MXPA01009549A - Resorcinol derivatives - Google Patents

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 resorcinol derivatives as skin lightening agents. BACKGROUND OF THE INVENTION In this document, the terms "clearing agent" and "depigmentation agent" are used interchangeably. In humans, the color of the skin arises from a complex series of cellular processes that take place within a single population of cells called melanocytes. The 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 harmful effects of ultraviolet radiation. When the skin is exposed to ultraviolet radiation, such as that contained in sunlight, the melanocytes increase their synthesis of melanin. The melanin is deposited in melanosomes, which are vesicles found in the cells. The melanosomes are extruded from the cell and carried to the surface of the skin by keratinocytes, which encompass melanosomes that contain melanin. The end result is that the visible layers of the skin exhibit a brown color typically known as "tanning". The darkness of the color observed in the skin is proportional to the amount of melanin synthesized by the melanocytes and transferred to the keratinocytes. The mechanism by which skin pigmentation is formed, elanogenesis, is particularly complex and schematically involves the following major steps: Tyrosine - > L-Dopa - > Dopaquinone - > Dopachrome - > Melanin. The first two reactions in this series are catalyzed by the tyrosinase enzyme. The activity of tyrosinase is promoted by the action of the a-melanocyte-stimulating hormone, or by UV rays, to eventually form melanin as a chromatism in the skin. It is well demonstrated that a substance has a depigmenting effect if it acts directly on the vitality of the epidermal melanocytes in which melanogenesis normally occurs, and / or if it interferes with one of the stages in the biosynthesis of melanin. The active compounds that are employed in various methods and compositions of this invention inhibit tyrosinase, and thereby inhibit or decrease melanin biosynthesis. There is a strong demand for agents that allow acquired deposition sites, such as moles and freckles, to return 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 in which vitamin C (L-ascorbic acid), which has a good reducing capacity, is administered orally in large quantities; (b) a method in which glutathione is administered parenterally; (c) a method in which a peroxide is administered, such as hydrogen peroxide, zinc peroxide, sodium peroxide and the like, which is believed to have melanin bleaching action; and (d) a method in which 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 it becomes so unstable in water-containing systems that cause changes in smell and color. The thiol compounds, such as glutathione and cysteine, do not exhibit a satisfactory depigmenting effect since the development of the effect is very slow. The substances most widely used at the present time as depigmenting agents are, in particular, hydroquinone and its derivatives, particularly its ethers such as the monomethyl ether of hydroquinone. These compounds, although effective, are known to produce side effects that can be dangerous. Hydroquinone, whose use is limited to a concentration of 2%, is irritating and cytotoxic to the melanocyte. U.S. Patent 4,526,179 relates to certain fatty esters of hydroquinone which have a good activity and are less irritating and more stable than hydroquinone.

Japanese Patent Application No. 27909/86 refers to other hydroquinone derivatives which do not have the disadvantages of hydroquinone, but have relatively poor efficacy. 5 U.S. Patent 5,449,518 refers to 2, 5-dihydroxyphenylcarboxylic acid derivatives as depigmentation agents. European Patent Application EP 341,664A1 refers to certain resorcinol derivatives as inhibitors} Q of tyrosinase and depigmentation agents of the skin. PCT International Publication WO 99/15148 relates to certain resorcinol derivatives as tyrosinase inhibitors and skin depigmentation agents. Particularly desirable is the use of topical depigmentation agents, which have good efficacy and are harmless, to treat the following: regional hyperpigmentation caused by melanocytic hyperactivity, such as idiopathic melasma arising well during pregnancy (gestational mask or chloasma) or secondary to estrogen-progesterone contraceptives; local hyperpigmentation caused by hyperactivity and benign melanocytic proliferation such as lentigo senilis or liver spots; accidental hyperpigmentation such as photosensitization and scarring after injury; and certain forms of leukoderma, such as vitiligo, in which, if the damaged skin can not be repigmented, the residual areas of normal skin are depigmented to give a homogeneous white color to the entire skin. SUMMARY OF THE 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 above dermatological conditions, as well as other dermatological conditions, some of which will be referred to later in this document, for which the treated patient wishes, for medical or cosmetic purposes, to clarify 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: R1 is a (C3-C8) cycloalkyl ring or cycloalkenyl ring (C ^ -Cg), the cycloalkyl ring or the cycloalkenyl ring being either substituted with one to three substituents independently selected from the group comprising cyano; halo; alkyl (C - ^ - Cg); aril; Heterocycloalkyl (C2-C8); heteroaryl (C2-C8); arylalkyl (C1-Cg); = 0; = CHOalkyl (C - ^ - Cg); Not me; hydroxy; alkoxy (C1-Cg); arylalkoxy (C1-C8) -; acyl (C1-Cg); alkyl (C1-Cg) -amino-; arylalkyl (C ^ -Cg) -amino-; aminoalkyl (Cj-Cg) -; (C1-Cg) -CO-NH- alkoxy; (C1-Cg) alkyl-amino-CO-, -alkenyl (C2-Cg); alkynyl (C2-Cg); hydroxyalkyl (C-j_-c6 ^ "; alco? i (CL-Cg) -alkyl (C - ^ - Cg) -; acyloxy (C? -Cg) -alkyl (C - ^ - Cg) -; nitro; cyanoalkyl (C - ^ - Cg) - haloalkyl (C -Cg) -, - nitroalkyl (C - ^ - Cg) -; trifluoromethyl; trifluo-romethylalkyl (C - ^ - Cg) -; acyl (C - ^ - Cg) amino-; acyl (C - ^ - Cg) -aminoalkyl (C - ^ - Cg) -; (C 1 -C 8) alkoxy-acyl (C-j-Cg) -amino-, -aminoacyl (C - ^ - Cg) -; aminoacyl (C-1-Cg) -alkyl (C 1 -Cg) -; alkyl (C-j ^ -Cg) -aminoacyl (C - ^ - Cg) -; (C 1 -C 8 alkyl) 2-amino-acyl (C 1 -Cg) -; -C02R2, - -alkyl (C-j ^ -Cg) -C02R2; C (0) N (R2) 2; -alkyl (C1-Cg) -C (0) N (R2) 2; R20N =; R20N = alkyl (C1-C8) -; R2ON = CR2alk0IC1-Cg) -; -NR2 (OR2); -alkyl (C1-Cg) -NR2 (OR2); -C (0) (NR20R2); -alkyl (C? -Cg) -C (0) (NR20R2); -S (0) mR2; wherein each R 2 is independently selected from hydrogen, alkyl (C] -Cg), aryl, or arylalkyl (C-Cg) -; R3C (0) 0-, wherein R3 is alkyl (C-L-Cg), aryl, or arylalkyl (C ^ Cg) -; R3C (O) O-alkyl (C1"C6) _; R4R5N-C (0) -0-; R4R5NS (0) 2-; R4R5NS (O) 2-alkyl (C1-C6) -; R4S (0) 2R5N-; R4S (0) 2R5N-alkyl? (C1-C8) -; where mO, 1 or 2, and R and R5 sg each independently select hydrogen or (C1-C6) alkyl; -C (= NR6) (N (R4) 2); or -alkyl IC1-C6) -C (= NR6) (N (R4) 2) in which R6 representsOR2 or R2, R2 being defined as before; with the proviso that the cycloalkenyl ring is not aromatic; with the proviso that R must be substituted with at least one of R3C (O) 0-, R3C (0) O-alkyl (C1-Cg) -, R20N =, R2ON = (C1-Cg) -, R2ON = CR2alquilo (C1-Cg) -, -NR2 (OR2), R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (C1-C8) -, R4S (0 ) 2R5N-, or R4S (0) 2R5N- (C1-Cg) alkyl-; with the proviso that when R is substituted only with one of R20N =, then R2 can not be hydrogen. When R1 is a ring or ciciohexenilo ciciohexilo, the ring is preferably substituted at the 3 or 4 position, and more preferably in the 4-position when R1 is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-position. In a preferred embodiment, R1 is monosubstituted.

In a further preferred embodiment, R1 is disubstituted. In a preferred embodiment, R1 is substituted by at least one of R3C (0) 0- or R3C (0) O- (C1-C6 E Enn uunnaa aaddiicciioonnaallmmeennttee rreeaalliizzaacciióónn ppreferida, R1 is substituted by at least one of R3C (0) 0-.

In a further preferred embodiment, R1 is substituted with at least one of R3C (0) O-alkyl (C? -Cg) -.

In a further preferred embodiment, R1 is substituted with at least one of R20N =, R2ON = alkyl (Cj-Cg) -, or R2ON = CR2alkyl (C, -C6) -; with the condition that, when R1 is substituted only by one of R20? =, Then R2 can not be hydrogen. In a further preferred embodiment, R1 is substituted with at least one of R 0? =, With the proviso that, when R is substituted only by one of R 0 =, then R can not be hydrogen. In a further preferred embodiment, R1 is substituted with at least one of -? R2 (0R2). In a further preferred embodiment, R1 is substituted by at least one of R4R5 S (0) 2-, S R4R5 (0) 2-alkyl (C C6?) -?, R4S (0) 2R5 -, or R4S (O) 2R5? -alkyl (C, -C6) -.

In a further preferred embodiment, R is substituted with at least one of R S (0) 2R? -. In a further preferred embodiment, R is substituted with at least one of R4S (0) 2? -alkyl (C- | _-Cg) -.

In a further preferred embodiment, R is a cycloalkyl (C3-Cg) cycloalkenyl ring or (C5-C8) cycloalkyl ring or cycloalkenyl ring substituted by one of RC (0) 0- being well, R3C (0) O- (C1-Cg) -, R20 = R20 = (C1-C) -?, R2O = CR2alquilo IC1-Cg) -, - R2 (0R2) R4R5 S (? 0) 2-, R4R5? S- (0) 2-alkyl (C ^ Cg) -, ^ S. { O) 2R ^ -, 0 R4S (O) 2R5N- (C1-Cg) alkyl-; wherein R2, R3, R4 and R5 are as defined above; with the proviso that the cycloalkenyl ring is not aromatic; and with the proviso that, when R1 is substituted 2 or with R ON =, then R can not be hydrogen. In a further preferred embodiment, R is a cycloalkyl ring (C-Cg) or cycloalkenyl ring (C5-Cg), either the cycloalkyl ring or the cycloalkenyl ring substituted with one of R3C (O) 0-, R3C (O) O- (C1-C3) alkyl-, R2ON =, or R4S (0) 2R5N-; in which R 2, R 3, R 4 and R 3"are as defined above, with the proviso that the cycloalkenyl ring is not aromatic, and with the proviso that, when R is substituted with, it can not be hydrogen. Further preferred, R1 is substituted with R3C (0) 0- or R3C (0) O-(C1-C8) alkyl- In a further preferred embodiment, R is substituted with R3C (0) 0- In a further preferred embodiment , R1 is substituted with R3C (0) O-alkyl (C - ^ - Cg) - In a further preferred embodiment, R1 is substituted with R20? =, R2O? = (C1-Cg) alkyl -I or R2O? = CR2alkyl (C - ^ - C8) -; with the proviso that, when R is substituted with 2QN =. ^ Then R2 can not be hydrogen.

In a further preferred embodiment, R1 is substituted with R2ON =, wherein R2 can not be hydrogen.

In a further preferred embodiment, R1 is substituted with -NR2 (OR2). In a further preferred embodiment, R1 is substituted with R4R5NS (0) 2-, R4R5NS (0) 2-(C1-C6) alkyl-, R4S (0) 2R5N-, or R4S (0) 2R5N- (C1-C3) alkyl ) -. In a further preferred embodiment, R1 is substituted with R4S (O) 2R5N-. In a further preferred embodiment, R1 is substituted with R4S (O) 2R5N-(C1-Cg) alkyl-. The heterocycloalkyl substituent (C2-C), when present in R1, is preferably a group of the formula: where m is as defined above, and Z is CH2, NR2, O, S, SO, or S02. For any of the aforementioned compounds of the present invention, R1 is preferably a group of the formula: which is substituted as described above for R1; wherein n is 0, 1 or 2; in which the broken line indicates an optional double bond in 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 in that position. In a further preferred embodiment, n is 1.

In a further preferred embodiment, Ri is substituted with = 0, = N0H, CH20H, .OH Me or a combination thereof. In a further preferred embodiment, n is 0; R is substituted with = NOH; and the dashed line represents a double bond in that position. In a further preferred embodiment, n is 1; R1 is substituted with = 0, = N0H, CH20H, or OH < Me or a combination thereof. The invention further provides a compound selected from the group comprising: O-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime; (+) - N - [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; (±) -0-Methyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; (±) -0-Benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; and a pharmaceutically acceptable salt thereof. The invention further provides a compound selected from the group comprising: (±) -0-methyl-4- (2,4-dihydroxyphenyl) cyclohexa-none oxime; (+) -4- [3- (Hydroxyamino) cyclohexyl] -1,3-benzenediol; ci s-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] -1-butanesulphonamide; trans-N- [4- (2,4-Dihydroxy-enyl) -cyclohexyl] -methanesulf-namide; cis-N- [4- (2,4-Dihydroxy-enyl) -cyclohexyl] -methanesulfonamide; 4- (Dimethylamino) benzoate of trans-4 - (2,4-dihydroxy-e-1) nil) cyclohexyl); 4- tert-Butylbenzoate of trans-4- (2, -dihydroxyphenyl) cyclohexyl; 4-Fluorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Trifluoromethylbenzoate of t_rai_s-4- (2,4-dihydroxyphenyl) cyclohexyl; Trans-4- (2,4-dihydroxyphenyl) cyclohexyl 4-methoxybenzoate; 4-Methylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Chlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-dimethylbenzoate of traps-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-Dichlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl, • [4- (2,4-dihydroxyphenyl) cyclohexyl] methyl propionate; cis / trans- 4 - [4- (Hydroxyamino) cyclohexyl] -1,3-benzene-diol; trans -4- [4- (Methoxyamino) cyclohexyl] -1,3-benzenediol; and a pharmaceutically acceptable salt of. the same. The present invention additionally provides a topical pharmaceutical composition for lightening the skin, or reducing skin pigmentation, in a human being, comprising a pharmaceutically acceptable carrier, and a skin lightening, or pigment reducing, amount of a composed of formula 'I: or a pharmaceutically acceptable salt thereof, wherein: R1 is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-C8), the cycloalkyl ring or the cycloalkenyl ring being either substituted with one to three substituents independently selected from the group comprising cyano; halo; alkyl (C -C8); aril; heterocycloalkyl. { C2 -C5); heteroaryl (C2-C); arylalkyl (C-j_-Cg); = 0; = CHOalkyl (C - ^ - Cg); Not me; hydroxy; (C1-C8) alkoxy; "arylalkoxy (C- | _-Cg) -; acyl (C ^ Cg); alkyl (C-j_- Cg) -amino-; arylalkyl (C-j_-Cg) -amino-; aminoalkyl (Cj ^ - Cg) -; alkoxy (CL-Cg) -CO-NH-; (C1-Cg) alkyl-amino-CO-; (C2-C8) alkenyl; (C2-C8) alkynyl; hydroxyalkyl (C - ^ Cg) - alkoxy (C- ^ Cg) -alkyl (C ^ Cg) -; acyloxy (C1-Cg) -20 alkyl (C - ^ - Cg) -; nitro; cyanoalkyl (C1-Cg) -; haloalkyl (C-1-Cg) -nitroalkyl (C 1 -C 8) -; trifluoromethyl; trifluoromethylalkyl (C 1 -Cg) -; acyl (C - ^ - Cg) amino-; acyl (C 1 -C 8) -aminoalkyl (C1-Cg) -; (C - ^ - Cg) -acyl (C ^ -Cg) -amino-; aminoacyl (C1-Cg) -; aminoacyl (C- ^ - Cg) -alkyl (C- ^) -Cg) -; _ril ^^ d ^ __ Mfid ^^^ alkyl (C1-Cg) -aminoacyl (C-_-Cg) -; (alkyl (C] _- Cg)) 2-amino-acyl (C1-Cg) -; -C02R2; -alkyl (C1-C8) -C02R2; C (0) N (R2) 2; -alkyl (C1-Cg) -C (0) (R2) 2; R2ON =; R20N = alkylo (C1-Cg) -; R20N = CR2alkyl (C1-C8) -; -NR2 (0R2); -alkyl (C? -Cg) -NR2 (OR2); -C (0) (NR2OR2); -alkyl (C] _- Cg) -C (O) (NR2OR2); -S (0) mR2, - in which each R is independently selected from hydrogen, alkyl (C-α-Cg), aryl, or arylalkyl (C- | _-Cg) -; R3C (0) 0-, wherein R3 is alkyl (C - ^ - Cg), aryl, or arylalkyl (C ^ Cg) -; R 3 C (O) O-alkyl (C, -C 6) -; R4R5N-C (O) -0-; R4R5NS (0) 2-; R4R5NS (0) 2 -alkyl (C1-Cg) -; R4S (0) 2R5N-; R4S (0) 2R5N-alkyl < C1-Cg) -; where m O, 1 6 2, and R 4 and R 5 are each independently selected from hydrogen or (C 1 -C 6) alkyl; -C (= NR6) (N (R4) 2); or -alkyl (c1-Cg) -C (=? Rd) (? (R4) 2) wherein Rd represents OR2 or R2, R2 being as defined above; with the proviso that the cycloalkenyl ring is not aromatic; with the proviso that R1 must be substituted with at least one of R3C (0) 0-, R3C (0) O-alkyl (C] _- Cg) -, R20? =, R2O? = alkyl (C1-Cg) -, R2O? = CR2alkyl (C1-Cg) -, -? R2 (OR2), R4R5? S (0) 2-, R4R5? S (0) 2-alkyl (C1-Cg) -, R4S (0) 2R5 ? -, or R4S (0) 2R5? -alkyl (C1-Cg) -. When R 1 is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3 or 4 position, and more preferably at the 4 position. When R 1 is a cyclopentyl or cyclopentenyl ring lo, the ring is preferably substituted in the 3-position. In a preferred embodiment, R is monosubstituted.

In a further preferred embodiment, R is disubstituted. In a preferred embodiment, R1 is substituted with at least one of R3C (0) 0- or R3C (0) O-alkyl (C, -C6) -. In a further preferred embodiment, R1 is substituted with at least one of R3C (0) 0-. In a further preferred embodiment, R1 is substituted - with at least one of R3C (0) O-alkyl (C ^ -8) -.

In a further preferred embodiment, R1 is substituted with at least one of R20N =, R2ON = (C1-Cg) alkyl-, or R2ON = CR2alkyl (C1-Cg) -. In a further preferred embodiment, R1 is substituted with at least one of R20? =. In a further preferred embodiment, R1 is substituted with at least one of - [R2] (OR2). In a further preferred embodiment, R1 is substituted with at least one of R4R5? S (0) 2-, R4R5? S (0) 2-alkyl (C1-C8) -, R4S (0) 2R5? -, or R4S ( O) 2R5? -alkyl (C] _- C6> - In a further preferred embodiment, R1 is substituted with at least one of R4S (O) 2R5? - In a further preferred embodiment, R is substituted with at least one of R4S (0) 2R5? -alkyl (C-_-Cg) -.

In a further preferred embodiment, R1 is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-C8), with either the cycloalkyl ring or the cycloalkenyl ring substituted with R3C (0) 0-, RJ3C (0) 0-C1-Cg alkyl-, R2ON =, R2ON = (C1-Cg) alkyl-, R20N = CR2alkyl (C1-Cg) -, -NR2 (OR2), R4R5NS (0) 2- , R4R5NS (0) 2-alkyl (C? -C6) -, or R4S (0) 2R5N-alkyl (Cj-Cg) -; in which R, R, R and R5 are as defined above; with the proviso that the cycloalkenyl ring is not aromatic. In a further preferred embodiment, R is a cycloalkyl ring (C3-C8) or cycloalkenyl ring (C? -Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one of R3C (O) 0- , R3C (0) O-(C1-C8) alkyl-, R20N =, or R4S (0) 2R5N-; wherein R, R, R and R5 are as defined above; with the proviso that the cycloalkenyl ring is not aromatic. In a further preferred embodiment, R1 is substituted with R3C (0) 0- or R3C (0) O-(C1-C8) alkyl-. In a further preferred embodiment, R1 is substituted with R3C (0) 0-. In a further preferred embodiment, R1 is substituted with R3C (0) 0-alkyl (C- | _-C8) -. In a further preferred embodiment, R1 is substituted with R20N =, R20N = (C1-Cg) alkyl-, or R20N = CR2alkyl (Ci-C) -. In a further preferred embodiment, R1 is substituted with R20N =. In a further preferred embodiment, R1 is substituted with -NR2 (0R2). In a further preferred embodiment, R1 is substituted with R R5NS (0) 2-, R4R5NS (0) 2-alkyl (Ci-C) -, R4S (0) 2R5N-, or R4S (0) 2R5N-alkyl? (Ci-Cg) -. In a further preferred embodiment, R1 is substituted with R4S (0) 2R5N-. In a further preferred embodiment, R1 is substituted with R4S (0) 2R5? -alkyl (Ci-Cg) -. The heterocycloalkyl substituent (C2-C8), when present in R1 of the compound of formula I, is preferably a group of the formula: wherein m is as defined above, and Z is CH2, R2, O, S, SO, or S02. For any of the aforementioned compositions 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; wherein n is 0, 1 or 2; in which the broken line indicates an optional double bond in 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 in that position. In a further preferred embodiment, n is 1. In a further preferred embodiment, R1 is substituted with = 0, = N0H, CH20H, or .OH Me or a combination thereof. In a further preferred embodiment, n is 0; R1 is substituted with = N0H; and the dashed line represents a double bond in that position. In a further preferred embodiment, n is 1; and R1 is substituted with = 0, = N0H, CH20H, or OH < Me or a combination thereof. The present invention further provides a topical pharmaceutical composition for lightening the skin, or reducing skin pigmentation, in a human being, comprising a pharmaceutically acceptable carrier, and an effective skin lightening, or pigment reducing, amount of a compound selected from the group comprising: 4- (2, -dihydroxyphenyl) cyclohexanone oxime; Oxime of 0-methyl-4- (2,4-dihydroxyphenyl) cyclohexanone; Oxi a of 0-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone; Oxime of 3- (2,4-dihydroxyphenyl) -2-cyclohexen-1-one; (±) -3- (2, -dihydroxyphenyl) cyclohexanone oxime; (+) - N - [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; (+) -4- [3- (Hydroxyamino) cyclohexyl] -1,3-benzenediol; (±) -0-Methyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime - (+) - O-benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; 3 - (2, -dihydroxyphenyl) cyclopentenone oxime; Oxime of (+) - 3 - (2,4-dihydroxyphenyl) cyclopentanone; and a pharmaceutically acceptable salt thereof.

