Glucocorticoid receptor agonists

Abstract

The present invention provides compounds of Formula I: wherein R is H or; r1 is H, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C2-C3 alkenyl group, or OCF3, R2 is H, halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, or a C2-C4 alkenyl group; r < 3 > is NH2 or CH2NH2; and X is O, OCH2, OCH2CH2, OCH (CH3), CH2O, SCH2, CHS, CH2, NHCH2, CH2NH, N (CH3) CH2, CH2CH2, C = C or a bond wherein X is attached to benzene ring A in ortho or meta position, or a pharmaceutically acceptable salt thereof wherein the compounds of formula I or pharmaceutically acceptable salts thereof are useful in the treatment of autoimmune and inflammatory diseases such as atopic dermatitis and rheumatoid arthritis. # imgabs0 #

Description

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

[0002] Atopic dermatitis is a chronic, pruritic, relapsing and remitting inflammatory skin disease that often occurs in children but also affects many adults. Current treatments for atopic dermatitis include phototherapy, topical creams containing glucocorticoids or calcineurin inhibitors, or subcutaneous injection of a biologic agent (called dupilumab). Despite progress in treating atopic dermatitis, there is still an urgent need for new compounds to treat atopic dermatitis and other inflammatory and autoimmune diseases.

[0003] WO2017 / 210471 discloses certain glucocorticoid receptor agonists and their immunoconjugates for treating autoimmune or inflammatory diseases. WO2018 / 0839373 discloses novel steroids, their protein conjugates, and methods for treating diseases, disorders, and conditions, which methods include administering the steroids and conjugates.

[0004] The present invention provides certain new compounds that are glucocorticoid receptor agonists. The present invention further provides certain new compounds that are prodrugs of glucocorticoid receptor agonists. In addition, the present invention provides certain new compounds that are glucocorticoid receptor agonists and 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] Accordingly, in one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] wherein R is H or

[0008]

[0009] R 1 is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0010] or

[0011] R 2is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C3 alkenyl;

[0012] R 3 is NH2 or CH2NH2; and

[0013] X is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, where X is attached to phenyl ring A at the ortho or meta position.

[0014] In one embodiment, the present invention provides a compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0015]

[0016] wherein R is H or

[0017]

[0018] R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0019] or

[0020] R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C4 alkenyl;

[0021] R 3 is NH2 or CH2NH2; and

[0022] X is O, OCH2, OCH2CH2, OCH2C≡C, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, where X is attached to phenyl ring A at the ortho or meta position.

[0023] In one embodiment, the present invention provides a compound of formula Ib or a pharmaceutically acceptable salt thereof:

[0024]

[0025] wherein R is H or

[0026]

[0027] R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0028]

[0029] R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C4 alkenyl;

[0030] R 3 is NH2 or CH2NH2; and

[0031] X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is attached to phenyl ring A at the ortho or meta position.

[0032] In one embodiment, the present invention provides a compound of formula Ic or a pharmaceutically acceptable salt thereof:

[0033]

[0034] wherein R is H or

[0035]

[0036] R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0037]

[0038] R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C4 alkenyl;

[0039] R 3 is NH2 or CH2NH2; and

[0040] X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is attached to phenyl ring A at the ortho or meta position.

[0041] In one embodiment, the present invention provides a compound of formula Ib(i):

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the present invention provides a compound of formula Ic(i):

[0045]

[0046] or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the present invention provides a compound of formula Ib(ii):

[0048]

[0049] or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the present invention provides a compound of formula Ic(ii):

[0051]

[0052] or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present invention provides a compound of formula Ib(iii):

[0054]

[0055] or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the present invention provides a compound of formula Ic(iii):

[0057]

[0058] or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the present invention provides a compound of formula II:

[0060]

[0061] wherein R is H or

[0062] and

[0063] R 1 is -CH3 or -OCH3,

[0064] or a pharmaceutically acceptable salt thereof.

[0065] In a specific embodiment, the present invention provides a compound of formula IIa:

[0066]

[0067] wherein R is H or

[0068] and

[0069] R 1 is -CH3 or -OCH3,

[0070] or a pharmaceutically acceptable salt thereof.

[0071] In one specific embodiment, the present invention provides a compound of formula IIb or a pharmaceutically acceptable salt thereof:

[0072]

[0073] wherein R is H or

[0074] and

[0075] R 1 is -CH3 or -OCH3.

[0076] In one specific embodiment, the present invention provides a compound of formula IIc or a pharmaceutically acceptable salt thereof:

[0077]

[0078] wherein R is H or

[0079] and

[0080] R 1 is -CH3 or -OCH3.

