Glucocorticoid receptor agonist

Abstract

The present invention relates to a compound of formula I, [Formula 1] TIFF2024510774000212.tif43128 wherein R is H, or [chemical 2] TIFF2024510774000213.tif25128 R 1 H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF 3 and [C3] TIFF2024510774000214.tif19128 R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R 3 But NH 2 or CH 2 NH 2 and X is O, OCH 2 , O.C.H. 2 CH 2 , OCH(CH 3 ), C.H. 2 O, S.C.H. 2 , C.H. 2 S, C.H. 2 , N.H.C.H. 2 , C.H. 2 NH, N(CH 3 )CH 2 , C.H. 2 CH 2 , C≡C, or a bond, and X is attached to the phenyl ring A at the ortho or meta position, or a pharma- ceutically acceptable salt thereof, wherein the compounds of formula I or the pharma- ceutically 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 for 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.

Background Art

[0002] Atopic dermatitis is a chronic, pruritic, relapsing and remitting inflammatory skin disease that occurs frequently in children but also affects many adults. Current treatments for atopic dermatitis include phototherapy, topical creams containing corticosteroids or calcineurin inhibitors, or subcutaneous injectable biologics known as dupilumab. Although the treatment of atopic dermatitis has advanced, there remains a significant need for new compounds for the treatment of atopic dermatitis as well as other inflammatory and autoimmune diseases.

[0003] WO 2017 / 210471 discloses certain glucocorticoid receptor agonists and their immunoconjugates useful for treating autoimmune or inflammatory diseases. WO 2018 / 089373 discloses novel steroids, their protein conjugates, and methods for treating diseases, disorders, and conditions, including administering the steroids and conjugates.

Summary of the Invention

[0004] The present invention provides a novel compound which is a glucocorticoid receptor agonist. The present invention further provides a novel compound which is a prodrug of a glucocorticoid receptor agonist. In addition, the present invention provides a novel compound which is a glucocorticoid receptor agonist useful for the treatment of autoimmune diseases 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,

[0006]

Chemical formula

[0007]

Chemical formula

[0008]

Chemical formula

[0009] In one embodiment, the present invention provides a compound of formula Ia,

[0010]

Chem.

[0011]

Chem.

[0012]

Chem.

[0013] In one embodiment, the present invention is a compound of formula Ib, wherein

[0014]

Chem.

[0015]

Chem.

[0016]

Chemical formula

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

[0018]

Chemical formula

[0019]

Chemical formula

[0020]

Chemical formula

[0021] In one embodiment, the present invention provides a compound of formula Ib(i):

[0022]

Chemical formula

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

[0024]

Chemical formula

[0025] In one embodiment, the present invention provides a compound of formula Ib(ii):

[0026]

Chemical formula

[0027] In one embodiment, the present invention provides a compound of formula Ic(ii):

[0028]

Chemical formula

[0029] In one embodiment, the present invention provides a compound of formula Ib(iii):

[0030] [Chemical formula] or a pharmaceutically acceptable salt thereof is provided.

[0031] In one embodiment, the present invention provides a compound of formula Ic(iii):

[0032] [Chemical formula] or a pharmaceutically acceptable salt thereof is provided.

[0033] In one embodiment, the present invention provides a compound of formula II,

[0034] [Chemical formula] wherein R is H or

[0035] [Chemical formula] R 1 is -CH3 or -OCH3, and the compound or a pharmaceutically acceptable salt thereof is provided.

[0036] In certain embodiments, the present invention provides a compound of formula IIa,

[0037] [Chemical formula] wherein R is H or

[0038] [Chemical formula] R 1is -CH3 or -OCH3, a compound, or a pharmaceutically acceptable salt thereof.

[0039] In certain embodiments, the present invention is a compound of formula IIb,

[0040]

Chemical formula

[0041]

Chemical formula

[0042] In certain embodiments, the present invention is a compound of formula IIc,

[0043]

Chemical formula

[0044]

Chemical formula

[0045] In one embodiment, the present invention is a compound of formula III,

[0046]

Chemical formula

[0047]

Chemical formula

[0048] In certain embodiments, the present invention is a compound of formula IIIa,

[0049]

Chem.

[0050]

Chem.

[0051] In certain embodiments, the present invention is a compound of formula IIIb,

[0052]

Chem.

[0053]

Chem.

[0054] In certain embodiments, the present invention is a compound of formula IIIc,

[0055]

Chem.

[0056]

Chem.

[0057] In one embodiment, R is H.

[0058] In one embodiment, R is

[0059]

Chemical formula

[0060] In one embodiment, R 1 is CH3.

[0061] In one embodiment, R 1 is H.

[0062] In one embodiment, R 1 is OCH3.

[0063] In one embodiment, R 1 is F.

[0064] In one embodiment, R 2 is H.

[0065] In one embodiment, R 2 is CH3.

[0066] In one embodiment, R 2 is F.

[0067] In one embodiment, R 2 is OCH3.

[0068] In one embodiment, X is O.

[0069] In one embodiment, X is OCH2.

[0070] In one embodiment, X is SCH2.

[0071] In one embodiment, X is CH2.

[0072] In one embodiment, X is a bond.

[0073] In one embodiment, R is H, R 1 is CH3, R 2 is F, and X is OCH2.

[0074] In one embodiment, R is H, R 1 is OCH3, R 2 is F, and X is OCH2.

[0075] In one embodiment, X is bonded to phenyl ring A at the meta position.

[0076] In one embodiment, X is bonded to phenyl ring A at the ortho position.

[0077] In one embodiment, the present invention also provides a method for treating an inflammatory disease in a patient in need thereof, 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 thereof, 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 thereof, 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 thereof, 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 thereof, 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 thereof, the method comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0078] 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 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 erythematosus.

[0079] 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 erythematosus.

[0080] 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, the process 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.

[0081] As used herein, the terms "treating," "treatment," or "treat" include suppressing, delaying, halting, or reversing the progression or severity of an existing symptom or disorder.

[0082] As used herein, the term "patient" refers to a mammal, particularly a human.

[0083] As used herein, the term "effective amount" refers to an amount or dosage of a compound of the present invention or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to a patient, produces the desired effect in a patient being diagnosed or treated.

[0084] The effective amount can be determined by one of ordinary skill in the art by using known techniques and observing the results obtained in similar circumstances. In determining an effective amount for a patient, several factors are considered by the attending diagnostician, including, but not limited to, the patient's race, size, age, and general health, the specific disease or disorder involved, the degree 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 preparation administered, the dosage regimen selected, the use of concomitant medications, and other relevant circumstances.

[0085] As used herein, formula I is understood to include 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 construed to include 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.

[0086] As used herein, formula II is understood to include formulas IIa, IIb, and IIc, and all references herein to formula II should be construed to include formulas IIa, IIb, and IIc.

[0087] As used herein, formula III is understood to include formulas IIIa, IIIb, and IIIc, and all references herein to formula III should be construed to include formulas IIIa, IIIb, and IIIc.

[0088] As used herein, "halogen" refers to F, Cl, Br, and I.

[0089] As used herein, "C1-C3 alkyl" refers to CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

[0090] As used herein, "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0091] As used herein, "C1-C3 alkoxy" refers to OCH3, OCH2CH3, OCH2CH2CH3, and OCH(CH3)2.

[0092] As used herein, "C2-C3 alkenyl" refers to HC=CH2 and C(CH3)=CH2.

[0093] As used herein, the ortho and meta positions on phenyl ring A are represented by the following formula I.

[0094]

Chemical formula

[0095] For example, the compound of formula I' shows X attached at the meta position to phenyl ring A,

[0096]

Chemical formula

[0097]

Chemical formula

[0098] When X is attached to phenyl ring A at the ortho position as shown in formula I”, it will be understood by those skilled in the art that R 2 is H.

[0099] 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 involves the attachment of 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. Such ADCs can deliver the compounds of the present invention to specific target tissues or cells. Accordingly, ADCs comprising the compounds of formula I are also provided herein. In some embodiments, the compounds of formula I are conjugated to an antibody via a linker, such as a cleavable linker or a non-cleavable linker.

[0100] The compounds or conjugates of the present invention can be formulated as pharmaceutical compositions, which can be administered by any route that makes the compound or conjugate bioavailable, such routes including, for example, oral, topical, or subcutaneous administration. Such pharmaceutical compositions containing an ADC can be prepared using techniques and methods known in the art. Such pharmaceutical compositions containing an ADC can be prepared using techniques and methods known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition, published in 2020 by Elsevier Science, International Publication No. 2017 / 062271, and International Publication No. 2017 / 210471).

[0101] Furthermore, the compounds of the present invention having a hydroxy group at the capped C21, wherein R is as follows,

[0102]

Chemical Formula

[0103] Pharmaceutically acceptable salts of Formula I are included within the scope of the present invention. Pharmaceutically acceptable salts of the compounds of the present invention, for example, compounds of Formula I, can be formed, for example, by reacting the appropriate free base of the compound of the present invention with an appropriate pharmaceutically acceptable acid in a suitable solvent such as diethyl ether under standard conditions well known in the art. See, for example, Berge, S.M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 66:1 - 19, (1977).

[0104] Certain compounds described in the following preparations 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 transformations being carried out, as will be understood by those skilled in the art. The conditions for protection and deprotection 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).

[0105]

Table 1-1

[0106]

Table 1-2

[0107] The compounds of the present invention or salts thereof can be readily prepared by various procedures known to those skilled in the art, some of which are illustrated in the following preparations and examples. It will be recognized by those skilled in the art that the specific synthetic steps for each of the described routes can be combined in different ways or with steps from different schemes 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. All substituents are as defined previously, 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 invention but are not to be construed as limiting the scope of the invention in any way.

