CN105294688B - 6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and preparation method as well as application thereof - Google Patents

6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and preparation method as well as application thereof Download PDF

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CN105294688B
CN105294688B CN201510873837.1A CN201510873837A CN105294688B CN 105294688 B CN105294688 B CN 105294688B CN 201510873837 A CN201510873837 A CN 201510873837A CN 105294688 B CN105294688 B CN 105294688B
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pyrrolo
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胡利明
剧仑
毛志杰
李志鹏
曾程初
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Beijing University of Technology
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a 6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and a preparation method as well as application thereof, belonging to the field of HIV-1 integrase inhibitors. The compound is represented by a general formula (I), wherein R1 represents -F, -Me, -OMe and -H; R2 represents -H, -F, -Me, -OMe and -Cl; R3 represents -H, -F, -Me, -OMe, -Cl, -Br, -CF3 and -SO2Me. The preparation method of the compound comprises the steps of synthetising N-(6-chloropyridine-2-tertiary butyl) amide by using 6-chloropyridine-2-amine as a raw material and pivaloyl chloride, performing pyridine ring iodination, then hydrolyzing to obtain 6-chlorine-3-iodine pyridine-2-amine, cyclizing to obtain a compound with a carboxylic acid structure, and finally reacting with various substituted benzyls to obtain the compound disclosed by the invention.

Description

6- chloro- N- (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds And its preparation method and application
Technical field
The present invention relates to 6- chloro- N- (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds, its preparation Method and the application as HIV-1 integrase inhibitors, belong to HIV-1 integrase inhibitors field.
Background technology
AIDS belongs to the AIDS caused by the HIV-1 (human immunodeficiency virus-I types) of retrovirus and (obtains Property acquired immunodeficiency syndrome, AIDS) virus, be a kind of progressively to destroy human immune system and seriously threaten human health With the great communicable disease of existence.Since being found from 1981 first, worldwide spread rapidly.2014, the whole world - 1 number of infected by HIV about 36,900,000, the death toll caused with AIDS-related diseases about 1,200,000.HIV-1 is positive thin with CD4 Born of the same parents group is target, destroys these immunocompetent cells, causes immune deficiency.Therefore, eradicate internal HIV-1 or suppress what which replicated Medicine can be effectively treated or prevent AIDS.
The medicine of the treatment AIDS of FDA approvals at present mainly has following several types：NRTI (nucleoside reverse transcriptase inhibitors), non-nucleoside reverse transcriptase inhibitor (non- Nucleoside reverse transcriptase inhibitors), protease inhibitors (protease Inhibitors), fusion inhibitor (fusion inhibitors), accessory receptor inhibitor (co-receptor Inhibitors) and integrase inhibitor (integrase inhibitors), the use of these medicines effectively can extend The life of AIDS patient.
HIV-1 integrases are the key enzymes in HIV-1 reproduction processes, and its function is that viral cDNA is incorporated into host cell DNA in, due to the not no homologous protein of the enzyme in human body, therefore, integrase be design efficiently, low toxicity anti-HIV-1 medicines Ideal targets, integrase inhibitor research have become the important directions of anti-AIDS drug research.Although ucleotides, peptides, Caffeoyl derivative class, natural extract class, Mg2+Chelates, styrene quinolines etc. are reported with suppression integrase Effect, but only compound of the part containing two ketone acid structures equal table in Inhibiting enzyme activity test and animal model experiment in vitro Reveal preferable selectivity and inhibitory activity.By the Mg between two ketone acid structures and the D64 and D116 of IN2+Interact mediation, Diketoacids partly combine to form compound with " D, D-35-E " and close the region, although its combination can not change IN pair The catalysis of 3'-p, but make second Mg between 1,3- dicarbapentaborane and D64 and E1522+With reference to the Mg2+It is the reaction site of ST, This causes, and diketoacids are alternative to suppress chain tra nsfer process.
The common trait for finding the structure of chain tra nsfer integrase inhibitor by investigating lot of documents is to contain energy in skeleton Mg is chelated enough2+Two ketone acids or similar two ketone acids construction unit, the construction unit can be connected on parent nucleus, it is also possible to into For constituting a part for parent nucleus.The row of segments such as the biology by two ketone acids are attached on pyrrolopyridine parent nucleus, then to parent nucleus week Enclose and modified, be desirably to obtain the compound with biologically active.
