CN118215655A - AHR agonists - Google Patents

AHR agonists Download PDF

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Publication number
CN118215655A
CN118215655A CN202280074746.XA CN202280074746A CN118215655A CN 118215655 A CN118215655 A CN 118215655A CN 202280074746 A CN202280074746 A CN 202280074746A CN 118215655 A CN118215655 A CN 118215655A
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alkyl
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pharmaceutically acceptable
compound according
acceptable salt
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L·M·绍维涅-海因斯
C·A·克拉克
D·L·格纳特
S·J·格林
B·M·沃森
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Eli Lilly and Co
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Eli Lilly and Co
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Priority claimed from PCT/US2022/043299 external-priority patent/WO2023039275A1/en
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Abstract

The present invention relates to certain substituted AHR agonist compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of immune-mediated diseases.

Description

AHR agonists
The present invention relates to novel AHR agonist compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat certain physiological disorders.
The present invention is in the field of the treatment of certain immune-mediated diseases (IMDs), particularly psoriasis, via activation of the Aromatic Hydrocarbon Receptor (AHR).
IMDs include a broad range of chronic and debilitating inflammatory conditions that affect about 4% of the population worldwide. In view of the limited efficacy of currently available therapies, the need for potent, selective and safe drugs to treat IMDs remains unmet.
AHR is a transcription factor that regulates aspects of immune function, most notably suppresses adaptive immune responses (Ehrlich et al, curr. Opin. Toxicol.,2,72-78 (2017)). Typical AHR agonists include halogenated dibenzodioxins such as 2,3,7, 8-Tetrachlorodibenzodioxin (TCDD), tryptophan metabolites such as L-kynurenine, bilirubin and PGE2. Results of studies with AHR agonists, particularly TCDD, have shown that immunosuppression is a result of AHR-induced regulatory T cell (Tregs), TH17 cell and Dendritic Cell (DC) expression (Rothhammer et al, nat. Rev, immunol.,19,184-197 (2019)). TCDD has been demonstrated in various mouse models preventing IMD, including type 1 diabetes (KERKVLIET et al, immunotherapy,1,539-547 (2009)), autoimmune encephalomyelitis (Quintana et al, nature,453,65-71, (2008)), autoimmune uveoretinitis (Zhang et 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 in multiple mouse models of transplant tolerance (Pauly et al, toxicol. Environ. Chem.,94,1175-1187 (2010)), and allergic disease (Schulz et al, toxicol. 123, toxicol. Sci., 5-1187 (2011), single et al, PLoS et al, 7, toxicol. Sci., 2011, 7 (2011), single et al, PLoS One,6 (2011)).
AHR also regulates the expression of CYP1A1, CYP1A2 and CYP1B1, CYP1A2 and CYP1B1 catalyzing the metabolism of Polycyclic Aromatic Hydrocarbons (PAHs) and other aromatic compounds (e.g., estrogens). Although in some cases (e.g., for benzo [ a ] pyrene) this metabolism leads to the formation of reactive species, CYP induction is also considered critical for detoxification and metabolic clearance of PAHs, which reduces the likelihood of bioactivation and DNA adduct formation. After FDA approval, some marketed drugs were found to activate AHR (thereby up-regulating CYP1A1, CYP1A2 and CYP1B 1), but their long-term use was not accompanied by dioxin-like toxicity (Ehrlich et al, curr. Opin. Toxicol.,2,72-78 (2017)). CYP induction is therefore no longer considered an obstacle to the use of AHR agonists in therapy (Ehrlich et al, curr. Opin. Toxicol.,2,72-78 (2017)).
Bacterial stilbene compound DMVT-505 (tapinarof) formulated into a 1% topical cream is currently undergoing phase 3 clinical trials for plaque psoriasis treatment in adults (NCT 04053387). Nonetheless, there remains a need for new oral, selective and potent AHR agonists to treat IMDs.
WO 2008/014307 discloses certain bicyclic heteroaryl amides as inhibitors of undecprenyl pyrophosphate synthase. EP 0059698 discloses certain heterocyclic carbamates, compositions comprising these compounds and methods of treatment with these compositions.
The present invention provides compounds that are agonists of AHR.