[0108] Preparation 1 6-Bromo-2-fluoro-3-methoxybenzaldehyde

[0109] [Chemistry]

[0110] The two reactions were carried out in parallel. To a solution of 4-bromo-2-fluoro-1-methoxybenzene (250 g, 1.2 mol) in THF (1500 mL), LDA (2 M, 730 mL) was slowly added at -78 °C over 30 minutes. After an additional 30 minutes, DMF (140 mL, 1.8 mol) was slowly added at -78 °C over 30 minutes. After 1 hour, the two reactants were combined and the mixture was diluted with aq citric acid (2000 mL) and extracted with EtOAc (1500 mL × 2). The combined organic layers were washed with saturated brine (1000 mL) and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (1000 mL) at room temperature for 12 hours to give the title compound (382 g, 67% yield). ES / MS m / z 233.9 (M+H).

[0111] Preparation 2 2-Fluoro-3-methoxy-6-methylbenzaldehyde

[0112] [Chemistry]

[0113] Three reactions were carried out in parallel. 6-Bromo-2-fluoro-3-methoxybenzaldehyde (120 g, 5.3 mol), methylboronic acid (47 g, 7.9 mol), Pd(dppf)Cl2 (12 g, 0.02 mol), and Cs2CO3 (340 g, 1.1 mol) were added to a mixture of dioxane (600 mL) and water (120 mL). The mixture was stirred at 120 °C. After 12 h, the three reaction products were combined, the mixture was diluted with satd aq NH4Cl (1000 mL), and extracted with MTBE (1500 mL × 2). The combined organic layers were washed with satd aq NaCl (1000 mL) and concentrated under reduced pressure to give a residue. The residue was purified by normal-phase chromatography, eluting with 40:1 Pet ether:EtOAc to give the title compound (180 g, 59% yield). ES / MS m / z 169.3 (M+H).

[0114] Preparation 3 2-Fluoro-3-hydroxy-6-methylbenzaldehyde

[0115] [Chemical formula]

[0116] 2-Fluoro-3-methoxy-6-methylbenzaldehyde (175 g, 1.0 mol) was added into DCM (1050 mL). BBr3 (200 mL, 2.1 mol) was slowly added into the solution at 0 °C. The reaction mixture was stirred at room temperature. After 1 h, the mixture was diluted with satd aq sodium bicarbonate (1000 mL) to pH = 7 - 8 and extracted with MTBE (1500 mL × 2). The combined organic layers were washed with satd aq NaCl (1000 mL) and concentrated under reduced pressure to give the title compound (110 g, 68% yield). ES / MS m / z 154.9 (M+H).

[0117] Preparation 4 tert-Butyl N-[3-[(2-fluoro-3-formyl-4-methyl-phenoxy)methyl]phenyl]carbamate

[0118]

Chem.

[0119] 2-Fluoro-3-hydroxy-6-methylbenzaldehyde (130 g, 0.84 mol), tert-butyl (3-(bromomethyl)phenyl)carbamate (200 g, 0.70 mol), and potassium carbonate (350 g, 2.5 mol) were added to acetonitrile (780 mL) at room temperature and then heated to 50 °C. After 5 h, the reaction mixture was diluted with water (600 mL) and extracted with EtOAc (800 mL × 2). The combined organic layers were washed with brine (800 mL) and concentrated under reduced pressure to give a residue. The residue was purified by normal-phase chromatography, eluting with 50:1 Pet ether:EtOAc to give the crude product. The crude product was triturated with MTBE (500 mL) at room temperature for 30 min to give the title compound (103 g, 32% yield). ES / MS m / z 382.1 (M+Na).

[0120] Preparation 5 (2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(2-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-aminobenzyl)oxy)-2-fluoro-6-methylphenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0121]

Chem.

[0122] 3 Å molecular sieve (5 g) was added at room temperature to (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-aminobenzyl)oxy)-2-fluoro-6-methylphenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one (150 mg, 0.24 mmol, Example 2 below), 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (155 mg, 0.37 mmol), and DCM (5 mL). After 1 hour, the reaction was cooled to 0 °C. Silver(I) oxide (115 mg, 0.49 mmol) and trimethylsilyl trifluoromethanesulfonate (45 μL, 0.24 mmol) were added. After 30 minutes, the reaction was quenched with satd aq sodium bicarbonate, filtered through diatomaceous earth, and rinsed with DCM (10 mL) and methanol (10 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography, eluting with 1:5 10 mM ammonium bicarbonate in water + 5% methanol:acetonitrile to give the title compound (43 mg, 19% yield). ES / MS m / z 948.0 (M+1).

[0123] Preparation 6 tert-Butyl (2-fluoro-4-methoxyphenoxy)diphenylsilane

[0124] [Chemical formula]

[0125] To a solution of 2-fluoro-4-methoxyphenol (25 g, 180 mmol) in DMF (350 mL, 0.5 M) were added imidazole (18 g, 260 mmol) and tert-butyldichlorophenylsilane (55 mL, 200 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate. The organic solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a crude residue. The residue was purified by normal-phase purification, eluting with 5:1 hexane:ethyl acetate to give the title compound (67 g, 93% yield). 1 1H NMR (399.8 MHz, d6-DMSO) δ 7.67 - 7.65 (m, 4H), 7.51 - 7.44 (m, 6H), 6.82 (dd, J = 2.9, 12.7 Hz, 1H), 6.59 (t, J = 9.4 Hz, 1H), 6.47 (ddd, J = 9.0, 3.0, 1.4 Hz, 1H), 3.64 (s, 3H), 1.06 (s, 9H).

[0126] Preparation 7 2-Fluoro-3-hydroxy-6-methoxybenzaldehyde

[0127] [Chemical formula]

[0128] tert-Butyl(2-fluoro-4-methoxyphenoxy)diphenylsilane(56g, 150mmol, Preparation 6) was dissolved in 50 mL of toluene and concentrated under vacuum for 18 hours. The dried solid was dissolved in THF (500 mL) and cooled to -80 °C. n-Butyllithium (1.7 M, 100 mL, 170 mmol) was rapidly added to the cooled solution via a large-bore cannula. After 1.5 hours, DMF (25 mL, 320 mmol) was added to the solution and the ice bath was removed. After 30 minutes, 5 N aqueous HCl (35 mL) was added to the reaction mixture, followed by tetrabutylammonium fluoride (1 M in THF, 185 mL, 185 mmol). After 2.5 hours, the organic layer was evaporated, acidified with 5 N aqueous HCl, and partitioned between ethyl acetate and water (500 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give a crude residue. The residue was purified by normal-phase purification, eluting with 1:1 hexane:ethyl acetate to give the title compound (22 g, 88% yield). MS m / z 170.8 (M+H).

[0129]

Chemical Structure

[0130] Preparation 8 tert-Butyl(3-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl)carbamate

[0131]

Chemical Structure

[0132] 2-Fluoro-3-hydroxy-6-methoxybenzaldehyde (2.5 g, 15 mmol) and tert-butyl N-[3-(bromomethyl)phenyl]carbamate (5.1 g, 18 mmol) were dissolved in acetonitrile (50 mL). Potassium carbonate (2.9 g, 29 mmol) was added to the slurry and the reaction was stirred at room temperature. After 1 hour, the reaction was heated to 40 °C. After 3 hours, the reaction was cooled, filtered, and the solvent was evaporated. The crude residue was purified by normal phase purification, eluting with 7:3 hexane:EtOAc to afford the title compound (3.1 g, 57% yield). MS m / z 374.4 (M-H).

[0133] The following compounds in Table 2 were prepared in a manner essentially similar to the procedure described in Preparation 8.

[0134]

Table 2-1

[0135]

Table 2-2

[0136]

Table 2-3

[0137]

Table 2-4

[0138]

Table 2-5

[0139]

Table 2-6

[0140]

Chem.

[0141] Preparation 51 tert-Butyl (3-((3-formyl-4-(furan-2-yl)phenoxy)methyl)phenyl)carbamate

[0142]

Chemical Structure

[0143] In a microwave tube, tert-butyl (3-((4-bromo-3-formylphenoxy)methyl)phenyl)carbamate (0.73 g, 1.8 mmol), 2-furylboronic acid (0.30 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol), and N,N-diisopropylethylamine (1.6 mL, 1.2 mmol) were dissolved in DMF (2 mL, 26 mmol). The tube was flushed with N2 and capped. The reaction mixture was microwave irradiated at 140 °C for 45 minutes. The reaction mixture was cooled, poured onto ice water, extracted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (0.70 g, 98% yield). MS m / z 392.2 (M-H).

[0144] The following compounds in Table 3 were prepared in a manner essentially similar to the procedure described for Preparation 51.

[0145]

Table 3

[0146]

Chemical Structure

[0147] Preparation 56 tert-Butyl (3’-formyl-[1,1’-biphenyl]-3-yl)carbamate

[0148]

Chem.

[0149] 3-Bromobenzaldehyde (1.5 g, 8.1 mmol), tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (2.1 g, 6.4 mmol), and potassium carbonate (3.3 g, 24 mmol) were dissolved in 1,4-dioxane (11 mL) and water (3 mL) in a 40 mL reaction vial. The resulting homogeneous mixture was stirred and degassed three times. 1,1'-Bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (530 mg, 0.81 mmol) was added, and the mixture was degassed, capped, and heated to 90 °C for 2.25 h. The reaction was cooled, filtered through diatomaceous earth, and the solvent was evaporated. The crude residue was purified by normal-phase chromatography, eluting with 7:3 hexane:EtOAc to give the title compound (1.5 g, 63% yield). MS m / z 315.4 (M+18).

[0150] The following compounds in Table 4 were prepared in a manner essentially similar to the procedure described in Preparation 56.

[0151]

Table 4

[0152]

Chem.