The present invention further provides a topical pharmaceutical composition for lightening the skin, or reducing skin pigmentation, in a human being, comprising a pharmaceutically acceptable carrier, and an effective skin lightening, or pigment reducing, amount of a compound selected from the group comprising: cis-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] -1-butanesulfonamide; trans-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide, - cis-N- [4- (2, -Dihydroxyphenyl) cyclohexyl] ethanesulfonamide, 4- (Dimethylamino) benzoate of rans-4- (2,4-dihydroxyphenyl) cyclohexyl); 4- tert-Butylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Fluorobenzoate of trans-4- (2, -dihydroxyphenyl) cyclohexyl; 4-Trifluoromethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Methoxy-benzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl, trans-4- (2,4-dihydroxyphenyl) cyclohexyl-4-methylbenzoate; 4-Chlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-dimethylbenzoate of traps-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-Dichlorobenzoate of trans-4- (2,4-dihydroxy-phenyl) -cyclohexyl; [4- (2,4-Dihydroxyphenyl) cyclohexyl] methyl propionate; cís / trans-4- [4- (Hydroxyamino) cyclohexyl] -1,3-benzene-diol, - trans-4- [4- (methoxyamino) cyclohexyl] -1,3-benzenediol; and a pharmaceutically acceptable salt thereof. In a further preferred embodiment, the skin-lightening, or pigment-reducing, effective amount of a compound of formula I of the pharmaceutical composition of the present invention is an effective amount of the compound, tyrosinase inhibitor. The present invention further provides a topical pharmaceutical composition for inhibiting tyrosinase in a human, comprising a pharmaceutically acceptable carrier., and an effective, tyrosinase inhibiting amount of a compound selected from the compounds of any of the aforementioned pharmaceutical compositions of the present invention. The present invention additionally provides a method for lightening the skin, or reducing skin pigmentation, in a human being, which comprises administering to said human being an effective amount of skin lightening, or reducing skin pigmentation, of a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (Cg-Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one to three substituents independently selected from the group comprising cyano; halo; alkyl (C ^ Cg); aril; Heterocycloalkyl (C2-C8); heteroaryl (C2-C8); Arylalkyl (C ~ Cg); = 0; = CHOalkyl (C1-Cg); Not me; hydroxy; (C1-Cg) alkoxy-arylalkoxy (C1-C) -; acyl (C1-C8); alkyl (C1-Cg) -amino-; arylalkyl (C) -amino-; aminoalkyl (C1-Cg) -; -alkoxy (C1-Cg) -C0-NH-; (C 1 -C 8) alkyl-amino-CO-; alkenyl (C2-Cg); (C2-C8) alkynyl; Hydroxyalkyl (C1-Cg) -; alkoxy (C ^ Cg) -alkyl (C1-Cg) -; acyloxy (? ~ Cg) -alkyl (C1-Cg) -; nitro; cyanoalkyl (C1-Cg) -; haloalkyl (Ci ~ Cg) -; Nitroalkyl (C1-C8) -; trifluoromethyl; trifluo-romethylalkyl (C1-Cg) -; acyl (C1-Cg) amino-; acyl (Ci ~ Cg) -aminoalkyl (C1-C8) -; alkoxy (Ci ~ Cg) -acyl (C ^ Cg) -amino-, -aminoacyl (C1-C8) -; aminoacyl (C1-Cg) -alkyl (C1-C) -; alkyl (Ci-Cg) -aminoacyl (Ci-Cg) -; (alkyl (c? ~ c?) 2-amino-acyl (Ci-Cg) -; -C02R2; -alkyl (Ci-Cg) -C02R2; C (0) N (R2) 2; -alkyl (Ci-Cg) ) -C (O) N (R2) 2; R2ON =; R2ON = alkyl (Ci-Cg) -; R2ON = CR2alkyl (Ci-Cg) -; -NR2 (OR2); -alkyl (Ci-Cg) -NR2 (OR2); -C (O) (NR2OR2); -alkyl (Ci-Cg) -C (O) (NR2OR2); -S (0) mR, - wherein each R2 is independently selected from hydrogen, alkyl ( C ^ C), aryl, or arylalkyl (Ci-Cg) -; R3C (0) 0-, wherein R3 is alkyl (Ci-Cg), aryl, or arylalkyl (Ci-Cg) -; R3C (O) O-alkyl (Ci-Cg) -; R4R5N-C (0) -O-; R4R5NS (0) 2-; R4R5NS (O) 2-alkyl? (Ci-Cg) -; R4S (0) 2R5N-; R4S (O) 2R5N-C ^ Cg alkyl) -; where m -0, 1 or 2, and R4 and R5 are each independently selected from hydrogen or alkyl (Ci-Cg); -C (= NR6) (N (R4) 2); or -alkyl (C ^ Cg) -C (= NRd) (N (R4) 2) in which R6 represents OR2 or R2, where R2 is as defined above, - with the proviso that the cycloalkenyl ring is not aromatic, - with the proviso that, when R1 is a cycloalkyl ring (C5-Cg), or when R1 is a cycloalkenyl ring (C5-Cg) having the following structure: wherein n is 0, 1, 2 or 3, such cycloalkyl ring (C5-Cß), or cycloalkenyl ring (C5-C8), substituted with hydroxy, alkoxy (C ^ Cg), arylalkoxy (C) ~ C) -, -OC (O) -alkyl (Ci-Cg), -OC (0) -arylalkyl (Ci-Cg), OC (O) phenyl, halo, alkyl (C ^ Cg) -, arylalkyl (Ci-Cg) -, -SH, -S-alkyl (Ci-Cg), arylalkyl (Ci-Cg) -S-, -NH2, -NH-alkyl (C-Cg), or arylalkyl (Ci-Cg) -NH-; then the cycloalkyl ring (C5-C8), or the cycloalkenyl ring (Cg-Cg), must be di- or trisubstituted. When R is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted in the 3 or 4 position, and more preferably in the 4 position. When R1 is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted in the 3 position. In a preferred embodiment, R is monosubstituted. In a further preferred embodiment, R1 is disubstituted. In a preferred embodiment, R1 of the compound of the method is substituted with at least one of R3C (O) 0-, R3C (0) O-alkyl (C, -C6) -, R0N =, R2ON = alkyl (C, -C6 ) -, R2ON = CR2alkyl (C ^ Cg) -, -NR2 (OR2), R4R5NS (0) 2-, R4R5NS (0) 2-alkyl? (Ci-Cg) -, R4S (0) 2R5N-, or R4S (O) 2R5N-alkyl (Ci-Cg) -. In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of R3C (0) 0- or R3C (0) O-alkyl (Ci-Cg) -.

In a further preferred embodiment, R 1 is substituted with at least one of R 3 C (0) 0-. In a further preferred embodiment, R1 is substituted with at least one of R3C (0) O-alkyl (Ci-C) -.

In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of R20N =, R2ON = alkyl? (Ci-Cg) -, or R2ON = CR2alkyl (Ci-Cg) -.

In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of R20N =. In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of -NR2 (OR2). In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of R4R5N? (0) 2-, R4R5NS (0) 2 -alkyl (Ci-Cg) -, R4S (O) 2R5N-, or R4S ( 0) 2R5N-alkyl (Ci-Cg) -. In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of R4S (0) 2R5N-. In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of R4S (0) 2R5N-alkyl (Ci-Cg) -. In a further preferred embodiment, R1 of the compound of the method is substituted with at least one of hydroxyalkyl (C ^ Cg) -.

In a further preferred embodiment, R1 is a (C3-C8) cycloalkyl ring or (C5-C8) cycloalkenyl ring, the cycloalkyl ring being either the cycloalkenyl ring substituted with one of RJC (O) 0-, R3C (0) O-alkyl (Ci-Cg) -, R2ON =, R2ON = alkyl (Ci-Cg) -, R20N = CR2 alkyl (C1-Cg) -, -NR2 (OR2), R4R5NS (0) 2- , R4R5NS- (0) 2-alkyl (Ci-Cg) -, R4S (0) 2R5N-, or R4S (O) 2R5N-alkyl (C ~ C) -; where R, R3, R4 and R5 are as defined above. In a further preferred embodiment, R1 is a cycloalkyl ring (C3-C8) or cycloalkenyl ring (Cg-Cg), either the cycloalkyl ring or the cycloalkenyl ring substituted with one of R3C (O) 0-, R3C (O) O-alkyl (Ci-Cg) -, R20N =, or R4S (0) 2R5N-; where R, R3, R4 and R5 are as defined above. In a further preferred embodiment, R is substituted with one of R3C (0) 0- or R3C (O) O-alkyl (Ci-Cg) -. In a further preferred embodiment, R1 is substituted with one of R3C (0) 0-. In a further preferred embodiment, R1 is substituted with one of R3C (0) O-alkyl (C ^ C) -. In a further preferred embodiment, R1 is substituted with one of R20N =, R20N = alkyl (Ci-Cg) -, or R20N = CR2alkyl (Ci-Cg) -. In a further preferred embodiment, R is substituted with one of R 0 N =.

In a further preferred embodiment, R1 is substituted with one of (OR). In a further preferred embodiment, R1 is substituted with one of R4R5NS (0) 2-, R4R5NS (0) 2 -alkyl (C1-Cg) -, RS (0) 2R5N-, or R4S (0) 2R5N-alkyl (C1 -C8) -. In a further preferred embodiment, R1 is substituted with one of R4S (0) 2R5N-. In a further preferred embodiment, R1 is substituted with one of R4S (0) 2R5N-alkyl (C ^ Cg) -. In a further preferred embodiment, R is substituted with one of hydroxyalkyl (C ^ Cg) -. The heterocycloalkyl (C2-C8) substituent, when present in R1 of the compound of formula I, is preferably a group of the formula: where m is as defined above, and Z is CHo, NR2, 0, S, SO, or S0. For any of the above-mentioned methods of the present invention, R1 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; in which the broken line indicates an optional double bond in 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 in that position. In a further preferred embodiment, n is 1. In a further preferred embodiment, R1 is substituted with = 0, = N0H, CH20H, or -.OH Me or a combination thereof. In a further preferred embodiment, n is 0; R1 is substituted with = N0H; and the dashed line represents a double bond in that position. In a further preferred embodiment, n is 1; R1 is substituted with = 0, = N0H, CH20H, or OH < Me or a combination thereof. In a preferred embodiment, the method of the present invention comprises administering to a human, a skin brightening or pigment reducing effective amount of a compound selected from the group comprising: 4- (2,4-Dihydroxyphenyl) Cyclohexanone; 4- (2, -dihydroxyphenyl) cyclohexanone oxime; Oxime of 0-methyl-4- (2,4-dihydroxyphenyl) cyclohexanone; O-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime; 3- (2,4-Dihydroxyphenyl) -2-cyclohexen-1-one; (±) -3- (2,4-Dihydroxyphenyl) cyclohexanone; 3- (2, -dihydroxyphenyl) -2-cyclohexen-1-one oxime; (±) -3- (2,4-Dihydroxyphenyl) -cyclohexanone oxime, - (+) -4- [3- (Piperazinyl) cyclohexyl] -1,3-benzenediol; (+) - N - [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; (+) -4- [3 - (Hydroxymethyl) cyclohexyl] -1, 3-benzenediol, - (+) -4- [3- (Hydroxyamino) cyclohexyl] -1, 3-benzenediol, - ci s / trans-A - [4- (Hydroxymethyl) cyclohexyl] -1,3-benzenediol; cis / trans- - (4-Hydroxy-4-methylcyclohexyl) -1,3-benzenediol; (±) -O-methyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; (±) -3- (2,4-Dihydroxyphenyl) -1-methylcyclohexanol; (+) - O-benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; Oxime of 3- (2,4-dihydroxyphenyl) cyclopentenone; (+) - 3 - (2,4-Dihydroxyphenyl) cyclopentanone; Oxime of (+) - 3 - (2,4-dihydroxyphenyl) cyclopentanone; and a pharmaceutically acceptable salt thereof. In a further preferred embodiment, the method of the present invention comprises administering to a human, a skin brightening or pigment reducing effective amount of a compound selected from the group comprising: 4- (2, 4- Dihydroxyphenyl) -3-cyclohexen-1-one; cis / trans-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] acetamide; ci s-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] -1-butanesulphonamide; trans-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulphonamide; cis-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; 4- [4- (4-Hydroxyphenyl) cyclohexyl] -1,3-benzenediol, methyl-cis / trans- [4- (2,4-dihydroxy phenyl) cyclohexyl] acetate; methyl trans- [4- (2, 4-Dihydroxyphenyl) cyclohexyl] acetate; ci s- [4- (2,4-Dihydroxyphenyl) cyclohexyl] methyl acetate; Trans- [4- (2,4-dihydroxyphenyl) cyclohexyl] acetic acid; Cis- [4- (2,4-dihydroxyphenyl) cyclohexyl] acetic acid; Cis / trans- [4- (2,4-dihydroxyphenyl) cyclohexyl] acetic acid; cis / trans- [4- (2, -Dihydroxyphenyl) cyclohexyl] acetonitrile; cís / trans-4- [4- (2-aminoethyl) cyclohexyl] -1,3-benzenediol, - (±) -4- (3,3-difluorocyclohexyl) -1,3-benzenediol; (+) - 3 - (2,4-Dihydroxyphenyl) cyclohexanecarboxamide, • (+) - 3 - (2,4-Dihydroxyphenyl) - N -hydroxycyclohexanecarbo-xamide; (±) -3- (2,4-Dihydroxyphenyl) -N-ethylcyclohexanecarboxamide; (+) -4- [3-Hydroxy -3- (hydroxymethyl) cyclohexyl] -1,3-benzenediol; (+) - N- [3- (2,4-Dihydroxyphenyl) cyclohexyl] acetamide; 4- (2,4-dihydroxyphenyl) cyclohexyl 4- (dimethylamino) benzoate); Acid / trans-4- (2,4-dihydroxyphenyl) cyclohexanecarboxylic acid; Ethylcarbamate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; Trans-4- (2,4-dihydroxyphenyl) cyclohexyl cyclohexylcarbamate; 4- tert-Butylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-trans-4- (2,4-dihydroxyphenyl) cyclohexyl-4-fluorobenzoate, trans-4- (2,4-dihydroxyphenyl) cyclohexyl-4-trifluoromethylbenzoate; Trans-4- (2, -dihydroxyphenyl) cyclohexyl 4-methoxybenzoate; 4-Methylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Chloro-benzoate of traps-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-dimethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-Dichlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; trans-A - [A- (Phenylsulfanyl) cyclohexyl] -1,3-benzenediol; trans -4- [4- (Phenylsulfonyl) cyclohexyl] -1,3-benzenediol; [4- (2,4-Dihydroxyphenyl) cyclohexyl] methyl propionate; 4- (2,4-Dihydroxyphenyl) -1-hydroxycyclohexanecarboxylate ethyl; cis / trans-A - [A - (Hydroxyamino) cyclohexyl] -1,3-benzene diol; trans-A - [A - (methoxyamino) cyclohexyl] -1,3-benzenediol; and a pharmaceutically acceptable salt thereof. In a preferred embodiment, the skin brightening or pigment reducing effective amount of a compound of the method of the present invention is an effective amount of the tyrosinase inhibiting compound.

The present invention further provides a method for inhibiting tyrosinase in a human being in need of such a treatment, comprising administering to said human an effective, tyrosinase inhibiting amount of a compound selected from 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., and for the treatment of dandruff, in a human being, 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 invention. present invention, which amount is effective to treat such disorder or condition. The present invention further provides a method for treating inflammatory disorders, such as psoriasis, dermatitis or acne, or a method for the treatment of dandruff, in a human being, which comprises administering to said human being 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 to treat 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, for preparing a medicament useful for lighten the skin or reduce skin pigmentation in a human being. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties, or combinations thereof. Any of the substituents or functional groups in the alkyl group, as indicated herein, may be substituted anywhere in 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, alkyl (Ci-Cg), alkoxy (C -C), amino, alkyl (Ci-Cg) -amino, di- (alkyl (c? G)) amino, nitro, cyano and trifluoromethyl. Any of the substituents or functional groups in the aryl group, as indicated herein, may be substituted anywhere in the aryl group. The term "one or more substituents", as used herein, refers to a number of substituents that is equal to one to the maximum number of possible substituents, based on the number of available linkage sites. '"Halo", as used herein, refers to halogen and, unless otherwise indicated, includes chloro, fluoro, bromo and iodo. 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 arylalkoxy, and the terms "alkyl" or "alkyl" arilo "are as defined above. The term "acyloxy", as used herein, includes O-acyl groups in which "acyl" is as defined above.

C2 ~ C ^ heterocycloalkyl), when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxy, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1 , 3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1, 2-tetrahydrothiazin-2-yl, 1, yl tetrahydrodiazin-2-yl-3-tetrahydrothiazin 1-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-, 1, 3 -tetrahidrodiazin-, c tetrahydroazepinyl , piperazinyl, chromanyl, etc. The person skilled in the art will understand that the connection of said heterocycloalkyl ring (C2-C8) can be through a carbon atom, or through a nitrogen heteroatom, when possible. Heteroaryl (C2-C8), when used herein, refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl,. imidazolyl, 1, 3, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1,2,3- oxadiazolyl, 1, 3, 5-thiadiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1, 2, 4 -triazinilo, 1, 2, 3-triazinyl, 1,3,5-triazinyl 15, pyrazolo [3, 4-b] pyridinyl, cinnolinyl, pteridinyl, purinyl, 6 , 7-dihydro-5H- [1] pyridinyl, benzo [b] thio- phenyl, 5, 6, 7, 8-tetrahydro-quinolin-3 -yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizin¬ -20 lo, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, etc. The person skilled in the art will understand that the connection of said heteroaryl rings (C2-C8) can be through a carbon atom or through a nitrogen heteroatom, when possible. The compounds of formula I may contain chiral centers and, therefore, may exist in different enantiomeric and diastereomeric 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 described, but which are differentiated by the fact that one or more hydrogens, carbons or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays. The present invention also relates to the pharmaceutically acceptable acid addition salts 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, ie salts containing pharmacologically acceptable anions, such as salts hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfa-to, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate , p-toluenesulfonate and pamoate (i.e., 1,1-methylene-bis- (2-hydroxy-3-naphthoate)). DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared as described in the following reaction and exposure schemes. Except as otherwise indicated, n, m, R, R, R, R, Z, and structural formula I in the reaction schemes -y. The exposition that follows are as defined above Scheme 1 d) (2) (3) Eßcruema 2 Scheme 3 (25) Scheme 4 Scheme 5 Scheme 6 (6), (8) or (9), (14) or (15) Scheme 7 Scheme 8 Scheme 9 Scheme 10 Scheme 11 Scheme 12 Y, Y ', Y' shown in the above schemes, each independently represents any of the various substituents on R1 as defined above, or hydrogen, as appropriate. Reaction Schemes 1 to 12 illustrate various methods for synthesizing compounds of formula I. PG refers to a protecting group. Referring to Scheme 1, the compounds of formula (2) can be formed by protecting commercially available 4-bromorresorcinol (1). A suitable protecting group, such as methoxymethyl (MOM), can be introduced by conventional methods that are well known to the person skilled in the art. For example, the alkylation of 4-bromorresorcinol can occur with two equivalents of methoxymethyl chloride in the presence of diisopropylamine in a halogenated solvent at about 0 ° C to room temperature. The compounds of general formula (3) can be obtained using conventional methods. For example, the reaction of the 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 triisopropyl borate and hydrolysis with aqueous acid, can produce compounds of formula (3). The compounds of general formula (5) can be obtained using conventional methods. For example, treatment of the compounds of formula (4) with triphenylphosphine and bromine in a chlorinated solvent will produce compounds of formula (5). Compound (4), wherein n = 1, is commercially available (Aldrich, Milwaukee, WI, USA). The 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 (triphenylphosphine) aladium (five mole percent), sodium carbonate (two equivalents) and heating in a suitable solvent system. { for example, dimethoxyethane / water) at about 80 ° C. The conversion of the compounds of formula (6) to the compounds of formula (8) can occur under standard reducing conditions such as, for example, hydrogen gas and a metal catalyst such as rhodium on alumina, at about room temperature and pressure. atmospheric Deprotection of the compounds of formula (6) or (8) under suitable conditions, for example, when the protecting group is MOM, heating at 50 ° C in methanol with Dowex acid, gives compounds of formula I in which R 1 is substituted with = 0 (7), (9). Additionally, derivatives of the compounds of formula (7) or (9) can be obtained, under standard conditions, to produce resorcinols of formula I in which R1 is substituted with = N0R2. For example, heating compounds of formula (7) in a suitable solvent. { for example, ethanol), at about 80 ° C, with the necessary hydroxylamine hydrochloride salt, and triethylamine, gives the analogues of formula I.

The compounds of formula I in which R1 is substituted or with NHOR2 can be prepared from compounds of formula I in which R1 is substituted with = NOR2 by a reduction under standard reaction conditions, eg sodium cyanoborohydride. in acetic acid at or around room temperature. Additionally, derivatives of the compounds of formula (8) can be obtained under standard conditions to give resorcinols of formula I in which R1 is disubstituted with fluoro. For example, treatment of the compounds of formula (8) with diethylaminosulfur trifluoride in a suitable solvent, for example dimethoxyethane, after appropriate deprotection would give analogs of formula I. Referring to Scheme 2, the compounds of the general formula ( 10) are well known and can be obtained using conventional methods (see, for example, Crombie et al. , 1982, J. Chem. Soc. Perkin Trans. I, 1485). The compounds of formula (11) can be obtained from the reaction of the compounds of formula (2) with n-butyllithium in the presence of N, N, N ', N' -tetramethylethylenediamine in an ethereal solvent, followed by addition of a compound of formula (10). Dehydration of compounds of formula (11) under standard conditions, for example, by heating compounds of formula (11) to about 110 ° C, in a Dean-Stark apparatus, in the presence of camphorsulfonic acid in a suitable solvent. { for example, toluene), gives compounds of formula (12). Hydrogenation under standard conditions, for example, using hydrogen gas and palladium on ethanol, gives compounds of the general formula (13). Deprotection under suitable conditions gives resorcinols of formula I wherein R 1 is substituted with = 0 (14). Additionally, derivatives of the compounds of formula (14) can be obtained under standard conditions to give resorcinols of formula I wherein R 1 is substituted with = NOR 2. For example, heating compounds of formula (14) in a suitable solvent. { for example, ethanol) at about 80 ° C with the required salt of hydroxylamine hydrochloride and triethylamine gives analogs of formula I. Further reduction under standard conditions would give compounds of formula I, wherein R 1 is substituted with NHOR 2. The compounds of formula (14) can also be protected with a suitable protecting group, such as tert-butyldimethylsilyl, under standard reaction conditions, to give compounds of formula (15). Derivatives of the compounds of formula (15) can be obtained using standard reaction conditions. For example, ethylenation, using the appropriate Wittig reaction, will give compounds of formula (16), for example, the treatment of methyltriphenylphosphonium bromide with potassium t-butoxide in a suitable solvent. { for example, tetrahydrofuran) at a temperature between -78 ° C and 0 ° C, followed by the addition of a compound of formula (15), will give compounds of formula (16). The subsequent conversion to compounds of formula (18), under standard conditions, for example, hydroboration, to give compounds of formula (17), and subsequent oxidation using suitable conditions, such as pyridinium dichromate in dimethylformamide at room temperature, gives compounds of formula (18). The compounds of formula (17) can be treated with an alkyl bromide in a suitable solvent. { for example, acetone), in the presence of potassium carbonate, to give compounds of formula I in which R1 is substituted with an ether group, after suitable deprotection has taken place, for example, when the protective group is tert-butyldimethylsilyl , tetrabutylammonium fluoride can be used. Alternatively, the compounds of formula (17) can also be esterified using standard conditions, for example, treatment with an acid chloride in the presence of triethylamine in a chlorinated solvent at about room temperature. Derivatives of the compounds of formula (18) can be obtained to form analogues such as esters and amides under conditions well known to those skilled in the art. For example, conditions for forming amides may involve treating compounds of formula (18) with isobutyl chloroformate and triethylamine in a chlorinated solvent at about 0 ° C, followed by the addition of a suitable amine. Deprotection under suitable conditions will give compounds of formula I, wherein R1 is substituted with an amide. The disproportionation of compounds of formula (16), (17) and (18) under standard conditions also provides compounds of formula I wherein R 1 is substituted with methylene, hydroxymethyl or a carboxylic acid, respectively. Referring to Scheme 3, the compounds of formula (20) can be prepared starting with the compound (19), which is commercially available. The conversion to compounds of formula (20) can occur under standard conditions such as, for example, when the protecting group is benzyl, condensation that can occur between the compound (19) and the benzyl alcohol, with removal of water using a Dean apparatus. -Stark in conjunction with well-known methodology. The condensation of compounds of formula (20) with compounds of formula (10) can occur with standard techniques, for example, the treatment of compounds of formula (20) with a base such as lithium diisopropylamide in an ethereal solvent, followed by addition of compounds of formula (10), would give compounds of formula (21). Treatment of compounds of formula (21) with a suitable reagent, such as N-bromosuccinimide in a chlorinated solvent at about room temperature, can give compounds of formula (22). The compounds of formula (23) can then be generated from compounds of formula (22) under suitable conditions. Such conditions may involve the treatment of compounds of formula (22) with a base such as 1,8-diazobicyclo [5.4.0] undec-7-ene in a suitable solvent such as N, N-dimethylformamide at about 140 ° C. . The treatment of compounds of formula (23) under standard hydrogenation conditions, for example, hydrogen gas and palladium on charcoal in ethanol, gives compounds of the general formula (24), when the protecting group is benzyl. The compounds of formula (14) can then be obtained by treating compounds of formula (24) under acidic conditions. The conversion of compounds of formula (14) into compounds of formula I may involve the need to use protecting groups that will be obvious to those skilled in the art. Some examples of such compounds of formula I are illustrated in Scheme 3. Conversion of compounds of formula (15) into compounds of formula I may involve reduction of the ketonic moiety under standard conditions, eg, sodium borohydride in ethanol. Further derivatization may occur, for example, using the chemistry described elsewhere herein, to give compounds of formula I where Y 'may be alkyl, acyl or a carbonylamino. In examples where protecting groups have been used, adequate deprotection will be required to give compounds of formula I.

Alternatively, the compounds of formula (15) can be manipulated to give compounds of formula I in which R1 is substituted with an amide or sulfonamide. The treatment of compounds of formula (15) with benzylamine under reductive amination conditions, for example, one equivalent of sodium triacetoxyborohydride in a suitable solvent (dichloroethane), followed by hydrogenolysis under standard conditions, for example, palladium on carbon, hydrogen gas, ethanol, provides compounds of formula (25). The synthesis of compounds of formula I can be obtained using conventional methods. For example, the compounds of formula (25) can be reacted with sulfonyl chlorides and acid chlorides in a chlorinated solvent in the presence of a base. { for example, triethylamine) at around room temperature. Deprotection using suitable reaction conditions provides compounds of formula I wherein Y is a sulfonamide or amide group. Referring to Scheme 4, the compounds of formula (26) can be synthesized using standard methods. For example, the compounds of formula (6) or (8) can be homologated using a Wittig reaction, and further manipulated as described above, to give compounds of formula I. The compounds of formula (26) or (16) of Scheme 2 may also undergo dihydroxylation under standard conditions, for example, catalytic osmium tetroxide and N-methylmorpholine in an ethereal solvent, and after appropriate deprotection, give compounds of formula I in which R 1 is substituted with - (OH ) (CH2OH). Referring to Scheme 5, the compounds of formula (29) can be obtained by reacting compounds (6) or (8) as described above in Scheme 3. Derivatives of the compounds of formulas (29) and ( 25) by treatment with an alkylating agent, eg, an alkyl iodide in a chlorinated solvent in the presence of triethylamine at about room temperature, to give the compound (30) prior to sulfonation or bond formation. amide and deprotection, to give compounds of formula I wherein Y is - (R5) S02R4, or equivalent amide, wherein R5 is not hydrogen. Referring to Scheme 6, the compounds of formula (6), (8) or (9), (14) or (15) can be treated with a suitable organometallic reagent, such as a Grignard reagent, in an ethereal solvent a a temperature between -78 ° C and 0 ° C, followed by deprotection, to give compounds of formula I in which R 1 is substituted with (R 2) OR 2. Referring to Scheme 7, the compounds of formula (31) can be formed under conditions well known to those skilled in the art. The treatment of the compounds (6) or (8) with an amine, such as piperidine, in a suitable solvent. { for example, dichloroethane) and a reducing agent such as sodium triacetoxyborohydride, followed by deprotection, will give compounds of formula I in which R1 is substituted with a nitrogen-containing heterocycle. Referring to Scheme 8, the compounds of general formula (33) can be obtained using conventional methods. For example, the reaction of compounds of formula (2) with n-butyl lithium, in the presence of N, N, N ', N' -tetrametylethylendiamine in a suitable solvent, such as tetrahydrofuran, followed by quenching with ketone. (32) (commercially available from Aldrich), and hydrolysis with aqueous acid, can give compounds of formula (33). The manipulation of the functional groups, as outlined in Schemes 1-7 and Scheme 8, then allows the synthesis of compounds of formula I. Referring to Scheme 9, derivatives of the compounds of formula (15) can also be obtained, ( 6) u (8) to give compounds of formula (34) using the Wittig or Wadworths-Emmons chemistry, followed by adequate deprotection. The compounds of formula (34) can be reduced using standard hydrogenation as described above, to give compounds wherein Y is OHhis.

