Carboxyl-substituted glucocorticoid receptor agonists

Abstract

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof: #imgabs0# wherein R 1 is H, halogen, C1-C3 alkyl or C1-C3 alkoxy; R 2 is H or halogen; and X is O, OCH2 or CH2; wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is used to treat autoimmune diseases and inflammatory diseases, such as atopic dermatitis, rheumatoid arthritis and lupus nephritis.

Description

[0001] The present application provides compounds that are glucocorticoid receptor agonists and can be used to treat autoimmune diseases and inflammatory diseases such as atopic dermatitis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis and rheumatoid arthritis, as well as methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions.

[0002] Atopic dermatitis is a chronic, pruritic, relapsing-remitting inflammatory skin disease that often develops in children but also affects many adults. Current treatments for atopic dermatitis include phototherapy, topical creams containing corticosteroids or calcineurin inhibitors, or a subcutaneous biologic drug called dupilumab. Despite advances in the treatment of atopic dermatitis, there remains a significant need for new compounds to treat atopic dermatitis and other inflammatory and autoimmune diseases.

[0003] WO2017 / 210471 discloses certain glucocorticoid receptor agonists and immunoconjugates thereof that can be used to treat autoimmune or inflammatory diseases. WO2018 / 089373 discloses novel steroids, protein conjugates thereof, and methods for treating diseases, disorders, and conditions comprising administering the steroids and conjugates.

[0004] The present invention provides certain novel compounds that are glucocorticoid receptor agonists. In addition, the present invention also provides certain novel compounds that are glucocorticoid receptor agonists that can be used to treat autoimmune and inflammatory diseases, such as atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis.

[0005] Thus, in one embodiment, the present invention provides a compound of formula I:

[0006]

[0007] where R 1 is H, halogen, C1-C3 alkyl or C1-C3 alkoxy;

[0008] R 2 is H or halogen; and

[0009] X is O, OCH2 or CH2,

[0010] or a pharmaceutically acceptable salt thereof.

[0011] In one embodiment, the present invention provides a compound of formula Ia:

[0012]

[0013] or a pharmaceutically acceptable salt thereof.

[0014] In one embodiment, the present invention provides a compound of formula Ib:

[0015]

[0016] or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the present invention provides a compound of formula Ic:

[0018]

[0019] or a pharmaceutically acceptable salt thereof.

[0020] In another embodiment, the present invention provides a compound of formula Ib(i):

[0021]

[0022] or a pharmaceutically acceptable salt thereof.

[0023] In another embodiment, the present invention provides a compound of formula Ic(i):

[0024]

[0025] or a pharmaceutically acceptable salt thereof.

[0026] In another embodiment, the present invention provides a compound of formula Ib(ii):

[0027]

[0028] or a pharmaceutically acceptable salt thereof.

[0029] In another embodiment, the present invention provides a compound of formula Ic(ii):

[0030]

[0031] or a pharmaceutically acceptable salt thereof.

[0032] In another embodiment, the present invention provides a compound of formula Ib(iii):

[0033]

[0034] or a pharmaceutically acceptable salt thereof.

[0035] In another embodiment, the present invention provides a compound of formula Ic(iii):

[0036]

[0037] or a pharmaceutically acceptable salt thereof.

[0038] In another embodiment, the present invention provides a compound of formula Ib(iv):

[0039]

[0040] or a pharmaceutically acceptable salt thereof.

[0041] In another embodiment, the present invention provides a compound of formula Ic(iv):

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, X is O.

[0045] In one embodiment, X is OCH2.

[0046] In one embodiment, X is CH2.

[0047] In one embodiment, R 1 It's F.

[0048] In one embodiment, R 1 It’s H.

[0049] In one embodiment, R 1 It is CH3.

[0050] In one embodiment, R 1 It is OCH3.

[0051] In one embodiment, R 2 It’s H.

[0052] In one embodiment, R 2 It's F.

[0053] In one embodiment, R 2 Does not exist.

