Glucocorticoid receptor agonists

Abstract

To provide a compound useful for treating autoimmune and inflammatory diseases, for example, atopic dermatitis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis, and rheumatoid arthritis.SOLUTION: The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Atopic dermatitis is a chronic, pruritic, relapsing and remitting inflammatory skin disease that Although it occurs frequently in children, many adults also develop it. Current treatments for atopic dermatitis include: phototherapy, topical creams containing corticosteroids or calcineurin inhibitors, or the subcutaneously injectable biologic known as dupilumab. Treatment of atopic dermatitis Although progress has been made in treating atopic dermatitis and other inflammatory and autoimmune diseases, There remains a significant need for new compounds for this purpose.

[0003] WO 2017 / 210471 describes a compound that is useful for treating autoimmune or inflammatory diseases. Certain useful glucocorticoid receptor agonists and immunoconjugates thereof are disclosed. WO 2018 / 089373 discloses novel steroids, their protein cores, and steroid conjugates and methods for treating diseases, disorders, and conditions and administering the conjugate. Summary of the Invention

[0004] The present invention provides certain novel compounds that are glucocorticoid receptor agonists. The present invention relates to certain novel chemical compounds that are prodrugs of glucocorticoid receptor agonists. Additionally, the present invention provides compounds for the treatment of autoimmune and inflammatory diseases, such as atopic dermatitis. dermatitis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis The present invention provides certain novel compounds that are glucocorticoid receptor agonists useful in the treatment of do.

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

[0006] [ka] wherein R is H or:

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

[0008] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 is alkenyl, R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, CH2O, SCH2, CH2S, CH2, NH CH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond; X is attached to the phenyl ring A at the ortho or meta position, or a pharmaceutically acceptable salt thereof Provide an acceptable salt.

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

[0010] [ka] wherein R is H or:

[0011] [ka] R 1 H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 Alkoxy, C2-C3 alkenyl, OCF3,

[0012] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 is alkenyl, R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, OCH2C≡C, OCH(CH3), CH2O , SCH2, CH2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2 CH2, C≡C, or a bond, and X is attached to the phenyl ring A at the ortho or meta position. The present invention provides a compound, or a pharmaceutically acceptable salt thereof,

[0013] In one embodiment, the present invention provides a compound of formula Ib:

[0014] [ka] wherein R is H or:

[0015] [ka] R 1 H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 Alkoxy, C2-C3 alkenyl, OCF3,

[0016] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 is alkenyl, R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH 2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond, and X is attached to the phenyl ring A in the ortho or meta position, or a pharmaceutically acceptable salt thereof.

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

[0018] [ka] wherein R is H or:

[0019] [ka] R 1H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 Alkoxy, C2-C3 alkenyl, OCF3,

[0020] [ka] and R 2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 is alkenyl, R 3 is NH2 or CH2NH2, X is O, OCH2, OCH2CH2, OCH(CH3), CH2O, SCH2, CH 2S, CH2, NHCH2, CH2NH, N(CH3)CH2, CH2CH2, C≡C, or a bond, and X is attached to the phenyl ring A in the ortho or meta position, or a pharmaceutically acceptable salt thereof.

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

[0022] [ka] or a pharmaceutically acceptable salt thereof.

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

[0024] [ka] or a pharmaceutically acceptable salt thereof.

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

[0026] [ka] or a pharmaceutically acceptable salt thereof.

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

[0028] [ka] or a pharmaceutically acceptable salt thereof.

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

[0030] [ka] or a pharmaceutically acceptable salt thereof.

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

[0032] [ka] or a pharmaceutically acceptable salt thereof.

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

[0034] [ka] wherein R is H or:

[0035] [ka] R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof.

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

[0037] [ka] wherein R is H or:

[0038] [ka] R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof.

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

[0040] [ka] wherein R is H or:

[0041] [ka] R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof. Provide.

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

[0043] [ka] wherein R is H or:

[0044] [ka] R 1 is —CH3 or —OCH3, or a pharmaceutically acceptable salt thereof. Provide.

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

[0046] [ka] wherein R is H or

[0047] [ka] or a pharmaceutically acceptable salt thereof.

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

[0049] [ka] wherein R is H or

[0050] [ka] or a pharmaceutically acceptable salt thereof.

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

[0052] [ka] wherein R is H or

[0053] [ka] or a pharmaceutically acceptable salt thereof.

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

[0055] [ka] wherein R is H or

[0056] [ka] or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, R is H.

[0058] In one embodiment, R is

[0059] [ka]

[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 and R 1 is CH3 and R 2 is F and X is It is OCH2.

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

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

[0076] In one embodiment, X is attached to the 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 of treatment. 1. A method for treating a patient suffering from a rheumatoid arthritis, 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, comprising administering 1. A method of treating atopic dermatitis in a patient in need of such treatment, comprising administering to the patient: and administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a method for treating inflammatory bowel disease in a patient in need of treatment. A method of treating a disease comprising administering to a patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a method for treating rheumatoid arthritis comprising administering a salt thereof to a patient. 1. A method of treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient an effective

[0023] The present invention further provides a method comprising administering to a patient a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of In one embodiment, the present invention also provides a method for treating systemic lupus erythematosus. A method of treating systemic lupus erythematosus in a patient, comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also provides a method for treating lupus nephritis in a patient in need thereof. The method comprises administering to a patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. and

[0078] In one embodiment, the present invention provides a compound of formula I or a pharmaceutical formulation thereof for use in therapy. In one embodiment, the present invention provides a compound of formula (I) for treating an inflammatory disease. In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof is provided for use in In one aspect, the present invention provides a compound of formula I for use in treating atopic dermatitis. In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis. 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 method for treating inflammatory bowel disease. In one embodiment, the present invention provides a compound of formula I: 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 for treating systemic lupus erythematosus. The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in

[0079] In one embodiment, the present invention also provides a method for the manufacture of a medicament for treating an inflammatory disease, comprising: In one embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof: The present invention relates to a compound of formula I or a compound thereof for the manufacture of a medicament for treating atopic dermatitis. In one embodiment, the present invention provides the use of a pharmaceutical acceptable salt thereof for treating rheumatoid arthritis. Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of In one embodiment, the present invention provides a method for the manufacture of a medicament for treating inflammatory bowel disease. Further provided is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of rheumatoid arthritis. The present invention provides a method for the preparation of a medicament for treating lupus nephritis, comprising administering to a subject a compound of formula I or The present invention further provides the use of a pharmaceutically acceptable salt thereof. A compound of formula I or a pharmaceutical composition thereof for the manufacture of a medicament for treating sexual lupus erythematosus. The present invention provides for the use of environmentally acceptable salts.

[0080] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, comprising one or more and a pharmaceutically acceptable carrier, diluent, or excipient of In one embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising: A compound of formula I or a pharmaceutically acceptable salt thereof is dissolved in one or more pharmaceutically acceptable carriers, diluents, or the like. In one embodiment, the present invention further provides a process comprising mixing the compound with an agent or excipient. The disclosure also encompasses novel intermediates and processes for the synthesis of compounds of formula I.

[0081] As used herein, the terms "treating," "treatment," or "treating" The term refers to any action that inhibits, slows, stops, or reduces the progression or severity of an existing condition or disorder. Including reversing.

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

[0083] As used herein, the term "effective amount" refers to a compound of the present invention or a pharmaceutical These refer to amounts or doses of salts that are acceptable for the patient when administered as single or multiple doses. , to produce the desired effect in the patient being diagnosed or treated.

