CN113121531B - N-heteroindole compound, synthesis method and medical application thereof - Google Patents
N-heteroindole compound, synthesis method and medical application thereof Download PDFInfo
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Abstract
The invention discloses an N-heteroindole compound shown in a formula (I), or pharmaceutically acceptable salt, isomer, solvent compound or prodrug thereof, wherein the definition of each group in the formula is shown in the specification. In addition, the invention also discloses a pharmaceutical composition containing the Songa compound and application thereof in preparing an inhibitor for inhibiting BRD4-BD1 protein.
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and in particular relates to an N-heteroindole compound, a synthetic method of the N-heteroindole compound and application of the N-heteroindole compound in medicines.
Background
The use of DNA encoding compounds (DNA encoded Library, DEL) with high throughput second generation sequencing (Next generation sequencing, NGS) can infer the molecular composition of the compounds with high efficiency by combinatorial chemistry, polymerase chain reaction Polymerase chain reaction, PCR). Thus, DEL is increasingly becoming an important tool for the discovery of new Miao ethnic compounds.
Bromodomain (BRD) is the "Reader" of acetylated lysines in histones and is the only protein domain that recognizes and binds to histone acetylated lysines. It is known that there are 61 bromodomain codes in the human genome, which are present in 46 different proteins. Bromine domains are divided into eight families based on structural similarity. Among them, BRD4-BD1 protein is closely related to the occurrence and development of various diseases (lung cancer, ovarian cancer, breast cancer, NUT midline carcinoma, prostate cancer, HIV-1, various inflammatory diseases, etc.), and has become a new target for treating various diseases.
Therefore, the development of an inhibitor for selectively inhibiting the BRD4-BD1 protein is a better direction, and the development of a medicament which has better inhibition activity and better selectivity on the BRD4-BD1 protein and can be used for treating, preventing and relieving diseases mediated by the BRD4-BD1 protein has important significance.
Disclosure of Invention
The invention aims to solve the technical problem of providing an N-heteroindole compound with a novel structure, which has the advantage of good activity as a BRD4-BD1 protein inhibitor.
In order to solve the above technical problems, in a first aspect, the present invention provides an N-heteroindole compound represented by formula (I), or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof:
in formula I:
R 1 is hydrogen, C 3 ～C 7 Cycloalkyl, substituted or unsubstituted C 1 ～C 6 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-to 6-membered heteroaryl, substituted or unsubstituted benzo 5-to 6-membered heteroaryl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted benzo 5-to 6-membered heterocycloalkyl, substituted or unsubstituted C 1 ～C 6 Alkyl-carbonyl, substituted or unsubstituted aryl-carbonyl, substituted or unsubstituted 5-to 6-membered heteroaryl-carbonyl, substituted or unsubstituted benzo 5-to 6-membered heteroaryl-carbonyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl-carbonyl, substituted or unsubstituted benzo 5-to 6-membered heteroarylCycloalkyl-carbonyl; r is R 1 Wherein said substitution is by 1, 2 or 3 members independently selected from halogen, hydroxy, cyano, C 1 ～C 3 Alkyl, halogenated C 1 ～C 3 Alkyl, C 1 ～C 3 Alkoxy, halogenated C 1 ～C 3 Substitution of the substituent of the alkoxy group;
R 2 is hydrogen, C 1 ～C 6 An alkyl group.
Specifically, the aromatic heterocyclic group or heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S.
Specifically, the aromatic ring group is selected from the group consisting of: phenyl, or naphthyl.
Specifically, the 5-to 6-membered aromatic heterocyclic group is selected from the group consisting of: pyridyl, pyrimidinyl, thiazolyl, isothiazolyl, furyl, thienyl, pyrrolyl.
Specifically, the benzo 5-6 membered heteroaryl ring group is selected from the group consisting of: benzopyridyl, benzopyrimidinyl, benzothiazolyl, benzisothiazolyl, benzopyrrolyl, benzofuranyl, or benzothienyl.
Specifically, the 5-to 6-membered heterocyclic group is selected from the group consisting of: morpholinyl, tetrahydrofuranyl, thiazolyl, dioxanyl, or dioxanyl.
Specifically, the benzo 5-6 membered heterocyclic group is selected from the group consisting of: benzodioxan, or benzodioxan.
Specifically, the C 1 ～C 6 The alkyl group is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.
Specifically, the C 5 ～C 7 Cycloalkyl is selected from the group consisting of: cyclopentyl, cyclohexyl, or cycloheptyl.
Specifically, the C 3 ～C 6 Cycloalkyl is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
An N-heteroindole compound is 2- (1- (5- (3- ((4-aminopiperidin-1-yl) methyl) -5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrole [2,3-b ] pyridin-1-yl) pentanoyl) -3-oxopiperazin-2-yl) -N-methylacetamide.
