AHR Agonist

Abstract

The present invention provides a pharmaceutical composition containing a specific substituted AHR agonist compound. [Solution] The following formula JPEG2026053339000044.jpg26128 An AHR agonist represented by [this symbol] is provided.

Description

[Technical Field]

[0001] The present invention relates to novel AHR agonist compounds, pharmaceutical compositions comprising the compounds, and methods for using the compounds to treat certain physiological disorders.

[0002] The present invention relates to the treatment of certain immune-mediated diseases (IMDs), particularly psoriasis, through the activation of aryl hydrocarbon receptors (AHRs). [Background technology]

[0003] Inflammatory melanin-mediated inflammatory diseases (IMDs) encompass a broad range of chronic and debilitating inflammatory conditions affecting approximately 4% of the world's population. Given the limited effectiveness of currently available treatments, there is a significant unmet need for potent, selective, and safe medications for the treatment of IMD.

[0004] AHRs are transcription factors that regulate many aspects of immunological function, most notably the suppression of adaptive immune responses (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Prototype AHR agonists include halogenated dibenzodioxins, such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and tryptophan metabolites, such as L-kynurenine, bilirubin, and PGE2. Results from studies on AHR agonists, particularly TCDD, suggest that immunosuppression occurs as a result of AHR-inducible expression in regulatory T cells (Treg), TH17 cells, and dendritic cells (DCs) (Rothhammer et al., Nat. Rev, Immunol., 19, 184-197 (2019)). TCDD is associated with type 1 diabetes (Kerkvliet et al., Immunotherapy, 1,539-547 (2009)), autoimmune encephalomyelitis (Quintana et al., Nature, 453, 65-71, (2008)), and autoimmune uveoretinitis (Zhang et al. al., Invest.Opthalmol.Vis.Sci.,51,2109-2117(2010)), inflammatory bowel disease (Takamura et al.,Immunol.Cell.Biol.,88,685-689(2010), Benson et al.,Toxicol.Sci.,120,68-78(2011), Singh et al.,PLoS One,6(8),e23522(2011)) and transplant tolerance (Pauly at It has been shown to be effective in the prevention of several mouse models of IMD, including several models of allergic diseases (Schulz et al., Toxicol. Environ. Chem., 94, 1175-1187 (2012)) and allergic diseases (Schulz et al., Toxicol. Sci., 123, 491-500 (2011), Li et al, PLoS One, 11, e0150551 (2016), Luebke et al., Toxicol. Sci., 62, 71-79 (2001)).

[0005] AHR also regulates the expression of CYP1A1, CYP1A2, and CYP1B1, which catalyze the metabolism of polycyclic aromatic hydrocarbons (PAHs) and other aromatic compounds (e.g., estrogens). In some cases (e.g., for benzo[a]pyrene), this metabolism leads to the formation of reactive species, but CYP induction is also thought to be important for the detoxification and metabolic clearance of PAHs, which reduces the probability of bioactivation and DNA adduct formation. Although several marketed drugs have been found to activate AHR after FDA approval (thus upregulating CYP1A1, CYP1A2, and CYP1B1), their long-term use has not been associated with dioxin-like toxicity (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Thus, CYP induction is no longer considered a barrier to the adoption of AHR agonists in therapy (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)).

[0006] The bacterial stilbenoid DMVT-505 (tapinarof), formulated as a 1% topical cream, is currently undergoing a Phase 3 clinical trial for the treatment of plaque psoriasis in adults (NCT04053387). Nevertheless, there remains a need for a new oral, selective, and potent AHR agonist for the treatment of IMD.

[0007] WO 2008 / 014307 discloses certain bicyclic heteroaryl amides as inhibitors of undecaprenyl pyrophosphate synthase. EP 0059698 discloses certain heterocyclic carboxamides, compositions containing these compounds, and methods of treatment with these compositions. SUMMARY OF THE INVENTION

[0008] The present invention provides certain compounds that are agonists of AHR.

[0009] Therefore, the present invention provides a compound of formula I, [Chemical formula] wherein, R 4 , , k , , 1 , , 2 , , , 4 , 2 , j ,

[0010] , , , k , , 3 , , 4 is selected from phenyl optionally substituted with one or two R i , heteroaryl having 5 to 6 members optionally substituted with R k and C3-C6 cycloalkyl optionally substituted with R j , R i is independently selected from halogen, C1-C4 alkyl, CF3, OH, O(C1-C4 alkyl), O(C1-C3)OCH3 and NH(C1-C3 alkyl)N(CH3)2, R k is selected from halogen, C1-C4 alkyl, nitrile, CF3 and O(C1-C4 alkyl), R j is O(C1-C4 alkyl), X is selected from N and -C(R 4 )-, R 2 is C1-C3 alkyl or forms a 5- to 6-membered heterocyclic fused ring together with R 4 , R 4 is hydrogen, halogen, NH(C1-C3 alkyl)N(CH3)2 or forms a 5- to 6-membered heterocyclic fused ring together with R 2 , R 3 is selected from hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, NH(C1-C3 alkyl)OH, NH(C1-C3 alkyl)N(C1-C3 alkyl)2 and O(C1-C3 alkyl)OH, a compound, or a pharmaceutically acceptable salt thereof.

[0010] The present invention also provides that R 1 is R kThe present invention provides compounds of formula I, which are 5-6 member heteroaryls optionally substituted with , or pharmaceutically acceptable salts thereof.

[0011] The present invention is R 1 The present invention further provides compounds of formula I, which are 5-6 member heteroaryl compounds, or pharmaceutically acceptable salts thereof.

[0012] The present invention also provides compounds of formula I, or pharmaceutically acceptable salts thereof, where X is CH.

[0013] The present invention is R 2 The present invention provides a compound of formula I, which is a C1-C3 alkyl group, or a pharmaceutically acceptable salt thereof.

[0014] The present invention is R 2 However, the present invention further provides a compound of formula I, which is CH3, or a pharmaceutically acceptable salt thereof.