[0153] Preparation 58 tert-Butyl (3-(3-formylbenzyl)phenyl)carbamate

[0154]

Chem.

[0155] 3-(Bromomethyl)benzaldehyde (320 mg, 1.5 mmol), tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (300 mg, 0.94 mmol), and potassium carbonate (410 mg, 3.0 mmol) were dissolved in toluene (9 mL) and water (1 mL) in a vial. The reaction mixture was purged with argon. 1,1’-Bis(di-tert-butylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (80 mg, 0.10 mmol) was added, the vial cap was closed, and the mixture was heated to 100 °C for 1.5 h. The reaction mixture was cooled, filtered through diatomaceous earth, and the solvent was evaporated. The crude residue was purified by normal phase chromatography, eluting with 7:3 heptane:EtOAc to give the title compound (300 mg, 54% yield). MS m / z 329.4 (M+18).

[0156] The following compounds in Table 5 were prepared in a manner essentially similar to the procedure described in Preparation 58.

[0157]

Table 5

[0158]

Chem.

[0159] Preparation 61 2,6-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0160]

Chem.

[0161] tert-Butyl 3-(bromomethyl)phenylcarbamate (1.5 g, 5.0 mmol), 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.5 g, 5.6 mmol), and potassium carbonate (2.1 g, 3.0 mmol) were placed in a reaction vial together with water (1 mL) and toluene (9 mL). The reaction mixture was purged with N2, 1,1’-bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (310 mg, 0.37 mmol) was added, the vial was capped, and heated at 100 °C for 10 minutes. The reaction was cooled, filtered, and the filtrate was evaporated. The crude residue was purified by normal phase chromatography, eluting with 1:1 heptane:EtOAc to give the title compound (1.38 g, 3.85 mmol, 77% yield). MS m / z 365.2 (M+NH4).

[0162] The following compounds in Table 6 were prepared in a manner essentially similar to the procedure described in Preparation 61.

[0163]

Table 6

[0164]

Chem.

[0165] Preparation 67 tert-Butyl (4-(3-formylphenoxy)phenyl)carbamate

[0166]

Chem.

[0167] (3-Formylphenyl)boronic acid (610 mg, 4.1 mmol), tert-butyl (4-hydroxyphenyl)carbamate (420 mg, 2.0 mmol), copper(II) acetate (370 mg, 2.0 mmol), triethylamine (1.4 mL, 10 mmol), and 4 Å molecular sieves (500 mg) were added to DCM (15 mL) in a vial. The reaction was incubated at room temperature for 10 h. The reaction was filtered through celite and the solvent was evaporated. The crude residue was purified by normal phase chromatography, eluting with 7:3 hexane:EtOAc to afford the title compound (180 mg, 29% yield). MS m / z 312.2 (M-H).

[0168] The following compounds in Table 7 were prepared in an essentially similar manner to the procedure described in Preparation 67.

[0169]

Table 7

[0170]

Chem.

[0171] Preparation 69 tert-Butyl (4-(3-formylphenoxy)phenyl)carbamate

[0172]

Chem.

[0173] 5-Hydroxy-2-methoxybenzaldehyde (1.00 g, 6.57 mmol), [4-(tert-butoxycarbonylamino)phenyl]boronic acid (3.12 g, 13.2 mmol), copper(II) acetate (1.19 g, 6.57 mmol), and 4 Å molecular sieves (1.0 g) were added to a flask. Then, DCM (60 mL) and triethylamine (4.6 mL, 33 mmol) were added. The reaction mixture was stirred overnight at room temperature. Additional [4-(tert-butoxycarbonylamino)phenyl]boronic acid (1.1 g, 4.6 mmol) and copper(II) acetate (400 mg, 2.2 mmol) were added, and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was filtered and the solvent was evaporated. The crude residue was purified by normal phase chromatography, eluting with heptane:EtOAc to give the title compound (400 mg, 18% yield). MS m / z 361.0 (M+NH4).

[0174] The following compounds in Table 8 were prepared in an essentially similar manner to the procedure described in Preparation 69.

[0175]

Table 8

[0176] Preparation 71 tert-Butyl (3-((2-fluoro-3-formylphenyl)ethynyl)phenyl)carbamate

[0177]

Chem.

[0178] 3-Ethynyl-2-fluorobenzaldehyde (0.25 g, 1.7 mmol) was mixed with tert-butyl N-(3-iodophenyl)carbamate (0.55 g, 1.7 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.025 g, 0.036 mmol), and copper(I) iodide (0.01 g, 0.05 mmol) in triethylamine (10 mL, 72 mmol) under N2. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was washed with 1 M aq HCl, brine, dried over Na2SO4, and filtered. The solvent was evaporated to give the title compound (0.57 g, 100% yield). MS m / z 338.2 (M-H).

[0179] [Chemical Structure]

[0180] Preparation 72 2-(6-Fluoro-3-methoxy-2-methylphenyl)-1,3-dioxolane

[0181] [Chemical Structure]

[0182] To a microwave vial was added 2-(2-bromo-6-fluoro-3-methoxyphenyl)-1,3-dioxolane (970 mg, 3.5 mmol), trimethylboroxin (50 wt%) in THF (600 μL, 4.3 mmol), and cesium carbonate (2.3 g, 7.1 mmol) in 1,4-dioxane (12 mL, 140 mmol) and water (2 mL, 110 mmol). The solution was degassed with N2 for 2 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (130 mg, 0.17 mmol) was added and the solution was degassed with N2 for 2 minutes. The vial cap was closed and the mixture was microwave-treated at 110 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4, filtered through paper, and rotary evaporated to give a crude oil. The crude oil was purified by normal-phase chromatography, eluting with 7:3 hexane:MTBE to give the title compound (0.61 g, 82% yield). MS m / z 212.8 (M+H).

[0183] The following compounds in Table 9 were prepared in a manner essentially similar to the procedure described in Preparation 72.

[0184]

Table 9

[0185] Preparation 79 6-Fluoro-3-hydroxy-2-methylbenzaldehyde

[0186] [Chemical Structure]

[0187] Boron tribromide (14 mL, 14 mmol, 1 mol / L) in DCM was added over a period of 2 minutes to a solution of 2-(6-fluoro-3-methoxy-2-methylphenyl)-1,3-dioxolane (600 mg, 2.8 mmol) in DCM (14 mL, 220 mmol) cooled to 0 °C. After addition, the bath was removed. After 30 minutes, the reaction was quenched with satd aq NH4Cl. The reaction was diluted with DCM, washed with 2 M aq NaOH, and then with 5 M aq HCl. The organic layer was dried over Na2SO4, filtered through paper, and rotary evaporated to give a crude residue. The crude residue was purified by normal phase chromatography, eluting with 7:3 hexane:EtOAc to give the title compound (130 mg, 30% yield). MS m / z 153.0 (M - H).

[0188] Preparation 80 tert-Butyl (4-fluoro-2-methoxyphenoxy)diphenylsilane

[0189] [Chemical Structure]

[0190] To a solution of 4-fluoro-2-methoxyphenol (2.3 g, 16 mmol) in DCM (35 mL) were added imidazole (2.8 g, 41 mmol) and tert-butyldichlorophenylsilane (6 mL, 23 mmol). After 1.75 h, the solvent was evaporated and the residue was partitioned between 200 mL of 10% EtOAc in hexane and 100 mL of water. The organic was washed once with brine, dried over MgSO4, filtered, and evaporated. The crude residue was purified by flash chromatography eluting with 9:1 hexane:EtOAc to afford the title compound (6.7 g, quantitative yield). 1 H NMR (399.8 MHz, d6-DMSO) δ 7.64 (dd, J = 1.5, 7.9 Hz, 4H), 7.48~7.43 (m, 6H), 6.82 (dd, J = 2.9, 10.5 Hz, 1H), 6.60 (dd, J = 5.9, 8.8 Hz, 1H), 6.48 (td, J = 8.5, 3.0 Hz, 1H), 3.56 (s, 3H), 1.05 (s, 9H)

[0191] Preparation 81 6-Fluoro-3-hydroxy-2-methoxybenzaldehyde

[0192]

Chemical Structure

[0193] tert-Butyl(4-fluoro-2-methoxyphenoxy)diphenylsilane(3.2 g, 8.5 mmol) was dissolved in tetrahydrofuran(30 mL) and cooled to -78 °C. n-Butyllithium(7 mL, 11 mmol, 1.6 M) was added over 3 minutes. After 1.5 hours, DMF(2 mL) was added at -78 °C. After 1 hour, about 4 mL of 10% aq NH4Cl was added and the mixture was warmed to room temperature over 1.5 hours. The solvent was evaporated to give a crude residue which was then acidified with 1 M aq HCl and partitioned between water and 300 mL of EtOAc. The organic layer was washed with water, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by normal phase chromatography, eluting with 3:2 hexane:EtOAc to give the title compound(0.79 g, 55% yield). MS m / z 171.0(M+H).

[0194] Preparation 82 tert-Butyl(3-((4-cyclopropyl-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate

[0195] [Chemical Structure]

[0196] tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (200 mg, 0.43 mmol), cyclopropylboronic acid (0.21 g, 2.4 mmol), and tripotassium phosphate (0.28 g, 1.3 mmol) were placed in a 25 mL vial purged with N2. Toluene (3 mL) and water (0.75 mL) were added. The reaction mixture was degassed with N2 for 5 minutes and then tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) was added all at once. The reaction was heated to 100 °C overnight. After cooling to room temperature, EtOAc and water were added, the phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a crude residue. The crude residue was purified by normal-phase chromatography, eluting with 1:1 hexane:EtOAc, to give the title compound (170 mg, 94% yield). MS m / z 428.4 (M-H).

