Glucocorticoid receptor agonists

Abstract

The present invention relates to a compound of formula I: [Formula 1] TIFF2025532110000087.tif35128 wherein R is H or [Case 2] TIFF2025532110000088.tif18128 and R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, [C3] TIFF2025532110000089.tif15128 and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R 3 is NH2 or CH2NH2, and X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, [C4] TIFF2025532110000090.tif5128 or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof; the compounds of formula I or the pharmaceutically acceptable salts thereof are useful for treating autoimmune and inflammatory diseases, such as atopic dermatitis and rheumatoid arthritis.

Description

[Technical Field]

[0001] The present disclosure provides compounds that are glucocorticoid receptor agonists and are useful in the treatment of autoimmune and inflammatory diseases such as atopic dermatitis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis, and rheumatoid arthritis, processes for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions are also provided. [Background technology]

[0002] Atopic dermatitis is a chronic, pruritic, relapsing and remitting inflammatory skin disease that frequently occurs in children but also affects many adults. Current treatments for atopic dermatitis include phototherapy, topical creams containing corticosteroids or calcineurin inhibitors, or a subcutaneously injectable biologic known as dupilumab. Although advances have been made 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] WO 2017 / 210471 discloses certain glucocorticoid receptor agonists and immunoconjugates thereof useful for treating autoimmune or inflammatory diseases. WO 2018 / 089373 discloses novel steroids, protein conjugates thereof, and methods for treating diseases, disorders, and conditions comprising administering the steroids and conjugates. Summary of the Invention [Means for solving the problem]

[0004] The present invention provides certain novel compounds that are glucocorticoid receptor agonists. The present invention further provides certain novel compounds that are prodrugs of glucocorticoid receptor agonists. Furthermore, the present invention provides certain novel compounds that are glucocorticoid receptor agonists that are useful in the treatment of 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] [ka] wherein R is H or

[0007] [ka] and R 1 is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0008] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 alkenyl; R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2,

[0009] [ka] or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment, the present invention provides a compound of formula Ia:

[0011] [ka] wherein R is H or

[0012] [ka] and R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0013] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2,

[0014] [ka] OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2,

[0015] [ka] or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the present invention provides a compound of formula Ib:

[0017] [ka] wherein R is H or

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

[0019] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2,

[0020] [ka] or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the present invention provides a compound of formula Ic:

[0022] [ka] wherein R is H or

[0023] [ka] and R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0024] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2,

[0025] [ka] or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof.

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

[0027] [ka] or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment, the present invention provides a compound of formula Ic(i):

[0029] [ka] or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the present invention provides a compound of formula Ib(ii):

[0031] [ka] or a pharmaceutically acceptable salt thereof.

[0032] In one embodiment, the present invention provides a compound of formula Ic(ii):

[0033] [ka] or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the present invention provides a compound of formula Ib(iii):

[0035] [ka] or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the present invention provides a compound of formula Ic(iii):

[0037] [ka] or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the present invention provides a compound of formula II:

[0039] [ka] wherein R is H or

[0040] [ka] and R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments, the present invention provides compounds of formula IIa:

[0042] [ka] wherein R is H or

[0043] [ka] and R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof.

[0044] In certain embodiments, the present invention provides compounds of formula IIb:

[0045] [ka] wherein R is H or

[0046] [ka] and R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof.

[0047] In certain embodiments, the present invention provides compounds of formula IIc:

[0048] [ka] wherein R is H or

[0049] [ka] and R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the present invention provides a compound of formula III:

[0051] [ka] wherein R is H or

[0052] [ka] a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0053] In certain embodiments, the present invention provides compounds of formula IIIa:

[0054] [ka] wherein R is H or

[0055] [ka] or a pharmaceutically acceptable salt thereof.

[0056] In certain embodiments, the present invention provides compounds of formula IIIb:

[0057] [ka] wherein R is H or

[0058] [ka] or a pharmaceutically acceptable salt thereof.

[0059] In certain embodiments, the present invention provides compounds of formula IIIc:

[0060] [ka] wherein R is H or

[0061] [ka] or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment, R is H.

[0063] 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 OCH. In one embodiment, R 1 OC( 2 H)3.

[0064] 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 OCH. In one embodiment, R 2 OC( 2 H)3.

[0065] 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.