[0084] An effective amount can be determined by one skilled in the art by the use of known techniques and results obtained under analogous circumstances. In determining an effective amount for a patient, some These factors are taken into consideration by the treating diagnostician, and include the patient's race, the patient's size, Age and general health, the specific disease or disorder involved, the severity or involvement of the disease or disorder, The severity, response of the individual patient, the specific compound administered, the mode of administration, the nature of the preparation administered, Bioavailability characteristics, selected dosing regimen, use of concomitant medications, and other relevant This includes, but is not limited to, situations where

[0085] As used herein, Formula I refers to Formulas Ia, Ib, Ic, Ib(i), Ic(i), Ib(ii), Ic(ii), Ib(iii), Ic(iii), II, IIa, IIb It is understood that the present invention encompasses the following: All references in the specification to Formula I refer to Formulas Ia, Ib, Ic, Ib(i), Ic(i), Ib(i). ii), Ic(ii), Ib(iii), Ic(iii), II, IIa, IIb, II c, III, IIIa, IIIb, and IIIc. .

[0086] As used herein, Formula II includes Formulas IIa, IIb, and IIc. It is understood that all references herein to Formula II include Formulas IIa, IIb, and IIc. This should be interpreted as

[0087] As used herein, Formula III encompasses Formulas IIIa, IIIb, and IIIc. It is understood that all references herein to Formula III refer to Formulas IIIa, IIIb, and IIIc.

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

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

[0090] As used herein, "C3-C6 cycloalkyl" includes cyclopropyl, ... It refers to 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" includes HC=CH2 and C(CH 3) = Refers to CH2.

[0093] As used herein, the ortho and meta positions on the phenyl ring A are as shown in Formula I below. will be done.

[0094] [ka]

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

[0096] [ka] Compounds of formula I" show X attached at the ortho position to the phenyl ring A:

[0097] [ka]

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

[0099] In addition, the compounds of the present invention can be conjugated to antibodies by methods understood by those of skill in the art. Gating to form antibody drug conjugates (ADCs) One example of such conjugation is the conjugation of an antibody to a nucleotide sequence via a linker compound. Linker compounds known to those skilled in the art include, for example, cleavable Such ADCs comprise compounds of the invention that are: It can be delivered to specific target tissues or cells. Therefore, AD containing the compound of formula I Also provided herein are compounds of formula I, wherein the linker C is conjugated to the antibody, e.g., via a cleavable or non-cleavable linker. It is being done.

[0100] The compounds or conjugates of the present invention may be formulated as pharmaceutical compositions. The compound may be administered by any route that makes the compound or conjugate bioavailable. Such routes include, for example, oral, topical, or subcutaneous administration. Such pharmaceutical compositions can be prepared using techniques and methods known in the art. Such pharmaceutical compositions containing DCs can be prepared using techniques and methods known in the art. (e.g., Remington: The Science and Practice ice of Pharmacy,A.Adejare,Editor,23nd Ed ition, 2020 publication, Elsevier Science, International Publication No. 2017 / 062271 and WO 2017 / 210471).

[0101] Additionally, compounds of the present invention having a capped hydroxy group at C21 include those having the formula: R is:

[0102] [ka] behave as prodrugs and are metabolized in vitro or in vivo to form a compound in which R is H, Active glucocorticoid receptor agonists are provided.

[0103] Pharmaceutically acceptable salts of Formula I are included within the scope of the present invention. Compounds of the present invention, such as Pharmaceutically acceptable salts of compounds of formula I can be prepared, for example, by reacting the appropriate free base of the compound of the invention with with an appropriate pharmaceutically acceptable acid in a suitable solvent such as diethyl ether, as described in the art under standard conditions known in the art. SM,et al.,``Pharmaceutical Salts'',Journ al of Pharmaceutical Sciences,66:1-19,(1 See 977).

[0104] Certain compounds described in the preparations below are suitable nitrogen-containing compounds, referred to herein as "Pg." Protecting groups may be used depending on the particular reaction conditions and procedures, as will be understood by those skilled in the art. It is understood that the conditions for protection and deprotection may vary depending on the particular transformation being carried out. It is well known to those skilled in the art and described in the literature (see, for example, "Greene's Protein ctive Groups in Organic Synthesis”, Fourt h Edition, by Peter GMWuts and Theodora See W. Greene, John Wiley and Sons, Inc. 2007 I want to be illuminated).

[0105] [Table 1-1]

[0106] [Table 1-2]

[0107] The compounds of the present invention or salts thereof can be readily prepared by a variety of procedures known to those skilled in the art. Some of these are exemplified in the preparations and examples below. The specific synthetic steps for each may be performed in different ways or from different schemes. It is well known that the compound of the present invention or a salt thereof can be prepared by combining the above steps. The product of each step is extracted, evaporated, precipitated, chromatographed, It may be recovered by conventional methods known in the art, including filtration, trituration, and crystallization. All substituents, unless otherwise indicated, are as previously defined. Reagents and Starting Materials Materials are readily available to one of skill in the art. The following preparations, examples, and assays are provided to illustrate the invention. are further illustrated, but should not be construed as limiting the scope of the invention in any way.

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

[0109] [ka]

[0110] Two reactions were carried out in parallel: 4-Bromo-2-fluoro-2-(2-methyl-2-propanol) in THF (1500 mL) A solution of 250 g of 1-chloro-1-methoxybenzene (1.2 mol) was added to a solution of 2 M LDA (73 0 mL) was added slowly over 30 min at -78 °C. After another 30 min, DMF ( 140 mL, 1.8 mol) was added slowly over 30 minutes at -78°C. After a period of time, the two reactions were combined and the mixture was diluted with aq citric acid (2000 mL). The combined organic layer was extracted with saturated brine (1500 mL x 2). (1000 mL) and concentrated under reduced pressure to give a residue. The residue was diluted with petroleum ether (1 000 mL) at room temperature for 12 hours to give the title compound (382 g, 67% ES / MS m / z 233.9 (M+H).

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

[0112] [ka]

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

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

[0115] [ka]

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

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

[0118] [ka]

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

[0120] Preparation 5 (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-((6a R,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-dodecahydro-8bH-naphtho[2',1':4, 5]Indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy (c) Tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0121] [ka]

[0122] 3Å molecular sieves (5 g) were mixed with (6aR, 6bS, 7S, 8aS, 8bS, 10 S,11aR,12aS,12bS)-10-(3-((3-aminobenzyl)oxy) -2-fluoro-6-methylphenyl)-7-hydroxy-8b-(2-hydroxyacetone (ethyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,1 2,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1 ,2-d][1,3]dioxol-4-one (150 mg, 0.24 mmol, Example 2) 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranoside To 155 mg (0.37 mmol) of benzoyl bromide and 5 mL of DCM was added at room temperature. After 1 h, the reaction was cooled to 0°C. Silver(I) oxide (115 mg, 0.49 mm ol) and trimethylsilyl trifluoromethanesulfonate (45 μL, 0.24 mmol) l) was added. After 30 min, the reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was filtered through diatomaceous earth and rinsed with DCM (10 mL) and methanol (10 mL). The combined organic layer was concentrated under reduced pressure to give a residue, which was purified by reverse phase chromatography. and purified by 1:5 10 mM ammonium bicarbonate water + 5% methanol:acetonite Elution with trityl gave 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] [ka]

[0125] 2-Fluoro-4-methoxyphenol (25 g) in DMF (350 mL, 0.5 M) To a solution of tert-imidazole (18 g, 260 mmol) and tert- Butylchlorodiphenylsilane (55 mL, 200 mmol) was added. The mixture was stirred for 8 hours at room temperature, diluted with ethyl acetate, and the organic solution was diluted with water and brine. The residue was purified by normal phase chromatography. Purification by HPLC and elution with 5:1 hexane:ethyl acetate gave the title compound (67 g, 9 3% yield). 1 H NMR(399.8MHz,d6-DMSO)δ7.67~ 7.65(m,4H),7.51~7.44(m,6H),6.82(dd,J=2.9 ,12.7Hz,1H),6.59(t,J=9.4Hz,1H),6.47(ddd, J=9.0,3.0,1.4Hz,1H),3.64(s,3H),1.06(s,9H ).

