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WO2022211518A1 - Novel compound and use thereof in treating psoriasis, asthma, or systemic lupus erythematosus - Google Patents

Novel compound and use thereof in treating psoriasis, asthma, or systemic lupus erythematosus Download PDF

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Publication number
WO2022211518A1
WO2022211518A1 PCT/KR2022/004585 KR2022004585W WO2022211518A1 WO 2022211518 A1 WO2022211518 A1 WO 2022211518A1 KR 2022004585 W KR2022004585 W KR 2022004585W WO 2022211518 A1 WO2022211518 A1 WO 2022211518A1
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Prior art keywords
indol
chloro
acetamide
thiazol
benzo
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PCT/KR2022/004585
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French (fr)
Korean (ko)
Inventor
서수길
이성민
원해정
윤은혜
장원희
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파렌키마바이오텍 주식회사
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Priority claimed from KR1020220040189A external-priority patent/KR20220137555A/en
Publication of WO2022211518A1 publication Critical patent/WO2022211518A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds and their use for the treatment of psoriasis, asthma or systemic lupus erythematosus.
  • the human body can be protected from pathogens through an immune response, and the biological defense mechanism against foreign microorganisms such as viruses or bacteria is divided into innate immunity and specific immunity, which are immune-related cells mediated primarily by cytokines secreted by
  • the immune system plays a role in protecting the body from antigens, which are harmful foreign substances.
  • antigens include bacteria, viruses, toxins, cancer cells, and blood and tissues from other humans or animals.
  • the immune system produces antibodies to destroy these harmful substances.
  • autoimmunity is abnormal, the immune system cannot distinguish its own body organs from harmful antigens and destroys normal tissues.
  • the disease is an autoimmune disease.
  • Aryl Hydrocarbon Receptor is a ligand-dependent transcription factor belonging to the PER-ARNT-SIM (PAS) superfamily and is mainly expressed in immune cells, epithelial cells, endothelial cells, and stromal cells of the barrier tissue. do.
  • AHR is an environmental sensor and detects not only xenobiotic ligands such as environmental pollutants (eg, dioxins), but also physiological ligands produced from cells, microorganisms, and food.
  • AHR chaperone complex forms an AHR chaperone complex with the Hsp90:XAP2:p23:Src chaperone in the cytoplasm to maintain a structure with high affinity for the ligand.
  • AHR is activated after ligand binding, the complex moves to the nucleus and AHR separates from the chaperone complex and binds to AHR-responsive DNA elements (xenobiotic response elements, XREs) located in regulatory regions upstream of the target gene to regulate the expression of the target gene. do.
  • a non-toxic immunomodulatory ligand capable of activating AHR in vivo could be developed as a new therapeutic agent for autoimmune diseases.
  • Chronic skin inflammatory disease is a chronic inflammatory disease that occurs in the epidermal layer of the skin of the human body. Immune imbalance caused by environmental-genetic factors is considered as an important pathogenesis factor, and psoriasis and atopic dermatitis are the main factors. .
  • Psoriasis is an intractable autoimmune skin disease accompanied by hyperproliferation of the epidermis layer and erythema and ulcers of various sizes.
  • the main etiological mechanism of psoriasis is hyperproliferation and hyperactivation of keratinocytes, which are induced by Th17 cell responses. Looking at the process, the production of TNF-a and lL-23 by the overactivation of the first skin dendritic cells maximizes the inflammatory effect of Th17 cells, which increases the production of IL-17, which leads to hyperproliferation of keratinocytes. .
  • keratinocytes generate additional inflammatory cytokines and chemokines by stimulation such as TNF-a, thereby promoting and sustaining tissue infiltration of inflammatory leukocytes.
  • antibody therapeutics that block the IL-23-IL-17 pathway are relatively effective, but the effect is temporary and the effect is weak in patients with high severity. Therefore, there is a need for effective drug development with a new mechanism.
  • Respiratory chronic inflammatory disease is a disease in which chronic respiratory difficulties are caused by inflammation in the lower respiratory tract, upper airways and lung parenchyma. Since the respiratory tract is continuously exposed to numerous non-pathogenic and pathogenic antigens, an immune tolerance mechanism to block the occurrence of fatal immunopathology along with immune defense against these antigens has been developed. However, if the immune tolerance mechanism is not smooth, it will progress to an inflammatory disease.
  • Asthma is a representative respiratory chronic inflammatory disease. Excessive Th2/Th17-mediated inflammatory response is the main etiological mechanism. Currently, steroids to control inflammation and ⁇ 2 agonists to relieve bronchial muscle contraction are used. The proportion of adults aged 19 and over in Korea increased from 61% in 2015 to 66% in 2019. The proportion of patients with non-allergic asthma is increasing.
  • Asthma cannot be cured with existing treatments, and the effect is weak and temporary, so there is a high need for developing new drugs. Because the etiological mechanism is diverse and complex, complex treatment is the basic, so it is necessary to develop target drugs with various novel mechanisms. In addition, a strategy that can effectively control the inflammatory response of the lesion and restore the damaged epithelial tissue is needed.
  • Lupus (systemic lupus erythematosus) is an autoimmune inflammatory disease that appears in joints, kidneys, skin, mucous membranes, and blood vessel walls. 70-90% of patients are women of childbearing age, and the prevalence is higher in blacks and Asians than in whites. It is characterized by the production of autoantibodies against nucleic acids in normal cells. Common among the various disease symptoms is the loss of immune tolerance of B-cells. Currently, antimalarial drugs, anti-inflammatory drugs, and immunosuppressive drugs are prescribed for treatment, but the effect is weak and side effects are high, so it is urgent to develop a new therapeutic agent that can restore B-cell immune tolerance.
  • Adoptive transfer of splenocytes from DBA/2 mice to BDF1 mice results in the production of anti-nucleic acid antibodies, a characteristic feature of the immune pathogenesis of lupus, and loss of immune tolerance of B-cells. Therefore, the development of a treatment for lupus is being mainly used.
  • An object of the present invention is to provide a novel compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a novel compound useful for the prevention and treatment of psoriasis, asthma, or systemic lupus erythematosus, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating psoriasis, asthma, or systemic lupus erythematosus, comprising a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for the treatment or prevention of psoriasis, asthma, or systemic lupus erythematosus comprising a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 to R 4 are each independently hydrogen or halogen
  • R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl
  • A is a C 5 -C 12 single or double cyclic group
  • Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms,
  • the cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy).
  • Q 1 to Q 15 are each independently C, N or S, and R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; If Q 4 is N, then R 11 is absent).
  • R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • a method of treating psoriasis, asthma, or systemic lupus erythematosus comprising administering to a subject in need thereof a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 to R 4 are each independently hydrogen or halogen
  • R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl
  • A is a C 5 -C 12 single or double cyclic group
  • Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms,
  • the cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy).
  • Q 1 to Q 15 are each independently C, N or S, and R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; If Q 4 is N, then R 11 is absent).
  • R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • novel compound of the present invention a stereoisomer thereof, or a pharmaceutically acceptable salt thereof induces AHR activity, which is an immunoregulatory transcription factor, to control inflammation as well as to restore immune balance and damaged tissues.
  • novel compound of the present invention a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has an effect of inhibiting the production of IL-6, an inflammatory factor, to control an excessive immune response, specifically, an autoimmune response.
  • novel compound of the present invention has an effect of inducing the activity of regulatory T cells (Treg).
  • novel compound of the present invention a stereoisomer thereof or a pharmaceutically acceptable salt thereof has an effect of preventing and treating psoriasis, asthma, or systemic lupus erythematosus by controlling the inflammatory factors.
  • 1 and 2 show the measurement of the expression level of CYP1A1 in order to confirm that the compound of the present invention is an AHR ligand in cell culture conditions.
  • 3 and 4 show the measurement of the inhibitory effect of the compound of the present invention on the production of the inflammatory factor IL-6.
  • Figure 5 shows the measurement of the effect of the compound of the present invention on Foxp3+ regulatory T cell generation.
  • the present invention relates to a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 to R 4 are each independently hydrogen or halogen, and specifically, may be hydrogen, fluorine, or chlorine, but is not limited thereto.
  • R 5 and R 6 may independently be hydrogen or C 1 -C 5 alkyl, specifically hydrogen, methyl or ethyl, and more specifically hydrogen or methyl, but are not limited thereto. it is not
  • A is a C 5 -C 12 single or double cyclic group, specifically, cyclopenta-1,3-diene, benzene, cyclohexane, indene, 4,5,6,7-tetrahydroindene , naphthalene, 1,2,3,4-tetrahydronaphthalene, 1,6-dihydropentalene, etc., but is not limited thereto.
  • Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms, for example, each independently 1 to 3 atoms may be substituted with N, S, O, etc., but is not limited thereto.
  • the hetero atom refers to an atom other than carbon or hydrogen.
  • the position at which the hetero atom may be substituted may be the same as Q 1 to Q 15 in the structures specifically listed below, but is not limited thereto.
  • the cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy, for example, F, Cl, methyl group, ethyl group, methoxy, ethoxy, etc., but may be limited thereto not.
  • positions that may be substituted with halogen, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy may be specifically the same as those of R 7 to R 30 , but is not limited thereto.
  • A may be selected from the following cyclic groups.
  • R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • A may be selected from the following cyclic groups.
  • R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • A may be selected from the following cyclic groups.
  • R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  • the present invention may relate to a compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may be a pharmaceutical composition for treatment or prevention of psoriasis, asthma, or systemic lupus erythematosus (SLE).
  • SLE systemic lupus erythematosus
  • the 'asthma' is a disease in which symptoms such as coughing and shortness of breath occur repeatedly due to inflammation of the bronchial tubes when exposed to a specific causative agent, and may be caused by infection, smoking, allergens, etc., but is not limited thereto .
  • the 'psoriasis' is an inflammatory disease that occurs in the skin or joints due to an abnormality of the immune system, and causes problems such as an ugly appearance, keratin, erythematous plaques, and pain.
  • Psoriasis may include any one or more diseases selected from psoriatic arthritis, psoriasis psoriasis, pustular psoriasis, erythema psoriasis, scalp psoriasis, nail psoriasis, and osseointegritis.
  • the 'systemic lupus erythematosus' also called 'lupus', is a chronic inflammatory autoimmune disease that refers to a systemic disease that invades various organs of the body, such as connective tissue, skin, joints, blood, and kidneys.
  • 'lupus' is a chronic inflammatory autoimmune disease that refers to a systemic disease that invades various organs of the body, such as connective tissue, skin, joints, blood, and kidneys.
  • the exact cause is not known, but according to previous studies, it is known that genetic factors are associated with the development of this disease.
  • the American College of Rheumatology (ACR) published 11 symptoms, signs, and test findings that help differentiate it from other diseases to help diagnose lupus. You can be diagnosed with lupus.
  • the pharmaceutical composition may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, which is the compound of the present invention, or may be administered to a mammal.
  • a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, which is the compound of the present invention, or may be administered to a mammal.
  • an excipient a disintegrant, a sweetener, a binder, a coating agent, an expanding agent, a lubricant, a lubricant, or a flavoring agent may be used.
  • composition of the present invention may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the above-described pharmaceutically effective amount of the active ingredient for administration.
  • the 'pharmaceutically effective amount' means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, activity of the drug, and the drug in the patient. Sensitivity, administration time, administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field may be determined.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, in general 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg, may be administered daily or every other day, or divided into 1 to 3 times a day.
  • the dosage may be increased or decreased according to the route of administration, the severity of obesity, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.
  • the 'pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not normally cause gastrointestinal disorders, allergic reactions such as dizziness or similar reactions when administered to humans.
  • Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • composition of the present invention is formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a subject in need of the pharmaceutical composition of the present invention, including humans.
  • can be Formulations may be powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • the present invention may relate to a method for treating psoriasis, asthma, or systemic lupus erythematosus, comprising administering the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention may relate to a method for inducing activity of AHR comprising administering the compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention acts as an agent inducing AHR activity by targeting the aryl hydrocarbon receptor (AHR), which is an immunomodulatory transcription factor, thereby controlling inflammation, regulating immune balance, and repairing damaged tissues to prevent psoriasis, asthma or It may be used for the treatment of systemic lupus erythematosus, but is not limited thereto.
  • AHR aryl hydrocarbon receptor
  • Existing ligands are toxic, have low affinity and structural stability, and have high target specificity, making them unsuitable for development as a pharmaceutical composition, whereas the compound having "drug-like properties" of the present invention induces AHR activity. It can be effectively used for the treatment and prevention of psoriasis, asthma or systemic lupus erythematosus.
  • the present invention may relate to a method for inhibiting the production of IL-6, comprising administering the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is known to cause psoriasis, asthma or systemic lupus erythematosus
  • the inflammatory factor IL-6 can be used for the treatment of psoriasis, asthma or systemic lupus erythematosus through a mechanism of inhibiting its production.
  • a number of therapeutics and related papers for psoriasis, asthma, or systemic lupus erythematosus targeting IL-6 inhibition are known.
  • the compound of the present invention is also expected to have an effect of reducing the autoimmune response as confirmed by the following experimental data to inhibit the production of IL-6, it can be used for the treatment and prevention of psoriasis, asthma, or systemic lupus erythematosus.
  • the present invention relates to the use of a pharmaceutical composition comprising the compound, a stereoisomer or a pharmaceutically acceptable salt thereof for the prevention or treatment of psoriasis, asthma or systemic lupus erythematosus.
  • the present invention relates to the use of the pharmaceutical composition of any one of claims 1 to 7 in the manufacture of a medicament for the prophylaxis or treatment of psoriasis, asthma or systemic lupus erythematosus.
  • the compound represented by Formula 1 of the present invention can be prepared by a method known in various literatures. Although the synthesis method of some of the compounds shown in Table 1 was briefly described in the following Preparation Examples, the present invention is not limited thereto.
  • the reaction was terminated by adding distilled water to the mixture.
  • the layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (140 mg, 33%).
  • the reaction was terminated by adding distilled water to the mixture.
  • the layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (170 mg, 35%).
  • DMEM-fetal bovine serum (FBS) 10% medium was recovered, and the viability was confirmed to be 97% or more through trypan blue staining, and then centrifuged at room temperature at 1200 rpm for 5 minutes. After separation, the cells were prepared by resuspending the cells in DMEM-fetal bovine serum 10% medium at 3 ⁇ 10 5 cells/mL. Thereafter, the cells were aliquoted in 3mL into a 60mm dish, and each dish was treated with 50 ⁇ L of each 5 ⁇ M compound diluted in DMEM medium, and then cultured in a cell incubator (5% CO2 incubator) for 24 hours. As a control, 50 ⁇ L of 0.05% dimethylsulfoxide (DMSO)/DMEM medium was treated.
  • DMSO dimethylsulfoxide
  • RNA samples were recovered to prepare mRNA samples.
  • mRNA was extracted from the recovered cells by phenol-chloroform precipitation using Trizol reagent (Invitrogen, Cat No. 15596018).
  • cDNA was synthesized from the isolated RNA by reverse transcription, and the expression of CYP1A1 was confirmed by real-time PCR using iQ SYBR-Green Supermix (Bio-rad) in a CFX96 (Bio-rad) detection system. Relative values of enzyme expression levels were compared in the ⁇ ct method using GAPDH as a control enzyme. A control was used to establish a fold of 1.
  • the real-time polymerase chain reaction was carried out under conditions of 45 cycles with an annealing temperature of 58° C., and the following primer sequences were used.
  • DMSO dimethylsulfoxide
  • RPMI dimethylsulfoxide
  • the medium of the cultured cells was recovered with a new microtube, and the cells were recovered with 1 mL of Trizol (invitrogen) and stored at -80°C.
  • Trizol invitrogen
  • DMSO dimethylsulfoxide
  • PE detection reagent After 1 hour, 1 ⁇ L of PE detection reagent and 49 ⁇ L of PE detection diluent were added to make 50 ⁇ L of PE detection solution per sample. After vortexing, 50 ⁇ L of PE detection solution was added per sample to the FACS tube containing the capture bead solution and sample. After vortexing the FACS tube, it was left at room temperature for 1 hour. After 1 hour, 1 mL of CBA wash buffer was added to each tube, and the supernatant was removed after centrifugation at 400 g for 5 minutes. After vortexing lightly, 150 ⁇ L of Fix buffer was added and vortexed lightly, followed by analysis using flow cytometry.
  • the T-cells collected by the above method were prepared by resuspending in RPMI-fetal bovine serum (FBS) 10% + 2-ME (mercaptoethanol) medium at 5 ⁇ 10 5 /mL.
  • FBS RPMI-fetal bovine serum
  • 2-ME mercaptoethanol
  • 150 ⁇ L of 10 ⁇ g/mL anti-CD3 (eBioscience) was dispensed into a 48-well plate, incubated in a cell incubator (37° C., 5% CO 2 incubator) for 3 hours, and washed with phosphate-buffered saline. did.
  • Each of the compounds at a concentration of 2.5 ⁇ M diluted in RPMI+2ME medium were treated with 5 ⁇ L each, and cultured in a cell incubator (37° C., 5% CO 2 incubator) for 7 days.
  • a cell incubator 37° C., 5% CO 2 incubator
  • 5 ⁇ L of 0.05% dimethylsulfoxide (DMSO)/RPMI medium was treated. After 7 days, the cultured cells were recovered to confirm the effect of generating regulatory T cells to confirm the Foxp3 protein.
  • DMSO dimethylsulfoxide
  • the recovered cells were placed in a 5 mL FACS tube (BD Falcon) and washed with 1 mL of phosphate buffered saline. Cells were resuspended in 0.1 mL of FACS buffer (0.1% NaN 3 , 1% FBS) and treated with 1 ⁇ g of human immunoglobulin G (Human IgG, Sigma) to prevent non-specific binding of antibodies. After incubation at 4° C. for 15 minutes, cells were washed with FACS buffer. 1mL of Fixation/Permeabilization solution (eBioscience) was added to each FACS tube containing the sample, reacted at 4°C for 1 hour, and washed twice with Permeabilization buffer (eBioscience).
  • Ker-CT being cultured in KGM-Gold Bulletkit medium was washed with HBSS solution, treated with trypsin solution (ATCC), and incubated for 5 minutes in a cell incubator (5% CO 2 incubator), followed by KGM-Gold Bulletkit medium. was used to recover cells.
  • the recovered cells were centrifuged at room temperature for 5 minutes at a speed of 250 g, the supernatant was removed, resuspended in KGM-Gold Bulletkit medium, and the viability was confirmed to be 97% or more through trypan blue staining, 1 x 10 5 /ml was dispensed to 6 wells by 2 ml each.
  • each well was treated with each compound at a concentration of 2 ⁇ M, and after incubation in a cell incubator (5% CO 2 incubator) for 2 hours, IFN- ⁇ 200 U/ml, TNF- ⁇ 5 ng 5 ⁇ L was treated to become /mL and incubated in a cell incubator (5% CO 2 incubator) for 24 hours.
  • a cell incubator 5% CO 2 incubator
  • 2 ⁇ L of 0.05% dimethylsulfoxide (DMSO, Sigma)/medium was treated.
  • the medium of the cultured cells is recovered in a new microtube, and the cells are recovered with 1 ml of Trizol (invitrogen) and stored at -80°C.
  • FACS tube FACS tube
  • After mixing the capture bead solution by voltexing put 50 ⁇ L of each sample into the FACS tube. After voltexing, let stand at room temperature for 1 hour.
  • mRNA samples were prepared from Ker-CT cells of each experimental condition. mRNA was extracted by phenol-chloroform precipitation using Trizol reagent (Invitrozen, Cat No. 15596018). Synthesize cDNA from isolated RNA by reverse transcription and confirm expression of inflammatory cytokines by real-time PCR using iQ SYBR-Green Supermix (Bio-rad) in CFX96 (Bio-rad) detection system did.
  • the real-time polymerase chain reaction was carried out under conditions of 45 cycles with an annealing temperature of 58° C., and the following primer sequences were used.
  • compound 8 (PB312), compound 40 (PB502), and compound 26 (PB504) of the present invention can significantly inhibit the inflammatory-promoting effect of keratinocytes, a useful therapeutic strategy can be suggested as a novel psoriasis therapeutic agent.
  • asthma was induced in C57BL/6 mice with HDM, and compound 40 (PB502) was administered to evaluate the efficacy.
  • HDM House Dust Mite; Greer Laboratories, Cat No. NC9756554
  • Alum inject Alum Adjuvant, ThermoFisher, Cat No. 77161
  • sensitized by intraperitoneal administration in an amount of 0.1 mL From the 14th to the 16th, 50 ⁇ g of HDM was intranasally administered once a day for 3 days. Specifically, 30 ml of HDM was administered to the sensitized mice by inhalation anesthesia with isoflurane, 15 ml each in both nasal passages.
  • the lungs of the mice were removed to prepare a tissue sample.
  • a tissue sample After the lungs of the extracted mice were fixed with 4% paraformaldehyde (sigma aldrich), paraffin infiltration was performed using a tissue processor (Leica), and a paraffin block was prepared using an Embedding center (Leica). did.
  • the prepared paraffin block was cut to a thickness of 5 ⁇ m with a microtome (Leica) to prepare a tissue section.