, O-alkyl, or an aminoalkyl. The standard Wadworths-Emmons chemistry can also give compounds of formula (35). The reduction under suitable conditions will give compounds of formula (36), from which derivatives can additionally be obtained using standard chemistry previously described herein, to give compounds wherein NY'Y "is an amide, sulfonamide or aminoalkyl. Scheme 10, compounds of formula 10 can be converted to compounds of formula (37) using standard alkylation procedures, For example, compound (10) can be treated with a suitable base such as lithium diisopropylamide 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 skilled in the art, and may include chlorine, bromine, or iodoalkyl compounds; epoxies; aldehydes; aziridines; esters or., ß-unsaturates, ketones or amides, - acyl chlorides; electrophilic oxygen sources such as Mo (CO) 5 • pyridine (Crimmons, M. T. Y. col., 1992, J. Am. Chem. Soc., 114: 5445); or electrophilic nitrogen sources such as 2,4,6-triisopropylbenzenesulfonyl 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 skilled in the art. The compounds of formula (37) can be further manipulated using a methodology similar to that described above. For example, the alkylation of compounds of formula (37) under conditions of kinetic deprotonation (see, for example, Kopka, I. and Rathke, M.W., 1981, J.

Org. Chem. 46: 3771), followed by alkylation as previously described, would give compounds of formula (38).

Alternatively, alkylation of compounds of formula (37) under conditions of thermodynamic deprotonation (Kopka and Rathke, 1981, supra), followed by alkylation as previously described, would give compounds of formula (45). Additional alkylation, or manipulation of functional groups, known to those skilled in the art, as described elsewhere herein, followed by removal of the carbonyl protecting group under standard conditions, eg, aqueous hydrochloric acid at about 0 ° C to 50 ° C, it would give compounds of formulas (40), (46) and (49). The compounds of formula (37) can also be protected with a suitable protecting group, eg, ethylenedithiocetal, and after removal of the cephalic protecting group under standard reaction conditions, eg, aqueous hydrochloric acid at about 0. ° C at 50 ° C, the subsequent functionalization of the cycloalkyl ring would be possible using the methodology described above to give compounds of formula (44). Referring to Scheme 11, compounds of formula (50) can be formed from compounds of formula (10) using known methodologies (see, for example, Adam, W. et al., 1989, Tetrahedron Let t 30: 6497 ) (Ts = tosyl). Standard manipulation of functional groups gives compounds of formula (55) and (57). The cleavage of the oxirane ring by an amine gives compounds of formula (51). Alternatively, acid hydrolysis gives compounds of formula (52). The conversion of the corresponding alcohol to a leaving group, such as para-toluenesulfonyl, would allow nucleophilic substitution with various nucleophiles under standard, well-known conditions. Such nucleophiles can include amines, thiolates, alkoxides, and carbon-based nucleophiles such as cyanide, which are commercially available or are prepared by standard procedures well known to those skilled in the art. The compounds of formula (40), (44) and (49) can be prepared using the methods described above, or other methods known in the art, such as substituents on R1 as defined above. Referring to Schemes 10 and 11, the ketones of formulas (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 can be converted to compounds of formula I as described in Schemes 2 and 3. Referring to Scheme 12, the compounds of formula I can also be prepared using the methodology described above. The compounds of formula (58) can be converted to compounds of formula I using the chemistry as described in Schemes 1-11 above. It will be appreciated by those skilled in the art that in the methods described above, the functional groups of the intermediates may need to be protected by protecting groups. The use of protecting groups is well known in the art, and is fully described, inter alia, in: Protecting Groups in Orqanic Chemistry, J. W. F. McOmie, (ed.), 1973, Plenum Press; and in.- Protectinq Groups in Orqanic Svnthesis, 2nd edition, T. W. Greene and P. G. M. Wutz, 1991, Wiley-Interscience. The compounds of formula I which are basic in nature are capable of forming a wide variety of different salts with various organic and inorganic 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 into the base compound. free by treatment with an alkaline reagent, and subsequently converting the latter free base to a pharmaceutically acceptable acid addition salt. The addition salts of. acids 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.

With careful evaporation of the solvent, the desired solid salt is easily obtained. Those compounds of formula I which 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 which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Non-toxic bases include - those obtained from pharmaceutically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily 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 alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness, as described above. In any case, stoichiometric amounts of the reactants are preferably employed, in order to ensure the completion of the reaction and maximum yields of the desired final products. The compounds of formula I and their pharmaceutically acceptable salts (hereinafter "the active compounds used in this invention") are useful in the treatment of human pigmentation disorders, including solar and simple lentigines (including age / liver spots) , melasma / chloasma and post-inflammatory inflammation. Such compounds reduce the levels of melanin in the skin by inhibiting the production of melanin, whether the latter is produced constitutively or in response to UV radiation (such as sun exposure). Thus, the active compounds used in this invention can be used to reduce the melanin content of the skin in non-pathological states to induce a lighter skin tone, as desired by the user, or to prevent the accumulation of melanin in the skin. skin that has been exposed to UV radiation. They can also be used in combination with skin exfoliating agents (including glycolic acid or trichloroacetic acid facial exfoliants), to lighten skin tone and prevent repigmentation. The appropriate dose regimen, the amount of each dose administered, and the specific intervals between doses of the active compound will depend on the particular active compound employed, the condition of the patient treated, and the nature and severity of the disorder or condition being treated. Preferably, the active compound is administered in an amount and at a range that results in the desired treatment or improvement of the disorder or condition being treated. An active compound used in the present invention can also be used in combination with sunscreens (UVA or UVB blockers) to prevent repigmentation, protect against sun induced or UV induced skin darkening, or to increase its ability to reduce the melanin of the skin and its decolorizing action of the skin. An active compound used in the present invention in combination with retinoic acid, or its derivatives, or any of the compounds that interact with retinoic acid receptors and accelerate or increase the ability of the invention to reduce skin melanin may also be used. and the decolorizing action on the skin, or increase the ability of the invention to prevent the accumulation of melanin in the skin. An active compound used in the present invention in combination with 4-hydroxyanisole can also be used. The active compounds used in the present invention are also used in combination with ascorbic acid, its derivatives and products based on ascorbic acid (such as magnesium ascorbate) or other products, with an antioxidant mechanism (such as resveratrol) that accelerates or increases the ability to reduce the melanin of the skin and its decolorizing action on the skin . This invention relates both to methods of clearance or reduction of skin pigmentation, wherein the compound of formula I, or the 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 to methods in which they are administered separately as part of an appropriate dose regimen designed to obtain the benefits of combination therapy. The appropriate dose regimen, the amount of each dose administered, and the specific intervals between doses of each active agent will depend on the specific combination of the active agents employed, the condition of the patient treated, and the nature and severity of the disorder or condition treated. . Such additional active ingredients will generally be administered in amounts less than or equal to those for which they are effective as unique topical therapeutic agents. Doses approved by the FDA for such active agents, which 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 carrier or diluent. Such compositions are generally formulated in a conventional manner using solid or liquid carriers or diluents as appropriate for topical administration, in the form of solutions, gels, creams, jellies, pastes, lotions, ointments, ointments, aerosols and the like. Examples of vehicles for the application of active compounds of this invention include an aqueous or water-alcohol solution, an oil-in-water or water-in-oil emulsion, 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, from which the vesicles are made, can be of ionic or non-ionic type, or a mixture thereof. As used herein, a "skin lightening or pigment reducing amount of a compound of formula I", and the like, means an amount or concentration of the compound capable of lightening the skin or reducing pigmentation detectably in humans, as determined by any standard test. 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, an "effective tyrosinase inhibiting 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 improving, reducing, eliminate, slow down, or detectably prevent the progression of any symptom or condition associated with or caused by such a disorder or condition, in a human being, as determined by any standard assay. In the depigmenting 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 may optionally also contain a wetting agent, a surfactant, a keratolytic agent, an anti-inflammatory agent, a complexing agent, an antioxidant, a preservative, a fragrance or a sunscreen. The ability of the compounds of formula I to inhibit tyrosinase can be determined using any of the following methods. 1. Tyrosinase assay (DOPA oxidase) using cell lysate: Human melanoma cell line, SKMEL 188 (licensed from Memorial Sloan-Kettering) is used in the cell lysate assay and in the evaluation. In the assay, the compounds and L-dihydroxyphenylalanine (L-DOPA) (100 μg / ml) are incubated with the cell lysates containing human tyrosinase, for 8 h, before the plates are read at 405 nm. The potency of the compounds in the DOPA oxidase assay correlates very well with that of the tyrosine hydroxylase assay, using 3H-tyrosine as the substrate. Most of the compounds of formula I that were tested in this assay exhibited an IC50 of less than 10 μM. For example, the compound of Example 23, ie, (±) -3- (2,4-dihydroxyphenyl) cyclopentanone oxime, had an IC 50 in this assay of about 2 μm. 2. Melanin assay in human primary melanocytes: The compounds are incubated with human primary melanocytes in the presence of a-melanocyte-stimulating hormone (a-MSH) for 2-3 days. The cells are then lysed with sodium hydroxide and sodium dodecylsulfate (SDS), and the melanin signals are read at 405 nm. Alternatively, I4C-DOPA is added to the cells, in combination with tyrosinase inhibitors, and the acid-insoluble 14C-melanin is quantified by a scintillation counter. The IC50 reflects the inhibitory potency of the compounds in the new synthesis of melanin that was stimulated by a-MSH. 3. Tyrosine kinase (TK) assay: TK assays can be performed using purified tyrosine kinase domains of c-met, erb-B2, or IGF-r. A specific antibody against phosphorylated tyrosine is used in the assay. Colorimetric signals are generated by horseradish peroxidase, which is conjugated with the antibody. . Equivalent model of human skin: A mixture of human melanocytes and keratinocytes is grown in an air-liquid interface. This tissue culture forms a three-dimensional structure that histologically and microscopically resembles the epidermis of human skin. The test compounds are added on top of the cells to mimic the topical application of the drug. After incubation with the compounds (10 μM) for 3 days, the cells were thoroughly washed and used for the DOPA oxidase assay. 5. IL-1 assay (interleukin-1 assay): An ELISA assay (R & D system) can be used to evaluate the effect of the compounds on IL-1 secretion in a euvalent model of human skin. IL-la is a pro-inflammatory cytokine, and plays a role in skin inflammation induced by UV rays. 6 • In vivo study: Black or dark brown guinea pigs with homogenous 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 control vehicle are applied to the animals twice a day, 5 days per week for 4-8 weeks. Using this assay, depigmentation can be determined by subtracting the light reflectance from the untreated skin, from the reflectance of the light from the 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. The melting points are uncorrected. The proton nuclear magnetic resonance spectra (400 MHz NMR?) Were measured for solutions in dß-DMSO, CDC13, or d4-MeOH, and the positions of the peaks are expressed in parts per million (ppm) downfield of tetra-ethylsilane (TMS). The contours of the peaks are denoted as follows: s, singlet, -d, doublet; t, triplet; q, quadruple; m, multiplet; b, width. The following examples are illustrative only, and are not intended to limit the scope of the present invention. EXAMPLES Intermediate 1 l-Bromo-2,4-bis (methoxymethoxy) benzene A 250 ml round bottom flask, oven dried, equipped with a magnetic stirrer, was charged under an argon atmosphere with 4-bromorresorcinol (9.45 g. g, 50 mmol) and CH2C12 (50 ml). The stirred suspension was cooled to 0 ° C, and diisopropylamine (19.1 ml, 110 mmol) was added in one portion via a syringe. The stirring of the red solution was continued for an additional ten minutes before methylchloromethyl ether (10.7 ml, 120 mmol) was added dropwise via a syringe, ensuring that 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 hour. The mixture was poured into a separatory funnel, and the phases separated. The aqueous phase was then extracted with CH2C12 (3x30 ml), and the combined organics were washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification was achieved by flash column chromatography, (SiO2, ethyl acetate / petroleum ether, 1: 1, v / v), affording the title product (10.7 g, 77%) as a pale yellow oil. dH (CDC13) 7.42 (1H, d), 6.88 (lH, d), 6.64 (1H, dd), 5.24 (2H, s), 5.15 (2H, s), 3 , 53 (3H, s), 3.48 (3H, s).

Intermediate 2 8- [2,4-Bis (methoxymethoxy) phenyl] -1,4-dioxaespiro [4.5] decan-8-ol A round bottom flask equipped with a magnetic stirrer was charged in an argon atmosphere with l- bromo-2,4-bis (methoxymethoxy) benzene (2.00 g, 7.2 mmol) and THF (50 ml). N, N, N ', N'-tetramethylethylenediamine (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 h at -78 ° C, and 1,4-cyclohexanedione monoethylene ketal (1.35 g, 8.7 mmol) was added slowly as a solution in THF (25 ml), via a syringe The resulting solution was stirred at -78 ° C for 1 h, and then allowed to warm to room temperature overnight. Hydrochloric acid (20 ml, 2M) was added, and the reaction mixture was stirred vigorously for 15 min. Ethyl acetate (100 ml) was added, and the mixture was poured into a separatory 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 sulfate, filtered and concentrated to give an orange oil which was purified by flash column chromatography (SiO2, ethyl acetate / petroleum ether, 45: 55, v / v). The title product (1.42 g, 56%) was isolated as a colorless oil, m / z (ES +) 337 (M-H20 + H +); dH (CDCl 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 (1H, dd), 6.82 (lH, d), O 7.20 (lH, d). Intermediate 3 8- [2,4-Bis (methoxymethoxy) phenyl] -1,4-dioxaespiro [4.5] dec-7-ene 8- [2, -bis (methoxymethoxy) phenyl] -1,4-dioxaes- was placed 0 pyro [4.5] decan-8-ol (1.40 g, 3.95 mmol) in a 50 ml round bottom flask equipped with a magnetic stirrer and a Dean-Stark apparatus. Toluene (30 ml) was added, followed by camphorsulfonic acid (10 g). The stirred solution was then heated to reflux for 1 h, cooled and saturated aqueous sodium bicarbonate solution (10 ml) was added. The mixture was poured into a separatory 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 sulfate, filtered and concentrated in vacuo to give an orange oil which was purified by flash column chromatography (SiO2, ethyl acetate / petroleum ether, 45:55, v / v), giving the title product (0.94 g) as a colorless oil. dH (CDCl3) 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), 5.58-563 (1H, m), 6.64 (1H, dd), 6.78 (1H, d), 7 , 08 (1H, d). Intermediate 4 8- [2,4-Bis (methoxymethoxy) phenyl] -1,4-dioxaespiro [4.5] deca-no ~~ 8- [2, -bis (methoxymethoxy) phenyl] -1,4-dioxaespi- ro [4.5] dec-7-ene (0.950 g, 2.83 mmol) and palladium (200 mg, 10% on carbon) in a hydrogen atmosphere for 15 h. The mixture was then filtered through a plug of Celite, washing with ethyl acetate. The filtrate was then evaporated to dryness, giving the title product (0.955 g, -100%) as a colorless oil. dH (CDCl 3) 1, 67-1.87 (8H, m), 2.90-2.99 (1H, m), 3.46 (3H, s), 3.48 (3H, s), 3, 97 (4H, s), 5.12 (2H, s), 5.18 (2H, s), 6.65 (1H, dd), 6.78 (2H, d), 7.12 (1H, d) ). Intermediate 5 4- [2, 4- (methoxymethoxy) phenyl] cyclohexanone A round bottom flask equipped with a magnetic stirrer was charged with 8- [2, -Jbis (methoxymethoxy) phenyl] -1,4-dioxaespiro [4.5] decane (3.20 g, 9.47 mmol) and methanol (50 ml). Aqueous hydrochloric acid (50 ml, 1.00M) was added over a period of 20 min to the stirred solution at room temperature, and the reaction mixture was stirred for 1.5 h. Solid sodium bicarbonate was added until the reaction mixture was neutralized, 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 (3 × 20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash column chromatography (SiO2, ethyl acetate / petroleum ether, 1: 4, v / v) to give the title compound (2.20 g, 60%) as a white powder. dH (CDCl3) 1.85-1.96 (2H, m), 2.14-2.22 (2H-m), 2.46-2.59 (4H, m), 3.39 (1H, tt) ), 3.49 (3H, s), 3.52 (3H, s), 5.16 (2H, s), 5.23 (2H, s), 6.67-6.71 (1H, m) 6.85 (1H, m), 7.08 (1H, d). Intermediate 6 3- [2, 4-Jis (methoxy-methoxy) phenyl] -2-cyclohexen-lo? .a Aqueous sodium carbonate (2 ml of a 6M solution) and 2,4-bis (methoxymethoxy) phenylboronic acid ( 120 mg) in ethanol (2 ml) was added to a solution of palladium tetrakis (triphenylphosphine) (57 mg) and 3-bromo-2-cyclohexen-1-one (87 mg) in dimethoxyethane (3 ml), and the mixture was heated at reflux. After 6 h, 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 give an oil which was purified by flash column chromatography (SiO2, ethyl acetate / petroleum ether, 1: 3, v / v), yielding the compound of the title as an oil (120 mg, 83%). dH (CDCl 3) 2,10 (2H, quintuplet), 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 (1H, m), 6, 71 (1H, dd), 6.85 (1H, d), 7.16 (1H, d). Intermediate 7 (+) - 3 - [2,4-Bis (methoxymethoxy) phenyl] cyclohexanone A suspension of 3- [2,4-Jbis (methoxymethoxy) phenyl] -2-cyclohexen-1-one (300 mg) was stirred. and palladium catalyst (50 mg, 10% palladium on carbon) in ethanol, at room temperature in 1 atmosphere of hydrogen. After 16 h, the mixture was filtered through celite, and the filtrate was evaporated in vacuo. The product was dissolved in dichloromethane (15 ml). Celite and pyridinium chlorpchromate (430 mg) were added, and the mixture was stirred at room temperature. After 3 h, 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 (SiO2). , petroleum ether / ethyl acetate, 4: 1, v / v), yielding the title compound as an oil (200 mg, 70%). dH (CDC13) 1.7-1.9 (2H, overlapping m), 2.05 (1H, ra), 2.15 (1H, m), 2.35-2.60 (4H, overlapping m), 3.37 (1H, m), 3.490 (3H, s), 3.492 (3H, s), 5.15 (2H-, s), 5.20 (2H, s), 6.70 (1H, dd) , 6.82 (1H, d), 7.09 (1H, d). Intermediate 8 3- (2,4-Dimethoxymethoxyphenyl) -2-cyclohexen-1-one oxime It was heated to reflux 3- [2,4-bis (methoxymethoxy) phenyl] -2-cyclohexen-1-one (200 mg) hydroxylamine hydrochloride (72 mg) and triethylamine (0.14 ml) in ethanol (10 ml). After 3 h, the cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated in vacuo yielding the title compound as an oil (206 mg, 99%). m / z (ES +) 308 (M + H) Intermediate 9 (+) -l-. { 3- [2,4-Bis (methoxymethoxyphenyl) cyclohexyl) piperazine 3- [2,4-bis (methoxymethoxy) phenyl] cyclohexanone (80 mg) and piperazine (24 mg) were dissolved in dichloroethane (5 mg). ml), and it was stirred at room temperature for 1 h in argon, tetramethylammonium hydrochloride tetramethyl ammonium (79 mg) was added, and stirring was continued under argon.After 16 h, additional portions of piperazine (24 mg) and triacetoxyborohydride were added. of tetramethylammonium (79 mg), and stirring was continued.After an additional 6 h, glacial acetic acid was added dropwise until a solution was obtained, and stirring was continued at room temperature. The reaction mixture was partitioned between sodium hydrogencarbonate (20 ml of a saturated solution) and ethyl acetate.The aqueous layer was extracted with ethyl acetate (3 × 20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated to vacuum The residue bru was purified by flash column chromatography (SiO2, dichloromethane / methanol, 9: 1, v / v), yielding the title compound as an off-white solid (52 mg, 53%) and a mixture of diastereoisomers; m / z (ES +) 365 (M + H) Intermediate 10 (+) - 3 - [2,4-Bis (methoxymethoxyphenyl) cyclohexylane Nickel chloride hexahydrate (77 mg) and sodium borohydride (24 mg) were added to a stirred solution of oxime ( +) -3- [2,4-bis (methoxymethoxy) phenyl] cyclohexanone (50 mg) in methanol (2 ml) After 0.5 h, water is added until the effervescence ceases, the reaction mixture is filtered and the residue is thoroughly washed with methanol.The combined filtrate and the washings are evaporated in vacuo, and the crude residue is purified by flash column chromatography (SiO2, dichloromethane / methanol, 9: 1, v / v), yielding the title compound as a colorless oil (31 mg, 65%) and a mixture of diastereoisomers: m / z (ES +) 295 (M + H) X Intermediate 11 (+) -N- { 3- [2, 4-Bis (methoxymethoxy) phenyl] cyclohexyl) methanesulfonamide. Triethylamine (0.014 ml) and methanesulfonyl chloride (8 μl) were added to a solution of (±) -3- [2,4-Jis (methoxymethoxyphenyl) cyclohexylamine. (27 mg) in diclo romethane (1 ml), and the mixture was stirred under argon at room temperature. After 1 h, the mixture was partitioned between ethyl acetate (20 ml) and sodium hydrogen carbonate (20 ml of an 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, yielding the title compound as an oil and a mixture of diastereomers; m / z (ES +) 374 (M + H) Intermediate 12 (+) -2, 4-Bis (methoxymethoxy) -1- (3-methylenecyclohexyl) benzene Potassium tert-butoxide (50 mg) was added to a suspension of methyltriphenylphosphonium bromide in tetrahydrofuran (4 ml) at 0 ° C. After 0.5 h, a solution of (+) - 3 - [2, -bis (methoxymethoxyphenyl) cyclohexane (100 mg) in tetrahydrofuran (1 ml) was added, and the mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was partitioned between ammonium chloride (30 ml of a saturated aqueous solution) and ethyl acetate.The aqueous layer was extracted with additional ethyl acetate (2x30 ml), and the combined organic extracts were evaporated. washed with brine (30 ml), dried over magnesium sulfate, and evaporated in vacuo.The crude residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 4: 1, v / v), yielding the title compound as a pale yellow oil (80 mg, 81%) .H (CDC13) 1.50 (2H, m), 1.90 (2H, m), 2.05 (1H, m), 2, 16 (1H, m), 2.35 (1H, m), 2.44 (1H, m), 2.97 (1H, m), 3.44 (3H, s), 3.48 (3H, s) ), 4.64 (1H, s), 4.69 (1H, s), 5.13 (2H, s), 5, 17 (2H, s), 6, 68 (1H, m), 6, 77 (1H, m), 7.12 (1H, d). Intermediate 13 (+) -. { 3- [2,4-Bis (methoxymethoxy) phenyl] cyclohexyl methanol 9-borabicyclononane (2.7 ml of a 0.5M solution in tetrahydrofuran) was added to a stirred solution of (+) -2, 4-Jbis ( methoxymethoxy) -1- (3-methylenecyclohexyl) benzene (80 mg) in tetrahydrofuran (2 ml) at 0 ° C in argon. After 1 h at 0 ° C, the reaction mixture was allowed to warm to room temperature, and stirring was continued. After 2 h, the reaction mixture was cooled to 0 ° C, and water (0.1 ml) was added. After the effervescence 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 room temperature. After an additional 16 h, the reaction mixture was cooled to 0 ° C. 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 (S? 02, ethyl acetate / petrol, 1: 1, v / v), yielding the title compound as a pale brown oil (46 mg, 54%); m / z (ES +) 311 (M + H) +.

