Glucocorticoid receptor agonists

Abstract

The present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof: wherein R is H or R 1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3, R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-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, CºC, or a bond, wherein X is attached to the phenyl ring A in the ortho or meta position, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is useful for the treatment of autoimmune and inflammatory diseases, such as atopic dermatitis and rheumatoid arthritis.

Description

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

[0002] Atopic dermatitis is a chronic, itchy, relapsing and remitting inflammatory skin condition that commonly affects children but also many adults. Current treatments for atopic dermatitis include phototherapy, topical creams containing corticosteroids or calcineurin inhibitors, or subcutaneous injections of biologics (called dupilumab). Despite advances in the treatment of atopic dermatitis, there is a pressing need for new compounds to treat atopic dermatitis and other inflammatory and autoimmune diseases.

[0003] WO2017 / 210471 discloses certain glucocorticoid receptor agonists and their immunoconjugates for the treatment of autoimmune or inflammatory diseases. WO2018 / 0839373 discloses novel steroids, their protein conjugates, and methods for treating diseases, patients, and symptoms, said methods comprising administering the steroid and the conjugate.

[0004] This invention provides certain novel compounds that are glucocorticoid receptor agonists. This invention further provides certain novel compounds that are prodrugs for glucocorticoid receptor agonists. Furthermore, this invention provides certain novel compounds that are glucocorticoid receptor agonists and can be used to treat autoimmune and inflammatory diseases, such as atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis.

[0005] Therefore, in one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Where R is H or

[0008]

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

[0010] R 2 It is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C3 alkenyl;

[0011] R 3 It is NH2 or CH2NH2; and

[0012] X is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is attached to the phenyl ring A in the ortho or meta position.

[0013] In one embodiment, the present invention provides a compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0014]

[0015] Where R is H or

[0016]

[0017] R 1 It is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0018] R 2 It is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C4 alkenyl;

[0019] R 3 It is NH2 or CH2NH2; and

[0020] X is O, OCH2, OCH2CH2, OCH2C≡C, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is attached to the phenyl ring A at the ortho or meta position.

[0021] In one embodiment, the present invention provides a compound of formula Ib or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Where R is H or

[0024]

[0025] R 1 It is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0026]

[0027] R 2It is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C4 alkenyl;

[0028] R 3 It is NH2 or CH2NH2; and

[0029] X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is attached to the phenyl ring A in the ortho or meta position.

[0030] In one embodiment, the present invention provides a compound of formula Ic or a pharmaceutically acceptable salt thereof:

[0031]

[0032] Where R is H or

[0033]

[0034] R 1 It is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF3,

[0035]

[0036] R 2 It is H, halogen, C1-C3 alkyl, C1-C3 alkoxy or C2-C4 alkenyl;

[0037] R 3 It is NH2 or CH2NH2; and

[0038] X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is attached to the phenyl ring A in the ortho or meta position.

[0039] In one embodiment, the present invention provides a compound of formula Ib(i):

[0040]

[0041] Or its pharmaceutically acceptable salt.

[0042] In one embodiment, the present invention provides a compound of formula Ic(i):

[0043]

[0044] Or its pharmaceutically acceptable salt.

[0045] In one embodiment, the present invention provides a compound of formula Ib(ii):

[0046]

[0047] Or its pharmaceutically acceptable salt.

[0048] In one embodiment, the present invention provides a compound of formula Ic(ii):

[0049]

[0050] Or its pharmaceutically acceptable salt.

[0051] In one embodiment, the present invention provides a compound of formula Ib(iii):

[0052]

[0053] Or its pharmaceutically acceptable salt.

[0054] In one embodiment, the present invention provides a compound of formula Ic(iii):

[0055]

[0056] Or its pharmaceutically acceptable salt.

[0057] In one embodiment, the present invention provides a compound of formula II:

[0058]

[0059] Where R is H or

[0060] And R 1 It is -CH3 or -OCH3.

[0061] Or its pharmaceutically acceptable salt.

[0062] In one specific embodiment, the present invention provides a compound of formula IIa:

[0063]

[0064] Where R is H or

[0065] And R 1 It is -CH3 or -OCH3.

[0066] Or its pharmaceutically acceptable salt.

[0067] In one specific embodiment, the present invention provides a compound of formula IIb or a pharmaceutically acceptable salt thereof:

[0068]

[0069] Where R is H or

[0070] and

[0071] R 1 It is -CH3 or -OCH3.

[0072] In one specific embodiment, the present invention provides a compound of formula IIc or a pharmaceutically acceptable salt thereof:

[0073]

[0074] Where R is H or

[0075] and

[0076] R 1 It is -CH3 or -OCH3.

[0077] In one specific embodiment, the present invention provides a compound of formula III:

[0078]

[0079] Where R is H or

[0080]

[0081] Or its pharmaceutically acceptable salt.

[0082] In one specific embodiment, the present invention provides a compound of formula IIIa:

[0083]

[0084] Where R is H or

[0085]

[0086] Or its pharmaceutically acceptable salt.

[0087] In one specific embodiment, the present invention provides a compound of formula IIIb:

[0088]

[0089] Where R is H or

[0090]

[0091] Or its pharmaceutically acceptable salt.

[0092] In one specific embodiment, the present invention provides a compound of formula IIIc:

[0093]

[0094] Where R is H or

[0095]

[0096] Or its pharmaceutically acceptable salt.

[0097] In one implementation, R is H.

[0098] In one implementation scheme, R is

[0099]

[0100] In one implementation scheme, R 1 It is CH3.

[0101] In one implementation scheme, R 1 It is H.

[0102] In one implementation scheme, R 1 It is OCH3.

[0103] In one implementation scheme, R 1 It is F.

[0104] In one implementation scheme, R 2 It is H.

[0105] In one implementation scheme, R 2 It is CH3.

[0106] In one implementation scheme, R 2 It is F.

[0107] In one implementation scheme, R 2 It is OCH3.

[0108] In one implementation, X is O.

[0109] In one implementation, X is OCH2.

[0110] In one implementation, X is SCH2.

[0111] In one implementation, X is CH2.

[0112] In one implementation, X is a key.

[0113] In one implementation, R is H, R 1 It is CH3, R2 It is F, and X is OCH2.

[0114] In one implementation, R is H, R 1 It is OCH3, R 2 It is F, and X is OCH2.

[0115] In one embodiment, X is linked to the phenyl ring A at the meta position.

[0116] In one embodiment, X is attached to the phenyl ring A at the ortho position.

[0117] In one embodiment, the present invention also provides a method for treating inflammatory diseases in patients requiring the treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating atopic dermatitis in patients requiring the treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention further provides a method for treating inflammatory bowel disease in patients requiring the treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention further provides a method for treating rheumatoid arthritis in patients requiring the treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention also provides a method for treating lupus nephritis in patients requiring the treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0118] In one embodiment, the present invention further provides a Formula I compound or a pharmaceutically acceptable salt thereof for treatment. In one embodiment, the present invention provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating inflammatory diseases. In one embodiment, the present invention provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating atopic dermatitis. In one embodiment, the present invention provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis. In one embodiment, the present invention provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating inflammatory bowel disease. In one embodiment, the present invention provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating lupus nephritis. In one embodiment, the present invention provides a Formula I compound or a pharmaceutically acceptable salt thereof for treating systemic lupus erythematosus.

[0119] In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating inflammatory diseases. In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating atopic dermatitis. In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating rheumatoid arthritis. In one embodiment, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating inflammatory bowel disease. In one embodiment, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lupus nephritis. In one embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating systemic lupus erythematosus.

[0120] In one embodiment, the present invention further provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention further provides a method for preparing a pharmaceutical composition 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 includes novel intermediates and methods for synthesizing compounds of formula I.

[0121] As used in this article, the term “treatment” or “to treat” includes suppressing, delaying, stopping, or reversing existing symptoms or the progression or severity of a patient’s condition.

[0122] As used in this article, the term "patient" refers to mammals, particularly humans.

[0123] As used herein, the term "effective amount" refers to the amount or dose of the compound of the present invention or a pharmaceutically acceptable salt thereof, which, when administered to a patient in a single or multiple doses, provides the desired effect in the diagnosis or treatment of the patient.

[0124] An effective dose can be determined by a person skilled in the art using known techniques and by observing results obtained under similar conditions. In determining an effective dose for a patient, the attending physician will consider many factors, including but not limited to: the type of patient; their size, age, and overall health status; the specific disease or ailment involved; the extent, scope, or severity of the disease or ailment; the individual patient's response; the specific compound administered; the route of administration; the bioavailability characteristics of the administered formulation; the chosen dosage regimen; the use of concomitant medications; and other relevant factors.

