CN111518095A - Azaindole derivatives, and preparation method and application thereof - Google Patents

Azaindole derivatives, and preparation method and application thereof Download PDF

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CN111518095A
CN111518095A CN201910107786.XA CN201910107786A CN111518095A CN 111518095 A CN111518095 A CN 111518095A CN 201910107786 A CN201910107786 A CN 201910107786A CN 111518095 A CN111518095 A CN 111518095A
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carboxamide
adamantan
pyridine
pyrrolo
compound
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于丽芳
谢欣
李娇娇
计悦阳
王志龙
李静
杨帆
汤杰
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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East China Normal University
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Abstract

The invention belongs to the technical field of medicines, and discloses azaindole derivatives shown in a formula (I) and/or medicinal salts thereof and a preparation method thereof, wherein the azaindole derivatives comprise the following steps: carrying out amidation reaction on the compound of the formula (II) and amantadine to obtain a compound of a formula (III); compounds of formula (III) and halogenated R1Through nucleophilic substitution reaction, the compound of formula (I) is obtained. The invention discloses azaindole-2-formamide derivatives of formula (I) which are a pairThe cannabinoid 2receptor (CB2) has high selectivity, high affinity, and high activity, and can be used for preventing and treating multiple sclerosis, autoimmune diseases, osteoporosis, neurodegeneration, organ transplantation immunological rejection, and tumor.

Description

Azaindole derivatives, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to azaindole derivatives and physiologically acceptable salts thereof, and a preparation method and application thereof, wherein the azaindole derivatives and the physiologically acceptable salts thereof can be used as selective cannabinoid 2-type receptor agonists and can be used for preparing medicines for preventing and/or treating related diseases mediated by cannabinoid 2-type receptors.
Background
The endocannabinoid system (ECS) is composed of phytocannabinoids such as trans- Δ 9-tetrahydrocannabinol (Δ 9-THC), cannabinoid ligands such as arachidonoyl glycolyl (Anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), cannabinoid receptors, and complex enzymes and transporters involved in ligand synthesis and degradation, and is involved in the regulation of a variety of physiological processes. In the Central Nervous System (CNS), these processes include regulation of appetite, pain sensation, mood and memory, in peripheral tissues including bone formation, spermatogenesis, sebum production, etc., and very important immune functions.
At present, two Cannabinoid receptor subtypes are identified and characterized, namely a Cannabinoid type 1receptor (CB 1) and a Cannabinoid type 2receptor (CB2), which belong to a large family of G protein coupled receptors and have a characteristic 7-order alpha helix transmembrane structure. The human CB 1receptor consists of 472 amino acids, and is mainly expressed in the central nervous system; the CB 2receptor consists of 360 amino acids and is mainly distributed in peripheral tissues, especially in immune tissues such as the splenic marginal zone, thymus, tonsil, B and T cells, macrophages, etc., and is mainly involved in the regulation of immune function (Di Marzo, v.et al. the endenocanbinding systems therapy administration, nat. rev. drug decov, 2004,3, 771-.
ECS is widely expressed in humans, including the innate and adaptive immune systems, which act as a steady-state "gatekeeper" of the immune system, preventing the onset of pathological immune responses. Research shows that endocannabinoids and several phytocannabinoid ligands exert important influence on immune function, so that inflammation, autoimmunity, tumor resistance, immune rejection prevention after solid organ transplantation, anti-pathogen immune response and the like are regulated.
In preventing acute and chronic rejection after solid organ transplantation, and in avoiding Graft Versus Host Disease (GVHD) after bone marrow transplantation, cannabinoid ligands are potential candidates for improving transplantation therapeutic regimens due to their superior anti-inflammatory effects, and there is a variety of evidence supporting the up-regulation of cannabinoid signaling to aid organ transplantation. Recent findings indicate that cardiac allograft rejection is accelerated in CB 2-/-mice compared to wild type recipients. In bone marrow-derived dendritic cells (BM-DC) of CB 2-/-mice, where Lipopolysaccharide (LPS) or CpG activates Toll-like receptors (TLRs), the secretion of the proinflammatory cytokines Interleukin (IL) -1 β, IL-6 and tumor necrosis factor and transforming growth factor- β 1 is increased. Furthermore, in CB2-/-BM-DC, Th1/Th17 promoted secretion of IL-12 and IL-23 cytokines was also increased, and the ability of KO mouse CD4+ T cells to differentiate into Interferon (IFN) - γ -or IL-17-effector cells was enhanced. Together, the above studies indicate that CB2 may be a potential clinical therapeutic target in graft-versus-host responses (Ol. sup. h A, Szekanechz, B. mu.r, T. targeting Cannabindioid signalling in the Immune System, "High" -ly inducing Questions, Possiblilities, and dChalenges [ J ]. Frontiers in Immunology,2017, 8).
Also, dysregulation of ECS plays an important role in autoimmune diseases. Missense Arg → Trp (R620W) polymorphism of the endocannabinoid synthase PTPN22 (encoding a lymphoprotein tyrosine phosphatase (LYP) which plays an important role in negatively regulating T lymphocyte activation) was found to be associated with increased risk of type 1 diabetes (T1DM), Rheumatoid Arthritis (RA), juvenile idiopathic arthritis, systemic lupus erythematosus, grignard disease, myasthenia gravis, systemic vitiligo and polymyositis granuloma. Furthermore, the common dinucleotide polymorphism of CB2 (leading to Gln → Arg substitution (Q63R), with a concomitant decrease in the ability of CB 2-mediated signaling to suppress T cell proliferation) is associated with an increased risk of celiac disease and immune thrombocytopenia. In addition to the above autoimmune diseases, cannabinoid receptors have been most extensively studied in Multiple Sclerosis (MS). The increased level of AEA in peripheral lymphocytes of MS patients compared to healthy individuals indicates a complex disorder in ECS of MS patients, and it has been reported that CB 2receptor is up-regulated in EAE (experimental autoimmune encephalomyelitis, an animal model with many similarities to MS) mice, and activated microglia and pathogenic T cells contribute to an increase in expression of CB2R, so CB 2receptor becomes a very important therapeutic target for autoimmune diseases, particularly multiple sclerosis (Ol a h A, Szekanecz, B ir t.targetting Cannabinoid in the imaging System, "High" -ly exciting questions, Possibilites, and scales [ J ]. Frontiers in Immunology,2017, 8).
Taken together, cannabinoid receptors are potential therapeutic targets for a variety of diseases, however they also face a number of challenges, such as potential mental and cardiac side effects, tolerance and dependence due to activation of CB1, and possible memory impairment due to activation of CB 1. In addition, antagonism/inverse agonism of CB1 located in the central nervous system may also lead to serious neuropsychiatric side effects such as memory decline, depression, decreased motor coordination, and the like. For example rimonabant, a CB 1receptor antagonist, marketed in europe in 2006, is used to treat obesity, but rapidly exits the market because it may cause side effects such as depression, anxiety, etc. In contrast, CB2 is mainly distributed in the peripheral system, avoiding this serious central nervous side effect, and is a promising target for pharmaceutical use due to its high safety.
At present, the research of the CB2 selective ligand is more focused on preclinical and clinical research stages, and no drug is on the market. In addition, CB 2receptor agonists generally have limited water solubility, which is an important factor in compound absorption, penetration, and oral bioavailability. Therefore, the CB2 ligand with high activity, high selectivity and better water solubility is found to have important significance for developing medicaments and treating related diseases.
Disclosure of Invention
The invention aims to provide a CB 2receptor ligand compound which has a novel structure and better activity. The invention obtains a series of CB 2receptor ligands with high activity, high selectivity and good water solubility by reasonable drug design, structural biology and molecular biology methods, taking the CB 2receptor ligands with higher affinity and high selectivity as target compounds, carrying out structural optimization aiming at the pharmacological action and water solubility of the compounds, and performing a kinetic water solubility test and a biological activity test of the compounds. The invention also provides a preparation method of the novel azaindole derivative shown in the general formula (I).
The azaindole derivatives and the pharmaceutically acceptable salts thereof provided by the invention have the structures shown as the following formulas (I) A and (I) B:
Figure BDA0001967117190000031
wherein n is more than or equal to 0;
R1selected from hydrogen, alkyl, six-membered heterocycle substituted by linear chain or branched alkyl, polyfluoro substituted linear chain or branched alkyl, hydroxyl, aldehyde group, tosyl, alkoxy substituted by linear chain or branched alkyl, ethoxy;
Z1、Z2、Z3and Z4Where one represents an N atom, the other 3 carbon atoms are simultaneously substituted by hydrogen.
Preferably, n is greater than or equal to 0;
R1selected from hydrogen, C1-C10 alkanesThe compound is characterized by comprising the following components in percentage by weight, six-membered heterocyclic rings substituted by C1-C10 straight chain or branched chain alkyl, C1-C10 straight chain or branched chain alkyl substituted by monofluorine, C1-C10 straight chain or branched chain alkyl substituted by difluoro, hydroxyl, C1-C10 fatty aldehyde group, p-toluenesulfonyl, alkoxy substituted by C1-C10 straight chain or branched chain alkyl, and ethoxy;
Z1、Z2、Z3and Z4Where one represents an N atom, the other 3 carbon atoms are simultaneously substituted by hydrogen.
Further preferably, 0. ltoreq. n.ltoreq.12;
R1selected from hydrogen, C1-C6 alkyl, C1-C10 straight chain or branched chain alkyl substituted six-membered nitrogen-oxygen heterocyclic ring, monofluorine substituted C1-C10 straight chain or branched chain alkyl, difluoro substituted C1-C10 straight chain or branched chain alkyl, hydroxyl, propyl, n-butyl, isobutyl, amyl, hexyl, p-toluenesulfonyl, C1-C10 straight chain or branched chain alkyl substituted alkoxy, ethoxy;
Z1、Z2、Z3and Z4Where one represents an N atom, the other 3 carbon atoms are simultaneously substituted by hydrogen.
