]-2 '-one 13c(100 mg, yellow oily), productive rate: 18 %.
1H NMR (400 MHz, CDCl 3)δ8.19 (br. s., 1H), 7.48 (d, J=7.03 Hz, 1H), 7.27-7.34 (m, 1H), 7.09-7.18 (m, 1H), 6.93 (d, J=8.03 Hz, 1H), 4.60 (d, J=8.03 Hz, 1H), 4.44 (d, J=9.54 Hz, 1H), 4.29 (d, J=8.03 Hz, 1H), 4.19 (d, J=9.54 Hz, 1H), 2.53 (td, J=6.78, 13.55 Hz, 1H), 1.14-1.22 (m, 6H)。
3rd step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 13c(100 mg; 0.41 mmol) be dissolved in 3 mL dry DMF; 60% sodium hydride (20 mg are added under condition of ice bath; 0.5 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (156 mg, 0.49 mmol), reaction solution stirring at room temperature 4 hours.Add reaction solution 50 mL water; extraction into ethyl acetate (50 mL × 2); merge organic phase; water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; with preparative high-performance liquid chromatographic purify obtain title product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 13(41 mg, white solid), productive rate: 19%.
MS m/z (ESI): 525.0 [M+1]
1H NMR (400MHz, CD 3OD) δ7.73 - 7.70 (m, 1H), 7.70 - 7.66 (m, 1H), 7.57 - 7.52 (m, 1H), 7.48 - 7.42 (m, 1H), 7.34 - 7.28 (m, 1H), 7.24 - 7.18 (m, 1H), 7.03 - 6.98 (m, 1H), 5.37 - 5.27 (m, 2H), 4.68 - 4.64 (m, 1H), 4.56 - 4.51 (m, 1H), 4.47 - 4.36 (m, 3H), 4.26 - 4.21 (m, 1H), 3.65 - 3.59 (m, 2H), 2.73 - 2.65 (m, 1H), 1.96 - 1.85 (m, 2H), 1.70 - 1.59 (m, 2H), 1.23 - 1.14 (m, 6H)。
Embodiment 14
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
The first step
1 '-(4-methoxy-benzyl)-1-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 14a(960 mg, 3.22 mmol) are dissolved in 4 mL methylene dichloride, and room temperature adds triethylamine (1000 mg, 9.9 mmol), drip Methanesulfonyl chloride (406 mg, 3.56 mmol), stirring at room temperature 1 hour under condition of ice bath.Add reaction solution 100 mL water; dichloromethane extraction (100 mL × 2); merge organic phase; use 1N hydrochloric acid (100 mL × 3), saturated sodium carbonate solution (100 mL × 2), water washing (100 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates 1 '-(4-methoxy-benzyl)-1-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 is purified with eluent system B with silica gel column chromatography '-one 14b(1.0 g, yellow oily), productive rate: 77 %.
1H NMR (400MHz, CDCl 3)δ 7.74 - 7.59 (m, 1H), 7.29 - 7.27 (m, 1H), 7.23 (d, J=8.3 Hz, 3H), 7.14 (s, 1H), 6.85 (d, J=8.5 Hz, 3H), 4.83 (s, 2H), 4.35 (s, 2H), 4.24 (s, 2H), 3.77 (s, 3H), 3.11 (s, 3H)。
Second step
1-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1 '-(4-methoxy-benzyl)-1-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 14b(0.6 g, 1.6 mmol) be dissolved in 10.5 mL acetonitriles and 3.5 mL water, add ceric ammonium nitrate (5.0 g, 9.1 mmol), 2, 6-pyridine dicarboxylic acid-1-oxynitride (1.6 g, 9.1mmol) stirring at room temperature 2 hours, add saturated sodium carbonate solution 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 3) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1-(methyl sulphonyl) spiral shell [azetidinyl-3, 3 '-indoline]-2 '-one 14c(150 mg, yellow oily), productive rate: 37 %.
1H NMR (400MHz, CDCl 3) δ 7.66 (d, J=7.5 Hz, 2H), 7.34 - 7.27 (m, 1H), 7.21 - 7.11 (m, 1H), 6.95 - 6.81 (m, 1H), 4.38 - 4.29 (m, 2H), 4.26 - 4.17 (m, 2H), 3.08 (s, 3H)。
3rd step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 14c(150 mg; 0.6 mmol) be dissolved in 2 mL dry DMF; 60% sodium hydride (48 mg are added under condition of ice bath; 1.2 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (228 mg, 0.72 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water; extraction into ethyl acetate (50 mL × 2); merge organic phase; water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; with preparative high-performance liquid chromatographic purify obtain title product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 14(60 mg, white solid), productive rate: 25.3%.
MS m/z (ESI): 533.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.93 - 7.88 (m, 1H), 7.87 - 7.85 (m, 1H), 7.84 - 7.80 (m, 1H), 7.80 - 7.74 (m, 1H), 7.43 - 7.35 (m, 1H), 7.34 - 7.26 (m, 1H), 7.11 - 7.03 (m, 1H), 5.58 (s, 2H), 4.62 (m, 2H), 4.42 (d, J=8.5 Hz, 2H), 4.20 (d, J=8.3 Hz, 2H), 3.65 (t, J=6.1 Hz, 2H), 3.13 (s, 3H), 2.11 - 1.99 (m, 2H), 1.78-1.60 (m, 2H)。
Embodiment 15
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
The first step
1-(Cyclopropylsulfonyl)-1 '-(4-methoxy-benzyl)-spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 15a(800 mg, 2.72 mmol) are dissolved in 10 mL methylene dichloride, and room temperature adds triethylamine (393 mg, 3.88 mmol), drip cyclopropyl sulfonyl chloride (573 mg, 4.08 mmol), stirring at room temperature 50 hours under condition of ice bath.Add reaction solution 100 mL water; dichloromethane extraction (100 mL × 2); merge organic phase; use 1N hydrochloric acid (100 mL × 3), saturated sodium carbonate solution (100 mL × 2), water washing (100 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates 1-(Cyclopropylsulfonyl)-1 '-(4-methoxy-benzyl) spiral shell [azetidinyl-3,3 '-indoline]-2 is purified with eluent system B with silica gel column chromatography '-one 15b(940 m g, yellow solid), productive rate: 87.1 %.
1H NMR (400 MHz, CDCl 3)δ 7.69 (d, J=7.5 Hz, 1H), 7.26 - 7.19 (m, 3H), 7.17 - 7.11 (m, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.80 (d, J=7.5 Hz, 1H), 4.83 (s, 2H), 4.51 (d, J=7.5 Hz, 2H), 4.19 (d, J=7.5 Hz, 2H), 3.78 (s, 3H), 2.71 - 2.59 (m, 1H), 1.26 (br. s., 2H), 1.18 - 1.11 (m, 2H)。
Second step
1-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
By 1-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 15b(850 mg, 2.17 mmol) be dissolved in 24 mL acetonitriles and 8 mL water, add ceric ammonium nitrate (7.03 g, 12.8 mmol), 2, 6-pyridine dicarboxylic acid-1-nitrogen superoxide (2.35 g, 12.8mmol) stirring at room temperature 2 hours, add saturated sodium carbonate solution 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 3) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3, 3 '-indoline]-2 '-one 15c(70 mg, yellow solid), productive rate: 11.6 %.
1H NMR (400 MHz, CDCl 3) δ 7.70 (d, J=7.5 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 4.48 (d, J=8.0 Hz, 2H), 4.20 (d, J=7.8 Hz, 2H), 2.63 (m, 1H), 1.29 - 1.26 (m, 2H), 1.18 - 1.12 (m, 2H)。
3rd step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one
General-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 15c(70 mg; 0.25 mmol) be dissolved in 1 mL dry DMF; 60% sodium hydride (15 mg are added under condition of ice bath; 0.37 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (96 mg, 0.3 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water; extraction into ethyl acetate (50 mL × 2); merge organic phase; water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; with preparative high-performance liquid chromatographic purify obtain title product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one 15(24 mg, white solid), productive rate: 17.1%.
MS m/z (ESI): 559.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.74 (d, J=7.0 Hz, 1H), 7.67 (br. s., 1H), 7.51 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.34 - 7.24 (m, 1H), 7.23 - 7.16 (m, 1H), 6.97 (d, J=7.8 Hz, 1H), 5.28 (s, 2H), 4.49 (d, J=7.8 Hz, 2H), 4.40 (t, J=6.9 Hz, 2H), 4.16 (d, J=7.8 Hz, 2H), 3.59 (m, 2H), 2.79 (m, 1H), 1.89 (m, 2H), 1.62 (m, 2H), 1.30 - 1.02 (m, 4H)。
Embodiment 16
The tertiary butyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters
The first step
Methyl-2-(2-nitrophenyl) acetic ester
By 2-(2-nitrophenyl) acetic acid 16a(60 g, 0.33 mmol) is dissolved in 300 mL MeOH, adds the 1 mL vitriol oil, reaction solution reflux 14 hours.Reaction solution is cooled to room temperature, concentrating under reduced pressure obtains oily matter, add 500 mL saturated sodium bicarbonate aqueous solutions, extraction into ethyl acetate (300 mL × 3), merges organic phase, uses water (200 mL × 3), saturated nacl aqueous solution to wash (200 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains methyl-2-(2-nitrophenyl) acetic ester 16b(64 g, yellow oily), productive rate: 99.1%.
1H NMR (400 MHz, CDCl 3) δ 8.11-8.09 (d, J=8.0 Hz, 1 H), 7.61-7.59 (t, J=7.6 Hz,1 H), 7.58-7.47 (t, J=71.2 Hz,1 H) , 7.45-7.35 (t, J=43.6 Hz,1 H), 4.02(s,2 H), 3.71(s,3 H)。
Second step
Methyl-2-(2-nitrophenyl) acrylate
By methyl-2-(2-nitrophenyl) acetic ester 16b(52 g, 0.27 mol) is dissolved in 416 mL toluene, adds paraformaldehyde (20.8 g, 0.63 mol), tetrabutyl iodate amine (3.95 g, 0.011 mol), salt of wormwood (109.2 g, 0.8 mol), reaction solution is heated to 80 oc, stirs 12 hours.Reaction solution is cooled to room temperature, add 500 mL water, extraction into ethyl acetate (300 mL × 3), merge organic phase, use water (200 mL × 3), saturated nacl aqueous solution to wash (200 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains methyl-2-(2-nitrophenyl) acrylate 16c(51.2 g, yellow oily), productive rate: 92.5%.
1H NMR (400 MHz, CDCl 3) δ 8.13-8.11(d, J=7.6 Hz,1 H), 7.67-7.65(t, J=8.8 Hz,1 H), 7.55-7.53(d, J=8.0 Hz,1 H) , 7.40-7.38(q, J=8.8 Hz,1 H), 6.54(s,1 H), 5.88(s,1 H), 3.73(s,3 H)。
3rd step
Methyl isophthalic acid-phenyl-3-(2-nitrophenyl) Pyrrolidine alkyl-3-carboxylicesters
By methyl-2-(2-nitrophenyl) acrylate 16c(6.2 g, 29.0 mmol) are dissolved in 50 mL chloroforms, add TFA (5.27 g, 46.3 mmol).N-benzyl-1-methoxyl group-N-((trimethyl silicon based) methyl) methylamine (8.25 g, 34.8 mmol) is dissolved in 25 mL chloroforms, under ice-water bath, instills reaction solution.Reaction solution is heated to 70 oc, reacts 12 hours.Reaction solution is cooled to room temperature, add 100 mL saturated sodium bicarbonate aqueous solutions, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (50 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system A, obtains methyl isophthalic acid-phenyl-3-(2-nitrophenyl) Pyrrolidine alkyl-3-carboxylicesters 16d(7.4 g, yellow oily), productive rate: 75%.
1H NMR (400 MHz, CDCl 3) δ 7.89-7.87(d, J=7.2 Hz,1H), 7.78-7.76(d, J=7.2 Hz,1 H), 7.57-7.37(t, J=79.6 Hz,1 H) , 7.35-7.31(t, J=14.0 Hz,5 H), 7.28-7.26(d, 1 H), 3.76-3.73(d, J=12.8 Hz, 1 H), 3.63-3.60(d, J=12.8 Hz,4 H), 3.33-3.31(d, J=10.0 Hz,1 H), 3.07-3.03(m,1 H), 2.84-2.81(d, J=10.8 Hz,2 H),2.64-2.62(d, J=8.4 Hz,1H), 2.16-2.14(d, J=6.4 Hz,1H),2.13-2.11(t, J=8.1 Hz,1 H)。
4th step
Spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
By methyl isophthalic acid-phenyl-3-(2-nitrophenyl) Pyrrolidine alkyl-3-carboxylicesters 16d(4.9 g, 14.5 mmol) are dissolved in 1 L methyl alcohol, add 50% wet palladium carbon (1.0 g), reaction solution under 55psi hydrogen pressure, 50 oc stirs 4 hours.Reacting liquid filtering, filtrate concentrates to obtain product spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 16e(2.7 g, colorless oil), product is not purified directly carries out next step reaction.
5th step
The tertiary butyl-2-oxygen spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters
By spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 16e(2.8 g, 14.8 mmol) are dissolved in 20 mL methylene dichloride, add 4.67 mL triethylamines, Boc2O (2.9 g, 13.3 mmol).Reaction solution stirring at room temperature half an hour.Add 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain the tertiary butyl-2-oxygen spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters 16f(1.4 g, yellow oily), productive rate: 36.8%.
1H NMR (400 MHz, CDCl 3) δ 7.54-7.45(t, J=45.6 Hz,1 H), 7.14-7.10(t, J=18.0 Hz,1 H), 7.01-7.00(t, J=15.6 Hz,1 H) , 6.85-6.83 (d, J=7.6 Hz,1 H), 3.78-3.67(m, 3 H), 3.64-3.48 (m, 1 H), 2.36-2.31(t, J=12.8 Hz,1 H),1.98(s, 1 H) ,2.13-2.11(t, J=18.8 Hz,9 H)。
6th step
The tertiary butyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters
By the tertiary butyl-2-oxygen spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters 16f(0.5 g, 1.74 mmol) be dissolved in 20 mL acetonitriles, add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (0.6 g, 1.91 mmol), salt of wormwood (0.7 g, 7.29 mmol), reaction solution reflux 10 hours.Reaction solution is cooled to room temperature, reacting liquid filtering, filtrate concentrates, gained resistates is purified with eluent system B with silica gel column chromatography, obtain the title product tertiary butyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters 16(0.38 g, white solid), productive rate: 38.5%.
MS m/z (ESI): 569.3 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.85(d, J=1.3 Hz, 1 H), 7.44-7.42(m, 1 H), 7.32-7.30(d, J=8.4 Hz, 1 H), 7.20-7.19(m, 1 H), 7.16-7.14(d, J=6.6 Hz, 1 H), 7.09(m, 1 H), 7.02-7.00(d, J=7.6 Hz, 1 H), 5.10-5.36(d, J=15.6 Hz, 0.5 H), 5.17-5.15(m, 1 H), 4.95-4.90(d, J=15.6 Hz, 0.5 H), 4.30-4.22(m, 1 H), 4.22-4.06(m, 1 H), 3.82-3.76(m, 1 H), 3.72-3.61(m, 4 H), 3.51-3.49(d, J=11.2 Hz, 1 H), 2.38-2.35(m, 1 H), 2.32-2.30(m, 1 H), 2.15-2.12(d, J=12.8 Hz, 2 H), 1.75-1.72(m, 2 H), 1.45-1.38(d, J=26.2 Hz, 9 H)。
Embodiment 17
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
The first step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
By the tertiary butyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) 2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1-carboxylicesters 17a(0.16 g, 0.28 mmol) is dissolved in 3 mL methyl alcohol, adds the methanol hydrochloride solution of 4 moles often liter of 3 mL, reaction solution stirring at room temperature 2 hours.By reaction solution concentrating under reduced pressure, obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 17(0.13 g, white solid), productive rate: 98.5%.
MS m/z (ESI): 469.0 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.90-7.87(d, J=11.2 Hz, 2 H), 7.76-7.74(m, 1 H), 7.58-7.56(d, J=7.6 Hz, 1 H), 7.40(m, 1 H), 7.28-7.26(m, 1 H), 7.15-7.13(m, J=8 Hz, 1 H), 5.56(s, 2 H), 4.64-4.60(m, 2 H), 3.84-3.76(m, 3 H), 3.68-3.62(m, 3 H), 2.62-2.57(m, 1 H), 2.53-2.48(m, 1 H), 2.06-2.02(m, 2 H), 1.72-1.27(m, 2 H)。
Embodiment 18
Sec.-propyl base-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters
The first step
Sec.-propyl base-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters
By 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 18a(0.09 g, 0.192 mmol) is dissolved in 2 mL anhydrous methylene chlorides, adds triethylamine (0.097 g, 0.96 mmol), reaction solution is cooled to-10 oc, slowly drips isopropoxy acyl chlorides (23.4 mg, 0.192 mmol).Reaction solution is slowly warming up to room temperature, stirs 1 hour.Add 50 mL water, extraction into ethyl acetate (30 mL × 2), merge organic phase, water (30 mL × 2), saturated nacl aqueous solution is used to wash (20 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product sec.-propyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) first)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters 18(56 mg, white solid), productive rate: 52.8%.
MS m/z (ESI): 555.1 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.73(s, 1 H), 7.69(m, 1 H), 7.50-7.47(d, J=8.4 Hz, 1 H), 7.42-7.24(m, 2 H), 7.11-7.08(m, 2 H), 5.32-5.27(s, J=18.1 Hz, 2 H), 4.93-4.90(m, 1 H), 4.39-4.36(m, 2 H), 3.86-3.67(m, 6 H), 2.43-2.41(m, 1 H), 2.40-2.24(m, 1 H), 1.85(s, 2 H), 1.62-1.59(m, 2 H), 1.31-1.25(m, 6 H)。
Embodiment 19
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
The first step
1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
By spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 19a(0.55 g, 2.928 mmol) be dissolved in 25 mL methylene dichloride, room temperature adds triethylamine (0.887 g, 8.782 mmol), 0 ° of C drips isobutyryl chloride (0.312 g, 2.975 mmol), stirring at room temperature 10 minutes, add 50 mL saturated ammonium chlorides, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 2) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain crude product 1 '-isobutyryl spiral shell [indoline-3, 3 '-Pyrrolidine alkyl]-2-ketone 19b(750 mg, white oil thing), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 8.49 - 8.20 (m, 1H), 7.20 - 7.13 (m, 1H), 7.08 (dd, J=3.3, 7.3 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.93 - 6.79 (m, 1H), 4.12 - 3.54 (m, 4H), 2.78 - 2.33 (m, 2H), 2.31 - 1.96 (m, 1H), 1.18 - 1.04 (m, 6H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
By 1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 19b(0.264 g, 1.023 mmol) be dissolved in 10 mL acetonitriles, room temperature adds 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (0.356 g, 1.126 mmol), salt of wormwood (0.430 g, 3.070 mmol), reflux 12 hours.Filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 19(240 mg, white solid), productive rate: 43.6%.
MS m/z (ESI): 539.1 [M+1]
1H NMR (400MHz, DMSO-d 6) δ 7.78 (s, 1H), 7.56 (dd, J=2.6, 8.8 Hz, 1H), 7.44 - 7.28 (m, 2H), 7.28 - 7.14 (m, 2H), 7.09 - 7.02 (m, 1H), 5.27 - 5.15 (m, 2H), 4.49 - 4.41 (m, 1H), 4.30 (t, J=7.1 Hz, 2H), 4.01 - 3.76 (m, 2H), 3.73 - 3.53 (m, 2H), 3.45 - 3.35 (m, 2H), 2.84 - 2.56 (m, 1H), 2.42 - 2.06 (m, 2H), 1.69 (br. s., 2H), 1.49 - 1.38 (m, 2H), 1.05 (t, J=7.3 Hz, 3H), 1.01 - 0.91 (m, 3H)。
Embodiment 20
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
The first step
1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
By spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 20a(0.55 g, 2.928 mmol) be dissolved in 25 mL methylene dichloride, room temperature adds triethylamine (0.887 g, 8.782 mmol), 0 ° of C drips methylsulfonyl chloride (0.335 g, 2.092 mmol), stirring at room temperature 10 minutes, add 50 mL saturated ammonium chlorides, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 2) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain crude product 1 '-(methyl sulphonyl) spiral shell [indoline-3, 3 '-Pyrrolidine alkyl]-2-ketone 20b(610 mg, white solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 8.09 (br. s., 1H), 7.24 (d, J=7.5 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.07 - 7.00 (m, 1H), 6.86 (d, J=7.9 Hz, 1H), 3.81 - 3.67 (m, 2H), 3.63 - 3.51 (m, 2H), 2.92 (s, 3H), 2.40 - 2.18 (m, 2H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone
By 1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 20b(0.152 g, 0.573 mmol) be dissolved in 5 mL acetonitriles, room temperature adds 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (0.199 g, 0.630 mmol), salt of wormwood (0.237 g, 1.719 mmol), reflux 10 hours.Filter; filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone 20(93 mg, white solid), productive rate: 29.7%.
MS m/z (ESI): 547.0 [M+1]
1H NMR (400MHz, CDCl 3) δ 7.85 (d, J=1.8 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.32 (dd, J=1.8, 8.8 Hz, 1H), 7.23 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.07 - 7.02 (m, 1H), 5.24 - 5.08 (m, 2H), 4.27 - 4.13 (m, 2H), 3.80 - 3.70 (m, 2H), 3.68 - 3.53 (m, 4H), 2.94 (s, 3H), 2.37 (td, J=6.4, 12.8 Hz, 1H), 2.23 (td, J=7.5, 12.8 Hz, 1H), 1.78 - 1.68 (m, 2H), 1.62 - 1.53 (m, 2H)。
Embodiment 21
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone
The first step
Methyl-2-(nitrophenyl) oxirane base-2-carboxylicesters
By methyl-2-(nitrophenyl) acrylate 21a(4.0 g, 19.28 mmol) are dissolved in 24 mL chloroforms, and reaction solution is cooled to 0 oc, adds metachloroperbenzoic acid (13.36 g, 77.2 mmol).Reaction solution is warming up to 70 oc, stirs 12 hours.Reaction solution is cooled to room temperature, add 100 mL saturated aqueous sodium thiosulfate, extraction into ethyl acetate (50 mL × 2), merge organic phase, use saturated aqueous sodium thiosulfate (30 mL × 2), saturated sodium bicarbonate aqueous solution (30 mL × 2) successively, sodium chloride solution washing (30 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain methyl-2-(nitrophenyl) oxirane base-2-carboxylicesters 21b(2.0 g, colorless oil), productive rate: 46.5%.