[0125] As used herein, it should be understood that Equation I includes Equations Ia, Ib, Ic, Ib(i), Ic(i), Ib(ii), Ic(ii), Ib(iii), Ic(iii), Equations II, IIa, IIb, IIc, Equations III, IIIa, IIIb, and IIIc, and all references to Equation I herein should be understood to include Equations Ia, Ib, Ic, Ib(i), Ic(i), Ib(ii), Ic(ii), Ib(iii), Ic(iii), Equations II, IIa, IIb, IIc, Equations III, IIIa, IIIb, and IIIc.

[0126] As used herein, it should be understood that Equation II includes Equations IIa, IIb and IIc, and all references to Equation II herein should be understood to include Equations IIa, IIb and IIc.

[0127] As used herein, it should be understood that Equation III includes Equations IIIa, IIIb and IIIc, and all references to Equation III herein should be understood to include Equations IIIa, IIIb and IIIc.

[0128] As used in this article, "halogen" refers to F, Cl, Br, and I.

[0129] As used in this article, “C1-C3 alkyl” refers to CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2.

[0130] As used in this article, "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0131] As used in this article, “C1-C3 alkoxy” refers to OCH3, OCH2CH3, OCH2CH2CH3 and OCH(CH3)2.

[0132] As used in this article, “C2-C3 alkenyl” refers to HC=CH2 and C(CH3)=CH2.

[0133] As used in this paper, the ortho and meta positions on the phenyl ring A are shown in Equation I below:

[0134]

[0135] For example, compounds of formula I' illustrate X being linked to the phenyl ring A at the meta position:

[0136]

[0137] Compounds of formula I illustrate X connected to the phenyl ring A at the ortho position:

[0138]

[0139] Those skilled in the art will understand that when X is connected to the phenyl ring A at the ortho position as shown in Formula I”, then R 2 It is H.

[0140] Furthermore, the compounds of the present invention can be conjugated with antibodies using methods understood by those skilled in the art to form antibody-drug conjugates (ADCs). One example of such conjugation would involve linking the compound of the present invention to an antibody via a linker compound. Linker compounds known to those skilled in the art include, for example, cleavable linkers and non-cleavable linkers. The ADC can deliver the compounds of the present invention to specific target tissues or cells. Therefore, ADCs comprising compounds of Formula I are also provided herein. In some embodiments, the compound of Formula I is conjugated with an antibody via a linker, such as a cleavable linker or a non-cleavable linker.

[0141] The compounds or conjugates of the present invention can be formulated into pharmaceutical compositions for administration via any route that makes the compounds or conjugates bioavailable, including, for example, oral, topical, or subcutaneous administration. The pharmaceutical compositions, including ADCs, can be prepared using techniques and methods known in the art. The pharmaceutical compositions, including ADCs, can be prepared using techniques and methods known in the art (see, for example, Remington: The Science and Practice of Pharmacy, ed. A. Adejare, 23rd edition, published 2020, Elsevier Science; WO 2017 / 062271 and WO 2017 / 210471).

[0142] Furthermore, it has a capped hydroxyl group at C21, where R is... The compounds of the present invention are presented as prodrugs and are metabolized in vitro or in vivo, providing an active glucocorticoid receptor agonist wherein R is H.

[0143] Pharmaceutically acceptable salts of Formula I are included within the scope of this invention. Pharmaceutically acceptable salts of compounds of this invention, such as compounds of Formula I, can be formed under standard conditions well known in the art, in a suitable solvent such as diethyl ether, by reacting a suitable free base of the compound of this invention with a suitable pharmaceutically acceptable acid. See, for example, Berge, SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).

[0144] Some of the compounds described in the preparations below may contain a suitable nitrogen protecting group, referred to herein as "Pg". It should be understood that, as those skilled in the art will appreciate, the protecting group can vary depending on the specific reaction conditions and the specific transformation to be performed. Protecting and deprotecting 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", 4th edition, by Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc., 2007).

[0145] Table 1: Abbreviations and Definitions

[0146]

[0147]

[0148] The compounds of the present invention or their salts can be readily prepared using various methods known to those skilled in the art, some of which are illustrated in the preparations and examples below. Those skilled in the art will understand that the specific synthetic steps of each route can be combined in different ways, or combined with steps from different schemes, to prepare the compounds of the present invention or their salts. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization. Unless otherwise stated, all substituents are as defined above. Reagents and starting materials are readily available to those skilled in the art. The following preparations, examples, and assays further illustrate the invention but should not be construed as limiting the scope of the invention in any way.

[0149] Preparation 1

[0150] 6-Bromo-2-fluoro-3-methoxybenzaldehyde

[0151]

[0152] The two reactions were carried out in parallel. At -78°C, LDA (2M, 730mL) was slowly added to a THF (1500mL) solution of 250g (1.2mol) of 4-bromo-2-fluoro-1-methoxybenzene at -78°C for 30 min. After another 30 min, DMF (140mL, 1.8mol) was slowly added at -78°C for 30 min. After 1 h, the two reactions were combined, and the mixture was diluted with an aqueous citric acid solution (2000mL) and extracted with EtOAc (1500mL x 2). The combined organic layers were washed with saturated brine (1000mL) and concentrated under reduced pressure to give the residue. The residue was milled with petroleum ether (1000mL) at room temperature for 12 h to give the title compound (382g, 67% yield). ES / MS m / z 233.9 (M+H).

[0153] Preparation 2

[0154] 2-Fluoro-3-methoxy-6-methylbenzaldehyde

[0155]

[0156] The 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 reactions were combined, and the mixture was diluted with saturated NH4Cl aqueous solution (1000 mL) and extracted with MTBE (1500 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution (1000 mL) and concentrated under reduced pressure to give the residue. The residue was purified by normal-phase chromatography, eluting with a 40:1 petroleum ether:EtOAc solution to give the title compound (180 g, 59% yield). ES / MS m / z 169.3 (M+H).

[0157] Preparation 3

[0158] 2-Fluoro-3-hydroxy-6-methylbenzaldehyde

[0159]

[0160] 175 g (1.0 mol) of 2-fluoro-3-methoxy-6-methylbenzaldehyde was added to DCM (1050 mL). 2.1 mol of BBr3 (200 mL) was slowly added to the solution at 0 °C. The reaction was stirred at rt. After 1 h, the mixture was diluted to pH 7–8 with saturated sodium bicarbonate aqueous solution (1000 mL) and extracted with MTBE (1500 mL x 2). The combined organic layers were washed with saturated NaCl aqueous solution (1000 mL) and concentrated under reduced pressure to give the title compound (110 g, 68% yield). ES / MS m / z 154.9 (M+H).

[0161] Preparation 4

[0162] N-[3-[(2-fluoro-3-formyl-4-methylphenoxy)methyl]phenyl]tert-butyl carbamate

[0163]

[0164] 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 reactants were diluted with water (600 mL) and extracted with EtOAc (800 mL x 2). The combined organic layers were washed with brine (800 mL) and concentrated under reduced pressure to give the residue. The residue was purified by normal-phase chromatography, eluting with a 50:1 petroleum ether:EtOAc solution to give the crude product. The crude product was milled 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).

[0165] Preparation 5

[0166] (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-((6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(3-((3-

[0167] (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-dodecylhydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopentene-8b-

[0168] 2-Oxoethoxy)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate

[0169]

[0170] At room temperature, Molecular sieve (5 g) was added 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-dodecylhydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-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 oxide (I) (115 mg, 0.49 mmol) and trimethylsilyl trifluoromethanesulfonate (45 μL, 0.24 mmol) were added. After 30 minutes, the reaction was quenched with saturated sodium bicarbonate aqueous solution, filtered through diatomaceous earth, and washed with DCM (10 mL) and methanol (10 mL). The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase chromatography, eluting with 1:5 10 mM ammonium bicarbonate-water + 5% methanol:acetonitrile to give the title compound (43 mg, 19% yield). ES / MS m / z 948.0 (M+1).

[0171] Preparation of 6

[0172] tert-butyl(2-fluoro-4-methoxyphenoxy)diphenylsilane

[0173]

[0174] To a solution of 2-fluoro-4-methoxyphenol (25 g, 180 mmol) in DMF (350 mL, 0.5 M), imidazole (18 g, 260 mmol) and tert-butyldiphenylchlorosilane (55 mL, 200 mmol) were added. 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 a crude residue. The residue was purified by normal-phase chromatography, eluting with a 5:1 hexane:ethyl acetate solution to give the title compound (67 g, 93% yield). 1HNMR(399.8MHz,d6-DMSO)δ7.67-7.65(m,4H),7.51-7.44(m,6H),6.82(dd,J=2.9,12.7Hz ,1H),6.59(t,J=9.4Hz,1H),6.47(ddd,J=9.0,3.0,1.4Hz,1H),3.64(s,3H),1.06(s,9H).