[0015] The present invention is R 3 The present invention provides a compound of formula I, selected from hydrogen, CH3, NH(CH3), N(CH3)2, N(CH2CH2)OH, N(CH2CH2)N(CH3)2, and O(CH2CH2)OH.

[0016] The present invention is R 3 The present invention provides a compound of formula I, selected from hydrogen and N(CH2CH2)N(CH3)2.

[0017] The present invention relates to a compound of formula I selected from the following: [ka] Or provide a pharmaceutically acceptable salt thereof.

[0018] The present invention also further provides compounds of formula I selected from the following: [ka]

[0019] The present invention further provides pharmaceutical compositions comprising a compound according to any of the above embodiments or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0020] The present invention provides a method for treating an immune-mediated disease in a patient, comprising administering an effective amount of a compound or pharmaceutical composition according to any of the above embodiments to a patient in need of such treatment.

[0021] The present invention also provides a method for treating a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis in a patient, the method comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutical composition according to any of the above embodiments.

[0022] The present invention provides compounds according to any of the above embodiments or pharmaceutically acceptable salts thereof for use in therapy.

[0023] The present invention also provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, for use in the treatment of a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis.

[0024] Furthermore, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, for the production of pharmaceuticals for the treatment of immune-mediated diseases. In addition, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, for the production of pharmaceuticals for the treatment of diseases or disorders selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis. [Modes for carrying out the invention]

[0025] As used herein, the term "alkyl," used alone or as part of a larger part, refers to a saturated, linear, or branched hydrocarbon group containing one or more carbon atoms.

[0026] As used herein, the term "cycloalkyl" refers to a saturated ring system containing at least three carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0027] As used herein, the term “heterocyclic” refers to an optionally substituted saturated ring system containing at least two carbon atoms and at least one heteroatom. Exemplary heteroatoms are oxygen, nitrogen, and sulfur. Exemplary heterocyclic rings include oxiranes, aziridines, oxetanes, oxolanes, pyrrolidines, piperidines, and morpholines.

[0028] As used herein, the term "heteroaryl" refers to a group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 π electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes oxidized forms of nitrogen or sulfur, and quaternized forms of basic nitrogen. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The term "bicyclic heteroaryl" includes groups in which a heteroaryl ring is fused to another aryl ring or heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.

[0029] As used herein, the term “immune-mediated disease” encompasses a group of autoimmune inflammatory disorders characterized by alterations in cellular homeostasis. Immune-mediated diseases can be caused by environmental factors, dietary habits, infectious agents, and genetic predispositions.

[0030] As used herein, the term “treating” includes limiting, slowing, stopping, or reversing the progression or severity of an existing condition or disorder.

[0031] As used herein, the term "patient" refers to a human being.

[0032] As used herein, the term “effective dose” means an amount or dose of the compound of the present invention or a pharmaceutically acceptable salt thereof that, when administered to a patient once or multiple times, provides a desired effect to a patient undergoing diagnosis or treatment.

[0033] The effective dose can be readily determined by those skilled in the art using known techniques. In determining the effective dose for a patient, several factors are considered, but are not limited to, the patient's species, size, age, and overall health status; the specific disease or disorder associated with the patient; the degree or involvement or severity of the disease or disorder; the individual patient's response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the chosen administration regimen; the use of concomitant medications; and other relevant circumstances.

[0034] The compounds of the present invention are generally effective across a wide range of dosages. For example, the daily dosage is typically in the range of about 0.1 to about 15 mg / kg body weight. In some cases, dosage levels lower than the lower limit of the aforementioned range may be sufficient, while in other cases, higher doses may be used, albeit with acceptable side effects. Therefore, the above dosage range is not intended to limit the scope of the present invention.

[0035] The compounds of the present invention are preferably formulated as pharmaceutical compositions to be administered by any route that makes the compound bioavailable, including oral and transdermal routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing them are well known in the art (e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23 rd (See Edition, Elsevier Academic Press, 2020).

[0036] The compounds of the present invention or their pharmaceutically acceptable salts can be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the scope of the art. Similarly, those skilled in the art will understand that synthetic intermediates can be isolated and / or purified by various well known techniques as needed or desired, and that in many cases, various intermediates can be used directly in subsequent synthetic steps with little or no purification. For example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, and can be isolated directly by filtration or crystallization. Furthermore, those skilled in the art will understand that, under certain circumstances, the order in which the moieties are introduced is not important. The specific order of steps required to produce the compounds of the present invention depends on the particular compound being synthesized, the starting compound, and the relative disadvantages of the substituted moieties, and is well understood by skilled chemists. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art.

[0037] Certain abbreviations are defined as follows: "BrettPhos Pd G3" refers to [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, "BSA" refers to bovine serum albumin, "DIEA" refers to N,N-diisopropylethylamine, "DMEM" refers to Dulbecco's modified Eagle medium, "DMSO" refers to dimethyl sulfoxide, "DPBS" refers to Dulbecco's phosphate-buffered saline, "EGFP" refers to enhanced green fluorescent protein, "Et2O" represents diethyl ether, "EtOH" represents ethyl alcohol, and HATU is (1 -[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. "hr." or "hrs." refers to singular or plural hours, "min" refers to minutes, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(0), "SCX" refers to strong cation exchange, "TBAF" refers to tetra-n-butylammonium fluoride, "tBuONa" refers to sodium tert-butoxide, "THF" refers to tetrahydrofuran, and "tBuXphos" refers to 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl.

[0038] In any step, a pharmaceutically acceptable salt of the compound according to any of the above embodiments may be formed by the reaction of a suitable free base with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions. The formation of such salts is well known and understood in the art. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986), Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000), and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977). See "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986). Those skilled in the art will understand that the compounds according to any of the above embodiments can be readily converted to pharmaceutically acceptable salts and isolated as pharmaceutically acceptable salts.