Further preferably, n is 0.
R1Selected from H,
Figure BDA0001967117190000041
Figure BDA0001967117190000042
Z1、Z2、Z3And Z4Where one represents an N atom, the other 3 carbon atoms are simultaneously substituted by hydrogen.
Further preferably, the azaindole derivative represented by formula (I) of the present invention is selected from the following compounds (1) to (38):
(1) n- (adamantan-1-yl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
(2) 1-pentyl-1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
(3) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide
(4) N- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide
(5) N- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
(6) n- (adamantan-1-yl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
(7) 1-pentyl-1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
(8) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide
(9) N- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide
(10) N- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
(11) n- (adamantan-1-yl) -1- (2- (ethoxyethoxy) ethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide
(12) N- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
(13) n- (adamantan-1-yl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
(14) n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
(15) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide
(16) N- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide
(17) N- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
(18) n- (adamantan-1-yl) -1H-benzo [ d ] imidazole-2-carboxamide;
(19) n- (adamantan-1-yl) -1-pentyl-1H-benzo [ d ] imidazole-2-carboxamide;
(20) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-benzo [ d ] imidazole-2-carboxamide
(21) N- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] imidazole-2-carboxamide
(22) N- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
(23) n- (adamantan-1-yl) -1- (2- (ethoxyethoxy) ethyl) -1H-benzo [ d ] imidazole-2-carboxamide
(24) N- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
(25) n- (adamantan-1-yl) -1- (5-oxopentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
(26) n- (adamantan-1-yl) -1- (5, 5-difluoropentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
(27) n- (adamantan-1-yl) -1H-pyrrolo [3,2-B ] pyridine-3-carboxamide;
(28) 1-pentyl-1H-pyrrolo [3,2-B ] pyridine-3-carboxamide;
(29) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-B ] pyridine-3-carboxamide;
(30) n- (adamantan-1-yl) -1H-pyrrolo [3,2-C ] pyridine-3-carboxamide;
(31) 1-pentyl-1H-pyrrolo [3,2-C ] pyridine-3-carboxamide;
(32) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-C ] pyridine-3-carboxamide;
(33) n- (adamantan-1-yl) -1H-pyrrolo [2,3-B ] pyridine-3-carboxamide;
(34) 1-pentyl-1H-pyrrolo [2,3-B ] pyridine-3-carboxamide;
(35) n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [2,3-B ] pyridine-3-carboxamide;
(36) n- (adamantan-1-yl) -1H-indazole-3-carboxamide;
(37) 1-pentyl-1H-indazole-3-carboxamide, N- (adamantan-1-yl) -amide;
(38) 1- (2-morpholinoethyl) -N- (adamantan-1-yl) -1H-indazole-3-carboxamide;
and pharmaceutically acceptable salts of the above specific compounds.
In the invention, the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulfate, hydrosulfate, phosphate, dihydrogen phosphate, methanesulfonate, monomethyl sulfate, cis-butenedioate, trans-butenedioate, succinate, ascorbate, lactate, tartrate, acetate, oxalate, malonate, glycolate, naphthalene-2-sulfonate, gluconate, citrate, isethionate, p-toluenesulfonate, 3, 5-dimethylbenzyl sulfonate or quaternary ammonium salt formed with halogenated alkane, wherein the halogenated alkane is fluorine, chlorine, bromine or iodoalkane.
The invention also provides a synthesis method of the azaindole derivative shown in the formula (I), wherein the azaindole derivative has a structure shown in the formula (I) (including the formula (IA) and the formula (IB));
the reaction synthesis route is shown as the following reaction formula (A):
Figure BDA0001967117190000061
wherein, in the reaction formula (A), the definition of each group is the same as that of the formula (I).
The synthesis reaction comprises the following steps:
(1) in a solvent, carrying out amidation reaction on a compound of a formula (II) A or (II) B and amantadine under the action of a condensing agent to synthesize a compound (III) A or (III) B;
(2) a compound of formula (III) A or (III) B with a halo R in a solvent with a base as catalyst1(X-R1) Carrying out nucleophilic substitution reaction to obtain azaindole-2-formamide or azaindole-3-formamide derivatives shown in formula (I), wherein X is halogen;
in the step (1), the solvent is one or more selected from diethyl ether, dichloromethane, tetrahydrofuran, N' -dimethylformamide, chloroform, acetonitrile, toluene, acetone and the like; preferably, dichloromethane.
In the step (1), the ratio of the amounts of the compound of formula (II) A or (II) B, amantadine and condensing agent is 1-3: 1-3: 1-3; preferably, 1: 1.2: 2.
in the step (1), the temperature of the amidation reaction is 0-50 ℃; preferably, it is room temperature 25 ℃.
In the step (1), the amidation reaction time is 1-24 h; preferably, it is 5 h.
In the step (1), the condensing agent is selected from one or more of oxalyl chloride, DMF, dicyclohexylcarbodiimide, HBTU, HATU, diisopropylcarbodiimide, EDCI, HCTU, PyBOP and the like; preferably, DMF and oxalyl chloride.
In the step (2), the solvent is selected from one or more aprotic solvents such as benzene, acetonitrile, diethyl ether, N' -dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, N-methylpyrrolidone and the like; preferably, anhydrous N, N' -dimethylformamide or anhydrous tetrahydrofuran.
In the step (2), the compound of formula (III) A or (III) B, X-R1The ratio of the amount of the alkali substances is 1-3: 1-3: 1-3; preferably, 1: 1.5: 2. x is halogen; preferably, it is Cl or Br.
In the step (2), the temperature of the nucleophilic substitution reaction is 25-130 ℃; preferably, it is 100 ℃.
In the step (2), the time of the nucleophilic substitution reaction is 1-12 h; preferably, it is 3 h.
In the step (2), the alkali is used for enabling a substrate to generate nitrogen negative ions, and can be one or more of potassium carbonate, potassium tert-butoxide, NaH, cesium carbonate, tripotassium phosphate, sodium carbonate, lithium hydroxide, sodium bicarbonate, sodium methoxide and the like; preferably, it is NaH.
The invention also provides application of the azaindole derivative shown in the formula (I) and pharmaceutically acceptable salts thereof in preparation of a selective CB 2receptor agonist.
The invention also provides an application of the azaindole derivative shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing a medicament for preventing and/or treating diseases related to a CB 2receptor, wherein the azaindole derivative shown in the formula (I) takes a CB 2receptor as a target point, so that the treatment of the related diseases is realized.
Wherein the disease includes multiple sclerosis, autoimmune diseases, neurodegenerative diseases, osteoporosis, cancer, inflammation, acquired immune syndrome, atherosclerosis, glaucoma, rheumatic diseases, allergy, pain, Alzheimer's disease, Parkinson's disease, Huntington's disease, obesity, etc.
The autoimmune diseases include type 1 diabetes, rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, myasthenia gravis, vitiligo widely, polyangiitis granuloma, autoimmune myocarditis, ulcerative colitis, Crohn's disease, scleroderma, systemic vasculitis, dermatomyositis, ulcerative colitis, thyroid autoimmune diseases, demyelinating diseases, multiple sclerosis, etc.
The cancer includes malignant melanoma of skin, basal cell carcinoma, squamous cell carcinoma, breast cancer, colon cancer, liver cancer, glioma, prostate cancer, lung cancer, endometrial cancer, etc.
The invention also provides application of the azaindole derivatives shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing anti-tumor medicaments.
Wherein, the anti-tumor means inhibiting proliferation, growth, migration and infiltration of tumor cells and promoting apoptosis of the tumor cells.
Wherein the tumor comprises malignant melanoma of skin, basal cell carcinoma, squamous cell carcinoma, breast cancer, colon cancer, liver cancer, glioma, prostatic cancer, lung cancer, endometrial cancer, etc.
The invention also provides a pharmaceutical composition, which comprises the azaindole derivative shown as the formula (I) and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Wherein, the pharmaceutical composition can be prepared into tablets, capsules, pills, coated tablets, granules, solutions, syrups, emulsions, suspensions, aerosols, powders, solutions and the like.
The azaindole derivative shown in the formula (I) and the pharmaceutically acceptable salt thereof have high agonistic activity, high selectivity and good water solubility on a CB2 receptor. The preparation method has the advantages of simple synthetic route, mild reaction conditions, environmental friendliness, cheap and easily-obtained raw materials and high reaction yield. The target compound prepared by the amide condensation and nucleophilic substitution reaction of the preparation method can be used as a CB 2receptor ligand, is used for preventing and/or treating diseases related to a CB 2receptor, and has a good application prospect.
Drawings
FIG. 1 is a graph of the effect of compounds 36(JYY-3-81) and 39(SY-2-47) on Con A-stimulated splenocyte proliferative responses in vitro, wherein panel A shows splenocytes from C57BL/6 mice (5X 105) co-cultured with different concentrations (0.1,1 and 10. mu.M) of compound 36(JYY-3-81), compound 19(JYY-3-103), compound 35(LSD-1-5) in the absence or presence of 5. mu.g/mL Con A for 72 h. Each concentration was tested three times, and the mean value ± SEM was taken; panel B shows spleen cells from C57BL/6 mice (5X 105) co-cultured with different concentrations (5,10 and 20. mu.M) of Compound 36(JYY-3-81), Compound 39(SY-2-47) in the absence or presence of 5. mu.g/mLCon A for 72 h. Each concentration was tested three times, and the mean value ± SEM was taken; panel C shows spleen cells from C57BL/6 mice (5X 105) co-cultured with different concentrations of the selective agonists CP55940(2.5,5 and 10. mu.M), JWH-015(5, 10 and 20. mu.M) for 72h in the absence or presence of 5. mu.g/mL Con A. Each concentration was tested in triplicate and the mean ± SEM taken.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, and procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. The starting materials used in the following examples are all commercially available analytical chemicals.