[0175] Preparation 7

[0176] 2-Fluoro-3-hydroxy-6-methoxybenzaldehyde

[0177]

[0178] tert-Butyl(2-fluoro-4-methoxyphenoxy)diphenylsilane (56 g, 150 mmol, preparation 6) was dissolved in 50 mL of toluene and concentrated under vacuum for 18 h. 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 using a large-bore tube. After 1.5 h, DMF (25 mL, 320 mmol) was added to the solution, and the ice bath was removed. After 30 min, 5N HCl aqueous solution (35 mL) was added to the reaction mixture, followed by tetrabutylammonium fluoride (1 M THF solution, 185 mL, 185 mmol). After 2.5 h, the organic layer was evaporated, acidified with 5N HCl aqueous solution, 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 a crude residue. The residue was purified by normal-phase chromatography, eluting with a 1:1 hexane:ethyl acetate solution to give the title compound (22 g, 88% yield). MS m / z 170.8 (M+H).

[0179] Process 1

[0180]

[0181] Preparation of 8

[0182] (3-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl)tert-butyl carbamate

[0183]

[0184] 2-Fluoro-3-hydroxy-6-methoxybenzaldehyde (2.5 g, 15 mmol) and N-[3-(bromomethyl)phenyl]carbamate tert-butyl ester (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 h, the reaction was heated to 40 °C. After 3 h, the reactants were cooled, filtered, and the solvent was evaporated. The crude residue was purified by normal-phase purification, eluting with a 7:3 hexane:EtOAc solution to give the title compound (3.1 g, 57% yield). MS m / z 374.4 (MH).

[0185] The following compounds in Table 2 were prepared using methods substantially similar to those described in Preparation 8.

[0186] Table 2: Preparation of 9-50

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] Process 2

[0193]

[0194] Preparation 51

[0195] (3-((3-formyl-4-(furan-2-yl)phenoxy)methyl)phenyl)tert-butyl carbamate

[0196]

[0197] In a microwave-safe tube, tert-butyl (3-((4-bromo-3-carboxyphenoxy)methyl)phenyl)carbamate (0.73 g, 1.8 mmol), 2-furanboronic 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 purged with nitrogen and capped. The reaction mixture was microwave-heated at 140°C for 45 min. The reaction mixture was cooled, poured into 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 (MH).

[0198] The following compounds in Table 3 were prepared using a method substantially similar to that described in Preparation 51.

[0199] Table 3: Preparation of 52-55

[0200]

[0201]

[0202] Process 3

[0203]

[0204] Preparation of 56

[0205] (3'-formyl-[1,1'-biphenyl]-3-yl)tert-butyl carbamate

[0206]

[0207] In a 40-mL reaction flask, 3-bromobenzaldehyde (1.5 g, 8.1 mmol), (3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)carbamate tert-butyl ester (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). The resulting homogeneous mixture was stirred and degassed three times. 1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloromethane complex (530 mg, 0.81 mmol) was added, the mixture was degassed, capped, and heated to 90 °C for 2.25 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 a 7:3 hexane:EtOAc solution to give the title compound (1.5 g, 63% yield). MS m / z 315.4 (M+18).

[0208] The following compounds in Table 4 were prepared using methods substantially similar to those described in Preparation 56.

[0209] Table 4: Preparation of 57

[0210]

[0211] Process 4

[0212]

[0213] Preparation of 58

[0214] (3-(3-formylbenzyl)phenyl)tert-butyl carbamate

[0215]

[0216] In a vial, 3-(bromomethyl)benzaldehyde (320 mg, 1.5 mmol), (3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)carbamate tert-butyl ester (300 mg, 0.94 mmol), and potassium carbonate (410 mg, 3.0 mmol) were dissolved in toluene (9 mL) and water (1 mL). The reaction mixture was purged with argon. 1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II)dichloromethane complex (80 mg, 0.10 mmol) was added, the vial was capped, and the mixture was heated to 100 °C and maintained 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 a 7:3 heptane:EtOAc solution to give the title compound (300 mg, 54% yield). MS m / z 329.4 (M+18).

[0217] The following compounds in Table 5 were prepared using methods substantially similar to those described in Preparation 58.

[0218] Table 5: Preparation of 59-60

[0219]

[0220] Process 5

[0221]

[0222] Preparation of 61

[0223] 2,6-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzaldehyde

[0224]

[0225] 3-(bromomethyl)phenylcarbamate tert-butyl ester (1.5 g, 5.0 mmol), 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzaldehyde (1.5 g, 5.6 mmol), and potassium carbonate (2.1 g, 3.0 mmol) were placed in a reaction flask containing water (1 mL) and toluene (9 mL). The reaction mixture was bubbled with N2, and 1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II)dichloromethane complex (310 mg, 0.37 mmol) was added. The flask was capped and heated at 100 °C for 10 min. The reaction mixture was cooled, filtered, and the filtrate was evaporated. The crude residue was purified by normal-phase chromatography, eluting with a 1:1 heptane:EtOAc solution to give the title compound (1.38 g, 3.85 mmol, 77% yield). MS m / z 365.2 (M+NH4).

[0226] The following compounds in Table 6 were prepared using a method substantially similar to that described in Preparation 61.

[0227] Table 6: Preparation of 62-66

[0228]

[0229] Process 6

[0230]

[0231] Preparation of 67

[0232] (4-(3-formylphenoxy)phenyl)tert-butyl carbamate

[0233]

[0234] (3-Formylphenyl)boronic acid (610 mg, 4.1 mmol), (4-hydroxyphenyl)carbamate tert-butyl ester (420 mg, 2.0 mmol), copper(II) acetate (370 mg, 2.0 mmol), triethylamine (1.4 mL, 10 mmol) and Molecular sieve (500 mg) was added to a vial of DCM (15 mL). The reaction mixture was incubated at room temperature for 10 h. The reaction mixture was filtered through diatomaceous earth, and the solvent was evaporated. The crude residue was purified by normal-phase chromatography, eluting with a 7:3 cyclohexane:EtOAc solution to give the title compound (180 mg, 29% yield). MS m / z 312.2 (MH).

[0235] The following compounds in Table 7 were prepared using methods substantially similar to those described in Preparation 67.

[0236] Table 7: Preparation of 68

[0237]

[0238] Process 7

[0239]

[0240] Preparation of 69

[0241] (4-(3-formylphenoxy)phenyl)tert-butyl carbamate

[0242]

[0243] 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 Molecular sieve (1.0 g) was 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. More [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 at room temperature for 3 days. The reactants were 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).

[0244] The following compounds in Table 8 were prepared using a method substantially similar to that described in Preparation 69.

[0245] Table 8: Preparation of 70

[0246]

[0247] Preparation 71

[0248] (3-((2-fluoro-3-formylphenyl)ethynyl)phenyl)tert-butyl carbamate

[0249]

[0250] Under a nitrogen atmosphere, 0.25 g (1.7 mmol) of 3-ethynyl-2-fluorobenzaldehyde was mixed with 0.55 g (1.7 mmol) of tert-butyl N-(3-iodophenyl)carbamate, 0.025 g (0.036 mmol) of bis(triphenylphosphine)palladium(II) dichloride, and 0.01 g (0.05 mmol) of cuprous iodide in triethylamine (10 mL, 72 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with 1 M HCl aqueous solution and 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 (MH).

[0251] Process 8

[0252]

[0253] Among them G 1 yes

[0254] Where L is

[0255]

[0256] Preparation of 72

[0257] 2-(6-fluoro-3-methoxy-2-methylphenyl)-1,3-dioxolane

[0258]

[0259] To a microwave-safe flask, add a THF solution (600 μL, 4.3 mmol) of 2-(2-bromo-6-fluoro-3-methoxyphenyl)-1,3-dioxolane (970 mg, 3.5 mmol), trimethylcycloboroxane (50 wt%), 1,4-dioxane (12 mL, 140 mmol) of cesium carbonate (2.3 g, 7.1 mmol), and water (2 mL, 110 mmol). Degas the solution with N2 for 2 min. Add [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (130 mg, 0.17 mmol), and degas the solution with N2 for 2 min. Cap the flask and microwave at 110 °C for 1 h. Dilute the reaction mixture with water (10 mL) and extract with EtOAc (10 mL). Dry the organic layer with Na2SO4, filter through filter paper, and rotary evaporate to obtain a crude oil. The crude oily substance was purified by normal-phase chromatography, eluting with a 7:3 hexane:MTBE solution to give the title compound (0.61 g, 82% yield). MS m / z 212.8 (M+H).

[0260] The following compounds in Table 9 were prepared using methods substantially similar to those described in Preparation 72.

