RESORCINOL DERIVATIVES

Abstract: The present invention relates to the use of certain resorcinol derivatives as skin lightening agents.

Description: RESORCINOL DERIVATIVES Field Of The Invention The present invention relates to the use of certain resorcmol derivatives as skin lightening agents Background Of The Invention The terms "lightening agent" and "depigmentation agent" are used interchangeably throughout this document Skin color in humans arises from a complex series of cellular processes that are carried out within a unique population of cells called melanocytes Melanocytes are located in the lower part of the epidermis, and their function is to synthesize a pigment, melanin, which protects the body from the damaging effects of ultraviolet radiation When skin is exposed to ultraviolet radiation, such as that contained in sunlight, melanocytes increase their synthesis of melanin Melanin is deposited in melanosomes, which are vesicles found within the cell The melanosomes are extruded from the cell and carried to the surface of the skin by keratmocytes, which internalize the melanin-containing melanosomes The end result is that the visible layers of the skin exhibit a brown color typically known as a "tan" The darkness of the color observed in the skin is proportionate to the amount of melanin synthesized by melanocytes and transferred to the keratmocytes The mechanism by which skin pigmentation is formed, melanogenesis, is particularly complex and schematically involves the following main steps Tyrosine→L- Dopa- > Dopaquιnone- > Dopachrome- » Melanιns The first two reactions in this series are catalyzed by the enzyme tyrosinase The activity of tyrosinase is promoted by the action of α- melanocyte stimulating hormone or UV rays to have melanin eventually formed as chromatism in the skin It is well established that a substance has a depigmenting effect if it acts directly on the vitality of the epidermal melanocytes where melanogenesis normally occurs and/or if it interferes with one of the stages in melanin biosynthesis The active compounds that are employed in the various methods and compositions of this invention inhibit tyrosinase and thus inhibit or decrease melanin biosynthesis There is a strong demand for agents that enable acquired deposition sites, such as spots or freckles, to be restored to a normal skin color For this purpose, a variety of agents and methods have been developed and put on the market Examples of such methods are (a) a method wherein vitamin C (L-ascorbic acid) having good reducing ability is administered orally in large amounts, (b) a method wherein glutathione is administered parenterally, (c) a method wherein a peroxide, such as hydrogen peroxide, zinc peroxide, sodium peroxide and the like, which is believed to have the bleaching action of melamine, is administered and (d) a method wherein vitamin C or cysteine is administered topically in the form of an ointment, cream, lotion or the like Vitamin C has a problem with respect to stability and becomes so unstable in water-containing systems that they will cause changes in odor and color Thiol compounds such as glutathione and cysteine do not exhibit a satisfactory depigmental effect since the development of the effect is very slow The substances in widest use at the present time as depigmentors are, in particular, hydroquinone and its derivatives, particularly its ethers such as hydroquinone monomethyl ether These compounds, while effective, are known to produce side effects that can be dangerous Hydroquinone, use of which is limited to a concentration of 2%, is both irritating and cytotoxic to the melanocyte United States Patent 4,526,179 refers to certain hydroquinone fatty esters that have good activity and are less irritating and more stable than hydroquinone Japanese Patent Application No. 27909/86 refers to other hydroquinone derivatives that do not have the drawbacks of hydroquinone but that have relatively poor efficacy United States Patent 5,449,518 refers to 2,5-dιhydoxyphenyl carboxylic acid derivatives as skin depigmentation agents European Patent Application EP 341 ,664A1 refers to certain resorcinol derivatives as tyrosinase inhibitors and skin depigmentation agents. PCT International Publication WO 99/15148 refers to certain resorcinol derivatives as tyrosinase inhibitors and skin depigmentation agents The use of topical depigmention agents that have good efficacy and are harmless is particularly desirable for treating the following regional hyperpigmentation caused by melanocytic hyperactivity, such as idiopathic melasma occurring either during pregnancy (mask of pregnancy or chloasma) or secondary to estrogen-progesterone contraception, local hyperpigmentation caused by benign melanocytic hyperactivity and proliferation such as lentigo senilis or liver spots, accidental hyperpigmentation such as post-lesional photosensitization and scarring, and certain forms of leukoderma such as viti go where, if the injured skin cannot be repigmented, the residual zones of normal skin are depigmented to impart a homogeneous white color to the entire skin Summary of Invention The resorcinol derivatives of formula I, which are defined below and used in the various methods and compositions of this invention, are useful in the treatment of the foregoing dermatological conditions as well as other dermatological conditions, some of which are referred to later in this document, for which the subject being treated desires, for medicinal or cosmetic purposes, to lighten or reduce the pigmentation of the skin affected by the condition The resorcinol derivatives of formula I are also useful for the treatment of inflammatory disorders such as psoriasis, dermatitis and acne, and for the treatment of dandruff The invention thus provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano, halo, (C C 6 )alkyl, aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 - C 9 )heteroaryl, aryl(C 1 -C 6 )alkyl-, =0, =CHO(C r C 6 )alkyl, ammo, hydroxy, (C r C 6 )alkoxy, aryl(C r C 6 )alkoxy-, (C r C 6 )acyl, (C r C 6 )alkylamιno-, ary C CgJalkylammo-, ammo(C 1 -C 6 )alkyl-, (C r C 6 )alkoxy-CO-NH-, (CrCsJalkylammo-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C r C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl-, nitro, cyano(C 1 -C 6 )alkyl-, haloCC CgJalkyl-, nιtro(C r C 6 )alkyl-, trifluoromethyl, tπfluoromethy C T -C^alkyl-, (C r C 6 )acylamιno-, (C 1 -C 6 )acylamιno(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamιno-, aminoiO,- C 6 )acyl-, amιno(C 1 -C 6 )acyl(C l -C 6 )alkyl-, (C 1 -C 6 )alkylamιno(C 1 -C 6 )acyl-, ((C,-C 6 ) alkyl) 2 amιno(C r C 6 )acyl-, -C0 2 R 2 , -(C 1 -C 6 )alkyl-C0 2 R 2 , -C(0)N(R 2 ) 2 , -(C C 6 )alkyl-C(0)N(R 2 ) 2 , R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, R 2 ON=CR 2 (C r C 6 )alkyl-, -NR 2 (OR 2 ), -(C 1 -C 6 )alkyl-NR 2 (OR 2 ), - C(0)(NR 2 OR 2 ), -(C,-C 6 )alkyl-C(0)(NR 2 OR 2 ), -S(0) m R 2 , wherein each R 2 is independently selected from hydrogen, (C r C 6 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl-, R 3 C(0)0-, wherein R 3 is (C r C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl-, R^O MCrC^alkyl-, R 4 R 5 N-C(0)-0-, R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl-, wherein m is 0, 1 or 2, and R 4 and R 5 are each independently selected from hydrogen or (C 1 -C 6 )alkyl, -C(=NR 6 )(N(R 4 ) 2 ), or -(C 1 -C 6 )alkyl-C(=NR 6 )(N(R ) 2 ) wherein R 6 represents OR 2 or R 2 wherein R 2 is defined as above, with the proviso that the cycloalkenyl ring is not aromatic, with the proviso that R 1 must be substituted by at least one of R 3 C(0)0-, R 3 C(0)0- (C,-C 6 )alkyl-, R 2 ON=, R 2 ON=(C r C 6 )alkyl-, R 2 ON=CR 2 (C,-C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C r C 6 )alkyl-, with the proviso that when R 1 is only substituted by one of R 2 ON=, then R 2 cannot be hydrogen Where R 1 is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3- or 4-posιtιon, and more preferably at the 4-posιtιon Where R 1 is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-posιtιon In a preferred embodiment, R 1 is monosubstituted In a further preferred embodiment, R 1 is disubstituted In a preferred embodiment, R 1 is substituted by at least one of R 3 C(0)0- or R 3 C(0)0- (C C-e alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R 3 C(0)0- In a further preferred embodiment, R' is substituted by at least one of R 3 C(0)0-(C,- C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, or R 2 ON=CR 2 (C 1 -C 6 )alkyl-, with the proviso that when R 1 is only substituted by one of R 2 ON=, then R 2 cannot be hydrogen In a further preferred embodiment, R 1 is substituted by at least one of R 2 ON=, with the proviso that when R 1 is only substituted by one of R 2 ON=, then R 2 cannot be hydrogen In a further preferred embodiment, R 1 is substituted by at least one of -NR 2 (OR 2 ) In a further preferred embodiment, R 1 is substituted by at least one of R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R S(0) 2 R 5 N-, or R 4 S(0) 2 R 6 N(C 1 -C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R S(0) 2 R 5 N- In a further preferred embodiment, R 1 is substituted by at least one of R 4 S(0) 2 R 5 N(C C 6 )alkyl- In a further preferred embodiment, R 1 is a (C 3 -C 8 )cycloalkyl πng or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, R 2 ON=(C r C 6 )alkyl-, R 2 ON=CR (C 1 -C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R R 5 NS(0) 2 (C,-C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl-, wherein R 2 , R 3 , R 4 and R 5 are as defined above, with the proviso that the cycloalkenyl ring is not aromatic, and with the proviso that when R 1 is substituted by R 2 ON=, then R 2 cannot be hydrogen In a further preferred embodiment, R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, or R S(0) 2 R 5 N-, wherein R 2 , R 3 , R 4 and R 5 are as defined above, with the proviso that the cycloalkenyl ring is not aromatic, and with the proviso that when R 1 is substituted by R 2 ON=, then R 2 cannot be hydrogen In a further preferred embodiment, R 1 is substituted by R 3 C(0)0- or R 3 C(0)0-(C,- C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R 3 C(0)0- In a further preferred embodiment, R 1 is substituted by R 3 C(0)0-(C 1 -C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, or R 2 ON=CR 2 (C 1 -C 3 )alkyl-, with the proviso that when R 1 is substituted by R 2 ON=, then R 2 cannot be hydrogen In a further preferred embodiment, R 1 is substituted by R 2 ON=, where R 2 cannot be hydrogen In a further preferred embodiment, R 1 is substituted by -NR 2 (OR 2 ) In a further preferred embodiment, R 1 is substituted by R R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C,- C 6 )alkyl-, R 4 S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R 4 S(0) 2 R 5 N- In a further preferred embodiment, R 1 is substituted by R 4 S(0) 2 R 5 N(C 1 -C 6 ) alkyl- The (C 2 -C 9 )heterocycloalkyl substituent, when present on R 1 , is preferably a group of the formula — N Z wherein m is as defined above, and Z is CH 2 , NR 2 , O, S, SO, or S0 2 For any of the aforementioned compounds of the present invention, R 1 is preferably a group of the formula which is substituted as described above for R 1 , wherein n is 0, 1 , or 2, wherein the dashed line indicates an optional double bond at that position In a preferred embodiment, n is 0 or 1 In a further preferred embodiment, n is 0, and the dashed line represents a double bond at that position In a further preferred embodiment, n is 1 In a further preferred embodiment, R 1 is substituted by =0, =NOH, CH 2 OH, .OH o Me . or a combination thereof In a further preferred embodiment, n is 0, R 1 is substituted by =NOH, and the dashed line represents a double bond at that position In further preferred embodiment, n is 1 , and R 1 is substituted by =0, =NOH, CH 2 OH, 0 or .OH Me or a combination thereof The invention further provides a compound selected from the group consisting of 0-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 5 (±)-W-[3-(2,4-Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, (±)-0-Methyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, (±)-0-Benzyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, and a pharmaceutically acceptable salt thereof The invention further provides a compound selected from the group consisting of 0 0-Methyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, (±)-4-f3-(Hydroxyamιno)cyclohexyl]-1 ,3-benzenedιol, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide, trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, 5 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl) 4-(dιmethylamιno)benzoate, trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fert-butylbenzoate, fraπs-4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fluorobenzoate, trans - 4-1/2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - tπfluoromethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methoxybenzoate, 0 trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - chlorobenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate, [4-(2,4-Dιhydroxyphenyl)cyclohexyl]methyl propionate, cis / trans - 4- [4-(hydroxyamιno)cyclohexyl]-1 ,3 - benzenediol, trans - 4-[4-(methoxyamιno)cyclohexyl]-1 ,3 - benzenediol, and a pharmaceutically acceptable salt thereof The present invention further provides a topical pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable earner, and a skin-lightening or pigmentation-reducmg amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 6 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano, halo, (C,-C 6 )alkyl, aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 - C 9 )heteroaryl, aryl(C 1 -C 6 )alkyl-, =0, =CHO(C 1 -C 6 )alkyl, ammo, hydroxy, (C C 6 )alkoxy, aryl(C 1 -C 6 )alkoxy-, (C 1 -C 6 )acyl, (C r C 6 )alkylamιno-, aryl(C,-C 6 )alkylamιno-, amιno(C,-C 6 )alkyl-, (C 1 -C 6 )alkoxy-CO-NH-, (C 1 -C 6 )alkylamιno-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C r C 6 )alkyl-, (C l -C 6 )alkoxy(C 1 -C 6 )alkyl-, (C 1 -C 6 )acyloxy(C,-C 6 )alkyl-, nitro, cyano(C 1 -C 6 )alkyl-, halo(C r Cg)alkyl-, nιtro(C r C 6 )alkyl-, trifluoromethyl, tπfluoromethylfCrC^alkyl-, (C r C 6 )acylamιno-, (C 1 -C 6 )acylamιno(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C,-C 6 )acylamιno-, amιno(C,- C 6 )acyl-, amιno(C 1 -C 6 )acyl(C l -C 6 )alkyl-, (C,-C 6 )alkylamιno(C,-C 6 )acyl-, ((C r C 6 ) alkyl) 2 amιno(C 1 -C 6 )acyl-, -C0 2 R 2 , -(C-C alkyl-COjR 2 , -C(0)N(R 2 ) 2 , -(C 1 -C 6 )alkyl-C(0)N(R 2 ) 2 , R 2 ON=, R 2 ON=(C r C 6 )alkyl-, R 2 ON=CR 2 (C,-C 6 )alkyl-, -NR 2 (OR 2 ), -(C r C 6 )alkyl-NR 2 (OR 2 ), - C(0)(NR 2 OR 2 ), -(C 1 -C 6 )alkyl-C(0)(NR OR 2 ), -S(0) m R 2 , wherein each R 2 is independently selected from hydrogen, (C r C 6 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl-, R C(0)0-, wherein R 3 is (C r C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl-, R 3 C(0)0-(C,-C 6 )alkyl-, R 4 R 5 N-C(0)-0-, R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, R 4 S(0) 2 R 5 N(C,-C 6 )alkyl-, wherein m is 0, 1 or 2, and R 4 and R 5 are each independently selected from hydrogen or (C 1 -C β )alkyl, -C(=NR 6 )(N(R 4 ) 2 ), or -(C 1 -C 6 )alkyl-C(=NR 6 )(N(R 4 ) 2 ) wherein R 6 represents OR 2 or R 2 wherein R 2 is defined as above, with the proviso that the cycloalkenyl ring is not aromatic, with the proviso that R 1 must be substituted by at least one of R 3 C(0)0-, R 3 C(0)0- (C,-Cg)alkyl-, R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C,-C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- Where R 1 is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3- or 4-posιtιon, and more preferably at the 4-posιtιon Where R 1 is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-posιtιon In a preferred embodiment, R 1 is monosubstituted In a further preferred embodiment, R 1 is disubstituted In a preferred embodiment, R 1 is substituted by at least one of R 3 C(0)0- or R 3 C(0)0- (C 1 -C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R 3 C(0)0- In a further preferred embodiment, R is substituted by at least one of R 3 C(0)0-(C 1 - C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R 2 ON=, R 2 ON=(C r C 6 )alkyl-, or R 2 ON=CR 2 (C,-C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R 2 ON=. In a further preferred embodiment, R 1 is substituted by at least one of -NR 2 (OR 2 ) In a further preferred embodiment, R 1 is substituted by at least one of R 4 R 5 NS(0) 2 -, R R NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R S(0) 2 R 5 N(C,-C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R S(0) 2 R 5 N- In a further preferred embodiment, R 1 is substituted by at least one of R 4 S(0) 2 R 5 N(C,- C 6 )alkyl- In a further preferred embodiment, R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by R 3 C(0)0-, R 3 C(0)0-(C 1 -C 6 )alkyl-, R 2 ON=, R 2 ON=(C r C 6 )alkyl-, R 2 ON=CR 2 (C,-C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C,-C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C,-C 6 )alkyl-, wherein R 2 , R 3 , R 4 and R 5 are as defined above, with the proviso that the cycloalkenyl ring is not aromatic In a further preferred embodiment, R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C,-C 6 )alkyl-, R 2 ON=, or R 4 S(0) 2 R 5 N-, wherein R 2 , R 3 , R 4 and R 5 are as defined above, with the proviso that the cycloalkenyl ring is not aromatic In a preferred embodiment, R 1 is substituted by R 3 C(0)0- or R 3 C(0)0-(C,-C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R 3 C(0)0- ln a further preferred embodiment, R 1 is substituted by R 3 C(0)0-(C,-C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, or R 2 ON=CR 2 (C 1 -C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R 2 ON= In a further preferred embodiment, R 1 is substituted by -NR 2 (OR 2 ) In a further preferred embodiment, R 1 is substituted by R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by R S(0) 2 R 5 N- In a further preferred embodiment, R 1 is substituted by R 4 S(0) 2 R 5 N(C,-C 6 )alkyl- The (C 2 -C 9 )heterocycloalkyl substituent, when present on R 1 of the compound of formula I, is preferably a group of the formula wherein m is as defined above, and Z is CH 2 , NR 2 , O, S, SO, or S0 2 For any of the aforementioned compositions of the present invention, R 1 of the compound of formula I is preferably a group of the formula which is substituted as described above for R\ wherein n is 0, 1 , or 2, wherein the dashed line indicates an optional double bond at that position In a further preferred embodiment, n is 0 or 1 In a further preferred embodiment, n is 0, and the dashed line represents a double bond at that position In a further preferred embodiment, n is 1 In a further preferred embodiment, R 1 is substituted by =0, =NOH, CH 2 OH or .OH Me or a combination thereof In a further preferred embodiment, n is 0, R 1 is substituted by =NOH, and the dashed line represents a double bond at that position In further preferred embodiment, n is 1 , and R 1 is substituted by =0, =NOH, CH 2 OH, or .OH Me or a combination thereof The present invention further provides a topical pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skm-lightenmg or pigmentation-reducmg effective amount of a compound selected from the group consisting of 4-(2, 4-Dιhydroxyphenyl)cyclohexanone oxime, 0-Methyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 0-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-Dιhydroxyphenyl)-2-cyclohexen-1 -one oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanone oxime, (±)-tV-[3-(2,4-Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, (±)-4-[3-(Hydroxyamιno)cyclohexyl]-1 ,3-benzenedιol, (±)-0-Methyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, (±)-0-Benzyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-Dιhydroxyphenyl)-2-cyciopentenone oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclopentanone oxime, and a pharmaceutically acceptable salt thereof The present invention further provides a topical pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skm-lightenmg or pigmentation-reducmg effective amount of a compound selected from the group consisting of cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide, trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, frans-4-(2,4-Dιhydroxyphenyl)cyclohexyl) 4-(dιmethylamιno)benzoate, trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fert-butylbenzoate, traπs-4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fluorobenzoate, trans - 4-(2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - tπfluoromethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methoxybenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - chlorobenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate, [4-(2,4-Dιhydroxyphenyl)cyclohexyl]methyl propionate, cis /trans - 4- [4-(hydroxyamιno)cyclohexyl]-1 ,3 - benzenediol, trans - 4-[4-(methoxyamιno)cyclohexyl]-1 ,3 - benzenediol, and a pharmaceutically acceptable salt thereof In a further preferred embodiment, the skm-lightenmg or pigmentation-reducmg effective amount of a compound of formula I of the pharmaceutical composition of the present invention is a tyrosinase-inhibitmg effective amount of the compound The present invention further provides a topical pharmaceutical composition for inhibiting tyrosinase in a human, comprising a pharmaceutically acceptable carrier, and a tyrosinase-inhibitmg effective amount of a compound selected from among the compounds of any of the aforementioned pharmaceutical compositions of the present invention The present invention further provides a method of lightening skin or reducing the pigmentation of skin in a human, comprising administering to said human a skm-lightenmg or skin pigmentation-reducmg effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano, halo, (C 1 -C 6 )alkyl, aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 - C 9 )heteroaryl, aryl(C,-C 6 )alkyl-, =0, =CHO(C r C 6 )alkyl, am o, hydroxy, (C,-C 6 )alkoxy, aryl(C r C 6 )alkoxy-, (C,-C 6 )acyl, aryl(C 1 -C 6 )alkylamιno-, amιno(C 1 -C 6 )alkyl-, (C C 6 )alkoxy-CO-NH-, (C r C 6 )alkylamιno-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C r C 6 )alkyl-, (C 1 -C 6 )alkoxy(C l -C 6 )alkyl-, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl-, nitro, cyano(C r C 6 )alkyl-, halo(C,-C 6 )alkyl-, nιtro(C,-C 6 )alkyl-, trifluoromethyl, tπfluoromethyl(C 1 -C 6 )alkyl-, (C r C 6 )acylamιno-, (C 1 -C 6 )acylamιno(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamιno-, amιno(C r C 6 )acyl-, amιno(C,-C 6 )acyl(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkylamιno(C 1 -C 6 )acyl-, ((C,-C 6 ) alkyl) 2 amιno(C,-C 6 )acyl-, -C0 2 R 2 , -(C,-C 6 )alkyl-C0 2 R 2 , -C(0)N(R 2 ) 2 , -(C 1 -C 6 )alkyl-C(0)N(R 2 ) 2 , R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, R 2 ON=CR 2 (C r C 6 )alkyl-, -NR 2 (OR 2 ), -(C,-C 6 )alkyl-NR 2 (OR 2 ), - C(0)(NR 2 OR 2 ), -(C,-C 6 )alkyl-C(0)(NR 2 OR 2 ), -S(Q) m R 2 , wherein each R 2 is independently selected from hydrogen, R 3 C(0)0-, wherein R 3 is (C,- C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl-, R 3 C(0)0-(C r C 6 )alkyl-, R 4 R 5 N-C(0)-0-, R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl-, wherein m is 0, 1 or 2, and R 4 and R 5 are each independently selected from hydrogen or (C r C 6 )alkyl, -C(=NR 6 )(N(R 4 ) 2 ), or -(C 1 -C 6 )alkyl-C(=NR 6 )(N(R 4 ) 2 ) wherein R 6 represents OR 2 or R 2 wherein R 2 is defined as above, with the proviso that the cycloalkenyl πng is not aromatic, with the proviso that when R 1 is a (C 5 -C 8 )cycloalkyl ring, or when R 1 is a (C 5 - C 8 )cycloalkenyl ring having the following structure wherein n is 0, 1 , 2 or 3, where such (C 5 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring is substituted by hydroxy, (C r C 6 )alkoxy-, aryl(C r C 6 )alkoxy-, -OC(0)(C r C 6 )alkyl, -OC(0)aryl(C C β )alkyl, -OC(0)phenyl, halo, (C 1 -C 6 )alkyl-, aryl(C r C 6 )alkyl-, -SH, -S(C r C 6 )alkyl, aryl(C,- C 6 )alkyl-S-, -NH 2 -NH(C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkyl-HN- I then the (C 5 -C 8 )cycloalkyl ring or the (C 5 -C 8 )cycloalkenyl ring must be di- or tπ-substituted Where R 1 is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3- or 4-posιtιon, and more preferably at the 4-posιtιon Where R 1 is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-posιtιon In a preferred embodiment, R 1 is monosubstituted In a further preferred embodiment, R 1 is disubstituted In a preferred embodiment, R 1 of the compound of the method is substituted by at least one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, R ON=CR 2 (C r C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R S(0) 2 R 5 N(C r C 6 )alkyl- In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of R 3 C(0)0- or R 3 C(0)0-(C r C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by