Intermediate 14 (+) - 3 - [2, 4-Bis (methoxymethoxy) phenyl] cyclohexanone oxime Hydroxylamine hydrochloride (71 mg), triethylamine (0.17 ml) and (+) - 3 - [2, 4-bis (methoxymethoxy) -phenyl] cyclohexanone (200 mg), in ethanol (8 ml) were heated to reflux. . After 0.75 h, 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 (SiO2, ethyl acetate / petrol, 1: 1, v / v), yielding the title compound as a pale yellow oil (197 mg, 94%); m / z (ES +) 310 (M + H) +. Intermediate 15 (+) -N-. { 3 - [2,4-Bis (methoxymethoxy) phenyl] cyclohexyl) hydroxylamine Borane (0.412 ml of a 1M solution in tetrahydrofuran) was added to a stirred solution of (+) - 3 - [2, 4-Jis (methoxymethoxy) oxime. phenyl] cyclohexanone (85 mg) in tetrahydrofuran (2 ml) at 0 ° C under argon. After 2 h, acetic acid (1 ml) was added, and the mixture was allowed to warm to room temperature. After 16 h, sodium hydrogencarbonate (20 ml of a saturated aqueous solution) was added, the mixture was extracted with ethyl acetate (3 × 20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, dichloromethane / methanol, 9: 1, v / v), yielding two compounds as clear gums which were identified as diastereomers of the title compound; trans isomer (12 mg, 14%) m / z (ES +) 312 (M + H) X cis isomer (0.017 g, 20%) m / z (ES +) 312 (M + H) +. Intermediate 16 4- (2, 4-Bis { [Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanone 4- (2,4-dihydroxyphenyl) cyclohexanone (400 mg) was dissolved in dimethylformamide ( 3 ml) with stirring. Tert-butyldimethylsilyl chloride (704 mg), imidazole (660 mg) and 4-dimethylaminopyridine (3 mg) were added sequentially. After 4 h, the solvent was removed in vacuo, and the residue was 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 magnesium sulfate, and concentrated under reduced pressure to give a brown oil. Purification via flash column chromatography (Si02, eluting with ethyl acetate / petroleum ether, 1: 9, v / v), afforded the title compound as white flakes (750 mg, 89%). dH (CDC13) 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 (lH, tt), 6.32 (lH, d), 6.39 (1H, dd), 6.94 (1H, d). m / z (ES +) 435 (M + 1) + Intermediate 17 tert-Butyl [3-T [te-r-butyl (dimethyl) silyl] oxy) -4- (4-methylenecyclohexyl) phenoxy] dimethylsilane Tert-butoxide was added of potassium (103 mg), in one portion, to a stirred suspension of methyltrife-nilphosphonium bromide (329 mg) in anhydrous THF (10 ml) at 0 ° C. After stirring for 30 min, a solution of 4- (2, 4-is. {[[Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanone (200 mg) in THF (5 ml) was added. The reaction mixture was stirred for an additional 30 min, at 0 ° C, and saturated aqueous ammonium chloride solution (20 ml) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, and concentrated in vacuo. Purification via flash column chromatography (Si02, eluting with diethyl ether: petroleum ether, 1: 4, v / v), afforded the title compound as a colorless oil (135 mg, 68%). dH (CDC13) 0.19 (6H, s), 0.24 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.41 (2H, dq), 1 , 84-93 (2H, m), 2.16 (2H, dt), 2.33-2.42 (2H, m), 3.01 (1H, tt), 4.66 (2H, s) ), 6.29 (1H, dd), 6. 40 (1H, dd), 6.94 (1H, d). Intermediate 18 trans / cis- [4- (2, 4-Bis { [Tert-butyl (dimethyl) silyl] -oxy-phenyl) cyclohexyl] methanol Tert-butyl [3-. { [tert -butyl (dimethyl) silyl] -oxi} -4- (4-methylenecyclohexyl) phenoxy] dimethylsilane (135 mg) in anhydrous THF (5 ml) with stirring, and cooled to -78 ° C. 9-Borabicyclo [3.3.1] nonane (3.13 ml, 0.5M in THF) was added to the stirred solution, and the resulting reaction mixture was allowed to warm to room temperature for 3 h, 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 mixture was allowed to warm to room temperature, with stirring over the course of 1 h, cooled to 0 ° C, and saturated aqueous sodium metabisulfite solution (30 ml) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification via flash column chromatography (Si02, eluting with petroleum ether: diethyl ether, 3:17, v / v), gave the desired product as a yellow oil (73 mg, 52%). dH (CDC13) 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 (1H, m), 3.47 (1H, d), 3.70 (1H, d), 6.26 -6.29 (1H,), 6.37-6.40 (1H, m ), 6.93-6.97 (1H, m). Intermediate 19 trans / cis- [4- (2,4-Bis { [Tert-butyl (dimethyl) silyl] -oxy} phenyl) -1-methylcyclohexanol 4- (2,4-Jis (tert-butyldimethylsilyloxy) was dissolved )) fe-nylcyclohexanone (50 mg) in anhydrous THF (10 ml), and cooled to 0 ° C. Methylmagne-sium chloride (59 ml, 22% w / v in THF) was added dropwise, and the reaction mixture was allowed to warm to room temperature, with stirring, for 2 days. The reaction mixture was partitioned between aqueous HCl (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 sulfate. Removal of the solvent under reduced pressure gave an oil which was purified via flash column chromatography (SiO2, eluting with ethyl acetate: petroleum ether, 1: 4 v / v) to give the title compound as a white solid and a mixture of diastereoisomers (29 mg, 56%). dH (CDC13) 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), 1.46-1.82 (8H, m), 2.73-2.91 (1H, m), 6.29-6.31 (1H, m) , 6.39, 6.42 (1H, m), 6.80 (0.5H, d), 7.20 (0.5H, d). Intermediate 20 trans / cis- [4- (2, 4-Bis { [Tert-butyl (dimethyl) silyl] -oxy} phenyl) cydohexylamine The oxime of 4- [2,4-Jbis (erc) was dissolved -butyldimethyl-silyloxy) phenyl] cyclohexanone (120 mg) in anhydrous methanol (10 ml). The solution was cooled to -40 ° C, and nickel chloride hexahydrate (133 mg) was added. Stirring was continued for 10 min before sodium borohydride (42 mg) was added in one portion. The reaction mixture was stirred at -40 ° C for 20 min, and water was added (0.5 ml). The reaction mixture was allowed to warm to room temperature with stirring. Silica gel was added, and the solvent was removed in vacuo. Purification via flash column chromatography (Si02, eluting with CH2Cl2 .-- MeOH: NH4OH, 44: 50: 6, v / v), gave the desired product as a pale brown oil (83 mg, 71%) and a mixture of diaste * reisomers. dH (CD3OD) 0.22 (6H, s), 0.27 (6H, s), 1.02 (9H, s), 1.08 (9H, S), 1.24-1.40 (1H, m), 1.42-1.57 (1H, m), 1.57-1.68 (1H, m), 1.71-1.90 (4H, m), 1.99-2.07 ( 1H, m), 2.84-2.98 (1H, m), 4.28-4.40 (1H, m), 6.34 (1H, d), 6.44 (1H, t), 7 , 04 (0.5H, d), 7.16 (0.5H, d); m / z (ES +) 436 (M + 1) + Intermediate 21 trans / cis-N- [4- (2, 4-Bis. { [tert -butyl (dimethyl) silyl] -oxi} phenyl) cyclohexyl] acetamide Trans / cis-A - (2,4-Jbis { [tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexylamine (27 mg) was dissolved in pyridine (0.5 ml) . Acetyl chloride (6 μl) and 4-dimethylaminopyridine (2 mg) were added sequentially, and the reaction mixture was stirred for 24 h. The solvent was removed in vacuo, and the residue was 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 sulfate, and concentrated to give a brown oil. Purification via flash column chromatography (SiO2, 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 diastereomers . dH (CDC13) 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 (1H, m), 3.76 - 3 , 87 (1H, m), 5.34 - 5.39 (0.5H, d), 5.72 - 5.77 (0.5H, d), 6.26 - 6.29 (1H, m) , 6.38-6.41 (1H,), 6.93 (0.5H, d), 6.95 (0.5H, d). m / z (ES +) 478 (M + 1) X Intermediate 22 3- [2,4-Bis (methoxymethoxy) phenyl] -2-cyclopenten-l-one 1,3-Bis (methoxymethoxy) -4-bromobenzene was dissolved (1.0 g) in THF (20 ml), and cooled to -78 ° C under argon. N, N, N ', N'-tetramethylethylenediamine was added, followed by the dropwise addition of n-BuLi (3.4 ml of a 2.2M solution in hexanes) over 10 min. After stirring at -78 ° C for 1 h, 3-methoxy-2-cyclopenten-1-one (605 mg) in THF (5 ml) was slowly added. The reaction mixture was stirred at -78 ° C for 1 h before heating to 0 ° C. 1M HCl (20 ml) was added and, after 10 min, the mixture was extracted with ethyl acetate (2 × 50 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 (SiO2, ethyl acetate / petrol, 1: 1, v / v) yielding the title compound as a yellow oil (128 mg, 13%); m / z (ES +) 279 (M + 1) X Intermediate 23 (+) - 3 - [2, 4-Bis (methoxymethoxy) phenyl] cyclopentanone 3- [2,4-bis (methoxymethoxy) phenyl] -2 was stirred -cyclopenten-1-one (50 mg) and palladium (10 mg, 10% on carbon) in a hydrogen atmosphere for 15 h. The mixture was then filtered through a plug of Celite, washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (Si02, ethyl acetate / petrol, 1: 1, v / v), yielding the title compound as a colorless oil (8 mg, 16%); m / z (ES +) 583 (2M + Na) Intermediate 24 3- (Benzyloxy) -2-cyclohexen-1-one Was added to a round bottom flask, equipped with a magnetic stirrer and a Dean-Stark apparatus, 1, 3-cyclohexanedione (60.0 g, 535 mmole), toluene (450 ml), p-toluenesulfonic acid monohydrate (1.35 g, 5.20 mmole) and benzyl alcohol (52.6 g, 487 mmole). The resulting solution was heated to reflux temperature for 12 h. 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 to give a brown oil (94.9 g) which crystallized on standing for 17 h. The crude crystalline material was suspended in isopropyl ether (20 ml). The mixture was filtered, and the crystalline material was washed with ice-cooled isopropyl ether (3x30 ml), then with cold petroleum ether (2x20 ml). The resulting peach-colored crystalline solid was dried overnight under reduced pressure, yielding the desired product (74.4 g, 76%). m / z (ES +) 203 (M + H +). Intermediate 25 (+) - 3 - (Benzyloxy) -6- (8-hydroxy-1,4-dioxaespiro [4.5] dec-8-yl) -2-cyclohexen-1-one was added to a round bottom flask, equipped with a magnetic stirrer, anhydrous tetrahydrofuran (600 ml) and diisspropylamine (38.1 ml, 272 mmol). The stirred solution was cooled to -78 ° C, and n-butyllithium (113.4 ml, 272 mmol, 2.4M in cyclohexanes) was added dropwise via a syringe in 20 ml portions. The resulting yellow solution was stirred for 35 min at -78 ° C, and then 3- (benzyloxy) -2-cyclohexen-1-one (50.0 g, 248 mmol) was added as an anhydrous tetrahydrofuran solution (100 ml. ). The solution was stirred for 1 h before the addition of the monoethylenic ketal of cyclohexane-1,4-dione (38.7 g, 248 mmol) as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 2 h at -78 ° C, then allowed to warm slowly to room temperature over 1 h. Saturated aqueous ammonium chloride (80 ml) was added, followed by dichloromethane (700 ml), and the mixture was stirred until there were no solids. The phases were separated, and the aqueous phase was extracted with dichloromethane (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, and then concentrated in vacuo. Trituration of the resulting solid with methanol gave the title compound (78.4 g, 88%). m / z (ES +) 359 (M + H +). Intermediate 26 (+) -1- (Benzyloxy) -6-bromo-3- (1,4-dioxaespiro [4.5] dec-8-yl) -2-oxabicyclo [2.2.2] octan-5-one An round bottom flask, equipped with a magnetic stirrer, with (+) - 3 - (benzyloxy) -6- (8-hydroxy-l, 4-dioxaespiro [4.5] dec-8-yl) -2-cyclohexen-1- ona (78.4 g, 219 mmol) and dichloromethane (600 ml). N-bromosucci nimide (40.9 g, 230 mmol) was added in one portion to the stirred solution, followed by aqueous hydrobromic acid (3 drops, 48% solution) when there was no more solid. The resulting solution was stirred at room temperature for 2 h, then poured into a separatory funnel containing solution of aqueous sodium metabisulfite (150 ral) and dichloromethane (200 ml), then the funnel was vigorously stirred. separated, and the organic layer was washed with brine (200 ml), dried over magnesium sulfate, it was filtered and then concentrated in vacuo, giving a solid. Trituration with methanol (500 ml) gave 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-dioxaespiro [4.5] dec-7-en-8-yl) phenol A round bottom flask was charged with (±) -1- (benzyloxy) -6-bromine -3- (1, 4-dioxaespiro [4.5] dec-8-yl) -2-oxabicyclo [2.2.2] octan-5-one (13.8 g, 31.6 mmol) and N, N- dimethyl-anhydrous formamide (140 ml). 1,8-diazabicyclo [5.4.0] undec-7-ene (9.92 ml, 66.3 mmol) was added in one portion to the stirred solution. The solution became dark brown immediately, and then heated at 140 ° C for 12 h with vigorous stirring. The reaction mixture was allowed to cool to room temperature and the best part 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 (200 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to an oily brown solid, which was adsorbed on silica gel. Purification via flash column chromatography (Si02, ethyl acetate / petroleum ether, 1: 1, v / v), yielded the desired product (7.1 g, 66%) as a white solid, m / z (ES + ) 339 (M + H +). Intermediate 28 4- (1, 4-Dioxaespiro [4.5] dec-8-yl) -1,3-benzenediol A round-bottomed flask, equipped with a magnetic stirrer, was charged with 5- (benzyloxy) -2- (1 , 4-dioxaespi-ro [4.5] dec-7-en-8-yl) phenol. { 6.90 g, 20.4 mmol), ethanol (300 ml) and palladium (2.00 g, 10% on carbon). The reaction vessel was then evacuated and placed in a hydrogen atmosphere. This procedure was repeated 15 times before stirring vigorously for 64 h in a hydrogen atmosphere. The reaction mixture was filtered through a plug of celite, washing with ethyl acetate. The filtrate was concentrated in vacuo to give 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-Jis. {[[Tert-butyl (dimethyl) silyl] -oxy) phenyl) cyclohexyl] amine A round-bottomed flask, equipped with an magnetic stirrer, with 4- (2, 4-bis {[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanone (3.20 g, 7.36 mmol). Anhydrous 1,2-dichloroethane (85 ml) was added, and benzylamine (0.97 ml, 8.83 mmol) was added to the stirred solution as a solution in 1,2-dichloroethane (20 ml). Activated powdered 4 A molecular sieves (5.80 g) were added, and the reaction mixture was stirred vigorously for 2.5 h. Tetramethylammonium triacetoxyborohydride was added (2.90 g, 11.0 mmol) in one portion, and the reaction mixture was stirred for 64 h at room temperature. Aqueous sodium hydroxide solution (30 ml, 0.4M) was added, and vigorous stirring was continued for 0.5 h. 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 (2 × 50 ml). The combined organic phases were washed with brine (100 ml), dried over magnesium sulfate, and concentrated in vacuo to give the crude product. Purification via flash column chromatography (Si02, ethyl acetate / petroleum ether, gradient elution using 1: 9, 1: 4, then 3: 7 v / v), afforded the title product (2.69 g, 70%) as a pale yellow oil. dH (CDC13) 0.01 (6H, s), 0.05 (6H, s), 0.77 (9H, s), 0.83 (9H, s), 1.31 (1H, b), 1 , 39 (4H, m), 1.51 (2H, m), 1.70 (2H, m), 2.69 (1H, m), 2.75 (1H, m), 6.10 (1H, d), 6.23 (1H, dd), 6.84 (1H, d), 7.15 (5H, m). Intermediate 30 N-Benzyl-N- [4- (2,4-bis. {[[Te-r-butyl (dimethyl) silyl] -oxy} phenyl) cyclohexylidene] mine A round bottom flask equipped with a magnetic stirrer, with 4- (2, 4-bis { [tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanone (817 mg, 1.88 mmol). Anhydrous dichloromethane (50 ml) was added, followed by benzylamine (0.82 ml, 7.52 mmol) and activated 4 A molecular sieves (10.0 g). The reaction mixture was stirred vigorously for 15 h, and then dichloromethane (50 ml) was added, and the reaction mixture was filtered through celite, washing with dichloromethane (50 ml). The filtrate was concentrated in vacuo to give the desired product (1.00 g, 86%) as a yellow oil. H (CDC13) 0.19 (6H, s), 0.26 (6H, s), 0.98 (9H, s), 1.03 (9H, s), 1.51 (1H, m),. 1.72 (1H, m), 2.03 (2H, m), 2.45 (1H, m), 2.60 (1H, m), 3.04 (1H, m), 3.22 (1H , m), 4.55 (1H, d), 4.60 (1H, d), 6.31 (1H, d), 6.41 (1H, dd), 6.93 (1H, d), 7 , 33 (5H, m). Intermediate 31 trans-N-Bene il-N- [4- (2,4-Sis { [Tert-butyl (dimethyl) silyl] -oxy} phenyl) cyclohexyl] amine was added to a round-bottomed flask , equipped with a magnetic stirrer, N-benzyl-N- [4- (2, 4-bis. {[[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexylidene] amine (4.00 g, , 63 mmol) and anhydrous tetrahydrofuran (480 ml), followed by anhydrous methanol (120 ml). Sodium borohydride (1.16 g, 30.5 mmol) was added to the solution, and the reaction mixture was stirred for 17 h. 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 min, the layers were separated, and the aqueous layer was 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 (SiO2, ethyl acetate / petroleum ether, gradient elution using 1: 9, 1: 4, then 3: 7 v / v), afforded the desired product as a cream solid (2). , 09 g, 54%). H (CDCl 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 (1H, m), 2.68 (1H, m), 6.12 (1H, d), 6.23 (1H , dd), 6.77 (1H, d), 7.17 (5H, m). Intermediate 32 trans-A - (2, 4-Bis { [Tert-butyl (dimethyl) silyl] oxy, phenyl) cyclohexylamine was added to a round bottom flask trans-N-benzyl-N- [4- (2 , A -bis { [Tert-Butyl (dimethyl) silyl] oxy-phenyl) cyclohexyllamine (500 g, 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 suspension in ethanol (5 ml). The reaction vessel was evacuated, then placed in hydrogen (10 cycles). The reaction mixture was stirred vigorously in a hydrogen atmosphere for 18 h, then filtered through a plug of celite, washing with methanol (100 ml). The solvent was removed in vacuo to give the desired product (402 mg, 97%) as a colorless oil. H (CDCl 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 (1H, d), 6.22 (1H, dd), 6, 78 (1H, d). Intermediate 33 cis-4- (2, 4-BÍJS. "[Fcerc-butyl (dimethyl) silyl] oxy} phenyl) cyclohexylamine was added to a round-bottomed flask, equipped with a magnetic stirrer, cy sN-benzyl- N- [4- (2, 4-bis. {[[Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] amine (700 mg, -1.33 mmoles). And ethanol (30 ml). To the stirred solution was added palladium (10% w / w on activated carbon, 283 mg, 0.27 mmol) as a suspension in ethanol (5 ml). The reaction vessel was evacuated, then placed in hydrogen (10 cycles). The reaction mixture was stirred vigorously in a hydrogen atmosphere for 18 h, then filtered through a plug of celite, washing with methanol (100 ml). The solvent was removed in vacuo to give the desired product (561 mg, 97%) as a colorless oil. dH (CDCI3) 0.01 (6H, s), 0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s), 1.21- 1.55 (10H, m), 2.64 (1H, m), 3.05 (1H, m), 6.11 (1H, d), 6.22 (1H, dd), 6 84 (1H, d). Intermediate 34 cis-N- [4- (2,4-Bis { [Tert-butyl (dimethyl) silyl] -oxy) phenyl) cyclohexyl] methanesulonamide A round bottom flask equipped with a magnetic stirrer was charged. with cis-4- (2, A -bis { [tert-butyl (dimethyl) silyl] oxyphhenyl) cyclohexylamine (47 mg, 0.108 mmol) and 1,2-dichloroethane (4 ml). Methanesulfonyl chloride (10 μL, 0.12 mmol), triethylamine (30 μL, 0.22 mmol) and 4-dimethylaminopyridine (catalytic amount) were added to the stirred solution. The solution was stirred for 17 h, 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 on silica gel and purified via flash column chromatography (Si02, ethyl acetate / petroleum ether, gradient elution using 1: 9, 1: 4, then 1: 3 v / v), giving the title compound (39 mg, 70%) that solidifies upon standing. dH (CDC13) 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 (1H, m), 2.99 (3H, s), 3.78 (1H, m), 4.83 (1H, d), 6.28 (1H, d), 6.42 (1H, dd), 6.97 (1H, d). Intermediate 35 trans-N- [4- (2,4-Bis { [Tert-butyl (dimethyl) silyl] -oxy) phenyl) cyclohexyl] methanesulfonamide It was added to a round-bottomed flask, equipped with a magnetic stirrer, trans -4- (2, 4-bis { [tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexylamine (248 mg, 0.57 mmol) and 1,2-dichloroethane (25 ml). Triethylamine (191 μL, 1.37 mmol) followed by methanesulfonyl chloride (53 μL, 0.68 mmol), and three crystals of 4-dimethylaminopyridine, were added to the stirred solution. The resulting solution was stirred at room temperature for 18 h, and then poured into a separatory funnel containing dichloromethane (100 ml) and water (20 ml). The layers were separated, and the aqueous phase was extracted with dichloromethane (1x50 ml). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (320 mg, 100%). dH (CDCl 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 (1H, m), 2.81 (3H, s), 3.19 (1H, m), 3.92 (1H, d), 6.13 (1H, d), 6.22 (1H, dd), 6, 66 (1H, d), Intermediate 36 4- (4-T [tert -Butyl (dimethyl) silyl] oxy} phenyl) cyclohexanone A 4- (4-hydroxy) phenylcyclohexanone was added to a round-bottomed flask equipped with a magnetic stirrer. (1.00 g, 5.26 mmol) (commercially available from Aldrich) and anhydrous N, N-dimethylfor amide (5 ml). Imidazole was added (0.90 g, 13.20 mmol), tert-butyldimethylsilyl chloride (1.19 g, 7.89 mmol), and 4-dimethylaminopyridine (catalytic amount) to the stirred solution. The reaction mixture was stirred for 17 h at room temperature, and then the N, N-dimethylformamide was 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 (Si02, ethyl acetate / petroleum ether, 2: 3, v / v), gave the title compound (1.39 g, 87%) as a pale yellow solid. H (CDC13) 0.19 (6H, s), 0.98 (9H, s), 1.87 (2H, m), 2.20 (2H, m), 2.46 (4H, m), 2 , 99 (1H, m), 6.77 (2H, d) -, 7.07 (2H, d) Intermediate 37 4- (4- { [Tert-Butyl (dimethyl) silyl] oxy} phenyl ) -1- [2,4-bis (methoxymethoxy) phenyl] cyclohexanol A round-bottomed flask, equipped with a magnetic stirrer, was charged with l-bromo-2,4-bis (methoxymethoxy) benzene (277 mg, 1, 00 mmoles) and anhydrous tetrahydrofuran (5 ml). The stirred solution was cooled to -78 ° C, and N, N, N 'was added. N'-tetramethylethylenediamine (0.32 ml, 2.10 mmol), followed by the dropwise addition of n-butyl lithium (0.88 ml, 2.10 mmol, 2.40 M solution in cyclohexanes). The resulting solution was stirred for 40 min at -78 ° C, then 4- (4- {[tert -butyl (dimethyl) silyl] oxy} phenyl-nyl) cyclohexanone (304 mg, 1.00 g) was added. mmoles) via a syringe as a solution in anhydrous tetrahydrofuran (2 ml), and the reaction mixture was stirred for 30 min at -78 ° C, then allowed to warm to room temperature over 3 h. The reaction was quenched with aqueous hydrochloric acid (5 mL, 0.10M), then poured into a separatory funnel containing ethyl acetate (50 mL) and water (10 mL). The layers were separated, and the aqueous phase was 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 (Si02, ethyl acetate / petroleum ether, 3: 7, v / v), yielding the title compound as a white solid (127 mg, 25%) and a mixture of diastereoisomers. dH (CDC13) 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 (1H,), 3.48 (3H, s), 3.49 (3H, s), 3.85 (1H, s), 5.15 (2H, s) ), 5.24 (2H, s), 6.68 (1H, dd), 6.73 (2H, d), 6.85 (1H, d), 7.05 (2H, d, 7.33 ( 1H, d) Intermediate 38 ter-c-Butyl (4 - (4- [2,4-bis (methoxymethoxy) phenyl] -3-cyclohe-xen-1-yl) phenoxy) dimethylsilane A round-bottomed flask was charged, equipped with a magnetic stirrer, with 4- (4-. {[[tert-butyl (dimethyl) silyl] o-xi.} phenyl) -1- [2,4-bis (methoxymethoxy) phenyl] cyclohexanol (125 mg 0.25 mmol), toluene (10 ml) and p-toluenesulfonyl-co-monohydrate acid (3 crystals) The reaction mixture was heated to reflux temperature for 30 min, then cooled to room temperature before adding baking soda. saturated aqueous sodium (5 ml) The layers were separated, and the aqueous phase was extracted with ethyl acetate (3x10 ml) The combined organic layers were washed with brine (10 ml), 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 diastereomers. dH (CDC13) 0.98 (9H, s), 1.84 (1H, m), 2.00 (1H, m), 2.27 (1H, m), 2.44 (2H, m), 2 , 56 (1H, m), 3.48 (3H, s), 3.49 (3H-, s), 5.15 (2x2H, s), 25.79 (1H, m), 6.67 (1H dd), 6.77 (2H, d), 6.78 (1H, d), 7, 07 (2H, d), 7.11 (1H, d). Intermediate 39 tert-Butyl (4- {4- [2,4-bis (methoxymethoxy) phenyl] cyclohexyl} - phenoxy) dimethylsilane A tert-butyl was added to a round-bottomed flask equipped with a magnetic stirrer. (4- {4- [2,4-bis (methoxymethoxy) phenyl] -3-cyclohexen-1-yl} phenoxy) dimethylsilane (118 mg, 0.24 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 then evacuated and placed in a hydrogen atmosphere. This procedure was repeated 10 cycles before leaving in a hydrogen atmosphere. The reaction mixture was stirred vigorously for 17 h, then filtered through celite, washing with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound as a colorless oil (118 mg, 100%) and a mixture of diastereomers. dH (CDC13) 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 (1H, m), 2.84 and 3.02 (1H, 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 (1H, m), 6.70 (3H, m), 7.03 (2H, m), 7.11 (1H, d). Intermediate 40 (+) -. { 4- [2,4-Bis (methoxymethoxy) phenyl] cyclohexylidene) acetate methylate A round bottom flask equipped with a magnetic stirrer was charged with sodium hydride (0.20 g, 5.10 mmol, 60% dispersion). in mineral oil), which had been 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. Trimethyl phosphonoacetate (756 μl, 5.10 mmol) was added dropwise via syringe, and the stirred mixture was allowed to warm to room temperature for 1 h. The mixture was cooled to 0 ° C before the addition of 4- [2,4-bis (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 h, 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 to give a yellow oil. Purification via flash column chromatography (Si02, ethyl acetate / petroleum ether, 1: 2, v / v), gave the title compound as a yellow oil (1.13 g, 95%). dH (CD3OD) 1.53-1.70 (2H, m), 2.00-2.13 (4H, m), 2.45 (2H, m), 3.26 (1H, m), 3, 48 (2H, s), 3.53 (3H, s), 3.71 (3H, s), 5.17 (2H, s) -, 5-, 24 (2H, s), 5.73 (1H , s), 6.67 and 6.68 (1H, d), 6.83 (1H, d), 7.08 (1H, d). Intermediate 41 cis / tJ ~ ans-. { 4- [2,4-Bis (methoxymethoxy) phenyl] cyclohexyl} methyl acetate was added to a round bottom flask, equipped with a magnetic stirrer, (±) -. { 4- [2, 4-bis (methoxymethoxy) phenyl] cyclohexylidene} Methyl 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 in an atmosphere of hydrogen. This procedure was repeated 10 cycles before leaving under a hydrogen atmosphere, and then vigorously stirred for 17 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was evaporated to dryness, giving the title compound (1.13 g, 99%) as a colorless oil, and a mixture of diastereomers. dH (CD3OD) 1.53 (2H, m), 1.62-1.78 (2H, m), 1.87 (4H, m), 2.93 (1H, 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 (1H, d), 6.79 and 6.80 (1H, s), 7, 12 and 7.15 (1H, d) Intermediate 42 Acid (+) - (4- [2 , 4-bis (methoxymethoxy) phenyl] cyclohexylidene-acetic acid. To a round-bottomed flask equipped with a magnetic stirrer was added trimethylsilyl-diethylphosphonoacetate (1.08 ml, 3.83 mmol) and anhydrous tetrahydrofuran (25 ml). ). The stirred solution was cooled to 0 ° C and n-butyllithium (1.80 ml, 3.83 mmol, 2.2M in cyclohexanes) was added dropwise via syringe over 5 min. The reaction mixture was allowed to slowly warm to room temperature, and was stirred for 17 h. 4- [2,4-B s (methoxymethoxy) phenyl] cyclohexanone (750 mg, 2.55 mmol) was added via syringe, as a solution in tetrahydrofuran (25 ml). After stirring 2 h at room temperature, the reaction mixture was poured into a separatory funnel containing aqueous sodium hydroxide solution (10 ml, 10% w / v). After extracting once with ethyl acetate (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 to give the title compound (422 mg, 52%) as an oil. dH (CDC13) 1.86 (2H, m), 2.00-2.13 (4H, m), 2.42 (2H, m), 3.19 (1H, m), 3.48 (3H, s), 3.51 (3H, s), 5.14 (2H, s), 5.21 (2H, s), 5.71 (1H, s), 6.67 (1H, dd), 6, 81 (1H, d), 7, 05 (1H, d). Intermediate 43 Acid (+) - (4- [2,4-Dihydroxyphenyl] cyclohexylidene.) Acetic A round bottom flask, equipped with a magnetic stirrer, was charged with (+) -. {4- [2, 4-bis (methoxymethoxy) phenyl] cyclohexylidene. Acetic acid (25 mg, 74 μmol), dowex acid resin (75 mg) and methanol (15 ml), then stirred at 60 ° C for 3 h. it was filtered through a plug of celite, washing with methanol.The solvent was removed under reduced pressure, giving a yellow oil (15 mg) which was purified by preparative TLC (ethyl acetate / petroleum ether, 3: 1). , v / v), giving the title compound (6.5 mg, 35%) as an oil, m / z (ES +) 339 (M + H +) Intermediate 44 (+) - { 4- [2 , 4-Bis (methoxymethoxy) phenyl] cyclohexylidene) acetonitrile was added to a round bottom flask, equipped with a magnetic stirrer, sodium hydride (40 mg, 0.95 mmol, 60% dispersion in mineral oil). After washing the sodium hydride with petroleum ether (2x20 rnl), the excess solvent was removed under reduced pressure. 1,2-dimethoxyethane (10 ml) was added, and the stirred suspension was cooled to 0 ° C. Diethyl cyanomethylphosphonoa-cetate (102 μL, 0.95 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature over 2 h. Then 4- [2,4-bis (methoxymethoxy) phenyl] cyclohexanone (200 mg, 0.68 mmol) was added as a solution in 1,2-dimethoxyethane (10 ml), and the reaction mixture was stirred for 17 h room temperature . The reaction mixture was poured into a separatory funnel containing water (50 ml) and diethyl ether (50 ml). The layers were separated, and the aqueous phase was 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 (Si02, ethyl acetate / petroleum ether, 1: 2, v / v), gave the title compound (141 mg, 66%) as a pale yellow oil. dR (CD3OD) 1.57-1.70 (2H, m), 2.02-2.25 (2H, m), 2.34-2.49 (2H, m), 2.60 (1H, m ), 3.03 (1H, m), 3.24 (1H, m), 3.47 (2H, s), 3.52 (3H, s), 5.17 (2H, s), 5.23 (2H, s), 5.33 (1H, s), 6.66 and 6.69 (1H, d), 6.83 (1H, d), 7, 09 (1H, d). Intermediate 45 (+) -. { 4- [2,4-Dihydroxyphenyl] cyclohexylidene) acetonitrile It was added to a round bottom flask, equipped with a magnetic stirrer, (+) -. { 4- [2, 4- is (methoxymethoxy) phenyl] cyclohexylidene} acetonitrile (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 slowly added. Heating was continued for 1 h, and the reaction mixture was allowed to cool to room temperature before 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 were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, ethyl acetate / petroleum ether, 1: 1, v / v) to give the title compound as a white solid (90 mg, 88%). m / z (ES +) 228 (M-H +); dH (CD3OD) 1.56-1.68 (2H, m), 2.02-2.14 (2H, m, 2.33-2.48 (2H, m), 2.57 (1H, m) , 3.01 (1H, m), 3.14 (1H, m), 5.31 (1H, s), 6.26 and 6.28 (1H, d), 6.32 (1H, d), 6.80 (1H, d) Intermediate 46 (+) -1- (3, 3-Difluorocyclohexyl) -2, -bis (methoxymethyl) benzene Dimethylaminosulfur trifluoride (34 μl) was added to a stirred solution of (± ) -3- [2,4-bi (methoxymethoxy) phenyl] cyclohexanone (40 mg) in anhydrous 1,2-dimethoxyethane at room temperature under argon After 1 h, additional dimethylaminosulfur trifluoride (170 μl) was added.

