Resorcinols, methods for their production, and uses thereof

Abstract

The present invention relates to a group of resorcinol derivatives as pharma- ceutically active compounds and methods for their preparation. Resorcinol derivatives have been used to treat a variety of diseases and disorders. Although such treatments show promise, there remains a need in the art for more effective treatments, which are provided by the resorcinol derivatives of the present invention.

Description

[Technical field]

[0001] Related Applications This application is related to and claims the benefit of GB2106787.1, filed May 12, 2021 (May 12, 2021), the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to a group of resorcinol derivatives, methods for their preparation, and the use of these compounds as research tools and pharmaceuticals. [Background technology]

[0003] Resorcinol is widely known as a versatile chemical compound that is widely used in the development of advanced chemicals and technologies (Durairaj, 2005). It has been used in a wide range of applications from medicine to chemistry, including the manufacture of resins, plastics, dyes, drugs, and many other organic chemical compounds.

[0004] Resorcinol occurs as white crystals or powder, has a faint characteristic aromatic odor with a sweet-bitter taste, and is readily soluble in water and alcohol. Other names for the compound include resorcin, meta-dihydroxybenzene, 1,3-dihydroxybenzene, 1,3-benzenediol, and 3-hydroxyphenol, and its empirical formula is C. 6 H 6 O 2 Structurally, this compound has two hydroxyl groups in an aromatic ring structure, located meta to each other. The high reactivity of resorcinol is primarily related to the location of these two hydroxyl groups in the benzene ring, with the hydrogen atom adjacent to the hydroxyl group being particularly reactive.

[0005] Resorcinol can be produced via synthetic routes, either using natural resins such as Brazilwood distillates, by dissolving any of a number of resins (such as galbanum and asafetida) and combining this with potassium hydroxide, or by a number of synthetic methods. One synthetic production method is to sulfonate benzene with sulfuric acid and fuse the resulting benzene disulfonic acid with sodium hydroxide, after which the resorcinol is extracted.

[0006] One of the uses of resorcinol is its role as a chemical intermediate for synthesizing drugs and other organic compounds. For example, it is used in the production of diazo dyes and plasticizers, and as a UV absorber in resins. As a medicine, resorcinol is used as a preservative and disinfectant in topical pharmaceutical products in the treatment of skin disorders and infections such as acne, seborrheic dermatitis, eczema, psoriasis, corns, calluses, and warts. Resorcinol works by helping to remove hard, scaly, or rough skin, since it exerts keratolytic activity. However, the main use of resorcinol is in the production of resins. Reaction with formaldehyde produces resins that are used to make rayon and nylon suitable for impregnation with rubber, and as adhesives. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT / GB2020 / 052942 [Patent Document 2] PCT / GB2020 / 052944 [Non-patent literature]

[0008] [Non-Patent Document 1] "Pharmaceutical Salts: Properties, Selection, and Use", 2nd edition, 2002, Stahl and Wermuth (Eds), Wiley-VCH, Weinheim, Germany. [Non-Patent Document 2] Remington: The Science and Practice of Pharmacy, 20th edition, 2000, pub. Lippincott, Williams & Wilkins [Non-Patent Document 3] Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press Summary of the Invention [Problem to be solved by the invention]

[0009] It is with respect to these considerations that the present invention has been conceived.

[0010] Most generally, the present invention relates to a group of resorcinol compounds that are biologically active and therefore useful in the treatment of disease. Such compounds may be administered by a wide variety of routes, including but not limited to oral, transdermal, buccal, nasal, pulmonary, rectal, or ocular. Such compounds may be used to treat or prevent medical conditions, including but not limited to epilepsy. [Means for solving the problem]

[0011] In a first aspect of the present invention, a compound of formula (I):

[0012] [ka]

[0013] [In the formula, R 1 is CH 3 , C.H.2 CH 3 , Cl,

[0014] [ka]

[0015] is] or a salt thereof.

[0016] In a second aspect of the present invention, a compound of formula (II):

[0017] [ka]

[0018] [In the formula, R 1 is CH 2 CH 2 CH 3 ,Br,

[0019] [ka]

[0020] and R 2 is CH 3 , F, or Cl, and R 3 is H or CH 3 is] or a salt thereof.

[0021] In a third aspect of the present invention, a compound of formula (III):

[0022] [ka]

[0023] [In the formula, R 1 is CH 2 CH 2 CH3 or (CH 2 ) 4 CH 3 and R 2 is H or CH 3 and R 3 is H or CH 3 is] or a salt thereof.

[0024] In a fourth aspect of the present invention, a compound of formula (IV):

[0025] [ka]

[0026] [In the formula, R 1 is CH 2 CH 2 CH 3 or

[0027] [ka]

[0028] is] or a salt thereof.

[0029] In a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first, second, third, fourth or fifth aspect, or a salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilisers, surfactants (e.g. wetting agents), masking agents, colourants, flavourings and sweetening agents.

[0030] In a preferred embodiment, the pharmaceutical composition of the sixth aspect is in a form selected from a liquid, solution, suspension, emulsion, syrup, electuary, mouthwash, drops, tablets, granules, powders, lozenges, pastilles, capsules, cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0031] In a seventh aspect of the invention there is provided a compound or salt thereof of the first, second, third, fourth or fifth aspect, or a pharmaceutical composition of the sixth aspect, for use in a method of treatment.

[0032] Preferably, the method of treatment of the seventh aspect is a method of treatment of epilepsy, generalized seizures, focal onset seizures, or tonic-clonic seizures.

[0033] In an eighth aspect of the invention there is provided a compound or salt thereof of the first, second, third, fourth or fifth aspect, or a pharmaceutical composition of the sixth aspect, for use as a medicament.

[0034] Preferably, the medicament of the eighth aspect is a medicament for treating epilepsy, generalized seizures, focal onset seizures, or tonic-clonic seizures.

[0035] In a ninth aspect of the present invention, there is provided a method of treatment comprising administering a therapeutically effective amount of a compound or salt thereof of the first, second, third, fourth or fifth aspect, or a pharmaceutical composition of the sixth aspect to a subject in need of treatment.

[0036] In a tenth aspect of the present invention, there is provided a method for preparing a compound of formula (I), comprising the steps of: i) reacting a compound of formula (V) with a compound of formula (VI):

[0037] [ka]

[0038] [In the formula, R 1 is H, Ac, Piv, Bz, or PMB, R 2 and R 3 is independently H, Ac, or Piv; R 4 and R 5 is OH or R 4 and R 5 Together, -C(Me) 2 C(Me) 2 Forming C- X 1 is Br, I, or OTf, and Y is

[0039] [ka]

[0040] Select from Reacting with A method is provided, comprising:

[0041] In an eleventh aspect of the present invention, there is provided a compound represented by formula (V) and (IX):

[0042] [ka]

[0043] [In the formula, R 1 is H, Ac, Piv, Bz, or PMB, R 2 and R 3 is independently H, Ac, or Piv; X 1 is Br, I, or OTf, and R 15 is H, Bz, or PMB. The intermediate is selected from the compounds of the formula:

[0044] These and other aspects and embodiments of the invention are described in further detail below.

[0045] The present invention will now be described with reference to the figures listed below. [Brief description of the drawings]

[0046] [Figure 1] FIG. 1 shows the effects of compounds 2, 46, and 56 in the mouse mini-MEST test. [Diagram 2] 1 shows the effect of Compound 3 in the mini-MEST test in mice. [Diagram 3] FIG. 1 shows the effects of compounds 5 and 10 in the mouse mini-MEST test. [Figure 4] FIG. 1 shows the effects of compounds 8 and 18 in the mouse mini-MEST test. [Diagram 5] FIG. 1 shows the effects of compounds 15, 16, 45, and 53 in the mouse mini-MEST test. [Figure 6] 1 shows the effect of compound 17 in the mouse mini-MEST test. [Figure 7] 1 shows the effects of compounds 19, 41, and 58 in mouse mini-MEST. [Figure 8] 1 shows the effect of Compound 7 in mouse mini-MEST. [Figure 9] 1 shows the effects of compounds 9, 49, and 52 in mouse mini-MEST. [Figure 10] 1 shows the effect of compound 26 in mouse mini-MEST. [Figure 11] 1 shows the effects of compounds 29, 30, 31, and 33 in mouse mini-MEST. [Figure 12] 1 shows the effects of compounds 35, 42, and 47 in mouse mini-MEST. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The present invention relates to a class of resorcinol compounds that are biologically active and therefore useful in the treatment of disease.

[0048] Resorcinol Formula (I) In a first aspect of the present invention, a compound of formula (I):

[0049] [ka]

[0050] [In the formula, R 1 is CH 3 , C.H. 2 CH 3 , Cl,

[0051] [ka]

[0052] is] or a salt thereof.

[0053] In a preferred embodiment, R 1 is CH 3 , C.H. 2 CH 3 , Cl,

[0054] [ka]

[0055] It is.

[0056] In a more preferred embodiment, R 1 is CH 2 CH 3 , Cl,

[0057] [ka]

[0058] It is.

[0059] In an even more preferred embodiment, R 1 , Cl,

[0060] [ka]

[0061] It is.

[0062] Formula (II) In a second aspect of the present invention, a compound of formula (II):

[0063] [ka]

[0064] [In the formula, R 1 is CH 2 CH 2 CH 3 ,Br,

[0065] [ka]

[0066] and R 2 is CH 3 , F, or Cl, and R 3 is H or CH 3 is] or a salt thereof.

[0067] In a preferred embodiment, R 1 is CH 2 CH 2 CH 3 ,Br,

[0068] [ka]

[0069] It is.

[0070] In a preferred embodiment, R 2 is CH 3 Or Cl.

[0071] In a preferred embodiment, R 3 is H.

[0072] Formula (III) In a third aspect of the present invention, a compound of formula (III):

[0073] [ka]

[0074] [In the formula, R 1 is CH 2 CH 2 CH 3 or (CH 2 ) 4 CH 3 and R 2 is H or CH 3 and R 3 is H or CH 3 is] or a salt thereof.

[0075] In a preferred embodiment, R 1 is CH 2 CH 2 CH 3 It is.

[0076] Formula (IV) In a fourth aspect of the present invention, a compound of formula (IV):

[0077] [ka]

[0078] [In the formula, R 1 is CH 2 CH 2 CH 3 or

[0079] [ka]

[0080] is] or a salt thereof.

[0081] In a preferred embodiment, R 1 is CH 2 CH 2 CH 3 It is.

[0082] salt In some embodiments, a compound of Formula (I), (II), (III), or (IV) is provided in the form of a free base.

[0083] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, e.g., a pharma- ceutically acceptable salt. Examples of pharma-ceutically acceptable salts are discussed in “Pharmaceutical Salts: Properties, Selection, and Use”, 2nd ed., 2002, Stahl and Wermuth (Eds), Wiley-VCH, Weinheim, Germany.

[0084] Thus, in some embodiments, compounds of Formula (I), (II), (III), or (IV) are provided as salts, e.g., in protonated form, with a suitable counter anion.

[0085] Suitable counter anions include both organic and inorganic anions. An example of a suitable inorganic anion is chloride (Cl - ), bromide (Br - ), iodide (I - ), sulfate (SO4 2- ), sulfite (SO 3 2- ), nitrates (NO 3 - ), nitrite (NO 2 - ), phosphate (PO 4 3- ), and phosphites (PO 3 3- Examples of suitable organic anions include those derived from inorganic acids, including 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, lactate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, phenylsulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartrate, toluenesulfonate, and valerate. Examples of suitable polymeric organic anions include those derived from tannic acid and carboxymethylcellulose.

[0086] Alternatively, in some embodiments, the compound of Formula (I), (II), (III), or (IV) is provided as a salt, e.g., in deprotonated form, with an appropriate counter cation.

[0087] Suitable countercations include both organic and inorganic cations. An example of a suitable inorganic cation is Na + and K + Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth cations such as Al 3+ Examples of suitable organic cations include the ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R+ , N.H. 2 R 2 + , N.H.R. 3 + , N.R. 4 + ). Examples of substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + It is.

[0088] solvate In some embodiments, the compound of Formula (I), (II), (III), or (IV) is provided in a desolvated form, e.g., a dehydrated form.

[0089] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle corresponding solvates of the compounds.

[0090] Thus, in some embodiments, a compound of Formula (I), (II), (III), or (IV) is provided in the form of a solvate (a complex of a solute (e.g., a compound, a salt of a compound) and a solvent). Examples of solvates include hydrates, such as monohydrates, dihydrates, and trihydrates.

[0091] Specific isomers Certain compounds of Formula (I), (II), (III), or (IV) may exist in one or more particular optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, or conformational forms, including, but not limited to, D- and L-, d- and I-, (+)- and (-), syn- and anti-, axial- and equatorial, boat-, chair-, twist-boat-, envelope-, and half-chair-forms, and combinations thereof, hereinafter collectively referred to as "isomers" or "isomeric forms".

[0092] As used herein, structural (or constitutional) isomers (i.e., isomers that differ not merely by the position of the atoms in space but by the bonds between the atoms) are specifically excluded from the term "isomer". For example, the methoxy group -OCH 3 Reference to its structural isomer, the hydroxymethyl group -CH 2 It should not be construed as a reference to OH.

[0093] The above exclusion does not pertain to tautomeric forms, e.g., keto, enol, and enolate forms, as in, for example, the following tautomeric pairs: keto / enol, imine / enamine, amide / iminoalcohol, nitroso / oxime, and lactam / lactim.

[0094] The term "isomer" includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T) may be in any isotopic form, and C may be in any isotopic form, including 12 C. 13 C, and 14 It can be in any isotopic form, including C, and O is 16 O and 18 It can be in the form of any isotope containing O, etc.

[0095] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic forms and other mixtures thereof.

[0096] Synthesis method Synthesis of resorcinol PCT / GB2020 / 052942 discloses a method for synthesizing a 6-hydroxy analogue of cannabidiol (CBD). PCT / GB2020 / 052944 discloses a method for synthesizing a 6-hydroxy analogue of cannabidivarin. Both methods involve the oxidation of natural cannabinoids using a chromium oxidizing agent.

[0097] The present inventors have discovered an improved synthetic method that allows for the production of 6-hydroxy compounds with higher yields and reliability. Furthermore, the method of the present invention allows for the use of late-stage cross-coupling reactions to introduce various functional groups to the resorcinol tail. Finally, the method avoids the use of toxic chromium-based oxidants.

[0098] Coupling step (step i): The present invention relates to a process for preparing a compound of formula (I), comprising the steps of: i) reacting a compound of formula (V) with a compound of formula (VI):

[0099] [ka]

[0100] [In the formula, R 1 is H, Ac, Piv, Bz, or PMB, R 2 and R 3 is independently H, Ac, or Piv; R 4 and R 5 is OH or R 4 and R 5 Together, -C(Me) 2 C(Me) 2 Forming C- X 1 is Br, I, or OTf, and Y is

[0101] [ka]

[0102] Select from Reacting with The present invention provides a method comprising:

[0103] Step (i) may be known as the coupling step.

[0104] In a preferred embodiment, R 1 is H, Ac, or Piv. In a more preferred embodiment, R 1 is H.

[0105] In a preferred embodiment, R 2 and R 3 is H.

[0106] In a preferred embodiment, X 1 is Br or OTf. In a more preferred embodiment, X 1 is OTf.

[0107] Typically, step (i) involves reacting a compound of formula (V) with a compound of formula (VI) and a palladium catalyst. A suitable palladium catalyst is Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , and SPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)).

[0108] In a preferred embodiment, step (i) further comprises reacting a compound of formula (V) with a compound of formula (VI) and a base. Suitable bases include cesium fluoride (CsF), sodium carbonate (Na 2 CO 3 ), Cesium carbonate (Cs 2 CO 3 ).

[0109] Typically, step (i) is carried out in a solvent. Suitable solvents include dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), water, and mixtures thereof.

[0110] Step (i) is typically carried out at elevated temperatures (above room temperature; about 20° C.). Methods for supplying heat during the reaction are known and include, for example, the use of a reaction vessel with an external heating jacket or the use of microwave heating.

[0111] Typically, step (i) comprises reacting a compound of formula (V) with a compound of formula (VI) at a temperature from 60°C to 140°C, preferably from 80°C to 140°C, more preferably from 80°C to 120°C.

[0112] Step (i) may be carried out for a time sufficient to allow for the formation of a desired amount of the coupling product. Typically, step (i) is carried out until substantially all of the compound of formula (QQ) is consumed.

