Novel diphenylether derivative and use thereof

Abstract

The present invention relates to a novel compound and a use thereof for treatment of dysuria, cough and erectile dysfunction. More specifically, the present invention relates to a novel diphenyl ether derivative compound capable of ameliorating and treating dysuria, cough, and erectile dysfunction related thereto by effectively activating a BKCa channel.

Description

Novel diphenyl ether derivatives and uses thereof

[0001] The present invention relates to novel diphenyl ether derivative compounds and their uses.

[0002] The present invention relates to a novel compound comprising a diphenyl ether derivative backbone, wherein the derivative is BK Ca You can activate the channel, BK Ca It can be used to treat various indications resulting from reduced channel activity.

[0003] BK Ca The channel is a unique type of potassium channel that is dually activated by membrane depolarization and intracellular calcium ions, and is widely distributed in neurons, smooth muscle, and endocrine cells. Structurally, this channel consists of various regulatory subunits including α, β, and γ subunits, each of which possesses various splice variants. Due to these characteristics, various BKs possess physiological properties unique to each tissue by altering sensitivity to intracellular calcium concentration and membrane potential. Ca You can create channel types. BK Ca Channels are involved in the negative feedback mechanism of cell membrane repolarization through potassium ion efflux, play a crucial role in maintaining homeostasis, and regulate neuronal excitability, vascular tone, and neurotransmitter release.

[0004] BK Ca If the function of the channel is impaired or lost, neuroexcitatory disorders may develop, and specifically, BK CaDiseases related to the channel include voiding disorders, coughing, and erectile dysfunction; specifically, voiding disorders include overactive bladder and urinary incontinence. Overactive bladder is a chronic disease with a high prevalence that is usually accompanied by frequent urination and nocturia, and its prevalence is rapidly increasing with the recent rise in the elderly population. Erectile dysfunction is a type of male sexual dysfunction that refers to the inability of a man's penis to become erect or to maintain an erection.

[0005] Accordingly, the inventors of the present invention BK Ca While researching novel compounds capable of activating channels, BK Ca The present invention was completed by inventing a diphenyl ether backbone derivative having a channel-activating function that can be used to treat urinary disorders, cough, and erectile dysfunction.

[0006] The present invention aims to provide a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] The present invention aims to provide a pharmaceutical composition for the prevention or treatment of urinary disorders, cough, or erectile dysfunction comprising a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] 1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009] [Chemical Formula 1]

[0010]

[0011] (wherein, R1 is -H, -F, -Cl, C1-C2 haloalkyl group, C1-C2 haloalkoxy, C1-C2 hydroxyalkyl group, hydroxyl group, methoxy group, amino group, nitro group, or cyano group; R2 is -H, hydroxyl group, or C2-C8 alkyl group; and R3 is -H, hydroxyl group, methoxy group, amide group, amido group, aminomethyl group, or -NR 10 R 11Alternatively, R3 is connected to R2 to form a 5-membered heterocyclic ring containing one or more N, R4 is -H, a hydroxyl group, or an amino group, and R5, R6, R7, R8, and R9 are independently -H, -F, -Cl, or trifluoromethyl groups, and R 10 and R 11 is independently -H, -O, a methyl group, a C2-C8 alkyl group, a C2-C8 heteroalkyl group, or a C6-C8 alkenyl group).

[0012] 2. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5, R6, R8, and R9 are each -F, and R7 is -Cl or a trifluoromethyl group.

[0013] 3. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein R5, R7, and R9 are each -H, and R6 and R8 are each trifluoromethyl groups.

[0014] 4. In 1 above, R3 is NR 10 R 11 and, here R 10 is -H, and R 11 It includes an amino group, a carboxyl group, , , or A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a C3-C8 alkyl group substituted with

[0015] 5. In 1 above, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:

[0016]

[0017]

[0018]

[0019]

[0020] .

[0021] 6. In 1 above, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:

[0022]

[0023] .

[0024] 7. In 1 above, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:

[0025]

[0026] .

[0027] 8. A pharmaceutical composition for the prevention or treatment of urinary disorders comprising any one of the compounds in 1 to 7 above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0028] 9. A pharmaceutical composition for preventing or treating urinary disorders, wherein the urinary disorder described in 8 is one or more selected from the group consisting of urinary incontinence, overactive bladder, overactive bladder, neurogenic bladder, frequent urination, nocturia, residual urine sensation, urgency, diabetes insipidus, and nocturia.

[0029] 10. A pharmaceutical composition for preventing or treating cough comprising any one of the compounds in 1 to 7 above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0030] 11. A pharmaceutical composition for the prevention or treatment of erectile dysfunction comprising any one of the compounds in 1 to 7 above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0031] The present invention provides a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0032] The present invention provides a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the treatment of urinary disorders, cough, or erectile dysfunction.

[0033] The present invention aims to provide a pharmaceutical composition for the prevention or treatment of urinary disorders, cough, or erectile dysfunction comprising a novel compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0034] FIGS. 1 to 22 illustrate the process of synthesizing the compound of the present invention.

[0035] Figure 23 is a graph confirming the in vivo treatment effect of the compound of the present invention on urinary incontinence, confirming that the frequency and volume of urination can be reduced even with a small amount when treating with the compound of the present invention.

[0036] Figure 24 is a graph showing the in vivo cough treatment effect of the compound of the present invention, confirming that the frequency of coughing can be reduced even with a small amount when treating with the compound of the present invention.

[0037] The present invention provides a novel compound and its use in treating urinary disorders, cough, and erectile dysfunction.

[0038] The present invention is BK Ca We provide a novel diphenyl ether derivative compound capable of improving and treating related urinary disorders, cough, and erectile dysfunction by effectively activating the channel.

[0039] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0040] [Chemical Formula 1]

[0041]

[0042] In the above formula, R1 may be -H, -F, -Cl, C1-C2 haloalkyl group, C1-C2 haloalkoxy, C1-C2 hydroxyalkyl group, hydroxyl group, methoxy group, amino group, nitro group, or cyano group.

[0043] In the above formula, R2 may be -H, a hydroxyl group, or a C2-C8 alkyl group, and R3 may be -H, a hydroxyl group, a methoxy group, an amide group, an amido group, an aminomethyl group, or -NR 10 R 11 Alternatively, R3 can be connected to R2 to form a 5-membered heterocyclic ring containing one or more Ns.

[0044] R4 can be -H, a hydroxyl group, or an amino group.

[0045] R5, R6, R7, R8, and R9 can independently be -H, -F, -Cl, or trifluoromethyl groups.

[0046] R 10 and R 11 It can independently be -H, -O, a methyl group, a C2-C8 alkyl group, a C2-C8 heteroalkyl group, or a C6-C8 alkenyl group.

[0047] In cases where a substituent is required at a position in a structural formula but no substituent is listed, the hydrogen substituent has been omitted, and this applies equally to all structural formulas of the present invention.

[0048] The functional groups or substituents of the present invention may be substituted or unsubstituted, and "substituted or unsubstituted" means, for example, being substituted with one or more substituents selected from the group consisting of halogen groups, amino groups, carboxyl groups, C1-C8 alkyl groups, and hexagonal nitrogen-containing heterocyclic groups, being substituted with a substituent in which two or more of the above substituents are connected, or having no substituents.

[0049] In a hydroxyalkyl group, the hydroxyl group can be bonded to any carbon among the carbons forming the alkyl group.

[0050] The compound of Formula 1 of the present invention may be synthesized or obtained from natural products.

[0051] According to one embodiment of the present invention, the 5-membered heterocyclic ring containing one or more Ns, in which R3 of the above formula 1 is connected to R2, may be a 5-membered heterocyclic ring containing one or two Ns.

[0052] According to one embodiment of the present invention, a 5-membered heterocyclic ring comprising one or more Ns is formed in which R3 in Formula 1 is interconnected with R2. , or It could be.

[0053] According to one embodiment of the present invention, R3 is NR 10 R 11 and, here R 10 is -H, and R 11 It includes an amino group, a carboxyl group, , , or It may be a C3-C8 alkyl group substituted with.

[0054] According to one embodiment of the present invention, R5, R6, R8, and R9 in Formula 1 are each -F, and R7 may be -Cl or a trifluoromethyl group.

[0055] According to one embodiment of the present invention, R5, R7, and R9 in Chemical Formula 1 may each be -H, and R6 and R8 may each be a trifluoromethyl group.

[0056] According to one embodiment of the present invention, R1 is -F, -Cl, a hydroxyl group, or a methoxy group, and R3 is a hydroxyl group, an amino group, an amido group, or NR 10 R 11 and R 10 and R 11 It can independently be -H, -O, a methyl group, a C2-C8 alkyl group, a C2-C8 heteroalkyl group, or a C6-C8 alkenyl group.

[0057] The present invention provides a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of the compounds in Table 1 below.

[0058] Compound Compound 3d 4a 4b 4c 4d 4e 4f 4g 4h 4i 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 9b 9c 9d 10a 10b 11a 11b 14a 14b 16a 16b 16c 16d 20 22a 22b 24 29 37a 37b 38a 38b 41a 41b 41c 41d 51a 51b 55 58 61 65a 65b 75a 75b 78a 78b 78c 81a 81b 81c 81d 83

[0059]

[0060] The present invention provides a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of the compounds in Table 2 below.

[0061] Compound Compound 4d 4i 6d 6g 6i 9b 9c 10b 16a 16b 37a 51b 55 58 61 65a 75a 78a 78b 78c 81a 81b 81c 81d

[0062] The present invention provides a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of the compounds in Table 3 below.

[0063] Compound Compound 89a 89b 89c 89d 95a 95b 95c 95d 95e 99 102 104a 105a 105b 105c

[0064]

[0065] "BK Ca The "channel" is a unique type of potassium channel that is doubly activated by membrane depolarization and intracellular calcium ions, and is widely distributed in neurons, smooth muscle, endocrine cells, etc. BK Ca Channels are composed of various regulatory subunits, including α, β, and γ subunits, and various BKs with physiological characteristics unique to each tissue Ca Channel types can be created. BK Ca Functionally, channels play a crucial role in maintaining homeostasis through a negative feedback mechanism of cell membrane repolarization via potassium ion efflux, and regulate neuronal excitability, vascular tone, and the release of neurotransmitters.

[0066] The present invention relates to BK comprising the compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Ca Provides a channel activator.

[0067] The present invention provides a pharmaceutical composition for the prevention or treatment of urinary disorders comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0068] "Urinary dysfunction" is a comprehensive term for all types of abnormal conditions that may occur in connection with the process of urination, and may be one or more selected from the group consisting of urinary incontinence, overactive bladder, neurogenic bladder, frequent urination, nocturia, residual urine sensation, urgency, diabetes insipidus, and nocturia.

[0069] The present invention provides a pharmaceutical composition for preventing or treating cough comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0070] The present invention provides a pharmaceutical composition for the prevention or treatment of erectile dysfunction comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0071] Erectile dysfunction is a type of male sexual dysfunction in which the male penis fails to become erect or maintain an erection.

[0072] "Pharmaceuticalally acceptable salt" means a salt or complex that possesses the desired biological activity of the compound of Formula 1 and exhibits minimal or no undesirable toxic effects, and may be, for example, an acid addition salt or a metal salt.

[0073] "Acid addition salts" can be formed from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, or phosphoric acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylate phenyl-substituted alkanoates, hydroxyalkanoates, and alkandioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butin-1,4-dioate, nucleus-1,6-dioate, benzosates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, It may include terephthalate, benzenesulfonate, ethylsulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate.

[0074] "Metal salts" may be sodium, potassium, or calcium salts. Metal salts can be prepared using a base, for example, alkali metal or alkaline earth metal salts can be obtained by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating or drying the filtrate.

[0075] The route of administration of the pharmaceutical composition of the present invention is not particularly limited and may be administered to an individual by adopting an appropriate route of administration. For example, oral, rectal, transdermal, parenteral (subcutaneous, intramuscular, vascular, abdominal cavity, etc.), dura mater, local, inhalation, or other methods of administration may be used.

[0076] "Individuals" can be humans or non-human animals (e.g., mammals).

[0077] In one embodiment, the object is BK Ca It may be an entity in which the function of the channel has been degraded or lost, or may be degraded or lost.

[0078] In one embodiment, the individual may be an individual who has developed or may develop urinary dysfunction, coughing, or erectile dysfunction.

[0079] The pharmaceutical composition of the present invention may further include suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions, and may be formulated and used in oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, suppositories, patches, sterile injectable solutions, and other suitable formulations according to conventional methods known in the field of pharmaceuticals, but is not limited thereto.

[0080] Examples of carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0081] When formulating, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants commonly used in the industry, but is not limited thereto.

[0082] Solid dosage forms for oral administration include tablets, capsules, pills, granules, etc., and solid dosage forms may be prepared by mixing at least one excipient, such as sucrose, lactose, starch, gelatin, calcium carbonate, etc., into the composition. In addition to excipients, lubricants such as magnesium stearate and talc may be used. Liquid dosage forms for oral administration include aqueous solutions, suspensions, syrups, emulsions, etc., and in addition to simple diluents such as water and liquid paraffin, various excipients, such as humectants, sweeteners, flavorings, and preservatives, may be used in these liquid dosage forms. For parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories may be used. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. Witepsol, Macrogol, Tween 61, Cacao G, Laurin G, Glycerozelatin, etc. can be used as bases for suppositories.

[0083] The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount. "Pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical prevention or treatment, and the effective dose level may be determined based on factors including the patient's condition and weight, the type and severity of the disease, the drug's activity, sensitivity to the drug, the time of administration, the route of administration and elimination rate, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents (e.g., conventional therapeutic agents), and may be administered sequentially or simultaneously with conventional therapeutic agents. It may also be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects, taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art.

[0084] The effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, gender, weight, etc., and, for example, 0.01 to 1000 mg / kg / day, 0.01 to 500 mg / kg / day, or 0.1 to 500 mg / kg / day may be administered in one or several doses. However, since the effective amount may increase or decrease depending on the route of administration, frequency of administration, severity of the disease, age, sensitivity to the drug, etc., the dosage does not limit the scope of the present invention in any way.

[0085] The present invention provides a health functional food for preventing or improving urinary disorders, cough, or erectile dysfunction, comprising the compound of the present invention, a stereoisomer thereof, or a food-grade salt thereof.

[0086]

[0087] Hereinafter, in order to specifically explain the present invention, it will be described in detail with reference to examples.

[0088]

[0089] Preparation Example

[0090] 1. General Procedure A: Synthesis of 3a-f, 5i-j, 8a-d, 13a-b, 16a-b, 19, 22a-b, 24, 27, 32, 34, 50a-b, 56, 59, 64a-b, 70, 71, 77a-b, 79a-d, and 83

[0091] K2CO3 (1.0–5.0 equiv) and alkyl / phenyl halides (1.0–3.0 equiv) substituted with phenyl starting material (1.0 equiv) substituted with DMF (2.0 mL / mmol) were added at room temperature (RT) to a stirred solution. The reaction mixture was stirred under an argon atmosphere under the specific reaction conditions described below. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, 1 M aqueous NaOH, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product.

[0092]

[0093] 2. General Procedure B: BBr3 demethylation for the synthesis of 4a-h, 6a-j, 10a-b, 11a-b, 29, 31, 37a-b, 51a-b, 54, 57, 65a-b, 75, 78a-b, 80a-d, 81, and 85

[0094] A BBr3 solution (1.0–4.0 equiv) dissolved in DCM (1.0 M) was added dropwise at room temperature to a stirred solution of a methoxy starting material (1.0 equiv) substituted in DCM (200% v / v of the BBr3 reagent below). The reaction mixture was stirred under an argon atmosphere under the specific reaction conditions described below. After the reaction was complete, the reaction mixture was cooled to 0 °C, diluted with EtOAc, and quenched by adding water to stop the reaction. The quenched mixture was further diluted with EtOAc and washed sequentially with water, a saturated aqueous NaHCO3 solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product.

[0095]

[0096] 3. General Procedure C: Chan-Lam coupling for the synthesis of 5a-h and 52

[0097] Substituted boronic acid (1.2–2.0 equiv), Cu(OAc)2 (0.2–0.5 equiv), and TEA or pyridine (5.0 equiv) were added at RT to a stirred solution of substituted phenolic starting material (1.0 equiv) in DCM (10 ml / mmol). The reaction mixture was stirred at RT for 24–48 hours under an oxygen atmosphere. After the reaction was complete, the reaction mixture was diluted with EtOAC and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product.

[0098]

[0099] 4. General Procedure D: Pd / C Hydrogenation and Hydrogenolysis for the Synthesis of 9a-d, 14a-b, 28, 43, 53 and 60

[0100] Pd / C (10% w / w) was added to a stirred solution of nitro or benzyl starting material (1.0 equiv) substituted in MeOH (5 ml / mmol). The reaction mixture was stirred at RT for 0.5–12 hours under an H2 atmosphere. After the reaction was complete, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the desired product.

[0101]

[0102] 5. General Procedure E: SN2 reaction for the synthesis of 41a-d

[0103] Aminoalkyl bromide hydrobromide (1.0 equiv) was added to a stirred solution of aniline starting material (1.0 equiv) substituted in EtOH (1 ml / mmol). The reaction mixture was stirred at 80 °C for 24 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (NH3-saturated CHCl3:MeOH = 10:1 to 5:1, gradient) to obtain the desired product.

[0104]

[0105] 6. Synthesis of 2,4-Dimethoxyphenol (Compound 2d)

[0106] mCPBA (1.4 g, 8.3 mmol, 1.5 equiv) and PTSA·H2O (1.1 g, 5.5 mmol, 1.0 equiv) were added at RT to a stirred solution of 1 (1.0 g, 5.5 mmol, 1.0 equiv) in ACN (11 ml, 2.0 ml / mmol). The reaction mixture was stirred at 80°C for 6 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and sequentially washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1) to obtain the desired product as a pale red oil (647 mg, 75.6%) (Fig. 1).

[0107] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.84 (d, J = 8.70 Hz, 1H), 6.50 (d, J = 2.75 Hz, 1H), 6.40 (dd, J = 2.75, 8.47 Hz, 1H), 5.27 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H). MS (ESI): m / z = 154.18 [M + H].

[0108]

[0109] 7. Synthesis of 1-chloro-2,3,5,6-tetrafluoro-4-(2-methoxyphenoxy)benzene (Compound 3a)

[0110] Compound 3a was synthesized from compound 2a (50 mg, 0.40 mmol, 1.0 equiv), chloropentafluorobenzene (67.6 μl, 0.52 mmol, 1.3 equiv), and K2CO3 (72.4 mg, 0.52 mmol, 1.3 equiv) at 60 °C for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (81.7 mg, 66.2%) (Fig. 1).

[0111] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.10-7.17 (m, 1H), 6.97-7.03 (m, 1H), 6.84-6.92 (m, 2H), 3.89 (s, 3H). MS (ESI): m / z = 305.3 [M - H].

[0112]

[0113] 8. Synthesis of 1-chloro-2,3,5,6-tetrafluoro-4-(3-methoxyphenoxy)benzene (Compound 3b)

[0114] Compound 3b was synthesized from compound 2b (44.2 mg, 0.40 mmol, 1.0 equiv), chloropentafluorobenzene (67.6 μl, 0.52 mmol, 1.3 equiv), and K2CO3 (72.4 mg, 0.52 mmol, 1.3 equiv) at 60 °C for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (82.1 mg, 75.2%) (Fig. 1).

[0115] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.23 (t, J = 8.24 Hz, 1H), 6.69 (dd, J = 2.06, 8.01 Hz, 1H), 6.56 (t, J = 2.29 Hz, 1H), 6.52 (dd, J = 1.83, 8.24 Hz, 1H), 3.81 (s, 3H). MS (ESI): m / z = 305.3 [M - H].

[0116]

[0117] 9. Synthesis of 1-chloro-2,3,5,6-tetrafluoro-4-(4-methoxyphenoxy)benzene (Compound 3c)

[0118] Compound 3c was synthesized from compound 2c (50.0 mg, 0.40 mmol, 1.0 equiv), chloropentafluorobenzene (67.6 μl, 0.52 mmol, 1.3 equiv), and K2CO3 (72.4 mg, 0.52 mmol, 1.3 equiv) at 60 °C for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (89.8 mg, 72.7%) (Fig. 1).

[0119] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92-6.97 (m, 2H), 6.85-6.87 (m, 2H), 3.80 (s, 3H). MS (ESI): m / z = 305.5 [M - H].

[0120]

[0121] 10. Synthesis of 1-Chloro-4-(2,4-Dimethoxyphenoxy)-2,3,5,6-Tetrafluorobenzene (Compound 3d)

[0122] Compound 3d was synthesized from compound 2d (23.6 mg, 0.15 mmol, 1.0 equiv), chloropentafluorobenzene (21.7 μl, 0.17 mmol, 1.1 equiv), and K2CO3 (23.3 mg, 0.17 mmol, 1.1 equiv) at 60 °C for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (35.0 mg, 67.9%) (Fig. 1).

[0123] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.87 (d, J = 8.70 Hz, 1H), 6.53 (d, J = 2.75 Hz, 1H), 6.34-6.38 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H). MS (ESI): m / z = 336.17 [M + H].

[0124]

[0125] 11. Synthesis of 1-Chloro-4-(3,5-Dimethoxyphenoxy)-2,3,5,6-Tetrafluorobenzene (Compound 3e)

[0126] Compound 3e was synthesized from compound 2e (40.0 mg, 0.26 mmol, 1.0 equiv), chloropentafluorobenzene (50.3 μl, 0.39 mmol, 1.5 equiv), and K2CO3 (53.8 mg, 0.39 mmol, 1.5 equiv) at 60 °C for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 15:1) to obtain the desired product, a colorless oil (73.5 mg, 75.1%) (Fig. 1).

[0127] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.22 (t, J = 2.14 Hz, 1H), 6.10 (d, J = 2.14 Hz, 2H), 3.76 (s, 6H). MS (ESI): m / z = 337.32 [M + H].

[0128]

[0129] 12. Synthesis of 1-Chloro-4-(3,4-Dimethoxyphenoxy)-2,3,5,6-Tetrafluorobenzene (Compound 3f)

[0130] Compound 3f was synthesized from compound 2f (40.0 mg, 0.26 mmol, 1.0 equiv), chloropentafluorobenzene (50.3 μl, 0.39 mmol, 1.5 equiv), and K2CO3 (53.8 mg, 0.39 mmol, 1.5 equiv) at 60 °C for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 15:1) to obtain the desired product, a colorless oil (77.9 mg, 79.6%) (Fig. 1).

[0131] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.76 (d, J = 8.85 Hz, 1H), 6.70 (d, J = 3.05 Hz, 1H), 6.39 (dd, J = 2.90, 8.70 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H). MS (ESI): m / z = 337.5 [M + H].

[0132]

[0133] 13. Synthesis of 1-Chloro-4-(2,5-Dimethoxyphenoxy)-2,3,5,6-Tetrafluorobenzene (Compound 3g)

[0134] 3 g of compound was synthesized from 2 g of compound (10.0 mg, 0.06 mmol, 1.0 equiv), chloropentafluorobenzene (12.5 μl, 0.10 mmol, 1.5 equiv), and K2CO3 (13.4 mg, 0.10 mmol, 1.5 equiv) at 40 °C for 3 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1) to obtain the desired product as a colorless oil (12.5 mg, 57.2%) (Fig. 1).

[0135] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.93 Hz, 1H), 6.64 (dd, J = 2.98, 8.93 Hz, 1H), 6.47 (d, J = 2.75 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H). MS (ESI): m / z = 334.76 [MH].

[0136]

[0137] 14. Synthesis of 2-(4-chloro-2,3,5,6-tetrafluorophenoxy)phenol (Compound 4a)

[0138] Compound 4a was synthesized from compound 3a (8.4 mg, 0.027 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (54 μl, 0.054 mmol, 2.0 equiv) at RT for 6 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1) to obtain the desired product as a colorless oil (5.1 mg, 63.6%) (Fig. 1).

[0139] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.05 (d, J = 3.66 Hz, 2H), 6.81 (td, J = 4.35, 8.39 Hz, 1H), 6.71 (d, J = 8.24 Hz, 1H), 5.60 (s, 1H). MS (ESI): m / z = 291.28 [M - H].

[0140]

[0141] 15. Synthesis of 3-(4-chloro-2,3,5,6-tetrafluorophenoxy)phenol (Compound 4b)

[0142] Compound 4b was synthesized from compound 3b (7.7 mg, 0.025 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (50 μl, 0.050 mmol, 2.0 equiv) at RT for 6 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1) to obtain the desired product as a colorless oil (4.1 mg, 55.8%) (Fig. 1).