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

[0127] [ka]

[0128] tert-Butyl(2-fluoro-4-methoxyphenoxy)diphenylsilane (56 g, 150 mmol, Preparation 6) was dissolved in 50 mL of toluene and heated 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 added to the cooled solution. After 1.5 hours, DMF (25 mL, 320 mm Hg) was added rapidly via a wide-bore cannula. ol) was added to the solution and the ice bath was removed. After 30 min, 5N aqueous HCl (35 mL) was added to the reaction, followed by tetrabutylammonium fluoride (1M in THF, After 2.5 hours, the organic layer was evaporated and washed with 5N The mixture was acidified with 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. The residue was purified by normal phase purification and dissolved in 1:1 hexane:ethyl acetate. The title compound (22 g, 88% yield) was obtained. MS m / z 170.8 (M+ H).

[0129] [ka]

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

[0131] [ka]

[0132] 2-Fluoro-3-hydroxy-6-methoxybenzaldehyde (2.5 g, 15 mm ol) and tert-butyl N-[3-(bromomethyl)phenyl]carbamate (5. 1 g, 18 mmol) was dissolved in acetonitrile (50 mL). 2.9 g, 29 mmol) was added to the slurry and the reaction was stirred at room temperature. The reaction was then warmed to 40° C. After 3 hours, the reaction was cooled, filtered and the solvent evaporated. The crude residue was purified by normal phase purification, eluting with 7:3 hexanes:EtOAc to give The title compound was obtained (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] [ka]

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

[0142] [ka]

[0143] In a microwave tube, tert-butyl (3-((4-bromo-3-formylphenoxy) )methyl)phenyl)carbamate (0.73g, 1.8mmol), 2-furylboron Acid (0.30 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.10 g, 0.09 mmol), and N,N-diisopropylethylamine ( The HCl (1.6 mL, 1.2 mmol) was dissolved in DMF (2 mL, 26 mmol). The reaction was flushed with N2 and capped. The reaction was microwaved at 140 °C for 45 min. The reaction 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 in Preparation 51: .

[0145] [Table 3]

[0146] [ka]

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

[0148] [ka]

[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 mm ol) 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. tert-Butylphosphino)ferrocenedichloropalladium(II) dichloromethane complex The mixture was degassed, capped, and The reaction was heated to 0° C. for 2.25 hours. The reaction was cooled, filtered through diatomaceous earth, and the solvent was evaporated. The crude residue was purified by normal phase chromatography and dissolved in 7:3 hexane:EtOAc. The title compound (1.5 g, 63% yield) was obtained. 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] [ka]

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

[0154] [ka]

[0155] 3-(Bromomethyl)benzaldehyde (320 mg, 1.5 mmol), tert- Butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) (phenyl)carbamate (300 mg, 0.94 mmol), and potassium carbonate (4 10 mg, 3.0 mmol) in a vial containing toluene (9 mL) and water (1 mL). The reaction was purged with argon. Sphino)ferrocene dichloropalladium(II) dichloromethane complex (80 mg, 0. 10 mmol) was added, the vial was capped, and heated to 100°C for 1.5 hours. The reaction was cooled, filtered through diatomaceous earth and the solvent was evaporated. The crude residue was purified by normal phase chromatography. Purification by filtration and elution with 7:3 heptane: EtOAc gave the title compound (300 ml). g, 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] [ka]

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

[0160] [ka]

[0161] tert-Butyl 3-(bromomethyl)phenylcarbamate (1.5 g, 5.0 mm ol), 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-diol) (2-oxaborolan-2-yl)benzaldehyde (1.5 g, 5.6 mmol), and carbon dioxide Sodium (2.1 g, 3.0 mmol) was dissolved in water (1 mL) and toluene (9 mL). The reaction mixture was purged with N2 and 1,1'-bis(di-tert- Butylphosphino)ferrocenedichloropalladium(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. Purification by chromatography and elution with 1:1 heptane:EtOAc gave 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] [ka]

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

[0166] [ka]

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

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

[0169] [Table 7]

[0170] [ka]

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

[0172] [ka]

[0173] 5-hydroxy-2-methoxybenzaldehyde (1.00 g, 6.57 mmol), [4-(tert-butoxycarbonylamino)phenyl]boronic acid (3.12 g, 13 0.2 mmol), copper(II) acetate (1.19 g, 6.57 mmol), and 4 Å molecular weight Sieves (1.0 g) were added to the flask. DCM (60 mL) and trifluoroacetate were then added. Ethylamine (4.6 mL, 33 mmol) was added and the reaction mixture was stirred at room temperature overnight. Further [4-(tert-butoxycarbonylamino)phenyl]boronic acid (1. 1 g, 4.6 mmol) and copper(II) acetate (400 mg, 2.2 mmol) were added, The reaction mixture was stirred at room temperature for 3 days. 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. The product (400 mg, 18% yield) was obtained. MS m / z 361.0 (M+NH4).

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

[0175] [Table 8]

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

[0177] [ka]

[0178] 3-Ethynyl-2-fluorobenzaldehyde (0.25 g, 1.7 mmol) was added to tert-Butyl N-(3-iodide) in triethylamine (10 mL, 72 mmol) (phenyl)carbamate (0.55 g, 1.7 mmol), bis(triphenylphosphine ) Palladium(II) dichloride (0.025 g, 0.036 mmol) and copper iodide (I) (0.01 g, 0.05 mmol) was mixed under N2. The reaction mixture was stirred at room temperature. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was Washed with 1M aq HCl, brine, dried over Na2SO4, and filtered. Evaporation gave the title compound (0.57 g, 100% yield). MS m / z 338. 2(MH).

[0179] [ka]

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

[0181] [ka]

[0182] In a microwave vial, add 2-(2-bromo-6-fluoro-3-methoxyphenyl)- 1,3-Dioxolane (970 mg, 3.5 mmol), THF (600 μL, 4.3 m mol) and 1,4-dioxane (12m L, 140 mmol) and cesium carbonate (2.3 g, 7.1 mmol) was added. The solution was degassed with N2 for 2 minutes. [1,1'-bis(diphenyl) [phenylphosphino]ferrocenedichloropalladium(II) (130 mg, 0.17 m mol) was added and the solution was degassed with N2 for 2 minutes. The vial was capped and 110 The reaction mixture was diluted with water (10 mL) and added EtOAc ( The organic layer was dried over Na2SO4, filtered through paper, and rotary evaporated. The crude oil was purified by normal phase chromatography and purified with 7:3 hexamethylpropional. Elution with MTBE gave the title compound (0.61 g, 82% yield). 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] *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,1 H),6.96(d,J=7.8Hz,1H),4.22(s,2H),1.46(s, 10H) **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),7.22~7.20(m,1H),7.14~7.12(m,1H),7.0 7~7.02(m,1H),6.95~6.91(m,1H),5.21(s,2H), 2.57(s,3H), 1.43(s,9H)

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

[0186] [ka]

[0187] Boron tribromide (14 mL, 14 mmol, 1 mol / L) in DCM for a period of 2 min 2-(6- Fluoro-3-methoxy-2-methylphenyl)-1,3-dioxolane (600 mg, 2.8 mmol). After the addition, the bath was removed. After 30 minutes, the reaction was The reaction was quenched with td aq NH4Cl. The reaction was diluted with DCM and quenched with 2M aq Na The organic layer was washed with OH and then with 5M aq HCl. The organic layer was dried over Na2SO4. The crude residue was purified by normal phase chromatography. Purification by filtration and elution with 7:3 hexane:EtOAc gave the title compound (130 ml). g, 30% yield), MS m / z 153.0 (M−H).

