CN105820104B

CN105820104B - A kind of indoles -2- amides compound with anti-inflammatory effect and its application in preparing anti-inflammatory drugs

Info

Publication number: CN105820104B
Application number: CN201610137580.8A
Authority: CN
Inventors: 刘志国; 张亚利; 唐龙光; 赵云洁; 郑素清; 冯建鹏; 梁广
Original assignee: Wenzhou Medical University
Current assignee: Wenzhou Medical University
Priority date: 2016-03-10
Filing date: 2016-03-10
Publication date: 2018-12-11
Anticipated expiration: 2036-03-10
Also published as: CN105820104A

Abstract

Indoles -2- the amides compound and its application in preparing anti-inflammatory drugs that the invention discloses a kind of with anti-inflammatory effect, the indoles -2- amides compound is one of formula (I)~(III), in formula (I), R₁Selected from alkoxy, halogen, R₂Selected from alkyl, piperazinyl, morpholinyl, aryl or the heteroaryl that can be optionally replaced by different substituent groups, R₃Selected from hydrogen, methoxyl group；In formula (II), R₄Selected from alkyl, benzyl；In formula (III), R₅Selected from can be by alkanoyl, sulfonyl.This kind of the invention is that the analog of mother nucleus structure has efficient, wide spectrum antiphlogistic use using indoles -2- amide.

Description

A kind of indoles -2- amides compound with anti-inflammatory effect and its anti-inflammatory preparing Application in drug

Technical field

The invention belongs to field of medicinal chemistry, and in particular to it is a kind of using indoles -2- amide as the analog of mother nucleus structure and Purposes.

Background technique

Inflammation is very common in human body as a kind of important pathologic process, and itself is as body for external Or a kind of autoimmune response of allogeneic stimulation.And when this response imbalance or excessively response lead to damaging certainly for body When, just evolve into inflammation.So most of disease is all along with the mediation of inflammation and generation, and the mediation of inflammation and generation Aggravate disease for the damage of body, such as acute lung injury, rheumatic arthritis, diabetic complications, cancer, artery Atherosis, inflammatory bowel disease etc..During these, proinflammatory factor such as TNF-α, IL-6, IL-1 β etc. play important work With.Therapeutic agent in currently available technology for inflammation is more, a large amount of drug improved technology also occurs, wherein being directed to Yin The invention and research of diindyl analog, become the important research field of those skilled in the art.

Indoles and its homologue and derivative are widely present in nature, certain very strong natural materials of physiological activity, such as Alkaloid, auximone, tryptophan and the protein containing tryptophan etc. are all the derivatives of indoles.Indoles can occur electrophilic Substitution reaction, it is polysubstituted in No. 3 positions.Substituted indole is the foundation structure of many tryptamines alkali, such as neurotransmitters serotonin, is taken off Melanocyte, hallucinogenic, dimethyltryptamine, 5- methoxyl group-dimethyltryptamine and LSD.Other benzazolyl compounds include plant growth Plain (indole-3-acetic acid), vasodilator drug pindolol, anti-inflammatory drug indocin (Indomethacin).Classical anti-inflammatory drug indoles Although U.S. is pungent to have good anti-inflammatory activity, since it is non-selective cox 2 inhibitor, patient is often accompanied by seriously Gastrointestinal side effect sometimes and cause gastrorrhagia and perforation such as Nausea and vomiting, abdominal pain, diarrhea, ulcer.Lot of documents table Using carboxylic acid as active group it is in bright traditional non-steroidal anti-inflammatory drugs the main reason for leading to its adverse reaction, and a new generation Non-steroidal anti-inflammatory drugs such as aulin not only increases anti-inflammatory activity using sulfonyl as functional group, and reduces these often The adverse reaction seen.It can be seen that a kind of drug for having efficient, broad spectrum antiphlogistic effect and adverse reaction is few of exploitation, becomes Those skilled in the art's technical problem urgently to be resolved.

Summary of the invention

The indoles -2- amides compound that the present invention provides a kind of with anti-inflammatory effect and its in preparing anti-inflammatory drug Application, the indoles -2- amides compound have efficiently, the antiphlogistic effects of wide spectrum.

A kind of indoles -2- amides compound with anti-inflammatory effect, structure are one of general formula:

In formula (I), R₁Independently selected from H, halogen or alkoxy；R₂Independently selected from H, alkoxy, piperazinyl, morpholinyl, Aryl, heteroaryl or substitutive benzyloxy；R₃Independently selected from H, alkoxy；Or R₂、R₃It is formed with two C for connecting them Five-membered ring or hexatomic ring；

N is the integer between 0~2；

In formula (II), R₄Independently selected from H, alkyl, allyl, substitution or unsubstituted benzyl；

In formula (III), R₅Independently selected from H, substitution or unsubstituted alkanoyl, substitution or unsubstituted sulfonyl.

Wherein, the five-membered ring or hexatomic ring may include one or two N, O or S, at the same time it can also contain Unsaturated bond.

Carboxylic acid and different types of aniline condensation are formed amide using Indomethacin as lead compound by the present inventor, It obtains a series of using indoles -2- amide as the compounds of mother nucleus structure, and tests its anti-inflammatory work from cell and animal level Property, test result shows that this kind of using indoles -2- amide is that the analog of mother nucleus structure has preferable anti-inflammatory activity, has and make For a kind of potentiality of new anti-inflammatory drug.

Preferably, the R₁Independently selected from H, chlorine or methoxyl group；

The R₂Independently selected from H, methoxyl group, ethyoxyl, morpholinyl, 4- methyl piperazine base, substitutive benzyloxy Or isobutyl alkenyloxy group, the substituent group on the benzyloxy are one or more of F, Cl, methyl, methoxyl group, trifluoromethyl；

The R₃Independently selected from H or methoxyl group；

The R₄Independently selected from H, methyl, allyl, substitution or unsubstituted benzyl, taking on the benzyl Dai Jiwei F, Cl, Br, CF₃, one or more in methoxyl group；

The R₅Independently selected from H, acryloyl group, propiono, 2- chloracetyl, mesyl, furans -2- acyl group, Dimethylamine acyl group.

Preferably, indoles -2- the amides compound, in following 10a-10w, 13a-13h or 14a-14g Any compound:

The present invention also provides the indoles -2- amides compound applications in preparing anti-inflammatory drugs described in one kind.

Preferably, the anti-inflammatory drug is for treating the acute lung injury as caused by inflammation or by inflammatory cytokine Disease relevant to inflammation caused by expressing and discharge beyond normal amount.

The cause of disease of the disease is caused by inflammation, and the disease includes but is not limited to following disease: slow Solve rheumatoid arthritis, osteoarthritis, SpA, urarthritis, rheumatic arthritis, various chornic arthritis The painful swelling of joints symptom of acute attack stage or duration；Non- arthrosis various soft tissue rheumatic pains are treated, such as shoulder pain, tendon Injury pain after vaginitis, bursal synovitis, myalgia and movement；Acute light, moderate pain, e.g., after operation, after wound, strain after, Primary dysmenorrhea, toothache, headache；Ischemic damage and reperfusion, e.g., cerebral ischemia re-pouring, myocardial ischemia-reperfusion；Atherosclerosis Change；Hepatitis；Lymphadenitis；Pneumonia；Dysentery；Ecphyaditis.

Preferably, the disease relevant to inflammation includes septicopyemia, rheumatoid arthritis, systemic red yabbi Sore and related syndromes, osteoarthritis, alimentary canal inflammation, polymyositis, dermatomyositis, vasculitic syndrome, gouty are closed Save inflammation, neuroinflamation, rheumatic arthritis, chemically pain, inflammatory pain, granuloma, granulomatous angiitis, arteritis, Scytitis, autoimmune disease, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, whole body Inflammatory reaction syndrome, septicemia, infectious shock.

The present invention also provides a kind of pharmaceutical composition, including effective component and pharmaceutic adjuvant, the effective component includes Indoles -2- the amides compound or its officinal salt.

Pharmaceutical composition of the invention can be used in combination with the anti-inflammatory drug listed, the prevention and treatment inflammation disease being prepared The composition of sick class drug, the anti-inflammatory drug listed include various Steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drug；Medicine Acceptable salt is salt some in this way on, they keep the ideal bioactivity of parent compound, and are not given to not Desired toxicological action, the example of such salt includes the salt formed with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid Deng；The salt formed with organic acid, such as acetic acid, oxalic acid, tartaric acid, maleic acid, citric acid, ascorbic acid；And by element yin The salt that ion is formed, such as chlorine, bromine and iodine；

Pharmaceutic adjuvant in pharmaceutical composition of the present invention refers to the pharmaceutical carrier of pharmaceutical field routine, including but not limited to any By Food and Drug Administration be approved as being acceptable for the adjuvant of people or domestic animal, carrier, excipient, glidant, sweetener, It is diluent, preservative, dyestuff/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic Agent, solvent or emulsifier.