[0143] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.18 (t, J = 8.24 Hz, 1H), 6.61 (ddd, J = 0.76, 2.37, 8.16 Hz, 1H), 6.51-6.55 (m, 1H), 6.48-6.51 (m, 1H), 5.13 (br. s., 1H). MS (ESI): m / z = 291.28 [M - H].

[0144]

[0145] 16. Synthesis of 4-(4-chloro-2,3,5,6-tetrafluorophenoxy)phenol (Compound 4c)

[0146] Compound 4c was synthesized from compound 3c (9.1 mg, 0.030 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (60 μl, 0.060 mmol, 2.0 equiv) at RT for 6 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1) to obtain the desired product as a colorless oil (5.9 mg, 67.9%) (Fig. 1).

[0147] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.87-6.91 (m, 2H), 6.77-6.80 (m, 2H), 4.98 (br. s., 1H). MS (ESI): m / z = 291.28 [M - H].

[0148]

[0149] 17. Synthesis of 4-(4-chloro-2,3,5,6-tetrafluorophenoxy)benzene-1,3-diol (Compound 4d)

[0150] Compound 4d was synthesized from compound 3d (28.0 mg, 0.083 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (166 μl, 0.17 mmol, 2.0 equiv) at RT for 6 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as a colorless oil (21.3 mg, 83.0%) (Fig. 1).

[0151] 1H NMR (400 MHz, DMSO-d6) δ 9.70 (br. s., 1H), 9.23 (br. s., 1H), 6.85 (d, J = 8.70 Hz, 1H), 6.36 (d, J = 2.75 Hz, 1H), 6.12 (dd, J = 2.75, 8.70 Hz, 1H), 19F NMR (376 MHz, DMSO-d6) δ -142.92, -155.46. MS (ESI): m / z = 309.10 [M + H].

[0152]

[0153] 18. Synthesis of 5-(4-chloro-2,3,5,6-tetrafluorophenoxy)benzene-1,3-diol (Compound 4e)

[0154] Compound 4e was synthesized from Compound 3e (62.9 mg, 0.19 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (411 μl, 0.41 mmol, 2.2 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product as a colorless oil (20.0 mg, 34.7%) (Fig. 1).

[0155] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.65 (d, J = 9.16 Hz, 1H), 6.56 (d, J = 3.21 Hz, 1H), 6.26-6.30 (m, 1H), 5.59 (s, 1H), 4.62 (s, 1H). MS (ESI): m / z = 306.34 [M - H].

[0156]

[0157] 19. Synthesis of 4-(4-chloro-2,3,5,6-tetrafluorophenoxy)benzene-1,2-diol (Compound 4f)

[0158] Compound 4f was synthesized from compound 3f (66.5 mg, 0.20 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (435 μl, 0.43 mmol, 2.2 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product as a colorless oil (40.1 mg, 65.8%) (Fig. 1).

[0159] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (br. s., 1H), 8.86 (br. s., 1H), 6.63 (d, J = 8.85 Hz, 1H), 6.51 (d, J = 3.05 Hz, 1H), 6.32 (dd, J = 3.05, 8.55 Hz, 1H). MS (ESI): m / z = 306.34 [M - H].

[0160]

[0161] 20. Synthesis of 2-(4-chloro-2,3,5,6-tetrafluorophenoxy)-5-methoxyphenol (compound 4g)

[0162] 4 g of compound was synthesized for 5 hours at RT according to general procedure B in compound 3d (28.0 mg, 0.083 mmol, 1.0 equiv), BBr3 (1.0 M) of DCM (166 μl, 0.17 mmol, 2.0 equiv), and DCM (1.2 ml). The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1–2:1, gradient) to obtain 4 g (4.4 mg, 16.4%) and 4 h (11.3 mg, 42.1%) of the desired product as a colorless oil (Fig. 1).

[0163] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.70 (td, J = 0.97, 9.04 Hz, 1H), 6.62 (d, J = 2.98 Hz, 1H), 6.35 (dd, J = 2.86, 9.04 Hz, 1H), 5.63 (s, 1H), 3.77 (s, 3H). MS (ESI): m / z = 322.81 [M + H].

[0164]

[0165] 21. Synthesis of 4-(4-chloro-2,3,5,6-tetrafluorophenoxy)-3-methoxyphenol (compound 4h)

[0166] 4 g of compound was synthesized for 5 hours at RT according to general procedure B in compound 3d (28.0 mg, 0.083 mmol, 1.0 equiv), BBr3 (1.0 M) in DCM (166 μl, 0.17 mmol, 2.0 equiv), and DCM (1.2 ml). The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1–2:1, gradient) to obtain 4 g (4.4 mg, 16.4%) and 4 h (11.3 mg, 42.1%) of the desired product as a colorless oil (Fig. 1).

[0167] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.83 (d, J = 8.70 Hz, 1H), 6.51 (d, J = 2.98 Hz, 1H), 6.32 (dd, J = 2.75, 8.70 Hz, 1H), 4.92 (s, 1H), 3.83 (s, 3H). MS (ESI): m / z = 322.80 [M + H].

[0168]

[0169] 22. Synthesis of 2-(4-chloro-2,3,5,6-tetrafluorophenoxy)benzene-1,4-diol (Compound 4i)

[0170] Compound 4i was synthesized at RT for 12 hours according to general procedure B in 3 g of compound (8.5 mg, 0.025 mmol, 1.0 equiv), BBr3 (1.0 M) in DCM (50.0 μl, 0.05 mmol, 2.0 equiv), and DCM (100 μl). The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1, gradient) to obtain 4 g (4.3 mg, 55.2%) of the desired product as a colorless oil (Fig. 1).

[0171] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.52 (dd, J = 2.98, 8.70 Hz, 1H), 6.26 (d, J = 2.75 Hz, 1H), 5.19 (br. s., 1H), 4.51 (br. s., 1H). MS (ESI): m / z = 306.66 [MH].

[0172]

[0173] 23. Synthesis of 1-(4-chlorophenoxy)-2,4-dimethoxybenzene (Compound 5a)

[0174] Compound 5a was synthesized from compound 2d (47.0 mg, 0.31 mmol, 1.0 equiv), 4-chlorophenylboronic acid (57.2 mg, 0.37 mmol, 1.2 equiv), Cu(OAc)2 (27.5 mg, 0.15 mmol, 0.5 equiv), and TEA (212 μl, 1.52 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 6:1) to obtain the desired product as a colorless oil (11.2 mg, 13.9%) (Fig. 2).

[0175] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.18-7.24 (m, 2H), 6.96 (d, J = 8.70 Hz, 1H), 6.79-6.84 (m, 2H), 6.59 (d, J = 2.75 Hz, 1H), 6.46 (dd, J = 2.75, 8.70 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H). MS (ESI): m / z = 265.4 [M + H].

[0176]

[0177] 24. Synthesis of 1-chloro-4-(2,4-dimethoxyphenoxy)-2-fluorobenzene (Compound 5b)

[0178] Compound 5b was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 4-chloro-3-fluorophenylboronic acid (77.9 mg, 0.44 mmol, 1.2 equiv), Cu(OAc)2 (13.4 mg, 0.074 mmol, 0.2 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product as a colorless oil (14.4 mg, 13.4%) (Fig. 2).

[0179] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.22-7.26 (m, 1H), 6.99 (d, J = 8.70 Hz, 1H), 6.62-6.67 (m, 2H), 6.59 (d, J = 2.75 Hz, 1H), 6.48 (dd, J = 2.98, 8.70 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H). MS (ESI): m / z = 282.91 [M + H].

[0180]

[0181] 25. Synthesis of 1,2-Dichloro-4-(2,4-Dimethoxyphenoxy)benzene (Compound 5c)

[0182] Compound 5c was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 3,4-dichlorophenylboronic acid (84.2 mg, 0.44 mmol, 1.2 equiv), Cu(OAc)2 (13.4 mg, 0.074 mmol, 0.2 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product, a colorless oil (9.7 mg, 8.8%) (Fig. 2).

[0183] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.31 (d, J = 8.93 Hz, 1H), 6.98 (d, J = 8.70 Hz, 1H), 6.93 (d, J = 2.98 Hz, 1H), 6.76 (dd, J = 2.98, 8.93 Hz, 1H), 6.59 (d, J = 2.75 Hz, 1H), 6.48 (dd, J = 2.75, 8.70 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H). MS (ESI): m / z = 298.86 [M + H].

[0184]

[0185] 26. Synthesis of 1-chloro-4-(2,4-dimethoxyphenoxy)-2-(trifluoromethyl)benzene (Compound 5d)

[0186] Compound 5d was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 4-chloro-3-(trifluoromethyl)phenyl-boronic acid (164.7 mg, 0.74 mmol, 2.0 equiv), Cu(OAc)2 (33.4 mg, 0.18 mmol, 0.5 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product, a colorless oil (32.8 mg, 26.8%) (Fig. 2).

[0187] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.33-7.38 (m, 1H), 7.21 (d, J = 2.98 Hz, 1H), 6.99 (d, J = 8.93 Hz, 1H), 6.90-6.95 (m, 1H), 6.60 (d, J = 2.75 Hz, 1H), 6.49 (dd, J = 2.75, 8.70 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H). MS (ESI): m / z = 332.85 [M + H].

[0188]

[0189] 27. Synthesis of 2,4-Dimethoxy-1-(3-(trifluoromethyl)phenoxy)benzene (Compound 5e)

[0190] Compound 5e was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 3-(trifluoromethyl)phenylboronic acid (83.8 mg, 0.44 mmol, 1.2 equiv), Cu(OAc)2 (13.4 mg, 0.074 mmol, 0.2 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 2–4 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product, a colorless oil (18.0 mg, 16.4%) (Fig. 2).

[0191] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.37 (t, J = 8.01 Hz, 1H), 7.25 (td, J = 0.77, 7.61 Hz, 1H), 7.10-7.13 (m, 1H), 7.04 (dd, J = 2.52, 8.24 Hz, 1H), 7.00 (d, J = 8.70 Hz, 1H), 6.61 (d, J = 2.75 Hz, 1H), 6.49 (dd, J = 2.75, 8.70 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H). MS (ESI): m / z = 298.93 [MH].

[0192]

[0193] 28. Synthesis of 4-(2,4-Dimethoxyphenoxy)-1-fluoro-2-(trifluoromethyl)benzene (Compound 5f)

[0194] Compound 5f was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 4-fluoro-3-(trifluoromethyl)phenyl-boronic acid (91.8 mg, 0.44 mmol, 1.2 equiv), Cu(OAc)2 (13.4 mg, 0.074 mmol, 0.2 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product, a colorless oil (5.9 mg, 5.1%) (Fig. 2).

[0195] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.05-7.12 (m, 2H), 6.99-7.03 (m, 1H), 6.97 (d, J = 8.71 Hz, 1H), 6.60 (d, J = 2.75 Hz, 1H), 6.48 (dd, J = 2.75, 8.71 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H). MS (ESI): m / z = 316.28 [MH].

[0196]

[0197] 29. Synthesis of 1-(3,5-bis(trifluoromethyl)phenoxy)-2,4-dimethoxybenzene (compound 5g)

[0198] 5 g of compound was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 3,5-bis(trifluoromethyl)phenylboronic acid (113.75 mg, 0.44 mmol, 1.2 equiv), Cu(OAc)2 (13.4 mg, 0.17 mmol, 0.2 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product as a colorless oil (5.9 mg, 4.4%) (Fig. 2).

[0199] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (s, 1H), 7.26 (s, 2H), 7.03 (d, J = 8.70 Hz, 1H), 6.62 (d, J = 2.75 Hz, 1H), 6.52 (dd, J = 2.75, 8.70 Hz, 1H), 3.86 (s, 3H), 3.77 (s, 3H). MS (ESI): m / z = 367.06 [M + H].

[0200]

[0201] 30. Synthesis of 1-(3,5-Dichlorophenoxy)-2,4-Dimethoxybenzene (Compound 5h)

[0202] Compound 5h was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), 3,5-dichlorophenylboronic acid (140.1 mg, 0.74 mmol, 2.0 equiv), Cu(OAc)2 (33.4 mg, 0.18 mmol, 0.5 equiv), and TEA (256 μl, 1.84 mmol, 5.0 equiv) at RT for 24 hours according to general procedure C. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product as a colorless oil (11.4 mg, 10.4%) (Fig. 2).

[0203] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.97-7.00 (m, 2H), 6.75 (d, J = 1.83 Hz, 2H), 6.59 (d, J = 2.75 Hz, 1H), 6.49 (dd, J = 2.75, 8.70 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H). MS (ESI): m / z = 298.85 [M + H].

[0204]

[0205] 31. Synthesis of 1-(2,4-Dimethoxyphenoxy)-2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)benzene (Compound 5i)

[0206] Compound 5i was synthesized from compound 2d (56.7 mg, 0.37 mmol, 1.0 equiv), octafluorotoluene (78.2 μl, 0.55 mmol, 1.5 equiv), and K2CO3 (76.5 mg, 0.55 mmol, 1.5 equiv) at RT for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product as a colorless oil (102.3 mg, 75.1%) (Fig. 2).

[0207] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.02 (d, J = 8.93 Hz, 1H), 6.54 (d, J = 2.75 Hz, 1H), 6.42 (dd, J = 2.86, 8.82 Hz, 1H), 3.81 (s, 3H), 3.81 (s, 3H). MS (ESI): m / z = 370.96 [M + H].

[0208]

[0209] 32. Synthesis of 5-(2,4-Dimethoxyphenoxy)-1,3-Difluoro-2-(Trifluoromethyl)benzene (Compound 5j)

[0210] Compound 5j was synthesized from compound 2d (34.0 mg, 0.22 mmol, 1.0 equiv), 3,4,5-trifluorobenzotrifluoride (44.9 μl, 0.33 mmol, 1.5 equiv), and K2CO3 (45.7 mg, 0.33 mmol, 1.5 equiv) at RT for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product, a colorless oil (6.7 mg, 9.1%) (Fig. 2).

[0211] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.24 (d, J = 7.79 Hz, 2H), 6.81 (d, J = 8.70 Hz, 1H), 6.56 (d, J = 2.75 Hz, 1H), 6.37 (dd, J = 2.75, 9.16 Hz, 1H), 3.85(s, 4H), 3.80(s, 3H). MS (ESI): m / z = 334.80 [M + H].

[0212]

[0213] 33. Synthesis of 4-(4-chlorophenoxy)benzene-1,3-diol (Compound 6a)

[0214] Compound 6a was synthesized from compound 5a (11.2 mg, 0.042 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (84.6 μl, 0.085 mmol, 2.0 equiv) at RT for 6 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (8.7 mg, 86.9%) (Fig. 2).

[0215] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.23-7.27 (m, 2H), 6.84-6.96 (m, 2H), 6.78 (d, J = 8.70 Hz, 1H), 6.56 (d, J = 2.75 Hz, 1H), 6.34 (dd, J = 2.75, 8.70 Hz, 1H), 5.49 (s, 1H), 4.97 (s, 1H). MS (ESI): m / z = 234.28 [MH].

[0216]

[0217] 34. Synthesis of 4-(4-chloro-3-fluorophenoxy)benzene-1,3-diol (Compound 6b)

[0218] Compound 6b was synthesized from compound 5b (13.0 mg, 0.046 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (92.0 μl, 0.092 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (10.4 mg, 88.8%) (Fig. 2).

[0219] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.31 (t, J = 8.59 Hz, 1H), 6.84 (d, J = 8.70 Hz, 1H), 6.75-6.79 (m, 1H), 6.70-6.75 (m, 1H), 6.58 (d, J = 2.98 Hz, 1H), 6.39 (dd, J = 2.98, 8.70 Hz, 1H), 5.24 (br. s., 1H). MS (ESI): m / z = 254.90 [M + H].

[0220]

[0221] 35. Synthesis of 4-(3,4-Dichlorophenoxy)benzene-1,3-diol (Compound 6c)

[0222] Compound 6c was synthesized from compound 5c (8.9 mg, 0.030 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (59.5 μl, 0.060 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (6.4 mg, 79.4%) (Fig. 2).

[0223] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.37 (d, J = 8.70 Hz, 1H), 7.06 (d, J = 2.75 Hz, 1H), 6.81-6.86 (m, 2H), 6.58 (d, J = 2.98 Hz, 1H), 6.39 (dd, J = 2.98, 8.70 Hz, 1H), 5.37 (br. s., 1H), 4.97 (br. s., 1H). MS (ESI): m / z = 270.83 [M + H].

[0224]

[0225] 36. Synthesis of 4-(4-chloro-3-(trifluoromethyl)phenoxy)benzene-1,3-diol (Compound 6d)

[0226] Compound 6d was synthesized from compound 5d (28.7 mg, 0.086 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (172.5 μl, 0.173 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (18.9 mg, 71.9%) (Fig. 2).

[0227] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.42 (d, J = 8.93 Hz, 1H), 7.31 (d, J = 2.98 Hz, 1H), 7.04 (dd, J = 2.98, 8.93 Hz, 1H), 6.82 (d, J = 8.70 Hz, 1H), 6.59 (d, J = 2.98 Hz, 1H), 6.40 (dd, J = 2.98, 8.70 Hz, 1H), 5.37-5.51 (m, 1H), 5.07-5.20 (m, 1H). MS (ESI): m / z = 304.86 [M + H].

[0228]

[0229] 37. Synthesis of 4-(3-(trifluoromethyl)phenoxy)benzene-1,3-diol (compound 6e)

[0230] Compound 6e was synthesized from compound 5e (15.5 mg, 0.052 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (104 μl, 0.10 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (12.8 mg, 91.2%) (Fig. 2).

[0231] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.43 (t, J = 8.01 Hz, 1H), 7.34 (d, J = 7.56 Hz, 1H), 7.23 (s, 1H), 7.13 (dd, J = 2.52, 8.24 Hz, 1H), 6.84 (d, J = 8.93 Hz, 1H), 6.60 (d, J = 2.98 Hz, 1H), 6.39 (dd, J = 2.98, 8.70 Hz, 1H), 5.50 (br. s., 1H), 5.11 (br. s., 1H). MS (ESI): m / z = 268.99 [MH].

[0232]

[0233] 38. Synthesis of 4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzene-1,3-diol (Compound 6f)

[0234] Compound 6f was synthesized from compound 5f (5.3 mg, 0.017 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (35.2 μl, 0.035 mmol, 2.0 equiv) at RT for 18 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (1.6 mg, 33.1%) (Fig. 2).

[0235] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.21 (dd, J = 2.98, 5.73 Hz, 1H), 7.09-7.18 (m, 2H), 6.80 (d, J = 8.94 Hz, 1H), 6.59 (d, J = 2.75 Hz, 1H), 6.38 (dd, J = 2.98, 8.71 Hz, 1H), 5.32 (br. s., 1H), 5.07 (br. s., 1H). MS (ESI): m / z = 287.18 [MH].

[0236]

[0237] 39. Synthesis of 4-(3,5-bis(trifluoromethyl)phenoxy)benzene-1,3-diol (compound 6 g)

[0238] 6 g of compound was synthesized from 5 g of compound (5.9 mg, 0.016 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (38.7 μl, 0.040 mmol, 2.4 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (3.2 mg, 58.7%) (Fig. 2).

[0239] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.58 (s, 1H), 7.38 (s, 2H), 6.87 (d, J = 8.70 Hz, 1H), 6.61 (d, J = 2.98 Hz, 1H), 6.43 (dd, J = 2.98, 8.70 Hz, 1H), 5.29 (br. s., 1H), 5.10 (br. s., 1H). MS (ESI): m / z = 336.93 [MH].

[0240]

[0241] 40. Synthesis of 4-(3,5-Dichlorophenoxy)benzene-1,3-diol (Compound 6h)

[0242] Compound 6h was synthesized from Compound 5h (9.5 mg, 0.032 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (63.5 μl, 0.063 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product, a colorless oil (8.1 mg, 78.4%) (Fig. 2).

[0243] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.07 (t, J = 1.83 Hz, 1H), 6.84-6.87 (m, 3H), 6.58 (d, J = 2.98 Hz, 1H), 6.40 (dd, J = 2.98, 8.70 Hz, 1H), 5.35(s, 1H), 4.93(s, 1H). MS (ESI): m / z = 270.82 [M + H].

[0244]

[0245] 41. Synthesis of 4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)benzene-1,3-diol (Compound 6i)

[0246] Compound 6i was synthesized from Compound 5i (102 mg, 0.28 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (663 μl, 0.66 mmol, 2.4 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as a colorless oil (47.3 mg, 50.0%) (Fig. 2).

[0247] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.72 (d, J = 8.70 Hz, 1H), 6.56 (d, J = 2.75 Hz, 1H), 6.31 (dd, J = 2.86, 8.82 Hz, 1H), 5.60 (s, 1H), 4.97 (s, 1H); MS(ESI): m / z = 340.89 [MH].

[0248]

[0249] 42. Synthesis of 4-(2,6-difluoro-4-(trifluoromethyl)phenoxy)benzene-1,3-diol (6j)

[0250] Compound 6j was synthesized from compound 5j (6.5 mg, 0.019 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (44.7 μl, 0.045 mmol, 2.3 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as white crystals (4.5 mg, 75.6%) (Fig. 2).

[0251] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.32 (d, J = 7.33 Hz, 2H), 6.62 (d, J = 9.16 Hz, 1H), 6.57 (d, J = 2.75 Hz, 1H), 6.27 (dd, J = 2.98, 8.93 Hz, 1H), 5.67 (br. s., 1H), 4.70 (br. s., 1H). MS (ESI): m / z = 306.44 [M + H].

[0252]

[0253] 43. Synthesis of 1,2,4,5-tetrafluoro-3-(4-methoxy-2-nitrophenoxy)-6-(trifluoromethyl)benzene (Compound 8a)

[0254] Compound 8a was synthesized from compound 7a (100 mg, 0.60 mmol, 1.0 equiv), octafluorotoluene (126 μl, 0.90 mmol, 1.5 equiv), and K2CO3 (123 mg, 0.90 mmol, 1.5 equiv) at RT for 2 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product as white crystals (217.5 mg, 95.5%) (Fig. 3).

[0255] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.58 (d, J = 3.05 Hz, 1H), 7.15 (dd, J = 3.05, 9.16 Hz, 1H), 7.08 (d, J = 9.16 Hz, 1H), 3.90 (s, 3H). MS (ESI): m / z = 383.74[MH].

[0256]

[0257] 44. Synthesis of 1,2,4,5-tetrafluoro-3-(2-methoxy-4-nitrophenoxy)-6-(trifluoromethyl)benzene (Compound 8b)

[0258] Compound 8b was synthesized from compound 7b (6.0 g, 36 mmol, 1.0 equiv), octafluorotoluene (7.5 ml, 54 mmol, 1.5 equiv), and K2CO3 (7.4 g, 54 mmol, 1.5 equiv) at RT for 2 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product as white crystals (12.3 g, 90.0%) (Fig. 3).

[0259] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.87-7.91 (m, 2H), 7.09 (d, J = 9.54 Hz, 1H), 3.97 (s, 4H). MS (ESI): m / z = 383.68[MH].

[0260]

[0261] 45. Synthesis of 1,2,4,5-tetrafluoro-3-(4-nitrophenoxy)-6-(trifluoromethyl)benzene (Compound 8c)

[0262] Compound 8c was synthesized from compound 7c (10.0 mg, 0.072 mmol, 1.0 equiv), octafluorotoluene (15.3 μl, 0.11 mmol, 1.5 equiv), and K2CO3 (14.9 mg, 0.11 mmol, 1.5 equiv) at RT for 1 hour according to general procedure A. After concentrating the organic layer without further purification, the product was obtained as a white solid (24.2 mg, 94.9%) (Fig. 3).

[0263] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.27-8.33 (m, 2H), 7.10-7.15 (m, 2H). MS (ESI): m / z = 353.81[MH].

[0264]

[0265] 46. ​​Synthesis of 5-nitro-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 8d)

[0266] Compound 8d was synthesized from compound 7d (200 mg, 1.30 mmol, 1.0 equiv), octafluorotoluene (184 μl, 1.30 mmol, 1.0 equiv), and K2CO3 (180 mg, 1.30 mmol, 1.0 equiv) at RT for 7 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (100% CHCl3) to obtain the desired product as bright yellow crystals (241.2 mg, 50.2%) (Fig. 3).

[0267] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (d, J = 2.75 Hz, 1H), 7.54-7.59 (m, 1H), 6.69 (d, J = 8.70 Hz, 1H), 4.32 (br. s., 2H). MS (ESI): m / z = 370.84 [M + H].

[0268]

[0269] 47. Synthesis of 5-methoxy-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 9a)

[0270] Compound 9a was synthesized from compound 8a (217 mg, 0.56 mmol, 1.0 equiv) for 5 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product of light brown crystals (186.9 mg, 93.2%) (Fig. 3).