The content of the invention
It is an object of the invention to provide 6- chloro- N- (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds Thing, its preparation method and the application as HIV-1 integrase inhibitors.
The invention provides 6- chloro- N- (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- acid amides that formula (I) is represented Compound,
Wherein, R2- F ,-Me ,-OMe or-H is represented, positioned at any position in two ortho positions on phenyl ring；R3Represent-H ,-F ,- Me ,-OMe or-Cl, positioned at any position of two metas on phenyl ring；R4Represent-H ,-F ,-Me ,-OMe ,-Cl ,-Br ,-CF3Or- SO2Me。
The system of 6- chloro- N- (substituted benzyl) provided by the present invention -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds Preparation Method, comprises the following steps：
A () pivaloyl chloride and 6- chloropyridines -2- amine co-dissolve are slowly added dropwise pivaloyl chloride in DMF.6h is stirred at room temperature, The compound that formula (II) is represented is obtained, the preferably ratio of the amount of the material of pivaloyl chloride and 6- chloropyridine -2- amine is 1.3:1.
B the compound that formula (II) is represented is dissolved in dry THF by (), be cooled to -20 DEG C, and nitrogen protection is lower to be added dropwise positive fourth The hexane solution of base lithium.Then reaction system is cooled to into -78 DEG C, stirs 1h, add the THF solution of elemental iodine afterwards, risen Warm to room temperature, continue stirring reaction, obtain the compound that formula (III) is represented, the chemical combination that preferably n-BuLi, iodine and formula (II) are represented The ratio of the amount of the material of thing is 2.2:1.2:1.
The dioxane solution of c compound that formula (III) is represented by (), adds the aqueous solution of HCl, heating stirring to react, Room temperature is naturally cooled to, the compound that formula (IV) is represented is obtained,
The DMF solution of d compound that () formula (IV) is represented, adds acetoacetate, DABCO and Pd (OAc)2, argon gas protection Lower stirring 20min, then heats to 105 DEG C, and stirring reaction obtains the compound that formula (V) is represented, preferably acetoacetate, DABCO, Pd(OAc)2The ratio of the amount of the material of the compound represented with formula (IV) is 3:3:0.02:1.
Under (e) room temperature, in the dichloromethane of the compound that formula (V) is represented, HATU and triethylamine is added, with various replacements Benzyl ammonia is stirred overnight, and the ratio of the amount of the material of compound, HATU, triethylamine and replacement benzyl ammonia that preferably formula (V) is represented is 1:1.5 ～2:3～3.5:1～1.5, column chromatography obtains the compound that formula (I) is represented.
The ratio of the amount of the material of formula (V) is represented in above-mentioned steps (e) compound, HATU, triethylamine and replacement benzyl ammonia is excellent Elect 1 as:1.5:3:1.
In above-mentioned steps (e), the volume ratio of the eluting solvent ethyl acetate and petroleum ether of column chromatography is 1:10～1:3.
The compounds of this invention synthesis chemical equation be：
Reaction condition：(i)tBuCO-Cl,DMF,rt,6h；(ii)n-BuLi,I2,N2,-78-rt℃；(iii)HCl· H2O,1,4-dioxane,80℃,2h；(iv)pyruvic acid,DMF,DABCO,Pd(OAc)2,rt-105℃,3h；(v) R1NH2, HATU, TEA, DCM, rt, overnight.
6- chloro- N- (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds of the present invention are selected from as follows：
Specific embodiment
With reference to embodiment, the present invention will be further described, but the present invention is not limited to following examples.
Embodiment 1
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
Pivaloyl chloride (18.7mL, 151.6mmol) and 6- chloropyridine -2- amine (15g, 116.7mmol) co-dissolves are in DMF (180mL), pivaloyl chloride (18.7mL, 151.6mmol) is then slowly added dropwise under agitation.Continue stirring 6h, then will reaction System is poured into water, point liquid, and organic layer is washed with saturated common salt, anhydrous sodium sulfate drying, filters, be evaporated compound (2) is thick Product 15.8g.It is directly used in next step.