The dosage form of the pharmaceutical composition can for injection, tablet, capsule, aerosol, suppository, film, Pill, ointment, controlled release agent, sustained release agent or nanometer formulation it is any.Preparation of the invention includes that those are suitable for taking orally, are straight Intestines, part, oral cavity, sublingual, parenteral (for example, subcutaneous, muscle, intravenous) and percutaneous dosing preparation, although any In the case where given, optimum route is by the property for depending on treated illness and seriousness and depends on used The property of particular active compounds.

In specification and claims of the invention, specified unless there are opposite, otherwise following term has meaning The meaning shown:

" alkyl " refers to the hydrocarbon chain radical of linear chain or branched chain, is only made of carbon and hydrogen atom, does not contain unsaturation, has One to 12 carbon atom, preferably one to eight carbon atom or one to six carbon atom, and it is connected to molecule by singly-bound Remaining part, such as methyl, ethyl, n-propyl, 1- Methylethyl (isopropyl), normal-butyl, n-pentyl, 1,1- dimethyl second Base (tert-butyl), 3- methylhexyl, 2- methylhexyl etc..

" aryl " refers to aromatic monocyclic or polycyclic hydrocarbon loop systems, is only made of hydrogen and carbon, and contains 6 to 19 carbon atoms, Wherein the loop system can be saturated for part.Aryl group includes but is not limited to the group such as fluorenyl, phenyl and naphthalene.

" replacing aroyl " refers to formula-CO-Ar-R.Group, wherein R is alkyl as defined above, contains one to 12 A carbon atom or the halogen that will hereafter define.

" halogen " refers to bromine, chlorine, fluorine or iodine.

" heteroaryl " refers to 5 to 18 yuan of non-aromatic ring radicals, and it includes three to 17 carbon atoms to be selected from one to ten The hetero atom of nitrogen, oxygen and sulphur.

Compared with the existing technology, the beneficial effects of the present invention are embodied in: indoles -2- amides compound of the invention has Good anti-inflammatory activity, and not using carboxylic acid as active group, it can be hopeful to reduce adverse reaction, be a kind of more potential Anti-inflammatory drug.

Detailed description of the invention

Figure 1A be the present invention synthesize using indoles -2- amide as the chemical structure of the analog (10a-10w) of mother nucleus structure.

Figure 1B be the present invention synthesize using indoles -2- amide as the chemical structure of the analog (13a-13h) of mother nucleus structure.

Fig. 1 C be the present invention synthesize using indoles -2- amide as the chemical structure of the analog (14a-13g) of mother nucleus structure.

Fig. 2A be it is of the invention using indoles -2- amide be the analog (10a-10w) of mother nucleus structure to lipopolysaccharides (LPS) pierce Swash the activity of the inhibition of 264.7 macrophage of RAW release IL-6 and TNF-α；

Fig. 2 B be it is of the invention using indoles -2- amide be the analog (13a-13h) of mother nucleus structure to lipopolysaccharides (LPS) pierce Swash the activity of the inhibition of 264.7 macrophage of RAW release IL-6 and TNF-α.

Fig. 2 C be it is of the invention using indoles -2- amide be the analog (14a-13g) of mother nucleus structure to lipopolysaccharides (LPS) pierce Swash the activity of the inhibition of 264.7 macrophage of RAW release IL-6 and TNF-α.

Fig. 3 A is reactive compound 14f, inhibitory activity of the 14g to myeloperoxidase in Pneumonia Mice lung tissue；

Fig. 3 B is reactive compound 14f, activity of the 14g to the inhibition of inflammatory factor TNF-α in Pneumonia Mice serum.

Fig. 4 A show reactive compound 14f, therapeutic effect of the 14g to the LPS mice with acute lung injury lung tissue induced Scheme (HE dyeing)；

Fig. 4 B show data statistics figure corresponding to A.

Fig. 5 A show reactive compound 14f, the mice with acute lung injury macrophage in lung tissues that 14g induces LPS Infiltration inhibitory effect (F4/80 immunohistochemistry)；

Fig. 5 B show data statistics figure corresponding to A.

Fig. 6 show reactive compound 14f, the pulmonary epithelial cells Beas-2B cell difference cell that 14g stimulates LPS because The inhibiting effect of the rna expression of son；A, B, C, D, E, F are respectively TNF-α, IL-6, IL-1 β, COX-2, IL-12 and IL-33.

Specific embodiment

Below in conjunction with specific attached drawing the present invention is described in detail specific embodiment.It should be noted that in following embodiments The combination of the technical characteristic or technical characteristic of description is not construed as isolated, they can be combined with each other to reaching To superior technique effect.

Of the invention is as follows as the preparation route of the analog of mother nucleus structure using indoles -2- amide:

Wherein, the compound (10a-10w) in type I synthesis step (step a- step b):

The synthesis of step a intermediate 5- nitroindoline -2- formic acid 8: it weighs raw material 7 (25.0g, 106.8mmol) and is dissolved in In 500ml methanol, then the NaOH (40g, 1.0mmol) being dissolved in 300ml water is added thereto.Solution becomes reddish brown, A large amount of solids are precipitated then with dilute HCl tune PH to 1 in fully reacting after stirring 3h at room temperature, and vacuum pump filters, and crude product is used again THF/ ethyl acetate/n-hexane mixed system is recrystallized to give 19.6g intermediate 8, yield 90%.

The synthesis of step b compound 10a-10w: 5- nitroindoline -2- formic acid 2 (0.102g, 0.50mmol) and benzene are weighed Amine 9a-9w (0.495mmol) is dissolved in 6ml DMA, then TBTU (0.40g, 1.24mmol) and DIPEA are added thereto (0.1mL,0.57mmol).It is stirred overnight at room temperature, ethyl acetate (3 × 20mL) is added thereto after completion of the reaction and is saturated NaHCO₃(20ml) extraction, organic layer are washed with NaCl (50ml) is saturated, and with anhydrous MgSO₄It is dry, it filters, vacuum pump is spin-dried for Concentration, silica gel column chromatography (EtOAc: petroleum ether=1:5) obtain 10a-10w, and product structure is as shown in Figure 1A.

Compound (13a-13h) in Type II synthesis (step c):

Step c weighs above-mentioned product 10j (0.5mmol) and alkyl halide (0.5mmol) is dissolved in acetonitrile, then is added thereto K₂CO₃(1mmol) is heated to 50 DEG C, stirs 8h, vacuum is spin-dried for acetonitrile after fully reacting, and H is added thereto₂O (10ml), then It is extracted with EtOAC (3 × 20mL), organic layer is washed with NaCl (50ml) is saturated, and with anhydrous MgSO₄It is dry, it filters, vacuum pump It is spin-dried for being concentrated, silica gel column chromatography (EtOAc: petroleum ether=1:6) obtains 13a-13h, and product structure is as shown in Figure 1B.

Compound (14b-14g) in Type II synthesis (step c):

Above-mentioned product 13g (22.6mmol) is dissolved in 150ml ethyl alcohol by step d, and 10% Pd/C (0.5g) is added, and H is passed through into reaction flask₂, 9h is stirred at room temperature.Suction filtered through kieselguhr is used after fully reacting, filter cake is washed with methanol.Filtrate is true Sky pump is spin-dried for obtaining aubergine solid 14a, yield 90%.

Step e weighs above-mentioned product 14a (100mg, 0.24mmol) and is dissolved in 8ml DMA, then DIPEA is added thereto (1ml) is added dropwise different acyl chlorides (0.3mmol) under condition of ice bath thereto, allows it to be warmed to room temperature naturally after dripping and reacted After fully reacting, saturation NaHCO is added in night thereto₃(10ml) is then extracted with EtOAC (3 × 20mL), and organic layer is used full It is washed with NaCl (50ml), and with anhydrous MgSO₄It is dry, it filters, vacuum pump is spin-dried for being concentrated, silica gel column chromatography (EtOAc: petroleum Ether=1:6) 14b-14g is obtained, product structure is as shown in Fig. 1 C.

