Cannabinoid receptor 2 modulator

Abstract

The present invention relates to a compound having general formula (I) that is useful as a modulator of cannabinoid receptor 2 (CB2R) (wherein R, R 1 ~R 3 The present invention provides compositions comprising the compound, a process for producing the compound, and a method for using the compound (as described herein). TIFF2026520065000196.tif43161

Description

[Technical Field]

[0001] This invention relates to organic compounds useful as modulators of cannabinoid receptor 2 (CB2R). Furthermore, this invention relates to organic compounds useful as selective fluorescent probes for cannabinoid receptor 2. [Background technology]

[0002] Addressing dysregulation of the signaling pathways of the endogenous cannabinoid system has been suggested as a promising target for treating numerous diseases. Modulation of CB2Rs to leverage their therapeutic potential has primarily focused on receptor activation by agonists. In contrast, the application of CB2R antagonists and inverse agonists to improve disease states remains largely unexplored, despite promising results in models of arthritis, neuroinflammation, and renal fibrosis (CALunn, et.al. Br.J. Pharmacol. 2008, 153, 226-39; SS. Alghamdi, et al. Bioorg. Med. Chem. 2021, 33, 116035; L. Zhou, et.al. Kidney Int. 2018, 94, 756-772). Investigations of CB2R pharmacology using fluorescent probes have significantly contributed to understanding receptor localization and expression in endogenous living cells and in vivo (RCSarott, et.al., J.Am.Chem.Soc., 2020, 142, 16953-16964; T.Gazzi, et.al., Chem.Sci. 2022, 13, 5539-5545). However, these validated probes are characterized by potent agonist-targeting ligands that, upon binding, activate CB2R, trigger downstream signaling pathways, and promote receptor internalization leading to desensitization. Previous attempts to develop CB2R reverse agonists have demonstrated how challenging these endeavors are. For example, fluorophore coupling of CB2R to known selective inverse agonists either completely abolished affinity for the receptor or induced a dramatic 260-fold decrease in affinity (AGCooper, et.al. Eur.J.Med.Chem.2018,145,770-789; Sexton, M., et.al. Chem Biol 2011,18,563-568). Reports of inverse agonists with high affinity and selectivity for CB2R have originated from a set of agonists, and the reported functionality is associated with specific linkers and fluorophores, as all other entities reported with the same ligand are agonists (S.Singh, et.al.,ACS Med.Chem.Lett.2019,10,209-214).It would be highly advantageous to discover a versatile, high-affinity CB2R-selective ligand suitable for functionalization with a wide range of fluorophores and functional groups while maintaining its favorable pharmacological profile, specifically its functional profile. Furthermore, it would be even more important if the functional response (% inverse agonism, antagonistism, partial agonism, agonism) could be specifically tuned to address the CB2R dysregulation identified in the disease. [Overview of the Initiative]

[0003] The limitations described above are addressed by the present invention, which reports rationally designed high-affinity CB2R-selective antagonist and inverse agonist ligands that can be functionalized with a wide range of functionalities while maintaining their excellent affinity, selectivity, and functionality. The novel compounds are proposed to interact with and modulate the movement of Trp258, a single residue referred to as a "toggle switch" for receptor activation (T. Hua, et al. Cell. 2020, 180, 655-665). The fluorescent probes reported herein can find applications in conventional and imaging flow cytometry experiments as well as fluorescence-activated cell sorting (FACS). Furthermore, these probes can be applied to fluorescence confocal microscopy. The inverse agonist properties of the probes reported herein allow for visualization of CB2R and monitoring of localization and receptor transport without receptor activation and associated internalization. Moreover, a wide range of fluorophores, spanning various molecular sizes, physicochemical properties, absorption and emission wavelengths, and Stokes shifts, allows for probe selection to be specifically tailored to desired applications. For example, an impermeable probe (containing AF488) targets CB2R at the plasma membrane, while a cell-permeable probe (containing NBD) visualizes the cytoplasmic receptor population. Furthermore, investigations into structural modifications of the targeted ligands have enabled the achievement of distinct pharmacological responses at CB2R, ranging from inverse agonists, antagonists, partial agonists, and full agonists. These ligands can find applications targeting disease conditions requiring precise levels of receptor activation or inactivation. These probes can also assist in the transition of preclinical pharmacological animal data to clinical applications.