  • Periodic Acid-Schiff (PAS, sigma aldrich) staining was performed on the completed tissue sections to perform histopathological analysis of the spinal cord.
  • mice On the 26th day of the experiment, the lungs of mice were removed to prepare mRNA samples. To extract mRNA, the lung tissue was ground with a homogenizer to obtain a homogenous suspension. mRNA from the homogeneous suspension was extracted by phenol-chloroform precipitation using Trizol reagent (Invitrozen, Cat No. 15596018). Synthesize cDNA from isolated RNA by reverse transcription and confirm expression of inflammatory cytokines by real-time PCR using iQ SYBR-Green Supermix (Bio-rad) in CFX96 (Bio-rad) detection system did. Relative values of enzyme expression levels were compared in the ⁇ ct method using GAPDH as a control enzyme. WT mouse spinal cords were used as controls to establish fold 1s.
  • mouse IL-4 forward 5'-TCA TCG GCA TTT TGA ACG AGG T-3' (SEQ ID NO: 9) and reverse, 5'-GCA TCG AAA AGC CCG AAA GAG-3' (SEQ ID NO: 10); mouse IL-1 ⁇ forward, 5'-CTC GTG CTG TCG GAC CCA TAT-3' (SEQ ID NO: 11) and reverse, 5'-TTG AAG ACA AAC CGC TTT TCC A-3' (SEQ ID NO: 12); Mouse TNF- ⁇ forward, 5′-CCA CAC CGT CAG CCG ATT TG-3′ (SEQ ID NO: 13) and reverse, 5′-CAC CCA TTC CCT TCA CAG AGC-3′ (SEQ ID NO: 14); mouse IL-17A forward, 5'-TTT AAC TCC CTT GGC GCA AAA-3
  • the expression levels of the inflammatory cytokines IL-4, TNF-a, IL-1 ⁇ , and IL-17A in the lung lesions were significantly decreased compared to the solvent control group due to the administration of Compound 40 (PB502) (compared to the solvent control group **, p ⁇ 0.01) ; ***, p ⁇ 0.001, see Fig. 7(B)).
  • the compound 40 (PB502) of the present invention has high therapeutic efficacy in a mouse model of asthma, so it can suggest a useful treatment strategy as a novel asthma treatment agent.
  • a BDA/2-> BDF1 immune cell adoptive transfer model was prepared as follows and the efficacy was evaluated by administering the compound.
  • the spleen (spleen) of DBA/2 mice (8 to 10 weeks old, female) was removed and crushed by adding RPMI medium, and then passed through a 40 ⁇ m cell strainer (BD Falcon) to obtain a single cell suspension. obtained.
  • the single cell suspension is centrifuged (1200 rpm, 5 min), then the supernatant is discarded, 1 mL of ACK (ammonium chloride/potassium bicarbonate) lysis buffer (0.15 M NH4Cl, 1 mM KHCO3, 0.1 mM Na2EDTA) is added and stirred for 1 minute. It was washed with phosphate buffered saline.
  • ACK ammonium chloride/potassium bicarbonate
  • Cells were prepared by resuspending in phosphate buffered saline at 1 ⁇ 10 8 /mL. 100 ⁇ L of DBA/2 splenocytes prepared in BDF1 mice (8-10 weeks old, female) were injected through the tail vein.
  • PB502 administration group according to the present invention
  • 20 mg/kg of compound per mouse was completely dissolved in DMSO corresponding to 10% (v/v) of the administered dose, and then final DMSO: Cremophor EL: phosphate buffer It was diluted in Cremophor EL-phosphate buffered saline mixture to obtain saline (1:1:8, v/v/v) and administered intraperitoneally every day for a total of 7 times from 1 to 7 days after transplantation in 200 ⁇ L.
  • the efficacy of the compounds was evaluated by measuring anti-nucleic acid IgG1 in blood 3 weeks after transplantation.
  • the anti-nucleic acid IgG1 in the blood was significantly lower in the compound 40 (PB502) administration group than in the solvent control group (compared to the solvent control group *, p ⁇ 0.05, see FIG. 8).
  • the compound 40 (PB502) of the present invention has a high therapeutic efficacy in a lupus mouse model, so it can present a useful therapeutic strategy as a novel lupus therapeutic agent.

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Abstract

The present invention pertains to a novel compound and a use thereof in treating psoriasis, asthma, or systemic lupus erythematosus. A pharmaceutical composition containing the novel compound of the present invention can not only control inflammation, but can also restore tissue homeostasis through immune balance and recovery from damaged tissues, and thus exhibits an excellent effect of treating and preventing psoriasis, asthma, or systemic lupus erythematosus.

Description

신규 화합물 및 이의 건선, 천식 또는 전신홍반루푸스의 치료 용도Novel compounds and their use for the treatment of psoriasis, asthma or systemic lupus erythematosus
본 발명은 신규 화합물 및 이의 건선, 천식 또는 전신홍반루푸스 치료 용도에 관한 것이다.The present invention relates to novel compounds and their use for the treatment of psoriasis, asthma or systemic lupus erythematosus.
사람의 신체는 면역 반응을 통하여 병원체로부터 보호받을 수 있는데, 바이러스나 박테리아와 같은 외래 미생물에 대한 생체방어 기작으로는 자연면역(innate immunity)과 특이면역(specific immunity)으로 나뉘어 지며, 이는 면역관련 세포에서 주로 분비되는 사이토카인에 의해 매개된다.The human body can be protected from pathogens through an immune response, and the biological defense mechanism against foreign microorganisms such as viruses or bacteria is divided into innate immunity and specific immunity, which are immune-related cells mediated primarily by cytokines secreted by
면역체계는 해로운 외부물질인 항원(antigen)으로부터 신체를 보호하는 역할을 한다. 이러한 항원의 종류로는 박테리아, 바이러스, 독소, 암세포와 다른 사람 혹은 동물로의 혈액과 조직이 이에 해당된다. 면역체계는 이러한 해로운 물질들을 파괴하기 위하여 항체를 생산하는데, 자가 면역에 이상이 생긴 경우, 면역체계는 자신의 신체 장기와 해로운 항원을 구분하지 못하여, 정상적인 조직을 파괴하게 되는데 이러한 반응을 통해 유발하는 질환이 자가면역질환(autoimmune disease)이다.The immune system plays a role in protecting the body from antigens, which are harmful foreign substances. Examples of these antigens include bacteria, viruses, toxins, cancer cells, and blood and tissues from other humans or animals. The immune system produces antibodies to destroy these harmful substances. When autoimmunity is abnormal, the immune system cannot distinguish its own body organs from harmful antigens and destroys normal tissues. The disease is an autoimmune disease.
아릴 하이드로카본 수용체(Aryl Hydrocarbon Receptor, AHR)는 PER-ARNT-SIM (PAS) superfamily에 속하는 리간드-의존성 전사 인자로서 장벽 조직의 면역세포, 상피세포, 내피세포, 기질세포(stromal)에서 주요하게 발현된다. AHR은 환경 센서(environmental sensor)이며 환경오염물질(예, 다이옥신)과 같은 xenobiotic 리간드(ligand) 뿐만 아니라 세포, 미생물, 음식물로부터 생성되는 생리적 리간드 또한 감지한다.Aryl Hydrocarbon Receptor (AHR) is a ligand-dependent transcription factor belonging to the PER-ARNT-SIM (PAS) superfamily and is mainly expressed in immune cells, epithelial cells, endothelial cells, and stromal cells of the barrier tissue. do. AHR is an environmental sensor and detects not only xenobiotic ligands such as environmental pollutants (eg, dioxins), but also physiological ligands produced from cells, microorganisms, and food.
불활성화형태의 AHR은 세포질에서 Hsp90:XAP2:p23:Src chaperone과 복합체(AHR chaperone complex)를 형성하여 리간드에 대한 높은 친화력을 지니는 구조를 유지하고 있다. 리간드 결합 후 AHR이 활성화되면, 복합체는 핵으로 이동하고 AHR은 chaperone 복합체로부터 떨어져 나와 표적 유전자의 upstream regulatory regions에 위치한 AHR-responsive DNA elements (xenobiotic response elements, XREs)에 결합하여 표적유전자의 발현을 조절한다. 생체 내 AHR을 활성화시킬 수 있는 무독성의 면역조절 리간드는 새로운 자가면역질환의 치료제로 개발될 수 있을 것이다.The inactivated form of AHR forms an AHR chaperone complex with the Hsp90:XAP2:p23:Src chaperone in the cytoplasm to maintain a structure with high affinity for the ligand. When AHR is activated after ligand binding, the complex moves to the nucleus and AHR separates from the chaperone complex and binds to AHR-responsive DNA elements (xenobiotic response elements, XREs) located in regulatory regions upstream of the target gene to regulate the expression of the target gene. do. A non-toxic immunomodulatory ligand capable of activating AHR in vivo could be developed as a new therapeutic agent for autoimmune diseases.
만성피부염증질환(chronic skin inflammatory disease)은 인체의 피부 표피층에 발생하는 만성적인 염증질환으로, 환경적-유전적 요인에 의한 면역불균형이 중요한 발병 요인으로 여겨지며 건선(psoriasis)과 아토피부염이 주요하다.Chronic skin inflammatory disease is a chronic inflammatory disease that occurs in the epidermal layer of the skin of the human body. Immune imbalance caused by environmental-genetic factors is considered as an important pathogenesis factor, and psoriasis and atopic dermatitis are the main factors. .
건선(psoriasis)은 피부 표피(epidermis) 층의 과증식과 다양한크기의 홍반 및 궤양 등이 동반되는 난치성 자가면역 피부질환이다. 건선의 주의 병인 기전은 각질형성세포(keratinocyte)의 과증식 및 과활성화가 주요 한데 이는 Th17 세포 반응에 의해 유도된다. 그 과정을 보면, 최초 피부 수지상세포의 과활성에 의한 TNF-a와 lL-23 생성이 Th17 세포의 염증 효력을 극대화시켜 IL-17의 생성이 증가하고 이에 의해 각질형성세포(keratinocyte)가 과증식 한다. 또한, TNF-a 등의 자극에 의해 각질형성세포가 추가 염증사이토카인 및 케모카인을 생성하여 염증백혈구의 조직 침윤을 촉진하고 지속화 시킨다. 최근 IL-23-IL-17 경로를 차단하는 항체치료제가 비교적 효과를 보이고 있지만 효과가 일시적이고 중증도가 높은 환자에서는 효과가 미약하다. 따라서 새로운 기전의 효과적인 신약개발이 요구되는 실정이다.Psoriasis is an intractable autoimmune skin disease accompanied by hyperproliferation of the epidermis layer and erythema and ulcers of various sizes. The main etiological mechanism of psoriasis is hyperproliferation and hyperactivation of keratinocytes, which are induced by Th17 cell responses. Looking at the process, the production of TNF-a and lL-23 by the overactivation of the first skin dendritic cells maximizes the inflammatory effect of Th17 cells, which increases the production of IL-17, which leads to hyperproliferation of keratinocytes. . In addition, keratinocytes generate additional inflammatory cytokines and chemokines by stimulation such as TNF-a, thereby promoting and sustaining tissue infiltration of inflammatory leukocytes. Recently, antibody therapeutics that block the IL-23-IL-17 pathway are relatively effective, but the effect is temporary and the effect is weak in patients with high severity. Therefore, there is a need for effective drug development with a new mechanism.
호흡기만성염증질환은 하기도, 상기도 및 폐실질 내 염증에 의해 만성적 호흡 곤란이 나타나는 질환이다. 호흡기는 수많은 비병원성 및 병원성 항원에 지속적으로 노출되기 때문에 이러한 항원들에 대한 면역방어와 함께 치명적인 면역병리 발생을 차단하기 위한 면역관용(immune tolerance) 기전이 발달되어 있다. 그러나 면역관용기전이 원활하지 못하면 염증질환으로 진행하게 된다.Respiratory chronic inflammatory disease is a disease in which chronic respiratory difficulties are caused by inflammation in the lower respiratory tract, upper airways and lung parenchyma. Since the respiratory tract is continuously exposed to numerous non-pathogenic and pathogenic antigens, an immune tolerance mechanism to block the occurrence of fatal immunopathology along with immune defense against these antigens has been developed. However, if the immune tolerance mechanism is not smooth, it will progress to an inflammatory disease.
천식은 대표적 호흡기만성염증질환으로 과도한 Th2/Th17-매개 염증반응이 주요 병인기전이며 현재 염증 조절을 위한 스테로이드와 기관지 근육 수축 완화를 위한 β2 항진제가 사용되고 있다. 국내 19세 이상 성인의 비율이 2015년 61%에서 2019년 66%로 증가. 비알레르기 천식 환자의 비중이 높아지는 추세이다.Asthma is a representative respiratory chronic inflammatory disease. Excessive Th2/Th17-mediated inflammatory response is the main etiological mechanism. Currently, steroids to control inflammation and β2 agonists to relieve bronchial muscle contraction are used. The proportion of adults aged 19 and over in Korea increased from 61% in 2015 to 66% in 2019. The proportion of patients with non-allergic asthma is increasing.
천식은 기존 치료법으로 완치가 불가능하고 효과가 미약하고 일시적이기 때문에 신약 개발의 필요성이 높은 실정이다. 병인기전이 다양하고 복잡하기 때문에 복합치료가 기본이기 때문에 다양한 신규 기전의 표적약물 개발이 필요하다. 또한 병소의 염증반응을 효과적으로 제어함과 동시에 손상된 상피조직을 회복시킬 수 있는 전략이 필요하다.Asthma cannot be cured with existing treatments, and the effect is weak and temporary, so there is a high need for developing new drugs. Because the etiological mechanism is diverse and complex, complex treatment is the basic, so it is necessary to develop target drugs with various novel mechanisms. In addition, a strategy that can effectively control the inflammatory response of the lesion and restore the damaged epithelial tissue is needed.
루프스(Lupus, systemic lupus erythematosus)는 관절, 신장, 피부, 점막, 혈관벽 등에 나타나는 자가면역 염증질환이다. 70-90%의 환자가 가임기 여성이고, 백인보다는 흑인과 아시아인에서 유병률이 높다. 정상 세포의 핵산(nucleic acid)에 대한 자가항체 생성이 특징이다. 다양한 질환 증상 중에 공동적인 것은 B-세포의 면역 관용(immune tolerance)이 소실되는 것이다. 현재 치료로 항말라리아제, 항염증 및 면역억제제가 처방되는데 효과가 미약하고 부작용이 높아 B-세포 면역 관용을 회복시킬 수 있는 새로운 치료제의 개발이 시급하다.Lupus (systemic lupus erythematosus) is an autoimmune inflammatory disease that appears in joints, kidneys, skin, mucous membranes, and blood vessel walls. 70-90% of patients are women of childbearing age, and the prevalence is higher in blacks and Asians than in whites. It is characterized by the production of autoantibodies against nucleic acids in normal cells. Common among the various disease symptoms is the loss of immune tolerance of B-cells. Currently, antimalarial drugs, anti-inflammatory drugs, and immunosuppressive drugs are prescribed for treatment, but the effect is weak and side effects are high, so it is urgent to develop a new therapeutic agent that can restore B-cell immune tolerance.
DBA/2 마우스의 비장세포를 BDF1 마우스에 양입(adoptive transfer)하면 루푸스의 면역 병인 특징인 항-nucleic acid 항체의 생성이 발생하고 B-세포의 면역 관용이 소실된다. 그래서 루프스의 치료제 개발이 주요하게 이용되고 있다.Adoptive transfer of splenocytes from DBA/2 mice to BDF1 mice results in the production of anti-nucleic acid antibodies, a characteristic feature of the immune pathogenesis of lupus, and loss of immune tolerance of B-cells. Therefore, the development of a treatment for lupus is being mainly used.
본 발명은 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a novel compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
본 발명은 건선, 천식 또는 전신홍반루푸스 예방 및 치료에 유용한 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a novel compound useful for the prevention and treatment of psoriasis, asthma, or systemic lupus erythematosus, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명은 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 포함하는 건선, 천식 또는 전신홍반루푸스 예방 또는 치료용 약학 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating psoriasis, asthma, or systemic lupus erythematosus, comprising a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
1. 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 포함하는 건선, 천식 또는 전신홍반루푸스의 치료 또는 예방용 약학 조성물: 1. A pharmaceutical composition for the treatment or prevention of psoriasis, asthma, or systemic lupus erythematosus, comprising a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2022004585-appb-img-000001
Figure PCTKR2022004585-appb-img-000001
(식 중, R1 내지 R4는 각각 독립적으로 수소 또는 할로겐이고, R5 및 R6은 독립적으로 수소 또는 C1-C5의 알킬이며,(Wherein, R 1 to R 4 are each independently hydrogen or halogen, R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl,
A는 C5-C12의 단일 또는 이중 환형기이고,A is a C 5 -C 12 single or double cyclic group,
상기 환형기의 각 환은 1 내지 3개의 헤테로 원자로 치환될 수 있으며,Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms,
상기 환형기는 할로겐, C1-C5의 알킬 또는 C1-C5의 알콕시로 치환될 수 있음).The cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy).
2. 위 1에 있어서, A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:2. The pharmaceutical composition according to the above 1, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000002
Figure PCTKR2022004585-appb-img-000002
(식 중, Q1 내지 Q15는 각각 독립적으로 C, N 또는 S이고, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시이며, Q4가 N이면 R11은 없음).(Wherein, Q 1 to Q 15 are each independently C, N or S, and R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; If Q 4 is N, then R 11 is absent).
3. 위 1에 있어서, A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:3. The pharmaceutical composition of 1 above, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000003
Figure PCTKR2022004585-appb-img-000003
(식 중, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
4. 위 1에 있어서, A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:4. The pharmaceutical composition of 1 above, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000004
Figure PCTKR2022004585-appb-img-000004
(식 중, R7 내지 R24는 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
5. 위 1에 있어서, A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:5. The pharmaceutical composition according to the above 1, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000005
Figure PCTKR2022004585-appb-img-000005
(식 중, R9 내지 R16은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
6. 위 1에 있어서, R2 및 R3가 각각 독립적으로 F, Cl 또는 Br인, 약학 조성물.6. The pharmaceutical composition of the above 1, wherein R 2 and R 3 are each independently F, Cl or Br.
7. 위 1에 있어서, 화학식 1로 표시되는 화합물은 다음 화합물로 이루어진 그룹으로부터 선택되는 것인, 약학 조성물:7. The pharmaceutical composition according to the above 1, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds:
N-(5-브로모-6-메틸피리딘-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
2-(1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
N-(3,5-디클로로페닐)-2-(1H-인돌-3-일)아세트아마이드;N-(3,5-dichlorophenyl)-2-(1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(3,5-디클로로페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,5-dichlorophenyl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(피리딘-4-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide;
N-(벤조[디]티아졸-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)-N-methylacetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)-N-methylacetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(6-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(6-chloro-1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(티아졸-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(thiazol-2-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(퀴놀린-2-일)아세트아마이드; 및2-(5-chloro-1H-indol-3-yl)-N-(quinolin-2-yl)acetamide; and
2-(5-클로로-1H-인돌-3-일)-N-(4,5,6,7-테트라히드로벤조[디]티아졸-2-일)아세트아마이드.2-(5-Chloro-1H-indol-3-yl)-N-(4,5,6,7-tetrahydrobenzo[di]thiazol-2-yl)acetamide.
8. 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 건선, 천식 또는 전신홍반루푸스의 치료 방법:8. A method of treating psoriasis, asthma, or systemic lupus erythematosus, comprising administering to a subject in need thereof a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2022004585-appb-img-000006
Figure PCTKR2022004585-appb-img-000006
(식 중, R1 내지 R4는 각각 독립적으로 수소 또는 할로겐이고, R5 및 R6은 독립적으로 수소 또는 C1-C5의 알킬이며,(Wherein, R 1 to R 4 are each independently hydrogen or halogen, R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl,
A는 C5-C12의 단일 또는 이중 환형기이고,A is a C 5 -C 12 single or double cyclic group,
상기 환형기의 각 환은 1 내지 3개의 헤테로 원자로 치환될 수 있으며,Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms,
상기 환형기는 할로겐, C1-C5의 알킬 또는 C1-C5의 알콕시로 치환될 수 있음).The cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy).
9. 위 8에 있어서, A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:9. The method of treatment according to 8 above, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000007
Figure PCTKR2022004585-appb-img-000007
(식 중, Q1 내지 Q15는 각각 독립적으로 C, N 또는 S이고, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시이며, Q4가 N이면 R11은 없음).(Wherein, Q 1 to Q 15 are each independently C, N or S, and R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; If Q 4 is N, then R 11 is absent).
10. 위 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:10. The method of treatment according to 8 above, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000008
Figure PCTKR2022004585-appb-img-000008
(식 중, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
11. 위 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:11. The method of treatment according to 8 above, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000009
Figure PCTKR2022004585-appb-img-000009
(식 중, R7 내지 R24는 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
12. 위 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:12. The method of treatment according to 8 above, wherein A is selected from the group consisting of the following cyclic groups:
Figure PCTKR2022004585-appb-img-000010
Figure PCTKR2022004585-appb-img-000010
(식 중, R9 내지 R16은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
13. 위 8에 있어서, R2 및 R3가 각각 독립적으로 F, Cl 또는 Br인, 치료 방법.13. The method of treatment according to 8 above, wherein R 2 and R 3 are each independently F, Cl or Br.
