Substituted hydroxystilbene compounds and derivatives, synthesis and uses thereof

Abstract

The present disclosure relates to substituted hydroxystilbene compounds and derivatives, particularly 2-substituted hydroxystilbene compounds and derivatives, the synthesis of such compounds, and their use in therapy.

Description

Technical Field

[0001] The present disclosure relates to substituted hydroxystilbene compounds and derivatives, specifically 2-substituted hydroxystilbene compounds and derivatives, the synthesis of such compounds, and their use in therapy.

Background Art

[0002] WO 2012 / 149608 pamphlet discloses novel prenylated polyhydroxystilbene derivatives and a method for preparing such compounds via a plurality of steps. One of the steps is an O- to C-prenyl rearrangement step generally outlined below.

[0003]

Chemical Formula

[0004] There is a need for alternative methods for generating substituted hydroxystilbene compounds and derivatives, specifically 2-substituted hydroxystilbene compounds and derivatives.

[0005] Any consideration of documents, acts, materials, devices, articles, etc. included in this specification should not be construed as an admission that any or all of these matters form part of the basis of the prior art or are common general knowledge in the relevant field of the present disclosure existing prior to the priority date of each of the appended patent claims.

Summary of the Invention

[0006] In the research leading up to the present disclosure, the inventors have synthesized a wide range of 2-substituted hydroxystilbene compounds by a novel method that provides an efficient and commercially viable route to several important compounds in drug therapy. The novel method has also made available various novel compounds that have been shown to be promising candidates for use in the treatment of, for example, cancer and skin diseases and disorders.

[0007] The present disclosure relates to formula (I)

[0008]

Chemical formula

[0009] As referred to herein, the 2-substituted hydroxystilbene compound according to formula (I) is represented by two benzene rings designated as ring A and ring B. The A-ring referred to herein represents a benzene ring carrying substituents R 1a、 R 1b 、R 1c and R 1d and the B-ring referred to herein represents a benzene ring carrying substituents R 1e 、R 1f and R 1g .

[0010] The present disclosure utilizes a modular approach for synthesizing compounds of formula (I). The A and B rings of the 2-substituted hydroxystilbene compounds are formed from two separate modules, Module A and Module B, respectively. Module A is a halo or hydroxyl benzaldehyde derivative, and Module B is an aromatic phosphonate derivative. According to the present disclosure, coupling of the halo / hydroxybenzaldehyde (Module A) with the aromatic phosphonate (Module B) provides the 2-halo or 2-hydroxy substituted hydroxystilbene derivative (Module C) mentioned above.

[0011] Throughout this specification, the 2-halo or 2-hydroxy substituted hydroxystilbene derivative (Module C) may be referred to as a 2-halo / hydroxyl substituted hydroxystilbene derivative, a 2-halo / hydroxyl hydroxystilbene derivative, a 2-halo / hydroxyl hydroxystilbene or Module C, and includes both 2-halo substituted hydroxystilbene derivatives and 2-hydroxy substituted hydroxystilbene derivatives, as well as variations of the equivalent names mentioned previously.

[0012] The inventors have surprisingly found that this methodology enables an alternative synthesis of 2-substituted hydroxystilbene compounds and the versatility of substitution at the 2-position of 2-substituted hydroxystilbene compounds such that the group substituted at the 2-position can be extended beyond a prenyl group. Accordingly, the present disclosure provides a method for preparing a 2-substituted hydroxystilbene compound of formula (I) as described above, wherein the addition of a 2-alkenyl or benzyl group at the R 1a position occurs by direct coupling of a 2-alkenyl or benzyl group of a boronic acid / derivative or an organostannane compound containing the same with a 2-halo / hydroxy substituted hydroxystilbene derivative.

[0013] In one embodiment, the synthesis of the compounds of formula (I) above is advantageously efficient in terms of having a small number of synthetic steps from the prepared starting modules and of the versatility and flexibility for use in the preparation of a wide range of synthetic derivatives. In another embodiment, each step of the synthesis starting from the prepared modules has a high yield.

[0014] In one embodiment, the method for preparing the compounds of formula (I) as defined above, when R 1a is a prenyl group, results in an improved yield over the steps disclosed in WO 2012 / 149608, whereby a mixture of products is formed.

[0015] One embodiment of the present disclosure provides a synthetic method in which the O- to C-prenyl rearrangement step disclosed in WO 2012 / 149608 is replaced by a direct coupling of a prenyl group to an aromatic ring via a coupling of a prenyl boronic acid / ester or prenyl tributylstannane with a 2-halo or 2-hydroxyl substituted hydroxystilbene derivative. Advantageously, groups other than prenyl can be added to the R 1a position of the hydroxystilbene structure.

[0016] Advantageously, the inventors are able to employ the general methodology disclosed herein to efficiently prepare previously identified 2-prenylhydroxystilbene compounds that are important for drug therapy on a commercial scale. Due to the generality of the methodology disclosed herein, the inventors were able to prepare a wide range of 2-substituted hydroxystilbene compounds of formula (I) that were previously impossible to prepare using the rearrangement method. The inventors have surprisingly found that the 2-substituted hydroxystilbene compounds of formula (I) prepared by the methodology disclosed herein are promising candidates for the development of new therapeutic agents in the treatment of diseases such as cancer and skin diseases and disorders such as atopic dermatitis and psoriasis.

[0017] In the first aspect, the present disclosure relates to formula (I)

[0018] [Chemical formula] (wherein R 1a is independently allyl, crotyl, prenyl, geranyl, farnesyl, benzyl or 2-alkenyl, 2-alkynyl, R 1b is independently CF 3 , OH or OR 2 , NO 2 , NHEt, NMe 2 , NMeEt, NHR 3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 , R 1c is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl, R 1d is independently CF 3 , OH or OR 2 , NHR 3 , NO 2 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 , R 1e is independently H, C 1 ~C 6 alkyl, OH, OR 2 , NO 2 , NMe 2 , NHR 3 , NMeR 3 , NHC(O)H or SR 2 , R 1f is independently H, OH, OR 2 , NO 2 , NHR 3 , NHC=NH(NH 2 )), COOR 2 , COOH, R1g is, independently, H, alkyl, CF 3 , OH or OR 2 and R 1e , R 1f or R 1g is at most one of which may be H, or R 1e is, independently, OH, NH 2 or NHMe, and when R 1f is NH 2 then R 1e and R 1f form a 5- or 6-membered heterocyclic ring containing a carbonyl group or (CO)CH 2 group, resulting in cross-linking of the nitrogen of R 1f to the carbonyl group or (CO)CH 2 group and to the oxygen or nitrogen of R 1e . R 2 is, independently, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR 4 , or, when R 2 is attached to O, an O-protecting group, R 3 is, independently, H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CH 2 COOH, CH 2 COOR 2 , CO(CH 2 ) n NH 2 , CONH 2 , CO(CH 2 ) n COOH or COCOOR 4 and n is 0, 1 or 2, R 4 is a method for synthesizing a compound by (C 1 ~C 6 alkyl), comprising i) coupling a compound of formula (II) (module A) with a compound of formula (III) (module B) to obtain a compound of formula (IV) (module C):

[0019] [Chemical formula] (wherein, In formula II (module A), R 2b is independently CF 3 , OH, OR 2 , NO 2 , NMe 2 , NHEt, NMeEt, NHR 3 or NMeR 3 , R 2c is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl, R 2d is independently CF 3 , OH or OR 2 , NO 2 , NHR 3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 , X is a halide or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I and At, R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, R 3 is independently H, OH, CH 3 , (CO)H, COMe, SO 2 Me, COCH 2 NH 2 or CH 2 COOR 2 , In formula III (module B), R 3e is independently H, C 1 ~C 6 alkyl, OH, OR 2 , NO2 、 NHMe, NMe 2 、 NHR 3 or NMeR 3 、 SR 2 and R 3f is independently H, OH, OR 2 、 NO 2 、 NHR 3 、 NHC=NH(NH 2 )、 COOH or COOR 2 and R 3g is independently H, alkyl, CF 3 、 OH or OR 2 and R 3e 、 R 3f or R 3g One or less of them can be H, or R 3e is OH, NH 2 or NHMe, and when R 3f is NH 2 and R 3e and R 3f form a 5- or 6-membered heterocyclic ring containing a carbonyl group or (CO)CH 2 group, and as a result, the nitrogen of R 3f is cross-linked to the carbonyl group or (CO)CH 2 group and the oxygen or nitrogen of R 3e and R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, and R 3 is independently H, CH 3 、 OH, (CO)H, COMe, SO 2 Me, COCH 2 NH 2 、 CH 2 COOH or CH 2 COOR 2 and In formula IV (module C), R 4bis independently CF 3 , OH or OR 2 , NO 2 , NMe 2 , NHEt, NMeEt, NHR 3 or NMeR 3 ; R 4c is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl; R 4d is independently CF 3 , OH or OR 2 , OR 3 , NO 2 or NHR 3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 ; R 4e is independently H, C 1 ~C 6 alkyl, OH, OR 2 , NO 2 , NMe 2 , NHR 3 or NMeR 3 , SR 2 ; R 4f is independently H, OH, OR 2 , NO 2 , NHR 3 , NHC=NH(NH 2 )), COOH or COOR 2 ; R 4g is independently H, alkyl, CF 3 , OH or OR 2 ; R 4e , R 4F or R 4g is at most one H; or R 4e is OH, NH 2 or NHMe and R 4f is NH 2 then R 4e and R4f forms a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group, such that the nitrogen of R 4f is cross-linked to the carbonyl group or (CO)CH 2 group and the oxygen or nitrogen of R 4e is cross-linked to the carbonyl group or (CO)CH R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, R 3 is independently H, CH 3 , OH, (CO)H, COMe, SO 2 Me, COCH 2 NH 2 , CH 2 COOH or CH 2 COOR 2 and X is a halide or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I, and At), provides a method.

[0020] The 2-substituted halo / hydroxy hydroxystilbene compound according to formula (IV) (module C) undergoes a further reaction to yield the compound of formula (I) described herein.

[0021] In one embodiment, the 2-substituted halohydroxy hydroxystilbene compound according to formula (IV) (module C) undergoes a further coupling reaction with a 2-alkenyl or benzylboronic acid or ester, a 2-alkenyl or benzyl trifluoroborate compound, or a 2-alkenyl or benzyl organostannane compound to yield the compound of formula (I).

[0022] In another embodiment, when X is hydroxyl in formula (IV), activation of the hydroxyl to a triflate group (OTf, trifluoromethylsulfonate) is required prior to coupling with a 2-alkenyl or benzyl boronic acid or ester, a 2-alkenyl or benzyl trifluoroborate compound or a 2-alkenyl or benzyl organostannane compound to obtain a compound of formula (I).

[0023] The compounds of formula (IV) or (I) may optionally undergo one or more additional reactions including, but not limited to, reaction with one or more -NH 2 , NO 2 and / or -OH substituents on formula (IV) or (I).

[0024] In a second aspect, the present disclosure provides a compound of formula (I)

[0025]

Chemical formula

[0026] In a third aspect, the present disclosure relates to a compound of formula (I)

[0027]

Chemical formula

[0028] In a fourth aspect, the present disclosure provides a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the second or third aspect of the present disclosure, or a pharmaceutically acceptable salt, solvate or pharmaceutical composition comprising said compound.

[0029] In a fifth aspect, the present disclosure provides a method for treating a skin disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the second or third aspect of the present disclosure, or a pharmaceutically acceptable salt, solvate or pharmaceutical composition comprising said compound.

[0030] Description of Embodiments Formula (I)

[0031] [Chemical formula] (In the formula, R 1a is independently allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl or 2-alkynyl, R 1b is independently CF 3 , OH, OR 2 , NO 2 , NHEt, NMe 2 , NMeEt, NHR 3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 and R 1c is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl, R 1d is independently CF 3 , OH, OR2 , NHR 3 , NO 2 , NMeR 3 , NHC=NH(NH 2 ), or COOR 2 and R 1e is independently H, C 1 ~C 6 alkyl, OH, OR 2 , NO 2 , NMe 2 , NHR 3 or NMeR 3 , NHC(O)H, SR 2 and R 1f is independently H, OH, OR 2 , NO 2 , NHR 3 , NHC=NH(NH 2 ), COOR 2 , COOH and R 1g is independently H, alkyl, CF 3 , OH or OR 2 and R 1e , R 1f or R 1g one or less of which may be H, or R 1e is independently OH, NH 2 or NHMe, and when R 1f is NH 2 , R 1e and R 1f form a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group, as a result, the nitrogen of R 1f is crosslinked to the carbonyl group or the (CO)CH 2 group and the oxygen or nitrogen of R 1e , R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR 4 , or, when R 2 is attached to O, it is an O-protecting group, R 3 is independently H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CH 2 COOH, CH 2 COOR 2 , CO(CH 2 ) n NH 2 , CONH 2 , CO(CH 2 ) n COOH or COCOOR 4 and n is 0, 1 or 2, R 4 is C 1 ~C 6 alkyl), a method for synthesizing a compound of i) coupling a compound of formula (II) (module A) with a compound of formula (III) (module B) to obtain a compound of formula (IV) (module C)

[0032]

Chemical formula

[0033] The O-protecting group can be selected from those known in the art. Suitable O-protecting groups for use in the present application may be known to those skilled in the art.

[0034] The O-protecting group can be COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 and can be.

[0035] According to the compounds defined herein by formula (I), formula (III) and formula (IV), R 1e、3e、4e and R 1f、3f、4f are such that when R 1e、3e、4e is OH, NH 2 or NHMe, and R 1f、3f、4f is NH 2 , a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group can be formed, such that the nitrogen of R 1f、3f、4f is cross-linked to the carbonyl group or the (CO)CH 2 group and the oxygen or nitrogen of R 1e、3e、4e . In one embodiment, the nitrogen of R 1f、3f、4f is cross-linked to the carbonyl group or the (CO)CH 2 group and the oxygen or nitrogen of R 1e、3e、4e to form a group selected from any one of the groups -NH-C(O)-O-, -NH-C(O)-CH 2 -O-, -NH-CH 2 C(O)-O-, -NH-C(O)-NH-, -NH-C(O)CH 2 -NH-, -NH-CH 2 C(O)-NH-, -NH-C(O)-N(Me)-, -NH-C(O)CH 2 -NMe- or -NH-CH 2 C(O)-N(Me)-. In one embodiment, R 1f、3f、4f is NH 2 , R 1e、3e、4e is NHMe, and the nitrogen of R 1f、3f、4f is cross-linked to the carbonyl group and the nitrogen of R 1e、3e、4e to form -NH-C(O)-N(Me)-, such that R 1e、3e、4e and R 1f、3f、4fforms a 5-membered heterocyclic ring. In another embodiment, R 1f、3f、4f is NH 2 and R 1e、3e、4e is OH, and the nitrogen of R 1f、3f、4f is cross-linked to the carbonyl group and the oxygen of R 1e、3e、4e to form -NH-C(O)-O-, and as a result, R 1e、3e、4e and R 1f、3f、4f form a 5-membered heterocyclic ring.

[0036] The 2-substituted halo / hydroxyhydroxystilbene compounds according to formula (IV) (module C) are subject to further reactions to yield the compounds of formula (I) described herein.

[0037] In modules A and C, the X group is a halide or a hydroxyl group. In one embodiment, X is a halide. When X is a halide, formulas (II) and (IV) may be referred to as the halide of formula (II) and the halide of formula (IV). In another embodiment, X is a hydroxyl group. When X is a hydroxyl, formulas (II) and (IV) may be referred to as the hydroxyl of formula (II) and the hydroxyl of formula (IV). The hydroxyl of formula (IV) can be activated to the corresponding triflate (trifluoromethylsulfonate) group and may be referred to as the triflate of formula (IV) or the 2-substituted triflate hydroxystilbene of formula (IV).

[0038] The conversion of the hydroxyl group to a triflate group can be carried out according to processes known in the art. In one embodiment, when X is a hydroxyl, the hydroxyl of formula (IV) is treated with trifluoromethanesulfonic anhydride in the presence of N-methylmorpholine to yield the triflate of formula (IV).

[0039] In one embodiment, when X is a halide in formula (IV) (the halide of formula (IV)), then a) an R 1a -substituted boronic acid compound or ester, b) an R1a - a substituted trifluoroborate compound, or c) R 1a - a substituted organostannane compound, undergoes a coupling reaction with one of them to form a compound of formula (I).

[0040] In one embodiment, the 2-substituted halohydroxystilbene compound according to formula (IV) (module C) undergoes a further coupling reaction with a 2-alkenyl or benzylboronic acid or ester to yield a compound of formula (I). In one embodiment, the 2-substituted halohydroxystilbene compound according to formula (IV) (module C) undergoes a further coupling reaction with a 2-alkenyl or benzyl trifluoroborate compound to yield a compound of formula (I). In another embodiment, the 2-substituted halohydroxystilbene compound according to formula (IV) (module C) undergoes a further coupling reaction with a 2-alkenyl or benzyl organostannane compound to yield a compound of formula (I).

[0041] In one embodiment, when X is hydroxyl in formula (IV) (the hydroxyl of formula (IV)), activation of the hydroxyl to a triflate group (OTf, trifluoromethylsulfonate) is required before coupling can occur. In one embodiment, the hydroxyl group of formula (IV) is converted to a triflate (trifluoromethylsulfonate) group to form the triflate of formula (IV), and the triflate of formula (I)) is as follows a) R 1a - a substituted boronic acid compound or ester, b) R 1a - a substituted trifluoroborate compound or c) R 1a - a substituted organostannane compound undergoes a coupling reaction with one of them to form a compound of formula (I).

[0042] In one embodiment, the 2-substituted hydroxy hydroxystilbene compound according to formula (IV) (module C) is activated to 2-substituted triflate hydroxystilbene, which then undergoes a coupling reaction with a 2-alkenyl or benzylboronic acid or ester to yield the compound of formula (I). In another embodiment, the triflate of formula (IV) undergoes a further coupling reaction with a 2-alkenyl or benzyl trifluoroborate compound to yield the compound of formula (I). In other embodiments, the triflate of formula (IV) undergoes a further coupling reaction with a 2-alkenyl or benzyl organostannane compound to yield the compound of formula (I).

[0043] In one embodiment, the halogen compound according to formula (IV) or the triflate of formula (IV) described herein undergoes a coupling reaction with an R 1a -substituted boronic acid compound to form the compound of formula (I), where R 1a is selected from the group consisting of allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl and 2-alkynyl.

[0044] In another embodiment, the halogen compound according to formula (IV) or the triflate of formula (IV) described herein undergoes a coupling reaction with an R 1a -substituted organostannane compound to form the compound of formula (I), where R 1a is selected from the group consisting of allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl and 2-alkynyl.

[0045] In another embodiment, the halogen compound according to formula (IV) or the triflate of formula (IV) described herein undergoes a coupling reaction with an R 1a -substituted trifluoroborate to form the compound of formula (I), where R 1a is selected from the group consisting of allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl and 2-alkynyl.

[0046] In another embodiment, R in formulas (II) and (IV) 1a substituents are selected from the group consisting of allyl, crotyl, prenyl, benzyl or 2-alkenyl. In another embodiment, R 1a is selected from the group consisting of allyl, crotyl, prenyl or benzyl.

[0047] The coupling reaction of the compound of formula (IV) or the triflate of formula (IV) described herein with an R 1a -substituted boronic acid compound, an R 1a -substituted organostannane compound or an R 1a -substituted trifluoroborate can be catalyzed by a suitable catalyst comprising a palladium compound. Palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0) and dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II). The coupling reactions described herein can also be carried out in the presence of a base including, but not limited to, alkali metal carbonates such as potassium carbonate (K 2 CO 3 ), bicarbonates, calcium carbonate, magnesium carbonate and alkylamines including triethylamine.

[0048] In one embodiment, the R 1a -substituted boronic acid compound is allyl, crotyl, prenyl, benzyl, 2-alkenylboronic acid pinacol ester. Prenylboronic acid pinacol ester includes, but is not limited to, 3-methylbut-2-enylboronic acid pinacol ester, crotylboronic acid pinacol ester, allylboronic acid pinacol ester, benzylboronic acid pinacol ester.

[0049] In one embodiment, the halogen compound according to formula (IV) or the triflate of formula (IV) as defined herein is catalyzed by a palladium catalyst in the presence of a base for an R 1a-Undergoes a coupling reaction with a substituted boronic acid pinacol ester. In another embodiment, the halogen compound according to formula (IV) is R catalyzed by tetrakis(triphenylphosphine)palladium(0). 1a -Undergoes a coupling reaction with a substituted tributylstannane.

[0050] In another embodiment, the halogen compound according to formula (IV) or the triflate of formula (IV) as defined herein is R 1a -Undergoes a coupling reaction with a substituted trifluoroborate. In a particular embodiment, the halide or triflate compound according to formula (IV) undergoes a coupling reaction with potassium allyltrifluoroborate catalyzed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and triethylamine. By this coupling method, an allyl group is obtained at the R 1a position on the A ring.

[0051] In one embodiment, formula (I) (wherein In formula (I), R 1a is independently allyl, crotyl, prenyl, benzyl or 2-alkenyl, R 1b is independently OH, OR 2 or NHC(O)Me, R 1c is H, R 1d is independently OH, NHR 3 , NH(CO)H or NO 2 , R 1e is independently OH, OR 2 , NMe 2 , NHR 3 , NMeR 3 , NHC(O)H or SR 2 , R 1f is independently H, OH, NO 2 , OR 2 , NHR 3, NHC=NH(NH 2 ) or COOH, and R 1g is independently H, alkyl, OH or OR 2 , and R 1e , R 1f or R 1g of one or less may be H, or R 1e is OH, NH 2 or NHMe, and when R 1f is NH 2 , R 1e and R 1f form a 5- or 6-membered heterocyclic ring containing a carbonyl group, resulting in the nitrogen of R 1f being cross-linked to the carbonyl group and the oxygen or nitrogen of R 1e , R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, or, when R 2 is attached to O, an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2. selected from the group consisting of, R 3 is independently H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CO(CH 2 ) n NH 2 , CH 2 COOR 2 , CO(CH 2 ) n COOH or COCOOR 4 , and n is 0, 1 or 2, R 4 is C 1 ~C 6 alkyl, In formula II (module A), R 2b is OH or OR 2 and R 2c is H R 2d is independently OH or OR 2 NO 2 NHR 3 or COOR 2 and X is a halide (Hal) or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I, and At R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or an O-protecting group R 3 is independently H, OH, CH 3 (CO)H, COMe, SO 2 Me, COCH 2 NH 2 or CH 2 COOR 2 and In formula III (module B), R 3e is independently OH, OR 2 NO 2 NHMe, NMe 2 NHR 3 NMeR 3 or SR 2 and R 3f is independently H, OH, OR 2 NO 2 NHR 3 NHC=NH(NH 2 )), COOH, COOR 2 and R 3g is independently H, alkyl, OH, OR 2 and R 3e R 3f or R 3g at most one of them may be H or R 3eis OH, NH 2 or NHMe, and R 3f is NH 2 in the case where R 3e and R 3f form a 5- or 6-membered heterocyclic ring containing a carbonyl group or (CO)CH 2 group, and as a result, the nitrogen of R 3f is cross-linked to the carbonyl group or (CO)CH 2 group and the oxygen or nitrogen of R 3e ; R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group; R 3 is independently H, CH 3 , OH, (CO)H, COMe, SO 2 Me, COCH 2 NH 2 , CH 2 COOH or CH 2 COOR 2 ; In Formula IV (Module C), R 4b is OH or OR 2 , NHC(O)Me; R 4c is H; R 4d is independently OH or OR 2 , NO 2 or NHR 3 , NMeR 3 ; R 4e is independently OH, OR 2 , NO 2 , NMe 2 , NHR 3 or NMeR 3 , NHC(O)H or SR 2 ; R 4f is independently H, OH, OR 2 , NO 2 , NHR3 , NHC=NH(NH 2 ), COOH or COOR 2 wherein R 4g is independently H, alkyl, CF 3 , OH or OR 2 wherein R 4e , R 4f or R 4g is at most one of H, or R 4e is OH, NH 2 or NHMe, and when R 4f is NH 2 , R 4e and R 4f form a 5- or 6-membered heterocyclic ring containing a carbonyl group or (CO)CH 2 group, such that the nitrogen of R 4f is cross-linked to the carbonyl group or (CO)CH 2 group and the oxygen or nitrogen of R 4e , R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, R 3 is independently H, CH 3 , OH, (CO)H, COMe, SO 2 Me, COCH 2 NH 2 , CH 2 COOH or CH 2 COOR 2 wherein X is a halide or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I and At), a method for synthesizing a compound is provided.

[0052] In one embodiment, formula (I)

[0053]

Chemical formula

[0054] [Chemical formula] (wherein in formula II (module A), R 2b is CF 3 , OH, OR 2 , NO 2 , NMe 2 , NHEt, NMeEt, NHR 3 or NMeR 3 and R 2c is H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl, R 2d is CF 3 , OH or OR 2 , NO 2 , NHR 3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 and X is a halide (Hal) or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I and At, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl or an O-protecting group, R 3 is H, OH, CH 3 , (CO)H, COMe, SO 2 Me, COCH 2 NH 2or CH 2 COOR 2 and, in formula III (module B), R 3e is independently OH, OR 2 , NO 2 , NHMe, NMe 2 , NHR 3 or NMeR 3 , (CO)H, NHC(O)H or SR 2 and, R 3f is independently H, OH, OR 2 , NO 2 , NHR 3 and, R 3g is independently H, alkyl, OH, OR 2 and, R 3e , R 3f or R 3g one or less of is optionally H, or R 3e is OH, NH 2 or NHMe and R 3f is NH 2 then R 3e and R 3f form a 5- or 6-membered heterocyclic ring containing a carbonyl or (CO)CH 2 group such that the nitrogen of R 3f is crosslinked to the carbonyl or (CO)CH 2 group and the oxygen or nitrogen of R 3e , R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, R 3 is H, CH 3 , (CO)H, COMe, SO 2 Me, COCH 2 NH 2 or CH 2 COOR 2 and, In formula IV (module C), R 4b is independently CF 3 , OH or OR 2 , NHC(O)Me, R 4c is H, R 4d is OH, NH 2 , N(CO)H, R 4e is independently OH, OR 2 , NO 2 , NHR 3 or NMeR 3 , SR 2 , R 4f is independently H, OH, OR 2 , NO 2 , NHR 3 , R 4g is independently H, alkyl, CF 3 , OH, OR 2 , R 4e , R 4f or R 4g only one of which may be H, R 2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, R 3 is independently H, (CO)H, COMe, SO 2 Me or CH 2 COOR 2 , X is a halide or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I and At) is provided for synthesis.

[0055] In one embodiment, formula (I)

[0056]

Chemical formula

[0057] [Chemical formula] (wherein In formula II R 2b is CF 3 , OH or OR 2 and R 2c is H R 2d is OH or NH 2 , N(CO)H X is a halide (Hal) or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I, and At The halide is selected from the group consisting of F, Cl, Br, I, and At R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), acetal, CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 selected from the group consisting of In formula III R 3e is OH, OR 2 , NO 2 , NHR 3 or NMeR 3 , SR 2 and R 3fare H, OH, OR 2 , NO 2 , NHR 3 and R 3g is H, alkyl, OH, OR 2 and R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 protects O, an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), acetal, CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 and is selected from the group consisting of R 3 is H, CH 3 , (CO)H, COMe, SO 2 Me or CH 2 COOR 2 , COCH 2 NH 2 and In formula IV R 4b is CF 3 , OH or OR 2 and R 4c is H R 4d is OH, NH 2 , N(CO)H R 4e is OH, OR 2 , NO 2 , NHR 3 or NMeR 3 , SR 2 and R 4f is H, OH, OR 2 , NO 2 , NHR 3 and R 4g is H, alkyl, OH, OR 2 and R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or, when R 2 is attached to O, is an O-protecting group, and the O-protecting group is COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), acetal, CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 selected from the group consisting of, R 3 is H, (CO)H, COMe, SO 2 Me or CH 2 COOR 2 and, X is a halide (Hal) or a hydroxyl group, and the halide is selected from the group consisting of F, Cl, Br, I and At), a method is provided.

[0058] In one embodiment, formula (I)

[0059]

Chemical formula

[0060]

Chemical formula

[0061] In one embodiment, formula (I) (wherein in formula (I), R 1a is crotyl, prenyl, R 1b is OR 2 and R 1c is H, R 1d is OH, R 1e is OR 2 and R 1f is NO 2 , NHR 3 , NHC=NH(NH 2 ) and R 1g is H R 2 is methyl or ethyl R 3 is H, (CO)H, (CO)Me, SO 2 Me, CH 2 COOR 2 , COCH 2 NH 2 , CO(CH 2 ) n COOH (where n = 0, 1 or 2) In formula II R 2b is OH or OR 2 and R 2c is H R 2d is OH, OSEM The halide is Br R 2 is methyl or ethyl In formula III R 3e is OH, OR 2 and R 3f is NO 2 , NHR 3 , NHC=NH(NH 2 ) and R 3g is H R 2 is methyl or ethyl R 3 is H, (CO)H, COMe, SO 2 Me or CH 2 COOR 2 , COCH 2 NH 2 or CO(CH 2 ) nis COOH, and n is 0, 1, or 2, In formula IV, R 4b is OR 2 ; R 4c is H; R 4d is OH; R 4e is OR 2 ; R 4f is NO 2 , NHR 3 , NHC=NH(NH 2 ); R 4g is H; R 2 is methyl or ethyl; R 3 is H, (CO)H, COMe, SO 2 Me, or CH 2 COOR 2 , COCH 2 NH 2 , CO(CH 2 ) n COOH; The halide is Br; Formula IV is a method for synthesizing a compound that is catalyzed by a palladium catalyst in the presence of a base and couples with an R boronic acid pinacol ester selected from the group consisting of 3-methylbut-2-enylboronic acid pinacol ester, crotylboronic acid pinacol ester, allylboronic acid pinacol ester, and benzylboronic acid pinacol ester to produce a compound of formula (I). 1a

[0062] In one embodiment of the above method, R in formula (I) 1f is NO 2 . The compound of formula (I) can be further reacted with a reducing agent to convert the NO 2 group to an NH 2 group. This enables the formation of amine compounds, such as compounds 23 and 24. In one embodiment, R 1f is NH 2 ​The compound of formula (I) is further reacted with methanesulfonyl chloride in the presence of a base, such as triethylamine, to give R 1f is NHSO 2 Me to form a compound of formula (I). This enables the formation of amine compounds, such as compounds 25 and 24. In another embodiment, R 1f is NH 2 The compound of formula (I) is further reacted with ethyl formate to form a compound of formula (I) where R 1f is NH(CO)H. This enables the formation of amine compounds, such as compounds 27 and 28. Preliminary results indicate that compounds 27 and 28 are promising lead candidates for therapeutic use in treating atopic dermatitis and psoriasis.