[0081] In one embodiment, the present invention provides a compound of formula III:

[0082]

[0083] wherein R is H or

[0084]

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In one specific embodiment, the present invention provides a compound of formula IIIa:

[0087]

[0088] wherein R is H or

[0089]

[0090] or a pharmaceutically acceptable salt thereof.

[0091] In a specific embodiment, the present invention provides a compound of formula IIIb:

[0092]

[0093] wherein R is H or

[0094]

[0095] or a pharmaceutically acceptable salt thereof.

[0096] In a specific embodiment, the present invention provides a compound of formula IIIc:

[0097]

[0098] wherein R is H or

[0099]

[0100] or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, R is H.

[0102] In one embodiment, R 1 is F, CH2CH3, OCH3 or OC( 2 H)3. In one embodiment, R 1 is F. In one embodiment, R 1 is CH2CH3. In one embodiment, R 1 is OCH3. In one embodiment, R 1 is OC( 2 H)3.

[0103] In one embodiment, R 2 is F, CH2CH3, OCH3 or OC( 2 H)3. In one embodiment, R 2 is F. In one embodiment, R 2 is CH2CH3. In one embodiment, R 2 is OCH3. In one embodiment, R 2 is OC( 2 H)3.

[0104] In one embodiment, X is CH2CH2, OCH2 or OCH2CH2. In one embodiment, X is CH2CH2. In one embodiment, X is OCH2. In one embodiment, X is OCH2CH2.

[0105] In one embodiment, R 3is NH2.

[0106] In one embodiment, X is attached to phenyl ring A at the meta position.

[0107] In one embodiment, X is attached to phenyl ring A at the ortho position.

[0108] In one embodiment, the present invention also provides a method for treating an inflammatory disease in a patient in need of such treatment, the method 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 such treatment, the method 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 further provides a method for treating inflammatory bowel disease in a patient in need of such treatment, the method 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 further provides a method for treating rheumatoid arthritis in a patient in need of such treatment, the method 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 such treatment, the method 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 lupus nephritis in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the present invention further 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 treating an inflammatory disease. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating atopic dermatitis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating inflammatory bowel disease. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating lupus nephritis. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating systemic lupus erythematosus.

[0110] In one embodiment, the present invention further 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 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 further 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 further 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 further 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.

[0111] 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 further provides a method for preparing a pharmaceutical composition, which comprises 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 further includes novel intermediates and methods for synthesizing a compound of formula I.

[0112] As used herein, the terms "treat" or "treating" include inhibiting, delaying, halting or reversing the progression or severity of existing symptoms or afflictions.

[0113] As used herein, the term "patient" refers to a mammal, particularly a human.

[0114] As used herein, the term "effective amount" refers to the amount or dose of a compound of the present invention or a pharmaceutically acceptable salt thereof that provides the desired effect in diagnosing or treating a patient after administration in a single or multiple doses.

[0115] The effective amount can be determined by those skilled in the art using known techniques and by observing results obtained in similar circumstances. When determining the effective amount for a patient, the attending diagnostician will consider a number of factors, including but not limited to: the type of patient; its size, age and general health; the particular disease or affliction involved; the degree, involvement or severity of the disease or affliction; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the chosen dosage regimen; the use of concomitant medications; and other relevant circumstances.

[0116] As used herein, it should be understood that Formula I includes Formula Ia, Formula Ib, Formula Ic, Formula Ib(i), Formula Ic(i), Formula Ib(ii), Formula Ic(ii), Formula Ib(iii), Formula Ic(iii), Formula II, Formula IIa, Formula IIb, Formula IIc, Formula III, Formula IIIa, Formula IIIb, and Formula IIIc, and all references herein to Formula I should be understood to include Formula Ia, Formula Ib, Formula Ic, Formula Ib(i), Formula Ic(i), Formula Ib(ii), Formula Ic(ii), Formula Ib(iii), Formula Ic(iii), Formula II, Formula IIa, Formula IIb, Formula IIc, Formula III, Formula IIIa, Formula IIIb, and Formula IIIc.

[0117] As used herein, it should be understood that Formula II includes Formula IIa, Formula IIb, and Formula IIc, and all references herein to Formula II should be understood to include Formula IIa, Formula IIb, and Formula IIc.

[0118] As used herein, it should be understood that Formula III includes Formula IIIa, Formula IIIb, and Formula IIIc, and all references herein to Formula III should be understood to include Formula IIIa, Formula IIIb, and Formula IIIc.