1H NMR (400MHz, CDCl 3) δ 8.16-8.14(d, J =8.4 Hz, 1H), 7.68 - 7.63(m, 2 H), 7.52 - 7.50(m, 1 H), 3.73- 3.71(d, J =8.4 Hz, 2 H), 3.67(s, 3H), 2.92-2.90(d, J =8.4 Hz, 2 H)。
Second step
Methyl-3-hydroxyl-4-((2-hydroxyethyl) methyl) amido)-3-(2 nitrophenyl)-2-Oxobutyric acid ester
By methyl-2-(nitrophenyl) oxirane base-2-carboxylicesters 21b(1.0 g, 4.48 mmol) are dissolved in 20 mL methyl alcohol, and add 2-(methyl amido) ethanol (0.53 g, 8.96 mmol), reaction solution is heated to 50 oc stirs 10 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains methyl-3-hydroxyl-4-((2-hydroxyethyl) methyl) amido)-3-(2 nitrophenyl)-2-Oxobutyric acid ester 21c(0.68 g, yellow oily), productive rate: 50.9%.
1H NMR (400MHz, CDCl 3) δ 7.99-7.93(m, 2H), 7.68-7.64(t, J =8.0 Hz, 1H), 7.51-7.46 (t, J =8.0 Hz, 1H), 3.84-3.80(d, J =14.0 Hz, 1H), 3.77-3.70(m, 4H), 3.69-3.65(m, 4 H), 2.94-2.91(d, J =14.0 Hz, 1H), 2.80-2.78(m, 2H), 2.36(s, 3 H)。
3rd step
Methyl-2 (4-methyl-2-(nitrophenyl) morpholine-2-base)-2-Oxobutyric acid ester
By methyl-3-hydroxyl-4-((2-hydroxyethyl) methyl) amido)-3-(2 nitrophenyl)-2-Oxobutyric acid ester 21c(0.38 g, 1.275 mmol) be dissolved in 1 of 4 mL, 4-dioxane, adds three (3,6-dioxo constructed from normal heptyl) amine (5.0 m g, 0.0153 mmol), potassium hydroxide (0.286 g, 5.1 mmol), slowly drips Tosyl chloride (0.322 g, 1.6 mmol) 2mL Isosorbide-5-Nitrae-dioxane solution.Reaction solution stirring at room temperature 12 hours, add 50 m water, extraction into ethyl acetate (50 mL × 2), merge organic phase, use saturated sodium bicarbonate aqueous solution (30 mL × 2) successively, sodium chloride solution washing (30 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain methyl-2 (4-methyl-2-(nitrophenyl) morpholine-2-base)-2-Oxobutyric acid ester 21d(0.16 g, yellow oily), productive rate: 44.6%.
1H NMR (400MHz, CDCl 3) δ 7.60 - 7.50 (m, 3H), 7.50 - 7.43 (m, 1H), 3.93 - 3.87 (m, 1H), 3.86 - 3.83 (m, 3H), 3.65 - 3.50 (m, 1H), 3.18 - 3.05 (m, 1H), 2.99 - 2.86 (m, 1H), 2.44 (t, J=4.8 Hz, 2H), 2.34 (s, 3H)。
4th step
4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone
By methyl-2 (4-methyl-2-(nitrophenyl) morpholine-2-base)-2-Oxobutyric acid ester 21d(0.2 g, 0.65 mmol) is dissolved in 100 mL methyl alcohol, adds 50% wet palladium carbon (100 mg), reaction solution under 30 psi hydrogen pressures, stirring at room temperature 2 hours.Reacting liquid filtering, concentrates to obtain product 4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone 21e(0.13 mg, yellow oil), product is not purified directly carries out next step reaction.
5th step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone
By 4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone 21e(0.124 g, 0.569 mmol) be dissolved in 3 mL acetonitriles, add 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (0.19 g, 0.626 mmol), salt of wormwood (0.294 g, 1.707 mmol), be heated to backflow, react 7 hours.Reaction solution adds 30 mL water, extraction into ethyl acetate (30 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4 '-methylspiro [indoline-3,2 '-tetrahydrochysene morpholine alkyl]-2-ketone 21(0.1 g, white solid), productive rate: 337.6%.
MS m/z (ESI): 499.1 [M+1]
1H NMR (400MHz, CDCl 3) δ 7.85 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.03 - 6.94 (m, 1H), 5.27 (d, J=15.4 Hz, 1H), 4.99 (d, J=15.4 Hz, 1H), 4.39 - 4.10 (m, 2H), 3.97 (br. s., 1H), 3.59 (br. s., 2H), 2.71 - 2.42 (m, 4H), 2.24 (s, 3H), 1.74 - 1.51 (m, 4H), 1.47 - 1.41 (m, 1H)。
Embodiment 22
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [imidazolidine-4,3 '-indoline]-2,2 ', 5-triketone
The first step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H benzo [d] imidazoles-2-base) methyl indoline 2,3-diketone
By indoline-2; 3-diketone (400 mg; 26.22 mmol) be dissolved in 4 mL dry DMF; 60% sodium hydride (125.6 mg are added under condition of ice bath; 5.24 mmol); stirred under nitrogen atmosphere 30 minutes, adds 4-(the bromo-2-of 5-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol 22a(624 mg, 2.62 mmol), reaction solution stirring at room temperature 8 hours.The water of 50 mL is added in reaction solution, extraction into ethyl acetate (100 mL × 2), merge organic phase, water (100 mL × 3), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H benzo [d] imidazoles-2-base) methyl indoline 2,3-diketone is obtained with purifying with eluent system B with silica gel column chromatography 22b(517 mg, white solid), productive rate: 46.2%.
1H NMR (400 MHz, CD 3OD)δ 7.91 (s, 1H), 7.62 - 7.53 (m, 3H), 7.41 (d, J =8.2 Hz, 1H), 7.24 (d, 1H), 7.14 - 7.11 (t, J =8.0 Hz 1H), 5.25 (s, 2H), 4.28 (t, 2H), 3.67 (t, 2H), 1.85 - 1.77 (m, 2H), 1.68 - 1.64 (m, 2H)。
Second step
1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [imidazolidine-4,3 '-indoline]-2,2 ', 5-triketone
By 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H benzo [d] imidazoles-2-base) methyl indoline 2,3-diketone 22b(390 mg, 0.91mmol) be dissolved in the mixing solutions of the ethanol of 4 mL and the water of 2 mL, add potassium cyanide (94.6 mg, 1.45 mmol) and volatile salt (401.5 mg, 6.37 mmol), stirring and refluxing 2 hours under nitrogen protection, reaction solution is poured in the aqueous sodium hydroxide solution (0.1M) of 50 mL and is stirred 10 minutes, the water of 50 mL will be added in reaction solution, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain target product 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [imidazolidine-4, 3 '-indoline]-2, 2 ', 5-triketone 22(66.5 mg, white solid), productive rate: 15.4%.
MS m/z (ESI): 497.9 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.98 (s, 1H), 7.87 (d, J =8.2 Hz, 1H), 7.75 (dd, J =8.0 Hz 1H), 7.55 - 7.44 (m, 2H), 7.31 - 7.25 (m, 2H), 5.64 - 5.50 (m, 2H), 4.61 - 4.52 (m, 2H), 3.67 - 3.55 (m, 2H), 2.03 - 1.92 (m, 2H), 1.69 - 1.58 (m, 2H)。
Embodiment 23
1-((1-(4-hydroxyl fourth collection)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one
The first step
O-aminoacetophenone
By ortho-nitroacetophenone 23a(3.0 g, 18.2 mmol) are dissolved in 50 mL methyl alcohol, and add 50% wet palladium carbon (300 mg), reaction solution, in room temperature, under hydrogen balloon pressure, stirs 2 hours.Reacting liquid filtering, concentrates to obtain product o-aminoacetophenone 23b(2.0 g, yellow oil), product is not purified directly carries out next step reaction.
1H NMR (400MHz, DMSO-d6) δ 7.73 (d, J= 8.0 Hz, 1H), 7.26-7.22 (m, 1H), 6.75 (d, J= 8.0 Hz, 1H), 6.54 (t, J= 8.0 Hz, 1H), 2.50 (s, 3H)。
Second step
N-(2-acetylphenyl)-2,2,2-trichoroacetic chlorides
By o-aminoacetophenone 23b(1.8 g, 13.32 mmol) are dissolved in 18 mL tetrahydrofuran (THF)s, and room temperature adds N, N-lutidine-4-amine (1.62 g, 13.28 mmol), drip 2,2 under condition of ice bath, 2-trichoroacetic chloride (3.63 g, 19.98 mmol), stirring at room temperature 2 hours.Reaction solution adds 200 mL water; extraction into ethyl acetate (200 mL × 2); merge organic phase, use saturated sodium bicarbonate solution (200 mL × 3), water (200 mL × 3), saturated nacl aqueous solution to wash (200 mL × 2), with anhydrous sodium sulfate drying successively; filter; filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains N-(2-acetylphenyl)-2; 2,2-trichoroacetic chloride 23c(3.7 g, faint yellow solid), productive rate: 99.0%.
1H NMR (400MHz, DMSO-d6) δ 12.92 (s, 1H), 8.39 (d, J= 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.74 (t, J= 8.0 Hz, 1H), 7.39 (t, J= 8.0 Hz, 1H), 2.70 (s, 3H)。
3rd step
4-methylquinazolin-2 (1H)-one
By N-(2-acetylphenyl)-2,2,2-trichoroacetic chlorides 23c(3.7 g, 13.2 mmol) are dissolved in 26 mL DMSO, and room temperature adds ammonium acetate (5.1 g, 65.9 mmol), stirring at room temperature 24 hours.Reaction solution adds 10 mL water, separates out solid filtering and obtains crude product, purify obtain product 4-methylquinazolin-2 (1H)-one with preparative high-performance liquid chromatographic 23d(110 mg, white solid), productive rate: 23.1%.
1H NMR (400MHz, CDCl3) δ 12.89 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.30 (d, J= 8.0 Hz, 1H), 2.85 (s, 3H)。
4th step
1-((1-(4-hydroxyl fourth collection)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one
By 4-methylquinazolin-2 (1H)-one 23d(56 mg, 0.35 mmol) is dissolved in 2 mL DMF, drips LiHMDS (1M, 0.36 mmol) under condition of ice bath, stirs 30 minutes under ice bath.Add 4-(2-chloromethyl-1H-benzo [d] imidazoles-1-base) butane-1-alcohol (122 mg, 0.51 mmol), 55-60 oc stirs 6 hours.Reaction solution adds 0.5 mL shrend and to go out reaction, purifies obtain title product 1-((1-(4-hydroxyl fourth collection)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one with preparative high-performance liquid chromatographic 23(91 mg, white solid), productive rate: 71.7%.
MS m/z (ESI): 363.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.16 (d, J = 8.0 Hz, 1H), 7.78 (t, J= 8.0 Hz, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 1H), 7.40 (t, J= 8.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.24 - 7.18 (m, 1H), 5.85 (s, 2H), 4.47 (t, J = 8.0 Hz, 2H), 3.62 (t, J= 6.0 Hz, 2H), 2.87-2.85 (m, 3H), 1.99-1.92 (m, 2H), 1.71-1.64 (m, 2H)。
Embodiment 24
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one
The first step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one
By 4-methylquinazolin-2 (1H)-one 24a(1.0 g; 6.27 mmol) be dissolved in 20 mL acetonitriles; add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (300 mg; 1.25 mmol), salt of wormwood (1.29 g; 9.4 mmol) and potassiumiodide (20.75 mg; 0.12 mmol), return stirring 14 hours under nitrogen protection.Reaction solution is poured in 20 mL hydrochloric acid solns (2N), pH to 7-8 is regulated with saturated sodium bicarbonate, be extracted with ethyl acetate (300 mL × 3), merge organic phase, water (300 mL × 2), saturated nacl aqueous solution is used to wash (300 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains target product and obtain 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one 24(159.7 mg, white solid), productive rate: 31.8%.
MS m/z (ESI): 440.8 [M+1]
1H NMR (400MHz, CD 3OD-d 4) δ 8.18 (d, J= 8.5 Hz, 1H), 7.79 (t, J= 8.7 Hz, 1H), 7.60 (m,3H), 7.43 (m, 2H), 5.84 (s, 2H), 4.47 (t, J= 8.6 Hz, 2H), 3.62 (t, J= 7.7 Hz, 2H), 2.87 (s, 3H), 2.01 -2.06 (m, 2H), 1.62 - 1.67 (m, 2H)。
Embodiment 25
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one
The first step
4-isopropylquinazolin-2 (1H)-one
Be dissolved in 20 mL ether by isopropyl magnesium bromide (56 mL, 55.87 mmol), room temperature drips 2-amino-benzene cyanogen 25a(2.0 g, 16.93 mmol) (being dissolved in 20 mL ether), return stirring 30 minutes.0-5 omethyl-chloroformate (2.4 g, 25.39 mmol) is dripped, return stirring 14 hours under C.Reaction solution is poured in 20 mL hydrochloric acid solns (2N), pH to 7-8 is regulated with saturated sodium bicarbonate, be extracted with ethyl acetate (300 mL × 3), merge organic phase, use water (300 mL × 2), saturated nacl aqueous solution to wash (300 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 4-isopropylquinazolin-2 (1H)-one 25b(1.2 g, faint yellow solid), productive rate: 37.6%.
1H NMR (400MHz, DMSO-d6) δ 11.69 (br. s., 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 3.81 – 3.70 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one
By 4-isopropylquinazolin-2 (1H)-one 25b(130 mg; 0.693 mmol) be dissolved in 10 mL dry DMF; 60% sodium hydride (30 mg are added under condition of ice bath; 0.76 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (200 mg, 0.63 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one 25(70 mg, white solid), productive rate: 23.6%.
MS m/z (ESI): 468.9 [M+1]
1H NMR (400MHz, DMSO-d6) δ 8.20 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.60 - 7.57 (m, 2H), 7.40 - 7.31 (m, 2H), 5.72 (s, 2H), 4.53 (br. s., 1H), 4.40 (t, J = 7.4 Hz, 2H), 3.91 – 3.85 (m, 1H), 3.46 – 3.42 (m, 2H), 1.84 – 1.76 (m, 2H), 1.55 - 1.45 (m, 2H), 1.30 (d, J = 6.8 Hz, 6H)。
Embodiment 26
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-cyclopropyl quinazoline-2 (1H)-one
The first step
4-cyclopropyl quinazoline-2 (1H)-one
By 2-amino-benzene cyanogen 26a(2.0 g; 16.93 mmol) be dissolved in the ether of 40 mL; diethyl ether solution (the 0.5M of cyclopropyl magnesium bromide is added under condition of ice bath; 111.6 mL); stirred under nitrogen atmosphere 30 minutes; add methyl-chloroformate (8.12 g, 55.87 mmol), reaction solution stirring at room temperature 10 hours.The water of 80 mL is added in reaction solution, extraction into ethyl acetate (100 mL × 2), merge organic phase, saturated sodium bicarbonate solution (100 mL × 3), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filtering, filtrate reduced in volume, obtaining product 4-cyclopropyl quinazoline-2 (1H)-one with purifying with eluent system B with silica gel column chromatography 26b(1.05 g, white solid), productive rate: 33.3%.
1H NMR (400MHz, MeOD-d 4) δ 8.30 (d, J= 8.2 Hz, 1H), 7.88 (t, J= 8.0 Hz, 1H), 7.49 - 7.27 (m, 2H), 2.94 - 2.73 (m, 1H), 1.45 - 1.38 (m, 2H), 1.30 - 1.24 (m, 2H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-cyclopropyl quinazoline-2 (1H)-one
By 4-cyclopropyl quinazoline-2 (1H)-one 26b(128 mg, 0.68mmol) be dissolved in the DMF of 3 mL, 60% sodium hydride (30.1 mg are added under condition of ice bath, 12.5 mmol), stirred under nitrogen atmosphere half an hour, add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (150 mg, 0.63 mmol), reaction solution stirring at room temperature 2 hours, stirring at room temperature 24 hours under nitrogen protection, reaction solution adds cancellation in the water of 50 mL, add extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain target product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-cyclopropyl quinazoline-2 (1H)-one 26(41.22 mg, white solid), productive rate: 13.8%.
MS m/z (ESI): 466.9 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.48 - 8.43 (d, J= 8.2 Hz, 1H), 7.84 - 7.77 (t, J= 8.0 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.48 - 7.40 (m, 2H), 5.84 (s, 2H), 4.54 - 4.42 (t, 2H), 3.69 - 3.59 (t, 2H), 2.98 - 2.86 (m, 1H), 2.01 - 1.90 (m, 2H), 1.73 - 1.63 (m, 2H), 1.51 - 1.44 (m, 2H), 1.32 (m, 2H)。
Embodiment 27
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-phenylquinazoline-2 (1H)-one
The first step
4-phenylquinazoline-2 (1H)-one
Be dissolved in 20 mL ether by phenyl-magnesium-bromide (56 mL, 55.87 mmol), room temperature drips 2-amino-benzene cyanogen 27a(2.0 g, 16.93 mmol) (being dissolved in 20 mL ether), return stirring 30 minutes.0-5 omethyl-chloroformate (2.4 g, 25.39 mmol) is dripped, return stirring 14 hours under C.Reaction solution is poured in 20 mL hydrochloric acid solns (2N), pH to 7-8 is regulated with saturated sodium bicarbonate, be extracted with ethyl acetate (300 mL × 3), merge organic phase, use water (300 mL × 2), saturated nacl aqueous solution to wash (300 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 4-phenylquinazoline-2 (1H)-one 27b(1.2 g, faint yellow solid), productive rate: 37.6%.
1H NMR (400MHz, DMSO-d6), δ 11.97 (s, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.70 - 7.54 (m, 6H), 7.38 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-phenylquinazoline-2 (1H)-one
By 4-phenylquinazoline-2 (1H)-one 27b(154 mg; 0.693 mmol) be dissolved in 5 mL dry DMF; 60% sodium hydride (30 mg are added under condition of ice bath; 0.76 mmol); stirred under nitrogen atmosphere half an hour; add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (200 mg, 0.63 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-phenylquinazoline-2 (1H)-one 27(200 mg, white solid), productive rate: 22.3%.
MS m/z (ESI): 502.8 [M+1]
1H NMR (400MHz, DMSO-d6) δ 7.86 - 7.77 (m, 2H), 7.76 - 7.67 (m, 4H), 7.67 - 7.61 (m, 4H), 7.41 - 7.30 (m, 2H), 5.80 (s, 2H), 4.53 (t, J= 5.0 Hz, 1H), 4.44 (t, J= 7.3 Hz, 2H), 3.46 (q, J = 6.0 Hz, 2H), 1.89 – 1.81 (m, 2H), 1.58 - 1.49 (m, 2H)。
Embodiment 28
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-dimethyl) quinazoline-2 (1H)-one
The first step
2,4-dichloroquinazoline
By quinazoline-2,4 (1H, 3H)-diketone 28a(4.86 g, 0.03 mol) is dissolved in 20 mL phosphorus oxychloride, drips diisopropylethylamine (7.76 g, 0.06 mol), return stirring 8 hours, reaction solution pours 100 mL water into, stirs 30 minutes, separate out solid, filter to obtain 2,4-dichloroquinazolines 28b(4.9 g, white solid), productive rate: 80.0%.
Second step
2-chloro-N, N-dimethyl quinazoline-4-amine
By 2,4-dichloroquinazoline 28b(1.5 g, 7.5 mmol) are dissolved in 20 mL tetrahydrofuran (THF)s, 0 oc drips 3 mL 33% triethylamine aqueous solutions, stirring at room temperature 30 minutes, reaction solution pours 50 mL aqueous ammonium chloride solution cancellation reactions into, with dichloromethane extraction (100 mL × 2), merges organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain product 2-chloro-N, N-dimethyl quinazoline-4-amine 28c(1.8 g, yellow oil), product is not purified directly carries out next step reaction.
3rd step
4-N, N-dimethyl quinazoline-2 (1H)-one
By chloro-for 2-N, N-dimethyl quinazoline-4-amine 28c(400 mg, 1.92 mmol) are dissolved in 4 mL acetic acid, and 70 oc stirs 1.5 hours, and reaction solution is in 65 oc concentrates to obtain product 4-N, N-dimethyl quinazoline-2 (1H)-one 28d(400 mg, yellow oil), product is not purified directly carries out next step reaction.
4th step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-dimethyl) quinazoline-2 (1H)-one
By 4-N, N-dimethyl quinazoline-2 (1H)-one 28d(200 mg, 1.05 mmol), be dissolved in 3 mL acetonitriles, add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (336 mg, 1.05 mmol), add salt of wormwood (483 mg, 3.50 mmol), return stirring 12 hours, reaction solution pours 50 mL aqueous ammonium chloride solution cancellation reactions into, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-dimethyl) quinazoline-2 (1H)-one 28(200 mg, white solid), productive rate: 40.0%.
MS m/z (ESI): 470.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.09-8.07 (d, J=8.0 Hz, 1 H), 7.59-7.67 (m, 2H), 7.46 -7.52 (m, 2 H), 7.40-7.42 (m, 1 H), 7.27 (t, J=7.7 Hz, 1 H), 5.75 (s, 2H), 4.42 (t, J=7.5 Hz, 2 H), 3.59 (t, J=6.0 Hz, 2 H), 3.42 (s,6 H), 1.89-1.85 (m, 2 H), 1.66-1.62 (m, 2 H)。
Embodiment 29
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-diethyl) quinazoline-2 (1H)-one
The first step
2-chloro-N, N-diethyl quinazoline-4-amine
By 2,4-dichloroquinazoline 29a(2 g, 10.0 mmol) are dissolved in 40 mL tetrahydrofuran (THF)s, 0 oc drips dimethylamine (1.5g, 20.0mmol), stirring at room temperature 30 minutes, adds 50 mL saturated ammonium chloride solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains product 2-chloro-N, N-diethyl quinazoline-4-amine 29b(2.3 g, yellow solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.89 (d, J=8.3 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.72 - 7.65 (m, 1H), 7.42 - 7.34 (m, 1H), 3.77 (q, J=6.9 Hz, 4H), 1.42 (t, J=7.0 Hz, 6H)。
Second step
4-N, N-diethyl quinazoline-2 (1H)-one
By chloro-for 2-N, N-diethyl quinazoline-4-amine 29b(1g, 4.2 mmol) are dissolved in 10 mL acetic acid, 70 oc stirs 1.5 hours, reaction solution concentrating under reduced pressure, purifies gained resistates, obtain 4-N, N-diethyl quinazoline-2 (1H)-one with silica gel column chromatography with eluent system A 29c(0.9 g, yellow solid), productive rate: 98%.