[0004] In the first aspect, the present invention relates to a compound of formula (I). [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 ~R 3 This is as defined herein. [Brief explanation of the drawing]

[0005] [Figure 1] The crystal structure of (S)-5-(2-methyl-8-((4-nitrobenzoyl)oxy)-3-phenyloctan-2-yl)-1,3-phenylenebis(4-nitrobenzoate) (Example 32) is shown. [Modes for carrying out the invention]

[0006] definition Features, integers, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described herein. The present invention extends to any novel one or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process disclosed herein.

[0007] The term "alkyl" refers to a monovalent or polyvalent, for example, monovalent or divalent, linear or branched saturated hydrocarbon group comprising 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms ("C1-C6-alkyl"). In some embodiments, alkyl groups contain 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of alkyl is methyl.

[0008] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably a fluorohydrogen atom. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably a fluorohydrogen atom. A particularly preferred but non-limiting example of a haloalkyl is trifluoromethyl (CF3).

[0009] The term "alkoxy" refers to the alkyl group defined above, bonded to the parent molecule via an oxygen atom. Unless otherwise specified, alkoxy groups contain 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, alkoxy groups contain 1 to 4 carbon atoms. In yet other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

[0010] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by halogen atoms, most preferably a fluoro atom. A particularly preferred but non-limiting example of a haloalkoxy is trifluoromethoxy(-OCF3).

[0011] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members ("C6- 10aryl is an aryl compound in which at least one ring is aromatic. Some non-limiting examples of aryls include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred but non-limiting example of an aryl is phenyl.

[0012] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system, preferably monocyclic, having a total of 5 to 14 ring members ("5-14 membered heteroaryl"), preferably 5 to 12 ring members, more preferably 5 to 10 ring members, and even more preferably 5 to 9 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-9 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5-8 membered or 5-6 membered heteroaryl containing 1 to 3, preferably 1 to 2, heteroatoms independently selected from O, S, and N.Some non-restrictive examples of heteroaryls include spiro[cyclopropane-1,3'-indoline] (e.g., spiro[cyclopropane-1,3'-indoline]-1'-yl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazine-2-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrimidine-6-yl, indole-1-yl, 1H-indole-2-yl, 1H-indole-3-yl, 1H-indole 1H-indole-4-yl, 1H-indole-5-yl, 1H-indole-6-yl, 1H-indole-7-yl, 1,2-benzoxazole-3-yl, 1,2-benzoxazole-4-yl, 1,2-benzoxazole-5-yl, 1,2-benzoxazole-6-yl, 1,2-benzoxazole-7-yl, 1H-indazole-3-yl, 1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, 1H- Ndazole-7-yl, pyrazole-1-yl, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, 1H-pyrazole-5-yl, imidazole-1-yl, 1H-imidazole-2-yl, 1H-imidazole-4-yl, 1H-imidazole-5-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiazole-2-yl, thiazole- Examples include 4-yl, thiazole-5-yl, pyridazine-3-yl, pyridazine-4-yl, 1,2,4-triazole-4-yl, 1,2,4-triazole-1-yl, 4H-1,2,4-triazole-3-yl, 4,5,6,7-tetrahydroindazole-2-yl, 6,7-dihydro-4H-pyrano[4,3-c]pyrazole-2-yl, thiazolyl, benzofurazan-4-yl, tetrazolyl, isoxazolyl, and morpholinil. Particularly preferred but non-limiting examples of heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, and triazolyl.

[0013] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I). Preferably, the term "halogen" or "halo" refers to fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro(F) and chloro(Cl).

[0014] The term "hydroxy" refers to the -OH group.

[0015] The term "amino" refers to the -NH2 group.

[0016] The term "cyano" refers to the -CN (nitrile) group.