After 48 h, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (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 (SiO, ethyl acetate / petrol, 1: 1, v / v), yielding the title compound as a gum (31 mg); m / z (ES +) 317 (M + H) +; Rf (ethyl acetate / petrol, 1: 1 v / v) 0.5. Intermediate 47 (+) - 3 - [2,4-Bis (methoxymethoxy) phenyl] -cyclohexanecarboxylic acid A solution of (±) - was added. { 3- [2, 4-Jbis (methoxymethoxy) phenyl] cyclohexyl} Methanol (50 mg) in acetone (1 ml) was added to a stirred solution of chromium (VI) oxide (64 mg) in 2M sulfuric acid (0.64 ml) at 0 ° C over 3 h. After 3 h at 0 ° C, and then 16 h at room temperature, 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 (2x20 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 (SiO2, ethyl acetate / petrol, 4: 1, v / v), giving the title compound as a colorless oil. (15 mg, 29%). Rf (ethyl acetate / petrol, 4: 1 v / v) 0.5. Intermediate 48 (+) -3- [2,4-Bis (methoxymethoxy) phenyl] cyclohexancarboxa one way Triethylamine (16 μl) and isobutyl chloroformate (14 μl) were added to a stirred solution of (±) -3- [2,4-bis (methoxymethoxy) phenyl] -cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0 ° C. under argon. After 30 min, 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 (2x20 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 diastereomers; m / z (ES +) 324 (M + H) X Intermediate 49 (+) - 3 - [2,4-Bis (methoxymethoxy) phenyl] -N-hydroxycyclohexanecarboxamide Triethylamine (11 μl) and isobutyl chloroformate were added ( 10 μl) to a stirred solution of (±) -3- [2,4-bis (methoxymethoxy) phenyl] cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0 ° C under argon. After 30 min, aqueous hydroxylamine solution was added (0.5 ml, 50% by weight). The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 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 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 - [2,4-Bis (methoxymethoxy) phenyl] -N-ethylcyclohexancarboxylate Triethylamine (11 μl) and isobutyl chloroformate (10 μl) were added to a stirred solution of acid (±) -3- [2, -bi s (methoxymethoxy) phenyl] -cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0 ° C under argon. After 30 min, 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 (2x20 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- [2, 4-Bis (methoxymethoxy) phenyl] -1- (hydroxymethyl) cyclohexanecarboxamide N-methylmorphine ol (120 mg) and osmium tetraoxide (100 μl, 2 N-oxide) were added. , 5% by weight in tert-butanol) to a solution of (±) -2,4-bis (methoxymethoxy) -1- (3-methylenecyclohexyl) benzene (30 mg) in tetrahydrofuran (0.7 ml) and water (0.3 ml) at room temperature. After 16 h, 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 brought to 20 ml. The aqueous layer was extracted with ethyl acetate (3x20 ml), and 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 (SiO2, 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 (+) -N-. { 3 - (2,4-Bis (methoxymethoxy) phenyl] cyclohexyl acetamide. Triethylamine (15 μl) and acetic anhydride (10 ml) were added to a stirred solution of (±) -3- [2, 4 - bis (methoxymetho-xi) phenyl] cyclohexylamine (29 mg) in anhydrous 1,2-dichloroethane (2 ml) at room temperature After 0.5 h, the reaction mixture was partitioned between water (20 ml) and ethyl acetate. ethyl acetate (50 ml), and the aqueous layer was extracted with ethyl acetate (3x20 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-A - (2,4-Bis { [Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanol cis-4- (2, 4) -Bis. {[Tert-Butyl (dimethyl) silyl] oxy} phenyl) cyclohexanol Sodium borohydride (164 mg) was added to a stirred solution of 4- (2,4-bis. {[Tert-butyl] (dimethyl) silyl] oxy}. phenyl) cyclohexanone (1.57 g) in ethanol (50 ml) at 0 ° C. After 2 h at 0 ° C and then 18 h at room temperature, the reaction mixture was partitioned between 2M HCl (20 ml), water (40 ml) and ethyl acetate (50 ml), and the aqueous layer was reextracted with acetate of ethyl (2x50 ml). 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 (SiO2, ethyl acetate / petrol, 3:17 v / v) to give the title trans compound as a white solid (546 mg, 35%), and the cis title compound as a white solid (83 mg, 5%). trans -dR (CDC13) 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 (1H, m), 3.60 - 3, 70 (1H, m), 6.28 (1H, d), 6.39 (1H, dd), 6.94 (1H, d). cis -dH (CDCl 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 (1H, m), 4.12 (1H, bs), 6.28 (1H, d), 6.49 (1H, dd), 7.02 (1H, d). Intermediate 55 4- (2,4-bis [tert-butyl (dimethyl) silyl] oxy) phenyl) cyclohexyl intermediate (dimethylamino) benzoate of trans-4- (2,4-bis) (triethylamine (20 μl), 4-dimethylaminopyridine (catalytic amount) and chloride of 4-dimethylaminobenzoyl (26 mg) a-a stirred solution of trans-4- (2,4-bis. {[[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanol (30 ml) in dry dichloromethane (2 ml) at room temperature under argon. After 24 h, 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 (2x20 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 (SiO2, 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 / trans-A - (2, 4- ^ 5 ^ [tert-butyl (dimethyl) silyl] -oxy) phenyl) cyclohexanecarboxylic acid pyridinium dichromate ( 146 mg) was added to a stirred solution of cis / trans- [A - (2,4-γ-is. {[[Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] methanol (50 mg) in N, N-dimethylformamide (1 ml) at room temperature under argon. After 24 h, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (30 ml). The layers were separated, and the aqueous layer was extracted with diethyl ether (2x30 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 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-bis [tert-butyl (dimethyl) -silyl] oxy] phenyl) cyclohexyl ethyl ester N, N-diisopropylethylamine (199 μl) and ethyl isocyanate (90 μl) were added. to a stirred solution of trans-A- (2, -bis { [tert-butyl (dimethyl) silyl] oxy} phenyl) cydohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature in argon. The reaction mixture was heated at 40 ° C for 120 h, and 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 (SiO2, ethyl acetate / petrol, 1: 2 v / v) to give the title compound as a solid (55 mg, 95%); Rf (ethyl acetate / petrol, 1: 2 v / v) 0.65. Intermediate 58 Trans-4- (2,4-bis. {[Tert-butyl (di methyl) -silyl] oxy} phenyl) cyclohexyl cyclohexylcarbamate N, N-diisopropylethylamine (199 μl) and cyclohexyl isocyanate were added. (128 μl) to a stirred solution of trans-4- (2,4-bis { [Erc-butyl (dimethyl) silyl] oxy} phenyl) ci- • Clohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated at 40 ° C for 120 h, and 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 (SiO2, ethyl acetate / petrol, 1: 2 v / v) to give the title compound as a pale yellow solid (30 mg, 47%); dH (CDCl 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 (1H, m), 3.36 - 3.50 (1H, m), 4.40 - 4.48 (1H, m), 4.50 - 4.62 (1H, m), 6.20 (1H, d), 6.32 (1H, dd), 6.86 (1H, d). Intermediate 59 traus-4- (2,4-Dihydroxyphenyl) cyclohexanol 4- (2,4-Dihydroxyphenyl) cyclohexanone (18 mg) was placed in a round bottom flask equipped with a magnetic stirrer. Ethanol (5 ml) was added, followed by sodium borohydride (3.3 mg), and the reaction mixture was stirred for 16 h. Aqueous HCl (20 ml, 1M) was added, followed by ethyl acetate (20 ml), and the organic phase was separated and washed with brine (15 ml), dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuum. The residue was purified by flash column chromatography (Si02, ethyl acetate / petroleum ether, 60:40, v / v) to give the title compound ('14 mg, 78%) as a white solid. dH (CD3OD) 1.38-1.56 (4H, m), 1.85-1.88 (2H, m), 2.04-207 (2H, m), 2.80 (1H, tt), 3.58 - 3.65 (1H, m), 6.24-6.29 (2H, m), 6.90 (1H d); m / z (ES ') 267 ((M + AcOH) -1) - Intermediate 60 cis-4- (2, -bis { [tert-Butyl (dimethyl) -silyl] oxy) phenyl) cyclohexyl methanesulfonate added to a round bottom flask, containing cis-4- (2,4-bis. {[[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanol (200 mg, 0.46 mmol), dichloromethane (10 ml), followed by triethylamine (96 μl, 0.69 mmol) and dimethylaminopyridine (catalytic amount). The flask was purged with argon, and methanesulfonyl chloride (53 μL, 0.69 mmol) was added, with stirring. Stirring was continued for a further 24 h, and the reaction mixture was poured into water and extracted with dichloromethane (4x20 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate / petrol, 1: 9), gave the title compound as an oil (194 mg, 82%). dR (CDC13) 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 (1H, m), 3.02 (3H, s) , 5.05 (1H, s), 6.30 (1H, d), 6, 43 (1H, dd), 7.00 (1H, d). Intermediate 61 [4- (2, 4-bis. {[[Tert-butyl (dimethyl) -silyl] oxy} phenyl) cyclohexyl] methyl] 4-dimethylaminopyridine (catalytic amount), triethylamine (68 μl) was added. , and propionyl chloride (42 μl) to a stirred solution of [4- (2, 4-bis. {[[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] methanol in anhydrous dichloromethane (3 ml. ) at room temperature under argon. After 16 h, 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 (2x20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 1: 9 v / v) to give the title compound as a yellow oil and a mixture of diastereoisomers (114 mg, 92%); dH (CDC13) -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 (1H, m), 6.49 (1H, dd), 6.94-6.98 (1H, m) Intermediates 62 and 63 Diastereoisomers ethyl 4- (2, 4-bis { [erc-butyl (dimethyl) -silyl] oxy} phenyl) -1-hydroxycyclohexanecarboxylate A round bottom flask, equipped with a magnetic stirrer, was charged with. tetrahydrofuran (6 ml), ethylvinyl ether (0.28 ml, 2.92 mmol), and cooled to -78 ° C. A solution of tert-butyllithium (1 mL, 1.7M, 1.7 mmol) was added dropwise, and the flask was allowed to reach 0 ° C. The flask was maintained at this temperature until the bright yellow color dissipated before re-cooling it to -78 ° C. A solution of 4- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexanone (250 mg, 0.58 mmol) in THF (4 ml) was added dropwise. After 30 min, the reaction was quenched with humid THF (0.5 mL of water in 5 mL of THF), poured into water (10 mL), and extracted with diethyl ether (3x10 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 ozonized oxygen was passed through the solution for 10 min. 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 (SiO2, ethyl acetate / petrol, 1: 6), gave the title compound. First diastereomer eluted (31 mg, 11%); dH (CDC13) 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 (1H, d), 6.42 (1H, dd ), 7.05 (1H, dd). Second diastereomer eluted (32 mg, 12%); dH (CDCl 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 (1H, d), 6.42 (1H, dd), 6.97 (1H, d). Intermediate 64 Oxima of 4-. { 2,4-bis [tert-butyl (dimethyl) silyloxy] phenylcyclohexanone was added to a round-bottomed flask equipped with a magnetic stirrer. { 2, 4-bis. { [tert -butyl (dimethyl) silyl] oxy} phenyl cyclohexanone (100 mg, 0.23 mmol) and ethanol (5 ml). To the stirred suspension was added hydroxylamine hydrochloride (32 mg, 0.46 mmol) and triethylamine (103 μl, 0.74 mmol); then the solution was heated at reflux temperature for 2.5 h. 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 were separated. The aqueous layer was extracted with ethyl acetate (3x20 ml), and the combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The title compound (103 mg, 100%) was isolated as a white. dH (CDCl 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 (1H, m), 1.93-2.04 (2H, m), 2.18-2.24 (1H, m), 2.46-2.53 ( 1H, m), 3.05-3.15 (1H, m), 3.41-3.50 (1H, m), 6.30 (1H, d), 6.40 (1H, dd), 6 , 79 (1H, b), 6.92 (1H, d). Example 1 4- (2,4-Dihydroxyphenyl) -3-cyclohexen-1-one A round bottom flask, equipped with a magnetic stirrer, was charged with 8- [2,4-bis (methoxymethoxy) phenyl] -1, 4-dioxaespiro [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 at reflux temperature for 1.5 h. After cooling to room temperature, saturated aqueous sodium bicarbonate (20 ml) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3x20 ml), and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate / petroleum ether, 1: 3, v / v) to give the title compound as a yellow solid (323 mg, 37%). m / z (ES +) 203 (M-H +); dH (CD3OD) 2.62 (2H, t), 2.86 (2H, t), 3.04 (2H, m), 5.78 (1H, m), 6.28 (1H, m), 6 , 32 (1H, m), 6.96 (1H, d). Example 2a 4- (2,4-Dihydroxyphenyl) cyclohexanone A round bottom flask, equipped with a magnetic stirrer, was charged with 8- [2,4-bis (methoxymethoxy) phenyl] -1,4-dioxaespiro [4.5] decane (1.30 g, 3.9 mmol) and methanol (15 ml). To the stirred solution was added aqueous HCl (15 mL,: 1M), in one portion. After stirring for 1 h at room temperature, the acid was quenched by adding saturated aqueous sodium bicarbonate solution (10 ml). After vigorously spinning for 10 min, the reaction mixture was transferred to a separatory funnel, the phases were separated, and the aqueous phase was extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with brine, and the solvent was evaporated. Methanol (30 ml) and acidic ion exchange resin (4 g) were added to the slightly moist crude product. The resulting mixture was heated to reflux, with stirring, for 5 h. Filtration through a plug of Celite, washing with ethyl acetate, followed by removal of the solvent in vacuo gave an orange oil. Purification via flash column chromatography (SiO2, ethyl acetate / petroleum ether, 1: 1, v / v), afforded the title compound as a white powder (0.54 g, 68%). m / z (ES +) 411 (2M-1); dH (CD30D) 1.94 (2H, ddd), 2.16-2.23 (2H, m), 2.41 2H, dt), 2.62 (1H, t), 2.63 (1H, t ), 2.64 (1H, dd), 6, 31 (1H, d), 6, 92 (1H, d) Example 2b 4- (2, 4 -Dihydroxyphenyl) cyclohexanone A round-bottomed flask was charged, equipped with a magnetic stirrer, with 4- (1, 4-dioxaespiro [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 pyridinium p-toluenesulfonate (1.14 g, 4.52 mmol) in one portion, and the reaction mixture was heated to reflux temperature for 8 h. 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 (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure, giving an off-white powder. After washing the powder with dichloromethane (100 ml), and removing the excess solvent under reduced pressure, the desired product (9.30 g, 100%) was obtained as an off-white powder, m / z (ES +) 207 (M + H +); dH (CD3OD) 1.84-1.97 (2H, m), 2.15-2.23 (2H, m), 2.36-2.45 (2H, m), 2.58-2.68 (2H,), 3.39 (1H, tt), 6.26 (1H, d), 6, 34 (1H, d), 6.97 (1H, d). Example 3 4- (2,4-Dihydroxyphenyl) cyclohexanone oxime 4- (2,4-dihydroxyphenyl) cyclohexanone (100 mg, 0.49 mmol), anhydrous ethanol (5 ml), triethylamine (102 ml) and hydrochloride were added. of hydroxylamine (51 mg, 0.73 mmol) to a round bottom flask, equipped with a magnetic stirrer. The reaction mixture was refluxed for 3 h, then evaporated in vacuo. The resulting solid was purified via flash column chromatography (Si02, ethyl acetate / petroleum ether, 35:65, v / v) to give the title compound as short white needles (107 mg, 100%). dH (CD3OD) 1.44-1.61 (2H, m), 1.81-1.88 (1H, m), 1.94-2.00 (2H, m), 2.19-2.27 (1H, m), 2.43 (1H, d), 3.04-3.10 (1H, m), 3.38 (1H, m), 6.22-6.25 (1H, m), 6.28 (1H, d), 6.84-6.86 (1H, m); m / z (El ') 220. Example 4 O-methyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime 4 - (2,4-dihydroxyphenyl) cyclohexanone (21 mg, 0.10 mmol), ethanol was added anhydrous (3 ml), sodium acetate (16 mg, 0.20 mmol) and O-methylhydroxylamine hydrochloride (9 mg, 0.22 mmol) were added to a round bottom flask equipped with a magnetic stirrer. The reaction mixture was refluxed for 6 h, then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was dried over anhydrous calcium sulfate, filtered and evaporated in vacuo to give a colorless oil. Purification via flash column chromatography (Si02, ethyl acetate / petroleum ether, 1: 1, v / v), gave the title compound as a white solid (11 mg, 47%). dH (CD30D) 1.43-1.63 (2H, m), 1.81-1.92 (2H, m), 1.93-2.20 (2H, m), 2.24 (1H, dt ), 2.38-2.44 (1H, m), 3.07 (1H, tt), 3.78 (3H, s), 6.20-6.23 (1H, m), 6.26 (1H, d), 6.85 (1H, d); m / z (ES ') 234. Example 5 Oxygen of 0-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone. 4- (2,4-Dihydroxyphenyl) cyclohexanone (21 mg, 0.10 mmol), anhydrous ethanol ( 3 ml), sodium acetate (17 mg, 0.21 mmol) and O-benzylhydroxylamine hydrochloride (18 mg, 0.21 mmol) were added to a round bottom flask equipped with a magnetic stirrer. The reaction mixture was refluxed for 6 h, then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was dried over anhydrous calcium sulfate, filtered and evaporated in vacuo to give a pale pink oil which was purified by flash column chromatography (SiO2, ethyl acetate / petroleum ether, 1: 1, v / v) , giving the title compound as a colorless oil (11 mg, 32%). dH (400, CDC13) 1.47-1.68 (2H, m), 1.86-1.95 (2H, m), 1.97-2.08 (2H, m), 2.25 (1H , dt), 2.49-2.57 (1H, m), 3.02 (1H, tt), 3.42-3.50 (1H, m), 4.78 (1H, s), 4, 89 (1H, s), 6.25-6.29 (1H, m), 6.33-6.37 (1H, m), 6.94 (1H, d), 7.26-7.39 ( 5H, m); m / z (ES-) 310. Example 6 3- (2,4-Dihydroxyphenyl) -2-cyclohexen-l-one Heated at 50 ° C 3- [2,4-bis (methoxymethoxy) phenyl] -2 - cyclohexen-1-one (50 mg) in methanol (4 ml) containing acid ion exchange resin (500 mg). After 2 h, the mixture was filtered, and the filtrate was evaporated in vacuo and purified by flash column chromatography (Si02, ether / petroleum ether, 9: 1, v / v), giving the title compound as a yellow solid (31 mg, 76%). d (DMSO) 1.95 (2H, quintuplet), 2.30: (2H, t), 2.69 (3H, t), 6.26 (2H, overlapping m), 6.35 (1H, m) , 7.10 (1H, d), 9.67 (1H, bs), 9.86 (1H, bs); m / z (ES ') 407 (2M-H)'. Example 7 (+) - 3 - (2,4-Dihydroxyphenyl) cyclohexanone. (+) - 3 - [2,4-bis (methoxymethoxy) phenyl] cyclohexa-none (35 mg) in methanol (4 ml) was stirred, which It contains acid ion exchange resin (300 mg), at 50 ° C for 6 h, and then at room temperature for 16 h. The mixture was evaporated in vacuo, the residue was redissolved in acetone (4 ml), containing water (2 drops), and stirred at 50 ° C for 8 h, and then at room temperature for 64 h. The mixture was filtered through celite, and purified by flash column chromatography (SiO2, petroleum ether / ethyl acetate, 1: 1, v / v), giving the title compound as a white solid containing a mixture. in equilibrium of cyclized and non-cyclized forms (31 mg, 76%). dH (DMS0) 1.1-2.3 (8H, overlapping m), 3.0 (1H, m), 6.08 (0.5H, bs), 6.16 (1H, 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 The oxime of 3- [2,4-bis (methoxymethoxy) phenyl] -2-cyclohexen-1- was heated at 50 ° C. ona (0.1 g) in methanol (5 ml), containing acid ion exchange resin (0.3 g). After 4 h, the mixture was filtered, and the resin was washed with ammonia solution (50 ml). Combine the filtrates and washings, evaporate in vacuo, and purify by flash column chromatography (SiO2, ethyl acetate / petroleum ether, 3: 2, v / v) to give the title compound as a yellow solid ( 0.058 g, 81%). dH (DMSO) (mixture of diastereoisomers) 1.68 (2H, m, major), 1.76 (2H, m, minor), 2.26 (2H, m, minor), 2.40-2.54 ( 4H, higher + 2H lower, overlapping m), 6.15-6.30 (3H higher + 2H lower, overlapping m), 6.85-6.95 (1H higher + 2H lower, overlapping m), 9.26 (1H, bs, greater), 9.32 (1H, bs, less), 9.35 (1H, bs, greater), 9.40 (1H, bs, minor), 10.17 (1H, s, less ), 10.49 (1H, s, major); m / z (ES ') 437 (2M-H) Example 9 (+) - 3 - (2,4-Dihydroxyphenyl) cyclohexanone oxime (+) - 3 - (2,4-dihydroxyphenyl) cyclohexanone (13) mg), hydroxylamine hydrochloride (0.0065 g), and triethylamine (16 μl) at 80 ° C in DMF (3 ml). After 3 h, 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 (SiO2, petroleum ether / ethyl acetate, 3: 2 v / v) to give the title compound as a white solid (12 mg, 86%). dH (CD3OD) 1.4-2.0 (6H, overlapping m), 2.10 (0.5H, m), 2.20 (0.5H, m), 2.35 (0.5H, m) , 2.46 (0.5Hm) 2.94 (1H, m), 6.22-6.26 (2H, overlapping m), 6.92-6.95 (1H, overlapping m);.m / z (ES +) 222 (M + H) '. Example 10 Salt of trifluoroacetic acid of (+) - 4- [3- (piperazinyl) cyclohexyl] -1,3-benzenediol It was heated (+) -1-. { 3- [2,4-bis (methoxymethoxyphenyl) cyclohexyl) piperazine (35 mg) under reflux in methanol containing acid ion exchange resin (0.3 g) for 0.5 h. The reaction mixture was filtered, and the resin was washed with methanol and aqueous ammonia, and the filtrate and the combined washings were concentrated in vacuo. The crude residue was purified by preparative HPLC to give the title compound as an off white solid (14 mg, 38%). dH (d4-MeOH) 1.7-1.9 (6H, overlapping m), 2.05 (1H, m), 2.20 (1H, m), 3.1- 3.5 (10H, overlapping m ), 6.26 (2H, overlapping m), 6.94 (1H, d); m / z (ES +) 277 (M + H) +.