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

[0189] [ka]

[0190] 4-Fluoro-2-methoxy-phenol (2.3 g, 16 m A solution of 1.2g (3.2g) of imidazole (2.8g, 41mmol) and tert-butylchloroisothiazolinone (2.8g, 41mmol) was added to the solution. Diphenylsilane (6 mL, 23 mmol) was added. After 1.75 h, the solvent was evaporated. The residue was diluted with 200 mL of 10% EtOAc in hexane and 100 mL of water. The organics were washed once with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by normal phase chromatography, eluting with 9:1 hexanes:EtOAc. Elution gave the title compound (6.7 g, quantitative yield). 1 H NMR (399.8 M z,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)

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

[0192] [ka]

[0193] tert-Butyl(4-fluoro-2-methoxyphenoxy)diphenylsilane (3. 2 g, 8.5 mmol) was dissolved in tetrahydrofuran (30 mL) and heated to -78°C. n-Butyllithium (7 mL, 11 mmol, 1.6 M) was added over a period of 3 min. After 1.5 hours, DMF (2 mL) was added at -78°C. After 1 hour, approximately 4 mL of 10% aq NH4Cl was added and allowed to warm to room temperature over 1.5 hours. Evaporation of the solvent gave a crude residue which was then acidified with 1M aq HCl and diluted with water for 30 minutes. The organic layer was washed with water, brine and diluted with MgSO4. It was dried, filtered and evaporated. The crude residue was purified by normal phase chromatography to give 3: Elution with hexane:EtOAc (2%) gave 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-dioxolane-2- (2-fluorophenoxy)methyl)phenyl)carbamate

[0195] [ka]

[0196] tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)- 2-Fluorophenoxy)methyl)phenyl)carbamate (200 mg, 0.43 mm ol), cyclopropylboronic acid (0.21 g, 2.4 mmol), and potassium phosphate tribasic. The cellulose (0.28 g, 1.3 mmol) was placed in a 25 mL vial purged with N2. Toluene (3 mL) and water (0.75 mL) were added, and the reaction mixture was purged with N2 for 5 minutes. The mixture was degassed for 1 hour, and then tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) was added in one portion. The reaction was heated to 100° C. overnight. After cooling to rt, 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 using 1:1 hexane:EtOA. Elution with HPLC at 0.5°C gave the title compound (170 mg, 94% yield). MS m / z 428 .4(MH).

[0197] Preparation 83 (2,6-dimethyl-3-nitrophenyl)methylene diacetate

[0198] [ka]

[0199] 2,6-Dimethyl-3-nitrobenzaldehyde (1.9 g, 10 mmol) was added to DC M (23 mL), and then acetic anhydride (1.3 mL, 14 mmol) and trimethylsilyl methylcellulose (1.4 mL, 14 mmol) were added. Copper(II) fluoromethanesulfonate (41 mg, 0.11 mmol) was added. The mixture was stirred at room temperature for 3.5 hours. The reaction was quenched with saturated aqueous NaHCO3. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by normal phase chromatography and purified with 3:2 hexachloroisothiazolinone. Elution with hexane: EtOAc gave the title compound (2.4 g, 81% yield). 1 HNM R(400.13MHz,DMSO-d6):7.96(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).

[0200] Preparation 84 (3-amino-2,6-dimethylphenyl)methylene diacetate

[0201] [ka]

[0202] 5 wt% platinum sulfide on carbon (1.0 g, 5.2 mmol) was added to a 500 mL Parr Add to a shaker bottle and degas with N2. Add 25 mL of EtOAc, then 25 mL (2,6-dimethyl-3-nitrophenyl)methylene diacetate (2 0.7 g, 9.6 mmol) was added to the bottle. The bottle was sealed and purged with N2. The mixture was purged with H2 and pressurized to 60 psi of H2 for 1.5 hours at room temperature. 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)methylene diacetate

[0204] [ka]

[0205] (3-amino-2,6-dimethylphenyl)methylenediacetate in DMF (3 mL) sodium phosphate (276 mg, 1.10 mmol) and potassium carbonate (435 mg, 3.15 mmol) The mixture of tert-butyl N-[3-(bromomethyl) phenyl]carbamate (300 mg, 1.05 mmol) was added to the slurry and the reaction The mixture 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 DMF was evaporated (azeotroped) with xylene to give a residue as a clear paste. The residue was purified by normal phase purification, eluting with 1:1 EtOAc:hexane to give the title compound. The product (363 mg, 76% yield) was obtained. MS m / z 457.2 (M+H).

[0206] [ka]

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

[0208] [ka]

[0209] tert-Butyl (3-formylphenyl)carbamate (1.2 g, 5.2 mmol ), methyl 3-amino-2-fluoro-6-methylbenzoate (950 mg, 4.8 m mol) and acetic acid (0.55 mL, 9.6 mmol) were dissolved in methanol (5 mL). The mixture was cooled to 0°C and sodium cyanoborohydride (0.61 g, 9.5 mmol) was added. l) 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 diluted with EtO The combined organic extracts were washed with brine and added Na2S Drying over O4, filtration, and concentration gave a crude residue which was purified by normal phase chromatography. Purification by elution with 3:2 Pet ether: EtOAc gave the title compound (1.9 g , 75% yield) MS m / z 389.0 (M+H).

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

[0211] [Table 10]

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

[0213] [ka]

[0214] N-Bromosuccinimide (5.8 g, 31 mmol) in carbon tetrachloride (36 mL) of methyl 6-bromo-2-fluoro-3-methylbenzoate (3.9 g, 14 mmol) ), followed by a solution of 2,2'-azobis(2-methylpropionitrile (0.2 4 g, 1.4 mmol) was added and the reaction mixture was stirred at 85° C. overnight. Diluted with CM, 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 The eluate was concentrated to give methyl 6-bromo-3-( Dibromomethyl-2-fluorobenzoate (1.9 g, 4.6 mmol) was obtained. The substance was dissolved in ethanol (15 mL). Silver nitrate (2.0 g, A mixture of 12 mmol) was added and the reaction mixture was heated at 75° C. for 6 h under N 2 . The reaction product was filtered and washed with EtOAc. The filtrate was concentrated to give a crude residue. The compound was purified by normal phase chromatography, eluting with 8% EtOAc:Pet ether. This gave the title compound (1.1 g, 91% yield).

[0215] [ka]

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

[0217] [ka]

[0218] Methyl 6-bromo-2-fluoro-3-formylbenzoate (1.0 g, 3.7 mm ol), tert-butyl N-(3-aminophenyl)carbamate (870 mg, 4. 1 mmol), and acetic acid (0.43 mL, 7.5 mmol) in methanol (9 mL) The solution was cooled to 0°C. Sodium cyanoborohydride (480 mg, 7.5 m mol) 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 mixture was stirred at rt. The reaction was quenched by the addition of water (30 mL). The combined organic extracts were washed with brine and added to a 100 ml solution of NaCl. The crude residue was purified by normal phase chromatography. The product was purified by column chromatography and eluted with 7:3 Pet ether: EtOAc to give the title compound (1. 7g, 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: Ta.

[0220] [Table 11]

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

[0222] [ka]

[0223] Methyl 3-((3-((tert-butoxycarbonyl)azoline)) in methanol (5 mL) (amino)benzyl)amino)-2-fluoro-6-methylbenzoate (1.7g, 3.3 To a solution of 1000 mg (420 mmol) of sodium cyanoborohydride (420 mg, 6.5 mmol) and acetic acid (0.5 mL, 9 mmol) were added. Then, formaldehyde (73 0 μL, 9.8 mmol, 37% by weight of HCl was added at 25° C. The mixture was heated at room temperature overnight under N The crude mixture was purified by normal phase chromatography and washed with 4:1 PetEt Elution with ether: EtOAc gave the title compound (1.3 g, 92% yield). m / z 403.0 (M+H).

[0224] [ka]

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

[0226] [ka]

[0227] Methyl 3-((3-((tert-butoxycarbonyl)amine)) in DCM (10 mL) (benzyl)(methyl)amino)-2-fluoro-6-methylbenzoate (1.2g , 2.8 mmol) solution in toluene. 0.0 mol / L) was added at 0°C. The reaction mixture was allowed to warm to room temperature for 3 hours. After cooling back to 0°C, saturated aqueous Rochelle's salt and DCM were added, followed by DCM. The organic layer was washed with brine, dried over Na2SO4, and purified by silica gel chromatography. The residue was purified by normal phase chromatography to give 1 Elution with Pet ether: EtOAc: 1 gave the title compound (640 mg, 57% yield) ) was obtained. 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: Ta.

[0229] [Table 12] *1 H 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).