The chemical structure characterize data of compound 10a synthesized by embodiment 1

Compound (10a): 5- nitro-N- phenethyl -1H- indole 2-carboxamides

5-Nitro-N-phenethyl-1H-indole-2-carboxamide

Yellow powder, yield: 72.8%, fusing point: 141.3-143.5 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 12.293 (s, 1H), 8.833 (t, J=6.0Hz, 1H), 8.703 (s, 1H), 8.065 (dd, J=2.4,9.0Hz, 1H), 7.566 (d, J=9.0Hz, 1H), 7.368 (s, 1H), 7.257-7.311 (m, 4H), 7.202 (t, J=7.2Hz, 1H), 3.519- 3.554 (m, 2H), 2.881 (t, J=7.2Hz, 2H)¹³C NMR(600MHz,DMSO-d₆)δ:160.15,146.10, 142.20,139.41,138.34,132.21×2,128.60×2,127.50×2,125.37,114.89,114.10, 112.20,40.72,35.21ppm.ESI-MS m/z:310.10(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10b synthesized by embodiment 2

Compound (10b): N- (4- methoxyphenethyl) -5- nitro -1H- indole 2-carboxamides

N-(4-Methoxyphenethyl)-5-nitro-1H-indole-2-carboxamide

White powder, yield: 70.6%, fusing point: 150.6-153.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 12.288 (s, 1H), 8.798 (t, J=6Hz, 1H), 8.703 (s, 1H), 8.065 (dd, J=2.4,9.0Hz, 1H), 7.565 (d, J=9.0Hz, 1H), 7.368 (s, 1H), 7.171 (d, J=8.4Hz, 2H), 6.856 (d, J=8.4Hz, 2H), 3.711 (s, 3H), 3.474-3.508 (m, 2H), 2.808 (t, J=7.8,2H)¹³C NMR(600MHz,DMSO-d₆)δ:160.12, 157.70,141.20,139.23,135.34,131.21×2,129.60,126.37,119.06,118.27,113.76×2, 112.75,104.59,54.95,34.17,25.30ppm.ESI-MS m/z:339.1(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10c synthesized by embodiment 3

Compound (10c): 5- nitro-N- benzyl -1H- indole 2-carboxamides

5-Nitro-N-phenyl-1H-indole-2-carboxamide

Yellow powder, yield: 75.6%, fusing point: 145.2-147.3 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.498 (s, 1H), 8.755 (s, 1H), 8.086 (d, J=9.0Hz, 1H), 7.820 (d, J=7.2Hz, 2H), 7.678 (s, 1H), 7.607 (d, J=9.0Hz, 1H), 7.385 (t, J=7.2Hz, 2H), 7.128 (t, J=7.2Hz, 2H)¹³C NMR (600MHz,DMSO-d₆)δ:162.60,146.10,142.30,138.52,137.80,132.30×2,128.80×2, 128.10,121.59×2,114.85,114.00,112.20ppm.ESI-MS m/z:282.07(M+H)⁺, specific structure is shown in figure 1A。

The chemical structure characterize data of compound 10d synthesized by embodiment 4

Compound (10d): N- (4- methoxyphenyl) -5- nitro -1H- indole 2-carboxamides

N-(4-Methoxyphenyl)-5-nitro-1H-indole-2-carboxamide

Yellow powder, yield: 75.6%, fusing point: 140.6-142.2 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.400 (s, 1H), 8.736 (s, 1H), 8.071 (d, J=7.8Hz, 1H), 7.715 (d, J=9.0Hz, 2H), 7.614 (s, 1H), 7.595 (d, J=9.6Hz, 1H), 6.959 (d, J=8.4Hz, 2H), 3.757 (s, 3H)¹³C NMR(600MHz,DMSO- d₆)δ:161.80,158.85,144.90,142.30,138.40,132.31×2,130.10,122.51×2,114.90, 114.50×2,113.91,112.10,55.60ppm.ESI-MS m/z:312.08(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10e synthesized by embodiment 5

Compound (10e): N- (4- ethoxyl phenenyl) -5- nitro -1H- indole 2-carboxamides

N-(4-Ethoxyphenyl)-5-nitro-1H-indole-2-carboxamide

Brownish-yellow powder, yield: 83.5%, fusing point: 155.6-157.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.440 (s, 1H), 12.440 (s, 1H), 10353 (s, 1H), 8.760 (d, J=2.4Hz, 1H), 8.101 (dd, J= 1.8,9.0Hz, 1H), 7.687 (d, J=9.0Hz, 2H), 7.648 (s, 1H), 7.608 (d, J=9.0Hz, 1H), 6.948 (d, J =9.0Hz, 2H), 4.004-4.039 (m, 2H), 1.319-1.342 (t, J=7.2Hz, 3H)¹³C NMR(600MHz,DMSO- d₆)δ:158.52,155.01,141.33,139.50,135.23,131.49,126.34,121.93×2,119.25,114.42 ×2,114.05,112.86,105.69,63.10,14.69ppm.ESI-MS m/z:326.1(M+H)⁺, specific structure is shown in figure 1A。

The chemical structure characterize data of compound 10f synthesized by embodiment 6

Compound (10f): 5- amino-N- (4- methoxyphenethyl) -1H- indole 2-carboxamides

5-Amino-N-(4-methoxyphenethyl)-1H-indole-2-carboxamide

Yellow-brown solid, yield: 80.5%, fusing point: 338.1-339.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.077 (s, 1H), 8.582 (t, J=6.0Hz, 1H), 7.770 (d, J=9.0Hz, 1H), 7.672 (s, 1H), 7.658 (d, J=9.0Hz, 1H), 7.454 (d, J=8.4Hz, 1H), 7.190 (d, J=8.4Hz, 2H), 6.863 (d, J=9.0Hz, 2H), 3.713 (s, 3H), 3.492-3.526 (m, 2H), 2.825 (t, J=7.2Hz, 2H)¹³C NMR(600MHz,DMSO-d₆) δ:160.25,157.60,143.85,138.55,133.21,131.53,129.75×3,115.10,114.20×2, 107.20,54.83ppm.ESI-MS m/z:341.3(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10g synthesized by embodiment 7

Compound (10g): 5- nitro-N- (3,4,5- trimethoxyphenyl) -1H- indole 2-carboxamides

5-Nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-2-carboxamide

Yellow solid, yield: 83.5%, fusing point: 250.4-253.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 12.455 (s, 1H), 10.379 (s, 1H), 8.777 (s, 1H), 8.112 (dd, J=1.8,9.0Hz, 1H), 7.668 (s, 1H), 7.616 (d, J=9.0Hz, 1H), 7.232 (s, 2H), 3.797 (s, 9H)¹³C NMR(600MHz,DMSO-d₆)δ:158.74, 152.70×2,141.39,139.55,135.06,134.68,133.98,126.33,119.37,118.76,112.90, 105.88,98.17×2,60.14,55.80×2ppm.ESI-MS m/z:371.3(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10h synthesized by embodiment 8

Compound (10h): N- (2- methyl-1-H- indoles-5- base)-5- nitro-1H- indole 2-carboxamides

N-(2-Methyl-1H-indol-5-yl)-5-nitro-1H-indole-2-carboxamide

Yellow solid, yield: 35%, fusing point: 135.9-137.8 DEG C of¹H NMR(600MH_Z,DMSO-d⁶)δ(ppm): 10.16(2H,s,Ar-OH),7.74-7.72(1H,m,N-CH2-Benzene-4),7.60-7.59(4H,m,N-CH2- Benzene-2,3,5,6),7.48(2H,s,H-β,H-β'),7.22(2H,dd,J₁=8.4H_Z,J₂=1.8H_Z,H-6,H-6'), 7.15 (2H, s, H-2, H-2'), 6.95 (2H, d, J=8.4H_Z,H-5,H-5'),6.05-5.98(2H,m,A,B-ArCH₂ CH= CH₂),5.13-5.08(4H,m,A,B-ArCH₂CH=CH₂ ),4.50(4H,s,piperidone-CH₂ -N-CH₂ ),3.36(2H, s,N-CH₂ Benzene),3.35(4H,s,A,B-ArCH₂ CH=CH₂).¹³C NMR(600MH_Z,DMSO-d⁶)δ(ppm): 186.1,156.4×2,136.6×2,134.9×2,132.4×2,130.6×2,130.5×2,129.1×2,128.7, 128.2×2,127.2,126.5×2,125.8×2,115.8×2,115.3×2,61.2,54.3×2,33.5×2.ESI- MS,m/z:476.0(M)^-, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10i synthesized by embodiment 9

Compound (10i): N- (4- morpholinyl phenyl) -5- nitro -1H- indole 2-carboxamides

N-(4-Morpholinophenyl)-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 85.5%, fusing point: 328.1-329.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.428 (s, 1H), 10.309 (s, 1H), 8.753 (d, J=1.8Hz, 1H), 8.098 (dd, J=2.4,9.0Hz, 1H), 7.655 (d, J=9.0Hz, 2H), 7.641 (s, 1H), 7.606 (d, J=9.0Hz, 1H), 6.972 (d, J=9.0Hz, 2H), 3.747 (m, J=5.6Hz, 4H), 3.088 (m, J=5.6Hz, 4H)¹³C NMR(600MHz,DMSO-d₆)δ:158.40, 147.72,141.32,139.49,135.34,130.62,126.37,121.46×2,119.22,118.56,115.30×2, 112.84,105.57,66.10×2,48.77×2ppm.ESI-MS m/z:367.5(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10j synthesized by embodiment 10

Compound (10j): N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- indole 2-carboxamides