[0066] In one embodiment, R 3 is NH2.

[0067] In one embodiment, X is attached to the phenyl ring A at the meta position.

[0068] In one embodiment, X is attached to the phenyl ring A at the ortho position.

[0069] In one embodiment, the present invention also provides a method of treating an inflammatory disease 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. In one embodiment, the present invention also provides a method of treating atopic dermatitis 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. In one embodiment, the present invention further provides a method of treating inflammatory bowel disease 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. In one embodiment, the present invention also provides a method of treating rheumatoid arthritis 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. In one embodiment, the present invention also provides a method of treating systemic lupus erythematosus 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. In one embodiment, the present invention also provides a method of treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, the present invention further provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. 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 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.

[0071] In one embodiment, the present invention also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture 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, for the manufacture 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, for the manufacture 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, for the manufacture 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, for the manufacture 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, for the manufacture of a medicament for treating systemic lupus erythematosus.

[0072] In one embodiment, the present invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention further provides a process 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 processes for the synthesis of compounds of Formula I. DETAILED DESCRIPTION OF THE INVENTION

[0073] As used herein, the terms "treating," "treatment," or "treat" include suppressing, slowing, arresting, or ameliorating the progression or severity of an existing condition or disorder.

[0074] As used herein, the term "patient" refers to a mammal, particularly a human.

[0075] As used herein, the term "effective amount" refers to an amount or dose of a compound of the present invention or a pharmaceutically acceptable salt thereof that, when administered in single or multiple doses to a patient, provides the desired effect in the patient being diagnosed or treated.

[0076] Effective amounts can be determined by those skilled in the art by using known techniques and observing results obtained under similar circumstances. In determining the effective amount for a patient, the attending diagnostician will take into account several factors, including but not limited to: the patient's species; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosage regimen; the use of concomitant medications; and other relevant circumstances.

[0077] As used herein, Formula I is understood to encompass Formulas Ia, Ib, Ic, Ib(i), Ic(i), Ib(ii), Ic(ii), Ib(iii), Ic(iii), II, IIa, IIb, IIc, III, IIIa, IIIb, and IIIc, and all references herein to Formula I should be interpreted as including Formulas Ia, Ib, Ic, Ib(i), Ic(i), Ib(ii), Ic(ii), Ib(iii), Ic(iii), II, IIa, IIb, IIc, III, IIIa, IIIb, and IIIc.

[0078] As used herein, Formula II is understood to encompass Formulas IIa, IIb, and IIc, and all references herein to Formula II should be interpreted as including Formulas IIa, IIb, and IIc.

[0079] As used herein, Formula III is understood to encompass Formulas IIIa, IIIb, and IIIc, and all references herein to Formula III should be interpreted as including Formulas IIIa, IIIb, and IIIc.

[0080] As used herein, "halogen" refers to F, Cl, Br, and I.

[0081] As used herein, "C1-C3 alkyl" refers to CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

[0082] As used herein, "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0083] As used herein, "C1-C3 alkoxy" refers to OCH3, OCH2CH3, OCH2CH2CH3, and OCH(CH3)2.

[0084] As used herein, "C2-C3 alkenyl" refers to HC=CH2 and C(CH3)=CH2.

[0085] As used herein, the ortho and meta positions on the phenyl ring A are shown in Formula I below.

[0086] [ka]

[0087] For example, compounds of formula I' show X attached at the meta position to the phenyl ring A:

[0088] [ka] Compounds of formula I" show X attached at the ortho position to the phenyl ring A:

[0089] [ka]

[0090] When X is attached to the phenyl ring A at the ortho position as shown in formula I″, R 2 It will be understood by those skilled in the art that .alpha. is H.

[0091] In some embodiments, the compound is selected from the compounds set forth in Table I, and pharmaceutically acceptable salts and stereoisomers thereof.

[0092] In some embodiments, the compound is selected from the compounds set forth in Table I, and pharmaceutically acceptable salts thereof.

[0093] In some embodiments, the compound is selected from the compounds set forth in Table I.

[0094] [Table 1-1]

[0095] [Table 1-2]

[0096] In some embodiments, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds disclosed herein.

[0097] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I, and pharmaceutically acceptable salts thereof.

[0098] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I.