[0230] [ka]

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

[0232] [ka]

[0233] tert-Butyl (3-(((2-fluoro-3-(hydro) (4-methylphenyl)(methyl)amino)methyl)phenyl)carbamate To a solution of 2-iodoxybenzoic acid (630 mg, 2 0.2 mmol) was added. The reaction mixture was stirred at 80°C for 6 hours. The solid was removed by filtration. The filtrate was concentrated to give a crude residue, which was purified by normal phase chromatography. Elution with 7:3 Pet ether: EtOAc gave 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: Ta.

[0235] [Table 13] *1 H NMR(400.15MHz,DMSO):δ10.331(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=1.0Hz, 2H) **1 H 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).

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

[0237] [ka]

[0238] 2-Fluoro-3-hydroxy-6-methylbenzyl in acetonitrile (10 mL) Aldehyde (250 mg, 1.5 mmol) and 4-((tert-butoxycarbonyl )Amino)phenethyl 4-methylbenzenesulfonate (760 mg, 1.9 mmol) To the solution was added potassium carbonate (670 mg, 4.9 mmol). The suspension was heated to 80°C. The mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in water (40 The combined organic layers were diluted with ethyl acetate (20 mL) and extracted with EtOAc (20 mL). Wash with ethanol (20 mL), dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure to give the residue The residue was purified by normal phase chromatography to give a 17:3 Pet ether: Elution with EtOAc gave 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,1 H),4.12(t,J=7.0Hz,2H),3.01(t,J=6.9Hz,2H) ,2.45(s,3H),1.45(s,8H).

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

[0240] [ka]

[0241] 6-Bromo-3-(bromo)-2-(2-bromo-2-methyl-2-methylpropional) in THF (100 mL) under a nitrogen atmosphere cooled in an ice bath To a solution of (4.9 g, 11 mmol) 2-fluorobenzoic acid in THF Lan-THF complex (35 mL, 35 mmol, 1 mol / L) was added dropwise. The reaction was cooled to room temperature and allowed to warm to room temperature overnight. The resulting residue was dissolved in 100 mL of 1M HCl and concentrated in vacuo. 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 using 7:3 Pet ether:EtO Elution with Ac gave 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).

[0242] [ka]

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

[0244] [ka]

[0245] 6-Bromo-3-(bromomethyl)-2-fluorobenzalkonium chloride in DCM (10 mL) aldehyde (620 mg, 1.9 mmol) and tert-butyl N-(3-sulfanyl A mixture of phenyl)carbamate (500 mg, 2.0 mmol) and triethylamine (530 μL, 3.8 mmol) was added under N2. The mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between DCM (30 mL) and water (30 mL). The combined organic extracts were concentrated in vacuo to give a crude residue, which was purified by normal phase chromatography. and eluted with 3:1 Pet ether: EtOAc to give the title compound (780m g, 89% yield). 1 H 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=8.6Hz,1H),7.19(t,J=7.9Hz ,1H),6.96(d,J=7.8Hz,1H),4.21(s,2H),1.46( s,9H).

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

[0247] [Table 14]

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

[0249] [ka]

[0250] Methyl 3-(((2-amino)methyl (phenyl)thio)methyl)-6-bromo-2-fluorobenzoate (1.3 g, 3.4 To a solution of di-tert-butyl dicarbonate (3.5 mL, 15 mmol) ) was added. The mixture was stirred at 50 °C overnight under N2. The reaction was concentrated in vacuo to give The residue was purified by normal phase chromatography and washed with 10:1 Pet Acetone. Elution with ether: EtOAc gave 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] [ka]

[0253] 3-Bromo-2-fluoro-4-methylbenzaldehyde (2 g, 6.6 To a solution of 100 mmol of methyl 2,000 sulphite (2.5 mmol), sodium borohydride (620 mg, 16 mmol) was added at 0°C. The mixture was stirred for 1 hour. The mixture was washed with 1 M aq HCl (30 mL) The reaction mixture was slowly quenched under N2 and adjusted to pH 6. The reaction mixture was concentrated in vacuo to give crude The residue was purified by normal phase chromatography using 1:2 Pet ether: Elution with EtOAc gave the title compound (820 mg, 51% yield).

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

[0255] [ka]

[0256] (3-bromo-2-fluoro-4-methyl) phenyl)methanol (650 mg, 2.7 mmol), tert-butyl(3-hydroxybenzoate) (870 mg, 4.0 mmol), and tetrabutylphosphine A solution of N,N,N',N'-tetramethylazodiamine (1.1 g, 5.4 mmol) was added to Carboxamide (940 mg, 5.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was stirred under anhydrous N2 for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The combined organic extracts were washed with brine (200 mL) and Dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue. Purification by chromatography eluting with 9:1 Pet ether: EtOAc gave the title compound. The compound (1.2 g, 96% yield) was obtained. MS m / z 355.8 (M-tBu+H). .

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

[0258] [ka]

[0259] tert-Butyl (3-((3-bromo-2-furan)) in THF (5 mL, 62 mmol) (fluoro-4-methylbenzyl)oxy)phenyl)carbamate (0.82g, 1.8m mol) solution, isopropylmagnesium chloride lithium chloride complex solution in THF (3.1 mL, 4.0 mmol, 1.3 mol / L) was added at 0°C and stirred for 30 minutes. DMF (450 μL, 5.7 mmol) was added to the mixture at 0° C. Warm to room temperature for 1.5 h, then add saturated aq NH4Cl (5 mL) The reaction mixture was quenched with 10 mL of EtOAc and 10 mL of water. The combined organic extracts were concentrated in vacuo to give the crude product. Purification was performed by phase chromatography, eluting with 95:5 Pet ether: EtOAc. The title compound (220 mg, 25% yield) was obtained. MS m / z 259.9 (MB oc+H).

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

[0261] [ka]

[0262] Cesium carbonate (230 mg, 0.71 mmol) was dissolved in tert -butyl(2-hydroxyphenyl)carbamate (100 mg, 0.47 mmol) and and 6-bromo-3-(bromomethyl)-2-fluoro-benzaldehyde (160 mg, The reaction mixture was stirred at room temperature for 1 hour under N2, The reaction mixture was then quenched by adding water. The combined organic extracts were concentrated in vacuo to give the crude product. The residue was purified by normal phase chromatography using 4:1 Pet ether:EtO Elution with Ac gave the title compound (210 mg, quantitative yield). 1 H NMR (400 .21MHz,DMSO):δ10.24(s,1H),8.08(s,1H),7.8 2(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).

[0263] [ka]

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

[0265] [ka]

[0266] S-(2-((tert-butyl)methyl)-2-((2- ... (Cyclohexyl)amino)benzyl)ethanethioate (670 mg, 2.2 mmol) To the solution of 3-bromo-2-fluoro-6-methyl-benzaldehyde (550 mg, 1 0.8mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl Isopropylbiphenyl (220 mg, 0.44 mmol), potassium carbonate (610 mg, 4.4 mmol) mol), and tris(dibenzylideneacetone)dipalladium(0) (210 mg, 0 0.22 mmol) was added. The mixture was heated to 100° C. overnight. Upon completion, the reaction mixture The product was concentrated under reduced pressure. The residue was diluted with water (20 mL) and added to EtOAc (20 mL x 2 The combined organic layers were washed with brine (40 mL) and extracted with Na2SO4 The residue was purified by normal phase chromatography. The title compound (670 mg, 5%) was obtained by elution with 95:5 Pet ether: EtOAc. 4% yield), MS m / z 275.9 (M-Boc+H).