14. 8에 있어서, 상기 화학식 1로 표시되는 화합물은 다음 화합물로 이루어진 그룹으로부터 선택되는 것인, 치료 방법:14. The method of treatment 8, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds:
N-(5-브로모-6-메틸피리딘-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
2-(1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
N-(3,5-디클로로페닐)-2-(1H-인돌-3-일)아세트아마이드;N-(3,5-dichlorophenyl)-2-(1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(3,5-디클로로페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,5-dichlorophenyl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(피리딘-4-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide;
N-(벤조[디]티아졸-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)-N-methylacetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)-N-methylacetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(6-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(6-chloro-1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(티아졸-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(thiazol-2-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(퀴놀린-2-일)아세트아마이드; 및2-(5-chloro-1H-indol-3-yl)-N-(quinolin-2-yl)acetamide; and
2-(5-클로로-1H-인돌-3-일)-N-(4,5,6,7-테트라히드로벤조[디]티아졸-2-일)아세트아마이드.2-(5-Chloro-1H-indol-3-yl)-N-(4,5,6,7-tetrahydrobenzo[di]thiazol-2-yl)acetamide.
15. 위 1 내지 7 중 어느 한 항의 약학 조성물의 건선, 천식 또는 전신홍반루푸스의 예방 또는 치료 용도.15. Use of the pharmaceutical composition of any one of 1 to 7 above for the prophylaxis or treatment of psoriasis, asthma, or systemic lupus erythematosus.
16. 건선, 천식 또는 전신홍반루푸스의 예방 또는 치료를 위한 약제의 제조에 있어 청구항 1 내지 7 중 어느 한 항의 약학 조성물의 용도.16. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for the prophylaxis or treatment of psoriasis, asthma or systemic lupus erythematosus.
본 발명의 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염은 면역조절 전사인자인 AHR 활성을 유도하여 염증제어뿐 아니라 면역 밸런스 및 손상 조직을 복구할 수 있는 효과가 있다.The novel compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof induces AHR activity, which is an immunoregulatory transcription factor, to control inflammation as well as to restore immune balance and damaged tissues.
본 발명의 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염은 염증인자인 IL-6의 생성을 억제하여 과도한 면역 반응, 구체적으로 자가면역반응을 조절할 수 있는 효과가 있다.The novel compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has an effect of inhibiting the production of IL-6, an inflammatory factor, to control an excessive immune response, specifically, an autoimmune response.
본 발명의 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염은 조절 T 세포(Treg)의 활성을 유도하는 효과가 있다. The novel compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has an effect of inducing the activity of regulatory T cells (Treg).
또한, 본 발명의 신규 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염은 상기 염증인자들의 조절을 통해 건선, 천식 또는 전신홍반루푸스 예방 및 치료 효과가 있다.In addition, the novel compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof has an effect of preventing and treating psoriasis, asthma, or systemic lupus erythematosus by controlling the inflammatory factors.
도 1 및 도 2는 본 발명 화합물의 세포배양 조건에서 AHR 리간드임을 확인하기 위해, CYP1A1 발현량을 측정하여 나타낸 것이다. 1 and 2 show the measurement of the expression level of CYP1A1 in order to confirm that the compound of the present invention is an AHR ligand in cell culture conditions.
도 3 및 도 4는 본 발명 화합물의 염증인자 IL-6 생성 억제 효과를 측정하여 나타낸 것이다. 3 and 4 show the measurement of the inhibitory effect of the compound of the present invention on the production of the inflammatory factor IL-6.
도 5는 본 발명 화합물의 Foxp3+ 조절 T 세포 생성 효과를 측정하여 나타낸 것이다.Figure 5 shows the measurement of the effect of the compound of the present invention on Foxp3+ regulatory T cell generation.
도 6은 본 발명에 따른 화합물의 건선 치료 효과 측정 결과를 도시한 것이다.6 shows the measurement results of the psoriasis treatment effect of the compound according to the present invention.
도 7은 본 발명에 따른 화합물의 천식 치료 효과 측정 결과를 도시한 것이다.7 shows the results of measuring the asthma treatment effect of the compound according to the present invention.
도 8은 본 발명에 따른 화합물의 루프스 치료 효과 측정 결과를 도시한 것이다.8 shows the results of measuring the lupus treatment effect of the compound according to the present invention.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다.All technical terms used in the present invention, unless otherwise defined, have the same meaning as commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염에 관한 것이다.The present invention relates to a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2022004585-appb-img-000011
Figure PCTKR2022004585-appb-img-000011
상기 구조식에서 치환기가 필요한 자리이나, 어떠한 치환기도 기재되지 않은 경우, 수소 치환기를 생략한 것이며, 이는 본 발명의 모든 구조식에서 동일하게 적용된다. In the above structural formula, if a substituent is required, but no substituent is described, a hydrogen substituent is omitted, and this is equally applied to all structural formulas of the present invention.
상기 식 중, R1 내지 R4는 각각 독립적으로 수소 또는 할로겐이고, 구체적으로 수소, 플루오르 또는 염소일 수 있으나, 이에 제한되는 것은 아니다. In the above formula, R 1 to R 4 are each independently hydrogen or halogen, and specifically, may be hydrogen, fluorine, or chlorine, but is not limited thereto.
상기 식 중, R5 및 R6은 독립적으로 수소 또는 C1-C5의 알킬일 수 있고, 구체적으로 수소, 메틸 또는 에틸일 수 있고, 더 구체적으로는 수소 또는 메틸일 수 있으나, 이에 제한되는 것은 아니다. In the above formula, R 5 and R 6 may independently be hydrogen or C 1 -C 5 alkyl, specifically hydrogen, methyl or ethyl, and more specifically hydrogen or methyl, but are not limited thereto. it is not
상기 식 중, A는 C5-C12의 단일 또는 이중 환형기이고, 구체적으로, 사이클로펜타-1,3-디엔, 벤젠, 사이클로헥산, 인덴, 4,5,6,7-테트라히드로인덴, 나프탈렌, 1,2,3,4-테트라히드로나프탈렌, 1,6-디히드로펜탈렌 등일 수 있으나, 이에 제한되는 것은 아니다. In the above formula, A is a C 5 -C 12 single or double cyclic group, specifically, cyclopenta-1,3-diene, benzene, cyclohexane, indene, 4,5,6,7-tetrahydroindene , naphthalene, 1,2,3,4-tetrahydronaphthalene, 1,6-dihydropentalene, etc., but is not limited thereto.
상기 환형기의 각 환은 1 내지 3개의 헤테로 원자로 치환될 수 있고, 예를 들어 각각 독립적으로 1 내지 3개의 원자가 N, S, O 등으로 치환될 수 있으나, 이에 제한되는 것은 아니다. 상기 헤테로 원자는 탄소나 수소가 아닌 원자를 의미한다. Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms, for example, each independently 1 to 3 atoms may be substituted with N, S, O, etc., but is not limited thereto. The hetero atom refers to an atom other than carbon or hydrogen.
또한, 상기 헤테로 원자가 치환될 수 있는 위치는 구체적으로 하기 나열된 구조에서 Q1 내지 Q15와 같을 수 있으나, 이에 제한되는 것은 아니다. In addition, the position at which the hetero atom may be substituted may be the same as Q 1 to Q 15 in the structures specifically listed below, but is not limited thereto.
Figure PCTKR2022004585-appb-img-000012
Figure PCTKR2022004585-appb-img-000012
상기 구조식에서 Q4가 N이면 Q4 위치에 추가로 치환될 수 없으므로, R11은 없는 경우라고 볼 수 있다. In the structural formula, if Q 4 is N, it cannot be further substituted at the Q 4 position, so it can be seen that R 11 is absent.
상기 환형기는 할로겐, C1-C5의 알킬 또는 C1-C5의 알콕시로 치환될 수 있고, 예를 들어 F, Cl, 메틸기, 에틸기, 메톡시, 에톡시 등일 수 있으나, 이에 제한되는 것은 아니다. The cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy, for example, F, Cl, methyl group, ethyl group, methoxy, ethoxy, etc., but may be limited thereto not.
상기 환형기에서 할로겐, C1-C5의 알킬 또는 C1-C5의 알콕시로 치환될 수 있는 위치는 구체적으로 R7 내지 R30과 같을 수 있으나, 이에 제한되는 것은 아니다. In the cyclic group, positions that may be substituted with halogen, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy may be specifically the same as those of R 7 to R 30 , but is not limited thereto.
본 발명의 일 실시예에 따르면, 상기 A는 다음의 환형기에서 선택될 수 있다. According to an embodiment of the present invention, A may be selected from the following cyclic groups.
Figure PCTKR2022004585-appb-img-000013
Figure PCTKR2022004585-appb-img-000013
(식 중, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
상기 본 발명의 일 실시예에 따르면, 구체적으로 상기 A는 다음의 환형기에서 선택될 수 있다.According to an embodiment of the present invention, specifically, A may be selected from the following cyclic groups.
Figure PCTKR2022004585-appb-img-000014
Figure PCTKR2022004585-appb-img-000014
(식 중, R7 내지 R24는 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
또한, 상기 본 발명의 일 실시예에 따르면, 더 구체적으로 상기 A는 다음의 환형기에서 선택될 수 있다.In addition, according to an embodiment of the present invention, more specifically, A may be selected from the following cyclic groups.
Figure PCTKR2022004585-appb-img-000015
Figure PCTKR2022004585-appb-img-000015
(식 중, R9 내지 R16은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
하기 화합물들은 화학식 1로 표시되는 화합물에서 구체적으로 R1 내지 R6 및 A의 조합을 통해 화학식 1로 표시되는 화합물 구조의 예시(화합물 1 내지 128)를 나타낸 것이다. The following compounds show examples of the structure of the compound represented by Formula 1 (Compounds 1 to 128) through a combination of R 1 to R 6 and A in the compound represented by Formula 1 specifically.
Figure PCTKR2022004585-appb-img-000016
Figure PCTKR2022004585-appb-img-000016
Figure PCTKR2022004585-appb-img-000017
Figure PCTKR2022004585-appb-img-000017
Figure PCTKR2022004585-appb-img-000018
Figure PCTKR2022004585-appb-img-000018
Figure PCTKR2022004585-appb-img-000019
Figure PCTKR2022004585-appb-img-000019
Figure PCTKR2022004585-appb-img-000020
Figure PCTKR2022004585-appb-img-000020
Figure PCTKR2022004585-appb-img-000021
Figure PCTKR2022004585-appb-img-000021
Figure PCTKR2022004585-appb-img-000022
Figure PCTKR2022004585-appb-img-000022
Figure PCTKR2022004585-appb-img-000023
Figure PCTKR2022004585-appb-img-000023
Figure PCTKR2022004585-appb-img-000024
Figure PCTKR2022004585-appb-img-000024
Figure PCTKR2022004585-appb-img-000025
Figure PCTKR2022004585-appb-img-000025
본 발명은 다음 화합물로 이루어진 그룹으로부터 선택되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염에 관한 것일 수 있다. The present invention may relate to a compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
N-(5-브로모-6-메틸피리딘-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
2-(1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
N-(3,5-디클로로페닐)-2-(1H-인돌-3-일)아세트아마이드;N-(3,5-dichlorophenyl)-2-(1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(3,5-디클로로페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,5-dichlorophenyl)acetamide;
N-(5-브로모-6-메틸피리딘-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(피리딘-4-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide;
N-(벤조[디]티아졸-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)-N-methylacetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)-N-methylacetamide;
N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)-N-methylacetamide;
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
N-(벤조[디]티아졸-2-일)-2-(6-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(6-chloro-1H-indol-3-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(티아졸-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(thiazol-2-yl)acetamide;
2-(5-클로로-1H-인돌-3-일)-N-(퀴놀린-2-일)아세트아마이드; 및2-(5-chloro-1H-indol-3-yl)-N-(quinolin-2-yl)acetamide; and
2-(5-클로로-1H-인돌-3-일)-N-(4,5,6,7-테트라히드로벤조[디]티아졸-2-일)아세트아마이드.2-(5-Chloro-1H-indol-3-yl)-N-(4,5,6,7-tetrahydrobenzo[di]thiazol-2-yl)acetamide.
또한, 본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물에 관한 것이다. Further, the present invention relates to a pharmaceutical composition comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
상기 약학 조성물은 건선, 천식 또는 전신홍반루푸스(Systemic lupus erythematosus; SLE)의 치료 또는 예방용 약학 조성물일 수 있다.The pharmaceutical composition may be a pharmaceutical composition for treatment or prevention of psoriasis, asthma, or systemic lupus erythematosus (SLE).
상기 '천식'은 특정한 유발 원인 물질에 노출되었을 때 기관지의 염증에 의해 기침, 호흡곤란 등의 증상이 반복적으로 발생하는 질환으로서, 감염, 흡연, 알레르기 항원 등에 의해 발생할 수 있으나, 이에 제한되는 것은 아니다.The 'asthma' is a disease in which symptoms such as coughing and shortness of breath occur repeatedly due to inflammation of the bronchial tubes when exposed to a specific causative agent, and may be caused by infection, smoking, allergens, etc., but is not limited thereto .
상기 '건선'은 면역 시스템 이상으로 피부 또는 관절에 발생하는 염증 질환으로, 외양이 흉하게 변하고, 각질이 일어나고, 홍반성 플라크(erythematous plaques)가 생기며, 고통을 수반하는 등의 문제점을 야기한다. 건선은 건선성 관절염, 방울 건선, 농포 건선, 홍색 피부 건선, 두피 건선, 손톱 건선 및 골부착 부위염으로부터 선택되는 어느 하나 이상의 질환들을 포함할 수 있다.The 'psoriasis' is an inflammatory disease that occurs in the skin or joints due to an abnormality of the immune system, and causes problems such as an ugly appearance, keratin, erythematous plaques, and pain. Psoriasis may include any one or more diseases selected from psoriatic arthritis, psoriasis psoriasis, pustular psoriasis, erythema psoriasis, scalp psoriasis, nail psoriasis, and osseointegritis.
상기 '전신홍반루푸스'는 '루푸스'라고도 호칭되며, 만성 염증성 자가면역질환으로 결합조직과 피부, 관절, 혈액, 신장 등 신체의 다양한 기관을 침범하는 전신성 질환을 의미한다. 정확한 원인은 알려져 있지 않으나, 그간의 연구에 의하면 유전적 요인이 이 병의 발생과 연관이 되어 있다고 알려져 있다. 미국류마티스학회(American College of Rheumatology, ACR)는 루푸스를 진단하는데 도움을 주기 위해 다른 질병과의 감별에 도움이 되는 11가지 증상, 징후 및 검사소견을 발표하였고, 11가지 항목 중 4가지 이상이 나타나면 루푸스로 진단을 내릴 수 있다.The 'systemic lupus erythematosus', also called 'lupus', is a chronic inflammatory autoimmune disease that refers to a systemic disease that invades various organs of the body, such as connective tissue, skin, joints, blood, and kidneys. The exact cause is not known, but according to previous studies, it is known that genetic factors are associated with the development of this disease. The American College of Rheumatology (ACR) published 11 symptoms, signs, and test findings that help differentiate it from other diseases to help diagnose lupus. You can be diagnosed with lupus.
본 발명에서 약학 조성물은 본 발명의 화합물인 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조되거나, 포유동물에게 투여될 수 있다. 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.In the present invention, the pharmaceutical composition may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, which is the compound of the present invention, or may be administered to a mammal. As the auxiliary agent, an excipient, a disintegrant, a sweetener, a binder, a coating agent, an expanding agent, a lubricant, a lubricant, or a flavoring agent may be used.
또한, 본 발명의 약학 조성물은 투여를 위해서 상기 기재한 약학적으로 유효한 양의 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.In addition, the pharmaceutical composition of the present invention may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the above-described pharmaceutically effective amount of the active ingredient for administration.
상기 '약학적으로 유효한 양'은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The 'pharmaceutically effective amount' means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, activity of the drug, and the drug in the patient. Sensitivity, administration time, administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field may be determined. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01 내지 100mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, in general 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg, may be administered daily or every other day, or divided into 1 to 3 times a day. However, the dosage may be increased or decreased according to the route of administration, the severity of obesity, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.
또한, 상기 '약제학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. In addition, the 'pharmaceutically acceptable' refers to a composition that is physiologically acceptable and does not normally cause gastrointestinal disorders, allergic reactions such as dizziness or similar reactions when administered to humans.
상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
또한, 본 발명의 조성물은 인간을 포함하는 본 발명의 약학 조성물을 필요로 하는 개체에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캡슐, 멸균 주사용액, 멸균 분말일 수 있다.In addition, the composition of the present invention is formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a subject in need of the pharmaceutical composition of the present invention, including humans. can be Formulations may be powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 건선, 천식 또는 전신홍반루푸스의 치료 방법에 관한 것일 수 있다.The present invention may relate to a method for treating psoriasis, asthma, or systemic lupus erythematosus, comprising administering the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
또한, 본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 투여하는 단계를 포함하는 AHR의 활성 유도 방법에 관한 것일 수 있다.In addition, the present invention may relate to a method for inducing activity of AHR comprising administering the compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
구체적으로, 본 발명의 화합물은 면역조절전사인자인 아릴 하이드로카본 수용체(AHR)을 표적으로 하여 AHR 활성을 유도하는 작용제로서의 역할을 하여 염증제어, 면역 밸런스 조절 및 손상 조직을 복구하여 건선, 천식 또는 전신홍반루푸스의 치료 용도로 쓰일 수 있으나, 이에 제한되는 것은 아니다. 기존 리간드들은 독성이 있고, 친화력 및 구조 안정성이 낮고, 표적 비특이성이 높아 약학 조성물로 개발하기 적합하지 못한 문제가 있었던 반면, 본 발명의 "Drug-like properties"를 가지는 화합물로 AHR 활성을 유도하게 되면, 효과적으로 건선, 천식 또는 전신홍반루푸스의 치료 및 예방에 사용될 수 있다. Specifically, the compound of the present invention acts as an agent inducing AHR activity by targeting the aryl hydrocarbon receptor (AHR), which is an immunomodulatory transcription factor, thereby controlling inflammation, regulating immune balance, and repairing damaged tissues to prevent psoriasis, asthma or It may be used for the treatment of systemic lupus erythematosus, but is not limited thereto. Existing ligands are toxic, have low affinity and structural stability, and have high target specificity, making them unsuitable for development as a pharmaceutical composition, whereas the compound having "drug-like properties" of the present invention induces AHR activity. It can be effectively used for the treatment and prevention of psoriasis, asthma or systemic lupus erythematosus.
본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 투여하는 단계를 포함하는 IL-6의 생성 억제 방법에 관한 것일 수 있다. The present invention may relate to a method for inhibiting the production of IL-6, comprising administering the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
구체적으로, 본 발명의 화합물은, 염증인자인 IL-6가 건선, 천식 또는 전신홍반루푸스를 유발하는 것으로 알려져 있으므로, 이의 생성을 억제하는 기전을 통해 건선, 천식 또는 전신홍반루푸스의 치료에 사용될 수 있고, 실제로 IL-6를 억제하는 것을 치료 타겟으로 하는 건선, 천식 또는 전신홍반루푸스의 치료제 및 관련 논문이 다수 공지되어 있다. 본 발명의 화합물도 IL-6의 생성을 억제하는 것이 하기 실험 데이터로 확인되어 자가면역반응을 감소시키는 효과가 있을 것으로 예상되므로, 건선, 천식 또는 전신홍반루푸스의 치료 및 예방에 사용될 수 있다. Specifically, since the compound of the present invention is known to cause psoriasis, asthma or systemic lupus erythematosus, the inflammatory factor IL-6, can be used for the treatment of psoriasis, asthma or systemic lupus erythematosus through a mechanism of inhibiting its production. In fact, a number of therapeutics and related papers for psoriasis, asthma, or systemic lupus erythematosus targeting IL-6 inhibition are known. Since the compound of the present invention is also expected to have an effect of reducing the autoimmune response as confirmed by the following experimental data to inhibit the production of IL-6, it can be used for the treatment and prevention of psoriasis, asthma, or systemic lupus erythematosus.
본 발명은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 포함하는 약학 조성물의 건선, 천식 또는 전신홍반루푸스의 예방 또는 치료 용도에 관한 것이다.The present invention relates to the use of a pharmaceutical composition comprising the compound, a stereoisomer or a pharmaceutically acceptable salt thereof for the prevention or treatment of psoriasis, asthma or systemic lupus erythematosus.
본 발명은 건선, 천식 또는 전신홍반루푸스의 예방 또는 치료를 위한 약제의 제조에 있어 청구항 1 내지 7 중 어느 한 항의 약학 조성물의 용도에 관한 것이다.The present invention relates to the use of the pharmaceutical composition of any one of claims 1 to 7 in the manufacture of a medicament for the prophylaxis or treatment of psoriasis, asthma or systemic lupus erythematosus.
본 발명의 화학식 1로 표시되는 화합물은 각종 문헌에 알려져 있는 방법으로 제조할 수 있다. 하기 제조예에서 상기 표 1에 기재된 화합물 중 일부의 합성 방법을 간략하게 기재하였으나, 이에 제한되는 것은 아니다. The compound represented by Formula 1 of the present invention can be prepared by a method known in various literatures. Although the synthesis method of some of the compounds shown in Table 1 was briefly described in the following Preparation Examples, the present invention is not limited thereto.