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 6.81 (d, J = 9.16 Hz, 1H), 6.35 (d, J = 3.21 Hz, 1H), 6.02 (dd, J = 2.98, 8.93 Hz, 1H), 5.17-5.46 (m, 2H). MS (ESI): m / z = 356.5 [M + H].

[0272]

[0273] 48. Synthesis of 3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 9b)

[0274] Compound 9b was synthesized from compound 8b (12.3 g, 32 mmol, 1.0 equiv) for 3 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 1:1) to obtain the desired product of light brown crystals (10.5 g, 92.6%) (Fig. 3).

[0275] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.89 (d, J = 8.70 Hz, 1H), 6.30 (d, J = 2.29 Hz, 1H), 6.21 (dd, J = 2.52, 8.47 Hz, 1H), 3.77 (s, 3H), 3.67 (br. s., 2H). MS (ESI): m / z = 355.77 [M + H].

[0276]

[0277] 49. Synthesis of 3-amino-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 10a)

[0278] Compound 10a was synthesized from compound 9a (20.0 mg, 0.056 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (113 μl, 0.113 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as light brown crystals (13.4 mg, 69.8%) (Fig. 3).

[0279] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 6.68 (d, J = 8.70 Hz, 1H), 6.21 (d, J = 2.75 Hz, 1H), 5.86 (dd, J = 2.86, 8.59 Hz, 1H), 5.14 (s, 2H). MS (ESI): m / z = 339.89[MH].

[0280]

[0281] 50. Synthesis of 5-amino-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 10b)

[0282] Compound 10b was synthesized from compound 9b (10.5 g, 29.5 mmol, 1.0 equiv) and BBr3 (1.0 M) in DCM (59 mL, 59 mmol, 2.0 equiv) at RT for 24 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as light brown crystals (7.9 g, 78.3%) (Fig. 3).

[0283] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.62-6.68 (m, 1H), 6.37 (d, J = 2.52 Hz, 1H), 6.15 (dd, J = 2.63, 8.59 Hz, 1H), 5.40 (br. s., 1H), 3.63 (br. s., 2H). MS (ESI): m / z = 339.96 [M - H].

[0284]

[0285] 51. Synthesis of 3-nitro-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 11a)

[0286] Compound 11a was synthesized from compound 8a (110 mg, 0.29 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (314 μl, 0.31 mmol, 1.1 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as a colorless oil (57.3 mg, 54.1%) (Fig. 3).

[0287] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.56 (d, J = 2.98 Hz, 1H), 7.11 (dd, J = 2.98, 8.93 Hz, 1H), 7.05 (d, J = 8.93 Hz, 1H), 5.40 (br. s., 1H). MS (ESI): m / z = 370.10 [M - H].

[0288]

[0289] 52. Synthesis of 5-nitro-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 11b)

[0290] Compound 11b was synthesized from compound 8b (110 mg, 0.29 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (314 μl, 0.31 mmol, 1.1 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as a colorless oil (41.4 mg, 39.1%) (Fig. 3).

[0291] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J = 2.75 Hz, 1H), 7.80 (dd, J = 2.52, 8.93 Hz, 1H), 6.87 (d, J = 8.93 Hz, 1H). MS (ESI): m / z = 370.44[MH].

[0292]

[0293] 53. Synthesis of 1,2,4,5-tetrafluoro-3-(4-nitro-2-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzene (Compound 13a)

[0294] Compound 13a was synthesized from compound 12a (100 mg, 0.45 mmol, 1.0 equiv), octafluorotoluene (69.9 μl, 0.49 mmol, 1.1 equiv), and K2CO3 (92.9 mg, 0.67 mmol, 1.5 equiv) at RT for 24 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane: EtOAc = 8:1) to obtain the desired product as bright yellow crystals (95.7 mg, 48.6%) (Fig. 4).

[0295] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.33 (dd, J = 1.15, 2.52 Hz, 1H), 8.23 ​​(dd, J = 2.75, 9.16 Hz, 1H), 7.07 (d, J = 9.16 Hz, 1H). MS (ESI): m / z = 437.61[MH].

[0296]

[0297] 54. Synthesis of (5-nitro-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)methanol (compound 13b)

[0298] Compound 13b was synthesized from compound 12b (50.0 mg, 0.30 mmol, 1.0 equiv), octafluorotoluene (41.9 μl, 0.30 mmol, 1.0 equiv), and K2CO3 (40.9 mg, 0.30 mmol, 1.0 equiv) at RT for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as white crystals (57.7 mg, 50.7%) (Fig. 4).

[0299] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (d, J = 3.21 Hz, 1H), 8.16 (dd, J = 2.75, 8.70 Hz, 1H), 6.78 (d, J = 9.16 Hz, 1H), 5.01 (d, J = 5.95 Hz, 2H), 2.04(t, J = 5.95 Hz, 1H). MS (ESI): m / z = 383.81 [MH].

[0300]

[0301] 55. Synthesis of 4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)-3-(trifluoromethoxy)aniline (Compound 14a)

[0302] Compound 14a was synthesized from Compound 13a (95.7 mg, 0.22 mmol, 1.0 equiv) for 3 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as white crystals (65.7 mg, 73.7%) (Fig. 4).

[0303] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.90 (d, J = 8.70 Hz, 1H), 6.62-6.66 (m, 1H), 6.55 (dd, J = 2.63, 8.82 Hz, 1H), 3.78 (br. s., 2H). MS (ESI): m / z = 409.70 [M + H].

[0304]

[0305] 56. Synthesis of (5-amino-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)methanol (compound 14b)

[0306] Compound 14b was synthesized from Compound 13b (57.0 mg, 0.15 mmol, 1.0 equiv) for 0.5 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as white crystals (28.9 mg, 54.8%) (Fig. 4).

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 6.73 (d, J = 2.98 Hz, 1H), 6.71 (d, J = 8.47 Hz, 1H), 6.36 (dd, J = 2.86, 8.59 Hz, 1H), 5.13 (t, J = 5.72 Hz, 1H), 5.03(s, 2H), 4.52(d, J = 5.72 Hz, 2H). MS (ESI): m / z = 355.64 [M + H].

[0308]

[0309] 57. Synthesis of 3-fluoro-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 16a)

[0310] Compound 16a was synthesized from compound 15a (50.0 mg, 0.39 mmol, 1.0 equiv), octafluorotoluene (61.3 μl, 0.43 mmol, 1.1 equiv), and K2CO3 (59.8 mg, 0.43 mmol, 1.1 equiv) at RT for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as white crystals (85.9 mg, 63.6%) (Fig. 4).

[0311] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.95 (t, J = 8.70 Hz, 1H), 6.47 (dd, J = 2.75, 12.36 Hz, 1H), 6.39 (tdd, J = 1.55, 2.78, 8.79 Hz, 1H), 3.74 (br. s., 2H). MS (ESI): m / z = 343.78 [M + H].

[0312]

[0313] 58. Synthesis of 3-chloro-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 16b)

[0314] Compound 16b was synthesized from compound 15b (30.0 mg, 0.21 mmol, 1.0 equiv), octafluorotoluene (32.6 μl, 0.23 mmol, 1.1 equiv), and K2CO3 (31.8 mg, 0.23 mmol, 1.1 equiv) at RT for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as white crystals (32.2 mg, 43.0%) (Fig. 4).

[0315] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.86 (d, J = 8.70 Hz, 1H), 6.75 (d, J = 2.52 Hz, 1H), 6.53 (dd, J = 2.86, 8.82 Hz, 1H), 3.71 (br. s., 2H). MS (ESI): m / z = 359.8 [M + H].

[0316]

[0317] 59. Synthesis of 4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)aniline (Compound 16c)

[0318] Compound 16c was synthesized from compound 15c (30.0 mg, 0.17 mmol, 1.0 equiv), octafluorotoluene (26.4 μl, 0.19 mmol, 1.1 equiv), and K2CO3 (25.7 mg, 0.19 mmol, 1.1 equiv) at RT for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as white crystals (32.5 mg, 48.8%) (Fig. 4).

[0319] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.97 (d, J = 2.52 Hz, 1H), 6.74-6.78 (m, 1H), 6.70-6.74 (m, 1H), 3.81 (br. s., 2H). MS (ESI): m / z = 394.0 [M + H].

[0320]

[0321] 60. Synthesis of 5-amino-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)benzonitrile (Compound 16d)

[0322] Compound 16d was synthesized from compound 15d (20.0 mg, 0.15 mmol, 1.0 equiv), octafluorotoluene (23.2 μl, 0.16 mmol, 1.1 equiv), and K2CO3 (22.7 mg, 0.16 mmol, 1.1 equiv) at RT for 5 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as white crystals (16.0 mg, 30.6%) (Fig. 4).

[0323] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.91-6.94 (m, 1H), 6.80-6.85 (m, 1H), 6.76 (d, J = 8.93 Hz, 1H), 3.84 (br. s., 2H). MS (ESI): m / z = 350.9 [M + H].

[0324]

[0325] 61. Synthesis of 5-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)-1H-benzo[d]imidazole (Compound 20)

[0326] BOC-anhydride (940 μl, 4.1 mmol, 1.1 equiv) and TEA (571 μl, 4.1 mmol, 1.1 equiv) were added at RT to a stirred solution of Compound 17 (500 mg, 3.7 mmol, 1.0 equiv) in THF (7.4 ml, 2.0 ml / mmol). The reaction mixture was stirred at RT for 5 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude regio-protected mixture (Compound 18a) was used without further purification.

[0327] Compound 19 was synthesized from crude mixture 18 (726 mg, 3.1 mmol, 1.0 equiv), octafluorotoluene (528 μl, 3.7 mmol, 1.2 equiv), and K2CO3 (514 mg, 3.7 mmol, 1.2 equiv) at RT for 5 hours according to general procedure A. The crude regio-protected mixture was used without further purification.

[0328] Compound 20 was synthesized from crude mixture 19. 3 ml of TFA was added dropwise at room temperature to a stirred solution of Compound 19 (1.3 g, 2.9 mmol, 1.0 equiv) dissolved in DCM (15 ml, 5.0 ml / mmol). The reaction mixture was stirred at room temperature under an argon atmosphere for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with EtOAc, and washed sequentially with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 10:1) to obtain the desired product as a white solid (635 mg, 62.8%) (Fig. 5).

[0329] 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (br. s., 1H), 8.25 (s, 1H), 7.59 (d, J = 8.70 Hz, 1H), 7.36-7.46 (m, 1H), 7.13 (dd, J = 2.29, 8.70 Hz, 1H). MS (ESI): m / z = 351.5 [M + H].

[0330]

[0331] 62. Synthesis of 5-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)-1H-indole (Compound 22a)

[0332] Compound 22a was synthesized from compound 21a (50.0 mg, 0.38 mmol, 1.0 equiv), octafluorotoluene (58.5 μl, 0.41 mmol, 1.1 equiv), and K2CO3 (77.8 mg, 0.56 mmol, 1.5 equiv) at RT for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as white crystals (91.5 mg, 70.0%) (Fig. 5).

[0333] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (br. s., 1H), 7.37 (td, J = 0.77, 8.76 Hz, 1H), 7.28 (d, J = 2.75 Hz, 1H), 7.23 (d, J = 2.52 Hz, 1H), 7.01 (dd, J = 2.52, 8.93 Hz, 1H), 6.52 (ddd, J = 0.92, 2.12, 3.15 Hz, 1H). MS (ESI): m / z = 349.8 [M + H].

[0334]

[0335] 63. Synthesis of 5-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)-1H-indazole (Compound 22b)

[0336] Compound 22b was synthesized from compound 21b (50.0 mg, 0.37 mmol, 1.0 equiv), octafluorotoluene (58.1 μl, 0.41 mmol, 1.1 equiv), and K2CO3 (56.7 mg, 0.41 mmol, 1.1 equiv) at RT for 5 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as white crystals (35.7 mg, 27.3%) (Fig. 5).

[0337] 1H NMR (400 MHz, CHLOROFORM-d) δ 10.28 (br. s., 1H), 8.04 (d, J = 1.15 Hz, 1H), 7.52 (td, J = 1.03, 8.70 Hz, 1H), 7.27-7.28 (m, 1H), 7.28-7.25 (m, 1H). MS (ESI): m / z = 350.6 [M + H].

[0338]

[0339] 64. Synthesis of 4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)benzamide (Compound 24)

[0340] Compound 24 was synthesized from Compound 23 (100 mg, 0.73 mmol, 1.0 equiv), octafluorotoluene (114 μl, 0.80 mmol, 1.1 equiv), and K2CO3 (111 mg, 0.80 mmol, 1.1 equiv) at RT for 5 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 25:1) to obtain the desired product as white crystals (110.5 mg, 42.9%) (Fig. 5).

[0341] 1 ¹H NMR(400 MHz, DMSO-d6) δ 7.99(base residue, 1H), 7.89–7.95(m, 2H), 7.38(base residue, 1H), 7.26–7.31(m, 2H). MS (ESI): m / z = 354.0[M + H].

[0342]

[0343] 65. Synthesis of Benzyl(4-hydroxy-3-methoxybenzyl)Carbamate (Compound 26)

[0344] Benzyl chloroformate (75 μl, 0.53 mmol, 1.0 equiv) was added at 0 °C to a stirred solution of Compound 25 (100 mg, 0.53 mmol, 1.0 equiv) and NaHCO3 (93 ml, 1.1 mmol, 2.1 equiv) in water / THF = 1 / 1 (1.1 ml, 2.0 ml / mmol). The reaction mixture was stirred at RT under an argon atmosphere for 5 hours. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired product as a colorless oil (170 mg, 64.2%) (Fig. 6).

[0345] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.32-7.40 (m, 5H), 6.87 (d, J = 8.01 Hz, 1H), 6.74-6.83 (m, 2H), 5.62 (s, 1H), 5.15 (s, 2H), 5.04 (br. s., 1H), 4.31 (d, J = 5.72 Hz, 2H), 3.86 (s, 3H). MS (ESI): m / z = 288.06 [M + H].

[0346]

[0347] 66. Synthesis of benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)benzyl)carbamate (Compound 27)

[0348] Compound 27 was synthesized from compound 26 (170.0 mg, 0.59 mmol, 1.0 equiv), octafluorotoluene (125 μl, 0.89 mmol, 1.5 equiv), and K2CO3 (123 mg, 0.89 mmol, 1.5 equiv) at RT for 3 hours according to general procedure A. After concentrating the organic layer without further purification, the product was obtained as a white solid (202.1 mg, 67.9%) (Fig. 6).

[0349] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.31-7.41 (m, 6H), 6.97 (d, J = 8.24 Hz, 1H), 6.91 (s, 1H), 6.83 (d, J = 8.01 Hz, 1H), 5.16 (s, 2H), 5.09 (br. s., 1H), 4.38 (d, J = 6.18 Hz, 2H), 3.81 (s, 3H). MS (ESI): m / z = 503.83 [M + H].

[0350]

[0351] 67. Synthesis of (3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)methaneamine (Compound 28)

[0352] Compound 28 was synthesized from Compound 27 (220.1 mg, 0.44 mmol, 1.0 equiv) for 2 hours according to general procedure D. After concentrating the organic layer without further purification, the product was obtained as a white solid (160.2 mg, 99.3%) (Fig. 6).

[0353] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.97-7.02 (m, 2H), 6.84-6.89 (m, 1H), 3.89 (s, 2H), 3.86 (s, 3H). MS (ESI): m / z = 369.82 [M + H].

[0354]

[0355] 68. Synthesis of 5-(aminomethyl)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (29)

[0356] Compound 29 was synthesized from Compound 28 (162 mg, 0.44 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (921 μl, 0.92 mmol, 2.1 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (NH3-saturated CHCl3:MeOH = 10:1) to obtain the desired product as white crystals (56.7 mg, 36.4%) (Fig. 6).

[0357] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.93 (d, J = 1.83 Hz, 1H), 6.79 (d, J = 8.24 Hz, 1H), 6.71-6.76 (m, 1H), 3.81 (s, 2H). MS (ESI): m / z = 353.53 [MH].

[0358]

[0359] 69. Synthesis of 5-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)pyridine-2-amine (Compound 32)

[0360] Compound 31 was synthesized from Compound 30 (56.9 mg, 0.46 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (917 μl, 0.92 mmol, 2.0 equiv) at RT for 12 hours according to general procedure B. The crude product was used without further purification.

[0361] Compound 32 was synthesized from crude product compound 31 (50.5 mg, 0.46 mmol, 1.0 equiv), octafluorotoluene (65.0 μl, 0.46 mmol, 1.0 equiv), and K2CO3 (63.4 mg, 0.46 mmol, 1.0 equiv) at RT for 3 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 1:1) to obtain the desired product, a colorless oil (32.5 mg, 21.8%) (Fig. 7).

[0362] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.93 (d, J = 2.75 Hz, 1H), 7.23 (dd, J = 3.21, 8.70 Hz, 1H), 6.50 (d, J = 9.16 Hz, 1H), 4.45 (br. s., 2H). MS (ESI): m / z = 326.99 [M + H].

[0363]

[0364] 70. Synthesis of 5-nitro-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)pyridine (Compound 34)

[0365] Compound 34 was synthesized from Compound 33 (100 mg, 0.68 mmol, 1.0 equiv), octafluorotoluene (97.0 μl, 0.68 mmol, 1.0 equiv), and K2CO3 (94.6 mg, 0.68 mmol, 1.0 equiv) at RT for 0.5 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 4:1) to obtain the desired product, a colorless oil (59.7 mg, 24.5%) (Fig. 7).

[0366] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (d, J = 3.66 Hz, 1H), 8.22-8.29 (m, 1H), 6.78 (d, J = 10.08 Hz, 1H). MS (ESI): m / z = 356.61 [M + H].

[0367]

[0368] 71. Synthesis of 6-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)pyridine-3-amine (Compound 35)

[0369] SnCl2·2H2O (64.8 mg, 0.34 mmol, 3.0 equiv) was added at RT to a stirred solution of Compound 34 (40.6 mg, 0.11 mmol, 1.0 equiv) dissolved in 1 M HCl solution:EtOH = 1:5 (0.6 ml, 5.3 ml / mmol). The reaction mixture was stirred at 60 °C for 0.5 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M NaOH aqueous solution and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 10:1) to obtain the desired product as a white solid (17.0 mg, 45.7%) (Fig. 7).

[0370] 1 H NMR (400MHz, DMSO-d6) δ 7.33 (dd, J =2.86, 9.73Hz, 1H), 6.77 (d, J =2.75Hz, 1H), 6.52 (d, J =9.85Hz, 1H), 4.65 (s, 2H). MS (ESI): m / z=326.81[M+H].

[0371]

[0372] 72. Synthesis of 3-methoxy-N-methyl-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 36a)

[0373] Iodomethane (30.7 μl, 0.49 mmol, 1.8 equiv) and K2CO3 (94.6 mg, 0.68 mmol, 2.5 equiv) were added at RT to a stirred solution of compound 9b (97.3 mg, 0.27 mmol, 1.0 equiv) dissolved in DMF (0.54 ml, 2.0 ml / mmol). The reaction mixture was stirred at 45°C for 12 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product 36a (27.0 mg, 26.7%) and a colorless oil 36a (33.0 mg, 32.4%) (Fig. 8).

[0374] 1H NMR (400 MHz, CHLOROFORM-d) d 6.94 (d, J = 8.70 Hz, 1H), 6.20 (d , J = 2.75 Hz, 1H), 6.12 (dd, J = 2.52, 8.70 Hz, 1H), 3.80 (s, 3H), 3.67-3.78(m, 1H), 2.84(s, 3H) . MS (ESI): m / z = 370.33 [M + H].

[0375]

[0376] 73. Synthesis of 3-Methoxy-N,N-Dimethyl-4-(2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)Phenoxy)aniline (Compound 36b)

[0377] Iodomethane (30.7 μl, 0.49 mmol, 1.8 equiv) and K2CO3 (94.6 mg, 0.68 mmol, 2.5 equiv) were added at RT to a stirred solution of compound 9b (97.3 mg, 0.27 mmol, 1.0 equiv) dissolved in DMF (0.54 ml, 2.0 ml / mmol). The reaction mixture was stirred at 45°C for 12 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product 36b (27.0 mg, 26.7%) and the colorless oil 36a (33.0 mg, 32.4%) (Fig. 8).

[0378] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.97 (d, J = 8.70 Hz, 1H), 6.30 (d, J = 2.75 Hz, 1H), 6.22 (dd, J = 2.86, 8.82 Hz, 1H), 3.82 (s, 3H), 2.96 (s, 6H). MS(ESI): m / z = 383.77 [M + H].

[0379]

[0380] 74. Synthesis of 5-(methylamino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 37a)

[0381] Compound 37a was synthesized from compound 36a (29.4 mg, 0.083 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (273 μl, 0.27 mmol, 3.3 equiv) at RT for 48 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as white crystals (17.8 mg, 63.0%) (Fig. 8).

[0382] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.70 (d, J = 8.70 Hz, 1H), 6.28 (d, J = 2.75 Hz, 1H), 6.07 (dd, J = 2.63, 8.82 Hz, 1H), 5.43 (br. s., 1H), 3.74 (br. s., 1H), 2.81 (s., 4H). MS (ESI): m / z = 355.87 [M + H].

[0383]

[0384] 75. Synthesis of 5-(dimethylamino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 37b)

[0385] Compound 37b was synthesized from compound 36b (23.4 mg, 0.063 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (209 μl, 0.21 mmol, 3.3 equiv) at RT for 48 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product as white crystals (15.2 mg, 67.4%) (Fig. 8).

[0386] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.74 (d, J = 8.93 Hz, 1H), 6.39 (d, J = 2.98 Hz, 1H), 6.17 (dd, J = 2.98, 8.93 Hz, 1H), 5.46 (br. s., 1H), 2.90 -2.94(m, 6H). MS (ESI): m / z = 369.71 [M + H].

[0387]

[0388] 76. Synthesis of 5-(ethylamino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 38a)

[0389] Acetaldehyde (8 μl, 0.15 mmol, 1.0 equiv) and NaBH(OAc)3 (34.2 ml, 0.16 mmol, 1.1 equiv) were added at RT to a stirred solution of compound 10b (50.0 mg, 0.15 mmol, 1.0 equiv) in acetic acid (0.75 ml, 5 ml / mmol). The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product as a white solid (41.7 mg, 77.1%) (Fig. 8).

[0390] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 9.16 Hz, 1H), 6.28 (d, J = 2.75 Hz, 1H), 6.06 (dd, J = 2.75, 8.70 Hz, 1H), 3.11 (q, J = 7.17 Hz, 2H), 1.25(t, J = 7.10 Hz, 3H). MS (ESI): m / z = 369.92 [M + H].

[0391]

[0392] 77. Synthesis of 5-(propylamino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 38b)

[0393] Propionaldehyde (11 μl, 0.15 mmol, 1.0 equiv) and NaBH(OAc)3 (34.2 ml, 0.16 mmol, 1.1 equiv) were added at RT to a stirred solution of compound 10b (50.0 mg, 0.15 mmol, 1.0 equiv) in acetic acid (0.75 ml, 5 ml / mmol). The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product as a white solid (45.2 mg, 80.5%) (Fig. 8).

[0394] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.68 (d, J = 9.16 Hz, 1H), 6.27 (d, J = 2.75 Hz, 1H), 6.06 (dd, J = 2.75, 8.70 Hz, 1H), 5.41 (br. s., 1H), 3.64 (br. s., 1H), 3.03 (t, J = 7.10 Hz, 2H), 1.61-1.69 (m, 2H), 1.00 (t, J = 7.33 Hz, 3H). MS (ESI): m / z = 384.4 [M + H].

[0395]

[0396] 78. Synthesis of 4-Bromobutane-1-Amium Bromide (Compound 40a)

[0397] Compound 39a (500 mg, 5.6 mmol, 1.0 equiv) was dissolved in a 48% HBr aqueous solution (5.6 ml, 1.0 ml / mmol) at RT. The reaction mixture was refluxed under an argon atmosphere for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude residue was dissolved in cold acetone and stirred under an argon atmosphere for 0.5 hours. The recrystallized solid was filtered and washed with acetone and hexane to obtain the desired product as a brown solid (1.1 g, 84.1%) (Fig. 9).

[0398] 1 ¹H NMR (400 MHz, deuterium oxide) δ 3.45 (t, J = 6.41 Hz, 2H), 2.93–3.00 (m, 2H), 1.83–1.92 (m, 2H), 1.71–1.80 (m, 2H). MS (ESI): m / z = 152.3 [M + H].