[0099] It will be appreciated that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by following the procedures disclosed in the schemes and / or examples described herein by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0100] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0101] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0102] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table I, and pharmaceutically acceptable salts thereof.

[0103] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table I.

[0104] In addition, the compounds of the present invention can be conjugated to antibodies to form antibody drug conjugates (ADCs) by methods understood by those skilled in the art. One example of such conjugation involves connecting the compounds of the present invention to antibodies via linker compounds. 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. Accordingly, ADCs comprising compounds of Formula I are also provided herein. In some embodiments, the compounds of Formula I are conjugated to the antibody via a linker, for example, a cleavable linker or a non-cleavable linker.

[0105] The compounds or conjugates of the invention can be formulated as pharmaceutical compositions, which can be administered by any route that makes the compound or conjugate bioavailable, including, for example, oral, topical, or subcutaneous administration. Such pharmaceutical compositions, including ADCs, can be prepared using techniques and methods known in the art. 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, A. Adejare, Editor, 23 nd Edition, published 2020, Elsevier Science, see WO 2017 / 062271 and WO 2017 / 210471).

[0106] Additionally, compounds of the invention having a capped hydroxy group at C21 include those compounds of the formula:

[0107] [ka] and It behaves as a prodrug and is metabolized in vitro or in vivo to provide the active glucocorticoid receptor agonist, where R is H.

[0108] Pharmaceutically acceptable salts of Formula I are included within the scope of the present invention. Pharmaceutically acceptable salts of compounds of the present invention, such as compounds of Formula I, can be formed, for example, by reacting a suitable free base of a compound of the present invention with a suitable pharmaceutically acceptable acid 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).

[0109] Certain compounds described in the preparations below may contain a suitable nitrogen protecting group, referred to herein as "Pg." It is understood that the protecting group may vary depending on the specific reaction conditions and the specific transformation being performed, as understood by those skilled in the art. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis," Fourth Edition, by Peter G.M.Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007). [Example]

[0110] The compounds of the present invention or salts thereof may be readily prepared by a variety of procedures known to those skilled in the art, some of which are illustrated in the preparations and examples below. Those skilled in the art will recognize that the specific synthetic steps for each of the routes described can be combined in different ways or steps from different schemes can be combined to prepare the compounds of the present invention or salts thereof. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. All substituents are as previously defined unless otherwise indicated. Reagents and starting materials are readily available to those skilled in the art. The following preparations, examples, and assays further illustrate the present invention but should not be construed as limiting the scope of the invention in any way.

[0111] [Table 2]

[0112] Example 1. Precursor preparation. Preparation 1. Synthesis of tert-butyl (3-((2-fluoro-3-formyl-4-(methoxy-d3)phenoxy)methyl)phenyl)carbamate

[0113] [ka] 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 min. tert-Butyl N-[3-(bromomethyl)phenyl]carbamate (1.5 g, 5.2 mmol) was added in one portion, and the reaction was stirred at room temperature. After 18 h, the reaction mixture was partitioned between EtOAc and HO. The phases were separated, the organic phase was transferred to a flask, and the solvent was evaporated under vacuum. Residual DMF was evaporated using xylene. The crude residue was purified by normal-phase purification, eluting with 0–50% EtOAc in hexanes, to give the title compound (1.9 g, 90% yield). MS m / z 377.2 (M−H).

[0114] Preparation 2. Synthesis of 2-fluoro-3-hydroxy-6-(methoxy-d3)benzaldehyde

[0115] [ka] To a solution of 3-[tert-butyl(diphenyl)silyl]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 h, the solvent was evaporated to give the crude product. The crude residue was purified by normal phase purification eluting with 0-2% MeOH in DCM to give the title compound (3.1 g, 85% yield). MS m / z 174.0 (M+H).

[0116] Preparation 3. Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-6-(methoxy-d3)benzaldehyde

[0117] [ka] tert-Butyl-[2-fluoro-4-(trideuteriomethoxy)phenoxy]-diphenyl-silane (11 g, 30 mmol) was dissolved in THF (130 mL) and cooled to −78 °C. To the cooled solution, nBuLi (31 mL, 50 mmol, 1.6 M in hexanes) was added over 20 min. 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 the addition of saturated aqueous NH4Cl (25 mL). The mixture was allowed to warm to room temperature. After 18 h, the organic solvent was evaporated and the crude residue was extracted 3× with 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 purification eluting with 0-40% EtOAc in hexanes to give the title compound (7.3 g, 60% yield). MS m / z 412.0 (M+H).