이하, 본 발명의 제조예 및 실시예를 통해 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail through preparation examples and examples of the present invention.
제조예production example
1. N-(5-브로모-6-메틸피리딘-2-일)-2-(5-클로로-1H-인돌-3-일)아세트 아마이드 (화합물 8)의 합성1. Synthesis of N-(5-bromo-6-methylpyridin-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide (Compound 8)
[반응식 1] [Scheme 1]
Figure PCTKR2022004585-appb-img-000026
Figure PCTKR2022004585-appb-img-000026
실온에서 2-(5-클로로-1H-인돌-3-일)아세트산(1.00g, 4.77mmol)의 CH2Cl2(30 mL) 용액을 교반하면서 5-브로모-6-메틸피리딘-2-아민(892 mg, 4.77 mmol), 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸[4,5-b]피리디늄-3-옥사이드헥사플루오로포스페이트(HATU, 2.18g, 5.72mmol)와 트리메틸아민(1.33 mL, 9.54 mmol)을 순차적으로 적가하였다. 반응 혼합물을 실온에서 3일간 교반하고, 혼합물에 증류수(10 mL)를 가하여 반응을 종결하였다. 층을 분리하고 유기층을 증류수로 세척하고, 무수 Na2SO4로 건조한 뒤, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피 (SiO2, hexanes:EtOAc = 4:1 - 2:1)로 정제하여 연한 회색의 화합물 (970 mg, 54%)을 얻었다. 5-bromo-6-methylpyridin-2-amine (892) with stirring a solution of 2-(5-chloro-1H-indol-3-yl)acetic acid (1.00 g, 4.77 mmol) in CH2Cl2 (30 mL) at room temperature mg, 4.77 mmol), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazole [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU, 2.18 g, 5.72 mmol) and trimethylamine (1.33 mL, 9.54 mmol) were sequentially added dropwise. The reaction mixture was stirred at room temperature for 3 days, and distilled water (10 mL) was added to the mixture to terminate the reaction. The layers were separated, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography (SiO 2 , hexanes:EtOAc = 4:1 - 2:1) to obtain a light gray compound (970 mg, 54%).
1H NMR (CDCl3, 400 MHz): δ 8.67 (br s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.97 (br s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.14 (m, 2H), 3.84 (s, 2H), 2.45 (s, 3H). 1 H NMR (CDCl 3 , 400 MHz): δ 8.67 (br s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.97 (br s, 1H), 7.55 (d, J = 4.0 Hz, 1H) ), 7.23 (d, J = 8.0 Hz, 1H), 7.14 (m, 2H), 3.84 (s, 2H), 2.45 (s, 3H).
2. N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트 아마이드(화합물 40)의 합성2. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide (compound 40)
[반응식 2][Scheme 2]
Figure PCTKR2022004585-appb-img-000027
Figure PCTKR2022004585-appb-img-000027
상기 제조예 1의 아민을 벤조[디]티아졸-2-아민으로 변경하여 동일한 실험방법으로 흰색의 표제 화합물(1.31 g, 80%)을 얻었다. The amine of Preparation Example 1 was changed to benzo [di] thiazol-2-amine, and the white title compound (1.31 g, 80%) was obtained by the same experimental method.
1H NMR (DMSO-d6, 400 MHz): δ 12.58 (br s, 1H), 11.20 (br s, 1H), 7.95 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.43 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.39 (m, 2H), 7.29 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.09 (dd, J = 8.0, 4.0 Hz, 1H), 3.91 (s, 2H). 1 H NMR (DMSO-d6, 400 MHz): δ 12.58 (br s, 1H), 11.20 (br s, 1H), 7.95 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 ( d, J = 4.0 Hz, 1H), 7.43 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.39 (m, 2H), 7.29 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.09 (dd, J = 8.0, 4.0 Hz, 1H), 3.91 (s, 2H).
3. 2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일) 아세트아마이드(화합물 26)의 합성3. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide (Compound 26)
[반응식 3][Scheme 3]
Figure PCTKR2022004585-appb-img-000028
Figure PCTKR2022004585-appb-img-000028
상기 제조예 1의 아민을 5-클로로-6-플루오로피리딘-2-아민으로 변경하여 동일한 실험방법으로 연한 노란색의 표제 화합물(560 mg, 35%)을 얻었다. The amine of Preparation Example 1 was changed to 5-chloro-6-fluoropyridin-2-amine to obtain a pale yellow title compound (560 mg, 35%) by the same experimental method.
1H NMR (CDCl3, 400 MHz): δ 8.38 (br s, 1H), 8.14 (dd, J = 8.0, 2.0 Hz, 1H), 7.87 (br s, 1H), 7.77 (dd, J = 8.0, 8.0 Hz, 1H), 7.54 (dd, J = 4.0, 2.0 Hz, 1H), 7.33 (dd, J = 8.0, 0.8 Hz, 1H), 7.21 (m, 2H), 3.87 (s, 2H). 1 H NMR (CDCl 3 , 400 MHz): δ 8.38 (br s, 1H), 8.14 (dd, J = 8.0, 2.0 Hz, 1H), 7.87 (br s, 1H), 7.77 (dd, J = 8.0, 8.0 Hz, 1H), 7.54 (dd, J = 4.0, 2.0 Hz, 1H), 7.33 (dd, J = 8.0, 0.8 Hz, 1H), 7.21 (m, 2H), 3.87 (s, 2H).
4. N-(5-브로모-6-메틸피리딘-2-일)-2-(5-플루오로-1H-인돌-3-일) 아세트아마이드(화합물 2)의 합성4. Synthesis of N-(5-bromo-6-methylpyridin-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide (Compound 2)
[반응식 4][Scheme 4]
Figure PCTKR2022004585-appb-img-000029
Figure PCTKR2022004585-appb-img-000029
상기 제조예 1의 아세트산을 2-(5-플루오로-1H-인돌-3-일)아세트산으로 변경하여 동일한 실험방법으로 연한 갈색의 표제 화합물(107 mg, 44%)을 얻었다.The acetic acid of Preparation Example 1 was changed to 2-(5-fluoro-1H-indol-3-yl)acetic acid, and the light brown title compound (107 mg, 44%) was obtained by the same experimental method.
1H NMR (CDCl3, 400 MHz): δ 9.09 (br s, 1H), 8.20 (br s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 4.0 Hz, 1H), 7.13 (dd, J = 8.0, 4.0 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.89 (m, 1H), 3.83 (s, 2H), 2.44 (s, 3H). 1 H NMR (CDCl 3 , 400 MHz): δ 9.09 (br s, 1H), 8.20 (br s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H) ), 7.20 (dd, J = 8.0, 4.0 Hz, 1H), 7.13 (dd, J = 8.0, 4.0 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.89 (m, 1H), 3.83 (s, 2H), 2.44 (s, 3H).
5. N-(벤조[디]티아졸-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일) 아세트아마이드 (화합물 45)의 합성5. Synthesis of N-(benzo[di]thiazol-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide (compound 45)
실온에서 N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드 (70.0 mg, 0.228 mmol)의 DMF (1 mL) 용액을 아르곤 대기 하에서 교반하면서 t-BuOK (74.0 mg, 0.456 mmol)을 적가하고 5분간 교반하였다. 혼합물에 MeI (28.4 μL, 0.456 mmol)를 적가하고 30분간 교반하였다. 혼합물에 증류수 (1 mL)를 가하여 반응을 종결하였다. 층을 분리하고 유기 층을 증류수 세척, 무수 MgSO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피 (SiO2, hexane:EtOAc = 4:1)로 정제하여 흰색의 표제 화합물 (39.0 mg, 51%) 얻었다.A solution of N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide (70.0 mg, 0.228 mmol) in DMF (1 mL) at room temperature was stirred under an argon atmosphere. t-BuOK (74.0 mg, 0.456 mmol) was added dropwise and stirred for 5 minutes. MeI (28.4 μL, 0.456 mmol) was added dropwise to the mixture and stirred for 30 minutes. The reaction was terminated by adding distilled water (1 mL) to the mixture. The layers were separated and the organic layer was washed with distilled water, dried over anhydrous MgSO4 and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography (SiO 2 , hexane:EtOAc = 4:1) to obtain the white title compound (39.0 mg, 51%).
1H NMR (CDCl3, 500 MHz): δ 7.83 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.43 (td, J = 7.8, 1.0 Hz, 1H), 7.29 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H), 4.17 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 7.83 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.43 ( td, J = 7.8, 1.0 Hz, 1H), 7.29 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H), 4.17 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H) ).
13C NMR (CDCl3, 125 MHz): δ 171.87, 160.26, 148.19, 137.08, 133.59, 127.73, 127.56, 126.01, 123.92, 122.20, 121.36, 121.18, 119.61, 118.76, 109.60, 105.76, 35.73, 32.93, 32.87. 13 C NMR (CDCl 3 , 125 MHz): δ 171.87, 160.26, 148.19, 137.08, 133.59, 127.73, 127.56, 126.01, 123.92, 122.20, 121.36, 121.18, 119.61, 118.76, 109.60, 105.76, 35.73, 32.76
6. N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸 아세트아마이드 (화합물 35)의 합성6. Synthesis of N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methyl acetamide (compound 35)
(1) 단계 1: 2-(1H-인돌-3-일)아세틸 클로라이드 합성(1) Step 1: Synthesis of 2-(1H-indol-3-yl)acetyl chloride
0℃에서 인돌-3-아세트산 (39.3 mg, 0.224 mmol)의 CH2Cl2 (1.5 mL) 용액을 아르곤 대기 하에서 교반하면서 oxalyl chloride (96.0 μL, 1.12 mmol)와 DMF (1 drop)을 순차적으로 적가하였다. 반응 혼합물을 1시간 교반하였다. 혼합물을 감압 농축 및 진공 건조하여 추가의 정제 없이 다음 반응에 사용하였다.While stirring a CH 2 Cl 2 (1.5 mL) solution of indole-3-acetic acid (39.3 mg, 0.224 mmol) at 0°C under argon atmosphere, oxalyl chloride (96.0 μL, 1.12 mmol) and DMF (1 drop) were sequentially added dropwise. did. The reaction mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and dried in vacuo, and used in the next reaction without further purification.
(2) 단계 2: N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드 합성(2) Step 2: Synthesis of N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide
0℃에서 5-클로로-6-플루오로-N-메틸피리딘-2-아민 (30.0 mg, 0.187 mmol)의 THF (1 mL) 용액을 아르곤 대기 하에서 교반하면서 n-BuLi (116 μL, 0.187 mmol)을 한 방울씩 적가하였다. 반응 혼합물을 1시간 교반하였다. 혼합물에 단계 1에서 제조한 2-(1H-인돌-3-일)아세틸 클로라이드의 CH2Cl2 (0.5 mL) 용액을 적가하였다. 혼합물을 5분간 교반한 후 증류수 (1 mL)를 가하여 반응을 종결하였다. 층을 분리하고 유기 층을 증류수 세척, 무수 MgSO4로 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피 (SiO2, hexane:EtOAc:CH2Cl2 = 3:3:1)로 정제하여 갈색의 표제 화합물 (19.0 mg, 27%)을 얻었다.A solution of 5-chloro-6-fluoro-N-methylpyridin-2-amine (30.0 mg, 0.187 mmol) in THF (1 mL) at 0° C. under argon atmosphere with stirring in n-BuLi (116 μL, 0.187 mmol) was added dropwise. The reaction mixture was stirred for 1 hour. To the mixture was added dropwise a CH 2 Cl 2 (0.5 mL) solution of 2-(1H-indol-3-yl)acetyl chloride prepared in step 1. After stirring the mixture for 5 minutes, distilled water (1 mL) was added to terminate the reaction. The layers were separated, and the organic layer was washed with distilled water, dried over anhydrous MgSO 4 and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography (SiO 2 , hexane:EtOAc:CH 2 Cl 2 = 3:3:1) to obtain the brown title compound (19.0 mg, 27%).
1H NMR (CDCl3, 500 MHz): δ 8.15 (s, 1H), 7.69 (t, J = 8.7 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 3.98 (s, 2H), 3.43 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 8.15 (s, 1H), 7.69 (t, J = 8.7 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 3.98 (s, 2H), 3.43 (s, 3H) ).
13C NMR (CDCl3, 125 MHz): δ 172.17, 159.28, 157.85, 142.29, 141.91, 141.90, 136.20, 127.17, 122.94, 122.44, 119.86, 118.77, 118.01, 117.97, 117.77, 117.73, 111.36, 108.76, 35.60, 29.83. 13 C NMR (CDCl 3 , 125 MHz): δ 172.17, 159.28, 157.85, 142.29, 141.91, 141.90, 136.20, 127.17, 122.94, 122.44, 119.86, 118.77, 118.01, 117.97, 117.60, 117.76, 35.60, 117.73 29.83.
7. 2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일) -N-메틸아세트아마이드 (화합물 32)의 합성7. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide (Compound 32)
상기 제조예 6의 아세트산을 2-(5-클로로-1H-인돌-3-일)아세트산으로 변경하여 동일한 실험방법으로 갈색의 표제 화합물 (11.6 mg, 15%)을 얻었다. The acetic acid of Preparation Example 6 was changed to 2-(5-chloro-1H-indol-3-yl)acetic acid to obtain the brown title compound (11.6 mg, 15%) by the same experimental method.
1H NMR (CDCl3, 500 MHz): δ 8.25 (s, 1H), 7.82 (t, J = 8.6 Hz, 1H), 7.74 (t, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.12 (dd, J = 8.6, 1.6 Hz, 1H), 7.06 (s, 1H), 3.92 (s, 2H), 3.43 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 8.25 (s, 1H), 7.82 (t, J = 8.6 Hz, 1H), 7.74 (t, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.12 (dd, J = 8.6, 1.6 Hz, 1H), 7.06 (s, 1H), 3.92 (s, 2H), 3.43 (s, 3H).
13C NMR (CDCl3, 125 MHz): δ 159.06, 157.93, 156.01, 151.70, 151.60, 142.09, 134.54, 128.35, 125.61, 124.52, 122.72, 119.05, 118.34, 117.99, 117.95, 117.26, 112.39, 35.67, 29.82. 13 C NMR (CDCl 3 , 125 MHz): δ 159.06, 157.93, 156.01, 151.70, 151.60, 142.09, 134.54, 128.35, 125.61, 124.52, 122.72, 119.05, 118.67, 29.82, 117.99, 117.82. 112.39, 35.26,
8. N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)-N- 메틸아세트아마이드(화합물 51)의 합성8. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)-N-methylacetamide (compound 51)
N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드를 사용하여 상기 제조예 5와 동일한 실험방법으로 흰색의 표제 화합물 (26.4 mg, 54%)을 얻었다. N-(benzo [di] thiazol-2-yl) -2- (5-chloro-1H-indol-3-yl) acetamide in the same experimental method as in Preparation Example 5 using the white title compound (26.4 mg, 54%) was obtained.
1H NMR (CDCl3, 500 MHz): δ 7.83 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.7, 1.5 Hz, 1H), 7.08 (s, 1H), 4.11 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 7.83 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.43 ( t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.7, 1.5 Hz, 1H), 7.08 ( s, 1H), 4.11 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H).
13C NMR (CDCl3, 125 MHz): δ 171.51, 160.22, 148.12, 135.51, 133.56, 129.19, 128.65, 126.09, 125.58, 124.03, 122.55, 121.42, 121.23, 118.28, 110.71, 105.57, 35.73, 33.16, 32.49. 13 C NMR (CDCl 3 , 125 MHz): δ 171.51, 160.22, 148.12, 135.51, 133.56, 129.19, 128.65, 126.09, 125.58, 124.03, 122.55, 121.42, 121.23, 118.28, 110.71, 105.57, 35.49
9. N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸-2-(1-메틸-1H-인돌-3- 일)아세트아마이드(화합물 36)의 합성9. Synthesis of N-(5-chloro-6-fluoropyridin-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide (Compound 36)
N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드를 사용하여 상기 제조예 5와 동일한 실험방법으로 노란색의 표제 화합물 (7.2 mg, 54%)을 얻었다. The yellow title compound (7.2 mg , 54%) was obtained.
1H NMR (CDCl3, 500 MHz): δ 7.69 (t, J = 8.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.0 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.95 (s, 1H), 3.96 (s, 2H), 3.75 (s, 3H), 3.43 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 7.69 (t, J = 8.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.0 Hz, 1H), 7.29 ( d, J = 8.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.95 (s, 1H), 3.96 (s, 2H), 3.75 ( s, 3H), 3.43 (s, 3H).
13C NMR (CDCl3, 125 MHz): δ 172.27, 157.85, 155.94, 151.78, 151.69, 141.87, 141.86, 136.99, 127.65, 127.61, 122.00, 119.36, 118.82, 118.03, 117.98, 112.96, 112.72, 109.46, 107.06, 35.56, 32.87, 32.82. 13 C NMR (CDCl 3 , 125 MHz): δ 172.27, 157.85, 155.94, 151.78, 151.69, 141.87, 141.86, 136.99, 127.65, 127.61, 122.00, 119.36, 118.82, 118.03, 117.98, 112.96 35.56, 32.87, 32.82.
10. 2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘 -2-일)-N-메틸아세트아마이드 (화합물 37)의 합성10. 2-(5-Chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide (Compound 37) synthesis
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드를 사용하여 상기 제조예 5와 동일한 실험방법으로 노란색의 표제 화합물 (17.7 mg, 56%)을 얻었다. 2- (5-chloro-1H-indol-3-yl) -N- (5-chloro-6-fluoropyridin-2-yl) acetamide in the same experimental method as in Preparation Example 5 using the yellow title The compound (17.7 mg, 56%) was obtained.
1H NMR (CDCl3, 500 MHz): δ 7.74 (t, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.35 (br s, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 8.7, 1.4 Hz, 1H), 6.98 (s, 1H), 3.90 (s, 2H), 3.72 (s, 3H), 3.43 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 7.74 (t, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.35 (br s, 1H), 7.19 (d, J = 8.6 Hz, 1H) , 7.15 (dd, J = 8.7, 1.4 Hz, 1H), 6.98 (s, 1H), 3.90 (s, 2H), 3.72 (s, 3H), 3.43 (s, 3H).
13C NMR (CDCl3, 125 MHz): δ 171.82, 157.89, 155.98, 151.69, 151.64, 142.02, 141.98, 135.39, 129.12, 128.67, 125.28, 122.27, 118.36, 117.98, 117.94, 113.23, 112.96, 110.54, 106.88, 35.61, 33.06, 32.43. 13 C NMR (CDCl 3 , 125 MHz): δ 171.82, 157.89, 155.98, 151.69, 151.64, 142.02, 141.98, 135.39, 129.12, 128.67, 125.28, 122.27, 118.36, 117.98, 117.94, 113.23, 106.94, 112.96, 110.23, 35.61, 33.06, 32.43.
11. 2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘 -2-일)아세트아마이드(화합물 38)의 합성11. Synthesis of 2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide (compound 38)
2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드를 사용하여 상기 제조예 5와 동일한 실험방법으로 흰색의 표제 화합물 (8.20 mg, 27%)을 얻었다. 2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide was used in the same experimental method as in Preparation Example 5 using the white title The compound (8.20 mg, 27%) was obtained.
1H NMR (CDCl3, 500 MHz): δ 8.14 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 8.7, 1.5 Hz, 1H), 7.09 (s, 1H), 3.84 (s, 2H), 3.81 (s, 3H). 1 H NMR (CDCl 3 , 500 MHz): δ 8.14 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.76 (t, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 8.7, 1.5 Hz, 1H), 7.09 (s, 1H), 3.84 (s, 2H), 3.81 (s, 3H).
13C NMR (CDCl3, 125 MHz): δ 169.98, 157.71, 155.80, 147.54, 147.44, 142.93, 135.85, 129.96, 128.47, 126.07, 123.10, 118.22, 111.79, 111.75, 111.00, 110.94, 110.68, 105.82, 34.50, 33.27. 13 C NMR (CDCl 3 , 125 MHz): δ 169.98, 157.71, 155.80, 147.54, 147.44, 142.93, 135.85, 129.96, 128.47, 126.07, 123.10, 118.22, 111.79, 111.75, 111.00, 105.82, 110.68, 110.94, 33.27.
12. N-(5-브로모-6-메틸피리딘-2-일)-2-(1-메틸-1H-인돌-3-일) 아세트아마이드 (화합물 6)의 합성12. Synthesis of N-(5-bromo-6-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide (Compound 6)
[반응식 5][Scheme 5]
Figure PCTKR2022004585-appb-img-000030
Figure PCTKR2022004585-appb-img-000030
실온에서 2-(1-메틸-1H-인돌-3-일)아세트산 (200 mg, 1.06 mmol)의 DMF (5 mL) 용액을 교반하면서 5-브로모-6-메틸피리딘-2-아민 (197 mg, 1.06 mmol), 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸[4,5-b]피리디늄-3-옥사이드 헥사플루오로포스페이트 (HATU, 402 mg, 1.06 mmol)와 trimethylamine (0.3 mL, 2.11 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (120 mg, 31%)을 얻었다. 5-bromo-6-methylpyridin-2-amine (197) with stirring a solution of 2-(1-methyl-1H-indol-3-yl)acetic acid (200 mg, 1.06 mmol) in DMF (5 mL) at room temperature mg, 1.06 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU, 402 mg, 1.06 mmol) and trimethylamine (0.3 mL, 2.11 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (120 mg, 31%).