[0039] Compounds of formula I or pharmaceutically acceptable salts thereof can be prepared by a variety of procedures known in the art, some of which are illustrated in the following schemes, preparations, and examples. The specific synthesis steps for each of the described routes may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of formula I or pharmaceutically acceptable salts thereof. The products of each step in the following schemes can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization. In the following schemes, all substituents are as previously defined unless otherwise indicated. Reagents and starting materials are readily available to those skilled in the art.

[0040] Scheme 1. General scheme for preparing the compound of formula I. [ka] Scheme 1 shows a general scheme for the synthesis of the compound of formula I.

[0041] The compound of formula I can be obtained by subjecting the condensed 2-oxo-1H-pyridine-3-carboxylic acid (1) to an amide coupling reaction.

[0042] Alternatively, (2) can be obtained by first subjecting the bromo-substituted condensed 2-oxo-1H-pyridine-3-carboxylic acid (2) to an amide coupling reaction, and then subjecting this to a palladium-catalyzed coupling reaction to obtain the compound of formula I.

[0043] Preparations and Examples The following preparations and examples further illustrate the present invention.

[0044] Intermediate 1 1-Methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid [ka]

[0045] Step A: A mixture of 2-amino-3-pyridinecarboxaldehyde (500 mg, 3.972 mmol), diethyl malonate (6 mL, 39.48 mmol), and piperidine (1.6 mL, 16 mmol) is stirred in EtOH (7 mL, 120 mmol) at ambient temperature for 1 hour. The mixture is refluxed for 2 hours, and the precipitate is collected by filtration. The solid is washed with cold EtOH and dried under vacuum to obtain ethyl 2-oxo-1H-1,8-naphthyridine-3-carboxylate (710 mg, 3.254 mmol, 81.93%). ES / MS (m / z): 219.0 (M+H). 1 H NMR(400MHz,d6-DMSO):12.40(s,1H),8.61(dd,J=1.8,4.7Hz,1H),8.50(s,1H),8.28(dd,J=1.8,7 .8Hz,1H),7.30(dd,J=4.7,7.8Hz,1H),4.29(q,J=7.1Hz,2H),3.33(s,1H),1.31(t,J=7.1Hz,4H).

[0046] Step B: Iodomethane (0.61 mL, 9.8 mmol) and potassium carbonate (372 mg, 2.69167 mmol) are added to a suspension of ethyl 2-oxo-1H-1,8-naphthirizine-3-carboxylate (710 mg, 3.254 mmol) in EtOH (8 mL, 198 mmol) and N,N-dimethylformamide (8 mL, 103 mmol). The mixture is stirred overnight at ambient temperature and then diluted with ethyl acetate. The quenched reaction product is sequentially washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography to obtain ethyl 1-methyl-2-oxo-1,8-naphthirizine-3-carboxylate (648 mg, 2.7344 mmol, 84.039% yield). ES / MS (m / z): 233.0 (M+H). 1H NMR(400MHz,d6-DMSO):8.75(dd,J=1.9,4.8Hz,1H),8.51(s,1H),8.35(dd,J=1.9,7.7Hz,1 H),7.39(dd,J=4.7,7.8Hz,1H),4.31(q,J=7.1Hz,2H),3.70(s,3H),1.32(t,J=7.1Hz,3H).

[0047] Step C; Intermediate 1: Dissolve ethyl 1-methyl-2-oxo-1,8-naphthyridine-3-carboxylate (648 mg, 2.734 mmol) in a mixture of THF (0.2 M, 168 mmol) and methanol (10.94 mmol). Add 1 M aqueous lithium hydroxide solution (10.94 mmol) and stir the reaction mixture overnight at ambient temperature. Concentrate the reaction mixture to dryness, then dissolve it in water and adjust the pH to 1 with 1 M aqueous HCl solution. Filter off the white solid and dry overnight under vacuum to obtain the title product (532 mg, 2.606 mmol, 95.287%). 1 H NMR(400MHz,d6-DMSO):8.94(s,1H),8.88(dd,J=1.9,4.7Hz,1H),8.54(dd,J=1.9,7.8Hz,1H),7.54(dd,J=4.7,7.8Hz,1H),3.83(s,3H).

[0048] Intermediate 2 Ethyl 7-bromo-1-dimethyl-2-oxoquinoline-3-carboxylate [ka]

[0049] Step A: A mixture of 2-amino-4-bromobenzaldehyde (3.0 g, 15 mmol), diethyl malonate (22 mL, 144.8 mmol), and piperidine (5.8 mL, 59 mmol) is refluxed in EtOH (40 mL, 687 mmol) for 3 hours. The reaction mixture is cooled to ambient temperature, filtered, and the solid is rinsed with cold EtOH, followed by Et2O to obtain 7-bromo-2-oxo-1H-quinoline-3-carboxylate ethyl (Step A; 2.71 g, 9.14 mmol, 62%). ES / MS (m / z)79 Br / 81 Br): 297.0 / 298.0 (M+H). 1 H NMR(400MHz,d6-DMSO):12.07(bs,1H),8.49(s,1H),7.78(d,J=8.5Hz,1H),7.50(d,J= 1.9Hz, 1H), 7.40 (dd, J=1.9, 8.4Hz, 1H), 4.27 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H).

[0050] Step B; Intermediate 2: Dissolve ethyl 7-bromo-2-oxo-1H-quinoline-3-carboxylate (2.707 g, 9.142 mmol) in N,N-dimethylformamide (30 mL, 388 mmol, 28.4 g). Add potassium carbonate (2.78 g, 20.1 mmol), followed by iodomethane (1.25 mL, 20.1 mmol, 2.85 g), and stir overnight at ambient temperature. Pour the reaction mixture into a saturated aqueous sodium bicarbonate solution, and extract the resulting mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over anhydrous magnesium sulfate, filter, and concentrate under vacuum. Purify the obtained substance by silica gel chromatography eluting with 0-100% ethyl acetate / hexane to obtain the title compound (2.58 g, 8.32 mmol, 91.0%). ES / MS (m / z) 79 Br / 81 Br): 310.0 / 311.0 (M+H). 1 H NMR(399.80MHz,DMSO):8.46(s,1H),7.83(d,J=8.4Hz,1H),7.79(d,J=1.7Hz,1H),7. 51(dd,J=1.8,8.4Hz,1H),4.28(q,J=7.1Hz,2H),3.62(s,3H),1.30(t,J=7.1Hz,3H).