[0054] In one embodiment, X is CH2, R 1 is F, and R 2 It’s H.

[0055] In one embodiment, X is O, and R 1 and R 2 Each is H.

[0056] In one embodiment, X is OCH2, R 1 is CH3, and R 2It's F.

[0057] In one embodiment, X is OCH2, R 1 is OCH3, and R 2 It's F.

[0058] In one embodiment, the present invention provides a compound of formula II:

[0059]

[0060] or a pharmaceutically acceptable salt thereof.

[0061] In a specific embodiment, the present invention provides a compound of formula IIa:

[0062]

[0063] or a pharmaceutically acceptable salt thereof.

[0064] In a specific embodiment, the present invention provides a compound of formula IIb:

[0065]

[0066] or a pharmaceutically acceptable salt thereof.

[0067] In a specific embodiment, the present invention provides a compound of formula IIc:

[0068]

[0069] or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, the present invention also provides a method for treating an inflammatory disease in a patient in need of said treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating an autoimmune disease in a patient in need of said treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating atopic dermatitis in a patient in need of said treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating inflammatory bowel disease in a patient in need of said treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating rheumatoid arthritis in a patient in need of said treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating systemic lupus erythematosus in a patient in need of said treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method of treating lupus nephritis in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treatment. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory diseases. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of autoimmune diseases. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of atopic dermatitis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of lupus nephritis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of systemic lupus erythematosus.

[0072] In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an inflammatory disease. In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an autoimmune disease. In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating atopic dermatitis. In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating rheumatoid arthritis. In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating inflammatory bowel disease. In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lupus nephritis. In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating systemic lupus erythematosus.

[0073] In one embodiment, the present invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention also provides a method for preparing a pharmaceutical composition comprising mixing a compound of Formula I or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention also encompasses novel intermediates and methods for synthesizing compounds of Formula I.

[0074] As used herein, the term "treating" includes inhibiting, slowing, stopping or reversing the progression or severity of an existing symptom or disorder.

[0075] As used herein, the term "patient" refers to a mammal, particularly a human.

[0076] As used herein, the term "effective amount" refers to the amount or dosage of a compound of the present invention or a pharmaceutically acceptable salt thereof that provides the desired effect in the patient being diagnosed or treated when administered to the patient in single or multiple doses.

[0077] An effective amount can be determined by one skilled in the art by using known techniques and by observing the results obtained under similar circumstances. In determining an effective amount for a patient, the attending diagnostician considers many factors, including, but not limited to: the species of the patient; their size, age, and general health; the specific disease or disorder involved; the extent or severity of the disease or disorder; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; the use of concomitant medications; and other relevant circumstances.

[0078] As used herein, Formula I is understood to encompass Formulas Ia, Ib, Ic, Ib(i), Ib(ii), Ib(iii), Ib(iv), Ic(i), Ic(ii), Ic(iii), Ic(iv), II, IIa, IIb, and IIc, and all references to Formula I herein are understood to include Formulas Ia, Ib, Ic, Ib(i), Ib(ii), Ib(iii), Ib(iv), Ic(i), Ic(ii), Ic(iii), Ic(iv), II, IIa, IIb, and IIc.

[0079] As used herein, "halogen" refers to F, Cl, Br and I.

[0080] As used herein, "C1-C3 alkyl" refers to CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

[0081] As used herein, "C1-C3 alkoxy" refers to OCH3, OCH2CH3, OCH2CH2CH3, and OCH(CH3)2.

[0082] In addition, the compounds of the present invention can be coupled to antibodies by methods understood by those skilled in the art to form antibody drug conjugates (ADCs). An example of such a conjugate includes connecting the compound of the present invention to an antibody via a linker compound. Linker compounds known to those skilled in the art include, for example, cleavable linkers and non-cleavable linkers. Such ADCs can deliver the compounds of the present invention to specific target tissues or cells. Therefore, ADCs comprising compounds of Formula I are also provided herein. In some embodiments, the compound of Formula I is conjugated to an antibody via a linker, such as a cleavable linker or a non-cleavable linker. Such ADCs can be administered by injection, for example, intravenously or subcutaneously.