[0197] Preparation 83 (2,6-Dimethyl-3-nitrophenyl)methylenediacetate

[0198] [Chemical Formula]

[0199] 2,6-Dimethyl-3-nitrobenzaldehyde (1.9 g, 10 mmol) was dissolved in DCM (23 mL), then acetic anhydride (1.3 mL, 14 mmol) and copper(II) trifluoromethanesulfonate (41 mg, 0.11 mmol) were added. The solution was stirred at room temperature for 3.5 h. The reaction was quenched with satd aq NaHCO3. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and concentrated to give a crude residue. The crude residue was purified by normal-phase chromatography, eluting with 3:2 hexane:EtOAc, to give the title compound (2.4 g, 81% yield). 11H NMR (400.13 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 2.58 (s, 3H), 2.53 (s, 2H), 2.12 (s, 6H).

[0200] Preparation 84 (3-Amino-2,6-dimethylphenyl)methylenediacetate

[0201]

Chemical formula

[0202] 5 wt% platinum sulfide on carbon (1.0 g, 5.2 mmol) was added to a 500 mL Parr shaker bottle and degassed with N2. 25 mL of EtOAc, followed by (2,6-dimethyl-3-nitrophenyl)methylenediacetate (2.7 g, 9.6 mmol) in 25 mL of EtOAc, was added to the bottle. The bottle was sealed, purged with N2, purged with H2, and pressurized with 60 psi of H2 at room temperature for 1.5 h. The reaction mixture was filtered and concentrated to give the title compound (2.1 g, quantitative yield). MS m / z 251.8 (M+H).

[0203] Preparation 85 (3-((3-((tert-Butoxycarbonyl)amino)benzyl)amino)-2,6-dimethylphenyl)methylenediacetate

[0204]

Chemical formula

[0205] A mixture of (3-amino-2,6-dimethylphenyl)methylenediacetate (276 mg, 1.10 mmol) and potassium carbonate (435 mg, 3.15 mmol) in DMF (3 mL) was stirred at room temperature for 1 hour. tert-Butyl N-[3-(bromomethyl)phenyl]carbamate (300 mg, 1.05 mmol) was added to the slurry and the reaction was stirred at 50 °C for 1 hour. After cooling, the reaction mixture was partitioned between ethyl acetate and water. The phases were separated. The organic phase was transferred to a round bottom flask and the solvent was evaporated in vacuo. The residue DMF was evaporated (azeotropically) with xylene to give the residue as a clear paste. The crude residue was purified by normal phase purification eluting with 1:1 EtOAc:hexane to give the title compound (363 mg, 76% yield). MS m / z 457.2 (M+H).

[0206]

Chemical Structure

[0207] Preparation 86 Methyl 3-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2-fluoro-6-methylbenzoate

[0208]

Chemical Structure

[0209] tert-Butyl (3-formylphenyl)carbamate (1.2 g, 5.2 mmol), methyl 3-amino-2-fluoro-6-methylbenzoate (950 mg, 4.8 mmol), and acetic acid (0.55 mL, 9.6 mmol) were dissolved in methanol (5 mL) and cooled to 0 °C. Sodium cyanoborohydride (0.61 g, 9.5 mmol) was carefully added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature overnight under N2. The reaction was quenched by the addition of water (10 mL). The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude residue. The crude residue was purified by normal phase chromatography, eluting with 3:2 Pet ether:EtOAc to give the title compound (1.9 g, 75% yield). MS m / z 389.0 (M+H).

[0210] The following compounds in Table 10 were prepared in an essentially similar manner to the procedure described in Preparation 86.

[0211]

Table 10

[0212] Preparation 88 Methyl 6-bromo-2-fluoro-3-formylbenzoate

[0213]

Chemical formula

[0214] N-Bromosuccinimide (5.8 g, 31 mmol) was added to a solution of methyl 6-bromo-2-fluoro-3-methylbenzoate (3.9 g, 14 mmol) in carbon tetrachloride (36 mL), followed by the addition of 2,2'-azobis(2-methylpropionitrile) (0.24 g, 1.4 mmol). The reaction mixture was stirred at 85 °C overnight. The mixture was diluted with DCM, washed with brine, dried over Na2SO4, and concentrated to give a crude residue. The residue was dissolved in ACN and purified by preparative C18 HPLC (35% - 60% water [0.225% FA]-ACN). The eluate was concentrated to give methyl 6-bromo-3-(dibromomethyl)-2-fluorobenzoate (1.9 g, 4.6 mmol). The substance was dissolved in ethanol (15 mL). A mixture of silver nitrate (2.0 g, 12 mmol) in water (10 mL) was added, and the reaction mixture was heated at 75 °C for 6 h under N2. The reaction product was filtered and washed with EtOAc. The filtrate was concentrated to give a crude residue. The crude residue was purified by normal-phase chromatography, eluting with 8% EtOAc:Pet ether to give the title compound (1.1 g, 91% yield).

[0215]

Chem.

[0216] Preparation 89 Methyl 6-bromo-3-(((3-((tert-butoxycarbonyl)amino)phenyl)amino)methyl)-2-fluorobenzoate

[0217]

Chem.

[0218] Methyl 6-bromo-2-fluoro-3-formylbenzoate (1.0 g, 3.7 mmol), tert-butyl N-(3-aminophenyl)carbamate (870 mg, 4.1 mmol), and acetic acid (0.43 mL, 7.5 mmol) were dissolved in methanol (9 mL) and cooled to 0 °C. Sodium cyanoborohydride (480 mg, 7.5 mmol) was carefully added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature overnight under N2. The reaction was quenched by the addition of water (30 mL). The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude residue. The crude residue was purified by normal phase chromatography, eluting with 7:3 Pet ether:EtOAc to give the title compound (1.7 g, 89% yield). MS m / z 454.9 (M+H).

[0219] The following compounds in Table 11 were prepared in a manner essentially similar to the procedure described in Preparation 89.

[0220]

Table 11

[0221] Preparation 91 Methyl 3-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-2-fluoro-6-methylbenzoate

[0222]

Chemical formula

[0223] To a solution of methyl 3-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2-fluoro-6-methylbenzoate (1.7 g, 3.3 mmol) in methanol (5 mL) was added sodium cyanoborohydride (420 mg, 6.5 mmol) and acetic acid (0.5 mL, 9 mmol). Then, formaldehyde in water (730 μL, 9.8 mmol, 37 wt%) was added at 25 °C. The mixture was stirred overnight at room temperature under N2. The crude mixture was purified by normal-phase chromatography, eluting with 4:1 Pet ether:EtOAc to give the title compound (1.3 g, 92% yield). MS m / z 403.0 (M+H).

[0224]

Chem.

[0225] Preparation 92 tert-Butyl (3-(((2-fluoro-3-(hydroxymethyl)-4-methylphenyl)(methyl)amino)methyl)phenyl)carbamate

[0226]

Chem.

[0227] To a solution of methyl 3-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-2-fluoro-6-methylbenzoate (1.2 g, 2.8 mmol) in DCM (10 mL) was added DIBAL-H in toluene (7 mL, 7.0 mmol, 1.0 mol / L) at 0 °C. The reaction mixture was warmed to room temperature over 3 h. The solution was cooled back to 0 °C, satd aq Rochelle salt and DCM were added, followed by extraction with DCM. The organic layer was washed with brine, dried over Na2SO4, passed through a silica gel plug and concentrated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 1:1 Pet ether:EtOAc to give the title compound (640 mg, 57% yield). MS m / z 375.0 (M+H).

[0228] The following compounds in Table 12 were prepared in a manner essentially similar to the procedure described in Preparation 92.

[0229] [Table 12] *1 H NMR (400.14 MHz, DMSO): δ 9.23 (s, 1H), 7.35 - 7.31 (m, 2H), 7.09 - 7.02 (m, 3H), 6.89 (d, J = 7.8 Hz, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.49 - 4.48 (m, 2H), 4.03 (q, J = 7.1 Hz, 1H), 2.79 - 2.72 (m, 4H), 2.33 (s, 3H), 1.46 (s, 9H).

[0230] [Chemical formula]

[0231] Preparation 99 tert - butyl (3 - (((2 - fluoro - 3 - formyl - 4 - methylphenyl)(methyl)amino)methyl)phenyl)carbamate

[0232] [Chemical formula]

[0233] To a solution of tert - butyl (3 - (((2 - fluoro - 3 - (hydroxymethyl)-4 - methylphenyl)(methyl)amino)methyl)phenyl)carbamate (590 mg, 1.5 mmol) in EtOAc (5 mL) was added 2 - iodoxybenzoic acid (630 mg, 2.2 mmol). The reaction mixture was stirred at 80 °C for 6 hours. The solid was removed by filtration and the filtrate was concentrated to give a crude residue. The residue was purified by normal - phase chromatography, eluting with 7:3 Pet ether:EtOAc to give the title compound (580 mg, 94% yield). MS m / z 373.0 (M + H).

[0234] The following compounds in Table 13 were prepared in a manner essentially similar to the procedure described in Preparation 99.

[0235] [Table 13] *1 H NMR (400.15 MHz, DMSO): δ 10.331 (d, J = 0.8 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.78 (dd, J = 0.8, 8.4 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H) **1 H NMR (400.15 MHz, DMSO): δ 10.42 (s, 1H), 9.23 (s, 1H), 7.44 - 7.40 (m, 1H), 7.36 - 7.33 (m, 2H), 7.09 - 7.05 (m, 3H), 2.92 - 2.81 (m, 4H), 2.50 (s, 3H), 1.47 (s, 9H).