N-[4-(4-Methylpiperazin-1-yl)phenyl]-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 82.5%, fusing point: 259.1-262.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.422 (s, 1H), 10.291 (s, 1H), 8.749 (d, J=2.4Hz, 1H), 8.096 (dd, J=2.4,9.0Hz, 1H), 7.639 (s, 1H), 7.630 (d, J=7.2Hz, 2H), 7.606 (d, J=9.0Hz, 1H), 6.955 (d, J=9.0Hz, 2H), 3.112 (t, J=4.8Hz, 4H), 2.456 (t, J=4.8Hz, 4H), 2.222 (s, 3H)¹³C NMR(600MHz,DMSO- d₆)δ:158.59,147.92,141.53,139.71,135.59,130.50,126.60,121.68×2,119.43, 118.77,115.74×2,113.06,105.76,54.83×2,48.60×2,45.98ppm.ESI-MS m/z:380.2(M+ H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10k synthesized by embodiment 11

Compound (10k): N- { [4- (3- methyl-2-butene) oxygroup] phenyl } -5- nitro -1H- indole 2-carboxamides

N-{4-[(3-Methylbut-2-en-1-yl)oxy]phenyl}-5-nitro-1H-indole-2-carboxa mide

Yellow-brown solid, yield: 85.5%, fusing point: 275.2-277.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.411 (s, 1H), 10.265 (s, 1H), 9.318 (s, 1H), 8.748 (d, J=2.4Hz, 1H), 8.095 (dd, J= 2.4,9.0Hz, 1H), 7.620 (d, J=8.4Hz, 2H), 7.604 (d, J=9.6Hz, 1H), 7.560 (d, J=6.6Hz, 2H), 6.776 (d, J=6.6Hz, 2H), 4.020 (t, J=6.6Hz, 1H), 1.985 (s, 3H), 1.725 (s, 3H)¹³C NMR (600MHz,DMSO-d₆)δ:158.40,151.53,146.73,141.20,139.79,138.75,135.19,133.44, 126.37,122.24×2,119.21,115.71,115.14×2,114.75,112.84,60.13,25.46, 14.08ppm.ESI-MS m/z:365.3(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10l synthesized by embodiment 12

Compound (10l): N- { [4- (4- methylbenzyl) oxygroup] phenyl } -5- nitro -1H- indole 2-carboxamides N- { 4- [(4-Methylbenzyl)oxy]phenyl}-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 85.5%, fusing point: 269.1-272.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.446 (s, 1H), 10.366 (s, 1H), 8.761 (d, J=1.8Hz, 1H), 8.103 (d, J=9.0Hz, 1H), 7.690 (d, J=9.0Hz, 2H), 7.647 (s, 1H), 7.608 (d, J=9.0Hz, 1H), 7.340 (d, J=7.8Hz, 2H), 7.201 (d, J=7.8Hz, 2H), 7.026 (d, J=9.0Hz, 2H), 5.052 (s, 2H)¹³C NMR(600MHz,DMSO-d₆) δ:158.54,154.82,141.33,139.51,137.03,135.20,134.09,131.73,128.96×2,127.78× 2,126.34,121.90×2,119.27,118.62,114.90×2,112.87,105.72,69.28,20.77ppm.ESI- MS m/z:401.1(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10m synthesized by embodiment 13

Compound (10m): N- { [4- (4- chlorobenzyl) oxygroup] phenyl } -5- nitro -1H- indole 2-carboxamides

N-{4-[(4-Chlorobenzyl)oxy]phenyl}-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 89.5%, fusing point: 217.8-220.5 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.448 (s, 1H), 10.381 (s, 1H), 8.763 (d, J=2.4Hz, 1H), 8.103 (d, J=9.0Hz, 1H), 7.718 (d, J=9.0Hz, 2H), 7.650 (s, 1H), 7.608 (d, J=9.0Hz, 1H), 7.525 (s, 1H), 7.433 (d, J= 6.0Hz, 1H), 7.428 (s, 1H), 7.389-7.408 (m, 1H), 7.051 (d, J=9.0Hz, 2H), 5.132 (s, 2H)¹³C NMR(600MHz,DMSO-d₆)δ:158.56,154.51,141.33,139.77,139.51,135.16,133.09,131.98, 130.36×2,127.70,127.27×2,126.33,126.14×2,121.92×2,119.27,118.63,114.93× 2,112.86,105.74,68.44ppm.ESI-MS m/z:423.0(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10n synthesized by embodiment 14

Compound (10n): N- { [4- (4- luorobenzyl) oxygroup] phenyl } -5- nitro -1H- indole 2-carboxamides

N-{4-[(3-Fluorobenzyl)oxy]phenyl}-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 81.2%, fusing point: 299.3-301.2 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.447 (s, 1H), 10.381 (s, 1H), 8.761 (s, 1H), 8.132 (d, J=9.0Hz, 1H), 7.707 (d, J= 9.0Hz, 1H), 7.608 (d, J=9.0Hz, 2H), 7.472 (s, 1H), 7.449-7.460 (m, 1H), 7.323 (d, J= 7.2Hz, 1H), 7.303 (d, J=7.8Hz, 1H), 7.049 (d, J=9.0Hz, 2H), 6.902 (s, 1H), 5.137 (s, 2H) .¹³C NMR(600MHz,DMSO-d₆)δ:163.01,161.40,158.56,154.55,141.34,140.11,139.52, 135.17,131.97,130.49,130.43,126.33,123.50,121.92×2,119.27,114.93×2,114.11, 112.87,105.75,68.53ppm.ESI-MS m/z:406.4(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10o synthesized by embodiment 15

Compound (10o): N- { [4- (3,5- difluorobenzyl) oxygroup] phenyl } -5- nitro -1H- indole 2-carboxamides

N-{4-[(3,5-Difluorobenzyl)oxy]phenyl}-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 89.5%, fusing point: 312.6-314.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.448 (s, 1H), 10.388 (s, 1H), 8.763 (s, 1H), 8.103 (dd, J=2.4,9.0Hz, 1H), 7.713 (d, J=9.0Hz, 1H), 7.649 (s, 1H), 7.609 (d, J=9.6Hz), 7.213 (d, J=2.4Hz, 1H), 7.188 (d, J= 7.8Hz, 2H), 7.053 (d, J=8.4Hz, 2H), 5.151 (s, 2H)¹³C NMR(600MHz,DMSO-d₆)δ:158.585× 2,154.306,141.348,139.527,135.156,132.130,126.336,121.935×3,119.289,118.647, 114.972×3,112.879,110.459,110.290,109.318,105.712,68.012ppm.ESI-MS m/z:423.0 (M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10p synthesized by embodiment 16

Compound (10p): N- [4- (benzyloxy) -3- chlorphenyl] -5- nitro -1H- indole 2-carboxamides

N-[4-(Benzyloxy)-3-chlorophenyl]-5-nitro-1H-indole-2-carboxamide

Yellow-brown solid, yield: 89.5%, fusing point: 238.7-239.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 11.409 (s, 1H), 8.649 (s, 1H), 8.054 (d, J=2.4Hz, 1H), 7.927 (d, J=8.4Hz, 1H), 7.712 (dd, J=2.4,9.0Hz, 1H), 7.476-7.516 (m, 4H), 7.402-7.438 (m, 3H), 7.343 (t, J=7.2Hz, 1H), 7.242 (d, J=9.0Hz, 1H), 5.199 (s, 2H)¹³C NMR(600MHz,DMSO-d₆)δ:149.752,145.786, 136.983×2,133.360,128.696×3,128.139×2,127.736×3,121.606,121.499,119.811× 2,119.112,114.883×2,105.763,70.508ppm.ESI-MS m/z:422.1(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10q synthesized by embodiment 17

Compound (10q): N- { the chloro- 4- of 3- [(2,5- dimethyl benzyl) oxygroup] phenyl } -5- nitro -1H- indoles -2- first Amide

N-{3-Chloro-4-[(2,5-dimethylbenzyl)oxy]phenyl}-5-nitro-1H-indole-2- carboxamide

Yellow-brown solid, yield: 85.3%, fusing point: 230.5-232.7 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 11.925 (s, 1H), 10.605 (s, 1H), 8.759 (d, J=1.8Hz, 1H), 8.166 (dd, J=2.4,9.0Hz, 1H), 7.935 (d, J=2.4Hz, 1H), 7.731 (d, J=9.0Hz, 1H), 7.670 (dd, J=2.4,9.0Hz, 1H), 7.514 (s, 1H), 7.335 (d, J=9.0Hz, 1H), 7.277 (s, 1H), 7.122 (d, J=7.2Hz, 1H), 7.076 (d, J= 7.8Hz, 1H), 5.135 (d, J=6.6Hz, 2H), 2.308 (s, 3H), 2.282 (s, 3H)¹³C NMR(600MHz,DMSO-d₆) δ:158.964,150.347,141.624,139.823,135.032,134.897,134.486,133.808,132.686, 130.351×2,129.516×2,128.969,126.516,122.149,121.413,120.378,119.631, 119.011,114.725,113.157,106.284,69.448ppm.ESI-MS m/z:449.1(M)⁺, specific structure is shown in figure 1A。

The chemical structure characterize data of compound 10r synthesized by embodiment 18

Compound (10r): N- { the chloro- 4- of 3- [(4- methoxy-benzyl) oxygroup] phenyl } -5- nitro -1H- indoles -2- formyl Amine

N-{3-Chloro-4-[(4-methoxybenzyl)oxy]phenyl}-5-nitro-1H-indole-2- carboxamide

Yellow-brown solid, yield: 86.5%, fusing point: 301.2-303.7 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.593 (s, 1H), 10.625 (s, 1H), 8.759 (d, J=2.4Hz, 1H), 8.099 (d, J=2.4,9.0Hz, 1H), 7.983 (d, J=2.4Hz, 1H), 7.717 (d, J=2.4,9.0Hz, 1H), 7.671 (s, 1H), 7.614 (d, J=9.0Hz, 1H), 7.405 (d, J=9.0Hz, 2H), 7.274 (d, J=9.0Hz, 1H), 6.964 (d, J=8.4Hz, 2H), 5.116 (s, 2H),3.761(s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:159.320,159.004,150.212,141.514, 140.003,132.781,129.638×3,128.693,126.535,122.043,121.512,120.242,119.554, 118.885,114.943,114.100×3,113.234,106.560,70.354ppm.ESI-MS m/z:452.0(M)⁺, tool Body structure is shown in Figure 1A.