[0051] Intermediate 3 5-Bromo-1-methyl-2-oxoquinoline-3-carboxylic acid [ka]

[0052] Step A: Add diethyl malonate (696 mg, 4.345 mmol) and potassium carbonate (910 mg, 6.519 mmol) to a solution of 2-bromo-6-nitro-benzaldehyde (1 g, 4.347 mmol) in acetic anhydride (10 mL). Stir the mixture with 806185 for 1 hour. Cool the reaction to ambient temperature, dilute with water (20 mL), and extract with dichloromethane (20 mL x 3). Combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain 2-[(2-bromo-6-nitrophenyl)methylene]propanedioate diethyl (1.6 g, 4.3 mmol, 99%). ES / MS (m / z) 79 Br / 81 Br): 370.0 / 372.0 (M+H).

[0053] Step B: Add iron (2.4 g, 37 mmol) to a solution of 2-[(2-bromo-6-nitrophenyl)methylene]propanedioate diethyl (1.6 g, 4.3 mmol) in glacial acetic acid (10 mL). The reaction mixture is stirred at 80°C for 12 hours and then filtered through a Celite pad. Adjust the pH to pH=8 with saturated sodium bicarbonate aqueous solution. Extract the reaction product with dichloromethane (50 mL x 3). Wash the combined organic layers with brine (30 mL x 2), dry over anhydrous sodium sulfate, and concentrate under vacuum. The crude product is pulverized with methanol at ambient temperature for 20 minutes and then filtered to obtain 5-bromo-2-oxo-1H-quinoline-3-carboxylate ethyl (200 mg, 0.540 mmol, 50.28%). ES / MS (m / z) 79 Br / 81 Br): 295.0 / 298.0 (M+H).

[0054] Step C: Cesium carbonate (573 mg, 1.76 mmol) and iodomethane (0.3 mL, 5 mmol) are added to a solution of ethyl 5-bromo-2-oxo-1H-quinoline-3-carboxylate (400 mg, 0.946 mmol) in dimethylformamide (10 mL). The resulting mixture is stirred at 50°C for 12 hours. The reaction mixture is quenched with water (10 mL) and extracted with dichloromethane (15 mL x 3). The organic layers are combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue is purified by silica gel chromatography eluting with a 0-40% ethyl acetate / petroleum ether gradient to obtain ethyl 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylate (150 mg, 0.339 mmol, 100%). ES / MS (m / z) 79 Br / 81 Br): 310.0 / 312.0 (M+H).

[0055] Step D; Intermediate 3: Add lithium hydroxide (40 mg, 0.934 mmol) in water (2 mL) to a solution of ethyl 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylate (100 mg, 0.323 mmol) in THF (2 mL). Stir the resulting mixture at 40°C for 1 hour. Cool the mixture to ambient temperature and adjust the pH to pH 4 with 1 N aqueous HCl solution. Dilute the mixture with water (5 mL) and extract with dichloromethane (10 mL x 3). Wash the combined organic layers with brine (10 mL), dry over anhydrous sodium sulfate, and concentrate under vacuum to obtain the title product (70 mg, 0.248 mmol, 77%). 1 H NMR (400.13MHz, d6-DMSO): 14.91-14.86 (m, 1H), 8.94 (s, 1H), 7.84-7.76 (m, 3H), 3.80 (s, 3H).

[0056] Example 1 N-(4-methoxyphenyl)-1-methyl-2-oxoquinoline-3-carboxamide [ka] 1-Methyl-2-oxoquinoline-3-carboxylic acid (418 mg, 2.057 mmol), 4-methoxyaniline (304 mg, 2.469 mmol), N,N-dimethylformamide (7 mL, 90.5 mmol), HATU (880 mg, 2.268 mmol), and N,N-diisopropylethylamine (1.8 mL, 10 mmol, 100) were added together. The reaction mixture was stirred overnight at ambient temperature and concentrated. The resulting substance was purified by silica gel chromatography eluting with a 0-5% dichloromethane / methanol gradient. The resulting solid was ground over Et2O to obtain the title product (548 mg, 1.777 mmol, 86.40%). ES / MS (m / z): 309.0 (M+H). 1 H NMR(400.13MHz,d6-DMSO):11.99(s,1H),8.98(s,1H),8.09(dd,J=1.3,7.9Hz,1H),7.86-7.8 1(m,1H),7.74-7.67(m,3H),7.46-7.42(m,1H),6.98-6.95(m,2H),3.81(s,3H),3.77(s,3H).

[0057] The following examples in Table 1 are essentially synthesized using appropriate starting materials and reagents, as described for N-(4-methoxyphenyl)-1-methyl-2-oxo-quinoline-3-carboxamide (Example 1).

[0058] [Table 1-1]

[0059] [Table 1-2]

[0060] [Table 1-3]

[0061] [Table 1-4]

[0062] [Table 1-5]

[0063] [Table 1-6]

[0064] [Table 1-7]

[0065] Intermediate 4 tert-butyl4-[4-[(11-oxo-1-azatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraene-10-carbonyl)amino]phenyl]piperidine-1-carboxylate [ka] The title intermediate was essentially synthesized using appropriate starting materials and reagents, as described for N-(4-methoxyphenyl)-1-methyl-2-oxo-quinoline-3-carboxamide (Example 1). ES / MS(m / z)(M+H)375.2.