Example 1: n- (adamantan-1-yl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide (1)
1H-pyrrole [3,2-B]Pyridine-2-carboxylic acid (800mg, 5.0mmol) was placed in a 50mL two-necked flask, dissolved in 10mL dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), replaced with nitrogen, stirred at room temperature for 1 hour, the system was dried, the above system, amantadine (899mg, 5.9mmol), and triethylamine (2g, 19.8mmol) were added to 15mL dichloromethane, stirred at room temperature for 8 hours, and the reaction was checked by TLCAfter completion of the reaction, the system was dried and purified by silica gel chromatography (dichloromethane) to obtain 1.1g (77%) of compound (1) as a white solid.1H NMR(400MHz,DMSO-d6)11.69(s,1H),8.37(s,1H),7.84–7.70(m,2H),7.32(s,1H),7.25–7.09(m,1H),2.18–2.01(m,9H),1.68(brs,6H).13C NMR(101MHz,DMSO-d6)160.0,145.1,143.6,135.0,129.1,119.4,118.1,102.7,51.7,40.9,36.0,28.9.
Example 2: n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [3,2-B ] pyridine-2-carboxamide (2)
Compound (1) (120mg,0.4mmol) was placed in a 25mL single neck flask, dissolved in 5mL anhydrous N-N' -dimethylformamide, NaH (32mg, 0.6mmol) was added, the reaction was stirred at room temperature for 30 minutes, 1-bromopentane was further added, the reaction was stirred at room temperature for 3 hours, the reaction was detected by TLC, after the completion of the reaction, 20mL water was added to quench the reaction, followed by extraction with ethyl acetate (25mL × 3), the organic layers were combined, water (25mL × 3), washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the organic phase was spin-dried under reduced pressure, and the compound (2) was purified by silica gel column chromatography (dichloromethane) to give 100mg (68%) of a yellow solid.1H NMR(400MHz,CDCl3)8.23(d,J＝7.8Hz,1H),7.69(d,J＝6.0Hz,1H),7.60(brs,1H),7.09(s,1H),7.08–7.03(m,1H),4.42(t,J＝7.4Hz,2H),2.24–2.12(m,9H),2.08–2.01(m,2H),1.78–1.68(m,8H),1.36–1.33(m,2H),0.89(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)163.6,155.4,143.7,140.1,131.2,129.8,111.8,92.9,57.4,51.9,41.6,36.5,29.6,28.9,28.8,22.2,13.8.
Example 3: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide (3)
Compound (3) was prepared in the same manner as Compound (2) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give 122mg (60%) of Compound (3) as a yellow solid.1H NMR(400MHz,CDCl3)8.22(d,J＝7.2Hz,1H),7.75(d,J＝5.0Hz,1H),7.57(brs,1H),7.13–6.97(m,2H),4.50(t,J＝4.9Hz,2H),3.73–3.56(m,4H),2.94(t,J＝4.9Hz,2H),2.52–2.40(m,4H),2.24–2.10(m,9H),1.78–1.69(m,6H).13C NMR(101MHz,CDCl3)162.7,154.6,142.7,138.9,131.2,129.1,110.4,91.4,65.8,55.3,53.3,52.6,50.8,40.6,35.5,28.5.
Example 4: n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide (4)
Compound (4) was prepared in the same manner as in the preparation of compound (2) except that 2-bromoethyl ether (76mg, 0.5mmol) was used in place of 1-bromopentane to give compound (4) as a yellow solid, 97mg (53%).1H NMR(400MHz,Chloroform-d)8.28(d,J＝7.7Hz,1H),7.85(d,J＝5.8Hz,1H),7.76(s,1H),7.11-7.06(m,2H),4.64–4.51(m,2H),3.91–3.80(m,2H),3.32(q,J＝6.9Hz,2H),2.19-2.04(m,9H),1.71-1.60(m,6H),1.00(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)161.1,151.7,140.2,137.9,133.1,129.1,111.8,92.8,65.9,65.8,56.2,51.4,40.4,35.5,28.5,13.8.
Example 5: n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide (5)
The production method of compound (5) was the same as that of compound (2) except that 1-bromopentane was replaced with 1-bromo-5-fluoropentane (87mg, 0.4mmol), to give compound (5) as a white solid, 48mg (47%).1H NMR(400MHz,CDCl3)8.24(d,J＝7.8Hz,1H),7.71(d,J＝5.8Hz,1H),7.62(s,1H),7.09-7.05(m,2H),4.51-4.45(m,3H),4.37(t,J＝5.6Hz,1H),2.25-2.05(m,11H),1.80-1.65(m,8H),1.54–1.45(m,2H).13C NMR(101MHz,CDCl3)163.5,155.5,143.6,139.9,131.4,129.9,111.9,92.8,84.3,82.7,57.2,51.9,41.6,36.5,29.9,29.7,29.5,28.7,22.8,22.8.
Example 6: n- (adamantan-1-yl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (6)
1H-pyrrole [3,2-C]Pyridine-2-carboxylic acid (800mg, 5.0mmol) was placed in a 50mL two-necked flask, dissolved in 10mL dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), nitrogen was replaced, stirred at room temperature for 1 hour, the system was dried, the above system, amantadine (899mg, 5.9mmol), triethylamine (2g, 19.8mmol) were added to 15mL dichloromethane, stirred at room temperature for 8 hours, the reaction was checked by TLC, after the reaction was completed, the system was dried, and purified by silica gel chromatography (dichloro-N-dimethylformamide)Methane) to give compound (6)1.1g (77%) of a white solid.1H NMR(400MHz,DMSO-d6)8.90(s,1H),8.20(d,J＝5.7Hz,1H),7.76(s,1H),7.36(d,J＝5.6Hz,1H),7.32(s,1H),2.14–2.05(m,9H),1.67(brs,6H).13C NMR(101MHz,DMSO-d6)159.9,144.7,141.4,139.2,133.8,124.4,107.2,101.9,51.7,40.9,36.0,28.9.
Example 7: n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (7)
Compound (6) (120mg,0.4mmol) was placed in a 25mL single neck flask, dissolved in 5mL of anhydrous N-N' -dimethylformamide, NaH (32mg, 0.6mmol) was added, the reaction was stirred at room temperature for 30 minutes, 1-bromopentane was further added, the reaction was stirred at room temperature for 3 hours, the reaction was detected by TLC, after the completion of the reaction, 20mL of water was added to quench the reaction, followed by extraction with ethyl acetate (25mL × 3), the organic layers were combined, water (25mL × 3), washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the organic phase was spin-dried under reduced pressure, and the compound (7) was purified by silica gel column chromatography (dichloromethane) to give 100mg (68%) of a white solid.1H NMR(400MHz,CDCl3)8.42(s,1H),7.74–7.61(m,2H),7.54(d,J＝4.9Hz,1H),7.38(s,1H),4.27(t,J＝6.8Hz,2H),2.26–2.09(m,9H),2.02–1.90(m,2H),1.81–1.67(m,6H),1.39–1.25(m,4H),0.90(t,J＝6.7Hz,3H).13C NMR(101MHz,MeOD)163.7,147.7,147.3,139.7,133.1,128.1,113.3,105.7,61.0,53.5,42.4,37.5,32.4,31.0,29.5,23.3,14.2.
Example 8: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (8)
The production method of the compound (8) was the same as that of the compound (7) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give 106mg (52%) of the compound (8) as a yellow solid.1H NMR(400MHz,CDCl3)8.55(s,1H),7.77–7.67(m,2H),7.64(d,J＝6.7Hz,1H),7.33(s,1H),4.41(t,J＝5.0Hz,2H),3.67–3.54(m,4H),2.83(t,J＝5.3Hz,2H),2.51–2.41(m,4H),2.21–2.00(m,9H),1.71–1.60(m,6H).13C NMR(101MHz,CDCl3)162.1,150.0,147.0,136.4,129.8,127.1,113.1,104.8,66.8,58.9,56.9,53.6,52.3,41.6,36.5,29.5.
Example 9: n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (9)
The production method of compound (9) was identical to that of compound (7) except that 2-bromoethyl ether (76mg, 0.5mmol) was used instead of 1-bromopentane to give compound (9) as a yellow solid 97mg (53%).1H NMR(400MHz,CDCl3)8.41(s,1H),7.66–7.52(m,3H),7.37(s,1H),4.38(t,J＝4.7Hz,2H),3.80(t,J＝4.7Hz,2H),3.42(q,J＝7.0Hz,2H),2.27-2.09(m,9H),1.78-1.67(m,6H),1.10(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)163.5,152.8,148.9,135.5,128.5,128.2,113.7,104.3,69.3,67.1,59.4,51.8,41.6,36.51,29.6,14.9.
Example 10: n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (10)
The production method of compound (10) was the same as that of compound (7) except that 1-bromopentane was replaced with 1-bromo-5-fluoropentane (87mg, 0.4mmol), to give compound (10) as a white solid, 48mg (47%).1H NMR(400MHz,CDCl3)8.32(s,1H),7.60(d,J＝6.9Hz,1H),7.55(s,1H),7.44(d,J＝6.8Hz,1H),7.35(s,1H),4.48(t,J＝5.6Hz,1H),4.36(t,J＝5.6Hz,1H),4.23(t,J＝7.2Hz,2H),2.22-2.08(m,9H),2.04–1.94(m,2H),1.76–1.67(m,8H),1.50–1.42(m,2H).13C NMR(101MHz,CDCl3)163.3,152.7,148.6,134.8,128.3,128.0,114.0,104.3,84.3,82.7,59.5,51.9,41.6,36.5,31.3,29.8,29.6,29.5,22.5,22.5.