at least one of R 3 C(0)0- In a further preferred embodiment, R 1 is substituted by at least one of R 3 C(0)0-(C r C 6 )alkyl- In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of R 2 ON= R 2 ON=(C r C 6 )alkyl-, or R 2 ON=CR 2 (C 1 -C 6 )alkyl- In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of R 2 ON= In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of -NR 2 (OR 2 ) In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of R 4 S(0) 2 R 5 N- In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of R S(0) 2 R 5 N(C r C 6 )alkyl- In a further preferred embodiment, R 1 of the compound of the method is substituted by at least one of hydroxy(C 1 -C 6 )alkyl- In a further preferred embodiment, R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloaikenyl ring, wherein either the cycloalkyl ring or cycloalkenyl πng is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, R 2 ON=CR 2 (C 1 -C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl-, wherein R 2 , R 3 , R 4 and R 5 are as defined above In a further preferred embodiment, R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, or R S(0) 2 R 5 N-, wherein R 2 , R 3 , R 4 and R 5 are as defined above In a preferred embodiment, R 1 is substituted by one of R 3 C(0)0- or R 3 C(0)0-(C r C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by one of R 3 C(0)0- In a further preferred embodiment, R 1 is substituted by one of R 3 C(0)0-(C,-C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by one of R 2 ON=, R 2 ON=(C r C 6 )alkyl-, or R 2 ON=CR 2 (C,-C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by one of R 2 ON= In a further preferred embodiment, R 1 is substituted by one of -NR 2 (OR 2 ) In a further preferred embodiment, R 1 is substituted by one of R R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C,-C 6 )alkyl-, R S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- In a further preferred embodiment, R 1 is substituted by one of R 4 S(0) 2 R 5 N- in a further preferred embodiment, R 1 is substituted by one of R S(0) 2 R 5 N(C r C 6 )alkyl- ln a further preferred embodiment, R' of the compound of the method is substituted by one of hydroxy(C 1 -C 6 )alkyl-. The (C 2 -C 9 )heterocycloalkyl substituent, when present on R 1 of the compound of formula I, is preferably a group of the formula: wherein m is as defined above, and Z is CH 2 , NR 2 , O, S, SO, or S0 2 . For any of the aforementioned methods of the present invention, R of the compound of formula I is preferably a group of the formula. which is substituted as described above for R 1 ; wherein n is 0, 1 , or 2; wherein the dashed line indicates an optional double bond at that position. In a further preferred embodiment, n is 0 or 1 In a further preferred embodiment, n is 0, and the dashed line represents a double bond at that position. In a further preferred embodiment, n is 1 In a further preferred embodiment, R 1 is substituted by =0, =NOH, CH 2 OH or .OH Me or a combination thereof. In a further preferred embodiment, n is 0; R 1 is substituted by =NOH; and the dashed line represents a double bond at that position In further preferred embodiment, n is 1 , and R 1 is substituted by =0, =NOH, CH 2 OH, or .OH Me , or a combination thereof In a preferred embodiment, the method of the present invention comprises administering to a human a skin-lightening or pigmentation-reducmg effective amount of a compound selected from the group consisting of 4-(2, 4-Dιhydroxyphenyl)cyclohexanone, 4-(2, 4-Dιhydroxyphenyl)cyclohexanone oxime, 0-Methyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 0-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-dιhydroxyphenyl)-2-cyclohexen-1 -one, (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanone, 3-(2,4-Dιhydroxyphenyl)-2-cyclohexen-1-one oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanone oxime, (±)-4-[3-(1 -Pιperazιnyl)cyclohexyl]-1 ,3-benzenedιol, (±)-/V-[3-(2,4-Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, (±)-4-[3-(Hydroxymethyl)cyclohexyl]-1 ,3-benzenedιol, (±)-4-[3-(Hydroxyamιno)cyclohexyl]-1 ,3-benzenedιol, cis /trans-4-[4-(Hydroxymethyl)cyclohexyl]-1 ,3-benzenedιol, cis / tτans-4-(4-Hydroxy-4-methylcyclohexyl)-1 ,3-benzenedιol, (±)-0-Methyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, (±)-3-(2,4-Dιhydroxyphenyl)-1-methylcyciohexanol, (±)-0-Benzyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-Dιhydroxyphenyl)-2-cyclopentenone oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclopentanone, (±)-3-(2,4-Dιhydroxyphenyi)cyclopentanone oxime, and a pharmaceutically acceptable salt thereof In a further preferred embodiment, the method of the present invention comprises administering to a human a skm-lightenmg or pigmentation-reducmg effective amount of a compound selected from the group consisting of 4 - (2, 4 - Dihydroxyphenyl) - 3 - cyclohexen - 1 - one, cis /trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide, trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, 4 - [4 - (4 - Hydroxyphenyl)cyclohexyl] - 1 , 3 - benzenediol, cis / trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate, trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate, cis - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate, trans - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid, cis - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid, cis /trans - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid, cis / trans - [4-(2, 4-Dιhydroxyphenyl)cyclohexyl]acetonιtπle, cis /trans - 4 - [4-(2-Amιnoethyl)cyclohexyl]-1 ,3-benzenedιol, (±)-4-(3,3-Dιfluorocyclohexyl)-1 ,3-benzenedιol, (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanecarboxamιde, (±)-3-(2,4-Dιhydroxyphenyl)-Λ/-hydroxycyclohexanecarboxamιde, (±)-3-(2,4-Dιhydroxyphenyl)-tv-ethylcyclohexanecarboxamιde, (±)-4-[3-Hydroxy-3-(hydroxymethyl)cyclohexyl]-1 ,3-benzenedιol, (±)-Λ/-[3-(2,4-dιhydroxyphenyl)cyclohexyl]acetamιde, .rans-4-(2,4-Dιhydroxyphenyl)cyclohexyl) 4-(dιmethylamιno)benzoate, cis /trans - 4-(2,4-Dιhydroxyphenyl)cyciohexanecarboxylιc acid, trans-4-(2,4-Dιhydroxyphenyl)cyclohexyl ethylcarbamate, fraπs-4-(2,4-Dιhydroxyphenyl)cyclohexyl cyclohexylcarbamate, trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-terf-butylbenzoate, frans-4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fluorobenzoate, trans - 4-(2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - tπfluoromethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methoxybenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - chlorobenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate, frans-4-[4-(Phenylsulfanyl)cyclohexyl]-1 ,3-benzenedιol, trans - 4-[4 - (Phenylsulfonyl)cyclohexyl] - 1 , 3 - benzenediol, [4-(2,4-Dιhydroxyphenyl)cyclohexyl]methyl propionate, ethyl 4 - (2, 4 - dihydroxyphenyl) - 1 - hydroxycyclohexane carboxylate, s /trans - 4- [4-(hydroxyamιno)cyclohexyl]-1 ,3 - benzenediol, trans - 4-[4-(methoxyamιno)cyclohexyl]-1 ,3 - benzenediol, and a pharmaceutically acceptable salt thereof In a preferred embodiment, the skm-lightenmg or pigmentation-reducing effective amount of a compound of the method of the present invention is a tyrosinase-inhibitmg effective amount of the compound The present invention further provides a method of inhibiting tyrosinase in a human in need of said treatment, comprising administering to said human a tyrosinase-inhibitmg effective amount of a compound selected from among the compounds used in any of the aforementioned methods of the present invention The present invention further provides a topical or transdermal pharmaceutical composition for the treatment of an inflammatory disorder such as psoriasis, dermatitis or acne, or for the treatment of dandruff, in a human, comprising a pharmaceutically acceptable carrier, and an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, used in any of the aforementioned pharmaceutical compositions of the present invention, which amount is effective in treating such disorder or condition The present invention further provides a method of treating inflammatory disorders, such as psoriasis, dermatitis or acne, or a method of treating dandruff, in a human, comprising administering to said human an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, used in any of the aforementioned methods of the present invention, which amount is effective in treating such disorder or condition The present invention further provides a use of any of the compounds used in any of the aforementioned methods of the present invention, or any of the compounds used in any of the aforementioned pharmaceutical compositions of the present invention, to prepare a medicament useful in lightening skin or reducing pigmentation of skin in a human The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof Any substituents or functional groups on the alkyl group, as indicated herein, can be substituted anywhere on the alkyl group The term "aryl", as used herein, refers to phenyl or naphthyl optionally substituted with one or more substituents, preferably from zero to two substituents, independently selected from halogen, OH, (C r C 6 )alkyl, (C Cg) alkoxy, ammo, dι-((C r Cg)alkyl))amιno, nitro, cyano and trifluoromethyl Any substituents or functional groups on the aryl group, as indicated herein, can be substituted anywhere on the aryl group The term "one or more substituents", as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites The "halo", as used herein, refers to halogen and, unless otherwise indicated, includes chloro, fluoro, bromo and lodo The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl, or arylalkyloxy and the terms "alkyl" or "aryl" are as defined above The term "acyloxy", as used herein, includes O-acyl groups wherein "acyl" is as defined above (C 2 -C 9 )Heterocycloalkyl, when used herein, refers to pyrrolidmyl, tetrahydrofuranyl , dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziπdinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidmyl, 1 ,3-oxazolιdιn-3-yl, isothiazolid yl, 1 ,3-thιazolιdιn-3-yl, 1 ,2- pyrazolιdιn-2-yl, 1 ,3-pyrazolιdιn-1-yl, pipendinyl, thiomorpholmyl, 1 ,2-tetrahydrothιazιn-2-yl, 1 ,3- tetrahydrothιazιn-3-yl, tetrahydrothiadiazmyl, morpholmyl, 1 ,2-tetrahydrodιazιn-2-yl, 1 ,3- tetrahydrodιazιn-1-yl, tetrahydroazepmyl, piperazmyl, chromanyl, etc One of ordinary skill in the art will understand that the connection of said (C 2 -C 9 )heterocycloalkyl ring can be through a carbon atom or through a nitrogen heteroatom where possible (C 2 -C 9 )Heteroaryl, when used herein, refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, tπazolyl, tetrazolyl, imidazolyl, 1 ,3,5-oxadιazolyl, 1,2,4- oxadiazolyl, 1 ,2,3-oxadιazolyl, 1 ,3,5-thιadιazolyl, 1 ,2,3-thιadιazolyl, 1 ,2,4-thιadιazolyl, pyπdyl, pyπmidyl, pyrazmyl, pyπdazinyl, 1 ,2,4-tπazιnyl, 1 ,2,3-tπazιnyl, 1 ,3,5-tπazιnyl, pyrazolo[3,4- b]pyπdιnyl, cmnolinyl, pteπdinyl, puπnyl, 6,7-dιhydro-5H-[1]pyπdιnyl, benzofb]thιophenyl, 5, 6, 7, 8-tetrahydro-quιnolιn-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, mdolyl, indolizmyl, mdazolyl, isoqu olyl, qumolyl, phthalazmyl, qumoxalinyl, quinazolmyl, benzoxazmyl, etc One of ordinary skill in the art will understand that the connection of said (C 2 - C 9 )heterocycloalkyl rings can be through a carbon atom or through a nitrogen heteroatom where possible Compounds of formula I may contain chiral centers and therefore may exist in different enantiomeπc and diastereomeπc forms This invention relates to all optical isomers, stereoisomers and tautomers of the compounds of formula I, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively Formula I, as defined above, also includes compounds identical to those depicted but for the fact that one or more hydrogen, carbon or other atoms are replaced by isotopes thereof Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays The present invention also relates to the pharmaceutically acceptable acid addition and base salts of any of the aforementioned compounds of formula I The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ι_§_, salts containing pharmacologically acceptable anions, such as the hydrochloπde, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, sucemate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i e , 1 ,1-methylene-bιs-(2-hydroxy-3-naphthoate)) salts Detailed Description of the Invention The compounds of formula I may be prepared as described in the following reaction schemes and discussion Unless otherwise indicated, n, m, R 2 , R 3 , R 4 , R 5 , Z, and structural formula I in the reaction schemes and discussion that follow are as defined above Scheme 1 (1) (2) (3) Scheme 2 Scheme 3 Scheme 4 Scheme 5 Scheme 6 (6), (8) or (9), (14) or (15) Scheme 7 (6)(8) (31 : Scheme 8 Scheme 9 Scheme 10 Scheme 11 Scheme 12 Y, Y 1 , Y" shown in the schemes above each independently represents any of the various substituents on R 1 as defined above, or hydrogen as appropriate Reaction Schemes 1 through 12 illustrate various methods of synthesizing compounds of formula I PG refers to a protecting group Referring to Scheme 1 , compounds of formula (2) can be formed by protecting commercially available 4-bromoresorcιnol (1) A suitable protecting group such as methoxymethyl (MOM) can be introduced by conventional methods that are well known to those skilled in the art For example, alkylation of 4-bromoresorcιnol can occur with two equivalents of methoxymethyl chloride in the presence of di/sopropylamine in a halogenated solvent at about 0°C to room temperature Compounds of general formula (3) can be obtained using conventional methods For example, the reaction of compounds of formula (2) with n-butyllithium in the presence of tv,Λ/,N,/V etramethylethylenedιamιne in a suitable solvent such as tetrahydrofuran, followed by quenching with trusopropyl borate and hydrolysmg with aqueous acid, can yield compounds of formula (3) Compounds of general formula (5) can be obtained using conventional methods For example, the treatment of compounds of formula (4) with tπphenylphosphine and bromine in a chlorinated solvent will yield compounds of formula (5) Compound (4) where n=1 is commercially available (Aldπch, Milwaukee, Wl, USA) Compounds of formula (6) can be obtained by reacting compounds of formula (3) with compounds of formula (5) under Suzuki coupling conditions For example, the Suzuki reaction can be carried out using palladium tetrakis (tπphenylphosphιne)palladιum (five mole percent), sodium carbonate (two equivalents) and heating in a suitable solvent system (e g , dimethoxyethane/water) at about 80°C Conversion of compounds of formula (6) to compounds of formula (8) can occur under standard reducing conditions, such as, e g , hydrogen gas and a metal catalyst such as rhodium on alumina, at about room temperature and atmospheric pressure Deprotection of compounds of formula (6) or (8) under suitable conditions, e g , where the protecting group is MOM, heating at 50°C in methanol with acidic Dowex, gives compounds of formula I where R 1 is substituted with =0 (7), (9) Compounds of formula (7) or (9) can be further deπvatised under standard conditions to yield resoremols of formula I where R 1 is substituted with =NOR 2 For example, heating compounds of formula (7) in a suitable solvent (e g , ethanol) at about 80°C with the required hydroxylamme hydrochloπde salt and tπethylamine yields the analogues of formula I Compounds of formula I where R 1 is substituted with NHOR 2 can be prepared from compounds of formula I where R 1 is substituted with =NOR 2 by a reduction under standard reaction conditions, e g , sodium cyanoborohydπde in acetic acid at or about room temperature Compounds of formula (8) can be further deπvatised under standard conditions to yield resoremols of formula I where R 1 is disubstituted with fluoro For example, treating compounds of formula (8) with diethylammosulfur trifluoπde in a suitable solvent, e g dimethoxyethane, after suitable deprotection, would give analogues of formula I Referring to Scheme 2, compounds of the general formula (10) are well known and can be obtained using conventional methods (see, e g , Crombie ef al , 1982, J Chem Soc Perkm Trans I, 1485) Compounds of formula (11) can be obtained from the reaction of compounds of formula (2) with n-butyllithium in the presence of Λ/.Λ/./V.tV- tetramethylethylenediamine in an ethereal solvent, followed by the addition of a compound of formula (10) Dehydration of compounds of formula (11) under standard conditions, e g , heating compounds of formula (11) at about 1 10°C in a Dean-Stark apparatus in the presence of camphor sulfonic acid in a suitable solvent (e g , toluene), yields compounds of formula (12) Hydrogenation under standard conditions, e g , using hydrogen gas and palladium on charcoal in ethanol, yields compounds of the general formula (13) Deprotection under suitable conditions yields resoremols of formula I where R 1 is substituted with =0 (14) Compounds of formula (14) can be further deπvatised under standard conditions to yield resoremols of formula I where R 1 is substituted with =NOR 2 For example, heating compounds of formula (14) in a suitable solvent (e g , ethanol) at about 80°C with the required hydroxylamine hydrochloπde salt and tπethylamine yields analogues of formula I Further reduction under standard conditions would yield compounds of formula I, where R 1 is substituted with NHOR 2 Compounds of formula (14) can also be reprotected with a suitable protecting group such as ferf-butyldimethylsilyl under standard reaction conditions to yield compounds of formula (15) Compounds of formula (15) can be further deπvatised using standard reaction conditions For example, methylenation using an appropriate Wittig will yield compounds of formula (16), e g , treatment of methyltπphenylphosphonium bromide with potassium f- butoxide in a suitable solvent (e g , tetrahydrofuran) at a temperature between -78°C and 0°C, followed by the addition of a compound of formula (15) will yield compounds of formula (16) Subsequent conversion to compounds of formula (18) under standard conditions, e g hydroboration, to give compounds of formula (17), and further oxidation using suitable conditions, such as pyπdinium dichromate in dimethylformamide at room temperature, gives compounds of formula (18) Compounds of formula (17) can be treated with an alkyl bromide in a suitable solvent (e g , acetone) in the presence of potassium carbonate to yield compounds of formula I where R' is substituted with an ether group after suitable deprotection has taken place, e g when the protecting group is tert-buty Id imethylsiiyl , tetrabutylammonium fluoride in tetrahydrofuran can be used Alternatively compounds of formula (17) can also be esteπfied under standard conditions, e g treatment with an acid chloride in the presence of tπethylamine in a chlorinated solvent at about room temperature Compounds of formula (18) can be deπvatised to form analogues such as esters and amides under conditions well known to those with skill in the art For example, conditions to form amides may involve treating compounds of formula (18) with /so-butylchloroformate and tπethylamine in a chlorinated solvent at about 0°C, followed by the addition of a suitable amine Deprotection under suitable conditions will yield compounds of formula I where R is substituted with an amide Deprotection of compounds of formula (16), (17) and (18) under standard conditions also provides compounds of formula I where R 1 is substituted with methylene, hydroxylmethyl or a carboxylic acid, respectively Referring to Scheme 3, compounds of formula (20) can be prepared starting with compound (19), which is commercially available Conversion to compounds of formula (20) can occur under standard conditions such as, for example, where the protecting group is benzyl, condensation can occur between compound (19) and benzyl alcohol with the removal of water using a Dean-Stark apparatus in conjunction with well known methodology Condensation of compounds of formula (20) with compounds of formula (10) can occur using standard techniques, for example, treatment of compounds of formula (20) with a base such as lithium di/sopropylamide in an ethereal solvent followed by the addition of a compound of formula (10) would give compounds of formula (21) Treatment of compounds of formula (21) with a suitable reagent such as / -bromosuccιnιmιde in a chlorinated solvent at about room temperature can give compounds of formula (22) Compounds of formula (23) can then be generated from compounds of formula (22) under suitable conditions Such conditions can involve treating compounds of formula (22) with a base such as 1 ,8-dιazobιcyclo[5 4 0]undec- 7-ene in a suitable solvent such as W,Λ/-dιmethylformamιde at about 140°C Treatment of compounds of formula (23) to standard hydrogenation conditions, e g , hydrogen gas and palladium on charcoal in ethanol, yields compounds of the general formula (24) when the protecting group is benzyl Compounds of formula (14) can then be obtained by treating compounds of formula (24) to acidic conditions Conversion of compounds of formula (14) to compounds of formula I may involve the need to use protecting groups that will be obvious to those of skill in the art Some examples of such compounds of formula I are illustrated in Scheme 3 Conversion of compounds of formula (15) to compounds of formula I may involve the reduction of the ketone moiety under standard conditions, e g , sodium borohydπde in ethanol Further deπvitisation can occur, e g using chemistry described elsewhere in this document, to give compounds of formula I where Y' may be alkyl, acyl or a earbonylammo In examples where protecting groups have been used, suitable deprotection will be required to yield compounds of formula I Alternatively, compounds of formula (15) can be manipulated to give compounds of formula I where R 1 is substituted with an amide or sulfonamide Treatment of compounds of formula (15) with benzylamme under reductive amination conditions, e g , one equivalent of sodium tπacetoxyborohydπde in a suitable solvent (dichloroethane) followed by hydrogenolysis under standard conditions, e g , palladium on charcoal, hydrogen gas, ethanol, provides compounds of formula (25) Synthesis of compounds of formula I can be obtained using conventional methods For example, compounds of formula (25) can react with sulfonyl chlorides and acid chlorides in a chlorinated solvent in the presence of a base (e g tπethylamine) at about room temperature Deprotection using suitable reaction conditions provides compounds of formula I where Y is a sulfonamide or amide group Referring to Scheme 4, compounds of formula (26) can be synthesized using standard methods For example, compounds of formula (6) or (8) can be homologated using a Wittig reaction and further manipulated as described above to yield compounds of formula I Compounds of formula (26) or (16) from Scheme 2 can also undergo dihydroxylation under standard conditions, e g catalytic osmium tetroxide and Λ/-methyl morpholme in an ethereal solvent, and after suitable deprotection yield compounds of formula I where R 1 is substituted Referring to Scheme 5, compounds of formula (29) can be obtained by reacting compounds (6) or (8) as described above in Scheme 3 Compounds of formulae (29) and (25) can also be deπvatised by treating with an alkylating agent, e , an alkyl iodide in a chlorinated solvent in the presence of tπethylamine at about room temperature, to give compound (30) prior to sulfonylation or amide bond formation and deprotection, to yield compounds of formula I wherein Y is -N(R 5 )S0 2 R 4 or equivalent amide where R 5 is not hydrogen Referring to Scheme 6, compounds of formula (6), (8) or (9), (14) or (15) can be treated with a suitable organometallic reagent such as a Gπgnard reagent, in an ethereal solvent at a temperature between -78°C and 0°C, followed by deprotection to yield compounds of formula I where R 1 is substituted with (R 2 )OR 2 Referring to Scheme 7, compounds of formula (31 ) can be formed under conditions well known to those skilled in the art Treatment of compounds (6) or (8) with an amine, such as pipeπdine, in a suitable solvent (e g , dichloroethane) and a reducing agent such as sodium tπacetoxyborohydπde, followed by deprotection will yield compounds of formula I where R 1 is substituted with a nitrogen-containing heterocycle Referring to Scheme 8, compounds of general formula (33) can be obtained using conventional methods For example, the reaction of compounds of formula (2) with n- butyllithium in the presence of N N N N -tetramethylethylenediamine in a suitable solvent such as tetrahydrofuran, followed by quenching with ketone (32) (commercially available from Aldπch), and hydrolysing with aqueous acid, can yield compounds