[0066] Example 40 7-Bromo-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide [ka] Trimethylaluminum (2M) in hexane (0.5 ml, 1.0 mmol) is slowly added to a 0°C solution of aniline (0.10 mL, 1.1 mmol) in toluene (2.1 mL, 20 mmol). The reaction mixture is warmed to ambient temperature and stirred for 10 minutes. Ethyl 7-bromo-1-methyl-2-oxoquinoline-3-carboxylate (0.208 g, 0.671 mmol) is added as a solid. The reaction mixture is sealed and heated to 100°C for 3 hours by microwave irradiation. The reaction mixture is poured into a separatory funnel containing Rochelle salt and extracted with ethyl acetate (×3). The combined organic matter is washed with 1N aqueous HCl solution, followed by brine, and concentrated under vacuum. The resulting substance is purified by silica gel chromatography eluting with a 0-100% ethyl acetate / hexane gradient to obtain the title product (0.140 g, 58.4%). ES / MS (m / z) 79 Br / 81 Br): (M+H) 357.0 / 359.0. 1 H NMR(399.80MHz,CDCl3):11.96(s,1H),8.97(s,1H),7.80-7.77(m,2H),7.69-7.65(m ,2H),7.50(dd,J=1.7,8.3Hz,1H),7.42-7.37(m,2H),7.18-7.14(m,1H),3.83(s,3H).

[0067] Example 41 N-(5-methyl-2-pyridyl)-11-oxo-1-azatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraen-10-carboxamide [ka] DIEA (0.12 mL, 0.66 mmol) is added to a solution of 4-oxo-1,2-dihydro-4h-pyrrolo[3,2,1-IJ]quinoline-5-carboxylic acid (0.075 g, 0.33 mmol), 2-amino-5-methylpyridine (0.041 g, 0.36 mmol), and 1-propanephosphonic anhydride (50% by mass) in ethyl acetate (0.39 mL, 0.66 mmol, 1.67 mol / L) and dichloromethane (2 mL). The resulting mixture is stirred at 80°C for 1 hour. The reaction product is cooled to ambient temperature and washed with saturated ammonium chloride aqueous solution. The organic matter is dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain the title product (3.9 mg, 0.013 mmol, 3.9%). ES / MS (m / z): 306.0 (M+H). 1 H NMR(399.80MHz,d6-DMSO):12.54(s,1H),9.05(s,1H),8.24-8.22(m,2H),7.82(dd,J=0.7,8.0Hz,1H),7.72-7.6 8(m,1H),7.63-7.61(m,1H),7.33(dd,J=7.3,8.0Hz,1H),4.51-4.47(m,2H),3.49(t,J=7.9Hz,2H),2.29(s,3H).

[0068] The following examples in Table 2 are essentially synthesized using appropriate starting materials and reagents, as described for N-(5-methyl-2-pyridyl)-11-oxo-1-azatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraen-10-carboxamide (Example 41).

[0069] [Table 2]

[0070] The following intermediates in Table 3 are essentially synthesized using appropriate starting materials and reagents, as described for N-(5-methyl-2-pyridyl)-11-oxo-1-azatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraen-10-carboxamide (Example 41).

[0071] [Table 3]

[0072] Intermediate 10 5-Bromo-1-methyl-2-oxo-N-(2-pyridyl)quinoline-3-carboxamide [ka] To a solution of 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid (500 mg, 1.7725 mmol) and pyridine-2-amine (205 mg, 2.178 mmol) in dichloromethane (5 mL), pyridine (255 mg, 3.224 mmol) and POCl3 (200 mg, 1.3044 mmol) are added. The resulting mixture is stirred at 20°C for 2 hours. The mixture is concentrated under reduced pressure. The resulting residue is pulverized with methanol at ambient temperature for 10 minutes, then filtered to obtain 5-bromo-1-methyl-2-oxo-N-(2-pyridyl)quinoline-3-carboxamide (600 mg, 1.675 mmol, 94.50% yield). ES / MS (m / z) 79 Br / 81 Br): 357.9 / 359.9 (M+H).

[0073] The intermediates listed in Table 4 are essentially synthesized using appropriate starting materials and reagents, as described for 5-bromo-1-methyl-2-oxo-N-(2-pyridyl)quinoline-3-carboxamide (intermediate 10).

[0074] [Table 4-1]

[0075] [Table 4-2]

[0076] Example 44 N-(4-methoxyphenyl)-1,7-dimethyl-2-oxoquinoline-3-carboxamide [ka] Dissolve 7-bromo-N-(4-methoxyphenyl)-1-methyl-2-oxoquinoline-3-carboxamide (0.100 g, 0.258 mmol) in 1,4-dioxane (1.5 mL, 18 mmol). Add methylboronic acid (0.038 g, 0.62 mmol) and cesium carbonate (0.165 g, 0.506 mmol). Blow nitrogen into the reaction mixture for 5 minutes. Add 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (0.036 g, 0.043 mmol), then seal and heat in a microwave at 100°C for 2 hours. The crude reaction product was purified by silica gel chromatography eluting with 0-50% ethyl acetate / hexane to obtain the title product (0.015 g, 0.047 mmol, 18% yield). ES / MS (m / z) (M+H): 323.0. 1 H NMR(399.80MHz,CDCl3):12.02-11.96(m,1H),8.99(s,1H),7.74-7.71(m,3H),7. 27(m,1H),7.21(d,J=7.7Hz,1H),6.94(d,J=8.8Hz,2H),2.59(s,3H),1.59(s,3H).

[0077] Example 45 7-Cyclopropyl-N-(4-methoxyphenyl)-1-methyl-2-oxoquinoline-3-carboxamide [ka] The title compound is essentially synthesized using appropriate starting materials and reagents, as described for N-(4-methoxyphenyl)-1,7-dimethyl-2-oxo-quinoline-3-carboxamide (Example 44). ES / MS (m / z)( 79 Br / 81 Br):(M+H)349.0.