[0083] The compound or conjugate of the present invention can be formulated as a pharmaceutical composition, which is administered by any route that makes the compound or conjugate bioavailable, including topical or subcutaneous administration. Such pharmaceutical compositions including ADCs can be prepared using techniques and methods known in the art (see, for example, Remington: The Science and Practice of Pharmacy, edited by A. Adejare, 23rd edition, published in 2020, Elsevier Science; WO 2017 / 062271 and WO 2017 / 210471).

[0084] Pharmaceutically acceptable salts of Formula I are included within the scope of the present invention. Compounds of the present invention (e.g., compounds of Formula I) can be formed into pharmaceutically acceptable salts, for example, by reacting a suitable free acid of the compound of the present invention with a suitable pharmaceutically acceptable base in a suitable solvent such as diethyl ether under standard conditions well known in the art. See, for example, Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19, (1977).

[0085] Certain abbreviations are defined as follows: “aq” refers to aqueous or water solution; “DMSO” refers to dimethyl sulfoxide; “EtOAc” refers to ethyl acetate; “THF” refers to tetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “DCM” refers to dichloromethane; “IPA” refers to isopropanol; “MeOH” refers to methanol; “ACN” refers to acetonitrile; “C18” refers to octadecylsilane; “DMEA” refers to dimethylethylamine; “MTBE” refers to methyl tert-butyl ether; “LDA” refers to lithium diisopropylamide; “Pd(dpp)” refers to octadecylsilane; f) “Cl2” refers to [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; “g” refers to gram; “rt” refers to room temperature; “h” refers to hour; “min” refers to minute; “mL” refers to milliliter; “mol” refers to mole; “mmol” refers to millimole; “nm” refers to nanometer; “SFC” refers to supercritical fluid chromatography; “ES / MS” refers to electrospray ionization mass spectrometry; “m / z” refers to mass-to-charge ratio by mass spectrometry; “NMR” refers to nuclear magnetic resonance; and “ROE” refers to rotating-frame Overhauser enhancement.

[0086] The compound of the present invention or its salt can be easily prepared by various methods known to those of ordinary skill in the art, some of which are described in the following preparation examples and examples. It will be appreciated by those of ordinary skill in the art that the specific synthesis steps described for each approach can be combined in various ways, or combined with the steps from different schemes, to prepare the compound of the present invention or its salt. The product of each step can be reclaimed by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, grinding and crystallization. Unless otherwise indicated, all substituents are as previously defined. Reagents and starting materials are readily available to those of ordinary skill in the art. The following preparation examples, examples and assays further illustrate the present invention, but should not be construed as limiting the scope of the present invention in any way.

[0087] Solution 1

[0088]

[0089] In Scheme 1, a compound of structure 1 is reacted with an aldehyde of structure 2 under conditions known to those skilled in the art to obtain a compound of formula I, wherein R 3 is hydrogen or a suitable alkyl group, such as tert-butyl or methyl.

[0090] More specifically, as shown in Scheme 1A below, a compound of structure 1a is reacted with an aldehyde of structure 2 under conditions known to those skilled in the art to give compounds of formula Ib and formula Ic, wherein R 3 is hydrogen or a suitable alkyl group, such as tert-butyl or methyl.

[0091] Option 1A

[0092]

