Compounds and Related Compositions and Methods of Use

Claim of Priority

This application claims priority from U.S. S.N. 61/510,189, filed July 21, 2011 which is incorporated herein by reference in its entirety.

Background

Migrastatin is a 14-membered ring macrolide natural product that was first isolated from a cultured broth of Steptomyces sp. MK929-43F1. Migrastatin and related compounds have been shown to inhibit migration and anchorage-independent growth of human tumor cells. Specifically, migration of tumor cells is part of the process of metastasis, which is a leading cause of death in cancer patients. Therefore, Migrastatin, derivatives thereof, and related compounds could be useful as therapeutic agents in the treatment of cancer. Summary of the invention

Described herein are acyclic compounds of formula (I), compositions comprising a compound of formula (I), and methods of using these compounds and compositions. In some embodiments, the compounds can inhibit cell migration, and be useful, for example, in the treatment of cancer.

In one aspect, the invention features a compound having formula (I), shown below.

formula (I),

wherein

n and m are each independently 0, 1, 2, 3 or 4;

X ¹ is -0-, -NR. ⁷ -, -CR ^9a R ^9b -, -C(0)-NR ⁷ - or -NR ⁷ -C(0)

X ² is a bond, -0-, -NR ¹¹ -, -C(0)-NR ⁿ -, -NR ⁿ -C(0)-or

R ¹ is halo, C _1-6 alkyl or C _1-6 alkoxy;

R ^a and R are each independently hydrogen or Ci_ ₆ alkyl; each R ^a and R are independently hydrogen, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy;

R ⁶ is hydrogen, amino, amido, C _1-10 alkyl, C _1-10 alkenyl, C _1-6 alkoxy, aryl, aralkyl,

g

heteroaryl or heteroaralkyl, each of which is substituted with 0-4 R ;

R is hydrogen, Ci_ ₆ alkyl, acyl, aryl or aralkyl;

g

each R is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, amino, amido, C _1-6 alkoxy, aryl or heteoraryl;

R ^9a and R ^9b are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo, amino, amido, aryl or heteroaryl;

R ¹⁰ is hydrogen or Ci_ ₆ alkyl; and

R ¹¹ is hydrogen, C _1-6 alkyl, acyl, aryl or aralkyl.

In one aspect, the invention features a composition comprising a compound of formula

(I).

In one aspect, the invention features a method of treating a subject, e.g., a method of treating cancer, comprising administering to the subject a compound of formula (I) or a composition comprising a compound of formula (I).

In one aspect, the invention features a kit comprising a compound of formula (I) or a composition comprising a compound of formula (I).

Detailed Description of the Invention

Definitions:

The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C _\ -Cu alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, and 3- phenylpropyl. The terms "heteroarylalkyl" or "heteroaralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by a heteroaryl group. Heteroaralkyl includes groups in which more than one hydrogen atom is replaced by a heteroaryl group. Examples or "heteroarylalkyl" or "heteroaralkyl" include methyl-3-pyridyl and methyl-2-pyridyl.

The term "alkylene" refers to a divalent alkyl, e.g., -CH ₂ -, -CH ₂ CH ₂ -, and -CH ₂ CH ₂ CH ₂ -.

The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent. The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

The terms "alkylamino" and "dialkylamino" refer to -NH(alkyl) and -NH(alkyl) ₂ radicals respectively. The term "aralkylamino" refers to a -NH(aralkyl) radical. The term alkylaminoalkyl refers to a (alkyl)NH-alkyl- radical; the term dialkylaminoalkyl refers to a (alkyl) ₂ N-alkyl- radical The term "alkoxy" refers to an -O-alkyl radical. The term "mercapto" refers to an SH radical. The term "thioalkoxy" refers to an -S-alkyl radical. The term thioaryloxy refers to an -S- aryl radical.

The term "aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., by one or more substituents). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "cycloalkyl" as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). The cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl. The term "cycloalkylenyl" refers to a divalent cycloalkyl.

The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 14-membered non- aromatic ring structures (e.g., 3- to 10-membered rings, more preferably 3- to 7-membered rings), whose ring structures include one to four heteroatoms independently selected from O, N and S. The heterocyclyl or heterocyclic groups can contain fused or spiro rings. Heterocycles can also be polycycles, with each group having, e.g., 5-7 ring members. The term "heterocyclyl" or "heterocyclic group" includes saturated and partially saturated heterocyclyl structures.

The term "heteroaryl" refers to a 5-14 membered (i.e., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic) aromatic ring system having 1-3 ring heteroatoms if monocyclic, 1-6 ring heteroatoms if bicyclic, or 1-9 ring heteroatoms if tricyclic, said ring heteroatoms independently selected from O, N, and S (e.g., 1-3, 1-6, or 1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any substitutable ring atom can be substituted (e.g., by one or more substituents). Heterocyclyl and heteroaryl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic or heteroaryl ring can be substituted at one or more positions with such substituents as described herein, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The term "cycloalkenyl" refers to partially unsaturated, nonaromatic, cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 5 to 12 carbons, preferably 5 to 8 carbons. The unsaturated carbon may optionally be the point of attachment of the cycloalkenyl substituent. Any substitutable ring atom can be substituted (e.g., by one or more substituents). The cycloalkenyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkenyl moieties include, but are not limited to, cyclohexenyl, cyclohexadienyl, or norbornenyl.

The term "heterocycloalkenyl" refers to a partially saturated, nonaromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S (e.g., 1-3, 1-6, or 1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). The unsaturated carbon or the heteroatom may optionally be the point of attachment of the heterocycloalkenyl substituent. Any substitutable ring atom can be substituted (e.g., by one or more substituents). The heterocycloalkenyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of heterocycloalkenyl include but are not limited to

tetrahydropyridyl and dihydropyranyl.

The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl group substituted with a heteroaryl group. The ring heteroatoms of the compounds provided herein may be in the form of N-O, S(O), or S(0) ₂ .

The term "oxo" refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.

The term "acyl" refers to an alkylcarbonyl, alkoxycarbonyl,

cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted (e.g., by one or more substituents).

The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any substitutable atom of that group. Any substitutable atom can be substituted. Unless otherwise specified, such substituents include, without limitation, alkyl (e.g., CI, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cll, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g.,

perfluoroalkyl such as CF ₃ ), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF ₃ ), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl amino, S0 ₃ H, sulfate, phosphate, methylenedioxy (-O-CH ₂ -O- wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C=S), imino (alkyl, aryl, aralkyl), S(0) _n alkyl (where n is 0-2), S(0) _n aryl (where n is 0-2), S(0) _n heteroaryl (where n is 0-2), S(0) _n heterocyclyl (where n is 0- 2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof). In one aspect, the substituents on a group are independently any one single, or any subset of the aforementioned substituents. In another aspect, a substituent may itself be substituted with any one of the above substituents. Compounds:

Described herein are comp

formula (I),

wherein

n and m are each independently 0, 1, 2, 3 or 4;

X ¹ is -0-, -NR ⁷ -, -CR ^9a R ^9b -, -C(0)-NR ⁷ - or -NR ⁷ -C(0)-;

X ² is a bond, -0-, -NR ¹¹ -, -C(0)-NR ⁿ -, -NR ⁿ -C(0)-or -S-;

R ¹ is halo, Ci- ₆ alkyl or Ci_6 alkoxy;

R ^2a and R ^2b are each independently hydrogen or Ci_ ₆ alkyl;

each R ^4a and R ^4b are independently hydrogen, hydroxyl, Ci_6 alkyl or Ci_6 alkoxy;

R ⁶ is hydrogen, amino, amido, Ci_io alkyl, Ci_io alkenyl, Ci_ ₆ alkoxy, aryl, aralkyl, heteroaryl or heteroaralkyl, each of which is substituted with 0-4 R ;

R ⁷ is hydrogen, C _1-6 alkyl, acyl, aryl or aralkyl;

each R ⁸ is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, amino, amido, C _1-6 alkoxy, aryl or heteoraryl;

R ^9a and R ^9b are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo, amino, amido, aryl or heteroaryl;

R ¹⁰ is hydrogen or C _1-6 alkyl; and

R ¹¹ is hydrogen, C _1-6 alkyl, acyl, aryl or aralkyl.

In certain embodiments, R ¹ is C _1-6 alkyl (e.g., methyl).

In certain embodiments, one of R ^2a and R ^2b is hydrogen and the other is C _1-6 alkyl (e.g., methyl).

In certain embodiments, one of R ^4a and R ^4b is hydrogen and the other is C _1-6 alkoxy (e.g., methoxy).

In certain embodiments, R ¹⁰ is hydrogen. In certain embodiments, X is -0-. In some embodiments, X is -NR -. In some

1 7 1 7

embodiments, X is -NR -C(O)-. In some embodiments, X is -C(0)-NR -. In some

7 7

embodiments, R is hydrogen. In some embodiments, R is C _1-6 alkyl (e.g., methyl).

In certain embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

2 2

In certain embodiments, X is a bond. In some embodiments, X is -0-. In some

2 11 2 11

embodiments, X is -NR -. In some embodiments, X" is -NR -C(O)-. In some embodiments, X ² is -C(0)-R ⁿ -. In some embodiments, R ¹¹ is hydrogen. In some embodiments, R ¹¹ is Ci_ ₆ alkyl (e.g., methyl).