[0113] Typically, step (1a) involves reacting a compound of formula (II) with a compound of formula (III) for a period of from 1 hour to 12 hours.

[0114] Triflation step (step II): The present invention also provides a process for preparing a compound of formula (V), comprising the steps of: ii) Formula (VII):

[0115] [ka]

[0116] [In the formula, R 6 is H, Bz, or PMB, R 7 and R 8 are independently H, Ac, or Piv. reacting the compound of formula (I) with a triflate reagent The present invention provides a method comprising:

[0117] Step (ii) may be known as the triflation step.

[0118] In a preferred embodiment, R 6 is H or Bz. In a more preferred embodiment, R 6 is Bz.

[0119] In a preferred embodiment, R 7 and R 8 is OH.

[0120] A suitable triflation reagent is trifluoromethanesulfonic anhydride (Tf 2 O), N-phenylbis(trifluoromethanesulfonimide) (PhNTf 2 ), Comins' reagent, 1-(trifluoromethanesulfonyl)-1H-benzotriazole, 1-(trifluoromethanesulfonyl)imidazole, and N-(2-pyridyl)-bis(trifluoromethanesulfonimide). In a preferred embodiment, Tf 2 O or PhNTf 2 In a more preferred embodiment, PhNTf 2 is used.

[0121] In a preferred embodiment, step (ii) comprises reacting the compound of formula (VII) with a triflation reagent and a base. Suitable bases include organic bases such as pyridine, leutidine, dimethylbenzylamine imidazole, benzimidazole, methylimidazole, triethylamine, tributylamine, diisopropylethylamine, tetramethylethylenediamine, DABCO, etc. In a preferred embodiment, triethylamine or lutidine is used. In a more preferred embodiment, triethylamine is used.

[0122] Typically, step (ii) is carried out in a solvent. Suitable solvents include dichloromethane.

[0123] Step (ii) is typically carried out at low temperature (below room temperature; about 20° C.). Methods for removing heat during the reaction are known and include, for example, the use of a reaction vessel with an external cooling jacket.

[0124] Typically, step (ii) comprises reacting the compound of formula (VII) with a triflating reagent at a temperature between -40°C and 25°C, preferably between -5°C and 20°C, more preferably between 0°C and 20°C.

[0125] Step (ii) may be carried out for a time sufficient to allow for the formation of a desired amount of triflated product. Typically, step (ii) is carried out until substantially all of the compound of formula (VII) is consumed.

[0126] Optionally, step (ii) comprises: ii-a) Formula (VIII):

[0127] [ka]

[0128] [In the formula, R 9 is independently H, Bz, or PMB; R 10 and R 11 are independently H, Ac, or Piv. reacting the compound of formula (I) with a halogen exchange reagent It may further include.

[0129] In a preferred embodiment, R 9 is Bz or PMB. In a more preferred embodiment, R 9 is Bz.

[0130] In a preferred embodiment, R 10 and R 11 is Ac or Piv. In a more preferred embodiment, R10 and R 11 is Piv.

[0131] Step (ii-a) can be carried out in one step (direct halogen exchange) or in multiple steps (indirect halogen exchange).

[0132] A suitable halogen exchange reagent for direct halogen exchange is [Cp * Ru(MeCN) 3 OTf].

[0133] A suitable halogen exchange reagent for indirect halogen exchange is Pd(POAc) 2 and optionally a ligand such as dppf, followed by copper(II) bromide in combination with B 2 Pin 2 Typically, high temperatures such as 60° C. to 90° C. are used. Indirect halogen exchange involves the reaction of the compound represented by formula (VIIIa):

[0134] [ka]

[0135] [In the formula, R 12 is independently H, Bz, or PMB; R 13 and R 14 are independently H, Ac, or Piv. The reaction may proceed via an intermediate of the formula:

[0136] Friedel-Crafts (Step III): The present invention also provides a process for preparing a compound of formula (VII), comprising the steps of: iii) Formula (IX):

[0137] [ka]

[0138] [In the formula, R15 is H, Bz, or PMB. reacting said compound with phloroglucinol (benzene-1,3,5-triol) The present invention provides a method comprising:

[0139] Step (iii) may be known as the Friedel-Crafts step.

[0140] In a preferred embodiment, R 15 is Bz or PMB. In a more preferred embodiment, R 15 is Bz.

[0141] In a preferred embodiment, step (iii) comprises reacting a compound of formula (IX) with phloroglucinol and an acid. Suitable acids are Lewis acids such as boron trifluoride and Bronsted acids such as triflic acid. In a preferred embodiment, triflic acid is used.

[0142] Step (iii) is typically carried out at low temperature (below room temperature; about 20° C.). Typically, step (ii) comprises reacting a compound of formula (IX) with phloroglucinol at a temperature between −15° C. and 20° C., preferably between 0° C. and 15° C., more preferably between 5° C. and 15° C.

[0143] Typically, step (ii) is carried out in a solvent. Suitable solvents include tetrahydrofuran and isopropyl acetate.

[0144] Preferred embodiment: In a preferred embodiment, iii) The Friedel-Crafts process described in paragraphs

[0080] to

[0085] ; ii) a triflation step as described in paragraphs

[0064] to

[0079] , and optionally i) The coupling step described in paragraphs

[0052] to

[0063] A method is provided, comprising:

[0145] Synthesis of key intermediates The present inventors have found that 6-hydroxy compounds can be produced from the key intermediate of formula (IX) via the Friedel-Crafts reaction. This method provides higher yields and reliability of the compounds compared to the late-stage oxidation method. Furthermore, the method of the present invention allows for the use of late-stage cross-coupling reactions to introduce various functional groups to the resorcinol tail.

[0146] Allylic oxidation (step iv): The present invention also relates to a process for preparing a compound of formula (IX), comprising the steps of: iv-a) reacting a compound of formula (X) with diphenyl diselenide to give a compound of formula (XI); and iv-b) reacting the compound of formula (XI) with an oxidizing agent:

[0147] [ka]

[0148] [In the formula, R 16 and R 17 are independently H, Bz, or PMB. The present invention provides a method comprising:

[0149] Steps (iv-a) and (iv-b) together may be known as the allylic oxidation step.

[0150] In a preferred embodiment, step (iv-a) comprises reacting a compound of formula (X) with diphenyl diselenide and a reducing agent. Suitable reducing agents include sodium borohydride.

[0151] In a preferred embodiment, step (iv-a) comprises reacting a compound of formula (X) with diphenyl diselenide and a base. Suitable bases include sodium hydroxide.

[0152] Suitable oxidizing agents include hydrogen peroxide, in a preferred embodiment, hydrogen peroxide is used.

[0153] Step (iv-b) may be carried out at elevated temperature (above room temperature; about 20° C.). Typically, step (iv-b) involves reacting a compound of formula (XI) with an oxidizing agent at a temperature between 0° C. and 20° C. for an initial period of time (selenium oxidation) and then increasing the temperature to a temperature between 20° C. and 60° C. for a second period of time (allylic oxidation).

[0154] Typically, steps (iv-a) and (iv-b) are carried out in a solvent. Suitable solvents include tetrahydrofuran, 2-methyltetrahydrofuran, and ethanol.

[0155] Epoxidation (step v): The present invention also provides a process for preparing a compound of formula (X), comprising the steps of: v) (+)-cis-Carveol, also known as formula (XII):

[0156] [ka]

[0157] reacting the compound with a peroxycarboxylic acid (peracid) The present invention provides a method comprising:

[0158] Step (v) may be known as the epoxidation step.

[0159] Suitable peroxycarboxylic acids include metachloroperoxybenzoic acid (mCPBA) and perbenzoic acid. In a preferred embodiment, mCPBA is used.

[0160] Step (v) is typically carried out at low temperature (room temperature; below about 20° C.). Typically, step (v) comprises reacting a compound of formula (QQ) with a peroxycarboxylic acid at a temperature between −40° C. and 0° C., preferably between −20° C. and 0° C.

[0161] Typically, step (v) is carried out in a solvent. Suitable solvents include dichloromethane.

[0162] Step (v) comprises preparing a compound of formula (Xa), which may be known as epoxycarveol:

[0163] [ka]

[0164] The compound is produced.

[0165] Optionally, step (v) comprises: va) reacting the compound of formula (Xa) with p-methoxybenzyl chloride or benzoyl chloride. It may further include.

[0166] In a preferred embodiment, step (va) further comprises reacting the compound of formula (Xa) with p-methoxybenzyl chloride or benzoyl chloride and a base. Suitable bases include sodium hydride and triethylamine.

[0167] Reduction (step vi): The present invention also provides a process for preparing a compound of formula (Xa), comprising the steps of: vi) S-Carvone:

[0168] [ka]

[0169] reacting with a reducing agent The present invention provides a method comprising:

[0170] Step (vi) may be known as the reduction step.

[0171] Suitable reducing agents include lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), diborane, and sodium borohydride. In a preferred embodiment, sodium borohydride is used.

[0172] In some preferred embodiments, an optional additive such as cerium(III) chloride is used.

[0173] Step (vi) is typically carried out at low temperature (room temperature; below about 20° C.). Typically, step (v) involves reacting S-carvone with a reducing agent at a temperature between −80° C. and 20° C., preferably between −40° C. and 0° C., more preferably between −20° C. and −10° C.

[0174] Typically, step (v) is carried out in a solvent. Suitable solvents include tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, and methanol.

[0175] Preferred embodiment: In a preferred embodiment, vi) A reduction step described in paragraphs

[0103] to

[0108] . v) an epoxidation step as described in paragraphs

[0095] to

[0102] , and optionally iv) The allylic oxidation process described in paragraphs

[0088] to

[0094] A method is provided, comprising:

[0176] In other embodiments: In one embodiment, the method comprises the steps of: i) reduction of carvone a to carveol b followed by epoxidation to generate intermediate c, which is reacted with any suitable protecting group to generate the corresponding epoxide d; ii) reacting epoxide d with diphenyl diselenide in sodium borohydride and treatment with hydrogen peroxide to give crude e, followed by heating e to form the corresponding allylic alcohol f; or refluxing epoxide d in the presence of dimethylamine to give crude g, which is then oxidized to N-oxide h by treatment with hydrogen peroxide and refluxed to provide f; iii) reacting allylic alcohol f with phloroglucinol i to give compound j, which is treated with acetic anhydride followed by triflic anhydride in the presence of 2,6-lutidine to produce compound k, followed by bromination of k to give l, and deprotection of l using cerium(IV) ammonium nitrate followed by sodium borohydride to give m, followed by subsequent metal catalyzed coupling using k or m to arrive at compounds of formula I-V; or reacting allylic alcohol f and phenol n to give product o, decarboxylating o in the presence of aqueous sodium hydroxide, followed by treatment with citric acid to give phenol p, and deprotecting the protecting groups using cerium(IV) ammonium nitrate to give compounds of formulae I-V. There is provided a process for the production of compounds of formulae (I)-(IV) comprising:

[0177] Preferably, the embodiment of paragraph

[0110] uses one of the following protecting groups: PMB, silicon-based protecting groups (TMS, TES, TBS, TBDPS, SEM), ethers (MOM, MEM, BOM, Bn, PMB, DMB, allyl), esters (Piv, Bz, Ac), carbamates, and carbonates (Troc, dimethylaminocarbamate), or no protecting group.

[0178] In one embodiment, vi) A reduction step described in paragraphs

[0103] to

[0108] . v) an epoxidation step described in paragraphs

[0095] to

[0102] ; iv) An allylic oxidation step described in paragraphs

[0088] to

[0094] ; iii) The Friedel-Crafts process described in paragraphs

[0080] to

[0085] ; ii) a triflation step as described in paragraphs

[0064] to

[0079] , and optionally i) The coupling step described in paragraphs

[0052] to

[0063] A method is provided, comprising:

[0179] Intermediates The present invention also relates to compounds of formula (V) and (IX):

[0180] [ka]

[0181] [In the formula, R 1 is H, Ac, Piv, Bz, or PMB, R 2 and R 3 is independently H, Ac, or Piv; X 1 is Br, I, or OTf, and R 15 is H, Bz, or PMB. The present invention provides an intermediate selected from the compounds of the formula:

[0182] In a preferred embodiment, R 1 is H, Ac, or Piv. In a more preferred embodiment, R 1 is H.

[0183] In a preferred embodiment, R 2 and R 3 is H.

[0184] In a preferred embodiment, X 1 is Br or OTf. In a more preferred embodiment, X 1 is OTf.

[0185] In a preferred embodiment, R 15 is Bz or PMB. In a more preferred embodiment, R 15 is Bz.

[0186] In a more preferred embodiment, the intermediate is

[0187] [ka]

[0188] is selected from.

[0189] Pharmaceutical Compositions While it is possible for a compound of Formula (I), (II), (III) or (IV) to be administered alone, it is preferable to administer a pharmaceutical composition (e.g., formulation, preparation, or medicament) that includes a compound of Formula (I), (II), (III) or (IV) together with one or more other pharma- ceutically acceptable ingredients.

[0190] Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV), or a salt thereof, in association with one or more pharma- ceutically acceptable ingredients.

[0191] Suitable pharma- ceutically acceptable ingredients (e.g., carriers, diluents, excipients, etc.) can be found in standard pharmaceutical textbooks, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th ed., 2020, pub. Pharmaceutical Press.

[0192] Examples of suitable pharma- ceutically acceptable ingredients include pharma- ceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavors, and sweeteners.

[0193] In a preferred embodiment, the pharmaceutical composition comprises one or more excipients selected from a carrier, an oil, a disintegrant, a lubricant, a stabilizer, a flavoring, an antioxidant, a diluent, and another pharma- ceutically effective compound.

[0194] The pharmaceutical composition may be in any suitable form. Examples of suitable forms include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0195] In a preferred embodiment, the pharmaceutical composition is selected from a tablet, a capsule, a granule, an oral liquid, a powder for inhalation, a sprinkle, an oral solution, and a suspension.

[0196] Medical treatment The present inventors have found that the compounds of formula (I), (II), (III) and (IV) are biologically active. The examples demonstrate that the compounds of formula (I), (II), (III) and (IV) exhibit anticonvulsant activity in a mouse model of seizures. Thus, the compounds of formula (I), (II), (III) and (IV) and their salts, as well as pharmaceutical compositions comprising the compounds of formula (I), (II), (III) or (IV) or their salts, are useful for medical treatment.

[0197] The present invention thus provides a compound of formula (I), (II), (III) or (IV), or a salt thereof, for use in a method of treatment, for example in a method of treatment of the human or animal body by therapy (i.e. a method of treatment).

[0198] The present invention also provides a compound of formula (I), (II), (III) or (IV), or a salt thereof, for use as a pharmaceutical.

[0199] The present invention also provides a method of treatment comprising administering a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV), or a salt thereof, to a subject in need of treatment.

[0200] The present invention also provides the use of a compound of formula (I), (II), (III) or (IV), or a salt thereof, for the manufacture of a medicament.

[0201] The invention also provides the use of a compound of formula (I), (II), (III) or (IV), or a salt thereof, in a method of treatment.

[0202] Symptoms being treated The present inventors have found that the compounds of formula (I), (II), (III) and (IV) exhibit anticonvulsant activity in a mouse model of generalized seizures. Thus, the compounds of formula (I), (II), (III) and (IV), their salts, and pharmaceutical compositions comprising the compounds of formula (I), (II), (III) and (IV) or their salts are useful for treating certain conditions associated with seizures.

[0203] Similarly, compounds of formula (I), (II), (III) and (IV), their salts, and pharmaceutical compositions comprising compounds of formula (I), (II), (III) and (IV) or their salts, are useful as medicaments (and in the manufacture of medicaments for the treatment) of certain symptoms associated with seizures.

[0204] In a preferred embodiment, the seizure-related condition is epilepsy.

[0205] In one embodiment, the seizure-related condition is a generalized seizure, for example a generalized seizure associated with epilepsy.

[0206] In one embodiment, the seizure-related condition is a focal onset seizure, for example a focal onset seizure associated with epilepsy.

[0207] In one embodiment, the seizure-related condition is a tonic-clonic seizure, for example a tonic-clonic seizure associated with epilepsy.

[0208] Subjects / Patients The methods of treatment typically include the step of administering to a subject or patient a compound of formula (I), (II), (III) and (IV), or a salt thereof.

[0209] The subject / patient may be a chordate, vertebrate, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0210] The subject / patient may be in any of its forms of development, for example, the subject / patient may be an infant or a child.