[0261] Table 9: Preparation of 73-78

[0262]

[0263] * 1 H NMR (400.14MHz, DMSO): δ10.40(s,1H),9.39(s,1H),7.55-7.50(m,2H),7.26(d,J=8.3Hz,1H), 7.19(t,J=7.9Hz,1H),7.08(d,J=7.9Hz,1H),6.96(d,J=7.8Hz,1H),4.22(s,2H),1.46(s,10H)

[0264] ** 1 H NMR (400.21MHz, DMSO): δ10.45(s,1H),7.97(s,1H),7.78(t,J=7.8Hz,1H),7.65-7.61(m,1H),7.22-7.2 0(m,1H),7.14-7.12(m,1H),7.07-7.02(m,1H),6.95-6.91(m,1H),5.21(s,2H),2.57(s,3H),1.43(s,9H)

[0265] Preparation 79

[0266] 6-Fluoro-3-hydroxy-2-methylbenzaldehyde

[0267]

[0268] After a 2-minute interval, a solution of boron tribromide in DCM (14 mL, 14 mmol, 1 mol / L) was added 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. The ice bath was removed after the addition. The reaction was quenched with saturated NH4Cl aqueous solution after 30 min. The reactants were diluted with DCM, washed with 2 M NaOH aqueous solution, and then washed with 5 M HCl aqueous solution. The organic layer was dried over Na2SO4, filtered through filter paper, and rotary evaporated to obtain the crude residue. The crude residue was purified by normal-phase chromatography, eluting with a 7:3 hexane:EtOAc solution to give the title compound (130 mg, 30% yield). MS m / z 153.0 (MH).

[0269] Preparation of 80

[0270] tert-butyl(4-fluoro-2-methoxyphenoxy)diphenylsilane

[0271]

[0272] To a solution of 4-fluoro-2-methoxyphenol (2.3 g, 16 mmol) in DCM (35 mL), imidazole (2.8 g, 41 mmol) and tert-butyldiphenylchlorosilane (6 mL, 23 mmol) were added. After 1.75 h, the solvent was evaporated, and the residue was partitioned between 200 mL of hexane containing 10% EtOAc and 100 mL of water. The organic matter was washed once with brine, dried over MgSO4, filtered, and evaporated. The crude residue was purified by normal-phase chromatography, eluting with a 9:1 hexane:EtOAc solution to give the title compound (6.7 g, quantitative yield). 1 H NMR(399.8MHz,d6-DMSO)δ7.64(dd,J=1.5,7.9Hz,4H),7.48-7.43(m,6H),6.82(dd,J=2.9,10 .5Hz,1H),6.60(dd,J=5.9,8.8Hz,1H),6.48(td,J=8.5,3.0Hz,1H),3.56(s,3H),1.05(s,9H)

[0273] Preparation of 81

[0274] 6-Fluoro-3-hydroxy-2-methoxybenzaldehyde

[0275]

[0276] 3.2 g (8.5 mmol) of tert-butyl(4-fluoro-2-methoxyphenoxy)diphenylsilane was dissolved in tetrahydrofuran (30 mL) and cooled to -78 °C. After 3 minutes, n-butyllithium (7 mL, 11 mmol, 1.6 M) was added. After 1.5 h, DMF (2 mL) was added at -78 °C. After 1 h, approximately 4 mL of a 10% NH₄Cl aqueous solution was added, and the mixture was warmed to room temperature for 1.5 h. The solvent was evaporated to obtain a crude residue, which was then acidified with a 1 M HCl aqueous solution and partitioned between water and 300 mL of EtOAc. The organic layer was washed with water and brine, dried over MgSO₄, filtered, and evaporated. The crude residue was purified by normal-phase chromatography, eluting with a 3:2 hexane:EtOAc solution to give the title compound (0.79 g, 55% yield). MS m / z 171.0 (M+H).

[0277] Preparation of 82

[0278] (3-((4-cyclopropyl-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)tert-butyl carbamate

[0279]

[0280] 200 mg (0.43 mmol) of tert-butyl (3-((4-bromo-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate, cyclopropylboronic acid (0.21 g, 2.4 mmol), and tripotassium phosphate (0.28 g, 1.3 mmol) were placed in a 25 mL vial rinsed with N2. Toluene (3 mL) and water (0.75 mL) were added. The reaction mixture was degassed with N2 for 5 min, and then tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) was added in a single batch. The reaction mixture 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 a crude residue. The crude residue was purified by normal-phase chromatography, eluting with a 1:1 hexane:EtOAc solution to give the title compound (170 mg, 94% yield). MS m / z 428.4 (MH).

[0281] Preparation of 83

[0282] (2,6-Dimethyl-3-nitrophenyl)methylene diacetate

[0283]

[0284] 2,6-Dimethyl-3-nitrobenzaldehyde (1.9 g, 10 mmol) was dissolved in DCM (23 mL), followed by the addition of acetic anhydride (1.3 mL, 14 mmol) and copper(II) trifluoromethanesulfonate (41 mg, 0.11 mmol). The solution was stirred at room temperature for 3.5 h. The reaction was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered, and concentrated to a crude residue. The crude residue was purified by normal-phase chromatography, eluting with a 3:2 hexane:EtOAc solution to give the title compound (2.4 g, 81% yield). 1 H NMR (400.13MHz, DMSO-d6): δ7.96(s,1H),7.80(d,J=8.3Hz,1H),7.35(d,J=8.4Hz,1H),2.58(s,3H),2.53(s,2H),2.12(s,6H).

[0285] Preparation of 84

[0286] (3-Amino-2,6-dimethylphenyl)methylene diacetate

[0287]

[0288] A 5 wt% Pt / C solution (1.0 g, 5.2 mmol) was added to a 500-mL Parr shaking flask and degassed with N2. 25 mL of EtOAc was added, followed by a 25 mL solution of (2,6-dimethyl-3-nitrophenyl)methylene diacetate (2.7 g, 9.6 mmol) in EtOAc. The flask was sealed, rinsed with N2, rinsed with H2, and pressurized to 60 psi 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).

[0289] Preparation of 85

[0290] (3-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2,6-dimethylphenyl)methylene diacetate

[0291]

[0292] A DMF solution (3 mL) of a mixture of (3-amino-2,6-dimethylphenyl)methylene diacetate (276 mg, 1.10 mmol) and potassium carbonate (435 mg, 3.15 mmol) was stirred at room temperature for 1 h. 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 h. 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 under vacuum. The remaining DMF was evaporated with xylene (azeotropic), giving a 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).

[0293] Process 9

[0294]

[0295] Preparation of 86

[0296] 3-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2-fluoro-6-methylbenzoate

[0297]

[0298] 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 overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with 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 a crude residue. The crude residue was purified by normal-phase chromatography, eluting with a 3:2 petroleum ether:EtOAc solution to give the title compound (1.9 g, 75% yield). MS m / z 389.0 (M+H).

[0299] The following compounds in Table 10 were prepared using methods substantially similar to those described in Preparation 86.

[0300] Table 10: Preparation of 87

[0301]

[0302] Preparation of 88

[0303] Methyl 6-bromo-2-fluoro-3-carboxymethyl benzoate

[0304]

[0305] N-bromosuccinimide (5.8 g, 31 mmol) was added to a carbon tetrachloride solution (36 mL) of methyl 6-bromo-2-fluoro-3-methylbenzoate (3.9 g, 14 mmol), followed by the addition of 2,2'-azobis(2-methylpropionitrile) (0.24 g, 1.4 mmol), and the reaction mixture was stirred overnight at 85 °C. The mixture was diluted with DCM, washed with brine, dried over Na₂SO₄, and concentrated to a crude residue. The residue was dissolved in ACN and purified by preparative C18 HPLC (35%–60% water [0.225% FA]-ACN). The eluent was concentrated to give methyl 6-bromo-3-(dibromomethyl)-2-fluorobenzoate (1.9 g, 4.6 mmol). This material was dissolved in ethanol (15 mL). A mixture of silver nitrate (2.0 g, 12 mmol) and water (10 mL) was added, and the reaction mixture was heated at 75 °C for 6 h under a N2 atmosphere. The reaction mixture 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:petroleum ether, to give the title compound (1.1 g, 91% yield).

[0306] Process 10

[0307]

[0308] Preparation of 89

[0309] 6-Bromo-3-(((3-((tert-butoxycarbonyl)amino)phenyl)amino)methyl)-2-fluorobenzoate

[0310]

[0311] Methyl 6-bromo-2-fluoro-3-carboxymethyl benzoate (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 overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with 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 a crude residue. The crude residue was purified by normal-phase chromatography, eluting with a 7:3 petroleum ether:EtOAc solution to give the title compound (1.7 g, 89% yield). MS m / z 454.9 (M+H).

[0312] The following compounds in Table 11 were prepared using a method substantially similar to that described in Preparation 89.