[0118] Preparation 4. Synthesis of tert-butyl(2-fluoro-4-(methoxy-d3)phenoxy)diphenylsilane

[0119] [ka] To a solution of 2-fluoro-4-(trideuteriomethoxy)phenol (9.2 g, 44 mmol) in DMF (100 mL) was added imidazole (4.5 g, 66 mmol) and tert-butylchlorodiphenylsilane (14 mL, 53 mmol). The reaction was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and washed 3 times with 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 purification eluting with 0-20% EtOAc in hexanes to give the title compound (15 g, 86% yield). MS m / z 400.9 (M+NH4).

[0120] Preparation 5. Synthesis of 2-fluoro-4-(methoxy-d3)phenol

[0121] [ka] To a pre-purged 70 mL Parr shaker bottle (N), 10% Pd / C (1.0 g, 9.7 mmol) was added, followed by purging again with N. To the charged shaker, 250 mL of MeOH was added, followed by 1-benzyloxy-2-fluoro-4-(trideuteriomethoxy)benzene (10 g, 44 mmol) in MeOH (250 mL). The bottle was sealed, purged with N, purged with H, and then pressurized to 60 psi of H. The bottle was shaken at room temperature for 2 h, then evacuated and degassed with N. The suspension was filtered through Celite with MeOH. The filtrate was concentrated to give a crude residue. The crude product was purified by normal phase purification, eluting with 0–20% EtOAc in hexanes, to give the title compound (9.2 g, 93% yield). 1H NMR (399.80MHz, DMSO): 9.22 (s, 1H), 6.86 (dd, J = 8.9, 10.1Hz, 1H), 6.78 (dd, J = 3.0, 13.0Hz, 1H), 6.58 (ddd, J = 8.9, 3.0, 1.4Hz, 1H).

[0122] Preparation 6. Synthesis of 1-(benzyloxy)-2-fluoro-4-(methoxy-d3)benzene

[0123] [ka] A suspension of 4-benzyloxy-3-fluorophenol (10 g, 46 mmol), CsCO (22 g, 69 mmol), and trideuterio(iodo)methane (3.1 mL, 50 mmol) in DMF (100 mL) was stirred at room temperature for 18 h. The reaction was diluted with EtOAc and washed 3× with water and brine. The solution was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by normal phase purification, eluting with 0-20% EtOAc in hexanes, to give the title compound (10 g, 96% yield). MS m / z 253.0 (M+NH).

[0124] Preparation 7. Synthesis of tert-butyl (3-((3-(1,3-dioxolan-2-yl)-4-ethyl-2-fluorophenoxy)methyl)phenyl)carbamate

[0125] [ka] To a pre-purged 70 mL Parr shaker bottle (N), 5% Pd / C (32 mg, 0.16 mmol) was added, followed by purging again with N. To the charged shaker, 2.5 mL of EtOAc was added, followed by tert-butyl N-[3-[[3-(1,3-dioxolan-2-yl)-2-fluoro-4-vinyl-phenoxy]methyl]phenyl]carbamate (110 mg, 0.25 mmol) in 2.5 mL of EtOAc. The bottle was sealed, purged with N, purged with H, and then pressurized to 60 psi of H. The bottle was shaken at room temperature for 8 hours, then evacuated and degassed with N. The suspension was filtered through Celite with EtOAc. The filtrate was concentrated to give the title compound (89 mg, 84% yield). MS m / z 434.8 (M+NH).

[0126] Preparation 8. Synthesis of tert-butyl (3-((3-(1,3-dioxolan-2-yl)-2-fluoro-4-vinylphenoxy)methyl)phenyl)carbamate

[0127] [ka] 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 CsCO (0.84 g, 2.6 mmol) were placed in a 25 mL microwave tube. The tube was purged with N, and THF (9 mL) and water (1 mL) were added. The solution was degassed by bubbling subsurface N for 5 min, and palladium(II) acetate (10 mg, 0.042 mmol) was added. The tube was capped, and the mixture was heated at 100 °C for 18 h. Upon cooling to room temperature, EtOAc and H2O were added. The phases were separated, and the aqueous layer was extracted 2x with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated to give a crude residue. The crude product was purified by normal phase purification eluting with 50-100% DCM in hexanes to give the title compound (110 mg, 29% yield). MS m / z 432.8 (M+NH4).