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
Compound 2 (15.8g, 74.2mmol) is dissolved in dry THF (150mL), is cooled to -20 DEG C, under nitrogen protection The hexane solution (96mL, 163mmol, 2.2eq.) of 1.7M n-BuLis, about 0.5h completion of dropping is added dropwise.Then by reactant System is cooled to -78 DEG C, stirs 1h, is disposably slowly added to the THF (60mL) of elemental iodine (22.6g, 89mmol, 1.2eq.) afterwards Solution, continues stirring 10min, then removes dry ice acetone bath, makes system warm naturally to room temperature, continues stirring 2h, adds salt Aqueous acid (1M, 75mL), decompression boil off THF, and residue adds ethyl acetate (800mL), point liquid, the organic phase thio sulphur of 1M Sour sodium (100mL) is washed, and saturated aqueous common salt (300mL x2) is washed, and water (300mL) is washed, and then with anhydrous sodium sulfate drying, is evaporated, is obtained Compound (3), white solid (17.2g).
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
Compound 3 (17.0g, 50.2mmol) is dissolved in dioxane (80mL), is subsequently adding the aqueous solution of 4N HCl (50mL), 80 DEG C of stirring 2h, naturally cool to room temperature, are eventually adding saturated sodium bicarbonate aqueous solution (200mL), use ethyl acetate Extraction (300mL x3), merges organic phase, and anhydrous sodium sulfate drying, evaporated under reduced pressure obtain compound (4), light tan solid, 12.8g。
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
Compound (4) (2.80g, 11.0mmol) is dissolved in DMF (30mL), add acetoacetate (2.29ml, 33.0mmol), DABCO (3.70g, 33.0mmol), Pd (OAc)2(54mg, 0.25mmol), argon gas protection, stirs 20min, so After be warming up to 105 DEG C (outward temperature), stir 3h, naturally cool to room temperature, evaporated under reduced pressure adds ethyl acetate (100mL), water (75mL), divide liquid, organic phase to be washed with the 2M NaOH aqueous solution (2x75mL), wash (2x75mL), organic phase is dry with anhydrous sodium sulfate It is dry, it is concentrated to give compound (5).LCMS:[M+H]+=197.2
The synthesis of the chloro- N- of (e) 6- (2- anisyls) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6a)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 2- methoxy benzene methanamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6a。
White powder, yield 37%.1H-NMR(400MHz,DMSO-d6)ppm 12.41(br.s.,1H),8.96 (br.s., 1H), 8.15 (d, 1H, J=8.1Hz), 7.14-7.27 (m, 3H), 7.01 (br.s., 1H), 6.93 (d, 1H, J= 8.1Hz), 4.85 (d, 2H, J=5.7Hz), 3.85 (s, 3H), 3.75 (s, 3H)；13C NMR(101MHz,DMSO-d6)160.9, 157.1,147.6,145.9,133.7,133.2,128.6,128.1,127.0,120.6,118.8,116.8,111.0, 102.4,55.8,38.7,37.9；HRMS m/z(ESI):calcd.for C16H15ClN3O2 316.0848 found 316.0851.
Embodiment 2
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3- methoxy benzene) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6b)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3- methoxy benzene methanamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6b。1H-NMR (400MHz, DMSO-d6) ppm 12.42 (br.s., 1H), 9.14 (br.s., 1H), 8.16 (d, 1H, J= 8.1Hz), 7.11-7.36 (m, 3H), 6.78-6.98 (m, 3H), 4.50 (d, 2H, J=5.4Hz), 3.74 (s, 3H)；13C-NMR (101MHz,DMSO-d6) 160.8,159.8,147.6,145.9,141.4,133.7,133.2,129.9,119.9,118.7, 116.8,113.5,112.7,102.4,55.5,42.7；HRMS m/z(ESI):calcd.for C16H15ClN3O2 316.0848 found 316.0849.
Embodiment 3
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- methoxy benzene) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6c)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 4- methoxy benzene methanamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6c。1H-NMR(400MHz,DMSO-d6) ppm 12.39 (br.s., 1H), 9.08 (bf.s., 1H), 8.15 (d, 1H, J= 8.1Hz), 7.11-7.35 (m, 3H), 6.74-6.98 (m, 3H), 4.44 (d, 2H, J=6.0Hz), 3.74 (s, 3H)；13C NMR (101MHz,DMSO-d6)160.7,147.6,133.7,133.3,131.7,129.2,128.4,118.7,116.8,114.2, 113.9,102.3,55.5,42.2；HRMS m/z(ESI):calcd.for C16H15ClN3O2 316.0848 found 316.0849.