[0399]

[0400] 79. Synthesis of 5-Bromopentane-1-Amium Bromide (Compound 40b)

[0401] Compound 39b (500 mg, 4.8 mmol, 1.0 equiv) was dissolved in a 48% HBr aqueous solution (4.8 ml, 1.0 ml / mmol) at RT. The reaction mixture was refluxed under an argon atmosphere for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude residue was dissolved in cold acetone and stirred under an argon atmosphere for 0.5 hours. The recrystallized solid was filtered and washed with acetone and hexane to obtain the desired product as a light brown solid (375 mg, 31.3%) (Fig. 9).

[0402] 1¹H NMR (400 MHz, deuterium oxide) δ 3.44 (t, J = 6.64 Hz, 2H), 2.90–2.97 (m, 2H), 1.77–1.87 (m, 2H), 1.56–1.67 (m, 2H), 1.40–1.50 (m, 2H). MS (ESI): m / z = 161.2 [M + H].

[0403]

[0404] 80 Synthesis of 5-((2-aminoethyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (compound 41a)

[0405] Compound 41a was synthesized from compound 10b (150 mg, 0.44 mmol, 1.0 equiv) and 2-bromoethylamine hydrobromide (90.1 mg, 0.44 mmol, 1.0 equiv) according to general procedure E. The desired product was obtained as a light brown oil (63.9 mg, 37.8%) (Fig. 9).

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 8.70 Hz, 1H), 6.14 (d, J = 2.29 Hz, 1H), 5.98 (dd, J = 2.75, 8.70 Hz, 1H), 2.93 (t, J = 6.18 Hz, 2H), 2.68(t, J = 6.41Hz, 2H). MS (ESI): m / z = 384.79 [M + H].

[0407]

[0408] 81. Synthesis of 5-((3-aminopropyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 41b)

[0409] Compound 41b was synthesized from compound 10b (150 mg, 0.44 mmol, 1.0 equiv) and 3-bromopropylamine hydrobromide (96.2 mg, 0.44 mmol, 1.0 equiv) according to general procedure E. The desired product was obtained as a light brown oil (60.4 mg, 34.5%) (Fig. 9).

[0410] 1 H NMR (400 MHz, DMSO-d6) δ 6.91 (d, J = 8.70 Hz, 1H), 6.15 (d, J = 2.75 Hz, 1H), 5.99 (dd, J = 2.52, 8.93 Hz, 1H), 3.00 (t, J = 6.87 Hz, 2H), 2.83-2.90(m, 2H), 1.75-1.82(m, 2H). MS (ESI): m / z = 398.84 [M + H].

[0411]

[0412] 82. Synthesis of 5-((4-aminobutyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 41c)

[0413] Compound 41c was synthesized from compound 10b (150 mg, 0.44 mmol, 1.0 equiv) and compound 40a (102 mg, 0.44 mmol, 1.0 equiv) according to general procedure E. The desired product was obtained as a light brown oil (62.7 mg, 34.6%) (Fig. 9).

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 8.70 Hz, 1H), 6.13 (d, J = 2.75 Hz, 1H), 5.98 (d, J = 2.75 Hz, 1H), 2.88-2.93 (m, 2H), 2.64-2.69 (m, 2H), 1.49-1.55(m, 4H). MS (ESI): m / z = 412.83 [M + H].

[0415]

[0416] 83. Synthesis of 5-((5-aminopentyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 41d)

[0417] Compound 41d was synthesized from compound 10b (150 mg, 0.44 mmol, 1.0 equiv) and compound 40b (109 mg, 0.44 mmol, 1.0 equiv) according to general procedure E. The desired product was obtained as a light brown oil (64.1 mg, 34.2%) (Fig. 9).

[0418] 1 H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 8.70 Hz, 1H), 6.13 (d, J = 2.75 Hz, 1H), 5.97 (dd, J = 2.52, 8.93 Hz, 1H), 2.90 (t, J = 6.87 Hz, 2H), 2.70-2.82(m, 2H), 1.45-1.60(m, 4H), 1.30-1.43(m, 2H). MS (ESI): m / z = 427.2 [M + H].

[0419]

[0420] 84. Synthesis of tert-butyl(2-methoxy-4-nitrophenoxy)dimethylsilane (Compound 42)

[0421] Imidazole (2.4 g, 35.5 mmol, 3.0 equiv) and TBDMS-Cl (5.3 g, 35.5 mmol, 3.0 equiv) were added at RT to a stirred solution of compound 7b (2.0 g, 11.8 mmol, 1.0 equiv) dissolved in DMF (11.8 ml, 1 ml / mmol). The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with diethyl ether and washed sequentially with an appropriate amount of water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired product as a colorless oil (3.3 g, 98.5%) (Fig. 10).

[0422] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.82 (dd, J = 2.75, 8.70 Hz, 1H), 7.75 (d, J = 2.75 Hz, 1H), 6.90 (d, J = 9.16 Hz, 1H), 3.90 (s, 3H), 0.99-1.03(m, 9H), 0.19-0.23(m, 6H). MS (ESI): m / z = 283.7 [M + H].

[0423]

[0424] 85. Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3-methoxycyaniline (Compound 43)

[0425] Compound 43 was synthesized from Compound 42 (3.3 g, 11.6 mmol, 1.0 equiv) for 12 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 2:1) to obtain the desired product of light brown crystals (2.5 g, 84.7%) (Fig. 10).

[0426] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.66 (d, J = 8.47 Hz, 1H), 6.27 (d, J = 2.75 Hz, 1H), 6.17 (dd, J = 2.52, 8.24 Hz, 1H), 3.73-3.78 (m, 3H), 3.24 (br. s., 1H), 0.96-1.01 (m, 10H), 0.10-0.14 (m, 6H). MS (ESI): m / z = 254.3 [M + H].

[0427]

[0428] 86. Synthesis of Ethyl 4-Morfollinobutanoate (Compound 45a)

[0429] Morpholine (3.6 ml, 42.0 mmol, 2.0 equiv) was added at RT to a stirred solution of compound 44a (3.0 ml, 21.0 mmol, 1.0 equiv) in ACN (30 ml, 1.4 ml / mmol). The reaction mixture was refluxed under an argon atmosphere for 24 hours. After the reaction was complete, the mixture was cooled to 0°C, and the residual morpholine, an HBr scavenger, was removed by filtration. The filtrate was concentrated under reduced pressure, dissolved in hexane, and the insoluble residue was filtered. After concentrating the filtrate, the desired product was obtained as a colorless oil (3.8 g, 90.1%) (Fig. 10).

[0430] 1 H NMR (400 MHz, DMSO-d6) δ 4.00 (q, J = 7.11 Hz, 2H), 3.43-3.56 (m, 4H), 2.23-2.34 (m, 6H), 2.21 (t, J = 7.11 Hz, 2H), 1.63 (t, J = 7.11 Hz, 2H) 1.14(t, J = 7.11Hz, 3H). MS (ESI): m / z = 202.5 [M + H].

[0431]

[0432] 87. Synthesis of Ethyl 5-Morfollinopentanoate (Compound 45b)

[0433] Morpholine (3.2 ml, 37.6 mmol, 2.0 equiv) was added at RT to a stirred solution of compound 44b (3.0 ml, 18.8 mmol, 1.0 equiv) in ACN (30 ml, 1.6 ml / mmol). The reaction mixture was refluxed under an argon atmosphere for 24 hours. After the reaction was complete, the mixture was cooled to 0°C, and the residual morpholine, an HBr scavenger, was removed by filtration. The filtrate was concentrated under reduced pressure, dissolved in hexane, and the insoluble residue was filtered. After concentrating the filtrate, the desired product was obtained as a colorless oil (3.5 g, 86.5%) (Fig. 10).

[0434] 1H NMR (400 MHz, CHLOROFORM-d) δ 4.13 (q, J = 7.10 Hz, 2H), 3.59-3.86 (m, 4H), 2.43-2.64 (m, 4H), 2.35-2.43 (m, 2H), 2.28-2.35 (m, 2H), 1.63-1.71(m, 2H), 1.51-1.62 (m, 2H), 1.26(t, J = 7.10 Hz, 3H). MS (ESI): m / z = 216.5 [M + H].

[0435]

[0436] 88. Synthesis of 4-(3-carboxypropyl)morpholine-4-ium chloride (Compound 46a)

[0437] Compound 45a (3.8 g, 18.9 mmol, 1.0 equiv) was dissolved in a 37% aqueous solution of HCl / water = 1 / 1 (19 ml, 1.0 ml / mmol) at RT. The reaction mixture was refluxed under an argon atmosphere for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude residue was dissolved in cold acetone and stirred under an argon atmosphere for 0.5 hours. The recrystallized solid was filtered and washed with acetone and hexane to obtain the desired product as a white solid (3.7 g, 93.5%) (Fig. 10).

[0438] 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (br. s., 1H), 10.91 (br. s., 1H), 3.82 (br. s., 4H), 2.88-3.13 (m, 4H), 2.30 (t, J = 7.34 Hz, 2H), 1.81-1.93(m, 2H). MS (ESI): m / z = 174.5 [M + H].

[0439]

[0440] 89. Synthesis of 4-(4-carboxybutyl)morpholine-4-ium chloride (Compound 46b)

[0441] Compound 45b (3.5 g, 16.3 mmol, 1.0 equiv) was dissolved in a 37% aqueous solution of HCl / water = 1 / 1 (16 ml, 1.0 ml / mmol) at RT. The reaction mixture was refluxed under an argon atmosphere for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude residue was dissolved in cold acetone and stirred under an argon atmosphere for 0.5 hours. The recrystallized solid was filtered and washed with acetone and hexane to obtain the desired product as a white solid (3.4 g, 93.9%) (Fig. 10).

[0442] 1 H NMR (400 MHz, deuterium oxide) δ 4.11 (dd, J = 3.66, 13.28 Hz, 2H), 3.74-3.86 (m, 2H), 3.47-3.59 (m, 2H), 3.10-3.24 (m, 4H), 2.43 (t, J = 7.21) Hz, 2H), 1.71-1.83 (m, 2H), 1.58-1.70 (m, 2H). MS (ESI): m / z = 188.5 [M + H].

[0443]

[0444] 90. Synthesis of N-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-4-morpholinobutanamide (Compound 47a)

[0445] Compound 46a (107.0 mg, 0.51 mmol, 1.3 equiv), EDC·HCl (98.5 mg, 1.3 mmol, 1.3 equiv), DMAP (62.5 mg, 1.3 mmol, 1.3 equiv), and TEA (200 μl, 1.38 mmol, 3.5 equiv) were added at RT to a stirred solution of compound 43 (100 mg, 0.39 mmol, 1.0 equiv) in DCM (2.0 ml, 5 ml / mmol). The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, 1 M aqueous HCl solution, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired product as a colorless oil (158.2 mg, 98.1%) (Fig. 10).

[0446] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.03 (s, 1H), 7.42 (d, J = 2.75 Hz, 1H), 6.77 (d, J = 8.24 Hz, 1H), 6.68 (dd, J = 2.52, 8.47 Hz, 1H), 3.81 (s, 3H), 3.70-3.77 (m, 4H), 2.48 (br. s., 4H), 2.39-2.46 (m, 4H), 1.92 (quin, J = 6.76 Hz, 2H), 0.97-1.01 (m, 9H), 0.12-0.17 (m, 6H). MS (ESI): m / z = 409.4 [M + H].

[0447]

[0448] 91. Synthesis of N-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-5-morpholinopentanamide (Compound 47b)

[0449] Compound 46b (114.0 mg, 0.51 mmol, 1.3 equiv), EDC·HCl (98.5 mg, 1.3 mmol, 1.3 equiv), DMAP (62.5 mg, 1.3 mmol, 1.3 equiv), and TEA (200 μl, 1.38 mmol, 3.5 equiv) were added at RT to a stirred solution of compound 43 (100 mg, 0.39 mmol, 1.0 equiv) in DCM (2.0 ml, 5 ml / mmol). The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, 1 M aqueous HCl solution, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired product as a colorless oil (162.6 mg, 97.5%) (Fig. 10).

[0450] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.36-7.46 (m, 2H), 6.73-6.80 (m, 2H), 3.81 (s, 3H), 3.78 (t, J = 4.58 Hz, 4H), 2.56 (br. s., 4H), 2.45-2.52 (m, 3H), 2.39 (t, J = 7.33 Hz, 2H), 1.74-1.84 (m, 2H), 1.60-1.70 (m, 2H), 0.98-1.00 (m, 9H), 0.11-0.18 (m, 6H). MS (ESI): m / z = 423.5 [M + H].

[0451]

[0452] 92. Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3-methoxy-N-(4-morpholinobutyl)aniline (Compound 48a)

[0453] LiAlH4 (2.0 ml, 3.9 mmol, 5 equiv) dissolved in THF (2.0 M) was added dropwise to a stirred solution of Compound 47a (343 mg, 0.79 mmol, 1.0 equiv) dissolved in THF (7.9 ml, 10 ml / mmol) over a period of 0.5 hours at -78°C. The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was cooled to 0°C, diluted with EtOAc, and the reaction was stopped by quenching with the addition of water. The quenched mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 15:1) to obtain the desired product as a colorless oil (188 mg, 56.8%) (Fig. 10).

[0454] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.47 Hz, 1H), 6.19 (d, J = 2.52 Hz, 1H), 6.08 (dd, J = 2.75, 8.47 Hz, 1H), 3.77 (s, 3H), 3.74 (t, J = 4.47 Hz, 4H), 3.05-3.12 (m, 2H), 2.42-2.51 (m, 4H), 2.40 (br. s., 2H), 1.62-1.66 (m, 4H), 0.99 (s, 9H), 0.10-0.13 (m, 6H). MS (ESI): m / z = 395.3 [M + H].

[0455]

[0456] 93. Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3-methoxy-N-(5-morpholinopentyl)aniline (Compound 48b)

[0457] LiAlH4 (15.6 ml, 31.2 mmol, 5 equiv) dissolved in THF (2.0 M) was added dropwise to a stirred solution of Compound 47b (2.6 g, 6.3 mmol, 1.0 equiv) dissolved in THF (63 ml, 10 ml / mmol) over a period of 0.5 hours at -78°C. The reaction mixture was stirred at RT for 18 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was cooled to 0°C, diluted with EtOAc, and the reaction was stopped by adding water and quenching. The quenched mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 15:1) to obtain the desired product, a colorless oil (1.5 g, 58.8%) (Fig. 10).

[0458] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.08 (dd, J = 2.75, 8.24 Hz, 1H), 3.77 (s, 3H), 3.71-3.75 (m, 4H), 3.07 (t, J = 7.10 Hz, 2H), 2.44 (br. s., 4H), 2.31-2.38 (m, 2H), 1.61-1.66 (m, 2H), 1.52-1.57 (m, 2H), 1.44 (d, J = 6.87) Hz, 2H), 0.96-1.01(m, 9H), 0.09-0.14(m, 6H). MS (ESI): m / z = 409.5 [M + H].

[0459]

[0460] 94. Synthesis of 3-Methoxy-N-(4-Morpolinobutyl)-4-(2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)Phenoxy)aniline (Compound 50a)

[0461] Acetic acid (57.2 μl, 1.0 mmol, 2.1 equiv) and TBAF (572 μl, 0.57 mmol, 1.2 equiv) dissolved in THF (1.0 M) were added at 0°C to a stirred solution of compound 48a (188 mg, 0.48 mmol, 1.0 equiv) dissolved in THF (4.8 ml, 10 ml / mmol). The reaction mixture was stirred at RT for 4 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product (compound 49a) was used without further purification.

[0462] Compound 50a was synthesized from crude product 49a (133.6 mg, 0.48 mmol, 1.0 equiv), octafluorotoluene (101.3 μl, 0.71 mmol, 1.5 equiv), and K2CO3 (98.8 mg, 0.71 mmol, 1.5 equiv) at RT for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product, a colorless oil (54.4 mg, 23.0%) (Fig. 10).

[0463] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.18 (d, J = 2.52 Hz, 1H), 6.10 (dd, J = 2.63, 8.59 Hz, 1H), 3.78 (s, 3H), 3.70-3.76 (m, 4H), 3.12 (t, J = 6.64 Hz, 2H), 2.47 (br. s., 4H), 2.40 (t, J = 6.98 Hz, 2H), 1.61-1.72 (m, 4H). MS (ESI): m / z = 497.2 [M + H].

[0464]

[0465] 95. Synthesis of 3-Methoxy-N-(5-Morpolinopentyl)-4-(2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)Phenoxy)aniline (Compound 50b)

[0466] Acetic acid (448 μl, 7.8 mmol, 2.1 equiv) and TBAF (3.9 ml, 3.9 mmol, 1.0 equiv) dissolved in THF (1.0 M) were added at 0°C to a stirred solution of compound 48b (1.6 g, 3.9 mmol, 1.0 equiv) dissolved in THF (39 ml, 10 ml / mmol). The reaction mixture was stirred at RT for 4 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product (compound 49b) was used without further purification.

[0467] Compound 50b was synthesized from crude product 49b (899 mg, 3.0 mmol, 1.0 equiv), octafluorotoluene (564 μl, 4.0 mmol, 1.3 equiv), and K2CO3 (549 mg, 4.0 mmol, 1.3 equiv) at RT for 18 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product, a colorless oil (1.1 g, 68.0%) (Fig. 10).

[0468] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.52, 8.70 Hz, 1H), 3.78 (s, 3H), 3.68-3.76(m, 4H), 3.10(t, J = 6.87 Hz, 2H), 2.39-2.50(m, 4H), 2.31-2.39(m, 2H), 1.63-1.70(m, 2H), 1.51-1.59(m, 2H), 1.39-1.50(m, 2H). MS (ESI): m / z = 511.3 [M + H].

[0469]

[0470] 96. Synthesis of 5-((4-morpholinobutyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 51a)

[0471] Compound 51a was synthesized from compound 50a (54.4 mg, 0.11 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (220 μl, 0.22 mmol, 2.0 equiv) at RT for 18 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a bright red oil (29.2 mg, 55.2%) (Fig. 10).

[0472] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.94 Hz, 1H), 6.24 (d, J = 2.75 Hz, 1H), 6.04 (dd, J = 2.75, 8.71 Hz, 1H), 3.61-3.78 (m, 4H), 2.99-3.11 (m, 2H), 2.40-2.52 (m, 4H), 2.32-2.40 (m, 2H), 1.52 -1.69 (m, 4H). MS (ESI): m / z = 483.4 [M + H].

[0473]

[0474] 97. Synthesis of 5-((5-morpholinopentyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 51b)

[0475] Compound 51b was synthesized from compound 50b (1.1 g, 2.1 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (4.2 ml, 4.2 mmol, 2.0 equiv) at RT for 18 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as light brown crystals (862 mg, 83.7%) (Fig. 10).

[0476] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.71 (d, J = 8.70 Hz, 1H), 6.23 (d, J = 2.75 Hz, 1H), 6.03 (dd, J = 2.75, 8.70 Hz, 1H), 3.70-3.77 (m, 4H), 3.05 (t, J = 7.10 Hz, 2H), 2.48 (br. s., 4H), 2.34-2.41 (m, 2H), 1.58-1.66 (m, 2H), 1.51-1.58 (m, 2H), 1.37-1.45 (m, 2H). MS (ESI): m / z = 497.2 [M + H].

[0477]

[0478] 98. Synthesis of 1-(3,5-bis(trifluoromethyl)phenoxy)-2-methoxy-4-nitrobenzene (Compound 53)

[0479] Compound 57 was synthesized from compound 52 (1.05 g, 6.73 mmol, 1.0 equiv), 3,5-bis(trifluoromethyl)phenol (1.02 ml, 6.73 mmol, 1.0 equiv), and K2CO3 (1.42 g, 10.0 mmol, 1.5 equiv) at 60°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane: EtOAc = 7:1) to obtain the desired product as a bright yellow solid (2.25 g, 87.7%) (Fig. 11).

[0480] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.69 (dd, J = 2.75, 9.16 Hz, 1H), 6.62 (d, J = 3.21 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H). MS (ESI): m / z = 368.60[MH].

[0481]

[0482] 99. Synthesis of 4-(3,5-bis(trifluoromethyl)phenoxy)-3-methoxyaniline (Compound 54)

[0483] Compound 54 was synthesized from Compound 53 (6.3 mg, 0.018 mmol, 1.0 equiv) for 5 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product in the form of a colorless oil (2.4 mg, 41.3%) (Fig. 11).

[0484] 1 H NMR (400MHz, CHLOROFORM-d) δ 7.48 (s, 1H), 7.26 (s, 2H), 6.89 (d, J = 8.55Hz, 1H), 6.38 (d, J = 2.75Hz, 1H), 6.31 (dd, J = 2.59, 8.39Hz, 1H), 3.74(s, 3H). MS (ESI): m / z = 351.93 [M + H].

[0485]

[0486]

[0487] 100. Synthesis of 5-amino-2-(3,5-bis(trifluoromethyl)phenoxy)phenol (Compound 55)

[0488] Compound 55 was synthesized from Compound 53 (2.1 mg, 0.0055 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (22 μl, 0.022 mmol, 4.0 equiv) at RT for 18 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 1:1) to obtain the desired product in the form of a colorless oil (1.7 mg, 84.3%) (Fig. 11).

[0489] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.56 (s, 1H), 7.38 (s, 2H), 6.80 (d, J = 8.70 Hz, 1H), 6.42 (d, J = 2.75 Hz, 1H), 6.27 (dd, J = 2.75, 8.70 Hz, 1H), 5.16 (br. s., 1H), 3.71 (br. s., 2H). MS (ESI): m / z = 335.96 [M - H].

[0490]

[0491] 101. Synthesis of 1-(2,5-Dimethoxyphenoxy)-2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)benzene (Compound 57)

[0492] Compound 57 was synthesized from Compound 56 (50 mg, 0.32 mmol, 1.0 equiv), octafluorotoluene (68.9 μl, 0.49 mmol, 1.5 equiv), and K2CO3 (67.2 mg, 0.49 mmol, 1.5 equiv) at RT for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 7:1) to obtain the desired product, a colorless oil (96.3 mg, 80.2%) (Fig. 12).

[0493] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.69 (dd, J = 2.75, 9.16 Hz, 1H), 6.62 (d, J = 3.21 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H). MS (ESI): m / z = 368.60[MH].

[0494]

[0495] 102. Synthesis of 2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)benzene-1,4-diol (Compound 58)

[0496] Compound 58 was synthesized from Compound 57 (96.2 mg, 0.26 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (779 μl, 0.78 mmol, 3.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product as a colorless oil (37.6 mg, 42.3%) (Fig. 12).

[0497] 1H NMR (400 MHz, DMSO-d6) δ 9.83 (br. s., 1H), 9.31 (br. s., 1H), 6.96 (d, J = 8.70 Hz, 1H), 6.37 (d, J = 2.75 Hz, 1H), 6.16 (dd, J = 2.98, 8.93 Hz, 1H). MS (ESI): m / z = 340.77 [M - H].

[0498]

[0499] 103. Synthesis of 4-nitro-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 60)

[0500] Compound 60 was synthesized from compound 59 (186.6 mg, 1.20 mmol, 1.0 equiv), octafluorotoluene (170.0 μl, 1.20 mmol, 1.0 equiv), and K2CO3 (149.3 mg, 1.08 mmol, 0.9 equiv) at RT for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:2) to obtain the desired product, a colorless oil (200.5 mg, 49.7%) (Fig. 13).

[0501] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.06 (dd, J = 2.63, 9.04 Hz, 1H), 7.69 (d, J = 2.52 Hz, 1H), 7.16 (d, J = 8.93 Hz, 1H), 6.69 (br. s., 1H). MS (ESI): m / z = 369.96 [MH].

[0502]

[0503] 104. Synthesis of 4-amino-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 61)

[0504] Compound 61 was synthesized from Compound 60 (200.5 mg, 0.54 mmol, 1.0 equiv) for 0.5 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:2) to obtain the desired product as white crystals (151.3 mg, 82.3%) (Fig. 13).

[0505] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.86 (d, J = 8.47 Hz, 1H), 6.43 (dd, J = 2.52, 8.47 Hz, 1H), 6.15 (d, J = 2.52 Hz, 1H), 4.99 (br. s., 1H), 3.44 (br. s., 2H). MS (ESI): m / z = 339.75 [MH].

[0506]

[0507] 105. Synthesis of 4-(6-bromohexyl)morpholine (Compound 63a)

[0508] Morpholine (0.5 ml, 5.8 mmol, 1.0 equiv) was added at RT to a stirred solution of 62a (0.88 ml, 5.8 mmol, 1.0 equiv) dissolved in THF (2.3 ml, 0.4 ml / mmol). The reaction mixture was stirred at 85°C for 12 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, dissolved in ether, and extracted with a 1 M aqueous HCl solution. The aqueous solution was basicized with a 5 M aqueous KOH solution until pH = 10, and then extracted with ether. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 30:1) to obtain the desired product (362 mg, 25.0%) in the form of a colorless oil (Fig. 14).