[0119] As used herein, "halogen" means F, Cl, Br, and I.

[0120] As used herein, "C1-C3 alkyl" means CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

[0121] As used herein, "C3-C6 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0122] As used herein, "C1-C3 alkoxy" means OCH3, OCH2CH3, OCH2CH2CH3, and OCH(CH3)2.

[0123] As used herein, "C2-C3 alkenyl" means HC=CH2 and C(CH3)=CH2.

[0124] As used herein, the ortho and meta positions on phenyl ring A are as shown in Formula I below:

[0125]

[0126] For example, the compound of Formula I' illustrates that X is connected to phenyl ring A at the meta position:

[0127]

[0128] The compound of Formula I'' illustrates that X is connected to phenyl ring A at the ortho position:

[0129]

[0130] One of ordinary skill in the art should understand that when X is connected to phenyl ring A in the ortho position as shown in Formula I, R 2 is H.

[0131] In some embodiments, the compound is selected from the compounds described in Table I and pharmaceutically acceptable salts and stereoisomers thereof.

[0132] In some embodiments, the compound is selected from the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0133] In some embodiments, the compound is selected from the compounds described in Table I.

[0134] Table I.

[0136]

[0137]

[0138] In some embodiments, the present disclosure provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any one of the compounds disclosed herein.

[0139] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0140] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table I.

[0141] It should be understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by carrying out the procedures and / or methods disclosed in the processes and / or examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0142] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0143] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the various formulas disclosed herein.

[0144] In some embodiments, the compound is a deuterium-labeled compound of the compounds described in Table I and pharmaceutically acceptable salts thereof.

[0145] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table I.

[0146] In addition, the compounds of the present invention can be conjugated with antibodies by methods understood by those skilled in the art to form antibody-drug conjugates (ADCs). An example of such conjugation will include linking the compounds 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. The ADCs can deliver the compounds of the present invention to specific target tissues or cells. Accordingly, ADCs comprising a compound 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.

[0147] The compounds or conjugates of the present invention can be formulated into pharmaceutical compositions for administration by any route that renders the compound or conjugate bioavailable, including, for example, oral, topical, or subcutaneous administration. The pharmaceutical compositions, including ADCs, can be prepared using techniques and methods known in the art. The 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).

[0148] In addition, having a blocked hydroxyl group at C21, wherein R is the compounds of the present invention act as prodrugs and are metabolized in vitro or in vivo to provide the active glucocorticoid receptor agonist in which R is H.

[0149] Pharmaceutically acceptable salts of Formula I are within the scope of the present invention. Pharmaceutically acceptable salts of the compounds of the present invention, such as compounds of Formula I, can be formed, for example, under standard conditions well known in the art, in a suitable solvent such as diethyl ether, by reacting the appropriate free base of the compound of the present invention with an appropriate pharmaceutically acceptable acid. See, for example, Berge, S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).

[0150] Certain compounds described in the preparations below may contain suitable nitrogen protecting groups, herein referred to as "Pg". It should be understood that, as would be understood by one of ordinary skill in the art, the protecting groups can vary depending on the specific reaction conditions and the particular transformation to be effected. Protection and deprotection conditions are well known to those of ordinary skill in the art and are described in the literature (see, for example, "Greene’s Protective Groups in Organic Synthesis", 4th Edition, Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007). Examples

[0151] The compounds of the present invention or salts thereof can be readily prepared using various methods known to those of ordinary skill in the art, some of which are illustrated in the preparations and examples below. Those of ordinary skill in the art will understand that the specific synthetic steps of each of the described routes can be combined in different ways, or combined with steps from different processes, to prepare the compounds of the present invention or salts thereof. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Unless otherwise stated, all substituents are as defined above. The reagents and starting materials are readily available to those of ordinary skill in the art. The following preparations, examples, and assays further illustrate the invention but should not be construed as limiting the scope of the invention in any way.

[0152] Table 1: Abbreviations and Definitions

[0153]

[0154]

[0155]

[0156] Example 1. Preparation of Precursors.