In certain embodiments, R ⁶ is C _1-10 alkyl substituted with 0-4 occurrences of R ⁸ . In some embodiments, R ⁶ is C _1-10 alkyl substituted with 0 occurrences of R ⁸ (e.g., methyl, ethyl, propyl or isobutyl).

In some embodiments, R ⁶ is C _1-10 alkenyl substituted with 0-4 occurrences of R ⁸ . In some embodiments, R ⁶ is C _1-10 alkenyl substituted with 0 occurrences of R ⁸ (e.g., 4-pentenyl, 3- butenyl or 2- propenyl). In some embodiments, R ⁶ is C _1-10 alkenyl substituted with 2

8 8 occurrences of R (e.g., 3,3-difluoro-6-heptenyl). In some embodiments, both R are halo (e.g., fluoro).

In certain embodiments, R ⁶ is aralkyl substituted with 0-4 occurrences of R ⁸ . In some embodiments, R ⁶ is aralkyl substituted with 0 occurrences of R ⁸ (e.g., benzyl). In some embodiments, R ⁶ is aralkyl substituted with 1 occurrence of R ⁸ (e.g., 4-chlorobenzyl). In some embodiments, R8 is halo (e.g., chloro).

In certain embodiments, R ⁶ is heteroaryl substituted with 0-4 occurrences of R ⁸ . In some embodiments, R ⁶ is heteroaryl substituted with 0 occurrences of R ⁸ (e.g., 2-pyrimidyl or 2- pyridyl). In some embodiments, R ⁶ is heteroaryl substituted with 1 occurrence of R ⁸ (e.g., 4- trifluoromethyl-2-pyrimidyl). In some embodiments R8 is haloalkyl (e.g., trifluoromethyl).

In certain embodiments, R ⁶ is heteroaralkyl substituted with 0-4 occurrences of R ⁸ . In some embodiments, R ⁶ is heteroaralkyl substituted with 0 occurrences of R ⁸ (e.g., methyl-2- pyrimidyl, methyl-2-pyridyl, methyl-4-pyrimidyl, methyl-2-pyrazinyl or methyl-2-thiazolyl). In some embodiments, R ⁶ is heteroaralkyl substituted with 1 occurrence of R ⁸ (e.g., 4- trifluoromethyl-(methyl-2-pyrimidyl), 4-methoxy-(methyl-2-pyrimidyl), 5-trifluoromethyl-(2-

Q

pyrimidyl) or 5-methoxy-(methyl-2-pyrimidyl)). In some embodiments, R is Ci_ ₆ alkoxy (e.g.,

Q

methoxy). In some embodiments, R is C _1-6 haloalkyl (e.g., trifluoromethyl). In certain embodiments, the compound of formula (I) is a compound of formula (la):

formula (la).

In certain embodiments, the compound is selected from the following:

In certain embodiments, the compound is selected from the following

Exemplary compounds are provided in Table 1 below.

Table 1.

*Activity is as measured in a cell migration assay. Numeric representation is depicted in nanomolar. + indicates the compound was active, but not quantified; ++ indicates the compound was very active, but not quantified, -/+ indicates the compound was marginally active, but not quantified; and - indicates the compound was not active. ND means the activity was not determined.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

Certain compounds disclosed herein may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. For example, if one chiral center is present in a molecule, the invention includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically pure compounds. The composition can contain, e.g., more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of a single enantiomer.

The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

ee = (90-10)/100 = 80%.

Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

Methods of preparing substantially isomerically pure compounds are known in the art. If, for instance, a particular enantiomer of a compound disclosed herein is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Alternatively, enantiomerically enriched mixtures and pure enantiomeric compounds can be prepared by using synthetic intermediates that are enantiomerically pure in combination with reactions that either leave the stereochemistry at a chiral center unchanged or result in its complete inversion. Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers are well known in the art, and it is well within the ability of one of skill in the art to choose an appropriate method for a particular situation. See, generally, Furniss et al. (eds.), Vogel's Encyclopedia of Practical Organic Chemistry 5 ^th Ed., Longman Scientific and Technical Ltd., Essex, 1991, pp. 809-816; and Heller, Acc. Chem. Res. 23: 128 (1990).

The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For example, deuterated compounds and compounds incorporating 13 C are intended to be encompassed within the scope of the invention.

Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming

pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term

"pharmaceutically acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds disclosed herein. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1- 19.)

In other cases, the compounds disclosed herein may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds disclosed herein. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine,

ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)

Methods of Making

The compounds described herein can be synthesized by conventional methods. As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those skilled in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein may be known in the art and include, for example, those described in R. Larock,

Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M.

Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons

(1995), and subsequent editions thereof.

The compounds described herein can be separated from a reaction mixture and further purified by methods such as column chromatography, high-pressure liquid chromatography, or recrystallization. Techniques useful for the separation of isomers, e.g., stereoisomers are within skill of the art and are described in Eliel E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of

Organic Compounds, Wiley Interscience, NY, 1994. Methods of use:

Described herein are methods of treating a subject having disorder associated with metastasis and/or increased angiogenic activity, such as cancer. For example, included herein are methods of inhibiting metastasis and/or the growth of tumor cells by administering to a subject a compound or composition described herein.

As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term "non-human animals" of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

Methods of treating cancer include administering a therapeutically effective amount of a compound of formula (I), as described herein, to a subject in need thereof. For example, a method for the treatment of cancer is can include administering a therapeutically effective amount of a compound described herein, or a pharmaceutical composition comprising an compound described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. Exemplary cancers include glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer). In an embodiment, a compound described herein can be used to treat ovarian cancer, for example, metastatic ovarian cancer.

As discussed above, the compounds of the present invention inhibit metastasis of tumor cells and/or inhibiting the growth of tumor cells. In general, the compounds are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer, to name a few. In certain embodiments, the compounds are active against leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) and malignant melanomas. In still other embodiments, the compounds are active against solid tumors. In certain exemplary embodiments, the compounds as useful for the treatment of ovarian cancer. In certain exemplary embodiments, the compounds as useful for the treatment of metastatic ovarian cancer. In another aspect, the present invention provides a method for the treatment for solid tumors.

In certain embodiments, the present invention provides a method for treating and/or preventing metastasis and/or proliferation of tumor cells in a subject comprising administering to a subject (including, but not limited to, a human or animal) in need thereof a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain exemplary embodiments, the method is used to treat and/or prevent metastasis and/or proliferation of prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer or lymphoma, leukemia, or multiple myeloma, to name a few. In preferred embodiments, the method is for treating and/or preventing ovarian and/or colon cancer. In preferred embodiments, the method is for treating and/or preventing metastatic ovarian and/or colon cancer.

In another aspect, the present invention provides methods for decreasing migration of tumor cells. In a further aspect, the present invention provides methods for decreasing anchorage-independent growth of tumor cells.

In yet a further aspect, the present invention provides methods for inhibiting

angiogenesis. In yet another aspect, the present invention provides methods for preventing unwanted angiogenesis in a subject (including, but not limited to, a human or animal). As used herein, the term "angiogenesis" means the generation of new blood vessels into a tissue or organ. Angiogenesis is prominent in solid tumor formation and metastasis. Angiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma. A tumor cannot expand without a blood supply to provide nutrients and remove cellular wastes. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas. Prevention of angiogenesis could halt the growth of these tumors and the resultant damage to the animal due to the presence of the tumor.

Angiogenesis has been associated with blood-born tumors such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.

Angiogenesis can be important in two stages of tumor metastasis. The first stage where angiogenesis stimulation is important is in the vascularization of the tumor which allows tumor cells to enter the blood stream and to circulate throughout the body. After the tumor cells have left the primary site, and have settled into the secondary, metastasis site, angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could lead to the prevention of metastasis of tumors and possibly contain the neoplastic growth at the primary site.

Thus, in certain embodiments, the invention provides a method for preventing unwanted angiogenesis in a subject (including, but not limited to, a human or animal) comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the invention in an amount effective to inhibit angiogenesis.

It will be appreciated that the compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with metastasis and/or angiogenesis. Thus, the expression "effective amount" as used herein, refers to a sufficient amount of agent to inhibit the growth of tumor cells, or refers to a sufficient amount to reduce the effects of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the diseases, the particular anticancer agent, its mode of administration, and the like.

Administration of compounds and formulations thereof

The compounds of the formulae described herein can, for example, be administered to a subject by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, e.g., between 0.001-lmg/kg, 1-lOOmg/kg, or 0.01-5mg/kg, every 4 to 120 hours, e.g., about every 6, 8, 12, 24, 48, or 72 hours, or according to the requirements of the particular compound. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect (e.g., reduction of feeding in a subject). Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day, for example, the compounds can be administered about 1 to about 4 (e.g., 1, 2, 3, or 4) hours prior to meal time. Alternatively, the compounds can be administered as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional compound including for example, a steroid or an analgesic; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. The compositions delineated herein include the compounds of the formulae delineated herein, as well as additional therapeutic compounds if present, in amounts effective for achieving a modulation of disease or disease symptoms, including kinase mediated disorders or symptoms thereof. The compositions are made by methods including the steps of combining one or more compounds delineated herein with one or more carriers and, optionally, one or more additional therapeutic compounds delineated herein.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase which can be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Cyclodextrins such as α -, β-, and γ-cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional compound should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. Additionally, combinations of a plurality of compounds described herein are also envisioned. The additional compounds may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those compounds may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

Dosages:

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound disclosed herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventncular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments, the dose will be 1-20, or 5-10 mg per kilogram of body weight, administed twice daily. Kits:

A compound described herein can be provided in a kit. The kit includes (a) a composition that includes a compound described herein, and, optionally (b) informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compound described herein for the methods described herein.