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

[0268] [Table 15]

[0269] [ka]

[0270] Preparation 117 tert-Butyl (2-(((2-fluoro-3-formyl-4-methylphenyl)acetate Aminomethylphenylcarbamate

[0271] [ka]

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

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

[0274] [Table 16]

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

[0276] [ka]

[0277] tert-Butyl (3-(bromomethyl)phenyl)carbamate (2.0 g, 6.7 (1.6 g, 14 mmol) and potassium thioacetate (1.6 g, 14 mmol) in DMF (9 mL, 12 The reaction was dissolved in 1000 mg of methylpropional (0.0 mmol) and stirred at room temperature under N2 for 2 hours. Quench by addition of NH4Cl (20 mL) and extract with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (20 mL) and Drying, filtration and concentration in vacuo gave the crude product. The residue was purified by normal phase chromatography. and eluted 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] [ka]

[0280] Diethyl (4-nitrobenzyl)phosphonate (1.7 g, 6.1 mmol) and 15-crown-5 (1.3 g, 5.7 mmol) in oil. Sodium hydride (340 mg, 8.5 mmol, 60% by weight) was added. After stirring for 10 minutes, methyl 6-bromo-2-fluoro-3-formylbenzoate (1. After 1.5 hours, the reaction was stirred at 4°C for 1 hour. The reaction was quenched by the addition of 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-phenyl Fluoro-6-methylbenzoate

[0282] [ka]

[0283] Methyl (E)-2-fluoro-6-methyl-3-(4-nitrophenyl)-2-(2-methyl-4-nitrophenyl)-2 ... A solution of palladium (65 0 mg, 0.31 mmol) and di-tert-butyl dicarbonate (0.57 mL, 2.5 mmol) was added. 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 the crude product. The residue was purified by normal phase chromatography using a 3:2 mixture of Pet ether:E Elution with tOAc gave the title compound (620 mg, 69% yield). 1 H NMR( 400.21MHz,DMSO):δ9.24(s,1H),7.34(d,J=8.3 Hz,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).

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

[0285] [ka]

[0286] With a Dean-Stark trap attached, add toluene (16 mL, 150 mmol) 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, A solution of 0.25 mmol) was refluxed at 135°C for 1 hour. The reaction solution was cooled to room temperature. The mixture was diluted with water (15 mL) and EtOAc (25 mL). The phases were separated and the aqueous phase was diluted with EtO The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by normal phase chromatography using 24:1 DCM: Elution with MeOH gave the title compound (1.2 g, 44% yield). MS m / z 4 86.8(M+NH4).

[0287] Alternative preparation 122 tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)- 2-Fluorophenoxy)methyl)phenyl)carbamate With a Dean-Stark trap attached, 6-bromo -2-fluoro-3-hydroxybenzaldehyde (1.04 g, 4.75 mmol), Ethylene glycol (1.1 mL, 20 mmol) and p-toluenesulfonic acid monohydrate A solution of the product (88 mg, 0.46 mmol) was refluxed at 135° C. for 1 hour. It was cooled to room temperature and washed with water (15 mL). The phases were separated. The organic layer was washed with Na2SO4 Drying, filtration and evaporation gave a crude residue which was purified by normal phase chromatography to give Purify and elute with 20:1 DCM:MeOH to give 4-bromo-3-(1,3-dioxo- (2-lan-yl)-2-fluoro-phenol (1.06 g, 4.03 mmol) was obtained. 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 minutes. Then, tert-butyl ether was added. Add ethyl 3-(bromomethyl)phenylcarbamate (1.21 g, 4.23 mmol) The mixture was then diluted with water (40 mL) and The mixture was extracted with HCl (40 mL). The phases were separated. The organic layer was dried over Na2SO4 and filtered. Filtration and evaporation gave a crude residue, which was purified by normal phase chromatography to give 3: Elution with 1 EtOAc:hexane gave tert-butyl (3-((4-bromo-3-( 1,3-Dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate Bamate (1.72 g, 3.66 mmol, 77% yield) was obtained. MS m / z 48 5.0, 487.2 (M+NH4).

[0288] [ka]

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

[0290] [ka]

[0291] tert-Butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)- 2-Fluorophenoxy)methyl)phenyl)carbamate (400 mg, 0.85 mm ol), potassium vinyltrifluoroborate (0.14 g, 1.0 mmol), and charcoal Cesium chloride (0.84 g, 2.6 mmol) was placed in a 25 mL N2-purged microcentrifuge. The mixture was placed in a vial and THF (9 mL) and water (1 mL, 56 mmol) were added. The mixture was degassed by bubbling subsurface N2 for 5 min, and palladium(II) acetate ( 10 mg, 0.04 mmol) was added and the reaction was heated to 100° C. overnight. The mixture was cooled to room temperature for 3 days. EtOAc and water were added, the phases were separated, and the aqueous layer was diluted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by normal phase chromatography using a 3:2 hexanes to give a crude residue. Elution with EtOAc gave the title compound (320 mg, 16% yield). MS m / z 369.6(MH).

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

[0293] [Table 17]

[0294] Preparation 125 tert-Butyl N-[3-[[3-(1,3-dioxolan-2-yl)-2-fluoro O-4-isopropyl-phenoxymethylphenylcarbamate

[0295] [ka]

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

[0299] In a microwave vial, tert-butyl ether was dissolved in DMF (2.5 mL, 32 mmol). 3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenyl) (240 mg, 0.50 mmol), cyanide Zinc (130 mg, 1.1 mmol) and zinc chloride (1.0 mL, 0.50 mmol) in THF A mixture of tetrakis(triphenylphosphine) and tetrakis(triphenylphosphine) (0.500 mol / L) was aerated with N2. (Nylphosphine)palladium(0) (31 mg, 0.03 mmol) was added to the reaction mixture. The mixture was purged with N2, capped, and microwaved at 110 °C for 1 h. Zinc cyanide (120 mg, 1.0 mmol) and tetrakis(triphenylphosphine ) Palladium(0) (27 mg, 0.02 mmol) was added. The reaction mixture was then purged with N The reaction mixture was vented, capped, and microwaved at 120° C. for 30 minutes. The organic layer was dried over Na2SO4, filtered through paper, and rotary evaporated. The residue was purified by normal phase chromatography and purified with 7:3 hexachloroisothiazolinone. Elution with EtOAc gave the title compound (90 mg, 43% yield). z 412.6(MH).

[0300] [ka]

[0301] In Scheme 17, a compound of structure 1 (wherein R is H) can be reacted with a compound of structure 2 wherein Pg is a suitable nitrogen protecting group, for example, tert-butyloxycarbonyl. , G is less than or equal to

[0302] [ka] Reacting under conditions well known to those skilled in the art to provide compounds of formula I, where R is hydrogen. do.

[0303] More specifically, as shown in Scheme 17A below, a compound of structure 1a, wherein: R is H) 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] [ka]

[0305] For example, about 1 equivalent of a compound of structure 1a (wherein R is H) and about 1 equivalent of structure Compound 2 (wherein Pg and G are as defined in Scheme 17) is reacted with a suitable The suspension is suspended in an organic solvent, such as acetonitrile, and the suspension is heated to about -10°C to about -25°C. and then add about 5 equivalents of a suitable acid, such as perchloric acid (70% in water) or trichloro The reaction mixture is then warmed to room temperature and stirred for about 1 to 8 hours. The addition of further organic solvents, such as acetonitrile and dimethylformamide, also The mixture is then allowed to stir for approximately another 2 hours. The reaction is then heated to 200°C using standard conditions. The product is quenched with, for example, saturated aqueous sodium bicarbonate, and purified by methods well known in the art. Standard techniques, e.g., extraction with a suitable organic solvent such as methylene chloride:isopropyl alcohol, The organic extract was isolated using HCl, dried over magnesium sulfate, filtered, and concentrated under vacuum. This crude mixture may be purified to give the compounds of formula Ib and formula Ic. The compounds are separated using techniques well known in the art, such as chromatography. Chromatography may be carried out in a suitable eluent such as MeOH in DCM. Phase chromatography and 2:1 10 mM ammonium bicarbonate solution + 5% methanol. HPLC: Reverse phase chromatography with a suitable eluent such as 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]dioxole- 4-on

[0307] [ka]

[0308] Perchloric acid (70% in water, 4.8 mL) was dissolved in acetonitrile (110 mL) and S,9S,10R,11S,13S,14S,16R,17S)-11,16,17- Trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9 ,11,12,14,15,16-Octahydro-6H-cyclopenta[a]phenanthrene Ren-3-one (4.4 g, 12 mmol, 16 alpha-hydroxyprednisolone ") and tert-butyl N-[3-[(2-fluoro-3-formyl-4 (4.0 g, 11 mmol, prepared The suspension of Preparation 4) was added at -10°C and allowed to warm to room temperature. After 1 hour, DMF (10 ml) L) was added to the suspension at room temperature. After 18 hours, the reaction was diluted with saturated aqueous sodium bicarbonate. The mixture was quenched with a solution of 100 ml of toluene and extracted with 9:1 methylene chloride:isopropanol. The extracts were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue. was purified by reverse phase chromatography and diluted 1:1 with 10 mM ammonium bicarbonate water. Elution with +5% methanol:acetonitrile gave the title compound, peak 1 (1.72 g, 25% yield) ES / MS m / z 618.6 (M+H). 1 H NMR(4 00.13MHz,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,3 H),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).