[0078] Example 46 N-(4-methoxyphenyl)-1-methyl-7-(methylamino)-2-oxoquinoline-3-carboxamide [ka] Dissolve 7-bromo-N-(4-methoxyphenyl)-1-methyl-2-oxoquinoline-3-carboxamide (0.154 g, 0.398 mmol) in toluene (2 mL). Add sodium tert-butoxide (0.100 g, 1.01 mmol). Blow nitrogen into the reaction mixture for 10 minutes. Add methylamine (2.0 mol / L) in tetrahydrofuran (0.600 mL, 1.2 mmol), followed by (R)-(+)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (0.035 g, 0.055 mmol), and then tris(dibenzylideneacetone)dipalladium(0) (0.040 g, 0.042 mmol). Seal the reaction mixture and heat it in a microwave at 80°C for 2 hours. The crude reaction product is purified by silica gel chromatography eluting with 0-10% (7N NH3 in methanol) / dichloromethane to obtain the crude product. The crude product is purified by SCX ion exchange column and rinsed with 1:1 methanol / dichloromethane, followed by methanol, and then 7N ammonia in methanol (×2). The rinse solution containing ammonia is concentrated under vacuum to obtain the title product (33 mg, 0.0978 mmol, 24.6%). ES / MS (m / z) (M+H) 338.0. 1H NMR(399.80MHz,CDCl3):11.99(s,1H),8.82(s,1H),7.73-7.70(m,2H),7.54(d,J=8.7Hz,1H),6 .93-6.91(m,2H),6.62(dd,J=2.0,8.6Hz,1H),6.34(d,J=1.9Hz,1H),3.83(s,3H),3.77(s,3H).

[0079] The following examples in Table 5 are essentially synthesized using appropriate starting materials and reagents, as described for N-(4-methoxyphenyl)-1-methyl-7-(methylamino)-2-oxo-quinoline-3-carboxamide (Example 46).

[0080] [Table 5-1]

[0081] [Table 5-2]

[0082] The intermediates listed in Table 6 are essentially synthesized using appropriate starting materials and reagents, as described for N-(4-methoxyphenyl)-1-methyl-7-(methylamino)-2-oxo-quinoline-3-carboxamide (Example 46).

[0083] [Table 6-1]

[0084] [Table 6-2]

[0085] Example 57 5-[2-(dimethylamino)ethylamino]-N-(5-fluoropyrimidine-2-yl)-1-methyl-2-oxoquinoline-3-carboxamide [ka] To a solution of 5-bromo-N-(5-fluoropyrimidine-2-yl)-1-methyl-2-oxoquinoline-3-carboxamide (100 mg, 0.2651 mmol), 2-(4,4-difluoro-1-piperidyl)ethanamine (150 mg, 0.3977 mmol), and t-BuONa (117 mg, 1.1930 mmol) in N,N-dimethylethylenediamine (185 mg, 1.994 mmol), BrettPhos Pd G3 (75 mg, 0.0786 mmol) and Pd2(dba)3 (73 mg, 0.0797 mmol) were added. The reaction mixture was stirred at 130°C for 12 hours, then concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography eluting with 0-5% methanol / dichloromethane to obtain the crude product. The crude product was ground with MeOH at 20°C for 5 minutes. The mixture was filtered to obtain the title product (17.74 mg, 0.0357 mmol, 8.973%). ES / MS (m / z) (M+H) 385.2. 1 H NMR(400.14MHz,d6-DMSO):12.93(s,1H),9.28(s,1H),8.82(s,2H),7.64-7.59(m,1H),7.20-7.13(m,1H), 6.87(d,J=8.5Hz,1H),6.66-6.62(m,1H),3.73(s,3H),3.66-3.63(m,2H),3.47-3.45(m,-2H),2.84(s,6H).

[0086] Alternative synthesis of Example 57 5-[2-(dimethylamino)ethylamino]-N-(5-fluoropyrimidine-2-yl)-1-methyl-2-oxoquinoline-3-carboxamide [ka] To a solution of 5-bromo-N-(5-fluoropyrimidine-2-yl)-1-methyl-2-oxoquinoline-3-carboxamide (100 mg, 0.2651 mmol), N,N-dimethylethylenediamine (185 mg, 1.994 mmol), and t-BuONa (117 mg, 1.1930 mmol) in DMF (4 mL), BrettPhos Pd G3 (75 mg, 0.0786 mmol) and Pd2(dba)3 (73 mg, 0.0797 mmol) are added. The reaction mixture is stirred at 130°C for 12 hours, then concentrated under vacuum to obtain the residue. The residue is purified by silica gel chromatography eluting with 0-5% methanol / dichloromethane to obtain the crude product. The crude product is ground with MeOH at 20°C for 5 minutes. The mixture was filtered to obtain the title product (17.74 mg, 0.0357 mmol, 8.973%). ES / MS (m / z) (M+H) 385.2. 1 H NMR(400.14MHz,d6-DMSO):12.93(s,1H),9.28(s,1H),8.82(s,2H),7.64-7.59(m,1H),7.20-7.13(m,1H), 6.87(d,J=8.5Hz,1H),6.66-6.62(m,1H),3.73(s,3H),3.66-3.63(m,2H),3.47-3.45(m,-2H),2.84(s,6H).

[0087] Intermediate 26 6-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-(5-fluoro-2-pyridyl)-1-methyl-2-oxoquinoline-3-carboxamide [ka] BrettPhos Pd G3 (32 mg, 0.033 mmol) was added to a solution of 6-bromo-N-(5-fluoro-2-pyridyl)-1-methyl-2-oxo-quinoline-3-carboxamide (250 mg, 0.6313 mmol), 2-(4,4-difluoro-1-piperidyl)ethanamine (150 mg, 0.3977 mmol), and t-BuONa (75 mg, 0.765 mmol) in THF (5 mL). The reaction mixture was stirred at 100 °C for 16 hours, then concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography eluted with 0-70% petroleum ether / ethyl acetate to obtain the title product (200 mg, 0.2975 mmol, 47.12%). ES / MS (m / z) (M+H) 471.2. 1 H NMR(400.14MHz,d6-DMSO):12.83(s,1H),8.81(s,1H),8.36-8.31(m,3H),7.83-7.75(m,1H),7.46(d,J=9.3Hz,1H),7.21(dd,J=2. 6,9.1Hz,1H),7.06(d,J=2.6Hz,1H),5.82(t,J=5.9Hz,1H),3.74-3.70(m,6H),3.20(q,J=5.9Hz,2H),0.83(s,10H),-0.00(s,6H).