The chemical structure characterize data of compound 10s synthesized by embodiment 19

Compound (10s): N- { the chloro- 4- of 3- [(3- methoxy-benzyl) oxygroup] phenyl } -5- nitro -1H- indoles -2- formyl Amine

N-{3-Chloro-4-[(3-methoxybenzyl)oxy]phenyl}-5-nitro-1H-indole-2- carboxamide

Yellow-brown solid, yield: 87.5%, fusing point: 269.3-272.1 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.571 (s, 1H), 10.620 (s, 1H), 8.754 (d, J=1.8Hz, 1H), 8.094 (dd, J=2.4,9.0Hz, 1H), 7.970 (d, J=2.4Hz, 1H), 7.694 (dd, J=2.4,9.0Hz, 1H), 7.669 (s, 1H), 7.614 (d, J= 9.0Hz, 1H), 7.449-7.486 (m, 1H), 7.331 (d, J=7.2Hz, 1H), 7.315 (d, J=12.0Hz, 1H), 7.270 (d, J=9.0Hz, 1H), 7.165-7.198 (m, 1H), 5.118 (s, 2H), 3.763 (s, 3H)¹³C NMR(600MHz,DMSO- d₆)δ:159.587,158.963,150.151,141.633,139.824,138.462,135.024,132.783,129.835, 126.508,122.125,121.540,120.317,119.716×2,119.619,119.003,114.861,113.490, 113.236,1113.155,106.299,70.301ppm.ESI-MS m/z:451.9(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10t synthesized by embodiment 20

Compound (10t): N- { the chloro- 4- of 3- [(3,5- dimethoxy-benzyl) oxygroup] phenyl } -5- nitro -1H- indoles -2- Formamide

N-{3-Chloro-4-[(3,5-dimethoxybenzyl)oxy]phenyl}-5-nitro-1H-indole-2- carboxamide

Yellow-brown solid, yield: 86.4%, fusing point: 275.7-277.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.469 (s, 1H), 10.476 (s, 1H), 8.781 (d, J=2.4Hz, 1H), 8.108 (dd, J=2.4,9.0Hz, 1H), 7.958 (d, J=2.4Hz, 1H), 7.678 (d, J=9.0Hz, 1H), 7.649 (s, 1H), 7.611 (d, J=9.0Hz, 1H), 7.244 (d, J=9.0Hz, 1H), 6.634 (d, J=2.4Hz, 1H), 6.458 (m, J=2.4Hz, 1H), 5.155 (s, 2H),3.748(s,6H).¹³C NMR(600MHz,DMSO-d₆)δ:160.794×2,158.960,150.090,141.626, 139.823,139.247,135.018,132.794,126.505,122.109,121.546,120.316,119.626, 119.007,114.860,113.154,106.302,105.445×2,99.628,70.267,55.401×2ppm.ESI-MS m/z:483.0(M+H)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10u synthesized by embodiment 21

Compound (10u): N- { the chloro- 4- of 3- [(3- luorobenzyl) oxygroup] phenyl } -5- nitro -1H- indole 2-carboxamides

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-nitro-1H-indole-2- carboxamide

Yellow-brown solid, yield: 82.3%, fusing point: 295.6-297.9 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.471 (s, 1H), 10.487 (s, 1H), 8.781 (d, J=1.8Hz, 1H), 8.109 (dd, J=2.4,9.0Hz, 1H), 7.972 (d, J=2.4Hz, 1H), 7.694 (dd, J=2.4,9.0Hz, 1H), 7.654 (s, 1H), 7.614 (d, J= 9.0Hz, 1H), 7.447-7.484 (m, 1H), 7.321 (d, J=7.2Hz, 1H), 7.305 (d, J=12Hz, 1H), 7.269 (d, J=9.0Hz, 1H), 7.162-7.195 (m, 1H), 5.239 (s, 2H)¹³C NMR(600MHz,DMSO-d₆)δ:161.617, 158.976,149.960,141.626,139.830,135.000,132.943,130.809,126.503,123.551, 122.133,121.541,120.320,119.635,119.016,114.858×2,114.329,11183,113.156, 106.320,69.628ppm.ESI-MS m/z:462.5(M+Na)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 10v synthesized by embodiment 22

Compound (10v): N- { the chloro- 4- of 3- [(2,6- dichloro benzyl) oxygroup] phenyl } -5- nitro -1H- indoles -2- formyl Amine

N-{3-Chloro-4-[(2,6-dichlorobenzyl)oxy]phenyl}-5-nitro-1H-indole-2- carboxamide

Yellow-brown solid, yield: 84.5%, fusing point: 309.2-311.6 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.486 (s, 1H), 10.523 (s, 1H), 8.790 (d, J=2.4Hz, 1H), 8.114 (dd, J=2.4,9.0Hz, 1H), 7.961 (d, J=2.4Hz, 1H), 7.749 (dd, J=2.4,9.0Hz, 1H), 7.670 (s, 1H), 7.620 (d, J= 9.0Hz, 1H), 7.585 (d, J=8.4Hz, 2H), 7.494 (t, J=8.4Hz, 1H), 7.419 (d, J=9.0Hz, 1H), 5.316(s,2H).¹³C NMR(600MHz,DMSO-d₆)δ:159.019,150.353,141.635,139.839,136.418× 2,134.995,133.376,131.990,131.543,129.058×2,126.512,122.148,121.880,120.402, 119.656,119.033,115.455,113.168,106.367,66.721ppm.ESI-MS m/z:490.5(M)⁺, specific to tie Structure is shown in Figure 1A.

The chemical structure characterize data of compound 10w synthesized by embodiment 23

Compound (10w): N- { the chloro- 4- of 3- { [4- (trifluoromethyl) benzyl] oxygroup } phenyl } -5- nitro -1H- indoles -2- Formamide

N-{3-Chloro-4-{[4-(trifluoromethyl)benzyl]oxy}phenyl}-5-nitro-1H- indole-2-carboxamide

Yellow-brown solid, yield: 80.4%, fusing point: 277.5-279.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.469 (s, 1H), 10.491 (s, 1H), 8.779 (d, J=1.8Hz, 1H), 8.108 (dd, J=2.4,9.0Hz, 1H), 7.980 (d, J=2.4Hz, 1H), 7.794 (d, J=8.4Hz, 2H), 7.684-7.707 (m, 3H), 7.651 (s, 1H), 7.614 (d, J=9.0Hz, 1H), 7.273 (d, J=9.0Hz, 1H), 5.333 (s, 2H)¹³C NMR(600MHz,DMSO-d₆) δ:158.981,149.913,141.767,141.633,139.826,134.991,133.009,128.058×3,126.500, 125.645,125.347,122.158,121.535,120.336,119.623,119.014,114.845,113.158, 106.327,69.602ppm.ESI-MS m/z:489.6(M)⁺, specific structure is shown in Figure 1A.