[0157] Preparation 1. Synthesis of tert-Butyl ((3-((2-Fluoro-3-formyl-4-(methoxy-d3)phenoxy)methyl)phenyl)carbamate

[0158]

[0159] A solution of 2-fluoro-3-hydroxy-6-(trideuteriomethoxy)benzaldehyde (870 mg, 5.0 mmol) in DMF (15 mL) was treated with potassium carbonate (2.2 g, 16 mmol) and stirred at room temperature for 15 minutes. N-[3-(Bromomethyl)phenyl]carbamic acid tert-butyl ester (1.5 g, 5.2 mmol) was added in one portion, and the reaction mixture was stirred at room temperature. After 18 hours, the reaction mixture was partitioned between EtOAc and H2O. The phases were separated, the organic phase was transferred to a flask, and the solvent was evaporated in vacuo. Residual DMF was evaporated off by means of xylene. The crude residue was purified by normal phase chromatography, eluting with 0 - 50% EtOAc in hexane, to afford the title compound (1.9 g, 90% yield). MS m / z 377.2 (M - H).

[0160] Synthesis of 2-Fluoro-3-hydroxy-6-(methoxy-d3)benzaldehyde

[0161]

[0162] To a solution of 3-[(tert-butyldiphenylsilyl)oxy]-2-fluoro-6-(trideuteriomethoxy)benzaldehyde (7.3 g, 18 mmol) in THF (60 mL) was added TBAF (20 mL, 20 mmol, 1 mol / L in THF). The mixture was stirred at room temperature. After 18 hours, the solvent was evaporated to give the crude product. The crude residue was purified by normal phase chromatography, eluting with 0 - 2% MeOH in DCM, to afford the title compound (3.1 g, 85% yield). MS m / z 174.0 (M + H).

[0163] Synthesis of 3-((tert-Butyldiphenylsilyl)oxy)-2-fluoro-6-(methoxy-d3)benzaldehyde

[0164]

[0165] tert-Butyl-[2-fluoro-4-(trideuteriomethoxy)phenoxy]-diphenyl-silane (11 g, 30 mmol) was dissolved in THF (130 mL) and cooled to -78 °C. nBuLi (31 mL, 50 mmol, 1.6 M in hexanes) was added to the cooled solution over 20 minutes. After 1.5 h, DMF (6.0 mL, 78 mmol) was added dropwise. The mixture was stirred at -78 °C for an additional 5 h. The reaction was quenched by addition of saturated aqueous NH4Cl (25 mL). The mixture was warmed to room temperature. After 18 h, the organic solvents were evaporated and the crude residue was extracted with 3 x EtOAc. The combined organic extracts were washed with water and brine. The organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified by normal phase chromatography, eluting with 0 - 40% EtOAc in hexanes to give the title compound (7.3 g, 60% yield). MS m / z 412.0 (M+H).

[0166] Synthesis of 4. tert-Butyl (2-fluoro-4-(methoxy-d3)phenoxy)diphenylsilane

[0167]

[0168] Imidazole (4.5 g, 66 mmol) and tert-butylchlorodiphenylsilane (14 mL, 53 mmol) were added to a solution of 2-fluoro-4-(trideuteriomethoxy)phenol (9.2 g, 44 mmol) in DMF (100 mL). The reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and washed with 3 x water and brine. The solution was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by normal phase chromatography, eluting with 0 - 20% EtOAc in hexanes to give the title compound (15 g, 86% yield). MS m / z 400.9 (M+NH4).

[0169] Synthesis of 5. 2-Fluoro-4-(methoxy-d3)phenol

[0170]

[0171] To a pre-purged 70 mL Parr shaker flask (N2), add 10% Pd / C (1.0 g, 9.7 mmol), and then purge again with N2. To the charged shaker flask, add 250 mL of MeOH, and then add 1-benzyloxy-2-fluoro-4-(trideuteriomethoxy)benzene (10 g, 44 mmol) in MeOH (250 mL). Seal the flask, purge with N2, purge with H2, and then pressurize to 60 psi H2. Shake the flask at room temperature for 2 hours, then reduce the pressure and degas with N2. Filter the suspension through celite with MeOH. Concentrate the filtrate to a crude residue. Purify the crude product by normal phase chromatography, eluting with 0 - 20% EtOAc in hexane to obtain the title compound (9.2 g, 93% yield). 1H NMR (399.80 MHz, DMSO): 9.22 (s, 1H), 6.86 (dd, J = 8.9, 10.1 Hz, 1H), 6.78 (dd, J = 3.0, 13.0 Hz, 1H), 6.58 (ddd, J = 8.9, 3.0, 1.4 Hz, 1H).