[0128] Preparation 9. Synthesis of tert-butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate

[0129] [ka] 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 trap attached. After 1 h, the reaction solution was cooled to room temperature and washed with HO (15 mL) and EtOAc (25 mL). The phases were separated, and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated to give a crude residue. The crude product was purified by normal-phase purification, eluting with 0-4% MeOH in DCM to give the title compound (500 mg, 44% yield). MS m / z 467.4 (MH).

[0130] Preparation 10. Synthesis of tert-butyl (3-((4-bromo-2-fluoro-3-formylphenoxy)methyl)phenyl)carbamate

[0131] [ka] To a solution of 6-bromo-2-fluoro-3-hydroxy-benzaldehyde (5 g, 23 mmol) and CsCO (15 g, 46 mmol) in DMF (76 mL) was added tert-butyl N-[3-(bromomethyl)phenyl]carbamate (7.2 g, 25 mmol). After 18 h at room temperature, the mixture was diluted with EtOAc and water. The organic layer was washed 3× with water, brine, dried over NaSO, filtered, and concentrated to give a crude residue. The crude product was purified by normal phase purification eluting with 0-20% EtOAc in hexanes to give the title compound (8.2 g, 85% yield). MS m / z 441.2 (M+NH).

[0132] Preparation 11. Synthesis of tert-butyl (4-(2-fluoro-3-formyl-4-methoxyphenethyl)phenyl)carbamate

[0133] [ka] tert-Butyl N-[4-[2-[2-fluoro-3-(hydroxymethyl)-4-methoxy-phenyl]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 NaHCO (4 mL) and NaSO (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 NaHCO, water, brine, dried over MgSO, filtered, and concentrated to give the crude residue. The crude product was purified by normal-phase purification, eluting with 10–100% DCM in hexanes, to give the title compound (1.2 g, 58% yield). MS m / z 391.0 (M+NH).

[0134] Preparation 12. Synthesis of tert-butyl (4-(2-fluoro-3-(hydroxymethyl)-4-methoxyphenethyl)phenyl)carbamate

[0135] [ka] To a cooled (0 °C) solution 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 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 biphasic mixture. The slurry was diluted with EtOAc, and the mixture was filtered through a pad of Celite 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 give the title compound (2.1 g, 79% yield). MS m / z 373.8 (MH).

[0136] Preparation 13. Synthesis of methyl 3-(4-((tert-butoxycarbonyl)amino)phenethyl)-2-fluoro-6-methoxybenzoate

[0137] [ka] 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 was heated to 50 °C. After 1 h, the reaction was cooled to room temperature and concentrated to give a crude residue. The material was dissolved in EtOAc and washed with 2 × 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 purification eluting with 0-10% EtOAc in DCM to give the title compound (2.5 g, 89% yield). MS m / z 421.2 (M+NH4).

[0138] Preparation 14. Synthesis of methyl 3-(4-aminophenethyl)-2-fluoro-6-methoxybenzoate

[0139] [ka] To a pre-purged 500 mL Parr shaker bottle (N), 10% Pd / C (380 mg, 0.36 mmol) was added, followed by purging again with N. To the charged shaker, 65 mL of MeOH was added, followed by methyl 2-fluoro-6-methoxy-3-[(E)-2-(4-nitrophenyl)vinyl]benzoate (2.5 g, 7.5 mmol) in MeOH (60 mL). The bottle was sealed, purged with N, purged with H, and then pressurized to 60 psi of H. The bottle was shaken at room temperature for 3 hours, then evacuated and degassed with N. The suspension was filtered through Celite with MeOH. The filtrate was concentrated to give the title compound (2.5 g, 86%). MS m / z 303.8 (M+H).

[0140] Preparation 15. Synthesis of methyl (E)-2-fluoro-6-methoxy-3-(4-nitrostyryl)benzoate

[0141] [ka] A solution of methyl 2-fluoro-3-formyl-6-methoxybenzoate (4.1 g, 20 mmol), diethyl 4-nitrobenzylphosphonate (6.0 g, 22 mmol), and 2-methyl-THF (200 mL) was cooled to -10 °C and treated with potassium tert-butoxide (2.7 g, 23 mmol). After 1 h, the reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase 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 purification, eluting with 0-100% EtOAc in hexanes, to give the title compound (5.6 g, 83% yield). MS m / z 332.0 (M+H).