Accordingly, the present invention provides a compound of formula I:
Wherein,
R 1 is selected from phenyl optionally substituted with 1-2R i, 5-to 6-membered heteroaryl optionally substituted with R k, and C 3-C6 cycloalkyl optionally substituted with R j;
R i is independently selected from halogen, C 1-C4 alkyl, CF 3、OH、O(C1-C4 alkyl), O (C 1-C3)OCH3 and NH (C 1-C3 alkyl) N (CH 3)2;
R k is selected from halogen, C 1-C4 alkyl, nitrile, CF 3 and O (C 1-C4 alkyl);
R j is O (C 1-C4 alkyl);
X is selected from N and-C (R 4) -;
R 2 is C 1-C3 alkyl or together with R 4 forms a 5-to 6-membered fused heterocycle;
R 4 is hydrogen, halogen, NH (C 1-C3 alkyl) N (CH 3)2, or together with R 2 forms a 5-to 6-membered fused heterocycle,
R 3 is selected from the group consisting of hydrogen, halogen, C 1-C4 alkyl, C 3-C6 cycloalkyl, NH (C 1-C3 alkyl), N (C 1-C3 alkyl) 2、NH(C1-C3 alkyl) OH, NH (C 1-C3 alkyl) N (C 1-C3 alkyl) 2, and O (C 1-C3 alkyl) OH;
Or a pharmaceutically acceptable salt thereof.
The invention also provides compounds of formula I wherein R 1 is 5-to 6-membered heteroaryl optionally substituted with R k, or a pharmaceutically acceptable salt thereof.
The invention further provides compounds of formula I wherein R 1 is 5-to 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof.
The invention also provides compounds of formula I wherein X is CH, or a pharmaceutically acceptable salt thereof.
The present invention provides compounds of formula I wherein R 2 is C 1-C3 alkyl, or a pharmaceutically acceptable salt thereof.
The invention further provides compounds of formula I wherein R 2 is CH 3, or a pharmaceutically acceptable salt thereof.
The present invention provides compounds of formula I wherein R 3 is selected from hydrogen 、CH3、NH(CH3)、N(CH3)2、N(CH2CH2)OH、N(CH2CH2)N(CH3)2 and O (CH 2CH2) OH.
The present invention provides compounds of formula I wherein R 3 is selected from hydrogen and N (CH 2CH2)N(CH3)2.
The present invention further provides a compound of formula I selected from:
Or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound of formula I selected from
The invention further provides a pharmaceutical composition comprising a compound of any of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present invention provides a method of treating an immune-mediated disorder in a patient, the method comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutical composition of any of the above embodiments.
The invention also provides a method of treating a disease or condition 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 of any of the above embodiments.
The present invention provides a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in therapy.
The invention also provides a compound according to any one of the above embodiments, 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.
Furthermore, the present invention provides a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of an immune-mediated disease. In addition, the present invention provides a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder selected from psoriasis, ulcerative colitis, crohn's disease, graft versus host disease and multiple sclerosis.
The term "alkyl" as used herein alone or as part of a larger moiety refers to a saturated straight or branched chain hydrocarbon group containing one or more carbon atoms.
The term "cycloalkyl" as used herein refers to a saturated ring system containing at least three carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "heterocycle" as used herein 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 heterocycles include oxirane, aziridine, oxetane, oxolane, pyrrolidine, piperidine, and morpholine.
The term "heteroaryl" as used herein refers to such rings: having 5 to 10 ring atoms, preferably 5,6, 9 or 10 ring atoms, sharing 6, 10 or 14 pi-electrons in the ring arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. The term "bicyclic heteroaryl" includes groups in which the heteroaryl ring is fused to another aryl or heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
The term "immune-mediated disease" as used herein encompasses a group of autoimmune inflammatory diseases characterized by alterations in intracellular homeostasis. Immune-mediated diseases can be triggered by environmental factors, eating habits, infectious agents, and genetic predisposition.
The term "treating" as used herein includes arresting, slowing, stopping or reversing the progress or severity of an existing symptom or disorder.
The term "patient" as used herein refers to a human.
The term "effective amount" as used herein refers to the following amount or dosage of a compound of the invention or a pharmaceutically acceptable salt thereof: when administered to a patient one or more times, provides the intended effect to the patient under diagnosis or treatment.
The effective amount can be readily determined by one skilled in the art using known techniques. In determining an effective amount for a patient, a number of factors are considered, including, but not limited to: patient species; its size, age and general health; the particular disease or disorder involved; the degree or involvement or severity of the disease or disorder; response of the individual patient; the particular compound being administered; mode of administration; bioavailability characteristics of the administered preparation; the selected dosing regimen; combining the medicines; and other related situations.
The compounds of the present invention are generally effective over a wide dosage range. For example, daily dosages typically fall within the range of about 0.1 to about 15mg/kg body weight. In some instances, dosage levels below the lower limit of the above range may be more than adequate, while in other cases, larger dosages may be employed with acceptable side effects, and thus the above dosage ranges are not intended to limit the scope of the invention in any way.
The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration by any route that makes the compounds bioavailable, including oral and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods of preparing them are well known in the art (see, e.g., remington: SCIENCE AND PRACTICE of Pharmacy, a. Adejare editor, 23 th edition, ELSEVIER ACADEMIC PRESS, 2020).
The compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared by methods well known and understood in the art according to the following preparations and examples. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and suitable substitutions of solvents and co-solvents are within the skill of the art. Also, it will be appreciated by those skilled in the art that synthetic intermediates can be isolated and/or purified as desired by a variety of well known techniques, and that various intermediates can often be used directly in subsequent synthetic steps with little or no purification. By way of illustration, the compounds of the preparations and examples can be isolated, for example, by purification on silica gel, isolation by direct filtration or crystallization. Moreover, those skilled in the art will appreciate that in some cases the order of introduction of the moieties is not critical. The particular sequence of steps required to produce the compounds of the present invention depends on the relative propensity (availability) of the particular compound being synthesized, the starting compound and the substituted moiety, as is well known to those skilled in the chemical arts. Unless otherwise indicated, all substituents are as defined above, and all reagents are well known and understood in the art.
Some abbreviations are defined below: "BrettPhos Pd G3" refers to [ (2-dicyclohexylphosphino-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's medium; "DMSO" refers to dimethyl sulfoxide; "DPBS" refers to Dulbecco's phosphate buffered saline; "EGFP" refers to an enhanced green fluorescent protein; "Et 2 O" represents diethyl ether; "EtOH" represents ethanol; HATU refers to (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate, "hr" or "hrs" refers to hours, "min" refers to minutes, "Pd 2(dba)3" refers to tris (bisbenzylidene acetone) dipalladium (0), "SCX" refers to strong cation exchange, "TBAF" refers to tetra-n-butylammonium fluoride, "tBuONa" refers to sodium t-butoxide, "THF" refers to tetrahydrofuran, and "tBuXphos" refers to 2-di-t-butylphosphino-2 ',4',6' -triisopropylbiphenyl.
In an optional step, a pharmaceutically acceptable salt of a compound according to any of the above embodiments may be formed by reacting the appropriate free base of the compound with an appropriate pharmaceutically acceptable acid in an appropriate solvent under standard conditions. The formation of such salts is well known and understood in the art. See, for example Gould,P.L.,"Salt selection for basic drugs,"International Journal of Pharmaceutics,33:201-217(1986);Bastin,R.J., et al ,"Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,"Organic Process Research and Development,4:427-435(2000); and Berge, s.m., et al ,"Pharmaceutical Salts,"Journal of Pharmaceutical Sciences,66:1-19,(1977)."Salt selection for basic drugs,"International Journal of Pharmaceutics,33:201-217(1986). those of skill in the art will appreciate that the compounds of any of the above embodiments can be readily converted to and isolated as pharmaceutically acceptable salts.
The compounds of formula I, or pharmaceutically acceptable salts thereof, may be prepared by a variety of methods known in the art, some of which are illustrated in the schemes, preparations and examples below. The specific synthetic steps of each of the routes described may be combined in different ways or with steps from different schemes to prepare the compounds of formula I or pharmaceutically acceptable salts thereof. The product from each step of the schemes below may be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the following schemes, all substituents are as defined above, unless otherwise indicated. Reagents and starting materials are readily available to those of ordinary skill in the art.
Scheme 1. General scheme for the preparation of Compounds of formula I
Scheme 1 depicts a general scheme for the synthesis of compounds of formula I.
The fused 2-oxo-1H-pyridine-3-carboxylic acid (1) may be subjected to amide coupling to give the compound of formula I.
Or bromine-substituted fused 2-oxo-1H-pyridine-3-carboxylic acid (2) may be first subjected to an amide coupling to give (2), which may then be subjected to a palladium-catalyzed coupling reaction to give the compound of formula I.
Preparation examples and examples
The following preparations and examples further illustrate the invention.
Intermediate 1
1-Methyl-2-oxo-1, 8-naphthyridine-3-carboxylic acid
Step 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) was stirred in EtOH (7 mL,120 mmol) at ambient temperature for 1hr. The mixture was refluxed for 2hrs and the precipitate was collected by filtration. The solid was washed with cold EtOH and dried in vacuo to give ethyl 2-oxo-1H-1, 8-naphthyridine-3-carboxylate (710mg,3.254mmol,81.93％)ES/MS(m/z):219.0(M+H).1H 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).
Step B methyl iodide (0.61 mL,9.8 mmol) and potassium carbonate (372 mg, 2.6967 mmol) were added to a suspension of ethyl 2-oxo-1H-1, 8-naphthyridine-3-carboxylate (710 mg,3.254 mmol) in EtOH (8 mL,198 mmol) and N, N-dimethylformamide (8 mL,103 mmol). The mixture was stirred at ambient temperature overnight and then diluted with ethyl acetate. The quenched reaction was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give ethyl 1-methyl-2-oxo-1, 8-naphthyridine-3-carboxylate (640 mg,2.7344mmol,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,1H),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).