Example 11 (+) -N- [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide Warmed (±) -N-. { 3 - [2,4-bis (methoxymethoxyphenyl) cyclohexyl) methanesulfonamide (34 mg) under reflux in methanol (2 ml) containing acidic ion exchange resin (0.3 g) for 5 h. The reaction medium was filtered, and the resin was washed with methanol.The filtrate and the combined washings were evaporated in vacuo, and the crude residue was purified by preparative HPLC to give a mixture of diastereomers of the title compound as a pale pink solid. (10 mg, 38%) dH (d4-MeOH) 1.20-2.00 (7H, overlapping m), 2.07 (1H, 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 (1H, dd), 6.87 (0.51-1, d), 6.89 (0.5H, d); m / z (ES ') 284 (MH ). Example 12 (±) -4- [3- (Hydroxymethyl) cyclohexyl] -1,3-benzenediol It was heated to 50 ° C (±) -. {3 - [2,4-bis (methoxymethoxyphenyl-nil) ] cyclohexyl] methanol (35 mg) in methanol (3.5 ml) containing acid ion exchange resin (350 mg) After 6 h, mixing it was filtered, the resin was washed with ethyl acetate, and the filtrate and the combined washings were evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 1: 1 v / v) to give a mixture of diastereomers of the title compound as a white solid (2 mg, 8%). dH (d4-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- [3- (Hydroxyamino) -cyclohexyl] -1,3-benzenediol trifluoroacetate salt Cis-N- was refluxed. { 3- [2, 4-bis (methoxymethoxy) -phenyl] cyclohexyl} hydroxylamine (0.015 g) in methanol (2 ml) containing acid ion exchange resin (0.3 g), for 5 h. The reaction mixture was filtered, and the resin was washed with aqueous ammonia and methanol, and the filtrate and the combined washings were concentrated in vacuo. The crude residue was purified by HPLC preparation to give the title compound as an off-white solid (0.005 g, 46%). dH (d4-MeOH) 1.25-1.60 (4H, overlapping m), 1.82 (1H, bd), 2.02 (1H, m), 2.17 (2H, overlapping m), 2, 93 (1H, m), 3.36 (1H, m), 6.24 (1H, dd), 6.27 (1H, d), 6.88 (1H, d); m / z (ES +) 224 (M + H) +. Example 14 4- (4-Methylenecyclohexyl) -1,3-benzenediol Tetrabutylammonium tetrafluoride (230 μl) was added to a stirred solution of tert-butyl- [3-. { [tert -butyl (dimethyl) silyl] oxy} -2- (4-methylenecyclohexyl) phenoxy] (isopropyl) dimethylsilane (40 mg) in tetrahydrofuran (2 ml) at room temperature. After 24 h, additional tetrabutylammonium tetrafluoride (50 μl) was added, and after 2 h, 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 (2x20 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 (SiO2, ethyl acetate / petrol, 2: 3 v / v) to give the title compound as a white solid (17 mg, 90%). dH (CD3OD) 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 (1H, tt), 3.20 (1H, m), 4.50 (2H, s), 6.10-6.16 (2H, m), 6.72 (1H, d); m / z (ES +) 205 (M + H) +. Example 15 cis / trans-A - [A - (Hydroxymethyl) cyclohexyl] -1,3-benzenediol cis / trans- [A - (2,4-bis. {[Tert -butyl (dimethyl) silyl] oxy] was dissolved phenyl) cyclohexyl] methanol (24 mg) 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 h, 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 magnesium sulfate and concentrated in vacuo. Purification via flash column chromatography (Si02, eluting with ethyl acetate: petroleum ether, 1: 1, v / v), gave the desired compound (7 mg, 59%) as a white solid. dH (CD-5OD) 0.95 - 1.06 (0.5H, m), 1.24 - 1.38 (9.5H, m), 1.43-1.60 (4H, m), 1.69 - 1.83 (4H, m), 2.62 - 2.77"( 1H, m), 3.30 (1H, d), 3.56 (1H, d), 6.11-6.17 (2H, m), 6.76-7.01 (1H, m); / z (ES ') 281 (M-1 + 60) "Example 16 cis / trans-4- [4- (Hydroxy-4-methylcyclohexyl) -1,3-benzenediol cis / trans-A- (2, 4-bis. {[[Tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methylcyclohexanol (29 mg) in THF (8 ml), and tetrabutylammonium fluoride (0.14 ml, 1 ml) was added. 0M in THF) in a portion with stirring. The resulting solution was stirred for 17 h, 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 were washed with brine (20 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification via flash column chromatography (Si02, eluting with ethyl acetate: petroleum ether, 1:19 v / v, gradually increasing polarity to 3: 7 v / v), gave the title product as diastereoisomers (solids Whites) 1,4-cis (5 mg, 36%) and 1,4-rans (9 mg, 64%). Cis isomer: dH (CD3OD) 1.30 (3H, s), 1.50 - 1.66 (4H, m), 1.69-1.77 (4H, m), 2.74-2.82 (1H, m), 6.20-6.26 (2H, m), 6.89 (1H, d), - m / z (ES ') 281 (M-1 + 60). Trans isomer: dH (CD3OD) 1.22 (3H, s), 1.46-1.60 (4H, m), 1.69-1.82 (4H, m), 2.75 (1H, tt), 6.22-6.26 (2H, m), 6.93 (1H, d); m / z (ES ") 281 (M-1 + 60) eg 17 cis / trans-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] acetamide To a round-bottomed flask, equipped with a magnetic stirrer, was added cis / trans-N- [A - (2, 4-bis. {[[Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] acetamide (15 mg, 31 μmol), tetrahydrofuran (3 ml) and tetra-n-butylammonium fluoride (93 μl, 93 μmol, 1.0 M solution in tetrahydrofuran). The resulting solution was stirred for 3 h. Tetra-n-butylammonium fluoride (90 μl, 90 μmol, 1.0M solution in tetrahydrofuran) was added, and the solution was stirred for an additional 64 h. Saturated aqueous sodium bicarbonate solution (3 ml) was added, and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (5 ml), and the aqueous layer was 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 (Si02, methanol / dichloromethane, 1: 9, v / v) gave an oily solid (6 mg) which is a mixture of isomers by NMR. Further purification via HPLC gave the title compound (0.5 mg, 6%) as a mixture of diastereomers and a colorless oil, m / z (ES ") 308 (M-1 + 60. {Acetate. ); dH (CD ^ OD) 1.41 (1H, m), 1.57 (1H, m), 1.70 (2H, m), 1.83 (1H, m), 1.87 (1H, m), 1.93 (1H, m), 1.96 (1.5H, m), 2.04 (1, 5H, m), 2.05 (1H, m), 2.82 (1H, 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 (+) - O-methyl-3 - (2,4-dihydroxyphenyl) cyclohexanone oxime It was heated to reflux, in ethanol, (±) -3- (2,4-dihydroxy-phenyl) -cyclohexanone (22 mg), methoxylamine hydrochloride. (18 mg), and sodium acetate (18 mg). After 6 h, methoxylamine (36 mg), and additional sodium acetate (36 mg) were added, and the mixture was heated to reflux for an additional 1 h. 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 (SiO2, ethyl acetate / petrol, 1: 1 v / v) to give the title compound as a mixture of isomers (18 mg, 72%). dH (CDC13) 1.5-2.2 (6H, overlapping m), 2.42 (0.5H, bd), 2.69 (0.5H, bd), 2.92 (0.5H, m), 3.24 - 3.38 (1H, 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 (1H, m), 7.06 (0.5H, bs); m / z (ES ') 469 (2M-1)' Example 19 (+) - 3 - (2,4-Dihydroxyphenyl) -1-methylcyclohexanol Methylmagnesium chloride (0.132 ml of a 22% w / w solution) was added. in tetrahydrofuran) to a solution of (±) -3- (2,4-dihydroxyphenyl) cyclohexanone (20 mg) in tetrahydrofuran (3 ml) at 0 ° C under argon. After 16 h, 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 give the title compound as a white solid (6 mg, 28%). dH (d4-MeOH) 1.20 (3H, s), 1.22-1.39 (2H, overlapping m), 1.46 (1H, t), 1.54-1.87 (5H, overlapping m ), 3.22 (1H, m), 6.19-6.25 (2H, overlapping m), 6.86 (1H d); m / z (ES ') 281 (M + 60-H)' Example 20 (+) - O-Benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime Refluxed in ethanol (3 ml ), (+) - 3- (2,4-dihydroxyphenyl) cyclohexanone (30 mg), 0-benzylhydroxylamine hydrochloride (46 mg), and sodium acetate (24 mg). After 16 h, 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 give a mixture of geometric isomers of the title compound as an off white solid (12 mg, 26%). dH (d4-MeOH) 1.42-2.06 (6H, overlapping), 2.12 (0.5H, dt), 2.22 (0.5H, t), 2.34 (0.5H, m ), 2.46 (0.5, m), 2.96 (1H, m), 5.02 (2H, s), 6.20-6.27 (2H, overlapping m), 6.92 (1H , m), 722-7.34 (5H, -lalapando m); m / z (ES ') 310 (MH)' Example 21 3 - (2,4-Dihydroxyphenyl) -2-cyclopentenone oxime Warmed to 50 ° C 3- [2,4-bis (methoxymethoxy) phenyl] -2 -c-Clo-enten-1-one (20 mg) in MeOH (4 ml) containing acid ion exchange resin (100 mg) for 3 h. The reaction mixture was filtered, and the resin was washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 7: 3 v / v) to give 3- (2,4-dihydroxyphenyl) -2-cyclopentene-1 ona (11 mg, 79%). 3- (2,4-Dihydroxyphenyl) -2-cyclopenten-l-one (6 mg), hydroxylamine hydrochloride (3.3 mg) and triethylamine (6.6 μl) in ethanol (3 ml) were heated to reflux for 3 h. 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 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 (SiO2, ethyl acetate / petrol, 1: 1 v / v) to give the title compound as a yellow solid, and as a major isomer (4 mg, 62%). Data supplied for the main isomer: dH (d-MeOH) 2.74-2.77 (2H, m), 2.96-2.99 (2H, m), 6.34 (1H, dd), 6, 38 (1H, d), 6.96 (1H, t), 7.22 (1H, d); m / z (ES ') 204 (MH)' Example 22 (+) - 3 - (2,4-Dihydroxyphenol) cyclopentanone Heated at 50 ° C (±) -3- [2,4-bi (methoxymethoxy) ) phenyl] cyclopentanone (8 mg) in MeOH (3 ml) containing acid ion exchange resin (0.1 g) for 3 h. The reaction mixture was filtered, and the resin was washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (SiO2, ethyl acetate) to give the title compound as a white solid (3.8 mg, 70%). dH (d4-MeOH) 2.52-2.13 (1H, m), 2.26-2.48 (4H, overlapping m), 2.53-2.60 (1H, m), 3.55- 3.61 (1H, m), 6.29 (1H, dd), 6.22 (1H, d), 6.96 (1H, d); m / z (ES ') 251 ((M + 60) -1) "Example 23 (+) - 3 - (2,4-Dihydroxyphenyl) cyclopentanone oxime (+) - 3 - (2,4-dihydroxyphenyl) ) cyclopentanone (5 mg), hydroxylamine hydrochloride (2.7 mg) and triethylamine (5.4 μM) in EtOH (4 ml) at reflux for 3 h. The reaction mixture was partitioned between ethyl acetate (20 g). ml) and water (20 ml) The aqueous phase was extracted with ethyl acetate (10 ml), and the 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 (SiO2, ethyl acetate / petrol, 4: 1 v / v) to give the title compound as a white solid and a mixture of isomers (3.8 mg, 71%). (d4-MeOH) 1.80-1.93 (1H, overlapping m), 2.05-2.20 (0.5H, m), 2.39-2.55 (3H, overlapping m), '2 , 68-2.74 (1H, overlapping m), 2.94 (0.5H, bdd), 6.26-6.33 (2H, overlapping m), 6.94 (0.5H, d), 6.96 (0.5H, d); m / z (ES ") 266 ((M + 60) -1) - Ei empl or 24 cis-N- [4- (2, -Dihydroxyphenyl) cyclohexyl] -1-butanesulfo-na ida A round-bottomed flask, equipped with a magnetic stirrer, was charged with cis-4- (2,4-bis. { [tert -butyl (dimethyl) silyl] oxy} phenyl) cyclohexylamine (150 mg, 0.34 mmol) and 1,2-dichloroethane (8 ml). Triethylamine (96 μL, 0.70 mmol) and n-butylsulfonyl chloride (55 μL, 0.40 mmol) were added at room temperature. 4-Dimethylaminopyridine (3 crystals) was added, and the mixture was stirred for 17 h. Aqueous sodium hydroxide solution (15 ml, 0.40M) was added, and the mixture was stirred for 10 min. The layers were divided, 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 hydrated tetra-n-butylammonium fluoride (360 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 1 h, 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 give an oil. Purification via flash column chromatography (Si02, ethyl acetate / petroleum ether, 1:10, then 1: 1, v / v), gave the title compound (40 mg, 35%) as a white solid, m / z (ES ') 326 (M-H +); dH (CD3OD) 0.95 (3H, t), 1.45-1.55 (2H, m), 1.55-1.95 (10H, m), 2.80-2.90 (1H, m ), 3.00-3.20 (2H, m), 3.65 (1H, m), 6.22-6.26 (2H, m), 6.96 (1H, d). Example 25 Trans- N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfone-ida A trans-N- [A - (2,4-bis) was added to a round-bottomed flask equipped with a magnetic stirrer. {[[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] methanesulfonamide (320 mg, 0.57 mmol) and 1,2-dichloroethane (50 ml). To the stirred solution was added trifluoroacetic acid (20 ml) and water (20 ml). The stirred reaction mixture was then heated to reflux for 18 h, and then cooled to room temperature. Toluene (70 ml) was added, and the solvent was removed in vacuo. Then methanol (50 ml) was added to the residue, and the solvent was removed under reduced pressure. The resulting oil was purified via flash column chromatography (Si02, ethyl acetate / petroleum ether, 1: 3, 1: 2, then 1: 1, v / v), giving the title product (115 mg, 71% ) as a white solid, m / z (ES +) 286 (M + H +); dH (CD3OD) 1.52 (4H, m), 1.89 (2H, m), 2.13 (2H, m), 2.80 (1H, m), 3.00 (3H, s), 3 , 28 (1H, m), 6.27 (1H, d), 6.29 (1H, dd), 6, 92 (1H, d). Example 26: cis-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide. Cis-N- [4- (2,4-bis { [tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] methanesulfonamide (44 mg, 100 μmol) and 1,2-dichloroethane (4 ml). To the stirred solution was added methanesulfonyl chloride (10 μl, 120 μmol), triethylamine (28 μl, 200 μmol) and three crystals of 4-dimethylaminopyridine. The reaction mixture was then left stirring for 17 h. The reaction mixture was 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 a gum. This gum was dissolved in dichloromethane (6 ml), then water (3 ml) and trifluoroacetic acid (3 ml) were added, and the mixture was allowed to stir for 17 h. 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. The azeotropic removal of residual trifluoroacetic acid was carried out 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 h. 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. The azeotropic removal of residual trifluoroacetic acid was carried out with methanol to give an oil (28 mg) which was purified via flash column chromatography (Si02, ethyl acetate / petroleum ether, elution gradient using 1: 3, 1: 2, then 1: 1, v / v), giving the title compound (13 mg, 81%) as a white solid, m / z (ES +) 286 (M + H +); dH (CD30D) 1. 71 (6H, m), 1.90 (2H, m), 2.87 (1H, m), 3.00 (3H, s), 3. 72 (1H, m), 6.28 (1H, d), 6.30 (1H, dd), 7.01 (1H, d) Example 27 4- [4- (4-Hydroxyphenyl) cyclohexyl] -1, 3-benzenediol Tert-butyl (4- {4- [2,4-bis (methoxymetho-xi) phenyl] -3-cyclohexyl} phenoxy was added to a round-bottomed flask equipped with a magnetic stirrer. dimethylsilane (118 mg, 0.24 mmol), methanol (10 ml) and Dowex® acid resin (500 mg). The reaction mixture was heated at reflux temperature for 5 h, then cooled to room temperature, and filtered through a plug of celite, washing with ethyl acetate. The filtrate was adsorbed on silica gel, and purified via flash column chromatography (SiO2, ethyl acetate / petroleum ether, 2: 3, v / v) to give a white solid (44 mg) which was further purified by HPLC. . The title compound was isolated as a white solid (12 mg, 17%). m / z (ES +) 286 (M-H +); dH (CD3OD) 1.52-1.96 (6H, m), 2.11 (2H, m), 2.53 and 3. 07 (1H, m), 2.90 (1H, m), 6, 28 (2H, m), 6.75 (2H, m), 6.95 (1H, m), 7.10 (1H, m), 7.19 (1H, m). Example 28 cis / trans- [4- (2, 4-Dihydroxyphenyl) cyclohexyl] methyl acetate It was added to a round bottom flask, equipped with a magnetic stirrer, cis / trans-. { A - (2,4-bi (methoxymethoxy) -phenyl] cyclohexyl) methyl 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, 1M) was added in aliquots (4x5 ml) at 10 min intervals After 2 h, the reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate (50 ml) was added. The reaction mixture was poured into a separatory 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 (SiO2, ethyl acetate). / petroleum ether !, 1: 2, v / v) gave the title compound (0.51 g, 69%)! as a mixture of diastereoisomers. z (ES +) 265 (M + H +); dH (CD3OD) 1.33-1.91 (9H, m), 2.30 (2H, m), 2.79 (1H, m), 3.72 ( 3H, s), 6.28 (2H, m), 6.95 (1H, m). ] Example 29! I methyl trans- [4- (2, 4-Dihydroxyphenyl) cyclohexyl] acetate i Purified cis / trans- [4- (2,4-dihydroxyphenyl) cyclohexy] methyl acetate (25 mg) Via HPLC (acetonitrile / water, :70 - 80:20, 20 min isocratic) to give the title compound as a white solid, m / z (ES +) 265 (M + H SH (CD30D) 1.21 (2H, m), 1.47 (2H, m), 1, 64 (1H, m), 1.88 (4H, m), 2.29 (2H, d), 2 , 79 (1H, m), 3.70, 3H, s), 6.28 (2H, m), I 6, 92 (1H, d). Example: 30 cis- [4- (2, 4-Dihydroxyphenyl) cyclohexyl] methyl acetate The methyl / trans- [A - (2, -dihydroxyphenyl) cyclohexyl] acetate (25 mg) was purified via HPLC (acetonitrile / water, 30:70 - 80:20, 20 min isocratic) to give the title as a white solid, m / z (ES +) 265 (M + H +); dH (CD30D) 1.60 - 1.79 (8H, m), 2.31 (1H, m), 2.54 (2H, d), 2.84 (1H, m) 3.71 (3H, s ), 6.27 (2H, m), 6.95 (1H, d). Example 31 Trans- [4- (2,4-dihydroxyphenyl) cyclohexyl] acetic acid Sodium hydroxide (32.mg, 0.78 mmol) was added to a 25 ml round bottom flask containing trans- [4- ( 2, 4-dihydroxyphenyl) cyclohexyl] methyl acetate (60 mg, 0.23 mmole) and water (4 ml), and the solution was heated to 40 ° C for 1 h. The solution was poured into a separatory funnel containing ethyl acetate (15 ml) and water (10 ml). Aqueous hydrochloric acid (10 ml, 1.0M) and ethyl acetate (20 ml) were then added to the aqueous layer. The layers were separated, and the aqueous layer was 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 to give the title compound (34 mg, 60%) as a solid, m / z (ES +) 251 (M + H +); dH (CD30D) 1.20 (2H, m), 1.48 (2H, m), 1.89 (4H, m), 2.25 (2H, d), 2.81 (1H, m), 6.27 (2H, m), 6.91 (1H, m).