[0172] Synthesis of 6. 1-(Benzyloxy)-2-fluoro-4-(methoxy-d3)benzene

[0173]

[0174] A suspension of 4-benzyloxy-3-fluorophenol (10 g, 46 mmol), Cs2CO3 (22 g, 69 mmol), and trideuteriomethane (iodide) (3.1 mL, 50 mmol) in DMF (100 mL) was stirred at room temperature for 18 hours. Dilute the reaction mixture with EtOAc and wash with 3x water and brine. Dry the solution over Na2SO4, filter, and evaporate to obtain the crude product. Purify the crude product by normal phase chromatography, eluting with 0 - 20% EtOAc in hexane to obtain the title compound (10 g, 96% yield). MS m / z 253.0 (M + NH4).

[0175] Synthesis of 7. (3-((3-(1,3-Dioxolan-2-yl)-4-ethyl-2-fluorophenoxy)methyl)phenyl)carbamic acid tert-butyl ester

[0176]

[0177] To a pre-purged 70 mL Parr shaker flask (N2), 5% Pd / C (32 mg, 0.16 mmol) was added, and then purged again with N2. To this charged oscillator, 2.5 mL of EtOAc was added, and then tert-butyl N-[3-[[3-(1,3-dioxolan-2-yl)-2-fluoro-4-vinyl-phenoxy]methyl]phenyl]carbamate (110 mg, 0.25 mmol) in EtOAc (2.5 mL) was added. The flask was sealed, purged with N2, purged with H2, and then pressurized to 60 psi H2. The flask was shaken at room temperature for 8 hours, then depressurized and degassed with N2. The suspension was filtered through celite with MeOH. The filtrate was concentrated to give the title compound (89 mg, 84% yield). MS m / z 434.8 (M+NH4)

[0178] Preparation 8. Synthesis of tert-butyl (3-((3-(1,3-dioxolan-2-yl)-2-fluoro-4-vinylphenoxy)methyl)phenyl)carbamate

[0179]

[0180] tert-Butyl N-[3-[[4-bromo-3-(1,3-dioxolan-2-yl)-2-fluoro-phenoxy]methyl]phenyl]carbamate (400 mg, 0.85 mmol), potassium vinyltrifluoroborate (0.14 g, 1.0 mmol), and Cs2CO3 (0.84 g, 2.6 mmol) were placed in a 25 mL microwave tube. The microwave tube was purged with N2, and THF (9 mL) and water (1 mL) were added. The solution was degassed by bubbling N2 under the surface for 5 minutes, palladium(II) acetate (10 mg, 0.042 mmol) was added, the microwave tube was closed, and the mixture was heated at 100 °C for 18 hours. After cooling to room temperature, EtOAc and H2O were added. The phases were separated, and the aqueous layer was extracted with 2x EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated to a crude residue. The crude product was purified by normal phase using 50 - 100% DCM in hexane as eluent to give the title compound (110 mg, 29% yield). MS m / z 432.8 (M+NH4).

[0181] Preparation 9. Synthesis of tert-butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate

[0182]

[0183] A solution of tert-butyl N-[3-[(4-bromo-2-fluoro-3-formyl-phenoxy)methyl]phenyl]carbamate (1.0 g, 2.4 mmol), ethylene glycol (0.55 mL, 9.8 mmol) and p-toluenesulfonic acid monohydrate (47 mg, 0.25 mmol) in toluene (16 mL) was refluxed at 135 °C with a Dean-Stark water separator attached. After 1 hour, the reaction solution was cooled to room temperature and washed with H2O (15 mL) and EtOAc (25 mL). The phases were separated and the aqueous layer was extracted with EtOAc 1x. The combined organic layers were dried over Na2SO4, filtered and concentrated to a crude residue. The crude product was purified by normal phase chromatography, eluting with 0 - 4% MeOH in DCM to give the title compound (500 mg, 44% yield). MS m / z 467.4 (M-H).

[0184] Preparation 10. Synthesis of tert-butyl (3-((4-bromo-2-fluoro-3-formylphenoxy)methyl)phenyl)carbamate

[0185]

[0186] To a solution of 6-bromo-2-fluoro-3-hydroxy-benzaldehyde (5 g, 23 mmol) and Cs2CO3 (15 g, 46 mmol) in DMF (76 mL) was added tert-butyl N-[3-(bromomethyl)phenyl]carbamate (7.2 g, 25 mmol). After 18 hours at room temperature, the mixture was diluted with EtOAc and water. The organic layer was washed with 3x water, brine, dried over Na2SO4, filtered and concentrated to a crude residue. The crude product was purified by normal phase chromatography, eluting with 0 - 20% EtOAc in hexane to give the title compound (8.2 g, 85% yield). MS m / z 441.2 (M+NH4).