1H NMR (400MHz, CD 3OD) δ 8.05 (d, J=8.5 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.48 - 7.32 (m, 1H), 3.98 (q, J=7.0 Hz, 1H), 3.98 (t, J=20.0 Hz, 4H)，1.51 (t, J=7.0 Hz, 6H)。
3rd step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-diethyl) quinazoline-2 (1H)-one
By 4-N, N-diethyl quinazoline-2 (1H)-one 29c(100 mg, 0.5 mmol) is dissolved in 5 mL acetonitriles, adds 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (144 mg, 0.5 mmol), salt of wormwood (125mg, 0.9 mmol), return stirring 2 hours.30 mL saturated ammonium chloride solutions add reaction solution dichloromethane extraction (50 mL × 2), merge organic phase, water (50 mL × 2), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-diethyl) quinazoline-2 (1H)-one 29(50 mg, white solid), productive rate: 22.0%.
MS m/z (ESI): 498.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.92 (d, J=8.0 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.49 (t, J=8.2 Hz, 2H), 7.43 - 7.38 (m, 1H), 7.27 (t, J=7.5 Hz, 1H), 5.74 (s, 2H), 4.42 (t, J=7.7 Hz, 2H), 3.81 (q, J=7.0 Hz, 4H), 3.59 (t, J=6.3 Hz, 2H), 1.89 (td, J=7.6, 15.2 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.44 (t, J=7.0 Hz, 6H)。
Embodiment 30
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-morpholine quinazoline-2 (1H)-one
The first step
4-(2-chloro-quinazoline-4-base) morpholine
By 2,4-dichloroquinazoline 30a(300mg, 1.5 mmol) are dissolved in 5 mL tetrahydrofuran (THF)s, 0 oc drips morpholine (328mg, 3.78mmol), stirring at room temperature 30 minutes, add 50 mL saturated ammonium chloride solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains product 4-(2-chloro-quinazoline-4-base) morpholine 30b(300 mg, yellow solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.92 - 7.80 (m, 2H), 7.79 - 7.69 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 3.89 (s, 1H)。
Second step
4-morpholine quinazoline-2 (1H)-one
By 4-(2-chloro-quinazoline-4-base) morpholine 30b(400 mg, 1.92 mmol) are dissolved in 4 mL acetic acid, 70 oc stirs 1.5 hours, reaction solution concentrating under reduced pressure, obtains product 4-morpholine quinazoline-2 (1H)-one 30c(400 mg, yellow solid), product is not purified directly carries out next step reaction.
3rd step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-morpholine quinazoline-2 (1H)-one
By 4-morpholine quinazoline-2 (1H)-one 30c(109 mg, 0.5 mmol) be dissolved in 3 mL acetonitriles, add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (100 mg, 0.3 mmol), salt of wormwood (174 mg, 1.3 mmol), return stirring 12 hours.30 mL saturated ammonium chloride solutions add reaction solution dichloromethane extraction (50 mL × 2), merge organic phase, water (50 mL × 2), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-morpholine quinazoline-2 (1H)-one 30(30 mg, white solid), productive rate: 19.0%.
MS m/z (ESI): 512.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.94 (d, J=8.3 Hz, 1 H), 7.60 - 7.70 (m, 2 H), 7.51 (t, J=9.4 Hz, 2 H), 7.37 - 7.45 (m, 1 H), 7.28 (t, J=7.7 Hz, 1 H), 5.76 (s, 2 H), 4.44 (t, J=7.7 Hz, 2 H), 3.93 (d, J=4.5 Hz, 4 H), 3.86 (d, J=4.5 Hz, 4 H), 3.62 (t, J=6.3 Hz, 2 H), 1.94 (quin, J=7.6 Hz, 2 H), 1.59 - 1.71 (m, 2 H)。
Embodiment 31
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one
The first step
The chloro-N-of 2-(3-morpholine propyl group) quinazoline-4-amine
By 2,4-dichloroquinazoline 31a(2 g, 10.0 mmol) are dissolved in 40 mL tetrahydrofuran (THF)s, 0 oc drips 3-morpholine propyl group-1-amine (2.9g, 20.0mmol), stirring at room temperature 30 minutes, add 50 mL saturated ammonium chloride solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains the chloro-N-of product 2-(3-morpholine propyl group) quinazoline-4-amine 31b(3 g, yellow solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 8.50 (s., 1H), 7.82 (d, J=8.0 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.51 - 7.41 (m, 1H), 3.85 (t, J=4.5 Hz, 4H), 3.81 - 3.67 (m, 2H), 2.71 - 2.65 (m, 2H), 2.60 (br. s., 4H), 1.98 - 1.81 (m, 2H)。
Second step
4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one
By chloro-for 2-N-(3-morpholine propyl group) quinazoline-4-amine 31b(500mg, 1.6 mmol) are dissolved in 5 mL acetic acid, 70 oc stirs 1 hour, reaction solution concentrating under reduced pressure, obtains product 4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one 31c(620 mg, yellow solid), product is not purified directly carries out next step reaction.
3rd step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one
By 4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one 31c(100 mg, 0.3 mmol) is dissolved in 5 mL acetonitriles, adds 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (110 mg, 0.3 mmol), salt of wormwood (142mg, 1.0 mmol), return stirring 2 hours.30 mL saturated ammonium chloride solutions add reaction solution dichloromethane extraction (50 mL × 2), merge organic phase, water (50 mL × 2), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one 31(70 mg, white solid), productive rate: 36.0%.
MS m/z (ESI): 569.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.55 - 7.43 (m, 2H), 7.42 - 7.35 (m, 1H), 7.27 (t, J=7.7 Hz, 1H), 5.74 (s, 2H), 4.43 (t, J=7.5 Hz, 2H), 3.77 - 3.65 (m, 6H), 3.59 (t, J=6.3 Hz, 2H), 2.62 - 2.42 (m, 6H), 2.01 - 1.81 (m, 4H), 1.70 - 1.59 (m, 2H)。
Embodiment 32
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methoxyquinazoline hydrochloride-2 (1H)-one
The first step
Methyl (2-cyanophenyl) carbamate
By 2-amino-benzene cyanogen 32a(3g, 25.4mmol) is dissolved in the anhydrous methyl-chloroformate of 50 mL, and 90 oc stirs 2 hours, concentration of reaction solution, add 200 mL water, extraction into ethyl acetate (200 mL × 2), merges organic phase, uses water (200 mL × 3), saturated nacl aqueous solution to wash (200 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude product methyl (2-cyanophenyl) carbamate 32b(4.4 g, colorless oil), product is not purified directly carries out next step reaction.
1H NMR (400 MHz, CDCl 3) δ 8.23 (d, J = 8.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.17-7.11 (m, 2H), 3.83 (s, 3H)。
Second step
4-methoxyquinazoline hydrochloride-2 (1H)-one
By methyl (2-cyanophenyl) carbamate 32b(400mg, 2.3mmol) is dissolved in 40 mL sodium methylate/methyl alcohol (0.05 N), refluxes 12 hours.Concentration of reaction solution, adds 20 mL water, and with acetic acid neutralization, filter, use water, methanol wash column successively, filtrate distills to obtain 4-methoxyquinazoline hydrochloride-2 (1H)-one 32c(0.3 g, faint yellow solid), productive rate: 75%.
1H NMR (400 MHz, CDCl 3) δ 11.43 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.25-7.17 (m, 2H), 4.04 (s, 3H)。
3rd step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methoxyquinazoline hydrochloride-2 (1H)-one
By 4-methoxyquinazoline hydrochloride-2 (1H)-one 32c(130mg, 0.8mmol), be dissolved in 5 mL acetonitriles, add salt of wormwood (173mg 1.3mmol), return stirring 2 hours, reaction solution adds 100 mL water, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methoxyquinazoline hydrochloride-2 (1H)-one 32(100 mg, white solid), productive rate: 38.0%.
MS m/z (ESI): 457.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.13 (m, J=8.4 Hz, 1 H), 7.75 (t, J=8.4 Hz, 1 H), 7.61 (s, 1 H), 7.50 - 7.54 (d, 2 H), 7.41 (t, J=8.8 Hz, 1 H), 7.36 (t, J=7.6 Hz, 1 H), 5.80 (s, 2 H), 4.46 (t, 2 H), 4.19 (s, 3 H), 3.62 (t, 2 H), 1.92 – 1.98(d, 2 H), 1.65 - 1.70 (d, 2 H)。
Embodiment 33
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropoxy quinazoline-2 (1H)-one
The first step
4-isopropoxy quinazoline-2 (1H)-one
By methyl (2-cyanophenyl) carbamate 33a(600mg, 3.4mmol) is dissolved in 6 mL Virahols, adds sodium isopropylate (280 mg, 3 mmol), reaction solution reflux 20 hours.Concentration of reaction solution, adds 20 mL water, and with acetic acid neutralization, filter, use water, methanol wash column successively, filtrate is distilled, and purifies gained resistates, obtain 4-isopropoxy quinazoline-2 (1H)-one with silica gel column chromatography with eluent system B 33b(0.4 g, faint yellow solid), productive rate: 57%.
1H NMR (400 MHz, CD 3OD) δ 7.78 - 7.57 (m, 3H), 7.27 (t, J=7.7 Hz, 1H), 5.06 - 4.93 (m, 1H), 1.32 (d, J=6.3 Hz, 6H)。
Second step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropoxy quinazoline-2 (1H)-one
By 4-isopropoxy quinazoline-2 (1H)-one 33b(100mg, 0.5mmol), be dissolved in 5 mL acetonitriles, add salt of wormwood (135 mg, 1.0 mmol), return stirring 2 hours, reaction solution adds 100 mL water, with dichloromethane extraction (100 mL × 2), merge organic phase, use water (100 mL × 2) successively, saturated nacl aqueous solution washing (100 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropoxy quinazoline-2 (1H)-one 33(60 mg, white solid), productive rate: 25.0%.
MS m/z (ESI): 485.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.79 - 7.60 (m, 3H), 7.57 - 7.30 (m, 4H), 5.24 (br. s., 2H), 4.99 (td, J=6.1, 12.3 Hz, 1H), 4.43 (br. s., 2H), 3.60 (t, J=6.3 Hz, 2H), 1.92 (m, J=7.5 Hz, 2H), 1.71 - 1.52 (m, 2H), 1.26 - 0.99 (m, 6H)。
Embodiment 34
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(pyridin-4-yl) quinazoline-2 (1H)-one
The first step
The chloro-4-of 2-(pyridin-4-yl) quinazoline
4-bromopyridine (0.47 g, 3.0 mmol) is dissolved in 30 mL ether, in-78 under nitrogen protection oslowly drip n-Butyl Lithium (1.1 mL, 2.7 mmol) under C condition, stir half an hour.In-78 oc adds 2,4-dichloroquinazoline 34a(0.5 g, 2.5 mmol), are slowly warming up to room temperature by reaction solution and continue stirring 2 hours.Add 50 mL saturated ammonium chloride solutions, with dichloromethane extraction (100 mL × 2), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains the chloro-4-of 2-(pyridin-4-yl) quinazoline 34b(0.4 g, yellow solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 8.90 (dd, J = 4.4Hz, 2H), 8.13 - 8.11(dd, J = 8.8 Hz, 1H), 8.07 - 8.01 (m, 2H), 7.70 - 7.68 (m, 3H)。
Second step
4-(pyridin-4-yl) quinazoline-2 (1H)-one
By chloro-for 2-4-(pyridin-4-yl) quinazoline 34b(0.2 g, 0.82 mmol) is dissolved in 5 mL acetic acid, 70 oc stirs 1.5 hours, reaction solution concentrating under reduced pressure, obtains product 4-(pyridin-4-yl) quinazoline-2 (1H)-one 34c(146 mg, yellow solid), product is not purified directly carries out next step reaction.
3rd step
1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one
By 4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one 34c(146 mg, 0.65 mmol) be dissolved in 5 mL acetonitriles, add 4-(the bromo-2-chloromethyl of 5--1H-benzo [d] imidazoles-1-base) butane-1-alcohol (207 mg, 0.65 mmol), salt of wormwood (165 mg, 1.2 mmol), return stirring 2 hours.30 mL saturated ammonium chloride solutions add reaction solution dichloromethane extraction (50 mL × 2), merge organic phase, water (50 mL × 2), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains title product 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(pyridin-4-yl) quinazoline-2 (1H)-one 34(50 mg, white solid), productive rate: 12%.
MS m/z (ESI): 504.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.82 - 8.81 (dd, J = 4.4 Hz, 2H), 7.85 - 7.77 (br, 4H), 7.68 (d, 1H), 7.59 - 7.52 (m, 2H), 7.43 - 7.37 (br, , 2H), 5.93 (s, 2H), 4.51 - 4.47 (t, J = 7.2 Hz, 2H), 3.65 - 3.62 (q, J = 6.0 Hz, 2H), 2.05 - 1.97 (br, 2H), 1.72 - 1.65 (br, 2H)。
Embodiment 35
1-((5-(aminomethyl)-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one
The first step
4-chloro-3-oil of mirbane cyanogen
By 4-chlorobenzonitrile 35a(27.4 g, 0.2 mol) is dissolved in 34 mL sulfuric acid and 10 mL acetic acid, and room temperature drips nitric acid (10 mL, 0.24 mol) and sulfuric acid (10 mL), stirring at room temperature 30 minutes, reaction solution pours 500 mL frozen water into, separate out solid, filter to obtain 4-chloro-3-oil of mirbane cyanogen 35b(13 g, faint yellow solid), productive rate: 36%.
Second step
4-((4-hydroxybutyl) amine)-3-oil of mirbane cyanogen
By chloro-for 4-3-oil of mirbane cyanogen 35b(13 g, 0.071 mol) is dissolved in 350 mL acetonitriles, and room temperature adds salt of wormwood (24.4 g, 0.177 mol), drips 4-amino-n-butyl alcohol (7.65 g, 0.085 mol) 40 oc stirs 12 hours.Add reaction solution 300 mL water, extraction into ethyl acetate (150 mL × 2), merge organic phase, water (150 mL × 3), saturated nacl aqueous solution is used to wash (150 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude product 4-((4-hydroxybutyl) amine)-3-oil of mirbane cyanogen 35c(14.6 g, yellow oil), product is not purified directly carries out next step reaction.
3rd step
3-amino-4-(4-hydroxybutyl) amino-benzene cyanogen
By crude product 4-((4-hydroxybutyl) amine)-3-oil of mirbane cyanogen 35c(14.6 g, 0.062 mol) is dissolved in 400 mL methyl alcohol, add 50% wet palladium carbon (1.4 g). reaction solution, in room temperature, under hydrogen balloon pressure, stirs 12 hours.Reacting liquid filtering, concentrates to obtain product 3-amino-4-(4-hydroxybutyl) amino-benzene cyanogen 35d(11.8 g, dark oil thing), product is not purified directly carries out next step reaction.
4th step
2-chloromethyl-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-5-nitrile
By crude product 3-amino-4-(4-hydroxybutyl) amino-benzene cyanogen 35d(12.7 g, 0.062 mol) is dissolved in 200 mL DMF, and room temperature adds triethylamine (6.9 g, 0.068 mol), and 0 oc drips chloroacetyl chloride (7.06 g, 0.062 mol), and 0 oc stirs 30 minutes, and 95 oc stirs 20 hours.Add reaction solution 300 mL water, extraction into ethyl acetate (300 mL × 2), merge organic phase, water (300 mL × 3), saturated nacl aqueous solution is used to wash (300 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 2-chloromethyl-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-5-nitrile 35e(6.1 g, yellow solid), productive rate: 41%.
1H NMR (400 MHz, CDCl 3) δ 8.10 (s, 1 H) 7.57-7.6 (m, J=10 Hz, 1 H) 7.49-7.51 (d, J=8 Hz, 1 H) 4.88 (s, 2 H) 4.35-4.39 (t, J=8 Hz, 2 H) 3.76-3.79 (t, J=6 Hz, 2 H) 2.02-2.09 (m, J=14 Hz, 2 H) 1.68-1.74 (m, J=12 Hz, 2 H)。
5th step
1-(4-hydroxybutyl)-2-((4-sec.-propyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-5-nitrile
By 4-isopropylquinazolin-2 (1H)-one (314 mg; 1.67 mmol) be dissolved in 25 mL dry DMF; 60% sodium hydride (73 mg are added under condition of ice bath; 1.82 mmol); stirred under nitrogen atmosphere half an hour, add 2-chloromethyl-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-5-nitrile 35e(400 mg, 1.52 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 1-(4-hydroxybutyl)-2-((4-sec.-propyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-5-nitrile 35f(600 mg, white solid), productive rate: 95.2%.
1H NMR (400MHz, CD 3OD) δ 8.26 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.80 – 7.76 (m, 2H), 7.62 - 7.58 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 5.88 (s, 2H), 4.53 (t, J = 7.5 Hz, 2H), 3.98 - 3.87 (m, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.01 - 1.93 (m, 2H), 1.73 - 1.63 (m, 2H), 1.42 (d, J = 6.5 Hz, 6H)。
6th step
1-((5-(aminomethyl)-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one
By 1-(4-hydroxybutyl)-2-((4-sec.-propyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-5-nitrile 35f(150 mg, 0.36 mmol) is dissolved in 20 mL tetrahydrofuran (THF)s, adds Raney's nickel (30 mg). and reaction solution, in room temperature, under hydrogen balloon pressure, stirs 30 minutes.Reacting liquid filtering, concentrated purify with preparative high-performance liquid chromatographic obtain title product 1-((5-(aminomethyl)-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one 35(16 mg, yellow solid), productive rate: 10.6%.
MS m/z (ESI): 420.1 [M+1]
1H NMR (400 MHz, DMSO-d6) δ 8.79 (br. s., 3H), 8.29 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.05 (s, 2H), 4.64 (t, J=7.3 Hz, 2H), 4.17 (d, J=5.3 Hz, 2H), 3.95-3.88 (m, 1H), 3.45 (t, J=6.1 Hz, 2H), 1.96 - 1.88 (m, 2H), 1.59 - 1.50 (m, 2H), 1.31 (d, J=6.5 Hz, 6H)。
Embodiment 36
1 '-((1-(4-hydroxybutyl)-4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
1 ' ((4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 2-(2 '-oxo spiral shell [cyclopropyl-1,3 ' indoline]-1 '-Ji) acetaldehyde 36a(203 mg, 1.0 mmol) are dissolved in 5 mL ethanol, add diphenylthanedione (210 mg, 1.0 mmol), ammonium acetate (462 mg, 6.0mmol) under room temperature successively.Reaction reflux 2 hours.After reaction terminates, be cooled to room temperature, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1 ' ((4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 36b(206 mg, yellow liquid), productive rate: 52.8%.
1H NMR (400MHz, CD 3OD)δ 7.376 (brs, 1H), 7.18 - 7.27 (m, 10H), 7.05 – 6.96 (m, 4H), 5.13(s, 2H), 1.75-1.69 (m, 2H), 1.59 - 1.55 (m, 2H)。
Second step
1 '-((1-(4-hydroxybutyl)-4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 1 ' ((4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 36b(100 mg, 025 mmol) be dissolved in 4 mL acetonitriles, 4-brombutyl acetic ester (58.5 mg are added successively under room temperature, 0.3 mmol), salt of wormwood (52.5 mg, 0.38 mmol), potassiumiodide (4.98 mg, 0.03 mmol), stirring at room temperature 12 hours.After reaction terminates, reaction solution is poured into water, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3), saturated nacl aqueous solution to wash (50 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtains crude product.Be dissolved in by crude product in 2 mL methyl alcohol, add sodium hydroxide (80 mg, 2.0 mmol) under room temperature, reaction solution was in stirring at room temperature 12 hours.Add reaction solution 5 mL water, extraction into ethyl acetate (5 mL × 2), merge organic phase, water (5 mL × 3), saturated nacl aqueous solution is used to wash (5 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((1-(4-hydroxybutyl)-4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 36(15.4 mg, white solid), productive rate: 32.4%.
MS m/z (ESI): 464.0 [M+1]
1H NMR (400MHz, DMSO-d 6)δ 7.21 - 7.14 (m, 9H), 7.19 - 7.01 (m, 5H), 5.159 (s, 2H), 4.293 (brs, 1H), 3.95-3.88 (t, J= 5.6, 2H), 3.126-3.112 (t, J= 5.6, 2H) 1.67-1.58 (m, 4H), 1.24-1.14 (m, 4H)。
Embodiment 37
1 '-((1-(4-hydroxybutyl)-4-phenyl-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
2-(benzyl oxygen base)-N-(2-oxo-2-phenylethyl) ethanamide
By 2-(benzyl oxygen base) acetic acid (1.3 g, 7.83 mmol) be dissolved in 10 mL DMF, HATU (3.6 g are added successively under room temperature, 9.4 mmol), diisopropyl ethyl amine (3.03 g, 23.5 mmol), stirred at ambient temperature 20 minutes, adds 2-amido-1-phenylethyl keto hydrochloride 37a(1.34 g, 7.83 mmol), stirred at ambient temperature 12 hours.Reaction solution thin up, be extracted with ethyl acetate (100 mL × 3), merge organic phase, water (100 mL × 2), saturated aqueous common salt (100 mL × 2) is used to wash successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates 2-(benzyl oxygen base)-N-(2-oxo-2-phenylethyl) ethanamide with silica gel column chromatography with eluent system B 37b(1.9 g, yellow oily), productive rate: 84.4 %.