Example 32 cis- [4- (2,4-dihydroxyphenyl) cyclohexyl] acetic acid Sodium hydroxide (5 mg, 0.13 mmol) was added to a 25 ml round bottom flask containing cis- [4- (2 4-dihydroxyphenyl) cyclohexyl] acetate (10 mg, 0.038 mmol) and water (4 ml), and the solution was heated at 40 ° C for 1 h. The solution was poured into a separatory funnel containing ethyl acetate (15 ml) and water (10 ml). Aqueous hydrochloric acid (10 ml, 1.0M) and ethyl acetate (20 ml) were then added to the aqueous layer. The layers were separated, and the aqueous layer was 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 to give the title compound (5 mg, 55%) as a solid, m / z (ES +) 251 (M + H +); dH (CD3OD) 1.61-1.77 (8H, m), 2.30 (1H, m), 2.49 (2H, d), 2.84 (1H, m), 6.27 (2H, m), 6.96 (1H, d). Example 33 cis / trans- [4- (2,4-dihydroxyphenyl) cyclohexyl] acetic acid Acid was added. { 4- [2,4-dihydroxyphenyl] cyclohexylidene-Jacético (50 mg, 0.20 mmol) and ethanol (15 ml) to a round bottom flask equipped with a magnetic stirrer. To the stirred solution was added palladium (catalytic amount, 10% on activated carbon), in one portion. The reaction vessel was evacuated, and then placed in an atmosphere 1 of hydrogen. This procedure was repeated ten times, and then stirred for 17 h in a hydrogen atmosphere at room temperature. The reaction mixture was filtered through a plug of celite, washing with ethanol. The solvent was removed in vacuo to give the title compound (50 mg, 100%) as a pale yellow oil, m / z (ES +) 251 (M + H +); dH (CD3OD) 1.33-1.91 (9H m), 2.30 (2H, m), 2.81 (1H, m), 6.28 (2H, m), 6.94 (1H, m). Example 34 cis / trans- [4- (2,4-Dihydroxyphenyl) cyclohexyl] acetonitrile was added. { 4- [2,4-dihydroxyphenyl] cyclohexylidene} acetonitrile (408 mg, 1.3 mmol) and methanol (20 ml) were added to a round bottom flask equipped with a magnetic stirrer. The resulting solution was heated to reflux temperature, and aqueous hydrochloric acid (20 ml, 1.0M) was added. The solution was heated for 1 h, then cooled and saturated aqueous sodium bicarbonate solution was added. (50 ml). The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml), and the aqueous layer was extracted with ethyl acetate (2 × 20 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. [[4- [2,4-Dihydroxyphenyl] cyclohexyl] -den] acetonitrile (about 224 mg, 0.98 mmol) and ethanol (15 ml) were added to a 50 ml round bottom flask equipped with a magnetic stirrer. . To the stirred solution was added palladium (catalytic amount, 10% on activated carbon), in one portion. The reaction vessel was evacuated, and then placed in a hydrogen atmosphere. This procedure was repeated 10 times before leaving the reaction mixture in a hydrogen atmosphere. The vigorous stirring was continued for 17 h, 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 (Si02, ethyl acetate / petroleum ether, 1: 1, v / v) to give the title compound (226 mg, 80% over 2 steps) as a colorless oil, m / z (ES +) 232 ( M + H +); dH (CD30D) 1.31 '(1H, m), 1.52 (lH m), 1.67 (1H, m), 1.77 (0.5 H m), 1.83 (1H, m), 1.92 (2H, m), 1.98 (2H, m), 2.22. (0.5H), 2.44 and 2.67 (2H, d), 2.84 (1H, m), 6.28 (2H, m), 6.96 (1H, m). Example 35 cis / trans-4- [4- (2-aminoethyl) cyclohexyl] -1,3-benzenediol hydrochloride cis / trans- [4- (2, 4-dihydroxyphenyl) cyclohexyl-] acetonitrile (214 mg, 0.95 mmol), ethanol (25 ml) and chloroform (1 ml) in a cylinder, and platinum (IV) oxide (25 mg, 0.11 g. mmoles). The cylinder was placed in a high pressure hydrogenation apparatus, and stirred for 4 h at about 345 kPa (50 psi) in a hydrogen atmosphere. The reaction mixture was filtered through a plug of celite, washing with methanol (30 ml). The solvents were removed in vacuo, and the residue was washed with ethyl acetate (3x10 ml) to give the title compound (161 mg, 64%) as a yellow oil, m / z (ES +) 236 (M + HX; dH (CD30D) 1.08-1.93 (11Hm), 2.79 and 2.97 (1H,), 2.99 (2H, m), 6.22 (2H, m), 6.88 ( 1H, m). Example 36 (+) -4- (3,3-Difluorocyclohexyl) -1,3-benzenediol A mixture of (±) -l- (3, 3-difluorocyclohexyl) -2,4-bis was heated at reflux for 4 h. (methoxymethoxy) benzene (30 mg), methanol (2 ml) and acid ion exchange resin (200 mg). The reaction mixture was filtered, and the resin was washed with methanol. The filtrate and the combined washings were evaporated in vacuo, and the crude residue was purified by HPLC preparation to give the title compound as a solid (5 mg, 23%). dH (CD3OD) 1.2-2.2 (8H, m), 3.08 (1H, m), 6.23-6.27 (2H, m), 6.87 (1H, d); m / z (ES ") 287 (M-1 + AcOH) 'Example 37 (+) - 3 - (2,4-Dihydroxyphenyl) cyclohexanecarboxamide It was refluxed for 5 h (+) - 3 - [2, 4- bis (methoxymethoxy) phenyl] cyclohexanecarboxaptide (22 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) The reaction mixture was filtered, and the resin was washed with methanol.The filtrate and the combined washes were evaporated in vacuo, and the crude residue was purified by HPLC preparation to give the title compound as a white solid (5 mg, 31%). dH (CD3OD) 1.45-1.82 (6H, m), 2, 07-2.19 (2H, m), 2.62-2.69 (1H, m), 3.00-3.09 (1H, m), 6. 20 - 6.28 (2H, m), 6.89 (1H, d); m / z (ES +) 236 (M + H) + Example 38 (+) - 3 - (2,4-Dihydroxyphenyl) -N-hydroxycyclohexanecarbo-xamide heated to reflux for 4 h (+) - 3 - [2, 4-bis (methoxymethoxy) phenyl] cyclohexyl J methanol (25 mg), methanol (2 ml) and acidic ion exchange resin (300 mg). The reaction mixture was filtered, and the resin was washed with methanol. The filtrate and combined 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%). dH (CD3OD) 1.28-2.40 (8H, m), 2.08-2.20 (0.5Hm), 2.78-2.94 (1H, m), 3.60-3, 72 (2H, m), 6.20-6.28 (2H,), 6.80-6.90 (1H, m); m / z (ES ') 250 (MH) + Example 39 (+) - 3 - (2,4-Dihydroxyphenyl) -N-ethylcyclohexanecarboxamide It was refluxed for 4 h (+) - 3 - [2, 4-bis] (methoxymethoxy) phenyl] -N-ethylcyclohexanecarboxamide (25 mg), methanol (2 ml) and acidic ion exchange resin (300 mg). The reaction mixture was filtered, and the resin was washed with methanol. The filtrate and combined washings were evaporated in vacuo, and the crude residue was purified by preparative HPLC to give the title compound as a solid (2 mg, 12%). dH (CD3OD) 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 (1H, m), 3.16 (2H) , q), 6.21-6.26 (2H, m), 6.88 (1H, d); m / z (ES +) 250 (M + H) + Example 40 (+) -4- [3-Hydroxy-3 - (hydroxymethyl) cyclohexyl] -1,3-benzenediol: It was refluxed for 3 h (±) - 3 - [2,4-bi (methoxymethoxy) phenyl] -1- (hydroxymethyl) cyclohexanol (29 mg), methanol (2 ml) and acidic ion exchange resin (300 mg). The reaction mixture was filtered, and the. The resin was washed with methanol. The filtrate and the combined washings were evaporated in vacuo, and the crude residue was purified by preparative HPLC to give the title compound as a cream solid (5 mg, 24%). dH (CD3OD) 1.20-2.00 (8H, m), 2.89 (1H, tt), 3.61 (1H, d), 3.69 (1H, d), 6.20-6, 26 (2H, m), 6.90 (1H, d); m / z (ES ') 237 (M-H)' Example 41 (+) -N- [3 - (2,4-Dihydroxyphenyl) cyclohexyl] acetamide It was heated to reflux for 3 h (±) -N-. { 3 - [2,4-bis (methoxymethoxy) phenyl] cyclohexyl} acetamide (20 mg), methanol (2 ml) and acid ion exchange resin (300 mg-). The reaction mixture was filtered, and the resin was washed with methanol. The filtrate and combined washings were evaporated in vacuo, and the crude residue was purified by preparative HPLC to give the title compound as a solid (5 mg, 34%). dH (CD30D) 1.10 - 2.00 (11H, 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 (1H, m); m / z (ES +) 250 (M + H) + Example 42 4- (2,4-Dihydroxyphenyl) cyclohexyl) 4- (Dimethylamino) benzoate) A mixture of trans-4 4- (dimethylamino) benzoate was stirred at room temperature. - (2, 4-bis { [Erc-butyl (di-methyl) silyl] oxy} phenyl) cyclohexyl (18 mg), methanol (5 ml) and an Amberlyst fluoride resin (0.5 g) for 24 h. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 2: 3, v / v) to give the title compound as a solid (8 mg, 73%). dH (CD3OD) 1.56-1.70 (4H, m), 1.88-1.94 (2H, m), 2.16-2.20 (2H, m), 2.80-2.90 (1H, m), 3.00 (6H, s), 6.20-2.26 (2H, m), 6.70 (2H, d), 6.92 (1H, d), 7.62 ( 2H, d); m / z (ES +) 356 (M + H) + Example 43 Cis / trans-A - (2,4-dihydroxyphenyl) cyclohexanecarboxylic acid Tetrabutylammonium fluoride (0.12 ml) was added to a stirred solution of sodium hydroxide. - (2,4-bis { [Tert-Butyl (dimethyl) silyl] oxy} phenyl) cyclohexanecarboxylic acid (22 mg) in tetrahydrofuran (1 ml) at room temperature in argon.

After 24 h, 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 (2x30 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, ethyl acetate / petrol, 7: 1 v / v, acetic acid < 1%) to give the title compound as an orange solid (10 mg, 89%). dH (CD30D) 1.40-1.65 (4H, m), 1.88-1J95 (2H, m), 2.06-2.14 (2H, m), 2.35 (1H, tt), 2.82 (1H, tt), 6.25-6.30 (2H, m), 6.90 (1H, d); m / z (ES ") 235 (MH) 'Example 44 Trans-4- (2,4-dihydroxyphenyl) cyclohexyl ethylcarbamate A mixture of trans-4- (2,4-bis) ethylcarbamate was stirred at room temperature. [tert-butyl (dimethyl) silyl] oxy] phenyl) cyclohexyl (18 mg), methanol (10 ml) and a fluoride resin Amberlyst (0.3 g) for 24 hrs. filtered, and the filtrate was evaporated in vacuo.The residue was purified by flash column chromatography (Si02, ethyl acetate / petrol, 1: 3 v / v) to give the title compound as a white solid (24 mg, 87% dH (CD3OD) 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 (1H, m), 3.10 (2H, t), 4.50-4.60 (1H, m), 6.20-6.26 (2H, m ), 6.88 (1H, d); m / z (ES +) 280 (M + H) + Example 45 Tracy-4- (2,4-dihydroxyphenyl) cyclohexyl Cyclohexylcarbamate A mixture of cyclohexate was stirred at room temperature. xylcarbamate trans-4- (2,4-bis { [tert-butyl (dimethyl) silyl-] ox i.) phenyl) cyclohexyl (28 mg), methanol (10 ml) and a fluoride resin Amberlyst (0.3 g), for 72 h. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 1: 3 v / v) to give the title compound as a white solid (6 mg, 36%). dH (CD30D) 1.10-2.12 (18H, m), 2.70-2.82 (1H, m), 4.46-4.60 (1H, m), 6.18-6.30 (2H, m), 6.80-6.92 (1H,); m / z (ES +) 334 (M + H) + General Preparation Procedure of Examples 46-53 A round bottom flask, with a stir bar, was charged with trans-4- (2,4-dihydroxyphenyl) cyclohexanol ( 208 mg, 1 mmol), dichloromethane (20 ml), triethylamine (1.4 ml, 10 mmol) and 4-dimethylaminopyridine (catalytic amount). The flask was purged with argon, and the appropriate acid chloride (5 mmol) was added dropwise, with stirring. The reaction mixture was removed for 24 h. 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 hydrogencarbonate (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 heated to 50 ° C until TLC analysis indicated complete conversion to the title compound. The reaction solution was concentrated to about one quarter of its original volume, diluted with water (10 ml) and extracted with ethyl acetate (3x10 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 (SiO2, ethyl acetate / petrol). Example 46 4- trans-4- (2,4-dihydroxyphenyl) cyclohexyl tert-butylbenzoate The title compound was isolated as an oil (180 mg, 49%), as described in the general procedure above. dH (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 (1H, m), 4.95 (1H, m), 6.24 (1H, dd), 6.27 (1H, d), 6.91 (1H, d), 7, 50 (2H, d), 7.94 (2H, d); m / z (ES +) 3-69 (M + H) + Example 47 4-Fluorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl The title compound was isolated as a white solid (133 mg, 40%), as described in the general procedure above. dH (d4-MeOH) 1.54-1.72 (4H, m), 1.82-1.95 (2H, m), 2.13-2.20 (2H, m), 2.86 (1H, m ), 4.96 (1H, m), 6.24 (1H, dd), 6.26 (1H, d), 6.91 (1H, d), 7.18 (2H,), 8.06 ( 2H, m), m / z (ES +) 331 (M + H) + Example 48 4-Trans-4- (2,4-dihydroxy phenyl) cyclohexyltrifluoromethylbenzoate The title compound was isolated as a white solid (261 mg , 69%), as described in the general procedure above. dH (d4-MeOH) 1.54-1.74 (4H, m), 1.88-1.96 (2H, m), 2.16-2.24 (2H, m), 2.88 (1H, m) ), 5.01 (1H, m), 6.25 (1H, dd), 6.28 (1H, d), 6.91 (1H, d), 7.79 (2H,), 8.17 ( 2H, m); m / z (ES +) 381 (M + H) + Example 49 4-methoxybenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl The title compound was isolated as a white solid (248 mg, 73%), as it is described in the general procedure above. dH (d4-MeOH) 1.54-1.74 (4H, m), 1.88-1.96 (2H, m), 2.16-2.24 (2H, m), 2.88 ( 1H, m), 5.01 (1H, m), 6.25 (1H, dd), 6.28 (1H, d), 6.91 (1H, d), 7.79 (2H, m), 8.17 (2H, m); m / z (ES +) 381 (M + H) + Example 50 4-Methylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyle The title compound was isolated as a white solid (75 mg, 23%), as described in the general procedure above. dH (d4-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 (1H, m), 4.98 (1H, m), 6.25 ( 2H, m), 6.92 (1H, d), 7.25 (2H, m), 7.90 (2H, m); m / z (ES +) 653 (M + H) + Example 51 4-Chlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl ° •. The title compound was isolated as a white solid (230 mg, 67%), as described in the general procedure above. dH (d4-MeOH) 1.54-1.75 (4H, m), 1.88-1.97 (2H, m), 2.15-2.24 (2H, m) 2.87 (1H, m), 4.98 (1H, m), 6.22-6.29 (2H, m), 6.92 (1H, d), 7.49 (2H, d) 8.00 (2H, d); m / z (ES +) 347 (M + H) + Example 52 3, 4-dimethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl The title compound was isolated as a white solid (84 mg, 25 mg). %), as described in the general procedure above. dH (d4-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 (1H, m), 4.95 (1H, m), 6.22-6.28 (2H, m), 6.92 (1H, d), 7.21 (1H, d), 7.75 (1H, d), 7.79 (1H, s). m / z (ES +) 341 (M + H) + Example 53 3,4-Dichlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl The title compound was isolated as a white solid (304 mg, 80%), as described in the general procedure above. dH (d4-MeOH) 1.56-1.78 (4H, m), 1.86-1.98 (2H, m), 2.12-2.23 (2H, m), 2.84 (1H , m), 4.99 (1H, m), 6.20-6.30 (2H, m), 6.92 (1H, d), 7.64 (1H, d), 7.92. (1H, d), 8.12 (1H, s), m / z (ES ') 379 (MH) "Example 54 tr < ans-4- [4- (phenylsulfanyl) cyclohexyl] -1, 3 - benzenediol A round bottom flask containing thiophenol (30 μl, 0.29 mmol), cesium fluoride was heated at 40 ° C. (44 mg, 0.29 mmol) and N, N-dimethylformamide (3 ml) during 1 hour. To this was added methane sulfonate of cis-4- (2, -bís. {[[Tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl (100 mg, 0.19 mmol) in N, N- dimethyl formamide (1 ml), and the reaction mixture was stirred at 50CC for 18 h. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (10 ml), and extracted with ethyl acetate (3x20 ml). The combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate / petrol, 1: 3) gave the title compound (23 mg, 40%) as an off-white solid. dH (d4-MeOH) 1.40-1.57 (4H, m), 1.82-1.90 (2H,), 2.04-2.16 (2H, m), 2.80 (1H, m), 3.13 (1H, m), 6.19-6.28 (2H, m), 6.88 (1H, d), 7.23 (1H, 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 trans-4- [4- (phenylsulfanyl) cyclohexyl] -1,3-benzene diol (18 mg, 0.06 mmol) and dichloromethane (2) was cooled to 0 ° C at 0 ° C. ml), and meta-chloroperbenzoic acid (50-60%, 41 mg, 0.24 mmol) was added, with stirring. After 30 min at this temperature, the reaction mixture was poured into saturated sodium thiosulfate solution (5 ml), and partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and dichloromethane (10 ml). The aqueous phase was further extracted with dichloromethane (2x10 ml), and the combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate / petrol, 30:70) gave the title compound (6 mg, 30%) as an off-white solid. dH (d4-MeOH) 1.40-1.62 (4H, m), 1.88-1.95 (2H, m), 2.05-2.13 (2H, m), 2.72 (1H , m), 3.18 (1H, m), 6.08-6.13 (2H, m), 6.82. (1H, d), 7.64 (2H, m), 7.75 (1H, m), 7.90 (2H, m); m / z (ES +) 333 (M + H) + Example 56 [4- (2,4-Dihydroxyphenyl) cyclohexyl ethyl propionate A mixture of [4- (2, 4-bis {[[tert-butyl (dimethyl) silyl] oxy} phenyl) cyclohexyl] methyl (110 mg), methanol was stirred at room temperature. (10 ml) and an Amberlyst fluoride resin (0.4 g), for 72 h. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate / petrol, 1: 2 v / v) to give the title compound as a cream solid and a mixture of diastereoisomers (44 mg, 73%). dH (CDC13) 1.17 (3H, t), 1.38-2.14 (9H, m), 2.34 -. 2.40 (2H, q), 2.64-2.80 (1H, m), 3.96 (0.6, d), 4.20 (0.4H, d), 5.10-5, 24 (2H, m), 6.28-6.33 (1H, m), 6.36-6.40 (1H,), 6.98 (1H, dd); m / z (ES +) 279 (M + H) + Examples 57 and 58 Diastereoisomers of ethyl 4- (2,4-dihydroxyphenyl) -1- hydroxycyclohexanecarboxylate A solution of an isomer of ethyl acetate was rapidly stirred. 4- (2, 4-bis { [Erc-butyl (dimethyl) silyl] oxy} phenyl) -1-hydroxy-cyclohexanecarboxylic acid ethyl ester (25 mg, 0.05 mmol) in methanol (2 ml) with Amberlyst A-26 (100 mg) for 18 h. After this time, the reaction mixture was filtered. The resin was then stirred rapidly for 1 h in a solution of methanol (2 ml) and glacial acetic acid (5 drops). The reaction mixture was filtered, and the combined filtrates were evaporated in vacuo. Purification via flash column chromatography (Si02, ethyl acetate / petrol, 2: 1) gave the title compound (3 mg, 21%) as a white solid. dH (d4-Me0H) 1.29 (3H, t) 1.61-1.69 (2H, m), 1.73-1.98 (6H, m), 2.81-2.90 (1H, m), 4.18 (2H, q), 6.21-6.27 (2H, m), 6.91 (1H, d), m / z (ES ") 279 (MH)" One was stirred rapidly dissolution of the other isomer of ethyl 4- (2, 4- bi s. {[[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-hydroxycyclohexanecarboxylate (25 mg, 0.05 mmol) in methanol ( 2 ml) with Amberlyst A-26 (100 mg) for 18 h. After this time, the reaction mixture was filtered. The resin was then stirred rapidly for 1 h in a solution of methanol (2 ml) and glacial acetic acid (5 drops). The reaction mixture was filtered, and the combined filtrates were evaporated in vacuo. Purification via flash column chromatography (Si02, ethyl acetate / petrol, 2: 1) gave the title compound (5 mg, 34%) as a white solid. dH (d4-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 (1H, m), 4.14 (2H, q), 6.11 (1H, dd), 6.15 (1H, d), 6.71 (1H, d); m / z (ES ") 279 (M-H)" Example 59 cis / trans-A - [A - (Hydroxyamino) cyclohexyl] -1,3-benzenediol Sodium cyanoborohydride was added in one portion (28 mg, 0.45 mmol) to a stirred solution of oxime from 4- (2,4-dihydroxyphenyl) cyclohexanone (90 mg, 0.41 mmol) in acetic acid (3 ml). After stirring for 16 h, an additional portion of sodium cyanoborohydride (28 mg) was added, and stirring was continued for an additional 48 h. The reaction mixture was poured into a mixture of either water (3 ml) and ethyl acetate (25 ml), and stirred for 30 min. The solution was partitioned, and the aqueous layer was further extracted with ethyl acetate (5x10 ml). The combined organics were washed with brine (15 ml), dried over magnesium sulfate, and concentrated in vacuo. Purification by HPLC gave the title compound as a pale pink solid (62 mg, -68%). dH (CD30D) 1. 57-77 (3H, m), 1.78-1.84 (1H, m), 1.90-2.09 (2H, rp), 2.27-2.12 (2H, m), 2.87 (0.6H, m), 3.03 (0.4H, m), 3. 58 (0.4H, m), 3.68 (0.6H, m), 6.25-6.32 (2H, m), 6.92 (0.6H, d), 6.99 (0, 4H, d); m / z (ES ') 222 (MH)' Example 60 traps-4- [4- (methoxyamino) cyclohexyl] -1,3-benzenediol Sodium cyanoborohydride (25 mg, 0.4 mmol) was added in one portion. ) to a stirred solution of O-methyl-4- (2) oxime., 4-dihydroxyphenyl) cyclohexanone (18 mg, 0.076 mmol) in acetic acid (1 ml). 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 hydrogencarbonate solution (10 ml), dried over magnesium sulfate, and concentrated in vacuo. Purification by flash column chromatography (SiO2, ethyl acetate / petrol, 2: 3) gave the title compound as a solid (12 mg, 66%). dH (CDC13) 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 (1H, m), 2.80-2.90 (1H, m), 3.49 (3H, s), 6.19 (1H, d), 6.24 (1H, dd), 6, 86 (1H, d); m / z (ES +) 279 (MH + CH3CN) + All patents, patent applications, and publications cited above are incorporated herein as a reference in their entirety. The present invention will not be limited in scope by the specific embodiments described herein, which are intended to be simple illustrations of individual aspects of the invention, and functionally-equivalent methods and components are within the scope of the invention. Certainly, various modifications of the invention, in addition to those shown and described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications would fall within the scope of the appended claims.

Claims (64)