[0063] In one embodiment, formula (I) (wherein in formula (I), R 1a is crotyl, prenyl, R 1b is OR 2 where R 1c is H, R 1d is OH, R 4e is OH or NH 2 and when R 4f is NH 2 then R 4e and R 4f form a 5- or 6-membered heterocyclic ring containing a carbonyl group, such that the nitrogen of R 4f is cross-linked to the carbonyl group and the oxygen or nitrogen of R 4e , R 1g is H, R 2 is methyl, ethyl, R 3 is H, (CO)H, (CO)Me, SO 2 Me, CH 2 COOR 2 COCH 2 NH 2 or CO(CH2 ) n is COOH (where n = 0, 1 or 2), In formula II, R 2b is OR 2 and R 2c is H, R 2d is OSEM, Hal is Br, R 2 is methyl or ethyl, In formula III, R 3e is OH or NH 2 and when R 3f is NH 2 then R 3e and R 3f form a 5- or 6-membered heterocyclic ring containing a carbonyl group, with the result that the nitrogen of R 3f is cross-linked to the carbonyl group and the oxygen or nitrogen of R 3e , R 3g is H, In formula IV, R 4b is OR 2 and R 4c is H, R 4d is OSEM, R 4e is OH or NH 2 and when R 4f is NH 2 then R 4e and R 4f form a 5- or 6-membered heterocyclic ring containing a carbonyl group, with the result that the nitrogen of R 4f is cross-linked to the carbonyl group and the oxygen or nitrogen of R 4e , R 4g is H, R 2 is methyl, ethyl, The halide is Br, Formula (IV) is a compound selected from the group consisting of 3-methylbut-2-enylboronic acid pinacol ester, crotylboronic acid pinacol ester, allylboronic acid pinacol ester, and benzylboronic acid pinacol ester, which is catalyzed by a palladium catalyst in the presence of a base for coupling with an R 1a boronic acid pinacol ester to produce a compound of formula (I)). A method for synthesizing the compound is provided.

[0064] In a specific embodiment of the above method, formula (IV) couples with 3-methylbut-2-enylboronic acid pinacol ester and is catalyzed by tetrakis(triphenylphosphine)palladium(0) in the presence of potassium carbonate. In one embodiment, the compound of formula (I) is selected from compounds 51 and 52.

[0065] In one embodiment of the method for synthesizing the compound of formula (I), the compound according to formula (I) is

[0066]

Chemical formula

[0067]

Chemical formula

[0068]

Chemical formula

[0069]

Chemical formula

[0070]

Chemical formula

[0071] In one embodiment of the method for synthesizing the compound of formula (I), the compound according to formula (I) is selected from the group consisting of compounds 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 36, 24, 33, 34, 35, 36, 37, 38, 39, 40.

[0072] The compound of formula (IV) or (I) may, optionally, undergo one or more additional reactions including, but not limited to, reactions with one or more -NH 2 , NO 2 and / or -OH substituents on formula (IV) or (I). In one embodiment, this additional reaction occurs at the R 1f substituent of formula (I). In one embodiment, one or more -OH substituents on formula (IV) or (I) are reacted with methyl chlorooxoacetate in the presence of a base, such as triethylamine, to convert the -OH-containing compound to a methoxyoxoacetamide (-NHC(O)C(O)OCH 3 ) substituent. In one embodiment, this additional reaction occurs at the R 1f substituent of formula (I).

[0073] In one embodiment, one or more -NH 2 substituents can be converted to methyl oxalate substituents by reacting a compound containing an NH 2 substituent with methyl chlorooxoacetate in the presence of a base, such as triethylamine. In one embodiment, this additional reaction occurs at the R 1f substituent of formula (I).

[0074] In one embodiment, one or more methoxyoxoacetamide substituents are hydrolyzed to -NHC(O)C(O)OH substituents by reacting a compound containing an N-methoxyoxoacetamide substituent with a base, such as LiOH. In one embodiment, this additional reaction occurs at the R 1f substituent of formula (I).

[0075] In one embodiment, one or more methyl oxalate substituents can be hydrolyzed to -OH substituents by reacting a compound containing a methyl oxalate substituent with a base, such as LiOH. In one embodiment, this further reaction occurs at the R 1f substituent of formula (I).

[0076] In one embodiment, one or more -NH 2 substituents can be converted to guanidine (-NHC(NH)NH 2 ) substituents by reacting a compound containing an -NH 2 substituent with cyanamide in the presence of an acid, such as p-toluenesulfonic acid. In one embodiment, this further reaction occurs at the R 1f substituent of formula (I).

[0077] In one embodiment, one or more -NH 2 substituents can be converted to formamide (-NHC(O)H) substituents by reacting a compound containing an -NH 2 substituent with ethyl formate. In one embodiment, this further reaction occurs at the R 1f substituent of formula (I).

[0078] In one embodiment, one or more -NH 2 substituents can be converted to acetamide (-NHC(O)CH 2 ) substituents by reacting a compound containing an -NH 3 substituent with acetic anhydride in the presence of a base, such as DIPEA (diisopropylethylamine). In one embodiment, this further reaction occurs at the R 1f substituent of formula (I).

[0079] In one embodiment, one or more -NH 2 substituents can be converted to amide derivatives (-NHC(O)CH 2 CH 2 CH 2can be converted to a C(O)OH) substituent. In one embodiment, this further reaction is of the R of formula (I) 1f occurring with the substituent.

[0080] In one embodiment, one or more -NH 2 substituents can be converted to methylamine substituents (-NHMe) by reacting a compound containing an NH 2 substituent with formaldehyde in the presence of triacetoxyborohydride. In one embodiment, this further reaction is of the R of formula (I) 1f occurring with the substituent.

[0081] In one embodiment, one or more -OH substituents can be converted to acetate (-OC(O)CH 3 ) substituents by reacting a compound containing an -OH substituent with acetic anhydride in the presence of a base such as DIPEA (diisopropylethylamine). In one embodiment, this further reaction is of the R of formula (I) 1f occurring with the substituent.

[0082] In one embodiment, one or more acetate substituents can be hydrolyzed by reacting a compound containing an acetate substituent with a base such as LiOH to form an -OH substituent. In one embodiment, this further reaction is of the R of formula (I) 1f occurring with the substituent.

[0083] In one embodiment, one or more -NO 2 substituents can be reduced to amine substituents, for example, by reacting a compound containing a NO 2 substituent with Zn in the presence of ammonium chloride. In one embodiment, this further reaction is of the R of formula (I) 1f occurring with the substituent.

[0084] Module A In one embodiment of the methods disclosed herein, the compound according to formula (II) is

[0085] [Chemical formula] (wherein R 2b = OMe, R 2d = OH or OSEM, R 2c = H, Hal is Br)

[0086] In one embodiment of the method disclosed herein, the compound according to formula (II) is prepared according to steps including: i) bromination of a mono- or dihydroxyl-substituted toluene compound, ii) protection of one hydroxyl group and / or alkylation of the other hydroxyl group, iii) removal of the protecting group, iv) acylation of the hydroxyl group, v) dibromination of the aromatic methyl, vi) hydrolysis of the dibromomethyl to form an aldehyde, and vii) protection of the hydroxyl. In one embodiment, in the step, i) bromination of the dihydroxyl-substituted toluene compound is shown. In one embodiment of the method disclosed herein, the compound according to formula (II) is prepared according to steps including: i) bromination of the dihydroxyl-substituted toluene compound at a position adjacent to the C-bonded substituent with a brominating agent, ii) protection of the hydroxyl group with an O-protecting group, followed by alkylation with a C1-C3 alkyl halide, iii) removal of the O-protecting group in the presence of a base, iv) acylation of the hydroxyl group with acetic anhydride in the presence of a base, v) dibromination of the aromatic methyl group with a brominating agent to form a dibromomethyl group, vi) hydrolysis of the dibromomethyl group to form an aldehyde, and vii) COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3) including, but not limited to, protection of the hydroxyl group by reaction with a suitable compound capable of providing an O - protecting group. In one embodiment, in step vii), protection of the hydroxyl group by reaction with 2 - (trimethylsilyl)ethoxymethyl (SEM) chloride, which provides an acetal protecting group, is shown. In a particular embodiment, the compound according to formula (II) is module A and is prepared according to the following process

[0087] [Chemical formula] is prepared according to

[0088] Module B In one embodiment of the method disclosed herein, the compound according to formula (III) can be prepared starting from a di - or tri - substituted hydroxyl and / or alkoxyl - substituted benzaldehyde compound according to steps including: i) protection of the hydroxyl group; ii) reduction of the aromatic aldehyde to benzyl alcohol; iii) coupling of the benzyl alcohol with a trialkyl phosphonate and zinc(II) iodide to form a dialkylbenzyl phosphonate.

[0089] In one embodiment, the compound according to formula (III) is module B

[0090] [Chemical formula] (wherein R 3g = H, R 3f = OSEM, R 3e = OMe, R4 = Et)

[0091] In one embodiment of the method disclosed herein, the compound according to formula (III) is module B and is prepared according to the following process

[0092]

Chem.

[0093] Module C In one embodiment, the compound according to formula (IV) is module C

[0094]

Chem.

[0095] In one embodiment of the method disclosed herein, the compound according to formula (IV) is prepared by the following process

[0096]

Chem.

[0097] In one embodiment of the method disclosed herein, according to the following, formula (II) is module A, formula (III) is module B, and formula (IV) is module C.

[0098]

Chem.

[0099]

Chemical formula

[0100] Compounds and Compositions Formula (I)

[0101]

Chemical formula

[0102] Formula (I)

[0103] [Chemical formula] (wherein, R 1a is Hal, allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl, 2-alkynyl, R 1b is CF 3 , OH or OR 2 , NO 2 , NHEt, NMe 2 , NMeEt, NHR 3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 and, R 1c is H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl, R 1d is CF 3 , OH or OR 2 , NO 2 , NHR3 , NMeR 3 , NHC=NH(NH 2 ) or COOR 2 and R 1e is H, C 1 ~C 6 alkyl, OH, OR 2 , NO 2 , NMe 2 , NHR 3 or NMeR 3 , SR 2 and R 1f is H, OH, OR 2 , NO 2 , NHR 3 , NHC=NH(NH 2 ) or COOR 2 and is COOH R 1g is H, alkyl, CF 3 , OH or OR 2 and R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR 4 , or when attached to O, is an O-protecting group, and the O-protecting group is COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), acetal, CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 selected from the group consisting of R 3 is H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CH 2 COOH, CH 2 COOR 2 , CO(CH 2 ) n NH 2 , CONH 2 , CO(CH 2 ) n COOH or COCOOR 4(where n = 0, 1 or 2), R 4 is C 1 ~C 6 alkyl, Hal is a halide selected from the group consisting of F, Cl, Br, I and At, R 1e , R 1f or R 1g only one of which may be H R 1e is OH, NH 2 or NHMe, and when R 1f is NH 2 the nitrogen of R 1f is cross-linked to the carbonyl group or (CO)CH 2 group and the oxygen or nitrogen of R 1e to form a 5- or 6-membered heterocyclic ring, provided that however, R 1a and / or R 1c is prenyl, R 1d is OH, R 1f is OH, R 1g is H, and R 1e is OH, OMe or OEt, then R 1b cannot be OH, OR, where R = methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or benzyl) are also disclosed herein.

[0104] In a particular embodiment, in formula (I) wherein R 1a is allyl, prenyl, benzyl, 2-alkenyl, R 1b is CF 3 , OH or OR 2 and R 1c is H, R 1d is OH, NH 2 , N(CO)H, R 1e is OH, OR 2 NO2 、 NHR 3 or NMeR 3 、 (CO)H, SMe, and R 1f is H, OH, OR 2 、 NO 2 、 NHR 3 、 NHC=NH(NH 2 )、 COOH, and R 1g is H, alkyl, OH, and R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and R 3 is H, CH 3 、 OH、 (CO)H、 (CO)Me、 SO 2 Me、 CH 2 COOR 2 、 COCH 2 NH 2 、 CO(CH 2 ) n COOH (where n = 0, 1, or 2), provided that however, R 1a or R 1c is prenyl, R 1d is OH, R 1f is OH, R 1g is H, R 1e is OH, OMe, or OEt, then R 1b cannot be OR, and R = methyl, ethyl, isopropyl, propyl, butyl, isobutyl, t-butyl, or benzyl). Compounds are provided.

[0105] In one embodiment, formula (I) is a compound selected from the group consisting of Compounds 2 to 7, 11, 13 to 19, 21 to 44, 46 to 49, 50, 51, 52 [KYN138, 139, 140, 153, 134, 136, 132, 114, 118, 158, 157, 120, 156, 160, 154, 124, 125, 141, 137, 129, 149, 143, 128, 142, 151, 148, 126, 147, 152, 150, 144, 155, 165, 159, 161, 162, 163, 164, 145, 167, 168, 169, 166, 171, KYN-170] disclosed herein.

[0106] R of formula (I) 1b and R 1d One embodiment where one of them is a substituent other than OH or OR 2 is also disclosed herein. In one embodiment, R 1b or R 1d At least one of them is CF 3 、NO 2 、NHR 3 、NMeR 3 、NHC=NH(NH 2 ) or COOR. Thus, formula (I)

[0107]

Chemical formula

[0108] In one embodiment, formula (I) is a compound selected from compounds 11, 43, 44, 46, 47, 48, 49, 50 [KYN-132, 163, 164, 145, 167, 168, 169, 170] disclosed herein.

[0109] The substituent R 1f on the B ring is not H, OH or OR 2 , but R 1eEmbodiments where it is not H are also disclosed in this specification. In one embodiment, formula (I)

[0110] [Chemical formula] (wherein R 1a is Hal, allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2 - alkenyl, 2 - alkynyl, R 1b is CF 3 , OH or OR 2 , NO 2 , NHMe, NHEt, NMe 2 , NMeEt, NHR 3 , NMeR 3 , NHC = NH(NH 2 ), or COOR2, NHR3, NMeR 3 , NHC = NH(NH 2 ), or COOR 2 , R 1c is H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl or benzyl, R 1d is CF 3 , OH or OR 2 , NHR 3 , NO 2 , NH 2 , NHMe, NHC = NH(NH 2 ), or COOR 2 , R 1e is OH, OR 2 , R 1f is NO 2 , NHR 3 , NHC = NH(NH 2 ), COOR 2 , COOH, NHSO 2 Me, NHC(O)(CH 2 ), COOH, NHC(O)COOH, NHC(O)(CH 2 )NNH 2 , NHC(O)CH 2NH 2 、NHCH 2 COOMe, NHC(O)H, NHC(O)CH 3 、NHC(O)(CH 2 ) 2 COOH, NHC(NH)NH 2 and, R 1g is H, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl or an O-protecting group, and the O-protecting group is COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), acetal, CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 selected from the group consisting of, R 3 is H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CH 2 COOH, CH 2 COOR 2 , COCH 2 NH 2 , CONH 2 , CO(CH 2 ) n COOH, CO(CH 2 ) n COOR 4 (n = 0, 1 or 2), R 4 is C1-C6 alkyl, Hal is a halide selected from the group consisting of F, Cl, Br, I and At, R 1e , R 1f or R 1g only one of which can be H, R 1e is OH, NH 2 or NHMe, and when R 1f is NH 2 then R 1fThe nitrogen of which is crosslinked to a carbonyl group or a (CO)CH 2 group and the oxygen or nitrogen of R 1e to form a 5- or 6-membered heterocyclic ring) are provided.

[0111] In one embodiment, formula (I) is a compound selected from Compounds 21 to 40, 50, 51, 52 [KYN-154, 124, 125, 141, 137, 129, 149, 143, 128, 142, 151, 148, 126, 147, 152, 150, 144, 155, 165, 159, 166, 170, 171] disclosed herein.

[0112] The substituent R on the B ring 1e is H, OH or OR 2 but not R 1fe is not H are also disclosed herein. In one embodiment, formula (I)

[0113]

Chemical formula

[0114] In one embodiment, formula (I) is a compound selected from compounds 13 to 16, 41 [KYN-114, 118, 158, 157, 161] disclosed herein.

[0115] Embodiments in which no prenyl group is present on ring A or B are also disclosed herein. In one embodiment, formula (I)

[0116]

Chemical formula

[0117] In certain embodiments, in formula (I) wherein R 1a is allyl, crotyl, geranyl, farnesyl, benzyl, 2-alkenyl, 2-alkynyl, R 1b is CF 3 , OH, OR 2 , R 1c is H, R 1d is OH or OR 2 , NH 2 , NH(CO)H, R 1e is OR 2 , R 4 , NO 2 , NH 2 , NHMe, NMe 2 , SR 2 , R 1f is OH, OR 2 , NO 2 , NH 2 , NHMe, NHR 3 , NHC=NH(NH 2 ), COOR 2 , COOH, R 1g is H, R 2is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, C(O)C(O)OR 4 or an O-protecting group, and the protecting group is selected from the group consisting of COMe, t-BuSi(CH 3 ) 2 , 2-(trimethylsilyl)ethoxymethyl (SEM), acetal, CH(OEt)CH 3 , tetrahydropyranyl or C(OEt)(CH 3 ) 2 selected from the group consisting of, R 3 is H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CH 2 COOH, CH 2 COOR 2 , COCH 2 NH 2 , CONH 2 , CO(CH 2 ) n COOH (where n = 0, 1 or 2), R 4 is C1-C6 alkyl, Hal is a halide selected from the group consisting of F, Cl, Br, I and At, R 1e , R 1f or R 1g only one of can be H, R 1e is OH, NH 2 or NHMe, and when R 1f is NH 2 , the nitrogen of R 1f is crosslinked to a carbonyl group or a (CO)CH 2 group and the oxygen or nitrogen of R 1e to form a 5- or 6-membered heterocyclic ring) compounds are provided.

[0118] In one embodiment, formula (I) is a compound selected from compounds 2, 3, 4, 5, 6, 7 [KYN-138, 139, 140, 153, 134, 136] disclosed herein.

[0119] In another embodiment, formula (I) (wherein R 1a is prenyl, R 1b is OR 2 and R 1c is H, R 1d is OH, R 1e is OR 2 and R 1f is NHR 3 , NHC=NH(NH 2 ) and R 1g is H, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, R 3 is H, CH 3 , OH, (CO)H, (CO)Me, SO 2 Me, CH 2 COOR 2 COCH 2 NH 2 CO(CH 2 ) n COOH (where n = 0, 1 or 2) compounds are provided.

[0120] In yet another embodiment, formula (I) (wherein R 1a is prenyl, R 1b is OR 2 and R 1c is H, R 1d is OH, R 1e is OR 2 and R 1f is OH, R 1g is alkyl, OH, R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and compounds wherein the alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl are provided.

[0121] Compounds according to formula (I) having at least one formamide group and / or ethoxide group on the A and / or B ring are also disclosed herein. In one embodiment, the A ring has at least one ethoxide substituent. The ethoxide substituent is R on the A ring 1b or R 1d and may be in the position. In another embodiment, the A ring has a formamide substituent. In another embodiment, the B ring has a formamide substituent. In another embodiment, the A ring has at least one ethoxide substituent and the B ring has a formamide substituent. In certain embodiments, the compound of formula (I) may be selected from compounds 8, 20, 24, 27, 28, 30, 32, 34, 35, 37 to 41, 50, 51 [KYN-119, 146, 141, 149, 143, 142, 148, 147, 152, 144, 155, 165, 159, 161, 170].

[0122] Treatment Methods A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or pharmaceutical composition comprising said compound as disclosed herein.

[0123] Preliminary Results Discussion WO 2012 / 149608 pamphlet discloses the anti-cancer activity of certain prenylated polyhydroxystilbene derivatives. Specifically, compound 1 [KYN-001] as disclosed herein has been found to have potent activity in inhibiting cancerous cells. The activity of the compounds of the present disclosure is compared to compound 1.

[0124] Preliminary studies indicate that compounds with at least one phenolic OH replaced by R 1b =OEt and / or a formamide group are extremely effective cancer inhibitors. From the IC 50 values (average activity) in 42 cancer cell lines in Table 6, the potencies are in the order of 28 > 27 > 8 > 20 > 1. Compound 28 using formamide and OEt was the most active, followed by R 1b =OMe and formamide, which was 27.

Brief Description of the Drawings

[0125]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 13.6

Figure 13.7

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

DETAILED DESCRIPTION OF THE INVENTION

[0126] Definitions Unless otherwise specifically defined herein, all technical and scientific terms used herein shall be construed to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in chemistry, biochemistry, pharmaceutical chemistry, microbiology, etc.). Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the appropriate methods and materials are described below. In case of conflict, the present specification, including definitions, will control. Further, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0127] As used herein, the term "and / or", e.g., "X and / or Y", is understood to mean either "X and Y" or "X or Y", and is to be construed as providing explicit support for both meanings or either meaning. For example, A and / or B includes the options of i) A, ii) B, or iii) A and B.

[0128] As used herein, the term "about", unless otherwise specified, refers to + / -20% of the specified value, typically + / -10%, and typically + / -5%.

[0129] As used herein, the terms "a", "an", and "the" include both singular and plural aspects unless the context clearly dictates otherwise.

[0130] It should be understood that certain features described herein in the context of separate embodiments may be provided in combination in a single embodiment for clarity. Conversely, various features described in the context of a single embodiment for brevity may be provided separately or in any sub-combination.

[0131] Throughout this specification, various aspects and components of the present invention may be presented in a range format. The range format is for convenience only and should not be construed as an inflexible limitation on the scope of the present invention. Thus, a range description should be considered to specifically disclose all possible sub-ranges and individual numerical values within that range, unless otherwise indicated. For example, a range description such as 1 to 5 should be considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., as well as individual and partial numbers within the recited range, such as 1, 2, 3, 4, 5, 5.5, and 6, etc., provided that integers are required or implied by the context. This applies regardless of the breadth of the disclosed range. When specific values are required, they are set forth herein.

[0132] Throughout this specification, the term "comprise", or variations such as "comprises" or "comprising", is understood to imply the inclusion of the stated element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0133] As used herein, the term "halogen" means fluorine, chlorine, bromine, iodine, or astatine.

[0134] As used herein, the term "hydrocarbon" includes compounds consisting of hydrogen atoms and carbon atoms.

[0135] As used herein, the term "alkyl" includes both straight-chain (i.e., linear) hydrocarbon groups and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups. In one example, an alkyl group is an alkyl group having 1 to 6 carbon atoms (i.e., C1~6 is (alkyl).

[0136] As used herein, the term "alkoxy" refers to an -O-alkyl group, where "alkyl" is as described above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups. In one example, an alkoxy group is an alkoxy group having 1 to 6 carbon atoms (i.e., -O-C 1~6 alkyl).

[0137] As used herein, the term "alkenyl" refers to both straight-chain and branched-chain unsaturated hydrocarbon groups having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups. In one example, an alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2~6 alkenyl). The term "2-alkenyl" refers to an alkene substituent having a double bond at the 2-position from the point of attachment. 2-alkenyl groups include allyl, crotyl, prenyl, geranyl, and farnesyl groups.

[0138] As used herein, the term "alkynyl" refers to both straight-chain and branched-chain unsaturated hydrocarbon groups having at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups. In one example, an alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2~6 alkynyl).

[0139] As used herein, the term "haloalkyl" refers to an alkyl group having at least one halogen substituent, where "alkyl" and "halogen" are as defined above. Similarly, the term "dihaloalkyl" means an alkyl group having two halogen substituents, and the term "trihaloalkyl" means an alkyl group having three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl, and fluorobutyl groups. Examples of dihaloalkyl groups include difluoromethyl and difluoroethyl groups. Examples of trihaloalkyl groups include trifluoromethyl and trifluoroethyl groups. In one example, the haloalkyl group is a haloalkyl group having 1 to 6 carbon atoms (i.e., C 1~6 haloalkyl).

[0140] As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic cyclic group that is similar to a carbocyclic group but in which one to three of the carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. The heterocyclyl group can be, for example, monocyclic or polycyclic (e.g., bicyclic). The heteroatom can be N, O, or S.

[0141] For use in therapy, it is contemplated that a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or solvate thereof may be administered as the chemical substance per se, but in one aspect of the invention, the active ingredient is presented as a pharmaceutical composition. Accordingly, in a further embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0142] When applicable, the compounds of the invention comprising a compound of formula (I) may be in the form of a pharmaceutically acceptable salt and / or may be administered as a pharmaceutically acceptable salt.

[0143] As used herein, the term "pharmaceutically acceptable salt" refers to a toxicologically safe salt for systemic administration. Pharmaceutically acceptable salts may include alkali or alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium, and amine cations, for example, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine, etc.

[0144] As used herein, the term "pharmaceutically acceptable excipient" refers to a solid or liquid filler, diluent, or encapsulating substance that can be safely used in systemic administration. Depending on the specific route of administration, various carriers well known in the art may be used. These carriers or excipients may be selected from the group including sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water.

[0145] As used herein, the term "solvate" refers to various stoichiometric complexes formed by a solute (in the present invention, a compound of formula (I) or (Ia), or a salt or physiologically functional derivative thereof) and a solvent. Such a solvent for the purposes of the present invention may not interfere with the biological activity of the solute. Suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. In particular, the solvent used is a pharmaceutically acceptable solvent. Suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, acetic acid, glycerol, liquid polyethylene glycol, and mixtures thereof. A particular solvent is water.

[0146] The administration of the compound of formula (I) may be in the form of a "prodrug". A prodrug is an inactive form of a compound that is converted into an active form in vivo. Suitable prodrugs include esters of the active form of the compound, phosphonate esters, and the like.

[0147] It should be understood that the formulation may, in addition to the components specifically described above, also contain other agents conventional in the art, taking into account the type of formulation under consideration.

[0148] The compounds of the present disclosure may be suitable for the treatment of diseases in human or animal patients. In one embodiment, the patient is a mammal including a human, a horse, a dog, a cat, a sheep, a cow, or a primate. In one embodiment, the patient is a human. In a further embodiment, the patient is not a human.

[0149] As used herein, the term "effective amount" means, for example, the amount of a drug or agent that elicits a biological or medical response in a tissue, system, animal, or human, as sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, compared to a corresponding subject not receiving such amount, results in an improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological functions.

[0150] As used herein, the term "treatment" refers to protecting or inhibiting symptoms, treating symptoms, delaying the appearance of symptoms, reducing the severity of the onset of symptoms, and / or reducing the number or type of symptoms experienced by an individual, compared to not administering a pharmaceutical composition comprising a compound of the present invention. The term "treatment" encompasses use in a palliative situation.

[0151] One skilled in the art will recognize that in the preparation of the compounds of the present invention, it is necessary to protect one or more sensitive groups within the molecule to prevent unwanted side reactions and / or it may be desirable. Protecting groups suitable for use according to the present invention are well known to those skilled in the art and can be used in conventional methods. See, for example, "Protective groups in organic synthesis" by T. W. Greene and P. G. M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by PJ. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g., formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g., benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g., 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl), and alkyl type protecting groups (e.g., benzyl, trityl, chlorotrityl).

[0152] According to a fourth aspect of the present disclosure, the compounds according to formula (I) are suitable for use in the treatment of cancer. Cancers to be treated include leukemia, non-small cell lung cancer, colorectal cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer. Most preferably, the cancer to be treated is leukemia or melanoma.

[0153] The antitumor effect of the compounds of the present invention may be applied as monotherapy or, additionally, may be accompanied by one or more other substances and / or treatments. Such combination treatments can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately. In the field of medical oncology, it is common practice to use combinations of different treatment modalities, such as combinations of surgery, radiotherapy, and / or chemotherapy, to treat each patient with cancer. In particular, it is known that irradiation or treatment with angiogenesis inhibitors and / or vascular permeability reducing agents can enhance the amount of hypoxic tissue within tumors. Thus, the efficacy of the compounds of the present invention can be improved by combination treatment with radiotherapy and / or angiogenesis inhibitors.

[0154] The individual elements of such combinations may be administered separately at different times during the course of treatment or may be administered simultaneously in divided or single combination forms. Thus, the present invention should be understood to encompass all such regimens of simultaneous or alternating treatment, and the term "administering" should be construed accordingly. The scope of combinations of the compounds of the present invention with other antitumor agents is understood, in principle, to include any combination with any pharmaceutical composition useful for the treatment of cancer.

[0155] When combined in the same formulation, the two compounds must be stable and compatible with each other and with the other elements of the formulation and may be formulated for administration. When formulated separately, they may be conveniently provided in any convenient formulation and in a manner known in the art for such compounds.

[0156] The pharmaceutical composition of the present invention may be formulated for administration by any suitable route, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Thus, the pharmaceutical composition of the present invention may be formulated as, for example, tablets, capsules, powders, granules, lozenges, creams, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Such pharmaceutical formulations can be prepared by any method known in the art of pharmacy, for example, by associating the active ingredient(s) with a carrier(s) or excipient(s). Such pharmaceutical formulations may be prepared as enteric-coated granules, tablets, or capsules suitable for oral administration formulations and extended-release formulations.

[0157] When the compounds are used in combination with a second therapeutic agent active against the same disease, the dosage of each compound may differ from that when the compound is used alone. Suitable dosages will be readily appreciated by those skilled in the art.

[0158] Modes for Carrying Out the Invention For a better understanding of the essence of the present invention, some examples are described as follows.

[0159] Preparation of Module A Module A is represented by formula (II) of the present disclosure as described herein.

[0160] In one embodiment, Module A is represented by A7 and A8 and is prepared according to the following process.