The chemical structure characterize data of compound 13a synthesized by embodiment 24

Compound (13a): 1- methyl-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- indoles -2- formyl Amine

1-Methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitro-1H-indole-2- carboxamide

White powder, yield: 72.8%, fusing point: 253.1-255.2 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.392 (s, 1H), 8.731 (d, J=2.4Hz, 1H), 8.151 (dd, J=2.4,9.0Hz, 1H), 7.787 (d, J=9.0Hz, 1H), 7.616 (d, J=9.0Hz, 2H), 7.497 (s, 1H), 6.937 (d, J=9.0Hz, 2H), 4.065 (s, 3H), 3.106 (t, J=4.8Hz, 4H), 2.450 (t, J=4.8Hz, 4H), 2.219 (s, 3H)¹³C NMR(600MHz,DMSO-d₆)δ: 159.009,147.741,141.483,141.019,136.015,130.399,124.794,121.418×2,118.909, 118.457,115.448×2,111.383,107.277,54.621×2,48.396×2,45.784,32.136ppm.ESI- MS m/z:394.4(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13b synthesized by embodiment 25

Compound (13b): 1- allyl-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- indoles -2- first Amide

1-Allyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitro-1H-indole-2- carboxamide

White powder, yield: 70.8%, fusing point: 253.2-254.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.415 (s, 1H), 8.751 (d, J=1.8Hz, 1H), 8.142 (dd, J=2.4,9.0Hz, 1H), 7.765 (d, J=9Hz, 1H), 7.605 (d, J=9.0Hz, 2H), 7.534 (s, 1H), 6.933 (d, J=9Hz, 2H), 6.045-5.982 (m, 1H), 5.295 (d, J=5.4Hz, 2H), 5.092 (dd, J=1.2,10.8Hz, 1H), 4.884 (dd, J=1.8,17.4Hz, 1H), 3.103 (t, J=4.8Hz, 4H), 2.450 (t, J=4.8Hz, 4H), 2.219 (s, 3H)¹³C NMR(600MHz,DMSO-d₆) δ:158.993,147.747,141.638,140.518,135.496,134.210,130.351,124.977,121.387×2, 118.993,118.609,116.285,115.434×2,111.609,107.714,54.597×2,48.391×2, 46.629,45.769ppm.ESI-MS m/z:420.4(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13c synthesized by embodiment 26

Compound (13c): 1- (2,6- dichloro benzyl)-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- Yin Diindyl -2- formamide

1-(2,6-Dichlorobenzyl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitro- 1H-indole-2-carboxamide

White powder, yield: 72.5%, fusing point: 252.1-253.8 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.415 (s, 1H), 8.751 (d, J=1.8Hz, 1H), 8.142 (dd, J=2.4,9.0Hz, 1H), 7.765 (d, J=9.0Hz, 1H), 7.605 (d, J=9.0Hz, 2H), 7.534 (s, 1H), 6.933 (d, J=9.0Hz, 2H), 6.045-5.982 (m, 1H), 5.295 (d, J=5.4Hz, 2H), 5.092 (dd, J=1.2,10.8Hz, 1H), 4.884 (dd, J=1.8,17.4Hz, 1H), 3.103 (t, J=4.8Hz, 4H), 2.450 (t, J=4.8Hz, 4H), 2.219 (s, 3H)¹³C NMR(600MHz,DMSO-d₆) δ:159.448,147.804,141.606,140.672,137.584,135.077×2,131.449,130.583,130.270, 129.316×2,125.440,121.486×2,119.000,118.761,115.451×2,111.127,107.406, 54.604×2,48.389×2,45.773,44.769ppm.ESI-MS m/z:538.1(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13d synthesized by embodiment 27

Compound (13d): 1- (3- luorobenzyl)-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- indoles - 2- formamide

1-(3-Fluorobenzyl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitro-1H- indole-2-carboxamide

White powder, yield: 69.2%, fusing point: 248.2-250.3 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.469 (s, 1H), 8.776 (d, J=2.4Hz, 1H), 8.131 (dd, J=2.4,9.6Hz, 1H), 7.795 (d, J=9.0Hz, 1H), 7.599 (s, 1H), 7.573 (d, J=9.0Hz, 2H), 7.340-7.303 (m, 1H), 7.070-7.043 (m, 1H), 6.924 (d, J=9.0Hz, 4H), 5.939 (s, 2H), 3.097 (t, J=4.8Hz, 4H), 2.445 (t, J=4.8Hz, 4H), 2.215(s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:162.840,162.616,147.865,146.150,145.213, 142.310,142.102,137.695,132.211,132.532,130.152,127.321,123.213,121.500×2, 115.475,114.135,113.193,112.595×2,108.299,54.619×2,48.390×2,47.087, 45.795ppm.ESI-MS m/z:488.1(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13e synthesized by embodiment 28

Compound (13e): 1- (4- chlorobenzyl)-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- indoles - 2- formamide

1-(4-Chlorobenzyl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitro-1H- indole-2-carboxamide

White powder, yield: 68.5%, fusing point: 224.8-226.5 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.446 (s, 1H), 8.767 (d, J=2.4Hz, 1H), 8.125 (dd, J=2.4,9.0Hz, 1H), 7.787 (d, J=9.6Hz, 1H), 7.599 (s, 1H), 7.573 (d, J=9.0Hz, 2H), 7.341 (d, J=8.4Hz, 2H), 7.127 (d, J=9.0Hz, 2H), 6.923 (d, J=9.0Hz, 2H), 5.911 (s, 2H), 3.100 (t, J=4.8Hz, 4H), 2.456 (t, J=4.8Hz, 4H),2.223(s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:159.034,147.803,141.855,140.685, 136.936,135.352,131.939,130.219,128.549×2,125.164,121.485×2,125.164,121.485 ×2,119.116,115.450×2,111.748,108.277,54.563×2,48.337×2,46.945, 45.721ppm.ESI-MS m/z:504.1(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13f synthesized by embodiment 29

Compound (13f): 1- (4- bromobenzyl)-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- indoles - 2- formamide

1-(4-Bromobenzyl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitro-1H- indole-2-carboxamide

White powder, yield: 70.6%, fusing point: 242.3-244.1 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.447 (s, 1H), 8.770 (d, J=2.4Hz, 1H), 8.125 (dd, J=2.4,9.0Hz, 1H), 7.785 (d, J=9.0Hz, 1H), 7.603 (s, 1H), 7.574 (d, J=8.4Hz, 2H), 7.475 (d, J=8.4Hz, 2H), 7.062 (d, J=7.8Hz, 2H), 6.923 (d, J=9.0Hz, 2H), 5.895 (s, 2H), 3.096 (t, J=4.8Hz, 4H), 2.443 (t, J=4.8Hz, 4H),2.214(s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:158.990,147.799,141.834,140.667, 137.352,135.324,131.441×2,130.188,128.809×2,125.137,121.452×2,120.404, 119.095,118.910,115.410×2,111.729,108.257,54.584×2,48.356×2,46.992,45.762, ESI-MS m/z:548.4(M)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13g synthesized by embodiment 30

Compound (13g): N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1- [4- (trifluoromethyl) benzyl] - 1H- indole 2-carboxamides

N-[4-(4-Methylpiperazin-1-yl)phenyl]-5-nitro-1-[4-(trifluoromethyl) benzyl]-1H-indole-2-carboxamide

White powder, yield: 72.6%, fusing point: 231.8-233.3 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.447 (s, 1H), 8.793 (d, J=2.4Hz, 1H), 8.130 (dd, J=2.4,9.0Hz, 1H), 7.773 (d, J=9.0Hz, 1H), 7.664 (s, 1H), 7.649 (s, 2H), 7.561 (d, J=9.0Hz, 2H), 7.276 (d, J=8.4Hz, 2H), 6.914 (d, J=9.0Hz, 2H), 6.027 (s, 2H), 3.091 (t, J=4.8Hz, 4H), 2.442 (t, J=4.8Hz, 4H), 2.213 (s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:158.931,145.428,142.775,141.929,140.748, 136.975,135.284,130.154,127.150×2,125.494×2,125.163,121.483×2,119.160, 119.032,117.398,115.402×2,111.685,108.320,54.577×2,48.345×2,47.320, 45.751ppm.ESI-MS m/z:538.0(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 13h synthesized by embodiment 31

Compound (13h): 1- (4- methylbenzyl)-N- [4- (4- methyl piperidine -1- base) phenyl] -5- nitro -1H- Yin Diindyl -2- formamide

1-(4-Methoxybenzyl)-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitro-1H- indole-2-carboxamide

White powder, yield: 75.7%, fusing point: 235.6-237.3 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.445 (s, 1H), 8.782 (d, J=2.4Hz, 1H), 8.127 (dd, J=2.4,9.0Hz, 1H), 7.780 (d, J=9.0Hz, 1H), 7.635 (s, 1H), 7.652 (s, 2H), 7.569 (d, J=9.0Hz, 2H), 7.365 (d, J=8.4Hz, 2H), 6.921 (d, J=9.0Hz, 2H), 6.012 (s, 2H), 3.842 (s, 3H), 3.094 (t, J=4.8Hz, 4H), 2.445 (t, J= 4.8Hz,4H),2.254(s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:162.437,158.120,149.251, 144.975,142.323,142.110,133.531,133.214,130.152×2,129.721,126.342,123.510× 2,114.921,114.100×2,113.972×2,112.110,54.533×2,52.677,48.376×2,47.120, 45.734ppm.ESI-MS m/z:500.21(M+H)⁺, specific structure is shown in Figure 1B.