1H NMR (CDCl3, 400 MHz): δ 7.99(m,2H), 7.72(d, 1H, J=12.0Hz), 7.58(d, 1H, J=12.0Hz), 7.35(d, 1H, J=8.0Hz), 7.27(m, 1H), 7.15(m,1H), 7.06(s, 1H), 3.87(s, 2H), 3.80(s, 3H), 2.42(s, 3H) 1 H NMR (CDCl 3 , 400 MHz): δ 7.99 (m,2H), 7.72 (d, 1H, J=12.0 Hz), 7.58 (d, 1H, J=12.0 Hz), 7.35 (d, 1H, J) =8.0Hz), 7.27(m, 1H), 7.15(m,1H), 7.06(s, 1H), 3.87(s, 2H), 3.80(s, 3H), 2.42(s, 3H)
13. N-(5-브로모-6-메틸피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드 (화합물 5)의 합성13. Synthesis of N-(5-bromo-6-methylpyridin-2-yl)-2-(1H-indol-3-yl)acetamide (Compound 5)
[반응식 6][Scheme 6]
Figure PCTKR2022004585-appb-img-000031
Figure PCTKR2022004585-appb-img-000031
상기 제조예 12의 아세트산을 2-(1H-인돌-3-일)아세트산으로 변경하여 동일한 실험방법으로 표제 화합물 (110 mg, 30%)을 얻었다.The acetic acid of Preparation Example 12 was changed to 2-(1H-indol-3-yl)acetic acid, and the title compound (110 mg, 30%) was obtained by the same experimental method.
1H NMR (CDCl3, 400 MHz): δ 8.37(s,1H), 7.99(d, 1H, J=12.0Hz), 7.74(d, 1H, J=8.0Hz), 7.60(d, 1H, J=8.0Hz), 7.40(d, 1H, J=8.0Hz), 7.25(m, 1H), 7.16(m,1H), 3.87(s, 2H), 3.90(s, 3H), 2.43(s, 3H) 1 H NMR (CDCl 3 , 400 MHz): δ 8.37 (s, 1H), 7.99 (d, 1H, J=12.0 Hz), 7.74 (d, 1H, J=8.0 Hz), 7.60 (d, 1H, J) =8.0Hz), 7.40(d, 1H, J=8.0Hz), 7.25(m, 1H), 7.16(m,1H), 3.87(s, 2H), 3.90(s, 3H), 2.43(s, 3H) )
14. N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드 (화합물 43)의 합성14. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide (Compound 43)
[반응식 7][Scheme 7]
Figure PCTKR2022004585-appb-img-000032
Figure PCTKR2022004585-appb-img-000032
실온에서 2-(1H-인돌-3-일)아세트산 (100 mg, 0.57 mmol)의 DMF (3 mL) 용액을 교반하면서 벤조[디]티아졸-2-아민 (197 mg, 0.57 mmol), 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸[4,5-b]피리디늄-3-옥사이드 헥사플루오로포스페이트 (HATU, 260 mg, 0.68 mmol)와 trimethylamine (0.16 mL, 1.14 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (10 mg, 6%)을 얻었다.With stirring a solution of 2-(1H-indol-3-yl)acetic acid (100 mg, 0.57 mmol) in DMF (3 mL) at room temperature, benzo[di]thiazol-2-amine (197 mg, 0.57 mmol), 1 -[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU, 260 mg, 0.68 mmol) and trimethylamine (0.16) mL, 1.14 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (10 mg, 6%).
1H NMR (CDCl3, 400 MHz): δ 8.99(s,1H), 8.32(s, 1H) 7.80(d, 1H, J=8.0Hz), 7.64(d, 1H, J=8.0Hz), 7.56(d, 1H, J=12.0Hz), 7.40(m, 2H), 7.29(m, 3H), 7.16(m,1H), 4.03(s, 2H) 1 H NMR (CDCl 3 , 400 MHz): δ 8.99(s,1H), 8.32(s, 1H) 7.80(d, 1H, J=8.0Hz), 7.64(d, 1H, J=8.0Hz), 7.56 (d, 1H, J=12.0 Hz), 7.40 (m, 2H), 7.29 (m, 3H), 7.16 (m, 1H), 4.03 (s, 2H)
15. N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일) 아세트아마이드 (화합물 23)의 합성15. Synthesis of N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)acetamide (Compound 23)
[반응식 8][Scheme 8]
Figure PCTKR2022004585-appb-img-000033
Figure PCTKR2022004585-appb-img-000033
상기 제조예 14의 아민을 5-클로로-6-플루오로피리딘-2-아민으로 변경하여 동일한 실험방법으로 표제 화합물 (6 mg, 3%)을 얻었다.The amine of Preparation Example 14 was changed to 5-chloro-6-fluoropyridin-2-amine to obtain the title compound (6 mg, 3%) by the same experimental method.
1H NMR (CDCl3, 400 MHz): δ 8.14(dd,1H, J=8.0Hz and 2.0Hz), 7.95(s, 1H) 7.75(m, 1H), 7.57(d, 1H, J=8.0Hz), 7.44(m, 1H), 7.24(m, 2H), 7.16(m, 1H), 3.92(s, 2H) 1 H NMR (CDCl 3 , 400 MHz): δ 8.14(dd,1H, J=8.0Hz and 2.0Hz), 7.95(s, 1H) 7.75(m, 1H), 7.57(d, 1H, J=8.0Hz) ), 7.44(m, 1H), 7.24(m, 2H), 7.16(m, 1H), 3.92(s, 2H)
16. 2-(1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드 (화합물 71)의 합성16. Synthesis of 2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (Compound 71)
[반응식 9][Scheme 9]
Figure PCTKR2022004585-appb-img-000034
Figure PCTKR2022004585-appb-img-000034
상기 제조예 14의 아민을 3,4,5-trimethoxyaniline로 변경하여 동일한 실험방법으로 표제 화합물 (10 mg, 5%)을 얻었다.The amine of Preparation Example 14 was changed to 3,4,5-trimethoxyaniline, and the title compound (10 mg, 5%) was obtained by the same experimental method.
1H NMR (DMSO-d6, 400 MHz): δ 7.59(d,1H, J=8.0Hz), 7.35(d,1H, J=8.0Hz), 7.25(m, 1H) 7.07(m, 1H), 7.00(s, 1H), 6.97(m, 1H), 3.71(s, 6H), 3.69(s, 2H), 3.59(s, 3H) 1 H NMR (DMSO-d6, 400 MHz): δ 7.59(d,1H, J=8.0Hz), 7.35(d,1H, J=8.0Hz), 7.25(m, 1H) 7.07(m, 1H), 7.00(s, 1H), 6.97(m, 1H), 3.71(s, 6H), 3.69(s, 2H), 3.59(s, 3H)
17. 2-(5-클로로-1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐) 아세트아마이드 (화합물 68)의 합성17. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (Compound 68)
[반응식 10][Scheme 10]
Figure PCTKR2022004585-appb-img-000035
Figure PCTKR2022004585-appb-img-000035
실온에서 2-(5-클로로-1H-인돌-3-일)아세트산 (100 mg, 0.47 mmol)의 DMF (3 mL) 용액을 교반하면서 3,4,5-trimethoxyaniline (87 mg, 0.47 mmol), 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸[4,5-b]피리디늄-3-옥사이드 헥사플루오로포스페이트 (HATU, 217 mg, 0.57 mmol)와 trimethylamine (0.13 mL, 0.95 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (10 mg, 5%)을 얻었다.3,4,5-trimethoxyaniline (87 mg, 0.47 mmol), with stirring at room temperature a solution of 2-(5-chloro-1H-indol-3-yl)acetic acid (100 mg, 0.47 mmol) in DMF (3 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU, 217 mg, 0.57 mmol) and trimethylamine ( 0.13 mL, 0.95 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (10 mg, 5%).
1H NMR (DMSO-d6, 400 MHz): δ 11.12(s, 1H), 10.05(s, 1H), 7.65(d,1H, J=4.0Hz), 7.38(s, 1H), 7.36(s, 1H),7.07(m, 1H), 6.99(s, 2H), 3.72(s, 6H), 3.68(s, 2H), 3.33(s, 3H) 1 H NMR (DMSO-d6, 400 MHz): δ 11.12(s, 1H), 10.05(s, 1H), 7.65(d,1H, J=4.0Hz), 7.38(s, 1H), 7.36(s, 1H),7.07(m, 1H), 6.99(s, 2H), 3.72(s, 6H), 3.68(s, 2H), 3.33(s, 3H)
18. N-(3,5-디클로로페닐)-2-(1H-인돌-3-일)아세트아마이드 (화합물 81)의 합성18. Synthesis of N-(3,5-dichlorophenyl)-2-(1H-indol-3-yl)acetamide (Compound 81)
[반응식 11][Scheme 11]
Figure PCTKR2022004585-appb-img-000036
Figure PCTKR2022004585-appb-img-000036
상기 제조예 14의 아민을 3,5-dichloroaniline로 변경하여 동일한 실험방법으로 표제 화합물 (8 mg, 4%)을 얻었다.The amine of Preparation Example 14 was changed to 3,5-dichloroaniline, and the title compound (8 mg, 4%) was obtained by the same experimental method.
1H NMR (CDCl3, 400 MHz): δ 8.50(s,1H), 7.60(s, 1H), 7.55(d, 1H, J=8.0Hz), 7.41(d, 1H, J=8.0Hz), 7.30(d, 1H, J=4.0Hz), 7.24(m, 1H), 7.16(m, 2H), 7.01(m,1H), 3.86(s, 2H) 1 H NMR (CDCl 3 , 400 MHz): δ 8.50(s,1H), 7.60(s, 1H), 7.55(d, 1H, J=8.0Hz), 7.41(d, 1H, J=8.0Hz), 7.30 (d, 1H, J=4.0 Hz), 7.24 (m, 1H), 7.16 (m, 2H), 7.01 (m, 1H), 3.86 (s, 2H)
19. 2-(5-클로로-1H-인돌-3-일)-N-(3,5-디클로로페닐)아세트아마이드 (화합물 78)의 합성19. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(3,5-dichlorophenyl)acetamide (Compound 78)
[반응식 12][Scheme 12]
Figure PCTKR2022004585-appb-img-000037
Figure PCTKR2022004585-appb-img-000037
상기 제조예 17의 아민을 3,5-dichloroaniline로 변경하여 동일한 실험방법으로 표제 화합물 (10 mg, 6%)을 얻었다.The amine of Preparation Example 17 was changed to 3,5-dichloroaniline, and the title compound (10 mg, 6%) was obtained in the same experimental manner.
1H NMR (CDCl3, 400 MHz): δ 8.33(s,1H), 7.56(s, 1H), 7.36(d, 1H, J=8.0Hz), 7.34(d, 1H, J=2.0Hz), 7.30(bs, 1H), 7.26(m, 1H), 7.23(m, 2H), 7.06(m,1H), 3.85(s, 2H) 1 H NMR (CDCl 3 , 400 MHz): δ 8.33(s,1H), 7.56(s, 1H), 7.36(d, 1H, J=8.0Hz), 7.34(d, 1H, J=2.0Hz), 7.30(bs, 1H), 7.26(m, 1H), 7.23(m, 2H), 7.06(m,1H), 3.85(s, 2H)
20. 2-(5-클로로-1H-인돌-3-일)-N-(피리딘-4-일)아세트아마이드 (화합물 88)의 합성20. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (Compound 88)
[반응식 13][Scheme 13]
Figure PCTKR2022004585-appb-img-000038
Figure PCTKR2022004585-appb-img-000038
상기 제조예 17의 아민을 pyridin-4-amine로 변경하여 동일한 실험방법으로 표제 화합물 (10 mg, 7%)을 얻었다.The amine of Preparation Example 17 was changed to pyridin-4-amine to obtain the title compound (10 mg, 7%) in the same experimental manner.
1H NMR (DMSO-d6, 400 MHz): δ 11.15(s, 1H), 10.49(s, 1H), 8.40(m,1H), 7.63(d, 1H, J=2.0Hz), 7.57(m, 1H) 7.37(d, 1H, J=8.0Hz), 7.34(d, 1H, J=4.0Hz),7.07(dd, 1H, J=12.0Hz and 2.0Hz), 3.72(s, 6H), 3.77(s, 2H) 1 H NMR (DMSO-d6, 400 MHz): δ 11.15(s, 1H), 10.49(s, 1H), 8.40(m,1H), 7.63(d, 1H, J=2.0Hz), 7.57(m, 1H) 7.37(d, 1H, J=8.0Hz), 7.34(d, 1H, J=4.0Hz), 7.07(dd, 1H, J=12.0Hz and 2.0Hz), 3.72(s, 6H), 3.77( s, 2H)
21. N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드 (화합물 44)의 합성21. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide (Compound 44)
[반응식 14][Scheme 14]
Figure PCTKR2022004585-appb-img-000039
Figure PCTKR2022004585-appb-img-000039
실온에서 2-(1H-인돌-3-일)아세트산 (960 mg, 5.48 mmol)의 DMF (35 mL) 용액을 교반하면서 N-메틸벤조[디]티아졸-2-아민 (600 mg, 3.65 mmol), N,N,N',N'-테트라메틸-O-(1H-벤조트리아졸-1-일)유로니움 헥사플루오로포스페이트 (HBTU, 2.77 g, 7.31 mmol)와 N,N-diisopropylethylamine (2.55 mL, 14.61 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (460 mg, 39%)을 얻었다.With stirring a solution of 2-(1H-indol-3-yl)acetic acid (960 mg, 5.48 mmol) in DMF (35 mL) at room temperature, N-methylbenzo[di]thiazol-2-amine (600 mg, 3.65 mmol) ), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 2.77 g, 7.31 mmol) and N,N-diisopropylethylamine ( 2.55 mL, 14.61 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (460 mg, 39%).
1H NMR (DMSO-d6, 400 MHz): δ 11.02(s, 1H), 7.93(m,1H), 7.79(m, 1H) 7.57(m, 1H), 7.38(m, 2H), 7.31(m, 2H), 7.08(m, 1H), 6.98(m, 1H), 4.23(s,2H), 3.84(s, 3H) 1 H NMR (DMSO-d6, 400 MHz): δ 11.02(s, 1H), 7.93(m,1H), 7.79(m, 1H) 7.57(m, 1H), 7.38(m, 2H), 7.31(m) , 2H), 7.08 (m, 1H), 6.98 (m, 1H), 4.23 (s, 2H), 3.84 (s, 3H)
22. N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)-N-메틸 아세트아마이드 (화합물 47)의 합성22. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)-N-methyl acetamide (compound 47)
[반응식 15][Scheme 15]
Figure PCTKR2022004585-appb-img-000040
Figure PCTKR2022004585-appb-img-000040
실온에서 N-메틸벤조[디]티아졸-2-아민 (100 mg, 0.61 mmol)의 CH2Cl2 (12 mL) 용액을 교반하면서 triethylamine (0.65 mL, 3.68 mmol)을 넣고 2-(5-chloro-1H-indol-3-yl)acetyl chloride (280 mg, 1.23 mmol)을 적가 하였다. 반응 혼합물을 실온에서 1일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (30 mg, 7%)을 얻었다.While stirring a CH 2 Cl 2 (12 mL) solution of N-methylbenzo[di]thiazol-2-amine (100 mg, 0.61 mmol) at room temperature, triethylamine (0.65 mL, 3.68 mmol) was added thereto, and 2-(5- Chloro-1H-indol-3-yl)acetyl chloride (280 mg, 1.23 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 day. The reaction was terminated by adding distilled water to the mixture. The layers were separated, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (30 mg, 7%).
1H NMR (DMSO-d6, 400 MHz): δ 11.22(s, 1H), 7.95(d,1H, J=8.0Hz), 7.80(d,1H, J=8.0Hz), 7.66(d,1H, J=4.0Hz), 7.42(m, 3H) 7.31(m, 1H), 7.09(dd, 1H, J=8.0Hz and 2.0Hz), 4.25(s,2H), 3.87(s, 3H) 1 H NMR (DMSO-d6, 400 MHz): δ 11.22(s, 1H), 7.95(d,1H, J=8.0Hz), 7.80(d,1H, J=8.0Hz), 7.66(d,1H, J=4.0Hz), 7.42(m, 3H) 7.31(m, 1H), 7.09(dd, 1H, J=8.0Hz and 2.0Hz), 4.25(s,2H), 3.87(s, 3H)
23. N-(벤조[디]티아졸-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드 (화합물 54)의 합성23. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide (Compound 54)
[반응식 16][Scheme 16]
Figure PCTKR2022004585-appb-img-000041
Figure PCTKR2022004585-appb-img-000041
실온에서 벤조[디]티아졸-2-아민 (214 mg, 1.43 mmol)의 CH2Cl2 (15 mL) 용액을 교반하면서 triethylamine (0.66 mL, 4.75 mmol)을 넣고 2-(1-메틸-1H-인돌-3-일)아세틸 클로라이드 (329 mg, 1.58 mmol)를 적가 하였다. 반응 혼합물을 실온에서 1일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (120 mg, 23%)을 얻었다.While stirring a CH 2 Cl 2 (15 mL) solution of benzo [di] thiazol-2-amine (214 mg, 1.43 mmol) at room temperature, triethylamine (0.66 mL, 4.75 mmol) was added thereto, and 2- (1-methyl-1H) -Indol-3-yl)acetyl chloride (329 mg, 1.58 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 day. The reaction was terminated by adding distilled water to the mixture. The layers were separated, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (120 mg, 23%).
1H NMR (CDCl3, 400 MHz): δ 8.96(s, 1H), 7.80(d,1H, J=8.0Hz), 7.63(d,1H, J=8.0Hz), 7.54(d,1H, J=8.0Hz), 7.30(m, 2H) 7.16(m, 1H), 7.10(s, 1H), 4.01(s,2H), 3.83(s, 3H) 1 H NMR (CDCl 3 , 400 MHz): δ 8.96(s, 1H), 7.80(d,1H, J=8.0Hz), 7.63(d,1H, J=8.0Hz), 7.54(d,1H, J =8.0Hz), 7.30(m, 2H) 7.16(m, 1H), 7.10(s, 1H), 4.01(s,2H), 3.83(s, 3H)
24. N-(벤조[디]티아졸-2-일)-2-(5-플루오로 -1H-인돌-3-일)-N-메틸아세트아마이드 (화합물 60)의 합성24. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)-N-methylacetamide (compound 60)
[반응식 17][Scheme 17]
Figure PCTKR2022004585-appb-img-000042
Figure PCTKR2022004585-appb-img-000042
실온에서 2-(5-플루오로-1H-인돌-3-일)아세트산 (352 mg, 1.83 mmol)의 DMF (12 mL) 용액을 교반하면서 N-메틸벤조[디]티아졸-2-아민 (200 mg, 1.22 mmol), N,N,N',N'-테트라메틸-O-(1H-벤조트리아졸-1-일)유로니움 헥사플루오로포스페이트 (HBTU, 923 mg, 2.44 mmol)와 N,N-diisopropylethylamine (0.9 mL, 4.87 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (140 mg, 33%)을 얻었다.With stirring a solution of 2-(5-fluoro-1H-indol-3-yl)acetic acid (352 mg, 1.83 mmol) in DMF (12 mL) at room temperature, N-methylbenzo[di]thiazol-2-amine ( 200 mg, 1.22 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 923 mg, 2.44 mmol) and N ,N-diisopropylethylamine (0.9 mL, 4.87 mmol) was added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (140 mg, 33%).
1H NMR (DMSO-d6, 400 MHz): δ 11.12(s, 1H), 7.95(d,1H, J=8.0Hz), 7.80(d,1H, J=8.0Hz), 7.37(m, 5H) 6.93(m, 1H), 4.23(s,2H), 3.86(s, 3H) 1 H NMR (DMSO-d6, 400 MHz): δ 11.12(s, 1H), 7.95(d,1H, J=8.0Hz), 7.80(d,1H, J=8.0Hz), 7.37(m, 5H) 6.93(m, 1H), 4.23(s,2H), 3.86(s, 3H)
25. N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일) 아세트아마이드 (화합물 56)의 합성25. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)acetamide (Compound 56).
[반응식 18][Scheme 18]
Figure PCTKR2022004585-appb-img-000043
Figure PCTKR2022004585-appb-img-000043
실온에서 2-(5-클로로-1-메틸-1H-인돌-3-일)아세트산 (300 mg, 1.34 mmol)의 DMF (13 mL) 용액을 교반하면서 벤조[디]티아졸-2-아민 (161 mg, 1.07 mmol), N,N,N',N'-테트라메틸-O-(1H-벤조트리아졸-1-일)유로니움 헥사플루오로포스페이트 (HBTU, 1.02 g, 2.68 mmol)와 N,N-diisopropylethylamine (0.9 mL, 5.37 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (170 mg, 35%)을 얻었다.With stirring a solution of 2-(5-chloro-1-methyl-1H-indol-3-yl)acetic acid (300 mg, 1.34 mmol) in DMF (13 mL) at room temperature, benzo[di]thiazol-2-amine ( 161 mg, 1.07 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)euronium hexafluorophosphate (HBTU, 1.02 g, 2.68 mmol) and N ,N-diisopropylethylamine (0.9 mL, 5.37 mmol) was added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (170 mg, 35%).