1H NMR (400MHz, DMSO-d 6)δ 8.002-7.984(d, J=7.2 Hz，2H), 7.649-7.613 (t, J=7.2 Hz，2H), 7.529-7.491 (t, J=7.6 Hz，2H), 7.704-7.347(m, 4H), 4.809-4.798(m, 2H), 4.656(s, 2H)，4.076(s, 2H)。
Second step
2-((benzyl oxygen base) methyl)-4-phenyl-1H-imidazoles
By 2-(benzyl oxygen base)-N-(2-oxo-2-phenylethyl) ethanamide 37b(1.9 g, 6.62 mmol) be dissolved in 10 mL formic acid, ammonium acetate (15.5 g are added under room temperature, 198.6 mmol), be heated to 100 degrees Celsius and maintain 18 hours, reaction is cooled to room temperature, pH to 8 is adjusted with sodium bicarbonate, be extracted with ethyl acetate (100 mL × 3), merge organic phase, use water (100 mL × 2) successively, saturated aqueous common salt (100 mL × 2) washs, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates 2-((benzyl oxygen base) methyl)-4-phenyl-1H-imidazoles is purified with eluent system B with silica gel column chromatography 37c(1.0 g, yellow oily), productive rate: 57.2%.
1H NMR (400MHz, DMSO-d 6)δ 7.777 – 7.759 (d, J=7.2 Hz, 2H), 7.670 (s, 1H), 7.373-7.168 (m, 8H), 7.168 (brs, 1H), 4.555 (s, 2H), 4.541(s, 2H)。
3rd step
4-(2-((benzyl oxygen base) methyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester
By 2-((benzyl oxygen base) methyl)-4-phenyl-1H-imidazoles 37c(500 mg, 1.9 mmol) be dissolved in 5 mL acetonitriles, 4-brombutyl acetic ester (443 mg are added successively under room temperature, 2.3 mmol), salt of wormwood (52.5 mg, 0.38 mmol), potassiumiodide (4.98 mg, 0.03 mmol), reaction is heated to 70 degrees Celsius and maintains 12 hours.After reaction terminates, reaction solution is poured into water, extraction into ethyl acetate (150 mL × 2), merge organic phase, use water (150 mL × 3), saturated nacl aqueous solution to wash (150 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 4-(2-((benzyl oxygen base) methyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester 37d(550 mg, yellow oily), productive rate: 76.5%.
1H NMR (400MHz, CDCl 3)δ 7.77 (s, 2H), 7.39-7.26(m, 9H),4.72 (s, 2H), 4.56(s, 2H), 4.07-4.02(m, 4H), 2.06(s, 3H)，1.89-1.85 (m, 2H), 1.70-1.644(m, 2H)。
4th step
4-(2-(hydroxymethyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester
By 4-(2-((benzyl oxygen base) methyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester 37d(550 mg, 1.45 mmol) be dissolved in 5 mL methylene dichloride, under dry ice acetone bath, slow dropping boron tribromide (1.82 g, 7.26 mmol), react 2 hours under-78 degrees Celsius, reaction solution sodium bicarbonate cancellation, extraction into ethyl acetate (150 mL × 2), merge organic phase, use water (150 mL × 2) successively, saturated nacl aqueous solution washing (150 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 4-(2-(hydroxymethyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester 37e(250 mg, colourless liquid), productive rate: 59.7%.
1H NMR (400MHz, CDCl 3)δ 7.670-7.651 (d, J=7.6 Hz，2H), 7.374-7.335(t, J=7.6 Hz，2H), 7.244-7.207 (m, 1H), 7.059 (s, 1H), 4.734(s, 2H), 4.047-4.015 (t, J=6.4 Hz, 2H), 3.945-3.908 (t, J=7.6 Hz, 2H), 2.065(s, 3H)，1.899-1.852 (m, 2H), 1.700-1.6446(m, 2H)。
5th step
4-(2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester
By 4-(2-(hydroxymethyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester 37ebe dissolved in 1.5 mL tetrahydrofuran (THF)s, triphenylphosphine (220 mg are added successively under ice bath, 0.84 mmol), spiral shell [cyclopropyl-1, 3 '-indoline]-2 '-one (80 mg, 0.5 mmol), DIAD (170 mg, 0.84 mmol), stirred at ambient temperature 12 hours, be extracted with ethyl acetate (150 mL × 2), merge organic phase, use water (150 mL × 2) successively, saturated nacl aqueous solution washing (150 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains crude product 4-(2-((2 '-oxo spiral shell [cyclopropyl-1, 3 '-indoline]-1 '-Ji) methyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester 37f(120 mg, colourless liquid), productive rate: 59.7%.Crude product is not purified is directly used in next step reaction.
6th step
1 '-((1-(4-hydroxybutyl)-4-phenyl-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 4-(2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-4-phenyl-1H-imidazoles-1-base) butylacetic acid ester 37f(120 mg, 0.28 mmol) is dissolved in 1 mL methyl alcohol, adds sodium hydroxide (80 mg, 2 mmol) under room temperature, and reaction solution was in stirring at room temperature 12 hours.Add reaction solution 5 mL water, extraction into ethyl acetate (5 mL × 2), merge organic phase, water (5 mL × 3), saturated nacl aqueous solution is used to wash (5 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((1-(4-hydroxybutyl)-4-phenyl-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 37(5 mg, white solid), productive rate: 32.4%.
MS m/z (ESI): 388.1 [M+1]
1H NMR (400MHz, CD 3OD)δ 7.74-7.72 (d, J=7.6 Hz, 2H), 7.49 (s, 1H), 7.39-7.35 (t, J=7.6 Hz, 2H), 7.30-7.24 (m, 3H), 7.03 (s,1H), 6.98 (s, 1H), 5.19 (s, 2H), 4.07-4.03(t, J=7.6 Hz, 2H), 3.49-3.46(t, J=7.6 Hz, 2H), 1.73-1.45 (m, 8H)。
Embodiment 38
1 '-((1-(4-hydroxybutyl)-3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one
The first step
Ethyl-2-(3-nitropyridine-4-base) acetic ester
By t-butylethyl malonic ester 38a(10 g, 52.9 mmol) be dissolved in 100 mL tetrahydrofuran (THF)s, add 60% sodium hydrogen (2.2 g under ice bath in batches, 55.4 mmol), stirring at room temperature 30 minutes, slowly adds 3-nitro-4 chloropyridine under ice bath, stirring at room temperature 1 hour, after reaction terminates, go out with shrend, and adjust pH to 5, reaction shrend is gone out, be extracted with ethyl acetate (150 mL × 2), merge organic phase, use water (150 mL × 2), saturated nacl aqueous solution to wash (150 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume obtains crude product.Crude product is dissolved in 60 mL methylene dichloride and 30 mL trifluoroacetic acids, reaction backflow maintenance 16 hours, after reaction terminates, reaction solution concentrates, resistates is poured in sodium hydrogen carbonate solution, be extracted with ethyl acetate (150 mL × 2), merge organic phase, water (150 mL × 3), saturated nacl aqueous solution is used to wash (150 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain ethyl-2-(3-nitropyridine-4-base) acetic ester 38b(4.0 g, red solid), productive rate: 75.7 %.
1H NMR (400MHz , CDCl 3) δ 9.31 (s, 1H), 8.79 (d, J=5.0 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 4.07 (s, 2H), 1.26 (d, J=2.8 Hz, 3H)。
Second step
Ethyl-1-(3-nitropyridine-4-base) cyclopropyl carboxylic acid esters
By ethyl-2-(3-nitropyridine-4-base) acetic ester 38b(1.1 g, 5.24 mmol) be dissolved in 10 mL DMSO, 1 is added successively under room temperature, 2-ethylene dibromide (1.97 g, 10.5 mmol) and salt of wormwood (2.89 g, 21 mmol), reaction is heated to 80 degrees Celsius and maintains 5 hours, after reaction terminates, be cooled to room temperature, reaction is poured in sodium hydrogen carbonate solution, be extracted with ethyl acetate (150 mL × 2), merge organic phase, use water (150 mL × 3) successively, saturated nacl aqueous solution washing (150 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain ethyl-1-(3-nitropyridine-4-base) cyclopropyl carboxylic acid esters 38c(250 mg, colourless liquid), productive rate: 20.2%.
1H NMR (400MHz , CDCl 3) δ 9.24 (s, 1H), 8.79 (d, J=5.3 Hz, 1H), 7.40 (d, J=5.0 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.85 – 1.80 (m, 2H), 1.28 - 1.23 (m, 2H), 1.15 (t, J=7.2 Hz, 3H)。
3rd step
Ethyl-1-(3-amido pyridin-4-yl) cyclopropyl carboxylic acid esters
By ethyl-1-(3-nitropyridine-4-base) cyclopropyl carboxylic acid esters 38c(250 mg, 1.06 mmol) be dissolved in 10 mL ethanol, palladium/carbon (80 mg) is added under room temperature, under the protection of hydrogen, heated overnight at reflux, after reaction terminates, be cooled to room temperature, filter, filtrate concentrates, residue with ethyl acetate extraction (150 mL × 2), merge organic phase, use water (150 mL × 3) successively, saturated nacl aqueous solution washing (150 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain ethyl-1-(3-amido pyridin-4-yl) cyclopropyl carboxylic acid esters 38d(150 mg, colourless liquid), productive rate: 68.8%.
1H NMR (400MHz , CDCl 3) δ 8.09 (s, 1H), 8.00 (d, J=4.8 Hz, 1H), 7.03 (d, J=4.8 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 1.72 - 1.66 (m, 2H), 1.22 - 1.11 (m, 5H)。
4th step
Spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine]-2 '-1 (1 ' H)-one
By ethyl-1-(3-amido pyridin-4-yl) cyclopropyl carboxylic acid esters 38d(100 mg, 0.49 mmol) be dissolved in 15 mL toluene, drip 1mL formic acid, reaction backflow 1 hour, after reaction terminates, be cooled to room temperature, reaction solution is concentrated, residue with ethyl acetate extraction (150 mL × 2), merge organic phase, use water (150 mL × 3) successively, saturated nacl aqueous solution washing (150 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain spiral shell [cyclopropyl-1, 3 '-pyrroles [2, 3-c] pyridine]-2 '-1 (1 ' H)-one 38e(70 mg, white solid), productive rate: 64.3%.
1H NMR (400MHz , CD 3OD) δ 8.21 - 8.15 (m, 2H), 7.08 (d, J=4.9 Hz, 1H), 1.81 - 1.75 (m, 4H)。
5th step
Ethyl-2,4-diketone-4-(thiazol-2-yl) butyric ester
By 1-(thiazol-2-yl) ethyl ketone 38f(5.0 g, 0.039 mol) be dissolved in 60 mL tetrahydrofuran (THF)s, potassium tert.-butoxide (5.3 g are added successively under room temperature, 0.047 mol), diethyl acetate (5.75g, 0.069 mol), stirred at ambient temperature 12 hours, be extracted with ethyl acetate (150 mL × 2), merge organic phase, use water (150 mL × 2), saturated nacl aqueous solution to wash (150 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains crude product ethyl-2,4-diketone-4-(thiazol-2-yl) butyric ester 38g(8.9 g, colourless liquid), productive rate: 100 %.Crude product is not purified is directly used in next step reaction.
6th step
Ethyl-3-(thiazol-2-yl)-1H-pyrazoles-5-carboxylicesters
By ethyl-2,4-diketone-4-(thiazol-2-yl) butyric ester 38g(8.9 g, 0.069mol) is dissolved in 60 mL tetrahydrofuran (THF)s, adds acetic acid (5.7 g, 0.095 mol) and hydrazine hydrate (2.6 g, 0.052 mol) successively, and reaction is heated to 90 degrees Celsius and maintains 2 hours.After reaction terminates, be cooled to room temperature, by reaction solution concentrating under reduced pressure, be extracted with ethyl acetate (150 mL × 2), merge organic phase, water (150 mL × 2), saturated nacl aqueous solution is used to wash (150 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains crude product, purify gained resistates with silica gel column chromatography with eluent system B, obtain ethyl-3-(thiazol-2-yl)-1H-pyrazoles-5-carboxylicesters 38 h(4.7 g, colourless liquid), productive rate: 53.4 %.
1H NMR (400MHz, CDCl 3)δ 7.91(s, 1H), 7.375-7.367 (d, J=3.2 Hz, 2H), 4.435-4.382(q, J=7.2 Hz, 2H), 1.399-1.364 (t,6.8 Hz, 3H)。
7th step
(3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl alcohol
By ethyl-3-(thiazol-2-yl)-1H-pyrazoles-5-carboxylicesters 38h(322 mg, 1.44 mmol) be dissolved in 4 mL tetrahydrofuran (THF)s, slowly add Lithium Aluminium Hydride (123 mg, 3.23 mmol) under ice bath, room temperature reaction 1 hour, after reaction terminates, add water under ice bath cancellation, adds anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, (3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl alcohol 38i(180 mg, colorless solid), productive rate 69%.
1H NMR (400MHz, CD 3OD)δ 7.91(s, 1H), 7.375-7.367 (d, J=3.2 Hz, 2H), 4.697(s, 2H)。
8th step
4-(5-(hydroxymethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester
By (3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl alcohol 38i(500 mg, 2.76 mmol) be dissolved in 10 mL acetonitriles, 4-brombutyl acetic ester (646 mg are added successively under room temperature, 3.3 mmol), salt of wormwood (571 mg, 4.2 mmol), potassiumiodide (23 mg, 0.138 mmol), be heated to 90 degrees Celsius and maintain 12 hours.After reaction terminates, be cooled to room temperature, filter, filtrate concentrates, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 4-(5-(hydroxymethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester 38j(600 mg, white solid), productive rate: 73.6%.
1H NMR (400MHz, CDCl 3)δ 7.853-7.845 (d, J= 3.2 Hz, 1H), 7.324-7.3.15 (d, J=3.6 Hz, 1H), 6.972 (s, 1H), 4.702 (s, 2H), 4.250-4.213 (t, J= 7.6 Hz, 2H), 4.138-4.106 (t, J= 6.4 Hz, 2H), 2.074 (s, 3H), 2.058-2.021 (m, 2H), 1.754-1.7165 (m, 2H)。
9th step
4-(5-(chloromethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester
By 4-(5-(hydroxymethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester 38j(300 mg, 1.0 mmol) be dissolved in 4 mL methylene dichloride, thionyl chloride (300 mg are slowly dripped under ice bath, 3.0 mmol), stirring at room temperature 1 hour, after reaction terminates, reaction solution is poured in sodium hydrogen carbonate solution, be extracted with ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 4-(5-(chloromethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester 38k(300 mg, white solid), productive rate: 94.2 %.
1H NMR (400MHz, CDCl 3)δ 7.853-7.845 (d, J= 3.2 Hz, 1H), 7.324-7.3.15 (d, J=3.6 Hz, 1H), 6.972 (s, 1H), 4.702 (s, 2H), 4.250-4.213 (t, J= 7.6 Hz, 2H), 4.138-4.106 (t, J= 6.4 Hz, 2H), 2.058-2.021 (m, 5H), 1.754-1.7165 (m, 2H)。
Tenth step
4-(5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine]-1 ' (2 ' H)-Ji) methyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester
By 4-(5-(chloromethyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester 38k(167 mg, 0.53 mmol) be dissolved in 3 mL DMF, 60% sodium hydrogen (32 mg are added successively under ice bath, 1.33 mmol) and spiral shell [cyclopropyl-1, 3 '-pyrroles [2, 3-c] pyridine]-2 '-1 (1 ' H)-one (83 mg, .52 mmol), stirred at ambient temperature 2 hours, reaction shrend is gone out, be extracted with ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 2) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains crude product 4-(5-((2 '-oxo spiral shell [cyclopropyl-1, 3 '-pyrroles [2, 3-c] pyridine]-1 ' (2 ' H)-Ji) methyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester 38l(150 mg, colourless liquid), productive rate: 65%.Crude product is not purified is directly used in next step reaction.
11 step
1 '-((1-(4-hydroxybutyl)-3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one
By 4-(5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine]-1 ' (2 ' H)-Ji) methyl)-3-(thiazol-2-yl)-1H-pyrazol-1-yl) butylacetic acid ester 38l(150 mg) is dissolved in 2 mL methyl alcohol, adds sodium hydroxide (80 mg, 2.0 mmol) under room temperature, and reaction solution was in stirring at room temperature 12 hours.Add reaction solution 5 mL water, extraction into ethyl acetate (5 mL × 2), merge organic phase, water (5 mL × 3), saturated nacl aqueous solution is used to wash (5 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((1-(4-hydroxybutyl)-3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one 38(15 mg, white solid), productive rate: 32.4%.
MS m/z (ESI): 396.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.36 (s, 1H), 8.29-8.28(d, J=4.8 Hz, 1H), 7.80-7.80 (d, J=3.2 Hz, 1H), 7.55-7.54 (d, J= 3.6 Hz, 1H), 7.19-7.17 (d, J=5.2 Hz, 1H), 6.86 (s, 1H), 5.27 (s, 2H), 4.33-4.29 (t, J= 7.4 Hz, 2H), 3.59-3.56 (t, J=6.4 Hz, 2H), 1.91-1.189 (m ,4H), 1.87-1.85 (m, 2H), 1.59-1.55 (m, 2H)。
Embodiment 39
1 '-((1-(4-hydroxybutyl)-4-(thiazol-2-yl)-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one
The first step
The bromo-1-of 2-(thiazol-2-yl) ethyl ketone
By 1-(thiazol-2-yl) ethyl ketone 39a(10 g, 77.4 mmol) are dissolved in the hydrogen bromide acetic acid solution of 200 mL 33%, and room temperature adds pyridinium tribromide (24.9 g, 77.4 mmol), and 60 oc stirs 2 hours, concentrated, resistates under agitation pours ethyl acetate/sodium carbonate mixture into, extraction into ethyl acetate (300 mL × 2), merges organic phase, uses water (200 mL × 2), saturated nacl aqueous solution to wash (200 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains the bromo-1-of crude product 2-(thiazol-2-yl) ethyl ketone 39b(15 g, yellow solid), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 8.06 (d, J= 3.0 Hz, 1H), 7.78 (d, J= 3.0 Hz, 1H), 4.73 (s, 2H)。
Second step
The bromo-1-of 2-(thiazol-2-yl) ethanol
By bromo-for 2-1-(thiazol-2-yl) ethyl ketone 39b(8.0 g, 38.4 mmol) are dissolved in 20 mL methyl alcohol and 100 mL ethanol, and 0 oc adds sodium borohydride (2.9 g, 76.9 mmol, 2.0 eq.) in batches, and 0 oc stirs 1 hour extraction into ethyl acetate (300 mL × 2), merge organic phase, water (200 mL × 2), saturated nacl aqueous solution is used to wash (200 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains the bromo-1-of crude product 2-(thiazol-2-yl) ethanol 39c(6.76 g, red oil), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.79 (d, J= 3.0 Hz, 1H), 7.38 (d, J= 3.3 Hz, 1H), 5.26 – 5.23 (m, 1H), 3.95 (dd, J= 3.8, 10.5 Hz, 1H), 3.77 (dd, J= 6.8, 10.5 Hz, 1H), 3.59 (d, J= 4.0 Hz, 1H)。
3rd step
2-amido-1-(thiazol-2-yl) ethanol hydrobromate
By bromo-for 2-1-(thiazol-2-yl) ethanol 39c(6.76 g, 32.2 mmol) are dissolved in 20 mL ethanol, and room temperature adds 25 mL ammoniacal liquor, and 100 oc stirs 12 hours, concentrating under reduced pressure, obtains crude product 2-amido-1-(thiazol-2-yl) ethanol hydrobromate 39d(7.27 g, red oil), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.81 (d, J= 3.0 Hz, 1H), 7.74 (d, J= 3.0 Hz, 1H), 6.95 (s, 1H), 5.11 (d, J= 6.5 Hz, 1H), 4.37 (s, 1H), 3.29 (dd, J= 3.5, 12.5 Hz, 1H), 3.06 – 3.00 (m, 1H)。
4th step
2-(benzyl oxygen base)-N-(2-hydroxyl-2-(thiazol-2-yl) ethyl) ethanamide
2-(benzyl oxygen base) acetic acid (5.91 g, 35.5 mmol) is dissolved in 80 mL DMF, adds HATU (14.73 g successively, 38.76 mmol), diisopropylethylamine (12.5 g, 96.9 mmol), stirring at room temperature 20 minutes.Room temperature drips 2-amido-1-(thiazol-2-yl) the ethanol hydrobromate being dissolved in 10 mL DMF 39d(7.27 g, 32.3 mmol, 1.0 eq.), stirring at room temperature 2 hours.Reaction solution adds 400 mL water, extraction into ethyl acetate (500 mL × 2), merge organic phase, water (300 mL × 2), saturated nacl aqueous solution is used to wash (300 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 2-(benzyl oxygen base)-N-(2-hydroxyl-2-(thiazol-2-yl) ethyl) ethanamide 39e(5.0 g, yellow oil), productive rate: 53.2%.
1H NMR (400MHz, CDCl 3) δ 7.76 (d, J= 3.0 Hz, 1H), 7.40 - 7.28 (m, 7H), 7.16 (s, 1H), 5.15 (s, 2H), 4.53 (s, 2H), 4.03 - 3.99 (m, 2H), 3.98 - 3.91 (m, 1H), 3.82 - 3.72 (m, 1H)。
5th step
2-(benzyl oxygen base)-N-(2-oxo-2-(thiazol-2-yl) ethyl) ethanamide
Pyridinium dichromate (10.0 g, 59.8 mmol) is dissolved in 100 mL DMF, and room temperature drips 2-(benzyl oxygen base)-N-(2-hydroxyl-2-(thiazol-2-yl) ethyl) ethanamide being dissolved in 50 mL DMF 39e(5.0 g, 17.1 mmol), stirring at room temperature 12 hours.Reaction solution adds 300 mL water, dichloromethane extraction (300 mL × 2), merge organic phase, water (300 mL × 2), saturated nacl aqueous solution is used to wash (300 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 2-(benzyl oxygen base)-N-(2-oxo-2-(thiazol-2-yl) ethyl) ethanamide 39f(4.0 g, yellow oil), productive rate: 80.6%.
1H NMR (400MHz, CDCl 3) δ 8.05 (d, J= 3.0 Hz, 1H), 7.75 (d, J= 3.0 Hz, 1H), 7.42 - 7.36 (m, 5H), 4.98 (d, J= 5.5 Hz, 2H), 4.66 (s, 2H), 4.10 (s, 2H)。
6th step
2-(2-((benzyl oxygen base) methyl)-1H-imidazol-4 yl) thiazole
By 2-(benzyl oxygen base)-N-(2-oxo-2-(thiazol-2-yl) ethyl) ethanamide 39fbe dissolved in 50 mL acetic acid, add ammonium acetate (10.6 g, 138 mmol), return stirring 1 hour.Concentrating under reduced pressure, with saturated sodium bicarbonate alkalization alkalization resistates, dichloromethane extraction (300 mL × 2), merge organic phase, use water (300 mL × 2), saturated nacl aqueous solution to wash (300 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 2-(2-((benzyl oxygen base) methyl)-1H-imidazol-4 yl) thiazole 39g(1.4 g, yellow solid), productive rate: 37.1%.