Example 11: n- (adamantan-1-yl) -1- (2- (ethoxyethoxy) ethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (11)
Compound (11) was prepared in the same manner as compound (7) except that 2- (2-ethoxyethoxy) ethyl bromide (98mg, 0.5mmol) was used in place of 1-bromopentane to give compound (11) as a yellow solid, 105mg (53%).1HNMR(400MHz,CDCl3)8.45(s,1H),7.62-7.56(d,J＝13.0Hz,3H),7.33(s,1H),4.45–4.36(m,2H),3.93–3.84(m,2H),3.56-3.52(m,2H),3.50–3.35(m,4H),2.24-2.10(m,9H),1.78-1.68(m,6H),1.15(t,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)163.5,152.5,148.8,135.8,128.7,128.1,113.6,104.3,70.9,70.1,69.7,66.7,59.1,51.8,41.6,36.5,29.5,15.1.
Example 12: n- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (12)
Step (12a) -preparation of N- (adamantan-1-yl) -1- (5- ((tert-butyldimethylsilyl) oxy) pentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (12 a): compound (12a) was prepared in the same manner as in (7) except that ((5-bromopentyl) oxy) (tert-butyl) dimethylsilane (99mg, 0.4mmol) was used in place of 1-bromopentane to give compound 12a as a white solid, 41mg (47.6%).
Step (12b) -N- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-pyrrole [3,2-C]Preparation of pyridine-2-carboxamide (12): compound (12a) (41mg, 0.1mmol) was added to 3mL of tetrahydrofuran solvent, tetrabutylammonium fluoride (39mg,0.1mmol) was further added thereto, the mixture was stirred overnight, the reaction system was spun dry, and purified by silica gel column chromatography (dichloromethane), whereby compound (12) was obtained as a pale yellow solid (29 mg, 93%).1H NMR(400MHz,MeOD)9.38(s,1H),8.48(d,J＝6.8Hz,1H),7.92(d,J＝6.9Hz,1H),7.61(s,1H),4.61(t,J＝7.4Hz,2H),3.56(t,J＝6.1Hz,2H),2.22-2.12(m,9H),2.09–2.00(m,2H),1.80-1.76(m,6H),1.64–1.57(m,2H),1.47–1.39(m,2H).13C NMR(101MHz,MeOD)160.4,142.6,142.1,141.1,136.6,126.6,111.6,105.7,62.4,61.8,54.2,42.2,37.5,32.9,32.4,31.0,23.7.
Example 13: n- (adamantan-1-yl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide (13)
1H-pyrrole [2,3-B]Pyridine-2-carboxylic acid (800mg, 4.9mmol) was placed in a 50mL two-necked flask, dissolved in 10mL of dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), nitrogen was replaced, and the mixture was stirred at room temperature for 1 hour, and the system was dried by spin-drying, and the above system, amantadine (899mg, 5.9mmol), and triethylamine (2g, 19.8mmol) were added to 15mL of dichloromethane, and stirred at room temperature for 8 hours, and the reaction was detected by TLC, and after the reaction was completed, the system was dried by spin-drying and purified by silica gel chromatography (dichloromethane), to obtain 1.1g (77%) of compound (13) as a white solid.1H NMR(400MHz,DMSO-d6)12.10(s,1H),8.31(d,J＝3.9Hz,1H),8.03(d,J＝7.7Hz,1H),7.73(s,1H),7.15–7.06(m,2H),2.19–2.04(m,9H),1.67(brs,6H).13C NMR(101MHz,DMSO-d6)159.7,148.2,145.0,133.1,129.7,119.2,116.2,102.3,51.7,40.9,36.0,28.9.
Example 14: n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [2,3-B ] pyridine-2-carboxamide (14)
Compound (13) (120mg,0.4mmol) was placed in a 25mL single neck flask, dissolved in 5mL anhydrous N-N' -dimethylformamide, NaH (32mg, 0.6mmol) was added, the reaction was stirred at room temperature for 30 minutes, 1-bromopentane was further added, the reaction was stirred at room temperature for 3 hours, the reaction was detected by TLC, after completion of the reaction, 20mL water was added to quench the reaction, followed by extraction with ethyl acetate (25mL × 3), the organic layers were combined, water (25mL × 3), washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried under reduced pressure, and the mixture was subjected to silica gel column chromatography (dichloromethane) to obtain 100mg (68%) of compound (14) as a white solid.1H NMR(400MHz,CDCl3)8.41(d,J＝4.0Hz,1H),7.90(d,J＝7.7Hz,1H),7.07(dd,J＝7.7,4.7Hz,1H),6.66(s,1H),5.89(s,1H),4.68(t,J＝7.3Hz,2H),2.14(brs,9H),1.82–1.69(m,8H),1.37–1.23(m,4H),0.86(t,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)161.7,148.6,145.1,133.8,129.6,118.7,116.6,100.9,52.6,42.9,41.7,36.3,30.5,29.5,29.0,22.5,14.0.
Example 15: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide (15)
Compound (15) was prepared in the same manner as compound (14) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give compound (15) as a white solid, 98mg (48%).1H NMR(400MHz,CDCl3)8.18(d,J＝7.3Hz,1H),7.77(d,J＝5.8Hz,1H),7.49(s,1H),6.87(t,J＝6.5Hz,1H),4.75(t,J＝5.5Hz,2H),3.73–3.61(m,4H),2.97(t,J＝5.8Hz,2H),2.61–2.51(m,4H),2.23–2.11(m,9H),1.80–1.68(m,6H).13C NMR(101MHz,CDCl3)163.9,149.4,147.1,133.5,132.0,130.7,109.5,102.7,66.9,57.3,53.7,51.4,49.8,41.7,36.5,29.6.
Example 16: n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide (16)
Compound (16) is produced in the same manner as compound (14) except that 2-bromoethyl ether (76mg, 0.5mmol) is used in place of 1-bromopentane to give 97.3mg (53%) of (16) as a yellow solid.1H NMR(400MHz,CDCl3)8.19(d,J＝7.4Hz,1H),7.85(d,J＝6.0Hz,1H),7.46(s,1H),7.28(s,1H),6.87(t,J＝6.7Hz,1H),4.92–4.76(m,2H),3.95(t,J＝4.8Hz,2H),3.45(q,J＝7.0Hz,2H),2.21-2.13(m,9H),1.77-1.69(m,6H),1.13(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)164.0,149.4,133.7,132.8,132.8,130.7,109.3,102.9,68.1,66.7,52.8,51.5,41.7,36.5,29.6,15.0.
Example 17: n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide (17)
Compound (17) was prepared in the same manner as compound (14) except that 1-bromopentane was replaced with 1-bromo-5-fluoropentane (87mg, 0.4mmol), to give compound (17) as a white solid, 48mg (47%).1H NMR(400MHz,CDCl3)8.20(d,J＝7.2Hz,1H),7.73(s,1H),7.61(s,1H),7.27(s,1H),6.93(s,1H),4.72(s,2H),4.52(t,J＝5.7Hz,1H),4.41(t,J＝5.5Hz,1H),2.25-2.20(m,6H),2.15-2.10(m,5H),1.79-1.68(m,8H),1.58-1.50(m,2H).13C NMR(101MHz,CDCl3)164.0,149.7,147.3,133.3,131.0,131.0,109.7,102.7,84.5,82.9,52.9,51.5,41.7,36.5,29.9,29.7,29.6,29.2,22.6,22.5.
Example 18: n- (adamantan-1-yl) -1H-benzo [ d ] imidazole-2-carboxamide (18)
1H-benzo [ d ]]Imidazole-2-carboxylic acid (800mg, 5.0mmol) was placed in a 50mL two-necked flask, dissolved in 10mL of dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), nitrogen was replaced, and the mixture was stirred at room temperature for 1 hour, and the system was dried by spin-drying, and the above system, amantadine (899mg, 5.9mmol), and triethylamine (2g, 19.8mmol) were added to 15mL of dichloromethane, and stirred at room temperature for 8 hours, and the reaction was detected by TLC, and after the reaction was completed, the system was dried by spin-drying, and purified by silica gel chromatography (dichloromethane), to obtain 0.8g (52%) of compound (18) as a white solid.1H NMR(400MHz,DMSO-d6)13.16(s,1H),7.74(s,1H),7.71(d,J＝7.6Hz,1H),7.53(d,J＝7.5Hz,1H),7.36–7.20(m,2H),2.19–2.06(m,9H),1.68(brs,6H).13C NMR(101MHz,DMSO-d6)157.7,146.2,142.3,134.5,124.0,122.5,119.8,112.5,51.6,40.8,35.9,28.8.
Example 19: n- (adamantan-1-yl) -1-pentyl-1H-benzo [ d ] imidazole-2-carboxamide (19)
Compound (18) (120mg,0.4mmol) was placed in a 25mL single-necked flask, dissolved in 5mL of anhydrous N-N' -dimethylformamide, NaH (32mg, 0.6mmol) was added, the reaction was stirred at room temperature for 30 minutes, 1-bromopentane was further added, the reaction was stirred at room temperature for 3 hours, the reaction was detected by TLC, after completion of the reaction, 20mL of water was added to quench the reaction, followed by extraction with ethyl acetate (25mL × 3), the organic layers were combined, water (25mL × 3), a saturated saline solution was washed, the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried under reduced pressure, and purification by silica gel column chromatography (dichloromethane) gave compound (19) as a white solid (73 mg (50%).1H NMR(400MHz,CDCl3)7.75(d,J＝7.2Hz,1H),7.52(s,1H),7.41(d,J＝7.1Hz,1H),7.36–7.30(m,1H),4.69(t,J＝6.5Hz,2H),2.24–2.10(m,9H),1.94–1.83(m,2H),1.78–1.67(m,6H),1.40–1.28(m,4H),0.95–0.81(m,3H).13C NMR(101MHz,CDCl3)158.7,144.1,140.9,136.5,124.2,123.2,120.5,110.7,52.4,45.4,41.5,36.4,30.2,29.5,29.0,22.4,14.0.