1H NMR (CDCl3, 400 MHz): δ 9.35(s, 1H), 7.81(d,1H, J=8.0Hz), 7.65(d,1H, J=8.0Hz), 7.48(m, 1H), 7.39(m, 1H), 7.25(m, 3H), 7.04(s, 1H), 3.94(s,2H), 3.76(s, 3H) 1 H NMR (CDCl 3 , 400 MHz): δ 9.35(s, 1H), 7.81(d,1H, J=8.0Hz), 7.65(d,1H, J=8.0Hz), 7.48(m, 1H), 7.39(m, 1H), 7.25(m, 3H), 7.04(s, 1H), 3.94(s,2H), 3.76(s, 3H)
26. N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일) 아세트아마이드 (화합물 64)의 합성26. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide (Compound 64)
[반응식 19][Scheme 19]
Figure PCTKR2022004585-appb-img-000044
Figure PCTKR2022004585-appb-img-000044
실온에서 2-(5-플루오로-1H-인돌-3-일)아세트산 (50 mg, 0.25 mmol)의 DMF (3 mL) 용액을 교반하면서 벤조[디]티아졸-2-아민 (31 mg, 0.20 mmol), N,N,N',N'-테트라메틸-O-(1H-벤조트리아졸-1-일)유로니움 헥사플루오로포스페이트 (HBTU, 196 mg, 0.51 mmol)와 N,N-diisopropylethylamine (0.2 mL, 1.04 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (10 mg, 12%)을 얻었다.With stirring at room temperature a solution of 2-(5-fluoro-1H-indol-3-yl)acetic acid (50 mg, 0.25 mmol) in DMF (3 mL) benzo[di]thiazol-2-amine (31 mg, 0.20 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 196 mg, 0.51 mmol) and N,N- Diisopropylethylamine (0.2 mL, 1.04 mmol) was added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (10 mg, 12%).
1H NMR (DMSO-d6, 400 MHz): δ 12.65(s, 1H), 11.10(s, 1H), 7.95(d,1H, J=8.0Hz), 7.74(d,1H, J=8.0Hz), 7.38(m, 4H), 7.28(m, 1H), 6.93(m, 1H), 3.90(s,2H) 1 H NMR (DMSO-d6, 400 MHz): δ 12.65(s, 1H), 11.10(s, 1H), 7.95(d,1H, J=8.0Hz), 7.74(d,1H, J=8.0Hz) , 7.38(m, 4H), 7.28(m, 1H), 6.93(m, 1H), 3.90(s,2H)
27. N-(벤조[디]티아졸-2-일)-2-(6-클로로-1H-인돌-3-일) 아세트아마이드 (화합물 41)의 합성27. Synthesis of N-(benzo[di]thiazol-2-yl)-2-(6-chloro-1H-indol-3-yl)acetamide (Compound 41)
[반응식 20][Scheme 20]
Figure PCTKR2022004585-appb-img-000045
Figure PCTKR2022004585-appb-img-000045
상기 제조예 26의 아세트산을 2-(6-클로로-1H-인돌-3-일)아세트산으로 변경하여 동일한 실험방법으로 표제 화합물 (6 mg, 3%)을 얻었다.The acetic acid of Preparation 26 was changed to 2-(6-chloro-1H-indol-3-yl)acetic acid to obtain the title compound (6 mg, 3%) by the same experimental method.
1H NMR (MeOD-d4, 400 MHz): δ 11.65(s, 1H), 11.10(s, 1H), 7.85(d,1H, J=8.0Hz), 7.74(d,1H, J=8.0Hz), 7.58(d, 1H, J=8.0Hz), 7.43(m, 2H), 7.31(m, 2H), 7.05(dd, 1H, J=8.0Hz and 4.0Hz), 4.87(s,2H) 1 H NMR (MeOD-d4, 400 MHz): δ 11.65(s, 1H), 11.10(s, 1H), 7.85(d,1H, J=8.0Hz), 7.74(d,1H, J=8.0Hz) , 7.58 (d, 1H, J=8.0 Hz), 7.43 (m, 2H), 7.31 (m, 2H), 7.05 (dd, 1H, J=8.0 Hz and 4.0 Hz), 4.87 (s, 2H)
28. 2-(5-클로로-1H-인돌-3-일)-N-(티아졸-2-일)아세트아마이드 (화합물 99)의 합성28. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(thiazol-2-yl)acetamide (Compound 99)
[반응식 21][Scheme 21]
Figure PCTKR2022004585-appb-img-000046
Figure PCTKR2022004585-appb-img-000046
실온에서 2-(5-클로로-1H-인돌-3-일)아세트산 (125 mg, 0.49 mmol)의 DMF (5 mL) 용액을 교반하면서 thiazol-2-amine (50 mg, 0.59 mmol), N,N,N',N'-테트라메틸-O-(1H-벤조트리아졸-1-일)유로니움 헥사플루오로포스페이트 (HBTU, 378 mg, 0.99 mmol)와 N,N-diisopropylethylamine (0.4 mL, 2.00 mmol)를 순차적으로 첨가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 혼합물에 증류수를 가하여 반응을 종결하였다. Ethyl acetate로 층을 분리하고 유기 층을 증류수 세척, 무수 Na2SO4 건조, 여과하였다. 여과액을 감압 농축한 후 농축액을 컬럼 크로마토그래피로 정제하여 표제 화합물 (19 mg, 13%)을 얻었다.With stirring a solution of 2-(5-chloro-1H-indol-3-yl)acetic acid (125 mg, 0.49 mmol) in DMF (5 mL) at room temperature, thiazol-2-amine (50 mg, 0.59 mmol), N, N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)euronium hexafluorophosphate (HBTU, 378 mg, 0.99 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.00 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 days. The reaction was terminated by adding distilled water to the mixture. The layers were separated with ethyl acetate, and the organic layer was washed with distilled water, dried over anhydrous Na 2 SO 4 , and filtered. After the filtrate was concentrated under reduced pressure, the concentrate was purified by column chromatography to obtain the title compound (19 mg, 13%).
1H NMR (DMSO-d6, 400 MHz): δ 12.31(s, 1H), 11.18(s, 1H), 7.66(d,1H, J=2.0Hz), 7.46(d,1H, J=4.0Hz), 7.38(s, 1H), 7.36(m, 1H), 7.18(d, 2H, J=4.0Hz), 7.07(dd, 1H, J=8.0Hz and 4.0Hz), 3.84(s,2H) 1 H NMR (DMSO-d6, 400 MHz): δ 12.31(s, 1H), 11.18(s, 1H), 7.66(d,1H, J=2.0Hz), 7.46(d,1H, J=4.0Hz) , 7.38(s, 1H), 7.36(m, 1H), 7.18(d, 2H, J=4.0Hz), 7.07(dd, 1H, J=8.0Hz and 4.0Hz), 3.84(s,2H)
29. 2-(5-클로로-1H-인돌-3-일)-N-(퀴놀린-2-일)아세트아마이드 (화합물 109)의 합성29. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(quinolin-2-yl)acetamide (Compound 109)
[반응식 22][Scheme 22]
Figure PCTKR2022004585-appb-img-000047
Figure PCTKR2022004585-appb-img-000047
상기 제조예 28의 아민을 quinolin-2-amine로 변경하여 동일한 실험방법으로 표제 화합물 (18 mg, 15%)을 얻었다.The amine of Preparation Example 28 was changed to quinolin-2-amine, and the title compound (18 mg, 15%) was obtained by the same experimental method.
1H NMR (DMSO-d6, 400 MHz): δ 11.16(s, 1H), 10.98(s, 1H), 8.30(m, 1H), 7.89(dd,1H, J=8.0Hz and 2.0Hz), 7.82(d,1H, J=4.0Hz), 7.72(m, 2H), 7.48(m, 1H), 7.40(d, 1H, J=2.0Hz), 7.37(d, 1H, J=12.0Hz),7.07(dd, 1H, J=8.0Hz and 4.0Hz), 3.86(s,2H) 1 H NMR (DMSO-d6, 400 MHz): δ 11.16(s, 1H), 10.98(s, 1H), 8.30(m, 1H), 7.89(dd,1H, J=8.0Hz and 2.0Hz), 7.82 (d,1H, J=4.0Hz), 7.72(m, 2H), 7.48(m, 1H), 7.40(d, 1H, J=2.0Hz), 7.37(d, 1H, J=12.0Hz),7.07 (dd, 1H, J=8.0Hz and 4.0Hz), 3.86(s,2H)
30. 2-(5-클로로-1H-인돌-3-일)-N-(4,5,6,7-테트라히드로벤조[디]티아졸-2-일)아세트아마이드 (화합물 104)의 합성30. Synthesis of 2-(5-chloro-1H-indol-3-yl)-N-(4,5,6,7-tetrahydrobenzo[di]thiazol-2-yl)acetamide (Compound 104)
[반응식 23][Scheme 23]
Figure PCTKR2022004585-appb-img-000048
Figure PCTKR2022004585-appb-img-000048
상기 제조예 28의 아민을 4,5,6,7-테트라히드로벤조[디]티아졸-2-아민으로 변경하여 동일한 실험방법으로 표제 화합물 (19 mg, 17%)을 얻었다.The amine of Preparation 28 was changed to 4,5,6,7-tetrahydrobenzo[di]thiazol-2-amine, and the title compound (19 mg, 17%) was obtained by the same experimental method.
1H NMR (DMSO-d6, 400 MHz): δ 12.07(s, 1H), 11.17(s, 1H), 7.63(d,1H, J=4.0Hz), 7.37(d, 1H, J=8.0Hz and 2.0Hz), 7.07(dd, 1H, J=8.0Hz and 4.0Hz), 3.78(s,2H), 2.52(m, 8H) 1 H NMR (DMSO-d6, 400 MHz): δ 12.07(s, 1H), 11.17(s, 1H), 7.63(d,1H, J=4.0Hz), 7.37(d, 1H, J=8.0Hz and 2.0Hz), 7.07(dd, 1H, J=8.0Hz and 4.0Hz), 3.78(s,2H), 2.52(m, 8H)
상기 제조예 30개 화합물들의 구조식 및 [반응식 1] 내지 [반응식 23]로 제조된 화합물의 분자량은 다음과 같다.The structural formulas of the 30 compounds of Preparation Example and the molecular weights of the compounds prepared by [Scheme 1] to [Scheme 23] are as follows.
Figure PCTKR2022004585-appb-img-000049
Figure PCTKR2022004585-appb-img-000049
Figure PCTKR2022004585-appb-img-000050
Figure PCTKR2022004585-appb-img-000050
Figure PCTKR2022004585-appb-img-000051
Figure PCTKR2022004585-appb-img-000051
Figure PCTKR2022004585-appb-img-000052
Figure PCTKR2022004585-appb-img-000052
화합물 번호compound number 분자량Molecular Weight 화합물 번호compound number 분자량 Molecular Weight
66 358.23358.23 8888 285.73285.73
55 344.21344.21 4444 321.40321.40
88 378.65378.65 4747 355.84355.84
4343 307.37307.37 5454 321.40321.40
4040 341.81341.81 6060 339.39339.39
2323 303.72303.72 5656 355.84355.84
2626 338.16338.16 6464 325.36325.36
7171 340.37340.37 4141 341.81341.81
6868 374.82374.82 9999 291.76291.76
8181 319.19319.19 109109 335.79335.79
7878 353.63353.63 104104 345.85345.85
22 362.20362.20
실시예. 화합물의 활성 측정-실험 프로토콜Example. Determination of the activity of compounds - experimental protocol
1. 화합물의 탐색 및 제조1. Search and Preparation of Compounds
제조된 화합물들의 표적 특이성(target specificity)을 확인하기 위해서 하기와 같은 방법으로 평가하였다. In order to confirm the target specificity of the prepared compounds, the following method was evaluated.
DMEM-우태혈청(fetal bovine serum, FBS) 10% 배지에 배양 중인 HepG2를 회수하여 트리판블루(trypan blue) 염색을 통해 생존율이 97% 이상임을 확인한 다음, 실온에서 1200 rpm의 속도로 5 분간 원심분리 후 세포를 DMEM-우태혈청 10% 배지에 3Х105개/mL로 재현탁시켜 준비하였다. 이후 세포를 60mm dish에 3mL씩 분주하고, 각 dish에 DMEM 배지에 희석된 5μM 농도의 화합물들을 각각 50 μL씩 처리한 다음, 24 시간 동안 세포배양기 (5% CO2 incubator)에서 배양하였다. 대조군으로는 0.05%의 디메틸설폭사이드(dimethylsulfoxide, DMSO)/DMEM 배지를 50 μL 처리하였다. HepG2 cultured in DMEM-fetal bovine serum (FBS) 10% medium was recovered, and the viability was confirmed to be 97% or more through trypan blue staining, and then centrifuged at room temperature at 1200 rpm for 5 minutes. After separation, the cells were prepared by resuspending the cells in DMEM-fetal bovine serum 10% medium at 3Х10 5 cells/mL. Thereafter, the cells were aliquoted in 3mL into a 60mm dish, and each dish was treated with 50 μL of each 5μM compound diluted in DMEM medium, and then cultured in a cell incubator (5% CO2 incubator) for 24 hours. As a control, 50 μL of 0.05% dimethylsulfoxide (DMSO)/DMEM medium was treated.
배양된 세포들을 회수하여 mRNA 샘플을 제작하였다. 회수한 세포에서 mRNA를 Trizol 시약(Invitrogen, Cat No. 15596018)을 이용한 페놀-클로로포름 침강방식으로 추출하였다. 분리한 RNA에서 역전사로 cDNA를 합성하고 CFX96 (Bio-rad) 검출 시스템에서 iQ SYBR-Green Supermix (Bio-rad)를 이용해 실시간 중합효소 연쇄반응(real-time PCR)으로 CYP1A1의 발현을 확인하였다. GAPDH를 대조효소로 사용한 △△ct 방식으로 효소 발현량의 상대값을 비교하였다. 대조군을 사용하여 1 배수를 설정하였다.Cultured cells were recovered to prepare mRNA samples. mRNA was extracted from the recovered cells by phenol-chloroform precipitation using Trizol reagent (Invitrogen, Cat No. 15596018). cDNA was synthesized from the isolated RNA by reverse transcription, and the expression of CYP1A1 was confirmed by real-time PCR using iQ SYBR-Green Supermix (Bio-rad) in a CFX96 (Bio-rad) detection system. Relative values of enzyme expression levels were compared in the ΔΔct method using GAPDH as a control enzyme. A control was used to establish a fold of 1.
실시간 중합효소 연쇄반응의 결합 온도 (annealing temperature)를 58℃로 하여, 45 회차(cycle)의 조건으로 수행되었으며, 다음과 같은 프라이머 서열을 사용하였다. 사람 CYP1A1 정방향, 5'-CCT CAT CAG TAA TGG TCA GA-3'(서열번호 1)과 역방향, 5'-GTG CTT ATC AGG ACC TC-3'(서열번호 2); 사람 GAPDH 정방향, 5'-TGA CAT CAA GAA GGT GG-3'(서열번호 3)과 역방향, 5'-CTC CTT GGA GGC CAT GT-3'(서열번호 4).The real-time polymerase chain reaction was carried out under conditions of 45 cycles with an annealing temperature of 58° C., and the following primer sequences were used. human CYP1A1 forward, 5'-CCT CAT CAG TAA TGG TCA GA-3' (SEQ ID NO: 1) and reverse, 5'-GTG CTT ATC AGG ACC TC-3' (SEQ ID NO: 2); Human GAPDH forward, 5'-TGA CAT CAA GAA GGT GG-3' (SEQ ID NO: 3) and reverse, 5'-CTC CTT GGA GGC CAT GT-3' (SEQ ID NO: 4).
그 결과, 실험한 화합물에서 대조군(vehicle)보다 CYP1A1 발현량이 높게 나타난 것을 확인할 수 있고, 유의하게 CYP1A1 발현을 유도함을 알 수 있다(도 1 및 도 2).As a result, it can be seen that the tested compound showed a higher level of CYP1A1 expression than the control (vehicle), and it can be seen that CYP1A1 expression was significantly induced ( FIGS. 1 and 2 ).
2. 염증 인자 IL-6의 생성 억제 효과2. Inhibitory effect on the production of the inflammatory factor IL-6
본 발명에 따른 화합물들의 대식세포 IL-6 생성 억제효과를 평가하기 위하여 하기와 같은 실험을 수행하였다.In order to evaluate the inhibitory effect of the compounds according to the present invention on the production of IL-6 macrophages, the following experiments were performed.
RPMI-우태혈청(fetal bovine serum, FBS) 10% + 2-ME (mercaptoethanol) 배지에 배양 중인 THP-1을 회수하여 트리판블루(trypan blue) 염색을 통해 생존율이 97% 이상임을 확인한 다음, 실온에서 1200 rpm의 속도로 5 분간 원심분리 후 세포를 RPMI-우태혈청 10% + 2-ME 배지에 5Х105개/mL로 재현탁시켜 준비하였다. 이후 세포를 24 웰 plate에 500μL씩 (한 샘플당 3 웰씩) 분주하고, 그 다음, 각 웰에 PMA를 200ng/mL에 맞게 0.5μL를 처리하고, RPMI+2ME 배지에 희석된 5μM 농도의 화합물들을 각각 10μL씩 처리한 다음, 48 시간 동안 세포배양기 (5% CO2 incubator)에서 배양 후에 dPBS에 녹여진 LPS를 100ng/mL에 맞게 5μL를 처리하고 24 시간 동안 세포배양기 (5% CO2 incubator)에서 배양하였다. After recovering THP-1 cultured in RPMI-fetal bovine serum (FBS) 10% + 2-ME (mercaptoethanol) medium, and confirming that the viability is 97% or more through trypan blue staining, After centrifugation at 1200 rpm for 5 minutes, the cells were resuspended in RPMI-fetal bovine serum 10% + 2-ME medium at 5Х10 5 cells/mL. Thereafter, the cells were aliquoted into a 24-well plate by 500 μL (3 wells per sample), and then, 0.5 μL of PMA was treated to 200 ng/mL in each well, and 5 μM of the compounds diluted in RPMI+2ME medium were added. After treating each 10 μL, incubate in a cell incubator (5% CO 2 incubator) for 48 hours, then process 5 μL of LPS dissolved in dPBS to 100 ng/mL and incubate in a cell incubator (5% CO 2 incubator) for 24 hours. cultured.
대조군으로는 0.05%의 디메틸설폭사이드(dimethylsulfoxide, DMSO)/RPMI 배지를 10μL 처리하였다. 배양된 세포들의 배지를 새로운 마이크로튜브로 회수하고 세포는 Trizol(invitrogen) 1mL로 회수하여 -80℃에 보관하였다. 회수한 배지 10μL, assay diluent buffer 40μL를 FACS용 튜브(BD falcon)에 넣어 샘플을 1/5 로 희석한 뒤, 한 샘플 당 capture bead를 볼텍싱 후 1μL, capture bead 희석 용액(capture bead diluent)을 49μL를 넣어 capture bead 용액(capture bead solution)을 한 샘플당 50μL 만들었다. Capture bead 용액을 볼텍싱으로 섞어준 후 각 샘플이 담긴 FACS용 튜브에 capture bead 용액을 50μL씩 넣고, 다시 볼텍싱 한 후 상온에서 1시간동안 놓아두었다. As a control, 10 μL of 0.05% dimethylsulfoxide (DMSO)/RPMI medium was treated. The medium of the cultured cells was recovered with a new microtube, and the cells were recovered with 1 mL of Trizol (invitrogen) and stored at -80°C. After diluting the sample to 1/5 by putting 10 μL of the recovered medium and 40 μL of assay diluent buffer into a FACS tube (BD falcon), after vortexing the capture bead per sample, 1 μL of the capture bead diluent solution (capture bead diluent) was added. 49 μL was added to make 50 μL of capture bead solution per sample. After mixing the capture bead solution by vortexing, 50 μL of the capture bead solution was added to the FACS tube containing each sample, vortexed again, and left at room temperature for 1 hour.
1시간 후 PE detection reagent 1μL, PE detection 희석용액(detection reagent diluent) 49μL를 넣어 PE detection 용액(PE detection solution)을 한 샘플당 50μL 만들었다. 볼텍싱 한 후 capture bead 용액과 샘플이 담긴 FACS용 tube에 PE detection 용액을 한 샘플당 50 μL씩 추가하였다. FACS용 tube를 볼텍싱 한 후 상온에서 1시간동안 놓아두었다. 1시간 후 CBA wash buffer를 한 tube당 1mL씩 넣고 400 g, 5 분 동안 원심분리 후 상층액을 제거하였다. 약하게 볼텍싱을 한 후 Fix buffer를 150μL 넣고 약하게 볼텍싱 한 후 유세포분석기(Flow cytometry)를 이용하여 분석하였다. After 1 hour, 1 μL of PE detection reagent and 49 μL of PE detection diluent were added to make 50 μL of PE detection solution per sample. After vortexing, 50 μL of PE detection solution was added per sample to the FACS tube containing the capture bead solution and sample. After vortexing the FACS tube, it was left at room temperature for 1 hour. After 1 hour, 1 mL of CBA wash buffer was added to each tube, and the supernatant was removed after centrifugation at 400 g for 5 minutes. After vortexing lightly, 150 μL of Fix buffer was added and vortexed lightly, followed by analysis using flow cytometry.