[0093] For example, about 1.1 equivalents of a compound of structure 1a and about 1 equivalent of a compound of structure 2 are suspended in a suitable organic solvent such as acetonitrile, wherein R 3 Is hydrogen or a suitable alkyl, such as tert-butyl. The suspension is cooled to about -10 ° C, then treated with about 5 equivalents of a suitable acid such as perchloric acid (70% aqueous solution). The reaction mixture is then warmed to room temperature and stirred for about 1 hour. Additional organic solvents, such as acetonitrile and dimethylformamide, can be added, and the mixture is stirred for about 2 more hours. The reaction is then quenched using standard conditions, such as quenching the reaction with a saturated aqueous sodium bicarbonate solution, and the product is isolated using standard techniques well known in the art, such as extraction with a suitable organic solvent such as dichloromethane: isopropanol (9: 1), drying the organic extract with magnesium sulfate, filtering, and vacuum concentration to obtain a crude product mixture. The crude product mixture can be purified using techniques well known in the art such as chromatography, for example using a suitable eluent such as a 2: 1 solution of 10 mM ammonium bicarbonate in water + 5% methanol: the reverse phase chromatography of acetonitrile and the product of Formula Ib and Formula Ic can be isolated.

[0094] Option 2

[0095]

[0096] Preparation Example 1

[0097] tert-Butyl 4-[(3-fluoro-4-formyl-phenyl)methyl]benzoate

[0098]

[0099] To a 20 mL sealed tube was added (3-fluoro-4-formyl-phenyl)boronic acid (10 g, 60 mmol), tert-butyl 4-(bromomethyl)benzoate (18 g, 66 mmol), potassium carbonate (27 g, 200 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and THF (100 mL):water (40 mL). The reaction was heated to 95 ° C. After 1 hour, the reaction was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to a crude residue. The residue was purified by normal phase purification (silica gel) eluting with 9:1 hexane:ethyl acetate to give the title compound (18.7 g, 86% yield). ES / MS m / z 257.0 (M-tBu-H).

[0100] In a manner substantially similar to the procedure described in Preparation 1, the following compounds in Table 1 were prepared.

[0101] Table 1

[0102]

[0103] Preparation Example 3

[0104] 4-[(3-Fluoro-4-formyl-phenyl)methyl]benzoic acid

[0105]

[0106] Tert-butyl 4-[(3-fluoro-4-formyl-phenyl)methyl]benzoate (16 g, 51 mmol, Preparation 1) was dissolved in DCM (300 mL) and cooled to 0°C. Trifluoroacetic acid (150 mL) was added dropwise and the reaction was allowed to warm to room temperature. After 1 hour, the reaction was concentrated under vacuum and the off-white solid was triturated with ether / hexane. The resulting solid was collected by filtration and dried in a vacuum oven to give the title compound (13.1 g, 96% yield). ES / MS m / z 257.0 (MH).

[0107] Option 3

[0108]

[0109] Preparation Example 4

[0110] 4-(4-Formylphenoxy)benzoic acid

[0111]

[0112] 4-Fluorobenzaldehyde (0.63 g, 5.0 mmol), methyl 4-hydroxybenzoate (0.81 g, 5.3 mmol), DMF (15 mL) and potassium carbonate (0.83 g, 6.0 mmol) were added to a microwave bottle. The reaction was heated in a microwave at 150 ° C for 1 hour and cooled to room temperature. The solution was partitioned between EtOAc and water. The organic layer was separated, washed with saturated sodium chloride aqueous solution (2×), saturated NaHCO3 aqueous solution, dried over MgSO4, filtered, and concentrated to a colorless oil. Hexane (50 mL) was added to the crude oil to give a white semi-solid. It was then ultrasonicated, cooled to 0 ° C, and filtered to separate the white solid. The white solid was washed with hexane and dried in vacuo.

[0113] The white solid was dissolved in methanol (8 mL) and aqueous sodium hydroxide (5 M, 2 mL) was added. The solution was heated to 50°C for 2 hours. The reaction was cooled to room temperature, diluted with water (10 mL), and acidified to pH 4 with 5N aqueous HCl. The white solid was collected by suction filtration, washed with water, and further dried under vacuum to give the title compound (790 mg, 84% yield). MS m / z 241.0 (MH).

[0114] In a manner substantially similar to the procedure described in Preparation 4, the following compounds in Table 2 were prepared.