Embodiment 4
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (2- tolyls) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6d)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 2- tolyl methylamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6d。1H-NMR(400MHz,DMSO-d6) ppm 12.40 (br.s., 1H), 8.99 (t, 1H, J=5.6Hz), 8.15 (d, 1H, J= 8.3Hz), 7.11-7.37 (m, 6H), 4.50 (d, 2H, J=5.6Hz), 2.34 (s, 3H)；13C NMR(101MHz,DMSO-d6) 160.7,147.6,145.9,137.3,136.1,133.7,133.2,130.4,128.1,127.4,126.2,118.8, 116.8,102.5,19.2；HRMS m/z(ESI):calcd.for C16H15ClN3O 300.0898 found 300.0902.
Embodiment 5
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3- tolyls) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6e)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3- tolyl methylamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6e。1H NMR(400MHz,DMSO-d6) ppm 12.41 (br.s., 1H), 9.12 (t, 1H, J=6.0Hz), 8.15 (d, 1H, J= 8.3Hz), 7.01-7.31 (m, 6H), 4.48 (d, 2H, J=5.9Hz), 2.30 (s, 3H))；13C NMR(101MHz,DMSO-d6) 160.8,147.6,145.9,139.7,137.9,133.7,133.2,128.7,128.4,128.0,124.9,118.8, 116.8,102.3,42.7,21.5；HRMS m/z(ESI):calcd.for C16H15ClN3O 300.0898 found 300.0902.
Embodiment 6
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- tolyls) -1H- pyrroles [2,3-b] pyridine-2-carboxamide (6f)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 4- tolyl methylamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6f。1H-NMR(400MHz,DMSO-d6) ppm 12.40 (br.s., 1H), 9.11 (t, 1H, J=5.9Hz), 8.15 (d, 1H, J= 8.3Hz), 7.06-7.33 (m, 6H), 4.47 (d, 2H, J=5.9Hz), 2.28 (s, 3H))；13C NMR(101MHz,DMSO-d6) 160.7,147.6,145.8,136.8,136.4,133.7,133.2,129.3,127.8,118.7,116.8,102.3,42.5, 21.1；HRMS m/z(ESI):calcd.for C16H15ClN3O 300.0898 found 300.0900.
Embodiment 7
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of the chloro- 1H- pyrroles of (d) 6- [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (2- fluorophenyls) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6g)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 2- fluorophenyl methylamines, is subsequently adding Saturated aqueous ammonium chloride, extracts (10ml x2) with dichloromethane, merges organic phase, and concentration, column chromatography obtain target compound 6g。1H-NMR(400MHz,DMSO-d6) ppm 12.42 (br.s., 1H), 9.14 (t, 1H, J=5.7Hz), 8.16 (d, 1H, J= 8.1Hz), 7.15-7.46 (m, 6H), 4.56 (d, 2H, J=5.9Hz))；13C NMR(101MHz,DMSO-d6)161.0, 145.8,133.7,130.1,129.5,126.4,126.3,124.9,124.8,118.8,116.7,115.7,115.5, 102.4,36.6；HRMS m/z(ESI):calcd.for C15H12ClFN3O 304.0648 found 304.0653.
Embodiment 8
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3- fluorobenzene) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6h)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3- fluorobenzene methylamines, is subsequently adding full And aqueous ammonium chloride solution, (10ml x2) is extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target compound 6h。1H-NMR(400MHz,DMSO-d6) ppm 12.43 (br.s., 1H), 9.20 (s, 1H), 8.16 (d, 1H, J=8.3Hz), 7.56 (dd, 1H, J=7.2,1.6Hz), 7.26-7.44 (m, 2H), 7.09-7.23 (m, 2H), 4.50 (d, 2H, J= 5.9Hz))；13C NMR(101MHz,DMSO-d6)160.9,147.6,146.0,142.8,133.8,133.0,130.8, 123.7,118.7,116.9,114.3,114.0,102.4,31.2；HRMS m/z(ESI):calcd.for C15H12ClFN3O 304.0648 found 304.0651.