[0161]

Chemical formula

[0162] An additional 270 g (2175 mmol, 1.0 eq) of compound A1 was treated in the same manner. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 L) and purified on silica gel (6 kg) eluting with a gradient of 0 - 100% ethyl acetate in heptane to give partially purified compound A2 (407 g, ~70% purity). This crude product was recrystallized twice from a 1:3 mixture of methanol and water (1.2 L). The solid was filtered, washed with water (500 mL), and dried at 45 °C under high vacuum for 16 hours to give compound A2 (163.78 g, 37% yield) as an off-white solid (LM-1-100).

[0163] 4-Bromo-3-methoxy-5-methylphenyl 4-methylbenzenesulfonate (A3): Potassium carbonate (886 g, 6402 mmol, 6.5 eq) was added to a solution of compound A2 (200 g, 985 mmol, 1.0 eq) in acetone (15 L). After stirring for 30 minutes, p-toluenesulfonyl chloride (187.8 g, 985 mmol, 1.0 eq) was added and the resulting mixture was refluxed for 16 hours. Methyl iodide (166 mL, 2660 mmol, 2.7 eq) was added to the reaction and reflux was continued for an additional 24 hours. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with acetone (4 L). The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 L) and passed through silica gel (6 kg) eluting with a gradient of 0 - 15% ethyl acetate in heptane to afford compound A3 (350 g, ~60% purity) which was used subsequently. (LM-6-1).

[0164] 4-Bromo-3-methoxy-5-methylphenol (A4): 6M sodium hydroxide (108 mL, 8.0 equivalents) was added to a solution of crude compound A3 (30 g, 1.0 equivalent) in a 1:1 mixture of tetrahydrofuran and methanol (400 mL). After refluxing for 16 hours, LCMS indicated that the reaction was complete. Another batch of crude compound A3 (300 g) was treated in the same manner and both batches were combined for workup. After cooling the mixture to room temperature, acetonitrile (4 L) was added and the mixture was washed with heptane (2 x 4 L). The heptane layer was discarded. The tetrahydrofuran / methanol / acetonitrile / water mixture was acidified to pH = 7 with 1N hydrochloric acid (ca. 6.2 L), saturated with sodium chloride (3 kg), and extracted with ethyl acetate (2 x 4 L). The combined organic layers were concentrated under reduced pressure. The residue was diluted in water (500 mL) and extracted with ethyl acetate (3 x 1 L). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with acetonitrile (1 L) and heptane (500 mL) and the layers were separated. The heptane layer was discarded. The acetonitrile layer was passed through a silica gel pad (300 g) which was eluted with ethyl acetate (2 L). The filtrate was concentrated under reduced pressure. The resulting solid was triturated with 10% ethyl acetate in heptane (1.1 L) to afford compound A4 (96.6 g, 45% yield, over 2 steps) as an off-white solid (LM-6-12, LM-6-14).

[0165] 4-Bromo-3-methoxy-5-methylphenyl acetate (A5): Acetic anhydride (63.1 mL, 668 mmol, 1.5 equivalents) was added to a solution of compound A4 (96.6 g, 445 mmol, 1.0 equivalent) in a mixture of pyridine (377 ml) and dichloromethane (1000 mL) at room temperature. The resulting mixture was stirred for 16 hours. Ice water (500 mL) was added to quench the reaction. The organic layer was washed with 1N ice-cold HCl (3 x 500 mL), saturated sodium bicarbonate (500 mL), saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further dried under high vacuum at 45 °C for 16 hours to afford compound A5 (114.53 g, 99% yield) as an off-white solid which was used subsequently. (LM-6-15).

[0166] 4-Bromo-3-(dibromomethyl)-5-methoxyphenyl acetate (A6): N-Bromosuccinimide (82.6 g, 464 mmol, 2.1 eq) and benzoyl peroxide (5.35 g, 22.1 mmol, 0.1 eq) were sequentially added to a solution of compound A5 (57.27 g, 221 mmol, 1.0 eq) in carbon tetrachloride (1 L). The resulting mixture was refluxed for 24 h, during which LCMS analysis indicated completion of the reaction. Another batch of compound A5 (57.27 g) was treated in the same manner and both batches were combined for workup. After cooling the mixture to room temperature, sodium bisulfite (250 g) was added and the reaction mixture was stirred at room temperature for 24 h (test with moist starch paper showed no peroxide). The resulting mixture was filtered through celite (200 g) and this was rinsed with dichloromethane (2 L). The filtrate was concentrated under reduced pressure to give crude compound A6 as a yellow solid, which was subsequently used. (LM-6-17)

[0167] 2-Bromo-5-hydroxy-3-methoxybenzaldehyde (A7): Ammonium formate (153 g, 2431 mmol, 5.5 eq), and a 1:1 mixture of ethanol and water (600 mL) were added to a solution of compound A6 (ca. 442 mmol, 1.0 eq) in ethanol (800 mL) at 50 °C. The resulting mixture was refluxed for 70 h. LCMS analysis indicated completion of the reaction. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid (15 mL) was added. The solvent was removed under reduced pressure. The residue was diluted in water (500 mL) and extracted with ethyl acetate (2 × 1 L) and methyl tert-butyl ether (2 × 1 L). The aqueous layer was filtered through a celite pad (50 g) and this was rinsed with ethyl acetate (2 L). The organic layers were separated. All the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was passed through a silica gel pad (300 g) which was eluted with tetrahydrofuran (3 L) and ethyl acetate (4 L). The filtrate was concentrated under reduced pressure to give crude compound A7 (141 g) as a black oil, which was subsequently used. (LM-6-18)

[0168] 2-Bromo-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (A8, typical of Module A): Diisopropylethylamine (16.5 mL, 94.7 mmol, 1.5 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (13.4 mL, 75.6 mmol, 1.2 eq) were sequentially added to a solution of crude compound A7 (20 g, about 63 mmol, 1.0 eq) in a 1:1 mixture of anhydrous tetrahydrofuran and dichloromethane (200 mL) at room temperature. After stirring at room temperature for 16 h, LCMS analysis indicated conversion of approximately 65% of the reactants. Additional diisopropylethylamine (16.5 mL, 94.7 mmol, 1.5 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (13.4 mL, 75.6 mmol, 1.2 eq) were added and the mixture was stirred for an additional 24 h. Saturated sodium bicarbonate (250 mL) was added to quench the reaction and the organic solvents were removed under reduced pressure. The remaining aqueous layer was extracted with methyl tert-butyl ether (500 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated system (330 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford A8 (typical of module A) (8.44 g) as a white solid (LM-6-20). An additional 120 g of crude compound 7 was treated in the same manner. Saturated sodium bicarbonate (250 mL) was added to quench the reaction and the solvent was removed under reduced pressure. The remaining aqueous layer was diluted with water (250 mL), saturated brine (250 mL), and extracted with methyl tert-butyl ether (2 x 1 L). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was filtered through a silica gel pad (1 kg) which was eluted with 20% ethyl acetate in heptane. The filtrate was concentrated under reduced pressure. The residue was divided into six equal parts. Each portion was purified on an Interchim automated system (330 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane. All of the isolated compound intermediates A were further purified by trituration with 5% dichloromethane in hexane (300 mL) to afford A8 (typical of module A) (26.73 g, 99% purity and 42.72 g, about 90% purity) as white solids after drying under vacuum at 45 °C for 16 h. The combined yield was 43% over 3 steps. (LM-6-21) White solid, melting point 58.3 - 59.1 °C; HPLC analysis: 99.6% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 10.80 minutes; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 378.0 (M+H 2 O) + ; C 14 H 21 BrO 4 Si; 1 H NMR (400 MHz, CDCl 3 ) δ = 10.40 (s,1H), 7.20 (d, J = 2.8 Hz,1H), 6.84 (d, J = 2.7 Hz, 1H), 5.25 (s, 2H), 3.92 (s, 3H), 3.78 - 3.73 (m, 2H), 0.97 - 0.93 (m, 2H), 0.00 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ = 191.82, 157.76, 157.12, 134.85, 109.31, 107.49, 106.62, 93.06, 66.72, 56.65, 18.02, -1.43.

[0169] In another embodiment, module A is represented by A9, which is prepared according to the following process.

[0170]

Chemical formula

[0171] 2-Bromo-3-hydroxy-5-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (A12): Compound A11 (49.64 g, 71% purity by QNMR, 131.3 mmol, 1.0 equiv) was placed under high vacuum (0.5 Torr) at 50 °C for 2 hours to remove residual 2-(trimethylsilyl)ethanol. After cooling to room temperature, anhydrous dichloromethane (700 mL) was added and the mixture was cooled to -17 °C. N-Bromosuccinimide (25.12 g, 141.1 mmol, 1.07 equiv) in anhydrous dichloromethane (1 L) was added dropwise over 1 hour while maintaining the temperature between -15 °C and -20 °C. After addition, NMR analysis indicated that the reaction was not complete (16% of compound A11 remained). Additional N-bromosuccinimide (4.62 g, 26 mmol, 0.2 equiv) in anhydrous dichloromethane (200 mL) was added dropwise over 10 minutes. The resulting mixture was stirred at -17 °C for an additional 30 minutes. Water (800 mL) was added and the mixture was warmed to room temperature. The organic layer was washed with saturated brine (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was divided into five equal parts. Each part was purified on an Interchim automated system (2 × 120 g column stack) eluting with a gradient of 0 - 12% ethyl acetate in heptane to give compound A12 (35.84 g, 79% yield) as a yellow oil (LM-6-87).

[0172] 2-Bromo-3-ethoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (A9, Module A): Triphenylphosphine (40.6 g, 154.8 mmol, 1.5 eq) and ethanol (9 mL, 154.8 mmol, 1.5 eq) were added to a solution of compound A12 (35.84 g, 103.2 mmol, 1.0 eq) in anhydrous tetrahydrofuran (1 L). After cooling to 0 °C for 10 minutes, diisopropyl azodicarboxylate (31 mL, 154.8 mmol, 1.5 eq) was added dropwise over 15 minutes. The resulting mixture was slowly warmed to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure. The residue was divided into five equal parts. Each part was purified on an Interchim automatic system (2 × 120 g column stack) eluting with 5% ethyl acetate in heptane to give A9 (17.5 g, 45% yield) as a yellow solid (LM-6-88).

[0173] Preparation of Module B Module B is represented by formula (III) of the present disclosure as described herein.

[0174] In one embodiment, module B is represented by B4, which is prepared according to the following process.

[0175]

Chemical formula

[0176] (3-Methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)methanol (B3): Sodium borohydride (250 g, 6.61 mol) was added portionwise over 20 minutes to a solution of compound B2 (2000 g, 7.10 mol) in methanol (8 L) while maintaining the temperature below 20 °C. After stirring overnight, water (1 L) was added slowly over 20 minutes. The mixture was combined with a reactant of equal scale and concentrated under reduced pressure to remove most of the methanol. The slurry was poured into a separatory funnel and diluted with MTBE (8 L). The layers were separated and the aqueous layer was back-extracted with MTBE (2 × 4 L). The combined organic layers were washed with saturated brine (4 L), dried over sodium sulfate (200 g), and concentrated under reduced pressure to give compound B3 (1970 g, 98% yield) as a yellow oil, which was used subsequently. (EK-22-153)

[0177] Diethyl (3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)phosphonate (B4, Module B): Into a 22 L flask, THF (7 L) and zinc(II) iodide (2.24 kg, 2.03 mol, 2 eq) were charged and the addition caused an exotherm to 40 °C. Triethyl phosphite (1.17 kg, 7.03 mol, 2 eq) and Compound B3 (1000 g, 3.52 mol, 1 eq) in THF (1 L) were added sequentially. After heating at 65 °C for 16 h, the reaction mixture was cooled to room temperature and diluted with water (5 L). Potassium carbonate (1.2 kg, 8.68 mol, 2.47 eq) was added portionwise over 5 min to adjust the pH to 9. There was no foaming observed during the addition. The salts were filtered off and the filter cake was washed with MTBE (2 × 4 L). The combined filtrates were washed with saturated brine (4 L), dried over sodium sulfate (500 g), and concentrated under reduced pressure. The resulting oil was purified on silica gel (2.0 kg) eluting with a gradient of 25 - 100% ethyl acetate in heptane to give B4 (1035 g, 72% yield) as a yellow oil (EK-22-154). C 18 H 33 PSiO 6 1 H NMR (400 MHz, CDCl 3 ) δ = 7.11 (d, J = 8.2 Hz, 1H), 6.89 (m, 1H), 6.80 (dm, J = 8.2 Hz, 1H), 5.26 (s, 2H), 4.08 - 3.98 (m, 4H), 3.88 (s, 3H), 3.82 (m, 2H), 3.10 (d, J = 21.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 6H), 0.98 - 0.93 (m, 2H), 0.00 (s, 9H).

[0178] Preparation of Module C Module C is represented by formula (IV) of the present disclosure as described herein.

[0179] In one embodiment, Module C is represented by C1, which is prepared according to the following process.

[0180]

Chemical formula

[0181] (E)-(2-((4-(2-Bromo-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-methoxyphenoxy)methoxy)ethyl)trimethylsilane (C1): A 60% dispersion of sodium hydride (1.07 g, 26.7 mmol, 2 eq) in mineral oil was added all at once to a solution of B4 (5.4 g, 13.4 mmol, 1.0 eq) in anhydrous tetrahydrofuran (120 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of A8 (4.82 g, 13.4 mmol, 1 eq) in anhydrous tetrahydrofuran (30 mL) was then added dropwise and the mixture was stirred at room temperature for 16 hours, at which point LCMS analysis indicated approximately 30% conversion to module C. An additional 60% dispersion of sodium hydride (1.07 g, 26.7 mmol, 2 eq) in mineral oil was added and according to LCMS analysis, it was approximately 50% converted after 8 hours. An additional 60% dispersion of sodium hydride (2.14 g, 53.4 mmol, 4 eq) in mineral oil was added and according to LCMS analysis, it was completely converted after 16 hours. The reaction was carefully quenched with saturated brine (100 mL, 1 drop per minute with the first 5 mL of brine) at 0 °C. The mixture was extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (220 column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to give C1 (5.2 g, 64% yield) as a yellow oil (LM-6-27). C 28 H 43 BrSiO 6 1 H NMR (400 MHz, CDCl 3) δ = 7.39 (d, J = 16.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 2.0, 8.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 16.2 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 5.29 (s, 2H), 5.25 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.83 - 3.77 (m, 4H), 1.00 - 0.94 (m, 4H), 0.02 (s, 9H), 0.00 (s, 9H). In another embodiment, module C is represented by C2, which is prepared according to the following process.

[0182]

Chemical formula

[0183] Preparation of Compound 1 [KYN-001]

[0184] [Chem.] (E)-(2-((2-Methoxy-4-(3-methoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)phenoxy)methoxy)ethyl)trimethylsilane (1-1): Tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol, 0.05 equiv), potassium carbonate (138 mg, 1 mmol, 2 equiv), 3-methylbut-2-enylboronic acid pinacol ester (147 mg, 0.75 mmol, 1.5 equiv) and water (5 mL) were sequentially added to a solution of C1 (306 mg, 0.5 mmol, 1 equiv) in tetrahydrofuran (5 mL). After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 50 °C for 20 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (15 mL) and the organic layer was concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (40 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 1-1 (190 mg, 63% yield) as a yellow oil (LM-6-29).

[0185] (E)-3-(4-Hydroxy-3-methoxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (1): 1M tetrabutylammonium fluoride in tetrahydrofuran (4.43 mL, 4.43 mmol, 14 equiv) was added to compound 1-1 (190 mg, 0.32 mmol, 1 equiv) at room temperature. After heating at 67 °C for 16 h, the mixture was cooled to room temperature and diluted with water (4 mL). The mixture was extracted with ethyl acetate (15 mL) and the organic layer was concentrated under reduced pressure. The residue was purified twice on an Interchim automated chromatography system (2×25 column) eluting with a gradient of 0 - 60% ethyl acetate in heptane each time to afford compound 1 (60 mg, 56% yield) as an off-white solid, dried under vacuum at 40 °C for 16 h (LM-6-30). White solid, melting point 132.3 - 134.0 °C; HPLC analysis: 96.3% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm, retention time: 8.4 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 341.2 (M+H) + ; C 21 H 24 O4 ; 1 1H NMR (400 MHz, CDCl 3 ) δ = 7.15 (d, J = 16.0 Hz, 1H), 7.00 (broad s, 1H), 6.99 (dd, J = 2.0, 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 16.1 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 5.12 (tm, J = 6.8 Hz, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.41 (broad d, J = 6.7 Hz, 2H), 1.81 (s, 3H), 1.68 (d, J = 1.1 Hz, 3H); 13 13C NMR (100 MHz, CDCl 3 ) δ = 158.52, 154.37, 146.65, 145.54, 138.13, 130.59, 130.40, 130.24, 124.24, 123.63, 120.65, 120.55, 114.53, 108.22, 103.85, 98.17, 55.86, 55.69, 25.78, 24.45, 17.97.

[0186] Preparation of Compounds 2, 3 and 4 4-((E)-But-2-en-1-yl)-3-((E)-4-hydroxy-3-methoxystyryl)-5-methoxyphenol (2) [KYN-138] 4-((Z)-But-2-en-1-yl)-3-((E)-4-hydroxy-3-methoxystyryl)-5-methoxyphenol (3) [KYN-139] (E)-4-(But-3-en-2-yl)-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (4) [KYN-140]

[0187]

Chem.

[0188] 4-((E)-But-2-en-1-yl)-3-((E)-4-hydroxy-3-methoxystyryl)-5-methoxyphenol (2) / 4-((Z)-but-2-en-1-yl)-3-((E)-4-hydroxy-3-methoxystyryl)-5-methoxyphenol 3) / (E)-4-(but-3-en-2-yl)-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (4): 1 M tetrabutylammonium fluoride in tetrahydrofuran (52.5 mL, 52.5 mmol, 14 equiv) was added to a mixture of compounds 2, 3, and 4 (2.2 g, 3.75 mmol, 1 equiv) at room temperature. After heating at 67 °C for 16 h, the mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with dichloromethane (2 × 150 mL), and the organic layer was concentrated under reduced pressure. The residue was purified three times on an Interchim automatic chromatography system (3 × 80 column) eluting each time with a gradient of 0–60% ethyl acetate in heptane to afford a mixture of compounds 2, 3, and 4 (760 mg) as a yellow oil. This oil mixture was subjected to supercritical fluid chromatography (Lotus Separations) to give three compounds, which appeared as a black residue oil. These residues were individually re-purified on an InterChim automatic chromatography system (25 column) eluting with a gradient of 0–60% ethyl acetate in heptane to afford compound 2 (90 mg, 7% yield), 3 (60 mg, 5% yield), and 4 (290 mg, 24% yield), which were obtained as off-white solids after drying under vacuum at 40 °C for 16 h (LM-6-44).

[0189] After SFC separation (conditions listed below), 400 mg of peak-1 (4, LM-6-44-P1), 108 mg of peak-2 (2, LM-6-44-P2), and 110 mg of peak-3 (3, LM-6-44-P3) were obtained. Chromatograms are included in this report.

[0190]

Table 1

[0191] Figure 1 shows LM-6-44 (mixture of compounds 2, 3, and 4) before separation.

[0192] Figure 2 shows LM-6-44-P1 (compound 4) after separation. Figure 3 shows LM-6-44-P2 (compound 2) after separation.

[0193] Figure 4 shows LM-6-44-P3 (Compound 3) after separation. Structural data: 4-((E)-But-2-en-1-yl)-3-((E)-4-hydroxy-3-methoxystyryl)-5-methoxyphenol (Compound 2) [KYN-138]: Off-white solid; HPLC analysis: 96.3% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.1 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 327.2 (M+H) + ; C 20 H 22 O 4 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.17 (d, J = 16.1 Hz, 1H), 7.03 - 6.98 (m, 2H), 6.93 - 6.89 (m, 1H), 6.86 (d, J = 16.1 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 5.67 (s, 1H), 5.59 - 5.49 (m, 1H), 5.47 - 5.36 (m, 1H), 4.73 (s, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.41 (td, J = 1.3, 5.9 Hz, 2H), 1.63 (qd, J = 1.4, 6.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.63, 154.50, 146.67, 145.59, 138.42, 130.41, 130.31, 129.67, 124.93, 124.34, 120.35, 119.57, 114.59, 108.56, 103.91, 98.24, 55.89, 55.78, 28.29, 17.91. 4-((Z)-but-2-en-1-yl)-3-((E)-4-hydroxy-3-methoxystyryl)-5-methoxyphenol (Compound 3) [KYN-139]: Off-white solid; HPLC analysis: 98.8% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.2 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 327.2 (M+H)+ ; C 20 H 22 O 4 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.15 (d, J = 16.0 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.90 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 5.68 (s, 1H), 5.53 - 5.32 (m, 2H), 4.87 (s, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.48 (d, J = 6.7 Hz, 2H), 1.81 (qd, J = 1.2, 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.60, 154.49, 146.68, 145.58, 138.29, 130.56, 130.24, 129.71, 124.20, 122.99, 120.59, 120.16, 114.56, 108.29, 104.00, 98.23, 55.86, 55.69, 23.37, 12.99. (E)-4-(but-3-en-2-yl)-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (Compound 4) [KYN-140]: Off-white solid; HPLC analysis: 96.1% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.2 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 327.2 (M+H) + ; C 20 H 22 O 4 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.32 (d, J = 16.0 Hz, 1H), 6.99 - 6.95 (m, 2H), 6.92 - 6.89 (m, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.22 (ddd, J = 4.8, 10.5, 17.4 Hz, 1H), 5.67 (s, 1H), 5.10 - 5.03 (m, 2H), 4.85 (s, 1H), 4.15 (tdq, J = 2.1, 4.6, 7.0 Hz, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 1.39 (d, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.72, 154.52, 146.69, 145.51, 143.90, 138.85, 130.37, 130.14, 125.60, 124.11, 120.38, 114.56, 111.76, 108.30, 105.18, 98.73, 55.86, 55.70, 34.49, 18.55. 4-((E)-but-2-en-1-yl)-3-ethoxy-5-((E)-4-hydroxy-3-methoxystyryl)phenol (Compound 5) [KYN-153]

[0194]

Chem.

[0195] 4-((E)-but-2-en-1-yl)-3-ethoxy-5-((E)-4-hydroxy-3-methoxystyryl)phenol (5): 1 M tetrabutylammonium fluoride in tetrahydrofuran (33.5 mL, 33.5 mmol, 14 equiv) was added to a mixture of compounds 5-1, 5-2, and 5-3 (1.44 g, 2.4 mmol, 1 equiv) in tetrahydrofuran (50 mL) at room temperature. After heating at 67 °C for 16 h, the mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The mixture was washed with saturated brine (50 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice on an Interchim automated chromatography system (2 × 40 g column stack, 2 × 25 g column stack) eluting each time with a gradient of 0–100% ethyl acetate in heptane to afford a mixture of compounds 5, 5-4, and 5-5 (610 mg) as a yellow oil. This oil mixture was subjected to supercritical fluid chromatography (Lotus Separations) to afford three compounds, which appeared as a black residue oil. The LM-6-85-P2 residue was re-purified on an InterChim automated chromatography system (25 column) eluting with a gradient of 0–60% ethyl acetate in hexane to afford compound 5 (60 mg, 7% yield) as an off-white solid dried under vacuum at 40 °C for 16 h (LM-6-85). After SFC separation (conditions listed below), 425 mg of peak-1 (5-5, LM-6-85-P1), 88 mg of peak-2 (5, LM-6-85-P2), and 70 mg of peak-3 (5-4, LM-6-85-P3) were obtained. Peak-2 was reprocessed to improve purity.

[0196] The chromatogram is included in this report.

[0197]

Table 2

[0198] Figure 5 shows LM-6-85 (mixture of compound 5, E-5-4 and E-5-5) before separation.

[0199] Figure 6 shows LM-6-85-P2 (compound 5) after separation.

[0200] Figure 7 shows LM-6-85-P1 (Compound 5-5) after separation.

[0201] Figure 8 shows LM-6-85-P3 (Compound 5-4) after separation. Structural data: Compound 5 [KYN-153] Off-white solid; HPLC analysis: 97.7% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.6 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 341.2 (M+H) + ; C 21 H 24 O 4 ; NMR (400 MHz, CDCl 3 ) δ = 7.19 (d, J = 16.1 Hz, 1H), 7.03 - 6.98 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 16.1 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.66 (s, 1H), 5.59 - 5.40 (m, 2H), 4.70 (s, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 3.42 (br d, J = 5.9 Hz, 2H), 1.65 - 1.61 (m, 3H), 1.41 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 157.95, 154.40, 146.68, 145.57, 138.31, 130.35, 130.29, 129.79, 124.88, 124.43, 120.34, 119.89, 114.59, 108.54, 103.84, 99.17, 63.99, 55.89, 28.49, 17.90, 14.87.

[0202] Preparation of (E)-4-allyl-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (6) [KYN-134]

[0203] [Chem.] (E)-(2-((4-(2-allyl-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-methoxyphenoxy)methoxy)ethyl)trimethylsilane (6-1): [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46 mg, 0.063 mmol, 0.25 equiv) and allyltributylstannane (248 mg, 0.75 mmol, 3 equiv) were added to a solution of compound C1 (module C) (153 mg, 0.25 mmol, 1 equiv) in anhydrous dimethylformamide (3 mL). After sparging with nitrogen for 10 minutes, the reaction was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and purified on an Interchim automated chromatography system (25 columns) packed with silica gel (10 g) in a 0 - 40% ethyl acetate gradient in heptane to afford compound 6-1 (140 mg, 98% yield) as a yellow oil (LM-6-33).

[0204] (E)-4-allyl-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (6) [KYN-134]: 1M tetrabutylammonium fluoride in tetrahydrofuran (3.5 mL, 3.5 mmol, 14 equiv) was added to compound 6-1 (140 mg, 0.25 mmol, 1 equiv) at room temperature and the mixture was heated at 67 °C for 16 hours. After cooling the mixture to room temperature, water (4 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL) and the organic layer was concentrated under reduced pressure. The residue was purified twice on an Interchim automated chromatography system (2×25 columns) eluting each time with a 0 - 60% ethyl acetate gradient in heptane to afford compound 6 (34 mg, 45% yield) as an off-white solid after drying under vacuum at 35 °C for 16 hours (LM-6-34). White solid; HPLC analysis: 96.3% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 7.48 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 313.1 (M+H) + ; C 19 H20 O 4 1 H NMR (400 MHz, CDCl 3 ) δ = 7.14 (d, J = 16.2 Hz, 1H), 7.00 (dd, J = 1.5, 7.7 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 16.1 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 5.94 (ddt, J = 5.9, 10.2, 17.0 Hz, 1H), 5.66 (br s, 1H), 4.99 (dq, J = 1.7, 8.5 Hz, 1H), 4.96 (dq, J = 1.7, 17.1 Hz, 1H), 4.76 (br s, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.48 (dt, J = 1.7, 5.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ = 158.73, 154.70, 146.70, 145.64, 138.71, 137.25, 130.63, 130.26, 124.22, 120.43, 118.57, 114.61, 114.40, 108.56, 104.03, 98.25, 55.92, 55.80, 29.50.

[0205] Preparation of (E)-4-benzyl-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (7) [KYN-136]

[0206]

Chem.

[0207] (E)-4-benzyl-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenol (7) [KYN-136]: 1M tetrabutylammonium fluoride in tetrahydrofuran (3.92 mL, 3.92 mmol, 14 eq) was added to compound 7-1 (172 mg, 0.28 mmol, 1 eq) at room temperature. After heating at 67 °C for 16 hours, the mixture was cooled to room temperature and diluted with water (4 mL). The mixture was extracted with ethyl acetate (15 mL), and the organic layer was concentrated under reduced pressure. The residue was purified twice on an Interchim automated chromatography system (40 & 25 columns) eluting each time with a gradient of 0 - 60% ethyl acetate in heptane to give compound 7 (37 mg, 37% yield), which was dried under vacuum at 35 °C for 16 hours to give an off-white solid (LM-6-36). Off-white solid; HPLC analysis: 96.4% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.09 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 363.1 (M+H) + ; C 23 H 22 O 4 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.24 - 7.00 (m, 2H), 7.18 - 7.10 (m, 3H), 7.09 (d, J = 16.1 Hz, 1H), 6.89 (dd, J = 1.7, 8.6 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.85 (d, J= 1.7 Hz), 6.82 (d, J = 15.9 Hz), 6.68 (d, J = 2.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.65 (br s, 1H), 4.87 (br s, 1H), 4.10 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ = 159.03, 154.85, 146.63, 145.58, 141.66, 138.83, 130.62, 130.12, 128.22, 128.16, 125.55, 124.31, 120.60, 119.60, 114.48, 108.23, 104.06, 98.21, 55.83, 55.72, 30.92.

[0208] Preparation of (E)-3-ethoxy-5-(4-hydroxy-3-methoxystyryl)-4-(3-methylbut-2-en-1-yl)phenol (8) [KYN-119]

[0209]

Chem.

[0210] 1-bromo-3-ethoxy-5-((3-methylbut-2-en-1-yl)oxy)benzene (8-3): A 60% dispersion of sodium hydride (1.1 g, 28.64 mmol, 1.1 eq) in mineral oil and 3,3-dimethylallyl bromide (4.27 g, 28.6 mmol, 1.1 eq) were sequentially added to a solution of compound 8-2 (5.65 g, 26.03 mmol, 1 eq) in anhydrous THF (500 mL). The reaction mixture was heated at 50 °C and stirred overnight. The reaction mixture was cooled to room temperature and transferred to a separatory funnel containing saturated ammonium chloride solution (400 mL). Ethyl acetate (700 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 × 200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech 120 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 8-3 (6.8 g, 88% yield) as a yellow oil (TA-1-102).