[0187] Preparation 11. Synthesis of tert-butyl (4-(2-fluoro-3-formyl-4-methoxyphenethyl)phenyl)carbamate

[0188]

[0189] tert-Butyl N-[4-[2-[2-fluoro-3-(hydroxymethyl)-4-methoxyphenyl]ethyl]phenyl]carbamate (2.1 g, 5.7 mmol) in DCM (60 mL) was cooled to 0 °C and treated with Dess-Martin periodinane (3.0 g, 7.1 mmol). After 1 h, the reaction was quenched with saturated aqueous NaHCO3 (4 mL) and Na2S2O3 (0.5 M in water, 4 mL). The organic solvent was removed and the solution was diluted with EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, water, brine, dried over MgSO4, filtered, and concentrated to a crude residue. The crude product was purified by normal phase chromatography, eluting with 10 - 100% DCM in hexanes to afford the title compound (1.2 g, 58% yield). MS m / z 391.0 (M+NH4).

[0190] Preparation 12. Synthesis of tert-Butyl (4-(2-fluoro-3-(hydroxymethyl)-4-methoxyphenethyl)phenyl)carbamate

[0191]

[0192] To a cooled solution (0 °C) of methyl 3-[2-[4-(tert-butoxycarbonylamino)phenyl]ethyl]-2-fluoro-6-methoxybenzoate (2.5 g, 6.2 mmol) in THF (31 mL) was added DIBAL (22 mL, 22 mmol, 1 mol / L in heptane) and the mixture was warmed to room temperature. After 1.5 h, the reaction was cooled back to 0 °C and treated with 6 mL of saturated aqueous NaHCO3. The ice bath was removed and the mixture was stirred vigorously; the resulting gel was diluted with 3 mL of water and EtOAc and stirred vigorously to give a two-phase mixture. The slurry was diluted with EtOAc and the mixture was filtered through a celite pad with additional EtOAc. The filtrate was placed in a separatory funnel and washed with water and brine. The combined organics were dried over MgSO4, filtered, and concentrated to afford the title compound (2.1 g, 79% yield). MS m / z 373.8 (M-H).

[0193] Preparation 13. Synthesis of Methyl 3-(4-((tert-butoxycarbonyl)amino)phenethyl)-2-fluoro-6-methoxybenzoate

[0194]

[0195] To methyl 3-[2-(4-aminophenyl)ethyl]-2-fluoro-6-methoxybenzoate (2.5 g, 7.0 mmol) in DCM (10 mL) was added tBuOH (24 mL), DIPEA (1.5 mL, 8.7 mmol) and di-tert-butyl dicarbonate (1.8 g, 8.4 mmol). The reaction mixture was heated to 50 °C. After 1 h, the reaction was cooled to room temperature and concentrated to a crude residue. The material was dissolved in EtOAc and washed with 2 x 0.5 N HCl, saturated aqueous NaHCO3 and brine. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by normal phase using 0 - 10% EtOAc in DCM as eluent to give the title compound (2.5 g, 89% yield). MS m / z 421.2 (M+NH4).

[0196] Preparation 14. Synthesis of methyl 3-(4-aminophenethyl)-2-fluoro-6-methoxybenzoate

[0197]

[0198] To a pre-purged 500 mL Parr shaker flask (N2) was added 10% Pd / C (380 mg, 0.36 mmol), which was then purged again with N2. To the charged oscillator was added 65 mL of MeOH, and then methyl 2-fluoro-6-methoxy-3-[(E)-2-(4-nitrophenyl)vinyl]benzoate (2.5 g, 7.5 mmol) in MeOH (60 mL). The flask was sealed, purged with N2, purged with H2, and then pressurized to 60 psi H2. The flask was shaken at room temperature for 3 h, then depressurized and degassed with N2. The suspension was filtered through celite with MeOH. The filtrate was concentrated to give the title compound (2.5 g, 86% yield). MS m / z 303.8 (M+H).

[0199] Preparation 15. Synthesis of methyl (E)-2-fluoro-6-methoxy-3-(4-nitrostyryl)benzoate

[0200]

[0201] The solution of methyl 2-fluoro-3-formyl-6-methoxybenzoate (4.1 g, 20 mmol), diethyl 4-nitrobenzylphosphonate (6.0 g, 22 mmol) in 2-methylTHF (200 mL) was cooled to -10 °C and treated with potassium tert-butoxide (2.7 g, 23 mmol). After 1 hour, the reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by normal phase chromatography, eluting with 0 - 100% EtOAc in hexane to give the title compound (5.6 g, 83% yield). MS m / z 332.0 (M+H).