Embodiment 9
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- fluorobenzene) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6i)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 4- fluorobenzene methylamines, is subsequently adding full And aqueous ammonium chloride solution, (10ml x2) is extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target compound 6i。1H-NMR (DMSO, δ ppm) 12.41 (s, 1H, NH), 9.16 (s, 1H ,-CONH-), 8.14 (d, 1H, J=8.2Hz), 7.50 7.33 (m, 2H), 7.17 (dd, 4H, J=17.5,9.3Hz), 4.50 (d, 2H, J=5.7Hz, benzyl-CH2-)；13C NMR(101MHz,DMSO-d6)162.9,160.5,147.5,145.9,136.0,133.7,133.1,129.8,118.7, 116.8,115.6,115.4,102.4,41.6；HRMS m/z(ESI):calcd.for C15H12ClFN3O 304.0648 found 304.0654.
Embodiment 10
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- chlorobenzenes) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6j)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, and Histol is stirred overnight, be subsequently adding full And aqueous ammonium chloride solution, (10ml x2) is extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target compound 6j。1H NMR(400MHz,DMSO-d6）Ppm 12.42 (br.s., 1H), 9.19 (t, 1H, J=6.0Hz), 8.16 (d, 1H, J= 8.3Hz), 7.34-7.44 (m, 4H), 7.08-7.28 (m, 2H), 4.50 (d, 2H, J=5.9Hz))；13C NMR(101 MHz, DMSO-d6)160.9,147.6,145.9,138.9,133.8,133.0,131.9,129.6,128.8,118.7,116.8, 102.4,42.1；HRMS m/z(ESI):calcd.for C15H12Cl2N3O 320.0352 found 320.0358.
Embodiment 11
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- bromobenzenes) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6k)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, and bromobenzene methylamine is stirred overnight, be subsequently adding full And aqueous ammonium chloride solution, (10ml x2) is extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target compound 6k。1H-NMR(400MHz,DMSO-d6) ppm 12.43 (br.s., 1H), 9.19 (t, 1H, J=5.9Hz), 8.16 (d, 1H, J= 8.3Hz), 7.55 (d, 2H, J=8.3Hz), 6.95-7.35 (m, 4H), 4.48 (d, 2H, J=6.1Hz)；13C NMR(101MHz, DMSO-d6)160.8,147.5,146.0,139.3,133.8,132.9,131.7,130.0,120.4,118.7,116.9, 102.4,42.1；HRMS m/z(ESI):calcd.for C15H12BrClN3O 363.9847 found 363.9854.
Embodiment 12
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- methylsulfonyl benzene) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6l)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, and methylsulfonyl benzene methanamine is stirred overnight, Ran Houjia Entering saturated aqueous ammonium chloride, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target chemical combination Thing 6l.1H NMR(400MHz,DMSO-d6) ppm 12.44 (bf.s., 1H), 9.29 (br.s., 1H), 8.17 (br.s., 1H), 7.91 (br.s., 2H), 7.61 (br.s., 1H), 7.22 (d, 2H, J=13.4Hz), 4.62 (br.s., 2H), 2.00 (br.s., 3H)；13C NMR(101MHz,DMSO-d6)161.0,147.6,146.0,146.0,139.8,133.8,132.9,128.5, 127.6,118.7,116.9,102.5,44.1,42.5；HRMS m/z(ESI):calcd.for C16H15ClN3O3 S 364.0517 found 364.0522.
Embodiment 13
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (4- benzotrifluorides) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6m)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, and benzotrifluoride methylamine is stirred overnight, Ran Houjia Entering saturated aqueous ammonium chloride, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target chemical combination Thing 6m.1H-NMR(400MHz,DMSO-d6) ppm 12.45 (br.s., 1H), 9.27 (t, 1H, J=5.6Hz), 8.17 (d, 1H, J =8.3Hz), 7.72 (d, 2H, J=7.8Hz), 7.57 (d, 2H, J=7.8Hz), 7.09-7.28 (m, 2H), 4.61 (d, 2H, J =5.6Hz)；13C NMR(101MHz,DMSO-d6)161.0,147.6,146.0,144.7,133.8,133.0,128.4, 125.7,118.7,116.9,102.5,42.4；HRMS m/z(ESI):calcd.for C16H12Cl F3N3O 354.0616 found 354.0616.