[0211] (2-((2-methoxy-4-vinylphenoxy)methoxy)ethyl)trimethylsilane (8-5): N,N-Diisopropylethylamine (8.8 mL, 50 mmol, 1.5 equiv) and 2-(trimethylsilyl)ethoxymethyl chloride (7.1 mL, 40 mmol, 1.2 equiv) were sequentially added to a solution of compound 8-4 (5 g, 33.33 mmol, 1.0 equiv) in anhydrous dichloromethane (50 mL) at room temperature. After stirring overnight at room temperature, saturated ammonium chloride (50 mL) was added to quench the reaction. The aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech 24 g column) eluting with a gradient of 0 - 10% ethyl acetate in heptane to afford compound 8-5 (6.5 g, 70% yield) as a clear oil (NK-1-45).

[0212] (E)-(2-((4-(3-Ethoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-2-methoxyphenoxy)methoxy)ethyl)trimethylsilane (8-6): Compound 8-5 (1.49 g, 5.32 mmol, 1.2 equiv), triphenylphosphine (110 mg, 0.443 mmol, 0.1 equiv), potassium acetate (868 mg, 8.86 mmol, 2 equiv) and palladium(II) acetate (50 mg, 0.221 mmol, 0.05 equiv) were added to a solution of compound 8-3 (1.26 g, 4.43 mmol, 1.0 equiv) in anhydrous toluene (30 mL). The reaction mixture was sparged with nitrogen for 15 min. After refluxing for 16 h (110 °C), the reaction mixture was cooled to room temperature and filtered through Celite (ca. 5 g). The filtrate was transferred to a separatory funnel containing saturated sodium bicarbonate (30 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Another batch using compound 3 (1.26 g) was treated in a similar manner. The combined residues were purified on an Interchim automated chromatography system (Sorbtech 24 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 8-6 (960 mg, 22% yield) as a pale yellow oil (NK-1-49).

[0213] (E)-4-(3-Ethoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-2-methoxyphenol (8-7): 1 M tetrabutylammonium fluoride in THF (14.0 mL, 13.88 mmol, 7 eq) was added to a solution of compound 8-6 (960 mg, 1.98 mmol, 1 eq) in anhydrous THF (40 mL) at room temperature. The mixture was refluxed overnight (66 °C), at which point LCMS indicated that the reaction was complete. After cooling the mixture to room temperature, water (10 mL) was added to quench the reaction. Volatiles were removed under reduced pressure, followed by the addition of ethyl acetate (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech 12 g column) eluting with a gradient of 0–50% ethyl acetate in heptane to afford compound 8-7 (503 mg, 71% yield) as a yellow oil (NK-1-44).

[0214] (E)-3-Ethoxy-5-(4-hydroxy-3-methoxystyryl)-4-(3-methylbut-2-en-1-yl)phenol (8) [KYN-119]: Montmorillonite K30 powder (500 mg) was added to a solution of compound 8-7 (500 mg, 1.41 mmol) in anhydrous dichloromethane (20 mL) at room temperature and the mixture was stirred overnight at room temperature. Formation of the product was not observed by LCMS. The mixture was filtered, fresh montmorillonite K30 powder (500 mg) was added, and the mixture was stirred overnight at room temperature, at which point LCMS indicated that 30–40% of the desired compound 8 had been formed along with two regioisomers as by-products and unreacted starting compound 7. The mixture was filtered and the solid was washed with dichloromethane (2 × 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech 24 g column) eluting with a gradient of 0–50% ethyl acetate in heptane. Trituration with 30% dichloromethane in heptane (10 mL) afforded pure compound 8 [KYN-119] (60 mg, 12% yield) as a white solid. (NK-1-52-C) Beige solid, melting point 133.9 - 134.7 °C; HPLC analysis: 96.7% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 9.10 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 355.2 (M+H) + ; C 22 H 26 O 4 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.16 (d, J = 16.1 Hz, 1H), 7.00 (br s, 1H), 6.99 (dd, J = 1.9, 9.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 16.1 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 5.13 (tm, J = 1.4, 7.0 Hz, 1H), 3.98 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.43 (d, J = 7.0 Hz, 2H), 1.81 (d, J = 1.0 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 157.88, 154.27, 146.68, 145.53, 138.12, 130.40, 130.34, 130.32, 124.39, 123.74, 120.89, 120.55, 114.56, 108.32, 103.86, 99.12, 63.94, 55.88, 25.78, 24.54, 18.01, 14.89.

[0215] Compound 8 (KYN - 119) can also be synthesized using the modular methodology of the present disclosure using equivalents of modules A, B, and C, and subsequent cross - coupling alkylation of halogenated aryls.

[0216] (E)-3-(4-Hydroxy-3-methoxystyryl)-4-(3-methylbut-2-en-1-yl)-5-propoxyphenol (9) [KYN-130] Preparation

[0217]

Chem.

[0218] 1-Bromo-3-((3-methylbut-2-en-1-yl)oxy)-5-propoxybenzene (9-3): Potassium carbonate (10.1 g, 73.36 mmol, 1.5 eq) and 3,3-dimethylallyl bromide (6.8 mL, 58.70 mmol, 1.2 eq) were sequentially added to a solution of compound 9-2 (11.3 g, 48.91 mmol, 1 eq) in acetonitrile (200 mL) at room temperature. The resulting suspension was refluxed for 16 h (80 °C). After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 9-3 (16.0 g, 99% yield) as a light brown oil (NRK-1-90), which was used subsequently without further purification.

[0219] (E)-(2-((2-Methoxy-4-(3-((3-methylbut-2-en-1-yl)oxy)-5-propoxystyryl)phenoxy)methoxy)ethyl)trimethylsilane (9-6): (2-((2-Methoxy-4-vinylphenoxy)methoxy)ethyl)trimethylsilane (9-5, see 8-5 for preparation) (12.3 g, 4.15 mmol, 1.1 eq), triphenylphosphine (2.1 g, 8.02 mmol, 0.2 eq), potassium carbonate (11 g, 80.26 mmol, 2 eq) and palladium(II) acetate (910 mg, 4.01 mmol, 0.1 eq) were added to a solution of compound 9-3 (12.0 g, 40.13 mmol, 1.0 eq) in anhydrous toluene (300 mL) at room temperature. The reaction mixture was sparged with nitrogen for 15 minutes. After refluxing for 16 hours (110 °C), the reaction mixture was cooled to room temperature and filtered through celite (ca. 30 g). The filtrate was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to give compound 9-6 (6.25 g, 31% yield) as a pale brown oil (NRK-1-91).

[0220] (E)-2-Methoxy-4-(3-((3-methylbut-2-en-1-yl)oxy)-5-propoxystyryl)phenol (8-7): 1M tetrabutylammonium fluoride in THF (139 mL, 138.59 mmol, 7 eq) was added to a solution of compound 9-6 (9.86 g, 19.8 mmol, 1 eq) in anhydrous THF (200 mL) at room temperature. The mixture was refluxed for 16 hours (66 °C), at which point LCMS indicated that the reaction was complete. After cooling the mixture to room temperature, water (20 mL) was added. The volatiles were removed under reduced pressure and subsequently ethyl acetate (150 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 50% ethyl acetate in heptane to give compound 9-7 (6.66 g, 92% yield) as a yellow solid (NRK-1-92).

[0221] (E)-3-(4-Hydroxy-3-methoxystyryl)-4-(3-methylbut-2-en-1-yl)-5-propoxyphenol (9) [KYN-130]: Montmorillonite K30 powder (6.66 g) was added to a solution of compound 8-7 (6.66 g, 18.09 mmol) in anhydrous dichloromethane (200 mL) at room temperature. After stirring overnight at room temperature, LCMS indicated that 30 - 40% of the desired compound 9 was formed along with two positional isomers as by-products and unreacted starting compound 9-7. The mixture was filtered through celite and washed with dichloromethane (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane. The product was triturated with 30% dichloromethane in heptane (20 mL) to give pure compound 9 [KYN-130] (1.02 g, 15% yield) as a white solid (NRK-1-95-C). White solid, melting point 141.6 - 142.8 °C; HPLC analysis: 99.48% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm, retention time: 9.4 min; mobile phase: ACN / formic acid / water; mass spectrum (negative mode) m / z = 367.2 (M-H) - ; C 23 H 28 O 4 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.16 (d, J = 16.1 Hz, 1H), 7.00 (br s, 1H), 6.99 (dd, J = 2.0, 8.2 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 15.9 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 5.14 (tm, J = 7.0 Hz, 1H), 3.93 (s, 3H), 3.88 (t, 6.4 Hz, 2H), 3.43 (d, J = 6.8 Hz, 2H), 1.83 (m, J = 6.4, 7.6 Hz, 2H), 1.81 (d, J = 1.0 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.02, 154.27, 146.68, 145.57, 138.14, 130.36, 130.33, 130.31, 124.42, 123.84, 120.88, 120.55, 114.56, 108.32, 103.75, 98.97, 69.90, 55.90, 25.78, 24.57, 22.68, 18.01, 10.68.

[0222] Compound 9 (KYN-130) can also be synthesized using the modular methodology of the present disclosure using equivalents of modules A, B, and C, as well as subsequent cross-coupling alkylation of the halogenated aryls.

[0223] 3-(4-Hydroxy-3-methoxystyryl)-5-isopropoxy-4-(3-methylbut-2-en-1-yl)phenol (10) [KYN-131] Preparation

[0224]

Chemical Structure

[0225] 3-Isopropoxy-5-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (10-3): A mixture of compound 10-2 (1.13 g, 6.27 mmol, 1 equiv), potassium carbonate (1.73 g, 12.5 mmol, 2 equiv) and 1-bromo-3-methylbut-2-ene (0.87 mL, 7.53 mmol, 1.2 equiv) in acetone (35 mL) was refluxed for 16 h. After cooling to room temperature, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (24 g SorbTech column) eluting with a gradient of 0 - 50% ethyl acetate in heptane to give compound 10-3 (1.33, 86% yield) as a yellow oil (QZH-RCI-6).

[0226] 2-((4-(3-Isopropoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-2-methoxyphenoxy)methoxy)ethyl)trimethylsilane (10-4): A solution of Module B (2.17 g, 5.36 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added to a suspension of a 60% dispersion of sodium hydride (0.43 g, 10.7 mmol, 2 equiv) in mineral oil in tetrahydrofuran (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. A solution of Compound 10-3 (1.33 g, 5.36 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added, and the reaction mixture was warmed to room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (24 g RediSep column) eluting with a gradient of 0 - 10% ethyl acetate in heptane to afford Compound 10-4 (1.65 g, 62% yield) as a yellow oil (QZH-RCI-9).

[0227] 4-(3-Isopropoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-2-methoxyphenol (10-5): A solution of Compound 10-4 (1.65 g, 3.3 mmol, 1 equiv) and tetrabutylammonium fluoride 1.0 M in tetrahydrofuran (16.5 mL, 16.5 mmol, 5 equiv) in tetrahydrofuran (20 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (12 g RediSep column) eluting with a gradient of 0 - 30% ethyl acetate in heptane to afford Compound 10-5 (0.85 g, 70% yield) as a brown oil (QZH-RCI-10).

[0228] 3-(4-Hydroxy-3-methoxystyryl)-5-isopropoxy-4-(3-methylbut-2-en-1-yl)phenol (10) [KYN-131]: Montmorillonite K10 powder (1 g, Sigma-Aldrich, catalog #69866) was added to a solution of compound 10-5 (0.85 g, 2.3 mmol, 1 equiv) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 h, at which point LC / MS indicated >90% conversion of the starting material. The solid was removed by filtration, and the filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated under reduced pressure. The residue was first purified on a Buchi automated chromatography system (25 g SorbTech column) eluting with a gradient of 0–30% ethyl acetate in heptane. Fractions containing the product (>85% purity by LC / MS) were collected and purified again on an InterChim automated chromatography system (25 g InterChim, 20–45 micron silica gel column) eluting with a gradient of 0–30% ethyl acetate in heptane to afford compound 10 [KYN-131] (75 mg, 9% yield, 99.2% purity by HPLC) as an off-white solid (QZH-RCI-12). Off-white solid; HPLC analysis: 99.2% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 9.2 min; mobile phase: ACN / formic acid / water; C 23 H 28 O 4 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.15 (d, J = 16.1 Hz, 1H), 7.00 (br s, 1H), 6.99 (dd, J = 2.0, 8.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 16.1 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 5.12 (tm, J = 1.4, 7.0 Hz, 1H), 4.49 (septet, J = 6.0 Hz, 1H), 3.94 (s, 3H), 3.41 (d, J = 6.9 Hz, 2H), 1.82 (d, J = 1.0 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.34 (d, J = 6.1 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ = 156.75, 154.19, 146.68, 145.57, 138.37, 130.34, 130.27, 130.23, 124.52, 123.87, 121.87, 120.55, 114.55, 108.32, 103.95, 100.46, 70.35, 55.90, 25.78, 24.69, 22.17, 18.10.

[0229] Compound 10 (KYN-131) can also be synthesized using the modular methodology of the present disclosure using equivalents of modules A, B, and C, and subsequent cross-coupling alkylation of the halogenated aryl.

[0230] (E)-3-(4-Hydroxy-3-methoxystyryl)-4-(3-methylbut-2-en-1-yl)-5-(trifluoromethoxy)phenol (11) [KYN-132] Preparation

[0231]

Chemical Structure

[0232] (E)-(2-((2-Methoxy-4-(3-((3-methylbut-2-en-1-yl)oxy)-5-(trifluoromethoxystyryl)phenoxy)methoxy)ethyl)trimethylsilane (11-5): (2-((2-Methoxy-4-vinylphenoxy)methoxy)ethyl)trimethylsilane (11-4, see 8-5 for preparation) (4.30 g, 15.38 mmol, 1.0 equiv), triphenylphosphine (800 mg, 3.07 mmol, 0.2 equiv), potassium carbonate (4.25 g, 30.76 mmol, 2 equiv) and palladium acetate (350 mg, 1.6 mmol, 0.1 equiv) were added to a solution of compound 11-2 (5.0 g, 15.38 mmol, 1.0 equiv) in anhydrous toluene (150 mL) at room temperature. The reaction mixture was sparged with nitrogen for 15 min. After refluxing for 16 h (110 °C), the reaction mixture was cooled to room temperature and filtered through Celite (ca. 20 g). The filtrate was transferred to a separatory funnel containing saturated sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0–20% ethyl acetate in heptane to give compound 11-5 (4.89 g, 61% yield) as a light brown oil (NRK-1-97).

[0233] (E)-2-Methoxy-4-(3-((3-methylbut-2-en-1-yl)oxy)-5-(trifluoromethoxystyryl)phenol (11-6): A 1 M solution of tetrabutylammonium fluoride in THF (66 mL, 65.24 mmol, 7 eq) was added to a solution of compound 11-5 (4.89 g, 9.32 mmol, 1 eq) in anhydrous THF (200 mL) at room temperature. After refluxing for 16 h (66 °C), LCMS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with water (20 mL). Volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 50% ethyl acetate in heptane to afford compound 11-6 (3.2 g, 87% yield) as a pale yellow oil (NRK-1-98).

[0234] (E)-3-(4-Hydroxy-3-methoxystyryl)-4-(3-methylbut-2-en-1-yl)-5-(trifluoromethoxy)phenol (11) [KYN-132]: Montmorillonite K30 powder (3.2 g) was added to a solution of compound 11-6 (3.2 g, 8.89 mmol) in anhydrous dichloromethane (100 mL) at room temperature and the mixture was stirred at room temperature overnight. LCMS indicated that 10 - 15% of the desired compound 11 was formed along with two positional isomers as by-products and unreacted starting compound 11-6. The mixture was filtered and further treated with fresh montmorillonite K30 powder (3.2 g) at room temperature for 24 h. The reaction mixture was filtered and the solid was washed with dichloromethane (2 × 50 mL). The combined filtrates were concentrated under reduced pressure. The residue was first purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford several mixed fractions containing compound 11. The fractions were pooled together and the resulting material was purified on a Reveleris automated chromatography system (Redisep Rf Gold HP C18, 100 g column) eluting with a gradient of 0 - 80% acetonitrile in water. The product was triturated with 30% dichloromethane in heptane (10 mL) to afford pure compound 11 (60 mg, 1.7% yield) as a white solid (NRK-1-99-C). White solid, melting point 141.6~142.6 °C; HPLC analysis: 98.81% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 9.8 minutes; mobile phase: ACN / formic acid / water; mass spectrum (negative mode) m / z = 393.0 (M-H) - ; C 21 H 21 F 3 O 4 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.09 (d, J = 15.9 Hz, 1H), 7.00 (dd, J = 1.8, 7.1 Hz, 1H), 6.99 (br s, 1H), 6.99 (m, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 16.1 Hz, 1H), 6.69 (m, 1H), 5.07 (tm, J = 6.9 Hz, 1H), 3.94 (s, 3H), 3.42 (d, J = 6.9 Hz, 2H), 1.80 (s, 3H), 1.69 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ = -56.88 (s, 3F); 13 C NMR (100 MHz, CDCl 3 ) δ = 153.95, 148.13, 146.73, 145.92, 139.81, 131.69, 131.66, 129.80, 124.31, 123.25, 122.29, 120.77, 114.64, 110.74, 108.43, 106.97, 55.90, 25.68, 25.02, 17.93.

[0235] Compound 11 (KYN-132) can also be synthesized using the modular methodology of the present disclosure using equivalents of modules A, B, and C, and subsequent cross-coupling alkylation of halogenated aryls.

[0236] Preparation of 3-(3-Ethoxy-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (12) [KYN-133]:

[0237]

Chem.

[0238] 1-Bromo-3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzene (12-3): Potassium carbonate powder (82 g, 594.20 mmol, 2 eq) and 3,3-dimethylallyl bromide (53 g, 355.7 mmol, 1.2 eq) were sequentially added to a solution of compound 12-2 (60 g, 297.02 mmol, 1.0 eq) in acetone (500 mL) at room temperature. After refluxing overnight (55 °C), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on an Interchim automated chromatography system (Sorbtech 220 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 12-3 (60 g, 75% yield) as a light brown oil (NK-1-8).

[0239] 3-Ethoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (12-5): 2-(Trimethylsilyl)ethoxymethyl chloride (3.4 mL, 19 mmol, 1.05 equiv) was added to a solution of compound 12-4 (3 g, 18.1 mmol, 1 equiv) and N,N'-diisopropylethylamine (9.5 mL, 54.3 mmol, 3 equiv) in dichloromethane (60 mL) at room temperature. The reaction mixture was stirred for 16 h, at which point LC / MS analysis indicated that the reaction was complete. The reaction mixture was washed sequentially with water (100 mL), saturated ammonium chloride (100 mL), and saturated brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 12-5 (6 g, > theoretical) as an orange oil, which was used subsequently. (QZH-RCI-34).

[0240] (2-((2-Ethoxy-4-vinylphenoxy)methoxy)ethyl)trimethylsilane (12-6): 2.5 M n-Butyllithium in hexanes (8 mL, 20 mmol, 1.1 equiv) was added to a mixture of methyltriphenylphosphonium bromide (7.1 g, 20 mmol, 1.1 equiv) in tetrahydrofuran (90 mL) at 0 °C. After stirring for 30 min, a solution of compound 12-5 (6 g, 18.1 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added at a rate such that the internal temperature of the reaction was maintained below 5 °C. Hexanes (150 mL) were added, and the resulting solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automated chromatography system (80 g column) eluting with a gradient of 0–30% ethyl acetate in heptane to afford compound 12-6 (4.43 g, 84% yield) as a clear oil (QZH-RCI-35).

[0241] ((2-((2-Ethoxy-4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)phenoxy)methoxy)ethyl)trimethylsilane (12-7): A mixture of Compound 12-6 (4.43 g, 15 mmol, 1 equiv), 1-bromo-3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzene (12-3) (4.3 g, 15.8 mmol, 1.05 equiv), palladium(II) acetate (0.34 g, 1.5 mmol, 0.1 equiv), triphenylphosphine (0.79 g, 3 mmol, 0.2 equiv) and potassium carbonate (4.14 g, 30 mmol, 2 equiv) in toluene (130 mL) was sparged with nitrogen for 10 minutes. After refluxing for 16 hours, the reaction was cooled to room temperature and diluted with heptane (150 mL). The solid was removed by filtration and discarded. The filtrate was concentrated under reduced pressure and the residue was purified on a Buchi automatic chromatography system (120 g column) eluting with a gradient of 0 - 25% ethyl acetate in heptane to give Compound 12-7 (3.18 g, 44% yield) as a brown oil (QZH-RCI-37).

[0242] 2-Ethoxy-4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)phenol (12-8): A solution of Compound 12-7 (3.18 g, 6.56 mmol, 1 equiv) in tetrahydrofuran (32 mL) and 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (45.9 mL, 45.9 mmol, 7 equiv) was refluxed overnight. After cooling to room temperature, water (100 mL) and saturated ammonium chloride (200 mL) were added. The reaction mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (24 g column) eluting with a gradient of 0 - 35% ethyl acetate in heptane to give Compound 12-8 (1.76 g, 76% yield) as a yellow oil (QZH-RCI-38).

[0243] 3-(3-Ethoxy-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (12) (KYN-133): Montmorillonite K10 powder (1.76 g, Sigma - Aldrich, catalog #69866) was added to a solution of compound 12 - 8 (1.76 g, 4.96 mmol, 1 equiv) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 24 h, at which point LC / MS analysis indicated >90% conversion of the starting material. The reaction mixture was directly absorbed onto celite (25 g) and purified on a Buchi automated chromatography system (80 g column) eluting with a gradient of 0 - 35% ethyl acetate in heptane to afford compound 12 [KYN - 133] (0.17 g, 10% yield, 99.4% purity by HPLC) as an off - white solid (QZH - RCI - 38). Off - white solid, melting point 126.6 - 129.1 °C; HPLC analysis: 99.4% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 9.1 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 355.2 (M + H) + ; C 22 H 26 O 4 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.12 (d, J = 16.2 Hz, 1H), 6.98 (s, 1H), 6.97 (dd, J = 2.0, 8.5 Hz, 1H), 6.90 (dm, J = 8.6 Hz, 1H), 6.82 (d, J = 15.9 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.74 (s, 1H), 5.13 (tm, J = 1.4, 6.9 Hz, 1H), 4.85 (s, 1H), 4.14 (q, J = 6.9 Hz, 2H), 3.78 (s, 3H), 3.40 (d, J = 6.9 Hz, 2H), 1.80 (d, J = 0.8 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.46 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ = 158.54, 154.34, 145.93, 145.65, 138.17, 130.58, 130.46, 130.24, 124.19, 123.66, 120.71, 120.44, 114.50, 109.28, 103.94, 98.23, 64.49, 55.68, 25.74, 24.45, 17.93, 14.87.

[0244] Compound 12 (KYN-133) can also be synthesized using the modular methodology of the present disclosure using equivalents of modules A, B, and C, as well as subsequent cross-coupling alkylation of the halogenated aryls.

[0245] (E)-3-(3-Ethyl-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (13) [KYN-114] Preparation

[0246]

Chemical Structure

[0247] 1-Bromo-3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzene (13-3): Potassium carbonate powder (350.0 g, 2532.5 mmol, 2 equivalents) and 3,3-dimethylallyl bromide (226.45 g, 1519.5 mmol, 1.2 equivalents) were sequentially added to a solution of compound 13-2 (257.1 g, 1266.2 mmol, 1.0 equivalent) in acetone (7500 mL) at room temperature. After refluxing overnight, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified on a Biotage-150 column eluting with a gradient of 0 - 10% ethyl acetate in heptane to afford compound 13-3 (358.0 g, >100% yield) as a brown oil (GB-27-174).

[0248] 3-Methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (13-4): 2.5 M n-Butyllithium in hexane (557 mL, 1392.6 mmol, 1.1 equivalents) was added dropwise to a solution of compound 13-3 (358.0 g, approximately 1266.2 mmol, 1.0 equivalent) in anhydrous THF (7000 mL) at -75 °C while maintaining the temperature below -70 °C. After stirring at -75 °C for 30 minutes, anhydrous DMF (147 mL, 1899.0 mmol, 1.5 equivalents) was added dropwise while maintaining the temperature below -70 °C. The resulting mixture was slowly warmed to room temperature overnight. Ice-cold water (500 mL) was added to quench the reaction. The mixture was diluted with ethyl acetate (5 L), and the layers were separated. The organic layer was washed with saturated brine (500 mL). The combined aqueous layers were extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage-150 column eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 13-4 (221.5 g, 79% overall yield in 2 steps) as a yellow oil (GB-27-175).

[0249] (3-Methoxy-5-((3-methylbut-2-en-1-yl)oxy)phenyl)methanol (13-5): Sodium borohydride (38.04 g, 1005.6 mmol, 1.0 equiv) was added portionwise at 0 °C to a solution of compound 13-4 (221.5 g, 1005.6 mmol, 1.0 equiv) in methanol (3500 mL) while maintaining the temperature below 10 °C. After stirring at 5 - 10 °C for 1 h, water (200 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure to remove most of the methanol. The residue was diluted with ethyl acetate (2.5 L) and washed with saturated brine (600 mL). The aqueous layer was extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 13-5 (218.61 g, 98% yield) as a yellow oil, which was used subsequently. (GB-27-178)

[0250] 1-(Bromomethyl)-3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzene (13-6): Carbon tetrabromide (358.76 g, 1081.84 mmol, 1.1 equiv) was added at room temperature to a solution of compound 13-5 (218.61 g, 983.49 mmol, 1.0 equiv) in dichloromethane (4400 mL). The resulting mixture was cooled to 0 °C and triphenylphosphine (283.76 g, 1081.84 mmol, 1.1 equiv) was added portionwise. After stirring at room temperature for 4 h, the mixture was concentrated under reduced pressure. The residue was purified on a Biotage-150 column eluting with a gradient of 0 - 10% ethyl acetate in heptane to give compound 13-6 (273.76 g, 97% yield) as a yellow oil (GB-27-181). Note: Compound 13-6 appears to be unstable when purified on some prepacked silica gel columns.

[0251] Diethyl (3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzyl)phosphonate (13-7): 1 M lithium hexamethyldisilazide in THF (6.57 mL, 6.57 mmol, 1.8 equiv) was added to a solution of diethyl phosphite (0.94 mL, 7.3 mmol, 2.0 equiv) in anhydrous THF (20 mL) at 0 °C. After stirring at 0 °C for 30 minutes, a solution of compound 13-6 (1.04 g, 3.65 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added and the mixture was stirred overnight at room temperature. The reaction was quenched with water (30 mL) and the mixture was washed with saturated brine (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 60 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (400 g column) eluting with a gradient of 0–10% methanol in dichloromethane to afford compound 13-7 (1.10 g, 88% yield) as a brown oil (LM-1-41).

[0252] 3-Ethyl-4-hydroxybenzaldehyde (13-9): [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.18 g, 2.98 mmol, 0.05 equiv) and cesium carbonate (38.9 g, 119.4 mmol, 2 equiv) were added to a solution of 3-bromo-4-hydroxybenzaldehyde (13-8) (12 g, 59.7 mmol, 1 equiv) in anhydrous THF (150 mL). A 1 M solution of triethylborane in THF (119.4 mL, 119.4 mmol, 1.8 equiv) was added and the mixture was refluxed overnight (66 °C). After cooling to room temperature, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 × 250 mL). The combined organic layers were washed with saturated brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was first purified on an InterChim automated chromatography system (220 g column) eluting with a gradient of 0–40% ethyl acetate in heptane. Second, it was purified on an InterChim automated chromatography system (80 g column) eluting with a gradient of 0–40% ethyl acetate in heptane to afford compound 13-9 (5.21 g, 58% yield) as a brown oil (LM-1-2).

[0253] 3-Ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (13-10): 2-(Trimethylsilyl)ethoxymethyl chloride (6.1 mL, 34.52 mmol, 1.1 eq) was added to a solution of compound 13-9 (4.71 g, 31.38 mmol, 1 eq) in anhydrous dichloromethane (120 mL). Diisopropylethylamine (8.2 mL, 47.07 mmol, 1.5 eq) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was first purified on an InterChim automated chromatography system (220 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane. Second, it was purified on an InterChim automated chromatography system (120 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 13-10 (6.77 g, 77% yield) as a clear oil (LM-1-4).

[0254] (E)-(2-((2-Ethyl-4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)phenoxy)methoxy)ethyl)trimethylsilane (13-11): A solution of 1.0 M potassium t-butoxide in THF (11.7 mL, 11.68 mmol, 2 eq) was added dropwise to a cooled solution of diethyl (3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzyl)phosphonate (13-7) (2 g, 5.84 mmol, 1 eq) in anhydrous THF (20 mL) at 0 °C. After stirring at room temperature for 15 min, a solution of compound 9 (2.5 g, 8.76 mmol, 1.5 eq) in anhydrous THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, then quenched with saturated brine (50 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified on an Interchim automated chromatography system (80 g column) eluting with a gradient of 0 - 30% ethyl acetate in heptane to afford compound 13-11 (1.32 g, 48% yield) as a clear oil (CSK-2-97).

[0255] (E)-2-Ethyl-4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)phenol (13-12): 1.0 M tetrabutylammonium fluoride in THF (19.7 mL, 19.7 mmol, 7 equiv) was added to a solution of compound 13-11 (1.32 g, 2.81 mmol, 1 equiv) in anhydrous THF (20 mL), and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was first purified on an InterChim automated chromatography system (80 g column) eluting with a gradient of 0-100% ethyl acetate in heptane. Second, purification on an InterChim automated chromatography system (40 g column) eluting with a gradient of 0-30% ethyl acetate in heptane gave compound 13-12 (770 mg, 80% yield) as a thick clear oil. (CSK-2-98)

[0256] (E)-3-(3-Ethyl-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (13)[KYN-114]: Montmorillonite K30 (620 mg) was added to a solution of compound 13-12 (620 mg, 1.83 mmol, 1 equiv) in anhydrous dichloromethane (12 mL), and the resulting mixture was stirred overnight at room temperature. The mixture was filtered through a Celite pad, which was rinsed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified on an Interchim automated chromatography system (25 g column) eluting with a gradient of 0-30% ethyl acetate in heptane to give compound 13 [KYN-114] (120 mg, 19% yield) as an off-white solid (CSK-2-99). 1 H NMR (400 MHz, methanol-d 3) δ = 7.22 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 2.0, 8.3 Hz, 1H), 7.11 (d, J = 16.1 Hz, 1H), 6.83 (d, J = 16.1 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.33 (d, J = 2.2 Hz, 1H), 5.06 (septet of triplets, J = 1.4, 6.8 Hz, 1H), 3.77 (s, 3H), 3.37 (br d, J = 6.6 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H), 1.80 (d, J = 1.0 Hz, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, methanol-d 3 ) δ = 159.69, 157.12, 156.09, 139,51, 131.92, 131.12, 130.70, 128.30, 126.20, 125.49, 124.54, 115.95, 104.67, 98.95, 55.96, 25.87, 25.09, 24.26, 18.06, 14.68.