[0211] In a preferred embodiment, the subject / patient is a human, more preferably an adult.

[0212] The subject / patient may also be a non-human mammal used in laboratory research, such as a rodent, which includes rats, mice, guinea pigs, and chinchillas.

[0213] Route of administration The method of treatment may include administering a compound of formula (I), (II), (III) or (IV), or a salt thereof, systemically / peripherally or locally (i.e., at the site of desired action) to a subject by any convenient route of administration.

[0214] Routes of administration can be oral (e.g., by ingestion), buccal, sublingual, transdermal (including, e.g., by patch, bandage, etc.), transmucosal (including, e.g., by patch, bandage, etc.), intranasal (e.g., by nasal spray), ocular (e.g., by eye drops), pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., used through the mouth or nose), rectal (e.g., by suppository or enema), vaginal (e.g., by vaginal suppository), parenteral, e.g., by injection or infusion, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal, or by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0215] Dosage Methods of treatment typically include administering to the subject a therapeutically effective amount of a compound of formula (I), (II), (III) or (IV), or a salt thereof.

[0216] The appropriate dosage of the compounds of formula (I), (II), (III) and (IV), their salts, and pharmaceutical compositions containing the compounds of formula (I), (II), (III) or (IV) or their salts may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or toxic side effects. The selected dosage level will depend on a variety of factors, including, but not limited to, the activity of the particular compound of formula (I), (II), (III) or (IV), the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other active agents, compounds and / or materials used in combination, the severity of the condition, and the patient's species, sex, age, weight, condition, general health and previous medical history. The dosage and route of administration are ultimately at the discretion of the clinician, but generally, the dosage is selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmful or toxic side effects.

[0217] Administration can be in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating clinician.

[0218] Other Aspects and Embodiments Every compatible combination of the above embodiments is expressly disclosed herein as if every combination was individually and explicitly listed.

[0219] Various important aspects and embodiments of the present invention will be apparent to those of skill in the art in light of this disclosure.

[0220] When used, "and / or" should be construed as a specific disclosure of each of the associated components or features individually as well as a specific disclosure of combinations of components or features. For example, "A and / or B" should be construed as a specific disclosure of i) A, ii) B, and ii) each of A and B, as if each were individually listed.

[0221] Unless otherwise indicated by context, the preceding feature descriptions and definitions are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described.

[0222] definition The following definitions are provided to aid in the understanding of the invention.

[0223] Epilepsy is considered to be a disease of the brain defined by any of the following symptoms: (1) at least two unprovoked (or reflex) seizures occurring more than 24 hours apart, (2) one unprovoked (or reflex) seizure occurring over the next 10 years and a probability of further seizures similar to the general risk of recurrence after two unprovoked seizures (at least 60%), and (3) a diagnosis of an epilepsy syndrome (practical clinical definition of epilepsy from the International League Against Epilepsy (ILAE), 2014).

[0224] The term "focal seizures" ("focal onset seizures") refers to seizures that occur within a network restricted to one hemisphere. They may be discretely localized or more widely distributed. Focal seizures may originate from subcortical structures (Operational Classification of Seizure Types by ILAE, 2017).

[0225] The term “generalized seizures” (generalized onset seizures) refers to seizures conceptualized as originating from one point in the brain and rapidly engaging bilaterally distributed networks ( Operational Classification of Seizure Types by ILAE, 2017 ).

[0226] The term "pharmaceutical acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are suitable for use in contact with the tissues of a subject of interest (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Each ingredient (e.g., carrier, diluent, excipient, etc.) must also be "acceptable" in the sense of being compatible with the other ingredients of the composition.

[0227] "Resorcinol" is a compound having the following structure, or any superstructure containing such a structure therein:

[0228] [ka]

[0229] The term "therapeutically effective amount" refers to an amount of a compound, or a material, composition or dosage form containing a compound, that is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen.

[0230] "Tonic-clonic seizures" occur in two phases; the tonic phase is typically accompanied by muscle stiffening and loss of consciousness, and the clonic phase is typically accompanied by rhythmic jerking of the limbs.

[0231] Bonds that end with a wavy line: "

[0232] [ka]

[0233] " is used to indicate a connection point.

[0234] Ac is the acetyl group (-C(=O)CH 3 ). Bz is a benzoyl group (-C(=O)Ph). Piv is a pivaloyl group (-C(=O)C(CH 3 ) 3 ). PMB is a para-methoxybenzyl group (-CH 2 -C 6 H 4 -OCH 3 ) Tf is a triflate group (-SO 2 CF 3 ). EXAMPLES

[0235] Certain aspects and embodiments of the present invention are described, by way of example only, and with reference to the above figures.

[0236] Analysis method NMR Bruker Avance 400MHz, 5mm QNP probes H, C, F, P, single Z gradient, 2 channel instrument running TopSpin 2.1

[0237] Bruker Avance III 400MHz, 5mm BBFO Plus probe, single Z gradient, 2 channel instrument running TopSpin 3.1.

[0238] LCMS

[0239] [Table 1]

[0240] [Table 2]

[0241] Example 1 Methods for synthesizing new compounds This example describes the novel synthetic methods used to generate novel resorcinols (1-58) that demonstrated pharmacological activity.

[0242] Schemes 1-3 below are numbered to represent each step of the synthesis: Scheme 1 shows the first step for preparing intermediate d, Schemes 2A and 2B are alternative routes for the second step using intermediate d from Scheme 1 to prepare intermediate f, and Schemes 3A and 3B describe the third and final step for preparing the novel compounds of the invention (compounds I-V) using intermediate f from either Scheme 2A or 2B, each of which is an equally alternative route.

[0243] It is understood that any combination of routes is within the scope of the present invention: Scheme 1 followed by Scheme 2A followed by Scheme 3A; Scheme 1 followed by Scheme 2A followed by Scheme 3B; Scheme 1 followed by Scheme 2B followed by Scheme 3A; Scheme 1 followed by Scheme 2B followed by Scheme 3B.

[0244] It is understood that any suitable leaving group can be used in place of the p-methoxybenzyl (PMB) group, and therefore the present invention is not limited to such leaving groups. Alternative protecting groups include silicon-based protecting groups (TMS, TES, TBS, TBDPS, SEM), ethers (MOM, MEM, BOM, Bn, PMB, DMB, allyl), esters (Piv, Bz, Ac), carbamates, and carbonates (Troc, dimethylaminocarbamate), or no protecting group (OH).

[0245] Scheme 1: Synthetic route for preparing intermediates

[0246] [ka]

[0247] (S)-(+)-carvone a was reduced using sodium borohydride and cerium(III) chloride at 0° C. to provide the desired (+)-cis-carveol b. The endocyclic alkene of (+)-cis-carveol b was then selectively epoxidized using m-CPBA in DCM at −40° C. to give epoxide c. Finally, the secondary alcohol c was protected in the presence of NaH and PMBCl in THF to give the target material d after column chromatography.

[0248] Scheme 2A: Synthetic Route for Preparing Intermediates

[0249] [ka]

[0250] Scheme 2B: Synthetic Route for Preparing Intermediates

[0251] [ka]

[0252] Scheme 2A: Epoxide d was reacted with diphenyl diselenide in the presence of sodium borohydride in ethanol at room temperature, which was then subsequently treated with aqueous hydrogen peroxide in ethanol to form crude e. The corresponding allylic alcohol f was then formed by heating e in ethanol.

[0253] Scheme 2B: Epoxide d was refluxed in a mixture of IPA / water in the presence of dimethylamine to give crude g, which was then oxidized to N-oxide h by treatment with hydrogen peroxide in acetonitrile and water. Finally, h was refluxed in toluene for 30 min to provide f.

[0254] Scheme 3A: Synthetic routes for preparing compounds I–V

[0255] [ka]

[0256] Scheme 3B: Synthetic Route for Preparing Compounds I-V

[0257] [ka]

[0258] Scheme 3A: Allyl alcohol f is reacted with phloroglucinol i and a catalytic amount of Sc(OTf). 3 in DCM at room temperature in the presence of to give the desired compound j, which was then treated with acetic anhydride in pyridine followed by triflic anhydride in DCM in the presence of 2,6-lutidine to arrive at compound k. Ruthenium catalyzed bromination of k gave l. Final deprotection using cerium(IV) ammonium nitrate followed by sodium borohydride in ethanol afforded the desired product m. Subsequent metal catalyzed coupling (using Pd, Pt, Ni, Ru, Rh, Au, Mg, Zn, etc.) can be carried out using k or m to arrive at further analogues of the invention.

[0259] Scheme 3B: Allylic alcohol f and phenol n are reacted with a catalytic amount of Sc(OTf) 3 Upon stirring at room temperature in the presence of aqueous sodium hydroxide at 70° C., the product o was obtained. Subsequent decarboxylation of o in the presence of aqueous sodium hydroxide at 70° C., followed by treatment with citric acid, afforded the desired phenol p. Finally, deprotection of the PMB protecting group using cerium(IV) ammonium nitrate in a mixture of water and acetonitrile affords the compounds of the invention.

[0260] The chemical names of the intermediate compounds a to p are listed in Table 1 below.

[0261] [Table 3]

[0262] (Example 1-1) Improved synthetic method for preparation of intermediates Synthesis of coupling partners Phase 1: Friedelcrafts

[0263] [ka]

[0264] (1S,2R,5R)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-3-en-1-yl benzoate (6-benzolyloxomethanedienol) was reacted with phloroglucinol (10.0 equiv.) and triflic acid (0.125 equiv.) in isopropyl acetate (35 vol.). The temperature was maintained between 7.5 and 12.5 °C.

[0265] Step 2: Triflation

[0266] [ka]

[0267] (1R,2R,4S)-2',4',6'-trihydroxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-4-yl benzoate was reacted with N-phenylbis(trifluoromethanesulfonimide) (1.20 equiv.) and triethylamine (4.5 equiv.) in DCM (15 vol.). The temperature was maintained between 0°C and 20°C.

[0268] Stage 3: Pivylation

[0269] [ka]

[0270] (1R,2R,4S)-2',6'-Dihydroxy-5-methyl-2-(prop-1-en-2-yl)-4'-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-4-ylbenzoate was reacted with pivaloyl chloride (2.05 equivalents) and cesium carbonate (2.2 equivalents) in acetonitrile (10 volumes). The temperature was maintained between 0°C and 5°C.

[0271] Step 4: Boronation

[0272] [ka]

[0273] (1'R,2'R,4'S)-4'-(benzoyloxy)-5'-methyl-2'-(prop-1-en-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diylbis(2,2-dimethylpropanoate) was reacted with bis(pinacolato)diboron (2.0 equiv.), palladium(II) acetate (0.05 equiv.), potassium acetate (3.0 equiv.), and dppf (0.1 equiv.) in acetonitrile (10 volumes). The temperature was maintained between 80°C and 85°C.

[0274] Step 5: Bromination

[0275] [ka]

[0276] (1'R,2'R,4'S)-4'-(benzoyloxy)-5'-methyl-2'-(prop-1-en-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diylbis(2,2-dimethylpropanoate) was reacted with copper(II) bromide (1.0 equiv.) in butanol (10 equiv.) and water (5 equiv.) in air. The temperature was maintained between 80°C and 85°C.

[0277] Paragraph 6: Deprotection

[0278] [ka]

[0279] (1'R,2'R,4'S)-4'-(benzoyloxy)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diylbis(2,2-dimethylpropanoate) was reacted with methylmagnesium bromide (10.0 equiv.) in THF (10 vol.). The reaction mixture was heated from 0°C to 50°C.

[0280] Synthesis of 6-benzolyloxomethanedienol Stage 1: Reduction

[0281] [ka]

[0282] S-Carvone was reacted with sodium borohydride and cerium(III) chloride heptahydrate in methanol. The temperature was maintained at -20°C.

[0283] Step 2: Epoxidation

[0284] [ka]

[0285] (1S,5S)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-ol ((+)-cis-carveol) was reacted with m-CPBA in dichloromethane. The temperature was maintained at -20°C.

[0286] Paragraph 3: Selenation

[0287] [ka]

[0288] (1S,2S,4R,6R)-1-Methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptan-2-ol was reacted with diphenyl diselenide, sodium borohydride, and sodium hydroxide in tetrahydrofuran. The temperature was maintained at 20°C.

[0289] Phase 4: Protection

[0290] [ka]

[0291] (1S,2S,4R,6S)-1-Methyl-6-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexane-1,2-diol was reacted with benzoyl chloride and DMAP in 2-methyltetrahydrofuran. The temperature was maintained at 20°C.

[0292] Step 5: Allylic oxidation

[0293] [ka]

[0294] (1S,2S,3S,5R)-2-hydroxy-2-methyl-3-(phenylselanyl)-5-(prop-1-en-2-yl)cyclohexyl benzoate was reacted with hydrogen peroxide in 2-methyltetrahydrofuran. The temperature was maintained at 0° C. The temperature was increased to 55° C.

[0295] (Example 1-2) Alternative synthetic methods for the preparation of novel compounds Synthesis of intermediates Intermediate 1: 5-(2-methoxyethyl)benzene-1,3-diol

[0296] [ka]

[0297] 2-(3,5-dibenzyloxyphenyl)ethanol Benzyl 2-(3,5-dibenzyloxyphenyl)acetate (12.3 g, 28.0 mmol) in tetrahydrofuran (178 mL) under nitrogen atmosphere was cooled in an ice / water bath and treated dropwise with 1 M lithium aluminum hydride (56 mL, 56.1 mmol). The reaction mixture was allowed to warm to room temperature overnight and then cooled in an ice / water bath. The reaction was diluted with diethyl ether and quenched by the dropwise addition of 2.1 mL water, 2.1 mL 15% aqueous sodium hydroxide, and 6.3 mL water. The mixture was allowed to warm to room temperature and stirred for 15 minutes. Magnesium sulfate was added and the reaction mixture was stirred for a further 15 minutes. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% diethyl ether in cyclohexane to give the title compound (5.44 g, 58%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 7.47 - 7.32 (m, 10H), 6.52 - 6.49 (m, 3H), 5.06 (s, 4H), 4.63 (t, J=5.3 Hz, 1H), 3.62 - 3.56 (m, 2H), 2.66 (dd, J=7.2, 7.2 Hz, 2H).

[0298] 1,3-Dibenzyloxy-5-(2-methoxyethyl)benzene A suspension of sodium hydride (60% dispersion in mineral oil, 1.30 g, 32.5 mmol) in N,N-dimethylformamide (80 mL) was cooled in an ice / water bath under a nitrogen atmosphere and treated with a solution of 2-(3,5-dibenzyloxyphenyl)ethanol (5.44 g, 16.3 mmol) in N,N-dimethylformamide (20 mL) followed by the addition of iodomethane (2.0 mL, 32.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 h, then quenched with saturated aqueous ammonium chloride solution (30 mL) and partitioned between water (40 mL) and diethyl ether (100 mL). The aqueous layer was extracted with diethyl ether (2 x 50 mL) and the combined organic layers were washed with water (50 mL) and dried (MgSO 4), and concentrated in vacuo to give the title compound (5.88 g, quantitative crude yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 7.46 - 7.32 (m, 10H), 6.54 - 6.50 (m, 3H), 5.07 (s, 4H), 3.52 (t, J=6.9 Hz, 2H), 3.24 (s, 3H), 2.74 (t, J=7.0 Hz, 2H).

[0299] 5-(2-Methoxyethyl)benzene-1,3-diol A solution of 1,3-dibenzyloxy-5-(2-methoxyethyl)benzene (5.80 g, 16.6 mmol) and 1-methyl-1,4-cyclohexadiene (15 mL, 0.133 mol) in ethanol (100 mL) was treated with 10% palladium on carbon (1.8 g), heated to 75° C. and stirred for 3 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (2.98 g, NMR indicates the presence of ethyl acetate, 88% yield taking into account the ethyl acetate content). 1 H NMR (400 MHz, DMSO) δ 9.06 (s, 2H), 6.07 (d, J=2.2 Hz, 2H), 6.05 (t, J=2.2 Hz, 1H), 4.04 (q, J=7.1 Hz, 1H), 3.46 (t, J=7.0 Hz, 2H), 3.24 (s, 3H), 2.61 (t, J=6.9 Hz, 2H).