[0236] Preparation 105 tert-Butyl (4-(2-(2-fluoro-3-formyl-4-methylphenoxy)ethyl)phenyl)carbamate

[0237] [Chemical formula]

[0238] A solution of 2-fluoro-3-hydroxy-6-methylbenzaldehyde (250 mg, 1.5 mmol) and 4-((tert-butoxycarbonyl)amino)phenethyl 4-methylbenzenesulfonate (760 mg, 1.9 mmol) in acetonitrile (10 mL) was added with potassium carbonate (670 mg, 4.9 mmol). The suspension was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (40 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by normal-phase chromatography, eluting with Pet ether:EtOAc of 17:3 to give the title compound (510 mg, 85% yield). 1 1H NMR (400.15 MHz, CDCl3): δ 10.47 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.96 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.37 - 6.35 (m, 1H), 4.12 (t, J = 7.0 Hz, 2H), 3.01 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 1.45 (s, 8H).

[0239] Preparation 106 (6-Bromo-3-(bromomethyl)-2-fluorophenyl)methanol

[0240]

Chemical Structure

[0241] A solution of 6-bromo-3-(bromomethyl)-2-fluorobenzoic acid (4.9 g, 11 mmol) in THF (100 mL) under a nitrogen atmosphere cooled in an ice bath was added dropwise with borane-THF complex (35 mL, 35 mmol, 1 mol / L) in THF. The reaction mixture was warmed to room temperature overnight. The reaction was quenched by the addition of MeOH (100 mL) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (100 mL) and 1 M HCl (30 mL), and the aqueous layer was extracted once with EtOAc (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 7:3 Pet ether:EtOAc to give the title compound (2.9 g, 62% yield). 1 1H NMR (400.15 MHz, DMSO): δ 7.50~7.42 (m, 2H), 5.38~5.23 (m, 1H), 4.70 (d, J = 0.5 Hz, 2H), 4.59 (d, J = 1.5 Hz, 2H).

[0242]

Chemical formula

[0243] Preparation 107 tert-Butyl (3-((4-bromo-2-fluoro-3-formylbenzyl)thio)phenyl)carbamate

[0244]

Chemical formula

[0245] To a mixture of 6-bromo-3-(bromomethyl)-2-fluorobenzaldehyde (620 mg, 1.9 mmol) and tert-butyl N-(3-sulfanylphenyl)carbamate (500 mg, 2.0 mmol) in DCM (10 mL) was added triethylamine (530 μL, 3.8 mmol) under N2. The mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (30 mL) and water (30 mL). The combined organic extracts were concentrated in vacuo to afford a crude residue. The residue was purified by flash chromatography eluting with 3:1 Pet ether:EtOAc to give the title compound (780 mg, 89% yield). 1 1H NMR (400.15 MHz, DMSO): δ 10.19 (s, 1H), 9.39 (s, 1H), 7.57 - 7.51 (m, 2H), 7.47 (s, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 4.21 (s, 2H), 1.46 (s, 9H).

[0246] The following compounds in Table 14 were prepared in a manner essentially similar to the procedure described in Preparation 107.

[0247]

Table 14

[0248] Preparation 109 Methyl 6-bromo-3-(((2-((tert-butoxycarbonyl)amino)phenyl)thio)methyl)-2-fluorobenzoate

[0249]

Chem.

[0250] To a solution of methyl 3-(((2-aminophenyl)thio)methyl)-6-bromo-2-fluorobenzoate (1.3 g, 3.4 mmol) in tert-butanol (13 mL, 140 mmol) was added di-tert-butyl dicarbonate (3.5 mL, 15 mmol). The mixture was stirred at 50 °C overnight under N2. The reaction was concentrated in vacuo to give a crude residue. The residue was purified by flash chromatography eluting with 10:1 Pet ether:EtOAc to give the title compound (1.6 g, quantitative yield). MS m / z 371.8 (M - Boc + H).

[0251] Preparation 110 (3-Bromo-2-fluoro-4-methylphenyl)methanol

[0252]

Chem.

[0253] To a solution of 3-bromo-2-fluoro-4-methylbenzaldehyde (2 g, 6.6 mmol) in MeOH was added sodium borohydride (620 mg, 16 mmol) at 0 °C. The mixture was stirred for 1 h. The mixture was slowly quenched with 1 M aq HCl (30 mL) under N2 to pH 6. The reaction mixture was concentrated in vacuo to give a crude residue. The residue was purified by flash chromatography eluting with 1:2 Pet ether:EtOAc to give the title compound (820 mg, 51% yield).

[0254] Preparation 111 tert-Butyl (3-((3-bromo-2-fluoro-4-methylbenzyl)oxy)phenyl)carbamate

[0255]

Chem.

[0256] A solution of (3-bromo-2-fluoro-4-methylphenyl)methanol (650 mg, 2.7 mmol), tert-butyl (3-hydroxyphenyl)carbamate (870 mg, 4.0 mmol), and tetrabutylphosphine (1.1 g, 5.4 mmol) in THF (10 mL, 120 mmol) was treated with N,N,N’,N’-tetramethylazodicarboxamide (940 mg, 5.4 mmol). The reaction mixture was stirred under anhydrous N2 at room temperature for 2 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a crude residue. The residue was purified by flash chromatography eluting with 9:1 Pet ether:EtOAc to afford the title compound (1.2 g, 96% yield). MS m / z 355.8 (M-tBu+H).

[0257] Preparation 112 tert-Butyl (3-((2-fluoro-3-formyl-4-methylbenzyl)oxy)phenyl)carbamate

[0258] [Chemical formula]

[0259] A solution of tert-butyl (3-((3-bromo-2-fluoro-4-methylbenzyl)oxy)phenyl)carbamate (0.82 g, 1.8 mmol) in THF (5 mL, 62 mmol) was added with a solution of isopropylmagnesium chloride lithium chloride complex in THF (3.1 mL, 4.0 mmol, 1.3 mol / L) at 0 °C and stirred for 30 minutes. DMF (450 μL, 5.7 mmol) was added to the mixture at 0 °C. The mixture was warmed to room temperature for 1.5 hours and then quenched by the addition of satd aq NH4Cl (5 mL). The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The combined organic extracts were concentrated in vacuo to afford the crude product. The residue was purified by normal-phase chromatography, eluting with 95:5 Pet ether:EtOAc to give the title compound (220 mg, 25% yield). MS m / z 259.9 (M-Boc+H).

[0260] Preparation 113 tert-Butyl (2-((4-bromo-2-fluoro-3-formylbenzyl)oxy)phenyl)carbamate

[0261] [Chemical formula]

[0262] Cesium carbonate (230 mg, 0.71 mmol) was added to a solution of tert-butyl (2-hydroxyphenyl)carbamate (100 mg, 0.47 mmol) and 6-bromo-3-(bromomethyl)-2-fluoro-benzaldehyde (160 mg, 0.51 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 1 hour under N2 and then quenched by the addition of water. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The combined organic extracts were concentrated in vacuo to afford the crude product. The residue was purified by normal-phase chromatography, eluting with 4:1 Pet ether:EtOAc to give the title compound (210 mg, quantitative yield). 11H NMR (400.21 MHz, DMSO): δ 10.24 (s, 1H), 8.08 (s, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 1.0, 8.1 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.95 - 6.91 (m, 1H), 5.21 (s, 2H), 1.44 (s, 9H).

[0263] [Chemical]

[0264] Preparation 114 tert-Butyl (2-(((2-fluoro-3-formyl-4-methylphenyl)thio)methyl)phenyl)carbamate

[0265] [Chemical]

[0266] To a solution of S-(2-((tert-butoxycarbonyl)amino)benzyl)ethanethioate (670 mg, 2.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added 3-bromo-2-fluoro-6-methyl-benzaldehyde (550 mg, 1.8 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (220 mg, 0.44 mmol), potassium carbonate (610 mg, 4.4 mmol), and tris(dibenzylideneacetone)dipalladium(0) (210 mg, 0.22 mmol). The mixture was heated at 100 °C overnight. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by normal-phase chromatography, eluting with 95:5 Pet ether:EtOAc to give the title compound (670 mg, 54% yield). MS m / z 275.9 (M - Boc + H).

[0267] The following compounds in Table 15 were prepared in a manner essentially similar to the procedure described in Preparation 114.

[0268]

Table 15

[0269]

Chem.

[0270] Preparation 117 tert-Butyl (2-(((2-fluoro-3-formyl-4-methylphenyl)amino)methyl)phenyl)carbamate

[0271]

Chem.

[0272] Manganese dioxide (2.2 g, 25 mmol) was added to a solution of tert-butyl (2-(((2-fluoro-3-(hydroxymethyl)-4-methylphenyl)amino)methyl)phenyl)carbamate (950 mg, 2.4 mmol) in THF (20 mL) at room temperature. The resulting mixture was stirred at 70 °C overnight. Further manganese dioxide (2.2 g, 25 mmol) was added to the incomplete reaction and stirring was continued at 70 °C for 4 hours. After completion, the reaction mixture was filtered through a pad of diatomaceous earth, washed with MeOH:DCM (1:1), and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by normal phase chromatography, eluting with 9:1 Pet ether:EtOAc to give the title compound (220 mg, 20% yield). MS m / z 359.0 (M+H).

[0273] The following compounds in Table 16 were prepared in a manner essentially similar to the procedure described in Preparation 117.

[0274]

Table 16

[0275] Preparation 119 S-(3-((tert-Butoxycarbonyl)amino)benzyl)ethanethioate

[0276] [Chem.]

[0277] tert-Butyl (3-(bromomethyl)phenyl)carbamate (2.0 g, 6.7 mmol) and potassium thioacetate (1.6 g, 14 mmol) were dissolved in DMF (9 mL, 120 mmol) and stirred at room temperature under N2 for 2 hours. The reaction was quenched by the addition of satd aq NH4Cl (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The residue was purified by normal-phase chromatography, eluting with 17:3 Pet ether:EtOAc to give the title compound (1.8 g, 89% yield). MS m / z 225.9 (M-tBu+H).