The chemical structure characterize data of compound 14a synthesized by embodiment 32

Compound (14a): 5- amino-N- [4- (4- methyl piperidine -1- base) phenyl] -1- [4- (trifluoromethyl) benzyl] - 1H- indole 2-carboxamides

5-Amino-N-[4-(4-methylpiperazin-1-yl)phenyl]-1-[4-(trifluoromethyl) benzyl]-1H-indole-2-carboxamide

White powder, yield: 72.6%, fusing point: 218.8-220.3 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.028 (s, 1H), 7.620 (d, J=8.4Hz, 2H), 7.556 (d, J=9.0Hz, 2H), 7.226 (d, J=7.8Hz, 2H), 7.190 (d, J=9.0Hz, 1H), 7.126 (s, 1H), 6.888 (d, J=9.0Hz, 2H), 6.914 (d, J=9.0Hz, 2H), 6.027 (s, 2H), 3.091 (t, J=4.8Hz, 4H), 2.442 (t, J=4.8Hz, 4H), 2.213 (s, 3H)¹³C NMR (600MHz,DMSO-d₆)δ:160.039,147.445,144.152,142.896,132.358,131.048,130.785, 127.392,127.068×2,126.832,125.263×2,123.349,121.283×2,115.595,115.469×2, 111.056,104.827,103.270,54.623×2,48.500×2,46.625,45.777ppm.ESI-MS m/z:508.3 (M+H)⁺, specific structure is shown in Fig. 1 C.

The chemical structure characterize data of compound 14b synthesized by embodiment 33

Compound (14b): 5- acrylamido-N- [4- (4- methyl piperidine -1- base) phenyl] -1- [4- (trifluoromethyl) Benzyl] -1H- indole 2-carboxamides

5-Acrylamido-N-[4-(4-methylpiperazin-1-yl)phenyl]-1-[4- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide

White powder, yield: 65.7%, fusing point: 231.2-233.2 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.190 (s, 1H), 10.152 (s, 1H), 8.202 (d, J=1.8Hz, 1H), 7.637 (d, J=8.4Hz, 2H), 7.569 (d, J =9.0Hz, 2H), 7.484 (d, J=9.0Hz, 1H), 7.412 (dd, J=2.4,9.0Hz, 1H), 7.382 (s, 1H), 7.250 (d, J=7.8Hz, 2H), 6.905 (d, J=9.0Hz, 2H), 6.494-6.449 (m, 1H), 6.250 (dd, J=1.8, 16.8Hz, 1H), 5.935 (s, 2H), 5.730 (dd, J=1.8,10.2Hz, 1H), 3.090 (t, J=4.8Hz, 4H), 2.459 (t, J=4.8Hz, 4H), 2.225 (s, 3H)¹³C NMR(600MHz,DMSO-d₆)δ:162.893,159.717,147.535, 143.694,135.146,132.678,132.259,132.118,130.574,127.085×2,126.206,125.693, 125.363×2,121.385×2,118.119,115.451×2,111.763,110.990,108.831,106.859, 106.230,54.553×2,48.388×2,46.794,45.688ppm.ESI-MS m/z:562.2(M+H)⁺, specific structure See Fig. 1 C.

The chemical structure characterize data of compound 14c synthesized by embodiment 34

Compound (14c): N- [4- (4- methyl piperidine -1- base) phenyl] -5- propionamido- -1- [4- (trifluoromethyl) benzyl Base] -1H- indole 2-carboxamides

N-[4-(4-Methylpiperazin-1-yl)phenyl]-5-propionamido-1-[4- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide

White powder, yield: 68.5%, fusing point: 222.2-224.1 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.167 (s, 1H), 9.801 (s, 1H), 8.092 (d, J=1.8Hz, 1H), 7.631 (d, J=7.8Hz, 2H), 7.565 (d, J =9.0Hz, 2H), 7.443 (d, J=9.0Hz, 1H), 7.350 (s, 1H), 7.333 (dd, J=1.8,9.0Hz, 1H), 7.242 (d, J=7.8Hz, 1H), 6.900 (d, J=9.0Hz, 2H), 5.925 (s, 2H), 3.459-3.424 (m, 1H), 3.081 (t, J =4.8Hz, 4H), 2.438 (t, J=4.8Hz, 4H), 2.320 (q, J=7.2Hz, 2H), 2.209 (s, 3H), 1.098 (t, J= 7.8Hz,3H).¹³C NMR(600MHz,DMSO-d₆)δ:171.598,159.751,147.554,143.730,134.903, 133.045,132.097,130.558,127.701,127.494,127.069×2,125.665,125.324×2, 125.102,121.376×2,118.107,115.425×2,111.402,110.807,106.122,56.007,54.600× 2,48.440×2,46.757,45.756ppm.ESI-MS m/z:564.4(M+H)⁺, specific structure is shown in Fig. 1 C.

The chemical structure characterize data of compound 14d synthesized by embodiment 35

Compound (14d): 5- (2- chloracetyl amido)-N- [4- (4- methyl piperidine -1- base) phenyl] -1- [4- (fluoroform Base) benzyl] -1H- indole 2-carboxamides

5-(2-Chloroacetamido)-N-[4-(4-methylpiperazin-1-yl)phenyl]-1-[4- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide

White powder, yield: 65.3%, fusing point: 216.2-218.1 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.171 (s, 1H), 9.702 (s, 1H), 8.162 (d, J=1.8Hz, 1H), 7.635 (d, J=7.8Hz, 2H), 7.567 (d, J =9.0Hz, 2H), 7.465 (d, J=9.0Hz, 1H), 7.402 (s, 1H), 7.346 (dd, J=1.8,9.0Hz, 1H), 7.248 (d, J=7.8Hz, 1H), 6.903 (d, J=9.0Hz, 2H), 5.944 (s, 2H), 4.714 (s, 2H), 3.473 (s, 1H), 3.097 (t, J=4.8Hz, 4H), 2.236 (t, J=4.8Hz, 4H), 2.126 (s, 3H)¹³C NMR(600MHz,DMSO-d₆) δ:164.370,161.393,148.138,147.542,143.675,143.641,132.553,130.607,127.758, 127.092×2,125.373×2,123.316,121.513×2,121.433,115.927,115.481,112.464, 111.994,54.492×2,48.311×2,46.845,43.606,42.302ppm.ESI-MS m/z:564.4(M+H)⁺, tool Body structure is shown in Fig. 1 C.

The chemical structure characterize data of compound 14e synthesized by embodiment 36

Compound (14e): N- [4- (4- methyl piperidine -1- base) phenyl] -5- (methylsulfonamides) -1- [4- (fluoroform Base) benzyl] -1H- indole 2-carboxamides

N-[4-(4-Methylpiperazin-1-yl)phenyl]-5-(methylsulfonamido)-1-[4- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide

White powder, yield: 65.7%, fusing point: 231.2-233.2 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.194 (s, 1H), 9.446 (s, 1H), 7.642 (d, J=8.4Hz, 1H), 7.567 (s, 1H), 7.552 (s, 1H), 7.517 (d, J=9.0Hz, 1H), 7.371 (s, 1H), 7.275 (d, J=8.4Hz, 2H), 7.154 (dd, J=1.8,9.0Hz, 1H), 6.907 (d, J=9.0Hz, 2H), 5.928 (s, 1H), 3.084 (t, J=4.8Hz, 4H), 2.912 (s, 3H), 2.440 (t, J= 4.8Hz,4H),2.211(s,3H).¹³C NMR(600MHz,DMSO-d₆)δ:159.659,147.630,143.546, 135.889,132.630,131.470,130.457,127.175×2,126.010,125.375,126.010,125.375× 2,121.426×2,120.237,115.434×2,114.459,111.509,106.025,54.600×2,48.427×2, 46.849,45.767,38.673ppm.ESI-MS m/z:562.2(M+H)⁺, specific structure is shown in Fig. 1 C.

The chemical structure characterize data of compound 14f synthesized by embodiment 37

Compound (14f): 5- (furans -2- formamido)-N- [4- (4- methyl piperidine -1- base) phenyl] -1- [4- (three Methyl fluoride) benzyl] -1H- indole 2-carboxamides

5-(Furan-2-carboxamido)-N-[4-(4-methylpiperazin-1-yl)phenyl]-1-[4- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide

White powder, yield: 67.2%, fusing point: 203.5-205.2 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.195 (s, 1H), 10.159 (s, 1H), 8.165 (s, 1H), 7.927 (s, 1H), 7.641 (d, J=7.8Hz, 2H), 7.576 (d, J=9.6Hz, 2H), 7.549 (d, J=1.8Hz, 1H), 7.504 (d, J=9.0Hz, 1H), 7.406 (s, 1H), 7.322 (d, J=3.6Hz, 1H), 7.259 (d, J=7.8Hz, 2H), 6.907 (d, J=9.0Hz, 2H), 6.700 (q, J=1.8Hz, 1H), 5.952 (s, 2H), 3.091 (t, J=4.8Hz, 4H), 2.460 (t, J=4.8Hz, 4H), 2.224 (s, 3H)¹³C NMR (600MHz,DMSO-d₆)δ:159.723,156.141,147.801,147.537,145.443,143.698,135.539, 132.256,131.969,130.575,127.088×2,125.596,125.347×2,125.112,119.291×2, 115.453×2,114.280,113.149,112.071,110.810,106.254,56.012,54.548×2,48.382× 2,46.810,45.676,18.543ppm.ESI-MS m/z:602.3(M+H)⁺, specific structure is shown in Fig. 1 C.