[0509] 1H NMR (400MHz, CHLOROFORM-d) δ 3.59-3.81 (m, 4H), 3.39 (t, J =6.87Hz, 2H), 2.35-2.62 (m, 4H), 2.20-2.34 (m, 2H), 1.72-1.94 (m, 2H), 1.38-1.62(m, 4H), 1.33(d, J =7.10Hz, 2H). MS (ESI): m / z=250.3[M+H].

[0510]

[0511] 106. Synthesis of 4-(7-bromoheptyl)morpholine (Compound 63b)

[0512] Morpholine (0.34 ml, 3.87 mmol, 1.0 equiv) was added at RT to a stirred solution of compound 62b (0.7 ml, 3.87 mmol, 1.0 equiv) dissolved in THF (2.0 ml, 0.52 ml / mmol). The reaction mixture was stirred at 85°C for 12 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, dissolved in ether, and extracted with a 1 M aqueous HCl solution. The aqueous solution was basicized with a 5 M aqueous KOH solution until pH = 10, and then extracted with ether. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH=30:1) to obtain the desired product (375 mg, 36.6%) in the form of a colorless oil (Fig. 14).

[0513] 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.68-3.75 (m, 4H), 3.41 (t, J =6.87Hz, 2H), 2.36-2.50 (m, 4H), 2.28-2.35 (m, 2H), 1.86 (quin, J =7.10Hz, 2H), 1.39-1.55(m, 4H), 1.28-1.38(m, 4H). MS (ESI): m / z=264.5[M+H].

[0514]

[0515] 107. Synthesis of 3-methoxy-N-(6-morpholinohexyl)-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 64a)

[0516] Compound 64a was synthesized from Compound 9b (291 mg, 0.82 mmol, 1.0 equiv), Compound 63a (205 mg, 0.82 mmol, 1.0 equiv), and K2CO3 (227 mg, 1.64 mmol, 2.0 equiv) at 70°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 50:1) to obtain the desired product, a colorless oil (119 mg, 27.6%) (Fig. 14).

[0517] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.85 (d, J = 8.70 Hz, 1H), 6.39 (dd, J = 2.75, 8.70 Hz, 1H), 6.32 (d, J = 2.75 Hz, 1H), 3.74 (s, 3H), 3.69-3.74(m, 4H), 3.04(t, J = 7.10 Hz, 2H), 2.38-2.51(m, 4H), 2.29-2.37(m, 2H), 1.58-1.64(m, 3H), 1.48-1.54(m, 2H), 1.33-1.44(m, 4H). MS (ESI): m / z = 525.5 [M + H].

[0518]

[0519] 108. Synthesis of 3-methoxy-N-(7-morpholinoheptyl)-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 64b)

[0520] Compound 64b was synthesized from Compound 9b (88.4 mg, 0.25 mmol, 1.0 equiv), Compound 63b (65.8 mg, 0.25 mmol, 1.0 equiv), and K2CO3 (68.8 mg, 0.5 mmol, 2.0 equiv) at 70°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (NH3-saturated CHCl3:MeOH = 50:1) to obtain the desired product as a colorless oil (37.8 mg, 28.2%) (Fig. 14).

[0521] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.85 (d, J = 8.70 Hz, 1H), 6.39 (dd, J = 2.75, 8.70 Hz, 1H), 6.32 (d, J = 2.75 Hz, 1H), 3.75 (s, 3H), 3.72 (d, J = 5.04 Hz, 4H), 3.03(t, J = 6.87 Hz, 2H), 2.44(br. s., 4H), 2.30-2.35(m, 3H), 1.57-1.62(m, 2H), 1.47-1.52(m, 2H), 1.31-1.39 (m, 6H). MS (ESI): m / z = 539.1 [M + H].

[0522]

[0523] 109. Synthesis of 5-((6-morpholinohexyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (compound 65a)

[0524] Compound 65a was synthesized from compound 64a (116 mg, 0.22 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.88 ml, 0.88 mmol, 4.0 equiv) at RT for 3 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 10:1) to obtain the desired product, a colorless oil (75.4 mg, 66.8%) (Fig. 14).

[0525] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.86 (d, J = 8.70 Hz, 1H), 6.35 (dd, J = 2.52, 8.70 Hz, 1H), 6.07 (d, J = 2.52 Hz, 1H), 3.70-3.75 (m, 4H), 2.98 (t, J = 7.10 Hz, 2H), 2.40-2.48 (m, 4H), 2.29-2.35 (m, 2H), 1.55-1.59 (m, 2H), 1.47-1.52 (m, 2H), 1.32-1.42 (m, 4H). MS (ESI): m / z = 511.6 [M + H].

[0526]

[0527] 110. Synthesis of 5-((7-morpholinoheptyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 65b)

[0528] Compound 65b was synthesized from compound 64b (33.0 mg, 0.06 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.25 ml, 0.25 mmol, 4.0 equiv) at RT for 3 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 30:1) to obtain the desired product, a colorless oil (9.4 mg, 29.2%) (Fig. 14).

[0529] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.86 (d, J = 8.70 Hz, 1H), 6.35 (dd, J = 2.06, 8.47 Hz, 1H), 6.06-6.10 (m, 1H), 3.73 (t, J = 4.81 Hz, 4H), 2.97 (t, J = 6.87 Hz, 2H), 2.45 (br. s., 4H), 2.30-2.36 (m, 2H), 1.52-1.58 (m, 2H), 1.46-1.51 (m, 2H), 1.29-1.37 (m, 6H). MS (ESI): m / z = 525.5 [M + H].

[0530]

[0531] 111. Synthesis of 6-Bromohexane-1-ol (Compound 67)

[0532] LiAlH4 (2.7 ml, 5.38 mmol, 0.6 equiv) dissolved in THF (2.0 M) was added dropwise over 0.5 hours at 0°C to a stirred solution of Compound 66 (1.6 ml, 8.96 mmol, 1.0 equiv) dissolved in ether (9.0 ml, 1 ml / mmol). The reaction mixture was stirred at RT for 4 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was cooled to 0°C, diluted with EtOAc, and the reaction was stopped by adding water and quenching. The quenched mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used without further purification (1.5 g, 92.7%) (Fig. 15).

[0533] 1H NMR (400 MHz, CHLOROFORM-d) δ 3.66 (t, J = 6.64 Hz, 2H), 3.43 (t, J = 6.87 Hz, 2H), 1.84-1.93 (m, 2H), 1.56-1.63 (m, 2H), 1.44-1.52 (m, 2H), 1.37-1.44(m, 2H).

[0534]

[0535] 112. Synthesis of 6-Bromohexanal (Compound 68)

[0536] Pyridinium chlorochloromethane (2.69 g, 12.4 mmol, 1.5 equiv) was added at RT to a stirred solution of compound 67 (1.50 ml, 8.3 mmol, 1.0 equiv) in DCM (21 ml, 2.5 ml / mmol). The reaction mixture was refluxed for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and resuspended in ether. The insoluble residue was filtered through a short silica pad. After evaporating the combined organic layer, the desired product was produced as a light green oil (761 mg, 51.2%) (Fig. 15).

[0537] 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.79 (t, J = 1.60 Hz, 1H), 3.42 (t, J = 6.64 Hz, 2H), 2.48 (dt, J = 1.37, 7.33 Hz, 2H), 1.85-1.93 (m, 2H), 1.63-1.72 (m, 2H), 1.47-1.54 (m, 2H).

[0538]

[0539] 113. Synthesis of 6-Bromo-1,1-Dimethoxyhexane (Compound 69)

[0540] Trimethyl orthoformate (0.93 ml, 8.5 mmol, 2.0 equiv) and PTSA·H2O (80.8 mg, 0.42 mmol, 0.1 equiv) were added at 0°C to a stirred solution of Compound 68 (761 g, 4.25 mmol, 1.0 equiv) dissolved in MeOH (4.3 ml, 1.0 ml / mmol). The reaction mixture was stirred at room temperature under an argon atmosphere for 12 hours. After the reaction was complete, the mixture was quenched with a saturated aqueous solution of NaHCO3 to stop the reaction, and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product (834 mg, 87.2%) in the form of a colorless oil (Fig. 15).

[0541] 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.37 (t, J = 5.72 Hz, 1H), 3.42 (t, J = 6.87 Hz, 2H), 3.32 (s, 6H), 1.84-1.91 (m, 2H), 1.59-1.65 (m, 2H), 1.35-1.49(m, 4H). MS (ESI): m / z = 223.0[MH].

[0542]

[0543] 114. Synthesis of N-(6,6-Dimethoxyhexyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 70)

[0544] Compound 70 was synthesized from Compound 9b (439 mg, 1.24 mmol, 1.0 equiv), Compound 69 (834.3 mg, 3.7 mmol, 3.0 equiv), and K2CO3 (342 mg, 2.5 mmol, 2.0 equiv) at 70°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1-2:1) to obtain the desired product, a colorless oil (543 mg, 88.0%) (Fig. 15).

[0545] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.52, 8.47 Hz, 1H), 4.38 (t, J = 5.72 Hz, 1H), 3.77-3.82 (m, 3H), 3.61 (br. s., 1H), 3.32-3.36 (m, 6H), 3.09 (t, J = 7.10 Hz, 2H), 1.60-1.67 (m, 4H), 1.38-1.48 (m, 4H). MS (ESI): m / z = 500.4 [M + H].

[0546]

[0547] 115. Synthesis of N-benzyl-N-(6,6-dimethoxyhexyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 71)

[0548] Compound 71 was synthesized from Compound 70 (543 mg, 1.08 mmol, 1.0 equiv), benzyl bromide (0.39 ml, 3.26 mmol, 3.0 equiv), and K2CO3 (752 mg, 5.44 mmol, 5.0 equiv) at 50 °C for 24 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product, a colorless oil (460 mg, 84.8%) (Fig. 15).

[0549] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.36-7.42 (m, 4H), 7.30-7.34 (m, 2H), 6.90 (d, J = 8.79 Hz, 1H), 6.22 (d, J = 2.93 Hz, 1H), 6.17 (dd, J = 2.93, 8.79 Hz, 1H), 4.52 (s, 2H), 4.35 (t, J = 5.62 Hz, 1H), 3.68 (s, 3H), 3.36-3.41 (m, 2H), 3.32 (s, 6H), 1.68 (br. s., 2H), 1.60 (br. s., 2H), 1.33-1.43(m, 4H). MS (ESI): m / z = 590.1 [M + H].

[0550]

[0551] 116. Synthesis of 6-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexanal (compound 72)

[0552] A 1M aqueous HCl solution (2.6 ml, 2.6 ml / mmol) was added at RT to a stirred solution of Compound 71 (451.2 mg, 0.77 mmol, 1.0 equiv) dissolved in THF (2.6 ml, 2.6 ml / mmol). The reaction mixture was stirred for 12 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with a saturated aqueous NaHCO3 solution and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to obtain the desired product as a colorless oil (167.4 mg, 40.3%) (Fig. 15).

[0553] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.77 (t, J = 1.47 Hz, 1H), 7.30-7.35 (m, 2H), 7.19-7.26 (m, 3H), 6.91 (d, J = 9.28 Hz, 1H), 6.23 (d, J = 2.44 Hz, 1H), 6.18 (dd, J = 2.69, 9.04 Hz, 1H), 4.52 (s, 2H), 3.68 (s, 3H), 3.36-3.42 (m, 2H), 2.45 (dt, J = 1.47, 7.33 Hz, 2H), 1.65-1.71 (m, 4H), 1.33-1.42(m, 2H). MS (ESI): m / z = 544.4 [M + H].

[0554]

[0555] 117. Synthesis of N-benzyl-3-methoxy-N-(6-(4-methylpiperazine-1-yl)hexyl)-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 73a)

[0556] 1-methylpiperazine (35.8 μl, 0.32 mmol, 2.0 equiv), NaBH(OAc)3 (102.4 mg, 0.48 mmol, 3.0 equiv), and acetic acid (27.0 μl, 0.48 mmol, 3.0 equiv) were added at RT to a stirred solution of compound 73a (87.5 mg, 0.16 mmol, 1.0 equiv) in MeOH (1.6 ml, 10 ml / mmol). The reaction mixture was stirred at RT for 12 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 30:1) to obtain the desired product as a colorless oil (65.0 mg, 64.3%) (Fig. 15).

[0557] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.29-7.36 (m, 3H), 7.20-7.25 (m, 3H), 6.89 (d, J = 8.55 Hz, 1H), 6.21 (d, J = 3.05 Hz, 1H), 6.14-6.20 (m, 1H), 4.52 (s, 2H), 3.68 (s, 3H), 3.33-3.42 (m, 2H), 2.46 (br. s., 6H), 2.25-2.40 (m, 7H), 1.61-1.69 (m, 2H), 1.43-1.55 (m, 2H), 1.31-1.41 (m, 4H). MS (ESI): m / z = 628.1 [M + H].

[0558]

[0559] 118. Synthesis of methyl(R)-1-(6-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylate (Compound 73b)

[0560] Methyl(R)-piperidine-3-carboxylate (158 mg, 1.1 mmol, 3.0 equiv), NaBH(OAc)3 (234 mg, 1.1 mmol, 3.0 equiv), and acetic acid (63.0 μl, 1.1 mmol, 3.0 equiv) were added at RT to a stirred solution of compound 73b (200 mg, 0.37 mmol, 1.0 equiv) in MeOH (3.7 ml, 10 ml / mmol). The reaction mixture was stirred at RT for 12 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 1:2) to obtain the desired product as a white solid (223 mg, 90.6%) (Fig. 15).

[0561] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.29 - 7.36 (m, 2H), 7.19 - 7.27 (m, 3H), 6.90 (d, J = 9.16 Hz, 1H), 6.22 (d, J = 2.75 Hz, 1H), 6.17 (dd, J = 2.98, 8.93 Hz, 1H), 4.52 (s, 2H), 3.68 (s, 6H), 3.34 - 3.41 (m, 2H), 2.99 (d, J = 10.08 Hz, 1H), 2.76 (d, J = 10.99 Hz, 1H), 2.58 (tt, J = 3.78, 10.65 Hz, 1H), 2.28 - 2.35 (m, 2H), 2.11 (t, J = 10.76 Hz, 1H), 1.91 - 2.00 (m, 2H), 1.67 - 1.75 (m, 2H), 1.40 - 1.57 (m, 4H), 1.33 (d, J = 3.66 Hz, 4H). MS (ESI): m / z = 671.5 [M + H].

[0562]

[0563] 119. Synthesis of 3-methoxy-N-(6-(4-methylpiperazine-1-yl)hexyl)-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 74a)

[0564] Compound 74a was synthesized from Compound 73a (22.0 mg, 0.035 mmol, 1.0 equiv) for 12 hours according to general procedure D. The crude residue was purified by silica gel column chromatography (NH3-saturated CHCl3) to obtain the desired product, a colorless oil (10.0 mg, 53.0%) (Fig. 15).

[0565] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.79 Hz, 1H), 6.19 (d, J = 2.44 Hz, 1H), 6.11 (dd, J = 2.93, 8.79 Hz, 1H), 3.78 (s, 3H), 3.09 (t, J = 7.08 Hz, 2H), 2.47 (br. s., 6H), 2.27-2.42 (m, 7H), 1.50-1.55 (m, 2H), 1.41-1.48 (m, 2H), 1.35-1.41 (m, 2H). MS (ESI): m / z = 538.2 [M + H].

[0566]

[0567] 120. Synthesis of methyl(R)-1-(6-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylate (Compound 74b)

[0568] Compound 74b was synthesized from compound 73b (95.1 mg, 0.14 mmol, 1.0 equiv) for 12 hours according to general procedure D. The crude product was used without further purification (82.1 mg, 99.0%) (Fig. 15).

[0569] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.91 (d, J = 8.70 Hz, 1H), 6.21 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.29, 8.70 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.46 - 3.54 (m, 1H), 3.20 - 3.35 (m, 2H), 3.09 (t, J = 6.87 Hz, 2H), 2.73 - 2.83 (m, 2H), 2.53 (t, J = 11.22 Hz, 2H), 2.31 - 2.45 (m, 2H), 2.21 (d, J = 12.82 Hz, 2H), 1.77 - 1.93 (m, 4H), 1.61 - 1.68 (m, 2H), 1.36 - 1.52 (m, 6H), 1.22 - 1.30 (m, 1H). MS (ESI): m / z = 581.5 [M + H].

[0570]

[0571] 121. Synthesis of 5-((6-(4-methylpiperazine-1-yl)hexyl)amino)-2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenol (Compound 75a)

[0572] Compound 75a was synthesized from compound 74a (9.6 mg, 0.018 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.07 ml, 0.070 mmol, 4.0 equiv) at RT for 5 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (NH3-saturated CHCl3:MeOH = 30:1) to obtain the desired product, a colorless oil (1.6 mg, 17.0%) (Fig. 15).

[0573] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.73 (d, J = 8.70 Hz, 1H), 6.22 (d, J = 2.75 Hz, 1H), 6.05 (dd, J = 2.75, 8.70 Hz, 1H), 3.06 (t, J = 7.10 Hz, 2H), 2.47 (br. s., 6H), 2.32-2.43 (m, 4H), 2.29 (s, 3H), 1.53 (br. s., 2H), 1.41-1.45 (m, 2H), 1.37 (d, J = 9.16 Hz, 2H). MS (ESI): m / z = 524.5 [M + H].

[0574]

[0575] 122. Synthesis of (R)-1-(6-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylic acid (Compound 75b)

[0576] Compound 75b was synthesized from compound 74b (66.1 mg, 0.11 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.46 ml, 0.46 mmol, 4.0 equiv) at RT for 5 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 8:1) to obtain the desired product as a white solid (22.5 mg, 37.1%) (Fig. 15).

[0577] 1H NMR (400 MHz, DMSO-d6) δ 9.57 (br. s., 1H), 6.84 (d, J = 8.79 Hz, 1H), 6.11 (d, J = 2.44 Hz, 1H), 5.92 (dd, J = 2.93, 8.79 Hz, 1H), 5.43 (br. s., 1H), 2.86 (t, J = 6.59 Hz, 2H), 2.80 (d, J = 11.72 Hz, 1H), 2.63 (br. s., 1H), 2.28 - 2.40 (m, 3H), 2.20 (br. s., 1H), 2.07 (br. s., 1H), 1.67 - 1.77 (m, 1H), 1.60 (dd, J = 3.91, 9.28 Hz, 1H), 1.36 - 1.53 (m, 6H), 1.24 - 1.34 (m, 4H). MS (ESI): m / z = 553.1 [M + H].

[0578]

[0579] 123. Synthesis of ethyl 6-((4-(3,5-bis(trifluoromethyl)phenoxy)-3-methoxyphenyl)amino)hexanoate (Compound 77a)

[0580] Compound 77a was synthesized from Compound 54 (200 mg, 0.57 mmol, 1.0 equiv), Compound 66 (101 μl, 0.57 mmol, 1.0 equiv), and K2CO3 (158 mg, 1.14 mmol, 2.0 equiv) at 60°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (165 mg, 59.0%) (Fig. 16).

[0581] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.47 (s, 1H), 6.91 (d, J = 8.30 Hz, 1H), 6.27 (d, J = 2.44 Hz, 1H), 6.20 (dd, J = 2.69, 8.55 Hz, 1H), 4.13-4.17 (m, 2H), 3.75 (s, 3H), 3.15 (t, J = 7.08 Hz, 2H), 2.33-2.38 (m, 2H), 1.66-1.74 (m, 4H), 1.48-1.53 ​​(m, 2H), 1.25-1.29 (m, 3H). MS (ESI): m / z = 494.2 [M + H].

[0582]

[0583] 124. Synthesis of ethyl 7-((4-(3,5-bis(trifluoromethyl)phenoxy)-3-methoxyphenyl)amino)heptanoate (Compound 77b)

[0584] Compound 77b was synthesized from Compound 54 (200 mg, 0.57 mmol, 1.0 equiv), Compound 76a (111 μl, 0.57 mmol, 1.0 equiv), and K2CO3 (158 mg, 1.14 mmol, 2.0 equiv) at 70 °C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (158 mg, 54.6%) (Fig. 16).

[0585] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.44-7.49 (m, 1H), 6.91 (d, J = 8.24 Hz, 1H), 6.27 (d, J = 2.75 Hz, 1H), 6.20 (dd, J = 2.52, 8.47 Hz, 1H), 4.12-4.17 (m, 2H), 3.75 (s, 3H), 3.70 (br. s., 1H), 3.14 (t, J = 7.10 Hz, 2H), 2.29-2.36 (m, 2H), 1.65-1.71 (m, 4H), 1.39-1.50 (m, 4H), 1.25-1.29 (m, 3H)

[0586]

[0587] 125. Synthesis of ethyl 8-((4-(3,5-bis(trifluoromethyl)phenoxy)-3-methoxyphenyl)amino)octanoate (Compound 77c)

[0588] Compound 77c was synthesized from Compound 54 (100 mg, 0.28 mmol, 1.0 equiv), Compound 76b (60.0 μl, 0.28 mmol, 1.0 equiv), and K2CO3 (78.7 mg, 0.57 mmol, 2.0 equiv) at 70 °C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (63.0 mg, 42.4%) (Fig. 16).

[0589] 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.34 (s, 2H), 6.93 (d, J = 8.55 Hz, 1H), 6.38 (d, J = 2.44 Hz, 1H), 6.17 (dd, J = 2.44, 8.55 Hz, 1H), 5.73 (t, J = 5.49 Hz, 1H), 4.04 (q, J = 6.92 Hz, 2H), 3.65 (s, 3H), 3.01 (d, J = 5.49 Hz, 2H), 2.24-2.30 (m, 2H), 1.50-1.59 (m, 4H), 1.34-1.40 (m, 2H), 1.25-1.33 (m, 4H), 1.14-1.19 (m, 3H).

[0590]

[0591] 126. Synthesis of 6-((4-(3,5-bis(trifluoromethyl)phenoxy)-3-hydroxyphenyl)amino)hexanoic acid (Compound 78a)

[0592] Compound 78a was synthesized from compound 77a (80.0 mg, 0.17 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.67 ml, 0.67 mmol, 4.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (43.0 mg, 59.0%) (Fig. 16).

[0593] 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br. s., 1H), 7.67 (s, 1H), 7.36 (s, 2H), 6.85 (d, J = 8.70 Hz, 1H), 6.21 (d, J = 2.75 Hz, 1H), 6.07 (dd, J = 2.75, 8.70 Hz, 1H), 5.60(br. s., 1H), 2.94(d, J = 4.58 Hz, 2H), 2.22(t, J = 7.33 Hz, 2H), 1.50-1.59(m, 4H), 1.38(d, J = 6.87 Hz, 2H). MS (ESI): m / z = 452.1 [M + H].

[0594]

[0595] 127. Synthesis of ethyl 7-((4-(3,5-bis(trifluoromethyl)phenoxy)-3-methoxyphenyl)amino)heptanoate (Compound 78b)

[0596] Compound 78b was synthesized from compound 77b (75.0 mg, 0.15 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.60 ml, 0.60 mmol, 4.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (10.4 mg, 14.9%) (Fig. 16).

[0597] 1 H NMR (400 MHz, DMSO-d6) 7.67 (s, 1H), 7.36 (s, 2H), 6.85 (d, J = 8.60 Hz, 1H), 6.21 (d, J = 2.54 Hz, 1H), 6.07 (dd, J = 2.54, 8.60 Hz, 1H), 5.60 (br. s., 1H), 2.87-2.95 (m, 2H), 2.21 (t, J = 7.33 Hz, 2H), 1.51-1.61 (m, 4H), 1.38 (d, J = 6.87 Hz, 2H), 1.21-1.30 (m, 2H)

[0598]

[0599] 128. Synthesis of ethyl 8-((4-(3,5-bis(trifluoromethyl)phenoxy)-3-methoxyphenyl)amino)octanoate (Compound 78c)

[0600] Compound 78c was synthesized from compound 77c (60.0 mg, 0.115 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.46 ml, 0.46 mmol, 4.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (20.0 mg, 36.3%) (Fig. 16).

[0601] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.36 (s, 2H), 6.84 (d, J = 8.55 Hz, 1H), 6.21 (d, J = 2.44 Hz, 1H), 6.07 (dd, J = 2.44, 8.55 Hz, 1H), 5.60 (t, J = 4.88 Hz, 1H), 2.89-2.97 (m, 2H), 2.19 (t, J = 7.32 Hz, 2H), 1.46-1.58 (m, 4H), 1.32-1.39 (m, 3H), 1.25-1.32 (m, 4H).

[0602]

[0603] 129. Synthesis of (3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentanoate (compound 79a)

[0604] Compound 79a was synthesized from Compound 9b (200 mg, 0.56 mmol, 1.0 equiv), Compound 44b (89.0 μl, 0.56 mmol, 1.0 equiv), and K2CO3 (156 mg, 1.13 mmol, 2.0 equiv) at 70 °C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (108 mg, 40.0%) (Fig. 17).