Example 20: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-benzo [ d ] imidazole-2-carboxamide (20)
Compound (20) was prepared in the same manner as compound (19) except that 2- (4-morpholine) ethyl bromide (96mg, 0.5mmol) was used in place of 1-bromopentane to give compound (20) as a yellow solid, 141mg (69%).1H NMR(400MHz,CDCl3)7.75(d,J＝7.6Hz,1H),7.52(s,1H),7.43(d,J＝7.8Hz,1H),7.39–7.29(m,2H),4.85(t,J＝6.6Hz,2H),3.70–3.59(m,4H),2.77(t,J＝6.6Hz,2H),2.58–2.47(m,4H),2.24–2.10(m,9H),1.81–1.68(m,6H).13C NMR(101MHz,CDCl3)158.7,144.4,140.9,136.5,124.3,123.3,120.5,110.7,67.0,58.1,53.9,52.4,42.8,41.5,36.3,29.5.
Example 21: n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] imidazole-2-carboxamide (21)
Preparation of Compound (21)Preparation was carried out in the same manner as in the preparation of compound (19) except that 2-bromoethyl ether (76mg, 0.5mmol) was used in place of 1-bromopentane to give compound (21) as a yellow solid, 97mg (53%).1H NMR(400MHz,CDCl3)7.74(d,J＝7.5Hz,1H),7.59–7.46(m,2H),7.37–7.30(m,2H),4.85(t,J＝5.2Hz,2H),3.85(t,J＝5.3Hz,2H),3.41(q,J＝6.9Hz,2H),2.19-2.12(m,9H),1.77-1.71(m,6H),1.07(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)158.8,144.1,140.7,137.2,124.2,123.3,120.2,111.6,70.0,66.6,52.4,45.6,41.5,36.3,29.5,15.1.
Example 22: n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-benzo [ d ] imidazole-2-carboxamide (22)
Compound (22) was prepared in the same manner as compound (19) except that 1-bromopentane was replaced with 1-bromo-5-fluoropentane (87mg, 0.4mmol) to give compound (22) as a white solid, 48mg (47%).1H NMR(400MHz,CDCl3)7.68(d,J＝7.7Hz,1H),7.46(s,1H),7.34(d,J＝7.7Hz,1H),7.32–7.22(m,2H),4.64(t,J＝7.2Hz,2H),4.41(t,J＝5.9Hz,1H),4.29(t,J＝5.8Hz,1H),2.11-2.05(m,9H),1.90-1.81(m,2H),1.71-1.61(m,8H),1.46-1.38(m,2H).13C NMR(101MHz,CDCl3)158.7,144.0,140.9,136.4,124.3,123.3,120.5,110.6,84.7,83.0,52.4,45.2,41.5,36.3,30.2,30.0,30.0 29.5,22.7,22.7.
Example 23: n- (adamantan-1-yl) -1- (2- (ethoxyethoxy) ethyl) -1H-benzo [ d ] imidazole-2-carboxamide (23)
Compound (23) was prepared in the same manner as compound (19) except that 2- (2-ethoxyethoxy) ethyl bromide (98mg, 0.5mmol) was used in place of 1-bromopentane to give compound (23) as a yellow solid, 105mg (53%).1H NMR(400MHz,MeOD)7.68(d,J＝7.9Hz,1H),7.63(d,J＝8.0Hz,1H),7.39-7.29(m,2H),4.82(t,J＝5.1Hz,2H),3.85(t,J＝5.2Hz,2H),3.54–3.45(m,2H),3.41-3.38(m,2H),3.32(q,J＝7.0Hz,2H),2.20-2.09(m,9H),1.79-1.76(s,6H),1.05(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)162.9,148.6,144.3,140.3,128.1,127.1,123.3,115.5,74.2,73.9,73.4,70.1,56.2,48.7,44.8,40.0,33.5,18.0.
Example 24: n- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-2-carboxamide (24)
Step (24a) -preparation of N- (adamantan-1-yl) -1- (5- ((tert-butyldimethylsilyl) oxy) pentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide (24 a): compound (24a) was prepared in the same manner as Compound (7) except that ((5-bromopentyl) oxy) (tert-butyl) dimethylsilane (99mg, 0.4mmol) was used in place of 1-bromopentane to give Compound (24a) as a white solid, 41mg (47.6%).
Step (24b) -N- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-pyrrole [3,2-C]Preparation of pyridine-2-carboxamide (24): compound (24a) (41mg, 0.1mmol) was added to 3mL of tetrahydrofuran solvent, tetrabutylammonium fluoride (39mg,0.1mmol) was further added thereto, the mixture was stirred overnight, the reaction system was spun dry, and purified by silica gel column chromatography (dichloromethane), to give (24) 28.9mg (93%) of a pale yellow solid.1H NMR(400MHz,CDCl3)9.08(s,1H),8.01(s,1H),7.60(s,3H),4.86(t,J＝7.3Hz,2H),3.64(t,J＝6.1Hz,2H),2.25-2.10(m,9H),2.02–1.91(m,2H),1.78–1.68(m,6H),1.64–1.58(m,2H),1.52–1.45(m,2H).13C NMR(101MHz,CDCl3)152.8,139.2,132.6,130.7,127.9,127.6,116.8,112.1,62.2,55.3,46.8,40.7,36.2,31.9,29.8,29.4,23.1.
Example 25: n- (adamantan-1-yl) -1- (5-oxopentyl) -1H-benzo [ d ] imidazole-2-carboxamide (25)
Compound (24) (150mg, 0.4mmol) was placed in a 25mL single neck flask, dissolved in 4mL dichloromethane, PDC (222mg,0.5mmol) was added, nitrogen was replaced, the reaction was stirred at room temperature for 14 hours, filtered using celite, washed, spin-dried under reduced pressure, and purified by silica gel column chromatography (DCM ═ 1to PE: EA ═ 3: 1) to give compound (25) as a pale yellow solid 46mg (31.5%).1HNMR(400MHz,CDCl3)9.74(s,1H),7.76(d,J＝7.7Hz,1H),7.54(s,1H),7.42(d,J＝7.8Hz,1H),7.39-7.30(m,2H),4.72(t,J＝7.1Hz,2H),2.50(t,J＝7.1Hz,2H),2.18-2.12(m,9H),1.96–1.88(m,2H),1.18-1.67(m,8H).13C NMR(101MHz,CDCl3)201.9,158.7,144,0,140.8,136.3,124.4,123.4,120.5,110.6,52.5,44.9,43.4,41.5,36.3,29.8,29.4,19.2.
Example 26: n- (adamantan-1-yl) -1- (5, 5-difluoropentyl) -1H-benzo [ d ] imidazole-2-carboxamide (26)
XtalFluor-E (200mg, 0.9mmol) was placed in a 25mL single-necked flask, dissolved in 7mL DCM, and compound (25) (165mg, 0.4mmol) and Et were added3N (141mg, 0.9mmol), nitrogen substitution, reaction stirring at room temperature, TLC detection, after completion of the reaction, 25mL of saturated sodium bicarbonate solution was added to quench the reaction, followed by extraction with ethyl acetate (30mL × 4), combination of organic phases, drying over anhydrous sodium sulfate, and purification by silica gel chromatography (PE: EA ═ 20: 1) to give compound (26) as a 20mg white solid (11%).1H NMR(400MHz,CDCl3)7.69(d,J＝7.7Hz,1H),7.46(s,1H),7.34(d,J＝7.6Hz,1H),7.31-7.23(m,2H),5.71(tt,J＝56.8,4.3Hz,1H),4.65(t,J＝7.3Hz,2H),2.11-2.05(m,9H),1.94–1.74(m,4H),1.71-1.62(m,6H),1.52–1.42(m,2H).13C NMR(101MHz,CDCl3)158.7,144.0,140.9,136.3,124.4,123.4,120.6,119.4,117.0,114.7,110.5,52.5,45.0,41.5,36.3,33.9,33.7,33.5,29.8,29.5,19.5,1.0.
Example 27: n- (adamantan-1-yl) -1H-pyrrolo [3,2-B ] pyridine-3-carboxamide (27)
1H-pyrrole [3,2-B]Pyridine-3-carboxylic acid (800mg, 5.0mmol) was placed in a 50mL two-necked flask, dissolved in 10mL of dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), replaced with nitrogen, stirred at room temperature for 1 hour, and the system was dried, added with amantadine (899mg, 5.9mmol), and triethylamine (2g, 19.8mmol) to 15mL of dichloromethane, stirred at room temperature for 8 hours, subjected to TLC detection reaction, and after completion of the reaction, the system was dried and purified by silica gel chromatography (dichloromethane) to obtain 1.1g (77%) of compound (27) as a white solid.1H NMR(400MHz,DMSO-d6)11.86(s,1H),8.64(s,1H),8.44(d,J＝3.4Hz,1H),8.08(s,1H),7.89(d,J＝7.9Hz,1H),7.22(dd,J＝7.3,4.6Hz,1H),2.18–2.02(m,9H),1.68(brs,6H).13C NMR(101MHz,DMSO-d6)162.2,143.0,142.2,132.6,129.1,120.1,117.1,111.1,50.5,41.6,36.0,28.9.