[0313] Table 11: Preparation of 90

[0314]

[0315] Preparation of 91

[0316] 3-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-2-fluoro-6-methylbenzoate

[0317]

[0318] To a methanol (5 mL) solution of methyl 3-((3-((tert-butoxycarbonyl)amino)benzyl)amino)-2-fluoro-6-methylbenzoate (1.7 g, 3.3 mmol), sodium cyanoborohydride (420 mg, 6.5 mmol) and acetic acid (0.5 mL, 9 mmol) were added. Then, an aqueous solution of formaldehyde (730 μL, 9.8 mmol, 37% by mass) was added at 25 °C. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. The crude mixture was purified by normal-phase chromatography, eluting with a 4:1 petroleum ether:EtOAc solution to give the title compound (1.3 g, 92% yield). MS m / z 403.0 (M+H).

[0319] Process 11

[0320]

[0321] Preparation of 92

[0322] (3-(((2-fluoro-3-(hydroxymethyl)-4-methylphenyl)(methyl)amino)methyl)phenyl)tert-butyl carbamate

[0323]

[0324] At 0 °C, a solution of DIBAL-H in toluene (7 mL, 7.0 mmol, 1.0 mol / L) was added to a solution of methyl 3-((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)-2-fluoro-6-methylbenzoate (1.2 g, 2.8 mmol) in 10 mL of DCM. The reaction mixture was heated to room temperature and maintained for 3 h. The solution was cooled back to 0 °C, and a saturated aqueous solution of 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 column, and concentrated to a crude residue. The residue was purified by normal-phase chromatography, eluting with a 1:1 petroleum ether:EtOAc solution to give the title compound (640 mg, 57% yield). MS m / z 375.0 (M+H).

[0325] The following compounds in Table 12 were prepared using methods substantially similar to those described in Preparation 92.

[0326] Table 12: Preparation of 93-98

[0327]

[0328] * 1H NMR (400.14MHz, DMSO): δ9.23 (s, 1H), 7.35-7.31 (m, 2H), 7.09-7.02 (m, 3H), 6.89 (d, J = 7.8Hz, 1H), 4.92 (t,J=5.3Hz,1H),4.49-4.48(m,2H),4.03(q,J=7.1Hz,1H),2.79-2.72(m,4H),2.33(s,3H),1.46(s,9H).

[0329] Process 12

[0330]

[0331] Preparation of 99

[0332] (3-(((2-fluoro-3-formyl-4-methylphenyl)(methyl)amino)methyl)phenyl)tert-butyl carbamate

[0333]

[0334] 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), 2-iodobenzoic acid (630 mg, 2.2 mmol) was added. The reaction mixture was stirred at 80 °C for 6 h. The solid was filtered off, and the filtrate was concentrated to a crude residue. The residue was purified by normal-phase chromatography, eluting with a 7:3 petroleum ether:EtOAc solution to give the title compound (580 mg, 94% yield). MS m / z 373.0 (M+H).

[0335] The following compounds in Table 13 were prepared using a method substantially similar to that described in Preparation 99.

[0336] Table 13: Preparation of 100-104

[0337]

[0338]

[0339] * 1 H NMR (400.15MHz, DMSO): δ10.31(d,J=0.8Hz,1H),7.90-7.86(m,1H),7.78(dd,J=0.8,8.4Hz,1H),4.84(d,J=1.0Hz,2H)

[0340] ** 1H NMR (400.15MHz, DMSO): δ10.42(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).

[0341] Preparation 105

[0342] (4-(2-(2-fluoro-3-formyl-4-methylphenoxy)ethyl)phenyl)tert-butyl carbamate

[0343]

[0344] Potassium carbonate (670 mg, 4.9 mmol) was added to a solution of 2-fluoro-3-hydroxy-6-methylbenzaldehyde (250 mg, 1.5 mmol) and 4-methylbenzenesulfonic acid 4-((tert-butoxycarbonyl)amino)phenethyl ester (760 mg, 1.9 mmol) in acetonitrile (10 mL). The suspension was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the 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 the residue. The residue was purified by normal-phase chromatography, eluting with a 17:3 petroleum ether:EtOAc solution to give the title compound (510 mg, 85% yield). 1 H NMR (400.15MHz, CDCl3): δ10.47(s,1H),7.24(d,J=8.4Hz,2H),7.15(d,J=8.5Hz,2H),6.96(t,J=8.4Hz,1H),6. 82(d,J=8.4Hz,1H),6.37-6.35(m,1H),4.12(t,J=7.0Hz,2H),3.01(t,J=6.9Hz,2H),2.45(s,3H),1.45(s,8H).

[0345] Preparation of 106

[0346] (6-bromo-3-(bromomethyl)-2-fluorophenyl)methanol

[0347]

[0348] Under a nitrogen atmosphere, a THF solution (35 mL, 35 mmol, 1 mol / L) of a borane-THF complex was added dropwise to a THF solution of 6-bromo-3-(bromomethyl)-2-fluorobenzoic acid (4.9 g, 11 mmol) cooled in an ice bath in 100 mL. The reaction mixture was heated to room temperature overnight. The reaction was quenched with MeOH (100 mL) and concentrated under vacuum. 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 a 7:3 petroleum ether:EtOAc solution to give the title compound (2.9 g, 62% yield). 1 H NMR (400.15MHz, DMSO): δ7.50-7.42(m,2H),5.38-5.23(m,1H),4.70(d,J=0.5Hz,2H),4.59(d,J=1.5Hz,2H).

[0349] Process 13

[0350]

[0351] Among them G 2 yes

[0352]

[0353] Where J is hydrogen or Boc.

[0354] Preparation of 107

[0355] (3-((4-bromo-2-fluoro-3-carboxybenzyl)thio)phenyl)tert-butyl carbamate

[0356]

[0357] Under a nitrogen atmosphere, triethylamine (530 μL, 3.8 mmol) was added to a DCM (10 mL) solution of a mixture of 6-bromo-3-(bromomethyl)-2-fluorobenzaldehyde (620 mg, 1.9 mmol) and N-(3-thioalkylphenyl)carbamate tert-butyl ester (500 mg, 2.0 mmol). 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 under vacuum to give a crude residue. The residue was purified by normal-phase chromatography, eluting with a 3:1 petroleum ether:EtOAc solution to give the title compound (780 mg, 89% yield). 1H NMR (400.15MHz, DMSO): δ10.19(s,1H),9.39(s,1H),7.57-7.51(m,2H),7.47(s,1H),7.27 (d,J=8.6Hz,1H),7.19(t,J=7.9Hz,1H),6.96(d,J=7.8Hz,1H),4.21(s,2H),1.46(s,9H).

[0358] The following compounds in Table 14 were prepared in a manner substantially similar to that described in Preparation 107.

[0359] Table 14: Preparation of 108

[0360]

[0361] Preparation 109

[0362] 6-Bromo-3-(((2-((tert-butoxycarbonyl)amino)phenyl)thio)methyl)-2-fluorobenzoate

[0363]

[0364] 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), ditert-butyl dicarbonate (3.5 mL, 15 mmol) was added. The mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum to give a crude residue. The residue was purified by normal-phase chromatography, eluting with a 10:1 petroleum ether:EtOAc solution to give the title compound (1.6 g, quantitative yield). MS m / z 371.8 (M-Boc+H).

[0365] Preparation of 110

[0366] (3-Bromo-2-fluoro-4-methylphenyl)methanol

[0367]

[0368] Sodium borohydride (620 mg, 16 mmol) was added to a MeOH solution of 3-bromo-2-fluoro-4-methylbenzaldehyde (2 g, 6.6 mmol) at 0 °C. The mixture was stirred for 1 h. Under a nitrogen atmosphere, the mixture was slowly quenched with 1 M HCl aqueous solution (30 mL) and the pH was adjusted to 6. The reaction mixture was concentrated under vacuum to give a crude residue. The residue was purified by normal-phase chromatography, eluting with a 1:2 petroleum ether:EtOAc solution to give the title compound (820 mg, 51% yield).

[0369] Preparation 111

[0370] (3-((3-bromo-2-fluoro-4-methylbenzyl)oxy)phenyl)tert-butyl carbamate

[0371]

[0372] To a solution of (3-bromo-2-fluoro-4-methylphenyl)methanol (650 mg, 2.7 mmol), (3-hydroxyphenyl)carbamate tert-butyl ester (870 mg, 4.0 mmol), and tetrabutylphosphine (1.1 g, 5.4 mmol) in THF (10 mL, 120 mmol), N,N,N′,N′-tetramethylazodicarbonamide (940 mg, 5.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h under an anhydrous N2 atmosphere. 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 under vacuum to give a crude residue. The residue was purified by normal-phase chromatography, eluting with a 9:1 petroleum ether:EtOAc solution to give the title compound (1.2 g, 96% yield). MS m / z 355.8 (M-tBu+H).