그 결과, 도 3 및 4에서 나타낸 바와 같이 LPS 자극에 의한 THP-1의 IL-6 생성이 화합물 처리에 의해 유의하게 감소하였다. 구체적으로, 대조군(vehicle)에서의 결과와 비교하여 본 발명의 화합물들에서 모두 낮은 결과를 나타냈고, 이는 화합물들이 IL-6 생성을 효과적으로 억제함을 의미한다. As a result, as shown in FIGS. 3 and 4 , IL-6 production of THP-1 by LPS stimulation was significantly reduced by compound treatment. Specifically, compared with the results in the control group (vehicle), all of the compounds of the present invention showed low results, which means that the compounds effectively inhibit IL-6 production.
3. 조절 T 세포 생성 효과3. Regulatory T cell-generating effect
본 발명에 따른 화합물들의 면역관용(immune tolerance) 유도 효과를 알아보기 위하여 하기와 같이 in vitro 조절 T 세포(Foxp3+ Treg)생성 실험을 실시하였다. In order to examine the immune tolerance-inducing effect of the compounds according to the present invention, an in vitro regulatory T cell (Foxp3+ Treg) generation experiment was performed as follows.
인간 말초혈액(AllCells)과 인산완충식염수(Phosphate buffered saline, PBS)를 1:1 비율로 섞어 혼합액을 만들고 Histopaque(Sigma) 상층에 섞이지 않도록 천천히 올려주었다. 350 g에서 20분간 원심분리 하여 중간층에 있는 단핵구 층만 수집한 후 HBSS (Hanks' Balanced Salt Solution, Gibco®)로 세척하였다. T-세포를 얻기 위해 MACS buffer(Miltenyi Biotec)로 한 번 더 세척한 후, CD4 Microbeads(Miltenyi Biotec)로 positive selection(autoMACS seperator, Miltenyi Biotec) 하였다. 위 방법으로 수집한 T-세포를 RPMI-우태혈청(fetal bovine serum, FBS) 10% + 2-ME (mercaptoethanol) 배지에 5Х105/mL로 재현탁시켜 준비하였다. T-세포 활성화를 위해 10μg/mL anti-CD3(eBioscience쪠)를 48 웰 plate에 150μL 분주하고 세포배양기(37℃, 5% CO2 incubator)에서 3시간동안 반응시킨 후 인산완충식염수로 세척하여 준비하였다. 준비된 plate에 재현탁시킨 T-세포를 250μL씩 분주하고 각 웰에 anti-CD28 2μg/mL(eBioscience쪠), TGF-β1 5ng/mL(R&D systems), 그리고 IL-2 50 U/mL(Miltenyi Biotec)을 처리하였다. RPMI+2ME 배지에 희석된 2.5 μM 농도의 화합물들을 각각 5μL씩 처리하고, 7일 동안 세포배양기(37℃, 5% CO2 incubator)에서 배양하였다. 대조군으로는 0.05% 디메틸설폭사이드(dimethylsulfoxide, DMSO)/RPMI 배지를 5μL 처리하였다. 7일 후 조절 T 세포 생성 효과를 확인하기 위해 배양된 세포를 회수하여 Foxp3 단백질을 확인하였다. Human peripheral blood (AllCells) and phosphate buffered saline (Phosphate buffered saline, PBS) were mixed in a 1:1 ratio to make a mixed solution, and the mixture was slowly placed on top of Histopaque (Sigma) so as not to mix. After centrifugation at 350 g for 20 minutes, only the monocyte layer in the middle layer was collected and washed with HBSS (Hanks' Balanced Salt Solution, Gibco®). After washing once more with MACS buffer (Miltenyi Biotec) to obtain T-cells, positive selection (autoMACS seperator, Miltenyi Biotec) was performed with CD4 Microbeads (Miltenyi Biotec). The T-cells collected by the above method were prepared by resuspending in RPMI-fetal bovine serum (FBS) 10% + 2-ME (mercaptoethanol) medium at 5Х10 5 /mL. For T-cell activation, 150 μL of 10 μg/mL anti-CD3 (eBioscience) was dispensed into a 48-well plate, incubated in a cell incubator (37° C., 5% CO 2 incubator) for 3 hours, and washed with phosphate-buffered saline. did. Dispense 250 μL of resuspended T-cells in the prepared plate, and 2 μg/mL of anti-CD28 (eBioscience), 5 ng/mL of TGF-β1 (R&D systems), and 50 U/mL of IL-2 (Miltenyi Biotec) in each well. ) was treated. Each of the compounds at a concentration of 2.5 μM diluted in RPMI+2ME medium were treated with 5 μL each, and cultured in a cell incubator (37° C., 5% CO 2 incubator) for 7 days. As a control, 5 μL of 0.05% dimethylsulfoxide (DMSO)/RPMI medium was treated. After 7 days, the cultured cells were recovered to confirm the effect of generating regulatory T cells to confirm the Foxp3 protein.
회수한 세포들을 5mL FACS용 튜브(BD Falcon)에 넣고 1mL의 인산완충식염수로 세척하였다. 세포를 0.1mL의 FACS 완충용액(0.1% NaN3, 1% FBS)에 재현탁시키고 항체의 비특이적 결합을 막기 위해 1μg의 인간 면역글로불린 G(Human IgG, Sigma)를 처리하였다. 4℃에서 15분간 반응시킨 후 FACS 완충용액으로 세포를 세척하였다. 샘플이 담긴 FACS용 tube에 Fixation/Permeabilization 용액(eBioscience쪠)을 한 샘플당 1mL씩 추가하고 4℃에서 1시간 반응시킨 후 Permeabilization buffer (eBioscience쪠)로 2회 세척하였다. 이후 0.25μg의 Foxp3 monoclonal antibody(eBioscience쪠)를 처리하고 4℃에서 30분간 염색하였다. Permeabilization buffer로 2회 세척하고 0.3mL의 FACS 완충용액에 현탁시킨 후 유세포분석기(Flow cytometry)로 측정하였다.The recovered cells were placed in a 5 mL FACS tube (BD Falcon) and washed with 1 mL of phosphate buffered saline. Cells were resuspended in 0.1 mL of FACS buffer (0.1% NaN 3 , 1% FBS) and treated with 1 μg of human immunoglobulin G (Human IgG, Sigma) to prevent non-specific binding of antibodies. After incubation at 4° C. for 15 minutes, cells were washed with FACS buffer. 1mL of Fixation/Permeabilization solution (eBioscience) was added to each FACS tube containing the sample, reacted at 4°C for 1 hour, and washed twice with Permeabilization buffer (eBioscience). Then, 0.25 μg of Foxp3 monoclonal antibody (eBioscience) was treated and stained at 4°C for 30 minutes. After washing twice with permeabilization buffer and suspended in 0.3 mL of FACS buffer, it was measured by flow cytometry.
그 결과, 실험한 화합물 5, 8, 43, 40, 23, 26, 71, 81, 2, 44, 47, 56, 64 및 41의 처리에 의해 Foxp3+ 조절 T 세포의 생성이 촉진됨을 확인할 수 있었다(도 5 참조). 이를 통해 상기 화합물들은 조절 T 세포를 효과적으로 생성 및 증식을 유도함을 알 수 있다.As a result, it was confirmed that the generation of Foxp3+ regulatory T cells was promoted by treatment with the tested compounds 5, 8, 43, 40, 23, 26, 71, 81, 2, 44, 47, 56, 64 and 41 ( see Fig. 5). Through this, it can be seen that the compounds effectively induce the generation and proliferation of regulatory T cells.
실시예1. 건선 치료 효과Example 1. Psoriasis treatment effect
본 발명에 따른 화합물들의 keratinocyte MCP-1 생성 억제효과를 평가하기 위하여 하기와 같은 실험을 수행하였다.In order to evaluate the inhibitory effect of the compounds according to the present invention on keratinocyte MCP-1 production, the following experiments were performed.
KGM-Gold Bulletkit 배지(lonza)에 배양 중인 Ker-CT를 HBSS 용액으로 세척한 후 트립신 용액(ATCC)을 처리하여 세포배양기(5% CO2 incubator)에서 5분 정도 배양한 후 KGM-Gold Bulletkit 배지를 이용하여 세포를 회수하였다. 회수한 세포는 실온에서 250 g의 속도로 5 분간 원심분리 후 상층액을 제거하고 KGM-Gold Bulletkit 배지에 재현탁하여 트리판블루 (trypan blue) 염색을 통해 생존율이 97% 이상임을 확인한 다음, 1 × 105/㎖ 로 6웰에 2 ㎖씩 분주하였다. 세포 밀도가 80% 이상 되었을 때 각 화합물을 2 μM 농도가 되도록 각 웰에 처리를 하고 2시간동안 세포배양기 (5% CO2 incubator)에서 배양 후 IFN-γ 200 U/㎖, TNF-α 5 ng/mL이 되도록 5 μL를 처리하고 24 시간동안 세포배양기(5% CO2 incubator)에서 배양하였다. 대조군으로는 0.05%의 디메틸설폭사이드(dimetylsulfoxide; DMSO, Sigma)/배지를 2 μL처리하였다. Ker-CT being cultured in KGM-Gold Bulletkit medium (lonza) was washed with HBSS solution, treated with trypsin solution (ATCC), and incubated for 5 minutes in a cell incubator (5% CO 2 incubator), followed by KGM-Gold Bulletkit medium. was used to recover cells. The recovered cells were centrifuged at room temperature for 5 minutes at a speed of 250 g, the supernatant was removed, resuspended in KGM-Gold Bulletkit medium, and the viability was confirmed to be 97% or more through trypan blue staining, 1 x 10 5 /ml was dispensed to 6 wells by 2 ml each. When the cell density reached 80% or more, each well was treated with each compound at a concentration of 2 μM, and after incubation in a cell incubator (5% CO 2 incubator) for 2 hours, IFN-γ 200 U/ml, TNF-α 5 ng 5 μL was treated to become /mL and incubated in a cell incubator (5% CO 2 incubator) for 24 hours. As a control, 2 μL of 0.05% dimethylsulfoxide (DMSO, Sigma)/medium was treated.
배양된 세포들의 배지를 새로운 마이크로튜브로 회수하고 세포는 Trizol(invitrogen) 1 ㎖로 회수하여 -80℃에 보관해 놓는다. 회수한 배지 16.6 μL, assay diluent buffer 33.4 μL를 FACS용 튜브(FACS tube, BD falcon)에 넣어 샘플을 1/3 로 희석한다. 한 샘플 당 capture bead를 voltexing 후 1 μL, capture bead 희석 용액(capture bead diluent)을 49 μL를 넣어 capture bead 용액(capture bead solution)을 한 샘플 당 50 μL씩 만든다. capture bead 용액을 voltexing으로 섞어준 후 각 샘플이 담긴 FACS용 tube에 50 μL씩 넣는다. voltexing 한 후 상온에서 1시간동안 놓아둔다. 1시간 후 PE detection 1 μL, PE detection 희석용액(detection reagent diluent) 49 μL를 넣어 PE detection 용액 (PE detection solution)을 한 샘플당 50 μL씩 만든다. voltexing 한 후 capture bead 용액과 샘플이 담긴 FACS용 tube에 PE detection 용액을 한 샘플 당 50 μL씩 추가하였다. FACS용 tube를 voltexing 한 후 상온에서 1시간동안 놓아둔다. 이 후 CBA wash buffer를 한 tube당 1㎖씩 넣고 400 g, 5분동안 원심분리 후 상층액을 제거하였다. 약하게 voltexing을 한 후 Fix buffer를 150 μL넣고 약하게 voltexing 한 후 유세포분석기 (Flow cytometry)를 이용하여 분석하였다. The medium of the cultured cells is recovered in a new microtube, and the cells are recovered with 1 ml of Trizol (invitrogen) and stored at -80°C. Add 16.6 µL of the recovered medium and 33.4 µL of assay diluent buffer to a FACS tube (BD falcon) to dilute the sample to 1/3. After voltexing the capture bead per sample, add 1 μL of capture bead diluent and 49 μL of capture bead diluent to make 50 μL of capture bead solution per sample. After mixing the capture bead solution by voltexing, put 50 μL of each sample into the FACS tube. After voltexing, let stand at room temperature for 1 hour. After 1 hour, add 1 µL of PE detection and 49 µL of PE detection diluent to make 50 µL of PE detection solution per sample. After voltexing, 50 μL of PE detection solution was added per sample to the FACS tube containing the capture bead solution and sample. After voltexing the FACS tube, leave it at room temperature for 1 hour. After that, 1 ml of CBA wash buffer was added to each tube, and the supernatant was removed after centrifugation at 400 g for 5 minutes. After lightly voltexing, 150 μL of Fix buffer was added, followed by weak voltexing, and analyzed using flow cytometry.
도 6에서 나타낸 바와 같이 IFN-γ와 TNF-α 자극에 의해 증가한 Ker-CT의 염증촉진인자인 MCP-1의 생성이 화합물 8(PB312), 화합물 40(PB502), 화합물 26(PB504) 처리에 의해 유의하게 감소하였다(용매대조군 대비 ***, p<0.001, 도 6의 A 참조). As shown in FIG. 6, the production of MCP-1, a pro-inflammatory factor of Ker-CT, increased by IFN-γ and TNF-α stimulation was observed in compound 8 (PB312), compound 40 (PB502), and compound 26 (PB504) treatment. was significantly decreased (compared to the solvent control group ***, p<0.001, see A in FIG. 6).
각 실험조건의 Ker-CT 세포로부터 mRNA 샘플을 제작하였다. mRNA를 Trizol 시약(Invitrozen, Cat No. 15596018)을 이용한 페놀-클로로포름 침강방식으로 추출하였다. 분리한 RNA에서 역전사로 cDNA를 합성하고 CFX96(Bio-rad) 검출 시스템에서 iQ SYBR-Green Supermix(Bio-rad)를 이용해 실시간 중합효소 연쇄반응(real-time PCR)으로 염증성 사이토카인의 발현을 확인하였다. mRNA samples were prepared from Ker-CT cells of each experimental condition. mRNA was extracted by phenol-chloroform precipitation using Trizol reagent (Invitrozen, Cat No. 15596018). Synthesize cDNA from isolated RNA by reverse transcription and confirm expression of inflammatory cytokines by real-time PCR using iQ SYBR-Green Supermix (Bio-rad) in CFX96 (Bio-rad) detection system did.
GAPDH를 대조효소로 사용한 △△ct 방식으로 효소 발현량의 상대값을 비교하였다. 배양 세포의 값을 1 배수를 설정하였다.Relative values of enzyme expression levels were compared in the ΔΔct method using GAPDH as a control enzyme. The value of cultured cells was set to 1 fold.
실시간 중합효소 연쇄반응의 결합 온도 (annealing temperature)를 58℃로 하여, 45 회차(cycle)의 조건으로 수행되었으며, 다음과 같은 프라이머 서열을 사용하였다. 사람 Cxcl9 정방향, 5'- CCA GTA GTG AGA AAG GGT CGC-3' (서열번호 5)과 역방향, 5'- AGG GCT TGG GGC AAA TTG TT -3'(서열번호 6); 사람 GAPDH 정방향, 5'-TGA TGA CAT CAA GAA GGT GG-3'(서열번호 7)과 역방향, 5'-TTA CTC CTT GGA GGC CAT GT-3' (서열번호 8).The real-time polymerase chain reaction was carried out under conditions of 45 cycles with an annealing temperature of 58° C., and the following primer sequences were used. Human Cxcl9 forward, 5'- CCA GTA GTG AGA AAG GGT CGC-3' (SEQ ID NO: 5) and reverse, 5'-AGG GCT TGG GGC AAA TTG TT -3' (SEQ ID NO: 6); Human GAPDH forward, 5'-TGA TGA CAT CAA GAA GGT GG-3' (SEQ ID NO: 7) and reverse, 5'-TTA CTC CTT GGA GGC CAT GT-3' (SEQ ID NO: 8).
도 6에서 나타낸 바와 같이 IFN-γ와 TNF-α 자극에 의해 증가한 Ker-CT의 염증촉진인자인 CXCL9 mRNA 발현이 화합물 8(PB312), 화합물 40(PB502) 처리에 의해 유의하게 감소하였다(용매대조군 대비 ***, p<0.001, 도 6의 B 참조).As shown in FIG. 6 , the expression of CXCL9 mRNA, a pro-inflammatory factor of Ker-CT increased by IFN-γ and TNF-α stimulation, was significantly reduced by treatment with compound 8 (PB312) and compound 40 (PB502) (solvent control group) Contrast ***, p<0.001, see Fig. 6B).
따라서 본 발명의 화합물 8(PB312), 화합물 40(PB502), 화합물 26(PB504)은 keratinocyte의 염증 촉진 효과를 유의하게 억제할 수 있기 때문에 신규 건선 치료제로써 유용한 치료 전략을 제시할 수 있다.Therefore, since compound 8 (PB312), compound 40 (PB502), and compound 26 (PB504) of the present invention can significantly inhibit the inflammatory-promoting effect of keratinocytes, a useful therapeutic strategy can be suggested as a novel psoriasis therapeutic agent.
실시예 2. 천식 치료효과Example 2. Asthma therapeutic effect
본 발명에 따른 화합물들의 천식에 대한 치료효과를 알아보기 위하여 하기와 같이 C57BL/6 마우스에 HDM으로 천식을 유도하고 화합물 40(PB502)을 투여하여 그 효능을 평가하였다. In order to examine the therapeutic effect of the compounds according to the present invention on asthma, as follows, asthma was induced in C57BL/6 mice with HDM, and compound 40 (PB502) was administered to evaluate the efficacy.
C57BL/6 마우스(7 주령, 암컷, 17±2 g)에 50 ㎍의 HDM(House Dust Mite, 집먼지진드기; Greer Laboratories, Cat No. NC9756554)과 Alum(Imject Alum Adjuvant, ThermoFisher, Cat No. 77161)을 섞어 0.1 mL 양으로 복강 투여하여 감작시켰다. 14일부터 16일까지 1일 1회 3일 동안 50 ㎍의 HDM을 비강(intranasal) 투여하였다. 구체적으로는, 감작 된 마우스를 이소플루란(isoflurane)으로 흡입 마취 후 30 ml의 HDM을 양쪽 비강에 15 ml씩 투여하였다. In C57BL/6 mice (7 weeks old, female, 17±2 g), 50 μg of HDM (House Dust Mite; Greer Laboratories, Cat No. NC9756554) and Alum (Imject Alum Adjuvant, ThermoFisher, Cat No. 77161) were administered. sensitized by intraperitoneal administration in an amount of 0.1 mL. From the 14th to the 16th, 50 μg of HDM was intranasally administered once a day for 3 days. Specifically, 30 ml of HDM was administered to the sensitized mice by inhalation anesthesia with isoflurane, 15 ml each in both nasal passages.
본 발명에 따른 화합물 40(PB502) 투여 군에는 마우스 한 마리당 20 ㎎/㎏의 화합물을 투여용량의 10%(v/v)에 해당하는 DMSO에 완전히 녹인 다음 최종 DMSO:크레모포어 EL:인산완충식염수(1:1:8, v/v/v)이 되도록 크레모포어 EL-인산완충식염수 혼합물에 희석하고, 화합물 40(PB502) 투여 군에는 마우스 한 마리당 20 ㎎/㎏의 화합물을 인산완충식염수에 희석하여 HDM 비강 투여 시 200 μL씩 복강 투여하였다(1차 14-16일, 2차 21-23일 1일 1회).In the compound 40 (PB502) administration group according to the present invention, 20 mg/kg of compound per mouse was completely dissolved in DMSO corresponding to 10% (v/v) of the administered dose, and then final DMSO: Cremophor EL: phosphate buffer It was diluted in the Cremophor EL-phosphate buffered saline mixture to obtain saline (1:1:8, v/v/v), and in the compound 40 (PB502) administered group, 20 mg/kg of the compound per mouse was administered in phosphate buffered saline. 200 μL of HDM was diluted and administered intraperitoneally (1st 14-16 days, 2nd 21-23 days once a day).
실험 26일째 마우스의 폐를 적출하여 조직 샘플을 제작하였다. 적출한 마우스의 폐를 4% 파라포름알데하이드(sigma aldrich)로 고정시킨 후 조직 포매기(tissue processor, Leica)를 이용하여 파라핀 침윤을 수행하고 조직포매기(Embedding center, Leica)로 파라핀 블록을 제작하였다. 상기 제작한 파라핀 블록을 마이크로톰(microtome, Leica)으로 5 ㎛ 두께로 절단하여 조직 절편을 제작하였다. 완성된 조직 절편에 Periodic Acid-Schiff(PAS, sigma aldrich) 염색을 수행하여 척수의 조직 병리학적 분석을 수행하였다. On the 26th day of the experiment, the lungs of the mice were removed to prepare a tissue sample. After the lungs of the extracted mice were fixed with 4% paraformaldehyde (sigma aldrich), paraffin infiltration was performed using a tissue processor (Leica), and a paraffin block was prepared using an Embedding center (Leica). did. The prepared paraffin block was cut to a thickness of 5 μm with a microtome (Leica) to prepare a tissue section. Periodic Acid-Schiff (PAS, sigma aldrich) staining was performed on the completed tissue sections to perform histopathological analysis of the spinal cord.