[0605] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.75, 8.70 Hz, 1H), 4.15 (q, J = 7.33 Hz, 2H), 3.68(br. s., 1H), 3.12(t, J = 6.87 Hz, 2H), 2.37(t, J = 7.33 Hz, 2H), 1.73-1.80(m, 2H), 1.64-1.71(m, 2H), 1.27(t, J = 7.10 Hz, 3H). MS (ESI): m / z = 484.2 [M + H].

[0606]

[0607] 130. Synthesis of ethyl 6-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexanoate (compound 79b)

[0608] Compound 79b was synthesized from 9b (200 mg, 0.56 mmol, 1.0 equiv), 66 (100 μl, 0.56 mmol, 1.0 equiv) and K2CO3 (156 mg, 1.13 mmol, 2.0 equiv) at 70°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (127 mg, 46.5%) (Fig. 17).

[0609] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.29 Hz, 1H), 6.11 (d, J = 8.70 Hz, 1H), 4.14 (q, J = 7.33 Hz, 2H), 3.78 (s, 3H), 3.10 (s, 2H), 2.34 (t, J = 7.56 Hz, 2H), 1.62-1.72 (m, 4H), 1.46 (s, 2H), 1.27 (t, J = 7.33 Hz, 3H). MS (ESI): m / z = 498.1 [M + H].

[0610]

[0611] 131. Ethyl 7-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)heptanoate (Compound 79c)

[0612] Compound 79c was synthesized from Compound 9b (200 mg, 0.56 mmol, 1.0 equiv), Compound 76a (110 μl, 0.56 mmol, 1.0 equiv), and K2CO3 (156 mg, 1.13 mmol, 2.0 equiv) at 70°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (146 mg, 50.7%) (Fig. 17).

[0613] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.29, 8.70 Hz, 1H), 4.14 (q, J = 7.33 Hz, 2H), 3.79(s, 3H), 3.09(t, J = 7.10 Hz, 2H), 2.32(t, J = 7.56 Hz, 2H), 1.60-1.70(m, 4H), 1.36-1.49(m, 4H), 1.23-1.30(m, 3H).

[0614]

[0615] 132. Synthesis of ethyl 8-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)octanoate (Compound 79d)

[0616] Compound 79d was synthesized from Compound 9b (200 mg, 0.56 mmol, 1.0 equiv), Compound 76b (211 μl, 1.01 mmol, 1.8 equiv), and K2CO3 (156 mg, 1.13 mmol, 2.0 equiv) at 70°C for 12 hours according to general procedure A. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 8:1) to obtain the desired product, a colorless oil (106 mg, 36.0%) (Fig. 17).

[0617] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.29, 8.70 Hz, 1H), 4.14 (q, J = 7.33 Hz, 2H), 3.79 (s, 3H), 3.08 (t, J = 7.10 Hz, 2H), 2.30 (t, J = 7.56 Hz, 2H), 1.58-1.68 (m, 4H), 1.41 (d, J = 7.79 Hz, 2H), 1.31-1.38 (m, 4H), 1.23-1.29(m, 3H).

[0618]

[0619] 133. Synthesis of ethyl 5-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentanoate (Compound 80)

[0620] Compound 80 was synthesized from compound 79a (100 mg, 0.21 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.85 ml, 0.85 mmol, 4.0 equiv) at RT for 2 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 30:1) to obtain the desired product as a white solid (76.2 mg, 76.0%) (Fig. 17).

[0621] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.70 Hz, 1H), 6.26 (d, J = 2.75 Hz, 1H), 6.05 (dd, J = 2.75, 9.16 Hz, 1H), 5.47 (br. s., 1H), 4.14 (q, J = 7.02 Hz, 2H), 3.64 (br. s., 1H), 3.09 (t, J = 6.64 Hz, 2H), 2.36 (t, J = 7.33 Hz, 2H), 1.69-1.79 (m, 2H), 1.65 (dd, J = 6.87, 8.70 Hz, 3H), 1.26(t, J = 7.10 Hz, 3H).

[0622]

[0623] 134. Synthesis of 5-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentanoic acid (Compound 81a)

[0624] A 3M aqueous HCl solution (0.28 ml, 3.1 ml / mmol) was added at RT to a stirred solution of Compound 80 (40.0 mg, 0.09 mmol, 1.0 equiv) in acetic acid (0.28 ml, 3.1 ml / mmol). The reaction mixture was stirred at 100°C for 2 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (25 mg, 63.0%) (Fig. 17).

[0625] 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (br. s., 1H), 9.49 (s, 1H), 6.88 (d, J = 8.70 Hz, 1H), 6.12 (d, J = 2.29 Hz, 1H), 5.97 (dd, J = 2.52, 8.93 Hz, 1H), 2.91(t, J = 6.18 Hz, 2H), 2.24(t, J = 7.10 Hz, 2H), 1.48-1.63(m, 4H).

[0626]

[0627] 135. Synthesis of 6-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexanoic acid (Compound 81b)

[0628] Compound 81b was synthesized from compound 79b (123 mg, 0.25 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.99 ml, 0.99 mmol, 4.0 equiv) at RT for 2 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (70.0 mg, 62.2%) (Fig. 17).

[0629] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.70 Hz, 1H), 6.27 (d, J = 2.75 Hz, 1H), 6.05 (dd, J = 2.75, 8.70 Hz, 1H), 3.08 (t, J = 7.10 Hz, 2H), 2.39(t, J = 7.33 Hz, 2H), 1.67-1.76(m, 2H), 1.59-1.67(m, 2H), 1.47(d, J = 7.33 Hz, 2H).

[0630]

[0631] 136. Synthesis of 7-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)heptanoic acid (Compound 81c)

[0632] Compound 81c was synthesized from compound 79c (143 mg, 0.28 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (1.12 ml, 1.12 mmol, 4.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (78.0 mg, 59.4%) (Fig. 17).

[0633] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.55 Hz, 1H), 6.27 (d, J = 2.44 Hz, 1H), 6.05 (dd, J = 2.75, 8.85 Hz, 1H), 3.06 (t, J = 7.02 Hz, 2H), 2.38(t, J = 7.32Hz, 2H), 1.61-1.68(m, 4H), 1.37-1.45(m, 4H). MS (ESI): m / z = 468.5[MH].

[0634]

[0635] 137. Synthesis of 8-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)octanoic acid (Compound 81d)

[0636] Compound 81d was synthesized from compound 79d (100 mg, 0.19 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.76 ml, 0.76 mmol, 4.0 equiv) at RT for 12 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 20:1) to obtain the desired product as a white solid (27.7 mg, 33.0%) (Fig. 17).

[0637] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J = 8.55 Hz, 1H), 6.27 (d, J = 3.05 Hz, 1H), 6.02-6.09 (m, 1H), 3.06 (t, J = 7.02 Hz, 2H), 2.37 (t, J = 7.63 Hz, 2H), 1.56-1.71 (m, 4H), 1.38 (br. s., 6H).

[0638]

[0639] 138. Synthesis of Ethyl (E)-8-Bromooct-2-enoate (Compound 82)

[0640] NaH (43.0 mg, 1.79 mmol, 1.0 equiv) and Compound 68 (320 mg, 1.79 mmol, 1.0 equiv) were added at 0 °C to a stirred solution of triethyl phosphonoacetate (354 μl, 1.79 mmol, 1.0 equiv) in THF (2.5 ml, 1.4 ml / mmol). The reaction mixture was stirred at RT for 12 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was quenched with water at 0 °C and concentrated under reduced pressure. The crude residue was diluted with EtOAc and washed with water and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to obtain the desired product (192 mg, 43.0%) in the form of a colorless oil (Fig. 18).

[0641] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.91 - 7.00 (m, 1H), 5.83 (td, J = 1.60, 15.57 Hz, 1H), 4.19 (q, J = 7.02 Hz, 2H), 3.39 - 3.43 (m, 2H), 2.23 (dd, J = 1.37, 6.87 Hz, 2H), 1.86 - 1.90 (m, 2H), 1.46 - 1.51 (m, 4H), 1.30 (t, J = 7.10 Hz, 3H).

[0642]

[0643] 139. Synthesis of ethyl(E)-8-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)oct-2-enoate (Compound 83)

[0644] Compound 83 was synthesized from Compound 82 (150 mg, 0.60 mmol, 1.8 equiv), Compound 9b (117 mg, 0.33 mmol, 1.0 equiv), and K2CO3 (92.5 mg, 0.67 mmol, 2.0 equiv) according to general procedure A at 70 °C for 15 hours. The crude residue was purified by silica gel column chromatography (hexane: EtOAc = 3:1) to obtain the desired product as a white solid (120 mg, 70.0%) (Fig. 18).

[0645] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.94 - 7.02 (m, 1H), 6.92 (d, J = 8.24 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.52, 8.47 Hz, 1H), 5.83 (td, J = 1.55, 15.69 Hz, 1H), 4.20 (q, J = 7.02 Hz, 2H), 3.79 (s, 3H), 3.62 (br. s., 1H), 3.10 (t, J = 7.10 Hz, 2H), 2.20 - 2.28 (m, 2H), 1.61 - 1.69 (m, 2H), 1.50 - 1.55 (m, 2H), 1.42 - 1.48 (m, 2H), 1.28 - 1.33 (m, 3H).

[0646]

[0647] 140. Synthesis of (E)-8-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)oct-2-enoic acid (Compound 84)

[0648] A 3M aqueous HCl solution (0.38 ml, 3.3 ml / mmol) was added at RT to a stirred solution of Compound 83 (60.0 mg, 0.11 mmol, 1.0 equiv) in acetic acid (0.38 ml, 3.3 ml / mmol). The reaction mixture was stirred at 100°C for 2 hours under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 30:1) to obtain the desired product as a white solid (36.5 mg, 64.0%) (Fig. 18).

[0649] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.02 - 7.11 (m, 1H), 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.29 Hz, 1H), 6.11 (dd, J = 2.75, 8.70 Hz, 1H), 5.85 (td, J = 1.55, 15.69 Hz, 1H), 3.78 (s, 3H), 3.10 (t, J = 7.10 Hz, 2H), 2.24 - 2.31 (m, 2H), 1.61 - 1.69 (m, 2H), 1.51 - 1.59 (m, 2H), 1.42 - 1.50 (m, 2H).

[0650]

[0651] 141. Synthesis of (E)-8-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)oct-2-enoic acid (Compound 85)

[0652] Compound 85 was synthesized from Compound 84 (36.5 mg, 0.074 mmol, 1.0 equiv) and BBr3 (1.0 M) of DCM (0.3 ml, 0.30 mmol, 4.0 equiv) at RT for 18 hours according to general procedure B. The crude residue was purified by silica gel column chromatography (CHCl3:MeOH = 30:1) to obtain the desired product as a white solid (18.0 mg, 50.5%) (Fig. 18).

[0653] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.07 (td, J = 7.10, 15.57 Hz, 1H), 6.69 (d, J = 8.70 Hz, 1H), 6.26 (d, J = 2.75 Hz, 1H), 6.05 (dd, J = 2.75, 8.70 Hz, 1H), 5.84 (td, J = 1.37, 15.57 Hz, 1H), 3.07 (t, J = 7.10 Hz, 2H), 2.21 - 2.32 (m, 2H), 1.62 (td, J = 7.33, 14.66 Hz, 2H), 1.50 - 1.56 (m, 2H), 1.40 - 1.47 (m, 2H).

[0654]

[0655] 142. Synthesis of 2-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)ethanol-1-ol (Compound 86a)

[0656] Ethanol (EtOH, 11 ml, 2.0 ml / mmol), 2-bromoethanol (480 μl, 6.8 mmol, 1.2 equiv), and K2CO3 (2.3 g, 16.9 mmol, 3.0 equiv) were added to the stirred 9b solution (2.0 g, 5.6 mmol, 1.0 equiv) at room temperature. The reaction mixture was stirred overnight at 80°C under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and sequentially washed with 1 M aqueous hydrochloric acid (HCl), water, aqueous saturated sodium bicarbonate (NaHCO3), and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 86a (450 mg, yield 20%) (Fig. 19).

[0657] 1H NMR (400 MHz, CHLOROFORM-d) d 6.93 (d,J= 8.70 Hz, 1H), 6.26 (d,J= 2.75 Hz, 1H), 6.15 - 6.19 (m, 1H), 3.84 - 3.89 (m, 3H), 3.79 (s, 3H), 3.27 - 3.32 (m, 3H).

[0658]

[0659] 143. Synthesis of N-(2-bromoethyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 87a)

[0660] CBr4 (680 mg, 2.1 mmol, 1.1 equiv) and PPh3 (538 mg, 2.1 mmol, 1.1 equiv) were added to a stirred DCM (18 ml, 10.0 ml / mmol) solution of compound 86a (745 mg, 1.9 mmol, 1.0 equiv) at 0°C and stirred for 2 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and washed with water and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 87a (588 mg, yield 68%) (Fig. 19).

[0661] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.95 (d, J = 8.70 Hz, 1H), 6.25 (d, J = 2.29 Hz, 1H), 6.16 (dd, J = 2.75, 8.70 Hz, 1H), 4.07 (br. s., 1H), 3.79 (s, 3H), 3.53 - 3.61 (m, 4H).

[0662]

[0663] 144. Synthesis of N-(3-bromopropyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 87b)

[0664] CBr4 (170 mg, 0.51 mmol, 1.1 equiv) and PPh3 (135 mg, 0.51 mmol, 1.1 equiv) were added to a stirred DCM (4.7 ml, 10.0 ml / mmol) solution of compound 86b (200 mg, 0.47 mmol, 1.0 equiv) at 0°C and stirred for 2 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and washed with water and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 87b (143 mg, yield 62%) (Fig. 19).

[0665] 1 H NMR (400 MHz, DMSO-d6) d 6.95 (d, J = 8.79 Hz, 1H), 6.28 - 6.31 (m, 1H), 6.03 - 6.07 (m, 1H), 5.68 (t, J = 5.62 Hz, 1H), 3.69 - 3.72 (m, 4H), 3.58 (s, 4H), 3.00 (d, J = 5.37 Hz, 2H), 2.80 (d, J = 11.72 Hz, 1H), 2.62 (br. s., 2H), 2.37 (dt, J = 2.44, 7.08 Hz, 3H), 2.18 (br. s., 1H), 2.01 (br. s., 1H), 1.78 (br. s., 1H), 1.59 - 1.70 (m, 4H), 1.35 - 1.52 (m, 3H), 1.30 (t, J = 7.08 Hz, 1H).

[0666]

[0667] 145. Synthesis of methyl (R)-1-(2-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)ethyl)piperidine-3-carboxylate (Compound 88a)

[0668] Methyl (R)-piperidine-3-carboxylate (50 mg, 0.35 mmol, 2.0 equiv) and K2CO3 (29 mg, 0.21 mmol, 1.2 equiv) were added at room temperature to a stirred solution of compound 87a (80 mg, 0.17 mmol, 1.0 equiv) in ACN (0.8 ml, 5.0 ml / mmol). The reaction mixture was stirred at 70°C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and washed sequentially with an aqueous solution of 1 M hydrochloric acid (HCl), water, an aqueous solution of saturated sodium bicarbonate (NaHCO3), and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 88a (71 mg, yield 78%) (Fig. 19).

[0669] 1 H NMR (400 MHz, DMSO-d6) d 6.95 (d, J = 8.79 Hz, 1H), 6.28 - 6.31 (m, 1H), 6.03 - 6.07 (m, 1H), 5.68 (t, J = 5.62 Hz, 1H), 3.69 - 3.72 (m, 4H), 3.58 (s, 4H), 3.00 (d, J = 5.37 Hz, 2H), 2.80 (d, J = 11.72 Hz, 1H), 2.62 (br. s., 2H), 2.37 (dt, J = 2.44, 7.08 Hz, 3H), 2.18 (br. s., 1H), 2.01 (br. s., 1H), 1.78 (br. s., 1H), 1.59 - 1.70 (m, 4H), 1.35 - 1.52 (m, 3H), 1.30 (t, J = 7.08 Hz, 1H).

[0670]

[0671] 146. Synthesis of methyl (R)-1-(3-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)propyl)piperidine-3-carboxylate (Compound 88b)

[0672] Methyl (R)-piperidine-3-carboxylate (50 mg, 0.35 mmol, 2.0 equiv) and K2CO3 (29 mg, 0.21 mmol, 1.2 equiv) were added at room temperature to a stirred solution of compound 87b (80 mg, 0.17 mmol, 1.0 equiv) in ACN (0.8 ml, 5.0 ml / mmol). The reaction mixture was stirred at 70°C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and washed sequentially with an aqueous solution of 1 M hydrochloric acid (HCl), water, an aqueous solution of saturated sodium bicarbonate (NaHCO3), and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 88b (Fig. 19).

[0673] 1 H NMR (400 MHz, DMSO-d6) d 6.95 (d, J = 8.79 Hz, 1H), 6.29 (d, J = 2.44 Hz, 1H), 6.04 (dd, J = 2.44, 8.79 Hz, 1H), 5.70 (s, 1H), 3.69 - 3.72 (m, 3H), 3.59 (s, 3H), 2.95 - 3.05 (m, 3H), 2.74 - 2.83 (m, 2H), 2.30 - 2.37 (m, 3H), 1.94 (t, J = 10.99 Hz, 2H), 1.76 - 1.84 (m, 3H), 1.62 - 1.71 (m, 3H), 1.47 - 1.61 (m, 3H), 1.30 (t, J = 7.08 Hz, 1H).

[0674]

[0675] 147. Synthesis of methyl 1-(2-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)ethyl)piperidine-4-carboxylate (Compound 88c)

[0676] Methylpiperidine-4-carboxylate (50 mg, 0.35 mmol, 2.0 equiv) and K2CO3 (29 mg, 0.21 mmol, 1.2 equiv) were added at room temperature to a stirred solution of compound 87a (80 mg, 0.17 mmol, 1.0 equiv) in ACN (0.8 ml, 5.0 ml / mmol). The reaction mixture was stirred at 70 °C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and washed sequentially with an aqueous solution of 1 M hydrochloric acid (HCl), water, an aqueous solution of saturated sodium bicarbonate (NaHCO3), and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 88c (64 mg, 70.5%) (Fig. 19).

[0677] 1 H NMR (400 MHz, DMSO-d6) d 6.95 (d, J = 8.79 Hz, 1H), 6.29 (d, J = 2.44 Hz, 1H), 6.04 (dd, J = 2.44, 8.79 Hz, 1H), 5.70 (s, 1H), 3.69 - 3.72 (m, 3H), 3.59 (s, 3H), 2.95 - 3.05 (m, 3H), 2.74 - 2.83 (m, 2H), 2.30 - 2.37 (m, 3H), 1.94 (t, J = 10.99 Hz, 2H), 1.76 - 1.84 (m, 3H), 1.62 - 1.71 (m, 3H), 1.47 - 1.61 (m, 3H), 1.30 (t, J = 7.08 Hz, 1H).

[0678]

[0679] 148. Synthesis of methyl-(3-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)propyl)piperidine-4-carboxylate (Compound 88d)

[0680] Methylpiperidine-4-carboxylate (37 mg, 0.26 mmol, 2.0 equiv) and K2CO3 (21.6 mg, 0.16 mmol, 1.2 equiv) were added at room temperature to a stirred solution of compound 87b (62 mg, 0.13 mmol, 1.0 equiv) in ACN (0.65 ml, 5.0 ml / mmol). The reaction mixture was stirred at 70 °C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate (EtOAc) and washed sequentially with an aqueous solution of 1 M hydrochloric acid (HCl), water, an aqueous solution of saturated sodium bicarbonate (NaHCO3), and brine. The organic layer was dried with sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 88d (73 mg, 92%) (Fig. 19).

[0681] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.70 Hz, 1H), 6.18 (d, J = 2.75 Hz, 1H), 6.10 (d, J = 8.70 Hz, 1H), 3.79 (s, 3H), 3.69 - 3.72 (m, 3H), 3.17 (t, J = 6.18 Hz, 2H), 2.95 (br. s., 2H), 2.49 (t, J = 6.41 Hz, 2H), 2.18 (s, 1H), 1.90 - 2.07 (m, 6H), 1.75 - 1.87 (m, 5H).

[0682]

[0683] 149. Synthesis of (R)-1-(2-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)ethyl)piperidine-3-carboxylic acid (Compound 89a)

[0684] Compound 89a was synthesized according to general procedure B from compound 88a (58 mg, 0.11 mmol, 1.0 equiv) and a DCM solution of BBr3 (1.0 M) (0.33 ml, 0.33 mmol, 3.0 equiv) at room temperature for 12 hours. The crude residue was purified by silica gel column chromatography to obtain the desired product (27 mg, 49.4%) (Fig. 19).

[0685] 1 H NMR (400 MHz, DMSO-d6) d 6.88 (d, J = 8.70 Hz, 1H), 6.13 (d, J = 2.29 Hz, 1H), 5.96 (dd, J = 2.29, 8.70 Hz, 1H), 2.94 (t, J = 6.87 Hz, 2H), 2.81 (d, J = 6.87 Hz, 1H), 2.58 - 2.68 (m, 2H), 2.33 - 2.45 (m, 4H), 2.17 (br. s., 1H), 2.02 (br. s., 1H), 1.70 - 1.82 (m, 2H), 1.58 - 1.70 (m, 4H), 1.34 - 1.52 (m, 3H).

[0686]

[0687] 150. Synthesis of (R)-1-(3-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)propyl)piperidine-3-carboxylic acid (Compound 89b)

[0688] Compound 89b was synthesized according to general procedure B from compound 88b (33 mg, 0.06 mmol, 1.0 equiv) and a DCM solution of BBr3 (1.0 M) (0.44 ml, 0.44 mmol, 4.0 equiv) at room temperature for 12 hours. The crude residue was purified by silica gel column chromatography to obtain the desired product (38 mg, 33%) (Fig. 19).

[0689] 1 H NMR (400 MHz, DMSO-d6) d 9.56 (br. s., 1H), 6.89 (d, J = 8.70 Hz, 1H), 6.14 (d, J = 2.75 Hz, 1H), 5.97 (dd, J = 2.52, 8.93 Hz, 1H), 2.90 - 3.00 (m, 4H), 2.22 - 2.35 (m, 2H), 1.92 - 1.99 (m, 1H), 1.81 - 1.89 (m, 2H), 1.70 - 1.78 (m, 2H), 1.60 - 1.68 (m, 2H), 1.21 - 1.26 (m, 1H), 0.84 (br. s., 1H).

[0690]

[0691] 151. Synthesis of 1-(2-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)ethyl)piperidine-4-carboxylic acid (Compound 89c)

[0692] Compound 89b was synthesized according to general procedure B from compound 88b (33 mg, 0.06 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.44 ml, 0.44 mmol, 4.0 equiv) at room temperature for 12 hours. The crude residue was purified by silica gel column chromatography to obtain the desired product (38 mg, 33%) (Fig. 19).

[0693] 1H NMR (400 MHz, DMSO-d6) d 9.56 (br. s., 1H), 6.89 (d, J = 8.70 Hz, 1H), 6.14 (d, J = 2.75 Hz, 1H), 5.97 (dd, J = 2.52, 8.93 Hz, 1H), 2.90 - 3.00 (m, 4H), 2.22 - 2.35 (m, 2H), 1.92 - 1.99 (m, 1H), 1.81 - 1.89 (m, 2H), 1.70 - 1.78 (m, 2H), 1.60 - 1.68 (m, 2H), 1.21 - 1.26 (m, 1H), 0.84 (br. s., 1H).

[0694]

[0695] 152. Synthesis of 1-(3-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)propyl)piperidine-4-carboxylic acid (Compound 89d)

[0696] Compound 89d was synthesized according to general procedure B from compound 88d (59 mg, 0.11 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.44 ml, 0.44 mmol, 4.0 equiv) at room temperature for 12 hours. The crude residue was purified by silica gel column chromatography to obtain the desired product (28 mg, 50%) (Fig. 19).

[0697] 1H NMR (400 MHz, DMSO-d6) d 9.62 (s, 1H), 6.89 (d, J = 8.70 Hz, 1H), 6.12 (d, J = 2.75 Hz, 1H), 5.95 (dd, J = 2.52, 8.93 Hz, 1H), 5.58 (br. s., 1H), 2.93 (t, J = 6.64 Hz, 2H), 2.79 (d, J = 10.99 Hz, 2H), 2.33 (t, J = 7.10 Hz, 2H), 2.16 (br. s., 1H), 1.86 - 1.99 (m, 4H), 1.73 - 1.81 (m, 3H), 1.61 - 1.69 (m, 3H), 1.48 - 1.59 (m, 3H), 0.83 (br. s., 2H).