[0017] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid (especially hydrochloric acid), and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. These salts may also be prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins. Certain pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride and trifluoroacetate salts.

[0018] The compound of formula (I) may contain several chiral centers and may exist in the form of an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a racemate of diastereoisomers, or a mixture of racemates of diastereoisomers.

[0019] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" stereoconfiguration.

[0020] The abbreviation "CB2" refers to cannabinoid receptor 2.

[0021] As used herein, the term “treatment” includes (1) suppressing a condition, disorder or symptom (e.g., stopping, reducing or delaying the onset of a disease, or the recurrence of a disease, or the onset of at least one clinical or subclinical symptom of a disease in the case of disease onset or maintenance treatment); and / or (2) alleviating a symptom (i.e., causing the regression of a condition, disorder or symptom, or at least one clinical or subclinical symptom thereof). The benefit to the patient to be treated is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the result does not necessarily have to be an effective treatment.

[0022] As used herein, the term “prevention” includes preventing or delaying the onset of clinical symptoms of a condition, disorder, or symptom in mammals, particularly humans, who may be susceptible to or prone to such conditions, disorders, or symptoms but have not yet experienced or shown any clinical or subclinical symptoms of such conditions, disorders, or symptoms.

[0023] The compound of the present invention In the first aspect, the present invention relates to a compound of formula (I). [ka] or a pharmaceutically acceptable salt thereof, is provided, R 1 is hydroxy, amino, and the group

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[0024] In a preferred embodiment, the present invention is R 1 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is selected from hydroxyl and amino compounds.

[0025] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, R 1 is, [ka] and; R 4 The following can be selected: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] ; p is an integer selected from 2, 3, 4, 5, and 6; R 4a and R 4b Each is independently selected from hydroxy, amino, and dimethylamino; R 4c and R 4d Each is independently selected from hydrogen and -SO3H; and Y is O.

[0026] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, R 1 is, [ka] and; R 4 The following can be selected: [ka] , [ka] , [ka] , and [ka] and p is an integer selected from 2 and 5.

[0027] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein R 1 The following can be selected: [ka] , [ka] , [ka] , and [ka] .

[0028] In one embodiment, the present invention is R 2 However, C1-C6-alkyl, halo-C1~C6 alkyl, C6-C 10 - Selected from aryls and 5-14 member heteroaryls; the C6-C 10 The following provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the aryl and 5- to 14-membered heteroaryl are optionally substituted with one substituent selected from halogens and C1-C6-alkyl groups.

[0029] In one embodiment, the present invention is R 2 The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein each compound comprises a C1-C6-alkyl, a halo-C1-C6-alkyl, a phenyl, and a 5-6 membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon; the phenyl and the 5-6 membered heteroaryl are optionally substituted with one substituent selected from a halogen and a C1-C6-alkyl.

[0030] In one embodiment, the present invention is R 2 The present invention provides compounds of formula (I) as described herein, selected from ethyl, 1-propyl, 2-propyl, CF3, phenyl, 4-fluorophenyl, 3-fluorophenyl, and 1-methylpyrazole-3-yl, or pharmaceutically acceptable salts thereof.

[0031] In a preferred embodiment, the present invention is R 2 C6-C 10 - Provided herein are compounds of formula (I) described herein, which are aryl compounds, or pharmaceutically acceptable salts thereof.

[0032] In a particularly preferred embodiment, the present invention is R 2 This specification provides compounds of formula (I) described herein, wherein is phenyl, or pharmaceutically acceptable salts thereof.

[0033] In a preferred embodiment, the present invention is R 3 The present invention provides compounds of formula (I) as described herein, selected from C1-C6-alkyl and azido-C1-C6-alkyl, or pharmaceutically acceptable salts thereof.

[0034] In a particularly preferred embodiment, the present invention is R 3 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is selected from pentyl and 5-azidopentyl.