[0202] Preparation 16. Synthesis of tert-butyl (4-(2-(2-fluoro-3-formyl-4-methoxyphenoxy)ethyl)phenyl)carbamate

[0203]

[0204] To 2-fluoro-3-hydroxy-6-methoxybenzaldehyde (500 mg, 2.9 mmol) and 2-[4-((tert-butoxycarbonyl)amino)phenyl]ethyl 4-methylbenzenesulfonate (1.4 g, 3.5 mmol) in MeCN (18 mL) was added K2CO3 (1.2 g, 8.8 mmol), and the suspension was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by normal phase chromatography, eluting with 0 - 30% EtOAc in hexane to give the title compound (0.9 g, 70% yield). MS m / z 387.8 (M-H).

[0205] Preparation 17. Synthesis of 2-[4-((tert-butoxycarbonyl)amino)phenyl]ethyl 4-methylbenzenesulfonate

[0206]

[0207] To a solution of tert-butyl N-[4-(2-hydroxyethyl)phenyl]carbamate (2.5 g, 11 mmol) in DCM (50 mL) was added Et3N (2.9 mL, 21 mmol), followed by p-toluenesulfonyl chloride (2.3 g, 12 mmol) and DMAP (130 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and washed with water and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by normal phase using 0 - 25% EtOAc in hexane as eluent to give the title compound (3.9 g, 94% yield). MS m / z 408.9 (M+NH4).

[0208] Preparation 18. Synthesis of tert-butyl (3-(2-(2-fluoro-3-formyl-4-methoxyphenoxy)ethyl)phenyl)carbamate

[0209]

[0210] To a solution of 2-fluoro-3-hydroxy-6-methoxy-benzaldehyde (600 mg, 3.5 mmol) and 2-[3-(tert-butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (1.5 g, 3.7 mmol) in MeCN (20 mL) was added K2CO3 (1.5 g, 11 mmol), and the resulting suspension was stirred at 80 °C for 20 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by normal phase using 0 - 25% EtOAc in hexane as eluent to give the title compound (0.96 g, 62% yield). MS m / z 388.4 (M-H).

[0211] Preparation 19. Synthesis of 2-[3-((tert-butoxycarbonyl)amino)phenyl]ethyl 4-methylbenzenesulfonate

[0212]

[0213] To a solution of tert-butyl N-[3-(2-hydroxyethyl)phenyl]carbamate (2.7 g, 11 mmol) in DCM (60 mL) was added Et3N (3.2 mL, 23 mmol), followed by p-toluenesulfonyl chloride (2.5 g, 13 mmol) and DMAP (140 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NH4Cl and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude product was purified by normal phase using 0 - 25% EtOAc in hexane as eluent to give the title compound (3.0 g, 67% yield). MS m / z 389.8 (M - H).

[0214] Preparation 20. Synthesis of tert-butyl (3-(2-hydroxyethyl)phenyl)carbamate

[0215]

[0216] To a solution of 2-[3-(tert-butoxycarbonylamino)phenyl]acetic acid (3.0 g, 12 mmol) in THF (60 mL) at 0 °C under N2 atmosphere was added dropwise borane-THF complex (17 mL, 17 mmol, 1 mol / L in THF). The mixture was warmed to room temperature while stirring under N2 for 16 h. The reaction mixture was cooled to 0 °C, MeOH was added, and the solution was warmed to room temperature. The crude reaction mixture was concentrated under reduced pressure to give a crude residue. The crude residue was purified by normal phase using 5 - 50% EtOAc in hexane as eluent to give the title compound (2.7 g, 93% yield). MS m / z 254.8 (M + NH4).

[0217] Example 2. Synthesis of (1S,2S,4R,6S,8S,9S,11S,12S,13R)-6-[3-[(3-aminophenyl)methoxy]-2-fluoro-6-(trideuteriomethoxy)phenyl]-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-5,7-dioxabicyclo[10.8.0.02,9.04,8.013,18]eicos-14,17-dien-16-one (Compound No. 1)

[0218]

[0219] At -10 °C, perchloric acid (70%, in water, 0.29 mL, 5 equiv) was added dropwise to a suspension of tert-butyl N-[3-[[2-fluoro-3-formyl-4-(trideuteriomethoxy)phenoxy]methyl]phenyl]carbamate (250 mg, 0.63 mmol) and (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]phenanthren-3-one (250 mg, 0.66 mmol) in MeCN (6 mL). The mixture was stirred at -10 °C for 1 h. The reaction was quenched cold, saturated aqueous NaHCO3 was added, and the mixture was partitioned between water and 10% IPA / DCM. The phases were separated and the aqueous layer was extracted 1x with 10% IPA / DCM. The combined organics were dried over MgSO4, filtered, and concentrated to give a crude solid. The solid was eluted by reverse-phase chromatography with 50 - 100% MeCN in 10 mM ammonium bicarbonate in water + 5% methanol to give the title compound (420 mg, 16% yield). MS m / z 637.4 (M+H).