[0373] Preparation 112

[0374] (3-((2-fluoro-3-formyl-4-methylbenzyl)oxy)phenyl)tert-butyl carbamate

[0375]

[0376] At 0 °C, a THF solution (3.1 mL, 4.0 mmol, 1.3 mol / L) of the magnesium chloride-lithium chloride complex was added to a THF solution (5 mL, 62 mmol) of (0.82 g, 1.8 mmol) of tert-butyl (3-((3-bromo-2-fluoro-4-methylbenzyl)oxy)phenyl)carbamate, and the mixture was stirred for 30 min. At 0 °C, DMF (450 μL, 5.7 mmol) was added to the mixture. The mixture was heated to room temperature and maintained for 1.5 h, then quenched by adding a saturated aqueous solution of NH4Cl (5 mL). The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The combined organic extracts were concentrated under vacuum to give the crude product. The residue was purified by normal-phase chromatography, eluting with a 95:5 petroleum ether:EtOAc solution to give the title compound (220 mg, 25% yield). MS m / z 259.9 (M-Boc+H).

[0377] Preparation of 113

[0378] (2-((4-bromo-2-fluoro-3-formylbenzyl)oxy)phenyl)tert-butyl carbamate

[0379]

[0380] Cesium carbonate (230 mg, 0.71 mmol) was added to a DMF solution (3 mL) of tert-butyl (2-hydroxyphenyl)carbamate (100 mg, 0.47 mmol) and 6-bromo-3-(bromomethyl)-2-fluorobenzaldehyde (160 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 h under a nitrogen atmosphere, followed by quenching with water. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The combined organic extracts were concentrated under vacuum to give a crude product. The residue was purified by normal-phase chromatography, eluting with a 4:1 petroleum ether:EtOAc solution to give the title compound (210 mg, quantitative yield). 1 H NMR (400.21MHz, DMSO): δ10.24(s,1H),8.08(s,1H),7.82(t,J=7.9Hz,1H),7.69(d,J=8.3Hz,1H),7.63(d, J=7.6Hz,1H),7.10(dd,J=1.0,8.1Hz,1H),7.06-7.02(m,1H),6.95-6.91(m,1H),5.21(s,2H),1.44(s,9H).

[0381] Process 14

[0382]

[0383] Preparation of 114

[0384] (2-(((2-fluoro-3-formyl-4-methylphenyl)thio)methyl)phenyl)tert-butyl carbamate

[0385]

[0386] To a solution of S-(2-((tert-butoxycarbonyl)amino)benzyl)thioacetate (670 mg, 2.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL), 3-bromo-2-fluoro-6-methylbenzaldehyde (550 mg, 1.8 mmol), 2-dicyclohexylphosphine-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) were added. The mixture was heated to 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 x 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by normal-phase chromatography, eluting with a 95:5 petroleum ether:EtOAc solution to give the title compound (670 mg, 54% yield). MS m / z 275.9 (M-Boc+H).

[0387] The following compounds in Table 15 were prepared using a method substantially similar to that described in Preparation 114.

[0388] Table 15: Preparation of 115-116

[0389]

[0390] Process 15

[0391]

[0392] Preparation of 117

[0393] (2-(((2-fluoro-3-formyl-4-methylphenyl)amino)methyl)phenyl)tert-butyl carbamate

[0394]

[0395] At room temperature, manganese dioxide (2.2 g, 25 mmol) was added to a THF (20 mL) solution of tert-butyl (2-(((2-fluoro-3-(hydroxymethyl)-4-methylphenyl)amino)methyl)phenyl)carbamate (950 mg, 2.4 mmol). The resulting mixture was stirred overnight at 70 °C. Further manganese dioxide (2.2 g, 25 mmol) was added to the incomplete reaction, and stirring was continued at 70 °C for 4 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat, 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 petroleum ether:EtOAc at a 9:1 ratio, to give the title compound (220 mg, 20% yield). MS m / z 359.0 (M+H).

[0396] The following compounds in Table 16 were prepared in a manner substantially similar to that described in Preparation 117.

[0397] Table 16: Preparation of 118

[0398]

[0399] Preparation of 119

[0400] S-(3-((tert-butoxycarbonyl)amino)benzyl)thioacetate

[0401]

[0402] 2.0 g (6.7 mmol) of tert-butyl (3-(bromomethyl)phenyl)carbamate and 1.6 g (14 mmol) of potassium thioacetate were dissolved in DMF (9 mL, 120 mmol) and stirred for 2 h at room temperature under N2 atmosphere. The reaction was quenched by adding 20 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The residue was purified by normal phase chromatography, eluting with 17:3 petroleum ether:EtOAc to give the title compound (1.8 g, 89% yield). MS m / z 225.9 (M-tBu+H).

[0403] Preparation 120

[0404] Methyl (E)-6-bromo-2-fluoro-3-(4-nitrostyryl)benzoate

[0405]

[0406] Sodium hydride (340 mg, 8.5 mmol, 60 wt%) placed in oil was added to a DMF (30 mL) solution of diethyl (4-nitrobenzyl) phosphate (1.7 g, 6.1 mmol) and 15-crown ether-5 (1.3 g, 5.7 mmol). After stirring at 0 °C for 30 min, methyl 6-bromo-2-fluoro-3-carboxylbenzoate (1.5 g, 5.7 mmol) was added under a N2 atmosphere. After 1.5 h, the reaction was quenched by adding 40 mL of saturated NH4Cl aqueous solution to precipitate a yellow solid. The solid was collected by 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).

[0407] Preparation 121

[0408] 3-(4-((tert-butoxycarbonyl)amino)phenethyl)-2-fluoro-6-methylbenzoate

[0409]

[0410] To a solution of (E)-2-fluoro-6-methyl-3-(4-nitrostyryl)benzoate (710 mg, 2.2 mmol) in MeOH (15 mL), palladium (650 mg, 0.31 mmol) and di-tert-butyl dicarbonate (0.57 mL, 2.5 mmol) were added. The mixture was stirred for 2 h at room temperature under a H2 (15 psi) atmosphere. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by normal-phase chromatography, eluting with a 3:2 petroleum ether:EtOAc solution to give the title compound (620 mg, 69% yield). 1 H NMR (400.21MHz, DMSO): δ9.24 (s, 1H), 7.34 (d, J = 8.3Hz, 2H), 7.26 (t, J = 7.9Hz, 1H), 7. 05(dd,J=8.2,14.8Hz,3H),3.87(s,3H),2.86-2.68(m,4H),2.26(s,3H),1.47(s,10H).

[0411] Preparation 122

[0412] (3-((4-bromo-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)tert-butyl carbamate

[0413]

[0414] With a Dean-Stark still attached, a toluene solution (16 mL, 150 mmol) of tert-butyl (3-((4-bromo-2-fluoro-3-carboxyphenoxy)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) was refluxed at 135 °C for 1 h. 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).

[0415] Alternative preparation 122

[0416] (3-((4-bromo-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)tert-butyl carbamate

[0417] 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-dioxolane-2-yl)-2-fluorophenol (1.06 g, 4.03 mmol). This substance 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 a 3:1 EtOAc:hexane solution to give tert-butyl (3-((4-bromo-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (1.72 g, 3.66 mmol, 77% yield). MS m / z 485.0, 487.2 (M+NH₄).

[0418] Process 16

[0419]

[0420] Among them G 3 yes

[0421]

[0422] Where K is hydrogen or methyl.

[0423] Preparation 123

[0424] (3-((2-fluoro-3-formyl-4-vinylphenoxy)methyl)phenyl)tert-butyl carbamate

[0425]

[0426] Tert-butyl (3-((4-bromo-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (400 mg, 0.85 mmol), potassium ethylene trifluoroborate (0.14 g, 1.0 mmol), and cesium carbonate (0.84 g, 2.6 mmol) were placed in a 25-mL microwave-safe flask rinsed with N2. THF (9 mL) and water (1 mL, 56 mmol) were added. The mixture was degassed by bubbling with N2 over a subsurface for 5 minutes, palladium(II) acetate (10 mg, 0.04 mmol) was added, and the reaction mixture was heated to 100 °C overnight. The reaction mixture was cooled to room temperature and kept for 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 a crude residue. The residue was purified by normal-phase chromatography, eluting with a 3:2 hexane:EtOAc solution to give the title compound (320 mg, 16% yield). MS m / z 369.6 (MH).

[0427] The following compounds in Table 17 were prepared in a manner substantially similar to that described in Preparation 123.

[0428] Table 17: Preparation of 124

[0429]

[0430] Preparation 125

[0431] N-[3-[[3-(1,3-dioxolane-2-yl)-2-fluoro-4-isopropylphenoxy]methyl]phenyl]tert-butyl carbamate

[0432]

[0433] Sulfurized 5 wt% platinum carbon (0.057 g, 0.29 mmol) was added to a 70-mL Parr shake flask and degassed with N2. 5 mL of EtOAc was added to the flask, followed by 6 mL of a solution of tert-butyl (3-((3-(1,3-dioxolane-2-yl)-2-fluoro-4-(prop-1-en-2-yl)phenoxy)methyl)phenyl)carbamate (0.231 g, 0.538 mmol). The flask was sealed, rinsed with N2, rinsed with H2, and pressurized to 60 psi 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 (MH).