Example 28: n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [3,2-B ] pyridine-3-carboxamide (28)
Compound (27) (120mg,0.4mmol)) Placing the mixture into a 25mL single-neck bottle, dissolving the mixture in 5mL of anhydrous N-N' -dimethylformamide, adding NaH (32mg, 0.6mmol), stirring the mixture at room temperature for reaction for 30 minutes, adding 1-bromopentane, stirring the mixture at room temperature for reaction for 3 hours, detecting the reaction by TLC, adding 20mL of water to quench the reaction after the reaction is finished, extracting the reaction product with ethyl acetate (25mL × 3), combining organic layers, washing the organic layers with water (25mL × 3), washing the organic layers with saturated saline, drying the organic layers with anhydrous sodium sulfate, spin-drying the organic layers under reduced pressure, and carrying out chromatographic separation and purification on the organic layers by silica gel column (dichloromethane), so as to obtain 100mg (68%) of a yellow solid of the compound (28).1H NMR(400MHz,CDCl3)8.70(s,1H),8.47(d,J＝4.3Hz,1H),7.97(s,1H),7.65(d,J＝8.2Hz,1H),7.15(dd,J＝8.2,4.7Hz 1H),4.11(t,J＝7.0Hz,2H),2.29–2.12(m,9H),1.89–1.71(m,8H),1.34–1.24(m,4H),0.87(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)163.3,143.3,143.3,134.6,129.6,117.4,116.7,111.8,51.6,47.0,42.0,36.6,29.8,29.6,28.9,22.2,13.8.
Example 29: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-B ] pyridine-3-carboxamide (29)
Compound (29) was prepared in the same manner as compound (28) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give 122mg (60%) of compound (29) as a yellow solid.1H NMR(400MHz,CDCl3)8.71(s,1H),8.48(d,J＝3.3Hz,1H),8.04(s,1H),7.69(d,J＝8.1Hz,1H),7.17(dd,J＝7.3,4.9Hz,1H),4.23(t,J＝6.1Hz,2H),3.66(brs,4H),2.74(t,J＝6.1Hz,2H),2.46(brs,4H),2.28–2.11(m,9H),1.81–1.69(m,6H).13C NMR(101MHz,CDCl3)163.2,143.5,143.2,134.9,129.7,117.5,116.8,112.1,66.8,58.2,53.8,51.7,44.4,42.0,36.6,29.6.
Example 30: n- (adamantan-1-yl) -1H-pyrrolo [3,2-C ] pyridine-3-carboxamide (30)
1H-pyrrole [3,2-C]Pyridine-3-carboxylic acid (800mg, 5.0mmol) was placed in a 50mL two-necked flask, dissolved in 10mL of dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), replaced with nitrogen, stirred at room temperature for 1 hour, the system was dried, and the above system, amantadine (899mg, 5.9mmol), triethylamine (2g, 19.8mmol) were addedAfter stirring the mixture in 15mL of dichloromethane at room temperature for 8 hours, the reaction was checked by TLC, and after completion of the reaction, the system was dried by spin-drying and purified by silica gel column chromatography (dichloromethane), whereby 1.1g (77%) of compound (30) was obtained as a white solid.1H NMR(400MHz,MeOD-d6)9.29(s,1H),8.21(d,J＝5.9Hz,1H),8.03(s,1H),7.49(d,J＝5.8Hz,1H),2.21–2.9(m,9H),1.81–1.75(m,6H).13C NMR(101MHz,MeOD-d6)166.2,144.0,142.3,140.3,130.5,124.6,114.1,108.9,53.4,42.7,37.6,31.1.
Example 31: n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [3,2-C ] pyridine-3-carboxamide (31)
Compound (30) (120mg,0.4mmol) was placed in a 25mL single neck flask, dissolved in 5mL of anhydrous N-N' -dimethylformamide, NaH (32mg, 0.6mmol) was added, the reaction was stirred at room temperature for 30 minutes, 1-bromopentane was further added, the reaction was stirred at room temperature for 3 hours, the reaction was detected by TLC, after the completion of the reaction, 20mL of water was added to quench the reaction, followed by extraction with ethyl acetate (25mL × 3), the organic layers were combined, water (25mL × 3), washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried under reduced pressure, and the organic phase was subjected to silica gel column chromatography purification (dichloromethane), to obtain compound (31) as a white solid 100mg (68%).1H NMR(400MHz,CDCl3)9.26(s,1H),8.37(d,J＝5.8Hz,1H),7.63(s,1H),7.25(d,J＝5.8Hz,1H),5.79(s,1H),4.08(t,J＝7.1Hz,2H),2.25–2.09(m,9H),1.87–1.70(m,8H),1.39–1.22(m,4H),0.87(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)163.3,143.4,141.4,140.3,131.5,122.4,112.8,105.2,52.3,46.7,42.1,36.4,29.7,29.5,28.8,22.2,13.8.
Example 32: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-C ] pyridine-3-carboxamide (32)
Compound (32) was prepared in the same manner as compound (31) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give 106mg (52%) of compound (32) as a yellow solid.1H NMR(400MHz,CDCl3)9.22(s,1H),8.39(d,J＝5.6Hz,1H),7.73(s,1H),7.37–7.23(m,1H),5.71(s,1H),4.23(t,J＝6.3Hz,2H),3.72–3.66(m,4H),2.74(t,J＝6.3Hz,2H),2.51–2.45(m,4H),2.24–2.11(m,9H),1.80–1.68(m,6H).13C NMR(101MHz,CDCl3)163.1,143.1,141.3,140.5,132.1,122.2,113.1,105.2,66.9,58.0,53.8,52.4,44.1,42.1,36.4,29.5.
Example 33: n- (adamantan-1-yl) -1H-pyrrolo [2,3-B ] pyridine-3-carboxamide (33)
1H-pyrrole [2,3-B]Pyridine-3-carboxylic acid (800mg, 4.9mmol) was placed in a 50mL two-necked flask, dissolved in 10mL of dichloromethane, added with a catalytic amount of N-N' -dimethylformamide, added with oxalyl chloride (1.3g, 9.9mmol), nitrogen was replaced, and the mixture was stirred at room temperature for 1 hour, and the system was dried by spin-drying, and the above system, amantadine (899mg, 5.9mmol), and triethylamine (2g, 19.8mmol) were added to 15mL of dichloromethane, and stirred at room temperature for 8 hours, and the reaction was detected by TLC, and after the reaction was completed, the system was dried by spin-drying, and purified by silica gel chromatography (dichloromethane), to obtain 1.1g (77%) of compound (33) as a white solid.1H NMR(400MHz,CDCl3)10.21(s,1H),8.42–8.32(m,2H),7.78(s,1H),7.22(dd,J＝7.8,4.8Hz,1H),5.58(s,1H),2.22–2.12(m,9H),1.79–1.70(m,6H).13C NMR(101MHz,DMSO-d6)163.6,148.3,143.2,129.3,127.9,118.7,116.6,110.3,51.0,41.3,36.1,28.9.
Example 34: n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [2,3-B ] pyridine-3-carboxamide (34)
Compound (33) (120mg,0.4mmol) was placed in a 25mL single-necked flask, dissolved in 5mL of anhydrous N-N' -dimethylformamide, NaH (32mg, 0.6mmol) was added, the reaction was stirred at room temperature for 30 minutes, 1-bromopentane was further added, the reaction was stirred at room temperature for 3 hours, the reaction was detected by TLC, after completion of the reaction, 20mL of water was added to quench the reaction, followed by extraction with ethyl acetate (25mL × 3), the organic layers were combined, water (25mL × 3), a saturated saline solution was washed, the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried under reduced pressure, and purification by silica gel column chromatography (dichloromethane) gave compound (34) as a white solid (100 mg (68%).1H NMR(400MHz,CDCl3)8.36(d,J＝4.6Hz,1H),8.26(d,J＝7.9Hz,1H),7.70(s,1H),7.17(dd,J＝7.2,4.8Hz,1H),5.56(s,1H),4.29(t,J＝7.2Hz,2H),2.21–2.11(m,9H),1.93–1.82(m,2H),1.80–1.69(m,6H),1.36–1.28(m,4H),0.88(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)163.8,147.6,143.5,130.1,128.7,118.1,117.2,110.5,52.2,45.0,42.2,36.5,29.9,29.6,28.9,22.3,13.9.
Example 35: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [2,3-B ] pyridine-3-carboxamide (35)
Compound (35) was prepared in the same manner as compound (34) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give compound (35) as a white solid, 98mg (48%).1H NMR(400MHz,CDCl3)8.34(d,J＝4.3Hz,1H),8.26(d,J＝7.8Hz,1H),7.80(s,1H),7.18(dd,J＝7.7,4.8Hz,1H),5.55(s,1H),4.43(t,J＝6.5Hz,2H),3.75–3.63(m,4H),2.81(t,J＝5.7Hz,2H),2.53(brs,4H),2.22–2.08(m,9H),1.79–1.70(m,6H).13C NMR(101MHz,DMSO-d6)163.3,147.1,142.9,131.0,129.5,118.9,116.9,109.3,66.1,57.6,53.1,51.1,41.3,41.1,36.1,28.9.