[0300] Intermediate 2: 4-Methyl-5-propylbenzene-1,3-diol

[0301] [ka]

[0302] 2-Bromo-1,5-dimethoxy-3-propylbenzene 1,3-Dimethoxy-5-propylbenzene (2.50 g, 13.9 mmol) in dichloromethane (30 mL) was cooled in an ice / water bath and treated with N-bromosuccinimide (2.47 g, 13.9 mmol). The reaction mixture was stirred for 2 h, then diluted with ethyl acetate (100 mL) and washed with half-saturated sodium thiosulfate solution (100 mL), 2 M aqueous sodium hydroxide solution (100 mL), and water (100 mL). The organic layer was dried (hydrophobic filter paper) and concentrated in vacuo to give the title compound (3.75 g, quantitative crude yield) as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 6.40 (d, J=2.9 Hz, 1H), 6.35 (d, J=2.8 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.73 - 2.68 (m, 2H), 1.69 - 1.59 (m, 2H), 0.98 (t, J=7.3Hz, 3H).

[0303] 1,5-Dimethoxy-2-methyl-3-propylbenzene 2-Bromo-1,5-dimethoxy-3-propylbenzene (3.46 g, 13.4 mmol) in tetrahydrofuran (100 mL) was cooled in a dry ice-acetone bath and treated with 2.5 M n-butyllithium solution (12 mL, 29.4 mmol) in portions over 10 minutes. The reaction mixture was stirred for 15 minutes, then treated with iodomethane (2.5 mL, 40.1 mmol) and allowed to warm to room temperature overnight. The reaction was quenched with saturated ammonium chloride solution (10 mL) and treated with 7 M ammonia in methanol (5 ml). The mixture was stirred for 2 hours, diluted with ethyl acetate (250 mL), washed with water (2×250 mL), dried (hydrophobic filter paper), and concentrated in vacuo. The crude product was combined with the crude product of a test reaction run on a 250 mg scale under the same conditions and purified by column chromatography on silica eluting with 0-60% dichloromethane in cyclohexane to give the title compound (2.42 g, 100%) as a colourless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.32 (s, 2H), 3.79 (s, 3H), 3.79 (s, 3H), 2.58 - 2.52 (m, 2H), 2.09 (s, 3H), 1.61 - 1.54 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

[0304] 4-Methyl-5-propylbenzene-1,3-diol 1,5-Dimethoxy-2-methyl-3-propylbenzene (2.4 g, 12.5 mmol) in dichloromethane (75 mL) was cooled in an ice / water bath and treated with 1 M boron tribromide (31 mL, 31.4 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was quenched with methanol (10 mL) and saturated aqueous sodium bicarbonate (10 mL) and diluted with dichloromethane (75 mL). The two phases were separated and the organic phase was washed with half-saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried (hydrophobic filter paper) and concentrated in vacuo to give a brown gum (1.73 g, 83%). 1 H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.76 (s, 1H), 6.14 (d, J=2.4 Hz, 1H), 6.03 (d, J=2.1 Hz, 1H), 2.42 - 2.37 (m, 2H), 1.94 (s, 3H), 1.52 - 1.42 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

[0305] General Method A General Method A is illustrated by the synthesis of intermediate 3: (1'R,2'R)-4-(methoxymethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol

[0306] [ka]

[0307] A solution of 5-(methoxymethyl)benzene-1,3-diol (2.68 g, 17.4 mmol) and p-toluenesulfonic acid monohydrate (248 mg, 1.30 mmol) in tetrahydrofuran (10 mL) and dichloromethane (120 mL) was cooled to 4° C. in an ice / water bath. (4R)-4-Isopropenyl-1-methyl-cyclohex-2-en-1-ol (2.60 mL, 16.0 mmol) was added dropwise over 60 min. The reaction mixture was stirred for a further 2 h and then quenched with a solution of sodium bicarbonate (450 mg) in water (50 mL). The layers were separated, the aqueous layer extracted with dichloromethane (50 mL) and the combined organic layers dried (hydrophobic frit paper) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% diethyl ether in cyclohexane to give the title compound (1.08g, 23%) as a brown oil. 1H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 6.20 (s, 2H), 5.14 (s, 1H), 4.55 - 4.52 (m, 1H), 4.46 (s, 1H), 4.21 (s, 2H), 3.94 - 3.87 (m, 1H), 3.28 (s, 3H), 3.14 - 3.06 (m, 1H), 2.20 - 2.11 (m, 1H), 2.02 - 1.94 (m, 1H), 1.78 - 1.67 (m, 2H), 1.66 (s, 3H), 1.64 (s, 3H).

[0308] General Method A using the appropriate resorcinol was used to produce the following compounds:

[0309] Intermediate 4: (1'R,2'R)-4-Bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 2H), 6.38 (s, 2H), 5.08 (s, 1H), 4.49 (d, J=2.8 Hz, 1H), 4.44 (dd, J=1.6, 2.8 Hz, 1H), 3.86 - 3.83 (m, 1H), 3.06 - 2.98 (m, 1H), 2.12 - 2.07 (m, 1H), 1.96 - 1.92 (m, 1H), 1.63 - 1.59 (m, 8H).

[0310] Intermediate 5: (1'R,2'R)-4-(2-methoxyethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1H NMR (400 MHz, DMSO) δ 8.73 (s, 2H), 6.06 (s, 2H), 5.09 (s, 1H), 4.51 (d, J=2.8 Hz, 1H), 4.44 - 4.41 (m, 1H), 3.87 - 3.83 (m, 1H), 3.45 (t, J=6.9 Hz, 2H), 3.24 (s, 3H), 3.09 - 3.01 (m, 1H), 2.56 (t, J=6.8 Hz, 2H), 2.16 - 2.06 (m, 1H), 1.97 - 1.89 (m, 1H), 1.69 - 1.63 (m, 2H), 1.62 (s, 3H), 1.61 (s, 3H).

[0311] Intermediate 6: (1'R,2'R)-3,5'-dimethyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1 H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 7.27 (s, 1H), 6.09 (s, 1H), 5.15 (s, 1H), 4.48 (d, J=2.2 Hz, 1H), 4.42 (dd, J=1.4, 2.7 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.03 - 2.94 (m, 1H), 2.39 - 2.32 (m, 2H), 2.16 - 2.09 (m, 1H), 2.00 - 1.92 (m, 1H), 1.96 (s, 3H), 1.73 - 1.66 (m, 2H), 1.64 (s, 3H), 1.60 (s, 3H), 1.51 - 1.40 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

[0312] Intermediate 7: (1'R,2'R)-4-Bromo-3,5,5'-trimethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.71 (s, 1H), 5.18 (s, 1H), 4.47 (d, J=2.5 Hz, 1H), 4.43 (dd, J=1.4, 2.5 Hz, 1H), 4.03 - 3.99 (m, 1H), 3.01 (dt, J=3.3, 11.0 Hz, 1H), 2.18 (s, 6H), 2.16 - 2.11 (m, 1H), 2.04 - 1.96 (m, 1H), 1.75 - 1.67 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H).

[0313] General Method B General Method B is illustrated by the preparation of intermediate 6: (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol

[0314] [ka]

[0315] [3-Acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]acetate 5-Bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (1305 mg, 4.04 mmol) in acetonitrile (30 mL) was treated with cesium carbonate (3289 mg, 10.1 mmol) followed by acetic anhydride (0.95 mL, 10.1 mmol). The reaction mixture was stirred for 1 h and then partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, the aqueous layer extracted with ethyl acetate (100 mL) and the combined organic phases dried (hydrophobic filter paper) and concentrated in vacuo to give the title compound (1.60 g, 93.4%) as an orange gum. 1H NMR (400 MHz, DMSO) δ 7.33 (s, 2H), 4.98 (s, 1H), 4.55 - 4.52 (m, 1H), 4.43 (d, J=1.5 Hz, 1H), 3.59 - 3.52 (m, 1H), 2.70 - 2.61 (m, 1H), 2.26 - 2.25 (m, 7H), 2.03 (d, J=16.9 Hz, 1H), 1.79 - 1.72 (m, 2H), 1.67 (s, 3H), 1.62 (s, 3H).

[0316] [3-Acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl]phenyl]acetate [3-Acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]phenyl]acetate (1560 mg, 3.83 mmol) and molecular sieves (3 Å, 5 g) in ethyl acetate (31.92 mL) were treated with manganese(III) acetate dihydrate (103 mg, 0.383 mmol) followed by a 5.5 M solution of tert-butyl hydroperoxide in nonane (3.5 mL, 19.2 mmol). The reaction mixture was stirred overnight at 20° C., then diluted with ethyl acetate (50 mL) and filtered through a pad of Celite. The filtrate was washed with saturated aqueous sodium thiosulfate (30 mL) and water (30 mL), separated and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% diethyl ether in cyclohexane to give the title compound (561 mg, 34.8%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 7.39 (s, 2H), 6.38 (t, J=1.8 Hz, 1H), 4.56 (s, 1H), 4.50 (s, 1H), 4.04 (td, J=2.3, 10.6 Hz, 1H), 3.20 - 3.11 (m, 1H), 2.85 - 2.76 (m, 1H), 2.35 - 2.19 (m, 7H), 1.71 (dd, J=1.5, 2.5 Hz, 3H), 1.62 (s, 3H).

[0317] (1'R,2'R,4'S)-4-Bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol To a solution of [3-acetoxy-5-bromo-2-[(1R,6R)-6-isopropenyl-3-methyl-4-oxo-cyclohex-2-en-1-yl]phenyl]acetate (1.10 g, 2.61 mmol) in methyl alcohol (25.0 mL) at 0° C., sodium borohydride (0.22 g, 5.74 mmol) was added in four equal portions over a period of 30 minutes and the mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (75 mL) and water (75 mL). The layers were separated and the organic phase was washed with brine (50 mL) and dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-80% ethyl acetate in cyclohexane to give the title compound (508 mg, 57.4%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 9.32 (s, 1H), 6.43 - 6.36 (m, 2H), 5.07 - 5.05 (m, 1H), 4.62 (d, J=6.7 Hz, 1H), 4.49 - 4.44 (m, 2H), 4.12 - 4.06 (m, 1H), 3.88 - 3.84 (m, 1H), 3.20 - 3.12 (m, 1H), 1.90 (ddd, J=2.4, 5.7, 12.0 Hz, 1H), 1.66 - 1.63 (m, 3H), 1.63 - 1.55 (m, 4H).

[0318] General Method C General Method C is illustrated by the synthesis of intermediate 7: (1'R,2'R,4'S)-2,4',6-trihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate

[0319] [ka]

[0320] (1'R,2'R)-5'-Methyl-2'-(prop-1-en-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate A solution of (1'R,2'R)-2,6-dihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (10.0 g, 25.5 mmol) in acetonitrile (200 mL) was treated with cesium carbonate (20.76 g, 63.7 mmol) and acetic anhydride (6.0 mL, 63.7 mmol). The reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with ethyl acetate (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried (phase separator paper) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-10% ethyl acetate in cyclohexane to give the title compound (8.08 g, 67%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.91 (s, 2H), 5.16 (s, 1H), 4.55 (s, 1H), 4.41 (s, 1H), 3.61 - 3.56 (m, 1H), 2.67 - 2.59 (m, 1H), 2.20 (s, 6H), 2.15 - 2.01 (m, 2H), 1.85 - 1.70 (m, 2H), 1.68 (s, 3H), 1.57 (s, 3H).

[0321] (1'R,2'R)-5'-Methyl-4'-oxo-2'-(prop-1-en-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate A solution of (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate (4.0 g, 8.40 mmol) in ethyl acetate (80 mL) was treated with 3 Å molecular sieves (4 g) followed by manganese(III) acetate dihydrate (270 mg, 1.01 mmol) and tert-butyl hydroperoxide (5.5 M solution in nonane, 8.5 mL, 47.0 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a pad of Celite, washed with ethyl acetate (80 mL) and the organic layer was washed with saturated sodium thiosulfate solution (50 mL) and brine (50 mL), dried (phase separator paper) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 10-25% ethyl acetate in cyclohexane to give the title compound (1.26g, 30%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.99 (s, 2H), 6.51 - 6.48 (m, 1H), 4.66 - 4.63 (m, 1H), 4.52 (s, 1H), 3.95 - 3.90 (m, 1H), 3.25 - 3.16 (m, 1H), 2.65 - 2.53 (m, 2H), 2.24 (s, 6H), 1.83 - 1.80 (m, 3H), 1.61 (s, 3H).

[0322] (1'R,2'R,4'S)-2,4',6-trihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate A solution of (1'R,2'R)-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate (1.26 g, 2.57 mmol) in methanol (20 mL) cooled to 0° C. was treated with sodium borohydride (243 mg, 6.42 mmol) in several portions. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate solution (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the organic layers were combined, washed with brine (50 mL), dried (Phase separator paper) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 10-40% ethyl acetate in cyclohexane to give the title compound (0.5g, 48%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.74 (s, 1H), 6.29 (s, 2H), 5.13 - 5.10 (m, 1H), 4.66 (d, J=6.8 Hz, 1H), 4.51 - 4.49 (m, 2H), 4.19 - 4.11 (m, 1H), 3.97 - 3.92 (m, 1H), 3.24 - 3.16 (m, 1H), 1.95 (ddd, J=2.4, 5.7, 12.0 Hz, 1H), 1.70 (s, 3H), 1.64 (s, 3H), 1.63 - 1.57 (m, 1H).

[0323] Synthesis of the final compound General Method D General method D is illustrated by the synthesis of (1'R,2'R,4'S)-4-(5-methoxypyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol compound 20:

[0324] [ka]

[0325] 5-Bromo-2-[(1R,4S,6R)-4-hydroxy-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]benzene-1,3-diol (70 mg, 0.206 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (73 mg, 0.310 mmol), and cesium fluoride (94 mg, 0.619 mmol) in 1,4-dioxane (2.0 mL) and water (0.50 mL) were degassed with nitrogen and treated with [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (7.7 mg, 0.0103 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with dichloromethane (2×20 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 20-80% ethyl acetate in cyclohexane and freeze-dried from acetonitrile / water to give the title compound (35.2 mg, 46%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 9.11 (s, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.25 (d, J=2.8 Hz, 1H), 7.39 (dd, J=1.9, 2.7 Hz, 1H), 6.50 (s, 2H), 5.11 (q, J=1.7 Hz, 1H), 4.62 (d, J=6.5 Hz, 1H), 4.55 (d, J=2.5 Hz, 1H), 4.46 (q, J=1.4 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.00 - 3.93 (m, 1H), 3.89 (s, 3H), 3.31 - 3.23 (m, 1H), 1.93 (ddd, J=2.2, 5.6, 12.1 Hz, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.63 - 1.55 (m, 1H). MS (ESI): m / z 368 (M+1). HPLC purity: 99.7%.

[0326] General method D using the appropriate boronic acid or boronic ester was used to generate the following compounds.

[0327] (1'R,2'R,4'S)-4-(2-methoxypyrimidin-5-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 21) 1 H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 9.14 (s, 1H), 8.70 (s, 2H), 6.44 (s, 2H), 5.12 - 5.09 (m, 1H), 4.62 (d, J=6.2 Hz, 1H), 4.54 (d, J=2.7 Hz, 1H), 4.45 (q, J=1.4 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.00 - 3.94 (m, 4H), 3.30 - 3.22 (m, 1H), 1.93 (ddd, J=2.4, 5.8, 12.1 Hz, 1H), 1.66 (s, 3H), 1.64 (s, 3H), 1.62 - 1.55 (m, 1H). MS (ESI): m / z 369 (M+1). HPLC purity: 99.3%.

[0328] (1'R,2'R,4'S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 11) 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.80 (s, 1H), 7.64 (s, 1H), 6.29 (s, 2H), 5.12 - 5.09 (m, 1H), 4.59 (d, J=6.6 Hz, 1H), 4.54 (d, J=2.4 Hz, 1H), 4.45 (q, J=1.4 Hz, 1H), 4.15 - 4.09 (m, 1H), 3.94 - 3.88 (m, 1H), 3.77 (s, 3H), 3.28 - 3.19 (m, 1H), 2.25 (s, 3H), 1.92 (ddd, J=2.3, 5.6, 11.9 Hz, 1H), 1.66 (s, 3H), 1.63 (s, 3H), 1.61 - 1.54 (m, 1H). MS (ESI): m / z 355 (M+1). HPLC purity: 95%.