The chemical structure characterize data of compound 14g synthesized by embodiment 38

Compound (14g): 5- (N,N-dimethylformamide base)-N- [4- (4- methyl piperidine -1- base) phenyl] -1- [4- (trifluoromethyl) benzyl] -1H- indole 2-carboxamides

5-(3,3-Dimethylureido)-N-[4-(4-methylpiperazin-1-yl)phenyl]-1-[4- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide

White powder, yield: 68.4%, fusing point: 132.8-134.9 DEG C of¹H NMR(600MHz,DMSO-d₆):δ(ppm) 10.140 (s, 1H), 8.196 (s, 1H), 7.789 (d, J=1.8Hz, 1H), 7.631 (d, J=8.4Hz, 2H), 7.567 (d, J =9.0Hz, 2H), 7.385 (d, J=9.0Hz, 1H), 7.325 (s, 1H), 7.307 (dd, J=1.8,9.0Hz, 1H), 7.239 (d, J=8.4Hz, 2H), 6.900 (d, J=9.0Hz, 2H), 5.922 (s, 2H), 3.085 (t, J=4.8Hz, 4H), 2.931 (s, 6H), 2.453 (t, J=4.8Hz, 4H), 2.220 (s, 3H)¹³C NMR(600MHz,DMSO-d₆)δ:159.829, 156.236,147.489,143.860,134.671,134.164,131.731,130.629,127.043×2,125.637, 125.310×2,121.365×2,119.885,115.440×2,112.352,110.283,105.976,56.009, 54.566×2,48.411×2,46.740,45.698,36.211×2,18.538ppm.ESI-MS m/z:579.2(M+H)⁺, Specific structure is shown in Fig. 1 C.

Embodiment 39 is of the invention to stimulate macrophage to lipopolysaccharides (LPS) using indoles -2- amide as the analog of mother nucleus structure Cell discharges the activity of the inhibition of inflammatory factor.

Compound stimulation 264.7 macrophage of RAW that Examples 1 to 38 is prepared discharge inflammatory factor (TNF-α and IL-6), the method for inhibition tests the external preliminary anti-inflammatory activity of compound, and the specific method is as follows: 1.2 × 10⁶A RAW 264.7 macrophages are incubated at 37 DEG C with DMEM culture solution, and culture solution is updated after 24 hours, and it is (dense eventually that tested compounds are added Degree is 10 μM) pretreatment 2 hours, then continued with 22 hours with the LPS of 0.5 μ g/mL, collect culture solution ELISA method detection TNF-α and IL-6 content；Collect cell detection total protein concentration, ELISA result be divided by with corresponding total protein concentration it is calibrated, with TNF-α and IL-6 the content calibration of LPS control group are 100；Each compound retest 3 times calculates average value and error amount. With positive drug Indomethacin and X12 (see " Synthesis and Anti-inflammatory Evaluation when test of Novel Benzimidazole and Imidazopyridine Derivatives”,ACS Med.Chem.Lett.2013,4,69-74 it) compares.Fig. 2 is the present invention using indoles -2- amide as the analog of mother nucleus structure The activity of the inhibition of IL-6 and TNF-α is discharged to lipopolysaccharides (LPS) stimulation 264.7 macrophage of RAW.

The result shows that the embodiment of the present invention 1~38 prepare using indoles -2- amide as the big portion of the analog of mother nucleus structure Dividing has preferable inhibitory activity to IL-6 and TNF-α, and wherein the activity of compound 14f and 14g is best, and is substantially better than on City's anti-inflammatory drug Indomethacin has the potentiality as anti-inflammatory new drug.Experimental data is shown in Fig. 2.

Embodiment 40

The present embodiment further tests reactive compound 14f and 14g that embodiment 37 and 38 is prepared to Pneumonia Mice The inhibitory activity of myeloperoxidase in lung tissue, myeloperoxidase (MPO) activity in lung tissue be in evaluation tissue in The index of property granulocyte Infiltrating.Method: lung homogenate is being contained into two hydrochloric acid dianisidines (0.167mg/Ml) 0.01% H₂O₂30min is incubated in solution.The variation that each sample OD value of absorption peak at 460nm is measured with microplate reader, from And extrapolate the vigor and H of MPO₂O₂The amount of reduction and the number of leucocyte, experimental data are shown in Fig. 3 A.Next activity is tested Compound 14f, 14g are to the activity of the inhibition of inflammatory factor TNF-α in Pneumonia Mice serum, and method is the same as embodiment 39.Test number According to seeing Fig. 3 B.

Embodiment 41

The reactive compound 14f that embodiment 37 and 38 is prepared, the pathology that 14g alleviates lipopolysaccharide-induced acute lung tissue become Change: experimental data is shown in Fig. 4.Compound 14f, 14g alleviate the Pathologic changes of lipopolysaccharide-induced acute lung tissue, and Normal group is big Mouse alveolar space is clear, structural integrity, and wall is smooth；After tracheal instillation LPS causes acute lung injury model, the obvious oedema of alveolar wall, It thickens, inflammatory cell infiltration increases；Give compound 14f, edema after 14g treatment is thickened and is obviously reduced, and inflammatory cell Infiltration significantly reduces, little with normal group difference, has identical effect with the reactive compound X12 reported before.

Embodiment 42

The mice with acute lung injury lung tissue that the reactive compound 14f and 14g that embodiment 37 and 38 is prepared induces LPS The inhibitory effect (F4/80 immunohistochemistry) of the infiltration of middle macrophage: experimental data is shown in Fig. 5.F4/80 is the mark of macrophage Object.LPS group discovery F4/80 marker increased significantly, and compound 14f is added, and find that the marker obviously subtracts after 14g treatment It is few, it is suitable with normal group, illustrate that the two compounds can obviously inhibit the infiltration of macrophage.

Embodiment 43

The pulmonary epithelial cells Beas-2B that the reactive compound 14f and 14g that embodiment 37 and 38 is prepared stimulates LPS is thin The inhibiting effect of the rna expression of born of the same parents' different cytokines: experimental data is shown in Fig. 6, and wherein A, B, C, D, E, F are respectively compound pair Inflammatory factor TNF-α, IL-6, the rna expression inhibitory effect of IL-1 β, COX-2, IL-12 and IL-33.The result shows that the two are changed The expression of these cell factor RNAs relevant to inflammation, and the effect of the compound X12 reported better than before can obviously be inhibited by closing object Fruit.

Above-mentioned detailed description is illustrating for the possible embodiments invented, and the embodiment is not to limit this hair Bright the scope of the patents, it is all without departing from equivalence enforcement or change of the invention, it should all be contained in the scope of the patents of the invention.

In addition, those skilled in the art can also the claims in the present invention scope of disclosure and spirit in do other forms and Various modifications, addition and replacement in details.Certainly, these spirit is done according to the present invention various modifications, addition and replacements It, all should be comprising within scope of the present invention Deng variation.

Claims

1. a kind of indoles -2- amides compound with anti-inflammatory effect, which is characterized in that be selected from compound 14f or compound 14g:

2. a kind of indoles -2- amides compound application in preparing anti-inflammatory drugs as described in claim 1.

3. indoles -2- amides compound application in preparing anti-inflammatory drugs according to claim 2, feature exist In the anti-inflammatory drug is for treating the acute lung injury as caused by inflammation or being expressed by inflammatory cytokine beyond normal amount With disease relevant to inflammation caused by release.

4. indoles -2- amides compound application in preparing anti-inflammatory drugs according to claim 3, feature exist In the disease relevant to inflammation is septicopyemia, osteoarthritis, alimentary canal inflammation, polymyositis, dermatomyositis, blood vessel Inflammatory syndrome, neuroinflamation, chemically pain, inflammatory pain, granuloma, granulomatous angiitis, arteritis, dermatitis Disease, autoimmune disease, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatorome are anti- Answer syndrome, septicemia or infectious shock.

5. indoles -2- amides compound application in preparing anti-inflammatory drugs according to claim 4, feature exist In the autoimmune disease is rheumatoid arthritis, systemic loupus erythematosus and related syndromes, gouty joint Scorching or rheumatic arthritis.

6. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes effective component and pharmaceutic adjuvant, it is described effectively Ingredient includes indoles -2- amides compound or its officinal salt described in claim 1.

7. pharmaceutical composition according to claim 6, which is characterized in that the dosage form of the pharmaceutical composition is note Penetrate any of agent, tablet, capsule, aerosol, suppository, film, pill, ointment, controlled release agent, sustained release agent or nanometer formulation Kind.