An N-heteroindole compound is 2-isopropyl-N- (1- ((5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (5- (2- (methylamino) -2-oxoethyl) -3-oxopiperazin-1-yl) -5-oxopentyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) piperidin-4-yl) isonicotinamide.
In a second aspect, the present invention also provides a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and optionally a pharmaceutically acceptable carrier.
In a third aspect, the invention also provides the following pharmaceutical uses:
use of a compound according to the first aspect of the foregoing, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the preparation of an inhibitor of BRD4-BD1 protein.
Use of a compound according to the first aspect of the foregoing, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment, prevention and alleviation of a disease mediated by the BRD4-BD1 protein. Among them, diseases mediated by BRD4-BD1 protein include lung cancer, ovarian cancer, breast cancer, NUT midline carcinoma, prostate cancer, HIV-1, and various inflammatory diseases.
The N-heteroindole compounds provided by the invention. The method comprises the following steps: and (3) carrying out DNA coding compound library affinity screening aiming at target proteins, sequencing the DNA coding compounds enriched by screening according to the calculated value and sequencing copy number of the DNA coding compounds from high to low, determining the molecular sequence and structure information of potential DNA coding Miao compounds, finally designing a synthesis path for removing DNA tag compounds, and finally synthesizing target molecules.
DEL-encoded compounds are a novel innovative prodrug screening technique by fusing high throughput screening techniques with DNA encoding sequencing techniques. The technology greatly reduces the economic and time costs of the drug discovery link on one hand and greatly improves the number of candidate compounds on the other hand. Through screening by using a DEL library platform, the invention successfully screens out a compound molecule specifically targeting BRD4-BD1 protein. The compounds have the same core skeleton, as shown in formula (I). Meanwhile, the KD value in the SPR test result of the compound reaches 84.5nmol, which shows the treatment prospect for diseases caused by BRD4-BD1 protein.
Method of drug administration
Because the compounds of the present invention have excellent inhibitory activity against BRD4-BD1 protein, the compounds of the present invention and pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, and pharmaceutical compositions containing the compounds of the present invention as a major active ingredient are included in the present application as products for the treatment, prevention and alleviation of diseases mediated by BRD4-BD1 protein.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-200mg of the compound of the invention per dose.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.
) Wetting agents (e.g. dodecylSodium sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, parenteral (intravenous, intramuscular), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention has the advantages that: the invention provides a compound with a structure shown in a formula I, which has excellent inhibitory activity on BRD4-BD1 protease.
The compound has simple preparation process and low production cost, and shows good positive results in experiments closely related to virus generation and development, so the compound is expected to be developed into medicines for treating related diseases (lung cancer, ovarian cancer, breast cancer, NUT midline carcinoma, prostatic cancer, HIV-1, various inflammatory diseases and the like) mediated by BRD4-BD1 protein.
Terminology
The term "aromatic ring group" means a group having aromaticity and consisting of two atoms of carbon and hydrogen. Preferably an aromatic ring group having 5 to 12 members, for example selected from the group consisting of (but not limited to): phenyl and naphthyl.
The term "5-to 6-membered heteroaryl ring radical" refers to a 5-to 6-membered aromatic radical having one or more heteroatoms selected from nitrogen, oxygen or sulfur. May be selected from the following group (but not limited to): pyridyl, pyrimidinyl, thiazolyl, isothiazolyl, furyl, thienyl, pyrrolyl.
The term "benzo 5-6 membered heteroaromatic group" refers to a group in which a 5-to 6-membered aromatic group having one or more heteroatoms selected from nitrogen, oxygen or sulfur is fused to a benzene ring. May be selected from the following group (but not limited to): benzopyridyl, benzopyrimidinyl, benzothiazolyl, benzisothiazolyl, benzopyrrolyl, benzofuranyl, benzothienyl.
The term "5-to 6-membered heterocycloalkyl" means a 5-to 6-membered cyclic group having one or more heteroatoms selected from nitrogen, oxygen or sulfur. May be selected from the following group (but not limited to): morpholinyl, tetrahydrofuranyl, thiazolyl, dioxanyl, and dioxanyl.
The term "benzo 5-6 membered heterocycloalkyl" refers to a group in which a 5-to 6-membered cyclic group having one or more heteroatoms selected from nitrogen, oxygen or sulfur is fused to a benzene ring. May be selected from the following group (but not limited to): benzodioxane, benzodioxolane.
The term "C 1 ～C 6 Alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. May be selected from the following group (but not limited to): methyl, ethyl, n-propyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The term "C 3 ～C 6 Cycloalkyl "refers to a cyclic group having 3 to 6 carbon atoms. May be selected from the following group (but not limited to): cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "C 5 ～C 7 Cycloalkyl "refers to a cyclic group having 5 to 7 carbon atoms. May be selected from the following group (but not limited to): cyclopentyl, cyclohexyl, cycloheptyl.