of formula (33) Functional group manipulation as outlined in Schemes 1 -7 and Scheme 8 then allows the synthesis of compounds of formula I Referring to scheme 9, compounds of formula (15), (6) or (8) can be further deπvatised to yield compounds of formula (34) using standard Wittig or Wadworths-Emmons chemistry, followed by suitable deprotection Compounds of formula (34) can be reduced using standard hydrogenation as described above to yield compounds where Y is OH, O- alkyl, or an ammoalkyl Standard Wadworths-Emmons chemistry can also yield compounds of formula (35) Reduction under suitable conditions will yield compounds of formula (36), which can be further deπvatised using standard chemistry described previously in this document to give compounds where NY'Y" ιs an amide, sulfonamide, or ammoalkyl Referring to Scheme 10, compounds of formula (10) can be converted into compounds of formula (37) using standard alkylation procedures For example, compound (10) can be treated with a suitable base such as lithium di/sopropyl amide in a suitable solvent such as tetrahydrofuran at a temperature between -78°C and 0°C, followed by the addition of a suitable alkylating agent Such alkylating agents are well known to those of skill in the art, and can include chloro, bromo, or lodoalkyl compounds, epoxides, aldehydes, aziπdines, α,β- unsaturated esters, ketones or amides, acyl chlorides, electrophilic sources of oxygen such as Mo(CO) 5 pyridme (Cπmmons, M T et al , 1992, J Am Chem Soc , 114 5445), or electrophilic sources of nitrogen such as 2,4,6-tπ/sopropylbenzene sulfonyl azide (Evans, P A et al , 1992, Tetrahedron Lett 33 6959) Such alkylating reagents are commercially available or can be prepared by standard procedures well known to those of skill in the art Compounds of formula (37) can be further manipulated using methodology similar to that described above For instance, alkylation of compounds of formula (37) under conditions of kinetic deprotonation (see, e g , Kopka, I and Rathke, M W , 1981 , J Org Chem 46 3771 ), followed by alkylation as previously described, would yield compounds of formula (38) Alternatively, alkylation of compounds of formula (37) under conditions of thermodynamic deprotonation (Kopka and Rathke, 1981 , above), followed by alkylation as previously described, would yield compounds of formula (45) Further alkylation or functional group manipulation known to those of skill in the art and, as described elsewhere in this document, followed by removal of the carbonyl protecting group under standard conditions, e , aqueous hydrochloric acid at about 0°C to 50°C, would yield compounds of formulae (40), (46), and (49) Compounds of formula (37) can also be protected with a suitable protecting group, e g , ethylenedithio ketal, and after removal of the ketal protecting group under standard reaction conditions, e.g., aqueous hydrochloric acid at about 0°C to 50°C, would allow further functionalisation of the cycloalkyl ring using the methodology described above to yield compounds of formula (44) Referring to Scheme 11 , compounds of formula (50) can be formed from compounds of formula (10) using known methodology (see, e.g., Adam, W et al , 1989, Tetrahedron Lett 30 6497) (Ts = tosyl) Standard functional group manipulation yields compounds of formula (55) and (57) Oxirane ring cleavage by an amine yields compounds of formula (51) Alternatively, acid hydrolysis yields compounds of formula (52) Conversion of the corresponding alcohol to a leaving group such as para-toluenesulfonyl would allow the nucleophilic displacement with a range of nucleophiles under standard, well-known conditions Such nucleophiles may include amines, thiolates, alkoxides, and carbon-based nucleophiles such as cyanide, which are commercially available or prepared by standard procedures well known to those of skill in the art Compounds of formula (40), (44) and (49) can be prepared using the above-described methods or other methods known in the art such that substituents on R 1 are as defined above Referring to Schemes 10 and 11 , ketones of formulae (37), (38), (40), (42), (43), (44), (45), (46), (47), (49), (51), (54), (55), and (57) can be further manipulated as described in Schemes 1-9 above, and converted into compounds of formula I as described in Schemes 2 and 3 Referring to Scheme 12, compounds of formula I can also be prepared using the methodology described above Compounds of formula (58) can be converted into compounds of formula I using the chemistry as described in Schemes 1 -1 1 above It will be appreciated by those of skill in the art that in the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups The use of protecting groups is well-known in the art, and is fully described, among other places, in Protecting Groups in Organic Chemistry, J W F McOmie, (ed ), 1973, Plenum Press, and in Protecting Groups in Organic Synthesis, 2 nd edition, T W Greene & P G M Wutz, 1991 , Wiley-lnterscience The compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt The acid addition salts of the active base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol Upon careful evaporation of the solvent, the desired solid salt is readily obtained Those compounds of formula I that are acidic in nature are capable of forming base salts with various pharmaceutically acceptable cations Examples of such salts include the alkali metal and alkaline earth metal salts and, particularly, the sodium and potassium salts These salts can be prepared by conventional techniques The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of formula I Such non-toxic base salts include those derived from such pharmaceutically acceptable cations as sodium, potassium, calcium and magnesium, etc These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure Alternatively, they can also be prepared by mixing lower alkano c solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness, as described above In either case, stoichiometπc quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final products Compounds of formula I and their pharmaceutically acceptable salts (hereinafter "the active compounds used in this invention") are useful in the treatment of disorders of human pigmentation, including solar and simple lentigmes (including age/liver spots), melasma/chloasma and postmflammatory hyperpigmentation Such compounds reduce skin melanin levels by inhibiting the production of melanin, whether the latter is produced constitutively or in response to UV irradiation (such as sun exposure) Thus, the active compounds used in this invention can be used to reduce skin melanin content in non- pathological states so as to induce a lighter skin tone, as desired by the user, or to prevent melanin accumulation in skin that has been exposed to UV irradiation They can also be used in combination with skin peeling agents (including glycolic acid or tπchloroacetic acid face peels) to lighten skin tone and prevent repigmentation The appropriate dose regimen, the amount of each dose administered, and specific intervals between doses of the active compound will depend upon the particular active compound employed, the condition of the patient being treated, and the nature and severity of the disorder or condition being treated Preferably, the active compound is administered in an amount and at an interval that results in the desired treatment of or improvement in the disorder or condition being treated An active compound used in the present invention can also be used in combination with sun screens (UVA or UVB blockers) to prevent repigmentation, to protect against sun or UV-mduced skin darkening or to enhance their ability to reduce skin melanin and their skin bleaching action An active compound used in the present invention can also be used in combination with retmoic acid or its derivatives or any compounds that interact with retinoic acid receptors and accelerate or enhance the invention's ability to reduce skin melanin and skin bleaching action, or enhance the invention's ability to prevent the accumulation of skin melanin An active compound used in the present invention can also be used in combination with 4-hydroxyanιsole The active compounds used in this invention can also be used in combination with ascorbic acid, its derivatives and ascorbic-acid based products (such as magnesium ascorbate) or other products with an anti-oxidant mechanism (such as resveratrol) which accelerate or enhance their ability to reduce skin melanin and their skin bleaching action This invention relates both to methods of lightening or reducing the pigmentation of skin in which the compound of formula I, or pharmaceutically acceptable salt thereof, and one or more of the other active ingredients referred to above are administered together, as part of the same pharmaceutical composition, as well as methods in which they are administered separately as part of an appropriate dose regimen designed to obtain the benefits of the combination therapy The appropriate dose regimen, the amount of each dose administered, and specific intervals between doses of each active agent will depend upon the specific combination of active agents employed, the condition of the patient being treated, and the nature and severity of the disorder or condition being treated Such additional active ingredients will generally be administered in amounts less than or equal to those for which they are effective as single topical therapeutic agents The FDA approved dosages for such active agents that have received FDA approval for administration to humans are publicly available The active compounds of the present invention are generally administered in the form of pharmaceutical compositions comprising at least one of the compounds of formula (I), together with a pharmaceutically acceptable vehicle or diluent Such compositions are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate for topical administration, in the form of solutions, gels, creams, jellies, pastes, lotions, ointments, salves, aerosols and the like Examples of vehicles for application of the active compounds of this invention include an aqueous or water-alcohol solution, an emulsion of the oil-m-water or water-in-oil type, an emulsified gel, or a two-phase system Preferably, the compositions according to the invention are in the form of lotions, creams, milks, gels, masks, microspheres or nanospheres, or vesicular dispersions In the case of vesicular dispersions, the lipids of which the vesicles are made can be of the ionic or nonionic type, or a mixture thereof As used herein, a "skm-lightenmg or pigmentation reducing amount of a compound of formula I", and the like, means an amount or concentration of the compound capable of detectably lightening skin or reducing pigmentation in a human, as determined by any standard assay The active compound is typically administered in a pharmaceutical composition and for a standard course of treatment that produces the desired result of skin depigmentation As used herein, a "tyrosinase-inhibitmg effective amount of a compound of formula I", and the like, means an amount or concentration of the compound capable of detectably inhibiting tyrosinase activity in a human, as determined by any standard assay As used herein, an "amount of a compound of formula I capable of treating an inflammatory disorder such as psoriasis, dermatitis or acne, or treating dandruff', and the like, means an amount or concentration of the compound capable of detectably ameliorating, reducing, eliminating, slowing, or preventing the progression of, any symptom or condition associated with or caused by such disorder or condition, in a human, as determined by any standard assay In the depigmentmg compositions according to the present invention, the concentration of the active compound of the invention is generally between 0 01 and 10%, preferably between 0 1 and 10%, relative to the total weight of the composition The compositions of this invention can optionally also contain a moistener, a surfactant, keratolytic, an anti-inflammatory agent, a complexmg agent, an antioxidant, a preservative, a fragrance, or a sunscreen The ability of compounds of formula I to inhibit tyrosinase may be determined using any of the following procedures 1 Tyrosinase (DOPA oxidase) assay using cell lysate Human melanoma cell line, SKMEL 188 (licensed from Memorial Sloan-Ketteπng), is used in the cell lysate assay and the screen In the assay, compounds and L-dihydroxyphenylalanine (L-DOPA) (100 μg/ml) are incubated with the cell lysates containing human tyrosinase for 8 hrs before the plates are read at 405 nm Potency of the compounds in DOPA oxidase assay is correlated very well with that in tyrosme hydroxylase assay using 3 H-tyrosιne as a substrate Most of the compounds of formula I that were tested in this assay exhibited an IC 50 of less than 10 μM For example, the compound of Example 23, / e , (±)-3- (2,4-Dιhydroxyphenyl)cyclopentanone oxime, had an IC 50 in this assay of about 2 μm 2 Melanin assay in human primary melanocytes Compounds are incubated with human primary melanocytes in the presence of α- melanocyte stimulating hormone (α-MSH) for 2-3 days Cells are then lysed with sodium hydroxide and sodium dodecyl sulfate (SDS) and melanin signals are read at 405 nm Alternatively, 14 C-DOPA is added to the cells in combination with tyrosinase inhibitors and acid-insoluble 14 C-melanιn is quantitated by a scintillation counter IC 50 's reflect the inhibitory potency of the compounds in the new melanin synthesis that was stimulated by α-MSH 3 Tyrosme kinase assay (TK) TK assays can be performed using purified tyrosme kinase domains of c-met, erb-B2, or IGF-r A specific antibody against phosphorylated tyrosme residue is used in the assay Coloπmetπc signals are generated by horse radish peroxidase, which is conjugated to the antibody 4 Human skin equivalent model A mixture of human melanocytes and keratmocytes is grown in an air-liquid mterphase This tissue culture forms a three dimensional structure that histologically and microscopically resembles the human skin epidermis Test compounds are added on top of the cells to mimic topical drug application After incubation with the compounds (10 μM) for 3 days, the cells are washed extensively and lysed for DOPA oxidase assay 5 IL-1 assay (lnterleukιn-1 assay) An IL-1α ELISA assay (R&D system) can be used to evaluate the effect of compounds on IL-1 secretion in a human skin equivalent model IL-1α is a pro-inflammatory cytok e and plays a role in UV-mduced skin inflammation 6 In vivo study Black or dark brown guinea pigs with homogeneous skin color can be used in this study A solution of the test compound of formula I (5% in ethanol propylene glycol, 70 30) and the vehicle control are applied to the animals twice daily, 5 days per week for 4-8 weeks Using this assay, depigmentation can be determined by subtracting the light reflectance of untreated skin from the light reflectance of treated skin The present invention is illustrated by the following examples It will be understood, however, that the invention is not limited to the specific details of these examples Melting points are uncorrected Proton nuclear magnetic resonance spectra (400 MHz 1 H NMR) were measured for solutions in d 6 -DMSO, CDCI 3 , or d 4 -MeOH, and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS) The peak shapes are denoted as follows s, singlet, d, doublet, t, triplet, q, quartet, m, multiplet, b, broad The following examples are illustrative only, and are not intended to limit the scope of the present invention EXAMPLES Intermediate 1 1 -Bromo-2,4-bis(methoxymethoxy)benzene An oven dried 250 ml round bottomed flask equipped with magnetic stirrer, under an argon atmosphere, was loaded with 4-bromoresorcιnol (9 45 g, 50 mmol) and CH 2 CI 2 (50 ml) The stirred suspension was cooled to 0°C and di/sopropylamine (19 1 ml, 110 mmol) was added in one portion via syringe Stirring of the red solution was continued for a further ten minutes before methyl chloromethyl ether (10 7 ml, 120 mmol) was added dropwise, via syringe, ensuring the internal temperature did not exceed 10°C The resulting yellow solution was then allowed to warm to room temperature overnight Ammonium hydroxide solution (50 mL, 50%) was poured into the reaction vessel and stirring was continued for one hr The mixture was poured into a separating funnel and the phases separated The aqueous phase was then extracted with CH 2 CI 2 (3x30 ml) and the combined organics washed with brine (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo affording an orange oil Purification was achieved by flash column chromatography, (Sι0 2 , ethyl acetate/petroleum ether, 1 1 , v/v), furnishing the title product (10 7 g, 77%) as a pale yellow oil δ H (CDCI 3 ) 7 42 (1 H, d), 6 88 (1 H, d), 6 64 (1 H, dd), 5 24 (2H, s), 5 15 (2H, s), 3 53 (3H, s), 3 48 (3H, s) Intermediate 2 8-[2,4-S s(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol A round bottomed flask, equipped with magnetic stirrer, under an argon atmosphere was loaded with 1-bromo-2,4-b/s(methoxymethoxy)benzene (2 00 g, 7 2 mmol) and THF (50 mL) N, N, N', N - Tetramethylethylene diamme (2 3 ml, 15 2 mmol) was added in one portion via syringe and the stirred solution was cooled to -78°C n-Butyl lithium (9 5 ml, 15 2 mmol, 1 6M in hexane) was added dropwise via syringe The resulting yellow solution was stirred for 1 hr at -78°C and 1 ,4-cyclohexanedιone monoethylene ketal (1 35 g, 8 7 mmol) was added as a solution in THF (25 ml) slowly, via syringe The resulting solution was stirred at -78°C for 1 hr and then allowed to warm to room temperature overnight Hydrochloric acid (20 ml, 2M) was added and the reaction mixture stirred vigorously for 15 mm Ethyl acetate (100 ml) was added and the mixture poured into a separating funnel The phases were separated and the aqueous phase was extracted with ethyl acetate (3x20 ml) The combined organics were washed with brine (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated affording an orange oil which was purified by flash column chromatography (Sι0 2 , ethyl acetate/petroleum ether, 45 55, v/v) The title product (1 42 g, 56%) was isolated as a colourless oil m/z (ES + ) 337 (M - H 2 0 + H + ), δ H (CDCI 3 ) 1 61 - 1 64(2H, m), 2 00 - 2.18(6H, m), 3.44(3H, s), 3.48(3H, s), 3.90 - 3.97(4H, m), 5 11 (2H, s), 5.24(2H, s), 6.64(1 H, dd), 6.82(1 H, d), 7.20(1 H, d). Intermediate 3 8-[2,4-B/s(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene 8-[2,4-S s(methoxymethoxy)phenyl]-1 ,4-dιoxaspιro[4.5]decan-8-ol (1.40 g, 3.95 mmol) was placed in a 50ml round bottomed flask equipped with magnetic stirrer and Dean-Stark apparatus. Toluene (30 ml) was added, followed by camphor sulphonic acid (10 mg) The stirred solution was then heated under reflux for 1 hr, cooled and saturated aqueous sodium bicarbonate solution (10 ml) added. The mixture was poured into a separating funnel and the phases separated. The aqueous phase was extracted with ethyl acetate (2x15 ml) and the combined organics were washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered and then concentrated in vacuo yielding an orange oil which was purified by flash column chromatography (Si0 2 , ethyl acetate/petroleum ether, 45:55, v/v) to afford the title product (0.94 g) as a colourless oil. δ H (CDCI 3 ) 1.84 (2H, t), 2.41 - 2.43 (2H, m), 2.56 - 2.62 (2H, m), 3.47 (6H, s), 3.98 - 4.02 (4H, m), 5.13 (4H, s), 5.58 - 5.63 (1 H, m), 6.64 (1H, dd), 6.78 (1 H, d), 7.08 (1 H, d) Intermediate 4 8-[2,4-B/s(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane 8-[2,4-β/s(methoxymethoxy)phenyl]-1 ,4-dιoxaspιro[4.5]dec-7-ene (0.950 g, 2.83 mmol) and palladium (200 mg, 10% on carbon) were stirred under an atmosphere of hydrogen for 15hr The mixture was then filtered through a plug of Celite, washing with ethyl acetate The filtrate was then evaporated to dryness, affording the desired product (0.955 g, 100%) as a colourless oil. δ H (CDCI 3 ) 1.67 - 1.87 (8H, m), 2.90 - 2.99 (1 H, m), 3 46 (3H, s), 3.48 (3H, s), 3.97 (4H, s), 5.12 (2H, s), 5.18 (2H, s), 6.65 (1 H, dd), 6.78 (1 H, d), 7.12 (1 H, d). Intermediate 5 4 - [2, 4 - 5/s(methoxymethoxy)phenyl]cyclohexanone A round bottomed flask equipped with magnetic stirrer was charged with 8 - [2, 4 - b/s(methoxymethoxy)phenyl] - 1 , 4 - dιoxaspιro[4.5]decane (3.20 g 9.47 mmol) and methanol (50 ml). Over a 20mιn period, aqueous hydrochloric acid (50 ml, LOOM) was added to the stirred solution, at room temperature and the reaction mixture stirred for 1.5 hr. Solid sodium bicarbonate was added until the reaction mixture was neutralised and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml), and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The crude product was purified via flash column chromatography (Si0 2 , ethyl acetate / petroleum ether, 1 4, v/v), affording the title compound (2 20 g, 60%) as a white powder δ H (CDCI 3 ) 1 85 - 1 96 (2H, m), 2 14 - 2 22 (2H, m), 2 46 - 2 59 (4H, m), 3 39 (1 H, tt), 3 49 (3H, s), 3 52 (3H, s), 5 16 (2H, s), 5 23 (2H, s), 6 67 - 6 71 (1 H, m), 6 85 (1 H, m), 7 08 (1 H, d) Intermediate 6 3-[2,4- j s(methoxymethoxy)phenyl]-2-cyclohexen-1-one Aqueous sodium carbonate (2 ml of a 6M solution) and 2,4- b/s(methoxymethoxy)phenylboronιc acid (120 mg) in ethanol (2 ml) were added to a solution of palladium tetrakιs(tπphenylphosphιne) (57 mg) and 3-bromo-2-cyclohexen-1-one (87 mg) in dimethoxyethane (3 ml) and the mixture was heated under reflux After 6 hr, the mixture was partitioned between water (50 ml) and ethyl acetate (100 ml) The organic layer was dried over magnesium sulfate and evaporated in vacuo to furnish an oil that was purified by flash column chromatography (Sι0 2 , ethyl acetate/petroleum ether, 1 3, v/v) to furnish the title compound as an oil (120 mg, 83%) δ H (CDCI 3 ) 2 10 (2H, quintet), 2 47 (2H, t), 2 74 (2H, m), 3 476 (3H, s), 3 484 (3H, s), 5 185 (2H, s), 5 190 (2H, s), 6 21 (1 H, m), 6 71 (1 H, dd), 6.85 (1 H, d), 7 16 (1 H, d) Intermediate 7 (±)-3-r2.4-5/s(methoxymethoxy)phenyllcyclohexanone A suspension of 3-[2,4-b/s(methoxymethoxy)phenyl]-2-cyclohexen-1-one (300 m g) and palladium catalyst (50 mg, 10% palladium on carbon) in ethanol was stirred at ambient temperature under 1 atmosphere of hydrogen After 16 hr, the mixture was filtered through celite and the filtrate was evaporated in vacuo The product was dissolved in dichloromethane (15 ml) Celite and pyπdinium chlorochromate (430 mg) were added and the mixture was stirred at room temperature After 3 hr, the mixture was filtered through a pad of silica and eluted with petroleum ether/ethyl acetate (10 3, v/v), then purified by flash column chromatography (Sι0 2 , petroleum ether/ethyl acetate 4 1 v/v) to furnish the title compound as an oil (200 mg, 70%) δ H (CDCI 3 ) 1 7-1 9 (2H, overlapping m), 2 05 (1 H, m), 2 15 (1 H, m), 2 35-2 60 (4H, overlapping m), 3 37 (1 H, m), 3 490 (3H, s), 3 492 (3H, s), 5 15 (2H, s), 5 20 (2H, s), 6 70 (1 H, dd), 6 82 (1 H, d), 7 09 (1 H, d) Intermediate 8 3-(2,4-Dimethoxymethoxyphenyl)-2-cyclohexen-1 -one oxime 3-[2,4-S;s(methoxymethoxy)phenyl]-2-cyclohexen-1-one (200 mg), hydroxylamine hydrochloπde (72 mg) and tπethylamine (0 14 ml) were heated under reflux in ethanol (10 ml) After 3 hr, the cooled reaction mixture was partitioned between water and ethyl acetate The organic layer was dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil (206 mg, 99%) m/z (ES * ) 308 (M+H) + Intermediate 9 (±)-1 3-r2.4-B/s(methoxymethoxy)phenvπcvclohexyl)piperazine (±)-3-[2,4-S/s(methoxymethoxy)phenyl]cyclohexanone (80 mg) and piperazme (24 mg) were dissolved in dichloroethane (5 ml) and stirred at ambient temperature for 1 hr under argon Tetramethylammonium tπacetoxyborohydride (79 mg) was added and stirring continued under argon After 16 hr, additional portions of piperazme (24 mg) and tetramethylammonium tπacetoxyborohydπde (79 mg) were added and stirring continued After a further 6 hr, glacial acetic acid was added dropwise until a solution was obtained, and stirring continued at ambient temperature After a further 16 hr, the reaction mixture was partitioned between sodium hydrogen carbonate (20 ml of a saturated solution) and ethyl acetate The aqueous layer was extracted with ethyl acetate (3x20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The crude residue was purified by flash column chromatography chromatography (Sι0 2 , dichloromethane/methanol, 9 1 v/v) to furnish the title compound as an off white solid (52 mg, 53%) and mixture of diastereoisomers, m/z (ES + ) 365 (M+H) + Intermediate 10 (±)-3-r2.4-B/stmethoxymethoxy)phenvπcyclohexylamine Nickel chloride hexahydrate (77 mg) and sodium borohydπde (24 mg) were added to a stirred solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexanone oxime (50 mg) in methanol (2 ml) After 0 5 hr, water was added until effervescence ceased, the reaction mixture was filtered, and the residue was washed thoroughly with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by flash column chromatography (Sι0 2 , dichloromethane/methanol, 9 1 v/v) to furnish the title compound as a colourless oil (31 mg, 65%) and a mixture of diastereoisomers, m/z (ES * ) 295 (M+H) + Intermediate 11 (±)-ιV-f3-f2.4-B/s(methoxymethoxy)phenyllcvclohexyl>methanesulfonamide Tπethylamine (0 014 ml) and methanesulfonyl chloride (8 μl) were added to a solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexylamιne (27 mg) in dichloromethane (1 ml), and the mixture was stirred under argon at ambient temperature After 1 hr, the mixture was partitioned between ethyl acetate (20 ml) and sodium hydrogen carbonate (20 ml of a saturated aqueous solution) The aqueous layer was extracted with ethyl acetate (2x20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil and a mixture of diastereoisomers, m/z (ES + ) 374 (M+H) + Intermediate 12 (±)-2,4--3/s(methoxymethoxy)-1 -(3-methylenecvclohexyl)benzene Potassium terf-butoxide (50 mg) was added to a suspension of methyltπphenylphosphonium bromide in tetrahydrofuran (4 ml) at 0°C After 0 5 hr, a solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexanone (100 mg) in tetrahydrofuran (1 ml) was added, and the mixture was allowed to warm to ambient temperature After 16 hr, the reaction mixture was partitioned between ammonium chloride (30 ml of a saturated aqueous solution) and ethyl acetate The aqueous layer was extracted with further ethyl acetate (2x 30 ml), and the combined organic extracts were washed with brine (30 ml), dried over magnesium sulfate, and evaporated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 4 1 v/v) to furnish the title compound as pale yellow oil (80 mg, 81 %) δ H (CDCI 3 ) 1 50 (2H, m), 1 90 (2H, m), 2 05 (1 H, m), 2 16 (1 H, m), 2 35 (1 H, m), 2 44 (1 H, m), 2 97 (1 H, m), 3 44 (3H, s), 3 48 (3H, s), 4 64 (1 H, s), 4 69 (1 H, s), 5 13 (2H, s), 5 17 (2H, s), 6 68 (1 H, m), 6 77 (1 H, m), 7 12 (1 H, d) Intermediate 13 (±H3-r2,4- β /s(methoxymethoxy)phenvπcvclohexyl)methanol 9-Borabιcyclononane (2 7 ml of a 0 5M solution in tetrahydrofuran) was added to a stirred solution of (±)-2,4-b/s(methoxymethoxy)-1-(3-methylenecyclohexyl)benzene (80 mg) in tetrahydrofuran (2 ml) at 0°C under argon After 1 hr at 0°C, the reaction mixture was allowed to warm to ambient temperature and stirring continued After 2 hr, the reaction mixture was cooled to 0°C and water (0 1 ml) was added After the effervescence had subsided, hydrogen peroxide (1 ml of a 30% w/v solution) and sodium hydroxide (1 ml of a 2M solution) were added and the mixture was allowed to warm to ambient temperature After a further 16 hr, the reaction mixture was cooled to 0°C Saturated aqueous sodium metabisulfite was added until no oxidant could be detected by starch iodide paper, and the reaction mixture was extracted with ethyl acetate (3x30 ml) The combined organic extracts were washed with water (20 ml), dried over magnesium sulfate, and evaporated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 1 v/v) to furnish the title compound as a pale brown oil (46 mg, 54%), m/z (ES + ) 31 1 (M+H) + Intermediate 14 (±)-3-r2,4-S/s(methoxymethoxy)phenvncvclohexanone oxime Hydroxylamine hydrochloπde (71 mg), tπethylamine (0 17 ml) and (±)-3-[2,4- b/s(methoxymethoxy)phenyl]cyclohexanone (200 mg) were heated under reflux in ethanol (8 ml) After 0 75 hr the reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml) The aqueous layer was extracted with ethyl acetate (2x100 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 1 v/v) to furnish the title compound as a pale yellow oil (197 mg, 94%), m/z (ES * ) 310 (M+H) + Intermediate 15 (±)-Λ/-f3-f2,4-S/s(methoxymethoxy)phenyllcyclohexyl>hvdroxylamine Borane (0 412 ml of a 1M solution in tetrahydrofuran) was added to a stirred solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexanone oxime (85 mg) in tetrahydrofuran (2 ml) at 0°C under argon After 2 hr, acetic acid (1 ml) was added and the mixture was allowed to warm to ambient temperature After 16 hr, sodium hydrogen carbonate (20 ml of a saturated aqueous solution) was added, the mixture was extracted with ethyl acetate (3x20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , dichloromethane/methanol, 9 1 v/v) to furnish two compounds as clear gums which were identified as diastereoisomers of the title compound, trans-isomer (12 mg, 14%) m/z (ES * ) 312 (M+H) * , c/s-isomer (0 017 g, 20%) m/z (ES * ) 312 (M+H) * Intermediate 16 4-(2,4-β/s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone 4-(2,4-Dιhydroxyphenyl)cyclohexanone (400 mg) was dissolved in dimethyl formamide (3ml) with stirring fe/t-Butyldimethylsilyl chloride (704 mg), imidazole (660 mg) and 4-dιmethylamιnopyπdιne (3 mg) were added sequentially After 4 hr, the solvent was removed in vacuo and the residue partitioned between ethyl acetate (20 ml) and water (5 ml) The aqueous phase was extracted with ethyl acetate (2x10 ml), and the combined organic phases were washed with brine (10 ml), dried over anhydrous magnesium sulphate, and concentrated under reduced pressure to give a brown oil Purification via flash column chromatography (Sι0 2 eluting with ethyl acetate/petroleum ether, 1 9 v/v) furnished the title compound as white flakes (750 mg, 89%) δ H (CDCI 3 ) 0 18 (6H, s), 0 20 (6H, s), 0 97 (9H, s), 1 03 (9H, s), 1 72 - 1 87 (2H, m), 2 15 - 2 17 (2H, m), 2 42 - 2 48 (4H, m), 3 33 (1 H, tt), 6 32 (1 H, d), 6 39 (1 H, dd), 6 94 (1 H, d), m/z (ES * ) 435 (M+1 ) * Intermediate 17 -ert-Butyl[3-{[terf-butyl(dιmethyl)silyl]oxy}-4-(4-methylenecyclohexyl)phenoxy]dimethyl silane To a stirred suspension of methyltπphenylphosphonium bromide (329 mg) in anhydrous THF (10 ml) at 0°C was added potassium ferf-butoxide (103 mg) in one portion After stirring for 30 m , a solution of 4-(2,4-b/s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl) cyclohexanone (200 mg) in THF (5 ml) was added The reaction mixture was stirred for a further 30 mm at 0°C, and saturated aqueous ammonium chloride solution (20 ml) was added The layers were separated and the aqueous layer extracted with ethyl acetate (3x20 ml) The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, and concentrated in vacuo Purification via flash column chromatography (Sι0 2 eluting with diethyl ether petroleum ether, 1 4 v/v) furnished the title compound as a colourless oil (135 mg, 68%) δ H (CDCI 3 ) 0 19 (6H, s), 0 24 (6H, s), 0 97 (9H, s), 1 03 (9H, s), 1 41 (2H, dq), 1 84 - 1 93 (2H, m), 2 16 (2H, dt), 2 33 - 2 42 (2H, m), 3 01 (1 H, tt), 4 66 (2H, s), 6 29 (1 H, dd), 6 40 (1 H, dd), 6 94 (1 H, d) Intermediate 18 trans I cis -[4-(2,4-B/s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol ter.-Butyl[3-{[ferf-butyl(dιmethyl)sιlyl]oxy}-4-(4-methyienecyclohexyl)phenoxy]dιmethyl silane (135 mg) was dissolved in anhydrous THF (5 ml) with stirring and cooled to -78°C 9- Borabιcyclo[3 3 1]nonane (3 13 ml, 0 5M in THF) was added to the stirred solution and the resulting reaction mixture allowed to warm to room temperature over 3 hr and then stirred for 3 days Cooling to 0°C was followed by addition of hydrogen peroxide (1 ml, 30% aqueous solution) and sodium hydroxide (1 ml, 2M aqueous solution) The reaction mixture was allowed to warm to room temperature with stirring over 1 hr, cooled to 0°C, and saturated aqueous sodium metabisulphate solution (30 ml) was added The layers were separated and the aqueous layer extracted with ethyl acetate (3x20 ml) The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, and concentrated in vacuo Purification via flash column chromatography (Sι0 2 eluting with petroleum ether diethyl ether, 3 17 v/v) afforded the desired product as a yellow oil (73 mg, 52%) δ H (CDCI 3 ) 0 18 (6H, s), 0 22 (6H, s), 0 97 (9H, s), 1 00 (9H, s), 1 03 - 1 15 (0 5H, m), 1 22 - 1 33 (0 5H, m), 1 43 - 1 61 (4H, m), 1 77 - 1 94 (4H, m), 2 75 - 2 92 (1 H, m), 3 47 (1 H, d), 3 70 (1 H, d), 6 26 - 6 29 (1 H, m), 6 37 - 6 40 (1 H, m), 6 93 - 6 97 (1 H, m) Intermediate 19 trans I cis -4-(2,4-B/s{[-er.-butyl(dιmethyl)silyl]oxy}phenyl)-1 -methylcyclohexanol 4-(2,4-β/s(.erf-butyldιmethylsιlyloxy))phenylcyclohexanone (50 mg) was dissolved in anhydrous THF (10 ml) and cooled to 0°C Methylmagnesium chloride (59 ml, 22% w/v in THF) was added dropwise and the reaction mixture allowed to warm to room temperature with stirring over 2 days The reaction mixture was partitioned between aqueous HCI (10 ml, 0 5M) and ethyl acetate (10 ml) The aqueous phase was extracted with ethyl acetate (2x10 ml) and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution (10 ml), brine (10 ml), and then dried over anhydrous magnesium sulphate Removal of the solvent under reduced pressure afforded an oil which was purified via flash column chromatography (Sι0 2 eluting with ethyl acetate petroleum ether, 1 4 v/v) affordmg the title compound as a white solid and a mixture of diastereoisomers (29 mg, 56%) δ H (CDCI 3 ): 0.19 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.02 (9H, s), 1.26 (1.5H, s), 1.32 (1.5H, s), 1.36 - 1.82 (8H, m), 2.73 - 2.91 (1 H, m), 6.29 - 6.31 (1 H, m), 6.39 - 6 42 (1 H, m), 6 80 (0.5H, d), 7.20 (0.5H, d). Intermediate 20 trans I cis - 4-(2,4-B/s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine 4-[2,4-β/s(terf-butyldιmethylsιlyloxy)phenyl]cyclohexanone oxime (120 mg) was dissolved in anhydrous methanol (10 ml) with stirring The solution was cooled to -40°C, and nickel chloride hexahydrate (133 mg) was added Stirring was continued for 10 mm before sodium borohydπde (42 mg) was added in one portion. The reaction mixture was stirred at - 40°C for 20 m and water (0.5 ml) was added. The reaction mixture was allowed to warm to room temperature with stirring. Silica gel was added and the solvent removed in vacuo Purification via flash column chromatography (Sι0 2 eluting with CH 2 CI 2 :MeOH:NH 4 OH, 44:50:6 v/v) afforded the desired product as a pale brown oil (83 mg, 71%) and a mixture of diastereoisomers. δ H (CD 3 OD)- 0.22 (6H, s), 0.27 (6H, s), 1.02 (9H, s), 1.08 (9H, s), 1.24 - 1.40 (1 H, m), 1.42 - 1.57 (1 H, m), 1.57 - 1.68 (1 H, pn), 1.71 - 1.90 (4H, m), 1.99 - 2.07 (1 H, m), 2.84 - 2.98 (1 H, m), 4.28 - 4.40 (1 H, m), 6.34 (1 H, d), 6 44 (1 H, t), 7.04 (0.5H, d), 7.16 (0.5H, d); m/z (ES * ) 436 (M+1 ) * Intermediate 21 trans I cis -ιV-[4-(2,4-B s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]acetamide trans / cis - 4-(2,4- β /s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexylamιne (27 mg) was dissolved in pyridme (0.5 ml) Acetyl chloride (6 μl) and 4-dιmethylamιnopyπdιne (2 mg) were added sequentially and the reaction mixture stirred for 24 hr. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and water (2 ml) The aqueous phase was extracted with ethyl acetate (2x5 ml) and the combined organic phases were washed with brine (10 ml), dried over anhydrous magnesium sulphate, and concentrated to give a brown oil Purification via flash column chromatography (Sι0 2 eluting with ethyl acetate:petroleum ether, 7 3 v/v) afforded the title product as a white solid (15 mg, 50%) and a mixture of diastereoisomers δ H (CDCI 3 ) 0 17 (3H, s), 0 19 (3H, s), 0.21 (3H, s), 0.22 (3H, s), 0.96 (9H, s), 1.02 (9H, s), 1 06 - 1 20 (2H, m), 1 36 - 1.54 (2H, m), 1 60 - 1 75 (2H, m), 1.80 - 1.92 (2H, m), 1.95 (1 5H, s), 2 00 (1 5H, s), 2 75 - 2 90 (1 H, m), 3.76 - 3 87 (1 H, m), 5.34 - 5.39 (0.5H, d), 5.72 - 5 77 (0 5H, d), 6.26 - 6.29 (1 H, m), 6.38 - 6 41 (1 H, m), 6.93 (0.5H, d), 6.95 (0.5H, d); m/z (ES * ) 478 (M + 1 ) * Intermediate 22 3-[2,4-B s(methoxymethoxy)phenyl]-2-cyclopenten-1-one 1 ,3-β/s(methoxymethoxy)-4-bromobenzene (1 0 g) was dissolved in THF (20 ml) and cooled to -78°C under argon Λ/,Λ/,N, V-Tetramethylethylene diamine was added followed by dropwise addition of n-BuLi (3 4 ml of a 2 2M solution in hexanes) over 10 mins After stirring at -78°C for 1 hr, a solution of 3-methoxy-2-cyclopentene-1-one (605 mg) in THF (5 ml) was added slowly The reaction mixture was stirred at -78°C for 1 hr before warming to 0°C 1 M HCI (20 ml) was added, and after 10 mm the mixture was extracted with ethyl acetate (2x50 ml) The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, and concentrated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 1 v/v) to furnish the title compound as yellow oil (128 mg, 13%), m/z (ES * ) 279 (M + 1 ) * Intermediate 23 (±)-3-r2,4-B/s(methoxymethoxy)phenvπcvclopentanone 3-[2,4-β/s(methoxymethoxy)phenyl]-2-cyclopenten-1-one (50 mg) and palladium (10 mg, 10% on carbon) were stirred under an atmosphere of hydrogen for 15 hr The mixture was then filtered through a plug of Celite, washing with ethyl acetate, and the filtrate was concentrated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 1 v/v) to furnish the title compound as a colourless oil (8 mg, 16%), m/z (ES * ) 583 (2M + Na) * Intermediate 24 3 - (Benzyloxy) - 2 - cyclohexen - 1 - one To a round bottomed flask equipped with magnetic stirrer and Dean - Stark apparatus was added 1 , 3 - cyclohexanedione (60 0 g, 535 mmol), toluene (450 ml), p - toluenesulfonic acid monohydrate (1 35 g, 5 20 mmol) and benzyl alcohol (52 6 g, 487 mmol) The resulting solution was heated to reflux temperature for 12hr The reaction mixture was cooled to room temperature and then washed with saturated aqueous sodium carbonate solution (2x100 ml) The organic layer was then washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a brown oil (94 9 g) which crystallised upon standing for 17hr The crude crystalline material was slurπed in /sopropyl ether (20 ml) The mixture was filtered and the crystalline material was washed with ice cold /sopropyl ether (3x30 ml), then with cold petroleum ether (2x20 ml) The resulting peach coloured crystalline solid was dried overnight under reduced pressure, furnishing the desired product (74 4g, 76%) m/z (ES*) 203 (M+H * ) Intermediate 25 (±)-3 - (Benzyloxy) - 6 - (8 - hvdroxy - 1 , 4 - dioxaspirof4.51dec - 8 - yl) - 2 - cyclohexen - 1 - one To a round bottomed flask equipped with magnetic stirrer was added anhydrous tetrahydrofuran (600 ml) and di/sopropylamme (38 1 ml, 272 mmol) The stirred solution was cooled to -78°C and n - butyl lithium (1 13 4 ml, 272 mmol, 2 4M in cyclohexanes) was added dropwise via syringe in 20 ml portions The resulting yellow solution was stirred for 35 m at -78°C, then 3 - (benzyloxy) - 2 - cyclohexen - 1 - one (50 0 g, 248 mmol) was added as a solution in anhydrous tetrahydrofuran (100 ml) The solution was stirred for 1 hr prior to the addition of cyclohexane - 1 , 4 - dione monoethylene ketal (38 7 g, 248 mmol) as a solution in anhydrous tetrahydrofuran (100 ml) The solution was stirred for 2 hr at -78°C, then allowed to warm slowly to room temperature over 1 hr Saturated aqueous ammonium chloride (80 ml) was added, followed by dichloromethane (700 ml), and the mixture was stirred until no solids remained The layers were separated and the aqueous phase extracted with dichloromethane (2x100 mi) The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, then concentrated in vacuo Tπturation of the resulting solid with methanol afforded the title compound (78 4 g, 88%) m/z (ES * ) 359 (M+H * ) Intermediate 26 (±)-1 - (Benzyloxy) - 6 - bromo - 3 - (1 , 4 - dioxaspiroM.δldec - 8 - yl) - 2 - oxabicyclo [2.2.2]octan - 5 - one A round bottomed flask equipped with magnetic stirrer was charged with (±)-3 - (benzyloxy) - 6 - (8 - hydroxy - 1 , 4 - dιoxaspιro[4 5]dec - 8 - yl) - 2 - cyclohexen - 1 - one (78 4 g, 219 mmol) and dichloromethane (600 ml) To the stirred solution was added Λ/ - bromosuccmimide (40.9 g, 230 mmol) in one portion, followed by aqueous hydrobromic acid (3 drops, 48% solution) when no more solid remained The resulting solution was stirred at room temperature for 2 hr then poured into a separating funnel containing aqueous sodium metabisulfite solution (150 ml) and dichloromethane (200 ml), then the funnel was shaken vigorously The layers were separated and the organic layer was washed with brine (200 ml), dried over magnesium sulfate, filtered, then concentrated in vacuo to give a solid Tπturation with methanol (500 ml) afforded the desired compound (82 8 g, 86%) as a white solid m/z (ES * ) 437 and 439 [(1 1 ), M+H * ] Intermediate 27 5 - (Benzyloxy) - 2 - (1 , 4 - dioxaspiro[4.5]dec - 7 - en - 8 - yl)phenol A round bottomed flask was charged with (±)-1 - (benzyloxy) - 6 - bromo - 3 - (1 , 4 - dιoxaspιro[4 5]dec - 8 - yl) - 2 - oxabιcyclo[2 2 2]octan - 5 - one (13 8 g, 31 6 mmol) and anhydrous N, N - dimethylformamide (140 ml) To the stirred solution was added 1 , 8 - dιazabιcyclo[5 4 0]undec - 7 - ene (9 92 ml, 66 3 mmol) in one portion The solution turned dark brown in colour immediately and was then heated to 140°C for 12 hr with vigorous stirring The reaction mixture was allowed to cool to room temperature and most of the solvent was removed under reduced pressure The remaining oil was partitioned between ethyl acetate (200 ml) and water (100 ml), then the layers were separated and the aqueous phase was extracted with ethyl acetate (3x50 ml) The combined organic layers were back extracted with water (3x30 ml) to remove any residual N, N - dimethylformamide The organic phase was washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown oily solid, which was adsorbed onto silica gel Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 1 , v/v) furnished the desired product (7 1 g, 66%) as a white solid m/z (ES * ) 339(M+H * ) Intermediate 28 4 - (1 , 4 - Dιoxaspιro[4.5]dec - 8 - yl) - 1 , 3 - benzenediol A round bottomed flask equipped with magnetic stirrer was charged with 5 - (benzyloxy) - 2 - (1 , 4 - dιoxaspιro[4 5]dec - 7 - en - 8 - yl)phenol (6 90 g, 204 mmol), ethanol (300 ml) and palladium (2 00 g, 10% on activated carbon) The reaction vessel was then evacuated and placed under a hydrogen atmosphere This process was repeated 15 times before stirring vigorously for 64 hr under a hydrogen atmosphere The reaction mixture was filtered through a celite plug, washing with ethyl acetate The filtrate was concentrated in vacuo, furnishing the title compound (5 10 g, 100%) as a solid m/z(ES * ) 251 (M+H * ) Intermediate 29 cis - N - Benzyl - N - [4 - (2, 4 - bis{[tert - butyl(dιmethyl)silyl]oxy}phenyl)cyclohexyl] amine To a round bottomed flask equipped with magnetic stirrer was loaded 4-(2, 4-b/s{[terf- butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanone (3 20 g, 7 36 mmol) Anhydrous 1 , 2- dichloroethane (85 ml) was added, and to the stirred solution was added benzylamme (0 97 ml, 8 83 mmol) as a solution in 1 , 2-dιchloroethane (20 ml) Activated powdered 4A molecular sieves (5 80 g) were added and the reaction mixture stirred vigorously for 2 5 hr Tetramethylammoniumtπacetoxyborohydπde (2 90 g, 1 1 0 mmol) was added in one portion and the reaction mixture stirred for 64 hr at room temperature Aqueous sodium hydroxide solution (30 ml, 0 4M) was added and vigorous stirring was continued for 0 5 hr The reaction mixture was then filtered through celite, washing with dichloromethane (100 ml) The layers were separated and the aqueous layer was extracted with dichloromethane (2x50 ml) The combined organic phases were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the crude product Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, gradient elution using 1 9, 1 4, then 3 7 v/v) furnished the title product (2 69 g, 70%) as a pale yellow oil δ H (CDCI 3 ) 0 01 (6H, s), 0 05 (6H, s), 0 77 (9H, s), 0 83 (9H, s), 1 31 (1 H, br), 1 39 (4H, m), 1 52 (2H, m), 1 70 (2H, m), 2 69 (1 H, m), 2 75 (1 H, m), 6 10 (1 H, d), 6 23 (1 H, dd), 6 84 (1 H, d), 7 15 (5H, m) Intermediate 30 N - Benzyl - N - [4 - (2, 4 - b/s{[ter -butyl(dimethyl)silyl]oxy}phenyl) cyclohexylidene] amine To a round bottomed flask equipped with magnetic stirrer was added 4-(2, 4-b/s{[ferr- butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanone (817 mg, 1 88 mmol) Anhydrous dichloromethane (50 ml) was added followed by benzylamme (0 82 ml, 7 52 mmol) and activated 4A molecular sieves (10 0 g) The reaction mixture was stirred vigorously for 15 hr, then dichloromethane (50 ml) was added and the reaction mixture filtered through celite, washing with dichloromethane (50 ml) The filtrate was concentrated in vacuo affording the desired product (1 00 g, 86%) as a yellow oil δ H (CDCI 3 ) 0 19 (6H, s), 0 26 (6H, s), 0 98 (9H, s), 1 03 (9H, s), 1 51 (1 H, m), 1 72 (1 H, m), 2 03 (2H, m), 2 45 (1 H, m), 2 60 (1 H, m), 3 04 (1 H, m), 3 22 (1 H, m), 4 55 (1 H, d), 4 60 (1 H, d), 6 31 (1 H, d), 6 41 (1 H, dd), 6 93 (1 H, d), 7 33 (5H, m) Intermediate 31 trans - N - Benzyl - N - [4 - (2, 4 - bis{[tert - butyl(dimethyl)silyl]oxy} phenyl) cyclohexyl]amine To a round bottomed flask equipped with magnetic stirrer was added N - benzyl - N - [4 - (2, 4 - bιs{[tert - butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexylιdene]amιne (4 00 g, 7 63 mmol) and anhydrous tetrahydrofuran (480 ml) followed by anhydrous methanol (120 ml) To the solution was added sodium borohydπde (1 16 g, 30 5 mmol) and the reaction mixture stirred for 17 hr The reaction mixture was then diluted with diethyl ether (600 ml) and aqueous sodium hydroxide (400 ml, 0 4M) was added After stirring for 10 mm, the layers were separated and the aqueous layer extracted with dichloromethane (3x100 ml) The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, gradient elution using 1 9, 1 4, then 3 7, v/v) furnished the desired product as a cream coloured solid (2 09 g, 54%) δ H (CDCI 3 ) 0 01 (6H, s), 0 05 (6H, s), 0 80 (9H, s), 0 85 (9H, s), 1 18 (4H, m), 1 66 (2H, m), 1 87 (2H, m), 2 19 (1 H, m), 2 68 (1 H, M), 6 12 (1 H, d), 6 23 (1 H, dd), 6 77 (1 H, d), 7 17 (5H, m) Intermediate 32 trans- 4 - (2, 4 - Bis{[tert - butyl(dιmethyl)silyl]oxy}phenyl)cyclohexylamine To a round bottom flask was added trans - N - benzyl - N - [4 - (2, 4 - bιs{[tert - butyl(dιmethyl)sιlyl]oxy} phenyl) cyclohexyl]amιne (500 mg, 0 95 mmol) and ethanol (20 ml) To the stirred solution was added palladium (10% w/w on activated carbon, 200 mg, 0 19 mmol) as a slurry in ethanol (5 ml) The reaction vessel was evacuated, then placed under hydrogen (10 cycles) The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 18 hr, then filtered through a celite plug, washing with methanol (100 ml) The solvent was removed in vacuo affording the desired product (402 mg, 97%) as a colourless oil δ H (CDCi 3 ) 0 01 (6H, s), 0 05 (6H, s), 0 78 (9H, s), 0 82 (9H, s), 1 08 (2H, m), 1 21 (2H, m), 1 62 (2H, m), 1 78 (2H, m), 2 59 (2H, m), 6 11 (1 H, d), 6 22 (1 H, dd), 6 78 (1 H, d) Intermediate 33 cis - 4 - (2, 4 - b/s{[-erf-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine To a round bottom flask equipped with magnetic stirrer was added cis - N - benzyl - N - [4 - (2, 4 - bιs{[tert - butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl]amιne (700 mg, 1 33 mmol) and ethanol (30 ml) To the stirred solution was added palladium (10% w/w on activated carbon, 283 mg, 0 27 mmol) as a slurry in ethanol (5 ml) The reaction vessel was evacuated then placed under hydrogen (10 cycles) The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 18 hr then filtered through a celite plug, washing with methanol (100 ml) The solvent was removed in vacuo affording the desired product (561 mg, 97%) as a colourless oil δ H (CDCI 3 ) 0 01 (6H, s), 0 04 (6H, s), 0 78 (9H, s), 0 83 (9H, s), 1 21 - 1 55 (10H, m), 2 64 (1 H, m), 3 05 (1 H, m), 6 11 (1 H, d), 6.22 (1 H, dd), 6 84 (1 H, d) Intermediate 34 cis - N - [4 - (2, 4 - B/s{[-er -butyl(dιmethyl)silyl]oxy}phenyl)cyclohexyl] methane sulfonamide A round bottomed flask equipped with magnetic stirrer was charged with cis - 4 - (2, 4 - b/s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexylamιne (47 mg, 0 108 mmol) and 1 , 2- dichloroethane (4 ml) To the stirred solution was added methanesulfonyl chloride (10 μl, 0 12 mmol), tπethylamine (30 μl, 0 22 mmol) and 4-dιmethylamιnopyπdιne (catalytic amount) The solution was stirred for 17 hr then partitioned between aqueous sodium hydroxide (5 ml, 0 2M) and dichloromethane (5 ml) The aqueous phase was extracted with dichloromethane (2x5 ml) and the combined organic layers were washed with brine (8 ml), dried over magnesium sulfate and concentrated in vacuo The crude product was adsorbed onto silica gel and purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, gradient elution using 1 9, 1 4, then 1 3, v/v) to give the title compound (39 mg, 70%) which solidified on standing δ H (CDCI 3 ) 0 17 (6H, s), 0 23 (6H, s), 0 97 (9H, s), 1 00 (9H, s), 1 53 (2H, m), 1 71 (4H, m) 1 94 (2H, m), 2 85 (1 H, m), 2 99 (3H, s), 3 78 (1 H, m), 4 83 (1 H, d), 