[0035] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, R 1 hydroxy, amino and group [ka] Selected from; R 2 These are C1-C6-alkyl, halo-C1~C6 alkyl, and C6-C 10- Selected from aryls and 5-14 member heteroaryls; the C6-C 10 -aryl and 5-14 member heteroaryl groups are optionally substituted with one substituent selected from halogens and C1-C6 alkyl groups; R 3 These are selected from C1-C6-alkyl and azido-C1-C6-alkyl; R 4 The following can be selected: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] ; p is an integer selected from 2, 3, 4, 5, and 6; R 4a and R 4b Each is independently selected from hydroxy, amino, and dimethylamino; R 4c and R 4d Each is independently selected from hydrogen and -SO3H; and Y is O.

[0036] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, R 1 hydroxy, amino and group [ka] Selected from; R 2 It is selected from C1-C6-alkyl, halo-C1-C6-alkyl, phenyl, and 5-6 membered heteroaryls comprising 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon; the phenyl and 5-6 membered heteroaryls are optionally substituted with one substituent selected from halogens and C1-C6-alkyls; R 3 These are selected from C1-C6-alkyl and azido-C1-C6-alkyl; R 4 The following can be selected: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] ; p is an integer selected from 2, 3, 4, 5, and 6; R 4a and R 4b Each is independently selected from hydroxy, amino, and dimethylamino; R 4c and R 4d Each is independently selected from hydrogen and -SO3H; and Y is O.

[0037] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, R 1 hydroxy, amino and group [ka] Selected from; R 2 It is selected from ethyl, 1-propyl, 2-propyl, CF3, phenyl, 4-fluorophenyl, 3-fluorophenyl, and 1-methylpyrazole-3-yl; R 3 It is selected from pentyl and 5-azidopentyl; R 4 The following can be selected: [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] ; p is an integer selected from 2, 3, 4, 5, and 6; R 4a and R 4b Each is independently selected from hydroxy, amino, and dimethylamino; R 4c and R 4d Each is independently selected from hydrogen and -SO3H; and Y is O.

[0038] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, R 1 is, [ka] and; R 2 C6-C 10-Aryl; R 3 These are selected from C1-C6-alkyl and azido-C1-C6-alkyl; R 4 The following can be selected: [ka] , [ka] , [ka] , and [ka] and p is an integer selected from 2 and 5.

[0039] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, R 1 The following can be selected: [ka] , [ka] , [ka] , and [ka] ; R 2 is phenyl; and R3 It is selected from pentyl and 5-azidopentyl.

[0040] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the following: 1-(6-((((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate; 6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)-1-(6-((((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)pyridine-1-ium-3-sulfonate; N-(((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide; ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine; ((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine; N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide; N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide; N-(((1S,4S,5S)-4-(4((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide; 1-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate; 1-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate; N-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxamide; N-(6-((((1S,4S,5S)-4-(4((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-6-carboxamide; 1-(6-((6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)amino)-6-oxohexyl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)indoline-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-3-(4-sulfobutyl)-3H-indole-1-ium-5-sulfonate; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-6-(3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5l4,6l4-dipyrrole[1,2-c:2',1'-f][1,3,2]diazabolinin-3-yl)propanamide)hexanamide; 3',6'-diamino-5-((6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; ((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((R)-3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-(3-isopropyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-(1-methyl-1H-pyrazole-3-yl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)oxy)heptanamide; and 1-(6-((2-(2-(4-(3-((4-((7-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)amino)-7-oxoheptyl)carbamoyl)-N-(cyanomethyl)phenyl)sulfonamide)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridin-1-ium-3-sulfonate).

[0041] In certain embodiments, the invention provides pharmaceutically acceptable salts of the compounds according to formula (I) described herein. In more particular embodiments, the invention provides the compounds according to formula (I) described herein as free bases.