[0115] Table 2

[0116]

[0117] Preparation Example 6

[0118] 6-Bromo-2-fluoro-3-methoxy-benzaldehyde

[0119]

[0120] The two reactions were carried out in parallel. At -78 ° C, over 30 minutes, LDA (2M, 730 mL) was slowly added to a solution of 4-bromo-2-fluoro-1-methoxybenzene (250 g, 1.2 mol) in THF (1500 mL). After another 30 minutes, DMF (140 mL, 1.8 mol) was slowly added to the reaction at -78 ° C for 30 minutes. After 1 hour, the two reactions were combined, the mixture was diluted with citric acid aqueous solution (2000 mL) and extracted with EtOAc (1500 mL × 2). The combined organic layer was washed with saturated sodium chloride aqueous solution (1000 mL) and concentrated under reduced pressure to obtain a residue. The residue was triturated with petroleum ether (1000 mL) at room temperature for 12 hours to obtain the title compound (382 g, 67% yield). ES / MS m / z 233.9 (M+H).

[0121] Preparation Example 7

[0122] 2-Fluoro-3-methoxy-6-methyl-benzaldehyde

[0123]

[0124] Three reactions were carried out in parallel. 6-Bromo-2-fluoro-3-methoxybenzaldehyde (120 g, 5.3 mol, see Preparation Example 6), methylboric acid (47 g, 7.9 mol), Pd(dppf)Cl2 (12 g, 0.02 mol) and Cs2CO3 (340 g, 1.1 mol) were added to dioxane (600 mL) and water (120 mL). The mixture was stirred at 120 ° C. After 12 hours, the three reactions were combined, the mixture was diluted with saturated NH4Cl aqueous solution (1000 mL), and extracted with MTBE (1500 mL × 2). The combined organic layer was washed with saturated sodium chloride aqueous solution (1000 mL) and concentrated under reduced pressure to obtain a residue. The residue was purified by normal phase chromatography, eluting with 40:1 petroleum ether:EtOAc to obtain the title compound (180 g, 59% yield). ES / MS m / z 169.3 (M+H).

[0125] Preparation Example 8

[0126] 2-Fluoro-3-hydroxy-6-methyl-benzaldehyde

[0127]

[0128] 2-Fluoro-3-methoxy-6-methyl-benzaldehyde (175 g, 1.0 mol, see Preparation 7) was added to DCM (1050 mL), and BBr 3 (200 mL, 2.1 mol) was slowly added to the solution at 0° C. The reaction was stirred at room temperature. After 1 hour, the mixture was diluted with saturated aqueous sodium bicarbonate solution (1000 mL) to pH = 7-8, and then extracted with MTBE (1500 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride solution (1000 mL) and concentrated under reduced pressure to give the title compound (110 g, 68% yield). ES / MS m / z 154.9 (M+H).

[0129] Option 4

[0130]

[0131] wherein G is methyl or methoxy.

[0132] wherein J is methyl or tert-butyl.

[0133] Preparation Example 9

[0134] tert-Butyl 3-((2-fluoro-3-formyl-4-methylphenoxy)methyl)benzoate

[0135]

[0136] A mixture of 2-fluoro-3-hydroxy-6-methyl-benzaldehyde (300 mg, 1.9 mmol, see Preparation Example 8), tert-butyl 3-(bromomethyl)benzoate (500 mg, 1.8 mmol) and cesium carbonate (1.2 g, 3.7 mmol) in DMF (6 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and water. The organic solution was washed with three parts of water and one part of a saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and evaporated to give a crude residue. The residue was purified by normal phase purification using 9:1 hexane: ethyl acetate to give the title compound (250 mg, 40% yield). MS m / z 362.0 (M+NH4 + ).

[0137] In a manner substantially similar to the procedure described in Preparation 9, the following compounds in Table 3 were prepared.

[0138] Table 3.