The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to use of the compound described herein to treat a disorder described herein.

In one embodiment, the informational material can include instructions to administer the compound described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein). Preferred doses, dosage forms, or modes of administration are parenteral, e.g., intravenous, intramuscular, subcutaneous, intraparenteral, bucosal, sublingual, intraoccular, and topical. In another embodiment, the informational material can include instructions to administer the compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein. For example, the material can include instructions to administer the compound described herein to such a subject.

The informational material of the kits is not limited in its form. In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about an compound described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

In addition to a compound described herein, the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, and/or a second compound for treating a condition or disorder described herein. Alternatively, the other ingredients can be included in the kit, but in different compositions or containers than the compound described herein. In such embodiments, the kit can include instructions for admixing the compound described herein and the other ingredients, or for using a compound described herein together with the other ingredients.

The compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that the compound described herein be substantially pure and/or sterile. When the compound described herein is provided in a liquid solution, the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred. When the compound described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent. The solvent, e.g., sterile water or buffer, can optionally be provided in the kit.

The kit can include one or more containers for the composition containing the compound described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein. For example, the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.

The kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device. In a preferred embodiment, the device is an implantable delivery device. Examples

Example 1. Synthesis of acyclic compounds. Scheme 1:

Int-13 1 THC-039

Tert-butyl(((3S,4S,5R,Z)-3,8-dimethoxy-5,7-dimethylocta-l ,6-dien-4-yl)oxy)dimethylsilane (2):

To a stirred solution of NaH (11 mg, 0.46 mmol, 60% dispersion in mineral oil) in DMF (1 mL), cooled to 0°C, Int-13 (0.1 g, 0.31 mmol) dissolved in DMF (1.0 mL) was slowly added. The reaction was slowly warmed to RT, stirred for 15 min and Mel (67 mg, 0.46 mmol) was added to the reaction mixture and continued for another 30 min. After consumption of the starting material (by TLC), the reaction was quenched with cold water (7 mL) and the aqueous layer was extracted with Et ₂ 0 (2 x 15 mL). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1 : 19) to afford compound 1 (0.1 g, 96%) as an oil.

TLC: 10% EtOAc/Hexane (R _f : 0.8)

1H NMR (500MHz, CDC1 ₃ ): δ 5.67-5.60 (m, 1H), 5.39 (d, J = 9.5 Hz, 1H), 5.27 (t, J = 11.5 Hz, 2H), 3.91 (d, J = 11.0 Hz, 1H), 3.84 (d, J = 11.0 Hz, 1H), 3.45-3.34 (m, 2H), 3.23 (d, J = 26.0 Hz, 6H), 2.64-2.60 (m, 1H), 1.72 (s, 3H), 1.26 (s, 3H), 0.91 (s, 9H), 0.01 (t, J = 12.5 Hz, 6H). Mass (ESI): 329.5 (M ⁺ +l).

(3S, 4S, 5R, Z)-3, 8-dimethoxy-5, 7-dimethylocta-l, 6-dien-4-ol (THC-039):

To a stirred solution of compound 1 (0.15 g, 0.45 mmol) in CH ₂ C1 ₂ (2 mL), cooled to

0°C, HC1 inl,4-dioxane (1 mL) was added. The reaction mixture was warmed to RT and stirred for 5 h. The volatiles from the reaction mixture were removed under reduced pressure and the crude material was purified by silica gel column chromatography (EtOAc/Hexane 1:9) to afford THC-039 (60 mg, 62%) as syrup.

TLC: 20% EtOAc/Hexane (R _f : 0.4) 1H NMR (500MHz, CDC1 ₃ ): δ 5.77-5.70 (m, 1H), 5.34-5.30 (m, 3H), 3.94 (d, J = 11.5 Hz, 1H), 3.88 (d, J = 11 Hz, 1H), 3.51-3.48 (m, 1H), 3.31-3.26 (m, 7H), 2.72-2.67 (m, 1H), 2.36 (d, J = 5.5 Hz, 1H), 1.76 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H).

Mass (ESI): 215 (M ⁺ +l).

Scheme 2:

Tert-butyl (((3S, 4S, 5R, Z)-3-methoxy-5, 7 -dimethyl- 8 -propoxyocta-1, 6-dien-4-yl) oxy) dimethyl silane (3):

To a stirred solution of NaH (9 mg, 0.38 mmol, 60% dispersion in mineral oil) in DMF (2 mL), cooled to 0°C, lnt-13 (0.1 g, 0.31 mmol) was added slowly and stirred for 20 min. 1- Bromopropane (2) (0.05 g, 0.38 mmol) was added to the reaction mixture and stirred at RT for another 2 h. The reaction was quenched with cold water (15 mL) and the aqueous layer was extracted with 77-hexane (2 x 15 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material was purified by silica gel column chromatography (EtOAc/Hexane 3:97) to afford compound 3 (70 mg, 62%) as liquid.

TLC: 10% EtOAc/Hexane (R _f : 0.55)

1H NMR (500MHz, CDC1 ₃ ): δ 5.66-5.59 (m, 1H), 5.38-5.23 (m, 3H), 3.96 (d, J = 11.5 Hz, 1H), 3.87 (d, J = 11.5 Hz, 1H), 3.45-3.36 (m, 2H), 3.30-3.27 (m, 2H), 3.20 (s, 3H), 2.63-2.60 (m, 1H), 1.72 (s, 3H), 1.61-1.55 (m, 3H), 0.93-0.89 (m, 14H), 0.01 (t, J = 11.5 Hz, 6H).

Mass (ESI): 358.1 (M ⁺ +2).

(3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-propoxyocta-l, 6-dien-4-ol (THC-040):

To a stirred solution of compound 3 (70 mg, 0.2 mmol) in CH ₂ CI ₂ (2 mL), cooled to 0°C,

HC1 inl,4-dioxane (2 mL) was added slowly. The reaction mixture was warmed to RT and stirred for 2 h. The volatiles from the reaction mixture were removed under reduced pressure to obtain the crude material which was purified by silica gel column chromatography (EtOAc/hexane 3: 17) to afford THC-040 (30.05 mg, 64%) as syrup.

TLC: 10% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 5.76-5.69 (m, 1H), 5.33-5.27 (m, 3H), 3.99 (d, J = 11 Hz, 1H), 3.91 (d, J = 11.5 Hz, 1H), 3.51-3.48 (m, 1H), 3.32-3.29 (m, 2H), 3.26-3.22 (s, 4H), 2.72-2.67 (m, 1H), 2.36 (s, 1H), 1.76 (s, 3H), 1.61-1.53 (m, 2H), 1.00 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 8.0 Hz, 3H).

Mass (ESI): 243 (M ⁺ +l).

Scheme 3:

Tert-butyl (((3S, 4S, 5R, Z)-8-isobutoxy-3-methoxy-5, 7-dimethylocta-l , 6-dien-4-yl) oxy) dimethyl silane (5):

To a stirred solution of lnt-13 (0.1 g, 0.31 mmol) in DMF (10 mL), cooled to 0°C, NaH

(9 mg, 0.38 mmol, 60% dispersion in mineral oil) was added portion-wise and stirred for 15 min. 1 -bromo-2-methylpropane (2) (0.05 g, 0.38 mmol) was added drop wise maintaining the temperature at 0°C and stirred for 30 min. The reaction was slowly warmed to RT and the stirred for another 2 h, quenched with cold water (15 mL) and the aqueous layer was extracted with n- hexane (2 x 15 mL). The combined organic extracts were dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 7:93) to afford compound 5 (65 mg, 55%) as an oil. TLC: 10% EtOAc/Hexane (R _f : 0.6)

1H NMR (500MHz, CDC1 ₃ ): δ 5.66-5.59 (m, 1H), 5.36 (d, J = 9.5 Hz, 1H), 5.28 (t, J = 10.5 Hz, 2H), 3.95 (d, J = 11.5 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.44-3.35 (m, 2H), 3.20 (s, 3H), 3.11- 3.05 (m, 2H), 2.63-2.59 (m, 1H), 1.86-1.81 (m, 1H), 1.72 (s, 3H), 0.89 (s, 18H), 0.01 (t, J = 10.5 Hz, 6H). Mass (ESI): 371 (M ⁺ +l).

(3S, 4S, 5R, Z)-8-isobutoxy-3-methoxy-5, 7-dimethylocta-l, 6-dien-4-ol (THC-041):

To a stirred solution of compound 5 (65 mg, 0.17 mmol) in CH ₂ CI ₂ (5 mL), cooled to 0°C, HC1 inl,4-dioxane (5 mL) was added slowly. The reaction mixture was slowly warmed to RT and stirred for 1 h. After consumption of the starting material (by TLC), the volatiles from the reaction mixture were removed under reduced pressure and the crude residue was purified by silica gel column chromatography (EtOAc/Hexane 3: 17) to afford THC-041 (26.9 mg, 60%) as a syrup.

TLC: 20% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 5.76-5.69 (m, 1H), 5.34-5.26 (m, 3H), 3.98 (d, J = 11.5 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.50-2.30 (m, 1H), 3.30-3.22 (m, 4H), 3.11 (d, J = 6.0 Hz, 2H), 2.71- 2.67 (m, 1H), 2.36 (d, J = 4.5 Hz, 1H), 1.87-1.82 (m, 1H), 1.76 (s, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.90 (d, .7 = 6.5 Hz, 6H).