[0278] Preparation 120 Methyl (E)-6-bromo-2-fluoro-3-(4-nitrostyryl)benzoate

[0279] [Chem.]

[0280] To a solution of diethyl(4-nitrobenzyl)phosphonate(1.7 g, 6.1 mmol) and 15-crown-5(1.3 g, 5.7 mmol) in DMF(30 mL) was added sodium hydride(340 mg, 8.5 mmol, 60 mass%) in oil. After stirring at 0 °C for 30 minutes, methyl 6-bromo-2-fluoro-3-formylbenzoate(1.5 g, 5.7 mmol) was added under N2. After 1.5 hours, the reaction was quenched by the addition of satd aq NH4Cl(40 mL) to precipitate a yellow solid. The solid was collected by suction filtration, washed with water and dried under vacuum to give the title compound(2.2 g, 89% yield). MS m / z 379.9, 381.9(M+H).

[0281] Preparation 121 Methyl 3-(4-((tert-butoxycarbonyl)amino)phenethyl)-2-fluoro-6-methylbenzoate

[0282] [Chemical formula]

[0283] To a solution of methyl (E)-2-fluoro-6-methyl-3-(4-nitrostyryl)benzoate(710 mg, 2.2 mmol) in MeOH(15 mL) were added palladium(650 mg, 0.31 mmol) and di-tert-butyl dicarbonate(0.57 mL, 2.5 mmol). The mixture was stirred at room temperature for 2 hours under H2(15 psi). The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give a crude product. The residue was purified by normal phase chromatography, eluting with 3:2 Pet ether:EtOAc to give the title compound(620 mg, 69% yield). 1 H NMR(400.21 MHz, DMSO):δ9.24(s, 1H), 7.34(d, J = 8.3 Hz, 2H), 7.26(t, J = 7.9 Hz, 1H), 7.05(dd, J = 8.2, 14.8 Hz, 3H), 3.87(s, 3H), 2.86~2.68(m, 4H), 2.26(s, 3H), 1.47(s, 10H).

[0284] Preparation 122 tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate

[0285]

Chemical Structure

[0286] A solution of tert-butyl (3-((4-bromo-2-fluoro-3-formylphenoxy)methyl)phenyl)carbamate (1.0 g, 2.5 mmol), ethylene glycol (0.55 mL, 9.8 mmol), and p-toluenesulfonic acid monohydrate (47 mg, 0.25 mmol) in toluene (16 mL, 150 mmol) was refluxed at 135 °C for 1 h using an attached Dean-Stark trap. The reaction solution was cooled to room temperature and diluted with water (15 mL) and EtOAc (25 mL). The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 24:1 DCM:MeOH to give the title compound (1.2 g, 44% yield). MS m / z 486.8 (M+NH4).

[0287] Alternative Preparation 122 tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate With an attached Dean-Stark trap, a solution of 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.04 g, 4.75 mmol), ethylene glycol (1.1 mL, 20 mmol), and p-toluenesulfonic acid monohydrate (88 mg, 0.46 mmol) in toluene (32 mL) was refluxed at 135 °C for 1 h. The reaction solution was cooled to room temperature and washed with water (15 mL). The phases were separated. The organic layer was dried over Na2SO4, filtered, and evaporated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 20:1 DCM:MeOH, to give 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluoro-phenol (1.06 g, 4.03 mmol). This material was dissolved in DMF (8.0 mL) and potassium carbonate (1.40 g, 10.1 mmol) was added. The mixture was stirred at room temperature for 5 min. Then tert-butyl 3-(bromomethyl)phenylcarbamate (1.21 g, 4.23 mmol) was added and the mixture was stirred for 75 min. The mixture was then diluted with water (40 mL) and extracted with EtOAc (40 mL). The phases were separated. The organic layer was dried over Na2SO4, filtered, and evaporated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 3:1 EtOAc:hexane, to give tert-butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (1.72 g, 3.66 mmol, 77% yield). MS m / z 485.0, 487.2 (M+NH4).

[0288]

Chemical formula

[0289] Preparation 123 tert-butyl (3-((2-fluoro-3-formyl-4-vinylphenoxy)methyl)phenyl)carbamate

[0290]

Chemical formula

[0291] tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (400 mg, 0.85 mmol), potassium vinyltrifluoroborate (0.14 g, 1.0 mmol), and cesium carbonate (0.84 g, 2.6 mmol) were placed in a 25 mL microwave vial purged with N2. THF (9 mL) and water (1 mL, 56 mmol) were added. The mixture was degassed by bubbling N2 under the surface for 5 minutes, palladium(II) acetate (10 mg, 0.04 mmol) was added, and the reaction was heated overnight to 100 °C. The reaction was cooled to room temperature over 3 days. EtOAc and water were added, the phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 3:2 hexane:EtOAc to give the title compound (320 mg, 16% yield). MS m / z 369.6 (M-H).

[0292] The following compounds in Table 17 were prepared in a manner essentially similar to the procedure described in Preparation 123.

[0293]

Table 17

[0294] Preparation 125 tert-Butyl N-[3-[[3-(1,3-dioxolan-2-yl)-2-fluoro-4-isopropyl-phenoxy]methyl]phenyl]carbamate

[0295]

Chem.

[0296] 5 wt% platinum sulfide (0.057 g, 0.29 mmol) on carbon was added to a 70 mL Parr shaker bottle and degassed with N2. 5 mL of EtOAc, followed by tert-butyl (3-((3-(1,3-dioxolan-2-yl)-2-fluoro-4-(prop-1-en-2-yl)phenoxy)methyl)phenyl)carbamate (0.231 g, 0.538 mmol) in 6 mL of EtOAc, was added to the bottle. The bottle was sealed, purged with N2, purged with H2, and pressurized with 60 psi of H2 at room temperature for 5 h. The reaction mixture was filtered and concentrated to give the title compound (255 mg, quantitative yield). MS m / z 430.4 (M-H).

[0297] Preparation 126 tert-butyl (3-((4-cyano-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate

[0298] [Chemical Structure]

[0299] In a microwave vial, a mixture of tert-butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (240 mg, 0.50 mmol), zinc cyanide (130 mg, 1.1 mmol), and zinc chloride in THF (1.0 mL, 0.50 mmol, 0.500 mol / L) in DMF (2.5 mL, 32 mmol) was aerated with N2. Tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.03 mmol) was added. The reaction mixture was aerated with N2, capped, and microwave-treated at 110 °C for 1 hour. Further zinc cyanide (120 mg, 1.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol) were added. The reaction mixture was aerated with N2, capped, and microwave-treated at 120 °C for 30 minutes. The reaction solution was washed with water (15 mL). The organic layer was dried over Na2SO4, filtered through paper, and rotary evaporated to give a crude residue. The residue was purified by normal-phase chromatography, eluting with 7:3 hexane:EtOAc to give the title compound (90 mg, 43% yield). MS m / z 412.6 (M-H).

[0300]

Chem.

[0301] In Scheme 17, the compound of Structure 1 (wherein R is H) reacts with the compound of Structure 2 (wherein Pg is a suitable nitrogen protecting group, such as tert-butyloxycarbonyl, and G is as follows) under conditions well known to those skilled in the art to provide the compound of Formula I (wherein R is hydrogen).

[0302]

Chem.

[0303] More specifically, as shown in Scheme 17A below, a compound of Structure 1a (wherein R is H) is reacted with a compound of Structure 2 (wherein Pg and G are defined as above) under conditions well known to those skilled in the art to provide compounds of Formula Ib and Formula Ic.

[0304]

Chemical formula

[0305] For example, about 1 equivalent of a compound of Structure 1a (wherein R is H) and about 1 equivalent of a compound of Structure 2 (wherein Pg and G are as defined in Scheme 17) are suspended in a suitable organic solvent, such as acetonitrile. The suspension is cooled to about -10 °C to about -25 °C and then treated with about 5 equivalents of a suitable acid, such as perchloric acid (70% in water) or trifluoroacetic acid. The reaction mixture is then warmed to room temperature and stirred for about 1 to 8 hours. Additional organic solvents, such as acetonitrile and dimethylformamide, may be added and the mixture stirred for an additional about 2 hours. The reaction is then quenched using standard conditions, such as with an aqueous solution of saturated sodium bicarbonate, and the product is isolated using standard techniques well known in the art, such as extraction with a suitable organic solvent, such as methylene chloride:isopropanol. The organic extract is dried over magnesium sulfate, filtered, and concentrated under vacuum to obtain a crude product mixture. This crude mixture may be purified and the products of Formula Ib and Formula Ic may be separated using techniques well known in the art, such as chromatography, which includes, for example, normal phase chromatography with a suitable eluent, such as MeOH in DCM, and reverse phase chromatography with a suitable eluent, such as 2:1 10 mM ammonium bicarbonate in water + 5% methanol:acetonitrile.

[0306] Example 1 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-Aminobenzyl)oxy)-2-fluoro-6-methylphenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0307]

Chem.