1H NMR (400MHz, CDCl 3) δ 7.78 (d, J= 3.3 Hz, 1H), 7.61 (s., 1H), 7.40 - 7.33 (m, 6H), 7.25 (d, J= 3.3 Hz, 1H), 4.73 (s, 2H), 4.63 (s, 2H)。
7th step
4-(2-((benzyl oxygen base) methyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester
By 2-(2-((benzyl oxygen base) methyl)-1H-imidazol-4 yl) thiazole 39g(1.4 g, 5.12 mmol) are dissolved in 15 mL acetonitriles, and room temperature adds 4-brombutyl acetic ester (1.2 g, 6.15 mmol), salt of wormwood (1.1 g, 7.68 mmol), potassiumiodide (10 mg), refluxes 12 hours.Concentrating under reduced pressure, with dichloromethane extraction (200 mL × 2), merge organic phase, water (200 mL × 2), saturated nacl aqueous solution is used to wash (200 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 4-(2-((benzyl oxygen base) methyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester 39h(1.4 g, yellow solid), productive rate: 76.1%.
1H NMR (400MHz, CDCl3) δ 7.77 (d, J= 3.3 Hz, 1H), 7.56 (s, 1H), 7.35 (m, 5H), 7.25 (d, J= 3.3 Hz, 1H), 4.69 (s, 2H), 4.57 (s, 2H), 4.06 - 4.02 (m, 4H), 2.03 (s, 3H), 1.90 - 1.82 (m, 2H), 1.67 - 1.59 (m, 2H)。
8th step
4-(2-(hydroxymethyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester
By 4-(2-((benzyl oxygen base) methyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester 39h(750 mg, 1.95 mmol) are dissolved in 15 mL methylene dichloride ,-78 oc drips boron tribromide (975 mg, 3.89 mmol), and-78 oc stirs 1 hour, 50 mL saturated sodium bicarbonate solutions add reaction solution, be extracted with ethyl acetate (100 mL × 3), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain 4-(2-(hydroxymethyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester 39i(200 mg, yellow solid), productive rate: 34.8%.
1H NMR (400MHz, CDCl 3) δ 7.72 (d, J= 2.5 Hz, 1H), 7.52 (s, 1H), 7.24 (d, J= 3.0 Hz, 1H), 4.76 (s, 2H), 4.14 - 4.03 (m, 4H), 2.06 (s, 3H), 1.96 – 1.88 (m, 2H), 1.75 - 1.65 (m, 2H)。
9th step
4-(2-(chloromethyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester
By 4-(2-(hydroxymethyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester 39i(200 mg, 0.68 mmol) is dissolved in 4 mL methylene dichloride, 0 oc drips thionyl chloride (161 mg, 1.35 mmol), and 0 oc stirs 15 minutes, 50 mL saturated sodium bicarbonate solutions add reaction solution, with dichloromethane extraction (100 mL × 3), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude product 4-(2-(chloromethyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester 39j(200 mg, yellow oily), product is not purified directly carries out next step reaction.
1H NMR (400MHz, CDCl 3) δ 7.78 (d, J= 3.3 Hz, 1H), 7.59 (s, 1H), 7.27 (s, 1H), 4.73 (s, 2H), 4.15 - 4.07 (m, 4H), 2.08 (s, 3H), 2.02 - 1.95 (m, 2H), 1.79 - 1.71 (m, 2H)。
Tenth step
1 '-((1-(4-hydroxybutyl)-4-(thiazol-2-yl)-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one
By spiral shell [cyclopropyl-1; 3 '-pyrroles [2; 3-c] pyridine]-2 '-1 (1 ' H)-one (102 mg; 0.63 mmol) be dissolved in 2 mL dry DMF; 60% sodium hydride (28 mg are added under condition of ice bath; 0.70 mmol), stirred under nitrogen atmosphere half an hour, add 4-(2-(chloromethyl)-4-(thiazol-2-yl)-1H-imidazoles-1-base) butylacetic acid ester 39j(199 mg, 0.63 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((1-(4-hydroxybutyl)-4-(thiazol-2-yl)-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one 39(21.5 mg, yellow solid), productive rate: 9.1%.
MS m/z (ESI): 396.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.56 (s, 1H), 8.23 (d, J= 4.8 Hz, 1H), 7.76 (d, J= 3.3 Hz, 1H), 7.71 (s, 1H), 7.49 (d, J= 3.3 Hz, 1H), 7.12 (d, J= 5.0 Hz, 1H), 5.23 (s, 2H), 4.14 (t, J= 7.5 Hz, 2H), 3.53 (t, J= 6.4 Hz, 2H), 1.88 (br, 4H), 1.78 – 1.71 (m, 2H), 1.56 - 1.47 (m, 2H)。
Embodiment 40
4-(the bromo-2-of 5-((2-trifluoromethyl)-1H-benzo [d] imidazoles-1-base) methyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol
The first step
2-(trifluoromethyl)-1H-benzo [d] imidazoles
By O-Phenylene Diamine 40a(2 g, 18.5 mmol) be dissolved in 20 mL acetic acid, return stirring 4 hours, by reaction solution concentrating under reduced pressure, add 50 mL water, pH to 7-8 is regulated with saturated aqueous sodium carbonate, extraction into ethyl acetate (100 mL × 2), merge organic phase, use water (100 mL × 2), saturated nacl aqueous solution to wash (100 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains 2-(trifluoromethyl)-1H-benzo [d] imidazoles 40b(2.7 g, white solid), productive rate: 77.1%.
1H NMR (400MHz, CDCl 3) δ 7.89 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.45-7.38 (m, 2H)。
Second step
4-(the bromo-2-of 5-((2-trifluoromethyl)-1H-benzo [d] imidazoles-1-base) methyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol
By 2-(trifluoromethyl)-1H-benzo [d] imidazoles 40b(65 mg; 0.347 mmol) be dissolved in 2 mL dry DMF; 60% sodium hydride (14 mg are added under condition of ice bath; 0.347 mmol); stirred under nitrogen atmosphere half an hour; add 4-(2-(chloromethyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol (100 mg, 0.316 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies with preparative high-performance liquid chromatographic and obtains title product 4-(the bromo-2-of 5-((2-trifluoromethyl)-1H-benzo [d] imidazoles-1-base) methyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol 40(20 mg, white solid), productive rate: 13.6%.
MS m/z (ESI): 467.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.97-7.92 (m, 1H), 7.65 (s, 1H), 7.57-7.55 (m, 2H), 7.49-7.46 (m, 3H), 6.08 (s, 2H), 4.43 (t, J= 7.6 Hz, 2H), 3.61 (t, J= 6.0 Hz, 2H), 1.91-1.90 (m, 2H), 1.63-1.59 (m, 2H)。
Embodiment 41
1 '-((the bromo-1-of 6-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
Ethyl-2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic ester
By spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 41a(6.0 g; 37.7 mmol) be dissolved in 60 mL dry DMF; 60% sodium hydride (1.09 g are added under condition of ice bath; 45.2 mmol); stirred under nitrogen atmosphere half an hour; add ethyl bromoacetate (7.55 g, 45.2 mmol), reaction solution stirring at room temperature 2 hours.Add reaction solution 50 mL water, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3), saturated nacl aqueous solution to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain ethyl-2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic ester 41b(3.5 g, white solid), productive rate: 38.3%.
1H NMR (400MHz, CDCl 3) δ 7.23 (dt, J= 0.8, 7.8 Hz, 1H), 7.05 (t, J= 7.4 Hz, 1H), 6.87 (d, J= 7.3 Hz, 1H), 6.80 (d, J= 7.8 Hz, 1H), 4.55 (s, 2H), 4.24 (q, J= 7.2 Hz, 2H), 1.80 (q, J= 3.9 Hz, 2H), 1.57 (q, J = 4.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H)。
Second step
2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid
By ethyl-2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic ester 41b(3.544 g, 14.4 mmol) are dissolved in 45 mL anhydrous tetrahydro furans and 15 mL water, and room temperature adds a hydronium(ion) Lithium Oxide 98min (1.515 g, 36.1 mmol), stirring at room temperature 12 hours.40 mL water add reaction solution, with 1N salt acid for adjusting pH to 5-6, extraction into ethyl acetate (200 mL × 2), merge organic phase, use water (200 mL × 3), saturated nacl aqueous solution to wash (200 mL × 2), with anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtains 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid 41c(2.9 g, white solid), productive rate: 92.7%.
1H NMR (400MHz, DMSO-d6) δ 7.25-7.17 (m, 1H), 7.07-6.96 (m, 3H), 4.51 (s, 2H), 1.68-1.59 (m, 2H), 1.58-1.49 (m, 2H)。
3rd step
1 '-((5-bromo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid 41c(0.5 g, 2.3 mmol) be dissolved in 10 mL dry DMF, room temperature adds HATU (1.05 g, 2.76 mmol) and diisopropylethylamine (593 mg, 4.6 mmol), stir 10 minutes, add 3, 4-bis-amido bromobenzene (0.43 g, 2.3 mmol), stirring at room temperature 4 hours, 30 mL water add reaction solution, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, 5 mL acetic acid join in resistates, return stirring 2 hours, reaction solution concentrating under reduced pressure, pH to 8 is regulated with saturated sodium bicarbonate, extraction into ethyl acetate (50 mL × 2), merge organic phase, use water (50 mL × 3) successively, saturated nacl aqueous solution washing (50 mL × 2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1 '-((5-bromo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1, 3 '-indoline]-2 '-one 41d(354 mg, white solid), productive rate: 93%.
1H NMR (400MHz, DMSO-d6) δ 7.35 (m, 1H) 7.19-7.15 (m, 1H) 7.04-7.00 (m, 2H) 6.99-6.90 (m, 1H) 5.27 (s, 2H) 4.58 (s, 1H) 1.79-1.76 (m, 2H) 1.71-1.67 (m, 2 H)。
4th step
1 '-((the bromo-1-of 6-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 1 '-((5-bromo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 41d(0.43 g, 2.3 mmol) be dissolved in 40 mL acetonitriles, room temperature adds 4-brombutyl acetic ester (1.498 g, 7.7 mmol), salt of wormwood (1.41 g, 10.2 mmol) and sodium iodide (382 mg, 2.55 mmol), return stirring 4 hours, temperature is down to 50 oc, adds 40 mL methyl alcohol, 50 oc stirs 4 hours, be cooled to room temperature, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((the bromo-1-of 6-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 41(27 mg, white solid), productive rate: 1.2%.
MS m/z (ESI): 440.2 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.74 (s, 1 H), 7.53-7.51 (d, J=8.8, 1H), 7.37-7.35 (m, 1H), 7.16-7.13 (m, 2H), 7.02-6.95(m, 2 H), 5.33 (s, 2 H), 4.33-4.29 (m, 2 H), 3.52-3.49 (m, 2 H), 1.74-1.67(m, 6 H), 1.67-1.54 (m, 2 H)。
Embodiment 42
1 '-((the bromo-1-of 4-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
4-((the bromo-2-nitrophenyl of 3-) amido) butyl-1-alcohol
By fluoro-for bromo-for 1-3-2-oil of mirbane 42a(5.0 g, 22.72 mmol) are dissolved in 40 mL acetonitriles, add salt of wormwood (9.4g, 68.1 mmol), potassiumiodide (0.37 g, 2.27 mmol) and 4-amino butanol (2.43 g, 27.26 mmol), stirring at room temperature 14 h.Reaction solution is poured in 20 mL hydrochloric acid solns (1M), extraction into ethyl acetate (100 mL × 3), saturated sodium bicarbonate regulates pH to 7 ~ 8, merge organic phase, use water (100 mL × 2), saturated aqueous common salt (100 mL × 2) to wash successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained 4-((the bromo-2-nitrophenyl of 3-) amido) butyl-1-alcohol with silica gel column chromatography with eluent system B 42b(5.38 g), productive rate: 82.0%.
1H NMR (400MHz, DMSO-d 6) δ 11.69 (br. s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 3.81 – 3.70 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H)。
Second step
4-((2-amido-3-bromophenyl) amido) butyl-1-alcohol
By 4-((the bromo-2-nitrophenyl of 3-) amido) butyl-1-alcohol 42b(5.38 g, 18.62 mmol) are dissolved in the water of 50 mL ethanol and 5 mL, add iron powder (3.12 g, 55.86 mmol) and ammonium chloride (1.99g, 37.23 mmol), reaction solution return stirring 2 hours.By reacting liquid filtering, get after filtrate concentrates and add 100 mL ethyl acetate, water (50 mL × 3), saturated nacl aqueous solution is used to wash (80 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, to purify with eluent system B with silica gel column chromatography and obtains 4-((2-amido-3-bromophenyl) amido) butyl-1-alcohol 42c(3.92 g), productive rate: 81.3% for product.
1H NMR (400MHz, CDCl 3) δ 6.93 (d, J=7.3 Hz, 1H), 6.70 - 6.64 (m, 1H), 6.61 - 6.56 (m, 1H), 3.69 (t, J=5.9 Hz, 2H), 3.12 (t, J=6.4 Hz, 2H), 1.78 - 1.67 (m, 4H)。
3rd step
1 '-((the bromo-1-of 4-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid (303 mg, 1.4 mmol) be dissolved in the DMF of 5 mL, add HATU (585 mg, 1.54 mmol), DIPEA (542 mg, 4.2 mmol), stirring at room temperature, after 20 minutes, adds 4-((2-amido-3-bromophenyl) amido) butyl-1-alcohol 42c(362 mg, 1.4 mmol) reaction solution stirring at room temperature 14 hours.Reaction solution is poured in 10 mL sodium hydroxide solutions (0.1M), extraction into ethyl acetate (30 mL × 3), use water (300 mL × 2) successively, saturated aqueous common salt (30 mL × 2) washs, anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains the crude product of 700 mg, add the acetic acid of 8 mL, reflux 2 hours, after reaction solution is concentrated, concentrated solution adds the ethyl acetate of 30mL, through sodium hydroxide (0.1M) solution (10mL), the aqueous solution (15mL × 3) and saturated common salt water washing (30 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, methyl alcohol and NaOH (280 mg of 8mL are added in enriched material, 7mmol), stirring at room temperature 0.5 hour, the ethyl acetate of 15mL is added after reaction solution concentrates, through the aqueous solution (15mL × 3) and saturated common salt water washing (30 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, enriched material preparative high-performance liquid chromatographic purifying obtains title product 1 '-((the bromo-1-of 4-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1, 3 '-indoline]-2 '-one 42(20.25 mg), productive rate: 3.1%.
MS m/z (ESI): 440.1 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.50 (m, 2H), 7.26 - 7.14 (m, 3H), 7.07- 6.95 (m, 2H), 5.39 (s, 2H), 4.30 (t, J=7.7 Hz, 2H), 3.47 (t, J=6.0 Hz, 2H), 1.76 (t, J=3.1 Hz, 2H), 1.73 - 1.66 (m, 2H), 1.64 - 1.44 (m, 4H)。
Embodiment 43
1 '-((the chloro-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
4-((the chloro-2-nitrophenyl of 4-) amido) butyl-1-alcohol
By fluoro-for chloro-for 4-1-2-oil of mirbane 43a(4 g, 22.8 mmol, 1.0 eq.) be dissolved in 40 mL acetonitriles, add salt of wormwood (9.45 g, 68.4 mmol, 3.0 eq.), (0.1 g) and 4-amino butanol (2.4 g, 26.9 mmol for potassiumiodide, 1.2 eq.), stirring at room temperature 14 h.Reaction solution is poured in 20 mL hydrochloric acid solns (1M), extraction into ethyl acetate (80 mL × 3), saturated sodium bicarbonate regulates pH to 7-8, merge organic phase, use water (100 mL × 2), saturated aqueous common salt (100 mL × 2) to wash successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains faint yellow oil product crude product 4-((the chloro-2-nitrophenyl of 4-) amido) butyl-1-alcohol 43b, be directly used in next step.
1H NMR (400MHz, CDCl 3) δ 8.16 (s, 1H), 7.44~7.51 (d, 1H), 6.81~6.86 (d, 1H), 3.73 (m, 2H), 3.28~3.41(m,2H), 1.76~1.89 (m,2H), 1.68~1.74 (m,2H)。
Second step
4-((2-amido-4-chloro-phenyl-) amido) butyl-1-alcohol
By 4-((the chloro-2-nitrophenyl of 4-) amido) butyl-1-alcohol 43b(5.8 g, 23.7 mmol, 1.0 eq.) be dissolved in the methylene dichloride of 40 mL methyl alcohol and 80mL, add Nickel dichloride hexahydrate (11.3 g, 47.4 mmol, 2.0 eq.) and sodium borohydride (3.583 g, 94.8 mmol, 4.0 eq.), reaction solution stirring at room temperature is until TLC display raw material reaction is complete.Add the methylene dichloride of 400mL, reacting liquid filtering, get filtrate concentrating, to purify with eluent system B with silica gel column chromatography and obtain 4-((2-amido-4-chloro-phenyl-) amido) butyl-1-alcohol 43cproduct (4.69 g, red solid), productive rate: 91.4%.
1H NMR (400MHz, CDCl 3) δ6.77 (dd, J= 2.3, 8.3 Hz, 1H), 6.70 (d, J= 2.3 Hz, 1H), 6.57 (d, J= 8.3 Hz, 1H), 3.72 (t, J= 6.0 Hz, 2H), 3.13 (t, J= 6.5 Hz, 2H), 1.81 - 1.68 (m, 4H)。
3rd step
1 '-((the chloro-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid (300 mg, 1.4 mmol) be dissolved in the DMF of 5 mL, add HATU (585 mg, 1.54 mmol), DIPEA (542 mg, 4.2 mmol) stirring at room temperature, after 20 minutes, adds 4-((2-amido-4-chloro-phenyl-) amido) butyl-1-alcohol 43c(304 mg, 1.4 mmol).Reaction solution stirring at room temperature 14 hours.Reaction solution is poured in 10 mL sodium hydroxide solutions (0.1M), extraction into ethyl acetate (30 mL × 3), use water (300 mL × 2) successively, saturated aqueous common salt (30 mL × 2) washs, anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains the crude product of 800 mg, add the acetic acid of 16 mL, reflux 2 hours, after reaction solution is concentrated, concentrated solution adds the ethyl acetate of 30mL, through sodium hydroxide (0.1M) solution (10mL), the aqueous solution (15mL × 3) and saturated common salt water washing (30 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, methyl alcohol and NaOH (280 mg of 8mL are added in enriched material, 7mmol), stirring at room temperature 0.5 hour, the ethyl acetate of 15mL is added after reaction solution concentrates, through the aqueous solution (15mL × 3) and saturated common salt water washing (30 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, enriched material preparative high-performance liquid chromatographic purifying obtains 1 '-((the chloro-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1, 3 '-indoline]-2 '-one 43(180 mg, white solid), productive rate: 32.5 %.
MS m/z (ESI): 396.1 [M+1]
1H NMR (400MHz, DMSO-d6) δ 7.68 (d, J= 1.8 Hz, 1H), 7.60 (d, J= 8.5 Hz, 1H), 7.27 (dd, J= 1.9, 8.7 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.05 - 6.97 (m, 2H), 5.29 (s, 2H), 4.48 (br, 1H), 4.31 (t, J= 7.7 Hz, 2H), 3.42 - 3.37 (m, 2H), 1.69 - 1.60 (m, 6H), 1.47 - 1.40 (m, 2H)。
Embodiment 44
1 '-((1-(4-hydroxybutyl)-5-iodo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
4-((the iodo-2-nitrophenyl of 4-) amido) butyl-1-alcohol
By iodo-for fluoro-for 1-4-2-oil of mirbane 44a(1.5 g, 5.6 mmol) and 4-amino-n-butyl alcohol (601 g, 6.7 mmol) be dissolved in 15 mL acetonitriles, room temperature adds salt of wormwood (2.4 g, 17.4 mmol) and the potassiumiodide (50 mg) of catalytic amount, stirred overnight at room temperature.100 mL water are added in reaction solution, extraction into ethyl acetate (100 mL × 2), merge organic phase, water (100 mL × 2) and saturated aqueous common salt (100 mL × 2) washing, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates 4-((the iodo-2-nitrophenyl of 4-) amido) butyl-1-alcohol with silica gel column chromatography with eluent system B 44b(1.8 g, yellow solid), productive rate: 95.3 %.
1H NMR (400MHz, CDCl 3) δ 8.47 (d, J=2.00 Hz, 1H), 8.07 (br. s., 1H), 7.63 (dd, J=2.01, 9.04 Hz, 1H), 6.65 (d, J=9.04 Hz, 1H), 3.73 (t, J=6.16 Hz, 2H), 3.47-3.19 (m, 2H), 1.93-1.65 (m, 4H)。
Second step
4-((2-amido-4-iodophenyl) amido) butyl-1-alcohol
By 4-((the iodo-2-nitrophenyl of 4-) amido) butyl-1-alcohol 44b(750 mg, 2.23 mmol) are dissolved in 10 mL methyl alcohol and 3 mL water, and room temperature adds reduced iron powder (250 mg, 4.46 mmol) and ammonium chloride (358 mg, 6.70 mmol), and be heated to backflow, stirring is spent the night.Add 100 mL water, extraction into ethyl acetate (100 mL × 2), merge organic phase, water (100 mL × 3), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain 4-((2-amido-4-iodophenyl) amido) butyl-1-alcohol 44c(400 mg, yellow solid), productive rate: 58.6 %.
1H NMR (400MHz, CDCl 3) δ 7.09 (dd, J=1.88, 8.40 Hz, 1H), 7.00 (d, J=1.76 Hz, 1H), 6.40 (d, J=8.28 Hz, 1H), 3.71 (t, J=6.00 Hz, 2H), 3.12 (t, J=6.40 Hz, 2H), 1.78-1.69 (m, 4H)。
3rd step
1 '-((1-(4-hydroxybutyl)-5-iodo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid (300 mg, 1.3 mmol), be dissolved in 8 mL dry DMF, room temperature adds HATU (547 mg, 1.44 mmol) and DIPEA (507 mg, 3.92 mmol), stirring at room temperature half an hour, add 4-((2-amido-4-iodophenyl) amido) butyl-1-alcohol 44c(284 mg, 1.30 mmol) reaction solution stirring at room temperature 40 hours.50 mL 1M sodium hydroxide solutions are added to reaction solution, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude product.With 18 mL Glacial acetic acid by this dissolving crude product, be heated to backflow, stir 2 hours.Reaction solution concentrating under reduced pressure, obtains crude product.With 9 these crude products of mL dissolve with methanol, add sodium hydrate solid (360 mg, 9 mmol), stirring at room temperature 40 minutes.50 mL water are added to reaction solution, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify with preparative high-performance liquid chromatographic and obtain title product 1 '-((1-(4-hydroxybutyl)-5-iodo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 44(220 mg, white solid), productive rate: 34.5%.