Mass (ESI): 257 (M ⁺ +l).

Scheme 4:

(((3S, 4S, 5R, Z)-8-(benzyloxy)-3-methoxy-5, 7-dimethylocta-l, 6-dien-4-yl) oxy) (tert-butyl) dimethyl silane (7):

To a stirred solution of NaH (14.9 mg, 0.58 mmol, 60% dispersion in mineral oil) in THF (1 mL) Benzyl alcohol (6) (47 mg, 0.43 mmol) was slowly added at rt and stirred for 1 h. A solution of compound Int-13 (0.15 g, 0.39 mmol) dissolved in THF (1 mL) was added to the reaction mixture and stirred at RT for another 1 h. The reaction was quenched with cold water (25 mL) and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1: 19) to afford compound 7 (0.15 g, 93%) as a colourless oil.

TLC: 10% EtOAc/Hexane (R _f : 0.8)

1H NMR (500MHz, CDC1 ₃ ): δ 7.36-7.26 (m, 5H), 5.55-5.47 (m, 1H), 5.41 (d, J = 9.5 Hz, 1H), 5.21 (d, J = 12.0 Hz, 2H), 4.45 (t, J = 12.0 Hz, 2H), 4.02 (d, J = 11.0 Hz, 1H), 3.93 (d, J = 12.0 Hz, 1H), 3.43-3.33 (m, 2H), 3.19 (s, 3H), 2.56-2.53 (m, 1H), 1.78 (s, 3H), 1.26 (s, 3H), 0.91 (s, 9H), 0.04 (d, J = 14.0 Hz, 6H).

Mass (ESI): 405.6 (M ⁺ +l).

HPLC (purity): 97.47%

(3S, 4S, 5R, Z)-8-(benzyloxy)-3-methoxy-5, 7-dimethylocta-l, 6-dien-4-ol (THC-042):

To a stirred solution of compound 7 (0.12 g, 0.29 mmol) in dry CH ₂ C1 ₂ (2 mL), 4M HC1 in 1,4-dioxane (2 mL) was added and stirred for 5 h (monitored by TLC). The volatiles from the reaction were removed under reduced pressure to provide the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1 :19) to furnish THC-042 (30 mg, 37.5%) as syrup.

TLC: 10% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 7.34 (s, 4H), 7.29-7.25 (m, 1H), 5.70-5.62 (m, 1H), 5.35-5.23 (m, 3H), 4.46 (t, J = 11.5 Hz, 2H), 4.05 (d, J = 11.0 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.48-3.46 (m, 1H), 3.24-3.21 (m, 3H), 2.66-2.62 (m, 1H), 2.35 (s, 1H), 1.81 (s, 3H), 1.00 (d, J = 6.0 Hz, 3H). Mass (ESI): 291 (M ⁺ +l).

HPLC (purity): 96.56% Scheme 5:

lnt-13 9 THC-043

- ₃ i - Tert-butyl (((3S, 4S, 5R, Z)-8-((4-chlorobenzyl) oxy)-3-methoxy-5, 7-dimethylocta-l, 6-dien-4- yl) oxy) dimethyl silane (9):

To a stirred solution of NaH (28 mg, 0.716 mmol) in DMF (1.5 mL), cooled to 0°C, Int- 13 (150 mg, 0.48 mmol) was slowly added. The reaction mixture was slowly allowed to warm to RT and l-(Bromomethyl)-4-chlorobenzene (8) (107 mg, 0.52 mmol) was added and stirred at RT for further 2 h. After consumption of the starting material (by TLC), the reaction mixture was diluted water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3: 17) to furnish compound 9 (0.12 g, 57.4%) as syrup.

TLC: 20% EtOAc/Hexane (R _f : 0.15)

1H NMR (500MHz, CDC1 ₃ ): δ 7.31 (d, J = 8.0 Hz, 4H), 5.52-5.40 (m, 2H), 5.23-5.19 (m, 2H),

4.41 (q, J = 12.5 Hz, 2H), 3.99 (d, J = 11.5 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.41-3.32 (m, 2H), 3.18 (s, 3H), 2.52-2.49 (m, 1H), 1.76 (s, 3H), 0.89 (d, J = 6.5 Hz, 12H), 0.01 (d, J = 7.0 Hz, 6H).

Mass (ESI): 439 (M ⁺ +l).

(3S, 4S, 5R, Z)-8-((4-chlorobenzyl) oxy)-3-methoxy-5, 7-dimethylocta-l, 6-dien-4-ol (THC- 043):

To a solution of compound 9 (0.1 g, 0.22 mmol) in dry CH ₂ C1 ₂ (1 mL), cooled to 0°C,

HC1 in 1,4-dioxane (1 mL) was slowly added. The reaction mixture was warmed to RT and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was diluted water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the crude material which was purified by silica gel column chromatography

(EtOAc/Hexane 1:4) to afford THC-043 (70 mg, 95.8%) as syrup.

TLC: 25% EtOAc/Hexane (R _f : 0.15)

1H NMR (500MHz, CDC1 ₃ ): δ 7.31 (d, J = 8.0 Hz, 4H), 5.67-5.61 (m, 1H), 5.36-5.24 (m, 3H),

4.42 (m, 2H), 4.04 (d, J = 11.0 Hz, 1H), 3.95 (d, J = 11.0 Hz, 1H), 3.48-3.45 (m, 1H), 3.24-3.21 (m, 4H), 2.62-2.60 (m, 1H), 1.80 (s, 3H), 0.99 (d, J = 6.5 Hz, 3H).

Mass (ESI): 325 (M ⁺ +l).

HPLC (purity): 97.61% cheme 6:

Methyl pyrimidine-2-carboxylate (11):

A stirred solution of cyano 10 (1.01 g, 9.52 mmol) in methanolic HC1 (20 mL, 4N solution) was refluxed for 16 h and concentrated under reduced pressure; the residue was diluted with water and neutralized with sodium bicarbonate solution. The aqueous layer was extracted with 20% IPA/CH ₂ CI ₂ , dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford ester 11 (0.43 g, 32.5%) as liquid.

TLC: 100% EtOAc (R _f : 0.1)

1H NMR (500MHz, CDC1 ₃ ): δ 8.96 (d, J = 5.0 Hz, 2H), 7.50 (t, J = 5.0 Hz, 1H), 4.08 (s, 3H). Mass (ESI): 139 (M ⁺ +l). Pyrimidin-2-ylmethanol (12):

To a stirred solution of ester 11 (0.43 g, 3.09 mmol) in EtOH (30 mL), cooled to 0°C, NaBH ₄ (0.114 g, 3.09 mmol) was added and stirred for 2 h. After consumption of the starting material (by TLC), the reaction was quenched with cold water and concentrated under vacuo to give the crude material which was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ 1 :49) to afford alcohol 12 (0.145 g, 37%) as syrup.

TLC: 10% MeOH/CHCl ₃ (R _f : 0.3)

1H NMR (500MHz, CDC1 ₃ ): δ 8.75 (d, J = 5.5 Hz, 2H), 7.26-7.22 (m, 1H), 4.85 (s, 2H).

Mass (ESI): 111.1 [M ⁺ +l]. 2-((((4R, 5S, 6S, Z)-5-((i<?ri-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l- yl) oxy) methyl) pyrimidine (13): To a stirred solution of alcohol 12 (55 mg, 0.5 mmol) in DMF (3 mL) at 0°C, NaH (12 mg, 0.5 mmol) was added and stirred for 20 min. The reaction mixture was warmed to RT, further stirred for 20 min and Int-14 (150 mg, 0.4 mmol) was added maintaining the temperature at 0°C. The reaction was slowly brought to RT and continued for another 2 h. After consumption of the starting material (by TLC), the reaction was quenched with ice cold water and extracted with Et ₂ 0 (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (MeOH/CH ₂ Cl ₂ 1 : 19) to afford compound 13 (100 mg, 49%) as an oil.

TLC: 5% MeOH/CH ₂ Cl ₂ (R _f : 0.35)

1H NMR (500MHz, CDC1 ₃ ): δ 8.75 (d, J = 4.5 Hz, 2H), 7.21 (t, J = 5.5 Hz, 1H), 5.60-5.52 (m, 1H), 5.45 (d, J = 10.0 Hz, 1H), 5.23-5.20 (m, 2H), 4.65 (q, J = 14.5 Hz, 2H), 4.25 (d, J = 11.5 Hz, 1H), 4.12 (d, 7 = 11.5 Hz, 1H), 3.44-3.42 (m, 1H), 3.35 (t, J = 8.0 Hz, 1H), 3.18 (s, 3H), 2.61-2.58 (m, 1H), 1.79 (s, 3H), 0.90 (s, 12H), 0.04 (d, J = 14.0 Hz, 6H).

Mass (ESI): 407 (M ⁺ +l).

(3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-(pyrimidin-2-ylmethoxy) octa-1 , 6-dien-4-ol (THC- 044):

To a stirred solution of compound 13 (100 mg, 0.24 mmol) in THF (10 mL), cooled to 0°C, TBAF (0.436 mL, 0.48 mmol, 1M solution in THF) was added and stirred for 50 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure to provide the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 4: 1) to furnish THC-044 (45.6 mg, 64%) as liquid.