[0698]

[0699] 153. Synthesis of N-(4,4-Dimethoxybutyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 90a)

[0700] 4-bromo-1,1-dimethoxybutane (240 mg, 1.2 mmol, 1.0 equiv) and K2CO3 (337 mg, 2.4 mmol, 2.0 equiv) were added at room temperature to a stirred solution of compound 9b (433 mg, 1.2 mmol, 1.0 equiv) in DMF (3.1 ml, 2.5 ml / mmol). The reaction mixture was stirred overnight at 70 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 90a (109 mg, 20%) (Fig. 20).

[0701] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.67 - 1.76 (m, 4 H) 3.13 (br. s., 2 H) 3.32 - 3.36 (m, 6 H) 3.78 (s, 3 H) 4.42 (s, 1 H) 6.11 (dd, J=8.70, 2.75 Hz, 1 H) 6.19 (d, J=2.29 Hz, 1 H) 6.92 (d, J=8.70 Hz, 1 H).

[0702]

[0703] 154. Synthesis of N-(5,5-Dimethoxypentyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 90b)

[0704] 5-bromo-1,1-dimethoxypentane (647 mg, 3.1 mmol, 1.0 equiv) and K2CO3 (847 mg, 6.1 mmol, 2.0 equiv) were added at room temperature to a stirred solution of compound 9b (1.1 g, 3.1 mmol, 1.0 equiv) in DMF (8.0 ml, 2.5 ml / mmol). The reaction mixture was stirred overnight at 70 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 90b (785 mg, 53%) (Fig. 20).

[0705] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.49 (d, J=7.33 Hz, 2 H) 1.63 - 1.69 (m, 4 H) 3.08 - 3.14 (m, 2 H) 3.33 - 3.34 (m, 6 H) 3.77 - 3.80 (m, 3 H) 4.39 (t, J=5.72 Hz, 1 H) 6.11 (dd, J=8.70, 2.75 Hz, 1 H) 6.19 (d, J=2.75 Hz, 1 H) 6.92 (d, J=8.70 Hz, 1 H).

[0706]

[0707] 155. Synthesis of N-(6,6-Dimethoxyhexyl)-3-methoxy-4-(2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)phenoxy)aniline (Compound 90c)

[0708] 6-bromo-1,1-dimethoxyhexane (2.3 g, 10.3 mmol, 3.0 equiv) and K2CO3 (954 mg, 6.9 mmol, 2.0 equiv) were added at room temperature to a stirred solution of compound 9b (1.2 g, 3.4 mmol, 1.0 equiv) in DMF (17.0 ml, 5.0 ml / mmol). The reaction mixture was stirred overnight at 70 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 90c (1.4 g, 83.8%) (Fig. 20).

[0709] 1H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.52, 8.47 Hz, 1H), 4.38 (t, J = 5.72 Hz, 1H), 3.77 - 3.82 (m, 3H), 3.61 (br. s., 1H), 3.32 - 3.36 (m, 6H), 3.09 (t, J = 7.10 Hz, 2H), 1.60 - 1.67 (m, 4H), 1.38 - 1.48 (m, 4H).

[0710] 156. Synthesis of N-benzyl-N-(4,4-dimethoxybutyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 91a)

[0711] Benzyl bromide (53 μl, 0.43 mmol, 2.0 equiv) and K2CO3 (122 mg, 0.87 mmol, 4.0 equiv) were added at room temperature to a stirred solution of compound 90a (102 mg, 0.22 mmol, 1.0 equiv) in DMF (0.44 ml, 2.0 ml / mmol). The reaction mixture was stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 91a (107 mg, 87%) (Fig. 20).

[0712] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.65 (dd, J=8.24, 5.50 Hz, 3 H) 1.73 (d, J=7.33 Hz, 2 H) 3.32 (s, 6 H) 3.38 - 3.44 (m, 2 H) 3.66 - 3.71 (m, 3 H) 4.37 - 4.41 (m, 1 H) 4.52 (s, 2 H) 6.18 (dd, J=8.93, 2.98 Hz, 1 H) 6.25 (d, J=2.75 Hz, 1 H) 6.90 (d, J=9.16 Hz, 1 H) 7.23 (t, J=7.10 Hz, 3 H) 7.30 - 7.35 (m, 3 H).

[0713]

[0714] 157. Synthesis of N-benzyl-N-(5,5-dimethoxypentyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 91b)

[0715] Benzyl bromide (382 μl, 3.2 mmol, 2.0 equiv) and K2CO3 (889 mg, 6.4 mmol, 4.0 equiv) were added at room temperature to a stirred solution of compound 90b (780 mg, 1.6 mmol, 1.0 equiv) in DMF (3.2 ml, 2.0 ml / mmol). The reaction mixture was stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 91b (840 mg, 91%) (Fig. 20).

[0716] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.40 (s, 2 H) 1.63 (dd, J=8.93, 6.64 Hz, 2 H) 1.66 - 1.72 (m, 2 H) 3.32 (s, 6 H) 3.36 - 3.41 (m, 2 H) 3.67 - 3.69 (m, 3 H) 4.35 (t, J=5.72 Hz, 1 H) 4.52 (d, J=2.75 Hz, 3 H) 6.17 (dd, J=8.93, 2.98 Hz, 1 H) 6.22 (d, J=2.75 Hz, 1 H) 6.90 (d, J=8.70 Hz, 1 H) 7.31 (d, J=7.33 Hz, 3 H) 7.35 - 7.43 (m, 3 H).

[0717]

[0718] 158. Synthesis of N-benzyl-N-(6,6-dimethoxyhexyl)-3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)aniline (Compound 91c)

[0719] Benzyl bromide (1.0 ml, 8.7 mmol, 2.0 equiv) and K2CO3 (2.0 g, 14.5 mmol, 4.0 equiv) were added at room temperature to a stirred solution of compound 90c (1.5 g, 2.9 mmol, 1.0 equiv) in DMF (5.8 ml, 2.0 ml / mmol). The reaction mixture was stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 91c (1.6 g, 92%) (Fig. 20).

[0720] 1H NMR (400 MHz, CHLOROFORM-d) d 7.36 - 7.42 (m, 4H), 7.30 - 7.34 (m, 2H), 6.90 (d, J = 8.79 Hz, 1H), 6.22 (d, J = 2.93 Hz, 1H), 6.17 (dd, J = 2.93, 8.79 Hz, 1H), 4.52 (s, 2H), 4.35 (t, J = 5.62 Hz, 1H), 3.68 (s, 3H), 3.36 - 3.41 (m, 2H), 3.32 (s, 6H), 1.68 (br. s., 2H), 1.60 (br. s., 2H), 1.33 - 1.43 (m, 4H).

[0721]

[0722] 159. Synthesis of 4-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butanal (compound 92a)

[0723] A 1 N HCl aqueous solution (0.63 ml) was added at room temperature to a THF (0.63 ml) solution of stirred compound 91a (105 mg, 0.19 mmol, 1.0 equiv). The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated NaHCO3 aqueous solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 92a (52.7 mg, 54%) (Fig. 20).

[0724] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.95 - 2.03 (m, 2 H) 2.53 (t, J=6.64 Hz, 2 H) 3.38 - 3.44 (m, 2 H) 3.76 (s, 3 H) 4.51 (s, 2 H) 6.21 (dd, J=9.16, 2.75 Hz, 1 H) 6.41 (d, J=2.75 Hz, 1 H) 6.91 (d, J=8.70 Hz, 1 H) 7.21 (d, J=7.33 Hz, 2 H) 7.29 - 7.35 (m, 3 H) 9.79 (s, 1 H).

[0725]

[0726] Synthesis of 160.5-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentanal (compound 92b)

[0727] A 1 N HCl aqueous solution (4.8 ml) was added at room temperature to a stirred THF (4.8 ml) solution of compound 91b (840 mg, 1.5 mmol, 1.0 equiv). The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated NaHCO3 aqueous solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 92b (632 mg, 81%) (Fig. 20).

[0728] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 0.94 (d, J=5.50 Hz, 4 H) 1.64 - 1.72 (m, 9 H) 3.35 - 3.41 (m, 5 H) 3.68 (d, J=5.95 Hz, 7 H) 4.52 (s, 5 H) 6.16 - 6.20 (m, 2 H) 6.21 - 6.24 (m, 2 H) 6.88 - 6.92 (m, 2 H) 7.20 - 7.26 (m, 6 H) 7.30 - 7.35 (m, 5 H) 9.78 (s, 1 H).

[0729]

[0730] Synthesis of 161.6-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexanal (compound 92c)

[0731] A 1 N HCl aqueous solution (9.0 ml) was added at room temperature to a THF (9.0 ml) solution of stirred compound 91c (1.6 g, 2.7 mmol, 1.0 equiv). The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated NaHCO3 aqueous solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 92b (1.1 g, 78.3%) (Fig. 20).

[0732] 1H NMR (400 MHz, CHLOROFORM-d) d 9.77 (t, J = 1.47 Hz, 1H), 7.30 - 7.35 (m, 2H), 7.19 - 7.26 (m, 3H), 6.91 (d, J = 9.28 Hz, 1H), 6.23 (d, J = 2.44 Hz, 1H), 6.18 (dd, J = 2.69, 9.04 Hz, 1H), 4.52 (s, 2H), 3.68 (s, 3H), 3.36 - 3.42 (m, 2H), 2.45 (dt, J = 1.47, 7.33 Hz, 2H), 1.64 - 1.73 (m, 5H), 1.33 - 1.42 (m, 2H).

[0733]

[0734] 162. Synthesis of methyl (R)-1-(4-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butyl)piperidine-2-carboxylate (Compound 93a)

[0735] Methyl (R)-piperidine-3-carboxylate (34.4 mg, 0.24 mmol, 2.5 equiv), NaBH(OAc)3 (42.4 mg, 0.19 mmol, 2.0 equiv), and acetic acid (14 μl, 0.24 mmol, 2.5 equiv) were added to a stirred solution of compound 92a (49.3 mg, 0.10 mmol, 1.0 equiv) in MeOH (1.0 ml, 10.0 ml / mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 93a (31.4 mg, 49%) (Fig. 20).

[0736] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.48 - 1.53 (m, 1 H) 1.64 - 1.72 (m, 4 H) 1.72 - 1.78 (m, 1 H) 1.92 - 1.99 (m, 2 H) 2.11 - 2.18 (m, 1 H) 2.34 - 2.39 (m, 2 H) 2.57 (s, 1 H) 2.72 (br. s., 1 H) 2.95 (br. s., 1 H) 3.37 - 3.42 (m, 2 H) 3.67 (s, 6 H) 4.52 (s, 2 H) 6.17 - 6.23 (m, 2 H) 6.90 (d, J=8.70 Hz, 1 H) 7.20 - 7.24 (m, 2 H) 7.29 - 7.35 (m, 3 H).

[0737]

[0738] 163. Synthesis of methyl (S)-1-(5-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentyl)piperidine-2-carboxylate (Compound 93b)

[0739] Methyl (R)-piperidine-3-carboxylate (345 mg, 2.4 mmol, 2.2 equiv), NaBH(OAc)3 (464 mg, 2.2 mmol, 2.0 equiv), and acetic acid (157 μl, 2.7 mmol, 2.5 equiv) were added to a stirred solution of compound 92b (580 mg, 1.1 mmol, 1.0 equiv) in MeOH (11 ml, 10.0 ml / mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 93b (634 mg, 88%) (Fig. 20).

[0740] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.31 - 1.38 (m, 2 H) 1.41 - 1.47 (m, 1 H) 1.53 (dd, J=7.56, 2.52 Hz, 2 H) 1.62 - 1.77 (m, 4 H) 1.95 (dd, J=11.68, 2.98 Hz, 2 H) 2.07 - 2.16 (m, 1 H) 2.30 - 2.36 (m, 2 H) 2.53 - 2.61 (m, 1 H) 2.75 (d, J=11.91 Hz, 1 H) 2.95 - 3.01 (m, 1 H) 3.35 - 3.41 (m, 2H) 3.68 (s, 6 H) 4.52 (s, 2 H) 6.17 (dd, J=8.70, 2.75 Hz, 1 H) 6.22 (d, J=3.21 Hz, 1 H) 6.90 (d, J=9.16 Hz, 1 H) 7.20 - 7.26 (m, 3 H) 7.30 - 7.35 (m, 3 H).

[0741]

[0742] 164. Synthesis of methyl (R)-1-(6-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylate (Compound 93c)

[0743] Methyl (R)-piperidine-3-carboxylate (158 mg, 1.1 mmol, 3.0 equiv), NaBH(OAc)3 (234 mg, 1.1 mmol, 3.0 equiv), and acetic acid (63 μl, 1.1 mmol, 3.0 equiv) were added to a stirred solution of compound 92c (200 mg, 0.37 mmol, 1.0 equiv) in MeOH (3.0 ml, 10.0 ml / mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 93c (213 mg, 86.5%) (Fig. 20).

[0744] 1 H NMR (400 MHz, CHLOROFORM-d) d 7.29 - 7.36 (m, 2H), 7.19 - 7.26 (m, 3H), 6.90 (d, J = 9.16 Hz, 1H), 6.22 (d, J = 2.75 Hz, 1H), 6.17 (dd, J = 2.98, 8.93 Hz, 1H), 4.52 (s, 2H), 3.68 (s, 6H), 3.34 - 3.41 (m, 2H), 2.99 (d, J = 10.08 Hz, 1H), 2.76 (d, J = 10.99 Hz, 1H), 2.58 (tt, J = 3.78, 10.65 Hz, 1H), 2.28 - 2.35 (m, 2H), 2.11 (t, J = 10.76 Hz, 1H), 1.91 - 2.00 (m, 2H), 1.64 - 1.76 (m, 3H), 1.40 - 1.57 (m, 4H), 1.33 (d, J = 3.66 Hz, 4H).

[0745]

[0746] 165. Synthesis of methyl (S)-1-(6-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylate (Compound 93d)

[0747] Methyl (S)-piperidine-3-carboxylate (36.6 mg, 0.25 mmol, 3.0 equiv), NaBH(OAc)3 (54.2 mg, 0.25 mmol, 3.0 equiv), and acetic acid (15 μl, 0.25 mmol, 3.0 equiv) were added to a stirred solution of compound 92c (46.3 mg, 0.09 mmol, 1.0 equiv) in MeOH (1.0 ml) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 93d (10.5 mg, 18.4%) (Fig. 20).

[0748] 1 H NMR (400 MHz, CHLOROFORM-d) d 7.29 - 7.35 (m, 5H), 7.20 - 7.26 (m, 6H), 6.91 (d, J = 3.21 Hz, 1H), 6.89 (d, J = 3.21 Hz, 1H), 6.22 (t, J = 2.52 Hz, 2H), 6.15 - 6.20 (m, 2H), 4.51 (s, 4H), 3.67 - 3.71 (m, 14H), 3.36 - 3.40 (m, 5H), 2.97 (t, J = 11.91 Hz, 2H), 2.50 (d, J = 13.74 Hz, 2H), 1.98 (s, 8H), 1.62 - 1.80 (m, 9H), 1.30 - 1.44 (m, 12H).

[0749]

[0750] 166. Synthesis of methyl 1-(6-(benzyl(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-4-carboxylate (compound 93e)

[0751] Methylpiperidine-4-carboxylate (158 mg, 1.1 mmol, 3.0 equiv), NaBH(OAc)3 (234 mg, 1.1 mmol, 3.0 equiv), and acetic acid (63 μl, 1.1 mmol, 3.0 equiv) were added at room temperature to a 3.0 ml MeOH solution of stirred compound 92c (200 mg, 0.37 mmol, 1.0 equiv). The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water, a saturated aqueous solution of NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 93e (237 mg, 96%) (Fig. 20).

[0752] 1 H NMR (400 MHz, CHLOROFORM-d) d 7.30 - 7.34 (m, 2H), 7.19 - 7.26 (m, 3H), 6.90 (d, J = 9.16 Hz, 1H), 6.21 (d, J = 2.75 Hz, 1H), 6.17 (dd, J = 2.75, 8.70 Hz, 1H), 4.52 (s, 2H), 3.68 (s, 3H), 3.68 (s, 3H), 3.34 - 3.41 (m, 2H), 2.86 (d, J = 11.91 Hz, 2H), 2.24 - 2.33 (m, 3H), 1.87 - 2.00 (m, 4H), 1.73 - 1.82 (m, 2H), 1.63 - 1.70 (m, 2H), 1.46 - 1.53 (m, 2H), 1.30 - 1.38 (m, 4H).

[0753]

[0754] 167. Synthesis of methyl (R)-1-(4-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butyl)piperidine-2-carboxylate (Compound 94a)

[0755] Compound 94a was synthesized overnight from compound 93a (28.2 mg) according to general procedure D. The crude residue was purified by silica gel column chromatography to obtain the desired product (21.2 mg, 88%) (Fig. 20).

[0756] 1 H NMR (400 MHz, DMSO-d6) d ppm 1.17 (t, J=7.33 Hz, 1 H) 1.23 (s, 1 H) 1.48 - 1.57 (m, 5 H) 1.61 - 1.73 (m, 2 H) 1.76 - 1.87 (m, 2 H) 1.99 (s, 1 H) 2.67 (br. s., 1 H) 2.88 (s, 1 H) 2.94 - 3.03 (m, 3 H) 3.49 - 3.53 (m, 2 H) 3.60 (s, 4 H) 3.69 - 3.73 (m, 3 H) 5.60 - 5.70 (m, 1 H) 6.05 (dd, J=8.70, 2.29 Hz, 1 H) 6.30 (d, J=2.29 Hz, 1 H) 6.95 (d, J=8.70 Hz, 1 H).

[0757]

[0758] 168. Synthesis of methyl(S)-1-(5-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentyl)piperidine-2-carboxylate (Compound 94b)

[0759] Compound 94b was synthesized overnight from Compound 93b (570 mg) according to general procedure D. The crude residue was purified by silica gel column chromatography to obtain the desired product (395 mg, 81%) (Fig. 20).

[0760] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.40 - 1.48 (m, 3 H) 1.48 - 1.52 (m, 1 H) 1.60 - 1.69 (m, 4 H) 1.70 - 1.78 (m, 2 H) 1.90 - 2.04 (m, 2 H) 2.11 - 2.19 (m, 1 H) 2.32 - 2.39 (m, 2 H) 2.55 - 2.64 (m, 1 H) 2.73 - 2.80 (m, 1 H) 2.95 - 3.02 (m, 1 H) 3.09 (t, J=7.10 Hz, 2 H) 3.68 (s, 3 H) 3.78 (s, 3 H) 6.11 (dd, J=8.70, 2.75 Hz, 1 H) 6.19 (d, J=2.75 Hz, 1 H) 6.92 (d, J=8.70 Hz, 1 H).

[0761]

[0762] 169. Synthesis of methyl (R)-1-(6-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylate (Compound 94c)

[0763] Compound 94c was synthesized overnight from Compound 93c (213 mg) according to general procedure D. The crude residue was purified by silica gel column chromatography to obtain the desired product (179 mg, 96.6%) (Fig. 20).

[0764] 1H NMR (400 MHz, CHLOROFORM-d) d 6.91 (d, J = 8.70 Hz, 1H), 6.21 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.29, 8.70 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.46 - 3.54 (m, 1H), 3.18 - 3.37 (m, 2H), 3.09 (t, J = 6.87 Hz, 2H), 2.73 - 2.83 (m, 2H), 2.53 (t, J = 11.22 Hz, 2H), 2.31 - 2.45 (m, 2H), 2.21 (d, J = 12.82 Hz, 3H), 1.77 - 1.93 (m, 4H), 1.60 - 1.69 (m, 3H), 1.36 - 1.52 (m, 6H), 1.22 - 1.30 (m, 1H).

[0765]

[0766] 170. Synthesis of methyl (S)-1-(6-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylate (Compound 94d)

[0767] Compound 94d was synthesized overnight from compound 93d (10.5 mg) according to general procedure D. The crude residue was purified by silica gel column chromatography to obtain the desired product (9.0 mg, 99%) (Fig. 20).

[0768] 1H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.70 Hz, 1H), 6.24 (d, J = 2.29 Hz, 1H), 6.12 (dd, J = 2.29, 8.70 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.56 (d, J = 6.87 Hz, 1H), 3.10 (s, 2H), 2.97 (br. s., 2H), 2.65 (t, J = 8.47 Hz, 1H), 2.50 (t, J = 11.91 Hz, 2H), 2.33 (d, J = 14.20 Hz, 1H), 1.96 (t, J = 11.45 Hz, 4H), 1.63 - 1.69 (m, 4H), 1.43 - 1.53 (m, 6H).

[0769]

[0770] 171. Synthesis of methyl 1-(6-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-4-carboxylate (compound 94e)

[0771] Compound 94e was synthesized overnight from Compound 93e (237 mg) according to general procedure D. The crude residue was purified by silica gel column chromatography to obtain the desired product (204 mg, 99.5%) (Fig. 20).

[0772] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.91 (d, J = 8.70 Hz, 1H), 6.22 (d, J = 2.29 Hz, 1H), 6.10 (dd, J = 2.75, 8.70 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.09 (t, J = 6.87 Hz, 2H), 2.84 (br. s., 2H), 2.24 (br. s., 3H), 1.90 (br. s., 4H), 1.65 (td, J = 6.93, 14.08 Hz, 4H), 1.34 - 1.54 (m, 6H).

[0773]

[0774] 172. Synthesis of (R)-1-(4-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butyl)piperidine-2-carboxylic acid (Compound 95a)

[0775] Compound 95a was synthesized overnight at room temperature from compound 94a (20.0 mg, 0.04 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.14 ml, 0.14 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (5.9 mg, 29%) (Fig. 20).

[0776] 1 H NMR (400 MHz, DMSO-d6) d ppm 1.20 - 1.28 (m, 1 H) 1.39 - 1.46 (m, 2 H) 1.50 (br. s., 5 H) 1.61 - 1.67 (m, 1 H) 1.68 - 1.76 (m, 1 H) 1.89 - 1.99 (m, 1 H) 2.01 - 2.08 (m, 1 H) 2.18 - 2.26 (m, 1 H) 2.28 - 2.34 (m, 3 H) 2.54 - 2.60 (m, 2 H) 2.67 (br. s., 1 H) 2.73 - 2.79 (m, 1 H) 2.88 - 2.95 (m, 3 H) 5.42 - 5.57 (m, 1 H) 5.95 (dd, J=8.70, 2.75 Hz, 1 H) 6.14 (d, J=2.29 Hz, 1 H) 6.87 (d, J=8.70 Hz, 1 H).

[0777]

[0778] 173. Synthesis of (S)-1-(5-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)pentyl)piperidine-2-carboxylic acid (Compound 95b)

[0779] Compound 95b was synthesized overnight at room temperature from compound 94b (389 mg, 0.69 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (2.8 ml, 2.8 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (55 mg, 16%) (Fig. 20).

[0780] 1 H NMR (400 MHz, DMSO-d6) d ppm 1.31 - 1.36 (m, 2 H) 1.39 - 1.49 (m, 4 H) 1.49 - 1.55 (m, 2 H) 1.58 - 1.66 (m, 1 H) 1.71 - 1.78 (m, 1 H) 2.00 - 2.08 (m, 1 H) 2.13 - 2.21 (m, 1 H) 2.30 (t, J=7.33 Hz, 2 H) 2.34 - 2.41 (m, 1 H) 2.58 - 2.65 (m, 1 H) 2.77 - 2.83 (m, 1 H) 2.87 - 2.93 (m, 2 H) 5.45 - 5.54 (m, 1 H) 5.96 (dd, J=8.93, 2.52 Hz, 1 H) 6.13 (d, J=2.75 Hz, 1 H) 6.88 (d, J=8.70 Hz, 1 H).

[0781]

[0782] 174. Synthesis of (R)-1-(6-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylic acid (Compound 95c)

[0783] Compound 95c was synthesized overnight at room temperature from compound 94c (66.1 mg, 0.11 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.46 ml, 0.46 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (9.6 mg, 15.8%) (Fig. 20).

[0784] 1 H NMR (400 MHz, DMSO-d6) d 9.47 - 9.59 (m, 1H), 6.88 (d, J = 8.70 Hz, 1H), 6.14 (d, J = 2.75 Hz, 1H), 5.96 (dd, J = 2.75, 8.70 Hz, 1H), 5.51 (br. s., 1H), 2.97 - 3.01 (m, 2H), 2.89 - 2.92 (m, 2H), 1.80 (br. s., 2H), 1.64 - 1.71 (m, 2H), 1.50 - 1.55 (m, 2H), 1.30 - 1.39 (m, 4H).