[0139]

[0140] Preparation Example 13

[0141] tert-Butyl 2-fluoro-4-methoxyphenoxydiphenylsilane

[0142]

[0143] To DMF (350mL 0.5M) solution of 2-fluoro-4-methoxyphenol (25g, 180mmol), add imidazoles (18g, 260mmol) and tert-butyldiphenylchlorosilane (55mL, 200mmol).The reaction was stirred at room temperature for 18 hours.The organic extract water and saturated sodium chloride solution merged are washed with Na2SO4, dried, filtered and concentrated to obtain thick residue.Residue is purified by normal phase purification method, uses 5:1 hexane: ethyl acetate wash-out, obtain title compound (67g, 93% yield). 1 H NMR(399.8MHz,d6-DMSO)δ7.67-7.65(m,4H),7.51-7.44(m,6H),6.82(dd,J=2.9,12.7Hz ,1H),6.59(t,J=9.4Hz,1H),6.47(ddd,J=9.0,3.0,1.4Hz,1H),3.64(s,3H),1.06(s,9H).

[0144] Preparation Example 14

[0145] 2-Fluoro-3-hydroxy-6-methoxybenzaldehyde

[0146]

[0147] Tert-butyl 2-fluoro-4-methoxyphenoxydiphenylsilane (56g, 150mmol, referring to Preparation Example 13) is dissolved in 50mL toluene and vacuum concentrated for 18 hours. The dry solid is dissolved in THF (500mL) and cooled to-80 ℃. By macroporous cannula, n-butyl lithium (100mL, 170mmol) is quickly added in the cooling solution. After 1.5 hours, DMF (25mL, 320mmol) is added in the solution and ice bath is removed. After 30 minutes, 5N HCl aqueous solution (35mL) is added in the reaction, and then tetrabutylammonium fluoride (1M THF solution, 185mL, 185mmol) is added. After 2.5 hours, the organic layer is evaporated, acidified with 5N HCl aqueous solution, and distributed between ethyl acetate and water (500mL). The organic extract water and saturated sodium chloride aqueous solution merged are washed, and MgSO4 is used for drying, filtered and concentrated to obtain thick residue. The residue was purified by normal phase purification using 1:1 hexane:ethyl acetate to afford the title compound (22 g, 88% yield). MS m / z 170.8 (M+H).

[0148] Option 5

[0149]

[0150] Where G is methyl or methoxy

[0151] Preparation Example 15

[0152] 2-((2-Fluoro-3-formyl-4-methoxyphenoxy)methyl)benzoic acid

[0153]

[0154] To a solution of methyl 2-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)benzoate (230 mg, 0.73 mmol) in MeOH (2 mL, 49 mmol) and THF (2 mL) was added LiOH (1.6 mL, 1.6 mmol, 1 M aqueous solution). The mixture was stirred overnight. The solvent was evaporated. The residue was diluted with water and the pH was adjusted to 6 with HCl (0.32 mL, 1.6 mmol, 5 M aqueous solution). The solid was collected by vacuum filtration and washed with water. The solid was left on the filter and suction dried for 5 hours to give the title compound (210 mg, 94% yield). MS m / z 305.0 (M+H).

[0155] In a manner essentially similar to the procedure described in Preparation 15, the following compounds were prepared.

[0156] Table 4

[0157]

[0158] Example 1

[0159] 4-(3-Fluoro-4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)benzoic acid (Isomer 1)

[0160]

[0161] Perchloric acid (70% aqueous solution, 1.7 mL, 5 equivalents) was added to a suspension of (8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-one (1.5 g, 4.1 mmol, also known as "16α-hydroxyprednisolone") and 4-[(3-fluoro-4-formyl-phenyl)methyl]benzoic acid (1.00 g, 3.87 mmol, Preparation 3) in acetonitrile (20 mL) at -10°C and warmed to room temperature. After 1 hour, additional acetonitrile (40 mL) and DMF (2 mL) were added to the suspension at room temperature. After 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with 9:1 dichloromethane:isopropanol. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by reverse-phase chromatography, eluting with a 2:1 solution of 10 mM ammonium bicarbonate in water + 5% methanol:acetonitrile to afford the title compound, Isomer 1, Peak 1 (1.48 g, 62% yield). ES / MS m / z 617.5 (M+H). 1 H NMR(400.13MHz,d6-DMSO)d 7.83(d,J=8.2Hz,2H),7.50(t,J=7.8Hz,1H),7.32-7.27(m,3H),7.14-7.11(m,2H),6.16 (dd,J=1.8,10.1Hz,1H),5.93(s,1H),5.60(s,1H),4.94(d,J=4.9Hz,1H),4.89-4.72(m, 1H),4.48(d,J=19.5Hz,1H),4.30-4.24(m,1H),4.21-4.16(m,1H),4.00(s,2H),2.38-2. 36(m,1H),2.08(s,3H),1.82-1.67(m,5H),1.39(s,3H),1.07-0.96(m,2H),0.86(s,3H).