Example 36: n- (adamantan-1-yl) -1H-indazole-3-carboxamide (36)
1H-indazole-3-carboxylic acid (400mg, 2.5mmol) was placed in a 50mL two-necked flask, dissolved in 10mL of dichloromethane, a catalytic amount of N-N' -dimethylformamide was added, oxalyl chloride (0.7g, 4.9mmol) was added, nitrogen was replaced, the mixture was stirred at room temperature for 1 hour, the system was dried, amantadine (450mg, 3.0mmol) and triethylamine (1g, 10mmol) were added to 15mL of dichloromethane, the mixture was stirred at room temperature for 8 hours, the reaction was detected by TLC, and after the reaction was completed, the system was dried and purified by silica gel chromatography (dichloromethane) to obtain 0.6g (77%) of compound (36) as a white solid. 1H NMR (400MHz, DMSO-d6)13.48(s,1H),8.16(d, J ═ 8.0Hz,1H),7.60(d, J ═ 8.4Hz,1H),7.40(t, J ═ 7.4Hz,1H), 7.24-7.22 (m,2H), 2.11-2.07 (m,9H), 1.76-1.61 (m,6H), 13C NMR (101MHz, DMSO-d6)161.4,141.2,138.8,126.4,121.9,121.6,121.3,110.6,51.0,41.1,36.0,28.9.
Example 37: n- (adamantan-1-yl) -1-pentyl-1H-indazole-3-carboxamide (37)
Placing compound (36) (41mg,0.2mmol) in a 25mL single-neck flask, dissolving in 5mL anhydrous N-N' -dimethylformamide, adding NaH (13mg, 0.3mmol), stirring at room temperature for reaction for 30 min, adding 1-bromopentane, stirring at room temperature for reaction for 3h, detecting by TLC, and after the reaction is finished, addingThe reaction was quenched with 20mL of water, extracted with ethyl acetate (25mL × 3), the organic layers were combined, washed with water (25mL × 3), saturated brine, and the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried under reduced pressure, and purified by silica gel column chromatography (dichloromethane) to give compound (37) as a white solid 36mg (71%). 1H NMR (400MHz, CDCl)3)8.38(d,J＝8.0Hz,1H),7.38–7.37(m,2H),7.26–7.22(m,1H),6.81(s,1H),4.34(t,J＝7.2Hz,2H),2.21–2.14(m,9H),1.96–1.89(m,2H),1.79–1.65(m,6H),1.39–1.31(m,4H),0.89(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)162.1,140.9,138.0,126.5,123.1,122.8,122.3,109.1,51.8,49.3,41.9,36.5,29.6,29.5,28.9,22.2,13.9.
Example 38: n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-indazole-3-carboxamide (38)
Compound (38) was prepared in the same manner as compound (37) except that 2- (4-morpholine) ethyl bromide (97mg, 0.5mmol) was used in place of 1-bromopentane to give compound (38) as a white solid, 122mg (60%). 1H NMR (400MHz, CDCl)3)8.38(d,J＝8.0Hz,1H),7.41–7.38(m,2H),7.26–7.25(m,1H),6.78(s,1H),4.49(t,J＝6.6Hz,2H),3.67(m,4H),2.87(t,J＝6.0Hz,2H),2.51(m,4H),2.20–2.14(m,9H),1.78–1.71(m,6H).13C NMR(101MHz,CDCl3)160.9,140.1,128.6,125.7,122.1,121.8,121.5,108.1,65.7,56.5,52.7,50.9,40.9,35.4,28.7,28.5.
Example 39: water solubility test
Water solubility is an important factor in the absorption, penetration and oral bioavailability of compounds. CB 2receptor agonists generally have limited water solubility. To assess the kinetic aqueous solubility of CB 2receptor agonists, the present invention uses an analytical High Performance Liquid Chromatography (HPLC) method and the solubility of the compounds is measured at pH1.4 and pH 7.4.
The experimental method comprises the following steps: the compounds of the present invention dissolved in DMSO were prepared as 10mM solutions, and diluted with 10mM phosphate buffer solution of pH1.4 or pH7.4 to give a final DMSO concentration of 1%. The final solution was shaken with ultrasound at room temperature for 10 minutes and filtered through a 0.22 μm ptfe needle filter. Then, a standard curve was drawn by analytical HPLC. The concentration of the compound was determined by analytical HPLC performed on a Waters e2695HPLC system using a ZORBAX SB-C18 column type, detected by a variable wavelength detector 2998PDA at 275nm and 290 nm. Compounds were tested using the gradient shown below: 80-95% methanol water solution (containing 0.5 ‰ trifluoroacetic acid) with flow rate of 1.2mL/min within 19 min. The calculated water solubilities and experimental water solubilities are shown in table 1.
Table 1 shows the water solubility data of the compound of the present invention, and the results show that the water solubility (pH 1.4 ═ 96.1 μ M/L) of the compound 24 of the present invention is significantly improved compared to the water solubility (pH 1.4 ═ 16.8 μ M/L) of the compound 39 (the reference compound, the structure is shown in formula 2), which provides a certain basis for the azaindole derivative compound to have good absorption, penetration and bioavailability.
TABLE 1 calculated and Experimental Water solubility of Compounds
Figure BDA0001967117190000231
Figure BDA0001967117190000241
Sa: water solubility (mol/L), the average of three measurements was made.
Figure BDA0001967117190000242
Example 40: pharmacological test example- -calcium flux screening model (calcium current assay)
After the cannabinoid receptor is activated, intracellular calcium flux is inhibited. The G protein G alpha 16 is transferred into cells to activate calcium flow, and other physiological functions are not influenced. By establishing cell lines co-transforming CB1 and ga 16, CB2 and ga 16, respectively, such that activation of the receptor results in activation of the ga 16 protein, activation of phospholipase c (plc) to produce IP3 and DAG, IP3 can bind to the IP3 receptor on the endoplasmic reticulum of the cell and then cause release of intracellular calcium. Thus, the determination of changes in intracellular calcium can be used as a means for detecting the activation state of CB1 and CB 2. Fluo-4\ AM is a calcium fluorescent probe indicator, can be used for measuring calcium ions and is used as a nonpolar fat-soluble compound, after entering cells, under the action of cell lipolytic enzyme, an AM group is dissociated to release Fluo-4: fluo-4 is a polar molecule that does not readily pass through lipid bilayer membranes, which allows Fluo-4 to remain in the cell for long periods of time. The level of activation of the G.alpha.protein is ultimately reflected by measuring the amount of excited photons. According to the principle, a calcium flux screening model is established.
The experimental method comprises the following steps: cells are transfected by human cannabinoid receptors (hCB1 and hCB2) and G alpha 16 at the same time, and stable transfected cell lines CHO-hCB1-G alpha 16 and CHO-hCB2-G alpha 16 are established by antibiotic screening. An appropriate concentration of CHO-hCB 1-G.alpha.16 or CHO-hCB 2-G.alpha.16 (about 2 ten thousand wells) was applied to a 96-well cell plate 24 hours prior to detection, so that each well had about 4-6 ten thousand cells/well at the time of detection. The cells were incubated overnight, the culture medium was removed after cell attachment, and incubated with 2. mu. mol/L fluo-4AM dye in an incubator at 37 ℃ for 50 minutes. Excess dye was aspirated and cells were washed once with Hank' Balanced Salt Solution (HBSS) buffer. In the antagonistic mode, cells are incubated for 10 minutes at room temperature by HBSS buffer solution containing positive control or a compound to be detected or negative control containing DMSO, 25 mu L of agonist is automatically added into a reaction system by a FlexStation detector, and the change of the fluorescence intensity of the dye caused by the change of calcium ion current is detected in real time. In the excitation mode, cells are incubated with HBSS buffer solution for 10 minutes at room temperature, HBSS buffer solution containing positive control or a compound to be detected or negative control containing DMSO is automatically added into a reaction system by a FlexStation detector, and the change of the fluorescence intensity of the dye caused by the change of calcium ion current is detected in real time. The inhibition rate or relative activation rate value of the tested compound can be obtained.
The inhibition rate is (peak value of calcium flux of negative control-peak value of calcium flux of test compound)/(peak value of calcium flux of negative control-peak value of calcium flux of positive control) × 100%
Relative agonism ratio (peak calcium flux of test compound-peak calcium flux of negative control)/(peak calcium flux of positive control-peak calcium flux of negative control) × 100%
The half inhibitory concentration IC50 or half effective amount EC50 of the compound of the invention is measured by the method, mainly by making response rate and dose curve, totally selecting eight dose concentrations of 10 muM, 1 muM, 100nM, 10nM, 1nM, 100pM, 10pM and 0pM, calcium flux detection is carried out according to the experimental steps, each concentration is measured in parallel three times, namely 8 gradient 3 multi-well plates, and each 3 multi-well plates are measured three times. Data were analyzed using GraphPad Prism software. Dose-dependent curves for compounds of the invention were fitted using non-linear regression methods and either IC50 or EC50 was calculated.
The activity data in table 2 show that the compound of the present invention generally shows higher calcium flux activity and very good selectivity for the human hemp receptor hCB2, and the compound CP55940 is used as a positive control, wherein the agonistic activity of the compounds prepared in examples 24, 34, 35, 36, 37 and 38 on the CB 2receptor is between 0.01 μ M and 0.1 μ M (0.065, 0.032, 0.077, 0.085, 0.087 and 0.055 μ M, respectively); the agonistic activity of the compounds of examples 13, 19 at the CB 2receptor ranged between 0.2. mu.M and 0.4. mu.M (0.28. mu.M and 0.29. mu.M, respectively); agonistic activity of the compounds of examples 1, 2, 14, 18 at the CB 2receptor ranged from 0.5. mu.M to 1. mu.M (0.59. mu.M, 0.86. mu.M, 0.93. mu.M, and 0.51. mu.M, respectively); the agonistic activity of the compounds of examples 6, 30, 33 at the CB 2receptor was between 1. mu.M and 10. mu.M (1.96. mu.M, 10. mu.M, 6.23. mu.M, respectively). In particular, the above bioactivity tests demonstrated that compound 24(EC50, CB2 ═ 65nM, EC50, CB1>10 μ M), compound 35(EC50, CB1>10 μ M, EC50, CB2 ═ 0.077 μ M) and compound 36(EC50, CB1>10 μ M, EC50, CB2 ═ 0.085 μ M) of the present invention can selectively act on the cannabinoid CB 2receptor, but not on the CB1 receptor. Therefore, the compound is a high-activity and high-selectivity CB 2receptor agonist and has a good drug development prospect.