[0434] Preparation 126

[0435] (3-((4-cyano-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)tert-butyl carbamate

[0436]

[0437] In a microwave-safe flask, a mixture of tert-butyl (3-((4-bromo-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (240 mg, 0.50 mmol), zinc cyanide (130 mg, 1.1 mmol), and a THF solution of zinc chloride (1.0 mL, 0.50 mmol, 0.500 mol / L) in DMF (2.5 mL, 32 mmol) was bubbled with N2. Tetra(triphenylphosphine)palladium(0) (31 mg, 0.03 mmol) was added. The reaction mixture was bubbled with N2, capped, and microwaved at 110 °C for 1 h. Additional zinc cyanide (120 mg, 1.0 mmol) and tetra(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol) were added. The reaction mixture was bubbled with N2, capped, and microwaved at 120 °C for 30 min. The reaction solution was washed with water (15 mL). The organic layer was dried over Na₂SO₄, filtered through filter paper, and rotary evaporated to obtain a crude residue. The residue was purified by normal-phase chromatography, eluting with a 7:3 hexane:EtOAc solution to give the title compound (90 mg, 43% yield). MS m / z 412.6 (MH).

[0438] Process 17

[0439]

[0440] In process 17, under conditions known to those skilled in the art, the compound of structure 1, where R is H, reacts with the compound of structure 2, where Pg is a suitable nitrogen protecting group such as tert-butoxycarbonyl, and where G is:

[0441]

[0442] We obtained a compound of formula I, in which R is hydrogen.

[0443] More specifically, as shown in process 17A below, under conditions known to those skilled in the art, a compound of structure 1a, wherein R is H, reacts with a compound of structure 2, wherein Pg and G are as defined above, to give compounds of formula Ib and Ic.

[0444] Process 17A

[0445]

[0446] For example, about 1 equivalent of compound 1a (where R is H) and about 1 equivalent of compound 2 (where Pg and G are as defined in process 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% aqueous solution) or trifluoroacetic acid. The reaction mixture is then heated 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 is stirred again for about 2 hours. The reaction is then quenched under standard conditions, such as with a saturated aqueous solution of sodium bicarbonate, and the products are separated using standard techniques well known in the art, such as extraction with a suitable organic solvent, such as dichloromethane:isopropanol, drying the organic extract with magnesium sulfate, filtering, and concentrating under vacuum to give a crude product mixture. The crude mixture can be purified using techniques well known in the art to separate the products of formula Ib and formula Ic, such as chromatography, including normal-phase chromatography, for example with a suitable eluent (e.g., DCM containing MeOH), and reversed-phase chromatography with a suitable eluent (e.g., 2:1 10 mM ammonium bicarbonate aqueous solution + 5% methanol:acetonitrile).

[0447] Example 1

[0448] (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-dodecylhydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-4-one

[0449]

[0450] At -10°C, perchloric acid (70% aqueous solution, 4.8 mL) was added to an acetonitrile (110 mL) 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-cyclopentadieno[a]phenanthrene-3-one (4.4 g, 12 mmol, also known as "16α-hydroxyprednisolone") and N-[3-[(2-fluoro-3-formyl-4-methyl-phenoxy)methyl]phenyl]carbamate tert-butyl ester (4.0 g, 11 mmol, preparation 4) and heated to room temperature. After 1 h, DMF (10 mL) was added to the suspension at room temperature. After 18 hours, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted with a 9:1 dichloromethane:isopropanol mixture. The organic layers were combined; dried over magnesium sulfate; filtered and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase chromatography, eluting with a 1:1 10 mM ammonium bicarbonate aqueous solution + 5% methanol:acetonitrile to give the title compound, peak 1 (1.72 g, 25% yield). ES / MS m / z 618.6 (M+H). 1 HNMR(400.13MHz,d6-DMSO)δ0.93-0.87(m,6H),1.40(s,3H),1.71-1.60(m,1H),1.89-1.76(m,4H),2.1 8-2.12(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=3.2Hz ,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=7.7Hz,1H),7.12(t,J=8.5Hz,1H),7.33-7.30(m,1H).

[0451] Example 2

[0452] (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-dodecylhydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-4-one

[0453]

[0454] From Example 1, the residue was purified by reversed-phase chromatography, eluting with a 1:1 aqueous solution of 10 mM ammonium bicarbonate + 5% methanol:acetonitrile to give peak 2 of the title compound (1.24 g, yield 18%). ES / MS m / z 618.6 (M+H). 1 H NMR (400.13MHz, d6-DMSO) δ 1 H NMR(400.13MHz, 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=5.2Hz,1H),4.12-4.00(m,1H),4.37-4.30(m,2H),4.79(d,J=3.1Hz,1H) ,5.00-4.93(m,2H),5.10-5.06(m,3H),5.31(d,J=6.7Hz,1H),5.95(s,1H),6.18(dd,J=1.8,10.1Hz,1H),6.34(s,1H),6. 53-6.48(m,2H),6.58(s,1H),6.87(d,J=8.5Hz,1H),6.99(t,J=7.7Hz,1H),7.09(t,J=8.5Hz,1H),7.33(d,J=10.1Hz,1H).

[0455] Example 3

[0456] (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-dodecano-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-4-one

[0457]

[0458] The (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,7,8,8 a,11a,12,12a,12b-dodecano-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-8b-yl)-2-oxoethoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (40 mg, 0.04 mmol, preparation 5) was added to methanol (2 mL) and potassium carbonate (20 mg, 0.20 mmol). After 1 h, the mixture was loaded onto diatomaceous earth and purified by reversed-phase chromatography, eluting with a 1:2 aqueous solution of 10 mM ammonium bicarbonate + 5% methanol:acetonitrile to give the title compound (19 mg, 57% yield). ES / MS m / z 780.4 (M+H). 1H NMR(500.11MHz,d6-DMSO)δ0.90(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,3 H),2.40-2.35(m,1H),3.50-3.46(m,1H),3.57-3.53(m,1H),3.64-3.6 1(m,1H),4.17-4.15(m,1H),4.34-4.32(m,1H),4.43-4.39(m,2H),4.5 7-4.52(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=0.4Hz,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. 5Hz,1H),7.00(t,J=7.7Hz,1H),7.12-7.08(m,1H),7.35-7.33(m,1H).

[0459] Example 4

[0460] (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-dodecylhydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-4-one

[0461]

[0462] At -20°C, perchloric acid (3.3 mL, 70% aqueous solution, 5 equivalents) was added dropwise to a suspension of (2.6 g, 6.9 mmol, preparation 8) and 16α-hydroxyprednisolone (2.5 g, 6.6 mmol) in acetonitrile (100 mL). The mixture was stirred at -20°C for 7 h. The solution was transferred to a separatory funnel. This solution was added dropwise to an aqueous solution of sodium hydroxide (7.5 mL of 5N NaOH in 1 L of aqueous solution). After the addition was complete, the pH was measured to be 5, and the pH was adjusted to 8 with 5N NaOH aqueous solution. The suspension was stirred for 10 min. The solid was collected by vacuum filtration and washed with water. The solid was dried on a filter overnight. The solid was purified by reversed-phase chromatography, eluting with a 1:1 aqueous solution of 10 mM ammonium bicarbonate in 5% methanol:acetonitrile to give the title compound, peak 1 (804 mg, yield 18%). MS m / z 634.2 (M+H).

[0463] 1 H NMR(399.8MHz,d6-DMSO)δ7.33(d,J=10.1Hz,1H),7.17(t,J=9.2Hz,1H),6.98(t,J=7.8Hz,1H),6.76(dd,J=1.0,9.2Hz,1H) ,6.56(d,J=1.6Hz,1H),6.52-6.48(m,2H),6.17(dd,J=1.9,10.1Hz,1H),5.96(s,1H),5.71(s,1H),5.17(t,J=6.0Hz,1H),5 .10(s,2H),4.94-4.90(m,3H),4.79(d,J=3.1Hz,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).

[0464] Example 5

[0465] (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-dodecylhydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-4-one

[0466]

[0467] From Example 4, the residue was purified by reversed-phase chromatography, eluting with a 1:1 aqueous solution of 10 mM ammonium bicarbonate + 5% methanol:acetonitrile to give peak 2 of the title compound (1.19 g, yield 27%). MS m / z 634.2 (M+H).

[0468] 1 H NMR(399.8MHz,d6-DMSO)δ7.32(d,J=10.0Hz,1H),7.17-7.12(m,1H),6.99(t,J=7.7Hz,1H),6.72(d,J=8.8Hz, 1H),6.58(s,1H),6.53-6.46(m,3H),6.18(dd,J=1.7,10.1Hz,1H),5.95(s,1H),5.25(d,J=6.5Hz,1H),5.10(s ,2H),5.00-4.90(m,3H),4.78(d,J=3.1Hz,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).