[0308] Perchloric acid (70% in water, 4.8 mL) 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]phenanthren-3-one (4.4 g, 12 mmol, also known as “16α-hydroxy prednisolone”) and tert-butyl N-[3-[(2-fluoro-3-formyl-4-methyl-phenoxy)methyl]phenyl]carbamate (4.0 g, 11 mmol, Preparation 4) in acetonitrile (110 mL) at -10 °C and the mixture was warmed to room temperature. After 1 hour, DMF (10 mL) was added to the suspension at room temperature. After 18 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with 9:1 methylene chloride:isopropanol. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography eluting with 1:1 10 mM ammonium bicarbonate + 5% methanol:acetonitrile to give the title compound, Peak 1 (1.72 g, 25% yield). ES / MS m / z 618.6 (M+H). 11H NMR (400.13 MHz, d6-DMSO) δ 0.93~0.87 (m, 6H), 1.40 (s, 3H), 1.71~1.60 (m, 1H), 1.89~1.76 (m, 4H), 2.18~2.12 (m, 2H), 2.29 (s, 4H), 4.23~4.17 (m, 1H), 4.32~4.30 (m, 1H), 4.50~4.43 (m, 1H), 4.81 (d, J = 3.2 Hz, 1H), 4.98~4.95 (m, 3H), 5.16~5.10 (m, 3H), 5.61 (s, 1H), 5.95 (s, 1H), 6.18~6.15 (m, 1H), 6.53~6.48 (m, 2H), 6.58 (s, 1H), 6.90~6.86 (m, 1H), 6.99 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 8.5 Hz, 1H), 7.33~7.30 (m, 1H).

[0309] Example 2 (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-Aminobenzyl)oxy)-2-fluoro-6-methylphenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0310]

Chem.

[0311] From Example 1, the residue was purified by reverse-phase chromatography and eluted with 1:1 10 mM ammonium bicarbonate aqueous solution + 5% methanol:acetonitrile to obtain the title compound peak 2 (1.24 g, 18% yield). ES / MS m / z 618.6 (M+H). 1 1H NMR (400.13 MHz, d6-DMSO) δ 11H NMR (400.13 MHz, DMSO): 0.88 (s, 3H), 1.24 - 1.12 (m, 2H), 1.40 (s, 3H), 1.69 - 1.56 (m, 1H), 1.91 - 1.76 (m, 4H), 2.08 - 2.01 (m, 2H), 2.22 (s, 3H), 2.39 - 2.29 (m, 1H), 3.18 (d, J = 5.2 Hz, 1H), 4.12 - 4.00 (m, 1H), 4.37 - 4.30 (m, 2H), 4.79 (d, J = 3.1 Hz, 1H), 5.00 - 4.93 (m, 2H), 5.10 - 5.06 (m, 3H), 5.31 (d, J = 6.7 Hz, 1H), 5.95 (s, 1H), 6.18 (dd, J = 1.8, 10.1 Hz, 1H), 6.34 (s, 1H), 6.53 - 6.48 (m, 2H), 6.58 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 7.09 (t, J = 8.5 Hz, 1H), 7.33 (d, J = 10.1 Hz, 1H).

[0312] Example 3 (6aR, 6bS, 7S, 8aS, 8bS, 10S, 11aR, 12aS, 12bS)-10-(3-((3-aminobenzyl)oxy)-2-fluoro-6-methylphenyl)-7-hydroxy-6a,8a-dimethyl-8b-(2-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)acetyl)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0313]

Chemical Structure

[0314] (2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(2-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-Aminobenzyl)oxy)-2-fluoro-6-methylphenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (40 mg, 0.04 mmol, Preparation 5) was added to methanol (2 mL) and potassium carbonate (20 mg, 0.20 mmol). After 1 hour, the mixture was loaded onto diatomaceous earth and purified by reverse-phase chromatography, eluting with 1:2 10 mM ammonium bicarbonate aqueous solution + 5% methanol:acetonitrile to give the title compound (19 mg, 57% yield). ES / MS m / z 780.4 (M+H). 1 H NMR (500.11 MHz, d6-DMSO) δ 0.90 (s, 3H), 1.28~1.27 (m, 2H), 1.41 (s, 3H), 1.72~1.69 (m, 1H), 1.92~1.88 (m, 4H), 2.11~2.10 (m, 2H), 2.22 (s, 3H), 2.40~2.35 (m, 1H), 3.50~3.46 (m, 1H), 3.57~3.53 (m, 1H), 3.64~3.61 (m, 1H), 4.17~4.15 (m, 1H), 4.34~4.32 (m, 1H), 4.43~4.39 (m, 2H), 4.57~4.52 (m, 1H), 4.64~4.62 (m, 1H), 4.75~4.72 (m, 2H), 5.00~4.93 (m, 3H), 5.12~5.08 (m, 2H), 5.31~5.29 (m, 1H), 5.95 (d, J = 0.4 Hz, 1H), 6.20~6.17 (m, 1H), 6.34 (s, 1H), 6.54~6.49 (m, 2H), 6.59 (s, 1H), 6.88 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 7.12~7.08 (m, 1H), 7.35~7.33 (m, 1H).

[0315] Example 4 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(3-((3-Aminobenzyl)oxy)-2-fluoro-6-methoxyphenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0316]

Chem.

[0317] To a suspension of tert-butyl (3-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl)carbamate (2.6 g, 6.9 mmol, Preparation 8) and 16α-hydroxy prednisolone (2.5 g, 6.6 mmol) in acetonitrile (100 mL) at -20 °C was added dropwise perchloric acid (70% in water, 3.3 mL, 5 eq). The mixture was stirred at -20 °C for 7 h. The solution was transferred to a separatory funnel. The solution was added dropwise to an aqueous solution of sodium hydroxide (7.5 mL of 5N aq NaOH in 1 L of water). After the addition was complete, the pH was measured to be 5 and adjusted to 8 with 5N aq NaOH. The suspension was stirred for 10 min. The solid was collected by vacuum filtration, washed with water, and dried on the filter overnight. The solid was purified by reverse-phase chromatography and eluted with 1:1 10 mM ammonium bicarbonate in water + 5% methanol:acetonitrile to give the title compound, Peak 1 (804 mg, 18% yield). MS m / z 634.2 (M+H).

[0318] 11H NMR (399.8 MHz, d6-DMSO) δ 7.33 (d, J = 10.1 Hz, 1H), 7.17 (t, J = 9.2 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.76 (dd, J = 1.0, 9.2 Hz, 1H), 6.56 (d, J = 1.6 Hz, 1H), 6.52 - 6.48 (m, 2H), 6.17 (dd, J = 1.9, 10.1 Hz, 1H), 5.96 (s, 1H), 5.71 (s, 1H), 5.17 (t, J = 6.0 Hz, 1H), 5.10 (s, 2H), 4.94 - 4.90 (m, 3H), 4.79 (d, J = 3.1 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.33 - 4.31 (m, 1H), 4.22 - 4.15 (m, 1H), 3.70 (s, 3H), 2.37 - 2.33 (m, 1H), 2.14 - 2.04 (m, 2H), 1.96 - 1.88 (m, 1H), 1.82 - 1.70 (m, 3H), 1.64 - 1.56 (m, 1H), 1.41 (s, 3H), 0.86 (s, 5H).

[0319] Example 5 (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-Aminobenzyl)oxy)-2-fluoro-6-methoxyphenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one

[0320]

Chemical Structure

[0321] From Example 4, the residue was purified by reverse-phase chromatography and eluted with 1:1 10 mM ammonium bicarbonate aqueous solution + 5% methanol:acetonitrile to obtain the title compound peak 2 (1.19 g, 27% yield). MS m / z 634.2 (M+H).

[0322] 11H NMR (399.8 MHz, d6-DMSO) δ 7.32 (d, J = 10.0 Hz, 1H), 7.17~7.12 (m, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 6.53~6.46 (m, 3H), 6.18 (dd, J = 1.7, 10.1 Hz, 1H), 5.95 (s, 1H), 5.25 (d, J = 6.5 Hz, 1H), 5.10 (s, 2H), 5.00~4.90 (m, 3H), 4.78 (d, J = 3.1 Hz, 1H), 4.37~4.31 (m, 2H), 4.02~3.96 (m, 1H), 3.63 (s, 3H), 2.34~2.31 (m, 1H), 2.11~2.02 (m, 2H), 1.88~1.76 (m, 4H), 1.60~1.54 (m, 1H), 1.40 (s, 3H), 1.23~1.18 (m, 2H), 0.87 (s, 3H).

[0323] Alternative preparation of Example 5 All solid processing steps, including the filling of 16 alpha-hydroxy prednisolone into the flask, the solid filtration step, and the step of transferring the solid, were processed in a disposable glove bag.

[0324] A suspension of tert-butyl (3-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl)carbamate (25 g, 67 mmol, Preparation 8) and 16α-hydroxy prednisolone (25 g, 65 mmol) in ACN (1000 mL) at -25 °C in a 2 L round-bottom flask was added dropwise with perchloric acid (31 mL, 330 mmol, 10.6 mol / L) in water. The mixture was stirred at -20 °C while monitoring the reaction by LCMS. Monitoring of the internal temperature showed a slight exotherm upon addition of perchloric acid. The internal temperature was maintained below -19 °C by adding dry ice. The mixture was held below -19 °C for 2 hours and then warmed to -10 °C. The mixture was divided into two and added dropwise to two separate beakers (Beaker 1 and Beaker 2) each containing 76 mL of 5 M aq NaOH in 2 L of water. The solids formed upon addition of perchloric acid and complete quenching were tested (pH 10). The sticky solids from each addition were transferred to and combined in a third beaker (Beaker 3) containing 10% MeOH in DCM. The mixture was stirred until the sticky solids were completely dissolved. The remaining solutions (Beaker 1 and Beaker 2) were then filtered through paper to collect the residue solids. The isolated solids were rinsed with water and transferred to Beaker 3. Beaker 3 was stirred until all solids were dissolved. The solution was dried with Na2SO4 for 2 hours, filtered, and evaporated to give a yellow-brown foam. The filtrate from the solid collection was extracted three times with 10% IPA in DCM. The combined organic extracts were dried with Na2SO4 while stirring overnight and then filtered and evaporated to give a further crude residue. The crude product was dissolved in 150 mL of 1% MeOH in DCM and purified by normal-phase chromatography using 0 - 5% MeOH in DCM to give a solid. The solid was diluted with 600 mL of EtOH and rotated in a rotary evaporator at 45 °C for 5 minutes. The heat bath was raised to 60 °C. When the heat bath reached 60 °C, the heat bath was stopped and the flask was rotated until the bath reached room temperature. The flask was removed from the rotary evaporator, capped, and left at room temperature overnight.