TLC: 50% EtOAc/Hexane (R _f : 0.1)

1H NMR (500MHz, CDC1 ₃ ): δ 8.75 (d, J = 5.0 Hz, 2H), 7.21 (t, J = 5.0 Hz, 1H), 5.73-5.66 (m, 1H), 5.38 (d, J = 10.0 Hz, 1H), 5.30-5.25 (m, 2H), 4.66 (q, J = 11.0 Hz, 2H), 4.28 (d, J = 12.0 Hz, 1H), 4.16 (d, J = 12.0 Hz, 1H), 3.49-3.47 (m, 1H), 3.25 (s, 4H), 2.71-2.66 (m, 1H), 2.36 (d, J = 5.0 Hz, 1H), 1.83 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H).

LC-MS: m/z = 293.3 (M ⁺ +l) at 3.60 RT (98.517% purity).

HPLC (purity): 99.86 Scheme 7:

lnt-13 15 THC-045

(9R, 10S, Z)-10-((S)-l-methoxyallyl)-7, 9, 12, 12, 13, 13-hexamethyl-2, 5, l l-trioxa-12- silatetradec-7-ene (15):

To a stirred solution of NaH (19 mg, 0.48 mmol, 60% dispersion in mineral oil) in dry DMF (1 mL) at 0°C, lnt-13 (100 mg, 0.32 mmol) taken in anhydrous DMF (1 mL) was slowly added. The reaction mixture was allowed to warm to RT and compound 14 (0.033 mL, 0.35 mmol) was added slowly and continued for further 2 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1 :9) to give compound 15 (100 mg, 84.7%) as syrup.

TLC: 20% EtOAc/Hexane (R _f : 0.15)

1H NMR (500MHz, CDC1 ₃ ): δ 5.66-5.59 (m, 1H), 5.41 (d, J = 10.0 Hz, 1H), 5.32-5.24 (m, 2H), 4.00 (d, J = 11.0 Hz, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.74-3.73 (m, 4H), 3.47-3.43 (m, 1H), 3.43- 3.41 (m, 3H), 3.20 (s, 3H), 1.71 (s, 3H), 0.90 (s, 12H), 0.06-0.00 (m, 8H).

Mass (ESI): 373 [M ⁺ ].

(3S, 4S, 5R, Z)-3-methoxy-8-(2-methoxyethoxy)-5, 7-dimethylocta- 1 , 6-dien-4-ol (THC-045):

To a stirred solution of compound 15 (100 mg, 0.241 mmol) in dry CH ₂ CI ₂ (1 mL) at 0°C, HC1 in dioxane (1 mL, 4M solution) was added. The reaction mixture was warmed to RT and stirred for 3 h. After consumption of the stating material (by TLC), the reaction was diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3: 17) to afford THC-045 (65 mg, 93.5%) as a syrup.

TLC: 20% EtOAc/Hexane (R _f : 0.1)

1H NMR (500MHz, CDC1 ₃ ): δ 5.76-5.68 (m, 1H), 5.33-5.26 (m, 3H), 4.07 (d, J = 12.0 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.54-3.46 (m, 5H), 3.38 (s, 3H), 3.28-3.22 (m, 4H), 2.71-2.68 (m, 1H), 1.76 (s, 3H), 1.00 (s, 3H).

Mass (ESI): 259.4 [M ⁺ +l].

Scheme 8:

2-(((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l- yl) oxy)-N, N-dimethyl ethanamine (17):

To a stirred solution of compound 16 (0.118 g, 1.33 mmol) in DMF (2 mL), cooled to 0°C, NaH (0.069 g, 1.59 mmol, 55% dispersion in mineral oil) was added and stirred for 20 min. The reaction mixture was slowly warmed to RT and stirred for further 30 min. The reaction was cooled to 0°C and Int-14 (0.501 g, 1.33 mmol) taken in DMF (2 mL) was added, slowly brought to RT and stirred for further 4 h. After consumption of the starting material (by TLC), the reaction was quenched with saturated NH ₄ C1 solution ( 2mL) and the volatiles were concentrated under vacuo to give the crude material which was purified by silica gel column chromatography (MeOH/CHCl ₃ 3:97) to afford compound 17 (111 mg, 22%) as liquid.

TLC: 5% MeOH/CHCl ₃ (R _f : 0.1)

1H NMR (500MHz, CDC1 ₃ ): δ 5.66-5.59 (m, 1H), 5.41 (d, J = 10.0 Hz, 1H), 5.32-5.24 (m, 2H), 4.00 (d, J = 11.0 Hz, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.74-3.73 (m, 2H), 3.42-3.36 (m, 2H), 3.20 (s, 3H), 3.01 (br s, 2H), 2.67 (s, 6H), 2.59-2.55 (m, 1H), 1.71 (s, 3H), 0.90 (s, 12H), 0.06-0.00 (m, 6H).

Mass (ESI): 386.6 (M ⁺ +l). (3S, 4S, 5R, Z)-8-(2-(dimethylamino) ethoxy)-3-methoxy-5, 7-dimethylocta-l, 6-dien-4-ol (THC-046):

To a stirred solution of compound 17 (111 mg, 0.286 mmol) in THF (0.9 mL), TBAF (0.343 mL, 0.343 mmol, 1M) was added and heated to 60°C for 50 h. After consumption of the starting material (by TLC), the volatiles from the reaction mixture were removed under reduced pressure to obtain the crude residue which was purified by silica gel column chromatography (Acetone/Hexane 3:2) to afford THC-046 (34.1 mg, 44%) as pale yellow syrup.

TLC: 10% MeOH/CHCl ₃ (R _f : 0.1)

1H NMR (500MHz, CDC1 ₃ ): δ 5.76-5.68 (m, 1H), 5.34-5.27 (m, 3H), 4.04 (d, J = 11.5 Hz, 1H), 3.93 (d, J = 12.0 Hz, 1H), 3.50-3.44 (m, 3H), 3.28-3.23 (m, 4H), 2.71-2.66 (m, 1H), 2.55 (t, J = 6.0 Hz, 2H), 2.30 (s, 6H), 1.95 (br s, 1H), 1.76 (s, 3H), 1.00 (d, J = 6.5 Hz, 3H).

Mass (ESI): 272 [M ⁺ +l].

Scheme 9:

(4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l-yl phenylcarbamate (19):

To a stirred solution of Int-13 (0.1 g, 0.32 mmol) in CH ₂ C1 ₂ (2 mL) at 0°C, Phenyl

Isocyanate (18) (70 mg, 0.38 mmol) was added followed by Et ₃ N (60 mg, 0.48 mmol) and stirred for 30 min. After consumption of the starting material (by TLC), the reaction mixture was diluted with hexane (20 mL) and washed with water followed by brine solution. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column

chromatography (EtOAc/Hexane 1 :49) to afford compound 19 (0.12 g, 87.5%) as liquid. TLC: 10% EtOAc/Hexane (R _f : 0.5)

1H NMR (500MHz, CDC1 ₃ ): δ 7.38 (d, J = 7.5 Hz, 2H), 7.32-7.29 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.58 (br s, 1H), 5.66-5.61 (m, 1H), 5.47 (d, J = 10.0 Hz, 1H), 5.30 (q, J = 10.5 Hz, 2H), 4.64 (q, J = 12.0 Hz, 2H), 3.50-3.48 (m, 1H), 3.39 (t, J = 8.0 Hz, 1H), 3.20 (s, 3H), 2.64 (t, J = 6.5 Hz, 1H), 1.76 (s, 3H), 0.88 (s, 12H), 0.04 (d, J = 16.5 Hz, 6H).

Mass (ESI): 434 (M ⁺ +l).

HPLC (purity): 93.41%

(4R, 5S, 6S, Z)-5-hydroxy-6-methoxy-2,4-dimethylocta-2,7-dien-l-yl phenylcarbamate (THC- 047):

To a stirred solution of compound 19 (0.12 g, 0.28 mmol) in CH ₂ CI ₂ (2 mL), cooled to 0°C, 4.0M HCl in 1,4-dioxane (2 mL) was added, the reaction mixture was slowly warmed to RT and stirred for 2 h. The volatiles from the reaction mixture were removed under reduced pressure to give the crude material was purified by silica gel column chromatography (EtOAc/Hexane 3 : 17) to afford THC-047 (70 mg, 70%) as syrup.

TLC: 10% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 7.38 (d, J = 8.5 Hz, 2H), 7.32-7.26 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.57 (br s, 1H), 5.76-5.69 (m, 1H), 5.41 (d, J = 10.0 Hz, 1H), 5.34 (q, J = 10.5 Hz, 2H), 4.72 (q, J = 11.5 Hz, 2H), 3.50-3.48 (m, 1H), 3.29-3.27 (m, 4H), 2.75-2.70 (m, 1H), 2.40 (d, J = 4.5 Hz, 1H), 1.80 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H).

Mass (ESI): 318.2 (M ⁺ -l).

HPLC (purity): 98.3%

Scheme 10:

(4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l-yl benzylcarbamate (21): To a stirred solution of Int-13 (0.2 g, 0.63 mmol) in CH ₂ C1 ₂ (5 mL) at 0°C, Et ₃ N (0.1 g, 0.95 mmol) was added followed by Benzyl Isocyanate (20) (0.1 g, 0.76 mmol) and stirred for 30 min. The reaction was slowly warmed to RT and stirred for further 16 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure and the residue was extracted with rc-hexane (3 x 10 mL). The solid was filtered off and the filtrate was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (EtOAc/Hexane 1: 19) to afford compound 21 (0.18 g, 64%) as liquid.