[0257] The compound of KYN-114 can also be synthesized by using the modular methodology of the present disclosure using equivalents of modules A, B and C, and subsequent cross-coupling alkylation of halogenated aryls.

[0258] (E)-3-(4-Hydroxy-3-(methylthio)styryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (14)[Preparation of KYN-118]

[0259]

Chemical Structure

[0260] (E)-(2-((4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-2-(methylthio)phenoxy)methoxy)ethyl)trimethylsilane (14-3): A solution of compound 13-7 (1.1 g, 3.2 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added dropwise to a 60% dispersion of sodium hydride in mineral oil in anhydrous THF (20 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of compound 14.2 (0.955 g, 3.2 mmol, 1.0 equiv) in anhydrous THF (10 mL) was then added dropwise, and the mixture was stirred overnight at room temperature. The reaction was quenched with water (30 mL), and the mixture was washed with saturated brine (70 mL).

[0261] The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (40 g column) eluting with a gradient of 0 - 20% ethyl acetate in heptane to afford compound 14-3 (1.01 g, 79% yield based on 0.17 g of the recovered starting material compound 14.2) as a yellow oil (LM-1-42).

[0262] (E)-4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-2-(methylthio)phenol (14.4): 1M tetrabutylammonium fluoride in THF (7 mL, 7 mmol, 7 equiv) was added to a solution of compound 14.3 (0.486 g, 1.0 mmol, 1.0 equiv) in anhydrous THF (10 mL) at room temperature. After refluxing overnight, the mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with saturated brine (30 mL). The combined aqueous layers were extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (25 g column) eluting with a gradient of 0 - 30% ethyl acetate in heptane to afford compound 14.4 (0.25 g, 70% yield) as a brown oil (LM-1-43).

[0263] (E)-3-(4-Hydroxy-3-(methylthio)styryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (14): Montmorillonite K30 powder (Aldrich #69866, 0.25 g) was added to a solution of compound 14.4 (0.25 g, 0.7 mmol) in anhydrous dichloromethane (15 mL) at room temperature and the mixture was stirred at room temperature overnight, at which point LCMS indicated that the reaction was complete. The mixture was filtered and the solid was rinsed with dichloromethane (2 × 15 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (25 g column, 20 - 45 μm) eluting with a gradient of 0 - 40% ethyl acetate in heptane to afford a mixture of compounds 14A, 14B, and 14 (0.18 g, 70% combined yield). (LM-1-44)

[0264] An additional 0.27 g of compound 14-4 used in 11) was treated in the same manner to afford a mixture of compounds 14A, 14B, and 14 (0.22 g, 81% combined yield). (LM-1-46)

[0265] The crude compounds 14A, 14B and 14 (LM-1-44 and LM-1-46) were further purified on an Interchim automated chromatography system (25 g column, 20 - 45 μm) eluting with a gradient of 0 - 40% ethyl acetate in heptane to afford compound 14B (50 mg, 10% yield) as a pale yellow solid, compound 14B (100 mg, 19% yield) as a pale yellow solid, and compound 14 (170 mg, 33% yield) as a white solid (LM-1-54A, LM-1-54B and LM-1-54C). Note: The structures of the three compounds were determined by NMR at the University of Florida.

[0266] Compound 14 can also be synthesized using the modular methodology of the present disclosure using equivalents of modules A, B and C, and subsequent cross-coupling alkylation of the halogenated aryl. (E)-3-(4-Hydroxy-3-(methylthio)styryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (14)[KYN-118]: White solid, melting point 124.5 - 125.2 °C; HPLC analysis: 98.9% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 9.00 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 357.1 (M+H) + ; C 21 H 24 O 3 S; 1 H NMR (400 MHz, CDCl 3) δ = 7.60 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 2.2, 8.3 Hz, 1H), 7.17 (d, J = 16.2 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 16.1 Hz, 1H), 6.66 (s, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 5.11 (septet of triplets, J = 1.3, 6.8 Hz, 1H), 4.71 (br s, 1H), 3.80 (s, 3H), 3.41 (br d, J = 6.8 Hz, 2H), 2.36 (s, 3H), 1.81 (d, J = 1.0 Hz, 3H), 1.68 (d, J = 1.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.61, 155.89, 154.39, 138.04, 132.98, 131.00, 130.83, 129.29, 128.98, 125.01, 123.58, 121.37, 120.92, 115.13, 103.93, 98.39, 55.74, 25.79, 24.47, 19.90, 17.98.

[0267] (E)-3-(4-Hydroxy-3-(methylamino)styryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (15) [KYN-158]

[0268]

Chem.

[0269] (3-Nitro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)methanol (15-3): Sodium borohydride (2.92 g, 79.12 mmol, 1.0 eq) was added in two portions to a solution of compound 15-2 (23.5 g, 79.12 mmol, 1.0 eq) in methanol at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with water (20 mL). Volatiles were removed under reduced pressure and the resulting crude residue was dissolved in ethyl acetate (150 mL) and washed with saturated ammonium chloride (100 mL). The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to afford compound 15-3 (23.7 g, 99% yield) as an orange oil, which was used subsequently. (NRK-1-120)

[0270] Diethyl (4-hydroxy-3-nitrobenzyl)phosphonate (15-4): Zinc iodide (21.31 g, 66.80 mmol, 2.0 eq) was added to triethyl phosphite (11.5 mL, 66.80 mmol, 2.0 eq). After stirring for 15 minutes at room temperature, a solution of compound 15-3 (10.0 g, 33.40 mmol, 1.0 eq) in anhydrous tetrahydrofuran (100 mL) was added. The resulting solution was refluxed for 4 hours (66 °C). After cooling to room temperature, the volatile materials were removed under reduced pressure. The crude residue was dissolved in ethyl acetate (150 mL) and washed with 1 M sodium hydroxide (150 mL). The aqueous layer was neutralized with 1 M HCl (250 mL). The resulting aqueous layer was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give compound 15-4 (7.12 g, 76% yield) as a yellow oil, which was used subsequently. (NRK-1-187)

[0271] Diethyl (3-nitro-4-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)phosphonate (15-5): 2-(Trimethylsilyl)ethoxymethyl chloride (4.1 g, 24.63 mmol, 1.0 eq) and N,N-diisopropylethylamine (6.5 mL, 36.94 mmol, 1.5 eq) were sequentially added to a solution of compound 15-4 (7.12 g, 24.63 mmol, 1.0 eq) in dichloromethane (100 mL) at room temperature. After stirring for 20 hours, the reaction mixture was diluted with saturated sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 15-5 (9.45 g, 92% yield) as a yellow oil, which was used subsequently. (NRK-1-189)

[0272] (E)-(2-((4-(2-Bromo-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-nitrophenoxy)methoxy)ethyl)trimethylsilane (15-6): A 60% dispersion of sodium hydride in mineral oil (3.6 g, 90.24 mmol, 4 eq) was added portionwise to a solution of compound 15-5 (9.45 g, 22.56 mmol, 1.0 eq) in anhydrous tetrahydrofuran (100 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of A8 (module A) (8.15 g, 22.56 mmol, 1 eq) in anhydrous tetrahydrofuran (20 mL) was added dropwise and the mixture was stirred at room temperature for 16 hours. The reaction was carefully quenched with saturated brine (20 mL, 1 drop per minute with the first 5 mL of brine) at 0 °C. Volatiles were removed under reduced pressure. Saturated ammonium chloride (100 mL) was added. The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was first purified on a Reveleris automated chromatography system (Sorbtech 330 g column) eluting with a gradient of 0-10% ethyl acetate in heptane. The product was further purified on a Reveleris automated chromatography system (Sorbtech 330 g column) eluting with a gradient of 0-10% ethyl acetate in heptane to afford compound 15-6 (1.63 g, 12% yield) as a yellow oil (NRK-1-190).

[0273] (E)-(2-((4-(3-Methoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-nitrophenoxy)methoxy)ethyl)trimethylsilane (15-7): Tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol, 0.1 eq), potassium carbonate (710 mg, 5.2 mmol, 2 eq), 3-methylbut-2-enylboronic acid pinacol ester (1.01 g, 5.2 mmol, 2 eq) and water (2 mL) were sequentially added to a solution of compound 15-6 (1.6 g, 2.60 mmol, 1 eq) in 1,4-dioxane (20 mL) in a sealed tube. After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was evaporated under reduced pressure. The residue was suspended in saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 10% ethyl acetate in heptane to give compound 15-7 (1.8 g, >100% yield) as an orange oil (NRK-6-25).

[0274] (E)-3-(4-Hydroxy-3-nitrostyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (15-8): 1M tetrabutylammonium fluoride in tetrahydrofuran (41 mL, 40.92 mmol, 14 eq) was added to a solution of compound 15-7 (1.8 g, 2.92 mmol, 1 eq) in tetrahydrofuran (20 mL) at room temperature. After heating at 67 °C for 16 hours, the mixture was cooled to room temperature and diluted with water (20 mL) and saturated ammonium chloride (100 mL). The volatile materials were removed under reduced pressure and the remaining aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Sorbtech 80 g column) eluting with a gradient of 0 - 80% ethyl acetate in heptane to give compound 15-8 (370 mg, 36% yield) as a yellow solid (NRK-6-26).

[0275] (E)-3-(3-Amino-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (15-9): Activated zinc powder (680 mg, 10.4 mmol, 10.0 equiv), ammonium chloride (560 mg, 10.4 mmol, 10.0 equiv) and water (6 mL) were sequentially added to a solution of compound 15-8 (370 mg, 1.04 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) at room temperature. The resulting suspension was stirred at room temperature for 16 h. The suspension was filtered through Celite and the solid was washed with ethyl acetate (20 mL). The filtrate was evaporated to dryness under reduced pressure. The residue was suspended in saturated ammonium chloride (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound 15-9 (270 mg, 81% yield) as an off-white solid, which was used subsequently. (NRK-6-32)

[0276] (E)-3-(4-Hydroxy-3-(methylamino)styryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (15): 37 wt% aqueous formaldehyde solution (52 μL, 0.62 mmol, 2.0 equiv) and sodium triacetoxyborohydride (262 mg, 1.24 mmol, 4.0 equiv) were sequentially added to a solution of compound 15-9 (100 mg, 0.31 mmol, 1.0 equiv) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate (15 mL). The aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was first purified on a Reveleris automated chromatography system (Sorbtech 24 g column) eluting with a gradient of 0 - 100% ethyl acetate in heptane to give compound 15[KYN-158] (52 mg, 52% yield) as an off-white solid (NRK-6-40). Note: In the experiment, compound 15-9 (50 mg) was converted to compound 15 using the above conditions. Purification of the crude product 15 obtained from this reaction on a Reveleris automated chromatography system (Redisep Rf Gold HP C18, 50 g column) eluting with a gradient of 0 - 80% acetonitrile in water formed an impurity (having a mass m / z = 2M - 1). LCMS analysis indicated that the ratio of this impurity exceeded 15 and increased over a certain period. Similar results were obtained when a solution of compound 15 was left standing in methanol for 16 hours, thus suggesting that compound 15 can become unstable in solution.

[0277] (E)-3-(3-(Dimethylamino)-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (16) [KYN-157]

[0278]

Chemical formula

[0279] (E)-5-(3-Methoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-N,N-dimethyl-2-((2-(trimethylsilyl)ethoxy)methoxy)aniline (16-2): 37 wt% aqueous formaldehyde solution (37 μL, 0.46 mmol, 1.0 equiv) and sodium triacetoxyborohydride (196 mg, 0.92 mmol, 2.0 equiv) were sequentially added to a solution of compound 16-1 (267 mg, 0.46 mmol, 1.0 equiv) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. LCMS analysis indicated the formation of both mono- and di-N-methylated products. An additional formaldehyde solution (0.5 mL, excess) was added to the reaction mixture, and it was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was first purified on a Reveleris automated chromatography system (Sorbtech 24 g column) eluting with a gradient of 0 - 15% ethyl acetate in heptane. The resulting product was further purified on a Reveleris automated chromatography system (Sorbtech 24 g column) eluting with a gradient of 0 - 15% ethyl acetate in heptane to afford compound 16-2 (194 mg, 69% yield) as a pale yellow oil (NRK-1-198).

[0280] (E)-3-(3-(Dimethylamino)-4-hydroxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (16) [KYN-157]: 1M tetrabutylammonium fluoride in tetrahydrofuran (4.5 mL, 4.42 mmol, 14 equiv) was added to a solution of compound 16-2 (194 mg, 0.32 mmol, 1 equiv) in tetrahydrofuran (10 mL) at room temperature. After heating at 67 °C for 8 hours, the mixture was cooled to room temperature and diluted with water (20 mL) and saturated ammonium chloride (20 mL). Volatiles were removed under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Reveleris automated chromatography system (Redisep Rf Gold HP C18, 50 g column) eluting with a gradient of 0 - 60% acetonitrile in water to afford compound 16[KYN-157] (40 mg, 36% yield) as a pale yellow solid (NRK-1-201). Pale yellow solid, melting point 45 - 53 °C; HPLC analysis: 97.0% purity; wavelength 210 nm, bandwidth 4; column: Water Atlantis T3, 2.1×50 mm, 3 μm; retention time: 5.75 minutes; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 354.2 (M+H) + ; C 22 H 27 NO 3 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.31 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 2.0, 8.3 Hz, 1H), 7.14 (d, J = 16.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 5.12 (septet of triplets, J = 1.3, 6.8 Hz, 1H), 3.79 (s, 3H), 3.41 (br d, J = 6.8 Hz, 2H), 2.69 (s, 6H), 1.82 (s, 3H), 1.69 (d, J = 1.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.55, 154.55, 151.23, 140.76, 138.25, 130.52, 130.27, 130.07, 124.75, 124.06, 123.76, 120.54, 118.70, 114.21, 103.93, 98.24, 55.69, 45.14 (2C), 25.77, 24.47, 17.98.

[0281] (E)-4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxy-6-methylphenol (17) [KYN-120]: Preparation of Compound 17 [KYN-120] (E)-4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxy-6-methylphenol (17)

[0282]

Chemical formula

[0283] (2-((4-Bromo-2-methoxy-6-methylphenoxy)methoxy)ethyl)trimethylsilane (17-6): N,N-Diisopropylethylamine (3.6 mL, 20.73 mmol, 1.5 equiv) and 2-(trimethylsilyl)ethoxymethyl chloride (2.9 mL, 16.58 mmol, 1.2 equiv) were sequentially added to a solution of Compound 17-5 (3 g, 13.82 mmol, 1.0 equiv) in anhydrous dichloromethane (60 mL) at room temperature. After stirring overnight, saturated ammonium chloride (100 mL) was added. The aqueous layer was extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automatic chromatography system (Sorbtech 12 g column) with a gradient of 0 - 20% ethyl acetate in heptane to give Compound 17-6 (2.37 g, 88% yield) as a pale yellow oil (NK-1-29).

[0284] (2-((2-Methoxy-6-methyl-4-vinylphenoxy)methoxy)ethyl)trimethylsilane (17-7): Potassium vinyltrifluoroborate (1.08 g, 8.06 mmol, 1.4 equiv), triethylamine (1.3 mL, 9.2 mmol, 1.6 equiv), and Pd(dppf)Cl 2(210 mg, 0.029 mmol, 0.05 eq) was added to a solution of compound 17-6 (2.0 g, 5.75 mmol, 1.0 eq) in 2-propanol (40 mL). After sparging with nitrogen for 10 minutes, the mixture was refluxed for 16 hours (80 °C). The reaction was cooled to room temperature and filtered through Celite (ca. 5 g). The filtrate was concentrated under reduced pressure, diluted with saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (Sorbtech 24 g column) with a gradient of 0–20% ethyl acetate in heptane to give compound 17-7 (1.06 g, 65% yield) as a colorless oil (NK-1-34).

[0285] (E)-(2-((2-Methoxy-4-(3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)styryl)-6-methylphenoxy)methoxy)ethyl)trimethylsilane (17-8): 1-Bromo-3-methoxy-5-((3-methylbut-2-en-1-yl)oxy)benzene (17-3) (1.49 g, 5.26 mmol, 1.2 eq), triphenylphosphine (114 mg, 0.438 mmol, 0.1 eq), potassium acetate (850 mg, 8.76 mmol, 2 eq) and palladium(II) acetate (50 mg, 0.219 mmol, 0.05 eq) were added to a solution of compound 17-7 (1.29 g, 4.38 mmol, 1.0 eq) in anhydrous toluene (60 mL). After sparging with nitrogen for 15 minutes, the mixture was refluxed for 16 hours (110 °C). The reaction mixture was cooled to room temperature and filtered through Celite (ca. 5 g). The filtrate was transferred to a separatory funnel containing saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (Sorbtech 24 g column) with a gradient of 0–30% ethyl acetate in heptane to give compound 17-8 (420 mg, 20% yield) as a colorless oil (NK-1-40).

[0286] 1 M tetrabutylammonium fluoride in THF (6.1 mL, 6.06 mmol, 7 equiv) was added to a solution of compound 17-8 (420 mg, 0.86 mmol, 1 equiv) in anhydrous THF (40 mL) at room temperature. After refluxing overnight (66 °C), LCMS indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with water (10 mL). The organic volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (Sorbtech 14 g column) with a gradient of 0–50% ethyl acetate in heptane to afford compound 17-9 (220 mg, 73% yield) as a yellow oil (NK-1-41).

[0287] (E)-4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxy-6-methylphenol (17) [KYN-120]: Montmorillonite K30 powder (220 mg) was added to a solution of compound 17-9 (220 mg, 0.45 mmol) in anhydrous dichloromethane (20 mL) at room temperature. After stirring overnight at room temperature, LCMS indicated that 30–40% of the desired compound 10 had formed, along with two positional isomers and unreacted starting compound 9. The mixture was filtered, washed with dichloromethane (2 × 15 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (Sorbtech 12 g column) with a gradient of 0–50% ethyl acetate in heptane. Trituration with 30% dichloromethane in heptane (10 mL) afforded pure compound 17 [KYN-120] (38 mg, 17% yield) as a white solid (NK-1-42-S3).

[0288] White solid, melting point 140.3–140.4 °C; HPLC analysis: 97.6% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 9.29 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 355 (M+H) + ; C 22 H 26 O 4 ;1 1H NMR (400 MHz, CDCl 3 ) δ = 7.14 (d, J = 16.1 Hz, 1H), 6.88 (m, 1H), 6.87 (m, 1H), 6.83 (d, J = 16.1 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 5.72 (d, J = 0.5 Hz, 1H), 5.13 (tm, J = 1.4, 6.9 Hz, 1H), 4.60 (s, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 3.42 (br d, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.82 (d, J = 1.0 Hz, 3H), 1.69 (d, J = 1.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl 3 ) δ = 158.58, 154.34, 146.37, 143.77, 138.32, 130.62, 130.53, 129.17, 124.00, 123.87, 123.73, 122.35, 120.71, 105.96, 103.87, 98.13, 56.00, 55.71, 25.78, 24.49, 17.97, 15.45.

[0289] Compound 17 can also be synthesized by the modular methodology of the present disclosure using equivalents to modules A, B, and C, and subsequent cross-coupling alkylation of the halogenated aryls.

[0290] (E)-5-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-3-methoxybenzene-1,2-diol (18) [KYN-156]

[0291]

Chemical Structure

[0292] (3-Methoxy-4,5-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)methanol (18-3): Sodium borohydride (176 mg, 4.66 mmol, 1.0 equiv) was added all at once to a solution of compound 18-2 (2 g, 4.66 mmol, 1.0 equiv) in methanol (50 mL) at 0 °C. After stirring at 0 °C for 1 h, water (50 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure to remove most of the methanol. The residue was diluted with saturated brine (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 18-3 (2 g) as a colorless oil, which was used subsequently (LM-6-104).

[0293] (3-Methoxy-4,5-bis((2-(trimethylsilyl)ethoxy)methoxy)benzyl)phosphonic acid diethyl (18-4): Zinc iodide (2.97 g, 9.32 mmol, 2.0 equiv) and triethyl phosphite (1.6 mL, 9.32 mmol, 2.0 equiv) were sequentially added to a solution of compound 18-3 (2 g, 4.66 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (100 mL) at room temperature. The mixture was refluxed (68 °C) for 16 h. After cooling to room temperature, water (50 mL), potassium carbonate (1.61 g, 2.5 equiv) and methyl tert-butyl ether (200 mL) were sequentially added. The mixture was filtered through a pad of celite (20 g), which was rinsed with ethyl acetate (300 mL). The layers were separated, the organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (80 g column) with a gradient of 0-100% ethyl acetate in heptane to give a mixture of compounds 4A and 4B (1 g). N,N-Diisopropylethylamine (2.52 mL, 14.4 mmol, 6 equiv) and 2-(trimethylsilyl)ethoxymethyl chloride (2.04 mL, 11.2 mmol, 4.8 equiv) were successively added to a solution of compounds 4A and 4B (1 g, 2.4 mmol, 1.0 equiv) in anhydrous dichloromethane (100 mL) at room temperature. After stirring at room temperature for 16 h, saturated sodium bicarbonate (100 mL) was added to quench the reaction. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (80 g column) with a gradient of 0-100% ethyl acetate in heptane to give compound 18-4 (1.15 g, 45% yield over 3 steps) as a colorless oil (LM-8-4, LM-8-5).

[0294] (E)-(((((5-(2-Bromo-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-3-methoxy-1,2-phenylene)bis(oxy))bis(methylene)bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane) (18-5): A 60% dispersion of sodium hydride in mineral oil (168 mg, 4.2 mmol, 2 equiv) was added all at once to a solution of compound 18-4 (1.15 g, 2.1 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (50 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of intermediate A (754 mg, 2.1 mmol, 1 equiv) in anhydrous tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was carefully quenched with saturated brine (20 mL, 1 drop per minute for the first 5 mL of brine) at 0 °C. The mixture was extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (80 g column) with a gradient of 0–20% ethyl acetate in heptane to give compound 18-5 (1.18 g, 75% yield) as a colorless oil (LM-8-6).

[0295] (E)-(((((3-Methoxy-5-(3-methoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-1,2-phenylene)bis(oxy))bis(methylene))bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane) (18-6): Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol, 0.05 equiv), potassium carbonate (428 mg, 3.1 mmol, 2 equiv), 3-methylbut-2-enylboronic acid pinacol ester (611 mg, 3.1 mmol, 2 equiv), and water (4 mL) were sequentially added to a solution of compound 18-5 (1.18 g, 1.56 mmol, 1 equiv) in 1,4-dioxane (12 mL). After sparging with nitrogen for 10 minutes, the reaction was heated at 95 °C for 16 hours. After cooling to room temperature, the mixture was extracted with methyl tert-butyl ether (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (80 g column) with a gradient of 0–20% ethyl acetate in heptane to give compound 18-6 (1 g, 86% yield) as a colorless oil (LM-8-7).

[0296] (E)-5-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-3-methoxybenzene-1,2-diol (18) [KYN-156]: 1 M tetrabutylammonium fluoride in tetrahydrofuran (25.3 mL, 25.3 mmol, 21 equiv) was added to a solution of compound 18-6 (900 mg, 1.2 mmol, 1 equiv) in tetrahydrofuran (25 mL) at room temperature. After heating at 67 °C for 16 h, the mixture was cooled to room temperature and diluted with water (20 mL) and saturated brine (20 mL). The mixture was extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified three times by elution with a gradient of 0–100% ethyl acetate in heptane on an Interchim automatic chromatography system (80 g column, 2 × 40 g column stack, 2 × 25 g column stack) to give compound 18 (70 mg, purity ca. 85%). This crude compound 18 was divided equally into seven portions. Each portion was purified by elution with a gradient of 0–100% acetonitrile in water on a reversed-phase ACCQPrep HP125 automatic chromatography system (SunFire Prep C18 OBD 5 μm 19 × 250 mm column) to give compound 18 (50 mg). This material was further purified by elution with a gradient of 0–100% ethyl acetate in hexane on an Interchim automatic chromatography system (25 g column) and dried under vacuum at 40 °C for 16 h to give compound 18 [KYN-156] (27 mg, 6.3% yield) as an off-white solid (LM-8-9).

[0297] Off-white solid; HPLC analysis: 96.0% purity; wavelength 254 nm, bandwidth 4; column: Luna C18(2), 2.0 × 20 mm, 3 μm; retention time: 7.7 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 357.1 (M+H) + ; C 21 H 24 O 5 ; 1 1H NMR (400 MHz, acetone-d 6) δ = 8.08 (s, 1H), 7.72 - 7.41 (m, 2H), 7.19 (d, J = 16.1 Hz, 1H), 6.84 (d, J = 16.0 Hz, 1H), 6.75 - 6.72 (m, 2H), 6.72 (d, J = 2.3 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 5.09 (septet of triplets, J = 1.3, 7.0 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.41 (br d, J = 7.0 Hz, 2H), 1.82 (d, J = 0.7 Hz, 3H), 1.64 (d, J = 1.1 Hz, 3H); 13 C NMR (100 MHz, acetone-d 6 ) δ = 158.88, 156.66, 148.63, 145.92, 138.33, 134.46, 130.72, 129.84, 129.52, 124.69, 124.46, 119.36, 107.91, 104.14, 102.28, 98.62, 55.95, 55.38, 25.38, 24.37, 17.58.

[0298] (E)-3-(3-Hydroxy-5-methoxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (19) [KYN-160]

[0299]

Chem.

[0300] 3-(Bromomethyl)-5-methoxyphenol (19-3): Carbon tetrabromide (2.55 g, 7.7 mmol, 1.1 equiv) was added to a solution of compound 19-2 (1.06 g, 7 mmol, 1.0 equiv) in a 1:2 mixture of anhydrous tetrahydrofuran and dichloromethane (75 mL) at room temperature. The mixture was cooled in an ice bath and triphenylphosphine (2.02 g, 7.7 mmol, 1.1 equiv) was added all at once. The mixture was then warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure. The residue was purified by elution on an InterChim automated chromatography system (80 g column) with a gradient of 0–50% ethyl acetate in heptane to give compound 19-3 (1.18 g, 79% yield) as an off-white solid (LM-8-18).

[0301] (3-Hydroxy-5-methoxybenzyl)diethylphosphonate (19-4): Triethyl phosphite (2.8 mL, 16.3 mmol, 3 equiv) was added to a solution of compound 19-3 (1.18 g, 5.4 mmol, 1.0 equiv) in anhydrous toluene (100 mL) at room temperature. After refluxing (110 °C) for 16 h, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by elution on an InterChim automated chromatography system (80 g column) with a gradient of 0–100% ethyl acetate in heptane to give compound 19-4 (1.32 g, 89% yield) as a colorless oil (LM-8-19).

[0302] (3-Methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)diethylphosphonate (19-5): N,N-Diisopropylethylamine (3.1 mL, 24 mmol, 5 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (3.4 mL, 19.3 mmol, 4 eq) were sequentially added to a solution of compound 19-4 (1.32 g, 4.8 mmol, 1.0 eq) in anhydrous dichloromethane (50 mL) at room temperature. After stirring at room temperature for 16 h, saturated sodium bicarbonate (50 mL) was added to quench the reaction. The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0 - 100% ethyl acetate in heptane on an InterChim automatic chromatography system (80 g column) to give compound 19-5 (1.27 g, 65% yield) as a colorless oil (LM-8-20).

[0303] (E)-(2-((3-(2-Bromo-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-5-methoxyphenoxy)methoxy)ethyl)trimethylsilane (19-6): A 60% dispersion of sodium hydride in mineral oil (204 mg, 5.1 mmol, 2 eq) was added all at once to a solution of compound 19-5 (1.03 g, 2.55 mmol, 1.0 eq) in anhydrous tetrahydrofuran (50 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 min. A solution of A8 (module A) (0.92 mg, 2.55 mmol, 1 eq) in anhydrous tetrahydrofuran (20 mL) was added dropwise and the mixture was stirred at room temperature for 16 h. The reaction was carefully quenched with saturated brine (20 mL, 1 drop per minute for the first 5 mL of brine) at 0 °C. The mixture was extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0 - 20% ethyl acetate in heptane on an InterChim automatic chromatography system (80 g column) to give compound 19-6 (1.23 g, 79% yield) as a colorless oil (LM-8-21).

[0304] (E)-(2-((3-Methoxy-5-(3-methoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)phenoxy)methoxy)ethyl)trimethylsilane (19-7): Tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol, 0.05 equiv), potassium carbonate (553 mg, 4 mmol, 2 equiv), 3-methylbut-2-enylboronic acid pinacol ester (785 mg, 4 mmol, 2 equiv), and water (5 mL) were successively added to a solution of compound 19-6 (1.23 g, 2 mmol, 1 equiv) in 1,4-dioxane (15 mL). After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 95 °C for 16 hours. After cooling to room temperature, the mixture was extracted with methyl tert-butyl ether (2 × 20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an InterChim automated chromatography system (80 g column) with a gradient of 0 - 15% ethyl acetate in heptane to give compound 19-7 (1.1 g, 91% yield) as a colorless oil (LM-8-22).

[0305] (E)-3-(3-Hydroxy-5-methoxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (19) [KYN-160]: 1M tetrabutylammonium fluoride in tetrahydrofuran (25.6 mL, 25.6 mmol, 14 equiv) was added to a solution of compound 19-7 (1.1 g, 1.83 mmol, 1 equiv) in tetrahydrofuran (25 mL) at room temperature. After heating at 67 °C for 16 hours, the mixture was cooled to room temperature and diluted with water (20 mL) and saturated brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by elution on an InterChim automated chromatography system (120 g column, 2 × 25 g column stacked) with a gradient of 0 - 100% ethyl acetate in heptane each time, and then dried in vacuo at 40 °C for 16 hours to give compound 19 (110 mg, 17% yield) as an off-white solid (LM-8-23).