[0142] Preparation 16. Synthesis of tert-butyl (4-(2-(2-fluoro-3-formyl-4-methoxyphenoxy)ethyl)phenyl)carbamate

[0143] [ka] To 2-fluoro-3-hydroxy-6-methoxy-benzaldehyde (500 mg, 2.9 mmol) and 2-[4-(tert-butoxycarbonylamino)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 purification eluting with 0-30% EtOAc in hexane to give the title compound (0.9 g, 70% yield). MS m / z 387.8 (MH).

[0144] Preparation 17. Synthesis of 4-((tert-butoxycarbonyl)amino)phenethyl 4-methylbenzenesulfonate

[0145] [ka] To a solution of tert-butyl N-[4-(2-hydroxyethyl)phenyl]carbamate (2.5 g, 11 mmol) in DCM (50 mL) was added EtN (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 for 18 h at room temperature. The reaction mixture was diluted with DCM and washed with water and brine. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude residue. The crude product was purified by normal phase purification, eluting with 0-25% EtOAc in hexanes, to give the title compound (3.9 g, 94% yield). MS m / z 408.9 (M+NH).

[0146] Preparation 18. Synthesis of tert-butyl (3-(2-(2-fluoro-3-formyl-4-methoxyphenoxy)ethyl)phenyl)carbamate

[0147] [ka] To 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 the crude residue. The crude product was purified by normal phase purification eluting with 0-25% EtOAc in hexanes to give the title compound (0.96 g, 62% yield). MS m / z 388.4 (MH).

[0148] Preparation 19. Synthesis of 3-((tert-butoxycarbonyl)amino)phenethyl 4-methylbenzenesulfonate

[0149] [ka] To a solution of tert-butyl N-[3-(2-hydroxyethyl)phenyl]carbamate (2.7 g, 11 mmol) in DCM (60 mL) was added EtN (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 approximately 18 h. The reaction 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 purification, eluting with 0-25% EtOAc in hexanes, to give the title compound (3.0 g, 67% yield). MS m / z 389.8 (MH).

[0150] Preparation 20. Synthesis of tert-butyl (3-(2-hydroxyethyl)phenyl)carbamate

[0151] [ka] To a solution of 2-[3-(tert-butoxycarbonylamino)phenyl]acetic acid (3.0 g, 12 mmol) in THF (60 mL) was added borane-THF complex (17 mL, 17 mmol, 1 mol / L in THF) dropwise at 0 °C under a N atmosphere. The mixture was allowed to warm to room temperature with stirring under N for 16 h. The reaction was cooled to 0 °C, MeOH was added, and the solution was allowed to warm to room temperature. The crude reaction was concentrated under reduced pressure to give a crude residue. The crude residue was purified by normal phase purification eluting with 5-50% EtOAc in hexanes to give the title compound (2.7 g, 93% yield). MS m / z 254.8 (M+NH).

[0152] 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-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one (Compound No. 1)

[0153] [ka] To a solution 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) at −10° C., perchloric acid (70% in water, 0.29 mL, 5 equiv.) was added dropwise. The mixture was stirred at −10° C. for 1 h. The reaction was quenched in the cold by the addition of saturated aqueous NaHCO3 and partitioned between water and 10% IPA / DCM. The phases were separated, and the aqueous layer was extracted once with 10% IPA / DCM. The combined organics were dried over MgSO4, filtered, and concentrated to give a crude solid. The solid was purified by reverse-phase chromatography, eluting with 50-100% MeCN + 5% methanol in 10 mM ammonium bicarbonate water, to give the title compound (420 mg, 16% yield). MS m / z 637.4 (M+H).

[0154] 1 H NMR(399.8MHz,d6-DMSO)δ7.33-7.31(m,1H),7.17-7.12(m,1H),6.99(t,J=7.7Hz,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=6.6Hz,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).

[0155] Example 3. Synthesis of Compounds Nos. 2 to 5. Compounds Nos. 2-5 were prepared essentially by the method of Example 2.