TLC: 10% EtOAc/Hexane (R _f : 0.4)

1H NMR (500MHz, CDC1 ₃ ): δ 7.35-7.25 (m, 5H), 5.67-5.60 (m, 1H), 5.42 (d, J = 9.5 Hz, 1H), 5.29-5.25 (m, 2H), 4.95 (br s, 1H), 4.60 (m, 2H), 4.38-4.34 (m, 2H), 3.47 (d, J = 7.5 Hz, 1H), 3.37 (t, J = 7.5 Hz, 1H), 3.19 (s, 3H), 2.62 (m, 1H), 1.72 (s, 3H), 0.90 (m, 12H), 0.05 (s, 6H). Mass (ESI): 448.4 (M ⁺ +l).

HPLC (purity): 89.79%

(4R, 5S, 6S, Z)-5-hydroxy-6-methoxy-2, 4-dimethylocta-2, 7-dien-l-yl benzylcarbamate (THC- 048):

To a stirred solution of compound 21 (0.16 g, 0.36 mmol) in CH ₂ C1 ₂ (10 mL) at 0°C, 4.0M HC1 in 1,4-dioxane (3 mL) was added and stirred for 2 h. After consumption of the starting material (by TLC), the volatiles from the reaction mixture were removed under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to afford THC-048 (0.1 g, 83%) as syrup.

TLC: 30% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 7.35-7.26 (m, 5H), 5.75-5.68 (m, 1H), 5.37-5.25 (m, 3H), 4.96 (br s, 1H), 4.66 (m, 2H), 4.38 (d, J = 6.0 Hz, 2H), 3.48 (m, 1H), 3.25 (t, J = 6.5 Hz, 4H), 2.72- 2.67 (m, 1H), 2.38 (d, J = 5.0 Hz, 1H), 1.76 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H).

Mass (ESI): 334 (M ⁺ +l).

HPLC (purity): 97.55% cheme 11 :

tert-Butyl (((3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-(pent-4-en-l-yloxy) octa-1 , 6-dien-4-yl) oxy) dimethyl silane (23):

To a stirred solution of alcohol 22 (37 mg, 0.43 mmol) in dry DMF (1 mL), cooled to 0°C, NaH (14 mg, 0.58 mmol, 60% dispersion in mineral oil) was added slowly under N ₂ atmosphere and stirred for 30 min. A solution of Int-14 (0.15 g, 0.39 mmol) in DMF (0.3 mL) was added slowly to the reaction mixture maintaining the temperature at 0°C. The reaction was warmed to RT and stirred for further 1 h. The reaction was quenched with cold water (5 mL), extracted with EtOAc (2 x 10 mL) and the combined organic extracts were washed with water (3 x 15 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1 :49) to afford compound 23 (0.11 g, 74.3%) as pale yellow syrup.

TLC: 5% EtOAc/Hexane (R _f : 0.55)

1H NMR (500MHz, CDC1 ₃ ): δ 5.84-5.78 (m, 1H), 5.66-5.59 (m, 1H), 5.38 (d, J = 10.0 Hz, 1H), 5.28 (t, J = 10.5 Hz, 2H), 5.01 (m, 2H), 3.95 (d, J = 11.0 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.44-3.32 (m, 4H), 3.20 (s, 3H), 2.62-2.60 (m, 1H), 2.13 (m, 2H), 1.72 (s, 3H), 1.68-1.63 (m, 2H), 0.91 (s, 12H), 0.04 (d, J = 16.0 Hz, 6H).

Mass (ESI): 383.4 (M ⁺ +l).

(3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-(pent-4-en-l-yloxy) octa-1 , 6-dien-4-ol (THC-049):

To a stirred solution of compound 23 (0.11 g, 0.28 mmol) in CH ₂ C1 ₂ (1 mL) at 0 °C, 4.0M HCl in 1 ,4-dioxane (2 mL) was added. The reaction mixture was warmed to RT and stirred for 2 h. After consumption of the starting material (by TLC), the volatiles from the reaction mixture were removed under reduced pressure and the residue was basified with saturated NaHC0 ₃ solution and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column

chromatography (EtOAc/hexane 2:48) to provide THC-049 (45 mg, 60%) as pale yellow syrup. TLC: 10% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 5.85-5.69 (m, 2H), 5.33-5.26 (m, 3H), 5.02 (m, 2H), 3.99 (d, J = 11.5 Hz, 1H), 3.90 (d, J = 12.0 Hz, 1H), 3.49 (d, J = 8.0 Hz, 1H), 3.39-3.35 (m, 2H), 3.28-3.23 (m, 4H), 2.71 (m, 1H), 2.34 (s, 1H), 2.14 (m, 2H), 1.76 (s, 3H), 1.69-1.63 (m, 2H), 1.00 (d, J = 6.5 Hz, 3H).

Mass (ESI): 269 (M ⁺ +l).

Scheme 12:

THC-013 THC-052

Tert-butyl allyl (3-(((4R, 5S, 6S, Z)-5-hydroxy-6-methoxy-2, 4-dimethylocta-2, 7-dien-l-yl) oxy) propyl) carbamate (THC-052):

To a stirred solution of THC-013 (90 mg, 0.176 mmol) in dry THF (20 mL), at 0°C HF- pyridine (2 mL) was added drop-wise. The reaction mixture was slowly warmed to RT, stirred for 36h and neutralized with saturated NaHC0 ₃ solution. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to afford THC-052 (30 mg, 43%) as a liquid.

TLC: 20% EtOAc/Hexane (R _f : 0.2)

1H NMR (500MHz, CDC1 ₃ ): δ 5.75-5.70 (m, 2H), 5.33-5.26 (m, 3H), 5.10 (d, J = 11.5 Hz, 2H), 3.98 (d, J = 12.0 Hz, 1H), 3.88 (d, J = 11.5 Hz, 1H), 3.82-3.79 (m, 2H), 3.50-3.47 (m, 2H), 3.35 (d, J = 6.0 Hz, 2H), 3.26 (m, 5H), 2.68-2.66 (m, 1H), 2.35 (d, J = 4.5 Hz, 1H, Exc), 1.79 (t, J = 6.5 Hz, 2H), 1.75 (s, 3H), 1.45 (s, 9H), 1.00 (d, J = 6.5 Hz, 3H). Mass (ESI): 398 (M ⁺ +l).

Scheme 13:

Pyrimidin-2-ylmethanamine (24):

To a stirred solution of pyrimidine-2-carbonitrile (10) (0.2 g, 0.9 mmol) in EtOH (1 mL), 10% Pd/C (20 mg) was added under N ₂ atmosphere. The reaction mixture was stirred under H ₂ at atmospheric pressure (balloon) for 12 h and filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the crude material which was passed through neutral alumina (EtOAc/Hexane 1 : 1) to afford compound 24 (0.19 g, 95%).

TLC: 50% EtOAc/Hexane (R _f : 0.1)

1H NMR (400MHz, CDC1 ₃ ): δ 8.70 (d, J = 5.2 Hz, 2H), 7.16 (t, J = 4.8 Hz, 1H), 4.19 (s, 1H), 4.11-4.08 (m, 1H). tert-Butyl (pyrimidin-2-ylmethyl) carbamate (25):

To a stirred solution of compound 24 (370 mg, 3.39 mmol) in THF (1 mL) at 0 °C, Et ₃ N (0.562 mL, 4.07 mmol) was added followed by (Boc) ₂ 0 (0.86 mL, 3.73 mmol). The reaction mixture was stirred at RT for 6 h and the solvent from the reaction was removed under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3:7) to furnish compound 25 (240 mg, 34%).

TLC: 50% EtOAc Hexane (R _f : 0.3)

1H NMR (400MHz, CDC1 ₃ ): δ 8.71 (d, J = 4.8 Hz, 2H), 7.19 (d, J = 4.8 Hz, 1H), 5.69 (br s, 1H), 4.61 (d, J = 4.4 Hz, 2H), 1.48 (s, 9H). tert-Butyl ((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7- dien-l-yl) (pyrimidin-2-ylmethyl) carbamate (26): To a stirred solution of compound 25 (33.17 mg, 0.15 mmol) in DMF (0.5 mL), cooled to 0°C, NaH (7.61 mg, 0.19 mmol, 60% dispersion in mineral oil) was added and stirred for 10 min. Int-14 (50 mg, 0.13 mmol) was added to the reaction mixture and slowly brought to RT and stirred for further 30 min. The reaction was quenched with ice-water and the aqueous layer was extracted with ether (2 x 5 mL). The combined organic extracts were dried over anhydrous

Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3: 17) to afford compound 26 (20 mg, 30%).

TLC: 30% EtOAc Hexane (R _f : 0.7)

1H NMR (400MHz, CDC1 ₃ ): δ 8.68 (d, J = 4.8 Hz, 2H), 7.15 (m, 1H), 5.42-5.29 (m, 2H), 5.10- 5.01 (m, 2H), 4.66-4.33 (m, 2H), 4.19-4.05 (m, 2H), 3.31-3.19 (m, 2H), 3.12 (s, 3H), 2.34-2.17 (m, 1H), 1.70 (d, J = 3.6 Hz, 3H), 1.50 (s, 4H), 1.30 (s, 5H), 0.88 (s, 9H), 0.76 (d, J = 5.0 Hz, 3H), 0.00 (s, 6H).

LC-MS: mlz = 506.8 [(M ⁺ +l)] at RT 7.39 (99.49% purity).