[0306] (E)-4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)benzene-1,2-diol (20) [KYN-146]

[0307]

Chemical formula

[0308] (3,4-Bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)methanol (20-3): Sodium borohydride (2.66 g, 70.3 mmol, 1.0 equiv) was added all at once to a solution of compound 20-2 (28.03 g, 70.3 mmol, 1.0 equiv) in methanol (200 mL) at 0 °C. After stirring at 0 °C for 1 h, water (75 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure to remove most of the methanol. The residue was diluted with saturated brine (75 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automatic chromatography system (120 g column) with a gradient of 0 - 100% ethyl acetate in heptane to give compound 20-3 (26.84 g, 95% yield) as a yellow oil (LM-1-80).

[0309] (3,4-Bis((2-(trimethylsilyl)ethoxy)methoxy)benzyl)diethylphosphonate (20-4): Zinc iodide (42.77 g, 134.0 mmol, 2.0 equiv) and triethyl phosphite (23 mL, 134.0 mmol, 2.0 equiv) were sequentially added to a solution of compound 20-3 (26.84 g, 67.0 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (400 mL) at room temperature. The mixture was refluxed (68 °C) for 4 h, at which point LCMS analysis indicated completion of the reaction. After cooling the mixture to room temperature, it was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was diluted with saturated sodium bicarbonate (150 mL) and extracted with methyl tert-butyl ether (2 × 400 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (220 g column) with a gradient of 0–100% ethyl acetate in heptane to afford compound 20-4 (24.18 g, 69% yield) as a yellow oil (LM-1-82).

[0310] (E)-(((((4-(2-Bromo-3-ethoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-1,2-phenylene)bis(oxy))bis(methylene)bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane)(20-5): A 60% dispersion of sodium hydride in mineral oil (2.43 g, 60.6 mmol, 2 equiv) was added all at once to a solution of compound 20-4 (15.76 g, 30.3 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (300 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 min. A solution containing compound A9 (module A) (11.36 g, 30.3 mmol, 1 equiv) in anhydrous tetrahydrofuran (100 mL) was added dropwise, and the mixture was stirred at room temperature for 16 h. The reaction was carefully quenched with saturated brine (250 mL, 1 drop per minute for the first 5 mL of brine) at 0 °C. The mixture was extracted with methyl tert-butyl ether (2 × 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (330 column) with a gradient of 0–15% ethyl acetate in heptane to afford compound 20-5 (15.5 g, 69% yield) as a yellow oil (LM-6-89).

[0311] (E)-(((((4-(3-Ethoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-1,2-phenylene)bis(oxy))bis(methylene))bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane)(20-6): Tetrakis(triphenylphosphine)palladium(0) (1.21 g, 1.05 mmol, 0.05 eq), potassium carbonate (5.78 g, 41.8 mmol, 2 eq), 3-methylbut-2-enylboronic acid pinacol ester (8.2 g, 41.8 mmol, 2 eq), and water (50 mL) were sequentially added to a solution of compound 20-5 (15.5 g, 20.9 mmol, 1 eq) in 1,4-dioxane (150 mL). After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 95 °C for 16 hours. After cooling the mixture to room temperature, it was extracted with methyl tert-butyl ether (2 × 300 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0–15% ethyl acetate in heptane on an Interchim automated chromatography system (330 column) to give compound 20-6 (15.28 g, 99% yield) as a yellow oil (LM-6-90).

[0312] (E)-4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)benzene-1,2-diol(20)[KYN-146]: 1 M tetrabutylammonium fluoride in tetrahydrofuran (513 mL, 513 mmol, 21 equiv) was added to a mixture of compound 20-6 (17.86 g, 24.4 mmol, 1 equiv) in tetrahydrofuran (500 mL) at room temperature. The mixture was heated at 67 °C for 16 h, then cooled to room temperature and diluted with water (350 mL) and saturated brine (350 mL). The mixture was extracted with methyl tert-butyl ether (1.5 L) and ethyl acetate (1.5 L). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified three times by Interchim automated chromatography system (2 × 40 g column stacking, 2 × 80 g column stacking, 2 × 40 g column stacking) eluting each time with a gradient of 0–100% ethyl acetate in heptane to afford a mixture of SEM-protected compound (3.94 g) and compound 20 (1.5 g, purity ~70%). This crude compound 20 was further purified by reverse Interchim automated chromatography system (300 g column) eluting with a gradient of 0–100% acetonitrile in water to afford compound 20 (480 mg). The mixture of SEM-protected compounds (3.94 g) was treated with 1 M tetrabutylammonium fluoride in tetrahydrofuran (58.7 mL, 58.7 mmol, 7.0 equiv) and the procedure was carried out in the same manner to afford compound 20 (450 mg). All the SEM-protected materials (480 mg, 450 mg, and 130 mg, LM-6-69) were combined and purified by Interchim automated chromatography system (40 g column) eluting with a gradient of 0–55% ethyl acetate in hexane and dried in vacuo at 40 °C for 16 h to afford compound 20 [KYN-146] (1.0 g, total yield 10%) as an off-white solid (LM-6-91).

[0313] Structural data: Compound 20[KYN-146] Off-white solid; HPLC analysis: 96.3% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 8.3 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 341.2 (M+H) + ; C 21 H24 O 4 ; 1 1H NMR (400 MHz, acetone-d 6 ) δ = 7.98 (br s, 2H), 7.18 (d, J = 16.1 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.90 (ddd, J = 0.4, 2.1, 8.1 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.70 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 5.11 (septet of triplets, J = 1.3, 7.0 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.42 (d, J = 7.0 Hz, 2H), 1.81 (d, J = 0.9 Hz, 3H), 1.64 (d, J = 1.1 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H); 13 13C NMR (100 MHz, acetone-d 6 ) δ = 158.18, 156.56, 145.65, 145.59, 138.34, 130.60, 130.33, 129.87, 124.65, 124.23, 119.52, 119.50, 115.75, 113.29, 104.08, 99.43, 63.86, 25.40, 24.44, 17.65, 14.75.

[0314] (E)-4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxybenzoic acid(21)[KYN-154]

[0315]

Chem.

[0316] (E)-4-(2-Bromo-3-methoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-methoxybenzoic acid(21-3): A 60% dispersion of sodium hydride in mineral oil (160 mg, 4 mmol, 2 equiv) was added all at once to a solution of compound 21-2 (0.63 g, 2 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (30 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of A8 (module A) (0.72 g, 2 mmol, 1 equiv) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was diluted with saturated brine (20 mL, 1 drop per minute for the first 5 mL of brine) at 0 °C. The mixture was extracted with methyl tert-butyl ether (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0 - 100% ethyl acetate in heptane on an Interchim automated chromatography system (40 columns) to give compound 21-3 (0.55 g, 55% yield) as a yellow solid (LM-6-93).

[0317] (E)-2-Methoxy-4-(3-methoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)benzoic acid(21-4): Tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol, 0.05 eq), potassium carbonate (415 mg, 3 mmol, 3 eq), 3-methylbut-2-enylboronic acid pinacol ester (392 mg, 2 mmol, 2 eq), and water (4 mL) were sequentially added to a solution of compound 21-3 (509 mg, 1 mmol, 1 eq) in 1,4-dioxane (12 mL). After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 95 °C for 16 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (25 g column) with a gradient of 0 - 80% ethyl acetate in heptane to give compound 21-4 (490 mg, 98% yield) as a yellow oil (LM-6-94).

[0318] (E)-4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxybenzoic acid(21)[KYN-154]: 1M tetrabutylammonium fluoride in tetrahydrofuran (7 mL, 7 mmol, 7 eq) was added to a mixture of compound 21-4 (490 mg, 1 mmol, 1 eq) in tetrahydrofuran (20 mL) at room temperature. The mixture was heated at 67 °C for 16 hours, then cooled to room temperature and diluted with ethyl acetate (200 mL). The mixture was washed with saturated brine (50 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (2 × 25 g column stack) twice with a gradient of 0 - 100% ethyl acetate in heptane each time, and then purified by elution on a reverse Interchim automated chromatography system (50 g column) twice with a gradient of 0 - 100% acetonitrile in water each time to give compound S10 (70 mg, purity ~70%). This material was equally divided into eight portions. Each divided portion was purified by elution on a reverse ACCQPrep HP125 automated chromatography system (SunFire Prep C18 OBD 5μm 19×250 mm column) with a gradient of 0 - 100% acetonitrile in water and freeze-dried for 16 hours to give compound 21[KYN-154] (30 mg, 8% yield) as an off-white solid (LM-6-95).

[0319] Off-white solid; HPLC analysis: 98.8% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.4 minutes; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 369.2 (M+H) + ; C 22 H 24 O 5 ; 1 1H NMR (400 MHz, acetone-d 6 ) δ = 7.92 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 16.1 Hz, 1H), 7.38 (d, J = 1.1 Hz, 1H), 7.30 (dd, J = 1.2, 8.2 Hz, 1H), 7.05 (d, J = 16.3 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 5.08 (septet of triplets, J = 1.3, 7.0 Hz, 1H), 4.09 (s, 3H), 3.80 (s, 3H), 3.45 (br d, J = 6.8 Hz, 2H), 1.81 (s, 3H), 1.64 (d, J = 1.0 Hz, 3H); 13 13C NMR (100 MHz, acetone-d 6 ) δ = 165.55, 159.48, 158.97, 156.82, 144.29, 137.40, 133.08, 130.20, 130.14, 129.15, 124.52, 120.27, 119.38, 118.33, 110.57, 104.49, 99.64, 56.36. 55.46, 25.36, 24.36, 17.57.

[0320] Preparation of Compound 22[KYN-124] and Compound 23[KYN-125]

[0321]

Chemical formula

[0322] Diethyl (3-methoxy-4-nitrobenzyl)phosphonate(22-2): Triethyl phosphite (26.8 mL, 156 mmol, 3.0 equiv) was added to a solution of compound 22-1 (12.8 g, 52 mmol, 1.0 equiv) in toluene (400 mL). After refluxing (110 °C) for 40 h, NMR analysis indicated that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by elution on an InterChim automatic chromatography system (330 g column) with a gradient of 0 - 100% ethyl acetate in heptane, followed by 10% methanol in dichloromethane to give compound 22-2 (15.5 g, 98% yield) as a pale yellow oil (CH-LM-02-27).

[0323] (E)-(2-((4-Bromo-3-methoxy-5-(3-methoxy-4-nitrostyryl)phenoxy)methoxy)ethyl)trimethylsilane(22-3): A 60% dispersion of sodium hydride in mineral oil (6.1 g, 153.3 mmol, 3.0 equiv) was added portionwise to a solution of compound 22-2 (15.5 g, 51.1 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (450 mL) at 0 °C in three portions. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of intermediate A (18.5 g, 51.1 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (150 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was carefully quenched with water (500 mL, 1 drop per minute for the first 5 mL of water) at 0 °C and extracted with methyl tert-butyl ether (1.5 L) and ethyl acetate (1 L). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was divided into three equal parts and purified by elution with a gradient of 10 - 50% ethyl acetate in heptane on an InterChim automated chromatography system (3 × 330 g columns) to give compound 22-3 (9.9 g, 38% yield) as a yellow solid (CH-LM-02-28).

[0324] (E)-(2-((3-Methoxy-5-(3-methoxy-4-nitrostyryl)-4-(3-methylbut-2-en-1-yl)phenoxy)methoxy)ethyl)trimethylsilane(22-4): Tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol, 0.05 equiv), potassium carbonate (10 g, 72 mmol, 2.0 equiv), 3-methylbut-2-enylboronic acid pinacol ester (14.1 g, 72 mmol, 2.0 equiv), and water (90 mL) were sequentially added to a solution of compound 22-3 (18.3 g, 36 mmol, 1.0 equiv) in 1,4-dioxane (270 mL) in a sealed tube. After sparging with nitrogen for 10 minutes, the reaction was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was extracted with methyl tert-butyl ether (500 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was divided into two equal parts and purified by elution with a gradient of 0 - 12% ethyl acetate in heptane on an InterChim automated chromatography system (2 × 220 g columns) to give compound 22-4 (15.1 g, 84% yield) as a yellow solid (CH-LM-02-29).

[0325] (E)-3-Methoxy-5-(3-methoxy-4-nitrostyryl)-4-(3-methylbut-2-en-1-yl)phenol (22): 1M tetrabutylammonium fluoride in tetrahydrofuran (366 mL, 366 mmol, 7.0 equiv) was added to a solution of compound 22-4 (26.1 g, 52.3 mmol, 1.0 equiv) in tetrahydrofuran (400 mL) at room temperature. The mixture was heated at 68 °C for 16 h, then cooled to room temperature and diluted with water (100 mL). Volatiles were removed under reduced pressure. The residue was diluted with saturated ammonium chloride (250 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was divided into three equal parts and purified by eluting with a gradient of 30 - 100% ethyl acetate in heptane on an InterChim automated chromatography system (3 × 330 g columns) to give compound 22 (17.1 g, 89% yield) as a yellow solid (CH-LM-02-30). Yellow solid, melting point 167.1 - 169.0 °C, HPLC analysis: 99.2% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 9.77 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 370.1 (M+H) + ; C 21 H 23 NO 5 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.91 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 16.1 Hz, 1H), 7.12 (ddd, J = 0.5, 1.7, 8.3 Hz, 1H), 7.11 (br d, J = 1.5 Hz, 1H), 6.91 (d, J = 16.1 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 5.09 (tm, J = 6.8 Hz, 1H), 4.76 (s, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 3.43 (d, J = 6.8 Hz, 2H), 1.80 (d, J = 0.7 Hz, 3H), 1.68 (d, J = 1.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ = 158.67, 154.55, 153.70, 144.15, 138.12, 136.81, 130.97, 130.89, 128.38, 126.57, 123.42, 121.71, 118.09, 111.20, 104.15, 99.44, 56.45, 55.76, 25.74, 24.46, 17.99.

[0326] (E)-3-(4-Amino-3-methoxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenol (23) [KYN-125]: Zinc powder (30.3 g, 463 mmol, 10.0 eq), ammonium chloride (25 g, 463 mmol, 10.0 eq), and water (70 mL) were sequentially added to a solution of compound 22 (17.1 g, 46.3 mmol, 1.0 eq) in tetrahydrofuran (700 mL) at room temperature. The resulting suspension was stirred at room temperature for 4 h. The suspension was filtered, and the solid was washed with ethyl acetate (1 L). The filtrate was evaporated to dryness under reduced pressure. The residue was divided into five equal parts and purified by elution with a gradient of 0 - 40% ethyl acetate in heptane on an InterChim automated chromatography system (5×120 g column) to obtain compound 23 (10.5 g, 67% yield) as an off-white solid (CH-LM-02-31). Melting point 159.3 - 163.3 °C; HPLC analysis: 94.8% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 7.80 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 340.2 (M+H) + ; C 21 H 25 NO 3 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.10 (d, J = 16.1 Hz, 1H), 6.95 (d, J = 1.7 Hz, 1H), 6.92 (dd, J = 1.9, 7.9 Hz, 1H), 6.81 (d, J = 15.9 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.12 (tm, J = 1.5, 6.9 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.41 (d, J = 6.6 Hz, 2H), 1.81 (d, J = 1.0 Hz, 3H), 1.67 (d, J = 0.9 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.56, 154.40, 147.42, 138.48, 136.08, 130.88, 130.49, 128.67, 123.77, 122.88, 120.54, 120.50, 114.86, 108.07, 103.83, 97.97, 55.69. 55.45, 25.77, 24.48, 17.97.

[0327] (E)-3-(4-Amino-3-methoxystyryl)-5-ethoxy-4-(3-methylbut-2-en-1-yl)phenol (24) [KYN-141]

[0328]

Chem.

[0329] (E)-(2-((3-Ethoxy-5-(3-methoxy-4-nitrostyryl)-4-(3-methylbut-2-en-1-yl)phenoxy)methoxy)ethyl)trimethylsilane (24-2): Tetrakis(triphenylphosphine)palladium(0) (1 g, 0.86 mmol, 0.05 eq), potassium carbonate (4.76 g, 34.47 mmol, 2.0 eq), 3-methylbut-2-enylboronic acid pinacol ester (6.76 g, 34.47 mmol, 2.0 eq), and water (30 mL) were sequentially added to a solution of compound 24-1 (9.04 g, 17.24 mmol, 1.0 eq) in 1,4-dioxane (120 mL) in a sealed tube. After sparging with nitrogen for 10 minutes, the reaction was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was extracted with methyl tert-butyl ether (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an InterChim automated chromatography system (2 × 200 g column stack) with a gradient of 0 - 7% ethyl acetate in heptane to give compound 24-2 (8.84 g, 99% yield) as a yellow oil (LM-8-99).

[0330] (E)-3-Ethoxy-5-(3-methoxy-4-nitrostyryl)-4-(3-methylbut-2-en-1-yl)phenol (24-3): 1 M tetrabutylammonium fluoride in tetrahydrofuran (130 mL, 130 mmol, 7.0 eq) was added to a solution of compound 24-2 (9.53 g, 18.55 mmol, 1.0 eq) in tetrahydrofuran (200 mL) at room temperature. The mixture was heated at 68 °C for 16 h, then cooled to room temperature and diluted with water (50 mL). Volatiles were removed under reduced pressure. The residue was diluted with saturated ammonium chloride (250 mL) and extracted with ethyl acetate (2 × 400 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on an InterChim automated chromatography system (330 g column) with a gradient of 0 - 60% ethyl acetate in heptane to give compound 24-3 (5.05 g, 71% yield) as a yellow solid (LM-8-100).

[0331] (E)-3-(4-Amino-3-methoxystyryl)-5-ethoxy-4-(3-methylbut-2-en-1-yl)phenol (24): Zinc powder (8.61 g, 131.7 mmol, 10.0 eq), ammonium chloride (7.1 g, 131.7 mmol, 10.0 eq), and water (20 mL) were sequentially added to a solution of compound 24-3 (5.05 g, 13.17 mmol, 1.0 eq) in tetrahydrofuran (200 mL) at room temperature. The resulting suspension was stirred at room temperature for 16 h. The suspension was filtered through a pad of Celite (50 g), which was rinsed with ethyl acetate (400 mL). The filtrate was evaporated to dryness under reduced pressure. The residue was purified twice by elution on an InterChim automated chromatography system (2 × 120 g column stack) with a gradient of 0 - 100% ethyl acetate in heptane each time to give compound 24 (4.56 g, 98% yield) as an off-white solid (LM-8-101). Off-white solid, melting point 187 - 196 °C; HPLC analysis: 97.9% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 8.3 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 354.2 (M+H) + ; C 22 H 27 NO 3 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.11 (broad doublet, J = 16.0 Hz, 1H), 6.95 (broad singlet, 1H), 6.92 (broad doublet, J = 7.7 Hz, 1H), 6.80 (broad doublet, J = 16.0 Hz, 1H), 6.70 (broad doublet, J = 7.9 Hz, 1H), 6.59 (broad singlet, 1H), 6.31 (broad singlet, 1H), 5.14 (broad triplet, J = 5.9 Hz, 1H), 4.90 (broad singlet, 1H), 3.99 (quartet, J = 6.6 Hz, 2H), 3.90 (singlet, 5H), 3.42 (broad doublet, J = 6.1 Hz, 2H), 1.91 - 1.74 (multiplet, 3H), 1.74 - 1.61 (multiplet, 3H), 1.41 (broad triplet, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 157.88, 154.28, 147.40, 138.44, 136.10, 130.80, 130.30, 128.66, 123.84, 122.96, 120.67, 120.51, 114.83, 108.10, 103.74, 98.82, 63.90, 55.46, 25.79, 24.55, 18.03, 14.93.

[0332] (E)-N-(4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)methanesulfonamide (25) [KYN-137] and (Z)-N-(4-(5-hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)methanesulfonamide (26) [KYN-129] (E * Z * )-3-Methoxy-5-(3-methoxy-4-(methylsulfonamido)styryl)-4-(3-methylbut-2-en-1-yl)phenylmethanesulfonate (25 and 26):

[0333]

Chemistry

[0334] A 1 M solution of tetrabutylammonium fluoride in THF (2 mL, 1.63 mmol, 7 eq) was added to a solution of compounds 25-1 and 26-1 (100 mg, 0.234 mmol, 1 eq) in anhydrous THF (10 mL) at room temperature. After refluxing (66 °C) for 16 h, LCMS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with saturated ammonium chloride (10 mL). The volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (RediSep Rf Gold HP C18, 50 g column) with a gradient of 0 - 40% acetonitrile in water to give compound 25 [KYN-137] (15.0 mg) as an off-white solid and compound 26 [KYN-129] (19 mg, 22% yield) as a light brown oil.

[0335] (E)-N-(4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)methanesulfonamide (25) [KYN-137] Off-white solid; melting point 170.7 - 173.5 °C; HPLC analysis: 92.4% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.4 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 418.1 (M+H) + ; C 22 H 27 NO 5 S; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.50 (d, J = 8.2 Hz, 1H), 7.27 (s, 1H), 7.26 (s, 1H), 7.25 - 7.22 (m, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 16.0 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 5.11 (triplet of septets, J = 1.3, 6.8 Hz, 1H), 4.92 (br s, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.42 (br d, J = 6.7 Hz, 2H), 2.97 (s, 3H), 1.81 (s, 3H), 1.68 (d, J = 1.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 158.60, 154.52, 149.51, 137.63, 135.35, 130.67, 129.64, 126.58, 125.48, 123.62, 120.99, 120.75, 120.06, 108.33, 104.01, 98.68, 55.77, 55.72, 39.14, 25.76, 24.47, 17.99.

[0336] (Z)-N-(4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)methanesulfonamide (26) [KYN-129] Light brown oily substance; HPLC analysis: 97.8% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 9.2 minutes; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 418.1 (M+H) + ; C 22 H 27 NO 5 S; 1 1H NMR (400 MHz, CDCl 3 ) δ = 7.31 (d, J = 8.3 Hz, 1H), 6.77 (dd, J = 1.7, 8.4 Hz, 1H), 6.66 (d, J = 1.7 Hz, 1H), 6.63 (d, J = 12.3 Hz, 1H), 6.50 (d, J = 12.2 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 6.19 (d, J = 2.2 Hz, 1H), 5.08 (tm, J = 1.4, 6.9 Hz, 1H), 3.79 (s, 3H), 3.50 (s, 3H), 3.27 (br d, J = 7.1 Hz, 2H), 2.90 (s, 3H), 1.68 (s, 3H), 1.58 (d, J = 0.9 Hz, 3H); 13 13C NMR (100 MHz, CDCl 3 ) δ = 158.87, 154.74, 148.69, 138.86, 134.39, 130.97, 129.90, 129.71, 124.78, 122.90, 122.67, 120.75, 120.01, 111.24, 107.31, 98.13, 55.65, 55.32, 39.14, 25.75, 25.66, 17.87.

[0337] (E)-N-(4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)formamide (27) [KYN-149]

Chem.

[0338] (E)-N-(4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)formamide (27) [KYN-149] White solid, melting point 181.2–181.7 °C; HPLC analysis: 99.6% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 8.4 min; mobile phase: ACN / formic acid / water; mass spectrum (negative mode) m / z = 733.3 (2M-H) - ; C 22 H 25 NO 4 ; 1 H NMR (400 MHz, DMSO-d 6) δ = 9.69 (s, 1H), 9.24 (s, 1H), 8.30 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H) 7.31 - 7.22 m, 2H), 7.09 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 16.1 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 5.00 (septet of triplets, J = 1.4, 6.8 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.36 (br d, J = 6.7 Hz, 2H), 1.76 (s, 3H), 1.60 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ = 160.45, 158.45, 156.69, 149.10, 137.43, 133.78, 129.85, 127.03, 125.99, 124.50, 120.63, 119.75, 118.74, 109.00, 104.13, 99.16, 56.25. 55.91, 25.96, 24.28, 18.21.

[0339] (E)-N-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)formamide (28) [KYN-143]

[0340]

Chem.

[0341] Off-white solid, melting point 173 - 176 °C, HPLC analysis: 98.9% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 9.0 min; mobile phase: ACN / formic acid / water; mass spectrum (negative mode) m / z = 761.3 (M-H) - ; C 23 H 27 NO 4 ; 1 H NMR (400 MHz, DMSO-d 6) δ = 9.69 (s, 1H), 9.20 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 16.1 Hz, 1H), 7.25 (d, J = 1.1 Hz, 1H), 7.10 (br d, J = 8.3 Hz, 1H), 6.90 (d, J = 16.0 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 5.01 (br t, J = 7.0 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 3.37 (br d, J = 6.7 Hz, 2H), 1.76 (s, 3H), 1.60 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ = 160.44, 157.71, 156.59, 149.09, 137.40, 133.79, 129.74 (2C), 127.01, 126.04, 124.52, 120.62, 119.72, 118.90, 109.03, 104.1, 99.96, 63.74, 56.27, 25.99, 24.34, 18.25, 15.25.

[0342] (E)-N-(4-(5-Hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (29) [KYN-128]:

[0343]

Chem.

[0344] Off-white solid, melting point 205.7–205.9 °C; HPLC analysis: 97.4% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 8.4 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 382.2 (M+H) + ; C 23 H 27 NO 4 ; 1 H NMR (400 MHz, CDCl 3) δ = 8.40 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.23 (d, J = 16.1 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 7.03 (dd, J = 1.7, 6.0 Hz, 1H), 6.88 (d, J = 16.1 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.24 (s, 1H), 5.12 (tm, J = 1.4, 6.8 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.42 (d, J = 6.7 Hz, 2H), 2.24 (s, 3H), 1.81 (d, J = 0.6 Hz, 3H), 1.67 (d, J = 1.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 168.65, 158.58, 155.07, 147.91, 137.68, 133.65, 130.42, 129.84, 127.11, 125.77, 123.86, 120.71, 120.44, 119.67, 106.87, 103.98, 98.62, 55.68, 55.65, 25.75, 24.88, 24.45, 17.98.

[0345] (E)-N-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (30) [KYN-142]

[0346]

Chem.

[0347] (E)-N-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (30) [KYN-142]: 1 M Lithium hydroxide (1.6 mL, 1.55 mmol, 5.0 eq) was added to a solution of compound 30-1 (136 mg, 0.31 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at room temperature. The resulting solution was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated ammonium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 12 g column) with a gradient of 0 - 50% ethyl acetate in heptane. The product was triturated with diethyl ether (5 mL) to give pure compound 30 [KYN-142] (20 mg, 17% yield) as a white solid (NRK-1-135).

[0348] Off-white solid, melting point 188 - 189 °C; HPLC analysis: 99.3% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 9.0 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 396.2 (M+H) + ; C 24 H 29 NO 4 ; 11H NMR (400 MHz, CDCl 3 ) δ = 8.41 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.26 - 7.22 (m, 1H), 7.06 - 7.00 m, 2H), 6.88 (d, J = 16.0 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.42 - 6.31 (m, 2H), 5.14 (septet of triplets, J = 1.2, 6.8 Hz, 1H), 4.00 (q, J = 6.9 Hz, 2H), 3.93 (s, 3H), 3.44 (br d, J = 6.7 Hz, 2H), 2.24 (s, 3H), 1.82 (s, 3H), 1.68 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H); 13 13C NMR (100 MHz, CDCl 3 ) δ = 168.71, 157.91, 155.05, 147.92, 137.60, 133.73, 130.22, 129.71, 127.06, 125.90, 123.96, 120.78, 120.55, 119.67, 106.82, 103.91, 99.52, 63.88, 55.68, 25.79, 24.88, 24.53, 18.04, 14.93.

[0349] (E)-2-Amino-N-(4-(5-hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (31) [KYN-151]

[0350]

Chemistry

[0351] (E)-2-Amino-N-(4-(5-hydroxy-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (31): 1 M lithium hydroxide (5 mL) was added to a solution of Compound 31-1 and Compound 31-2 (330 mg) in tetrahydrofuran at room temperature. After stirring for 16 h, the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 24 g column) with a gradient of 0–5% methanol in dichloromethane containing 1% 7 M ammonia in methanol to afford Compound 31 (25.0 mg, 23% yield over 2 steps) as an off-white solid (NRK-1-164).

[0352] (E)-2-Amino-N-(4-(5-hydroxy-3-methoxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (31) [KYN-151] Off-white solid, melting point 196.0 - 201.9 °C; HPLC analysis: 98.7% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 5.78 minutes; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 397.2 (M+H) + ; C 23 H 28 N 2 O 4 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.10 (br s, 1H), 9.24 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.10 (dd, J = 1.7, 8.4 Hz, 1H), 6.90 (d, J = 16.0 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 5.00 (septet of triplets, J = 1.2, 7.0 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 3H), 3.38 - 3.33 (m, 2H), 3.28 - 3.24 (m, 2H), 2.33 (br s, 2H), 1.76 (s, 3H), 1.60 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ = 171.88, 158.45, 156.68, 148.71, 137.47, 133.12, 129.92, 129.83, 127.42, 125.67, 124.51, 119.96, 118.87, 118.69, 108.71, 104.09, 99.11, 56.30. 55.91, 45.67, 25.95, 24.28, 18.20.

[0353] (E)-2-Amino-N-(4-(3-ethoxy-5-hydroxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (32) [KYN-148]

[0354]

Chem.

[0355] (E)-2-Amino-N-(4-(3-ethoxy-5-hydroxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)acetamide (32) [KYN-148]: A 1 M lithium hydroxide solution (5 mL) was added to a solution of Compound 32-1 and Compound 32-2 (550 mg) in tetrahydrofuran (20 mL) at room temperature. After stirring for 16 hours, the volatiles were removed under reduced pressure. The crude product was dissolved in ethyl acetate (30 mL) and washed with saturated ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was first triturated with 30% ethyl acetate in heptane (30 mL) to obtain a beige solid, which was further purified by eluting with a gradient of 0 - 5% methanol in dichloromethane containing 1% of 7 M ammonia in methanol on a Reveleris automated chromatography system (Sorbtech 24 g column) to give Compound 32 [KYN-148] (30.0 mg, 13% yield over 2 steps) as an off-white solid (NRK-1-162).