The term "C 1 ～C 3 Alkoxy "refers to a straight or branched chain alkoxy group having 1 to 3 carbon atoms. May be selected from the following group (but not limited to): methoxy, ethoxy, n-propoxy, isopropoxy.
The term "halogen" refers to fluorine, chlorine, bromine, iodine.
The term "halogenated" refers to fluoro, chloro, bromo, iodo.
The individual groups of the invention may be unsubstituted or substituted, by which is meant substituted by a substituent selected from the group consisting of: hydroxy, halogen, C 1 ～C 6 Alkyl, halogenated C 1 ～C 6 Alkyl, C 1 ～C 3 Alkoxy, halogenated C 1 ～C 3 Alkoxy, cyano, t-butylamino, -O- (CH) 2 ) n -O-; wherein n is an integer between 1 and 3. The substituents may be substituted at various positions on each group.
Drawings
FIG. 1 shows ASMS verification results for compounds I-1 and I-2 of example 3.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Synthesis of 2- (1- (5- (3- ((4-aminopiperidin-1-yl) methyl) -5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridin-1-yl) pentanoyl) -3-oxopiperazin-2-yl) -N-methylacetamide Compound (I-1)
50mL of dichloroethane solvent was added to the reaction flask, and 1 (2.0 g,8.89mmol,1.0 equiv) was weighed into the reaction flask. Then 2 (1.96 g,9.78mmol,1.1 eq.) and acetic acid (5.34 mg,88.8umol,5.08uL,0.01 eq.) were added in sequence, and finally sodium triacetate borohydride (9.42 g,44.4mmol,5.0 eq.) was added. The reaction was allowed to react at room temperature and checked by TLC for completion. After the reaction is completed, H is added 2 The reaction was quenched with O (10 ml). After quenching the reaction, ethyl acetate (20 mL. Times.2) was added for extraction, the organic phase solution was collected and taken up in Na 2 SO 4 And (5) drying. Filtering out Na 2 SO 4 After that, the organic solvent was spin-dried. Isolation using column chromatography separation techniques gave the final product 3 (white solid, 3.30g,7.74mmol,87.09% yield).
To the reaction flask was added 10mL of DMF solvent, and 3 (500 mg,1.22mmol,1.0 eq) and cesium carbonate (1.19 g,3.66mmol,3.0 eq) were weighed into the reaction flask. Then 4 (640 mg,1.83mmol,1.5 eq) was added. The reaction was allowed to react at 60℃and checked by TLC for completion. And after the reaction is finished, spin-drying the organic solvent to obtain a white solid crude product. The separation was performed using column chromatography separation techniques to give final product 5 (yellow liquid 320mg,463umol,37.89% yield).
Step 3 Synthesis of tert-butyl (1- ((5-bromo-1- (5- (2- (2- (2- (methylamino) -2-oxoethyl) -3-oxopiperazin-1-yl) -5-oxopentyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methylpiperidin-4-ylcarbamate 6)
5 (320 mg, 470 umol,1.0 eq) was added to a reaction flask containing methylamine (48.9 mg, 470 umol,15mL,1.0 eq). The reaction was allowed to react at 30℃for 4 hours, and the completion of the reaction was checked by TLC. After the reaction, the organic solvent was spin-dried. A mixture of final product 6 was obtained (320 mg,415umol,87.9% yield).
Synthesis of tert-butyl (1- ((5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (5- (2- (2- (methylamino) -2-oxoethyl) -3-oxapiperazin-1-yl) -5-oxopentyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) piperidin-4-ylcarbamate 8
To the reaction flask was added 4mL of dioxane, and 3 (200 mg, 302. Mu. Ol,1.0 eq) and 7 (106 mg, 457. Mu. Ol, 106. Mu.L, 1.5 eq) were weighed into the reaction flask. Then add H 2 O (1 mL), potassium carbonate (125 mg,906umol,3 eq) and palladium catalyst (48.0 mg,60.4umol,0.2 eq) were reacted at 80℃for 1.5 hours. The reaction was checked by TLC for completion. And after the reaction is finished, spin-drying the organic solvent to obtain a solid crude product. Then separating by column chromatography separation technique to obtain the final product 8 (yellow liquid, 160mg,197umol, 65.2%yieldd)
Step 5.Synthesis of 2- (1- (5- (3- ((4-aminopiperidin-1-yl) methyl) -5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridin-1-yl) pentanoyl) -3-oxopiperazin-2-yl) -N-methylacetamide I-1
To the reaction flask was added 8 (159 mg, 23)0umol,1.0 eq) and then HCl/ethyl acetate (4M, 1.15mL,20 eq) was added. The reaction was allowed to react at room temperature and checked by TLC for completion. After the reaction is completed, H is added 2 The reaction was quenched with O (15 ml). After quenching the reaction, CH is added 2 Cl 2 (20 mL. Times.2) extraction, collection of the organic phase solution, and Na 2 SO 4 And (5) drying. Filtering out Na 2 SO 4 After that, the organic solvent was spin-dried. Separation by reverse phase HPLC gave the final product I-1 (white solid, 37.6mg,59.11umol,25.68% yield,98.6% purity, hcl).