Step C; intermediate 1 Ethyl 1-methyl-2-oxo-1, 8-naphthyridine-3-carboxylate (640 mg, 2.284 mmol) was dissolved in a mixture of THF (0.2M, 168 mmol) and methanol (10.94 mmol). 1M aqueous lithium hydroxide (10.94 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to dryness and then dissolved in water and the pH was adjusted to 1 with 1M aqueous HCl. The white solid was filtered off and dried overnight under indoor vacuum to give the title product (532mg,2.606mmol,95.287％).1H 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).
Intermediate 2
7-Bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester
Step 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) was refluxed in EtOH (40 mL,687 mmol) for 3hrs. The reaction was cooled to ambient temperature, filtered, and the solid was rinsed with cold EtOH and then Et 2 O to give ethyl 7-bromo-2-oxo-1H-quinoline-3-carboxylate (step A;2.71g,9.14mmol,62％).ES/MS(m/z)(79Br/81Br):297.0/298.0(M+H).1H 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).
Step B, performing a step B; intermediate 2 Ethyl 7-bromo-2-oxo-1H-quinoline-3-carboxylate (2.707 g,9.142 mmol) was dissolved in N, N-dimethylformamide (30 mL, 3838 mmol,28.4 g). Potassium carbonate (2.78 g,20.1 mmol) was added followed by methyl iodide (1.25 mL,20.1mmol,2.85 g) and stirred at ambient temperature overnight. The reaction was poured into saturated aqueous sodium bicarbonate and the resulting mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with a 0-100% ethyl acetate/hexane gradient to give the title product (2.58g,8.32mmol,91.0％).ES/MS(m/z)(79Br/81Br):310.0/311.0(M+H).1H 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).
Intermediate 3
5-Bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid
Step A diethyl malonate (696 mg,4.345 mmol) and potassium carbonate (910 mg, 6.719 mmol) were added to a solution of 2-bromo-6-nitro-benzaldehyde (1 g, 4.349 mmol) in acetic anhydride (10 mL). The mixture was stirred at 806185 for 1hr. The reaction was cooled to ambient temperature, diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give diethyl 2- [ (2-bromo-6-nitro-phenyl) methylene ] propane dicarboxylate (1.6 g,4.3mmol, 99%). ES/MS (M/z) (79Br/81 Br): 370.0/372.0 (M+H).
Step B iron (2.4 g,37 mmol) was added to a solution of diethyl 2- [ (2-bromo-6-nitro-phenyl) methylene ] propane dicarboxylate (1.6 g,4.3 mmol) in glacial acetic acid (10 mL). The reaction mixture was stirred at 80 ℃ for 12hrs, then filtered through a celite pad. The pH was adjusted to ph=8 with saturated aqueous sodium bicarbonate. The reaction was extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (30 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was triturated with methanol at ambient temperature for 20min and then filtered to give ethyl 5-bromo-2-oxo-1H-quinoline-3-carboxylate (200 mg,0.540mmol, 50.28%). ES/MS (M/z) (79Br/81 Br): 295.0/298.0 (M+H).
Step C cesium carbonate (573 mg,1.76 mmol) and methyl iodide (0.3 mL,5 mmol) were 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 was stirred at 50℃for 12hrs. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with a 0 to 40% ethyl acetate/petroleum ether gradient to give 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (150 mg, 0.399 mmol, 100%). ES/MS (M/z) (79Br/81 Br): 310.0/312.0 (M+H).
Step D, performing step D; intermediate 3A solution of lithium hydroxide (40 mg,0.934 mmol) in water (2 mL) was added to a solution of ethyl 5-bromo-1-methyl-2-oxo-quinoline-3-carboxylate (100 mg,0.323 mmol) in THF (2 mL). The resulting mixture was stirred at 40℃for 1hr. The mixture was cooled to ambient temperature and the pH was adjusted to pH 4 with 1N aqueous HCl. The mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (70mg,0.248mmol,77％).1H 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).
Example 1
N- (4-methoxyphenyl) -1-methyl-2-oxo-quinoline-3-carboxamide
1-Methyl-2-oxo-quinoline-3-carboxylic acid (418 mg,2.057 mmol), 4-methoxyaniline (304 mg,2.469 mmol), N-dimethylformamide (7 mL,90.5 mmol), HATU (830 mg,2.268 mmol) and N, N-diisopropylethylamine (1.8 mL,10mmol, 100) were added together. The reaction was stirred at ambient temperature overnight and concentrated. The resulting material was purified by silica gel chromatography eluting with a 0-5% dichloromethane/methanol gradient. The resulting solid was triturated with Et 2 O to give the title product (548mg,1.777mmol,86.40％).ES/MS(m/z):309.0(M+H).1H NMR(400.13MHz,d6-DMSO):11.99(s,1H),8.98(s,1H),8.09(dd,J＝1.3,7.9Hz,1H),7.86-7.81(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).