[0356] Off-white solid, melting point 200.0 - 203.7 °C; HPLC analysis: 99.5% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 8.25 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 411.2 (M+H) + ; C 24 H 30 N 2 O 4 ; 1 H NMR (400 MHz, DMSO-d 6) δ = 10.08 (br s, 1H), 9.20 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.11 (dd, J = 1.5, 8.4 Hz, 1H), 6.90 (d, J = 16.0 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 5.01 (br t, J = 7.0 Hz, 1H), 3.95 (q, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.40 - 3.34 (m, 2H), 3.29 - 3.24 (m, 2H), 2.33 (br s, 2H), 1.77 (s, 3H), 1.61 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ = 171.88, 157.72, 156.59, 148.71, 137.46, 133.14, 129.87, 129.73, 127.41, 125.74, 124.54, 119.93, 118.86, 108.74, 104.08, 99.92, 63.74, 56.32, 45.67, 25.99, 24.35, 18.25, 15.25.

[0357] (E)-Methyl (4-(5-hydroxy-3-methoxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)glycinate (33) [KYN-126]:

[0358]

Chem.

[0359] Off-white solid, melting point 147.3–160.2 °C; HPLC analysis: 98.1% purity; wavelength 210 nm, bandwidth 4; column: Luna C18(2), 2.0 × 20 mm, 3 μm; retention time: 3.84 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 412.2 (M+H) + ; C 24 H 29 NO 5 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.10 (d, J = 16.2 Hz, 1H), 6.97 (dd, J = 1.6, 6.7 Hz, 1H), 6.96 (br s, 1H), 6.84 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 8.6 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.13 (tm, J = 1.5, 6.9 Hz, 1H), 4.92 (br t, J= 4.3 Hz, 1H), 4.75 (br s, 1H), 3.98 (d, J = 5.1 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.41 (d, J = 6.6 Hz, 2H), 1.82 (d, J = 0.7 Hz, 3H), 1.68 (d, J = 1.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 171.44, 158.55, 154.37, 147.19, 138.52, 137.00, 130.88, 130.47, 127.54, 123.79, 122.63, 120.85, 120.50, 109.64, 107.10, 103.78, 97.92, 55.69, 55.47, 52.26, 45.43, 25.76, 24.47, 17.98.

[0360] (E)-Methyl (4-(3-ethoxy-5-hydroxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)glycinate (34) [KYN-147]

[0361]

Chem.

[0362] Off-white solid, melting point 144 - 169 °C; HPLC analysis: 97.3% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 10.06 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 426.2 (M+H) + ; C 25 H 31 NO 5 ; 1 H NMR (400 MHz, CDCl 3) δ = 7.11 (d, J = 16.0 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.84 (br d, J = 16.0 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 6.45 (d, J = 8.6 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 5.14 (septet of triplets, J = 1.3, 7.0 Hz, 1H), 4.92 (br s, 1H), 4.73 (br s, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.97 (s, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.43 (br d, J = 6.8 Hz, 2H), 1.82 (s, 3H), 1.68 (d, J = 0.9 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 171.44, 157.88, 154.27, 147.20, 138.45, 136.96, 130.77, 130.28, 127.59, 123.86, 122.74, 120.82, 120.65, 109.66, 107.14, 103.69, 98.79, 63.91, 55.48, 52.25, 45.44, 25.79, 24.54, 18.04, 14.92.

[0363] (E)-2-((4-(3-ethoxy-5-hydroxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)amino)-2-oxoacetic acid (35) [KYN-152]

[0364]

Chem.

[0365] (E)-2-((4-(3-ethoxy-5-hydroxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)amino)-2-oxoacetic acid (35) [KYN-152]: 1M Lithium hydroxide (0.75 mL, 0.75 mmol, 3.0 eq) was added to a solution of compound 35-1 (130 mg, 0.25 mmol, 1.0 eq) in tetrahydrofuran (20 mL) at room temperature. After stirring for 16 h, the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with 1M HCl (10 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with 10% ethyl acetate in heptane (20 mL) to give compound 35 [KYN-152] (42.0 mg, 38% yield) as an off-white solid (NRK-1-170).

[0366] Off-white solid, melting point 207.8 - 207.9 °C; HPLC analysis: 99.1% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 8.24 min; mobile phase: ACN / formic acid / water; mass spectrum (negative mode) m / z = 424.1 (M-H) - ; C 24 H 27 NO 6 ; 11H NMR (400 MHz, DMSO-d 6 ) δ = 9.63 (s, 1H), 9.21 (br s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.18 (br d, J = 8.4 Hz, 1H), 6.93 (d, J = 16.1 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 2.1 Hz, 1H), 5.01 (br t, J = 7.0 Hz, 1H), 4.06 - 3.91 (m, 5H), 3.38 (br d, J = 6.8 Hz, 2H), 1.76 (s, 3H), 1.60 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H); 13 13C NMR (100 MHz, DMSO-d 6 ) δ = 162.25, 157.73, 156.61,156.08, 149.59, 137.30, 135.11, 129.78, 129.62, 126.77, 125.77, 124.51, 120.32, 119.82, 119.04, 109.14, 104.17, 100.10, 63.75, 56.53, 25.99, 24.35, 18.26, 15.25.

[0367] (E)-4-((4-(5-hydroxy-3-methoxy-2-(3-methylbuta-2-en-1-yl)styryl)-2-methoxyphenyl)amino)-4-oxobutanoic acid (Compound 36) [KYN-150]

[0368]

Chem.

[0369] (E)-N-((4-(3-Methoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)amino)-4-oxobutanoic acid (Compound 36) [KYN-150] Light gray solid, melting point 169.4 - 175.7 °C; HPLC analysis: 97.8% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 7.98 min; mobile phase; ACN / formic acid / water; mass spectrum (negative mode) m / z = 438.2 (M-H) - ; C 25 H 29 NO 6 ; 1 H NMR (400 MHz, acetonitrile-d 3) δ = 8.25 (broad s, 1H), 8.21 (broad d, J = 8.3 Hz, 1H), 7.28 (d, J = 16.1 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 1.8, 8.4 Hz, 1H), 6.94 (d, J = 16.1 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 5.05 (septet of triplets, J = 1.4, 6.8 Hz, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.41 (broad d, J = 6.8 Hz, 2H), 2.70 - 2.65 (m, 2H), 2.64 - 2.60 (m, 2H), 1.80 (d, J = 0.7 Hz, 3H), 1.64 (d, J = 1.1 Hz, 3H); 13 C NMR (100 MHz, acetonitrile-d 3 ) δ = 174.42, 171.50, 159.61, 156.96, 138.79, 131.50, 130.93, 128.74, 126.52, 124.90, 120.85, 120.77, 120.69, 109.17, 104.80, 99.68, 56.67, 56.39, 32.51, 29.64, 25.88, 24.99, 18.23.

[0370] (E)-4-((4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)amino)-4-oxobutanoic acid (37) [KYN-144]

[0371]

Chem.

[0372] Light gray solid, melting point 173~180 °C; HPLC analysis: 96.4% purity; wavelength 254 nm, bandwidth 4; column: SorbTech C18AQ, 2.1×50 mm, 3 μm; retention time: 8.52 min; mobile phase: ACN / formic acid / water; mass spectrum (negative mode) m / z = 452.2 (M-H) - ; C 26 H 31 NO 6 ; 1 H NMR (400 MHz, acetonitrile-d 3) δ = 8.25 (broad s, 1H), 8.21 (broad d, J = 8.3 Hz, 1H), 7.29 (d, J = 16.1 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 1.7, 8.3 Hz, 1H), 6.94 (d, J = 16.1 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 5.07 (septet of triplets, J = 1.5, 7.0 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 3.43 (broad d, J = 7.0 Hz, 2H), 2.70 - 2.65 (m, 2H), 2.64 - 2.60 (m, 2H), 1.80 (s, 3H), 1.64 (d, J = 1.0 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, acetonitrile-d 3 ) δ = 174.41, 171.48, 158.91, 156.86, 149.80, 138.77, 134.49, 131.38, 130.85, 128.72, 126.61, 124.95, 120.95, 120.84, 120.68, 109.18, 104.74, 100.55, 64.93, 55.67, 32.52, 29.64, 25.90, 25.07, 18.32, 15.30.

[0373] (E)-1-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)guanidine (38) [KYN-155]

[0374]

Chemical Structure

[0375] After refluxing for 16 h (79 °C), additional cyanamide (237 mg, 5.66 mmol, 20.0 eq) and p-toluenesulfonic acid (1.07 g, 5.66 mmol, 20.0 eq) were added to the reaction mixture, and it was refluxed for an additional 16 h. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. An additional 100 mg of Compound 24 was converted to Compound 38 in a similar manner. The combined residue was first purified by elution on a Reveleris automated chromatography system (Sorbtech 24 g column) with a gradient of 0 - 15% methanol in dichloromethane containing 5% 7M ammonia in methanol to give relatively pure Compound 38. The product was further purified by elution on a Reveleris automated chromatography system (Redisep Rf Gold HP C18, 50 g column) with a gradient of 0 - 45% acetonitrile in water containing 10 mM ammonium bicarbonate and 5% methanol to give Compound 38 [KYN-155] (37.0 mg, 16% yield) as a white solid (NRK-1-177).

[0376] White solid, melting point 130.5 - 130.6 °C; HPLC analysis: 99.7% purity; wavelength 210 nm, bandwidth 4; column: SorbTech C18AQ, 2.1 × 50 mm, 3 μm; retention time: 6.45 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 396.2 (M + H) + ; C 23 H 29 N 3 O 3 ; 1 H NMR (400 MHz, DMSO-d 6) δ = 7.20 (d, J = 16.0 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.96 - 6.80 (m, 2H), 6.62 (d, J = 2.2 Hz, 1H), 6.30 (d, J = 2.2 Hz, 1H), 5.06 - 4.98 (m, 1H), 3.94 (q, J = 6.9 Hz, 2H), 3.82 - 3.72 (m, 3H), 3.35 (br d, J = 6.8 Hz, 2H), 1.77 (s, 3H), 1.61 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ = 157.70, 156.60, 153.04, 137.68, 130.36, 129.71, 124.83, 124.59, 124.37, 120.26, 118.60, 110.05, 103.97, 99.72, 63.74, 55.76, 25.99, 24.34, 18.27, 15.27.

[0377] (E)-N-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenyl)-N-hydroxyacetamide (Compound 39) [KYN-165]

[0378]

Chem.

[0379] HPLC analysis: 97.2% purity; wavelength 254 nm, bandwidth 4; column: Waters Atlantis T3, 2.1×50 mm, 3 μm; retention time: 8.3 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 412.2 (M+H) + ; C 24 H 29 NO 5 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 9.69 - 7.44 (m, 1H), 7.40 - 7.28 (m, 2H), 7.08 (br d, J = 6.6 Hz, 1H), 7.02 (s, 1H), 6.87 (br d, J = 15.4 Hz, 1H), 6.70 (br s, 1H), 6.41 (br s, 1H), 5.12 (br t, J = 6.7 Hz, 1H), 3.98 (q, J = 6.9 Hz, 2H), 3.86 (s, 3H), 3.43 (br d, J = 6.5 Hz, 2H), 1.97 (br s, 3H), 1.80 (s, 3H), 1.67 (s, 3H), 1.40 (t, J = 6.9 Hz, 3H); 1313C NMR (100 MHz, CDCl 3 ) δ = 167.75, 157.86, 155.23, 154.91, 141.36, 136.98, 130.47, 130.07, 128.96, 126.01, 123.73, 120.97, 119.27, 109.83, 104.13, 100.11, 63.93, 55.75, 25.75, 24.48, 19.41, 18.01, 14.87.

[0380] (E)-N-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-hydroxyphenyl)formamide (40) [KYN-159]

[0381]

Chem.

[0382] 5-(Bromomethyl)-2-nitrophenol (40-3): Carbon tetrabromide (4.05 g, 12.18 mmol, 2.0 equiv) was added portionwise to a solution of compound 40-2 (1.0 g, 6.09 mmol, 1.0 equiv) and triphenylphosphine (3.19 g, 12.18 mmol, 2.0 equiv) in dichloromethane (50 mL) at 0 °C in 4 portions. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of 1 M HCl (40 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 40 g column) with a gradient of 0 - 40% ethyl acetate in heptane to give compound 40-3 (1.5 g, 92% yield) as a yellow solid (NRK-6-23).

[0383] (3-Hydroxy-4-nitrobenzyl)diethylphosphonate (40-4): Triethyl phosphite (3.3 mL, 19.39 mmol, 3.0 equiv) was added to a solution of compound 40-3 (1.5 g, 6.46 mmol, 1.0 equiv) in toluene (30 mL). The resulting solution was refluxed (110 °C) for 20 h. After cooling to room temperature, the volatiles were removed under reduced pressure. The crude residue was dissolved in dichloromethane (50 mL) and washed with 1 M sodium hydroxide (100 mL). The aqueous layer was neutralized with 1 M hydrochloric acid (150 mL). The resulting aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give compound 40-4 (1.0 g, 56% yield) as a yellow solid, which was used without further purification (NRK-6-24).

[0384] (4-Nitro-3-((2-(trimethylsilyl)ethoxy)methoxy)benzyl)diethylphosphonate (40-5): 2-(Trimethylsilyl)ethoxymethyl chloride (0.6 mL, 3.46 mmol, 1.0 equivalent) and N,N-diisopropylethylamine (0.9 mL, 5.19 mmol, 1.5 equivalents) were sequentially added to a solution of compound 40-4 (1.0 g, 3.46 mmol, 1.0 equivalent) in dichloromethane (50 mL) at room temperature. After stirring for 20 hours, the reaction mixture was diluted with saturated sodium bicarbonate (30 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and compound 5 (1.02 g, 71% yield) was obtained as a yellow oil and used subsequently (NRK-6-29).

[0385] (E)-(2-((5-(2-Bromo-3-ethoxy-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-nitrophenoxy)methoxy)ethyl)trimethylsilane (40-6): Potassium tert-butoxide (800 mg, 7.06 mmol, 2 equivalents) was added to a solution of compound 5 (1.02 g, 3.53 mmol, 1.0 equivalent) in anhydrous tetrahydrofuran (50 mL) in three portions at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes. A solution of module D (1.32 g, 3.53 mmol, 1 equivalent) in anhydrous tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was carefully quenched with saturated brine (20 mL, 1 drop per minute for the first 5 mL of brine) at 0 °C. The volatiles were removed under reduced pressure. Saturated ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (2 × 60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 40 g column) with a gradient of 0 - 20% ethyl acetate in heptane to give compound 40-6 (867 mg, 39% yield) as a yellow oil (NRK-6-31).

[0386] (E)-(2-((5-(3-Ethoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-nitrophenoxy)methoxy)ethyl)trimethylsilane (40-7): Tetrakis(triphenylphosphine)palladium(0) (156 mg, 0.14 mmol, 0.1 equiv), potassium carbonate (373 mg, 2.7 mmol, 2 equiv), 3-methylbut-2-enylboronic acid pinacol ester (530 mg, 2.7 mmol, 2 equiv), and water (3 mL) were successively added to a solution of compound 40-6 (867 mg, 1.4 mmol, 1 equiv) in 1,4-dioxane (30 mL) in a sealed tube. After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 100 °C for 16 hours. LCMS analysis indicated the formation of the desired compound 40-7 (70% conversion). An additional 3-methylbut-2-enylboronic acid pinacol ester (530 mg, 2.7 mmol, 2 equiv) was added and the reaction mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was suspended in saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 40 g column) with a gradient of 0-30% ethyl acetate in heptane to give compound 40-7 (852 mg, 99% yield) as a yellow oil (NRK-6-37).

[0387] (E)-3-Ethoxy-5-(3-hydroxy-4-nitrostyryl)-4-(3-methylbut-2-en-1-yl)phenol (40-8): 1M tetrabutylammonium fluoride in tetrahydrofuran (19 mL, 18.90 mmol, 14 equiv) was added to a solution of compound 40-7 (852 mg, 1.36 mmol, 1 equiv) in tetrahydrofuran (20 mL) at room temperature. After heating at 67 °C for 16 hours, the mixture was cooled to room temperature and diluted with water (10 mL) and saturated ammonium chloride (30 mL). The volatiles were removed under reduced pressure and the remaining aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 40 g column) with a gradient of 0-80% ethyl acetate in heptane to give compound 40-8 (410 mg, 83% yield) as a yellow solid (NRK-6-26).

[0388] (E)-3-(4-Amino-3-hydroxystyryl)-5-ethoxy-4-(3-methylbut-2-en-1-yl)phenol (40-9): Activated zinc powder (730 mg, 11.1 mmol, 10.0 equiv), ammonium chloride (590 mg, 11.1 mmol, 10.0 equiv) and water (5 mL) were sequentially added to a solution of compound 40-8 (410 mg, 1.11 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) at room temperature. The resulting suspension was stirred at room temperature for 16 h. The suspension was filtered and the solid was washed with ethyl acetate (20 mL). The filtrate was evaporated to dryness under reduced pressure. The residue was suspended in saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0-80% ethyl acetate in heptane on a Reveleris automated chromatography system (Sorbtech 24 g column) to give compound 40-9 (234 mg, 63% yield) as a pale yellow solid (NRK-6-39).

[0389] (E)-N-(4-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-hydroxyphenyl)formamide (40)[KYN-159]: Compound 40-9 (100 mg, 0.3 mmol, 1.0 equiv) was added to ethyl formate (10 mL) and the reaction mixture was heated at 55 °C for 20 h. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0-80% ethyl acetate in heptane on a Reveleris automated chromatography system (Sorbtech 24 g column). The product was triturated with 10% ethyl acetate in heptane (10 mL) to give compound 40 (74 mg, 69% yield) as an off-white solid (NRK-6-41).

[0390] Off-white solid; melting point 157.9 - 162.9 °C; HPLC analysis: 97.0% purity; wavelength 210 nm, bandwidth 4; column: Waters Atlantis T3, 2.1×50 mm, 3 μm; retention time: 8.4 minutes; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 368.2 (M+H) + ; C 22 H 25 NO 4 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.04 (br s, 1H), 9.63 (s, 1H), 9.19 (br s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 16.1 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.97(dd, J = 1.7, 8.3 Hz, 1H), 6.83 (d, J = 16.1 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.31 (d, J = 2.1 Hz, 1H), 5.02 (br t, J = 7.0 Hz, 1H), 3.94 (q, J = 6.9 Hz, 2H), 3.34 (br s, 2H), 1.75 (s, 3H), 1.62 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ = 160.41, 157.69, 156.59, 147.23, 137.32, 133.69, 130.08, 129.78, 126.32, 125.48, 124.32, 121.06, 118.76, 118.45, 112.80, 104.10, 99.93, 63.75, 25.99, 24.29, 18.28, 15.25.

[0391] (E)-N-(5-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-hydroxyphenyl)formamide (41)[KYN-161]

[0392]

Chem.

[0393] (E)-(2-((4-(3-Ethoxy-2-(3-methylbut-2-en-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)styryl)-2-nitrophenoxy)methoxy)ethyl)trimethylsilane (41-2): Tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.1 mmol, 0.1 eq), potassium carbonate (276 mg, 2.0 mmol, 2 eq), 3-methylbut-2-enylboronic acid pinacol ester (400 mg, 2.0 mmol, 2 eq), and water (2 mL) were sequentially added to a solution of compound 41-1 (640 mg, 1.0 mmol, 1 eq) in 1,4-dioxane (10 mL) in a sealed tube. After sparging with nitrogen for 10 minutes, the reaction mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0-20% ethyl acetate in heptane on a Reveleris automated chromatography system (Sorbtech 40 g column) to give compound 41-2 (525 mg, 71% yield) as a yellow oil (NRK-6-53).

[0394] (E)-3-Ethoxy-5-(4-hydroxy-3-nitrostyryl)-4-(3-methylbut-2-en-1-yl)phenol (41-3): 1M tetrabutylammonium fluoride in tetrahydrofuran (12 mL, 11.68 mmol, 14 eq) was added to a solution of compound 41-2 (525 mg, 0.84 mmol, 1 eq) in tetrahydrofuran (12 mL) at room temperature. After heating at 67 °C for 16 hours, the mixture was cooled to room temperature and diluted with water (20 mL) and 1M HCl (30 mL). The volatiles were removed under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by elution with a gradient of 0-60% ethyl acetate in heptane on a Reveleris automated chromatography system (Sorbtech 80 g column) to give compound 41-3 (120 mg, 40% yield) as a yellow solid (NRK-6-54).

[0395] (E)-3-(3-Amino-4-hydroxystyryl)-5-ethoxy-4-(3-methylbut-2-en-1-yl)phenol (41-4): Activated zinc powder (210 mg, 3.26 mmol, 10.0 equiv), ammonium chloride (176 mg, 3.26 mmol, 10.0 equiv) and water (2 mL) were successively added to a solution of compound 41-3 (120 mg, 0.326 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) at room temperature. The resulting suspension was stirred at room temperature for 16 h. The suspension was filtered through celite and washed with ethyl acetate (20 mL). The filtrate was concentrated and dried under reduced pressure. The residue was suspended in saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 24 g column) with a gradient of 0 - 60% ethyl acetate in heptane to give compound 41-4 (100 mg, 91% yield) as a pale yellow solid (NRK-6-55).

[0396] (E)-N-(5-(3-Ethoxy-5-hydroxy-2-(3-methylbut-2-en-1-yl)styryl)-2-hydroxyphenyl)formamide (41)[KYN-161]: A solution of compound 41-4 (100 mg, 0.3 mmol, 1.0 equiv) in ethyl formate (10 mL) was heated at 55 °C for 20 h. The reaction mixture was cooled to room temperature and concentrated and dried under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated ammonium chloride (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by elution on a Reveleris automated chromatography system (Sorbtech 24 g column) with a gradient of 0 - 60% ethyl acetate in heptane to give compound 41 (80 mg, 73% yield) as a pale yellow solid (NRK-6-57).

[0397] Pale yellow solid; HPLC analysis: 97.5% purity; wavelength 254 nm, bandwidth 4; column: Waters Atlantis T3, 2.1 × 50 mm, 3 μm; retention time: 8.3 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 368.2 (M + H) + ; C 22 H 25 NO 4 ; 11H NMR (400 MHz, DMSO-d 6 ) δ = 10.08 (broad singlet, 1H), 9.58 (singlet, 1H), 9.16 (broad singlet, 1H), 8.31 (doublet, J = 1.7 Hz, 1H), 8.28 (doublet, J = 2.1 Hz, 1H), 7.20 - 7.02 (multiplet, 2H), 6.91 - 6.78 (multiplet, 2H), 6.63 - 6.58 (multiplet, 1H), 6.30 (doublet, J = 2.2 Hz, 1H), 5.00 (broad triplet, J = 7.0 Hz, 1H), 3.94 (quartet, J = 6.9 Hz, 2H), 3.35 (broad singlet, 1H), 3.31 - 3.28 (multiplet, 1H), 1.77 - 1.70 (multiplet, 3H), 1.67 - 1.47 (multiplet, 3H), 1.33 (triplet, J = 7.0 Hz, 3H); 13 13C NMR (100 MHz, DMSO-d 6 ) δ = 160.55, 157.67, 156.57, 147.20, 137.62, 130.08, 128.90, 126.77, 124.51, 124.29, 123.97, 123.49, 118.83, 118.52, 115.61, 103.97, 99.69, 63.74, 25.96, 24.34, 18.24, 15.26.

[0398] (E)-2-Methoxy-4-(3-methoxy-2-(3-methylbut-2-en-1-yl)-5-nitrostyryl)phenol (42)[KYN-162] (E)-4-(5-Amino-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenol (S16)(43)[KYN-163] (E)-N-(3-(4-Hydroxy-3-methoxystyryl)-5-methoxy-4-(3-methylbut-2-en-1-yl)phenyl)formamide (S17)(44)[KYN-164]

[0399]

Chemical formula

[0400] (E)-2-(4-Hydroxy-3-methoxystyryl)-6-methoxy-4-nitrophenyl trifluoromethanesulfonate (42-3): Trifluoromethanesulfonic anhydride (1.9 g, 6.7 mmol, 1.07 equiv) was added dropwise to a solution of compound 42-2 (2.8 g, 6.26 mol, 1.0 equiv) and N-methylmorpholine (1.03 mL, 9.4 mmol, 1.5 equiv) in dichloromethane (100 mL) at 0 °C over 5 min while maintaining the reaction temperature at 0 °C. After stirring at 0 °C for 3 h, the reaction mixture was quenched by adding 10% citric acid (100 mL) over 15 min while maintaining the reaction temperature below 5 °C. The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by eluting with a gradient of 0-60% ethyl acetate in heptane on an Interchim automated chromatography system (80 g column) to give compound 42-3 (2.26 g, 80% yield) as a yellow solid (LM-8-47).

[0401] (E)-2-Methoxy-4-(3-methoxy-2-(3-methylbut-2-en-1-yl)-5-nitrostyryl)phenol (42) [KYN-162]: Tetrakis(triphenylphosphine)palladium(0) (237 mg, 0.2 mmol, 0.05 equiv), potassium carbonate (1.2 g, 8.2 mmol, 2 equiv), 3-methylbut-2-enylboronic acid pinacol ester (1.6 g, 8.2 mmol, 2 equiv) and water (11 mL) were sequentially added to a solution of compound 42-3 (1.83 g, 4.1 mmol, 1 equiv) in 1,4-dioxane (33 mL). After sparging with nitrogen for 10 min, the reaction was heated at 95 °C for 16 h. After cooling to room temperature, the mixture was diluted with saturated ammonium chloride solution (30 mL) and extracted with methyl tert-butyl ether (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by eluting with a gradient of 0-60% ethyl acetate in heptane on an Interchim automated chromatography system (120 g column) to give compound 42 (0.82 g, 54% yield) as a yellow oil. HPLC analysis: 97.3% purity; wavelength 254 nm, bandwidth 4; column: Waters Atlantis T3, 2.1 × 50 mm, 3 μm; retention time: 10.7 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 370.2 (M+H) +; C 21 H 23 NO 5 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 8.10 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.08 - 7.01 (m, 3H), 6.94 (d, J = 8.2 Hz, 1H), 5.71 (s, 1H), 5.07 (septet of triplets, J = 1.3, 6.8 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.55 (br d, J = 6.8 Hz, 2H), 1.84 (d, J = 0.9 Hz, 3H), 1.70 (d, J = 1.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 157.84, 147.03, 146.73, 146.17, 138.48, 135.17, 132.87, 132.61, 129.45, 122.31, 121.10, 120.63, 114.73, 113.29, 108.83, 103.38, 56.10, 55.91, 25.75, 25.52, 18.09.

[0402] (E)-4-(5-Amino-3-methoxy-2-(3-methylbut-2-en-1-yl)styryl)-2-methoxyphenol (43) [KYN-163]: Water (6 mL), ammonium chloride (613 mg, 11.4 mmol, 10 equiv), and zinc powder (743 mg, 11.4 mmol, 10 equiv) were sequentially added to a solution of compound 42 (420 mg, 1.14 mmol, 1 equiv) in tetrahydrofuran (60 mL) at room temperature. The resulting suspension was stirred at room temperature for 3 h. The suspension was filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was evaporated to dryness under reduced pressure. The residue was purified by elution on an Interchim automated chromatography system (80 g column) with a gradient of 0 - 100% ethyl acetate in heptane and dried in vacuo at 40 °C for 16 h to give compound 43 (60 mg, purity > 95% and 180 mg, purity ~ 90%; yield 62%) as an off - white solid (LM - 8 - 53).

[0403] Off-white solid; HPLC analysis: 97.6% purity; wavelength 254 nm, bandwidth 4; column: Waters Atlantis T3, 2.1×50 mm, 3 μm; retention time: 6.7 min; mobile phase: ACN / formic acid / water; mass spectrum (positive mode) m / z = 340.2 (M+H) + ; C 21 H 25 NO 3 ; 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.08 (s, 1H), 7.12 - 7.04 (m, 2H), 6.91 (dd, J = 1.9, 8.3 Hz, 1H), 6.81 - 6.73 (m, 2H), 6.43 (d, J = 2.0 Hz), 6.17 (d, J = 2.0 Hz), 4.99 (septet of triplets, J = 1.3, 6.8 Hz, 1H), 4.88 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.28 (br d, J = 7.0 Hz, 2H), 1.75 (d, J = 0.6 Hz, 3H), 1.60 (d, J = 0.7 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ= 158.21, 148.28, 147.79...