6 28 (1 H, d), 6 42 (1 H, dd), 6 97 (1 H, d) Intermediate 35 trans - N - [4 - (2, 4 - B/s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl] methane sulfonamide To a round bottomed flask equipped with magnetic stirrer was added trans - 4 - (2, 4 - bιs{[tert - butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexylamιne (248 mg, 0 57 mmol) and 1 , 2- dichloroethane (25 ml) To the stirred solution was added tπethylamine (191 μl, 1 37 mmol) followed by methanesulfonyl chloride (53 μl, 0 68 mmol) and three crystals of 4- dimethylaminopyπdine The resulting solution was stirred at room temperature for 18 hr and then poured into a separating funnel containing dichloromethane (100 ml) and water (20 ml) The layers were separated and the aqueous phase extracted with dichloromethane (1x50 ml) The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound as a pale yellow oil (320 mg, 100%) δ H (CDCI 3 ) 0 02 (6H, s), 0 05 (6H, s), 0 78 (9H, s), 0 82 (9H, s), 1 22 (4H, m), 1 70 (2H, m), 1 99 (2H, m), 2 61 (1 H, m), 2 81 (3H, s), 3 19 (1 H, m), 3 92 (1 H, d), 6 13 (1 H, d), 6 22 (1 H, dd), 6 66 (1 H, d) Intermediate 36 4 - (4 - {[-erf - Butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone To a round bottomed flask equipped with magnetic stirrer was added 4-(4- hydroxy)phenylcyclohexanone (1 00 g, 5 26 mmol) (commercially available from Aldπch) and anhydrous tv.tV-dimethylformamide (5 ml) To the stirred solution was added imidazole (0 90 g, 13 20 mmol), terf-butyl(dιmethyl)sιlyl chloride (1 19 g, 7 89 mmol) and 4- dimethylaminopyπdine (catalytic amount) The reaction mixture was stirred for 17 hr at room temperature and then the Λ/,Λ/-dιmethylformamιde removed in vacuo The residue was partitioned between ethyl acetate (100 ml) and water (5 ml) The layers were separated and the aqueous phase was extracted with ethyl acetate (3x20 ml) The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 2 3, v/v) afforded the title compound (1 39 g, 87%) as a pale yellow solid δ H (CDCI 3 ) 0 19 (6H, s), 0 98 (9H, s), 1 87 (2H, m), 2 20 (2H, m), 2 46 (4H, m), 2 99 (1 H, m), 6 77 (2H, d), 7 07 (2H, d) Intermediate 37 4 - (4 - {[tert - Butyl(dιmethyl)silyl]oxy}phenyl) - 1 - [2, 4 - b/s(methoxymethoxy) phenyl] cyclohexanol A round bottomed flask equipped with magnetic stirrer was charged with 1-bromo-2,4- bιs(methoxymethoxy)benzene (277 mg, 1 00 mmol) and anhydrous tetrahydrofuran (5 ml) The stirred solution was cooled to -78°C and N, N, N', tv'-tetramethylethylene diamine (0 32 ml, 2 10 mmol) was added followed by dropwise addition of n-butyl lithium (0 88 ml, 2 10 mmol, 2 40M solution in cyclohexanes) The resulting solution was stirred for 40 m at - 78°C, then 4 - (4 - {[tert - butyl(dιmethyl)sιlyl]oxy}phenyl) cyclohexanone (304 mg, 1 00 mmol) was added via syringe as a solution in anhydrous tetrahydrofuran (2 ml) and the reaction mixture stirred for 30 m at -78 °C, then allowed to warm to room temperature over 3 hr The reaction was quenched with aqueous hydrochloric acid (5 ml, 0 10M), then poured into a separating funnel containing ethyl acetate (50 ml) and water (10 ml) The layers were separated and the aqueous phase extracted with ethyl acetate (3x5 ml) The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The resulting oil was purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 3 7, v/v) furnishing the title compound as a white solid (127 mg, 25%) and a mixture of diastereoisomers δ H (CDCI 3 ) 0 19 (6H, s), 0 98 (6H, s), 1 63 (2H, m), 1 84 (2H, m), 1 96 (2H, m), 2 56 (2H, m), 2 70 (1 H, m), 3 48 (3H, s), 3 49 (3H, s), 3 85 (1 H, s), 5 15 (2H, s), 5 24 (2H, s), 6 68 (1 H, dd), 6 73 (2H, d), 6 85 (1 H, d), 7 05 (2H, d), 7 33 (1 H, d) Intermediate 38 tert- Butyl (4 - {4 - [2, 4-b/s(methoxymethoxy)phenyl]-3-cyclohexen-1-yl} phenoxy) dimethylsilane A round bottomed flask equipped with magnetic stirrer was charged with 4 - (4 - {[tert - butyl(dιmethyl)stlyl]oxy}phenyl) - 1 - [2, 4 - b/s(methoxymethoxy) phenyl]cyclohexanol (125 mg, 0 25 mmol), toluene (10 ml) and p-toluene sulfonic acid monohydrate (3 crystals) The reaction mixture was heated to reflux temperature for 30 m , then cooled to room temperature before adding saturated aqueous sodium bicarbonate (5 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (3x 10ml) The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The title compound was isolated without further purification as an oil (118 mg, 98%) and a mixture of diastereoisomers δ H (CDCI 3 ) 0 19 (6H, s), 0 98 (9H, s), 1 84 (1 H, m), 2 00 (1 H, m), 2 27 (1 H, m), 2 44 (2H, m), 2 56 (1 H, m), 3 48 (3H, s), 3 49 (3H, s), 5 15 (2x2H, s), 5 79 (1 H, m), 6 67 (1 H, dd), 6 77 (2H, d), 6 78 (1 H, d), 7 07 (2H, d), 7 1 1 (1 H, ) Intermediate 39 tert - Butyl (4 - {4 - [2, 4 - b/s(methoxymethoxy)phenyl]cyclohexyl}phenoxy) dimethyl silane To a round bottomed flask equipped with magnetic stirrer was added tert - butyl (4 - {4 - [2, 4-b/s(methoxymethoxy)phenyl]-3-cyclohexen-1-yl}phenoxy) dimethylsilane (118 mg, 0 24 mmol) and ethanol (15 ml) To the stirred solution, palladium (catalytic amount, 10% on activated carbon) was added in one portion The reaction vessel was then evacuated and placed under an atmosphere of hydrogen This process was repeated for 10 cycles before leaving under a hydrogen atmosphere The reaction mixture was stirred vigorously for 17 hr then filtered through celite, washing with ethyl acetate The filtrate was concentrated in vacuo affording the title compound as a colourless oil (118 mg, 100%) and a mixture of diastereoisomers δ H (CDCI 3 ) 0 15 (6H, s), 0 92 (9H, s), 1 51 (2H, m), 1 63 (2H, m), 1 81 (2H, m), 1 94 (2H, m), 2 43 and 2 90 (1 H, m), 2 84 and 3 02 (1 H, m), 3 38 and 3 39 (3H, s), 3 40 (2x1 5H, s), 5 04 and 5 06 (2H, s), 5 08 and 5 10 (2H, s), 6 56 and 6 61 (1 H, m), 6 70 (3H, m), 7 03 (2H, m), 7 1 1 (1 H, d) Intermediate 40 (±)-Methyl (4 - f2, 4 - b/s(methoxymethoxy)phenvπcvclohexylidene}acetate A round bottomed flask equipped with magnetic stirrer was loaded with sodium hydride (0 20 g, 5 10 mmol, 60% dispersion in mineral oil) which was washed with petroleum ether (4x20 ml) The excess petroleum ether was removed under reduced pressure Anhydrous tetrahydrofuran (120 ml) was added and the stirred solution was cooled to 0°C Tπmethylphosphonoacetate (756 μl, 5 10 mmol) was added dropwise via syringe and the stirred mixture was allowed to warm to room temperature over 1 hr The mixture was cooled to 0°C prior to the addition of 4 - [2, 4 - b/s(methoxymethoxy)phenyl] cyclohexanone (1 00 g, 3 40 mmol) as a solution in tetrahydrofuran (30 ml) The pale yellow mixture was heated to reflux temperature for 0 75 hr, then cooled to room temperature and partitioned between ethyl acetate (100 ml) and saturated aqueous ammonium chloride solution (30 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (3x30 ml) The combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a yellow oil Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 2, v/v) furnished the title compound as a yellow oil (1 13 g, 95%) δ H (CD 3 OD) 1 53 - 1 70 (2H, m), 2 00 - 2 13 (4H, m), 2 45 (2H, m), 3 26 (1 H, m), 3 48 (3H, s), 3 53 (3H, s), 3 71 (3H, s), 5 17 (2H, s), 5 24 (2H, s), 5 73 (1 H, s), 6 67 and 6 68 (1 H, d), 6 83 (1 H, d), 7 08 (1 H, d) Intermediate 41 cis I trans - Methyl {4 - [2, 4 - b s(methoxymethoxy)phenyl]cyclohexyl} acetate To a round bottomed flask equipped with magnetic stirrer was added (±)-methyl {4 - [2, 4 - b/s(methoxymethoxy)phenyl]cyclohexylιdene}acetate (1 13 g, 3 23 mmol) and ethanol (50 ml) To the stirred solution was added palladium (catalytic amount, 10% on activated carbon) in one portion The reaction vessel was evacuated and placed under an atmosphere of hydrogen This process was repeated for 10 cycles before leaving under a hydrogen atmosphere and then stirred vigorously for 17 hr The reaction mixture was filtered through celite, washing with ethanol and the filtrate was evaporated to dryness, furnishing the title compound (1 13 g, 99%) as a colourless oil and a mixture of diastereoisomers δ H (CD 3 OD) 1 53 (2H, m), 1 62 - 1 78 (2H, m), 1 87 (4H, m), 2 93 (1 H, m), 3 47 (3H, s), 3 51 (3H, s), 3 71 and 3 72 (3H, s), 5 16 and 5 17 (2H, s), 5 22 and 5 23 (2H, s), 6 66 and 6 68 (1 H, d), 6 79 and 6 80 (1 H, s), 7 12 and 7 15 (1 H, d) Intermediate 42 (±H4 - f2. 4 - B/s(methoxymethoxy)phenvncvclohexylidene>acetic acid To a round bottomed flask equipped with magnetic stirrer was added tπmethylsilyldiethylphosphonoacetate (1 08 ml, 3 83 mmol) and anhydrous tetrahydrofuran (25 ml) The stirred solution was cooled to 0°C and n-butyl lithium (1 80 ml, 3 83 mmol, 2 2M in cyclohexanes) was added dropwise, via syringe over 5 mm The reaction mixture was allowed to warm slowly to room temperature and stirred for 17 hr 4 - [(2, 4 - β/s(methoxymethoxy)phenyl)]cyclohexanone (750 mg, 2 55 mmol) was added via syringe as a solution in tetrahydrofuran (25 ml) After 2 hr stirring at room temperature, the reaction mixture was poured into a separating funnel containing aqueous sodium hydroxide solution (10 ml, 10% w/v) After extracting once with diethyl ether (10 ml), the aqueous layer was acidified by adding concentrated hydrochloric acid (10 ml), then extracted with diethyl ether (3x20 ml) The combined organic layers were washed with water (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (422 mg, 52%) as an oil δ H (CDCI 3 ) 1 86 (2H, m), 2 00 - 2 13 (4H, m), 2 42 (2H, m), 3 19 (1 H, m), 3 48 (3H, s), 3 51 (3H, s), 5 14 (2H, s), 5 21 (2H, s), 5 71 (1 H, s), 6 67 (1 H, dd), 6 81 (1 H, d), 7 05 (1 H, d) Intermediate 43 (+)-{4 - [2. 4 - Dιhydroxyphenyl]cvclohexylιdene)acetic acid A round bottomed flask equipped with magnetic stirrer was loaded with (±)-{4 - [2, 4 - b/s(methoxymethoxy)phenyl]cyclohexylιdene}acetιc acid (25 mg, 74 μmol), acidic dowex resin (75 mg) and methanol (15 ml) then stirred at 60°C for 3 hr The reaction mixture was filtered through a celite plug, washing with methanol The solvent was removed under reduced pressure to give a yellow oil (15 mg) which was purified by preparative TLC (ethyl acetate / petroleum ether, 3 1 , v/v), furnishing the title compound (6 5mg, 35%) as an oil m/z(ES * ) 339 (M+H * ) Intermediate 44 (±H4-f2, 4-B;s(methoxymethoxy)phenyllcvclohexylidene>acetonitrile To a round bottomed flask equipped with magnetic stirrer was added sodium hydride (40 mg, 0 95 mmol, 60% dispersion in mineral oil) After washing the sodium hydride with petroleum ether (2x20 ml), the excess solvent was removed under reduced pressure 1 , 2- Dimethoxyethane (10 ml) was added and the stirred suspension cooled to 0°C Diethyl cyanomethylphosphonate (102 μl, 0 95 mmol) was added dropwise The reaction mixture was allowed to warm slowly to room temperature over 2 hr 4-[(2, 4 - β/s(methoxymethoxy)phenyl)]cyclohexanone (200 mg, 0 68 mmol) was then added as a solution in 1 , 2-dιmethoxyethane (10 ml) and the reaction mixture stirred for 17 hr at room temperature The reaction mixture was poured into a separating funnel containing water (50 ml) and diethyl ether (50 ml) The layers were separated and the aqueous phase extracted with diethyl ether (2x20 ml) The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, to give an oil Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 2, v/v) afforded the title compound (141 mg, 66%) as a pale yellow oil δ H (CD 3 OD) 1 57 - 1 70 (2H, m), 2 02 - 2 25 (2H, m), 2 34 - 2 49 (2H, m), 2 60 (1 H, m), 3 03 (1 H, m), 3 24 (1 H, m), 3 47 (3H, s), 3 52 (3H, s), 5 17 (2H, s), 5 23(2H, s), 5 33 (1 H, s), 6 66 and 6 69 (1 H, d), 6 83 (1 H, d), 7 09 (1 H, d Intermediate 45 (+)- [4-(2, 4-Dihvdroxyphenyl)cyclohexylidenelacetonitrile To a round bottomed flask equipped with magnetic stirrer was added (±)-{4-[2, 4- b/s(methoxymethoxy)phenyi]cyclohexylιdene}acetonιtπle (141 mg, 0 45 mmol) and methanol (5 ml) The reaction mixture was stirred, the solution was heated to reflux temperature and aqueous hydrochloric acid (5 ml, 1 0M) was added slowly Heating was continued for 1 hr and the reaction mixture was allowed to cool to room temperature prior to the addition of saturated aqueous sodium bicarbonate solution (12 ml) The reaction mixture was then partitioned between ethyl acetate (30 ml) and water (10 ml) The aqueous layer was extracted with ethyl acetate (3x15 ml) and the combined organic layers washed with brine (20 ml), dried over magnesium sulfate filtered and concentrated in vacuo The residue was purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 1 , v/v) to afford the title compound as a white solid (90 mg, 88%) m/z (ES ) 228 (M-H * ), δ H (CD 3 OD) 1 56 - 1 68 (2H, m), 2 02 - 2 14 (2H, m), 2 33 - 2 48 (2H, m), 2 57 (1 H, m), 3 01 (1 H, m), 3 14 (1 H, m), 5 31 (1 H, s), 6 26 and 6 28 (1 H, d), 6 32 (1 H, d), 6 80 (1 H, d) Intermediate 46 (±)-1-(3.3-Difluorocyclohexyl)-2,4-b/s(methoxymethoxy)benzene Diethylaminosulfur tπfluoπde (34 μl) was added to a stirred solution of (±)-3-[2,4- b/s(methoxymethoxy)phenyl]cyclohexanone (40 mg) in anhydrous 1 ,2-dιmethoxyethane at room temperature under argon After 1 hr further diethylaminosulfur trifluoπde (170 μl) was added After 48 hr, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml) The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combmed organic extracts were dried over magnesium sulfate and evaporated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 1 v/v) to give the title compound as a gum (31 mg), m/z (ES * ) 317 (M+H) * , R f (ethyl acetate/petrol, 1 1 v/v) 0 5 Intermediate 47 (±)-3-f2,4-B/s(methoxymethoxy)phenyl1cvclohexanecarboxylic acid A solution of (±)-{3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexyl}methanol (50 mg) in acetone (1 ml) was added to a stirred solution of chromium (VI) oxide (64 mg) in 2M sulfuπc acid (0 64 ml) at 0°C over 3 hr After 3 hr at 0°C and then 16 hr at room temperature, the reaction mixture was partitioned between water (10ml) and ethyl acetate (20 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 ml) The combined organic extracts were washed with water (20 ml), dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 4 1 v/v) to give the title compound as a colourless oil (15 mg, 29%) R f (ethyl acetate/petrol, 4 1 v/v) 0 5 Intermediate 48 (±)-3-r2,4-β s(methoxymethoxy)phenvπcyclohexanecarboxamide Tπethylamine (16 μl) and isobutylchloroformate (14 μl) were added to a stirred solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexanecarboxylιc acid in anhydrous tetrahydrofuran (2 ml) at 0°C under argon After 30 mm, aqueous ammonia solution (0 5 ml, 28% w/w) was added The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound (26 mg, 87%) as a mixture of diastereoisomers, m/z (ES * ) 324 (M+H) * Intermediate 49 (±)-3-[2,4-β/s(methoxymethoxy)phenyll-tV-hvdroxycyclohexanecarboxamide Tπethylamine (11 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexanecarboxylιc acid in anhydrous tetrahydrofuran (2 ml) at 0°C under argon After 30 mm, aqueous hydroxylamme solution (0 5 ml, 50 wt%) was added The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (26 mg, quant ) and a mixture of diastereoisomers, m/z (ES * ) 340 (M+H) * Intermediate 50 (±)-3-r2,4-B/s(methoxymethoxy)phenvn-A/-ethylcyclohexanecarboxamide Tπethylamine (1 1 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexanecarboxylιc acid in anhydrous tetrahydrofuran (2 ml) under argon at 0°C After 30 m , ethylamine (0 5 ml, 2M solution in tetrahydrofuran) was added The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (24 mg, quant ) and a mixture of diastereoisomers, m/z (ES * ) 352 (M+H) * Intermediate 51 (±)-3-f2,4-B/s(methoxymethoxy)phenvn-1 -(hydroxymethyl)cyclohexanol A/-Methyl morpholme Λ/-oxιde (120 mg) and osmium tetroxide (100 μl, 2 5 wt% in tert- butanol) were added to a solution of (±)-2,4-b/s(methoxymethoxy)-1-(3-methylenecyclohexyl) benzene (30 mg) in tetrahydrofuran (0 7 ml) and water (0 3 ml) at room temperature After 16 hr, celite was added to the reaction mixture followed by water (5 ml) and sodium persulfite (20 mg) The reaction mixture was filtered, the filtrate was adjusted to pH 4 with 2M hydrochloric acid solution and the aqueous volume was made up to 20 ml The aqueous layer was extracted with ethyl acetate (3x 20 ml), the combined organic extracts were washed with brine (20 ml), dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate) to give the title compound as a solid (30 mg, 89%) and a mixture of diastereoisomers, m/z (ES * ) 327 (M+H) * Intermediate 52 (±)-Λ -f3-[2,4-b/s(methoxymethoxy)phenvncvclohexyl>acetamide Tπethylamine (15 μl) and acetic anhydride (10 ml) were added to a stirred solution of (±)-3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexylamιne (29 mg) in anhydrous 1 ,2- dichloroethane (2 ml) at room temperature After 0 5 hr, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) and the aqueous layer was extracted with ethyl acetate (3 x 20 ml) The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (22 mg, 66%) and a mixture of diastereoisomers, m/z (ES * ) 338 (M+H) * Intermediates 53 and 54 trans-4-(2,4-B/s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol c s-4-(2,4-β/s{[ferf-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol Sodium borohydπde (164 mg) was added to a stirred solution of 4-(2,4-b/ ' s{(fert- butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanone (1.57 g) in ethanol (50 ml) at 0°C. After 2 hr at 0°C and then 18 hr at room temperature, the reaction mixture was partitioned between 2M HCI (20 ml), water (40 ml) and ethyl acetate (50 ml) and the aqueous layer was re-extracted with ethyl acetate (2 x 50ml) The combined organic extracts were washed with brine (40 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (Si0 2 , ethyl acetate/petrol, 3:17 v/v) to give the trans-title compound as a white solid (546 mg, 35%), and the c/s-title compounds as a white solid (83 mg, 5%). trans - δ H (CDCI 3 ) 0.18 (6H, s), 0.22 (6H, s), 0.98 (9H, s), 1.02 (9H, s), 1.18 - 1.22 (4H, m), 1.80 - 1.84 (3H, m), 2.00 - 2.05 (2H, m), 2.78 - 2.86 (1 H, m), 3.60 - 3.70 (1 H, m), 6.28 (1 H, d), 6.39 (1 H, dd), 6.94 (1 H, d). s - δ H (CDCI 3 ) 0.18 (6H, s), 0.22 (6H, s), 0.98 (9H, s), 1.02 (9H, s), 1.58 - 1.78 (6H, m), 1.84 - 1.92 (2H, m), 2.70 - 2.80 (1 H, m), 4.12 (1 H, bs), 6.28 (1 H, d), 6 40 (1 H, dd), 7.02 (1 H, d) Intermediate 55 trans-4-(2,4-β/s{[-er -butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl 4-(dimethylamino) benzoate Tπethylamine (20 μl), 4-dιmethylamιnopyrιdιne (catalytic amount) and 4- dimethylaminobenzoyl chloride (26 mg) were added to a stirred solution of frans-4-(2,4- b/ ' s{[rerr-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanol (30 mg) in dry dichloromethane (2 ml) at room temperature under argon After 24 hr, the solvent was removed under reduced pressure and the residue was partitioned between water (10 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (2x 20 ml) and the combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Si0 2 , ethyl acetate/petrol, 1.24 v/v) to give the title compound as a white solid (18 mg, 45%), m/z (ES * ) 585 (M+H) * Intermediate 56 cis I trans - 4-(2,4-B/s{[-ert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanecarboxylic acid Pyπdinium dichromate (146 mg) was added to a stirred solution of cis / trans - [4-(2,4- b/s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl]methanol (50 mg) in /V,tv-dιmethylform- amide (1 ml) at room temperature under argon. After 24 hr, the reaction mixture was partitioned between water (20 ml) and diethyl ether (30 ml) The layers were separated and the aqueous layer was extracted with diethyl ether (2 x 30 ml) The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 9 v/v) to give the title compound as a cream solid (23 mg, 44%), m/z (ES * ) 465 (M+H) * Intermediate 57 trans-4-(2,4-B/s{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl ethylcarbamate Λ/N-Di/sopropylethylamme (199 μl) and ethyl isocyanate (90 μl) were added to a stirred solution of trans-4-(2,4-b/s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon The reaction mixture was heated to 40°C for 120h, and was partitioned between water (50 ml) and ethyl acetate (50 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml) The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 2 v/v) to give the title compound as a solid (55 mg, 95%), R f (ethyl acetate/petrol, 1 2 v/v) 0 65 Intermediate 58 trans-4-(2,4-B/s{[-ert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl cyclohexylcarbamate Λ/,Λ/-Dι/sopropylethylamιne (199 μl) and cyclohexyl isocyanate (128 μl) were added to a stirred solution of 4-(2,4-b/s{[terf-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanol (50mg) in dry dichloroethane (1 ml) at room temperature under argon The reaction mixture was heated to 40°C for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (2x50 ml) The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 2 v/v) to give the title compound as a pale yellow solid (30 mg, 47%), δ H (CDCI 3 ) 0 12 (6H, s), 0 18 (6H, s), 0 90 (9H, s), 0 95 (9H, s) 1 00 - 2 10 (18H, m), 2 70 - 2 80 (1 H, m), 3 36 - 3 50 (1 H, m), 4 40 - 4 48 (1 H, m), 4 50 - 4 62 (1 H, m), 6 20 (1 H, d), 6 32 (1 H, dd), 6 86 (1 H, d) Intermediate 59 -rans-4-(2,4-Dihydroxyphenyl)cyclohexanol 4-(2,4-Dιhydroxyphenyl)cyclohexanone (18 mg) was placed in a round-bottomed flask equipped with magnetic stirrer Ethanol (5 ml) was added, followed by sodium borohydπde (3 3 mg), and the reaction mixture was stirred for 16 hr Aqueous HCI (20 ml, 1 M), followed by ethyl acetate (20 ml), was added, and the organic phase removed and washed with brine (15 ml), dried over anhydrous magnesium sulphate, filtered, and then concentrated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petroleum ether, 60 40, v/v) to afford the title compound (14 mg, 78%) as a white solid δ H (CD 3 OD) 1 38-1 56 (4H, m), 1 85-1 88 (2H, m), 2 04 - 2 07 (2H, m), 2 80 (1 H, tt), 3 58 - 3 65 (1 H, m), 6 24-6 29 (2H, m), 6 90 (1 H, d), m/z (ES ) 267 ((M+AcOH) - 1 ) Intermediate 60 cis - 4-(2,4-β/s{[tert-Butyl(dιmethyl)silyl]oxy}phenyl)cyclohexyl methanesulfonate To a round bottom flask containing c/s-4-(2,4-b/s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl) cyclohexanol (200 mg, 0 46 mmol) was added dichloromethane (10 ml) followed by tπethylamine (96 μl, 0 69 mmol) and dimethylaminopyπdine (catalytic amount) The flask was purged with argon and methane sulfonyl chloride (53 μl, 0 69 mmol) was added with stirring Stirring was continued for a further 24 hr and the reaction mixture was poured into water and extracted with dichloromethane (4 x 20 ml) The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo Purification via flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 9) afforded the title compound as an oil (194 mg, 82%) δ H (CDCI 3 ) 0 19 (6H, s), 0 22 (6H, s), 0 97 (9H, s), 1 01 (9H, s), 1 20 - 1 35 (2H, m), 1 65 - 1 78 (4H, m), 2 15 - 2 22 (2H, m), 2 85 - 2 95 (1 H, m), 3 02 (3H, s), 5 06 (1 H, s), 6 30 (1 H, d), 6 43 (1 H, dd), 7 00 (1 H, d) Intermediate 61 [4-(2,4-β s{[-ert-butyl(dιmethyl)silyl]oxy}phenyl)cyclohexyl]methyl propionate 4-Dιmethylamιnopyrιdιne (catalytic amount), tπethylamine (68 μl) and propionyl chloride (42 μl) were added to a stirred solution of [4-(2,4-b/s{[ter.