[0220] 1 H NMR (399.8 MHz, d6-DMSO) δ 7.33 - 7.31 (m, 1H), 7.17 - 7.12 (m, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.73 - 6.70 (m, 1H), 6.58 (s, 1H), 6.53 - 6.46 (m, 3H), 6.19 - 6.16 (m, 1H), 5.95 (s, 1H), 5.25 (d, J = 6.6 Hz, 1H), 5.10 (s, 2H), 5.00 - 4.93 (m, 3H), 4.80 - 4.78 (m, 1H), 4.37 - 4.30 (m, 2H), 4.04 - 3.98 (m, 1H), 2.37 - 2.31 (m, 1H), 2.11 - 2.07 (m, 2H), 1.89 - 1.82 (m, 4H), 1.62 - 1.59 (m, 1H), 1.40 (s, 3H), 1.26 - 1.24 (m, 2H), 0.87 (s, 3H).

[0221] Example 3. Synthesis of Compound Nos. 2 - 5.

[0222] Compound 2 - 5 was prepared essentially by the method of Example 2.

[0223]

[0224]

[0225] Example 4. hGR Coactivator Recruitment Assay

[0226] The activity of the glucocorticoid compounds was measured using the LanthaScreen TR-Fret GR coactivator assay from Life Technologies (A15899). The compounds were transferred to the assay plate by sonication and serially diluted 3-fold in 10-point dilutions with a maximum concentration of 200 nM. 10 μL of a 2x solution of GR-LBD was added to the compound plate and incubated for 10 min. Then, 10 μL of a 2x solution of Fluoresein-SRC1-4 and Tb-labeled anti-GST antibody was 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 with Genedata. To obtain percent activity, the data was compared to a DMSO negative control and a 4 μM dexamethasone positive control. The compounds exemplified below were tested according to a method essentially as described above and showed the following activities listed in Table 2.

[0227] Table 2: In vitro potencies of compounds numbered 1 - 5 in the hGR coactivator recruitment assay

[0228] Compound number <![CDATA[EC 50 (nM)]]> 1 1.93 2 1.52 3 1.65 4 1.48 5 2.25

Claims

1. A compound of the following formula: wherein R is H or R 1 is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C3 alkenyl; R 3 is NH2 or CH2NH2; and X is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, where X is attached to phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R 3 is NH2, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R is H, or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein the compound has the formula or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein R 1 is F, CH2CH3, OCH3 or OC( 2 H)3, or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-4, wherein R 1 is F, or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-4, wherein R 1 is CH2CH3, or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-4, wherein R 1 is OCH3, or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-4, wherein R 1 is OC( 2 H)3, or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-4, wherein R 2is F, CH2CH3, OCH3 or OC( 2 H)3, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1-4, wherein R 2 is F, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1-4, wherein R 2 is CH2CH3, or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1-4, wherein R 2 is OCH3, or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1-4, wherein R 2 is OC( 2 H)3, or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1-14, wherein X is CH2CH2, OCH2 or OCH2CH2, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1-14, wherein X is CH2CH2, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1-14, wherein X is OCH2, or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1-14, wherein X is OCH2CH2, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19, wherein the compound is:

21. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein the compound is:

23. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23, wherein the compound is:

25. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, wherein the compound is:

27. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27, wherein the compound is:

29. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

30. A method for treating atopic dermatitis in a patient, which comprises administering to a patient in need of said treatment an effective amount of the compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof.

31. A method for treating rheumatoid arthritis in a patient, which comprises administering to a patient in need of said treatment an effective amount of the compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, for use in therapy.

33. The compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, for use in treating atopic dermatitis.

34. The compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, for use in treating rheumatoid arthritis.

35. Use of the compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating atopic dermatitis.

36. Use of the compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating rheumatoid arthritis.

37. A pharmaceutical composition comprising the compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

38. A method for preparing a pharmaceutical composition, which comprises mixing a compound according to any one of claims 1-29 or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

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