[0329] (1'R,2'R,4'S)-4-(2-methoxypyridin-4-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 16) 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 9.16 (s, 1H), 8.19 (dd, J=0.6, 5.4 Hz, 1H), 7.07 (dd, J=1.5, 5.4 Hz, 1H), 6.82 (dd, J=0.7, 1.6 Hz, 1H), 6.54 (s, 2H), 5.12 - 5.09 (m, 1H), 4.62 (d, J=6.5 Hz, 1H), 4.53 (d, J=2.5 Hz, 1H), 4.45 (q, J=1.5 Hz, 1H), 4.17 - 4.10 (m, 1H), 3.98 - 3.94 (m, 1H), 3.89 MS (ESI): m / z 368 (M+1). HPLC purity: 99.2%.

[0330] (1R,2R,4S)-3''-Methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (Compound 15) 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 9.03 (s, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.02 (t, J=2.0 Hz, 1H), 6.93 (ddd, J=0.8, 2.5, 8.3 Hz, 1H), 6.52 (s, 2H), 5.15 (q, J=1.6 Hz, 1H), 4.64 (d, J=6.6 Hz, 1H), 4.59 (d, J=2.4 Hz, 1H), 4.51 - 4.48 (m, 1H), 4.21 - 4.12 (m, 1H), 4.03 - 3.96 (m, 1H), 3.84 (s, 3H), 3.35 - 3.26 (m, 1H), 1.97 (ddd, J=2.3, 5.6, 11.9 Hz, 1H), 1.70 (s, 3H), 1.68 (s, 3H), 1.67 - 1.58 (m, 1H). MS (ESI): m / z 367 (M+1). HPLC purity: 97.3%.

[0331] (1'R,2'R,4'S)-4-(6-methoxypyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 17) 1H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 9.07 (s, 1H), 8.31 (dd, J=0.6, 2.6 Hz, 1H), 7.82 (dd, J=2.5, 8.6 Hz, 1H), 6.92 (dd, J=0.7, 8.6 Hz, 1H), 6.47 (s, 2H), 5.16 - 5.14 (m, 1H), 4.64 (d, J=6.6 Hz, 1H), 4.58 (d, J=2.6 Hz, 1H), 4.49 (q, J=1.3 Hz, 1H), 4.21 - 4.14 (m, 1H), 4.01 - 3.98 (m, 1H), 3.93 MS (ESI): m / z 368 (M+1). HPLC purity: 98.9%.

[0332] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-(pyridin-3-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 22) 1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 9.12 (s, 1H), 8.68 (dd, J=0.9, 2.4 Hz, 1H), 8.53 (dd, J=1.6, 4.7 Hz, 1H), 7.85 (ddd, J=1.7, 2.4, 8.0 Hz, 1H), 7.45 (dd, J=4.8, 8.3 Hz, 1H), 6.49 (s, 2H), 5.13 - 5.11 (m, 1H), 4.62 (d, J=6.5 Hz, 1H), 4.55 (d, J=2.5 Hz, 1H), 4.46 (s, 1H), 4.14 - 4.11 (m, 1H), MS (ESI): m / z 338 (M+1). HPLC purity: 99.1%.

[0333] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 23) 1H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 9.25 (s, 1H), 8.88 (d, J=2.1 Hz, 1H), 8.13 (dd, J=1.9, 8.2 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 6.54 (s, 2H), 5.13 - 5.11 (m, 1H), 4.63 (d, J=6.5 Hz, 1H), 4.55 (d, J=2.5 Hz, 1H), 4.46 (q, J=1.3 Hz, 1H), 4.17 - 4.11 (m, 1H), 4.06 - 3.97 (m, 1H), 3.32 - 3.23 (m, MS (ESI): m / z 406 (M+1). HPLC purity: 98.5%.

[0334] (1'R,2'R,4'S)-4-(5-chloropyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 24) 11H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 9.18 (s, 1H), 8.64 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H), 7.95 (t, J = 2.1 Hz, 1H), 6.49 (s, 2H), 5.11 (d, J = 1.5 Hz, 1H), 4.63 (d, J = 6.7 Hz, 1H), 4.54 (d, J = 2.5 Hz, 1H), 4.47 - 4.44 (m, 1H), 4.16 - 4.10 (m, 1H), 3.99 - 3.95 (m, 1H), 3.32 - 3.23 (m, 1H), 1.94 (ddd, J = 2.3, 5.5, 12.0 Hz, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.62 - 1.56 (m, 1H). MS (ESI): m / z 372 (M+1). HPLC purity: 96.2%.

[0335] (1'R,2'R,4'S)-5'-Methyl-4-(2-methylthiazol-5-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 13) 1 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 9.14 (s, 1H), 7.70 (s, 1H), 6.43 (s, 2H), 5.10 - 5.08 (m, 1H), 4.62 (d, J = 6.7 Hz, 1H), 4.51 (d, J = 2.6 Hz, 1H), 4.44 (q, J = 1.4 Hz, 1H), 4.14 - 4.09 (m, 1H), 3.94 - 3.90 (m, 1H), 3.30 - 3.19 (m, 1H), 2.65 (s, 3H), 1.91 (ddd, J = 2.3, 5.7, 12.1 Hz, 1H), 1.65 (s, 3H), 1.62 (s, 3H), 1.61 - 1.54 (m, 1H). MS (ESI): m / z 358 (M+1). HPLC purity: 93.9%.

[0336] (1'R,2'R,4'S)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 43) 1 H NMR (400 MHz, DMSO) δ 9.29 - 9.25 (m, 1H), 9.11 - 9.07 (m, 1H), 7.48 - 7.43 (m, 2H), 7.30 - 7.26 (m, 1H), 6.43 - 6.42 (m, 2H), 5.11 (d, J=1.5 Hz, 1H), 4.62 (d, J=6.5 Hz, 1H), 4.54 (d, J=2.6 Hz, 1H), 4.47 - 4.45 (m, 1H), 4.13 (d, J=5.6 Hz, 1H), 3.97 - 3.92 (m, 1H), 3.30 - 3.22 (m, 1H), 1.96 - 1.89 (m, 1H), 1.67 - 1.63 (m, 6H), 1.63 - 1.55 (m, 1H). MS (ESI): m / z 417 (M+1). HPLC purity: 96.3%.

[0337] (1'R,2'R,4'S)-5'-Methyl-4-(2-methylpyridin-4-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 28) 1H NMR (400 MHz, DMSO) δ 9.37 - 9.36 (m, 1H), 9.14 - 9.12 (m, 1H), 8.45 (d, J=5.3 Hz, 1H), 7.32 (s, 1H), 7.25 (dd, J=1.4, 5.2 Hz, 1H), 6.56 (s, 2H), 5.11 (d, J=1.5 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.53 (d, J=2.6 Hz, 1H), 4.45 (dd, J=1.4, 2.5 Hz, 1H), 4.13 (d, J=4.4 Hz, 1H), 3.99 - 3.95 (m, 1H), 3.29 - 3.22 (m, 1H), 2.53 (s, 3H), 1.96 - 1.90 (m, 1H), 1.68 - 1.63 (m, 6H), 1.62 - 1.55 (m, 1H). MS (ESI): m / z 352 (M+1). HPLC purity: 98.4%.

[0338] (1R,2R,4S)-2''-Methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (Compound 29) 11H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.88 - 8.79 (m, 1H), 7.35 - 7.30 (m, 1H), 7.22 (dd, J=1.8, 7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.41 - 6.39 (m, 2H), 5.16 (d, J=1.5 Hz, 1H), 4.65 - 4.62 (m, 2H), 4.53 - 4.51 (m, 1H), 4.18 - 4.14 (m, 1H), 4.02 - 3.97 (m, 1H), 3.80 (s, 3H), 3.35 - 3.29 (m, 1H), 2.05 - 1.94 (m, 1H), 1.70 - 1.69 (m, 6H), 1.66 - 1.58 (m, 1H). MS (ESI):m / z 367 (M+1). HPLC purity: 99.5%.

[0339] (1R,2R,4S)-4''-Fluoro-3''-methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (Compound 30) 1 1H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 9.07 - 8.98 (m, 1H), 7.32 - 7.21 (m, 2H), 7.04 (ddd, J=1.8, 4.1, 8.4 Hz, 1H), 6.53 - 6.49 (m, 2H), 5.15 (s, 1H), 4.66 - 4.57 (m, 2H), 4.49 (s, 1H), 4.16 (d, J=5.3 Hz, 1H), 4.00 - 3.96 (m, 1H), 3.95 - 3.93 (m, 3H), 3.34 - 3.26 (m, 1H), 1.99 - 1.95 (m, 1H), 1.72 - 1.67 (m, 6H), 1.66 - 1.59 (m, 1H). MS (ESI):m / z 385 (M+1). HPLC purity: 97.4%.

[0340] (1R,2R,4S)-3''-(difluoromethoxy)-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (compound 31) 1 H NMR (400 MHz, DMSO) δ 9.36 - 9.28 (m, 1H), 9.14 - 9.09 (m, 1H), 7.55 - 7.15 (m, 5H), 6.58 - 6.53 (m, 2H), 5.17 - 5.14 (m, 1H), 4.65 (d, J=6.6 Hz, 1H), 4.58 (s, 1H), 4.49 (s, 1H), 4.19 - 4.14 (m, 1H), 4.01 - 3.98 (m, 1H), 3.34 - 3.27 (m, 1H), 1.98 ( dd, J=5.8, 9.9 Hz, 1H), 1.72 - 1.67 (m, 6H), 1.67 - 1.59 (m, 1H). MS (ESI): m / z 403 (M+1). HPLC purity: 95.1%.

[0341] (1R,2R,4S)-3''-(aminomethyl)-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (compound 32) 11H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 8.87 (t, J=12.8 Hz, 1H), 7.36 - 7.28 (m, 3H), 7.15 - 7.13 (m, 1H), 6.46 - 6.39 (m, 2H), 5.05 (d, J=1.3 Hz, 1H), 4.54 - 4.45 (m, 2H), 4.37 (d, J=1.3 Hz, 1H), 4.09 - 4.01 (m, 1H), 3.90 - 3.86 (m, 1H), 3.36 (s, 2H), 3.24 - 3.15 (m, 1H), 2.11 - 2.09 (m, 6H), 1.88 - 1.78 (m, 1H), 1.60 - 1.55 (m, 6H), 1.55 - 1.48 (m, 1H). MS (ESI):m / z 394 (M+1). HPLC purity: 92.7%.

[0342] (1R,2R,4S)-4''-Methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (Compound 33) 1 1H NMR (400 MHz, DMSO) δ 9.26 - 9.19 (m, 1H), 9.05 - 8.99 (m, 1H), 7.51 - 7.48 (m, 2H), 7.10 - 7.07 (m, 2H), 6.52 - 6.51 (m, 2H), 5.22 - 5.20 (m, 1H), 4.71 - 4.63 (m, 2H), 4.55 - 4.54 (m, 1H), 4.25 - 4.18 (m, 1H), 4.05 - 4.02 (m, 1H), 3.89 - 3.88 (m, 3H), 3.39 - 3.32 (m, 1H), 2.06 - 1.99 (m, 1H), 1.77 - 1.73 (m, 6H), 1.71 - 1.64 (m, 1H). MS (ESI):m / z 367 (M+1). HPLC purity: 94.8%.

[0343] (1R,2R,4S)-5-Methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (Compound 14) 1 H NMR (400 MHz, DMSO) δ 9.29 - 9.20 (m, 1H), 9.03 (s, 1H), 7.53 - 7.44 (m, 4H), 7.38 - 7.33 (m, 1H), 6.53 - 6.51 (m, 2H), 5.16 (d, J=1.5 Hz, 1H), 4.66 - 4.58 (m, 2H), 4.51 - 4.49 (m, 1H), 4.19 - 4.13 (m, 1H), 4.01 - 3.96 (m, 1H), 3.34 - 3.27 (m, 1H), 2.00 - 1.94 (m, 1H), 1.72 - 1.68 (m, 6H), 1.67 - 1.59 (m, 1H). MS (ESI): m / z 337 (M+1). HPLC purity: 99.2%.

[0344] (1'R,2'R,4'S)-4-(6-ethoxypyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 34) 1H NMR (400 MHz, DMSO) δ 9.31 - 9.20 (m, 1H), 9.07 - 8.98 (m, 1H), 8.24 (d, J=2.5 Hz, 1H), 7.76 (dd, J=2.5, 8.7 Hz, 1H), 6.86 - 6.83 (m, 1H), 6.43 - 6.40 (m, 2H), 5.11 (s, 1H), 4.61 (d, J=6.5 Hz, 1H), 4.54 (s, 1H), 4.45 (s, 1H), 4.33 (q, J=7.0 Hz, 2H), 4.15 - 4.11 (m, 1H), 3.96 - 3.93 (m, 1H), 3.30 - 3.26 (m, 1H), 1.95 - 1.90 (m, 1H), 1.68 - 1.63 (m, 6H), 1.62 - 1.55 (m, 1H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m / z 382 (M+1). HPLC purity: 93.3%.

[0345] (1'R,2'R,4'S)-4-(2-methoxypyridin-4-yl)-3,5,5'-trimethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 52) 1H NMR (400 MHz, DMSO) δ 8.20 (dd, J=0.6, 5.2 Hz, 1H), 7.89 (s, 1H), 7.51 (s, 1H), 6.73 - 6.67 (m, 1H), 6.50 (s, 1H), 5.18 (s, 1H), 4.57 (s, 1H), 4.48 (dd, J=1.4, 2.5 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.89 (s, 3H), 3.31 (t, J=11.7 Hz, 1H), 1.95 (ddd, J=2.3, 5.3, 11.9 Hz, 1H), 1.74 (s, 3H), 1.71 (s, 3H), 1.69 (s, 3H), 1.65 (s, 3H), 1.67 - 1.61 (m, 1H). (OH not observed) MS (ESI): m / z 396 (M+1). HPLC purity: 99%.

[0346] General Method E General method E is illustrated by the synthesis of (1'R,2'R,4'S)-5'-methyl-2'-(prop-1-en-2-yl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 25):

[0347] [ka]

[0348] A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 9.79 μmol), (1'R,2'R,4'S)-2,4',6-trihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (80 mg, 0.196 mmol), sodium carbonate (83 mg, 0.784 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (59 mg, 0.215 mmol) in 1,4-dioxane (2.0 mL) and water (0.50 mL) was heated in a sealed tube at 100 °C for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), brine (10 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% ethyl acetate in cyclohexane followed by reverse phase preparative HPLC to give the title compound (35 mg, 44%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.21 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.94 - 8.92 (m, 1H), 8.18 (t, J=2.0 Hz, 1H), 6.59 - 6.55 (m, 2H), 5.13 - 5.10 (m, 1H), 4.64 (d, J=6.8 Hz, 1H), 4.54 (d, J=2.7 Hz, 1H), 4.46 (dd, J=1.4, 2.7 Hz, 1H), 4.17 - 4.09 (m, 1H), 4.01 - 3.96 (m, 1H), 3.31 - 3.23 (m, 1H), 1.94 (ddd, J=2.4, 5.7, 11.9 Hz, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.63 - 1.56 (m, 1H). MS (ESI): m / z 406.3 (M+1). HPLC purity: 98.6%.

[0349] General method E using the appropriate boronic acid or boronic ester was used to produce the following compounds:

[0350] (1'R,2'R,4'S)-4-(3,6-dihydro-2H-pyran-4-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 26) 1 H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.83 (s, 1H), 6.29 (s, 2H), 6.01 - 5.98 (m, 1H), 5.08 (q, J=1.5 Hz, 1H), 4.60 (d, J=6.8 Hz, 1H), 4.50 (d, J=2.4 Hz, 1H), 4.42 (q, J=1.4 Hz, 1H), 4.19 (q, J=2.7 Hz, 2H), 4.15 - 4.07 (m, 1H), 3.92 - 3.86 (m, 1H), 3.79 (t, J=5.4 Hz, 2H), 3.26 - 3.17 (m, 1H), 2.33 - 2.27 (m, 2H), 1.91 (ddd, J=2.3, 5.7, 12.1 Hz, 1H), 1.65 (s, 3H), 1.61 (s, 3H), 1.60 - 1.53 (m, 1H). MS (ESI): m / z 342.4 (M+1). HPLC purity: 94.4%.