HNMR:δ8.45(s,1H),8.35-8.43(m,2H),8.28(br s,1H),7.99-8.08(m,1H),7.94(br d,J＝8.4Hz,1H),7.61(br s,1H),6.69(br d,J＝8.8Hz,1H),5.02(br t,J＝5.6Hz,0.5H),4.53(br d,J＝13.6Hz,0.5H),4.37(br s,2H),4.02-4.26(m,2H),3.86-4.02(m,0.5H),3.69(s,3H),3.46-3.65(m,1H),3.15-3.28(m,2H),3.08(br d,J＝13.2Hz,0.5H),2.32-2.85(m,10H),2.10(br s,2H),1.94(br s,2H),1.66-1.89(m,2H),1.41-1.63(m,2H).
Example 2
Synthesis of 2-isopropyl-N- (1- ((5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (5- (2- (2- (methylamino) -2-oxoethyl) -3-oxopiperazin-1-yl) -5-oxopentyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) piperidin-4-yl) isonicotinamide I-2
To a reaction flask containing 3ml of DCM were added I-1 (46.0 mg, 77.9. Mu.l, 1 eq) and 9 (19.3 mg, 117. Mu.l, 1.5 eq) followed by triethylamine (39.4 mg, 389. Mu.l, 54.2. Mu.l, 5.0 eq) and T3P (149 mg, 234. Mu.l, 139. Mu.l, 50% purity,3 eq). The reaction was allowed to react at room temperature and checked by TLC for completion. After the reaction is completed, H is added 2 The reaction was quenched with O (15 ml). After quenching the reaction, CH is added 2 Cl 2 (20 mL. Times.2) extraction, collection of the organic phase solution, and Na 2 SO 4 And (5) drying. Filtering out Na 2 SO 4 After that, the organic solvent was spin-dried. Separation by reverse phase HPLC gave the final product I-2 (white solid 3.3mg,4.45umol,5.71％yield,99.5％purity)。
EXAMPLE 3 ASMS and SPR verification examples of Compound I-1 and Compound I-2
3.1ASMS test method: compound I-1 and compound I-2 were incubated with equal amounts of BRD4-BD1 protein in buffer, respectively. After incubation, small molecules and impurities not bound to the protein are removed using SEC techniques. The remaining pooled molecular solution was collected. Meanwhile, a small molecule incubation system without adding protein is set for a control experiment. And taking a sample from the collected solution to test MS and molecular test results.
The ASMS detection results are shown in fig. 1. The ASMS results in FIG. 1 show that the peak time of the signal of both compound I-1 and compound I-2 can be found in the system after incubation with the protein, compared with the control group, and thus it can be confirmed that both compound I-1 and compound I-2 exhibit specific adsorption to BRD4-BD 1.
3.2 SPR test: BRD4-BD1 protein was immobilized on NTA sensor chip surface by Hits Tag, and GSK1324726 compound was used as positive control sample (K D 60.5 nM). The structure of GSK1324726 is shown below, as it has been demonstrated to inhibit BRD4-BD1 protein, and can be used as a positive control sample.
Structural formula of GSK1324726 compound
The results of testing both compounds I-1 and I-2 against positive compounds are shown in Table 1.
TABLE 1 SPR results for Compound I-1 and Compound I-2
As can be seen from Table 1, both I-1 and I-2 exhibit excellent binding ability, K D The values are 274nmol and 84.5nmol, respectively. This means that the compounds represented by the compounds I-1 and I-2 have the characteristic structuresHas good inhibitory activity on BRD4-BD1 protein.
In summary, the above embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, but any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (5)
1. An N-heteroindole compound shown in formula (I) or pharmaceutically acceptable salt thereof,
in formula I:
R 1 pyridinyl-carbonyl substituted with hydrogen or isopropyl;
R 2 methyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2- (1- (5- (3- ((4-aminopiperidin-1-yl) methyl) -5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrrole [2,3-b ] pyridin-1-yl) pentanoyl) -3-oxopiperazin-2-yl) -N-methylacetamide; or (b)
2-isopropyl-N- (1- ((5- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (5- (2- (2- (methylamino) -2-oxoethyl) -3-oxopiperazin-1-yl) -5-oxopentyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) methyl) piperidin-4-yl) isonicotinamide.
3. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of an inhibitor of BRD4-BD1 protein.
5. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention and alleviation of diseases mediated by BRD4-BD1 protein.
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