[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]dioxole- 4-on

[0310] [ka]

[0311] From Example 1, the residue was purified by reverse phase chromatography using a 1:1 10 mM charcoal Elution with aqueous ammonium hydrogen carbonate + 5% methanol:acetonitrile gave the title compound peak. Compound 2 (1.24 g, 18% yield) was obtained. ES / MS m / z 618.6 (M+H) . 1 H NMR (400.13 MHz, d6-DMSO) δ 1 H NMR (400.13 MHz,DMSO):0.88(s,3H),1.24~1.12(m,2H),1.4 0(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,1 H),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).

[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,5 R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 H-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] [ka]

[0314] (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(2-((6a R,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-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 0.04 mmol, Preparation 5) was dissolved in methanol (2 mL) and potassium carbonate (20 mg, 0 After 1 hour, the mixture was loaded onto diatomaceous earth and purified by reverse phase chromatography. Purified by filtration and diluted in 1:2 10 mM ammonium bicarbonate water + 5% methanol. Elution with acetonitrile gave the title compound (19 mg, 57% yield). MS m / z 780.4 (M+H). 1 H NMR (500.11 MHz, d6-DM SO)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,3H),2.40~2.35(m,1H),3.5 0~3.46(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),4.4 3~4.39(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),5.1 2~5.08(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).

[0315] Example 4 (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS) -10-(3-((3-aminobenzyl)oxy)-2-fluoro-6-methoxyphenyl (2-hydroxyacetyl)-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]dioxole -4-on

[0316] [ka]

[0317] tert-Butyl (3-((2-furan)) in acetonitrile (100 mL) at -20 °C (Fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl)carbamate (2 0.6 g, 6.9 mmol, Preparation 8) and 16 alpha-hydroxyprednisolone (2 To a suspension of 0.5 g, 6.6 mmol) perchloric acid (70% in water, 3.3 mL, 5 equiv.) The mixture was stirred at -20°C for 7 hours. The solution was transferred to a separatory funnel. , dropwise into 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 at 5 and adjusted to pH 8 with 5N aqueous NaOH. The suspension was stirred for 10 minutes. The solid was collected by vacuum filtration and the solid was washed with water. The solid was dried on the filter overnight. The solid was purified by reverse phase chromatography. and purified by 1:1 10 mM ammonium bicarbonate water + 5% methanol:acetonitrile Elution with trityl gave the title compound, peak 1 (804 mg, 18% yield). MS m / z 634.2 (M+H).

[0318] 1 H NMR(399.8MHz,d6-DMSO)δ7.33(d,J=10.1H z,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=1.6 Hz,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).

[0319] Example 5 (6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS) -10-(3-((3-aminobenzyl)oxy)-2-fluoro-6-methoxyphenyl (2-hydroxyacetyl)-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]dioxole -4-on

[0320] [ka]

[0321] From Example 4, the residue was purified by reverse phase chromatography using a 1:1 10 mM charcoal Elution with aqueous ammonium hydrogen carbonate + 5% methanol:acetonitrile gave the title compound peak. Compound 2 (1.19 g, 27% yield) was obtained. MS m / z 634.2 (M+H).

[0322] 1 H NMR(399.8MHz,d6-DMSO)δ7.32(d,J=10.0H z,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,1 H),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).

[0323] Alternative preparation of Example 5 Filling the flask with 16alpha-hydroxyprednisolone, solid filtration step, and All solids handling steps, including solids transfer steps, were performed inside disposable glove bags. I understood.

[0324] in ACN (1000 mL) in a 2 L round bottom flask at -25 °C. (3-((2-fluoro-3-formyl-4-methoxyphenoxy)methyl)phenyl) Carbamate (25 g, 67 mmol, Preparation 8) and 16 alpha-hydroxypred A suspension of nisolone (25 g, 65 mmol) was added to a solution of perchloric acid (31 mL, 330 mm H O) in water. The mixture was stirred for 1 hour at 20°C for 1 hour, and the reaction was monitored by LCMS. The mixture was stirred at -20°C. Monitoring of the internal temperature revealed a slight exotherm during the addition of perchloric acid. The internal temperature was maintained below -19°C by adding dry ice. The mixture was kept below -19°C for 2 hours and then allowed to warm to -10°C. The mixture was divided into two portions. and two separate beakers, each containing 76 mL of 5 M aq NaOH in 2 L of water. (Beaker 1 and Beaker 2). Upon addition of perchloric acid and complete quenching, The resulting solid was tested (pH 10). The sticky solid from each addition was diluted with 10% DCM The mixture was transferred to a third beaker containing MeOH (Beaker 3) and combined. The remaining solution (beaker 1 and beaker 2) was then added to the sieve and stirred until the adhesive solid was completely dissolved. 2) was filtered through paper to collect the residual solid. The isolated solid was rinsed with water and The solution was transferred to beaker 3. Beaker 3 was stirred until all solids were dissolved. The solution was stirred for 2 hours. Dried over Na2SO4, filtered and evaporated to give a tan foam. The solution was extracted three times with 10% IPA in DCM. The combined organic extracts were stirred overnight. Dried over Na2SO4 with stirring, 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. The solid was purified by filtration using 0-5% MeOH in DCM to give a solid. Dilute with 600 mL of EtOH and evaporate on a rotary evaporator at 45 °C for 5 min. The heating bath was heated to 60°C. When the heating bath reached 60°C, the heating bath was turned off. The flask was rotated until the bath reached room temperature. The flask was then removed from the rotary evaporator. The tube was removed from the flask, the cap was closed, and the tube was left at room temperature overnight.

[0325] The solid was collected in a glove bag by vacuum filtration. The solid was rinsed with EtOH. The solid was dissolved in 20% EtOH in DCM (1.5 L) and dried on the filter for 5 h. More DCM was added to give a nearly clear solution (some cloudiness persisted). Solvent exchange was achieved by rotary evaporation at 450 mbar and 45°C to obtain DC Once the distillation had stopped, the pressure was reduced to 100 mbar and EtOH was added. Bring to approximately 600 mL. Remove the mixture from the rotary evaporator and let it stand at room temperature for 5 hours. The solid was collected by vacuum filtration and the solid was washed twice with additional EtOH. The cake was dried in a vacuum oven at room temperature for 48 hours to give the title compound (42 g, 38% The yield was 100 mg / ml. MS m / z 634.6 (M+H).

[0326] Structural assignment by NMR

[0327] [ka]

[0328] Two-dimensional through-space ROE NMR analysis of the acetal isomers consistently reveals the R configuration. Cross peaks were given for H22 (acetal) and H16. Alternatively, the S configuration H22 consistently gave a shift of greater than about 1 ppm. All other compounds were It was essentially attributed by method.