-butyl(dιmethyl)sιlyl]oxy} phenyl) cyclohexyl]methanol in anhydrous dichloromethane (3 ml) at room temperature under argon After 16 hr, the reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 ml) The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 19 v/v) to give the title compound as a yellow oil and a mixture of diastereoisomers (1 14 mg, 92%), δ H (CDCI 3 ) -0 04 (6H, s), 0 02 (6H, s), 0 96 (9H, s), 1 00 (9H, s), 1 08 - 1 18 (3H, m), 1 20 - 2 10 ( 9H, m), 2 24 - 2 40 (2H, m), 2 76 - 2 92 (1H, m), 3 94 (0 6H, d), 4 18 (0 4H, d), 6 26 (1 H, m), 6 40 (1 H, dd), 6 94 - 6 98 (1 H, m) Intermediates 62 and 63 Diastereoisomers of ethyl 4 - (2, 4 - bis{[.ert - butyl(dimethyl)silyl]oxy}phenyl) - 1 - hydroxycyclohexanecarboxylate A round bottom flask equipped with stirrer bar was charged with tetrahydrofuran (6 ml), ethyl vinyl ether (0 28 ml, 2 92 mmol) and cooled to -78°C A solution of ferf-butyl lithium (1 ml, 1 7 M, 1 7 mmol) was added dropwise and the flask allowed to reach 0°C The flask was maintained at this temperature until the bright yellow colour had been discharged before being re-cooled to -78 °C A solution of 4 - (4 - {[tert - butyl(dιmethyl)sιlyl]oxy}phenyl) cyclohexanone (250 mg, 0 58 mmol) in THF (4 ml) was added dropwise After 30 mm the reaction was quenched with wet THF (0 5 ml water in 5 ml of THF), poured into water (10 ml) and extracted with diethyl ether (3 x 10 ml) The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo This residue was dissolved in methanol (40 ml), cooled to -78 °C and ozonised oxygen passed through the solution for 10 mm After this time the excess ozone was removed by passing oxygen through the solution The reaction mixture was allowed to warm to room temperature and concentrated in vacuo Purification via flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 6) afforded the title compounds First eluted diastereoisomer (31 mg, 11 %), δ H (CDCI 3 ) 0 18 (6H, s), 0 25 (6H, s), 0 97 (9H, s), 1 02 (9H, s), 1 30 (3H, t), 1 80 - 1 95 (8H, m), 2 82 - 2 95 (2H, m), 4 23 (2H, q), 6 28 (1 H, d), 6 42 (1 H, dd), 7 05 (1 H, d) Second eluted diastereoisomer (32 mg, 12%), δ H (CDCI 3 ) 0 20 (6H, s), 0 25 (6H, s), 0 95 (9H, s), 1 00 (9H, s), 1 36 (3H, t), 1 62 - 1 85 (6H, m), 2 10 - 2 22 (2H, m), 2 87 - 2 98 (2H, m), 4 28 (2H, q), 6 28 (1 H, d), 6 42 (1 H, dd), 6 97 (1 H, d) Intermediate 64 4-{2, 4-B/s [terf-butyl(dιmethyl)silyloxy]phenyl cyclohexanone oxime To a round bottomed flask equipped with magnetic stirrer was added 4-{2, 4-b/s [tert- butyl(dιmethyl)sιlyloxy]phenyl cyclohexanone (100 mg, 0 23 mmol) and ethanol (5 ml) To the stirred suspension was added hydroxylamme hydrochloπde (32 mg, 0 46 mmol) and tπethylamine (103 μl, 0 74 mmol), then the solution was heated under reflux temperature for 2 5 hr The solution was allowed to cool to room temperature then evaporated to dryness in vacuo The residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the layers separated The aqueous layer was extracted with ethyl acetate (3x20 ml) and the combined organic layers washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The title compound was isolated (103 mg, 100 %) as a white δ H (CDCI 3 ) 0 19 (6H, s), 0 24 (6H, s), 0 95 (9H, s), 1 02 (9H, s), 1 43-1 62 (2H m), 1 77-1 87 (1 H m), 1 93-2 04 (2H, m), 2 18-2 24 (1 H m), 2 46-2 53 (1 H, m), 3 05-3 15 (1 H, m), 3 41-3 50 (1 H, m), 6 30 (1 H, d), 6 40 (1 H, dd) 6 79 (1 H, br), 6 92 (1 H, d) Example 1 4 - (2, 4 - Dihydroxyphenyl) - 3 - cyclohexen - 1 - one A round bottomed flask equipped with magnetic stirrer was charged with 8 - [2, 4 - b/s(methoxymethoxy)phenyl] - 1 4 - dιoxaspιro[4 5]dec - 7- ene (1 50 g 4 24 mmol) and methanol (30 ml) To the stirred solution was added aqueous hydrochloric acid (30 ml, 1 0M) and the solution was heated to reflux temperature for 1 5 hr After cooling to room temperature, saturated aqueous sodium bicarbonate (20 ml) was added and the layers separated The aqueous layer was extracted with ethyl acetate (4x20 ml) and the combined organic layers washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The resulting oil was purified via flash column chromatography (Sι0 2 , ethyl acetate/ petroleum ether, 1 3, v/v) to afford the title compound as a yellow solid (323 mg, 37%) m/z (ES ) 203 (M-H * ), δ H (CD 3 OD) 2 62 (2H, t), 2 86 (2H, t), 3 04 (2H, m), 5 78 (1 H, m), 6 28 (1 H, m), 6 32 (1 H, m), 6 96 (1 H, d) Example 2a 4-(2, 4-Dihydroxyphenyl)cyclohexanone A round bottomed flask equipped with magnetic stirrer was loaded 8-[2,4- b/s(methoxymethoxy)phenyl]-1 ,4-dιoxaspιro[4 5]decane (1 30 g, 3 9 mmol) and methanol (15 ml) To the resulting stirred solution was added aqueous HCI (15 ml, 1 M) in one portion After stirring for one hr at room temperature the acid was quenched by adding saturated aqueous sodium bιca r bonate solution (10 ml) After stirring vigorously for 10 m , the reaction mixture was transferred to a separating funnel and the phases separated and the aqueous phase was extracted with ethyl acetate (3x20 ml) The combined organic phases were washed with brine and the solvent evaporated To the slightly wet crude product was added methanol (30 ml) and acidic ion exchange resin (4 g) The resulting mixture was heated under reflux, with stirring, for 5 hr Filtering through a plug of Celite, washing with ethyl acetate, followed by removal of solvent in vacuo afforded an orange oil Purification by flash column chromatography, (Sι0 2 , ethyl acetate/petroleum ether, 1 1 , v/v) furnished the title compound as a white powder (0 54 g, 68%) m/z (ES ) 411 (2M - 1 ), δ H (CD 3 OD) 1 94 (2H, ddd), 2 16 - 2 23 (2H, m), 2 41 (2H, dt), 2 62 (1 H, t), 2 63 (1 H, t), 6 24 (1 H, dd), 6 31 (1 H, d), 6 92 (1 H, d) Example 2b 4 - (2, 4 - Dιhydroxyphenyl)cyclohexanone A round bottomed flask equipped with magnetic stirrer was charged with 4 - (1 , 4 - dιoxaspιro[4 5]dec - 8 - yl) - 1 , 3 - benzenediol (11 3 g, 45 2 mmol), acetone (250 ml) and water (50 ml) To the stirred solution was added pyπdinium p - toluenesulfonate (1 14 g, 4 52 mmol) in one portion and the reaction mixture was then heated to reflux temperature for 8 hr After allowing the reaction mixture to cool to room temperature, most of the acetone was removed in vacuo and the remaining mixture was partitioned between ethyl acetate (200 ml) and water (50 ml) The aqueous layer was extracted with ethyl acetate (3x50 ml) and the combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an off white powder After washing the powder with dichloromethane (100 ml) and removal of excess solvent under reduced pressure, the desired product (9 30 g, 100%) was obtained as an off-white white powder m/z (ES * ) 207 (M+H * ), δ H (CD 3 OD) 1 84 - 1 97 (2H, m), 2 15 - 2 23 (2H, m), 2 36 - 2 45 (2H, m), 2 58 - 2 68 (2H, m), 3 39 (1 H, tt) 6 26 (1 H, dd), 6 34 (1 H, d), 6 96 (1 H, d) Example 3 4-(2, 4-Dιhydroxyphenyl)cyclohexanone oxime To a round bottomed flask, equipped with magnetic stirrer was added 4-(2, 4- dιhydroxyphenyl)cyclohexanone (100 mg, 0 49 mmol), anhydrous ethanol (5 ml), tπethylamine (102 ml) and hydroxylamme hydrochloπde (51 mg, 0 73 mmol) The reaction mixture was heated under reflux for 3 hr, then evaporated in vacuo The resulting solid was purified by flash column chromatography, (Sι0 2 , ethyl acetate/petroleum ether, 35 65, v/v), furnishing the title compound as short white needles (107 mg, 100%) δ H (CD 3 OD) 1 44 - 1 61 (2H, m), 1 81 - 1 88 (1 H, m), 1 94 - 2 00 (2H, m), 2 19 - 2 27 (1 H, m), 2 43 (1 H, d), 3 04 - 3 10 (1 H, m), 3 38 (1 H, m), 6 22 - 6 25 (1 H, m), 6 28 (1 H, d), 6 84 - 6 86 (1 H, m), m/z (El ) 220 Example 4 Q-Methyl-4-(2, 4-dihydroxyphenyl)cyclohexanone oxime To a round bottomed flask, equipped with magnetic stirrer was added 4-(2, 4- dιhydroxyphenyl)cyclohexanone (21 mg, 0 10 mmol), anhydrous ethanol (3 ml), sodium acetate (16 mg, 0 20 mmol) and O-methylhydroxylamine hydrochloπde (9 mg, 0 22 mmol) The reaction mixture was heated under reflux for 6 hr, then partitioned between ethyl acetate (10 ml) and water (10 ml) The organic layer was dried over anhydrous calcium sulphate, filtered and evaporated in vacuo furnishing a colourless oil Purification via flash column chromatography (Sι0 2 , ethyl acetate/petroleum ether, 1 1 , v/v), afforded the title compound as a white solid (11 mg, 47%) δ H (CD 3 OD) 1 43 - 1 63 (2H, m), 1 81 - 1 92 (2H, m), 1 93 - 2 20 (2H, m), 2 24 (1 H, dt), 2 38 - 2 44 (1 H, m), 3 07 (1 H, tt), 3 78 (3H, s), 6 20 - 6 23 (1 H, m), 6 26 (1 H, d), 6 85 (1 H, d), m/z (ES ) 234 Example 5 Q-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime To a round bottomed flask, equipped with magnetic stirrer, was added 4-(2,4- dιhydroxyphenyl)cyclohexanone (21 mg, 0 10 mmol), anhydrous ethanol (3 ml), sodium acetate (17 mg, 0 21 mmol) and O-benzylhydroxylamine hydrochloπde (18 mg, 0 21 mmol) The reaction mixture was heated under reflux for 6 hr, then partitioned between ethyl acetate (10 ml) and water (10 ml) The organic layer was dried over anhydrous calcium sulphate, filtered and evaporated in vacuo furnishing a pale pink oil which was purified by flash column chromatography (Sι0 2 , ethyl acetate/petroleum ether, 1 1 , v/v) to afford the title compound as a colourless oil (11 mg, 32%) δ H (400, CDCI 3 ) 1 47 - 1 68 (2H, m), 1 86 - 1 95 (1 H, m), 1 97 - 2 08 (2H, m), 2 25 (1 H, dt), 2 49 - 2 57 (1 H, m), 3 02 (1 H, tt), 3 42 - 3 50 (1 H, m), 4 78 (1 H, s), 4 89 (1 H, s), 6 25 - 6 29 (1 H, m), 6 33 - 6 37 (1 H, m), 6 94 (1 H, d), 7 26 - 7 39 (5H, m), m/z (ES ) 310 Example 6 3-(2,4-dihydroxyphenyl)-2-cyclohexen-1-one 3-[2,4-β/s(methoxymethoxy)phenyl]-2-cyclohexen-1-one (50 m g) was heated to 50°C in methanol (4 ml) containing acidic ion exchange resin (500 mg) After 2 hr, the mixture was filtered and the filtrate was evaporated in vacuo and purified by flash column chromatography (Sι0 2 , ether/petroleum ether, 9 1 , v/v) to furnish the title compound as a yellow solid (31 mg, 76%) δ H (DMSO) 1 95 (2H, quintet), 2 30 (2H, t), 2 69 (2H, t), 6 26 (2H, overlapping m), 6 35 (1 H, m), 7 10 (1 H, d), 9 67 (1 H, bs), 9 86 (1 H, bs), m/z (ES ) 407 (2M-H) Example 7 (±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (±)-3-[2,4-β/s(methoxymethoxy)phenyl]cyclohexanone (35 mg) in methanol (4 ml) containing acidic ion exchange resin (300 mg) was stirred at 50°C for 6 hr, and then at ambient temperature for 16 hr The mixture was evaporated in vacuo and the residue was redissolved in acetone (4 ml) containing water (2 drops) and stirred at 50°C for 8 hr, then at ambient temperature for 64 hr The mixture was filtered through celite and purified by flash column chromatography (Sι0 2 , petroleum ether/ethyl acetate 1 1 v/v) to furnish the title compound as a white solid containing an equilibrium mixture of cychzed and uncychzed forms (31 mg, 76%) δ H (DMSO) 1 1 - 2 3 (8H, overlapping m), 3 0 (1 H, m), 6 08 (0 5H, bs), 6 16 (1 H, bd), 6 25 (0 5H, bs), 6 53 (0 5H, bs), 6 75 (0 5H, d), 6 89 (0 5H, b), 8 98 (0 5H, bs), 9 02 (0 5H, bs), 9 17 (0 5H, bs), m/z (ES ) 205 (M-H) Example 8 3-(2,4-Dihydroxyphenyl)-2-cyclohexen-1 -one oxime 3-[2,4-β/s(methoxymethoxy)phenyl]-2-cyclohexen-1-one oxime (0 1 g) was heated to 50°C in methanol (5 ml) containing acidic ion exchange resin (0 3 g) After 4hr, the mixture was filtered and the resin was washed with ammonia solution (50 ml) Filtrate and washings were combined, evaporated in vacuo and purified by flash column chromatography (Sι0 2 , ethyl acetate/petroleum ether, 3 2, v/v) to furnish the title compound as a yellow solid (0 058 g, 81 %) δ H (DMSO) (mixture of stereoisomers) 1 68 (2H, m, major), 1 76 (2H, m, minor), 2 26 (2H, m, minor), 2 40-2 54 (4H major + 2H minor, overlapping m), 6 15-6 30 (3H major + 2H minor, overlapping m), 6 85-6 95 (1 H major + 2H minor, overlapping m), 9 26 (1 H, bs, major), 9 32 (1 H, bs, minor), 9 35 (1 H, bs, major), 9 40 (1 H, bs, minor), 10 17 (1 H, s, minor), 10 49(1 H, s, major), m/z (ES ) 437 (2M-H) Example 9 (+)-3-(2.4-Dihvdroxyphenyl)cvclohexanone oxime (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanone (13 mg), hydroxylamme hydrochloπde (0 0065 g), and tπethylamine (16 μl) were heated at 80°C in DMF (3 ml) After 3 hr, the reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , petroleum ether/ethyl acetate 3 2 v/v) to furnish the title compound as a white solid (12 mg, 86%) δ H (CD 3 OD) 1 4- 2 0 (6H, overlapping m), 2 10 (0 5H, m), 2 20 (0 5H, m), 2 35 (0 5H, m), 2 46 (0 5H, m), 2 94 (1 H, m), 6 22-6 26 (2H, overlapping m), 6 92-6 95 (1 H, overlapping m), m/z (ES * ) 222 (M+H) Example 10 (±)-4-r3-(1-Piperazinyl)cvclohexyn-1,3-benzenediol trifluoroacetic acid salt (±)-1 -{3-[2,4-β/s(methoxymethoxy)phenyl]cyclohexyl}pιperazιne (35 mg) was heated under reflux in methanol containing acidic ion exchange resin (0 3 g) for 5 hr The reaction mixture was filtered, and the resin was washed with methanol and aqueous ammonia, and the combined filtrate and washings were concentrated in vacuo The crude residue was purified by preparative HPLC to furnish the title compound as an off white solid (14 mg, 38%) δ H (d - MeOH) 1 7 - 1 9 (6H, overlapping m), 2 05 (1 H, m), 2 20 (1 H, m), 3 1 - 3 5 (1 OH, overlapping m), 6 26 (2H, overlapping m), 6 94 (1 H, d), m/z (ES * ) 277 (M+H) * Example 11 (±)-ιV-f3-(2,4-Dihvdroxyphenyl)cvclohexyllmethanesulfonamide (±)-Λ/-{3-[2,4-β/s(methoxymethoxy)phenyl]cyclohexyl}methanesulfonamιde (34 mg) was heated under reflux in methanol (2 ml) containing acidic ion exchange resin (0 3 g) for 5 hr The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish a mixture of diastereoisomers of the title compound as a pale pink solid (10 mg, 38%) δ H (d 4 -MeOH) 1 20 - 2 00 (7H, overlapping m), 2 07 (1 H, m), 2 90 (0 5H, m), 2 93 (1 5H, s), 2 97 (1 5H, s), 3 13 (0 5H, m), 3 30 (0 5H, m), 3 80(0 5H, m), 6 21 - 6 26 (1 H, dd), 6 87 (0 5H, d), 6 89 (0 5H, d), m/z (ES ) 284 (M-H) Example 12 (±)-4-[3-(Hvdroxymethyl)cyclohexyn-1 ,3-benzenediol (±)-{3-[2,4-β/s(methoxymethoxy)phenyl]cyclohexyl}methanol (35 mg) was heated at 50°C in methanol (3 5 ml) containing acidic ion exchange resin (350 mg) After 6 hr, the mixture was filtered, the resin was washed with ethyl acetate, and the combined filtrate and washings were evaporated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 '1 v/v) to furnish a mixture of diastereoisomers of the title compound as a white solid (2 mg, 8%). δ H (d 4 -MeOH) 0.9 - 1.9 (9H, overlapping m), 2.80 (0.5H, m), 2.90 (0.5H, m), 3.20 - 3 40 (2H, overlapping m), 6.15 (2H, m), 6.80 (0.5H, d), 6.85 (0.5H, d); m/z (ES " ) 221 (M-H) ' Example 13 (±)-4-f3-(Hydroxyamino)cvclohexyll-1 ,3-benzenediol trifluoroacetate salt C/s-/V-{3-[2,4-b/ ' s(methoxymethoxy)phenyl]cyclohexyl}hydroxylamιne (0.015 g) was heated under reflux in methanol (2 ml) containing acidic ion exchange resin (0.3 g) for 5 hr. The reaction mixture was filtered, and the resin was washed with aqueous ammonia and methanol and the combined filtrate and washings were concentrated in vacuo. The crude residue was purified by preparative HPLC to furnish the title compound as an off white solid (0 005 g, 46%). δ H (d 4 -MeOH) 1.25 - 1.60 (4H, overlapping m), 1.82 (1 H, bd), 2.02 (1 H, m), 2 17 (2H, overlapping m), 2.93 (1 H, m), 3.36 (1 H, m) 6.24 (1 H, dd), 6.27 (1 H, d), 6.88 (1 H, d); m/z (ES * ) 224 (M+H) * Example 14 4-(4-Methylenecyclohexyl)-1 ,3-benzenediol Tetrabutylammonium fluoride (230 μl) was added to a stirred solution of tert-butyl-[3- {[tert-butyl(dιmethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy](ιsopropyl)dιmethylsilane (40 mg) in tetrahydrofuran (2 ml) at room temperature After 24 hr, further tetrabutylammonium fluoride (50 μl) was added, and after 2 hr the solvent was removed under reduced pressure The residue was partitioned between water (20 ml) and ethyl acetate (20 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (2x 20 ml) The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 2:3 v/v) to give the title compound as a white solid (17 mg, 90%). δ H (CD 3 OD) 1.25 - 1.40 (2H, m), 1.75 - 1.82 (2H, m), 2.04 - 2 15 (2H, m), 2.22 - 2.30 (2H, m), 2.86 (1 H, tt), 3 20 (1 H, m), 4.50 (2H, s), 6 10 - 6 16 (2H, m), 6 72 (1 H, d); m/z (ES * ) 205 (M+H) * Example 15 cis I traπs-4-[4-(Hydroxymethyl)cyclohexyl]-1 ,3-benzenediol cis / trans-[4-(2,4- β /s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl]methanol (24 mg) was dissolved in THF (5 ml), and tetrabutylammonium fluoride (0.12 ml, 1.0M in THF) was added The resulting solution was stirred at room temperature for 15 hr and then partitioned between ethyl acetate (20 ml) and water (2 ml) The aqueous phase was extracted with ethyl acetate (3x20 ml) and the combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, and concentrated in vacuo Purification via flash column chromatography (Sι0 2 eluting with ethyl acetate petroleum ether, 1 1 v/v) furnished the desired compound (7 mg, 59%) as a white solid δ H (CD 3 OD) 0 95 - 1 06 (0 5H, m), 1 24 - 1 38 (0 5H, m), 1 43 - 1 60 (4H, m), 1 69 - 1 83 (4H, m), 2 62 - 2 77 (1 H, m), 3 30 (1 H, d), 3 56 (1 H, d), 6 11 - 6 17 (2H, m), 6 76 - 7 01 (1 H, m), m/z (ES ) 281 (M - 1 + 60) Example 16 cis I -raπs-4-(4-Hydroxy-4-methylcyclohexyl)-1 ,3-benzenedιol c/s/frans-4-(2,4-β/s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl)-1 -methylcyclohexanol (29 mg) was dissolved in THF (8 ml), and tetrabutylammonium fluoride (0 14 ml, 1 0M in THF) was added in one portion with stirring The resulting solution was stirred for 17 hr and then partitioned between ethyl acetate (30 ml) and water (5 ml) The aqueous phase was extracted with ethyl acetate (2x10 ml), and the combined organic phases washed with brine (20 ml), dried over anhydrous magnesium sulphate, and concentrated in vacuo Purification via flash column chromatography (Sι0 2 eluting with ethyl acetate petroleum ether, 1 19 v/v gradually increasing polarity to 3 7 v/v) afforded the title product as the individual 1 ,4-c/s (5 mg, 36%) and 1 ,4-trans (9 mg, 64%) diastereoisomers (white solids) Cis isomer δ H (CD 3 OD) 1 30 (3H, s), 1 50 - 1 66 (4H, m), 1 69 - 1 77 (4H, m), 2 74 - 2 82 (1 H, m), 6 20 - 6 26 (2H, m), 6 89 (1 H, d), m/z (ES ) 281 (M - 1 +60) Trans isomer δ H (CD 3 OD) 1 22 (3H, s), 1 46 - 1 60 (4H, m), 1 69 - 1 82 (4H, m), 2 75 (1 H, tt), 6 22 - 6 26 (2H, m), 6 93 (1 H, d), m/z (ES ) 281 (M - 1 + 60) Example 17 cis I trans - N - [4 - (2, 4 - Dihydroxyphenyl)cyclohexyl]acetamιde To a round bottomed flask equipped with magnetic stirrer was added cis I trans - N - [4 - (2, 4 - b/s{[fert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl] acetamide (15 mg, 31 μmol), tetrahydrofuran (3 ml) and tetra-n-butylammonium fluoride (93 μl, 93 μmol 1 0M solution in tetrahydrofuran) The resulting solution was stirred for 3 hr Tetra-n-butylammonium fluoride (90 μl, 90 μmol, 1 0M solution in tetrahydrofuran) was added and the solution stirred for a further 64 hr Saturated aqueous sodium bicarbonate solution (3 ml) was added and the solvents removed in vacuo The residue was partitioned between ethyl acetate (20 ml) and water (5 ml) and the aqueous layer extracted with ethyl acetate (3x10 ml) The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo Purification via flash column chromatography (Sι0 2 , methanol / dichloromethane, 1 9, v/v) afforded an oily solid (6 mg) which was a mixture of isomers by NMR Further purification via HPLC afforded the title compound (0 5 mg 6%) as a mixture of diastereoisomers and a colourless oil m/z (ES ) 308 (M-1 +60{acetate}) δ H (CD 3 OD) 1 41 (1 H, m), 1.57 (1 H, m), 1.70 (2H, m), 1.83 (1 H, m), 1.87 (1 H, m), 1.93 (1 H, m), 1 96 (1.5H, m), 2.04 (1 5H, m), 2.05 (1 H, m), 2 82 (1 H, m), 3.72 (0.5H, m), 4 14 (0.5H, m), 6.28 (2H, m), 6.92 (0.5H, dd), 6.97 (0 5H, dd) Example 18 (±)-0-Methyl-3-(2,4-dihydroxyphenyl)cvclohexanone oxime (±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (22 mg), methoxylamine hydrochloπde (18 mg) and sodium acetate (18 mg) were heated under reflux in ethanol After 6 hr, further methoxylamine (36 mg) and sodium acetate (36 mg) were added and the mixture heated under reflux for a further 1 hr The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was extracted with ethyl acetate (2x20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 "1 v/v) to furnish the title compound as a mixture of isomers (18 mg, 72%) δ H (CDCI 3 ) 1.5 - 2.2 (6H, overlapping m), 2.42 (0.5H, bd), 2.69 (0.5H, bd), 2.92 (0.5H, m), 3.06 (0.5H, m), 3.24 - 3.38 (1 H, m), 3.81 (1.5H, s), 3.88 (1.5H, s), 5.42 (0.5H, bs), 5.47 (0.5H, bs), 6.28 - 6 42 (2H, overlapping m), 6.86 (0.5H, bs), 6.98 (1 H, m), 7.06 (0.5H, bs); m/z (ES-) 469 (2M-1 )\ Example 19 (±)-3-(2,4-Dihvdroxyphenyl)-1-methylcvclohexanol Methyl magnesium chloride (0.132 ml of a 22% w/w solution in tetrahydrofuran) was added to a solution of (±)-3-(2,4-dιhydroxyphenyl)cyclohexanone (20 mg) in tetrahydrofuran (3 ml) at 0°C under argon After 16 hr, dilute hydrochloric acid (1 ml) was added dropwise and the reaction mixture was partitioned between ethyl acetate (50 ml) and brine (50 ml) The aqueous layer was extracted with ethyl acetate (2x50 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The crude residue was purified by preparative HPLC to furnish the title compound as a white solid (6 mg, 28%) δ H (d 4 - MeOH) 1.20 (3H, s), 1.22 - 1.39 (2H, overlapping m), 1 46 (1 H, t), 1 54 - 1.87 (5H, overlapping m), 3 22 (1 H, m), 6 19 - 6.25 (2H, overlapping m), 6 86 91 H, d), m/z (ES " ) 281 (M+60-H)- Example 20 (+)-0-Benzyl-3-(2,4-dihvdroxyphenyl)cvclohexanone oxime (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanone (30 mg), O-benzylhydroxylamine hydrochloπde (46 mg) and sodium acetate (24 mg) were heated under reflux in ethanol (3 ml) After 16 hr, the reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (50 ml) and brine (50 ml) The aqueous layer was extracted with ethyl acetate (2x50 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The crude residue was purified by preparative HPLC to furnish a mixture of geometric isomers of the title compound as an off white solid (12 mg, 26%) δ H (d 4 - MeOH) 1 42 - 2 06 (6H, overlapping m), 2 12 (0 5H, dt), 2 22 (0 5H, t), 2 34 (0 5H, m), 2 46 (0 5H, m), 2 96 (1 H, m), 5 02 (2H, s), 6 20 - 6 27 (2H, overlapping m), 6 92 (1 H, m), 7 22 - 7 34 (5H, overlapping m), m/z (ES ) 310 (M-H) Example 21 3-(2,4-Dihydroxyphenyl)-2-cyclopentenone oxime 3-[2,4-β/s(methoxymethoxy)phenyl]-2-cyclopenten-1-one (20 mg) was heated at 50°C in MeOH (4 ml) containing acidic ion exchange resin (100 mg) for 3 hr The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml) The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 7 3 v/v) to furnish 3-(2,4-dιhydroxyphenyl)-2-cyclopenten-1-one (11 mg, 79%) 3-(2,4- Dιhydroxyphenyl)-2-cyclopenten-1-one (6 mg), hydroxylamme hydrochloπde (3 3 mg) and triethylamme (6 6 μl) were heated in ethanol (3 ml) under reflux for 3 hr The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml) The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 1 v/v) to furnish the title compound as a yellow solid and as one major isomer (4 mg, 62%) Data reported for the major isomer δ H (d 4 -MeOH) 2 74-2 77 (2H, m), 2 96-2 99 (2H, m), 6 34 (1 H, dd), 6 38 (1 H, d), 6 96 (1 H, t), 7 22 (1 H, d), m/z (ES ) 204 (M-H) Example 22 (±)-3-(2,4-Dihvdroxyphenyl)cvclopentanone (±)-3-[2,4-β/s(methoxymethoxy)phenyl]cyclopentanone (8 mg) was heated at 50°C in MeOH (3 ml) containing acidic ion exchange resin (0 1 g) for 3 hr The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml) The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (Sι0 2 , ethyl acetate) to furnish the title compound as a white solid (3 8 mg, 70%) δ H (d 4 -MeOH) 2 52-2 13 (1 H, m), 2 26-2 48 (4H, overlapping m), 2 53-2 60 (1 H, m), 3 55-3 61 (1 H, m), 6 29 (1 H, dd), 6 33 (1 H, d), 6 96 (1 H, d), m/z (ES ) 251 ((M + 60)-1 ) Example 23 (+)-3-(2,4-Dihvdroxyphenyl)cvclopentanone oxime (±)-3-(2,4-Dιhydroxyphenyl)cyclopentanone (5 mg), hydroxylamme hydrochloπde (2 7 mg) and triethylamme (5 4μM) were heated in EtOH (4 ml) under reflux for 3 hr The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml) The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo The crude residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 4 1 v/v) to furnish the title compound as a white solid and a mixture of isomers (3 8 mg, 71 %) δ H (d -MeOH) 1 80- 1 93 (1 H, overlapping m), 2 05-2 20 (0 5H, m), 2 39-2 55 (3H, overlapping m), 2 68-2 74 (1 H, overlapping m), 2 94 (0 5H, br dd), 6 26-6 33 (2H, overlapping m), 6 94 (0 5H, d), 6 96 (0 5H, d), m/z (ES ) 266 ((M + 60)-1 ) Example 24 cis - N - [4 - (2, 4 - Dihydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide To a round bottomed flask equipped with magnetic stirrer charged with cis - 4 - (2, 4 - b/s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexylamιne (150 mg, 0 34 mmol) and 1 , 2- dichloroethane (8 ml), was added triethylamme (96 μl, 0 70 mmol) and n-butylsulfonyl chloride (55 μl, 0 40 mmol) at room temperature 4-Dιmethylamιnopyπdιne (3 crystals) was added and the mixture stirred for 17 hr Aqueous sodium hydroxide solution (15 ml, 0 40M) was added and the mixture stirred for 10 mm The layers were partitioned and the aqueous layer was extracted with dichloromethane (15 ml) The combined organic layers were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo The resulting solid was then dissolved in tetrahydrofuran (10 ml) and acetic acid (0 15 ml), then tetra-n- butylammonium fluoride hydrate (360 mg, 1 4 mmol) was added The mixture was stirred at room temperature for 1 hr, then ethyl acetate (10 ml) and water (15 ml) were added The layers were partitioned and the aqueous layer was extracted with ethyl acetate (10 ml) The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to leave an oil Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 10 then 1 1 , v/v) furnished the title compound (40 mg, 35%) as a white solid m/z (ES ) 326 (M - H * ), δ H (CD 3 OD) 0 95 (3H, t), 1 45 - 1 55 (2H, m), 1 55 - 1 95 (10H, m), 2 80 - 2 90 (1 H, m), 3 00 - 3 20 (2H, m), 3 65 (1 H, m), 6 22 - 6 26 (2H, m), 6 96 (1 H, d) Example 25 trans - N • [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamide To a round bottomed flask equipped with magnetic stirrer was added trans - N - [4 - (2, 4 - b/s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl] methanesulfonamide (320 mg, 0 57 mmol) and 1 , 2-dιchloroethane (50 ml) To the stirred solution was added tπfluoroacetic acid (20 ml) and water (20 ml) The stirred reaction