[0042] In some embodiments, the compounds of formula (I) are isotopically labeled by having one or more atoms therein replaced by atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this disclosure. Exemplary isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, <000​​​​​​I may be mentioned, but is not limited thereto. Certain isotopically labeled compounds of formula (I), for example those incorporating a radioisotope, are useful in studies of the tissue distribution of drugs and / or substrates. Radioisotopes such as tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and readily detectable means. For example, the compounds of formula (I) can be enriched to 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0043] Substitution with heavier isotopes, such as deuterium, i.e., 2 H, etc., results in higher metabolic stability, for example, a longer in vivo half-life or a lower required dosage, and certain therapeutic advantages can be obtained. Thus, in one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms are replaced with deuterium. In a preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein 1 to 10 hydrogen atoms are replaced with deuterium. In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein 1 to 6 hydrogen atoms, for example, 1, 2, 3, 4, 5, or 6 hydrogen atoms are replaced with deuterium.

[0044] 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N may be useful in positron emission tomography (PET) studies for examining receptor occupancy of substrates. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents, in a manner similar to that described in the examples described below.

[0045] Manufacturing method The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques necessary for reacting and purifying the obtained products are known to those skilled in the art. Substituents and indicators used in the following description of the method have the meaning given herein unless otherwise indicated.

[0046] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (such as those described in "Protective Groups in Organic Chemistry," TW Greene and PGMWutts, 5th edition (2014), John Wiley & Sons, New York) can be introduced before a critical step by applying methods well known in the art. Such protecting groups can be removed at later stages of synthesis using standard methods described in the literature.

[0047] If the starting material or intermediate contains a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated into their counterparts, for example, via diastereomer salts by crystallization with an optically pure acid, or by separating the counterparts by a specific chromatographic method using either a chiral adsorbent or a chiral eluent. It is also possible to separate the starting material and intermediate containing a stereocenter to obtain diastereomerically / enantiomerically enriched starting material and intermediate. When such diastereomerically / enantiomerically enriched starting material and intermediate are used in the synthesis of the compound of formula (I), typically the respective diastereomerically / enantiomerically enriched compound of formula (I) is obtained.

[0048] Those skilled in the art will recognize that, in the synthesis of compounds of formula (I) (unless another method is desired), the “orthogonal protection group strategy” can be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and is also described in the literature (e.g., Barany and RBMerrifield, J.Am.Chem.Soc. (1977), Vol. 99, p. 7363; H.Waldmann et al., Angew.Chem.Int.Ed.Engl. (1996), Vol. 35, p. 2056).

[0049] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and properties of the intermediates.

[0050] More specifically, the compound of formula (I) can be prepared by the method shown below, the method shown in the examples, or a similar method. Suitable reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that may affect the described reaction, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY. 1999). The reaction could be carried out readily with or without a solvent. There are no particular restrictions on the properties of the solvent used, as long as it does not adversely affect the reagents involved in the reaction and can dissolve the reagents to at least some extent. Since the described reaction can be carried out over a wide range of temperatures, the exact reaction temperature is not important to the present invention. It is convenient to carry out the described reaction in the temperature range from -78°C to reflux. The time required for the reaction can also vary greatly depending on many factors, particularly the reaction temperature and the properties of the reagents. However, a period of 0.5 hours to several days is usually sufficient to produce the described intermediates and compounds. The reaction sequence is not limited to the order shown in the scheme; the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity.

[0051] If the starting materials or intermediates are not commercially available, or if their synthesis is not documented in the literature, they may be prepared in the same manner as existing procedures for similar analogs, or as outlined in the experimental section.