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ａ is independently allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl, or 2-alkynyl; R １ｂ is independently ３ , O.H., O.R. ２ , NO ２ , NHEt, NMe ２ , NMeEt, NHR ３ , NMeR ３ ,NHC=NH(NH ２ ) or COOR ２ and R １ｃ is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl, or benzyl; R １ｄ is independently ３ , O.H., O.R. ２ , N.H.R. ３ , NO ２ , NMeR ３ ,NHC=NH(NH ２ ) or COOR ２ and R １ｂ and R １ｄ is not the same, R １ｅ are independently H, C １ ~C ６ Alkyl, OH, OR ２ , NO ２ , NMe ２ , N.H.R. ３ NMeR ３ , or S.R. ２ and R １ｆ are independently H, OH, OR ２ , NO ２ , N.H.R. ３ , N(OH)(CO)CH ３ ,NHC=NH(NH ２ ), COOR ２ , COOH, R １ｇ are independently H, alkyl, CF ３ , OH or OR ２ and R １ｅ , R １ｆ Or R １ｇ may be H, Or, R １ｅ However, independently, OH, NH ２ Or NHMe, R １ｆ NH ２ If R １ｅ and R １ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R １ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R １ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR ４ or R ２ is an O-protecting group when attached to O, R ３ are independently H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , CO(CH ２ ) ｎ N.H. ２ , CO(CH ２ ) ｎ COOH or COCOOR ４ where n is 0, 1 or 2; R ４ is C １ ~C ６ wherein the compound is an alkyl group, the method comprising: i) coupling of a compound of formula (II) (module A) with a compound of formula (III) (module B) to obtain a compound of formula (IV) (module C); 【Chemistry 2】 (In the formula, In Formula II (Module A), R ２ｂ is independently ３ , OR ２ , NO ２ , NMe ２ , NHEt, NMeEt, NHR ３ or NMeR ３ and R ２ｃ is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl, or benzyl; R ２ｄ is independently ３ , OR ２ , NO ２ , N.H.R. ３ , NMeR ３ ,NHC=NH(NH ２ ) or COOR ２ and X is a halide or a hydroxyl group, said halide being selected from the group consisting of F, Cl, Br, I and At; R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ３ are independently H, OH, CH ３ , (CO)H, COMe, SO ２ Me, COCH ２ N.H. ２ or CH ２ COOR ２ and In formula III (module B), R ３ｅ are independently H, C １ ~C ６ Alkyl, OR ２ , NO ２ , NHMe, NMe ２ , N.H.R. ３ or NMeR ３ , or S.R. ２ and R ３ｆ are independently H, OR ２ , NO ２ , N.H.R. ３ ,NHC=NH(NH ２ ), COOH or COOR ２ and R ３ｇ are independently H, alkyl, CF ３ OR ２ and R ３ｅ , R ３ｆ Or R ３ｇ may be H, Or R ３ｅ But, OH, NH ２ Or NHMe, R ３ｆ NH ２ If R ３ｅ and R ３ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R ３ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R ３ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ３ are independently H, CH ３ , OH, (CO)H, COMe, SO ２ Me, COCH ２ N.H. ２、 CH ２ COOH or CH ２ COOR ２ and In Formula IV (Module C), R ４ｂ is independently ３ , OR ２ , NO ２ , NMe ２ , NHEt, NMeEt, NHR ３ or NMeR ３ and R ４ｃ is independently H, alkyl, alkenyl, alkynyl, alkanedienyl, prenyl, geranyl, farnesyl, or benzyl; R ４ｄ is independently ３ , OR ２ , OR ３ , NO ２ , N.H.R. ３ , NMeR ３ ,NHC=NH(NH ２ ) or COOR ２ and R ４ｅ are independently H, C １ ~C ６ Alkyl, OR ２ , NO ２ , N.H.R. ３ , NMeR ３ , NHC(O)H or SR ２ and R ４ｆ are independently H, OR ２ , NO ２ , N.H.R. ３ ,NHC=NH(NH ２ ), COOH or COOR ２ and R ４ｇ are independently H, alkyl, CF ３ OR ２ and R ４ｅ , R ４ｆ Or R ４ｇ may be H, Or R ４ｅ But, OH, NH ２ Or NHMe, R ４ｆ NH ２ If R ４ｅ and R ４ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R ４ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R ４ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ３ are independently H, CH ３ , OH, (CO)H, COMe, SO ２ Me, COCH2NH2, CH2COOH or CH ２ COOR ２ and X is a halide, a hydroxyl group, said halide being selected from the group consisting of F, Cl, Br, I and At; The O-protecting group is COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ (selected from the group consisting of:

2. R １ａ is independently allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl, or 2-alkynyl; R １ｂ is independently ３ , OR ２ , or N.H.R. ３ and R １ｃ are independently H; R １ｄ are independently OH, OR ２ , N.H.R. ３ , or NO ２ and R １ｂ and R １ｄ is not the same, R １ｅ is independently １ ~C ６ Alkyl, OH, OR ２ , NO ２ , N.H.R. ３ , NMeR ３ , or S.R. ２ and R １ｆ are independently H, OH, NO ２ , N.H.R. ３ , N(OH)(CO)CH ３ ,NHC=NH(NH ２ ), or COOH; R １ｇ are independently H, C １ ~C ６ Alkyl, OH, or OR ２ and R １ｆ and R １ｇ may be H, Or, R １ｅ However, independently, OH, NH ２ Or NHMe, R １ｆ NH ２ If R １ｅ and R １ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R １ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R １ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ３ are independently H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOR ２ , CO(CH ２ ) ｎ N.H. ２ , or CO(CH ２ ) ｎ COOH, n is 0, 1 or 2, R ４ is C １ ~C ６ a compound of formula (I) wherein R is an alkyl group, In Formula II (Module A), R ２ｂ is independently ３ , OR ２ , N.H.R. ３ and R ２ｃ is H, R ２ｄ are independently OR ２ , or NO ２ and X is a halide or a hydroxyl group, said halide being selected from the group consisting of F, Cl, Br, I and At; R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ３ is independently H, (CO)H, or COMe; In formula III (module B), R ３ｅ is independently １ ~C ６ Alkyl, OR ２ , NO ２ , or S.R. ２ and R ３ｆ are independently H, OR ２ , NO ２ , or COOR ２ and R ３ｇ are independently H, alkyl, or OR ２ and R ３ｆ and R ３ｇ may be H, Or R ３ｅ But, OH, NH ２ Or NHMe, R ３ｆ NH ２ If R ３ｅ and R ３ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R ３ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R ３ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ４ is C １ ~C ６ is alkyl, In Formula IV (Module C), R ４ｂ is independently ３ , OR ２ , or N.H.R. ３ and R ４ｃ are independently H; R ４ｄ are independently OR ２ , or NO ２ and R ４ｅ is independently １ ~C ６ Alkyl, OR ２ , NO ２ , or S.R. ２ and R ４ｆ are independently H, OR ２ , NO ２ , COOH, R ４ｇ are independently H, C １ ~C ６ Alkyl, or OR ２ and R ４ｅ , R ４ｆ Or R ４ｇ may be H, Or R ４ｅ But, OH, NH ２ Or NHMe, R ４ｆ NH ２ If R ４ｅ and R ４ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R ４ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R ４ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, R ３ is independently H, (CO)H, or COMe; X is a halide or a hydroxyl group, said halide being selected from the group consisting of F, Cl, Br, I and At; The O-protecting group is COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ 2. The method of claim 1 , comprising:

3. (i) X in formulas (II) and (IV) is a halide; The halogenated compound of formula (IV) a) R １ａ -substituted boronic acid compounds or esters, b) R １ａ -substituted trifluoroborate compounds, or c) R １ａ - substituted organostannane compounds, to form said compound of formula (I), R １ａ is selected from the group consisting of allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl, or 2-alkynyl; or (ii) X in formulas (II) and (IV) is hydroxyl; wherein the hydroxyl group is converted to a triflate (trifluoromethylsulfonate) group to form a triflate of formula (IV), a) R １ａ -substituted boronic acid compounds or esters, b) R １ａ -substituted trifluoroborate compounds, or c) R １ａ - substituted organostannane compounds, to form said compound of formula (I), R １ａ is selected from the group consisting of allyl, crotyl, prenyl, geranyl, farnesyl, benzyl, 2-alkenyl, or 2-alkynyl; Optionally, said coupling reaction in (i) and / or (ii) is catalyzed by a palladium compound in the presence of a base; the palladium compounds include tetrakis(triphenylphosphine)palladium(0) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); The method according to claim 1 or 2.

4. The method of claim 3, wherein the R 1a -substituted boronic acid compound or ester in (i) is an R 1a -substituted boronic acid pinacol ester.

5. The method of claim 3, wherein the R 1a -substituted trifluoroborate compound in (i) is potassium R 1a -substituted trifluoroborate.

6. The method of claim 3, wherein the R 1a -substituted organostannane compound in (i) is an R 1a -substituted tributylstannane.

7. The method of claim 3, wherein the R 1a -substituted boronic acid compound or ester in (ii) is an R 1a -substituted boronic acid pinacol ester.

8. The method of claim 3, wherein the R 1a -substituted trifluoroborate compound in (ii) is potassium R 1a -substituted trifluoroborate.

9. The method of claim 3, wherein the R 1a -substituted organostannane compound in (ii) is an R 1a -substituted tributylstannane.

10. In formula (I), R １ａ is independently allyl, crotyl, prenyl, or benzyl; R １ｂ But independently, CF ３ , OR ２ , N.H. ２ , NHC(O)H, or NHC(O)Me; R １ｃ is H, R １ｄ But independently, OH, OR ２ , N.H. ２ , NHC(O)H, NHC(O)Me, or NO ２ and R １ｂ and R １ｄ is not the same, R １ｅ But independently, C １ ~C ６ Alkyl, OH, OR ２ , NO ２ , NMe ２ , NHC(O)Me, NMeH, NHC(O)H, or SMe; R １ｆ are independently H, OH, and NO ２ , N.H. ２ , N(OH)(CO)CH ３ , N.H.S.O. ２ Me, NHC(O)H, NHC(O)Me, NHCO(CH ２ ) ｎ N.H. ２ , NHCO(CH ２ ) ｎ， COOH,NHC=NH(NH ２ ), N.H.H. ２ COOR ２ or COOH, n is 0, 1 or 2; R １ｇ However, independently, H, C １ ~C ６ Alkyl, OH or OR ２ and R １ｆ Or R １ｇ may be H; Or R １ｅ But, OH, NH ２ Or NHMe, R １ｆ NH ２ If R １ｅ and R １ｆ forms a 5- or 6-membered heterocyclic ring containing a carbonyl group, such that R １ｆ The nitrogen atom of R １ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, or R ２ is an O-protecting group when attached to O, In Equation II (Module A), R ２ｂ But, CF ３ , OR ２ , or NH ２ and R ２ｃ is H, R ２ｄ But independently, OR ２ , or NO ２ and X is a halide or a hydroxyl group, said halide being selected from the group consisting of F, Cl, Br, I and At; R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, In formula III (module B): R ３ｅ But independently, C １ ~C ６ Alkyl, OR ２ , NO ２ , or S.R. ２ and R ３ｆ But independently, H, OR ２ , NO ２ , or COOR ２ and R ３ｇ However, independently, H, C １ ~C ６ Alkyl, or OR ２ and R ３ｆ Or R ３ｇ may be H; Or R ３ｅ But, OH, NH ２ Or NHMe, R ３ｆ NH ２ If R ３ｅ and R ３ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R ３ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R ３ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, In Equation IV (Module C), R ４ｂ But, CF ３ , OR ２ , or NH ２ and R ４ｃ is H, R ４ｄ But independently, OR ２ , or NO ２ and R ４ｅ But independently, C １ ~C ６ Alkyl, OR ２ , NO ２ , or S.R. ２ and R ４ｆ But independently, H, OR ２ , NO ２ or COOH, R ４ｇ However, independently, H, C １ ~C ６ Alkyl, or OR ２ and R ４ｆ Or R ４ｇ may be H; Or R ４ｅ But, OH, NH ２ Or NHMe, R ４ｆ NH ２ If R ４ｅ and R ４ｆ is a carbonyl group or (CO)CH ２ forming a 5- or 6-membered heterocyclic ring containing a group, such that R ４ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R ４ｅ is bridged to oxygen or nitrogen of R ２ are independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group when attached to O, X is a halide or a hydroxyl group, said halide being selected from the group consisting of F, Cl, Br, I and At; The O-protecting group is COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ Selected from the group consisting of:

10. The method according to any one of claims 1 to 9.

11. The compound according to formula (I) 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 【Chemistry 3-4】 【Chemistry 3-5-1】 The method of any one of claims 1 to 10, wherein the compound is selected from the group consisting of:

12. In formula (I), R １ａ is allyl, crotyl, prenyl, or benzyl; R １ｂ But, OR ２ , NHC(O)Me, or NHC(O)H; R １ｃ is H, R １ｄ is OH, R １ｅ is OH or OR ２ and R １ｆ But NO ２ , N.H.R. ３ or NHC=NH(NH ２ ) and R １ｇ is H, R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; R ３ is H, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOR ２ , COCH ２ N.H. ２ or CO(CH ２ ) ｎ COOH (n=0, 1 or 2); In formula II, R ２ｂ But, OR ２ or NH ２ and R ２ｃ is H, R ２ｄ But, OR ２ and X is a halide selected from the group consisting of F, Cl, Br, I and At; R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxymethyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of In formula III: R ３ｅ is OH or OR ２ and R ３ｆ But NO ２ , N.H.R. ３ or NHC=NH(NH ２ ) and R ３ｇ is H, R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; R ３ H, (CO)H, COMe, SO ２ Me or CH ２ COOR ２ , COCH ２ N.H. ２ , or CO(CH ２ ) ｎ COOH (n=0, 1 or 2); In formula IV, R ４ｂ But, OR ２ , or NH ２ and R ４ｃ is H, R ４ｄ OR ２ and R ４ｅ is OH or OR ２ and R ４ｆ But NO ２ , N.H.R. ３ or NHC=NH(NH ２ ) and R ４ｇ is H, R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; R ３ H, (CO)H, COMe, SO ２ Me, or CH ２ COOR ２ , COCH ２ N.H. ２ , or CO(CH ２ ) ｎ COOH (n=0, 1 or 2); X is a halide selected from the group consisting of F, Cl, Br, I and At; Formula IV is a compound represented by the formula (IV) which is catalyzed by a palladium catalyst in the presence of a base to form a compound represented by the formula (IV) having an R group selected from the group consisting of 3-methylbut-2-enylboronic acid pinacol ester, crotylboronic acid pinacol ester, allylboronic acid pinacol ester and benzylboronic acid pinacol ester. １ａ 10. The method of claim 1 , wherein the compound of formula (I) is produced by coupling with a boronic acid pinacol ester.

13. In formula (I), R １ａ is crotyl or prenyl; R １ｂ OR ２ and R １ｃ is H, R １ｄ is OH, R １ｅ OR ２ and R １ｆ But NO ２ , N.H.R. ３ or NHC=NH(NH ２ ) and R １ｇ is H, R ２ is methyl or ethyl, R ３ is H, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOR ２ , COCH ２ N.H. ２ , or CO(CH ２ ) ｎ COOH (n=0, 1 or 2); In formula II, R ２ｂ But, OR ２ and R ２ｃ is H, R ２ｄ OR ２ and X is Br; R ２ is methyl or ethyl, In formula III: R ３ｅ is OH or OR ２ and R ３ｆ But NO ２ , N.H.R. ３ or NHC=NH(NH ２ ) and R ３ｇ is H, R ２ is methyl or ethyl, R ３ is H, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOR ２ , COCH ２ N.H. ２ , or CO(CH ２ ) ｎ COOH (n=0, 1 or 2); In formula IV, R ４ｂ OR ２ and R ４ｃ is H, R ４ｄ OR ２ and R ４ｅ is OH or OR ２ and R ４ｆ But NO ２ , N.H.R. ３ or NHC=NH(NH ２ ) and R ４ｇ is H, R ２ is methyl or ethyl, R ３ is H, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOR ２ , COCH ２ N.H. ２ , or CO(CH ２ ) ｎ COOH (n=0, 1 or 2); X is Br; Formula IV is catalyzed by a palladium catalyst in the presence of a base to form a compound represented by the formula R selected from the group consisting of 3-methylbut-2-enylboronic acid pinacol ester, crotylboronic acid pinacol ester, allylboronic acid pinacol ester and benzylboronic acid pinacol ester. １ａ 13. The method of claim 12, wherein said compound of formula (I) is produced by coupling with a boronic acid pinacol ester.

14. 14. The method of claim 13, wherein the compound according to formula (I) is selected from the group consisting of the following compounds: 【Chemistry 101-1】 【Chemistry 101-2】

15. The compound of formula (IV) or (I) comprises one or more of the following: One or more -NH in formula (IV) or formula (I) ２ , NO ２ and / or reaction with -OH substituents; methoxyoxoacetamide (-NHC(O)C(O)OCH) of a -NH2 substituent by reacting the compound containing the -NH2 substituent with methyl chlorooxoacetate in the presence of a base. ３ ) conversion to a substituent; conversion of one or more -OH substituents to methyl oxalate substituents by reacting the compound containing said -OH substituents with methyl chlorooxoacetate in the presence of a base; hydrolysis of one or more methoxyoxoacetamide substituents to --NHC(O)C(O)OH substituents by reacting a compound containing N-methoxyoxoacetamide substituents with a base; hydrolysis of one or more methyl oxalate substituents to -OH substituents by reacting a compound containing said methyl oxalate substituents with a base; N.H. ２ Reacting a compound containing said -NH substituent with cyanamide in the presence of an acid to form one or more of said -NH ２ The substituent, guanidine (-NHC(NH)NH ２ ) conversion to a substituent; N.H. ２ Reacting a compound containing one or more of the -NH substituents with ethyl formate. ２ Conversion of a substituent to a formamide (-NHC(O)H) substituent; N.H. ２ Reacting a compound containing one or more of the -NH substituents with acetic anhydride in the presence of a base. ２ The substituent, acetamide (-NHC(O)CH ３ ) conversion to a substituent; N.H. ２ Reacting a compound containing one or more of the -NH substituents with succinic anhydride in the presence of a base. ２ The amide derivative of the substituent (-NHC(O)CH ２ CH ２ Conversion to a C(O)OH) substituent; N.H. ２ Reacting a compound containing one or more of the -NH substituents with formaldehyde in the presence of triacetoxyborohydride. ２ Conversion of the substituent to a methylamine substituent (-NHMe); Conversion of one or more of the —OH substituents to acetates (—OC(O)CH) by reacting a compound containing said —OH substituents with acetic anhydride in the presence of a base. ３ ) conversion to a substituent; hydrolysis of one or more acetate substituents to form -OH substituents by reacting a compound containing said acetate substituents with a base; NO ２ Reacting a compound containing said -NO substituent with Zn in the presence of ammonium chloride to produce one or more of said -NO ２ Reduction of the substituent to an amine substituent; 5. The method of claim 1 , wherein the reaction is further reacted with one or more of the following:

16. The compound of formula (IV) or (I), wherein the compound has one or more of the following: reaction with one or more -NH 2 , NO 2 and / or -OH substituents on formula (IV) or formula (I); conversion of an --NH.sub.2 substituent to a methoxyoxoacetamide (--NHC(O)C(O)OCH.sub.3) substituent by reacting a compound containing said --NH.sub.2 substituent with methyl chlorooxoacetate in the presence of a base, said base being triethylamine; conversion of one or more -OH substituents to methyl oxalate substituents by reacting a compound containing said OH substituents with methyl chlorooxoacetate in the presence of a base, said base being triethylamine; hydrolysis of one or more methoxyoxoacetamide substituents to -NHC(O)C(O)OH substituents by reacting a compound containing N-methoxyoxoacetamide substituents with a base, said base being LiOH; hydrolysis of one or more methyl oxalate substituents to -OH substituents by reacting a compound containing said methyl oxalate substituents with a base, said base being LiOH; conversion of one or more -NH2 substituents to guanidine (-NHC(NH)NH2) substituents by reacting a compound containing said NH2 substituents with cyanamide in the presence of an acid, said acid being p-toluenesulfonic acid; conversion of one or more -NH2 substituents to formamide (-NHC(O)H) substituents by reacting the compound containing said NH2 substituents with ethyl formate; conversion of one or more -NH 2 substituents to acetamide (-NHC(O)CH 3 ) substituents by reacting a compound containing said NH 2 substituents with acetic anhydride in the presence of a base, said base being DIPEA (diisopropylethylamine); conversion of one or more -NH 2 substituents to an amide derivative (-NHC(O)CH 2 CH 2 C(O)OH) substituent by reacting the compound containing said NH 2 substituents with succinic anhydride in the presence of a base, said base being DIPEA (diisopropylethylamine); conversion of one or more -NH2 substituents to a methylamine substituent (-NHMe) by reacting the compound containing said -NH2 substituents with formaldehyde in the presence of triacetoxyborohydride; conversion of one or more -OH substituents to acetate (-OC(O)CH 3 ) substituents by reacting a compound containing said substituents with acetic anhydride in the presence of a base, said base being DIPEA (diisopropylethylamine); hydrolysis of one or more acetate substituents to form -OH substituents by reacting a compound containing said acetate substituents with a base, said base being LiOH; reduction of one or more -NO 2 substituents to an amine substituent by reacting the compound containing said -NO 2 substituents with Zn in the presence of ammonium chloride; 16. The method of claim 15, wherein the reaction is further reacted with one or more of the following:

17. The compound according to formula (II) 【Chemistry 4】 (In the formula, R ２ｂ =OMe, R ２ｄ = OSEM, R ２ｃ = H, Hal is Br; The compound according to formula (III) 【Chemistry 6】 (In the formula, R ３ｇ = H, R ３ｆ = OSEM, R ３ｅ =OMe, R ４ = Et); The compound according to formula (IV) 【Chemistry 8】 (In the formula, R ４ｂ =OMe, R ４ｃ = H, R ４ｄ = OSEM, R ４ｇ = H, R ４ｅ =OMe, R ４ｆ = OSEM, 17. The method of claim 1, wherein Hal=Br.

18. Formula (II) is module A, formula (III) is module B, and formula (IV) is module C according to the following: 【Chemistry 10】 According to the following: i) coupling of module C with 3-methylbut-2-enylboronic acid pinacol ester in the presence of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to give compound 1.1; 20. The method of claim 17, wherein compound 1.1 is treated with tetrabutylammonium fluoride to give compound 1. 【Chemistry 11】

19. Formula (I) 【Chemistry 13】 (In the formula, R １ａ is allyl, crotyl, prenyl, or benzyl; R １ｂ CF ３ , OR ２ , or N.H.R. ３ and R １ｃ is H, R １ｄ OH, NO ２ , or N.H.R. ３ and R １ｅ is H, C １ ~C ６ Alkyl, OH, OR ２ , NO ２ , N.H.R. ３ , NMeR ３ , or S.R. ２ and R １ｆ H, OH, NO ２ , N.H.R. ３ ,NHC=NH(NH ２ ), COOH, or N(OH)(CO)CH ３ and R １ｇ is H, C １ ~C ６ Alkyl, OH, or OR ２ and R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR ４ or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of R ３ is H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , CO(CH ２ ) ｎ N.H. ２ , C.O.N.H. ２ , CO(CH ２ ) ｎ COOH or COCOOR ４ (n=0, 1 or 2), R ４ is C １ ~C ６ is alkyl, R 1e , R １ｆ Or R １ｇ can be H, R １ｅ But, OH, NH ２ or NHMe, R １ｆ NH ２ When R 1e and R 1f are joined to form a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group, then R １ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ through the R １ｅ is bridged to oxygen or nitrogen, however, (i) R １ａ is prenyl, R １ｄ is OH, R １ｆ is OH, R １ｇ is H, and R １ｅ When is OH, OR2, R １ｂ cannot be OR2, where R2=methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; (ii) R 1a is prenyl, R 1d is OH, R 1f is OH, R 1e is H, R 1g is OH, then R 1b cannot be OR 2 if OR 2 is R 2 =methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; (iii) R １ｂ and R １ｄ are not the same) Compound.

20. 20. The compound of claim 19, wherein the compound of formula (I) is a compound selected from the group consisting of the following compounds: 【Chemistry 102-1】 【Chemistry 102-2】 【Chemistry 102-3】 【Chemistry 102-4】 【Chemistry 102-5】

21. R １ａ is allyl, crotyl, prenyl, or benzyl; R １ｂ CF ３ , OR ２ , or N.H.R. ３ and R １ｃ is H, R １ｄ OH, NO ２ , or N.H.R. ３ and R １ｂ and R １ｄ is not the same, R １ｅ is C １ ~C ６ Alkyl, OH, OR ２ , NO ２ , N.H.R. ３ , or S.R. ２ and R １ｆ H, OH, NO ２ , N.H.R. ３ ,NHC=NH(NH ２ ), or COOH, R １ｇ is H, C １ ~C ６ Alkyl, OH, or OR ２ and R １ｂ Or R １ｄ At least one of the following is CF ３ , NO ２ , or N.H.R. ３ and R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR ４ or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of R ３ is H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , CO(CH ２ ) ｎ N.H. ２ , C.O.N.H. ２ , CO(CH ２ ) ｎ COOH or COCOOR ４ (n=0, 1 or 2), R ４ is C １ ~C ６ is alkyl, R １ｆ Or R １ｇ can be H, Or R １ｅ But, OH, NH ２ or NHMe, R １ｆ NH ２ When R 1e and R 1f are joined to form a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group, then R １ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ through the R １ｅ 20. The compound of claim 19, wherein the oxygen or nitrogen of

22. R １ａ is allyl, crotyl, prenyl, or benzyl; R １ｂ CF ３ , OR ２ , or N.H.R. ３ and R １ｃ is H, R １ｄ OH, NHR ３ , or NO ２ and R １ｂ and R １ｄ is not the same, R １ｅ is OH or OR ２ and R １ｆ No. ２ , N.H.R. ３ ,NHC=NH(NH ２ ), or COOH, R １ｇ is H, R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of R ３ is H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , COCH ２ N.H. ２ , C.O.N.H. ２ , CO(CH ２ ) ｎ COOH, or CO(CH ２ ) ｎ COOR ４ (n=0, 1 or 2), R ４ is C １ ~C ６ is alkyl, Or R １ｅ But, OH, NH ２ or NHMe, R １ｆ NH ２ When R 1e and R 1f are joined to form a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group, then R １ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ via the R １ｅ 20. The compound of claim 19, wherein the oxygen or nitrogen of

23. R １ａ is allyl, crotyl, prenyl, or benzyl; R １ｂ CF ３ , OR ２ , or N.H.R. ３ and R １ｃ is H, R １ｄ OH, NHR ３ , or NO ２ and R １ｂ and R １ｄ is not the same, R １ｅ is C １ ~C ６ Alkyl, NO ２ , N.H.R. ３ , or S.R. ２ and R １ｆ is OH or OR ２ and R １ｇ is H, R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of R ３ is H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , COCH ２ N.H. ２ , C.O.N.H. ２ , CO(CH ２ ) ｎ 20. The compound of claim 19, wherein n is COOH (n=0, 1 or 2).

24. R １ａ is allyl, crotyl, or benzyl; R １ｂ CF ３ , OR ２ , or N.H.R. ３ and R １ｃ is H, R １ｄ OH, NHR ３ , or NO ２ and R １ｂ and R １ｄ is not the same, R １ｅ , OH, OR ２ , NO ２ NHR ３ , or S.R. ２ and R １ｆ H, OH, NO ２ , N.H.R. ３ ,NHC=NH(NH ２ ), or COOH, R １ｇ is H, C １ ~C ６ Alkyl, OH or OR ２ and R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, C(O)C(O)OR ４ or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of R ３ is H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , COCH ２ N.H. ２ , C.O.N.H. ２ , CO(CH ２ ) ｎ COOH (n=0, 1 or 2); R ４ is C １ ~C ６ is alkyl, R １ｆ Or R １ｇ can be H, Or R １ｅ But, OH, NH ２ or NHMe, R １ｆ NH ２ When R 1e and R 1f are joined to form a 5- or 6-membered heterocyclic ring containing a carbonyl group or a (CO)CH 2 group, then R １ｆ The nitrogen atom of the carbonyl group or (CO)CH ２ group and R １ｅ 20. The compound of claim 19, wherein the oxygen or nitrogen of

25. R １ａ is prenyl, R １ｂ OR ２ and R １ｃ is H, R １ｄ is OH, R １ｅ OR ２ and R １ｆ However, N.H.R. ３ or NHC=NH(NH ２ ) and R １ｇ is H, R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; R ３ But, H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOR ２ , COCH ２ N.H. ２ , CO(CH ２ ) ｎ 20. A compound of formula (I) according to claim 19, which is COOH (wherein n=0, 1 or 2).

26. R １ａ is prenyl, R １ｂ OR ２ and R １ｃ is H, R １ｄ is OH, R １ｅ OR ２ and R １ｆ is OH, R １ｇ is C 1 -C 6 alkyl, OH; R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; 20. The compound of formula (I) according to claim 19, wherein alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl.

27. R １ａ is allyl, crotyl, prenyl, or benzyl; R １ｂ CF ３ , OR ２ , or N.H.R. ３ and R １ｃ is H, R １ｄ OH, NO ２ , or N.H.R. ３ and R １ｂ and R １ｄ is not the same, R １ｅ is C １ ~C ６ Alkyl, OH, OR ２ , NO ２ , N.H.R. ３ , or S.R. ２ and R １ｆ H, OH, NO ２ , N.H.R. ３ ,NHC=NH(NH ２ ), or COOH, R １ｇ is H, C １ ~C ６ Alkyl, OH or OR ２ and R ２ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, trifluoromethyl, COCOOR ４ or R ２ is an O-protecting group, and the O-protecting group is selected from the group consisting of COMe, t-BuSi(CH ３ ) ２ , 2-(trimethylsilyl)ethoxy]methyl (SEM), CH(OEt)CH ３ , tetrahydropyranyl or C(OEt)(CH ３ ) ２ is selected from the group consisting of R ３ But, H, CH ３ , OH, (CO)H, (CO)Me, SO ２ Me, C.H. ２ COOH, CH ２ COOR ２ , CO(CH ２ ) ｎ N.H. ２ , C.O.N.H. ２ , CO(CH ２ ) ｎ COOH or COCOOR ４ (n=0, 1 or 2), R ４ But, C １ ~C ６ is alkyl, R １ｆ Or R １ｇ can be H, R １ｅ Or R １ｆ 20. The compound of claim 19, wherein at least one of is -NHC(O)H or NHC(O)Me.

28. The compound below. 【Chemistry 103】

29. The compound below. 【Chemistry 104】

30. 30. A medicament or pharmaceutical composition comprising a compound, or a pharma- ceutically acceptable salt, or solvate, according to any one of claims 19 to 29 for the treatment of cancer or skin diseases and / or disorders.

31. the cancer is skin cancer, melanoma, leukemia, CNS cancer, ovarian cancer, renal cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, colon cancer, breast cancer, lung cancer, liver cancer, brain tumor, glioblastoma, osteosarcoma cell cancer; selected from the group consisting of bone Ewing's sarcoma, muscle Ewing's sarcoma, fibrosarcoma, hypopharyngeal cancer, pharynx cancer, leiomyosarcoma, liposarcoma, connective tissue sarcoma, osteosarcoma, rhabomyosarcoma, tongue cancer, tongue SCC, base of tongue SCC, pharyngeal SCC, hypopharyngeal SCC, pharyngeal cancer, and neuroblastoma; 31. A pharmaceutical agent or pharmaceutical composition according to claim 30.

32. The skin disease and / or disorder is selected from the group consisting of atopic dermatitis and psoriasis.

31. A pharmaceutical agent or pharmaceutical composition according to claim 30.

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