mixture was then heated under reflux for 18 hr and then cooled to room temperature Toluene (70 ml) was added and the solvent removed in vacuo Methanol (50 ml) was then added to the residue and the solvent removed under reduced pressure The resulting oil was purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 3, 1 2, then 1 1 v/v) to furnish the title product (115 mg, 71 %) as a white solid m/z (ES * ) 286 (M+H * ), δ H (CD 3 OD) 1 52 (4H, m), 1 89 (2H, m), 2 13 (2H, m), 2 80 (1 H, m), 3 00 (3H, s), 3 28 (1 H, m), 6 27 (1 H, d), 6 29 (1 H, dd), 6 92 (1 H, d) Example 26 cis - N - [4 - (2, 4 - Dihydroxyphenyl)cyclohexyl]methanesulfonamide To a round bottomed flask equipped with magnetic stirrer was added cis - N - [4 - (2, 4 - b/s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl]methanesulfonamιde (44 mg, 100 μmol) and 1 , 2-dιchloroethane (4 ml) To the stirred solution was added methanesulfonyl chloride (10 β, 120 //mol), triethylamme (28 β, 200 ΛTIOI) and three crystals of 4- dimethylaminopyπdine The reaction mixture was then left stirring for 17 hr The reaction mixture was then partitioned between aqueous sodium hydroxide (5 ml, 0 2M), and dichloromethane (5 ml) The aqueous phase was extracted with dichloromethane (2x5 ml) and the combined organic phases were washed with brine (7 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a gum This gum was dissolved in dichloromethane (6 ml), then water (3 ml) and tπfluoroacetic acid (3 ml) were added and the mixture left to stir for 17 hr The reaction mixture was diluted with toluene (15 ml) and the solvents were removed in vacuo More toluene (15 ml) was added and evaporated under reduced pressure Azeotropic removal of residual tπfluoroacetic acid was effected with methanol to give a gum (38 mg) The residue was dissolved in dichloromethane (4 5 ml) and methanol (4 5 ml), then water (3 ml) and trifluoroacetic acid (3 ml) were added The reaction mixture was stirred at room temperature for 64 hr The reaction mixture was diluted with toluene (15 ml) and the solvents were removed in vacuo More toluene (15 ml) was added and evaporated under reduced pressure Azeotropic removal of residual trifluoroacetic acid was effected with methanol to give an oil (28 mg) which was purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, gradient elution using 1 3, 1 2, then 1 1 v/v) to afford the title compound (13 mg, 81%) as a white solid m/z (ES * ) 286 (M+H * ), δ H (CD 3 OD) 1 71 (6H, m), 1 90 (2H, m), 2 87 (1 H, m), 3 00 (3H, s), 3 72 (1 H, m), 6 28 (1 H, d), 6 30 (1 H, dd), 7 01 (1 H, d) Example 27 4 - [4 - (4 - Hydroxyphenyl)cyclohexyl] - 1 , 3 - benzenediol To a round bottomed flask equipped with magnetic stirrer was added terf-butyl(4 - {4 - [2, 4 - b/s(methoxymethoxy)phenyl]cyclohexyl}phenoxy)dιmethylsιlane (118 mg, 0 24 mmol), methanol (10 ml) and acidic Dowex® resin (500 mg) The reaction mixture was heated to reflux temperature for 5 hr then cooled to room temperature and filtered through a celite plug, washing with ethyl acetate The filtrate was adsorbed onto silica gel and purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 2 3 v/v) to afford a white solid (44 mg) which was purified further by HPLC The title compound was isolated as a white solid (12 mg, 17%) m/z (ES ) 283 (M-H * ), δ H (CD 3 OD) 1 52 - 1 96 (6H, m), 2 11 (2H, m), 2 53 and 3 07 (1 H, m), 2 90 (1 H, m), 6 28 (2H, m), 6 75 (2H, m), 6 95 (1 H, m), 7 10 (1 H, m), 7 19 (1 H, m) Example 28 cis I trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate To a round bottomed flask equipped with magnetic stirrer was added cis / trans - methyl {4 - [2, 4 - b/s(methoxymethoxy)phenyl]cyclohexyl} acetate (1 00 g, 2 84 mmol) and methanol (20 ml) The stirred solution was heated to reflux temperature and aqueous hydrochloric acid (20 ml, 1 M) was added in aliquots (4x5ml) at 10 mm intervals After 2 hr, the reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (50 ml) added The reaction mixture was poured into a separating funnel containing ethyl acetate (100 ml) and water (30 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (3x30 ml) The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid Purification via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 2, v/v) afforded the title compound (0 51 g, 69%) as a mixture of diastereoisomers m/z (ES * ) 265 (M+H * ), δ H (CD 3 OD) 1 33-1 91 (9H, m), 2 30 (2H, m), 2 79 (1 H, m), 3 72 (3H, s), 6 28 (2H, m), 6 95 (1 H, m) Example 29 trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate cis / trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate (25 mg) was purified via HPLC (acetonitrile / water, 30 70 - 80 20, 20 mm isocratic) to afford the title compound as a white solid m/z(ES * ) 265 (M+H * ), δ H (CD 3 OD) 1 21 (2H, m), 1 47 (2H, m), 1 64 (1H, m), 1 88 (4H, m), 2 29 (2H, d), 2 79 (1 H, m), 3 70 (3H, s), 6 28 (2H, m), 6 92 (1 H, d) Example 30 cis - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate cis / trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate (25 mg) was purified via HPLC (acetonitrile / water, 30 70 - 80 20, 20 m isocratic) to afford the title compound as a white solid m/z(ES * ) 265 (M+H * ), δ H (CD 3 OD) 1 60 - 1 79 (8H, m), 2 31 (1 H, m), 2 54 (2H, d), 2 84 (1 H, m), 3 71 (3H, s), 6 27 (2H, m), 6 95 (1 H, d) Example 31 trans - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid To a round 25ml bottomed flask containing trans - methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate (60 mg, 0 23 mmol) and water (4 ml) was added sodium hydroxide (32 mg, 0 78 mmol) and the solution heated to 40°C for 1 hr The solution was poured into a separating funnel containing ethyl acetate (15 ml) and water (10 ml) To the aqueous layer was then added aqueous hydrochloric acid (10 ml, 1 0M) and ethyl acetate (20 ml) The layers were separated and the aqueous layer extracted with ethyl acetate (3x10 ml) The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (34 mg, 60%) as a solid m/z (ES * ) 251 (M+H * ), δ H (CD 3 OD) 1.20 (2H, m), 1 48 (2H, m), 1 89 (4H, m), 2 25 (2H, d), 2 81 (1 H, m), 6.27 (2H, m), 6 91 (1 H, m) Example 32 cis - [4 - (2, 4 - Dihydroxyphenyl)cyclohexyl]acetic acid To a round 25ml bottomed flask containing cis - methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate (10 mg, 0 038 mmol) and water (4 ml) was added sodium hydroxide (5 mg, 0 13 mmol) and the solution heated to 40°C for 1 hr The solution was poured into a separating funnel containing ethyl acetate (15 ml) and water (10 ml). To the aqueous layer was then added aqueous hydrochloric acid (10 ml, 1 0M) and ethyl acetate (20 ml) The layers were separated and the aqueous layer extracted with ethyl acetate (3x10 ml) The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (5 mg, 55%) as a solid m/z (ES * ) 251 (M+H * ), δ H (CD 3 OD) 1 61 - 1 77 (8H, m), 2 30 (1 H, m), 2 49 (2H, d), 2 84 (1 H, m), 6.27 (2H, m), 6.96 (1 H, d) Example 33 cis I trans - [4 - (2, 4 - Dihydroxyphenyl)cyclohexyl]acetic acid To a round bottomed flask equipped with magnetic stirrer was added {4 - [2, 4 - dιhydroxyphenyl]cyclohexylιdene}acetιc acid (50 mg, 0 20 mmol) and ethanol (15 ml) To the stirred solution was added palladium (catalytic amount, 10% on activated carbon) in one portion The reaction vessel was evacuated and then placed under an atmosphere of hydrogen This was repeated ten times and then stirred for 17 hr under a hydrogen atmosphere at room temperature The reaction mixture was filtered through a celite plug, washing with ethanol The solvent was removed in vacuo to give the title compound (50mg, 100%) as a pale yellow oil m/z (ES * ) 251 (M+H * ), δ H (CD 3 OD) 1 33 - 1 91 (9H, m), 2 30 (2H, m), 2 81 (1 H, m), 6 28 (2H, m), 6 94 (1 H, m) Example 34 cis / trans - [4-(2, 4-Dihydroxyphenyl)cyclohexyl]acetonitrile To a round bottomed flask equipped with magnetic stirrer was added {4-[2, 4- b/s(methoxymethoxy)phenyl]cyclohexylιdene}acetonιtrιle (408 mg, 1 3 mmol) and methanol (20 ml) The resulting solution was heated to reflux temperature and aqueous hydrochloπc acid (20 ml, 1 0M) was added The solution was heated for 1 hr then cooled and saturated aqueous sodium bicarbonate solution (50ml) added The mixture was partitioned between ethyl acetate (100 ml) and water (20 ml) and the aqueous layer was extracted with ethyl acetate (2x20 ml) The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording an oil To a 50 ml round bottomed flask equipped with magnetic stirrer was added crude [4-(2, 4- dιhydroxyphenyl)cyclohexylιdene]acetonιtπle (ca 224 mg, 0 98 mmol) and ethanol (15 ml) To the stirred solution was added palladium (catalytic amount, 10% on activated carbon) in one portion The reaction vessel was evacuated and then placed under a hydrogen atmosphere This process was repeated 10 times before leaving the reaction mixture under a hydrogen atmosphere Vigorous stirring was continued for 17 hr, then the reaction mixture was filtered through celite washing with methanol The solvent was removed under reduced pressure and the residue was purified via flash column chromatography (Sι0 2 , ethyl acetate / petroleum ether, 1 1 , v/v), furnishing the title compound (226 mg, 80% over 2 steps) as a colourless oil m/z (ES * ) 232 (M+H * ), δ H (CD 3 OD) 1 31 (1 H, m), 1 52 (1 H, m), 1 67 (1 H, m), 1 77 (0 5H, m), 1 83 (1 H, m), 1 92 (2H, m), 1 98 (2H, m), 2 22 (0 5H), 2 44 and 2 67 (2H, d), 2 84 (1 H, m), 6 28 (2H, m), 6 96 (1 H, m) Example 35 cis / trans - 4 - [4-(2-Aminoethyl)cyclohexyl]-1 ,3-benzenediol hydrochloride (Cis / trans) - [4-(2, 4-dιhydroxyphenyl)cyclohexyl]acetonιtπle (214 mg, 0 95 mmol), ethanol (25 ml) and chloroform (1 ml) were placed in a bomb and platinum (IV) oxide (25 mg, 0 1 1 mmol) was added The bomb was placed in a high pressure hydrogenation apparatus and shaken for 4 hr at ca 50 psi under a hydrogen atmosphere The reaction mixture was filtered through a celite plug, washing with methanol (30 ml) The solvents were removed in vacuo and the residue was washed with ethyl acetate (3x10 ml) to yield the title compound (161 mg, 64%) as a yellow oil m/z (ES * ) 236 (M+H * ), δ H (CD 3 OD) 1 08 - 1 93 (11 H, m), 2 79 and 2 97 (1 H, m), 2 99 (2H, m), 6 22 (2H, m), 6 88 (1 H, m) Example 36 (±)-4-(3.3-Difluorocyclohexyl)-1 ,3-benzenediol A mixture of (±)-1-(3,3-dιfluorocyclohexyl)-2,4-b/s(methoxymethoxy)benzene (30 mg), methanol (2 ml) and acidic ion exchange resin (200 mg) was heated under reflux for 4h The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to give the title compound as a solid (5 mg, 23%) δ H (CD 3 OD) 1 2 - 2 2 (8H, m), 3 08 (1 H, m), 6 23 - 6 27 (2H, m), 6 87 (1 H, d), m/z (ES ) 287 (M-1 +AcOH) Example 37 (±)-3-(2.4-Dihvdroxyphenyl)cvclohexanecarboxamιde (±)-3-[2,4-β/s(methoxymethoxy)phenyl]cyclohexanecarboxamιde (22 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated to reflux for 5 hr The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to give the title compound as a white solid (5mg, 31%) δ H (CD 3 OD) 1 45 - 1 82 (6H, m), 2 07 - 2 19 (2H, m), 2 62 - 2 69 (1 H, m), 3 00 - 3 09 (1 H, m), 6 20 - 6 28 (2H, m), 6 89 (1 H, d), m/z (ES * ) 236 (M+H) * Example 38 (±)-3-(2.4-Dihvdroxyphenyl)-/V-hydroxycvclohexanecarboxamide (±)-3-[2,4-β/s(methoxymethoxy)phenyl]cyclohexyl}methanol (25 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 4 hr The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to give the title compound as a solid (5 mg, 27%) δ H (CD 3 OD) 1 28 - 2 40 (8H, m), 2 08 - 2 20 (0 5H, m), 2 78 - 2 94 (1H, m), 3 60 - 3 72 (2H, m), 6 20 - 6 28 (2H, m), 6 80 - 6 90 (1 H, m), m/z (ES ) 250 (M-H) Example 39 (±)-3-(2.4-Dihvdroxyphenyl)-N-ethylcvclohexanecarboxamide (±)-3-[2,4-β/s(methoxymethoxy)phenyl]-A/-ethylcyclohexanecarboxamιde (25 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated to reflux for 4 hr The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a solid (2 mg, 12%) δ H (CD 3 OD) 1 80 (3H, t), 1 30 - 1 60 (4H, m), 1 74 - 1 94 (4H, m), 2 26 - 2 36 (1H, m), 2 82 - 2 92 (1 H, m), 3 16 (2H, q), 6 21 - 6 26 (2H, m), 6 88 (1 H, d), m/z (ES * ) 264 (M+H) * Example 40 (+)-4-r3-Hvdroxy-3-(hvdroxymethyl)cyclohexyn-1 ,3-benzenediol (±)-3-[2,4- β /s(methoxymethoxy)phenyl]-1-(hydroxymethyl)cyclohexanol (29 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 3 hr The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a cream solid (5 mg 24%) δ H (CD 3 OD) 1 20 - 2 00 (8H, m), 2 89 (1 H, tt), 3 61 (1 H, d), 3 69 (1 H, d), 6 20 - 6 26 (2H, m), 6 90 (1 H, d), m/z (ES ) 237 (M-H) Example 41 (±)-Λ/-f3-(2,4-dihvdroxyphenyl)cyclohexyllacetamide (±)-Λ/-{3-[2,4-b/s(methoxymethoxy)phenyl]cyclohexyl}acetamιde (20 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 3 hr The reaction mixture was filtered and the resin was washed with methanol The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a solid (5 mg, 34%) δ H (CD 3 OD) 1 10 - 2 00 (11 H, m), 2 90 (0 3H, tt), 3 08 (0 7H, tt), 3 70 - 3 80 (0 3H, m), 4 16 (0 7H, m), 6 20 - 6 26 (2H, m), 6 84 - 6 90 (1 H, m), m/z (ES * ) 250 (M+H) * Example 42 -rans-4-(2,4-Dihydroxyphenyl)cyclohexyl) 4-(dimethylamino)benzoate A mixture of frans-4-(2,4-b/s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl 4- (dιmethylamιno)benzoate (18 mg), methanol (5 ml) and Amberlyst fluoride resin (0 5 g) were stirred at room temperature for 24 hr The reaction mixture was filtered, and the filtrate was evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 2 3 v/v) to give the title compound as a white solid (8 mg, 73%) δ H (CD 3 OD) 1 56 - 1 70 (4H, m), 1 88 - 1 94 (2H, m), 2 16 - 2 20 (2H, m), 2 80 - 2 90 (1 H, m), 3 00 (6H, s), 6 20 - 2 26 (2H, m), 6 70 (2H, d), 6 92 (1 H, d), 7 62 (2H, d), m/z (ES * ) 356 (M+H) * Example 43 cis I trans - 4-(2,4-Dihydroxyphenyl)cyclohexanecarboxylιc acid Tetrabutylammonium fluoride (0 12 ml) was added to a stirred solution of 4-(2,4- b/s{[ferf-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexanecarboxylιc acid (22 mg) in tetrahydrofuran (1 ml) at room temperature under argon After 24 hr, the reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml) The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 ml) The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 7 1 v/v, <1 % acetic acid) to give the title compound as an orange solid (10 mg, 89%) δ H (CD 3 OD) 1 40 - 1 65 (4H, m), 1 88 - 1 95 (2H, m), 2 06 - 2 14 (2H, m), 2 35 (1 H, tt), 2 82 (1 H, tt), 6 25 - 6 30 (2H, m), 6 90 (1 H, d), m/z (ES ) 235 (M-H) Example 44 -raπs-4-(2,4-Dihydroxyphenyl)cyclohexyl ethylcarbamate A mixture of trans-4-(2,4-b/s{[tert-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl ethylcarbamate (18 mg) methanol (10ml) and Amberlyst fluoride resin (0 3 g) were stirred at room temperature for 24 hr The reaction mixture was filtered, and the filtrate was evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 3 v/v) to give the title compound as a white solid (24 mg, 87%) δ H (CD 3 OD) 1 10 (3H, t), 1 40 - 1 60 (4H, m), 1 80 - 1 90 (2H, m), 2 00 - 2 10 (2H, m), 2 72 - 2 80 (1 H, m), 3 10 (2H, t), 4 50 - 4 60 (1 H, m), 6 20 - 6 26 (2H, m), 6 88 (1 H, d), m/z (ES * ) 280 (M+H) * Example 45 -raπs-4-(2,4-Dihydroxyphenyl)cyclohexyl cyclohexylcarbamate A mixture of .rans-4-(2,4-b/s{[ferf-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl cyclohexylcarbamate (28 mg), methanol (10 ml) and Amberlyst fluoride resin (0 3 g) were stirred at room temperature for 72 hr The reaction mixture was filtered and the filtrate was evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 3 v/v) to give the title compound as a white solid (6 mg, 36%), δ H (CD 3 OD) 1 10 - 2 12 (18H, m), 2 70 - 2 82 (1 H, m), 4 46 - 4 60 (1 H, m), 6 18 - 6 30 (2H, m), 6 80 - 6 92 (1 H, m), m/z (ES * ) 334 (M+H) * General Procedure for Preparation for Examples 46-53 A round bottom flask equipped with stirrer bar was charged with frans-4-(2,4- dιhydroxyphenyl)cyclohexanol (208 mg, 1 mmol), dichloromethane (20 ml), triethylamme (1 4 ml, 10 mmol) and 4-dιmethylamιnopyπdιne (catalytic amount) The flask was purged with argon and the appropriate acid chloride (5 mmol) added dropwise with stirring The reaction mixture was then set aside for 24 hr The reaction mixture was then diluted with dichloromethane (20 ml) and washed successively with hydrochloric acid (10 ml of a 2M aqueous solution), saturated aqueous sodium hydrogen carbonate (10 ml), brine (10 ml), dried over magnesium sulfate and evaporated in vacuo The resulting residue was suspended in a mixture of tetrahydrofuran (20 ml) and methanol (5 ml) and cesium carbonate (685 mg, 2 1 mmol) in water (5 ml) was added The reaction mixture was warmed at 50°C until TLC analysis indicated complete conversion to the title compound The reaction solution was concentrated to approximately one quarter its original volume, diluted with water (10 ml) and extracted with ethyl acetate (3 x 10 ml) The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo The residue was purified using flash column chromatography (Sι0 2 , ethyl acetate/petrol) Example 46 trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-ter -butylbenzoate The title compound was isolated as an oil (180 mg, 49%), as described in the general procedure above δ H (d -MeOH) 1 34 (9H, s) 1 54 - 1 71 (4H, m), 1 87 - 1 94 (2H, m), 2 14 - 2.21 (2H, m), 2.86 (1 H, m), 4.95 (1 H, m), 6.24 (1 H, dd), 6.27 (1 H, d), 6.91 (1 H, d), 7.50 (2H, d), 7.94 (2H, d); m/z (ES * ) 369 (M+H) * . Example 47 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-fluorobenzoate The title compound was isolated as a white solid (133 mg, 40%), as described in the general procedure above. δ H (d 4 -MeOH) 1.54 - 1.72 (4H, m), 1.86 - 1.95 (2H, m), 2.13 - 2.20 (2H, m), 2.86 (1H, m), 4.96 (1 H, m), 6.24 (1 H, dd), 6.26 (1 H, d), 6.91 (1 H, d), 7.18 (2H, m), 8.06 (2H, m); m/z (ES * ) 331 (M+H) * . Example 48 trans - 4-(2, 4 - Dihydroxyphenyl)cyclohexyl 4 - trifluoromethylbenzoate The title compound was isolated as a white solid (261 mg, 69%), as described in the general procedure above. δ H (d -MeOH) 1.54 - 1.74 (4H, m), 1.88 - 1.96 (2H, m), 2.16 - 2.24 (2H, m), 2.88 (1 H, m), 5.01 (1 H, m), 6.25 (1 H, dd), 6.28 (1 H, d), 6.91 (1 H, d), 7.79 (2H, m), 8.17 (2H, m); m/z (ES + ) 381 (M+H) * . Example 49 trans - 4 - (2, 4 - DihydroxyphenyQcyclohexyl 4 - methoxybenzoate The title compound was isolated as a white solid (248 mg, 73%), as described in the general procedure above. δ H (d 4 -MeOH) 1.54 - 1.74 (4H, m), 1.88 - 1.96 (2H, m), 2.16 - 2.24 (2H, m), 2.88 (1 H, m), 5.01 (1 H, m), 6.25 (1 H, dd), 6.28 (1 H, d), 6.91 (1 H, d), 7.79 (2H, m), 8.17 (2H, m); m/z (ES * ) 381 (M+H) * . Example 50 trans - 4 - (2, 4 - Dihydroxyphenyl)cyclohexyl 4 - methylbenzoate The title compound was isolated as a white solid (75 mg, 23%), as described in the general procedure above. δ H (d 4 -MeOH) 1.53- 1.75 (4H, m), 1.89 - 1.96 (2H, m), 2.12 - 2.23 (2H, m), 2.40 (3H, s), 2.86 (1 H, m), 4.98 (1 H, m), 6.25 (2H, m), 6.92 (1 H, d), 7.25 (2H, m), 7.90 (2H, m); m/z (ES * ) 653 (2M+H) * . Example 51 trans - 4 - (2, 4 - Dihydroxyphenyl)cyclohexyl 4 - chlorobenzoate The title compound was isolated as a white solid (230 mg, 67%), as described in the general procedure above. δ H (d 4 -MeOH) 1.54 - 1.75 (4H, m), 1.88 - 1.97 (2H, m), 2.15 - 2.24 (2H, m), 2.87 (1 H, m), 4.98 (1 H, m), 6.22 - 6.29 (2H, m), 6.92 (1 H, d), 7.49 (2H, d), 8.00 (2H, d); m/z (ES * ) 347 (M+H) * . Example 52 trans - 4 - (2, 4 - Dihydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate The title compound was isolated as a white solid (84 mg, 25%), as described in the general procedure above δ H (d -MeOH) 1.55 - 1 72 (4H, m), 1 88 - 1 95 (2H, m), 2 14 - 2.21 (2H, m), 2 32 (3H, s), 2 33 (3H, s), 2 85 (1 H, m), 4.95 (1 H, m), 6 22 - 6 28 (2H, m), 6.92 (1 H, d), 7 21 (1 H, d), 7 75 (1 H, d), 7.79 (1 H, s); m/z (ES * ) 341 (M+H) * Example 53 trans - 4 - (2, 4 - Dihydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate The title compound was isolated as a white solid (304 mg, 80%), as described in the general procedure above δ H (d -MeOH) 1.56 - 1 78 (4H, m), 1 86 - 1 98 (2H, m), 2 12 - 2.23 (2H, m), 2.84 (1 H, m), 4 99 (1 H, m), 6.20 - 6.30 (2H, m), 6 92 (1 H, d), 7 64 (1 H, d), 7.92 (1 H, d), 8.12 (1 H, s), m/z (ES " ) 379 (M-H) ~ Example 54 fraπs-4-[4-(Phenylsulfanyl)cyclohexyl]-1 ,3-benzenediol A round bottom flask containing thiophenol (30 μl, 0.29 mmol), cesium fluoride (44 mg, 0.29 mmol) and Λ/,Λ/-dιmethylformamιde (3 ml) was warmed at 40 °C for 1 hr To this was added cis - 4-(2,4-b/s{[terf-butyl(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl methanesulfonate (100 mg, 0 19 mmol) in N, t -dimethylformamide (1 ml) and the reaction mixture stirred at 50 °C for 18 hr The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (10 ml) and extracted with ethyl acetate (3x 20 ml) The combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo Purification via flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 3) afforded the title compound (23 mg, 40%) as an off-white solid δ H (d 4 -MeOH) 1 40 - 1 57 (4H, m), 1 82 - 1 90 (2H, m), 2 04 - 2 16 (2H, m), 2 80 (1 H, m), 3 13 (1 H, m), 6 19 - 6 28 (2H, m), 6 88 (1 H, d), 7 23 (1 H, m), 7 30 (2H, m), 7 40 (2H, m), m/z (ES * ) 301 (M+H) * Example 55 trans - 4-[4 - (Phenylsulfonyl)cyclohexyl] - 1, 3 - benzenediol A round bottom flask containing frans-4-[4-(phenylsulfanyl)cyclohexyl]-1 ,3- benzenediol (18 mg, 0 06 mmol) and dichloromethane (2 ml) was cooled to 0 °C and mefa- chloroperbenzoic acid (50-60%, 41 mg, 0 24 mmol) was added with stirring After 30 mm at this temperature the reaction mixture was poured into saturated sodium thiosulfate solution (5 ml) and partitioned between saturated aqueous sodium hydrogen carbonate (10 ml) and dichloromethane (10 ml) The aqueous phase was further extracted with dichloromethane (2 x 10 ml) and the combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo Purification via flash column chromatography (Sι0 2 , ethyl acetate/petrol, 30 70) afforded the title compound (6 mg, 30%) as an off-white solid δ H (d 4 - MeOH) 1 40 - 1.62 (4H, m), 1.88 - 1 95 (2H, m), 2 05 - 2 13 (2H, m), 2.72 (1 H, m), 3.18 (1 H, m), 6.08 - 6.13 (2H, m), 6.82 (1 H, d), 7.64 (2H, m), 7.75 (1 H, m), 7.90 (2H, m); m/z (ES * ) 333 (M+H) * Example 56 [4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate A mixture of [4-(2,4-β/s{[.erf-butyi(dιmethyl)sιlyl]oxy}phenyl)cyclohexyl]methyl propionate (1 10 mg), methanol (10 ml) and Amberlyst fluoride resin (0.4 g) were stirred at room temperature for 72 hr The reaction mixture was filtered, and the filtrate was evaporated in vacuo The residue was purified by flash column chromatography (Sι0 2 , ethyl acetate/petrol, 1 :2 v/v) to give the title compound as a cream solid and a mixture of diastereoisomers (44 mg, 73%). δ H (CDCI 3 ) 1.17 (3H, t), 1.38 - 2.14 (9H, m), 2.34 - 2.40 (2H, q), 2.64 - 2.80 (1 H, m), 3.96 (0.6H, d), 4.20 (0 4H, d), 5.10 - 5.24 (2H, m), 6.28 - 6.33 (1 H, m), 6.36 - 6.40 (1 H, m), 6.98 (1 H, dd); m/z (ES * ) 279 (M+H) * Examples 57 and 58 Diastereoisomers of ethyl 4 - (2, 4 - dihydroxyphenyl) - 1 - hydroxycyclohexane carboxylate A solution of one isomer of ethyl 4 - (2, 4 - bιs{[fert - butyl(dιmethyl)silyl]oxy}phenyl) - 1 - hydroxycyclohexanecarboxylate (25 mg, 0.05 mmol) in methanol (2 ml) was stirred rapidly with Amberlyst A-26 (100 mg) for 18 hr After this time the reaction mixture was filtered. The resin was then stirred rapidly for 1 hr in a solution of methanol (2 ml) and glacial acetic acid (5 drops) The reaction mixture was filtered and the combined filtrates concentrated in vacuo Purification via flash column chromatography (Sι0 2 , ethyl acetate/petrol, 2.1 ) afforded the title compound (3 mg, 21 %) as a white solid. δ H (d -MeOH) 1.29 (3H, t), 1.61 - 1.69 (2H, m), 1.73 - 1 98 (6H, m), 2 81 - 2.90 (1 H, m), 4.18 (2H, q), 6.21 - 6.27 (2H, m), 6.91 (1 H, d), m/z (ES " ) 279 (M-H) ~ A solution of the other isomer of ethyl 4 - (2, 4 - bis{[tert - butyl(dιmethyl)sιlyl] oxy}phenyl) - 1 - hydroxycyclohexanecarboxylate (25 mg, 0.05 mmol) in methanol (2 ml) was stirred rapidly with Amberlyst A-26 (100 mg) for 18 hr After this time the reaction mixture was filtered The resin was then stirred rapidly for 1 hr in a solution of methanol (2 ml) and glacial acetic acid (5 drops) The reaction mixture was filtered and the combined filtrates concentrated in vacuo Purification via flash column chromatography (Si0 2 , ethyl acetate/petrol, 2.1 ) afforded the title compound (5 mg, 34%) as a white solid. δ H (d -MeOH) 1.22 (3H, t), 1.40 - 1.54 (4H, m), 1.63 - 1.74 (2H, m), 2 18 - 2.25 (2H, m), 2.68 - 2.78 (1 H, m), 4 14 (2H, q), 6.11 (1 H, dd), 6 15 (1 H, d), 6 71 (1 H, d), m/z (ES ' ) 279 (M-H)- Example 59 Cis I trans - 4 - [4 - (hydroxyamιno)cyclohexyl]-1, 3, benzenediol To a stirred solution of 4 - (2, 4 - dιhydroxyphenyl)cyclohexanoπe oxime (90 mg, 0 41 mmol) in acetic acid (3 ml) was added sodium cyanoborohydπde (28 mg 0 45 mmol) in one portion After stirring for 16 hr, a further portion of sodium cyanoborohydπde (28 mg) was added and stirring continued for a further 48 hr The reaction mixture was poured into a mixture of water (3 ml) and ethyl acetate (25 ml) and stirred for 30 m The solution was partitioned, and the aqueous layer further extracted with ethyl acetate (5 x 10 ml) The combined organics were washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo Purification by HPLC afforded the title compound as a pale pink solid (62 mg, 68%) δ H (CD 3 OD) 1 57 - 1 77 (3H, m), 1 78 - 1 84 (1 H, m), 1 90 - 2 09 (2H, m), 2 27 - 2 12 (2H, m), 2 87 (0 6 H, m), 3 03 (0 4 H, m), 3 58 (0 4 H, m), 3 68 (0 6 H, m), 6 25 - 6 32 (2H, m), 6 92 (0 6H, d), 6 99 (0 4H, d), m/z (ES " ) 222 (M-H) " Example 60 Trans ■ 4 - [4 - (methoxyamino)cyclohexyl]-1 , 3, benzenediol To a stirred solution of O-methyl-4 -(2, 4 - dιhydroxyphenyl)cyclohexanone oxime (18 mg, 0 076 mmol) in acetic acid (1 ml) was added sodium cyanoborohydπde (25 mg, 0 4 mmol) in one portion After stirring overnight the reaction mixture was partitioned between water (10 ml) and ethyl acetate (10 ml) The aqueous layer was further extracted with ethyl acetate (10 ml) and the combined organic phases were washed with saturated sodium hydrogen carbonate solution (10 ml), dried over magnesium sulfate and concentrated in vacuo Purification by flash column chromatography (Sι0 2 ethyl acetate/petrol 2 3) afforded the title compound as a solid (12 mg, 66%) δ H (CDCI 3 ) 1 13 - 1 26 (2H, m), 1 30 - 1 45 (2H, m), 1 80 - 1 89 (2H, m), 1 90 - 2 00 (2H, m), 2 68 - 2 78 (1 H, m), 2 80 - 2 90 (1 H, m), 3 49 (3H, s), 6 19 (1 H, d), 6 24 (1 H, dd), 6 86 (1 H, d), m/z (ES * ) 279 (MH+CH 3 CN) * All patents, patent applications, and publications cited above are incorporated herein by reference in their entirety The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description Such modifications are intended to fall within the scope of the appended claims