MS m/z (ESI): 488.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 8.04 (s, 1H), 7.85 (d, J=8.52 Hz, 1H), 7.66 (d, J=8.76 Hz, 1H), 7.34-7.20 (m, 1H), 7.18-6.99 (m, 3H), 5.56 (s, 2H), 4.52 (t, J=7.92 Hz, 2H), 3.58 (t, J=6.16 Hz, 2H), 1.89 (quin, J=7.72 Hz, 2H), 1.81-1.69 (m, 4H), 1.67-1.54 (m, 2H)。
Embodiment 45
1 '-((1-(4-hydroxybutyl)-5-methyl isophthalic acid H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
1 '-((1-(4-hydroxybutyl)-5-methyl isophthalic acid H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 45a(439 mg, 1.0 mmol) are dissolved in the water of 2 mL anhydrous dioxane and 1 mL, add salt of wormwood (276 m g, 2.0 mmol.) and tetra-triphenylphosphine palladium (1.12 g, 1.1mmol), at microwave and 110 ounder C condition, stir 20 minutes.Reaction solution adds in 10 mL hydrochloric acid solns (0.1M), extraction into ethyl acetate (30 mL × 3), saturated sodium bicarbonate regulates pH to 7-8, merge organic phase, water (80 mL × 2), saturated aqueous common salt (80 mL × 2) is used to wash successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, enriched material preparative high-performance liquid chromatographic purifying obtains title product 1 '-((1-(4-hydroxybutyl)-5-methyl isophthalic acid H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one 45(60 mg, white solid), productive rate: 16.0 %.
MS m/z (ESI): 376.3 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.86 (d, J= 9.28 Hz, 1H), 7.48-7.58 (m, 2H), 7.27-7.37 (m, 1H), 7.06-7.22 (m, 3H), 5.67 (s, 2H), 4.56-4.67 (m, 2H), 3.62 (t, J = 6.16 Hz, 2H), 2.56 (s, 3H), 1.99 (td, J= 7.84, 15.43 Hz, 2H), 1.74-1.86 (m, 4H), 1.58-1.71 (m, 2H)。
Embodiment 46
1 '-((1-(4-hydroxybutyl)-5-Trifluoromethyl-1 H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
The first step
4-((2-nitro-4-trifluoromethyl) amido) butyl-1-alcohol
By fluoro-for 1-2-nitro-4-trifluoromethylbenzene 46a(3.0 g, 14.4 mmol, 1.0 eq.) are dissolved in 40 mL acetonitriles, add salt of wormwood (5.95 g, 43.0 mmol, 3.0 eq.) and 4-amino butanol (1.92 g, 21.5 mmol, 1.5 eq.), stirring at room temperature 3h.Reaction solution is poured in 20 mL hydrochloric acid solns (1M), extraction into ethyl acetate (100 mL × 3), saturated sodium bicarbonate regulates pH to 7-8, merge organic phase, use water (100 mL × 2), saturated aqueous common salt (100 mL × 2) to wash successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude product 4-((2-nitro-4-trifluoromethyl) amido) butyl-1-alcohol 46b(4.39 g, faint yellow oily).
1H NMR (400MHz, CDCl 3) δ 8.48 (s, 1H), 8.32 (s, 1H), 7.62 (dd, J= 1.5, 9.0 Hz, 1H), 6.96 (d, J= 9.0 Hz, 1H), 3.76 (t, J= 6.0 Hz, 2H), 3.46 - 3.37 (m, 2H), 1.93 - 1.83 (m, 2H), 1.79 - 1.69 (m, 2H), 1.40 (s, 1H)。
Second step
4-((2-amido-4-trifluoromethyl) amido) butyl-1-alcohol
By 4-((2-nitro-4-trifluoromethyl) amido) butyl-1-alcohol 46b(4.39 g; 15.8 mmol; 1.0 eq.) be dissolved in 80 mL methyl alcohol; add palladium-carbon catalyst (439 mg).; stirring at room temperature 3 hours under nitrogen protection; filter, filtrate reduced in volume obtains 4-((2-amido-4-trifluoromethyl) amido) butyl-1-alcohol 46cproduct (3.6 g, dark oil), productive rate: 92.2%.
1H NMR (400MHz, CDCl 3) δ 7.10 (d, J= 8.0 Hz, 1H), 6.94 (d, J= 1.8 Hz, 1H), 6.64 (d, J= 8.0 Hz, 1H), 3.74 (t, J= 6.0 Hz, 2H), 3.50 (s, 1H), 3.21 (t, J= 6.7 Hz, 2H), 1.84 - 1.70 (m, 4H)。
3rd step
1 '-((1-(4-hydroxybutyl)-5-Trifluoromethyl-1 H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one
By 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid (150 mg, 0.604 mmol) be dissolved in the DMF of 3 mL, add HATU (252 mg, 0.664 mmol), DIPEA (234 mg, 1.812 mmol), stirring at room temperature, after 20 minutes, adds 4-((2-amido-4-trifluoromethyl) amido) butyl-1-alcohol 46c(131 mg, 0.604 mmol).Reaction solution stirring at room temperature 14 hours.Reaction solution is poured in 10 mL sodium hydroxide solutions (0.1M), extraction into ethyl acetate (25 mL × 3), use water (300 mL × 2) successively, saturated aqueous common salt (30 mL × 2) washs, anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains the crude product of 320mg, add the acetic acid of 5 mL, reflux 3 hours, after reaction solution is concentrated, concentrated solution adds the ethyl acetate of 30mL, through sodium hydroxide (0.1M) solution (10mL), the aqueous solution (15mL × 3) and saturated common salt water washing (30 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, methyl alcohol and NaOH (80 mg of 2mL are added in enriched material, 2mmol), stirring at room temperature 1 hour, the ethyl acetate of 15mL is added after reaction solution concentrates, through the aqueous solution (15mL × 3) and saturated common salt water washing (30 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, enriched material preparative high-performance liquid chromatographic purifying obtains title product 1 '-((1-(4-hydroxybutyl)-5-Trifluoromethyl-1 H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1, 3 '-indoline]-2 '-one 46(65 mg), productive rate: 25.1 %.
MS m/z (ESI): 430.1 [M+1]
1H NMR (400MHz, DMSO-d6) δ 8.00 (s, 1H), 7.84 (d, J= 8.5 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.07 - 6.98 (m, 2H), 5.37 (s, 2H), 4.39 (t, J= 7.7 Hz, 2H), 3.38 (t, J = 6.4 Hz, 2H), 1.71 - 1.59 (m, 6H), 1.49 - 1.40 (m, 2H)。
Embodiment 47,48
1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen
1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-6-cyanogen
The first step
2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen
3,4-bis-amido benzene cyanogen (0.5 g, 2.3mmol) is dissolved in the DMF of 10 mL, adds DIPEA (397mg, 3.1mmol) and HATU (1.05g, 2.76mmol), stirring at room temperature 15 minutes.Add 2-(2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) acetic acid 47a(306mg, 2.3mmol) stirring at room temperature 1 hour.20 mL water are added in reaction solution, extraction into ethyl acetate (20 mL × 3), merge organic phase, use water (50 mL × 2), saturated aqueous common salt (100 mL × 2) to wash successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain crude product 0.7 g, the 500mg (1.5 mmol) got wherein adds acetic acid (7 mL), 90 oc stirs 1 hour, reaction solution concentrates, water (5 mL) and ethyl acetate (2 mL) is added in concentrated solution, through in saturated sodium bicarbonate and after, separate out solid, filter, filter cake send a small amount of water and ethyl acetate washing to obtain product, 2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen 47b(470mg).Productive rate: 90%.
Second step
1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen and
1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-6-cyanogen
By 2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen 47b(660mg, 2.10mmol) is dissolved in 13 mL acetonitriles, adds 4-bromo fourth ethyl ester (490mg; 2.52mmol), sodium iodide (158mg; 1.05mmol) with salt of wormwood (581mg, 4.20mmol), 90 under nitrogen protection oc stirs 8 hours, and filter, filtrate reduced in volume obtains crude product 950 mg, and the 940mg got wherein is dissolved in methyl alcohol (20 mL), adds salt of wormwood (0.91g, 6.58mmol), 23 oc stirs 1 hour, filter, get filtrate concentrating, add the ethyl acetate of 100 mL, warp, the aqueous solution (50 mL × 3) and saturated common salt water washing (50 mL × 2) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, to purify with eluent system B with silica gel column chromatography and obtains 1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen 47(220mg, white solid), productive rate: 27.1% and 1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-6-cyanogen 48(40mg, white solid), productive rate: 4.5%.
Compound 47:mS m/z (ESI): 387.1 [M+1]
1H NMR (400 MHz, CDCl 3) δ 8.10 (s, 1 H), 7.50 (q, J = 8.4 Hz, 1 H), 7.46 (d, J= 8.2 Hz, 1 H), 7.38 (d, J= 8.4 Hz, 1 H), 7.20 (t, J= 8.2 Hz, 1 H), 7.03 (t, J= 8.2 Hz, 1 H), 6.80 (d, J= 7.2 Hz, 1 H), 5.32 (s, 1 H), 4.31 (t, J= 15.6 Hz, 2 H), 3.64 (q, J= 15.6 Hz, 2 H), 1.79 (m, J= 7.6 Hz, 2 H), 1.71-1.75(m, 2 H), 1.61-1.65(m, 2 H),1.59-1.58(m, 2 H)。
Compound 48: MS m/z (ESI): 387.1 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.81 (d, J = 8.4 Hz, 1 H), 7.67 (s, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.44 (d, J= 8.2 Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.00 (t, J = 8.4 Hz, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 5.33(s, 2 H), 4.31 (t, J = 16.4 Hz, 2 H), 3.65 (t, J = 12.0 Hz, 2 H), 1.84-1.81(m,2 H), 1.80-1.66(m,2 H), 1.64-1.62(m, 2 H), 1.60-1.58(m, 2 H)。
Embodiment 49
1'-((1-((3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
The first step
1,1-bis-bromo-2,2-bis-(chloromethyl) cyclopropane
By chloro-for 3-2-(chloromethyl) propane-1-alkene 49a(155 g, 1.24 mol), tetramethyl ethylene ketone (5.13 g, 0.043 mol), dibenzo-18-crown-6 (DB18C6) (3.35 g, 9.3 mmol) is at 0-15 oc adds in bromofom (568.7 g, 2.25 mol), stirs and forms white suspension liquid, 0-15 oc adds 50% aqueous sodium hydroxide solution (456 g, 11.41 mol), and reacting liquid temperature rose to 45 in 1 hour oc, cools the temperature to 35-40 with water-bath oc, and stir 2 days in this temperature, 500 mL methylene dichloride and 500 mL water add reaction solution, filter, filtrate adds 500 mL water, with dichloromethane extraction (500 mL × 2), merges organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, 1L normal heptane adds in resistates, stirring-5-0 oc stirs 30 minutes, separates out solid, filters, obtains 1,1-bis-bromo-2,2-bis-(chloromethyl) cyclopropane 49b(151 g, yellow solid), productive rate: 41%.
1H NMR (400 MHz, CDCl 3) δ 4.03-3.96 (dd, J =12. 6 Hz, 4 H), 1.85 (s, 2H)。
Second step
Three ring [1.1.1.0 1,3] pentane
By bromo-for 1,1-bis-2,2-bis-(chloromethyl) cyclopropane 49b(40 g, 0.135 mol) is dissolved in 40mL anhydrous diethyl ether ,-30 oc drips lithium methide (253 mL, 0.405 mol), stirring at room temperature 2 hours under nitrogen protection.0-15 oc slowly adds 100 mL water, extracted with diethyl ether (150 mL × 2), merges organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, obtain three ring [1.1.1.0 1,3] pentane 49cfiltrate is not treated directly carries out next step reaction.
1H NMR (400 MHz, CDCl 3) δ 2.07 (s, 6H)。
3rd step
1,1'-(two rings [1.1.1] pentane-1,3-bis-base) diethyl ketone
Benzenethiol (5.95 g, 0.054 mol) is in 15 oc adds three ring [1.1.1.0 1,3] pentane 49cdiethyl ether solution in, keep 15 with high voltage mercury lamp radiation ostir 24 hours under C, concentrated, purify gained resistates with silica gel column chromatography with eluent system B, obtain 1,1'-(two rings [1.1.1] pentane-1,3-bis-base) diethyl ketone 49d(4.0 g, white solid), productive rate: 61.9%.
1H NMR (400 MHz, CDCl 3) δ 2.24 (s, 6 H), 2.13 (s, 6 H)。
4th step
Two rings [1.1.1] pentane-1,3-dicarboxylic acid
Sodium hydroxide is dissolved in 72 mL water, adds bromine (18.2 g, 0.11 mol), 0-3 oc drips 1,1'-(two rings [1.1.1] pentane-1, the 3-bis-base) diethyl ketone being dissolved in 8 mL dioxane 49d(2.3 g, 0.015 mol), 0 oc stirs 1 hour, room temperature 12 hours, add 0.4 g sodium bisulfite, dichloromethane extraction (100 mL × 2), 8 mL concentrated hydrochloric acids add aqueous phase, regulate pH to 2, methylene dichloride and isopropyl alcohol extraction (2:1,100 mL × 3), merge organic phase, water (100 mL × 2), saturated nacl aqueous solution is used to wash (100 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain product two ring [1.1.1] pentane-1,3-dicarboxylic acid 49e(2.0 g, yellow oil), productive rate: 85.8%.
1H NMR (400 MHz, CDCl 3) δ 2.14 (s, 6H)。
5th step
Dimethyl-two ring [1.1.1] pentane-1,3-dicarboxylic ester
By two rings [1.1.1] pentane-1,3-dicarboxylic acid 49e(1.0 g, 6.5 mmol) are dissolved in 20 mL thionyl chloride, return stirring 17 hours, the thionyl chloride that concentrated removing is excessive, and 0 oc slowly drips 25 mL methyl alcohol, return stirring 1 hour, concentrates to obtain crude product dimethyl-two ring [1.1.1] pentane-1,3-dicarboxylic ester 49f(16 g, colorless oil), product is not purified directly carries out next step reaction.
1H NMR (400 MHz, CDCl 3) δ 3.69 (s, 6H), 2.32 (s, 6H)。
6th step
Two rings [1.1.1] pentane-1,3-bis-base dimethanol
By dimethyl-two ring [1.1.1] pentane-1,3-dicarboxylic ester 49f (800 mg, 4.35 mmol) be dissolved in 30 mL tetrahydrofuran (THF)s, 0 oc adds Lithium Aluminium Hydride (727 mg, 19.1 mmol), and 0 oc stirs 1 hour.8 mL water add reaction solution, concentrated, purify gained resistates, obtain two rings [1.1.1] pentane-1,3-bis-base dimethanol with silica gel column chromatography with eluent system B 49g(557 mg, colorless oil), productive rate: 100%.
1H NMR (400 MHz, CDCl 3) δ 3.59 (s, 4H), 1.62 (s, 6H)。
7th step
(3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl-4-toluene sulfonic acide ester
By two rings [1.1.1] pentane-1,3-bis-base dimethanol 49g (200 mg, 1.56 mmol) be dissolved in 20 mL methylene dichloride, 0 oc adds triethylamine (0.22 mL, 1.56 mmol), 4-N, N-lutidine (catalytic amount), Tosyl chloride (446 mg, 2.34 mmol), stirring at room temperature 17 hours, concentrated, purify gained resistates with silica gel column chromatography with eluent system B, (3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl-4-toluene sulfonic acide ester 49h(265 mg, colorless oil), productive rate: 60%.
1H NMR (400 MHz, CDCl 3) δ 7.80 (d, J=8.28 Hz, 2 H), 7.36 (d, J=8.03 Hz, 2 H), 4.05 (s, 2 H), 3.61 (s, 2 H), 2.47 (s, 3 H), 1.66 (s, 6 H)。
8th step
1'-((1-((3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
By 1'-((1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone (326 mg, 1.13 mmol) be dissolved in 5 mL DMF, room temperature adds (3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl-4-toluene sulfonic acide ester 49h (265 mg, 0.94 mmol), salt of wormwood (324 mg, 2.35 mmol), 80 oc microwave stirs 2 hours, concentrated, purify with preparative high-performance liquid chromatographic and obtain title product 1'-((1-((3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 49(96 mg, white solid), productive rate: 25.6%.
MS m/z (ESI): 400.4 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.77-7.83 (m, 1H), 7.57 (d, J=8.03 Hz, 1H), 7.32-7.37 (m, 1H), 7.25-7.28 (m, 2H), 7.19-7.25 (m, 1H), 7.03 (t, J=7.53 Hz, 1H), 6.84 (d, J=7.28 Hz, 1H), 5.30 (s, 2H), 4.45 (s, 2H), 3.51 (d, J=5.52 Hz, 2H), 1.83 (q, J=3.93 Hz, 2H), 1.60 (br. s., 8H), 1.11 (t, J=5.90 Hz, 1H)。
Embodiment 50
Methyl-3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylicesters
The first step
Methyl-3-(hydroxymethyl) two ring [1.1.1] pentane-1-carboxylicesters
By dimethyl-two ring [1.1.1] pentane-1,3-dicarboxylic ester 50a (2.15 g, 11.7 mmol) be dissolved in 20 mL tetrahydrofuran (THF)s, 0 oc adds lithium borohydride (378 mg, 18.0 mmol), stirring at room temperature 17 hours.Reaction solution adds 8 mL water, concentrated, purifies gained resistates, obtain methyl-3-(hydroxymethyl) two ring [1.1.1] pentane-1-carboxylicesters with silica gel column chromatography with eluent system B 50b(1 g, colorless oil), productive rate: 54.9%.
1H NMR (400 MHz,CDCl 3) δ 3.70 (s, 3H), 3.66 (s, 2H) , 2.02 (s, 6 H)。
Second step
Methyl-3-((tosyl group oxygen base) methyl) two rings [1.1.1] pentane-1-carboxylicesters
By methyl-3-(hydroxymethyl) two ring [1.1.1] pentane-1-carboxylicesters 50b (500 mg, 3.2 mmol) be dissolved in 20 mL methylene dichloride, 0 oc adds triethylamine (0.45 mL; 3.2 mmol); 4-N; N-lutidine (catalytic amount), Tosyl chloride (917 mg, 4.8 mmol); stirring at room temperature 17 hours; concentrated, purify gained resistates with silica gel column chromatography with eluent system B, obtain methyl-3-((tosyl group oxygen base) methyl) two rings [1.1.1] pentane-1-carboxylicesters 50c(190 mg, colorless oil), productive rate: 19.1%.
1H NMR (400 MHz, CDCl 3) δ 7.78 (d, J=8.03 Hz, 2 H), 7.35 (d, J=8.03 Hz, 2 H), 4.03 (s, 2 H), 3.66 (s, 3 H), 2.46 (s, 3 H), 1.97 (s, 6 H)。
3rd step
Methyl-3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylicesters
By 1'-((1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone (89 mg, 0.31 mmol) be dissolved in 5 mL DMF, room temperature adds methyl-3-((tosyl group oxygen base) methyl) two rings [1.1.1] pentane-1-carboxylicesters 50c (80 mg, 0.258 mmol), salt of wormwood (89 mg, 0.645 mmol), 80 oc microwave stirs 3 hours, concentrated, purify with preparative high-performance liquid chromatographic and obtain title product methyl-3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylicesters 50(40 mg, white solid), productive rate: 36.3%.
MS m/z (ESI): 428.3 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.79-7.84 (m, 1 H), 7.57 (d, J=8.03 Hz, 1 H), 7.29-7.34 (m, 2 H), 7.24 (t, J=7.28 Hz, 2 H), 7.04 (t, J=7.53 Hz, 1 H), 6.84 (d, J=7.28 Hz, 1 H), 5.28 (s, 2 H), 4.47 (s, 2 H), 3.61 (s, 3 H), 1.92 (s, 6 H), 1.72-1.68 (m, 2H), 1.63-1.59 (m, 2H)。
Embodiment 51
3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylic acid
The first step
3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylic acid
By methyl 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylicesters 51a (40 mg, 0.0937 mmol) be dissolved in 16 mL tetrahydrofuran (THF)s, room temperature adds sodium hydroxide (22 mg, 0.562 mmol) and 2 mL water, stirring at room temperature 10 minutes, petroleum ether extraction (20 mL × 3).Aqueous phase hcl acidifying pH to 5, extraction into ethyl acetate (50 mL × 6), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylic acid 51(30 mg, white solid), productive rate: 77.5%.
MS m/z (ESI): 414.3 [M+1]
1H NMR (400 MHz, CD 3OD) δ 7.76 (d, J=7.78 Hz, 1 H), 7.72 (d, J=7.53 Hz, 1 H), 7.47-7.57 (m, 2 H), 7.25-7.32 (m, 1 H), 7.15-7.20 (m, 1 H), 7.10-7.15 (m, 1 H), 7.05-7.09 (m, 1 H), 5.49 (s, 2 H), 4.71 (s, 2 H), 1.99 (s, 6 H), 1.74-1.84 (m, 4 H)。
Embodiment 52
3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-acid amides
The first step
3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-acid amides
By 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylic acid 52a (20 mg, 0.048 mmol) be dissolved in 5 mLDMF, room temperature adds diisopropylethylamine (25 mg, 0.192 mmol), HATU (36 mg, 0. 096 mmol) and ammonium chloride (8 mg, 0.145 mmol), stirring at room temperature 1.5 hours.20 mL water add reaction solution, extraction into ethyl acetate (50 mL × 2), merge organic phase, water (50 mL × 3), saturated nacl aqueous solution is used to wash (50 mL × 2) successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-acid amides 52(5 mg, white solid), productive rate: 25%.