폐조직의 기도와 실질 내 염증세포의 침윤과 점액의 축척이 화합물 40(PB502) 투여로 인해 용매대조군 대비 현저히 감소하였다(도 7의 (A) 참조).The infiltration of inflammatory cells in the airways and parenchyma of the lung tissue and the accumulation of mucus were significantly reduced compared to the solvent control group by the administration of Compound 40 (PB502) (see FIG. 7(A) ).
실험 26일째 마우스의 폐를 적출하여 mRNA 샘플을 제작하였다. mRNA를 추출하기 위해 폐 조직을 분쇄기(homogenizer)로 갈아서 균질 현탁액을 획득하였다. 균질 현탁액에서 mRNA를 Trizol 시약 (Invitrozen, Cat No. 15596018)을 이용한 페놀-클로로포름 침강방식으로 추출하였다. 분리한 RNA에서 역전사로 cDNA를 합성하고 CFX96(Bio-rad) 검출 시스템에서 iQ SYBR-Green Supermix(Bio-rad)를 이용해 실시간 중합효소 연쇄반응(real-time PCR)으로 염증성 사이토카인의 발현을 확인하였다. GAPDH를 대조효소로 사용한 △△ct 방식으로 효소 발현량의 상대값을 비교하였다. WT 마우스 척수를 대조군으로 사용하여 1 배수를 설정하였다.On the 26th day of the experiment, the lungs of mice were removed to prepare mRNA samples. To extract mRNA, the lung tissue was ground with a homogenizer to obtain a homogenous suspension. mRNA from the homogeneous suspension was extracted by phenol-chloroform precipitation using Trizol reagent (Invitrozen, Cat No. 15596018). Synthesize cDNA from isolated RNA by reverse transcription and confirm expression of inflammatory cytokines by real-time PCR using iQ SYBR-Green Supermix (Bio-rad) in CFX96 (Bio-rad) detection system did. Relative values of enzyme expression levels were compared in the ΔΔct method using GAPDH as a control enzyme. WT mouse spinal cords were used as controls to establish fold 1s.
실시간 중합효소 연쇄반응의 결합 온도(annealing temperature)를 58℃로 하여, 45 회차(cycle)의 조건으로 수행되었으며, 다음과 같은 프라이머 서열을 사용하였다. 마우스 IL-4 정방향, 5'-TCA TCG GCA TTT TGA ACG AGG T-3'(서열번호 9)과 역방향, 5'-GCA TCG AAA AGC CCG AAA GAG-3'(서열번호 10); 마우스 IL-1β 정방향, 5'-CTC GTG CTG TCG GAC CCA TAT-3'(서열번호 11)과 역방향, 5'-TTG AAG ACA AAC CGC TTT TCC A-3'(서열번호 12); 마우스 TNF-α 정방향, 5′-CCA CAC CGT CAG CCG ATT TG-3′(서열번호 13)과 역방향, 5′-CAC CCA TTC CCT TCA CAG AGC-3′(서열번호 14); 마우스 IL-17A 정방향, 5'-TTT AAC TCC CTT GGC GCA AAA-3'(서열번호 15)과 역방향, 5'-CTT TCC CTC CGC ATT GAC AC-3'(서열번호 16); 마우스 GAPDH 정방향, 5'-TTC ACC ACC ATG GAG AAG GC-3'(서열번호 17)과 역방향, 5'-GGC ATG GAC TGT GGT CAT GA-3'(서열번호 18).The real-time polymerase chain reaction was carried out under conditions of 45 cycles with an annealing temperature of 58° C., and the following primer sequences were used. mouse IL-4 forward, 5'-TCA TCG GCA TTT TGA ACG AGG T-3' (SEQ ID NO: 9) and reverse, 5'-GCA TCG AAA AGC CCG AAA GAG-3' (SEQ ID NO: 10); mouse IL-1β forward, 5'-CTC GTG CTG TCG GAC CCA TAT-3' (SEQ ID NO: 11) and reverse, 5'-TTG AAG ACA AAC CGC TTT TCC A-3' (SEQ ID NO: 12); Mouse TNF-α forward, 5′-CCA CAC CGT CAG CCG ATT TG-3′ (SEQ ID NO: 13) and reverse, 5′-CAC CCA TTC CCT TCA CAG AGC-3′ (SEQ ID NO: 14); mouse IL-17A forward, 5'-TTT AAC TCC CTT GGC GCA AAA-3' (SEQ ID NO: 15) and reverse, 5'-CTT TCC CTC CGC ATT GAC AC-3' (SEQ ID NO: 16); Mouse GAPDH forward, 5'-TTC ACC ACC ATG GAG AAG GC-3' (SEQ ID NO: 17) and reverse, 5'-GGC ATG GAC TGT GGT CAT GA-3' (SEQ ID NO: 18).
폐 병변 내 염증성 사이토카인 IL-4, TNF-a, IL-1β, IL-17A의 발현양이 화합물 40(PB502) 투여로 인해 용매대조군 대비 유의하게 감소하였다(용매대조군 대비 **, p<0.01; ***, p<0.001, 도 7의 (B) 참조). The expression levels of the inflammatory cytokines IL-4, TNF-a, IL-1β, and IL-17A in the lung lesions were significantly decreased compared to the solvent control group due to the administration of Compound 40 (PB502) (compared to the solvent control group **, p<0.01) ; ***, p<0.001, see Fig. 7(B)).
따라서 본 발명의 화합물 40(PB502)은 천식 마우스 모델에서 높은 치료 효능을 지니기 때문에 신규 천식 치료제로써 유용한 치료 전략을 제시할 수 있다.Therefore, the compound 40 (PB502) of the present invention has high therapeutic efficacy in a mouse model of asthma, so it can suggest a useful treatment strategy as a novel asthma treatment agent.
실시예 3. 루프스 치료효과Example 3. Lupus treatment effect
본 발명에 따른 화합물들의 루프스에 대한 치료효과를 알아보기 위하여 하기와 같이 BDA/2-> BDF1 면역세포 양입(adoptive transfer) 모델을 제작하고 화합물을 투여하여 그 효능을 평가하였다.In order to examine the therapeutic effect of the compounds according to the present invention on lupus, a BDA/2-> BDF1 immune cell adoptive transfer model was prepared as follows and the efficacy was evaluated by administering the compound.
DBA/2 마우스(8주 내지 10 주령, 암컷)의 비장(spleen)을 적출하고 RPMI 배지를 첨가하여 분쇄한 다음, 40 μm cell strainer (BD Falcon)에 통과시켜 단일세포현탁액(single cell suspension)을 획득하였다. 단일세포현탁액은 원심분리(1200 rpm, 5 분) 후 상층액을 버리고 ACK(ammonium chloride/potassium bicarbonate) lysis buffer (0.15 M NH4Cl, 1 mM KHCO3, 0.1 mM Na2EDTA) 1mL를 첨가하여 1 분간 교반한 다음 인산완충식염수로 세척하였다. 세포는 1 × 108/mL로 인산완충식염수에 재현탁해 준비하였다. BDF1 마우스(8 내지 10 주령, 암컷)에 준비한 DBA/2 비장 세포를 100μL씩 꼬리 정맥을 통해 주입하였다. 본 발명에 따른 화합물 40(PB502) 투여 군에는 마우스 한 마리당 20 ㎎/㎏의 화합물을 투여용량의 10%(v/v)에 해당하는 DMSO에 완전히 녹인 다음 최종 DMSO:크레모포어 EL:인산완충식염수(1:1:8, v/v/v)이 되도록 크레모포어 EL-인산완충식염수 혼합물에 희석하여 200μL씩 이식 후 1일부터 7일까지 총 7회 매일 복강 투여하였다. 이식 3주 후 혈중 항-nucleic acid IgG1의 측정하여 화합물 효능을 평가하였다.The spleen (spleen) of DBA/2 mice (8 to 10 weeks old, female) was removed and crushed by adding RPMI medium, and then passed through a 40 μm cell strainer (BD Falcon) to obtain a single cell suspension. obtained. The single cell suspension is centrifuged (1200 rpm, 5 min), then the supernatant is discarded, 1 mL of ACK (ammonium chloride/potassium bicarbonate) lysis buffer (0.15 M NH4Cl, 1 mM KHCO3, 0.1 mM Na2EDTA) is added and stirred for 1 minute. It was washed with phosphate buffered saline. Cells were prepared by resuspending in phosphate buffered saline at 1 × 10 8 /mL. 100 μL of DBA/2 splenocytes prepared in BDF1 mice (8-10 weeks old, female) were injected through the tail vein. In the compound 40 (PB502) administration group according to the present invention, 20 mg/kg of compound per mouse was completely dissolved in DMSO corresponding to 10% (v/v) of the administered dose, and then final DMSO: Cremophor EL: phosphate buffer It was diluted in Cremophor EL-phosphate buffered saline mixture to obtain saline (1:1:8, v/v/v) and administered intraperitoneally every day for a total of 7 times from 1 to 7 days after transplantation in 200 μL. The efficacy of the compounds was evaluated by measuring anti-nucleic acid IgG1 in blood 3 weeks after transplantation.
분석 결과, 화합물 40(PB502) 투여군에서 용매대조군에 비해 유의하게 혈중 항-nucleic acid IgG1가 낮게 검출되었다(용매대조군 대비 *, p<0.05, 도 8 참조).As a result of the analysis, the anti-nucleic acid IgG1 in the blood was significantly lower in the compound 40 (PB502) administration group than in the solvent control group (compared to the solvent control group *, p<0.05, see FIG. 8).
따라서 본 발명의 화합물 40(PB502)은 루푸스 마우스 모델에서 높은 치료 효능을 지니기 때문에 신규 루푸스 치료제로써 유용한 치료 전략을 제시할 수 있다.Therefore, the compound 40 (PB502) of the present invention has a high therapeutic efficacy in a lupus mouse model, so it can present a useful therapeutic strategy as a novel lupus therapeutic agent.

Claims (16)

  1. 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 포함하는 건선, 천식 또는 전신홍반루푸스의 치료 또는 예방용 약학 조성물: A pharmaceutical composition for the treatment or prevention of psoriasis, asthma, or systemic lupus erythematosus, comprising a compound represented by the following formula (1), a stereoisomer or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022004585-appb-img-000053
    Figure PCTKR2022004585-appb-img-000053
    (식 중, R1 내지 R4는 각각 독립적으로 수소 또는 할로겐이고, R5 및 R6은 독립적으로 수소 또는 C1-C5의 알킬이며,(Wherein, R 1 to R 4 are each independently hydrogen or halogen, R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl,
    A는 C5-C12의 단일 또는 이중 환형기이고,A is a C 5 -C 12 single or double cyclic group,
    상기 환형기의 각 환은 1 내지 3개의 헤테로 원자로 치환될 수 있으며,Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms,
    상기 환형기는 할로겐, C1-C5의 알킬 또는 C1-C5의 알콕시로 치환될 수 있음).The cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy).
  2. 청구항 1에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:The pharmaceutical composition according to claim 1, wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000054
    Figure PCTKR2022004585-appb-img-000054
    (식 중, Q1 내지 Q15는 각각 독립적으로 C, N 또는 S이고, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시이며, Q4가 N이면 R11은 없음).(Wherein, Q 1 to Q 15 are each independently C, N or S, and R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; If Q 4 is N, then R 11 is absent).
  3. 청구항 1에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:The pharmaceutical composition according to claim 1, wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000055
    Figure PCTKR2022004585-appb-img-000055
    (식 중, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  4. 청구항 1에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:The pharmaceutical composition according to claim 1, wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000056
    Figure PCTKR2022004585-appb-img-000056
    (식 중, R7 내지 R24는 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  5. 청구항 1에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 약학 조성물:The pharmaceutical composition according to claim 1, wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000057
    Figure PCTKR2022004585-appb-img-000057
    (식 중, R9 내지 R16은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  6. 청구항 1에 있어서, R2 및 R3가 각각 독립적으로 F, Cl 또는 Br인, 약학 조성물.The pharmaceutical composition of claim 1, wherein R 2 and R 3 are each independently F, Cl or Br.
  7. 청구항 1에 있어서, 상기 화학식 1로 표시되는 화합물은 다음 화합물로 이루어진 그룹으로부터 선택되는 것인, 약학 조성물:The method according to claim 1, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds, the pharmaceutical composition:
    N-(5-브로모-6-메틸피리딘-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
    N-(5-브로모-6-메틸피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
    N-(5-브로모-6-메틸피리딘-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
    N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
    2-(1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
    N-(3,5-디클로로페닐)-2-(1H-인돌-3-일)아세트아마이드;N-(3,5-dichlorophenyl)-2-(1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(3,5-디클로로페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,5-dichlorophenyl)acetamide;
    N-(5-브로모-6-메틸피리딘-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(피리딘-4-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)-N-methylacetamide;
    N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)-N-methylacetamide;
    N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
    2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
    2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)-N-methylacetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(6-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(6-chloro-1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(티아졸-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(thiazol-2-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(퀴놀린-2-일)아세트아마이드; 및2-(5-chloro-1H-indol-3-yl)-N-(quinolin-2-yl)acetamide; and
    2-(5-클로로-1H-인돌-3-일)-N-(4,5,6,7-테트라히드로벤조[디]티아졸-2-일)아세트아마이드.2-(5-Chloro-1H-indol-3-yl)-N-(4,5,6,7-tetrahydrobenzo[di]thiazol-2-yl)acetamide.
  8. 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용되는 염을 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 건선, 천식 또는 전신홍반루푸스의 치료 방법:A method of treating psoriasis, asthma, or systemic lupus erythematosus, comprising administering to a subject in need thereof a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2022004585-appb-img-000058
    Figure PCTKR2022004585-appb-img-000058
    (식 중, R1 내지 R4는 각각 독립적으로 수소 또는 할로겐이고, R5 및 R6은 독립적으로 수소 또는 C1-C5의 알킬이며,(Wherein, R 1 to R 4 are each independently hydrogen or halogen, R 5 and R 6 are independently hydrogen or C 1 -C 5 alkyl,
    A는 C5-C12의 단일 또는 이중 환형기이고,A is a C 5 -C 12 single or double cyclic group,
    상기 환형기의 각 환은 1 내지 3개의 헤테로 원자로 치환될 수 있으며,Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms,
    상기 환형기는 할로겐, C1-C5의 알킬 또는 C1-C5의 알콕시로 치환될 수 있음).The cyclic group may be substituted with halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy).
  9. 청구항 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:The method of claim 8 , wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000059
    Figure PCTKR2022004585-appb-img-000059
    (식 중, Q1 내지 Q15는 각각 독립적으로 C, N 또는 S이고, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시이며, Q4가 N이면 R11은 없음).(Wherein, Q 1 to Q 15 are each independently C, N or S, and R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; If Q 4 is N, then R 11 is absent).
  10. 청구항 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:The method of claim 8 , wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000060
    Figure PCTKR2022004585-appb-img-000060
    (식 중, R7 내지 R30은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 30 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  11. 청구항 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:The method of claim 8 , wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000061
    Figure PCTKR2022004585-appb-img-000061
    (식 중, R7 내지 R24는 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 7 to R 24 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  12. 청구항 8에 있어서, 상기 A는 다음의 환형기로 이루어진 군에서 선택되는 것인, 치료 방법:The method of claim 8 , wherein A is selected from the group consisting of the following cyclic groups:
    Figure PCTKR2022004585-appb-img-000062
    Figure PCTKR2022004585-appb-img-000062
    (식 중, R9 내지 R16은 각각 독립적으로 수소, 할로겐, C1-C3의 알킬 또는 C1-C3의 알콕시임).(Wherein, R 9 to R 16 are each independently hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy).
  13. 청구항 8에 있어서, R2 및 R3가 각각 독립적으로 F, Cl 또는 Br인, 치료 방법.The method of claim 8 , wherein R 2 and R 3 are each independently F, Cl or Br.
  14. 청구항 8에 있어서, 상기 화학식 1로 표시되는 화합물은 다음 화합물로 이루어진 그룹으로부터 선택되는 것인, 치료 방법:The method of claim 8, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds:
    N-(5-브로모-6-메틸피리딘-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
    N-(5-브로모-6-메틸피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
    N-(5-브로모-6-메틸피리딘-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)acetamide;
    N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
    2-(1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(3,4,5-트리메톡시페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide;
    N-(3,5-디클로로페닐)-2-(1H-인돌-3-일)아세트아마이드;N-(3,5-dichlorophenyl)-2-(1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(3,5-디클로로페닐)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(3,5-dichlorophenyl)acetamide;
    N-(5-브로모-6-메틸피리딘-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(5-bromo-6-methylpyridin-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(피리딘-4-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1H-indol-3-yl)-N-methylacetamide;
    N-(5-클로로-6-플루오로피리딘-2-일)-2-(1H-인돌-3-일)-N-메틸아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-2-(1H-indol-3-yl)-N-methylacetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)-N-methylacetamide;
    N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(5-chloro-6-fluoropyridin-2-yl)-N-methyl-2-(1-methyl-1H-indol-3-yl)acetamide;
    2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)-N-메틸아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)-N-methylacetamide;
    2-(5-클로로-1-메틸-1H-인돌-3-일)-N-(5-클로로-6-플루오로피리딘-2-일)아세트아마이드;2-(5-chloro-1-methyl-1H-indol-3-yl)-N-(5-chloro-6-fluoropyridin-2-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)-N-메틸아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)-N-methylacetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-클로로-1-메틸-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-chloro-1-methyl-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(5-플루오로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(5-fluoro-1H-indol-3-yl)acetamide;
    N-(벤조[디]티아졸-2-일)-2-(6-클로로-1H-인돌-3-일)아세트아마이드;N-(benzo[di]thiazol-2-yl)-2-(6-chloro-1H-indol-3-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(티아졸-2-일)아세트아마이드;2-(5-chloro-1H-indol-3-yl)-N-(thiazol-2-yl)acetamide;
    2-(5-클로로-1H-인돌-3-일)-N-(퀴놀린-2-일)아세트아마이드; 및2-(5-chloro-1H-indol-3-yl)-N-(quinolin-2-yl)acetamide; and
    2-(5-클로로-1H-인돌-3-일)-N-(4,5,6,7-테트라히드로벤조[디]티아졸-2-일)아세트아마이드.2-(5-Chloro-1H-indol-3-yl)-N-(4,5,6,7-tetrahydrobenzo[di]thiazol-2-yl)acetamide.
  15. 청구항 1 내지 7 중 어느 한 항의 약학 조성물의 건선, 천식 또는 전신홍반루푸스의 예방 또는 치료 용도.The preventive or therapeutic use of the pharmaceutical composition of any one of claims 1 to 7 for psoriasis, asthma, or systemic lupus erythematosus.
  16. 건선, 천식 또는 전신홍반루푸스의 예방 또는 치료를 위한 약제의 제조에 있어 청구항 1 내지 7 중 어느 한 항의 약학 조성물의 용도.Use of the pharmaceutical composition of any one of claims 1 to 7 in the manufacture of a medicament for the prophylaxis or treatment of psoriasis, asthma or systemic lupus erythematosus.
PCT/KR2022/004585 2021-04-02 2022-03-31 Novel compound and use thereof in treating psoriasis, asthma, or systemic lupus erythematosus WO2022211518A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965582A (en) * 1994-08-03 1999-10-12 Asta Medica Aktiengesellschaft N-benzylindole and benzopyrazole derivatives with anti-asthmatic, anti-allergic, anti-inflammatory and immunemodulating effect
KR101110404B1 (en) * 2003-05-16 2012-02-17 아스트라제네카 아베 New benzimidazole derivatives
WO2018229195A1 (en) * 2017-06-14 2018-12-20 European Molecular Biology Laboratory Bicyclic heteroaromatic amide compounds for use in therapy
WO2020150417A2 (en) * 2019-01-17 2020-07-23 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity
KR20210040803A (en) * 2019-10-04 2021-04-14 파렌키마바이오텍 주식회사 Compounds and pharmaceutical compositions for treating autoimmune diseases

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965582A (en) * 1994-08-03 1999-10-12 Asta Medica Aktiengesellschaft N-benzylindole and benzopyrazole derivatives with anti-asthmatic, anti-allergic, anti-inflammatory and immunemodulating effect
KR101110404B1 (en) * 2003-05-16 2012-02-17 아스트라제네카 아베 New benzimidazole derivatives
WO2018229195A1 (en) * 2017-06-14 2018-12-20 European Molecular Biology Laboratory Bicyclic heteroaromatic amide compounds for use in therapy
WO2020150417A2 (en) * 2019-01-17 2020-07-23 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity
KR20210040803A (en) * 2019-10-04 2021-04-14 파렌키마바이오텍 주식회사 Compounds and pharmaceutical compositions for treating autoimmune diseases

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