The following examples in table 1 were synthesized essentially as for N- (4-methoxyphenyl) -1-methyl-2-oxo-quinoline-3-carboxamide (example 1) using the appropriate starting materials and reagents.
TABLE 1 examples 2 to 39
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Intermediate 4
4- [4- [ (11-Oxo-1-azatricyclo [6.3.1.04,12] dodeca-4 (12), 5,7, 9-tetraene-10-carbonyl) amino ] phenyl ] piperidine-1-carboxylic acid tert-butyl ester
The title intermediate was synthesized essentially as described for N- (4-methoxyphenyl) -1-methyl-2-oxo-quinoline-3-carboxamide (example 1) using the appropriate starting materials and reagents. ES/MS (M/z) (M+H) 375.2.
Example 40
7-Bromo-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide
Trimethylaluminum (2M) in hexane (0.5 mL,1.0 mmol) was slowly added to a0℃solution of aniline (0.10 mL,1.1 mmol) in toluene (2.1 mL,20 mmol). The reaction was warmed to ambient temperature and stirred for 10min. 7-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (0.208 g,0.671 mmol) was added as a solid. The reaction was sealed and heated to 100 ℃ for 3hrs by microwave irradiation. The reaction was poured into a separatory funnel containing Rochelle's salt and extracted with ethyl acetate (×3). The combined organics were washed with aqueous 1nh cl then brine and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate/hexane to give the title product (0.140 g, 0.399mmol, 58.4% yield) ).ES/MS(m/z)(79Br/81Br):(M+H)357.0/359.0.1H 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).
Example 41
N- (5-methyl-2-pyridinyl) -11-oxo-1-azatricyclo [6.3.1.04,12] dodeca-4 (12), 5,7, 9-tetraene-10-carboxamide
DIEA (0.12 mL,0.66 mmol) was added to a solution of 4-oxo-1, 2-dihydro-4 h-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-propane phosphoric anhydride (50% by mass) in ethyl acetate (0.39 mL,0.66mmol,1.67 mol/L) and dichloromethane (2 mL). The resulting mixture was stirred at 80℃for 1hr. The reaction was cooled to ambient temperature and washed with saturated aqueous ammonium chloride. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to give the title product (3.9mg,0.013mmol,3.9％).ES/MS(m/z):306.0(M+H).1H 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),7.72-7.68(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).
The following examples in Table 2 were synthesized essentially as described for N- (5-methyl-2-pyridinyl) -11-oxo-1-azatricyclo [6.3.1.04,12] dodeca-4 (12), 5,7, 9-tetraene-10-carboxamide (example 41) using the appropriate starting materials and reagents.
TABLE 2 examples 42 and 43
The following intermediates in table 3 were synthesized essentially as for N- (5-methyl-2-pyridinyl) -11-oxo-1-azatricyclo [6.3.1.04,12] dodeca-4 (12), 5,7, 9-tetraene-10-carboxamide (example 41) using the appropriate starting materials and reagents.
TABLE 3 intermediates 5-9
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Intermediate 10
5-Bromo-1-methyl-2-oxo-N- (2-pyridinyl) quinoline-3-carboxamide
Pyridine (255 mg,3.224 mmol) and POCl 3 (200 mg,1.3044 mmol) were added 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). The resulting mixture was stirred at 20℃for 2hrs. The mixture was concentrated under reduced pressure. The resulting residue was triturated with methanol at ambient temperature for 10min and then filtered to give 5-bromo-1-methyl-2-oxo-N- (2-pyridinyl) quinoline-3-carboxamide (600 mg, 1.6755 mmol,94.50% yield) ES/MS (M/z) (79Br/81 Br): 357.9/359.9 (M+H).
The following intermediates in table 4 were synthesized essentially as described for 5-bromo-1-methyl-2-oxo-N- (2-pyridinyl) quinoline-3-carboxamide (intermediate 10) using the appropriate starting materials and reagents.
TABLE 4 intermediates 11-17
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Example 44
N- (4-methoxyphenyl) -1, 7-dimethyl-2-oxo-quinoline-3-carboxamide
7-Bromo-N- (4-methoxyphenyl) -1-methyl-2-oxo-quinoline-3-carboxamide (0.100 g,0.258 mmol) was dissolved in 1, 4-dioxane (1.5 mL,18 mmol). Methyl boric acid (0.038 g,0.62 mmol) and cesium carbonate (0.165 g,0.506 mmol) were added. Nitrogen was purged into the reaction mixture for 5min. 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.036 g,0.043 mmol) was added, then sealed and heated to 100℃for 2hrs by microwave. The crude reaction was purified by silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to give the title product (0.015 g,0.047mmol,18% yield) ).ES/MS(m/z)(M+H):323.0.1H 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).