[0351] General Method F General method F is illustrated by the synthesis of (1'R,2'R,4'S)-4-(3,5-dimethylisoxazol-4-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 12):

[0352] [ka]

[0353] (1'R,2'R,4'S)-4-Bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (100 mg, 0.295 mmol) was dissolved in dry N,N-dimethylformamide (1.70 mL) and water (0.30 mL). The mixture was degassed and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (92 mg, 0.413 mmol), cesium fluoride (90 mg, 0.590 mmol), and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.0295 mmol) were added. The mixture was heated at 95° C. overnight. The reaction was diluted with ethyl acetate (4 mL) and washed with water (2 mL) and brine (3 mL). The aqueous layer was further extracted with ethyl acetate (2 x 4 mL). The organic phases were combined, dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (12.0 mg, 10.7%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 9.01 (s, 1H), 6.21 (s, 2H), 5.13 - 5.10 (m, 1H), 4.61 (d, J=6.4 Hz, 1H), 4.55 (d, J=2.6 Hz, 1H), 4.46 (q, J=1.4 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.96 - 3.92 (m, 1H), 3.29 - 3.21 (m, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 1.93 (ddd, J=2.4, 5.7, 12.0 Hz, 1H), 1.66 (s, 3H), 1.64 (s, 3H), 1.62 - 1.54 (m, 1H). MS (ESI): m / z 355.4 (M+1). HPLC purity: 93.7%.

[0354] General method F using the appropriate boronic acid or boronic ester was used to generate the following compounds:

[0355] (1R,2R,4S)-4''-Fluoro-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (Compound 18) 1 H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 9.01 (s, 1H), 7.51 - 7.47 (m, 2H), 7.28 - 7.23 (m, 2H), 6.44 (s, 2H), 5.13 - 5.10 (m, 1H), 4.62 (d, J=6.7 Hz, 1H), 4.54 (d, J=2.6 Hz, 1H), 4.47 - 4.44 (m, 1H), 4.17 - 4.08 (m, 1H), 3.97 - 3.93 (m, 1H), 3.29 - 3.21 (m, 1H), 1.93 (ddd, J=2.3, 5.7, 11.9 Hz, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.62 - 1.55 (m, 1H). MS (ESI): m / z 355 (M+1). HPLC purity: 98.3%.

[0356] General Method G General method G is illustrated by the synthesis of (1'R,2'R,4'S)-4-(benzo[d][1,3]dioxol-5-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 41):

[0357] [ka]

[0358] A solution of (1'R,2'R,4'S)-2,4',6-trihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl trifluoromethanesulfonate (80 mg, 0.196 mmol) in 1,4-dioxane (4.0 mL) and water (1.0 mL) was treated with 3,4-(methylenedioxy)phenylboronic acid (49 mg, 0.294 mmol) and sodium carbonate (62 mg, 0.588 mmol), followed by SPhos Pd G2 (14 mg, 0.0196 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 1 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (5 mL), dried (phase separator paper) and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (24 mg, 32%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 9.22 - 9.17 (m, 1H), 8.94 (s, 1H), 6.98 - 6.93 (m, 3H), 6.39 - 6.37 (m, 2H), 6.05 (s, 2H), 5.11 (d, J=1.4 Hz, 1H), 4.62 - 4.53 (m, 2H), 4.47 - 4.45 (m, 1H), 4.15 - 4.08 (m, 1H), 3.95 - 3.91 (m, 1H), 3.29 - 3.22 (m, 1H), 1.95 - 1.89 (m, 1H), 1.67 - 1.63 (m, 6H), 1.62 - 1.55 (m, 1H). MS (ESI): m / z 381 (M+1). HPLC purity: 99.1%.

[0359] General method G using the appropriate boronic acid or boronic ester was used to generate the following compounds.

[0360] (1'R,2'R,4'S)-4-(6-(difluoromethoxy)pyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 19) 1 H NMR (400 MHz, DMSO) δ 9.36 - 9.32 (m, 1H), 9.13 (s, 1H), 8.35 - 8.35 (m, 1H), 7.99 (dd, J=2.7, 8.7 Hz, 1H), 7.74 (t, J=72.9 Hz, 1H), 7.17 - 7.14 (m, 1H), 6.47 - 6.44 (m, 2H), 5.11 (d, J=1.5 Hz, 1H), 4.63 - 4.61 (m, 1H), 4.55 (d, J=2.5 Hz, 1H), 4.46 (dd, J=1.4, 2.6 Hz, 1H), 4.13 (d, J=5.4 Hz, MS (ESI): m / z 404 (M+1). HPLC purity: 99%.

[0361] (1'R,2'R,4'S)-4-(benzo[d][1,3]dioxol-4-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 42) 11H NMR (400 MHz, DMSO) δ 9.24 - 9.18 (m, 1H), 9.00 (d, J=3.8 Hz, 1H), 7.00 - 6.90 (m, 3H), 6.64 (s, 2H), 6.09 (s, 2H), 5.16 (d, J=1.5 Hz, 1H), 4.65 - 4.57 (m, 2H), 4.49 (dd, J=1.4, 2.7 Hz, 1H), 4.17 - 4.13 (m, 1H), 4.02 - 3.96 (m, 1H), 3.34 - 3.26 (m, 1H), 2.00 - 1.94 (m, 1H), 1.71 - 1.67 (m, 6H), 1.66 - 1.59 (m, 1H). MS (ESI):m / z 381 (M+1). HPLC purity: 95.8%.

[0362] (1'R,2'R,4'S)-4-(2-Methoxypyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 35) 1 1H NMR (400 MHz, DMSO) δ 9.10 - 8.99 (m, 1H), 8.82 (s, 1H), 8.03 (dd, J=1.9, 4.9 Hz, 1H), 7.52 (dd, J=1.8, 7.3 Hz, 1H), 6.96 (dd, J=5.1, 7.3 Hz, 1H), 6.33 (bs, 2H), 5.02 (d, J=1.5 Hz, 1H), 4.52 - 4.47 (m, 2H), 4.39 - 4.38 (m, 1H), 4.07 - 4.00 (m, 1H), 3.89 - 3.84 (m, 1H), 3.79 (s, 3H), 3.22 - 3.15 (m, 1H), 1.88 - 1.80 (m, 1H), 1.58 - 1.55 (m, 6H), 1.53 - 1.46 (m, 1H). MS (ESI):m / z 368 (M+1). HPLC purity: 99.2%.

[0363] 1-(4-((1'R,2'R,4'S)-2,4',6-trihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (compound 36) 1 H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 8.91 - 8.83 (m, 1H), 6.32 - 6.28 (m, 2H), 5.97 (d, J=3.8 Hz, 1H), 5.12 (d, J=1.3 Hz, 1H), 4.62 (d, J=6.6 Hz, 1H), 4.53 (d, J=2.3 Hz, 1H), 4.46 (s, 1H), 4.18 - 4.07 (m, 3H), 3.95 - 3.90 (m, 1H), 3.68 - 3.60 (m, 2H), 3.29 - 3.21 (m, 1H), 2.45 (s, 1H), 2.35 - 2.31 (m, 1H), 2.09 (d, J=15.9 Hz, 3H), 1.98 - 1.91 (m, 1H), 1.70 - 1.64 (m, 6H), 1.64 - 1.57 (m, 1H). MS (ESI): m / z 384 (M+1). HPLC purity: 97.1%.

[0364] (1R,2R,4S)-3''-(2-methoxyethoxy)-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (compound 37) 1H NMR (400 MHz, DMSO) δ 9.21 - 9.16 (m, 1H), 9.01 - 8.98 (m, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.90 (dd, J=1.8, 8.2 Hz, 1H), 6.47 - 6.46 (m, 2H), 5.11 (d, J=1.5 Hz, 1H), 4.61 (d, J=6.7 Hz, 1H), 4.55 (d, J=2.5 Hz, 1H), 4.46 (d, J=1.3 Hz, 1H), 4.16 - 4.10 (m, 3H), 3.98 - 3.93 (m, MS (ESI): m / z 411 (M+1). HPLC purity: 97%.

[0365] (1'R,2'R,4'S)-5'-Methyl-4-((E)-prop-1-en-1-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 7) 1H NMR (400 MHz, DMSO) δ 8.99 - 8.93 (m, 1H), 8.76 (s, 1H), 6.21 - 6.11 (m, 3H), 5.97 (ddd, J=4.5, 11.1, 17.7 Hz, 1H), 5.08 (d, J=1.5 Hz, 1H), 4.59 (d, J=6.7 Hz, 1H), 4.49 (d, J=2.6 Hz, 1H), 4.42 (dd, J=1.4, 2.6 Hz, 1H), 4.09 (d, J=5.1 Hz, 1H), 3.91 - 3.85 (m, 1H), 3.24 - 3.15 (m, 1H), 1.91 - 1.83 (m, 1H), 1.82 - 1.79 (m, 3H), 1.64 (s, 3H), 1.60 (s, 3H), 1.57 - 1.52 (m, 1H). MS (ESI): m / z 301 (M+1). HPLC purity: 97.4%.

[0366] (1'R,2'R,4'S)-4-(cyclopent-1-en-1-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 9) 1 H NMR (400 MHz, DMSO) δ 8.99 - 8.94 (m, 1H), 8.76 (s, 1H), 6.35 - 6.27 (m, 2H), 5.97 (d, J=1.9 Hz, 1H), 5.08 (d, J=1.5 Hz, 1H), 4.60 - 4.57 (m, 1H), 4.50 - 4.47 (m, 1H), 4.43 - 4.41 (m, 1H), 4.10 (d, J=5.4 Hz, 1H), 3.90 - 3.87 (m, 1H), 3.25 - 3.16 (m, 1H), 2.48 - 2.41 (m, 2H), 1.97 - 1.88 (m, 3H), 1.66 - 1.59 (m, 9H). MS (ESI): m / z 327 (M+1). HPLC purity: 97.3%.

[0367] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-(6-(trifluoromethoxy)pyridin-3-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 38) 1 H NMR (400 MHz, DMSO) δ 9.47 - 9.42 (m, 1H), 9.26 - 9.18 (m, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.11 (dd, J=2.5, 8.6 Hz, 1H), 7.41 - 7.37 (m, 1H), 6.57 - 6.48 (m, 2H), 5.15 (d, J=1.5 Hz, 1H), 4.67 - 4.57 (m, 2H), 4.51 - 4.49 (m, 1H), 4.17 (dd, J=2.8, 5.1 Hz, 1H), 4.03 - 3.99 (m, 1H), 3.34 - 3.27 (m, 1H), 2.01 - 1.94 (m, 1H), 1.72 - 1.68 (m, 7H). MS (ESI): m / z 422 (M+1). HPLC purity: 97.8%.

[0368] (1'R,2'R,4'S)-4-(2-(difluoromethoxy)pyridin-4-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 39) 1H NMR (400 MHz, DMSO) δ 9.47 - 9.40 (m, 1H), 9.28 - 9.20 (m, 1H), 8.28 (d, J=5.4 Hz, 1H), 7.75 (t, J=73.1 Hz, 1H), 7.36 (dd, J=1.6, 5.4 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 6.59 - 6.53 (m, 2H), 5.11 (d, J=1.5 Hz, 1H), 4.64 - 4.62 (m, 1H), 4.53 (d, J=2.5 Hz, 1H), 4.45 (dd, J=1.4, 2.6 Hz, 1H), 4.14 - 4.10 (m, 1H), 4.00 - 3.96 (m, 1H), 3.30 - 3.22 (m, 1H), 1.97 - 1.90 (m, 1H), 1.68 - 1.63 (m, 7H). MS (ESI): m / z 404 (M+1). HPLC purity: 95.4%.

[0369] (1'R,2'R,4'S)-4-(2-(difluoromethoxy)pyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 40) 1 H NMR (400 MHz, DMSO) δ 9.32 - 9.26 (m, 1H), 9.10 - 9.06 (m, 1H), 8.23 ​​- 8.21 (m, 1H), 7.86 - 7.78 (m, 2H), 7.34 (dd, J=4.9, 7.5 Hz, 1H), 6.42 - 6.39 (m, 2H), 5.13 (d, J=1.5 Hz, 1H), 4.63 - 4.56 (m, 2H), 4.49 - 4.48 (m, 1H), 4.13 (d, J=5.5 Hz, 1H), 3.99 - 3.96 (m, 1H), 3.32 - 3.25 (m, 1H), 1.97 - 1.90 (m, 1H), 1.68 - 1.64 (m, 7H). MS (ESI): m / z 404 (M+1). HPLC purity: 98.9%.

[0370] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 58) 1 H NMR (400 MHz, DMSO) δ 9.49 - 9.45 (m, 1H), 9.27 - 9.25 (m, 1H), 8.79 (d, J=5.1 Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J=1.4, 5.1 Hz, 1H), 6.66 (d, J=1.9 Hz, 2H), 5.11 (d, J=1.5 Hz, 1H), 4.64 (d, J=6.7 Hz, 1H), 4.53 (d, J=2.5 Hz, 1H), 4.45 (dd, J=1.4, 2.6 Hz, 1H), 4.16 - 4.09 (m, 1H), 4.01 - 3.97 (m, MS (ESI): m / z 406 (M+1). HPLC purity: 99.2%.

[0371] (1'R,2'R,4'S)-4-(6-(2,2-difluoroethyl)-5-fluoropyridin-3-yl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 59) 1H NMR (400 MHz, DMSO) δ 9.47 - 9.20 (m, 2H), 8.23 ​​- 8.22 (m, 1H), 8.07 - 7.97 (m, 1H), 7.63 - 7.61 (m, 1H), 6.57 - 6.50 (m, 2H), 5.14 (d, J=1.5 Hz, 1H), 4.67 - 4.64 (m, 1H), 4.58 (d, J=2.5 Hz, 1H), 4.50 (d, J=1.3 Hz, 1H), 4.17 (d, J=5.6 Hz, 1H), 4.04 - 4.00 (m, 1H), 3.34 - 3.26 (m, 1H), 2.01 - 1.93 (m, 1H), 1.72 - 1.67 (m, 7H). MS (ESI): m / z 422 (M+1). HPLC purity: 95.2%.

[0372] General method B (three-step oxidation with LAH reduction) using the appropriate 4-substituted (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol was used to generate the following compounds:

[0373] (1'R,2'R,4'S)-5'-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 10) 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.82 (s, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 6.34 (s, 2H), 5.12 - 5.11 (m, 1H), 4.60 (d, J=6.7 Hz, 1H), 4.53 - 4.50 (m, 1H), 4.45 - 4.43 (m, 1H), 4.15 - 4.08 (m, 1H), 3.94 - 3.87 (m, 1H), 3.86 - 3.85 (m, 3H), 3.25 - 3.19 (m, 1H), 1.91 (ddd, J=2.3, 5.8, 12.0 Hz, 1H), 1.67 - 1.61 (m, 6H), 1.57 (d, J=22.7 Hz, 1H). MS (ESI): m / z 341 (M+1). HPLC purity: 98.6%.

[0374] (1'R,2'R,4'S)-4-(Methoxymethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 4) 1 H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.78 (s, 1H), 6.18 (s, 2H), 5.08 (q, J=1.9 Hz, 1H), 4.58 (d, J=6.7 Hz, 1H), 4.49 (d, J=2.7 Hz, 1H), 4.42 (q, J=1.4 Hz, 1H), 4.17 (s, 2H), 4.14 - 4.06 (m, 1H), 3.93 - 3.86 (m, 1H), 3.24 (s, 3H), 3.23 - 3.17 (m, 1H), 1.91 (ddd, J=2.4, 5.6, 12.0 Hz, 1H), 1.65 (s, 3H), 1.60 (s, 3H), 1.60 - 1.54 (m, 1H). MS (ESI): m / z 303 (M-1) (only negative ions observed). HPLC purity: 92.5%.

[0375] (1'R,2'R,4'S)-4-(2-methoxyethyl)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 5) 1 H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.66 (s, 1H), 6.08 (s, 2H), 5.08 - 5.05 (m, 1H), 4.58 (d, J=7.0 Hz, 1H), 4.50 (d, J=2.6 Hz, 1H), 4.42 (q, J=1.4 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.91 - 3.85 (m, 1H), 3.45 (t, J=6.9 Hz, 2H), 3.24 (s, 3H), 3.23 - 3.16 (m, 1H), 2.55 (t, J=6.9 Hz, 2H), 1.89 (ddd, MS (ESI): m / z 319 (M+1). HPLC purity: 95.6%.