(3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-((pyrimidin-2-ylmethyl) amino) octa-1, 6-dien-4-ol (THC-102):

To a stirred solution of compound 26 (0.11 g, 0.22 mmol) in CH ₂ C1 ₂ (2 mL) at 0°C, HCl/l,4-dioxane (2 mL) was added and slowly brought to RT. The reaction was continued at RT for 2h and basified (pH 8) with 10% NaHC0 ₃ solution. The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was passed through a neutral alumina column (EtOAc/Hexane 1 : 1) to afford THC-102 (30 mg, 48%).

TLC: 30% EtOAc Hexane (R _f : 0.1)

1H NMR (400MHz, CDC1 ₃ ): δ 8.70 (d, J = 4.8 Hz, 2H), 7.17 (t, J = 5.2 Hz, 1H), 5.75-5.66 (m, 1H), 5.29 (d, J = 8.8 Hz, 3H), 4.00 (s, 2H), 3.51-3.47 (m, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.25 (s, 5H), 2.70-2.61 (m, 1H), 1.82 (s, 3H), 0.75 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 292.4 [(M ⁺ +l)] at RT 2.61 (96% purity). Scheme 14:

2-(((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l- yl) oxy) pyrimidine (28):

To a stirred suspension of NaH (4.7 mg, 0.114 mmol) in DMF (2 mL), cooled to 0°C, lnt-13 (30.2 mg, 0.095 mmol) was added dropwise, stirred for 15 min and 2-bromopyrimidine (1) (18.2 mg, 0.114 mmol), dissolved in dry DMF (1.0 mL) was added slowly maintaining the temperature at 0°C under N ₂ atmosphere. The reaction was slowly warmed to RT, stirred for another 7 h and quenched with aqueous NH ₄ C1 solution. The reaction mixture was diluted with Et ₂ 0 (20 mL), the organic layer was separated, washed with water (3 x 4 mL), brine, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by prep HPLC to afford compound 28 (28.3 mg, 76%).

TLC: 10% EtOAc/Hexane (R _f : 0.3)

1H NMR (400MHz, CDC1 ₃ ): δ 8.55 (d, J = 4.8 Hz, 2H), 6.97 (t, J = 4.8 Hz, 1H), 5.70-5.61 (m, 1H), 5.45 (d, J = 9.6 Hz, 1H), 5.29-5.21 (m, 2H), 4.87 (s, 2H), 3.53-3.50 (m, 1H), 3.42 (t, J = 7.6 Hz, 1H), 3.19 (s, 3H), 2.76-2.72 (m, 1H), 1.83 (s, 3H), 0.92 (s, 12H), 0.04 (d, J = 14.4 Hz, 6H). LC-MS: mlz = 393 J [(M ⁺ +l)] at RT 6.60 (94.08% purity). (3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-(pyrimidin-2-yloxy) octa-1, 6-dien-4-ol (THC-105):

To a stirred solution of compound 28 (28.3 mg, 0.072 mmol) in THF (1 mL), TBAF (0.22 mL, 0.23 mmol, 1M solution in THF) was added and stirred at RT for 16 h. The solvent from the reaction was evaporated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 1 :4) to furnish THC-105 (16.2 mg, 81 %) as colorless syrup.

TLC: 15% EtOAc/Hexane (R _f : 0.05) 1H NMR (400MHz, CDC1 ₃ ): δ 8.54 (d, J = 4.8 Hz, 2H), 6.96 (t, J = 4.8 Hz, 1H), 5.79-5.70 (m, 1H), 5.39-5.25 (m, 3H), 4.95 (q, J = 11.6 Hz, 2H), 3.55-3.52 (m, 1H), 3.30-3.27 (m, 1H), 3.24 (s, 3H), 2.87-2.78 (m, 1H), 2.38 (d, J = 5.2 Hz, 1H), 1.87 (s, 3H), 1.04 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 279 [(M ⁺ +l)] at RT 3.07 (97.44% purity).

Scheme 15:

2-((((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l- yl) oxy) methyl) pyridine (30):

To a stirred solution of Pyridin-2-ylmethanol (29) (17.3 mg, 0.15 mmol) in DMF (0.05 mL), cooled to 0°C, NaH (10.1 mg, 0.26 mmol, 60% dispersion in mineral oil) was added and stirred for 10 min. Int-14 (50 mg, 0.13 mmol) was dissolved in DMF (0.05 mL) was added to the reaction mixture maintaining the temperature at 0°C and stirred for further 30 min. The reaction was quenched with ice and the aqueous layer was extracted with ether (2 x 10 mL). The combined organic extracts were dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column

chromatography (EtOAc/Hexane 1 :9) to afford compound 29 (35 mg, 65.5%).

TLC: 20% EtOAc/Hexane (R _f : 0.5)

1H NMR (400MHz, CDC1 ₃ ): δ 8.54 (d, J = 4.4 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.19-7.16 (m, 1H), 5.59-5.50 (m, 1H), 5.43 (d, J = 8.8 Hz, 1H), 5.23 (s, 2H), 4.09 (q, J = 13.6 Hz, 2H), 4.10 (d, 7 = 11.2 Hz, 1H), 4.02 (d, J = 11.2 Hz, 1H), 3.44-3.42 (m, 1H), 3.35 (t, J = 8.0 Hz, 1H), 3.18 (s, 3H), 2.61-2.54 (m, 1H), 1.79 (s, 3H), 0.90 (s, 12H), 1.03 (d, J = 10.8 Hz, 6H).

Mass (ESI): 406 (M ⁺ +l). (3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-(pyridin-2-ylmethoxy)octa-l, 6-dien-4-ol (THC- 106):

To a stirred solution of compound 2 (35 mg, 0.086 mmol) in CH2CI2 (1 mL), Ether-HCl (1 mL) was added and the reaction mixture was stirred at RT for 3 h. The volatiles were removed under reduced pressure to give the crude residue which was purified by silica gel column chromatography (EtOAc/Hexane 1 : 1) to afford THC-106 (20 mg, 79.5%) as viscous oil.

TLC: 50% EtOAc/Hexane (R _f : 0.2)

1H NMR (400MHz, CDC1 ₃ ): δ 8.56 (d, J = 4.4 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.19-7.16 (m, 1H), 5.73-5.64 (m, 1H), 5.38 (d, J = 10.0 Hz, 1H), 5.31-5.24 (m, 2H), 4.64 (s, 2H), 4.17 (d, J = 11.2 Hz, 1H), 4.07 (d, J = 11.2 Hz, 1H), 3.50 (q, J = 5.6 Hz, 1H), 3.25 (m, 4H), 2.69-2.64 (m, 1H), 1.82 (s, 3H), 1.01 (d, J = 6.8 Hz, 3H).

LC-MS: m/z = 292.5 [(M ⁺ +l)] at RT 2.89 (97.22% purity).

Scheme 16:

2-(((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l- yl) oxy) pyridine (32):

To a stirred suspension of NaH (3.4 mg, 0.086 mmol, 60% dispersion in mineral oil) in THF (2 mL), cooled to 0°C, lnt-13 (22.4 mg, 0.072 mmol) was added dropwise and stirred for 15 min. 2-fluoropyridine (31) (8.4 mg, 0.086 mmol), dissolved in THF (1.0 mL), was added slowly maintaining the temperature at 0°C under N ₂ atmosphere. The reaction was warmed to RT, stirred for another 7.5 h and quenched with aqueous NH ₄ CI solution. The reaction mixture was diluted with Et ₂ 0 (30 mL), the organic layer was separated and washed with water (2 x 5 mL), brine, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude material was filtered through a short pad of silica gel (EtOAc/hexane 1 :49) to give compound 32 (19.7 mg, 70%) along with impurities which could not be separated.

TLC: 10% EtOAc/Hexane (R _f : 0.7) (3S, 4S, 5R, Z)-3-methoxy-5, 7-dimethyl-8-(pyridin-2-yloxy) octa-1, 6-dien-4-ol (THC-108):

To a stirred solution of compound 2 (14.7 mg, 0.037 mmol) in THF (1 mL), TBAF (0.075 mL, 0.075 mmol, 1M solution in THF) was added and refluxed for 4 h. After

consumption of the starting material (by TLC), the volatiles were removed under reduced pressure to give the crude residue which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford THC-108 (1.01 mg, 81%) as a colorless syrup.

TLC: 10% EtOAc/Hexane (R _f : 0.15)

1H NMR (400MHz, CDC1 ₃ ): δ 8.14 (d, J = 4.4 Hz, 1H), 7.58 (t, J = 4.4 Hz, 1H), 6.85 (t, J = 5.6 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.76-5.67 (m, 1H), 5.39 (d, J = 10.0 Hz, 1H), 5.30-5.24 (m, 2H), 4.82 (s, 2H), 3.54-3.51 (m, 1H), 3.31 (q, J = 5.2 Hz, 1H), 3.24 (s, 3H), 2.85-2.76 (m, 1H), 2.42 (d, J = 5.2 Hz, 1H), 1.84 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 278.3 [(M ⁺ +l)] at RT 3.67 (96.133% purity).