NOVELTY OF THE INVENTION CLAIMS
1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: R1 is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one to three substituents independently selected from the group comprising cyano; halo; alkyl (C-j_-Cg); aril; Heterocycloalkyl (C2-C9); heteroaryl (C2-C8); arylalkyl (C1-C8); = 0; = CHOalkyl (C - ^ - Cg); Not me; hydroxy; alkoxy (C - ^ - Cg); Arylalkoxy (C-L-Cg) -; acyl (C1-Cg); alkyl (C] _-Cg) -amino-; arylalkyl (C - ^ - Cg) -amino-, - aminoalkyl (C] _- Cg) -; (C1-Cg) -CO-NH- alkoxy; alkyl (C ^ Cg) -amino-CO-; alkenyl (C2-Cg); alkynyl (C2-Cg); hydroxyalkyl (C - ^ - C6) -; (C1-Cg) alkoxy-alkyl (C] _-Cg) -; acyloxy (C ^ Cg) -alkyl (C ^ -Cg) -; nitro; cyanoalkyl (C-β-Cg) -; haloalkyl (C1-Cg) -; Nitroalkyl (C1-Cg) -; trifluoromethyl; trifluo-romethylalkyl (C1-Cg) -; acyl (C - ^ - Cg) amino-, - acyl (C ^ -Cg) -aminoalkyl (C1-Cg) -; (C 1 -C 8) alkoxy-acyl (C 1 -C 6) -amino-, -aminoacyl (C - ^ - Cg) -; aminoacyl (C - ^ - Cg) -alkyl (C 1 -C 8) -; (C 1 -C 8) alkyl-aminoacyl (C 1 -C 8) -; (alkyl (C? -C6)) 2-amino-acyl (C1-C6) -; -C02R2; -alkyl (C-j ^ -Cg) -C02R2; C (0) N (R2) 2; -alkyl (C1 ~ Cg) -C (0) N (R2) 2; R2ON =; R2ON = alkyl (C1-Cg) -; R2ON = CR2alquÍl? (C1-Cg) -; -NR2 (OR2); -alkyl (C1-Cg) -NR2 (OR2); -C (0) (NR20R2); -alkyl (C1-C8) -C (O) (NR2OR2); -S (0) mR2; wherein each R2 is independently selected from hydrogen, (C- ^ - Cg) alkyl, aryl, or arylalkyl (C-j_-C8) -; R3C (0) 0-, wherein R3 is alkyl ^ cl ~ 6 ^ 'aryl, or arylalkyl (C1-C8) -; R3C (0) O-(C1-Cg) alkyl-; R4R5N-C (0) -0-; R4R5NS (0) 2-; R4R5NS (0) 2.-alkyl? (C1-Cg) -; R4S (0) 2R5N-; R4S (0) 2R5N- (C1-Cg) alkyl-; where m 0, 1 or 2, and R 4 and R 2 are each independently selected from hydrogen or alkyl (C 2 -Cg); -C (= NR6) (N (R4) 2); or -alkyl (C] _- Cg) -C (= NR6) (N (R4) 2) in which R6 represents 0R2 or R2, where R2 is defined is defined as above; with the proviso that the cycloalkenyl ring is not aromatic; with the proviso that R1 must be substituted with at least one of R3C (0) 0-, R3C (O) O- (C1-C8) alkyl-, R20N =, R20N = (C1-C8) alkyl-, R2ON = CR2alkyl (C] _- Cg) -, -NR2 (OR2), R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (C1-Cg) -, R4S (0) 2R5N-, or R4S (O) 2R5N -alkyl (Cj-Cg) -; with the proviso that when R1 is substituted only by one of R ^ ON =, then R can not be hydrogen.
2. 2. The compound of claim 1, wherein R 1 is a cyclohexyl or cyclohexenyl ring substituted at the 3 or 4 position, or a cyclopentyl or cyclopentenyl ring substituted at the 3 position.
3. 3. The compound of claim 1, wherein R is monosubstituted.
4. 4. The compound of claim 1, wherein R1 is disubstituted.
5. 5. The compound of claim 1, wherein R is substituted with at least one of R3C (0) 0- or R3C (0) 0-alkyl (C1-Cg) -.
6. 6. The compound of claim 1, wherein R1 is substituted with at least one of R2ON =, R2ON = alkyl (C-_-C6) -, or R2ON = CR2alkyl (C1-Cg) -.
7. 7. The compound of claim 1, wherein R1 is substituted with at least one of -NR (OR2).
8. 8. The compound of claim 1, wherein R1 is substituted with at least one of R4R5NS (0) 2-, R4R5NS- (0) 2-(C1-C8) alkyl-, R4S (O) 2R5N-, or R4S ( 0) 2R5N-alkyl (C ^ Cg) -.
9. 9. The compound of claim 1, wherein Rl is substituted with at least one of R4S (0) 2R5N- or R4S (0) _2R5N- (C1-C8) alkyl-.
10. 10. The compound of claim 1, wherein R1 is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-Cg), the cycloalkyl ring being either the cycloalkenyl ring substituted with one of R3C (0). ) 0-, R3C (0) O- (C1-Cg) alkyl-, R20N =, R20N = (C1-Cg) alkyl-, R20N = CR2alkyl? (C1-Cg) -, -NR2 (OR2), R4R5NS (O) 2 -, R4R5NS (0) 2-alkyl (C1-Cg) -, R4S (0) 2R5N-, or R4S (0) 2R5N-alkyl ( C1-C8) -. ?
11. 11. The compound of claim 10, wherein R is a cycloalkyl ring (C ~ Cg) or cycloalkenyl ring (C5-Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one of R3C (0). ) 0-, R3C (0) O- (C1-Cg) alkyl-, R2ON =, or R4S (0) 2R5N-.
12. 12. The compound of claim 10, wherein R1 is substituted with R3C (0) 0- or R3C (O) O-(C1-C8) alkyl-.
13. 13. The compound of claim 10, wherein R1 is substituted with R20N =, R2ON = (C1-Cg) alkyl-, or R20N = CR2alkyl (C1-Cg) -.
14. 14. The compound of claim 10, wherein Rl is substituted with R2ON =.
15. 15. The compound of claim 10, wherein R1 is substituted with -NR2 (OR2).
16. 16. The compound of claim 10, wherein R1 is substituted with R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (C-_-R4S (0) 2R5N-, or R4S (0) 2R5N-alkyl ( Ci-C)
17. 17. The compound of claim 1, wherein R1 is substituted with R4S (0) 2R5N- or R4S (O) 2R5N-alkyl. { C? -C.X--
18. 18. The compound of claim 1, wherein the heterocycloalkyl (C2-C8) substituent is a group of the formula: where m is 0, 1 or 2, and Z is CH2, NR, O, S, SO, or S02
19. 19. The compound of claim 1, selected from the group comprising: O-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime; (+) -N- [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; (±) -0-Methyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; (+) - 0-Benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; and a pharmaceutically acceptable salt thereof.
20. 20. The compound of claim 1, selected from the group comprising: O-methyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime; (+) -4- [3- (Hydroxyamino) cyclohexyl] -1,3-benzenediol, -i-N- [A - (2,4-Dihydroxyphenyl) cyclohexyl] -1-butanesulphonamide; trans-N- [A - (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide; cis-N- [A - (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide, 4- (2,4-dimethylamino) benzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl), trans-4-tert-butylbenzoate -4- (2,4-dihydroxy e-nyl) cyclohexyl; 4-Fluorobenzoate of trans-4- (2,4-dihydroxyifenyl) cyclohexyl; 4-Trifluoromethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-trans-4- (2,4-dihydroxyphenyl) cyclohexyl 4-methoxybenzoate; trans-4- (2,4-dihydroxyphenyl) cyclohexyl 4-methylbenzoate; 4-Chlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-dimethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3,4-Dichlorobenzoate of trans -A- (2,4-dihydroxyphenyl) cyclohexyl, - [4- (2,4-dihydroxy-phenyl) -cyclohexyl] -methyl-propionate; ci s / trans-A - [4- (Hydroxyamino) cyclohexyl] -1,3-benzenediol; trans -4- [4- (Methoxyamino) cyclohexyl] -1,3-benzenediol; and a pharmaceutically acceptable salt thereof.
21. 21. A topical pharmaceutical composition for lightening the skin, or reducing skin pigmentation, in a human being, comprising a pharmaceutically acceptable carrier, and a skin brightening, or reductive pigmentation, amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one to three substituents independently selected from the group comprising cyano; halo; alkyl • (C - ^ - Cg); aril; heterocycloalkyl (C -C8); heteroaryl (C2-C8); arylalkyl (Ci-Cg); = 0; = CHOalkyl (C - ^ - Cg); Not me; hydroxy; alkoxy (Ci-Cg); arylalkoxy (Ci-Cg) -; acyl (C ^ Cg); alkyl (C1-Cg) -amino-; arylalkyl (C ^ -Cg) -amino-; aminoalkyl (Ci-Cg) -; alkoxy (Ci-Cg) -CO-NH-; alkyl (Ci-Cg) -amino-CO-; alkenyl (C2-Cg); alkynyl (C2-Cg); hydroxyalkyl (Ci-Cg) -; alkoxy (Ci-Cg) -alkyl (Ci-Cg) -; acyloxy (C ^ Cg) -alkyl (Ci-C) -, • nitro; cyanoalkyl (Ci-Cg) -; haloalkyl (C1-Cg) -; nitroalkyl (Ci-Cg) -; trifluoromethyl; trifluo-romethylalkyl (Ci-Cg) -; acyl (C ^ Cg) amino-; acyl (Ci ~ Cg) -aminoalkyl (C -C) -; alkoxy (C ^ Cg) -acyl (Ci-C8) -amino-; aminoacyl (C ^ Cg) -; aminoacyl (C ^ Cg) -alkyl (C ^ Cg) -; alkyl (C-C8) -aminoacyl (Ci-Cg) -; (alkyl (C? -Cg)) 2-amino-acyl (Ci ~ Cg) -; -C02R2; -alkyl (Ci-Cg) -C02R2; C (0)? (R2) 2; -alkyl (C ^ Cg) -C (0)? (R2) 2; R20? =; R2O? = Alkyl (Ci-Cg) -; R2ON = CR2alkyl (I-C6) -; -NR2 (0R2); -alkyl (Ci- Cg) -NR2 (OR2); CÍO) (NR20R2); -alkyl (C1-Cg) -C (O) (NR2OR2); - S (0) mR2, - in which each R2 is independently selected from hydrogen, alkyl (C-Cg), aryl, or arylalkyl (Ci- Cg) -; R3C (0) 0-, wherein R3 is alkyl (Ci-C), aryl, or arylalkyl (Ci-Cg) -; R3C (O) O-alkyl (C ^ Cg) -; R4R5N-C (O) -O-; R4R5NS (0) 2-; R4R5NS (O) 2 -alkyl (Ci-Cg) -; R4S (O) 2R5N-; R4S (0) 2R5N-alkyl (Ci-Cg) -; where mO, 1 or 2, and R4 and R5 are each independently selected from hydrogen or alkyl (Ci-Cg); -C (= NR6) (N (R4) 2); or -alkyl (C ^ Cg) - 'C (= NR6) (N (R) 2) in which Rd represents OR2 or R2,' R2 being as defined above; with the proviso that the cycloalkenyl ring is not aromatic; with the proviso that R1 must be substituted with at least one of R3C (0) 0-, R3C (O) O-alkyl (Ci-C) -, R2ON =, R2ON = alkyl (Ci-Cg) -, R2ON = CR2alkyl (Ci-Cg) -, -NR2 (OR2), R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (Ci-Cg) -, R4S (0) 2R5N-, or R4S (0) 2R5N-alkyl (Ci-Cg) -.22. The composition of claim 21, wherein
22. R of the compound is a cyclohexyl or cyclohexenyl ring substituted in the 3 or 4 position, or a cyclopentyl or cyclopentenyl ring substituted in the 3-position.
23. 23. The composition of claim 21, wherein R1 of the compound is monosubstituted.
24. 24. The composition of claim 21, wherein R of the compound is disubstituted.
25. 25. The composition of claim 21, wherein R1 of the compound is substituted with at least one of R3C (0) 0- or R3C (O) O-alkyl (Ci-Cg) -.
26. 26. The composition of claim 21, wherein Rx of the compound is substituted with at least one of R ^ ON =, R2ON = (Ci-Cg) alkyl, or R2ON = CR2alkyl (Ci-Cg) -.
27. 27. The composition of claim 21, wherein R1 of the compound is substituted with at least one of -NR2 (OR2).
28. 28. The composition of claim 21, wherein R1 of the compound is substituted with at least one of R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (C ^ Cg) -, R4S (0) 2R5N-, or R4S (0) 2R5N-alkyl (C- XX)
29. 29. The composition of claim 21, wherein R of the compound is substituted with at least one of R4NS (0) 2R5- or R4NS (O) 2R5-alkyl (C, -C6) -.
30. 30. The composition of claim 21, wherein R1 of the compound is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one of R3C (O) O-, R3C (O) O-alkyl (C ^ Cg) -, R2ON =, R2ON = alkyl (Ci-Cg) -, R2ON = CR2alkyl (Ci-Cg) -, -NR2 (OR2), R R5NS (0) 2-, R4R5NS (0) 2-alkyl (Ci-Cg) -, R4S (0) 2R5N-, or R4S (O) 2R5? -alkyl (Ci-Cg) -.
31. 31. The composition of claim 30, wherein Rx of the compound is a cycloalkyl ring (C-Cg) or cycloalkenyl ring (C5-C8), with either the cycloalkyl ring or the cycloalkenyl ring being substituted with one of R3C (O) O-, R3C (O) O-alkyl (Ci-Cg) -, R2O? =, Or R4S (0) 2R5? -.
32. 32. The composition of claim 30, wherein R1 of the compound is substituted with R3C (0) 0- or R3C (0) 0-alkyl (Ci-Cg) -.
33. 33. The composition of claim 30, wherein R1 of the compound is substituted with R 0? =, R2O? = Alk? (Ci-Cg) -, or R20? = CR2alkyl (C1-Cg) -.
34. 34. The composition of claim 30, wherein R1 of the compound is substituted with R2O? =.
35. 35. The composition of claim 30, wherein R1 of the compound is substituted with -NR2 (OR2).
36. 36. The composition of claim 30, wherein R1 of the compound is substituted with R4R5NS (0) 2-, R4R5NS- (0) 2-alkyl (Ci-Cg) -, R4S (O) 2R5N-, or R4S (O) 2R5N-alkyl
37. 37. The composition of claim 30, wherein R of the compound is substituted with R4S (O) 2R5N- or R4S (O) _ 2R5N-alkyl (Ci-Cg) - ..
38. 38. The composition of claim 21, wherein the heterocycloalkyl substituent (C2-C) is a group of the formula: where m is 0, 1 or 2, and Z is CH9, NRZ, O, S, SO, or SO-
39. 39. The composition of claim 21, comprising a compound selected from the group comprising: 4- (2,4-dihydroxyphenyl) cyclohexanone oxime; Oxima of 0-methyl-4- (2, -dihydroxyphenyl) cyclohexanone; O-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime, - 3- (2,4-dihydroxyphenyl) -2-cyclohexen-l-one oxime - (+) - 3 - (2, 4-dihydroxyphenyl) cyclohexanone; (+) -N- [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide, - (±) -A - [3- (Hydroxyamino) cyclohexyl] -1,3-benzenediol, - (O) -0-oxime -methyl-3- (2,4-dihydroxyphenyl) cyclohexa-none; (+) - O-benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none oxime; 3 - (2,4-dihydroxyphenyl) cyclopentenone oxime; (+) - 3 - (2,4-Dihydroxyphenyl) cyclopentanone oxime; and a pharmaceutically acceptable salt thereof.
40. 40. The composition of claim 21, which comprises a compound selected from the group comprising: ci s-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] -1-butanesulphonamide; trans-N- [A - (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfo-nami.d.a; cis-N- [A- (2,4-Dihydroxy phenyl) cyclohexyl] methanesulfonamide; 4- (Dimethylamino) benzoate of trans-4 - (2,4-dihydroxy e-nyl) cyclohexyl); 4-tert-Butylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Fluorobenzoate of trans-A - (2,4-dihydroxyphenyl) cyclohexyl; 4-Trifluoromethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; Trans-4- (2,4-dihydroxyphenyl) cyclohexyl 4-methoxybenzoate; 4-Methylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 4-Chlorobenzoate of trans-4- (2; 4-dihydroxyphenyl) cyclohexyl; 3, 4-dimethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, trans-4- (2,4-dihydroxyphenyl) cyclohexyl dichlorobenzoate; [4- (2,4-Dihydroxyphenyl) cyclohexyl] methyl propionate; ci s / trans-A - [A - (Hydroxy-indo) cyclohexyl] -1, 3-benzene-diol; trans -4- [4- (Methoxyamino) cyclohexyl] -1,3-benzenediol, and a pharmaceutically acceptable salt thereof.
41. 41. The composition of claim 21, wherein the skin brightening or pigment reducing effective amount of a compound of formula I is an effective amount of the tyrosinase inhibiting compound.
42. 42. A method for lightening the skin, or reducing skin pigmentation, in a human being, comprising administering to said human being an effective skin lightening, or skin pigment reducing, amount of a compound of formula I : or a pharmaceutically acceptable salt thereof, wherein: R1 is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (Cg-Cg), either the cycloalkyl ring or the cycloalkenyl ring being substituted with one to three substituents independently selected from the group comprising cyano; halo; alkyl (C ^ Cg); aril; Heterocycloalkyl (C2-C8); heteroaryl (C2-C); Arylalkyl (Ci ~ Cg); = 0; = CHOalkyl (Ci-Cg); Not me; hydroxy; alkoxy (Ci-Cg); arylalkoxy (Ci-Cg) -; acyl (C -Cg); alkyl (Ci-Cg) -amino-; arylalkyl (Ci-Cg) -amino-; aminoalkyl (Ci-Cg) -; -alkoxy (Ci-Cg) -CO-NH-; alkyl (Ci-Cg) -amino-CO-; alkenyl (C2-C8); (C2-C8) alkynyl; hydroxyalkyl (Ci-Cg) -; alkoxy (Ci-Cg) -alkyl (C ^ Cg) -;; acyloxy (C ^ Cg) -alkyl (Ci-C) -; nitro; cyanoalkyl (Ci-Cg) -; haloalkyl (Ci-Cg) -; nitroalkyl (Ci-Cg) -; trifluoromethyl; trifluo-romethylalkyl (Ci-Cg) -; acyl (C ^ Cg) amino-, - acyl (C ^ Cg) -aminoalkyl (C ^ Cg) -; alkoxy (Ci-Cg) -acyl (C ^ Cg) -amino-; aminoacyl (Ci ~ Cg) -; aminoacyl (C ~ Cg) -alkyl (Ci-C) -; alkyl (C-Cg) -aminoacyl (Ci-Cg) -; (alkyl (-C8)) 2-amino-acyl (Ci-Cg) -; -C02R2; -alkyl (Ci-Cg) -C02R2; C (0) N (R2) 2; -alkyl (C ^ Cg) -C (0) N (R2) 2; R2ON =; R2ON = alkyl (Ci-Cg) -; R2ON = CR2alkyl (Ci-Cg) -; -NR2 (0R); -alkyl (Ci-Cg) -NR2 (OR2); CÍO) (NR2OR2); -alkyl (Ci-Cg) -C (O) (NR2OR2); -S (0) "R2; wherein each R 2 is independently selected from hydrogen, alkyl (C 1 -Cg), aryl, or arylalkyl (C 1 -C 6); R 3 C (0) 0-, wherein R 3 is alkyl (C 1 Cg), aryl, or arylalkyl (Ci-Cg) -; R3C (O) O-alkyl (Ci-Cg) -; R4R5N-C (O) -O-; R4R5NS (0) 2-; R R5NS (O) 2 -alkyl (Ci) -Cg) -; R4S (0) 2R5N-; R4S (O) 2R5N-alkyl (Ci "Cg) -; wherein m 0, 1 or 2, and R4 and R5 are each independently selected from hydrogen or alkyl (C ^) Cg); -C (= NR6) (N (R4) 2); or -alkyl (C ^ Cg) -C (= NR6) (N (R4) 2) where Rd represents OR2 or R2, R2 being defined as before, with the proviso that the cycloalkenyl ring is not aromatic, with the proviso that, when R1 is a cycloalkyl ring (Cg-Cg), or when R1 is a cycloalkenyl ring (C ^ -Cg) ) that has the following structure: wherein n is 0, 1, 2 or 3, such cycloalkyl ring (Cg-Cg), or cycloalkenyl ring (Cg-Cg), substituted with hydroxy, alkoxy (C ^ Cg), arylalkoxy (C "Cg) ) -, -OC (O) -alkyl (Ci-Cg), -OC (0) -arylalkyl (Ci-Cg), OC (O) phenyl, halo, alkyl (Ci-Cg) -, arylalkyl (C ^ Cg) ) -, -SH, -S-alkyl (Ci-Cg), arylalkyl (Ci-Cg) -S-, -NH2, -NH-alkyl (Ci-Cg), or arylalkyl (Ci-Cg) -NH-; then the cycloalkyl ring (C5-Cg), or the cycloalkenyl ring (Cg-Cg), must be di- or trisubstituted.
43. 43. The method of claim 42, wherein R1 of the compound is a cyclohexyl or cyclohexenyl ring substituted at the 3 or 4 position, or a cyclopentyl or cyclopentenyl ring substituted at the 3 position.
44. 44. The method of claim 42, wherein R of the compound is monosubstituted.
45. 45. The method of claim 42, wherein R1 of the compound is disubstituted.
46. 46. The method of claim 42, wherein R1 of the compound is substituted with at least one of RJC (O) 0- or R3C (O) O-alkyl (C ^ Cg) -.
47. 47. The method of claim 42, wherein R1 of the compound is substituted with at least one of R2QN_
48. 48. The method of claim 42, wherein R1 of the compound is substituted with at least one of -NR (OR2).
49. 49. The method of claim 42, wherein R of the compound is substituted with at least one of R R5NS- (0) 2-, R4R5NS (0) 2 -alkyl (Ci-Cg) -, R4S (0) 2R5N-, or R4S (0) _ 2R5N-alkyl (Ci-C) -.
50. 50. The method of claim 42, wherein R1 of the compound is substituted with at least one of R4S- (0) 2R5N- or R4S (0) 2R5N-alkyl (Ci-Cg) -. ?
51. 51. The method of claim 42, wherein R of the compound is a cycloalkyl ring (C-Cg) or cycloalkenyl ring (C5-C8), with either the cycloalkyl ring or the cycloalkenyl ring being substituted with one of R3C (0) 0-, R3C (0) O-alkyl (Ci-Cg) -, R20N =, R20N = alkyl (Ci-Cg) -, R20N = CR2alkyl (Ci-Cg) -, -NR2 (OR2j, R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (Ci-Cg) -, R4S (0) 2R5N-, or R4S (0) 2R5N-alkyl (Ci-Cg) -.
52. 52. The method of claim 51, wherein R1 of the compound is a cycloalkyl ring (C3-Cg) or cycloalkenyl ring (C5-Cg), either the cycloalkyl ring or the cycloalkenyl ring substituted with one of R3C (0) 0-, R3C (0) O-alkyl (Ci-Cg) -, R2ON =, or R4S (O) 2R5N-.
53. 53. The method of claim 51, wherein R1 of the compound is substituted with R3C (0) 0- or R3C (0) 0-alkyl (Ci-Cg) -.
54. 54. The method of claim 51, wherein R1 • of the compound is substituted with R2ON =, R2ON = alkyl (Ci-Cg) -, or R2ON = CR2alkyl (Ci-Cg) -.
55. 55. The method of claim 51, wherein R ^ of the compound is substituted with R2ON =.
56. 56. The method of claim 51, wherein R1 of the compound is substituted with -NR2 (OR2).
57. 57. The method of claim 51, wherein R1 of the compound is substituted with R4R5NS (0) 2-, R4R5NS (0) 2-alkyl (Ci-Cg) -, R4S (0) 2R5N-, or R4S (O) 2R5N -alkyl (Ci ~
58. 58. The method of claim 51, wherein R of the compound is substituted with R4S (0) 2R5N- or R4S (0) 2R5N-alkyl (C ^ Cg) -.
59. 59. The method of claim 42, wherein the heterocycloalkyl substituent. { C2 - Q) is a group of the formula: where m is 0, 1 or 2, and Z is CH2, NR2, 0, S, SO, or S02
60. 60. The method of claim 46, wherein R1 is a group of the formula: which is substituted according to claim 1; wherein n is 0, 1 or 2; and in which the broken line indicates an optional double bond in that position.
61. 61. The method of claim 60, wherein R of the compound is substituted with = 0, = N0H, CH20H, OH < Me or a combination thereof.
62. 62. The method of claim 42, wherein the compound is selected from the group comprising: 4- (2,4-Dihydroxyphenyl) cyclohexanone; • Oxima of 4-. (2,4-dihydroxyphenyl) cyclohexanone; O-methyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime, O-benzyl-4- (2,4-dihydroxyphenyl) cyclohexanone oxime; 3 - . 3 - (2,4-Dihydroxyphenyl) -2-cyclohexen-1-one; (±) -3 - (2,4-Dihydroxyphenyl) cyclohexanone; 3- (2,4-Dihydroxyphenyl) -2-cyclohexen-1-one oxime; Oxime of (±) -3- (2,4-dihydroxyphenyl) cyclohexanone; (±) -4 - [3 - (Piperazinyl) cyclohexyl] -1, 3-benzenediol, - (+) - N - [3- (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfonamide, - (±) -4- [ 3- (Hydroxymethyl) cyclohexyl] -1,3-benzenediol; (±) -4- [3- (Hydroxyamino) cyclohexyl] -1, 3-benzenediol; ci s / trans-A - [A - (Hydroxymethyl) cyclohexyl] -1,3-benzenediol; cis / trans- A - (4-Hydroxy-4-methylcyclo-? exyl) -1,3-benzenediol; (±) -O-methyl-3- (2, -dihydroxyphenyl) cyclodextrone, - (±) -3- (2,4-Dihydroxyphenyl) -1-methylcyclohexanol; Oxime of (+) - 0-benzyl-3- (2,4-dihydroxyphenyl) cyclohexa-none; Oxime of 3- (2,4-dihydroxyphenyl) cyclopentenone; (±) -3- (2,4-Dihydroxyphenyl) cyclopentanone; Oxime of (±) -3- (2,4-dihydroxyphenyl) cyclopentanone; and a pharmaceutically acceptable salt thereof.
63. 63. The method of claim 42, wherein the compound is selected from the group comprising: 4- (2,4-Dihydroxyphenyl) -3-cyclohexen-1-one, - cis / trans-N- [A- (2, 4 -Dihydroxyphenyl) cyclohexyl] acetamide; ci s-N- [4- (2,4-Dihydroxyphenyl) cyclohexyl] -1-butanesulphonamide; trans -N- [A - (2, -Dihydroxyphenyl) cyclohexyl] methanesulfonamide, - cis-N- [A - (2,4-Dihydroxyphenyl) cyclohexyl] methanesulfone-mide; 4- [4- (4-Hydroxyphenyl) cyclohexyl] -1,3-benzenediol; cis / trans- [4 - (2,4-Dihydroxyphenyl) cyclohexyl] methyl acetate; methyl- [4- (2, 4-Dihydroxyphenyl) cyclohexyl] acetate; ci s- [A - (2, -Dihydroxyphenyl) cyclohexyl] methyl acetate; Trans- [A - (2,4-dihydroxyphenyl) cyclohexyl] acetic acid; Ci s- [A - (2,4-dihydroxyphenyl) cyclohexyl] acetic acid, - cis / trans- [A - (2,4-dihydroxyphenyl) cyclohexyl] acetic acid; cis / trans- [A - (2,4-Dihydroxyphenyl) cyclohexyl] acetonitrile; cis / trans- A - [4 - (2-aminoethyl) cyclohexyl] -1,3-benzene diol; (±) -A- (3, 3-Difluorocyclohexyl) -1, 3-benzenediol; (±) -3- (2,4-Dihydroxyphenyl) cyclohexanecarboxamide; (±) -3- (2,4-Dihydroxyphenyl) - N-hydroxydichexanocarbo-xamide; (+) - 3 - (2,4-Dihydroxyphenyl) -N-ethylcyclohexanecarboxamia-da; (±) - A - [3-Hydroxy -3- (hydroxymethyl) cyclohexyl] -1,3-benzenediol; (+) - N- [3- (2,4-Dihydroxyphenyl) cyclohexyl] acetamide; 4- (2,4-Dihydroxyphenyl) cyclohexyl) 4- (Dimethylamino) benzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl) - cis / trans-A - (2,4-dihydroxyphenyl) cyclohexanecarboxylic acid; Ethylcarbamate of trans-A - (2,4-dihydroxyphenyl) cyclohexyl; Trans-4- (2,4-dihydroxyphenyl) cyclohexyl cyclohexylcarbamate; 4- trans-butylbenzoate of trans -A- (2,4-dihydroxyphenyl) cyclohexyl; 4-Fluorobenzoate of trans-A - (2,4-dihydroxyphenyl) cyclohexyl; 4-Trifluoromethylbenzoate of trans-A- (2,4-dihydroxyphenyl) cyclohexyl; 4-trans-4- (2,4-dihydroxyphenyl) cyclohexyl 4-methoxybenzoate; trans-4- (2,4-dihydroxyphenyl) cyclohexyl 4-methylbenzoate; 4-Chlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-dimethylbenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; 3, 4-Dichlorobenzoate of trans-4- (2,4-dihydroxyphenyl) cyclohexyl; trans -4- [4- (Phenylsulfanyl) cyclohexyl] -1,3-benzenediol; trans-4- [A - (Phenylsulfonyl) cyclohexyl] -1,3-benzenediol, - [4- (2,4-dihydroxyphenyl) cyclohexyl] methyl] propionate, 4- (2,4-dihydroxyphenyl) -1-hydroxycyclohexanecarboxylate or ethyl; ci s / trans- A - [A - (Hydroxyamino) cyclohexyl] -1,3-benzenediol; trans -4- [4- (Methoxyamino) cyclohexyl] -1,3-benzenediol; and a pharmaceutically acceptable salt thereof.
64. 64. The method of claim 42, wherein the skin brightening or pigment reducing effective amount of a compound of formula I is an effective amount of the tyrosinase inhibiting compound.