Embodiment 14
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3,4- dimethylbenzene) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6n)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3,4- dimethylbenzene methylamines, Ran Houjia Entering saturated aqueous ammonium chloride, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target chemical combination Thing 6n.1H-NMR(400MHz,DMSO-d6）Ppm 12.39 (br.s., 1H), 9.07 (t, 1H, J=5.9Hz), 8.14 (d, 1H, J =8.3Hz), 7.16-7.23 (m, 2H), 7.03-7.14 (m, 3H), 4.44 (d, 2H, J=5.9Hz), 2.20 (d, 6H, J= 4.6Hz)；13C NMR(101MHz,DMSO-d6)160.7,147.6,145.8,137.1,136.4,135.1,133.7,133.3, 129.9,129.1,125.3,118.8,116.8,102.3,42.5,19.9,19.5；HRMS m/z(ESI):calcd.for C17H16ClN3O 314.1055 found 314.1058.
Embodiment 15
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3,4- dimethoxy-benzenes) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6o)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3,4- dimethoxy-benzene methylamines, then Saturated aqueous ammonium chloride being added, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain targeted Compound 6o.1H-NMR (400MHz, CHLOROFORM-d) ppm 9.55 (br.s., 1H), 7.93 (d, 1H, J=8.3Hz), 7.18 (d, 1H, J=8.3Hz), 6.84-7.00 (m, 4H), 6.80 (s, 1H), 4.63 (d, 2H, J=4.6Hz), 3.90 (s, 6H)；13C NMR(101MHz,DMSO-d6)161.0,149.1,148.3,148.1,145.6,133.9,133.5,132.2,120.0, 118.9,116.4,112.2,112.0,102.1,56.0,55.9,42.6；HRMS m/z(ESI):calcd.for C17H17ClN3O3346.0953 found 346.0961.
Embodiment 16
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrroles [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (2,4- dimethoxy-benzenes) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6p)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 2,4- dimethoxy-benzene methylamines, then Saturated aqueous ammonium chloride being added, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain targeted Compound 6p.1H-NMR(400MHz,DMSO-d6) ppm l2.37 (br.s., 1H), 8.84 (br.s., 1H), 8.14 (d, 1H, J= 8.1Hz), 7.09-7.32 (m, 3H), 6.58 (br.s., 1H), 6.50 (d, 1H, J=8.1Hz), 4.40 (d, 2H, J= 4.9Hz),3.82(s,3H),3.75(s,3H))；13C NMR(101MHz,DMSO-d6)160.7,160.2,158.1,147.6, 145.8,133.7,133.3,129.3,119.2,118.8,116.8,104.8,102.4,98.7,55.9,55.7,37.6； HRMS m/z(ESI):calcd.for C17H17ClN3O3 346.0953 found 346.0959.
Embodiment 17
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3,4- difluorobenzenes) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6q)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3,4- difluoro benzene methanamines, Ran Houjia Entering saturated aqueous ammonium chloride, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target chemical combination Thing 6q.1H-NMR(400MHz,DMSO-d6) ppm 12.43 (br.s., 1H), 9.20 (t, 1H, J=5.7Hz), 8.16 (d, 1H, J =8.3Hz), 7.31-7.53 (m, 2H), 7.08-7.29 (m, 3H), 4.50 (d, 2H, J=5.9Hz))；13C NMR(101MHz, DMSO-d6)160.9,147.6,146.0,137.7,133.8,133.0,124.4,118.7,117.9,117.7,116.9, 116.8,116.7,102.5,41.9；HRMS m/z(ESI):calcd.for C15H11ClF2N3O 322.0553 found 322.0555.
Embodiment 18
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (3,4- dichloro-benzenes) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6r)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, is stirred overnight with 3,4- dichloro benzene methanamines, Ran Houjia Entering saturated aqueous ammonium chloride, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target chemical combination Thing 6r.1H-NMHz,DMSO-d6) ppm 12.44 (br.s., 1H), 9.22 (t, 1H, J=6.0Hz), 8.17 (d, 1H, J= 8.3Hz), 7.54-7.76 (m, 2H), 7.35 (dd, 1H, J=8.3,1.7Hz), 7.16-7.24 (m, 2H), 4.51 (d, 2H, J= 5.9Hz)；13C NMR(101MHz,DMSO-d6)161.0,147.6,146.0,141.1,133.8,132.9,131.4,131.0, 129.9,129.8,128.2,118.7,116.9,102.5,41.8；HRMS m/z(ESI):calcd.for C15H11Cl3N3O 353.9632 found 353.9961.