[0785]

[0786] 175. Synthesis of (S)-1-(6-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-3-carboxylic acid (Compound 95d)

[0787] Compound 95d was synthesized overnight at room temperature from compound 94d (9.0 mg, 0.02 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.06 ml, 0.06 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (3.7 mg, 43.2%) (Fig. 20).

[0788] 1H NMR (400 MHz, DMSO-d6) d 6.87 (d, J = 8.70 Hz, 1H), 6.16 (d, J = 2.29 Hz, 1H), 5.94 (dd, J = 2.52, 8.93 Hz, 1H), 5.41 - 5.54 (m, 1H), 2.89 (br. s., 2H), 2.82 (d, J = 11.45 Hz, 1H), 2.62 (br. s., 1H), 2.29 (br. s., 3H), 2.11 (br. s., 1H), 1.99 (br. s., 1H), 1.74 (br. s., 1H), 1.60 (br. s., 1H), 1.50 (d, J = 6.87 Hz, 3H), 1.42 (d, J = 7.33 Hz, 4H), 1.32 (dd, J = 6.18, 11.68 Hz, 4H).

[0789]

[0790] 176. Synthesis of 1-(6-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)hexyl)piperidine-4-carboxylic acid (compound 95e)

[0791] Compound 95e was synthesized overnight at room temperature from compound 94e (97.1 mg, 0.17 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.67 ml, 0.67 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (50 mg, 54.1%) (Fig. 20).

[0792] 1H NMR (400 MHz, DMSO-d6) d 6.89 (d, J = 8.70 Hz, 1H), 6.13 (d, J = 2.29 Hz, 1H), 5.97 (dd, J = 2.52, 8.93 Hz, 1H), 5.50 (br. s., 1H), 2.86 - 3.01 (m, 6H), 2.00 (d, J = 14.20 Hz, 3H), 1.76 (br. s., 2H), 1.59 - 1.66 (m, 2H), 1.50 - 1.56 (m, 2H), 1.21 - 1.44 (m, 6H).

[0793]

[0794] 177. Synthesis of ethyl 4-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butanoate (Compound 96)

[0795] Ethyl 4-bromobutyrate (324 μl, 2.3 mmol, 1.2 equiv) and K2CO3 (521 mg, 3.8 mmol, 2.0 equiv) were added at room temperature to a stirred solution of compound 9b (670 mg, 1.9 mmol, 1.0 equiv) in DMF (4.0 ml, 2.0 ml / mmol). The reaction mixture was stirred overnight at 70 °C under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 96 (410 mg, 46%) (Fig. 21).

[0796] 1H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.79 Hz, 1H), 6.21 (d, J = 2.93 Hz, 1H), 6.11 (dd, J = 2.69, 8.55 Hz, 1H), 4.15 (q, J = 7.33 Hz, 2H), 3.79 (s, 4H), 3.17 (s, 2H), 2.44 (t, J = 7.08 Hz, 2H), 1.92 - 2.00 (m, 2H), 1.27 (t, J = 7.08 Hz, 3H).

[0797]

[0798] 178. Synthesis of 4-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butanoic acid (Compound 97)

[0799] A 3 N HCl aqueous solution (2.8 ml) was added at room temperature to a stirred acetic acid (2.8 ml) solution of compound 96 (400 mg, 0.85 mmol, 1.0 equiv). The reaction mixture was stirred at 100 °C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 97 (320 mg, 90%) (Fig. 21).

[0800] 1 H NMR (400 MHz, CHLOROFORM-d) d 7.79 (d, J = 2.52 Hz, 1H), 7.03 (d, J = 8.70 Hz, 1H), 6.84 (dd, J = 2.52, 8.93 Hz, 1H), 3.87 - 3.90 (m, 2H), 3.86 (s, 4H), 2.64 (t, J = 8.13 Hz, 2H), 2.14 - 2.23 (m, 2H).

[0801]

[0802] 179. Synthesis of ethyl (4-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butanoyl)glycinate (Compound 98)

[0803] Glycine ethyl ester (8.5 mg, 0.06 mmol, 0.9 equiv), HATU (28.5 mg, 0.07 mmol, 1.1 equiv), and DIPEA (24 μl, 0.14 mmol, 2.0 equiv) were added to a stirred solution of compound 97 (30 mg, 0.07 mmol, 1.0 equiv) in THF (0.68 ml, 10 ml / mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with a 1 M aqueous HCl solution, water, a saturated aqueous NaHCO3 solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 98 (22 mg, 61.5%) (Fig. 21).

[0804] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.91 (d, J = 8.70 Hz, 1H), 6.22 (d, J = 2.75 Hz, 1H), 6.11 (dd, J = 2.29, 8.70 Hz, 1H), 6.01 (br. s., 1H), 4.23 (q, J = 6.87 Hz, 2H), 4.04 (d, J = 5.50 Hz, 2H), 3.94 (br. s., 1H), 3.78 (s, 3H), 3.18 (t, J = 6.64 Hz, 2H), 2.40 (t, J = 6.87 Hz, 2H), 2.00 (t, J = 6.87 Hz, 2H), 1.30 (t, J = 7.33 Hz, 3H).

[0805]

[0806] 180. Synthesis of (4-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)butanoyl)glycine (Compound 99)

[0807] Compound 99 was synthesized overnight at room temperature from Compound 98 (20 mg, 0.04 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.15 ml, 0.15 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (18 mg, 98%) (Fig. 21).

[0808] 1 H NMR (400 MHz, DMSO-d6) d 12.50 (br. s., 1H), 9.45 - 9.61 (m, 1H), 8.15 (t, J = 5.72 Hz, 1H), 6.89 (d, J = 8.70 Hz, 1H), 6.12 (d, J = 2.75 Hz, 1H), 5.97 (dd, J = 2.75, 8.70 Hz, 1H), 5.56 (br. s., 1H), 3.73 (d, J = 5.95 Hz, 2H), 2.92 (t, J = 6.87 Hz, 2H), 2.22 (t, J = 7.56 Hz, 2H), 1.70 - 1.81 (m, 2H).

[0809]

[0810] 181. N 1 Synthesis of -(3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)propane-1,3-diamine (Compound 100)

[0811] Compound 100 was synthesized from compound 9b (500 mg, 1.4 mmol, 1.0 equiv) and 3-bromopropylamine hydrobromide (194.3 mg, 1.4 mmol, 1.0 equiv) according to general procedure E (212 mg, 26%) (Fig. 21).

[0812] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.79 (quin, J=6.58 Hz, 2 H) 2.89 (t, J=6.53 Hz, 2 H) 3.17 - 3.22 (m, 2 H) 3.77 - 3.79 (m, 3 H) 6.12 (dd, J=8.70, 2.52 Hz, 1 H) 6.21 (d, J=2.52 Hz, 1 H) 6.92 (d, J=8.70 Hz, 1 H).

[0813]

[0814] 182. Synthesis of methyl 3-((3-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)propyl)amino)propanoate (Compound 101)

[0815] Methyl 3-bromopropionate (62 μl, 0.57 mmol, 1.1 equiv) and K2CO3 (142 mg, 1.0 mmol, 2.0 equiv) were added at room temperature to a stirred solution of Compound 100 (212 mg, 0.51 mmol, 1.0 equiv) in DMF (1.0 ml, 2 ml / mmol). The reaction mixture was stirred at 70 °C for 8 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, Compound 101 (65 mg, 25%) (Fig. 21).

[0816] 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.81 (quin, J=6.41 Hz, 2 H) 2.55 (t, J=6.41 Hz, 2 H) 2.80 (t, J=6.41 Hz, 2 H) 2.92 (t, J=6.41 Hz, 2 H) 3.19 (t, J=6.64 Hz, 2 H) 3.69 (s, 3 H) 3.79 (s, 3 H) 6.11 (dd, J=8.70, 2.75 Hz, 1 H) 6.22 (d, J=2.75 Hz, 1 H) 6.91 (d, J=8.70 Hz, 1 H).

[0817]

[0818] 183. Synthesis of 3-((3-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy)phenyl)amino)propyl)amino)propionic acid (Compound 102)

[0819] Compound 102 was synthesized overnight at room temperature from Compound 101 (65 mg, 0.13 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.52 ml, 0.52 mmol, 4.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (37 mg, 61%) (Fig. 21).

[0820] 1 H NMR (400 MHz, DMSO-d6) d ppm 1.73 - 1.80 (m, 2 H) 2.23 (t, J=6.18 Hz, 2 H) 2.84 (t, J=7.10 Hz, 2 H) 2.89 (t, J=6.18 Hz, 2 H) 2.99 (t, J=6.64 Hz, 2 H) 5.58 (br. s., 1 H) 5.97 (dd, J=8.70, 2.75 Hz, 1 H) 6.20 (d, J=2.29 Hz, 1 H) 6.89 (d, J=8.70 Hz, 1 H).

[0821]

[0822] 184. Synthesis of 7-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)heptanoic acid (Compound 103)

[0823] A 3 N HCl aqueous solution (6.1 ml) was added at room temperature to a stirred acetic acid (6.1 ml) solution of compound 77b (937 mg, 1.8 mmol, 1.0 equiv). The reaction mixture was stirred at 100 °C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 97 (834 mg, 94%) (Fig. 22).

[0824] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.29 Hz, 1H), 6.11 (d, J = 8.70 Hz, 1H), 3.79 (s, 3H), 3.09 (t, J = 7.10) Hz, 2H), 2.38 (t, J = 7.33 Hz, 2H), 1.59 - 1.72 (m, 4H), 1.37 - 1.50 (m, 4H).

[0825]

[0826] Synthesis of 185.7-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)heptanamide (compound 104a)

[0827] Ethyl chloroformate (19 μl, 0.2 mmol, 1.2 equiv), 28% aqueous NH4OH solution (16 μl, 0.83 mmol, 5.0 equiv), and TEA (28 μl, 0.2 mmol, 1.2 equiv) were added to a stirred solution of compound 103 (80 mg, 0.17 mmol, 1.0 equiv) in THF (0.83 ml, 5 ml / mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl solution, water, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 104a (42.3 mg, 53%) (Fig. 22).

[0828] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.70 Hz, 1H), 6.20 (d, J = 2.29 Hz, 1H), 6.11 (dd, J = 2.75, 8.70 Hz, 1H), 5.37 (br. s., 2H), 3.79 (s, 3H), 3.09 (t, J = 7.10 Hz, 2H), 2.25 (t, J = 7.56 Hz, 2H), 1.53 - 1.74 (m, 10H), 1.40 - 1.53 (m, 4H).

[0829]

[0830] 186. Synthesis of 7-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)-N-methylheptanamide (Compound 104b)

[0831] Ethyl chloroformate (19 μl, 0.2 mmol, 1.2 equiv), methylamine (33% w / w in EtOH) (90 μl, 0.83 mmol, 5.0 equiv), and TEA (28 μl, 0.2 mmol, 1.2 equiv) were added to a stirred solution of compound 103 (80 mg, 0.17 mmol, 1.0 equiv) in THF (0.83 ml, 5 ml / mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with 1 M aqueous HCl, water, saturated aqueous NaHCO3, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 104b (48.6 mg, 59%) (Fig. 22).

[0832] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.92 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.75 Hz, 1H), 6.10 (dd, J = 2.29, 8.70 Hz, 1H), 3.79 (s, 3H), 3.63 (br. s., 1H), 3.08 (t, J = 7.10 Hz, 2H), 2.82 (d, J = 5.04 Hz, 3H), 2.18 (t, J = 7.56 Hz, 2H), 1.65 (td, J = 7.33, 14.66 Hz, 5H), 1.33 - 1.49 (m, 4H).

[0833]

[0834] 187. Synthesis of 7-((3-methoxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)-N,N-dimethylheptanamide (Compound 104c)

[0835] Ethyl chloroformate (19 μl, 0.2 mmol, 1.2 equiv), dimethylamine (2.0 M in MeOH) (414 μl, 0.83 mmol, 5.0 equiv), and TEA (28 μl, 0.2 mmol, 1.2 equiv) were added to a stirred solution of compound 103 (80 mg, 0.17 mmol, 1.0 equiv) in THF (0.83 ml, 5 ml / mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. After the reaction was complete, the mixture was diluted with EtOAc and washed sequentially with a 1 M aqueous HCl solution, water, a saturated aqueous NaHCO3 solution, and brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain the desired product, compound 104c (69.1 mg, 81.8%) (Fig. 22).

[0836] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.91 (d, J = 8.70 Hz, 1H), 6.19 (d, J = 2.29 Hz, 1H), 6.10 (dd, J = 2.75, 8.70 Hz, 1H), 3.78 (s, 3H), 3.65 (br. s., 1H), 3.09 (t, J = 6.87 Hz, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.33 (t, J = 7.33 Hz, 2H), 1.62 - 1.71 (m, 4H), 1.35 - 1.50 (m, 4H).

[0837]

[0838] 188. Synthesis of 7-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)heptanamide (Compound 105a)

[0839] Compound 105a was synthesized overnight at room temperature from compound 104a (38 mg, 0.08 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.24 ml, 0.24 mmol, 3.0 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (6.6 mg, 17.6%) (Fig. 22).

[0840] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.74 (d, J = 8.70 Hz, 1H), 6.28 (d, J = 2.29 Hz, 1H), 6.04 (dd, J = 2.75, 9.16 Hz, 1H), 5.37 - 5.58 (m, 2H), 3.06 (t, J = 7.10 Hz, 2H), 2.26 (t, J = 7.10 Hz, 2H), 1.63 - 1.72 (m, 4H), 1.36 - 1.45 (m, 4H).

[0841]

[0842] 189. Synthesis of 7-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)-N-methylheptanamide (Compound 105b)

[0843] Compound 105b was synthesized overnight at room temperature from compound 104b (48.6 mg, 0.10 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.12 ml, 0.12 mmol, 1.2 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (40.4 mg, 85.5%) (Fig. 22).

[0844] 1H NMR (400 MHz, CHLOROFORM-d) d 6.75 (d, J = 8.70 Hz, 1H), 6.30 (d, J = 2.75 Hz, 1H), 6.03 (dd, J = 2.52, 8.93 Hz, 1H), 5.57 (br. s., 1H), 3.05 (t, J = 7.10 Hz, 2H), 2.81 (d, J = 4.58 Hz, 3H), 2.20 (t, J = 7.33 Hz, 2H), 1.60 - 1.74 (m, 6H), 1.33 - 1.44 (m, 4H).

[0845]

[0846] 190. Synthesis of 7-((3-hydroxy-4-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phethoxy)phenyl)amino)-N,N-dimethylheptanamide (Compound 105c)

[0847] Compound 105c was synthesized overnight at room temperature from compound 104c (69.1 mg, 0.14 mmol, 1.0 equiv) and a 1.0 M BBr3 DCM solution (0.16 ml, 0.16 mmol, 1.2 equiv) according to general procedure B. The crude residue was purified by silica gel column chromatography to obtain the desired product (19.5 mg, 29%) (Fig. 22).

[0848] 1 H NMR (400 MHz, CHLOROFORM-d) d 6.75 (d, J = 8.70 Hz, 1H), 6.40 (d, J = 2.75 Hz, 1H), 6.02 (dd, J = 2.75, 8.70 Hz, 1H), 3.69 (br. s., 1H), 3.05 - 3.10 (m, 2H), 3.03 (s, 4H), 2.96 (s, 3H), 2.35 (t, J = 6.87 Hz, 2H), 1.62 - 1.75 (m, 5H), 1.42 (td, J = 3.61, 6.98 Hz, 5H).

[0849]

[0850] Examples

[0851] 1. Confirmation of in vitro activity of a compound

[0852] 1-1. Establishment of G803D / N806K mutant cell lines

[0853] Wild-type (WT) human BK Ca The channel coding region (GenBank accession number NM002247) was subcloned into the pcDNA3.1(+) mammalian expression vector (Invitrogen, Carlsbad, CA). BK Ca A variant of the channel (G803D / N806K) was prepared via site-directed mutagenesis of the WT plasmid using the QuikChange Site-Directed Mutagenesis Kit (Stratagene, Santa Clara, CA). AD-293 cells (Stratagene), a derivative of the HEK293 cell line, were cultured in Dulbecco's Modified Eagle's Medium (Thermo, Waltham, MA) supplemented with 10% fetal bovine serum (Thermo) and antibiotics at 37°C under 5% CO2. To obtain a stable cell line, WT BK Ca The pcDNA3.1 vector containing the channel or G803D / N806K mutation was transformed into AD-293 cells using Polyfect reagent (Qiagen, Valencia, CA). Cells were cultured in medium containing 1 mg / ml geneticin (Gibco-RRL, Carlsbad, CA), and the medium was changed every 2 days.

[0854]

[0855] 1-2. Cell Culture and Cell Line-Based Fluorescence Assay

[0856] Mutant BK CaA cell-based assay was performed using modified human embryonic kidney cells (AD-293 cells) stably expressing the channel (G803D / N806K). Cells were cultured in high-glucose Dulbecco's modified Eagle's medium (Hyclone, Logan, UT) containing 10% fetal bovine serum (Hyclone) and 1 mg / ml geneticin (Gibco / Life Technologies, Waltham, MA). Approximately 20,000 cells per well were seeded into 96-well clear-bottom black plates (Corning Incorporated, Corning, NY) coated with poly(d-lysine) (Sigma-Aldrich). The cell-based assay was performed using the FluxOR potassium channel assay kit (Invitrogen, Eugene, OR) in the following steps. First, the cell growth medium was removed, and 80 μl of loading buffer containing FluxOR fluorescent dye was added to each well. Afterward, the plate was incubated at room temperature for 1 hour under dark conditions. After incubation, the loading buffer was removed, and 100 μl of assay buffer containing DMSO (1%) control and test compounds was added to each well and incubated at room temperature for 20-30 minutes. Subsequently, the plate was inserted into a FlexStation 3 instrument, and fluorescence was measured every 2 seconds in each well using a FlexStation 3 multimode microplate reader (Molecular Devices, Sunnyvale, CA) and SoftMax Pro software.At this time, the fluorescence excitation wavelength was set to 485 nm and the emission wavelength to 528 nm. 20 seconds after the start of fluorescence measurement, the FlexStation 3 automatically injected a high concentration of TI into each well. + Depolarization of the cell membrane was chemically induced by adding 20 μl of stimulus buffer containing [subject]. The fluorescence signal was analyzed in relative fluorescence units (RFU). The RFU value was the RFU measured relative to the positive control substance on each assay plate. max It is the relative value based on expressed as a percent. Specifically, it was calculated using the following formula:

[0857] RFU (% of RFU max ) = 100*(RFU compound -RFU DMSO ) / (RFU max -RFU DMSO ).

[0858] RFU values ​​and EC of each compound 50 Based on the values, cell-based activities are shown in Tables 4 to 10 below. In Tables 4 to 10 below, EC 50 Values ​​were indicated as +++ for values ​​1 μM or less, ++ for values ​​greater than 1 μM and less than or equal to 5 μM, and + for values ​​greater than 5 μM.

[0859] CompoundsR cell-based activation 4a +4b +4c +4d ++4e +4f +3d +4g +4h +4i ++

[0860]

[0861] CompoundsR cell-based activation 4d ++6a +6b +6c +6d ++6e +6f +6g ++6h ++6i +++6j ++

[0862]

[0863] CompoundsR cell-based active 6i +++11a +10a +11b +10b +++9b ++9c ++9d +58 +++61 +++55 (full structure)+++

[0864]

[0865] CompoundsR cell-based active 10bOH+++16aF++16bCl++16cCF3+14aOCF3+16dCN+14bCH2OH+

[0866]

[0867] CompoundsR cell-based active 10b +++22a +22b +20 +29 +24 +37a +++37b +38a ++38b +

[0868]

[0869] Compounds R1R2 cell-based active 10bH +++41a +41b +41c +41d ++51a +51b ++65a ++65b +75a ++75b ++81a ++81b ++81c ++81d ++78a ++78b ++78c ++85 ++

[0870]

[0871] CompoundsR cell-based activity 89a +89b +89c +89d +95a +95b ++95c ++95d ++95e +99 +102 +104a ++105a +++105b ++105c ++

[0872]

[0873] 2. Confirmation of in vivo activity of the compound

[0874] 2-1. Evaluation of In vivo Efficacy in a Rat Model of Urinary Incontinence

[0875] The in vivo efficacy evaluation of compounds 51a and 51b in a rat model of urinary incontinence was performed at ChemOn Inc., an AAALAC-accredited institution. The experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of ChemOn, Inc. 16-week-old male SHRs (Japan SLC Inc.), an animal model of urinary incontinence, were used as the vehicle group. Animals were selected with a target body weight of approximately 300–350 g, and among them, SHRs with a blood pressure of 150 mmHg or higher were additionally selected (N size for each group: 5–12). The compounds were dissolved to form a clear solution through sequential vortexing and sonication using DMSO, PEG400, and distilled water, and the final vehicle composition was DMSO:PEG400:distilled water = 5:40:55 v / v. Prior to drug administration, each animal was dehydrated for 15 hours, and water was provided freely starting 2 hours before administration. The compound was administered orally, and the animals' urination frequency, total urine volume, and general symptoms were observed in a metabolic cage for 3 hours. Total urine volume was measured to the nearest 0.01 g using a urine collection cup placed on a scale.

[0876] As a result, the frequency of urination decreased by approximately 43.2% for compound 51a and by approximately 61.4% for compound 51b. In addition, the volume of urine decreased by approximately 49.2% for compound 51a and by approximately 62.6% for compound 51b (Fig. 23).

[0877]

[0878] 2-2. Evaluation of In vivo Efficacy in a Cough Guinea Pig Model

[0879] The evaluation of the in vivo efficacy of Compound 51b in a cough guinea pig model was performed at ChemOn Inc., an AAALAC-accredited institution. The experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of ChemOn, Inc. First, the body weight of 6-week-old female Dunkin Martley guinea pigs (KOATECH) was measured. To ensure a uniform distribution of mean body weight, the animals were divided into five groups of N=9. Prior to drug administration, the animals were fasted for 16 hours. Compound 51b was dissolved into a clear solution through sequential vortexing and sonication using DMSO, PEG400, and distilled water, and the final vehicle composition was DMSO:PEG400:distilled water = 5:40:55 v / v. The drug was administered orally at a dose of 8-50 ml / kg per animal, and 3 hours and 55 minutes after administration, the animals were placed in cough measurement containers and stabilized for 5 minutes. Based on in vivo guinea pig PK results, 4 hours after drug administration, a 17.5% w / v citric acid solution was administered to experimental animals via an ultrasonic nebulizer at a rate of 0.25 ml / min for 8 minutes, and cough frequency and respiratory patterns were recorded for 10 minutes. Cough measurement and data analysis were performed using a cough measurement device (emka TECHNOLOGIES & HUGO SACHS ELEKTRONIK HARVARD APPARATUS, SW: PULMODYNR Pennock W).

[0880] As a result, as the dosage of compound 51b increased, the frequency of coughing decreased, decreasing to 25.4% at 8 mg / kg, 54.4% at 20 mg / kg, and 69.3% at 50 mg / kg, confirming the cough-inhibiting effect of the compound of the present invention (Fig. 24).

Claims

A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] (wherein, R1 is -H, -F, -Cl, C1-C2 haloalkyl group, C1-C2 haloalkoxy, C1-C2 hydroxyalkyl group, hydroxyl group, methoxy group, amino group, nitro group, or cyano group; R2 is -H, hydroxyl group, or C2-C8 alkyl group; and R3 is -H, hydroxyl group, methoxy group, amide group, amido group, aminomethyl group, or -NR 10 R 11 Alternatively, R3 is connected to R2 to form a 5-membered heterocyclic ring containing one or more N, R4 is -H, a hydroxyl group, or an amino group, and R5, R6, R7, R8, and R9 are independently -H, -F, -Cl, or trifluoromethyl groups, and R 10 and R 11 is independently -H, -O, a methyl group, a C2-C8 alkyl group, a C2-C8 heteroalkyl group, or a C6-C8 alkenyl group). A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein R5, R6, R8, and R9 are each -F, and R7 is -Cl or a trifluoromethyl group. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein R5, R7, and R9 are each -H, and R6 and R8 are each trifluoromethyl groups. In claim 1, R3 is NR 10 R 11 and, here R 10 is -H, and R 11 It includes an amino group, a carboxyl group, , , or A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a C3-C8 alkyl group substituted with The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds: . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds: . The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds: . A pharmaceutical composition for the prevention or treatment of urinary disorders comprising a compound of any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating urinary disorders according to claim 8, wherein the urinary disorder is one or more selected from the group consisting of urinary incontinence, overactive bladder, overactive bladder, neurogenic bladder, frequent urination, nocturia, residual urine sensation, urgency, diabetes insipidus, and nocturia. A pharmaceutical composition for preventing or treating cough comprising a compound of any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for the prevention or treatment of erectile dysfunction comprising a compound of any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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