Example 45
7-Cyclopropyl-N- (4-methoxyphenyl) -1-methyl-2-oxo-quinoline-3-carboxamide
The title compound was synthesized essentially as described for N- (4-methoxyphenyl) -1, 7-dimethyl-2-oxo-quinoline-3-carboxamide (example 44) using the appropriate starting materials and reagents. ES/MS (M/z) (79Br/81 Br): (M+H) 349.0.
Example 46
N- (4-methoxyphenyl) -1-methyl-7- (methylamino) -2-oxo-quinoline-3-carboxamide
7-Bromo-N- (4-methoxyphenyl) -1-methyl-2-oxo-quinoline-3-carboxamide (0.154 g,0.398 mmol) was dissolved in toluene (2 mL). Sodium tert-butoxide (0.100 g,1.01 mmol) was added. Nitrogen was purged into the reaction for 10min. A solution of methylamine (2.0 mol/L) in tetrahydrofuran (0.600 mL,1.2 mmol) was added followed by (R) - (+) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (0.035 g,0.055 mmol) and then tris (bisbenzylidene acetone) dipalladium (0) (0.040 g,0.042 mmol). The reaction was sealed and heated to 80 ℃ for 2hrs via microwaves. The crude reaction was purified by silica gel chromatography eluting with 0-10% (7N NH 3 in methanol)/dichloromethane to give the crude product. The crude product was purified by SCX ion exchange column, rinsed with 1:1 methanol/dichloromethane, then methanol, then 7N ammonia in methanol (×2). The ammonia-containing rinse was concentrated in vacuo to afford the title product (33mg,0.0978mmol,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).
The following examples in table 5 were synthesized essentially as for N- (4-methoxyphenyl) -1-methyl-7- (methylamino) -2-oxo-quinoline-3-carboxamide (example 46) using the appropriate starting materials and reagents.
TABLE 5 examples 47-56
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The following intermediates in table 6 were synthesized essentially as described for N- (4-methoxyphenyl) -1-methyl-7- (methylamino) -2-oxo-quinoline-3-carboxamide (example 46) using the appropriate starting materials and reagents.
TABLE 6 intermediates 18-25
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Example 57
5- [2- (Dimethylamino) ethylamino ] -N- (5-fluoropyrimidin-2-yl) -1-methyl-2-oxo-quinoline-3-carboxamide
BrettPhos Pd G3 (75 mg,0.0786 mmol), pd 2(dba)3 (73 mg,0.0797 mmol) was added to a solution of 5-bromo-N- (5-fluoropyrimidin-2-yl) -1-methyl-2-oxo-quinoline-3-carboxamide (100 mg,0.2651 mmol), 2- (4, 4-difluoro-1-piperidinyl) ethylamine (150 mg,0.3977 mmol) and t-Buona (117 mg,1.1930 mmol) in N, N-dimethylethylenediamine (185 mg,1.994 mmol). The reaction mixture was stirred at 130 ℃ for 12hrs, then concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 0-5% methanol in dichloromethane to give the crude product. The crude product was triturated with MeOH at 20℃for 5min. The mixture was filtered to give the title product (17.74mg,0.0357mmol,8.973％).ES/MS(m/z)(M+H)385.2.1H 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).
Alternative Synthesis of example 57
5- [2- (Dimethylamino) ethylamino ] -N- (5-fluoropyrimidin-2-yl) -1-methyl-2-oxo-quinoline-3-carboxamide
BrettPhos Pd G3 (75 mg,0.0786 mmol), pd 2(dba)3 (73 mg,0.0797 mmol) was added to a solution of 5-bromo-N- (5-fluoropyrimidin-2-yl) -1-methyl-2-oxo-quinoline-3-carboxamide (100 mg,0.2651 mmol), N-dimethylethylenediamine (185 mg,1.994 mmol) and t-Buona (117 mg,1.1930 mmol) in DMF (4 mL). The reaction mixture was stirred at 130 ℃ for 12hrs, then concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 0-5% methanol in dichloromethane to give the crude product. The crude product was triturated with MeOH at 20℃for 5min. The mixture was filtered to give the title product (17.74mg,0.0357mmol,8.973％).ES/MS(m/z)(M+H)385.2.1H 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).