N-((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l- yl)pyrimidin-2-amine (33):

To a stirred solution of the amine (100.1 mg, 0.319 mmol) and 2-bromopyrimidine (42.6 mg, 0.268 mmol) in DCE (10 mL), DMAP (70.4 mg, 0.574 mmol) was added. The reaction mixture was refluxed for 40 h and diluted with water (10 mL). The aqueous layer was extracted with CH ₂ CI ₂ (3 x 10 mL) and the combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 3:47) to afford compound 33 (21 mg) as mixture which was carried forward for the next step without further purification. TLC: 10% EtOAc/Hexane (R _f : 0.5)

(3S,4S,5R,Z)-3-methoxy-5, 7-dimethyl-8-(pyrimidin-2-ylamino) octa-l,6-dien-4-ol (THC-109):

To a stirred solution of compound 33 (20.1 mg, 0.051 mmol) in THF (2 mL), TBAF (0.102 mL) was added and refluxed for 4 h. The reaction was diluted with water (5 mL) and aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material (23 mg) which was purified by chiral prep HPLC to afford THC-109A (2.6 mg) & THC-109B (2.1 mg).

Analytical data for THC-109A:

1H NMR (400 MHz, CDC1 ₃ ): δ 8.27 (d, J = 4.8 Hz, 2H), 6.52 (t, J = 4.8 Hz, 1H), 5.77-5.68 (m, 1H), 5.32 (d, J = 9.6 Hz, 3H), 5.17 (br s, 1H), 4.07-3.97 (m, 2H), 3.53-3.50 (m, 1H), 3.32 (t, J = 5.2 Hz, , 1H), 3.28 (s, 3H), 2.84-2.77 (m, 1H), 2.52 (br s, 1H), 1.79 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H).

LC-MS: m/z = 278.4 [(M ⁺ +l)] at RT 2.88 (95.65% purity). Analytical data for THC-109B:

1H NMR (400 MHz, CDC1 ₃ ): δ 8.27 (d, J = 4.8 Hz, 2H), 6.52 (t, J = 4.8 Hz, 1H), 5.77-5.68 (m, 1H), 5.32-5.20 (m, 4H), 3.97 (d, J = 5.6 Hz, 2H), 3.48-3.45 (m, 1H), 3.22 (s, 3H), 3.21 (m, 1H), 2.69-2.60 (m, 1H), 2.27 (br s, 1H), 1.68 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H).

LC-MS: m/z = 278.6 [(M ⁺ +l)] at RT 2.80 (90.75% purity).

cheme 18:

Pyrimidine-2-carboxylic acid (11):

To a stirred solution of pyrimidine-2-carbonitrile (10) (201 mg, 1.914 mmol) in water (5 mL), KOH (214.3 mg, 3.83 mmol) was added and the reaction was refluxed for 3 h. After consumption of the starting material (by TLC), the reaction was slowly brought to RT, neutralized with 2N HC1 and water was removed from the reaction mixture to give the crude residue which was extracted with EtOAc. The combined organic extracts were filtered through a pad of celite and the filtrate was concentrated under reduced pressure to provide compound 11 (84 mg, 35.4%) which was carried for the next step without any purification.

TLC: 80% EtOAc/Hexane (R _f : 0.05)

1H NMR (400MHz, CD ₃ OD-d ₄ ): δ 8.83 (br s, 2H), 7.47 (t, J = 4.8 Hz, 1H).

N-((4R,5S,6S,Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2,4-dimethylocta-2,7-dien-l-yl) pyrimidine-2-carboxamide (35):

To a stirred solution of compound 11 (20 mg, 0.16 mmol) in dry DMF (1 mL) at 0°C,

DIPEA (148.6 mL, 0.81 mmol) followed by HATU (91.93 mg, 0.242 mmol) were added under

N ₂ atmosphere and stirred for 10 min. Compound 34 (62.9 mg, 0.193 mmol) was added to the reaction mixture and stirred at RT 16 h. The reaction was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic extracts was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude residue (180mg) which was carried forward for the next step without purification.

TLC: 100% EtOAc (R _f : 0.5) Mass (ESI): 420 (M ⁺ +l).

LC-MS: mlz = 420.7 [(M ⁺ +l)] at RT 5.54 (13.3% purity) & 420.6 [(M ⁺ +l)] at RT 5.81 (46% purity). N-((4R,5S,6S,Z)-5-hydroxy-6-methoxy-2,4-dimethylocta-2,7-die n-l-yl) pyrimidine-2- carboxamide (36):

To a stirred solution of crude compound 35 (125 mg, 0.298 mmol) in THF (2 mL) at 0 °C, HF-pyridine (0.375 mL) was added and stirred at RT for 16 h. The reaction was quenched with NaHC0 ₃ solution and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over anhydrous Na ₂ S04, filtered and concentrated under reduced pressure to provide the crude material which was purified by silica gel column chromatography (MeOH/CHCl ₃ 1 : 19) to afford compound 36 (35 mg, 39%) as mixture of isomers. The isomers were separated by chiral prep HPLC to furnish THC-134 (20 mg) and THC-135 (3 mg). Analytical data for THC-134:

1H NMR (400 MHz, CDC1 ₃ ): δ 8.88 (d, J = 4.8 Hz, 2H), 7.98 (br s, 1H), 7.44 (t, J = 4.8 Hz, 1H), 5.78-5.69 (m, 1H), 5.38-5.28 (m, 3H), 4.16 (m, 2H), 3.52 (t, J = 5.6 Hz, 1H), 3.35-3.31 (m, 1H), 3.29 (s, 3H), 2.82-2.73 (m, 1H), 2.50 (d, J = 4.8 Hz, 1H), 1.81 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 306.6 [(M ⁺ +l)] at RT 3.10 (97.1 % purity). Analytical data for THC-135:

1H NMR (400 MHz, CDC1 ₃ ): δ 8.88 (d, J = 4.8 Hz, 2H), 8.04 (br s, 1H), 7.44 (t, J = 4.8 Hz, 1H), 5.76-5.67 (m, 1H), 5.34-5.27 (m, 3H), 4.07 (m, 2H), 3.50 (t, J = 5.6 Hz, 1H), 3.29 (br s, 4H), 2.69-2.60 (m, 1H), 2.39 (d, J = 5.2 Hz, 1H), 1.70 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 306.5 [(M ⁺ +l)] at RT 3.02 (98.78% purity). cheme 19:

N-((4R,5S,6S,Z)-5-((ieri-butyldimethylsilyl)oxy)-6-methox y-2,4-dimethylocta-2,7-dien-l-yl)-4- (trifluoromethyl) pyrimidin-2-amine (39):

To a stirred solution of amine 38 (150 mg, 0.479 mmol) in dry DMF (2 mL), K ₂ C0 ₃ (66 mg, 0.479 mmol) was added at RT and stirred for 10 min. 2-chloro-4-(trifluoromethyl) pyrimidine (37) (104.6 mg, 0.575 mmol) was added to the reaction and stirred for further 3 h at RT. The reaction was quenched with water and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column

chromatography (EtOAc/Hexane 1 :19) to furnish compound 39 (114 mg, 52%) as a mixture of diastereomers.

TLC: 15% EtOAc/Hexane (R _f : 0.5)

1H NMR (400MHz, CD ₃ OD-d ₄ ): δ 8.46 (br s, 1H), 6.80 (d, J = 5.2 Hz, 1H), 5.70-5.61 (m, 1H), 5.59-5.39 (m, 2H), 5.37-5.20 (m, 2H), 4.13-3.92 (m, 2H), 3.51-3.36 (m, 2H), 3.22 (s, 3H), 2.73- 2.54 (m, 1H), 1.75 (s, 2H), 1.74 (s, 1H), 0.92 (s, 12H), 0.05 (d, J = 6.8 Hz, 6H).

LC-MS: mlz = 460 [(M ⁺ +l)] at RT 6.59 (70.9% purity) & 460 [(M ⁺ +l)] at RT 6.15 (28.9% purity). (3S,4S,5R,Z)-3-methoxy-5,7-dimethyl-8-((4-(trifluoromethyl)p yrimidin-2-yl)amino)octa-l,6- dien-4-ol (THC-137A & THC-137B):

To a stirred solution of compound 39 (125 mg, 0.298 mmol) in THF (2 mL), cooled to 0°C, HF-pyridine (0.375 mL) was added and stirred at RT for 16 h. The reaction was quenched with NaHC0 ₃ solution and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the crude material which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to provide THC-137A (15 mg) and THC-137B (11 mg) (30% combined yield). 18 mg of mixture of THC-137A & THC-137B were also collected from the column fractions. TLC: 15% EtOAc/Hexane (R _f : 0.2, 0.25)

Analytical data for THC-137A:

1H NMR (400MHz, CDC1 ₃ ): δ 8.46 (br s, 1H), 6.80 (d, J = 4.8 Hz, 1H), 5.78-5.70 (m, 1H), 5.43 (br s, 1H), 5.34-5.27 (m, 3H), 4.16 (dd, J = 5.2, 17.5 Hz, 1H), 4.01-3.97 (m, 1H), 3.52 (m, 1H), 3.31 (br s, 4H), 2.83-2.74 (m, 1H), 2.45 (d, J = 4.8 Hz, 1H), 1.79 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 346.7 [(M ⁺ +l)] at RT 4.37 (95.15% purity) Analytical data for THC-137B:

1H NMR (400MHz, CDC1 ₃ ): δ 8.46 (br s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 5.76-5.67 (m, 1H), 5.41 (br s, 1H), 5.35-5.20 (m, 3H), 4.00 (d, J = 6.0 Hz, 2H), 3.45 (m, 1H), 3.24 (br s, 4H), 2.67-2.61 (m, 1H), 2.29 (d, J = 5.2 Hz, 1H), 1.68 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H).

LC-MS: mlz = 346.7 [(M ⁺ +l)] at RT 4.25 (91.95% purity)

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.