[0329] The following compounds of Table 18a were prepared in a manner essentially similar to the procedures described in Examples 1-4: Using the corresponding starting material of structure 1a and the corresponding starting material of structure 2, Preparations and Tables 2-17 may be prepared or may be prepared using standard procedures known to those skilled in the art. Purification of the final product was carried out essentially by the following method. He carried out the A. C using an eluent of 10 mM NH4HCO3 in water + 5% MeOH:ACN 18 columns B. C18 column using an eluent of 0.1% FA:ACN in water C. SFC Chiral using EtOH + 0.05% DEA:CO2 eluent pak AY D. Chiralpak IC using an eluent of MeOH + 0.2% IPAm E. SFC Lux Amy using IPA + 0.5% DMEA:CO2 eluent lose-2 F. SFC Chiralp using IPA + 0.5% DMEA:CO2 eluent ak AD-H G. Chiralp using EtOH + 0.1% NH3H2O:Heptane eluent ak IC Heptane H. SFC Chira using IPA + 0.1% NH3H2O:CO2 eluent lpack AD I. EtOH + ACN (0.1% DEA): Chira using heptane eluent lcel IH Heptane J. SFC Chiralp using EtOH + 0.5% DEA:CO2 eluent ack AD K. Chiralpa using EtOH + 0.1% NH3H2O:ACN eluent kIE Chiralpak using an eluent of L.EtOH:ACN + 0.2% IPAm AD-H Chiralpak AD-H using M EtOH:ACN eluent SFC Chira using an eluent of N.EtOH + 0.05% DMEA:CO2 lpak IC SFC Chiral using 0.MeOH + 0.5% DMEA:CO2 eluent cel OJ-H

[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,7 S,8aS,8bS,10S,11aR,12aS,12bS)-7-Hydroxy-8b -(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6 b,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] [ka]

[0368] Trifluoromethanesulfonic acid (920 μL, 10 mmol) was dissolved in ACN (5 mL, 9 16alpha-hydroxyprednisolone (140 mg, 0.36 m mol) and tert-butyl (3-((4-cyano-3-(1,3-dioxolane-2 -yl)-2-fluorophenoxy)methyl)phenyl)carbamate (140 mg, 0 The reaction was added dropwise to a suspension of NaHCO (0.34 mmol) at 0°C. The mixture was quenched with 3 and extracted with 10% IPA in DCM. The combined organic layers were washed with Mg Drying over SO4, filtering and concentration gave a crude residue which was purified by reverse phase purification. and eluted with 10 mM NH4HCO3 in 1:1 water + 5% MeOH:ACN. The title compound was obtained (12 mg, 6% yield). MS m / z 630.0 (M+H). 1 H 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,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),1.9 2~1.88(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 glucocorticoid compounds was evaluated using La nthaScreen TR-Fret GR Coactivator Assay( Compounds were added to the assay plate at a maximum concentration of 200 nM. Ten microliters of GR-LBD were sonicated in a 3-fold, 10-point serial dilution of the concentration. A 2x solution of 1000 mg ... Two microliters of Fluoresein-SRC1-4 and Tb-labeled anti-GST antibody were used. The diluted solution was added to the plate. The plate was incubated in the dark for 2 hours, and then In the Envision plate reader, excitation was at 340 nm and 520 nm (F The readings were taken at 520 / 490 nm (fluorescein) and 490 nm (terbium). The emission ratios were analyzed in Genedata. The data were then recalculated to obtain percent activity. , compared to a negative control of DMSO and a positive control of 4 uM dexamethasone. Compounds were tested essentially according to the procedures described above and are listed in Table 19. The following activities were observed:

[0370] [Table 20]

[0371] The compounds of Examples 6 to 44, 46 to 51, 53 to 79, and 81 to 158 were administered at 200 nM Relative IC less than 50 The compounds of Examples 45, 52, and 80 gave rise to 200 nM Super relative IC 50 This resulted in...

Claims

1. The following formula: 【Chemical 1】 wherein R is H or the following: 【Chemistry 2】 and R １ is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1- C3 alkoxy, C2-C3 alkenyl, OCF ３ , 【Chemistry 3】 and R ２ is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 is alkenyl, R ３ But NH ２ or CH ２ NH ２ and X, O, OCH ２ 、OCH ２ CH ２ ,H ２ O, SCH ２ ,H ２ S、CH ２ 、NH CH 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 pharmaceutically acceptable salt thereof Acceptable salts.

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

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

4. R is: 【Chemistry 4】 3. The compound of claim 1 or 2, wherein:

5. R １ is C1-C3 alkyl; or is a pharmaceutically acceptable salt thereof.

6. R １ But CH ３ The compound according to any one of claims 1 to 4, or a pharmaceutical composition thereof, Acceptable salts.

7. R １ is C1-C3 alkoxy; or a pharmaceutically acceptable salt thereof.

8. R １ But OCH ３ The compound according to any one of claims 1 to 4, or a pharmaceutical composition thereof, A commercially acceptable salt.

9. R １ is F, or a pharmaceutically acceptable salt thereof. Acceptable salt.

10. R ２ is F, or a pharmaceutically acceptable salt thereof. Acceptable salt.

11. X is OCH ２ The compound according to any one of claims 1 to 10, or a pharmaceutical composition thereof, A commercially acceptable salt.

12. 11. The compound according to any one of claims 1 to 10, wherein X is O, or a pharmaceutically acceptable salt thereof. Acceptable salt.

13. X is CH ２ The compound according to any one of claims 1 to 10, or a pharmaceutical composition thereof, Acceptable salts.

14. X is SCH ２ The compound according to any one of claims 1 to 10, or a pharmaceutical composition thereof, A commercially acceptable salt.

15. 11. The compound according to any one of claims 1 to 10, wherein X is a bond, or a pharmaceutically acceptable salt thereof. Acceptable salts.

16. The compound has the following formula: 【Chemistry 5】 2. The compound of claim 1, wherein:

17. The compound has the following formula: 【Chemistry 6】 2. The compound of claim 1, wherein:

18. The compound is selected from the group consisting of: 【Chemistry 7】 18. The compound of claim 17, wherein:

19. The following formula: 【Chemistry 8】 19. The compound of claim 18, wherein:

20. The compound is selected from the group consisting of: 【Chemistry 9】 2. The compound of claim 1, wherein:

21. the below described: 【Chemistry 10】 21. The compound of claim 20, wherein:

22. The compound is selected from the group consisting of: 【Chemistry 11】 17. The compound of claim 16, wherein:

23. the below described: 【Chemistry 12】 23. The compound of claim 22, wherein:

24. The compound is selected from the group consisting of: 【Chemistry 13】 2. The compound of claim 1, wherein:

25. the below described: 【Chemistry 14】 25. The compound of claim 24,

26. The compound is selected from the group consisting of: 【Chemistry 15】 2. The compound of claim 1, wherein:

27. the below described: 【Chemistry 16】 27. The compound of claim 26, wherein:

28. The compound is selected from the group consisting of: 【Chemistry 17】 2. The compound of claim 1, wherein:

29. the below described: 【Chemistry 18】 29. The compound of claim 28, wherein:

30. The table below: 【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】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 The compound of claim 1 selected from the group consisting of: salt.

31. A method of treating atopic dermatitis in a patient, comprising administering to a patient in need of such treatment 2. A method for treating a patient, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof. The method comprises administering a salt thereof.

32. A method of treating rheumatoid arthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof The method of claim 1, wherein the

33. A compound or a drug thereof according to any one of claims 1 to 30 for use in therapy. A physiologically acceptable salt.

34. 31. A method according to claim 1 for use in treating atopic dermatitis. Item 1. The compound according to item 1, or a pharmaceutically acceptable salt thereof.

35. A compound according to any one of claims 1 to 30 for use in treating rheumatoid arthritis. The compound or a pharmaceutically acceptable salt thereof.

36. Any of claims 1 to 30 for the manufacture of a medicament for treating atopic dermatitis. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

37. A compound according to any one of claims 1 to 30 for the manufacture of a medicament for treating rheumatoid arthritis. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

38. A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising the above together with a pharmaceutically acceptable carrier, diluent, or excipient.

39. A process for preparing a pharmaceutical composition according to any one of claims 1 to 30. The compound or a pharmaceutically acceptable salt thereof is dissolved in one or more pharmaceutically acceptable carriers, diluents, or the like. A process comprising mixing the compound with an agent or excipient.

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