Intermediate 26
6- [2- [ Tert-butyl (dimethyl) silyl ] oxyethylamino ] -N- (5-fluoro-2-pyridinyl) -1-methyl-2-oxo-quinoline-3-carboxylic acid
Amines
BrettPhos Pd G3 (32 mg,0.033 mmol) was added to a solution of 6-bromo-N- (5-fluoro-2-pyridinyl) -1-methyl-2-oxo-quinoline-3-carboxamide (250 mg,0.6313 mmol), 2- (4, 4-difluoro-1-piperidinyl) ethylamine (150 mg,0.3977 mmol) and t-Buona (75 mg,0.765 mmol) in THF (5 mL). The reaction mixture was stirred at 100 ℃ for 16hrs and then concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 0-70% petroleum ether/ethyl acetate to give the title product (200mg,0.2975mmol,47.12％).ES/MS(m/z)(M+H)471.2.1H 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).
Alternative Synthesis of intermediate 26
6- [2- [ Tert-butyl (dimethyl) silyl ] oxyethylamino ] -N- (5-fluoro-2-pyridinyl) -1-methyl-2-oxo-quinoline-3-carboxylic acid
Amines
BrettPhos Pd G3 (32 mg,0.033 mmol) was added to a solution of 6-bromo-N- (5-fluoro-2-pyridinyl) -1-methyl-2-oxo-quinoline-3-carboxamide (250 mg,0.6313 mmol), 2- [ tert-butyl (dimethyl) silyl ] oxyethylamine (335 mg,1.91 mmol) and t-Buona (75 mg,0.765 mmol) in THF (5 mL). The reaction mixture was stirred at 100 ℃ for 16hrs and then concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 0-300% ethyl acetate/petroleum ether to give the title product (200mg,0.2975mmol,47.12％).ES/MS(m/z)(M+H)471.2.1H 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).
Example 58
6- (2-Hydroxyethoxy) -1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide
Step A6-bromo-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (2.005 g,5.052 mmol) and 1, 4-dioxane (10 mL) were added together. Tri (dibenzylidene) dipalladium (0) (trisdibenzilidenedipalladium (0)) (4635 mg,0.508 mmol), tBuXphos (447 mg,1.012 mmol) and potassium hydroxide (876 mg,15.15 mmol) in water (10 mL,555.1 mmol) were then added. The mixture was stirred at 100 ℃ for 15hrs and then cooled to ambient temperature. Water (100 mL) was added to the cooled reaction. The resulting mixture was extracted with ethyl acetate (50 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 0 to 50% ethyl acetate/petroleum ether to give 6-hydroxy-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (1g,3.058mmol,60.54％).ES/MS(m/z)(M+H)370.2.1H 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).
Step B6-hydroxy-1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (101 mg,0.309 mmol) was dissolved in dimethylformamide (2 mL). 2- (2-Bromoethoxy) tetrahydropyran (101 mg, 0.4813 mmol) and cesium carbonate (403 mg,1.237 mmol). The mixture was stirred at 80 ℃ for 12hrs and then cooled to ambient temperature. Water (50 mL) was added to the cooled reaction. The mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 0 to 100% ethyl acetate/petroleum ether to give 1-methyl-2-oxo-N-phenyl-6- (2-tetrahydropyran-2-yloxyethoxy) quinoline-3-carboxamide (60mg,0.128mmol,41.38％)ES/MS(m/z)(M+H)423.2.1H 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).
Step C; example 58 1-methyl-2-oxo-N-phenyl-6- (2-tetrahydropyran-2-yloxyethoxy) quinoline-3-carboxamide (60 mg,0.1278 mmol) was dissolved in 1M hydrochloric acid in ethyl acetate (2 mL). The mixture was stirred at ambient temperature for 2hrs. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with methanol (10 mL) at ambient temperature for 10min. The resulting mixture was filtered to give the title product (example 81;14mg,0.0398mmol,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).
The following examples in table 7 were synthesized essentially as for 6- (2-hydroxyethoxy) -1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (example 58) using the appropriate starting materials and reagents.
TABLE 7 examples 59-61
Example 62
6- (2-Hydroxyethylamino) -1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide
6- [2- [ Tert-butyl (dimethyl) silyl ] oxyethylamino ] -1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (140 mg,0.275 mmol) was dissolved in THF (1.5 mL). A1M solution of tetrabutylammonium fluoride in THF (0.38 mL) was slowly added at 0deg.C. The reaction was warmed to ambient temperature and stirred for 2hrs. The reaction was poured into saturated aqueous ammonium chloride (30 mL) and stirred at ambient temperature for 10min. The resulting mixture was extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with saturated aqueous ammonium chloride (30 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. Purification of the residue gave the title product (10mg,0.0288mmol,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).
The following examples in table 8 were synthesized essentially as described for 6- (2-hydroxyethylamino) -1-methyl-2-oxo-N-phenyl-quinoline-3-carboxamide (example 62) using the appropriate starting materials and reagents.