[0088] Alternative synthesis of intermediate 26 6-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-(5-fluoro-2-pyridyl)-1-methyl-2-oxoquinoline-3-carboxamide [ka] BrettPhos Pd G3 (32 mg, 0.033 mmol) was added to a solution of 6-bromo-N-(5-fluoro-2-pyridyl)-1-methyl-2-oxoquinoline-3-carboxamide (250 mg, 0.6313 mmol), 2-[tert-butyl(dimethyl)silyl]oxyethaneamine (335 mg, 1.91 mmol), and t-BuONa (75 mg, 0.765 mmol) in THF (5 mL). The reaction mixture was stirred at 100 °C for 16 hours, then concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography eluted with 0-300% ethyl acetate / petroleum ether to obtain the title product (200 mg, 0.2975 mmol, 47.12%). ES / MS (m / z) (M+H) 471.2. 1 H NMR(400.14MHz,d6-DMSO):12.83(s,1H),8.81(s,1H),8.36-8.31(m,3H),7.83-7.75(m,1H),7.46(d,J=9.3Hz,1H),7.21(dd,J=2. 6,9.1Hz,1H),7.06(d,J=2.6Hz,1H),5.82(t,J=5.9Hz,1H),3.74-3.70(m,6H),3.20(q,J=5.9Hz,2H),0.83(s,10H),-0.00(s,6H).

[0089] Example 58 6-(2-hydroxyethoxy)-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide [ka]

[0090] Step A: Add 6-bromo-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide (2.005 g, 5.052 mmol) and 1,4-dioxane (10 mL) together. Then add trisdibenzylidene dipalladium (0) (465 mg, 0.508 mmol), tBuXphos (443 mg, 1.012 mmol), and potassium hydroxide (876 mg, 15.15 mmol) in water (10 mL, 555.1 mmol). Stir the mixture at 100 °C for 15 hours, then cool to ambient temperature. Add water (100 mL) to the cooled reaction mixture. Extract the resulting mixture with ethyl acetate (50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the residue. The residue was purified by silica gel chromatography eluted with 0-50% ethyl acetate / petroleum ether to obtain 6-hydroxy-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide (1g, 3.058 mmol, 60.54%). ES / MS(m / z)(M+H)370.2. 1 H NMR(400.15MHz,d6-DMSO):12.38(s,1H),8.79(s,1H),7.74(d,J=7.6Hz,2H),7.52(d,J=9.3Hz,1H ),7.39(t,J=7.9Hz,2H),7.30-7.25(m,1H),7.23(d,J=2.6Hz,1H),7.15-7.11(m,1H),3.76(s,3H).

[0091] Step B: Dissolve 6-hydroxy-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide (101 mg, 0.309 mmol) in dimethylformamide (2 mL). Add 2-(2-bromoethoxy)tetrahydropyran (101 mg, 0.483 mmol) and cesium carbonate (403 mg, 1.237 mmol). Stir the mixture at 80°C for 12 hours, then cool to ambient temperature. Add water (50 mL) to the cooled reaction mixture. Extract the mixture with ethyl acetate (20 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the residue. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate / petroleum ether to obtain 1-methyl-2-oxo-N-phenyl-6-(2-tetrahydropyran-2-yloxyethoxy)quinoline-3-carboxamide (60 mg, 0.128 mmol, 41.38%). ES / MS(m / z)(M+H)423.2. 1 H NMR(400.14MHz,CDCl3):12.24-12.20(m,1H),8.97(s,1H),7.82(d,J=7.8Hz,2H),7.42-7.38(m,3H),7.18-7.14(m,1H),4.75(dd,J=3.2,3 .8Hz,1H),4.31-4.27(m,2H),4.17-4.12(m,2H),3.86(s,6H),3.62-3.57(m,1H),1.93-1.91(m,2H),1.73-1.71(m,4H),1.30-1.27(m,1H).

[0092] Step C; Example 58: Dissolve 1-methyl-2-oxo-N-phenyl-6-(2-tetrahydropyran-2-yloxyethoxy)quinoline-3-carboxamide (60 mg, 0.1278 mmol) in 1 M hydrochloric acid in ethyl acetate (2 mL). Stir the mixture at ambient temperature for 2 hours. Concentrate the reaction mixture under vacuum to obtain a residue. Grind the residue with methanol (10 mL) for 10 minutes at ambient temperature. Filter the resulting mixture to obtain the title product (Example 81; 14 mg, 0.0398 mmol, 31.14%). ES / MS (m / z) (M+H) 339.3. 1H NMR(400.15MHz,d6-DMSO):12.27(s,1H),8.96(s,1H),7.75(d,J=7.6Hz,2H),7.69-7.65(m,2H),7.47(dd, J=2.9,9.3Hz,1H),7.40(t,J=7.9Hz,2H),7.14(t,J=7.4Hz,1H),4.10(t,J=4.9Hz,2H),3.80-3.76(m,5H).

[0093] The following examples in Table 7 are essentially synthesized using appropriate starting materials and reagents, as described for 6-(2-hydroxyethoxy)-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide (Example 58).