[0376] (1'R,2'R,4'S)-4,5'-Dimethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 1) 11H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.62 (s, 1H), 6.00 (s, 2H), 5.07 (q, J=1.6 Hz, 1H), 4.58 (d, J=6.5 Hz, 1H), 4.49 (d, J=2.8 Hz, 1H), 4.41 (q, J=1.4 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.89 - 3.83 (m, 1H), 3.24 - 3.15 (m, 1H), 2.05 (s, 3H), 1.89 (ddd, J=2.5, 5.8, 12.2 Hz, 1H), 1.64 (s, 3H), 1.60 (s, 3H), 1.59 - 1.52 (m, 1H). MS (ESI):m / z 275 (M+1). HPLC purity: 95.2%.

[0377] (1'R,2'R,4'S)-4-Ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 3) 1 1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.64 (s, 1H), 6.04 (s, 2H), 5.08 - 5.05 (m, 1H), 4.58 (d, J=6.3 Hz, 1H), 4.50 (d, J=2.6 Hz, 1H), 4.42 (q, J=1.3 Hz, 1H), 4.13 - 4.06 (m, 1H), 3.89 - 3.84 (m, 1H), 3.24 - 3.16 (m, 1H), 2.35 (q, J=7.6 Hz, 2H), 1.90 (ddd, J=2.4, 5.6, 12.0 Hz, 1H), 1.64 (s, 3H), 1.61 (s, 3H), 1.59 - 1.52 (m, 1H), 1.09 (t, J=7.6 Hz, 3H). MS (ESI):m / z 289 (M+1). HPLC purity: 99.6%.

[0378] 2-((1'R,2'R,4'S)-2,4',6-trihydroxy-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-4-yl)acetonitrile (Compound 6) 1 H NMR (400 MHz, DMSO) δ 9.32 - 9.27 (m, 1H), 9.06 - 9.04 (m, 1H), 6.22 (s, 2H), 5.12 - 5.10 (m, 1H), 4.64 - 4.62 (m, 1H), 4.53 (d, J=2.8 Hz, 1H), 4.46 (dd, J=1.4, 2.7 Hz, 1H), 4.14 (d, J=5.8 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.84 (s, 2H), 3.29 - 3.20 (m, 1H), 1.98 - 1.91 (m, 1H), 1.70 - 1.63 (m, 6H), 1.62 - 1.58 (m, 1H). MS (ESI): m / z 298 (M-1) (only anion observed). HPLC purity: 93.4%.

[0379] (1'R,2'R,4'S)-3,5'-Dimethyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 44) 11H NMR (400 MHz, DMSO) δ 8.69 - 8.41 (m, 1H), 7.70 - 7.26 (m, 1H), 6.13 - 6.05 (m, 1H), 5.15 - 5.07 (m, 1H), 4.61 - 4.47 (m, 2H), 4.41 (s, 1H), 4.12 (s, 1H), 3.93 - 3.89 (m, 1H), 3.25 - 3.12 (m, 1H), 2.38 - 2.32 (m, 2H), 1.99 - 1.92 (m, 3H), 1.91 - 1.87 (m, 1H), 1.68 - 1.57 (m, 7H), 1.48 - 1.43 (m, 2H), 0.94 - 0.89 (m, 3H). MS (ESI): m / z 317 (M+1). HPLC purity: 93.7%.

[0380] (1'R,2'R,4'S)-4-Bromo-3,5,5'-trimethyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 51) 1 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.85 (s, 1H), 5.13 (dd, J = 1.5, 3.3 Hz, 1H), 4.67 (d, J = 6.5 Hz, 1H), 4.46 (d, J = 2.5 Hz, 1H), 4.42 (dd, J = 1.4, 2.5 Hz, 1H), 4.15 - 4.11 (m, 1H), 4.06 - 4.02 (m, 1H), 3.22 (ddd, J = 2.2, 10.7, 12.8 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 1.92 (ddd, J = 2.4, 5.7, 12.0 Hz, 1H), 1.67 (s, 3H), 1.65 - 1.61 (m, 1H), 1.60 (s, 3H). MS (ESI): m / z 367 / 369 (M+1). HPLC purity: 95.2%.

[0381] General method C using the appropriate 4-substituted (1'R,2'R)-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (NaBH 4 A three-step oxidation followed by reduction was used to produce the following compounds:

[0382] (1'R,2'R,4'S)-4-chloro-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 2) 1 H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 9.32 (s, 1H), 6.24 (s, 2H), 5.11 - 5.04 (m, 1H), 4.66 - 4.57 (m, 1H), 4.51 - 4.42 (m, 2H), 4.12 - 4.10 (m, 1H), 3.92 - 3.86 (m, 1H), 3.20 - 3.11 (m, 1H), 2.14 - 2.07 (m, 1H), 1.95 - 1.87 (m, 1H), 1.68 - 1.56 (m, 6H). Peak broadening possibly caused by atropisomerism. MS (ESI): m / z 293, 295 (M+1). HPLC purity: 99.2%.

[0383] General Method H General method H is illustrated by the synthesis of (1'R,2'R,4'S)-3-fluoro-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol compound 45:

[0384] [ka]

[0385] (1'R,2'R,4'S)-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (50 mg, 0.165 mmol) in methanol (2.0 mL) was treated with Selectfluor® fluorination reagent (59 mg, 0.165 mmol) and stirred at room temperature overnight. The reaction mixture was poured into saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 10-80% ethyl acetate in cyclohexane followed by reverse phase preparative HPLC to give the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 8.92 - 8.65 (m, 2H), 6.02 (s, 1H), 5.10 (s, 1H), 4.62 (d, J=6.7 Hz, 1H), 4.48 (d, J=2.0 Hz, 1H), 4.45 - 4.42 (m, 1H), 4.14 - 4.06 (m, 1H), 3.92 - 3.87 (m, 1H), 3.24 - 3.15 (m, 1H), 2.45 - 2.36 (m, 2H), 1.91 (ddd, J=2.2, 5.6, 12.0 Hz, 1H), 1.65 (s, 3H), 1.60 (s, 3H), 1.58 - 1.46 (m, 3H), 0.89 (t, J=7.3 Hz, 3H). MS (ESI): m / z 319 (M-1) (only negative ions observed). HPLC purity: 94.9%.

[0386] Using general method H the following compounds were prepared:

[0387] (1'R,2'R,4'S)-3-Fluoro-5'-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 48) 1 H NMR (400 MHz, DMSO) δ 9.14 - 8.83 (m, 2H), 7.94 (d, J=1.6 Hz, 1H), 7.64 (s, 1H), 6.38 (s, 1H), 5.15 - 5.11 (m, 1H), 4.64 (d, J=6.7 Hz, 1H), 4.51 (d, J=2.0 Hz, 1H), 4.46 - 4.43 (m, 1H), 4.15 - 4.09 (m, 1H), 3.95 - 3.90 (m, 1H), 3.89 (s, 3H), 3.26 - 3.18 (m, 1H), 1.93 (ddd, J=2.4, 5.9, 12.0 Hz, 1H), 1.66 (s, 3H), 1.62 (s, 3H), 1.60 - 1.55 (m, 1H). MS (ESI): m / z 359 (M+1). HPLC purity: 90.9%.

[0388] General Method I General method I is illustrated by the synthesis of (1'R,2'R,4'S)-3-chloro-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol compound 46:

[0389] [ka]

[0390] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (50 mg, 0.165 mmol) in methanol (2.0 mL) was treated with N-chlorosuccinimide (22 mg, 0.165 mmol) and stirred at room temperature overnight. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (2 x 25 ml). The combined organic layers were dried (hydrophobic filter paper) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 30-80% diethyl ether in cyclohexane to give the title compound (30.2 mg, 54%) as an off-white solid. 1 H NMR (400 MHz, CD 3 CN) δ 6.93 - 6.48 (m, 2H), 6.32 (s, 1H), 5.29 - 5.26 (m, 1H), 4.52 - 4.49 (m, 2H), 4.32 - 4.25 (m, 1H), 4.04 - 3.98 (m, 1H), 3.13 - 3.06 (m, 1H), 2.89 (d, J=6.7 Hz, 1H), 2.63 - 2.55 (m, 2H), 2.04 (ddd, J=2.4, 5.7, 12.1 Hz, 1H), 1.76 (s, 3H), 1.74 - 1.67 (m, 4H), 1.66 - 1.56 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS (ESI): m / z 335 (M-1) (only negative ions observed). HPLC purity: 96.2%.

[0391] Using general method I the following compounds were prepared:

[0392] (1R,2R,4S)-3'-chloro-3''-methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol Compound 49 Acetonitrile was used as the solvent instead of methanol.1 H NMR (400 MHz, DMSO) δ 9.50 - 9.27 (m, 1H), 8.79 - 8.60 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.95 - 6.87 (m, 3H), 6.34 - 6.29 (m, 1H), 5.16 - 5.13 (m, 1H), 4.67 (d, J=6.5 Hz, 1H), 4.56 (d, J=2.4 Hz, 1H), 4.51 - 4.48 (m, 1H), 4.17 - 4.12 (m, 1H), 4.05 - 4.01 (m, 1H), 3.79 - 3.78 (m, 3H), 3.29 - 3.25 (m, 1H), 1.97 - 1.92 (m, 1H), 1.69 - 1.65 (m, 6H), 1.64 - 1.58 (m, 1H). MS (ESI): m / z 399 (M-1) (only anion observed). HPLC purity: 92.1%.

[0393] (1'R,2'R,4'S)-4-Bromo-3-chloro-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol Compound 47 1 H NMR (400 MHz, DMSO) δ 9.80 - 9.58 (m, 1H), 9.20 - 9.03 (m, 1H), 6.68 - 6.62 (m, 1H), 5.12 - 5.07 (m, 1H), 4.67 (d, J=6.5 Hz, 1H), 4.46 (s, 2H), 4.11 (d, J=5.0 Hz, 1H), 3.96 - 3.95 (m, 1H), 3.21 - 3.15 (m, 1H), 1.94 - 1.90 (m, 1H), 1.67 - 1.60 (m, 6H), 1.59 - 1.56 (m, 1H). MS (ESI): m / z 371 / 373 (M-1) (only anion observed). HPLC purity: 93.3%.

[0394] (1'R,2'R,4'S)-4'-Methoxy-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 53)

[0395] [ka]

[0396] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (200 mg, 0.66 mmol) and cesium carbonate (474 ​​mg, 1.45 mmol) in acetonitrile (10 mL) were treated dropwise with 2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.39 mmol) over 20 min. The reaction mixture was stirred overnight and then poured into water (50 mL) and extracted with dichloromethane (3 x 50 mL) followed by ethyl acetate (3 x 50 mL). The organic layer was dried (hydrophobic filter paper) and concentrated in vacuo to give crude (1R,2R,4S)-5-methyl-2-(prop-1-en-2-yl)-4'-propyl-2',6'-bis((2-(trimethylsilyl)ethoxy)methoxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-4-ol (316 mg, 85%) as a colorless gum. Without further purification, a portion of this (233 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (3.0 mL) and treated with sodium hydride (60% dispersion in mineral oil, 25 mg, 0.62 mmol) followed by iodomethane (39 μL, 0.62 mmol). The reaction mixture was stirred overnight and then treated with additional sodium hydride (25 mg, 60% dispersion in mineral oil, 0.62 mmol) followed by iodomethane (39 μL, 0.62 mmol) and stirred over the weekend. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (1 mL), diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The organic layer was dried (hydrophobic filter paper) and concentrated in vacuo to give crude ((((((1'R,2'R,4'S)-4'-methoxy-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(methylene))bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane) as a purple gum (148 mg, 62%).Without further purification, a portion of this (120 mg, 0.21 mmol) in methanol (10 mL) was treated with 2 M aqueous hydrochloric acid (2 mL, 2 mmol) and stirred overnight. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-80% ethyl acetate in cyclohexane followed by reverse phase preparative HPLC to give the title compound (10.4 mg, 16%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.69 (s, 1H), 6.03 (s, 2H), 5.20 - 5.16 (m, 1H), 4.51 (d, J=2.5 Hz, 1H), 4.46 - 4.42 (m, 1H), 3.92 - 3.84 (m, 2H), 3.29 (s, 3H), 3.25 - 3.16 (m, 1H), 2.30 (t, J=7.6 Hz, 2H), 2.10 - 2.04 (m, 1H), 1.63 (s, 3H), 1.62 (s, 3H), 1.57 - 1.46 (m, 3H), 0.88 (t, J=7.3 Hz, 3H). MS (ESI): m / z 317 (M+1). HPLC purity: 97.2%.

[0397] General Method J General method J is illustrated by the synthesis of (1'R,2'R)-4',5'-dimethyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol compound 54:

[0398] [ka]

[0399] (1'R,2'R)-5'-methyl-4'-oxo-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl diacetate (184 mg, 0.479 mmol) in tetrahydrofuran (10 mL) was cooled to -78°C and treated with a 3.1 M solution of methyllithium in dimethoxymethane (1.5 mL, 4.79 mmol). The reaction mixture was stirred at -78°C for 2 h and then allowed to warm to room temperature over 2 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL), poured into water (50 mL) and extracted with dichloromethane (50 mL). The aqueous layer was acidified to pH 2 with hydrochloric acid and further extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 10-50% diethyl ether in cyclohexane followed by reverse phase preparative HPLC to give the title compound (14.2 mg, 9.1%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.71 (s, 1H), 6.08 - 6.03 (m, 2H), 5.00 (s, 1H), 4.56 - 4.53 (m, 1H), 4.47 (s, 1H), 4.33 (s, 1H), 3.91 - 3.84 (m, 1H), 3.35 - 3.27 (m, 1H), 2.33 (t, J=7.9 Hz, 2H), 1.84 (t, J=12.9 Hz, 1H), 1.70 - 1.68 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.59 - 1.48 (m, 2H), 1.34 (s, 3H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI): m / z 315 (M-1). HPLC purity: 96.8%.

[0400] General method J using the appropriate enone was also used to generate the following compounds:

[0401] (1'R,2'R)-4',5'-dimethyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 55): 1 H NMR (400 MHz, DMSO) δ 8.82 (d, J=0.9 Hz, 1H), 8.67 (s, 1H), 6.04 - 5.98 (m, 2H), 4.97 - 4.94 (m, 1H), 4.50 (d, J=2.5 Hz, 1H), 4.45 - 4.42 (m, 1H), 4.30 (s, 1H), 3.86 - 3.80 (m, 1H), 3.31 - 3.23 (m, 1H), 2.30 (t, J=7.6 Hz, 2H), 1.80 (t, J=12.8 Hz, 1H), 1.65 - 1.64 (m, 1H), 1.64 - 1.62 (m, MS (ESI): m / z 343 (M-1). HPLC purity: 93.3%.

[0402] (1'R,2'R,4'S)-4-Cyclopropyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (compound 8)

[0403] [ka]

[0404] A solution of (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (60 mg, 0.177 mmol), potassium cyclopropyltrifluoroborate (39 mg, 0.265 mmol), and potassium phosphate tribasic (113 mg, 0.531 mmol) in toluene (2.0 mL) and water (0.5 mL) was degassed with nitrogen and treated with bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 8.84 μmol). The reaction mixture was heated at 100° C. for 90 min, then poured into water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (hydrophobic filter paper) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 20-100% diethyl ether in cyclohexane followed by reverse phase preparative HPLC to give the title compound (0.78 mg, 1.5%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.63 (s, 1H), 5.91 (s, 2H), 5.07 - 5.04 (m, 1H), 4.57 (d, J=6.7 Hz, 1H), 4.49 (d, J=2.6 Hz, 1H), 4.43 - 4.40 (m, 1H), 4.13 - 4.05 (m, 1H), 3.87 - 3.82 (m, 1H), 3.22 - 3.15 (m, 1H), 1.89 (ddd, J=2.3, 5.6, 11.7 Hz, 1H), 1.63 (s, 3H), 1.59 (s, 3H), 1.59 - 1.52 (m, 2H), 0.86 - 0.80 (m, 2H), 0.49 - 0.45 (m, 2H). MS (ESI): m / z 301 (M+1). HPLC purity: 96.3%.