TABLE 8 examples 63-70
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HAHR Nuclear translocation analysis
Stable cell lines were established using a Jump-In TMT-RExTM HEK293 RETARGETING KIT (Life Technologies). The human AhR cDNA was cloned into pJTI R CMV-TO EGFP vector. EGFP was cloned into the C-terminus of AHR to form AhR-EGFP chimeras. UsingHD pJTI R4CMV-TO AhR-EGFP vector was transfected into Jump-In TMT-RExTM HEK293 cells. Transfected cells were selected using 2.5mg/ml G418 for 10-14 days, then expanded, harvested, suspended in frozen medium (FBS with 8% DMSO) at 2X10 7 cells/ml, and aliquots were stored in liquid nitrogen. The day before the test, cells were thawed, resuspended in DMEM with 5% FBS in the presence of 1 μg/ml doxycycline, plated onto poly-L-lysine coated CELLCARRIER-384ULTRA Microplates (PERKIN ELMER) at 12,000-15,000 cells/well and incubated overnight at 37 ℃ with 5% CO 2. On the date of analysis, compounds were serially diluted (1:2) with DMSO into 384-well nunc plates using acoustic partitioning (ECHO). Dose response was a 20-point curve. The compounds were resuspended in 40 μl DMEM plus 0.1% BSA. The medium was allowed to wet, 25. Mu.l of DMEM plus 0.1% BSA was added, and then 25. Mu.l of a solution of the compound in DMEM plus 0.1% BSA was added to the cell plate. Cells were incubated with the compound at 37℃and 5% CO 2 for 45 min. The final DMSO concentration was 0.2%. After 45 minutes of incubation, the medium was allowed to wet. The cells were fixed with 40. Mu.l of cold methanol (-20 ℃) for 20 min. Methanol was allowed to wet and 50. Mu.l of DPBS containing 1. Mu.g/ml Hochst was added to the cell plate. By using OPERAOr the operaetta TM high content image system (PERKIN ELMER) quantified for EGFP density with 20x Water Objective, five fields per well. The ratio of EGFP fluorescence intensity in the nucleus to cytosol was analyzed using a 4-parameter nonlinear logistic equation to determine the efficacy of AhR agonists.
Table 9 shows the hAHR nuclear translocation analysis EC 50 values for the compounds of the examples.
Table 9.HAHR nuclear translocation analysis EC 50 values
The results of this analysis demonstrate that the compounds of the examples are AhR agonists.

Claims (15)

1.A compound of the formula:
R 1 is selected from phenyl optionally substituted with 1-2R i, 5-to 6-membered heteroaryl optionally substituted with R k, and C 3-C6 cycloalkyl optionally substituted with R j;
R i is independently selected from halogen, C 1-C4 alkyl, CF 3、OH,O(C1-C4 alkyl), O (C 1-C3)OCH3 and NH (C 1-C3 alkyl) N (CH 3)2;
R k is selected from halogen, C 1-C4 alkyl, nitrile, CF 3 and O (C 1-C4 alkyl);
R j is O (C 1-C4 alkyl);
X is selected from N and-C (R 4) -;
R 2 is C 1-C3 alkyl or together with R 4 forms a 5-to 6-membered fused heterocycle;
R 4 is hydrogen, halogen, NH (C 1-C3 alkyl) N (CH 3)2, or together with R 2 forms a 5-to 6-membered fused heterocycle,
R 3 is selected from the group consisting of hydrogen, halogen, C 1-C4 alkyl, C 3-C6 cycloalkyl, NH (C 1-C3 alkyl), N (C 1-C3 alkyl) 2、NH(C1-C3 alkyl) OH, NH (C 1-C3 alkyl) N (C 1-C3 alkyl) 2, and O (C 1-C3 alkyl) OH;
Or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R 1 is 5-to 6-membered heteroaryl optionally substituted with R k, or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 or 2, wherein R 1 is 5-to 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof.
4. A compound according to any one of claims 1 to 3 wherein X is CH, or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 4 wherein R 2 is C 1-C3 alkyl, or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5, wherein R 2 is CH 3, or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 6 wherein R 3 is selected from hydrogen 、CH3、NH(CH3)、N(CH3)2、N(CH2CH2)OH、N(CH2CH2)N(CH3)2 and O (CH 2CH2) OH.
8. A compound according to any one of claims 1 to 7, wherein R 3 is selected from hydrogen and N (CH 2CH2)N(CH3)2).
9. A compound according to any one of claims 1 to 8 which is:
Or a pharmaceutically acceptable salt thereof.
10. A compound according to any one of claims 1 to 9 which is:
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 of treating an immune-mediated disease in a patient, the method 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 of 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 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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