Claims: What is claimed is: A compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyi ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano, halo, (C C 6 )a\kγ\, aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 - C 9 )heteroaryl, aryl(C r C 6 )alkyl-, =0, =CHO(C 1 -C 6 )alkyl, amino, hydroxy, (C,-C 6 )alkoxy, aryl(C,-C 6 )alkylamιno-, amιno(C 1 -C 6 )alkyl-, (C r C 6 )alkoxy-CO-NH-, (C r C 6 )alkylamιno-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C r C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl-, nitro, cyano(C 1 -C 6 )alkyl-, halo(C 1 -C 6 )alkyl-, nιtro(C r C 6 )alkyl-, trifluoromethyl, tπfluoromethyKCrCeJalkyl-, (C r C 6 )acylamιno-, (C 1 -C 6 )acylamιno(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamιno-, amιno(C r C 6 )acyl-, amιno(C 1 -C 6 )acyl(C 1 -C 6 )alkyl-, (C l -C 6 )alkylamιno(C 1 -C 6 )acyl-, ((C,-C 6 ) alkyl) 2 amιno(C r C 6 )acyl-, -C0 2 R 2 , -(C,-C 6 )alkyl-C0 2 R 2 , -C(0)N(R 2 ) 2 , -(C 1 -C 6 )alkyl-C(0)N(R 2 ) 2 , R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, R 2 ON=CR 2 (C 1 -C 6 )alkyl-, -NR 2 (OR 2 ), -(C,-C 6 )aikyl-NR 2 (OR 2 ), - C(0)(NR 2 OR 2 ), -(C 1 -C 6 )alkyl-C(0)(NR 2 OR 2 ), -S(0) m R 2 , wherein each R 2 is independently selected from hydrogen, (C 1 -C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl-, R 3 C(0)0-, wherein R 3 is (C r C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl-, R 3 C(0)0-(C,-C 6 )alkyl-, R 4 R 5 N-C(0)-0-, R 4 R 5 NS(0) 2 -, R R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, R 4 S(0) 2 R 5 N(C r C 6 )alkyl-, wherein m is 0, 1 or 2, and R 4 and R 5 are each independently selected from hydrogen or (C r C 6 )alkyl, -C(=NR 6 )(N(R 4 ) 2 ), or -(C 1 -C 6 )alkyl-C(=NR 6 )(N(R 4 ) 2 ) wherein R 6 represents OR 2 or R 2 wherein R 2 is defined as above, with the proviso that the cycloalkenyl ring is not aromatic, with the proviso that R 1 must be substituted by at least one of R 3 C(0)0-, R 3 C(0)0- (C r C 6 )alkyl-, R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, R 2 ON=CR 2 (C r C 6 )alkyl-, -NR 2 (0R 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C,-C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C,-C 6 )alkyl-, with the proviso that when R 1 is only substituted by one of R 2 ON=, then R 2 cannot be hydrogen 2 The compound of claim 1 , wherein R 1 is a cyclohexyl or cyclohexenyl ring substituted at the 3- or 4-posιtιon, or a cyclopentyl or cyclopentenyl ring substituted at the 3- position 3 The compound of claim 1 , wherein R 1 is monosubstituted 4 The compound of claim 1 , wherein R 1 is disubstituted 5 The compound of claim 1 , wherein R 1 is substituted by at least one of R 3 C(0)0- or R 3 C(0)0-(C 1 -C 6 )alkyl- 6 The compound of claim 1 , wherein R 1 is substituted by at least one of R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, or R 2 ON=CR 2 (C 1 -C 6 )alkyl- 7 The compound of claim 1 , wherein R 1 is substituted by at least one of - NR 2 (OR 2 ) 8 The compound of claim 1 , wherein R 1 is substituted by at least one of R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl- 9 The compound of claim 1 , wherein R 1 is substituted by at least one of R 4 S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C 1 -C β )alkyl- 10 The compound of claim 1 , wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 - C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C,-C e )alkyl-, R 2 ON=, R 2 0N=(C r C 6 )alkyl-, R 2 ON=CR 2 (C,-C 6 )alkyl- , -NR 2 (OR 2 ), R R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R S(0) 2 R 5 N(C r C 6 )alkyl- 11 The compound of claim 10, wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 - C β )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R C(0)0-(C 1 -C 6 )alkyl-, R 2 ON=, or R S(0) 2 R 5 N- 12 The compound of claim 10, wherein R 1 is substituted by R 3 C(0)0- or R 3 C(0)0-(C,-C 6 )alkyl- 13 The compound of claim 10, wherein R 1 is substituted by R 2 ON=, R 2 ON=(C r C 6 )alkyl-, or R 2 ON=CR 2 (C r C 6 )alkyl- 14 The compound of claim 10, wherein R 1 is substituted by R 2 ON= 15 The compound of claim 10, wherein R 1 is substituted by -NR 2 (OR 2 ) 16 The compound of claim 10, wherein R 1 is substituted by R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R S(0) 2 R 5 N- or R S(0) 2 R 5 N(C r C 6 )alkyl- 17 The compound of claim 1 , wherein R 1 is substituted by R 4 S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- 18 The compound of claim 1 , wherein the (C 2 -C 9 )heterocycloalkyl substituent is a group of the formula / \ — N Z ) m wherein m is 0, 1 or 2, and Z is CH 2 , NR 2 , O, S, SO, or S0 2 19 The compound of claim 1 selected from the group consisting of 5 0-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, (±)-Λ/-[3-(2,4-Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, (±)-0-Methyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, (±)-0-Benzyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, and a pharmaceutically acceptable salt thereof o 20 The compound of claim 1 selected from the group consisting of 0-Methyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, (±)-4-[3-(Hydroxyamιno)cyclohexyl]-1 ,3-benzenedιol, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide, trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, 5 cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, trans-4-(2,4-Dιhydroxyphenyl)cyclohexyl) 4-(dιmethylamιno)benzoate, trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-tert-butylbenzoate, fraπs-4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fluorobenzoate, trans - 4-(2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - trifluoromethylbenzoate, 0 trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methoxybenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - chlorobenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate, 5 [4-(2,4-Dιhydroxyphenyl)cyclohexyl]methyl propionate, cis /trans - 4- [4-(hydroxyamιno)cyclohexyl]-1 ,3 - benzenediol, trans - 4-[4-(methoxyamιno)cyclohexyl]-1 ,3 - benzenediol, and a pharmaceutically acceptable salt thereof 21 A topical pharmaceutical composition for lightening skin or reducing the 0 pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skm-lightenmg or pigmentation-reducmg amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano, halo, (C r C 6 )alkyl, aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 - C 9 )heteroaryl, aryl(C r C 6 )alkyl-, =0, =CHO(C 1 -C 6 )alkyl, ammo, hydroxy, (C r C 6 )alkoxy, ary C^C alkoxy-, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamιno-, aryl(C r C 6 )alkylamino-, amιno(C 1 -C 6 )alkyl-, (C CeJalkoxy-CO-NH-, (C r C 6 )alkylamιno-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C r C 6 )alkyl-, (C 1 -C 6 )alkoxy(C l -C 6 )alkyl-, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl-, nitro, cyano(C r C 6 )alkyl-, halo(C r C 6 )alkyl-, (C,- C 6 )acylamιno-, (C 1 -C 6 )acylamιno(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamιno-, amιno(C 1 - C 6 )acyl-, amιno(C 1 -C 6 )acyl(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkylamιno(C 1 -C 6 )acyl-, ((C r C 6 ) alkyl) 2 amιno(C r C 6 )acyl-, -C0 2 R 2 , -(C r C 6 )alkyl-C0 2 R 2 , -C(0)N(R 2 ) 2 , -(C 1 -C 6 )alkyl-C(0)N(R 2 ) 2 , R 2 ON=, R 2 ON=(C r C 6 )alkyl-, R 2 ON=CR 2 (C r C 6 )alkyl-, -NR 2 (OR 2 ), -(C 1 -C 6 )alkyl-NR 2 (OR 2 ), - C(0)(NR 2 OR 2 ), -(C 1 -C 6 )alkyl-C(0)(NR 2 OR 2 ), -S(0) m R 2 , wherein each R 2 is independently selected from hydrogen, (C,-C 6 )alkyl, aryl, or aryKCrC^alkyl-, R 3 C(0)0-, wherein R 3 is (C C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl-, R C(0)0-(C,-C 6 )alkyl-, R R 5 N-C(0)-0-, R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl-, wherein m is 0, 1 or 2, and R 4 and R 5 are each independently selected from hydrogen or (C C 6 )alkyl, -C(=NR 6 )(N(R 4 ) 2 ), or -(C r C 6 )alkyl-C(=NR 6 )(N(R 4 ) 2 ) wherein R 6 represents OR 2 or R 2 wherein R 2 is defined as above, with the proviso that the cycloalkenyl ring is not aromatic, with the proviso that R 1 must be substituted by at least one of R 3 C(0)0-, R 3 C(0)0- (C r C 6 )alkyl-, R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, R 2 ON=CR 2 (C,-C 6 )alkyl-, -NR 2 (0R 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C 1 -C 6 )alkyl- 22 The composition of claim 21 , wherein R 1 of the compound is a cyclohexyl or cyclohexenyl ring substituted at the 3- or 4-posιtιon, or a cyclopentyl or cyclopentenyl ring substituted at the 3-posιtιon 23 The composition of claim 21 , wherein R 1 of the compound is monosubstituted 24 The composition of claim 21 , wherein R 1 of the compound is disubstituted 25 The composition of claim 21 , wherein R 1 of the compound is substituted by at least one of R 3 C(0)0- or R 3 C(0)0-(C 1 -C 6 )alkyl- 26 The composition of claim 21 , wherein R 1 of the compound is substituted by at least one of R 2 ON=, R 2 0N=(C 1 -C 6 )alkyl-, or R 2 ON=CR 2 (C r C 6 )alkyl- 27 The composition of claim 21 , wherein R 1 of the compound is substituted by at least one of -NR 2 (OR 2 ) 28 The composition of claim 21 , wherein R 1 of the compound is substituted by at least one of R 4 R 5 NS(0) 2 -, R R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R S(0) 2 R 5 N(C,-C 6 )alkyl- 29 The composition of claim 21 , wherein R 1 of the compound is substituted by at least one of R 4 S(0) 2 R 5 N- or R S(0) 2 R 5 N(C 1 -C 6 )alkyl- 30 The composition of claim 21 , wherein R 1 of the compound is a (C 3 - C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C 1 -C 6 )alkyl-, R 2 ON=, R 2 0N=(C 1 -C 6 )alkyl-, R 2 ON=CR 2 (C r C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- 31 The composition of claim 30, wherein R 1 of the compound is a (C 3 - C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl πng or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, or R 4 S(0) 2 R 5 N- 32 The composition of claim 30, wherein R 1 of the compound is substituted by R 3 C(0)0- or R 3 C(0)0-(C r C 6 )alkyl- 33 The composition of claim 30, wherein R 1 of the compound is substituted by R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, or R 2 ON=CR 2 (C 1 -C 6 )alkyl- 34 The composition of claim 30, wherein R 1 of the compound is substituted by R 2 ON= 35 The composition of claim 30 wherein R 1 of the compound is substituted by - NR (OR 2 ) 36 The composition of claim 30, wherein R 1 of the compound is substituted by R 4 R 5 NS(0) 2 -, R R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C,-C 6 )alkyl- 37 The composition of claim 30, wherein R 1 of the compound is substituted by R 4 S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- 38 The composition of claim 21 , wherein the (C 2 -C 9 )heterocycloalkyl substituent is a group of the formula wherein m is 0, 1 or 2 and Z is CH 2 , NR 2 , O, S, SO, or S0 2 39 The composition of claim 21 , comprising a compound selected from the group consisting of 4-(2, 4-Dιhydroxyphenyl)cyclohexanone oxime, 0-Methyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 0-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-Dιhydroxyphenyl)-2-cyclohexen-1 -one oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanone oxime, (±)-Λ/-[3-(2,4-Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, (±)-4-[3-(Hydroxyamιno)cyclohexyl]-1 ,3-benzenedιol, (±)-0-Methyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, (±)-0-Benzyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-Dιhydroxyphenyl)-2-cyclopentenone oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclopentanone oxime, and a pharmaceutically acceptable salt thereof 40 The composition of claim 21 , comprising a compound selected from the group consisting of cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide, trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, trans-4-(2,4-Dιhydroxyphenyl)cyclohexyl) 4-(dιmethylamιno)benzoate, trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-ferf-butylbenzoate, frans-4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fluorobenzoate, trans - 4-(2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - tπfluoromethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methoxybenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - chlorobenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate, [4-(2,4-Dιhydroxyphenyl)cyclohexyl]methyl propionate, cis / trans - 4- [4-(hydroxyamιno)cyclohexyl]-1 ,3 - benzenediol, trans - 4-[4-(methoxyamιno)cyclohexyl]-1 ,3 - benzenediol, and a pharmaceutically acceptable salt thereof 41 The composition of claim 21 , wherein the skm-lightenmg or pigmentation- reducmg effective amount of a compound of formula I is a tyrosinase-inhibitmg effective amount of the compound 42 A method of lightening skin or reducing the pigmentation of skin in a human, comprising administering to said human a skm-lightenmg or skin pigmentation-reducmg effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one to three substituents independently selected from the group consisting of cyano, halo, (C r C 6 )alkyl, aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 - C 9 )heteroaryl, ary C C^alkyl-, =0, =CHO(C 1 -C 6 )alkyl, am o, hydroxy, (C r C 6 )alkoxy, aryl(C r C 6 )alkoxy-, (C r C 6 )acyl, aryl(C 1 -C 6 )alkylamιno-, amιno(C,-C 6 )alkyl-, (C r C 6 )alkoxy-CO-NH-, (C 1 -C 6 )alkylamιno-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C r C 6 )alkyl-, (C,-C 6 )alkoxy(C 1 -C 6 )alkyl-, (C 1 -C 6 )acyloxy(C,-C 6 )alkyl-, nitro, cyano(C C 6 )alkyl-, halo(C 1 -C 6 )alkyl-, nιtro(C r C 6 )alkyl-, trifluoromethyl, tπfiuoromethyl(C 1 -C 6 )alkyl-, (C C 6 )acylamιno-, (C 1 -C 6 )acylamιno(C l -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )acylamιno-, amιno(C r C 6 )acyl-, amιno(C 1 -C 6 )acyl(C 1 -C 6 )alkyl-, (C l -C 6 )alkylamιno(C 1 -C 6 )acyl-, ((C,-C 6 ) alkyl) 2 amιno(C 1 -C 6 )acyl-, -C0 2 R 2 , -(C 1 -C 6 )alkyl-C0 2 R 2 , -C(0)N(R 2 ) 2 , -(C 1 -C 3 )alkyl-C(0)N(R 2 ) 2 , R 2 ON=, R 2 ON=(C,-C 6 )alkyl-, R 2 ON=CR 2 (C 1 -C 6 )alkyl-, -NR 2 (OR 2 ), -(C,-C 6 )alkyl-NR 2 (OR 2 ), - C(0)(NR 2 OR 2 ), -(C 1 -C β )alkyl-C(0)(NR 2 OR 2 ), -S(0) m R 2 , wherein each R 2 is independently selected from hydrogen, (^-C^alky!, aryl, or aryl(C r C 6 )alkyl-, R 3 C(0)0-, wherein R 3 is (C r C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl-, R 3 C(0)0-(C 1 -C 6 )alkyl-, R 4 R 5 N-C(0)-0-, R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R S(0) 2 R 5 N-, R 4 S(0) 2 R 5 N(C r C 6 )alkyl-, wherein m is 0, 1 or 2, and R 4 and R 5 are each independently selected from hydrogen or (C 1 -C 6 )alkyl, -C(=NR 6 )(N(R ) 2 ), or -(C r C 6 )alkyl-C(=NR 6 )(N(R 4 ) 2 ) wherein R 6 represents OR 2 or R 2 wherein R 2 is defined as above, with the proviso that the cycloalkenyl ring is not aromatic, with the proviso that when R 1 is a (C 5 -C 8 )cycloalkyl ring, or when R 1 is a (C 5 - C 8 )cycloalkenyl ring having the following structure wherein n is 0, 1 , 2 or 3, where such (C 5 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring is substituted by hydroxy, (C,-C 6 )alkoxy-, aryl(C r C 6 )alkoxy-, -OC(0)(C r C 6 )alkyl, -OC(0)aryl(C r C 6 )alkyl, -OC(0)phenyl, halo, (C,-C 6 )alkyl-, aryl(C r C 6 )alkyl-, -SH, -S(C r C 6 )alkyl. aryl(C C 6 )alkyl-S-, -NH 2 -NH(C 1 -C 6 )alkyl, or ary CrC^alkyl-HN-, then the (C 5 -C 8 )cycloalkyl ring or the (C 5 -C 8 )cycloalkenyl ring must be di- or tπ-substituted 43 The method of claim 42, wherein R 1 of the compound is a cyclohexyl or cyclohexenyl ring substituted at the 3- or 4-posιtιon, or a cyclopentyl or cyclopentenyl ring substituted at the 3-posιtιon 44 The method of claim 42, wherein R 1 of the compound is monosubstituted 45 The method of claim 42, wherein R 1 of the compound is disubstituted 46 The method of claim 42, wherein R 1 of the compound is substituted by at least one of R 3 C(0)0- or R 3 C(0)0-(C r C 6 )alkyl- 47 The method of claim 42, wherein R 1 of the compound is substituted by at least one of R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, or R 2 ON=CR 2 (C,-C 6 )alkyl- 48 The method of claim 42, wherein R 1 of the compound is substituted by at least one of -NR 2 (OR 2 ) 49 The method of claim 42 wherein R 1 of the compound is substituted by at least one of R R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C 1 -C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C,-C 6 )alkyl- 50 The method of claim 42, wherein R 1 of the compound is substituted by at least one of R S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- 51 The method of claim 42, wherein R 1 of the compound is a (C 3 -C 8 )cycloalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R 3 C(0)0-(C r C 6 )alkyl-, R 2 ON=, R 2 ON=(C 1 -C 6 )alkyl-, R 2 ON=CR 2 (C,-C 6 )alkyl-, -NR 2 (OR 2 ), R 4 R 6 NS(0) 2 -, R R 5 NS(0) 2 (C C 6 )alkyl-, R 4 S(0) 2 R 5 N-, or R 4 S(0) 2 R 5 N(C,-C 6 )alkyl- 52 The method of claim 51 , wherein R 1 of the compound is a (C 3 -C 8 )cycioalkyl ring or (C 5 -C 8 )cycloalkenyl ring, wherein either the cycloalkyl ring or cycloalkenyl ring is substituted by one of R 3 C(0)0-, R C(0)0-(C r C 6 )alkyl-, R 2 ON=, or R S(0) 2 R 5 N- 53 The method of claim 51 , wherein R 1 of the compound is substituted by R 3 C(0)0- or R 3 C(0)0-(C,-C 6 )alkyl- 54 The method of claim 51 , wherein R 1 of the compound is substituted by R 2 ON= R 2 ON=(C,-C 6 )alkyl- or R 2 ON=CR 2 (C,-C 6 )alkyl- 55 The method of claim 51 , wherein R 1 of the compound is substituted by R 2 ON= 56 The method of claim 51 , wherein R 1 of the compound is substituted by -NR 2 (OR 2 ) 57 The method of claim 51 , wherein R 1 of the compound is substituted by R 4 R 5 NS(0) 2 -, R 4 R 5 NS(0) 2 (C r C 6 )alkyl-, R S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C r C 6 )alkyl- 58 The method of claim 51 , wherein R 1 of the compound is substituted by R 4 S(0) 2 R 5 N- or R 4 S(0) 2 R 5 N(C,-C 6 )alkyl- 59 The method of claim 42, wherein the (C 2 -C 9 )heterocycloalkyl substituent is a group of the formula wherein m is 0, 1 or 2, and Z is CH 2 , NR 2 , O, S, SO, or S0 2 60 The method of claim 46, wherein R 1 is a group of the formula which is substituted according to claim 1 , wherein n is 0, 1 , or 2, and wherein the dashed line indicates an optional double bond at that position 61 The method of claim 60, wherein R 1 of the compound is substituted by =0, =NOH, CH 2 OH, .OH Me or a combination thereof 62 The method of claim 42, wherein the compound is selected from the group consisting of 4-(2, 4-Dιhydroxyphenyl)cyclohexanone, 4-(2, 4-Dιhydroxyphenyl)cyclohexanone oxime, 0-Methyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 0-Benzyl-4-(2, 4-dιhydroxyphenyl)cyclohexanone oxime, 3-(2,4-dιhydroxyphenyl)-2-cyclohexen-1 -one, (+)-3-(2,4-Dιhydroxyphenyl)cyclohexanone, 3-(2,4-Dιhydroxyphenyl)-2-cyclohexen-1 -one oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyciohexanone oxime, (±)-4-[3-(1 -Pιperazιnyl)cyclohexyl]-1 ,3-benzenedιol, (±)-W-[3-(2,4-Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, (±)-4-[3-(Hydroxymethyl)cyclohexyl]-1 ,3-benzenedιol, (±)-4-[3-(Hydroxyamιno)cyclohexyl]-1 ,3-benzenedιol, cis / frans-4-[4-(Hydroxymethyl)cyclohexyl]-1 ,3-benzenedιol, cis /trans-4-(4-Hydroxy-4-methylcyclohexyl)-1 ,3-benzenedιol, (±)-0-Methyl-3-(2,4-dιhydroxyphenyl)cyclohexanone oxime, (±)-3-(2,4-Dιhydroxyphenyl)-1-methylcyclohexanol, (±)-0-Benzyl-3-(2,4-dιhydroxyphenyl)cyciohexanone oxime, 3-(2,4-Dιhydroxyphenyl)-2-cyclopentenone oxime, (±)-3-(2,4-Dιhydroxyphenyl)cyclopentanone, (±)-3-(2,4-Dιhydroxyphenyl)cyclopentanone oxime, and a pharmaceutically acceptable salt thereof 63 The method of claim 42, wherein the compound is selected from the group consisting of 4 - (2, 4 - Dihydroxyphenyl) - 3 - cyclohexen - 1 - one, cis /trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl] - 1 - butanesulfonamide, trans - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, cis - N - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]methanesulfonamιde, 4 - [4 - (4 - Hydroxyphenyl)cyclohexyl] - 1 , 3 - benzenediol, cis / trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate, trans - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate, cis - Methyl [4 - (2, 4 - dιhydroxyphenyl)cyclohexyl]acetate, trans - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid, cis - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid, cis /trans - [4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl]acetιc acid, cis / trans - [4-(2, 4-Dιhydroxyphenyl)cyclohexyl]acetonιtπle, cis /trans - 4 - [4-(2-Amιnoethyl)cyclohexyl]-1 ,3-benzenedιol, (±)-4-(3,3-Dιfluorocyclohexyl)-1 ,3-benzenedιol, (±)-3-(2,4-Dιhydroxyphenyl)cyclohexanecarboxamιde, (±)-3-(2,4-Dιhydroxyphenyl)-Λ/-hydroxycyclohexanecarboxamιde, (±)-3-(2,4-Dιhydroxyphenyl)-/V-ethylcyclohexanecarboxamιde, (±)-4-[3-Hydroxy-3-(hydroxymethyl)cyclohexyl]-1 ,3-benzenedιol, (±)-t -[3-(2,4-dιhydroxyphenyl)cyclohexyl]acetamιde, frans-4-(2,4-Dιhydroxyphenyl)cyclohexyl) 4-(dιmethylamιno)benzoate, cis / trans - 4-(2,4-Dιhydroxyphenyl)cyclohexanecarboxylιc acid, fraπs-4-(2,4-Dιhydroxyphenyl)cyclohexyl ethylcarbamate, frans-4-(2,4-Dιhydroxyphenyl)cyclohexyl cyclohexylcarbamate, trans - 4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-rert-butylbenzoate, frans-4-(2,4-Dιhydroxyphenyl)cyclohexyl 4-fluorobenzoate, trans - 4-(2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - tπfluoromethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methoxybenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - methylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 4 - chlorobenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dimethylbenzoate, trans - 4 - (2, 4 - Dιhydroxyphenyl)cyclohexyl 3,4 - dichlorobenzoate, trans-4-[4-(Phenylsulfanyl)cyclohexyl]-1 ,3-benzenedιol, trans - 4-[4 - (Phenylsulfonyl)cyclohexyl] - 1 , 3 - benzenediol, [4-(2,4-Dιhydroxyphenyl)cyclohexyl]methyl propionate, ethyl 4 - (2, 4 - dihydroxyphenyl) - 1 - hydroxycyclohexane carboxylate, cis /trans - 4- [4-(hydroxyamιno)cyclohexyl]-1 ,3 - benzenediol, trans - 4-[4-(methoxyamιno)cyclohexyl]-1 ,3 - benzenediol, and a pharmaceutically acceptable salt thereof 64 The method of claim 42, wherein the skm-lightenmg or pigmentation-reducmg effective amount of a compound of formula I is a tyrosinase-inhibitmg effective amount of the compound

Inventors: BROWNING ANDREW FRANCIS, COLLINGTON ERIC WILLIAM, GEDEN JOANNA VICTORIA, PROCTER MARTIN JAMES, BROWNING, ANDREW, FRANCIS, COLLINGTON, ERIC, WILLIAM, GEDEN, JOANNA, VICTORIA, PROCTER, MARTIN, JAMES
Applicants: BROWNING ANDREW FRANCIS, COLLINGTON ERIC WILLIAM, GEDEN JOANNA VICTORIA, PFIZER, PROCTER MARTIN JAMES, BROWNING, ANDREW, FRANCIS, COLLINGTON, ERIC, WILLIAM, GEDEN, JOANNA, VICTORIA, PFIZER INC., PROCTER, MARTIN, JAMES
Application year: 2000
Main classification: C07C251
IPC codes: A61K8, A61K31, A61P17, A61P43, A61Q17, A61Q19, C07C39, C07C49, C07C59, C07C62, C07C69, C07C215, C07C229, C07C233, C07C235, C07C239, C07C251, C07C255, C07C259, C07C271, C07C311, C07C317, C07C323, C07D295