MS m/z (ESI): 413.1 [M+1]
1H NMR (400 MHz, CD 3OD) δ 7.66 (d, J=7.53 Hz, 1 H), 7.53 (d, J=7.53 Hz, 1 H), 7.27-7.36 (m, 2 H), 7.19-7.26 (m, 2 H), 7.04-7.10 (m, 1 H), 6.98-7.03 (m, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H), 1.90 (s, 6 H), 1.72-1.81 (m, 4 H)。
Embodiment 53
3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-nitrile
The first step
3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-nitrile
By 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-acid amides 53a (30 mg, 0.073 mmol) be dissolved in 10 mL methylene dichloride, room temperature adds triethylamine (33 mg, 0.33 mmol), trifluoro-acetic anhydride (31 mg, 0.15 mmol), stirring at room temperature 15 minutes, concentrated, purify with preparative high-performance liquid chromatographic and obtain title product 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-nitrile 53(5 mg, white solid), productive rate: 17.4%.
MS m/z (ESI): 395.1 [M+1]
1H NMR (400 MHz, CDCl 3) δ 7.81 - 7.86 (m, 1 H), 7.55 (d, J=7.78 Hz, 1 H), 7.29 - 7.34 (m, 2 H), 7.20 - 7.27 (m, 2 H), 7.06 (t, J=7.53 Hz, 1 H), 6.87 (d, J=7.28 Hz, 1 H), 5.27 (s, 2 H), 4.45 (s, 2 H), 2.09 (s, 6 H), 1.84 (q, J=3.76 Hz, 2 H), 1.64 - 1.66 (m, 2 H)。
Embodiment 54
1'-((the bromo-1-of 5-(the fluoro-4-hydroxy phenyl of 5,5,5-tri-)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
The first step
4-(the bromo-2-of 5-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) butyraldehyde-n
By 1'-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 54a(500 mg, 1.136 mmol) are dissolved in 8 mL methylene dichloride, and room temperature adds pyridinium chlorochromate (490 mg, 2.273 mmol), stirring at room temperature 2 hours.Reaction solution concentrates, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 4-(the bromo-2-of 5-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) butyraldehyde-n 54b(280 mg, white oil thing), productive rate: 56.2 %.
1H NMR (400MHz, CDCl 3) δ 9.74 (s, 1H), 7.91 (d, J=1.52 Hz, 1H), 7.28-7.48 (m, 3H), 7.14-7.22 (m, 1H), 7.00 (t, J=7.52 Hz, 1H), 6.80 (d, J=7.28 Hz, 1H), 5.28 (s, 2H), 4.18-4.36 (m, 2H), 2.53 (t, J=6.84 Hz, 2H), 1.68-1.94 (m, 6H)。
Second step
1'-((the bromo-1-of 5-(the fluoro-4-hydroxy phenyl of 5,5,5-tri-)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
By 4-(the bromo-2-of 5-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) butyraldehyde-n 54b(230 mg, 0.525 mmol) be dissolved in 5 mL anhydrous tetrahydro furans, trimethylammonium trifluoromethyl silicon (108 mg are added under condition of ice bath, 0.76 mmol) and tetrabutyl ammonium fluoride (10 uL of catalytic amount, 1 mole of often liter of tetrahydrofuran solution), reaction solution stirs 1.5 hours under condition of ice bath, and slowly gos up to room temperature.Additionally add trimethylammonium trifluoromethyl silicon (95 mg, 0.668 mmol) and tetrabutyl ammonium fluoride (10 uL, 1 mole of often liter of tetrahydrofuran solution), driving a reaction is complete.Reaction solution added excessive tetrabutyl ammonium fluoride (3.6 mL, 1 mole of often liter of tetrahydrofuran solution) cancellation, by its stirred at ambient temperature 5 hours.Reaction solution concentrates, and purifies gained resistates, obtain crude product with silica gel column chromatography with eluent system B.Crude product preparative high-performance liquid chromatographic purifying obtains title product 1'-((the bromo-1-(5 of 5-, 5, the fluoro-4-hydroxy phenyl of 5-tri-)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 54(20 mg, white solid), productive rate: 7.5%.
MS m/z (ESI): 508.0 [M+1]
1H NMR (400MHz, CDCl 3) δ 7.96 (d, J=1.24 Hz, 1H), 7.56 (d, J=7.76 Hz, 1H), 7.41 (dd, J=1.51, 8.52 Hz, 1H), 7.18-7.27 (m, 2H), 7.06 (t, J=7.52 Hz, 1H), 6.85 (d, J=7.28 Hz, 1H), 5.33 (s, 2H), 4.14-4.44 (m, 2H), 4.00 (br. s., 1H), 3.86 (br. s., 1H), 1.95-1.58 (m, 8H)
19F NMR (400MHz, CD 3OD) δ-81.35 (s, 3F)。
Embodiment 55
1'-((the bromo-1-of 5-(3,4-dihydroxyl butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
The first step
1'-((the bromo-1-of 5-(4-bromo butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
By 1'-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 55a(439 mg, 1.0 mmol) are dissolved in 10 mL methylene dichloride, and room temperature adds triphenylphosphine (524 mg, 2.0 mmol) and carbon tetrabromide (664 mg, 2.0 mmol), stirring at room temperature 12 hours.100 mL water are added to reaction solution, dichloromethane extraction (100 mL × 2), merge organic phase, water (100 mL × 2), saturated aqueous common salt (100 mL × 2) is used to wash successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1'-((the bromo-1-of 5-(4-bromo butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 55b(600 mg), productive rate: 95 %.
1H NMR (400MHz, CDCl 3) δ 7.93 (d, J=1.3 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.38 (dd, J=1.6, 8.7 Hz, 1H), 7.25 - 7.13 (m, 2H), 7.02 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.3 Hz, 1H), 5.30 (s, 2H), 4.27 (t, J=7.5 Hz, 2H), 3.33 (t, J=6.4 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.83 - 1.78 (m, 2H), 1.77 - 1.69 (m, 2H), 1.60 - 1.55 (m, 2H)。
Second step
1'-((the bromo-1-of 5-(butyl-3-alkene-1-base)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
By 1'-((the bromo-1-of 5-(4-bromo butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 55b(503 mg, 1.0 mmol) are dissolved in the 10 mL trimethyl carbinols, and room temperature adds potassium tert.-butoxide (224 mg, 2.0 mmol), and reaction solution is heated to 90 0c, stirs 12 hours.Reaction solution concentrates, residuum 100 mL methylene dichloride dissolve, water (100 mL × 2), saturated aqueous common salt (100 mL × 2) is used to wash successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1'-((the bromo-1-of 5-(butyl-3-alkene-1-base)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 55c(200 mg), productive rate: 50 %.
1H NMR (400MHz, CDCl 3) δ 7.93 (br. s., 1H), 7.40 (dd, J=8.3, 14.8 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 5.77 - 5.61 (m, 1H), 5.30 (s, 3H), 5.02 - 4.83 (m, 2H), 4.31 (t, J=7.3 Hz, 2H), 2.33 (d, J=6.5 Hz, 2H)。
3rd step
1'-((the bromo-1-of 5-(3,4-dihydroxyl butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone
By 1'-((the bromo-1-of 5-(butyl-3-alkene-1-base)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 55c(105 mg, 0.25 mmol) be dissolved in the mixed solvent of 7 mL water and 7 mL acetone, room temperature adds perosmic anhydride (5 mg) and the N-methylmorpholine-N-oxide compound (234 mg, 2.0 mmol) of catalytic amount, stirring at room temperature 1 hour.Reaction solution 100 mL sodium thiosulfate solution cancellation, extraction into ethyl acetate (100 mL × 2), merge organic phase, sodium thiosulfate solution (100 mL × 2), saturated aqueous common salt (100 mL × 2) is used to wash successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain 1'-((the bromo-1-(3 of 5-, 4-dihydroxyl butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone 55(24 mg), productive rate: 50 %.
MS m/z (ESI): 456.0 [M+1]
1H NMR (400MHz, CD 3OD) δ 7.75 (d, J=1.3 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.42 (dd, J=1.6, 8.7 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.14 - 7.09 (m, 1H), 7.04 (d, J=7.5 Hz, 1H), 7.01 - 6.97 (m, 1H), 5.51 - 5.26 (m, 2H), 4.53 - 4.44 (m, 2H), 3.55 (br. s., 1H), 3.41 (d, J=4.3 Hz, 2H), 1.95 - 1.84 (m, 1H), 1.82 - 1.73 (m, 3H), 1.73 - 1.66 (m, 2H)。
Embodiment 56
4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium
The first step
4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid two hydrogen ester
By 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoles]-2 '-one 56a(0.44 g, 1.0 mmol) are dissolved in 4 mL triethyl phosphates, are cooled to 0 oc adds 0.6 mL phosphorus oxychloride, and reaction solution is in 0 oc continues reflection 1 hour.Add 2 moles and rise aqueous sodium hydroxide solution adjustment pH to 7, add extraction into ethyl acetate (20 mL × 2), the direct lyophilize of residue aqueous phase obtains white solid.By this solid washed with water, residuum filters, dry 4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid two hydrogen ester 56b(0.16 g), productive rate: 31 %.
1H NMR (400MHz, CD 3OD) δ 7.75 (s, 1H), 7.57-7.55 (d, J=8.8Hz, 1H), 7.44-7.41 (t, 1H), 7.18-7.16 (t, 1H), 7.12-7.10 (d, J=7.6Hz, 1H), 7.04-7.00 (m, 2H), 5.37 (s, 2H), 4.40-4.36 (t, 2H), 3.89-3.85 (t, 2H), 1.78-1.69 (m, 8H)
31P NMR (400MHz, CD 3OD) δ -1.14 (s, 1P)。
Second step
4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium
By 4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid two hydrogen ester 56b(0.10 g, 0.19 mmol) is dissolved in 1 mL acetonitrile and 4 mL water, adds sodium hydroxide (0.012 g, 0.3 mmol), reaction solution stirring at room temperature 2 hours.By reacting liquid filtering, mother liquor lyophilize obtains title product 4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium 56(0.07 g), productive rate: 65 %.
MS m/z (ESI): 520.1 [M-2Na+2H+1]
1H NMR (400MHz, CD 3OD) δ 7.73 (s, 1H), 7.60-7.58 (d, J=8.4Hz, 1H), 7.43-7.41 (t, 1H), 7.18-7.16 (t, 1H), 7.09-7.00 (m, 3H), 5.38 (s, 2H), 4.42-4.38 (t, 2H), 3.86-3.82 (t, 2H), 1.81-1.65 (m, 8H)
31P NMR (400MHz, CD 3OD) δ -5.37 (s, 1P)。
Embodiment 57
4-(the bromo-2-of 5-((1-(isopropyloxycarbonyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium
The first step
1 '-((the bromo-1-of 5-(4-mono phosphoric acid ester oxo) butyl-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylic acid isopropyl
By sec.-propyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters 57a(0.54 g, 1.0 mmol) are dissolved in 4 mL triethyl phosphates, are cooled to 0 oc adds 0.6 mL phosphorus oxychloride, and reaction solution is in 0 oc continues reflection 1 hour.Add 2 moles and rise aqueous sodium hydroxide solution adjustment pH to 7, add extraction into ethyl acetate (20 mL × 2), the direct lyophilize of residue aqueous phase obtains white solid.By this solid washed with water, residuum filters, dry 1 '-((the bromo-1-of 5-(4-mono phosphoric acid ester oxo) butyl-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylic acid isopropyl 57b(0.12 g), productive rate: 19 %.
1H NMR (400MHz, CD 3OD) δ 7.98 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.82 (dd, J=1.4, 8.9 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.32 - 7.25 (m, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.62 (s, 2H), 4.98 - 4.94 (m, 1H), 4.67 (t, J=7.8 Hz, 2H), 4.39 (d, J=8.3 Hz, 2H), 4.24 (d, J=8.0 Hz, 2H), 4.10 (q, J=6.0 Hz, 2H), 2.13 (quin, J=7.6 Hz, 2H), 1.89 (td, J=6.4, 13.3 Hz, 2H), 1.29 (d, J=6.3 Hz, 6H)
31P NMR (400MHz, CD 3OD) δ -0.01 (s, 1P)。
Second step
4-(the bromo-2-of 5-((1-(isopropyloxycarbonyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium
By 1 '-((the bromo-1-of 5-(4-mono phosphoric acid ester oxo) butyl-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylic acid isopropyl 57b(0.12 g, 0.19 mmol) is dissolved in 1 mL acetonitrile and 4 mL water, adds sodium hydroxide (0.012 g, 0.3 mmol), reaction solution stirring at room temperature 2 hours.By reacting liquid filtering, mother liquor lyophilize obtains title product 4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium 57(0.065 g), productive rate: 51 %.
MS m/z (ESI): 621.2 [M-2Na+2H+1]
1H NMR (400MHz, CD 3OD) δ 7.74 - 7.53 (m, 3H), 7.42 (d, J=8.5 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.20 - 7.14 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 4.95 (br. s., 1H), 4.61 - 4.32 (m, 4H), 4.21 (d, J=8.3 Hz, 2H), 3.94 - 3.84 (m, 2H), 2.04 - 1.92 (m, 2H), 1.77 - 1.65 (m, 2H), 1.29 (d, J=6.3 Hz, 6H)
1H NMR (400MHz, CD 3OD) δ 5.43 (s, 1P)。
Embodiment 58
4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid disodium
The first step
4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid two hydrogen ester
By 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one 58a(0.44 g, 1.0 mmol) are dissolved in 4 mL triethyl phosphates, are cooled to 0 oc adds 0.6 mL phosphorus oxychloride, and reaction solution is in 0 oc continues reflection 1 hour.Add 2 moles and rise aqueous sodium hydroxide solution adjustment pH to 7, add extraction into ethyl acetate (20 mL × 2), the direct lyophilize of residue aqueous phase obtains white solid.By this solid washed with water, residuum filters, dry 4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid two hydrogen ester 58b(0.18 g), productive rate: 35 %.
1H NMR (400MHz, CD 3OD) δ 8.18 (d, J= 8.5 Hz, 1H), 7.83 (t, J= 8.6 Hz, 1H), 7.62 (m,3H), 7.53(m, 2H), 5.82 (s, 2H), 4.52 (t, J= 8.6 Hz, 2H), 3.85 (t, J= 7.7 Hz, 3H), 2.85 (s, 3H), 2.09 -2.05 (m, 2H), 1.67 - 1.63 (m, 2H).
1H NMR (400MHz, CD 3OD) δ -0.02 (s, 1P)。
Second step
4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid disodium
By 4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid two hydrogen ester 58b(0.1 g, 0.19 mmol) is dissolved in 1 mL acetonitrile and 4 mL water, adds sodium hydroxide (0.012 g, 0.3 mmol), reaction solution stirring at room temperature 2 hours.By reacting liquid filtering, mother liquor lyophilize obtains title product 4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid disodium 58(0.05 g), productive rate: 47 %.
MS m/z (ESI): 521.0 [M-2Na+2H+1]
1H NMR (400MHz, CD 3OD) δ 8.87 (d, J= 8.5 Hz, 1H), 8.25 (t, J= 8.6 Hz, 1H), 7.96 (m,3H), 7.53(m, 2H), 5.89 (s, 2H), 4.88 (t, J= 8.6 Hz, 2H), 4.01 (t, J= 7.7 Hz, 3H), 2.86 (s, 3H), 2.11 -2.07 (m, 2H), 1.70 - 1.65 (m, 2H).
1H NMR (400MHz, CD 3OD) δ 5.57 (s, 1P)。
Experimental example 1: in-vitro evaluation
RSV long CPE assay
Experiment purpose:
The EC of anti-RSV respiratory syncytial virus compound is detected with cytopathy political reform 50and CC 50value.
Experiment material:
Clone: Hep2
Virus strain: RSV inhales road syncytial virus (A long strain)
Cell culture medium (DMEM/F12, Gibco#11330, add 10% serum Gibco#16140, and 1% dual anti-(penicillin 5000 IU/mL, Streptomycin sulphate 10 mg/mL), Gibco#15140)
Pancreatin (Gibco#12605010)
PBS (Thermo#SH30264.01)
Trypan blue (Cat. Invitrogen#15250061)
CCK-8 (Dojindo#CK04-20)
CO 2incubator, Thermo 240 I
Multidrop automatic liquid separation device, Thermo
The full-automatic microwell plate pretreatment system of POD 810 Plate Assembler, Labcyte
Scepter Handheld Automated Cell Counter hand-held automatic cell counter, Millipore
Microplate Spectrophotometer microplate spectrophotometer, Molecular Device.
Experimental procedure and method:
A) cell inoculation (Hep2 cell)
1) sop up the substratum of cell cultures, clean with 10mL PBS;
2) add preheated pancreatin in cleaned culturing bottle, rotating and culturing bottle makes pancreatin uniform fold culturing bottle.Again it is sopped up and be put into 37 DEG C, 5% CO 2digest in incubator;
3) each T150 10 ~ 15mL substratum overhangs cell, draws 0.1mL and then dilutes 2 times of countings with trypan blue solution;
4) use substratum diluting cells to 5 × 10 4/ mL, with automatic liquid separation device (Thermo Scientific), joins corning 384 plate (Cat. 3701) (30 uL/ holes, 1500 cells/ holes) by the cell diluted.Centrifugal for cell plate (300 turns) are made cell attachment, is positioned over 37 DEG C, 5% CO 2incubator spends the night.
B) compound application of sample:
1) by rare with half-log for the compound being dissolved in 100%DMSO, be added in cell plate with Echo sound wave liquid shifting equipment (Echo liquid handler).Ensure that DMSO final concentration is 1%;
EC50 (uM) CC50 (uM)
50-0.07 uM (8 some half-logs) 100-0.14 uM (8 some half-logs)
2) cell control well: do not add compound and virus; Virus control wells: do not add compound.
C) virus inoculation:
With 4 othe virus Multidrop automatic liquid separation device diluted to 100 TCID50/30uL, then is added cell plate (30 uL/ hole) by RSV viral dilution by the substratum of C cell cultures, is then positioned over 37 oc, 5% CO 2cultivate 5 days in incubator.
D) cytopathy detects:
1), after 5 days, the pathology situation in each hole is observed.Pathology is not had under normal circumstances, in the complete pathology of the beautiful cell of virus control wells cell control well;
2) CCK-8 (Dojindo-CK04-20,6 uL/ holes) to 384 orifice plate is added with Multidrop automatic liquid separation device;
3) 37 DEG C are positioned over, 5% CO 2hatch 3-4 hour in incubator, read absorption photometric value by microplate reader (SPECTRA max 340PC_Molecular device) at wavelength 450nm and 630nm;
4) analytical data.
Experimental result is in table 1:
Table 1 CPE assay EC50/CC50 test result
Note: EC 50show the activity of the In Vitro Anti respiratory syncytial virus of molecule, EC 50be less than 1 uM and representation compound has external activity.Two intervals have been divided: A (EC according to the size of activity 50< 0. 1 uM); B (0. 1 uM < EC 50< 1 uM).CC 50numerical value show the size of the in vitro toxicity of molecule, toxicity more fractional value is larger, is greater than 100 uM and namely represents that molecule does not have toxicity.
Conclusion: compared with BMS433771, the external activity of the compounds of this invention and toxicity are quite even more excellent.

Claims (34)

1. compound or its pharmacy acceptable salt shown in formula I, (II), (III) or (IV),
(I)
（Ⅱ）
（Ⅲ）
（Ⅳ）
Wherein,
A, E, A ', E ', A ' ', E ' ', A ' ' ', the E ' ' ' CH that separately represents N or be optionally substituted;
Y, Y ', Y ' ', Y ' ' ' separately represent (the CH be optionally substituted 2) p, p is the integer of 0-3, Y, Y when p is 0 ', Y ' ', Y ' ' ' representative only plays the singly-bound of ligation;
Represented by dotted arrows singly-bound, double bond or not Cheng Jian, when , , , , , , or when middle dotted line all can not represent key, this structural unit does not exist;
D, D ', D ' ', D ' ' ' separately represent C or N, as D, D ', D ' ' or D ' ' ' are the represented by dotted arrows singly-bound that during C, it connects, as D, D ', D ' ' or D ' ' ' is the represented by dotted arrows not Cheng Jian that during N, it connects;
M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' [OH, SH, NH of separately representing H, halogen, CN or being optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
R 1, R 1', R 1' ' [OH, SH, NH of being separately selected from H, halogen, CN or being optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
R 1' ' ' represent fluorine, chlorine, bromine, iodine, CN, OH, SH, NH 2, halo or hydroxyl generation or unsubstituted [C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl];
M, m ', m ' ' is independently selected from 0,1,2,3 or 4;
M ' ' ' is selected from 1,2,3 or 4;
R 2, R 2', R 2' ', R 2[OH, SH, NH that ' ' ' is separately selected from H, halogen, CN or is optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
Z, Z ' separately represent [the NH, (R that are optionally substituted 5) t(CH 2) qor (CH 2) q(R 5) t], R 5be selected from C=O, C=S, S(=O), S(=O) 2, O or S, t be 0 or 1, q be 0,1,2 or 3, t and q different time be 0;
U or V separately represents (NH) that be optionally substituted r1(R 6) r2(CH 2) r3, (R 6) r2(NH) r1(CH 2) r3, (CH 2) r3(NH) r1(R 6) r2, (NH) r1(CH 2) r3(R 6) r2, (R 6) r2(CH 2) r3(NH) r1or (CH 2) r3(R 6) r2(NH) r1, R 6be selected from C=O, C=S, S(=O), S(=O) 2, O or S, r 1, r 3separately be selected from 0,1,2 or 3, r 2be 0 or 1, r 1, r 2and r 3be the singly-bound that 0 expression U or V representative only plays ligation simultaneously, and be singly-bound when U with V is different;
L represents heteroatoms or heteroatoms group;
[OH, SH, NH that T ', T ' ' separately represent H, halogen, CN or be optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl];
B represents 3 ~ 8 yuan of alicyclic hydrocarbon be optionally substituted;
Q, Q ', Q ' ', Q ' ' ' separately represent optionally be substituted 5-12 unit cyclic hydrocarbon or 5-12 unit heterocyclic hydrocarbon; With
Optionally, described compound or its pharmacy acceptable salt have one or more chiral centre.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that wherein represented by dotted arrows singly-bound or double bond, M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent the CH be optionally substituted 2or CH.
3. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that wherein , , , do not exist, M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent [the C be optionally substituted 1-12alkyl, C 1-12assorted alkyl, C 1-12hydrocarbon is mixed base, C 1-12hydrocarbon is mixed base C 1-12alkyl ,-C 1-12oH ,-C 0-12cOOH ,-OC 1-12cOOH ,-C 1-12cN ,-C 0-12cONH 2,-C 0-12o C 1-12,-C 0-12cO C 1-12,-C 0-12cOO C 1-12,-C 0-12o(O=) C C 1-12,-C 0-12s (=O) C 1-12or-C 0-12s (=O) 2c 1-12], wherein, above-mentioned group itself optionally exists with the form of aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, and the number of described aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, ring member nitrogen atoms and number, ring and ring or ring and chain or the mode of connection between chain and chain are arbitrary under the prerequisite that chemically Absorbable organic halogens realizes, heteroatoms or heteroatoms are rolled into a ball and are separately selected from O, S, N, S (=O) and/or S (=O) 2, the number of heteroatoms or heteroatoms group is arbitrary under the prerequisite that chemically Absorbable organic halogens realizes.
4. compound according to claim 3 or its pharmacy acceptable salt, is characterized in that wherein M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent halo or hydroxyl generation amine generation or unsubstituted [C 6-12aryl or heteroaryl or heterocyclic base, C 3-8alicyclic radical or heteroalicyclyl or alicyclic ring are mixed base, C 1-6alkyl, C 1-6alkane is mixed base, C 1-6assorted alkyl, C 2-6alkenyl or alkynyl, C 2-6assorted thiazolinyl or assorted alkynyl, C 2-6mix base or alkynes of alkene is mixed base], described heteroatoms or heteroatoms group are separately selected from O, S, N, S (=O) and/or S (=O) 2, the number of heteroatoms or heteroatoms group is arbitrary under the prerequisite that chemically Absorbable organic halogens realizes.
5. compound according to claim 4 or its pharmacy acceptable salt, is characterized in that wherein M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ' separately represent halo or hydroxyl generation amine generation or unsubstituted [phenyl, , xenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidyl, 1,3-oxygen five rings base, pyrazolyl, 2-pyrazolinyl, pyrazolidyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-azoles base, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl group, 4 h-pyranyl, pyridyl, piperidyl, 1,4-dioxane base, morpholinyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,3,5-trithian base, 1,3,5-triazinyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnolines base or quinoxalinyl].
6. the compound according to Claims 1 to 5 any one or its pharmacy acceptable salt, is characterized in that wherein Q, Q ', Q ' ', Q ' ' ' separately structural unit shown in representative formula (a):
（a）
Wherein, X a, X b, X c, X dthe CH separately representing N or be optionally substituted.
7. the compound according to Claims 1 to 5 any one or its pharmacy acceptable salt, is characterized in that wherein B represents the cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or suberyl or ring octyl group that are optionally substituted.
8. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that its structural formula is such as formula shown in (V), (VI), (VII) or (VIII):
（Ⅴ）
（Ⅵ）
（Ⅶ）
（Ⅷ）
Wherein, X 1, X 2, X 3, X 4, X 1', X 2', X 3', X 4', X 1' ', X 2' ', X 3' ', X 4' ', X 1' ' ', X 2' ' ', X 3' ' ', X 4the CH that ' ' ' separately represents N or be optionally substituted.
9. the compound according to claim 1,2 or 6 ~ 8 any one or its pharmacy acceptable salt, is characterized in that wherein R 1, R 1', R 1' ' be selected from fluorine, chlorine, bromine, iodine, CN, the NH that is optionally substituted independently of one another 2, halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl, halo or hydroxyl generation or amine generation or unsubstituted C 2-6alkenyl or alkynyl.
10. compound according to claim 9 or its pharmacy acceptable salt, is characterized in that wherein R 1, R 1', R 1' ' be selected from fluorine, chlorine, bromine, iodine, CN, CF independently of one another 3, NH 2, CH 3, CH 2nH 2or CH(NH 2) 2.
11. compounds according to claim 1,2 or 6 ~ 8 any one or its pharmacy acceptable salt, is characterized in that wherein R 1' ' ' be selected from fluorine, chlorine, bromine, iodine, CH 3, CF 3, CN, OH, SH or NH 2.
12. compounds according to claim 1 ~ 8 any one or its pharmacy acceptable salt, is characterized in that wherein R 2, R 2', R 2' ', R 2' ' ' be separately selected from-the C be optionally substituted 1-10r 3, carbochain or carbocyclic ring optionally insert one or more heteroatoms or heteroatoms group, wherein,
R 3be selected from OR 4, H, halogen, CN ,=O or the [NH that is optionally substituted 2, acid amides ,-COOH or-OS(=O) 2cH 3];
R 4be selected from phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester,-sulfinate or H;
Heteroatoms on carbochain or carbocyclic ring or heteroatoms group are selected from O, N, Si and/or Si (OH).
13. compounds according to claim 1 ~ 8 any one or its pharmacy acceptable salt, is characterized in that wherein R 2, R 2', R 2' ', R 2' ' ' be selected from , C 1-6r 2b, or C 1-6alkyl;
H 1-5, f 1-3be selected from 0,1,2,3 independently of one another;
R 2a, R 2bbe selected from CN, OR independently of one another 2x, C(=O) R 2y;
R 2xbe selected from H, phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester or-sulfinate;
R 2ybe selected from optionally by [OH, NH of halogen, methyl, trifluoromethyl or methoxy substitution 2or-OC 1-6];
R 2cbe selected from O, S, C=O, C=S, S(=O), S(=O) 2, CR 2c1r 2c2, NR 2c3;
R 2dbe selected from N, CR 2d1;
R 2c1, R 2c2, R 2c3, R 2d1[OH, SH, NH of being separately selected from H, halogen, CN or being optionally substituted 2, PH 2, mix base or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl].
14. compounds according to claim 1 ~ 8 any one or its pharmacy acceptable salt, is characterized in that wherein R 2, R 2', R 2' ', R 2' ' ' be selected from
。
15. compounds according to claim 12 ~ 14 any one or its pharmacy acceptable salt, is characterized in that wherein said phosphonic acid ester or phosphonate are selected from-P (=O) (O C 2h 5) 2,-P(=O) (ONa) 2or-P(=O) (OK) 2.
16. compounds according to claim 1 ~ 15 any one or its pharmacy acceptable salt, is characterized in that wherein Z, Z ' CH that represents C=O, C=S or be optionally substituted 2.
17. compounds according to claim 1 ~ 15 any one or its pharmacy acceptable salt, is characterized in that wherein U or V separately represents [the CH be optionally substituted 2, (CH 2) 2, O(CH 2) 2, (CH 2) 2o, NH(C=O), (C=O) NH] or C=O.
18. compounds according to claim 1 ~ 15 any one or its pharmacy acceptable salt, is characterized in that wherein L represents O, S, S=O, S(=O) 2or the NH be optionally substituted.
19. compounds according to claim 1 ~ 15 any one or its pharmacy acceptable salt, is characterized in that wherein T ', T ' ' are separately selected from halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl, halo or hydroxyl generation or amine generation or unsubstituted C 2-6alkenyl or alkynyl, halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkoxyl group, the NH be optionally substituted 2, optionally 5-12 unit's cyclic group of being substituted or heterocyclic radical or ring to mix base, described NH 2substituting group be selected from C 1-6alkyl, C 5-8heterocyclic radical, C 5-8heterocyclic radical C 1-6alkyl or C 5-8ring is mixed base C 1-6alkyl, NH 2substituting group number be 1 or 2, described heteroatoms or heteroatoms group are selected from O, S, N, S(=O) or S(=O) 2.
20. compounds according to claim 19 or its pharmacy acceptable salt, is characterized in that wherein T ', T ' ' are separately selected from CF 3, halo or hydroxyl generation or amine generation or unsubstituted [CH 3, CH(CH 3) 2, cyclopropyl, OCH 3, OCH(CH 3) 2, N(CH 3) 2, N(CH 2cH 3) 2, , phenyl, , , or ].
21., according to the compound described in claim 1 ~ 20 or its pharmacy acceptable salt, is characterized in that wherein A, A ', A ' ', A ' ' ', E, E ', E ' ', E ' ' ', Y, Y ', Y ' ', Y ' ' ', M, W, M ', W ', M ' ', W ' ', M ' ' ', W ' ' ', R 1, R 1', R 1' ', R 1' ' ', R 2, R 2', R 2' ', R 2' ' ', R 3, Z, Z ', U, V, L, T ', T ' ', Q, Q ', the substituting group of Q ' ' or Q ' ' ' [OH, SH, NH of being selected from halogen, CN ,=O ,=S or being optionally substituted 2, PH 2, mix base and/or hydrocarbon of alkyl, assorted alkyl, hydrocarbon mix base alkyl].
22. compounds according to claim 21 or its pharmacy acceptable salt, is characterized in that wherein said alkyl, alkyl of mixing, hydrocarbon mix base or hydrocarbon is mixed, and base alkyl be selected from the [C be optionally substituted 1-12alkyl, C 1-12assorted alkyl, C 1-12hydrocarbon is mixed base, C 1-12hydrocarbon is mixed base C 1-12alkyl ,-C 1-12oH ,-C 0-12cOOH ,-OC 1-12cOOH ,-C 1-12cN ,-C 0-12cONH 2,-C 0-12o C 1-12,-C 0-12cO C 1-12,-C 0-12cOO C 1-12,-C 0-12o(O=) C C 1-12,-C 0-12s (=O) C 1-12or-C 0-12s (=O) 2c 1-12], wherein, above-mentioned group itself optionally exists with the form of aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, and the number of described aromatic nucleus, hetero-aromatic ring, cycloaliphatic ring, assorted cycloaliphatic ring, aliphatic chain and/or assorted aliphatic chain, ring member nitrogen atoms and number, ring and ring or ring and chain or the mode of connection between chain and chain are arbitrary under the prerequisite that chemically Absorbable organic halogens realizes, heteroatoms or heteroatoms are rolled into a ball and are separately selected from O, S, N, S (=O) and/or S (=O) 2, the number of heteroatoms or heteroatoms group is arbitrary under the prerequisite that chemically Absorbable organic halogens realizes.
23. compounds according to claim 3,21 or 22 or its pharmacy acceptable salt, is characterized in that the substituting group wherein replaced is selected from halogen, OH, SH, NH 2, PH 2, CN ,=O ,=S, CF 3,-OCF 3,-OCH 3, protecting group and/or leavings group.
24. compounds according to claim 21 ~ 23 any one or its pharmacy acceptable salt, is characterized in that the substituting group of wherein Z or Z ' is selected from halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl, halo or hydroxyl generation or amine generation or unsubstituted C 2-6alkenyl or alkynyl, the NH be optionally substituted 2, the optional 5-12 unit cyclic group or heterocyclic radical that is substituted, described NH 2substituting group be selected from C 1-6alkyl, C 5-8heterocyclic radical, C 5-8heterocyclic radical C 1-6alkyl or C 5-8ring is mixed base C 1-6alkyl, NH 2substituting group number be 1 or 2, described heteroatoms or heteroatoms group are selected from O, S, N, S(=O) or S(=O) 2.
25. compounds according to claim 24 or its pharmacy acceptable salt, is characterized in that the substituting group of wherein Z or Z ' is selected from CF 3, or , substituent number is 1 or 2.
26. compounds according to claim 21 ~ 23 any one or its pharmacy acceptable salt, is characterized in that the substituting group of wherein L is selected from halo or hydroxyl generation or amine generation or unsubstituted C 1-6alkyl ,-COO C 1-6alkyl ,-COO alkylene phenyl ,-CO C 1-6alkyl ,-S(=O) 2c 1-6alkyl, C 1-6cycloalkyl or C 1-6heterocyclylalkyl, described heteroatoms is selected from O, S or N, and heteroatomic number is 1 or 2.
27. compounds according to claim 26 or its pharmacy acceptable salt, is characterized in that the substituting group of wherein L is selected from methyl ,-COOC(CH 3) 3,-COOCH(CH 3) 2, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) ,-C(=O) CH(CH 3) 2,-S(=O) 2cH 3, or .
Compound or its pharmacy acceptable salt shown in 28. formulas (Ⅸ),
(Ⅸ)
Wherein,
R 7be selected from-R 8aoR 8bor ;
R 8abe selected from optionally by the-C of halogen, methyl, trifluoromethyl or methoxy substitution 1-10alkyl;
R 8bbe selected from phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester or-sulfinate;
J 1-5be selected from 0,1,2,3 independently of one another;
R 9be selected from CN, OR 9a, C(=O) R 9b;
R 9abe selected from H, phosphonic acid ester, phosphonate, sulphonate, sulfonate,-sulfinic acid ester or-sulfinate;
R 9bbe selected from H, optionally by [OH, NH of halogen, methyl, trifluoromethyl or methoxy substitution 2or-OC 1-6].
29., according to compound described in claim 28 or its pharmacy acceptable salt, is characterized in that wherein R 8abe selected from .
30., according to compound described in claim 28 or its pharmacy acceptable salt, is characterized in that wherein structural unit be selected from:
。
31. compounds according to claim 28 or 29 or its pharmacy acceptable salt, is characterized in that wherein R 8bor R 9abe selected from-P (=O) (O C 2h 5) 2,-P(=O) (ONa) 2or-P(=O) (OK) 2.
32. compounds according to claim 1 ~ 8 or 28 or its pharmacy acceptable salt, is characterized in that being selected from:
1) 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone;
2) 1-((1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-spiral shell [indoline-3,4 '-piperidines]-2-ketone;
3) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 ', 3 ', 5 ', 6 '-tetrahydrochysene spiral shell [indoline-3,4 '-pyrans]-2-ketone;
4) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone;
5) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(oxa-ring fourth-3-base) spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone;
7) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Thietane base]-2-ketone-1 ', 1 '-dioxide;
8) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4,5-dihydro-2H-spiral shells [furans-3,3 '-indoline]-2 '-one;
9) tertiary butyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters;
10) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methylspiro [azetidinyl-3,3 '-indoline]-2 '-one;
11) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-methylspiro [azetidinyl-3,3 '-indoline]-2 '-one;
12) sec.-propyl-1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1-carboxylicesters;
13) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-isobutyryl spiral shell [azetidinyl-3,3 '-indoline]-2 '-one;
14) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(methyl sulphonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one;
15) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl isophthalic acid-(Cyclopropylsulfonyl) spiral shell [azetidinyl-3,3 '-indoline]-2 '-one;
16) tertiary butyl-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters;
17) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone;
18) sec.-propyl base-1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-2-oxo spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-1 '-carboxylicesters;
19) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-isobutyryl spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone;
20) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-1 '-(methyl sulphonyl) spiral shell [indoline-3,3 '-Pyrrolidine alkyl]-2-ketone;
21) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4 '-methylspiro [indoline-3,2 '-morpholine alkyl]-2-ketone;
22) 1 '-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [imidazolidine-4,3 '-indoline]-2,2 ', 5-triketone;
23) 1-((1-(4-hydroxyl fourth collection)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one;
24) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methylquinazolin-2 (1H)-one;
25) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one;
26) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-cyclopropyl quinazoline-2 (1H)-one;
27) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-phenylquinazoline-2 (1H)-one;
28) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-dimethyl) quinazoline-2 (1H)-one;
29) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(N, N-diethyl) quinazoline-2 (1H)-one;
30) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-morpholine quinazoline-2 (1H)-one;
31) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-((3-morpholine propyl group) is amino) quinazoline-2 (1H)-one;
32) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-methoxyquinazoline hydrochloride-2 (1H)-one;
33) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropoxy quinazoline-2 (1H)-one;
34) 1-((the bromo-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-(pyridin-4-yl) quinazoline-2 (1H)-one;
35) 1-((5-(aminomethyl)-1-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl)-4-isopropylquinazolin-2 (1H)-one;
36) 1 '-((1-(4-hydroxybutyl)-4,5-phenylbenzene-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
37) 1 '-((1-(4-hydroxybutyl)-4-phenyl-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
38) 1 '-((1-(4-hydroxybutyl)-3-(thiazol-2-yl)-1H-pyrazoles-5-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one;
39) 1 '-((1-(4-hydroxybutyl)-4-(thiazol-2-yl)-1H-imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-pyrroles [2,3-c] pyridine-2 ' (1 ' H)-one;
40) 4-(the bromo-2-of 5-((2-trifluoromethyl)-1H-benzo [d] imidazoles-1-base) methyl)-1H-benzo [d] imidazoles-1-base) butyl-1-alcohol;
41) 1 '-((the bromo-1-of 6-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
42) 1 '-((the bromo-1-of 4-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
43) 1 '-((the chloro-1-of 5-(4-hydroxybutyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
44) 1 '-((1-(4-hydroxybutyl)-5-iodo-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
45) 1 '-((1-(4-hydroxybutyl)-5-methyl isophthalic acid H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
46) 1 '-((1-(4-hydroxybutyl)-5-Trifluoromethyl-1 H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3 '-indoline]-2 '-one;
47) 1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-5-cyanogen;
48) 1-(4-hydroxybutyl)-2-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-6-cyanogen;
49) 1'-((1-((3-(hydroxymethyl) two ring [1.1.1] pentane-1-base) methyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone;
50) methyl-3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylicesters;
51) 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-carboxylic acid;
52) 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-acid amides;
53) 3-((2-((2'-oxo spiral shell [cyclopropyl-1,3'-indoline]-1'-base) methyl)-1H-benzo [d] imidazoles-1-base) methyl) two rings [1.1.1] pentane-1-nitrile;
54) 1'-((the bromo-1-of 5-(the fluoro-4-hydroxy phenyl of 5,5,5-tri-)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone;
55) 1'-((the bromo-1-of 5-(3,4-dihydroxyl butyl)-1H-benzo [d] imidazoles-2-base) methyl) spiral shell [cyclopropyl-1,3'-indoline]-2'-ketone;
56) 4-(the bromo-2-of 5-((2 '-oxo spiral shell [cyclopropyl-1,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium salt;
57) 4-(the bromo-2-of 5-((1-(isopropyloxycarbonyl)-2 '-oxo spiral shell [azetidinyl-3,3 '-indoline]-1 '-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid ester disodium; With
58) 4-(the bromo-2-of 5-((4-methyl-2-oxoquinazolin-1 (2H)-Ji) methyl)-1H-benzo [d] imidazoles-1-base) butyl phosphoric acid disodium,
Optionally, above-claimed cpd or its pharmacy acceptable salt have one or more chiral centre.
33. 1 kinds of pharmaceutical compositions, comprise the compound according to claim of right1~32 any one or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
The application in the medicine of preparation treatment respiratory syncytial virus infection of compound described in 34. claim of right1~32 any one or its pharmacy acceptable salt or pharmaceutical composition according to claim 33.
CN201310661317.5A 2013-12-10 2013-12-10 Imidazole derivative as antiviral agent and pharmaceutical application thereof Pending CN104693211A (en)

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PCT/CN2014/090771 WO2015085844A1 (en) 2013-12-10 2014-11-11 Imidazole derivative used as antiviral agent and use thereof in preparation of medicament
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PT148703812T PT3081569T (en) 2013-12-10 2014-11-11 Imidazole derivative used as antiviral agent and use thereof in preparation of medicament
ES14870381T ES2757570T3 (en) 2013-12-10 2014-11-11 Imidazole derivative used as antiviral agent and use thereof in the preparation of a medicine
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JP2016539200A JP6118470B2 (en) 2013-12-10 2014-11-11 Imidazole derivatives used as antiviral agents and their use in the manufacture of pharmaceuticals
TW103142944A TWI730936B (en) 2013-12-10 2014-12-09 Imidazole derivatives as antiviral agents and their pharmaceutical uses
HK16110640.5A HK1223607A1 (en) 2013-12-10 2016-09-07 Imidazole derivatives used as antiviral agents and use thereof in preparation of medicament
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US20160068531A1 (en) * 2013-05-14 2016-03-10 Hoffmann-La Roche Inc. Novel aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection
WO2017004405A1 (en) * 2015-07-01 2017-01-05 Northwestern University Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
CN106749295A (en) * 2017-01-11 2017-05-31 中国药科大学 A kind of synthetic method of volution Oxoindole gamma-butyrolacton class compound
US9850251B2 (en) 2013-12-10 2017-12-26 Shandong Danhong Pharmaceutical Co., Ltd. Imidazole derivative used as antiviral agent and use therof in preparation of medicament
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US10189838B2 (en) * 2013-05-14 2019-01-29 Hoffman-La Roche Inc. Aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection
US20160068531A1 (en) * 2013-05-14 2016-03-10 Hoffmann-La Roche Inc. Novel aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection
US9850251B2 (en) 2013-12-10 2017-12-26 Shandong Danhong Pharmaceutical Co., Ltd. Imidazole derivative used as antiviral agent and use therof in preparation of medicament
US10030029B2 (en) 2013-12-10 2018-07-24 Shandong Danhong Pharmaceutical Co., Ltd. Imidazole derivative used as antiviral agent and use thereof in preparation of medicament
US10501435B2 (en) 2015-07-01 2019-12-10 Northwestern University Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
JP2018525345A (en) * 2015-07-01 2018-09-06 ノースウェスタン ユニバーシティ Substituted quinazoline compounds and their use for modulation of glucocerebrosidase activity
WO2017004405A1 (en) * 2015-07-01 2017-01-05 Northwestern University Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
US10934270B2 (en) 2015-07-01 2021-03-02 Northwestern University Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
CN107922407A (en) * 2015-07-30 2018-04-17 美迪维尔公司 Respiratory Syncytial Virus(RSV) inhibitor
CN105384697A (en) * 2015-12-16 2016-03-09 郑州轻工业学院 2-subsituted quinazoline preparation method
US11065233B2 (en) 2016-04-01 2021-07-20 Recurium Ip Holdings, Llc Estrogen receptor modulators
US11065234B2 (en) 2016-04-01 2021-07-20 Recurium Ip Holdings, Llc Estrogen receptor modulators
CN109476677A (en) * 2016-08-08 2019-03-15 南京明德新药研发股份有限公司 Anti- HCMV virus compound
CN106749295A (en) * 2017-01-11 2017-05-31 中国药科大学 A kind of synthetic method of volution Oxoindole gamma-butyrolacton class compound
CN111465600A (en) * 2017-07-20 2020-07-28 瑞威有限公司 Pharmaceutical compounds
US11278532B2 (en) 2019-08-06 2022-03-22 Recurium Ip Holdings, Llc Estrogen receptor modulators for treating mutants
CN112057453A (en) * 2019-08-26 2020-12-11 中检科医药科技(北京)集团有限公司 Use of ENC002 and its analogs in the treatment or prevention of enterovirus infection
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