[0325] The solid was collected in a glove bag by vacuum filtration. The solid was rinsed with EtOH and dried on the filter for 5 hours. The solid was redissolved in 20% EtOH in DCM (1.5 L). Further DCM was added to obtain a nearly clear solution (some turbidity persisted). Solvent exchange was achieved by rotary evaporation at 450 mbar and 45 °C to remove DCM. When the distillation stopped, the pressure was reduced to 100 mbar to bring the EtOH to approximately 600 mL. The mixture was removed from the rotary evaporator and left at room temperature for 5 hours. The solid was collected by vacuum filtration and the solid was washed twice with additional EtOH. The filter cake was dried in a vacuum oven at room temperature for 48 hours to obtain the title compound (42 g, 38% yield). MS m / z 634.6 (M+H).

[0326] Structure assignment by NMR

[0327]

Chemical formula

[0328] 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, H22 in the S configuration consistently gave a shift greater than about 1 ppm. All other compounds were essentially assigned by the same method.

[0329] The following compounds in Table 18a were prepared in an essentially similar manner to the procedures described in Examples 1 - 4 using the corresponding starting materials of Structure 1a and the corresponding starting materials of Structure 2, as prepared in the corresponding preparations above and in Tables 2 - 17, or as prepared using standard procedures well known to those skilled in the art. Purification of the final product was essentially carried out by the following methods. A. C18 column using an eluent of 10 mM NH4HCO3 + 5% MeOH:ACN in water B. C18 column using an eluent of 0.1% FA:ACN in water C. SFC Chiralpak AY using EtOH + 0.05% DEA as the CO2 eluent D. Chiralpak IC using MeOH + 0.2% IPAm as the eluent E. SFC Lux Amylose - 2 using IPA + 0.5% DMEA as the CO2 eluent F. SFC Chiralpak AD - H using IPA + 0.5% DMEA as the CO2 eluent G. Chiralpak IC heptane using EtOH + 0.1% NH3H2O as the heptane eluent H. SFC Chiralpack AD using IPA + 0.1% NH3H2O as the CO2 eluent I. Chiralcel IH heptane using EtOH + ACN (0.1% DEA) as the heptane eluent J. SFC Chiralpack AD using EtOH + 0.5% DEA as the CO2 eluent K. Chiralpak IE using EtOH + 0.1% NH3H2O as the ACN eluent L. Chiralpak AD - H using EtOH:ACN + 0.2% IPAm as the eluent M. Chiralpak AD - H using EtOH:ACN as the eluent N. SFC Chiralpak IC using EtOH + 0.05% DMEA as the CO2 eluent O. SFC Chiralcel OJ - H using MeOH + 0.5% DMEA as the CO2 eluent

[0330]

Table 18 - 1

[0331]

Table 18 - 2

[0332]

Table 18 - 3

[0333]

Table 18-4

[0334]

Table 18-5

[0335]

Table 18-6

[0336]

Table 18-7

[0337]

Table 18-8

[0338]

Table 18-9

[0339]

Table 18-10

[0340]

Table 18-11

[0341]

Table 18-12

[0342]

Table 18-13

[0343]

Table 18-14

[0344]

Table 18-15

[0345]

Table 18-16

[0346]

Table 18-17

[0347]

Table 18-18

[0348]

Table 18-19

[0349]

Table 18-20

[0350]

Table 18-21

[0351]

Table 18-22

[0352]

Table 19-1

[0353]

Table 19-2

[0354]

Table 19-3

[0355]

Table 19-4

[0356]

Table 19-5

[0357]

Table 19-6

[0358]

Table 19-7

[0359]

Table 19-8

[0360]

Table 19-9

[0361]

Table 19-10

[0362]

Table 19-11

[0363]

Table 19-12

[0364]

Table 19-13

[0365]

Table 19-14

[0366] Example 159 4-((3-Aminobenzyl)oxy)-3-fluoro-2-((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)benzonitrile

[0367]

Chemical Structure

[0368] Trifluoromethanesulfonic acid (920 μL, 10 mmol) was added dropwise to a suspension of 16α-hydroxy prednisolone (140 mg, 0.36 mmol) and tert-butyl (3-((4-cyano-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (140 mg, 0.34 mmol) in ACN (5 mL, 95 mmol) at 0 °C. The reaction was quenched with satd aq NaHCO3 and extracted with 10% IPA in DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated to give a crude residue. The crude residue was purified by reverse-phase purification and eluted with 10 mM NH4HCO3 + 5% MeOH:ACN in 1:1 water to give the title compound (12 mg, 6% yield). MS m / z 630.0 (M+H). 1 H NMR (400.13 MHz, d6-DMSO) δ 7.70~7.67 (m, 1H), 7.45~7.41 (m, 1H), 7.33 (d, J = 10.1 Hz, 1H), 7.04~7.00 (m, 1H), 6.61~6.51 (m, 3H), 6.45 (s, 1H), 6.20~6.17 (m, 1H), 5.95 (s, 1H), 5.37~5.35 (m, 1H), 5.15 (s, 4H), 4.86~4.84 (m, 1H), 4.32~4.31 (m, 2H), 4.07~4.01 (m, 1H), 2.14~2.12 (m, 2H), 1.92~1.88 (m, 4H), 1.67~1.66 (m, 1H), 1.40~1.39 (m, 3H), 1.25~1.20 (m, 2H), 0.89~0.88 (m, 3H).

[0369] hGR coactivator recruitment assay The activity of the glucocorticoid compounds was measured using the LanthaScreen TR-Fret GR Coactivator Assay (A15899) from Life Technologies. The compounds were acoustically transferred to the assay plates in a 3-fold 10-point serial dilution at a maximum concentration of 200 nM. 10 microliters of a 2-fold solution of GR-LBD was added to the compound plates and incubated for 10 minutes. Then, 10 microliters of a 2-fold solution of Fluoresein-SRC1-4 and Tb-labeled anti-GST antibody was added to the plates. The plates were incubated in the dark for 2 hours and then read on an Envision plate reader at an excitation of 340 nm and emissions at 520 nm (fluorescein) and 490 nm (terbium). The 520 / 490 emission ratio was analyzed in Genedata. To obtain the percent activity, the data was compared to a negative control of DMSO and a positive control of 4 μM dexamethasone. The following exemplary compounds were tested essentially according to the above procedure, and these compounds showed the following activities listed in Table 19.

[0370]

Table 20

[0371] The compounds of Examples 6 - 44, 46 - 51, 53 - 79, and 81 - 158 resulted in a relative IC 50 below 200 nM. The compounds of Examples 45, 52, and 80 resulted in a relative IC 50 above 200 nM.

Claims

1. The following formula: 【Chemical 1】 (wherein R is H or the following: 【Chemical 2】 and R １ is halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF ３ , 【Chemical Formula 3】 and R ２ is halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 alkenyl, X is O, OCH ２ 、OCH ２ CH ２ 、CH ２ O, SCH ２ 、CH ２ S, CH ２ 、NHCH ２ 、CH ２ NH, N(CH ３ )CH ２ 、CH ２ CH ２ 、C≡C, or a bond), or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1, wherein R is H, or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 1, wherein R is the following: [Chemical Formula 4] or a pharmaceutically acceptable salt thereof.

4. R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is C1-C3 alkyl.

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

6. R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is C1-C3 alkoxy.

7. R １ is OCH ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is OCH.

8. R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is F.

9. R ２ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is F.

10. X is OCH ２ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is OCH ２ .

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

12. X is CH ２ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is CH

13. X is CH₂S or SCH ２ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is CH₂S or SCH.

14. The compound according to any one of Claims 1 to 9, wherein X is a bond, or a pharmaceutically acceptable salt thereof.

15. The compound according to Claim 1, which has the following formula: 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof.

16. The compound according to Claim 1, which has the following formula: 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof.

17. The compound according to Claim 16, which has the following: 【Chemical Formula 7】 or a pharmaceutically acceptable salt thereof.

18. The compound according to Claim 17, which has the following formula: 【Chemical 8】

19. The compound according to Claim 1, which has the following: 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof.

20. The following: 【Chemical 10】 which is the compound according to Claim 19.

21. The compound according to Claim 15, which has the following: 【Chemical Formula 11】 or a pharmaceutically acceptable salt thereof.

22. The following: 【Chemical 12】 which is the compound according to Claim 21.

23. The compound according to Claim 1, which has the following: 【Chemical 13】 or a pharmaceutically acceptable salt thereof.

24. The following: 【Chemical Formula 14】 which is the compound according to Claim 23.

25. The compound according to Claim 1, which has the following: 【Chemical Formula 15】 or a pharmaceutically acceptable salt thereof.

26. The following: 【Chemical Formula 16】 which is the compound according to Claim 25.

27. The compound according to Claim 1, which has the following: 【Chemical 17】 or a pharmaceutically acceptable salt thereof.

28. The following: 【Chemical Formula 18】 which is the compound according to Claim 27.

29. The following: or a pharmaceutically acceptable salt thereof, which is the compound according to Claim 1.

30. The compound according to Claim 1, and a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following table: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】

31. A pharmaceutical composition for treating atopic dermatitis, which comprises administering an effective amount of the compound according to any one of Claims 1 to 30 or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition for the treatment of rheumatoid arthritis, comprising administering an effective amount of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

33. A medicament comprising the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

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

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

36. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

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

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