[0094] [Table 7]

[0095] Example 62 6-(2-hydroxyethylamino)-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide [ka] Dissolve 6-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide (140 mg, 0.275 mmol) in THF (1.5 mL). Slowly add 1 M tetrabutylammonium fluoride in THF (0.38 mL) at 0°C. Warm the reaction mixture to ambient temperature and stir for 2 hours. Pour the reaction mixture into saturated ammonium chloride aqueous solution (30 mL) and stir at ambient temperature for 10 minutes. Extract the resulting mixture with ethyl acetate (30 mL x 3). Combine the organic layers, wash with saturated ammonium chloride aqueous solution (30 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the residue. Purify the residue to obtain the title product (10 mg, 0.0288 mmol, 10.45%). ES / MS (m / z) (M+H) 338.1. 1H NMR(400.14MHz,CDCl3):12.33-12.29(m,1H),8.92(s,1H),7.84-7.81(m,2H),7.41-7.31(m,3H),7.18-7.12(m, 2H),6.97-6.95(m,1H),4.28-4.26(m,1H),4.01-3.93(m,2H),3.84(s,3H),3.43-3.37(m,2H),1.76-1.74(m,1H).

[0096] The following examples in Table 8 are essentially synthesized using appropriate starting materials and reagents, as described for 6-(2-hydroxyethylamino)-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (Example 62).

[0097] [Table 8-1]

[0098] [Table 8-2]

[0099] hAHR Nuclear Transition Assay A stable cell line was established using the Jump-In® T-REx® HEK 293 Retargeting Kit (Life Technologies). Human AhR cDNA was cloned into a pJTI R4 CMV-TO EGFP vector. EGFP was cloned into the C-terminus of AhR to form an AhR-EGFP chimera. The pJTI R4 CMV-TO AhR-EGFP vector was transfected into Jump-In® T-REx® HEK293 cells using FuGENE® HD. Transfected cells were selected for 10-14 days using 2.5 mg / ml G418, then grown, harvested, and 2 × 10⁶ cells were collected. 7Cells / ml were suspended in frozen medium (FBS containing 8% DMSO), and aliquots were stored in liquid nitrogen. One day before the assay day, cells were thawed, resuspended in DMEM containing 5% FBS in the presence of 1 μg / ml doxycycline, seeded at 12,000–15,000 cells / well in ploy-L-lysine-coated CELLCARRIER-384 ULTRA microplates (Perkin Elmer), and incubated overnight at 37°C and 5% CO2. On the assay day, the compound was serially diluted (1:2) in 384-well nunc plates with DMSO using acoustic dispensing (ECHO). The dose-response curve was 20 points. The compound was resuspended in 40 μl of DMEM + 0.1% BSA. The culture medium was decayed, 25 μl of DMEM + 0.1% BSA was added, and then 25 μl of the compound in DMEM + 0.1% BSA was added to the cell plate. Cells were incubated with the compound at 37°C and 5% CO2 for 45 minutes. The final DMSO concentration was 0.2%. After 45 minutes of incubation, the medium was decayed. Cells were fixed with 40 μl of cold methanol (-20°C) for 20 minutes. The methanol was decayed, and 50 μl of DPBS containing 1 μg / ml Hochst was added to the cell plate. EGFP intensity was quantified using an OPERA PHENIX® or Operetta® high-content imaging system (Perkin Elmer) with a 20×Water Objective and 5 fields per well. To determine the efficacy of the AhR agonist, the ratio of EGFP fluorescence intensity from the nucleus to the cytoplasm was analyzed using a four-parameter nonlinear logistic equation.

[0100] Table 9 shows the hAHR nuclear translocation assay EC of the example compounds. 50 Show the value.

[0101] [Table 9]

[0102] The results of this assay demonstrate that the example compound is an AhR agonist.

Claims

1. The following compound is given by the formula: 【Chemistry 1】 R １ However, 1 to 2 R ｉ Phenyl, R, which is optionally substituted with ｋ A 5-6 member heteroaryl, optionally substituted with R ｊ C arbitrarily replaced by ３ ~C ６ Selected from cycloalkyl groups, R ｉ is independently halogen, C １ -C ４ alkyl, CF ３ , OH, O(C １ -C ４ alkyl), O(C １ -C ３ ), OCH ３ , and NH(C １ -C ３ alkyl)N(CH ３ ) ２ selected from, R ｋ However, halogen, C １ ~C ４ Alkyl, nitrile, CF ３ , and O(C １ ~C ４ Selected from alkyl groups, R ｊ However, O(C １ ~C ４ It is alkyl, X is N and -C(R ４ ) - Selected from, R ２ However, C １ ~C ３ Alkyl or R ４ Together with them, they form a 5-6 member heterocyclic fused ring. R ４ However, hydrogen, halogens, NH(C) １ ~C ３ Alkyl)N(CH ３ ) ２ is or R ２ Together with them, they form a 5-6 member heterocyclic fused ring. R ３ However, hydrogen, halogen, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, NH(C １ ~C ３ Alkyl), N (C １ ~C ３ Alkyl) ２ NH(C １ ~C ３ Alkyl)OH,NH(C １ ~C ３ Alkyl)N(C １ ~C ３ Alkyl) ２ , and O(C １ ~C ３ A compound selected from alkyl)OH, or a pharmaceutically acceptable salt thereof.

2. R １ However, R ｋ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a 5-6 member heteroaryl optionally substituted with .

3. R １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a 5-6 member heteroaryl compound.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is CH.

5. R ２ However, C １ ~C ３ A compound according to any one of claims 1 to 4, which is alkyl, or a pharmaceutically acceptable salt thereof.

6. R ２ However, CH ３ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R ３ However, hydrogen, CH ３ NH(CH ３ ), N (CH ３ ) ２ , N (CH ２ CH ２ )OH, N(CH ２ CH ２ )N(CH ３ ) ２ , and O(CH ２ CH ２ A compound according to any one of claims 1 to 6, selected from )OH.

8. R ３ However, hydrogen and N(CH) ２ CH ２ )N(CH ３ ) ２ A compound selected from any one of claims 1 to 7.

9. The compound according to any one of claims 1 to 8 is as follows: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 9 is as follows: 【Transformation 3】

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. A method for treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11.

13. A method for treating a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11.

14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.

15. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis.

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