TABLE 2 data on the agonistic activity of a part of the compounds of the invention and of a positive control compound CP55940 in a calcium flux screening model
Figure BDA0001967117190000261
Figure BDA0001967117190000271
NA: inactive, defined as < 50% activation or < 50% inhibitory activity at 10 μ M in the primary assay.
ND: not determined, for compounds defined as inactive, the maximum effect was not determined.
Example 41: pharmacological test example- -experiment of in vitro proliferation of splenocytes
Experimental method of the assay, 8 weeks old C57 female mouse spleen with flat forceps is crushed and then lysed by RBC to obtain spleenocyytes, which are resuspended in culture medium (RPM1640+ 10% FBS +2mM L-glutamine + 50. mu.M β -ME), and inoculated into 96-well plate at a density of 2X 105/well (200. mu.L), 5. mu.g/ml ConA and the drug to be tested are added (blank control group is not treated, negative control group is only added with ConA, CsA: cyclosporine, positive control for inhibition of proliferation, all compound powders are dissolved in DMSO at a concentration of 10 mM) and cultured for 72 hours at 37 ℃ and 5% CO2, the cytometric data is obtained and analyzed, and the results are shown in FIG. 1 (influence of compounds 36(JYY-3-81) and 39(SY-2-47) on in vitro Con A stimulation of splenocyte proliferation reaction), wherein FIG. 1A shows spleen cells of C BL/6 mouse (5 SY- ×)5) Co-culture with different concentrations (0.1,1 and 10. mu.M) of Compound 36(JYY-3-81), Compound 19(JYY-3-103), Compound 35(LSD-1-5) for 72h in the absence or presence of 5. mu.g/mL Con A three times per concentration, mean. + -. SEM. FIG. 1B shows splenocytes from C57BL/6 mice (5 × 10. mu.M)5) Co-culture with different concentrations (5,10 and 20. mu.M) of Compound 36(JYY-3-81), Compound 39(SY-2-47) in the absence or presence of 5. mu.g/mLCon A for 72 h. three times per concentration, mean. + -. SEM. FIG. 1C shows splenocytes from C57BL/6 mice (5 × 10)5) Co-culture with different concentrations of the selective agonists CP55940(2.5,5 and 10. mu.M), JWH-015(5, 10 and 20. mu.M) in the absence or presence of 5. mu.g/mLCon A for 72 h. Each concentration was tested in triplicate and the mean ± SEM taken.
The experimental results are as follows: as shown in FIGS. 1A and 1B, for compounds 19(JYY-3-103), 35(LSD-1-5), 36(JYY-3-81) and 39(SY-2-47), compounds 36(JYY-3-81) and 39(SY-2-47) resulted in a significant inhibition of splenocyte proliferation (p <0.05) at a concentration of 10. mu.M, and at a concentration of 20. mu.M, splenocytes proliferated without Con stimulation were compared with the positive control CsA group and the blank control group, when compounds 36(JYY-3-81) and 39(SY-2-47) were applied to Con-stimulated splenocytes, the same results were obtained as in the control, the results show that compounds 36(JYY-3-81) and 39(SY-2-47) showed complete inhibition of splenocyte proliferation. As shown in FIGS. 1B and 1C, in comparison with the results of spleen cell proliferation experiments with synthetic CB 2receptor selective agonists JWH-015 and CP55940, the study showed that compound 36(JYY-3-81) has better spleen cell proliferation inhibitory activity than the CB 2receptor selective agonist JWH-015, and is similar to the inhibitory effect of CP55940 on spleen cell proliferation. These data indicate that compound 36(JYY-3-81) of the present invention has excellent inhibitory effect on splenocyte proliferation, and is dose dependent.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.

Claims (12)

1. An azaindole derivative and a pharmaceutically acceptable salt thereof are characterized in that the structure of the azaindole derivative is shown as the following formula (I):
Figure FDA0001967117180000011
wherein n is more than or equal to 0;
R1selected from hydrogen, C1-C10 alkyl, C1-C10 straight chain or branched chain alkyl substituted six-membered heterocycle, monofluoro substituted C1-C10 straight chain or branched chain alkyl, difluoro substituted C1-C10 straight chain or branched chain alkyl, hydroxyl, C1-C10 fatty aldehyde group, p-toluenesulfonyl, C1-C10 straight chain or branched chain alkyl substituted alkoxy, ethoxy;
Z1、Z2、Z3and Z4Where one represents an N atom, the other 3 carbon atoms are simultaneously substituted by hydrogen.
2. Azaindole derivatives and pharmaceutically acceptable salts thereof according to claim 1, wherein n is 0. ltoreq. n.ltoreq.12; r1 is selected from hydrogen, C1-C6 alkyl, C1-C10 straight chain or branched chain alkyl substituted six-membered nitrogen-oxygen heterocycle, fluorine substituted C1-C10 straight chain or branched chain alkyl, difluoro substituted C1-C10 straight chain or branched chain alkyl, hydroxyl, propionaldehyde, n-butyraldehyde, isobutyl aldehyde, amyl aldehyde, hexanaldehyde, C1-C10 straight chain or branched chain alkyl substituted alkoxy, ethoxy;
Z1、Z2、Z3and Z4Where one represents an N atom, the other 3 carbon atoms are simultaneously substituted by hydrogen.
3. Azaindole derivatives and pharmaceutically acceptable salts thereof according to claim 2, wherein n is 0; r1Selected from H,
Figure FDA0001967117180000012
Figure FDA0001967117180000013
Z1、Z2、Z3And Z4Where one represents an N atom, the other 3 carbon atoms simultaneously represent hydrogen.
4. Azaindole derivatives and pharmaceutically acceptable salts thereof according to claim 1, wherein the azaindole derivatives comprise:
n- (adamantan-1-yl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
1-pentyl-1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [3,2-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
1-pentyl-1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2- (ethoxyethoxy) ethyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-pyrrolo [3,2-C ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1-pentyl-1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-pyrrolo [2,3-B ] pyridine-2-carboxamide;
n- (adamantan-1-yl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1-pentyl-1H-benzo [ d ] imidazole-2-carboxamide;
1- (2-morpholinoethyl) -N- (adamantan-1-yl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1- (5-fluoropentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1- (2- (ethoxyethoxy) ethyl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1- (5-hydroxypentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1- (5-oxopentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1- (5, 5-difluoropentyl) -1H-benzo [ d ] imidazole-2-carboxamide;
n- (adamantan-1-yl) -1H-pyrrolo [3,2-B ] pyridine-3-carboxamide;
1-pentyl-1H-pyrrolo [3,2-B ] pyridine-3-carboxamide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-B ] pyridine-3-carboxamide;
n- (adamantan-1-yl) -1H-pyrrolo [3,2-C ] pyridine-3-carboxamide;
1-pentyl-1H-pyrrolo [3,2-C ] pyridine-3-carboxamide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [3,2-C ] pyridine-3-carboxamide;
n- (adamantan-1-yl) -1H-pyrrolo [2,3-B ] pyridine-3-carboxamide;
1-pentyl-1H-pyrrolo [2,3-B ] pyridine-3-carboxamide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-pyrrolo [2,3-B ] pyridine-3-carboxamide;
n- (adamantan-1-yl) -1H-indazole-3-carboxamide;
1-pentyl-1H-indazole-3-carboxamide, N- (adamantan-1-yl) -amide;
n- (adamantan-1-yl) -1- (2-morpholinoethyl) -1H-indazole-3-carboxamide.
5. An azaindole derivative according to any one of claims 1to 4, wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulphate, hydrosulphate, phosphate, dihydrogenphosphate, methanesulphonate, monomethyl sulphate, cis-butenedioate, trans-butenedioate, succinate, ascorbate, lactate, tartrate, acetate, oxalate, malonate, glycolate, naphthalene-2-sulphonate, gluconate, citrate, isethionate, p-toluenesulphonate, 3, 5-dimethylbenzyl sulphonate, or a quaternary ammonium salt with an alkyl halide which is fluorine, chlorine, bromine or iodoalkane.
6. Use of azaindole derivatives according to any one of claims 1to 4 and pharmaceutically acceptable salts thereof for the preparation of selective CB 2receptor agonists.
7. Use of azaindole derivatives as claimed in any one of claims 1to 4 and pharmaceutically acceptable salts thereof for the preparation of a medicament for the prevention and/or treatment of diseases associated with the CB2 receptor.
8. The use of claim 7, wherein the disease is selected from the group consisting of multiple sclerosis, autoimmune diseases, neurodegenerative diseases, atherosclerosis, glaucoma, osteoporosis, cancer, inflammation, acquired immune syndrome, rheumatic diseases, allergy, pain, Alzheimer's disease, Parkinson's disease, Huntington's disease, obesity.
9. Use of azaindole derivatives as claimed in any one of claims 1to 4 and pharmaceutically acceptable salts thereof for the preparation of anti-tumor medicaments.
10. The use of claim 9, wherein the anti-tumor is inhibiting proliferation, growth, migration and infiltration of tumor cells and promoting apoptosis of tumor cells.
11. The use of claim 9, wherein the tumor comprises malignant melanoma of the skin, basal cell carcinoma, squamous cell carcinoma, breast cancer, colon cancer, liver cancer, glioma, prostate cancer, lung cancer, endometrial cancer.
12. A pharmaceutical composition comprising an azaindole derivative according to any one of claims 1to 4, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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