[0156] [Table 3]

[0157] Example 4. hGR coactivator recruitment assay The activity of glucocorticoid compounds was measured using the LanthaScreen TR-Fret GR Coactivator Assay (A15899) from Life Technologies. Compounds were transferred to assay plates in 10-point, 3-fold serial dilutions with a top concentration of 200 nM by acoustic transfer. Ten microliters of a 2x solution of GR-LBD was added to the compound plate and incubated for 10 minutes, after which 10 microliters of a 2x solution of fluorescein-SRC1-4-labeled and Tb-labeled anti-GST antibody was added to the plate. The plate was incubated in the dark for 2 hours and then read on an Envision plate reader with excitation at 340 nm and emission at 520 nm (fluorescein) and 490 nm (terbium). The 520 / 490 emission ratio was analyzed by Genedata. Data were compared to a negative control of DMSO and a positive control of 4 μM dexamethasone to obtain activity ratios. The following exemplary compounds were tested essentially according to the procedures described above and exhibited the following activities, as listed in Table 2.

[0158] [Table 4]

Claims

1. formula: 【Chemical 1】 wherein R is H or 【Chemistry 2】 and R １ is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF ３ , 【Chemistry 3】 and R ２ is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 alkenyl; R ３ But NH ２ or CH ２ NH ２ and X, O, OCH ２ ,OCH ２ CH ２ 、H ２ O, SCH ２ ,H ２ S、CH ２ 、NHCH ２ 、H ２ NH、N(H) ３ )CH ２ 、H ２ CH ２ 、 【Chemistry 4】 or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof.

2. R ３ NH ２ 2. The compound of claim 1, wherein:

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

4. The compound has the formula 【Chemistry 5】 4. The compound according to claim 1, wherein the compound is:

5. R １ But F, CH ２ CH ３ , OCH ３ , or OC ( ２ H) ３ 5. The compound according to any one of claims 1 to 4, wherein:

6. R １ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein

7. R １ is CH ２ CH ３ 5. The compound according to any one of claims 1 to 4, wherein:

8. R １ OCH ３ 5. The compound according to any one of claims 1 to 4, wherein:

9. R １ OC ( ２ H) ３ 5. The compound according to any one of claims 1 to 4, wherein:

10. R ２ But F, CH ２ CH ３ , OCH ３ , or OC ( ２ H) ３ 5. The compound according to any one of claims 1 to 4, wherein:

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

12. R ２ is CH ２ CH ３ 5. The compound according to any one of claims 1 to 4, wherein:

13. R ２ OCH ３ 5. The compound according to any one of claims 1 to 4, wherein:

14. R ２ OC ( ２ H) ３ 5. The compound according to any one of claims 1 to 4, wherein:

15. X is CH ２ CH ２ , OCH ２ , or OCH ２ CH ２ 15. The compound according to any one of claims 1 to 14, wherein:

16. X is CH ２ CH ２ 15. The compound according to any one of claims 1 to 14, wherein:

17. X is OCH ２ 15. The compound according to any one of claims 1 to 14, wherein:

18. X is OCH ２ CH ２ 15. The compound according to any one of claims 1 to 14, wherein:

19. The compound is 【Chemistry 6】 2. The compound of claim 1, wherein:

20. The compound is 【Chemistry 7】 20. The compound of claim 19, wherein:

21. The compound is 【Chemistry 8】 2. The compound of claim 1, wherein:

22. The compound is 【Chemistry 9】 22. The compound of claim 21, wherein:

23. The compound is 【Chemistry 10】 2. The compound of claim 1, wherein:

24. The compound is 【Chemistry 11】 24. The compound of claim 23, wherein:

25. The compound is 【Chemistry 12】 2. The compound of claim 1, wherein:

26. The compound is 【Chemistry 13】 26. The compound of claim 25, wherein:

27. The compound is 【Chemistry 14】 2. The compound of claim 1, wherein:

28. The compound is 【Chemistry 15】 28. The compound of claim 27, wherein:

29. The compound is 【Table 1】 2. The compound of claim 1, wherein:

30. 30. A method of treating atopic dermatitis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

31. 30. A method of treating rheumatoid arthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

32. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in therapy.

33. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.

34. 30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis.

35. 30. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating atopic dermatitis.

36. 30. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating rheumatoid arthritis.

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

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

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