[0162] Example 2

[0163] 4-(3-Fluoro-4-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)benzoic acid (Isomer 2)

[0164]

[0165] The residue from Example 1 was purified by reverse phase chromatography using a 2:1 10 mM ammonium bicarbonate solution in water + 5% methanol:acetonitrile as eluent to afford the title compound, Isomer 2, Peak 2 (122 mg, 5% yield). ES / MS m / z 617.4 (M+H). 1 H NMR(400.13MHz,d6-DMSO)d 7.84(d,J=8.2Hz,2H),7.33-7.29(m,3H),7.21(t,J=7.8Hz,1H),7.11-7.05(m,2H),6.2 7(s,1H),6.19-6.16(m,1H),5.94(s,1H),5.30(d,J=6.4Hz,1H),4.83-4.79(m,1H),4.3 1(s,1H),4.19(d,J=19.1Hz,1H),4.03-3.98(m,3H),2.37-2.30(m,1H),2.08-2.02(m,3 H),1.87-1.77(m,5H),1.39(s,3H),1.26-1.14(m,1H),1.08-1.02(m,1H),0.87(s,3H).

[0166] Example 3

[0167] 3-((2-Fluoro-3-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)-4-methylphenoxy)methyl)benzoic acid

[0168]

[0169] Perchloric acid (320 uL, 3.7 mmol, 70% by mass in water) was added dropwise to a suspension of (8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-one (290 mg, 0.77 mmol, also known as "16α-hydroxyprednisolone") and tert-butyl 3-[(2-fluoro-3-formyl-4-methyl-phenoxy)methyl]benzoate (250 mg, 0.7375 mmol) in acetonitrile (7 mL) at -10°C. The reaction was stirred at -10°C for 2 hours. The reaction was poured into a rapidly stirred flask containing a saturated aqueous NaHCO solution. The mixture was stirred for 5 minutes and then extracted with 10% IPA / DCM (3×). The combined organic extracts were washed with brine, dried over NaSO, filtered and concentrated to give a crude residue. The residue was purified by reverse phase chromatography using 10 mM NaHCO in water + 5% MeOH:ACN to give a mixture of diastereomers. The mixture was subjected to chiral SFC chromatography using a Chiralpak AS-H eluting with 35% EtOH (w / 0.5% DMEA):65% CO to give the title compound (190 mg, 40% yield). MS m / z 647.2 (M+H). 1 HNMR (399.80MHz,,d6-DMSO): δ7.97(s,1H),7.88(d,J=7.7Hz,1H),7.58(d,J=7.5Hz,1H),7.45(t,J=7.7Hz,1H),7.32(d,J=10 .0Hz,1H),7.17(t,J=8.5Hz,1H),6.92(d,J=8.4Hz,1H),6.16(dd,J=1.8,10.1Hz,1H),5.94(s,1H),5.61(s,1H),5.21(s,2H),4 .96(d,J=5.7Hz,1H),4.81-4.81(m,1H),4.47(d,J=19.4Hz,1H),4.31(s,1H),4.20(d,J=19.5Hz,1H),3.47-3.41(m,1H),2.30( s,4H),2.18-2.14(m,2H),1.86-1.75(m,3H),1.64(td,J=13.2,5.8Hz,1H),1.40(s,3H),1.26-1.16(m,2H),0.90-0.85(m,3H).