[0052] The following abbreviations are used in this specification: AcOH = Acetic acid, ACN = Acetonitrile, AIBN = Azobisisobutyronitrile, Boc = Tert-butyloxycarbonyl, BuLi = Butyllithium CAS RN = Chemical Literature Abstract Registration Number, CH2Cl2 = Dichloromethane, COMU = (1-Cyano-2-Ethoxy-2-Oxoethylideneaminooxy)dimethylaminomorpholino-carbenium hexafluorophosphate, DCC = N,N'-Dicyclohexylcarbodiimide, DIBAL = Diisobutylaluminum hydride, DIC = N,N'-Diisopropylcarbodiimide, N,N'-Dicyclohexylcarbodiimide, DMAP = 4-Dimethylaminopyridine, DMA = N,N-Dimethylacetamide, DMF = N,N-Dimethylformamide, DMP = 3-Oxo-1λ 5,2-Benziodoxol-1,1,1(3H)-triyltriacetate, DMSO=dimethyl sulfoxide, i-Pr2NEt=N,N-diisopropylethylamine, EDCI=N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, ESI=electrospray ionization, Et3N=triethylamine, Et2O=diethyl ether, siRNA=ethyl acetate, EtOH=ethanol, h=hour, H2O=water, HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate, HCl=hydrochloric acid, HPLC=high-performance liquid chromatography, K2CO3=potassium carbonate, KHMDS=potassium bis(trimethylsilyl)amide, MeOH=methanol, MgSO4 = magnesium sulfate, min = minute, mL = milliliter, MS = mass spectrum, NaH = sodium hydride, NaHCO3 = sodium bicarbonate, NaOH = sodium hydroxide, Na2SO4 = sodium sulfate, NET3 = triethylamine (TEA), NH4Cl = ammonium chloride, PG = protecting group, R = any group, Rochelle salt = L(+)-potassium sodium tartrate tetrahydrate, rt = room temperature, T3P = propylphosphonic anhydride, TBAF = tetra-n-butylammonium fluoride, TBTU = O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TLC = thin-layer chromatography, SFC = supercritical fluid chromatography.

[0053] R 1 , R 2 , R 4 , R 5 Compounds of formula I, where p is as described herein, can be synthesized as in the literature and / or as shown in scheme 1, for example. [ka] Scheme 1.

[0054] Therefore, nitrile type A is reacted with an organometallic reagent such as alkyllithium to obtain B (step a). Subsequently, B is reacted with an organometallic reagent such as organolithium and optionally catalyzed with a Lewis acid such as CeCl3 or LaCl3 to obtain alcohols D1-D7 (step b). In a similar manner starting from ketone C, alcohol D8 can be achieved by treatment with an organometallic reagent (step c). Alcohols D1-D3 are removed and subsequently hydrogenated to obtain saturated intermediates E1-E3 (steps d and e). Finally, resorcinols F2-F4 are obtained by double demethylation of E1-E3 (step f). Alkenes G1-G5 are removed to obtain alkenes G1-G5 (step g), which are subsequently demethylated and hydrogenated to obtain resorcinols F5-F9 (steps h and i). Aldehyde H is subjected to a nucleophilic trifluoromethylation reaction followed by oxidation to obtain ketone I (steps j and k). Ketone I can be subjected to a Wittig reaction with a phosphonium ylide, followed by hydrogenation and double demethylation to obtain resorcinol F1. Racemic resorcinols F1-F9 could be optionally separated by chiral resolution methods such as half-chiral SFC to obtain optically concentrated enantiomers. Those skilled in the art will recognize that other methods of racemic resolution exist, including, for example, chiral derivatization, crystallization, or resolution. Finally, Examples 1-13 were obtained by acid-catalyzed allylation of F1-F8 followed by methylation and deprotection (steps o, p, and q). Examples 14 and 15 can be achieved from resorcinol F9 by a similar series of allylation (step o), double methylation (step p), substitution with a desired terminal functional group such as an azide (step r), and final deprotection (step s). Examples 16-31 can be achieved by functionalizing a primary amine, as seen in Examples 14-15, into an amide by direct reaction with a desired carboxylic acid (step t) or its equivalent, or optionally by pre-setting a suitable linker element (steps u and v).This type of amide coupling can be achieved by using one of the well-known coupling reagents, such as DCC, HATU, EDCI, TBTU, or T3P, with a base such as i-Pr2NEt, Et3N, or DMAP, in a suitable solvent such as DMF, DMA, CH2Cl2, or dioxane, preferably at 0°C to room temperature.

[0055] The absolute configuration of the C(2') homobenzyl α relative to the gem-dimethyl group in Examples 14, 15, and 17-31, which contain resorcinol F9, was determined as shown in Scheme 2. [ka] Scheme 2.