Embodiment 19
The synthesis of (a) N- (the 6- chloropyridine -2- tert-butyl groups) acid amides 2
With embodiment 1
The synthesis of (b) N- (the chloro- 3- iodine pyridines -2- tert-butyl groups of 6-) acid amides 3
With embodiment 1
The synthesis of the chloro- 3- iodine pyridines -2- amine of (c) 6- 4
With embodiment 1
The synthesis of (d) 6- chloro- 1H- pyrrolo-es [2,3-b] pyridine-2-carboxylic acids 5
With embodiment 1
The synthesis of the chloro- N- of (e) 6- (the fluoro- 4- chlorobenzenes of 3-) -1H- pyrrolo-es [2,3-b] pyridine-2-carboxamide (6s)
Under room temperature, compound 5 (100mg, 0.51mmol) is dissolved in 5mL dichloromethane, addition HATU (293mg, 0.77mmol), triethylamine (155mg, 1.53mmol) is then slowly added into, 4- Histols fluoro- with 3- are stirred overnight, Ran Houjia Entering saturated aqueous ammonium chloride, (10ml x2) being extracted with dichloromethane, merge organic phase, concentration, column chromatography obtain target chemical combination Thing 6s.1H-NMR(400MHz,DMSO-d6) ppm 12.43 (br.s., 1H), 9.20 (s, 1H), 8.16 (d, 1H, J=8.3Hz), 7.56 (dd, 1H, J=7.2,1.6Hz), 7.26-7.44 (m, 2H), 7.09-7.23 (m, 2H), 4.50 (d, 2H, J= 5.9Hz))；13C NMR(101MHz,DMSO-d6)160.9,157.9,155.5,147.6,146.0,137.8,133.8, 132.9,129.8,128.5,119.7,118.7,117.1,102.5,41.8；HRMS m/z(ESI):calcd.for C15H11Cl2FN3O 338.0258 found 338.0621.
Embodiment 20
Suppress HIV-1 determination of activity processes as follows：(with MT4As a example by) take the MT of 24 hours after liquid4Cell 2,500,000, uses It is standby that 1640 full culture mediums of RPMI are diluted to 10mL, is first grouped the line of 96 orifice plates during experiment, and per one group of medicine, 6 per group dense Degree, each 3 multiple holes of concentration are initially charged 100 μ L RPMI, 1640 full culture mediums per hole, different pharmaceutical are pressed doubling dilution degree then Each group is separately added into, then 100 μ L (2.5 × 104Cells/well) cytotoxic control and normal cell controls group is separately added into, so Afterwards the HIV IIIB of 100TCID50 viral with remaining MT4Cell is mixed, and is put into 5%CO2In incubator, 37 DEG C of cultures 1.5 are little When, cell is taken out, in centrifuge, 2000 revs/min are centrifuged 15 minutes, abandon supernatant, are washed twice with 1640 full culture mediums of RPMI Removing is attached to the virus on cell membrane.Take the cell (2.5 × 10 that 100 μ L are handled well4Cell/100 μ L) add each administration group Corresponding hole in, place 5%CO2In incubator, 37 DEG C are continued culture 3 days, and dressing after 3 days once, used P24 antigens in the 6th day Kit is passed judgment on to result.Setup Experiments cytotoxic control, virus control, positive drug control and normal cell controls group. Experimental result will also be repeated to active compound.Measure inhibiting rate.With the toxicity of MTS test evaluation target compounds.
1 compound of table suppresses to integrate enzyme assay result in 0.3125 μ g/ml dosage
Compound number Inhibiting rate (%)
6a 2.84
6b 15.76
6c 14.19
6d 11.64
6e 18.62
6f 9.94
6g 10.57
6h 26.19
6i 37.48
6j 20.39
6k 29.27
6l 9.57
6m 16.41
6n 3.24
6o 2.84
6p 27.89
6q 26.13
6r 37.59
6s 20.88

Claims (2)

1.6- chloro- N- (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds, it is characterised in that compound is tied Structure formula：
2. prepared by the chloro- N- of the 6- of claim 1 (substituted benzyl) -1H- pyrrolo-es [2,3-b] pyridine -2- amide compounds Application in HIV-1 integrase inhibitors.
CN201510873837.1A 2015-12-02 2015-12-02 6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and preparation method as well as application thereof Expired - Fee Related CN105294688B (en)

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