[0170] Example 4

[0171] 3-((2-Fluoro-3-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)-4-methylphenoxy)methyl)benzoic acid

[0172]

[0173] Purification by chiral SFC as described in Example 3 afforded the title compound as the second diastereomer (61 mg, 13% yield). MS m / z 647.3 (M+H). 1 H NMR (399.80MHz, DMSO): δ7.97(s,1H),7.87(d,J=7.7Hz,1H),7.59(d,J=7.7Hz,1H),7.47(t,J=7.7Hz,1H),7.34-7.3 2(m,1H),7.17-7.13(m,1H),6.90(d,J=8.4Hz,1H),6.34(s,1H),6.18(dd,J=1.9,10.0Hz,1H),5.95(s,1H),5.31(d, J=6.7Hz,1H),5.22-5.15(m,2H),4.78(d,J=2.6Hz,1H),4.32(d,J=18.9Hz,2H),4.02(d,J=19.0Hz,1H),3.17(s,1H) ,2.40-2.39(m,2H),2.22(s,3H),2.11-2.08(m,2H),1.91-1.86(m,2H),1.40(s,3H),1.31-1.19(m,3H),0.88(s,3H).

[0174] The following compounds listed in Table 5 were prepared in a manner substantially similar to the procedures described in Examples 3 and 4 using the corresponding aldehyde starting materials shown in the table. Purification of the final products was primarily carried out by the following methods:

[0175] A. C18 column, eluted with 10 mM NH4HCO3 in water + 5% MeOH: ACN

[0176] B. C18 column, eluted with 0.1% FA aqueous solution: ACN

[0177] C. Chiral SFC using Chiralcel OJ-H, eluting with MeOH + 0.5% DMEA:CO2

[0178] Table 5.

[0179]

[0180]

[0181] NMR structure assignment

[0182]

[0183] Two-dimensional through-space ROE NMR analysis of the acetal isomers consistently gave cross peaks for H22 (acetal) and H16 in the R configuration. Alternatively, the H22 consistency in the S configuration produced a larger shift of about 1 ppm. All other compounds were assigned structures essentially by the same method.

[0184] hGR CoActivator recruitment assay

[0185] The activity of glucocorticoid compounds was measured using the LanthaScreen TR-Fret GR Coactivator assay (A15899) from Life Technologies. Three-fold 10-point serial dilutions of the compound (maximum concentration 200 nM) were acoustically transferred to the assay plate. 10 microliters of 2x GR-LBD solution were added to the compound plate and incubated for 10 minutes. 10 microliters of 2x Fluoresin-SRC1-4 solution and Tb-labeled anti-GST antibody were then added to the plate. The plate was incubated in the dark for two hours and then read on an Envision plate reader with an excitation wavelength of 340 nm and emission wavelengths of 520 nm (fluorescein) and 490 nm (terbium). The emission ratio of 520 / 490 was analyzed in Genedata. The data were compared with a DMSO negative control and a 4 μM dexamethasone positive control to obtain the percentage of activity.

[0186] Following essentially the procedure described above, the compound of Example 1 produced a relative IC of 2.14 nM. 50 , the compound of Example 2 produced a relative IC of 4.50 nM 50 , the compounds of Examples 3-9, 11, 12, 14 and 15 each produced a relative IC of less than 200 nM 50 Examples 10 and 13 each produced a relative IC greater than 200 nM. 50 .

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: in, R 1 is H, halogen, C1-C3 alkyl or C1-C3 alkoxy; R 2 is H or halogen; and X is O, OCH2 or CH2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It's F.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is CH3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is OCH3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It’s H.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 It’s H.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 It's F.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is O.

10. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is OCH2.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the following formula:

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the following formula:

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

16. The compound according to claim 15, which is:

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

18. The compound according to claim 17, which is:

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

20. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating atopic dermatitis.

21. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lupus nephritis.

22. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating rheumatoid arthritis.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

24. A process for preparing a pharmaceutical composition, the process comprising mixing a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

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