[0469] Alternative preparation in Example 5

[0470] All solids handling steps were performed using disposable glove bags, including filling flasks with 16α-hydroxyprednisolone, solids filtration, and solids transfer.

[0471] At -25°C, an aqueous perchloric acid solution (31 mL, 330 mmol, 10.6 mol / L) was added dropwise to a suspension of (25 g, 67 mmol, 2-fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl)carbamate (25 g, 65 mmol) in ACN (1000 mL) in a 2-L round-bottom flask. The mixture was stirred at -20°C while the reaction was monitored by LCMS. Internal temperature monitoring showed a small amount of exothermic reaction upon the addition of perchloric acid. After the addition of dry ice, the internal temperature was maintained below -19°C. The mixture was maintained below -19°C for 2 h and then heated to -10°C. The mixture was divided in two and added dropwise to two separate beakers (beaker 1 and beaker 2), each containing 76 mL of a 2 L aqueous solution of 5 M NaOH. The solid formed after the addition of perchloric acid and complete quenching was tested (pH 10). Each addition of viscous solid was transferred and combined into a third beaker (beaker 3) containing DCM containing 10% MeOH. The mixture was stirred until the viscous solid was completely dissolved. The remaining solution (beakers 1 and 2) was then filtered through filter paper to collect the residual solid. The separated solid was rinsed with water and transferred to beaker 3. Beaker 3 was stirred until all the solid was dissolved. The solution was dried with Na₂SO₄ for 2 hours, filtered, and evaporated to obtain a brown foam. The filtrate containing the collected solid was extracted with three portions of DCM containing 10% IPA. The combined organic extracts were dried with Na₂SO₄ overnight with stirring, then filtered and evaporated to obtain another crude residue. The crude product was dissolved in 150 mL of DCM containing 1% MeOH and purified by normal phase chromatography, eluting with DCM containing 0–5% MeOH to obtain a solid. It was diluted with 600 mL of EtOH and rotated on a rotary evaporator at 45 °C for 5 minutes. The water bath was heated to 60 °C. When the water bath reaches 60°C, turn off the water bath and rotate the flask until the water bath reaches room temperature. Remove the flask from the rotary evaporator, cap it, and leave it at room temperature overnight.

[0472] The solid was collected by vacuum filtration in a glove bag. The solid was washed with EtOH and dried on a filter for 5 h. The solid was redissolved in 1.5 L of DCM containing 20% ​​EtOH. Additional DCM was added to obtain a nearly clear solution (some haze remained). Solvent exchange was achieved by rotary evaporation at 450 mbar and 45 °C. After distillation was stopped, the pressure was reduced to 100 mbar, allowing the EtOH to decrease to approximately 600 mL. The mixture was removed from the rotary evaporator and allowed to stand at room temperature for 5 h. The solid was collected by vacuum filtration and washed twice with additional EtOH. The filter cake was dried in a vacuum oven at room temperature for 48 h to give the title compound (42 g, 38% yield). MS m / z 634.6 (M+H).

[0473] Structural identification by NMR

[0474]

[0475] Two-dimensional ROE NMR analysis of the acetal isomer consistently yielded cross-peaks of H22 (acetal) and H16 in the R configuration. Alternatively, H22 in the S configuration consistently showed a large shift of approximately 1 ppm. All other compounds were identified using essentially the same method.

[0476] The following compounds in Table 18a were prepared using the starting materials of the corresponding structures 1a and 2, prepared in accordance with the corresponding preparations described above and in Tables 2–17, or prepared using standard methods known to those skilled in the art, in a manner substantially similar to that described in Examples 1–4. Purification of the final products was primarily carried out by the following methods:

[0477] A.C18 column, using 10mM NH4HCO3 aqueous solution as eluent + 5% MeOH:ACN

[0478] B.C18 column, using 0.1% FA aqueous solution as eluent: ACN

[0479] C.SFC Chiralpak AY, using eluent EtOH + 0.05% DEA:CO2

[0480] D. Chiralpak IC, using eluent MeOH + 0.2% IPAm

[0481] E.SFC Lux Amylose-2, using eluent IPA + 0.5% DMEA:CO2

[0482] F.SFC Chiralpak AD-H, using eluent IPA + 0.5% DMEA:CO2

[0483] G. Chiralpak IC, using the eluent EtOH + 0.1% NH3H2O: heptane

[0484] H.SFC Chiralpack AD, using eluent IPA + 0.1% NH3H2O:CO2

[0485] I. Chiralcel IH, using eluent EtOH + ACN (0.1% DEA): heptane

[0486] J.SFC Chiralpak AD, using eluent EtOH + 0.5% DEA:CO2

[0487] K. Chiralpak IE, using the eluent EtOH + 0.1% NH3H2O:ACN

[0488] L. Chiralpak AD-H, using the eluent EtOH:ACN+0.2% IPAm

[0489] M. Chiralpak AD-H, using the eluent EtOH:ACN

[0490] N.SFC Chiralpak IC, using EtOH + 0.05% DMEA:CO2 as eluent

[0491] O.SFC Chiralcel OJ-H, using MeOH + 0.5% DMEA:CO2 as eluent

[0492] Table 18a: Examples 6-158 (Structures)

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514] Table 18b: 6-158 (Chemical Name)

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537] Example 159

[0538] 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-dodecylhydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-10-yl)benzonitrile

[0539]

[0540] At 0 °C, trifluoromethanesulfonic acid (920 μL, 10 mmol) was added dropwise to a suspension of 16α-hydroxyprednisolone (140 mg, 0.36 mmol) and tert-butyl 3-((4-cyano-3-(1,3-dioxolane-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate (140 mg, 0.34 mmol) in ACN (5 mL, 95 mmol). The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM containing 10% IPA. The combined organic layers were dried over MgSO4, filtered, and concentrated to a crude residue. The crude residue was purified by reverse-phase purification with 1:1 aqueous solution of 10 mM NH4HCO3 + 5% MeOH:ACN to give the title compound (12 mg, 6% yield). MS m / z 630.0 (M+H). 1H NMR(400.13MHz,d6-DMSO)δ7.70-7.67(m,1H),7.45-7.41(m,1H),7.33(d,J=10.1Hz,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,1 H),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).

[0541] hGR coactivator recruitment experiment

[0542] The activity of glucocorticoid compounds was measured using a LanthaScreen TR-Fret GR coactivator assay from Life Technologies (A15899). Compounds were acoustically transferred to assay plates at 3-fold serial dilutions (10-point), with a maximum concentration of 200 nM. 10 μL of a 2x solution of GR-LBD was added to the compound plate and incubated for 10 min. Then, 10 μL of a 2x solution of Fluoresein-SRC1-4 and Tb-labeled anti-GST antibody was added to the plate. The plate was incubated in the dark for two hours and then read on an Envision plate reader with excitation at 340 nm and emission at 520 nm (fluorescein) and 490 nm (terbium). The 520 / 490 emission ratio was analyzed using Genedata. To obtain percentage activity, data were compared to a DMSO negative control and a 4 μM dexamethasone positive control. The compounds exemplified below were tested according to the method described essentially as above and exhibited the activities listed in Table 19.

[0543] Table 19: In vitro potency of Examples 1, 2, 4 and 5 in hGR coactivator recruitment experiments.

[0544] 1 2.12 2 1.44 4 2.47 5 1.40

[0545] The compounds in Examples 6-44, 46-51, 53-79, and 81-158 provide relative IC50 values ​​of less than 200 nM. 50 The compounds in Examples 45, 52, and 80 provide relative IC50 values ​​greater than 200 nM. 50 .

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: Where R is H or ； R 1 It contains Cl, F, Br, I, CN, CH3, CH(CH3)2, OCH3, OCH2CH3, CH=CH2, cyclopropyl, OCF3, ； R 2 It is Cl, F, Br, I, CN, CH3, CH(CH3)2, OCH3, OCH2CH3, CH=CH2, cyclopropyl, or OCF3; R 3 It is NH2; and X is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C or a bond, wherein X is connected to ring A in the adjacent or metaposition.

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

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R is... 。 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is CH3.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is OCH3.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is F.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is F.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X is OCH2.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X is O.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X is CH2.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X is SCH2.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X is CH2S.

13. The compound according to any one of claims 1 and 4-6, or a pharmaceutically acceptable salt thereof, wherein said compound is a compound of the following formula: 。 14. The compound according to any one of claims 1 and 4-6, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the following formula: 。 15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the following formula: 。 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 17. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 22. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-21 in the preparation of a medicament for the treatment of atopic dermatitis.

23. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-21 in the preparation of a medicament for treating rheumatoid arthritis.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

25. A method for preparing a pharmaceutical composition comprising mixing a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

26. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is 。

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