[0405] (1'R,2'R,4'S)-5'-Methyl-2'-(prop-1-en-2-yl)-4-(pyridin-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (Compound 27)

[0406] [ka]

[0407] A solution of (1'R,2'R,4'S)-4-bromo-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4',6-triol (100 mg, 0.295 mmol) in dry 1,4-dioxane (2.0 mL) was degassed with nitrogen, treated with 2-(tributylstannyl)pyridine (150 μL, 0.463 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.0295 mmol) and heated at 95° C. overnight. The reaction mixture was diluted with ethyl acetate (4 mL), water (2 mL), and brine (3 mL) and filtered. The aqueous layer was further extracted with ethyl acetate (2×4 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (3.1 mg, 3.1%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 9.03 (s, 1H), 8.60 (ddd, J=0.9, 1.8, 4.8 Hz, 1H), 7.84 (dt, J=1.9, 7.8 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.29 (ddd, J=1.0, 4.8, 7.5 Hz, 1H), 6.95 (s, 2H), 5.15 - 5.12 (m, 1H), 4.62 (d, J=6.8 Hz, 1H), 4.52 (d, J=2.6 Hz, 1H), 4.44 (dd, J=1.4, 2.6 Hz, 1H), 4.16 - 4.09 (m, 1H), 4.00 - 3.94 (m, 1H), 3.30 - 3.22 (m, 1H), 1.93 (ddd, J=2.3, 5.6, 12.1 Hz, 1H), 1.67 (s, 3H), 1.64 (s, 3H) 1.65 - 1.57 (m, 1H). MS (ESI): m / z 338 (M+1). HPLC purity: 99.5%.

[0408] (1R,2R,4S)-3'-Fluoro-3''-methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1':4',1''-terphenyl]-2',4,6'-triol (compound 50)

[0409] [ka]

[0410] A solution of (1R,2R,4S)-3″-methoxy-5-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1′:4′,1″-terphenyl]-2′,4,6′-triol (130 mg, 0.355 mmol) in dry dichloromethane (12 mL) was cooled in an ice / water bath and treated with 1-fluoropyridinium triflate (100 mg, 0.405 mmol). The reaction mixture was allowed to warm to room temperature overnight, ice was added and stirred when melted, then left at room temperature overnight, then further treated with 1-fluoropyridinium triflate (100 mg, 0.405 mmol). After a further 24 hours the reaction was diluted with water (5 mL) and saturated aqueous sodium bicarbonate (1 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (2×4 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography eluting with 0-100% diethyl ether in cyclohexane to give the title compound (15.0 mg, 10%) as an off-white solid. 1 H NMR (400 MHz, DMSO) δ 9.28 - 8.99 (m, 2H), 7.42 - 7.37 (m, 1H), 7.07 - 6.96 (m, 3H), 6.32 - 6.30 (m, 1H), 5.16 (s, 1H), 4.68 (d, J=6.6 Hz, 1H), 4.59 (d, J=1.8 Hz, 1H), 4.52 - 4.52 (m, 1H), 4.19 - 4.14 (m, 1H), 4.02 - 3.98 (m, 1H), 3.83 - 3.83 (m, 3H), 3.34 - 3.27 (m, 1H), 2.01 - 1.94 (m, 1H), 1.72 - 1.67 (m, 6H), 1.67 - 1.59 (m, 1H). MS (ESI): m / z 383 (M-1). HPLC purity: 92.0%.

[0411] List of compounds

[0412] [ka] [ka] [ka] [ka]

[0413] Example 2 Evaluation of novel resorcinols for anticonvulsant activity using the mouse maximal electroshock seizure threshold (MEST) test (mini-MEST) with minimal sample size The efficacy of the novel resorcinols 2, 3, 5, 8, 10, 15, 16, 17, 18, 19, 41, 45, 46, 53, 56, and 58 was tested in a novel mouse model of generalized seizures, the mini-MEST (maximum electroshock seizure threshold) test, using a lower n number than typically used.

[0414] The maximal electroshock seizure threshold (MEST) test is widely used preclinically to evaluate the proconvulsant or anticonvulsant properties of test compounds (Loscher et al., 1991).

[0415] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce a tonic-extension convulsion of the hind limbs is measured according to the "up-and-down" method of shock titration (Kimball et al., 1957). An increase in the seizure threshold indicates an anticonvulsant effect. All antiepileptic drugs, including sodium channel blockers (e.g., lamotrigine), with clinically proven efficacy against generalized tonic-clonic seizures, exhibit anticonvulsant properties in this test in mice.

[0416] Conversely, a lowering of the seizure threshold indicates a proconvulsant effect such as that observed with known convulsant drugs such as picrotoxin.

[0417] The ability of test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the presence of tonic hindlimb extension convulsions is assessed in the MEST. The current (CC) that elicits tonic hindlimb extension in 50% of the animals in the treatment group is 50 The seizure threshold of the treatment group was determined by the presence (+) or absence (0) of tonic hindlimb extensor convulsions observed from the CC group, and the effect was then compared with that of the vehicle control group. 50 Compared to.

[0418] method Research details: Naïve mice were habituated to the procedure room in their home cages for up to 7 days and allowed free access to food and water.

[0419] All animals were weighed at the start of the study and randomly assigned to treatment groups based on the mean distribution of body weight across groups. All animals were dosed via intraperitoneal (ip) injection with either vehicle, 5-50 mg / kg test compound, or 2.5 mg / kg diazepam at 10 mL / kg.

[0420] Animals were individually assessed for the occurrence of tonic hindlimb extensor convulsions following a single electric shock, 30 min after vehicle administration, 15-30 min (depending on compound) after test compound administration, and 30 min after diazepam administration.

[0421] The first animal in a treatment group was assigned a predicted or estimated CC 50 The animals were shocked with a current that was either decreased or increased in logarithmic intervals for subsequent animals depending on the outcome of the seizure from the previous animal.

[0422] Using the data generated from each treatment group, CC of the treatment group was calculated. 50 Values ​​were calculated ±SEM.

[0423] Test Compounds: Vehicle: (5% ethanol, 10% solutol in 85% saline) was prepared as follows: 1 mL ethanol, 2 mL solutol warmed to 60° C. in 17 mL saline (1:2:17).

[0424] Positive control: diazepam was used at 2.5 mg / kg.

[0425] The test compounds used were 2, 3, 5, 8, 10, 15, 16, 17, 18, 19, 41, 45, 46, 53, 56, and 58. Test compounds were administered at 5-50 mg / kg (ip) in a 1:2:17 ethanol:soltol:saline mix.

[0426] Sample Collection: Each animal was humanely killed immediately following the onset of convulsions due to destruction of the brain from the blow to the skull, followed by confirmation of complete cessation of circulation by decapitation in accordance with The Humane Killing of Animals, Schedule 1 of the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collections were performed following decapitation.

[0427] Blood was collected into lithium heparin tubes and centrifuged at 1500×g for 10 min at 4° C. The resulting plasma was removed (>100 μL) and divided into two aliquots in 0.5 mL Eppendorf tubes containing 10 μL of ascorbic acid (100 mg / mL) for stabilization. Brains were removed, washed with saline, and halved. Each half was placed into a separate 2 mL screw-cap cryovial, weighed, and frozen on dry ice.

[0428] statistical analysis Data for each treatment group was recorded as the number of +'s and 0's at each current level used, and this information was then used to calculate the CC 50 The value (current required for 50% of the animals to show seizure behavior) ± standard error is calculated.

[0429] The effects of test compounds were also measured using CC from the vehicle control group. 50 was calculated as the percentage change in

[0430] Significant differences between drug-treated animals and controls were assessed according to Litchfield and Wilcoxon (1949).

[0431] result Figures 1 to 7 and Tables 2 to 8 illustrate the data obtained in this experiment.

[0432] In the vehicle group, CC 50 The value was calculated to be between 22.5 and 26.5 mA.

[0433] In the diazepam (2.5 mg / kg) treatment group, which was administered ip 30 min before the test, CC 50 Values ​​ranged from 85.0 to 128.0 mA. These results were statistically significant (p<0.001) when compared to their respective vehicle controls.

[0434] In the test compound treatment groups administered ip between 15 and 30 minutes prior to testing, all 13 compounds demonstrated statistically significant CC increases compared to vehicle at at least one dose. 50 brought value.

[0435] Such data indicate that these compounds have therapeutic benefit.

[0436] [Table 4]

[0437] [Table 5]

[0438] [Table 6]

[0439] [Table 7]

[0440] [Table 8]

[0441] [Table 9]

[0442] [Table 10]

[0443] [Table 11]

[0444] [Table 12]

[0445] [Table 13]

[0446] [Table 14]

[0447] [Table 15]

[0448] conclusion These data demonstrate the therapeutic efficacy of the compounds.

[0449] These data are important because they provide previously unknown evidence that these novel resorcinols may have therapeutic value.

[0450] The compounds tested were those detailed as Compound 2, Compound 3, Compound 5, Compound 8 and Compound 10, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 41, Compound 45, Compound 46, Compound 53, Compound 56, and Compound 58. Such compounds are examples of novel resorcinols of general formulas I-V.

[0451] Further compounds tested were those detailed as Compound 7, Compound 9, Compound 26, Compound 29, Compound 30, Compound 31, Compound 33, Compound 35, Compound 42, Compound 47, Compound 49, and Compound 52.

[0452] Such therapeutic efficacy may be attributed to the novel compounds of general formulae I-V of the present invention, as representative compounds have shown efficacy in the mini-MEST study.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is CH 3 , C.H. 2 CH 3 , Cl, 【Chemistry 2】 is] or a salt thereof.

2. R 1 is CH 3 , CH 2 CH 3 , Cl, 【Chemistry 3】 2. The compound of claim 1,

3. R 1 But, CH 2 CH 3 , Cl, 【Chemistry 4】 2. The compound of claim 1,

4. Formula (II): 【Chemistry 5】 [In the formula, R 1 is CH 2 CH 2 CH 3 ,Br, 【Chemistry 6】 and R 2 is CH 3 , F, or Cl, and R 3 is H or CH 3 is] or a salt thereof.

5. R 1 CH 2 CH 2 CH 3 5. The compound of claim 4,

6. R 2 The compound according to claim 4 or 5, wherein is F or Cl.

7. R 3 The compound of claim 4, wherein is H.

8. Formula (III): 【Chemistry 7】 [In the formula, R 1 is CH 2 CH 2 CH 3 or (CH 2 ) 4 CH 3 and R 2 is H or CH 3 and R 3 is H or CH 3 is] or a salt thereof.

9. R 1 CH 2 CH 2 CH 3 9. The compound of claim 8, wherein

10. Formula (IV): 【Chemistry 8】 [In the formula, R 1 is CH 2 CH 2 CH 3 or 【Chemistry 9】 is] or a salt thereof.

11. R 1 CH 2 CH 2 CH 3 11. The compound of claim 10,

12. A pharmaceutical composition comprising a compound of claim 1 together with one or more additional ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents.

13. 13. The pharmaceutical composition of claim 12, in a form selected from liquid, solution, suspension, emulsion, syrup, electuary, mouthwash, drops, tablets, granules, powders, lozenges, pastilles, capsules, cachets, pills, ampoules, bolus injections, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

14. 13. A pharmaceutical composition comprising a compound according to claim 1 for use as a medicament.

15. 13. A pharmaceutical composition comprising a compound according to claim 1 for use as a medicament for treating epilepsy.

16. 13. A pharmaceutical composition comprising a compound of claim 1 for use as a medicament for treating generalized seizures, focal onset seizures, or tonic-clonic seizures.

17. Use of a compound according to claim 1 in the manufacture of a medicament.

18. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of epilepsy.

19. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of generalized seizures, focal onset seizures, or tonic-clonic seizures.

20. A process for preparing a compound of formula (I), comprising the steps of: i) reacting a compound of formula (V) with a compound of formula (VI): 【Chemistry 10】 [In the formula, R 1 is H, Ac, Piv, Bz, or PMB, R 2 and R 3 is independently H, Ac, or Piv; R 4 and R 5 is OH or R 4 and R 5 Together, -C(Me) 2 C(Me) 2 Forming C- X 1 is Br, I, or OTf, and Y is 【Chemistry 11】 Select from Reacting with A method comprising:

21. R 1 The method of claim 20, wherein is H, Ac, or Piv.

22. R 2 and R 3 The method of claim 20, wherein is H.

23. X 1 The method of claim 20, wherein is Br or OTf.

24. Step (i) comprises reacting a compound of formula (V) with a compound of formula (VI) and a palladium catalyst, such as Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 and SPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)).

25. Step (i) comprises reacting a compound of formula (V) with a compound of formula (VI) and a base, such as cesium fluoride (CsF), sodium carbonate (Na 2 CO 3 ), Cesium carbonate (Cs 2 CO 3 21. The method of claim 20, further comprising reacting with a base selected from:

26. A process for preparing a compound of formula (V), comprising the steps of: ii) Formula (VII): 【Chemistry 12】 [In the formula, R 6 is H, Bz, or PMB, and R 7 and R 8 are independently H, Ac, or Piv. reacting the compound of formula (I) with a triflate reagent A method comprising:

27. R 6 The method of claim 26, wherein is H or Bz.

28. R 7 and R8 is H.

29. The reagent is trifluoromethanesulfonic anhydride (Tf 2 O), N-phenylbis(trifluoromethanesulfonimide) (PhNTf 2 27. The method of claim 26, wherein the reactant is selected from the group consisting of 1-(trifluoromethanesulfonyl)-1H-benzotriazole, 1-(trifluoromethanesulfonyl)imidazole, and N-(2-pyridyl)-bis(trifluoromethanesulfonimide).

30. 27. The method of claim 26, wherein step (ii) comprises reacting the compound of formula (VII) with a triflating reagent and an organic base, such as an organic base selected from pyridine, leutidine, dimethylbenzylamine imidazole, benzimidazole, methylimidazole, triethylamine, tributylamine, diisopropylethylamine, tetramethylethylenediamine, DABCO.

31. A process for preparing a compound of formula (VII), comprising the steps of: iii) Formula (IX): 【Chemistry 13】 [In the formula, R 15 is H, Bz, or PMB. reacting said compound with phloroglucinol (benzene-1,3,5-triol) A method comprising:

32. R 15 The method of claim 31, wherein is Bz or PMB.

33. 32. The method of claim 31 , wherein step (iii) comprises reacting a compound of formula (IX) with phloroglucinol and an acid, such as an acid selected from boron trifluoride and triflic acid.

34. A process for preparing a compound of formula (I), comprising the steps of: iii) a Friedel-Crafts process as defined in claim 31; ii) a triflation step as defined in claim 26, and optionally i) a coupling step as defined in claim 20 A method comprising:

35. A process for preparing a compound of formula (IX), comprising the steps of: iv-a) reacting a compound of formula (X) with diphenyl diselenide to give a compound of formula (XI); and iv-b) reacting the compound of formula (XI) with an oxidizing agent: 【Chemistry 14】 [In the formula, R 16 and R 17 are independently H, Bz, or PMB. A method comprising:

36. 36. The method of claim 35, wherein step (iv-a) comprises reacting the compound of formula (X) with diphenyl diselenide and a reducing agent, such as sodium borohydride.

37. 36. The method of claim 35, wherein step (iv-a) comprises reacting the compound of formula (X) with diphenyl diselenide and a base, such as sodium hydroxide.

38. 36. The method of claim 35, wherein the oxidizing agent is hydrogen peroxide.

39. A process for preparing a compound of formula (X), comprising the steps of: v) Formula (XII): 【Chemistry 15】 reacting the compound with a peroxycarboxylic acid (peracid) A method comprising:

40. 40. The method of claim 39, wherein the peroxycarboxylic acid is selected from chloroperoxybenzoic acid (mCPBA) and perbenzoic acid.

41. A process for preparing a compound of formula (XII), comprising the steps of: vi) S-Carvone: 【Chemistry 16】 reacting with a reducing agent A method comprising:

42. 42. The method of claim 41, wherein the reducing agent is selected from lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), diborane, and sodium borohydride.

43. A process for preparing a compound of formula (IX), comprising the steps of: vi) a reduction step as defined in claim 41 or 42, v) an epoxidation step as defined in claim 39 or 40, iv) an allylic oxidation step as defined in claim 35 A method comprising:

44. A process for preparing a compound of formula (I), comprising the steps of: vi) a reduction step as defined in claim 41 or 42, v) an epoxidation step as defined in claim 39 or 40, iv) an allylic oxidation step as defined in claim 35; iii) a Friedel-Crafts process as defined in claim 31; ii) a triflation step as defined in claim 26, and optionally i) a coupling step as defined in claim 20 A method comprising:

45. Formulae (V) and (IX): 【Chemistry 17】 [In the formula, R 1 is H, Ac, Piv, Bz, or PMB, R 2 and R 3 is independently H, Ac, or Piv; X 1 is Br, I, or OTf, and R 15 is H, Bz, or PMB. The intermediate is selected from the compounds of formula (I).

46. The intermediate is 【Chemistry 18】 46. ​​The intermediate of claim 45, selected from:

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