[0056] Therefore, the racemic mixture F9 was separated into individual enantiomers by supercritical fluid chromatography (SFC) using a chiral stationary phase (step a). The first enantiomer to elute, F9-A, was hydrolyzed to JA (step b) and derivatized with p-nitrobenzoyl chloride to obtain Example 32 (step c). The structure of nitrobenzoate Example 32 was elucidated by X-ray crystallography, and its C(2') configuration was evaluated as S.

[0057] TR-FRET hCB2R binding assay Cell culture: Cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS) with blastosidine (5 μg / mL; Invitrogen) and Zeocin (20 μg / mL; Invitrogen) under humidified conditions of 37°C and 5% CO2. For inducible expression, SNAP-tagged human CB2 receptor cDNA in pcDNA4 / TO was introduced via transfection of HEK293TR cells (expressing Tet repressor protein to enable inducible expression) using PEI. Mixed population stable lines were selected based on their resistance to blastosidine (TR vector, 5 μg / mL) and Zeocin (receptor plasmid, 20 μg / mL). For receptor inducible expression, cells were cultured in t175cm². 2 Cells were seeded in a flask and grown to 70% confluence, after which DMEM containing 1 μg / ml tetracycline was added. After 24 hours, the cells were labeled with SNAP-Lumi4-Tb(CisBio), and membranes were prepared as described in detail below.

[0058] Terbium labeling of SNAP-tagged CB2R HEK293-TR cells: Cell culture medium was removed from a t175cm2 flask containing confluent, adherent CB2HEK293-TR cells. After washing the cells once in PBS (GIBCO, Carlsbad, California), excess cell culture medium was removed by washing once with Tag-lite labeled medium (LABMED, CisBio). Then, 10 ml of LABMED containing 100 nM SNAP-Lumi4-Tb was added to the flask and incubated at 37°C for 1 hour under 5% CO2. Excess SNAP-Lumi4-Tb was removed by washing the cells once in PBS (GIBCO, Carlsbad, California). Then, the cells were detached using 5 mL of GIBCO enzyme-free Hanks-based cell dissociation buffer (GIBCO, Carlsbad, California) and collected in a vial containing 5 ml of DMEM (Sigma-Aldrich) supplemented with 10% fetal bovine serum. The cells were pelletized by centrifugation (1500 rpm for 5 minutes), and the pellets were frozen to -80°C. To prepare the membrane, a homogenization step was performed at 4°C (to avoid receptor degradation) as described in CKHerenbrink, et.al., Nat.Commun., 2016, 7, 10842.

[0059] Fluorescent ligand binding assays: All fluorescent ligand binding experiments were performed in white 384-well Optiplate plates in either Hanks equilibrium salt solution (HBSS), 5 mM HEPES, 0.5% BSA, 0.02% Pluronic® F-127 pH 7.4, or 100 μM GppNHp assay buffer. Since the Motulsky-Mahan model is only suitable for ligands competing at a single site, GppNHp was included to eliminate the G protein-coupled receptor population, which could result in two distinct populations of binding sites in the membrane preparation. In all cases, nonspecific binding was determined by the presence of 1 μM SR144528. Data are shown mean ± SEM from representatives of 3–8 experiments.

[0060] Determination of fluorescent ligand binding kinetics and equilibrium affinity: To accurately determine the association rate (kon) and dissociation rate (koff) values, the observed association rate (kob) was calculated using at least five different concentrations of 8-SiR or the fluorescent tracer D77 (see T. Gazzi et al. Chem. Sci., 2022, 13, 5539-5545 for a description of 8-SiR and the assay). [ka]

[0061] Appropriate concentrations of fluorescent ligands were incubated with human CB2R HEK293-TR cell membranes (4 μg / well) in assay binding buffer (final assay volume, 40 μL). HTRF detection allowed assessment of the degree of receptor-bound fluorescent ligand at multiple time points, enabling the construction of association rate curves. The obtained data were globally fitted to an association rate model (Equation 1, see Signal Detection and Data Analysis below) to derive a single best-fit estimate for kon and koff, as described in the Data Analysis section. Saturation analysis was performed at equilibrium, and the total binding data and non-specific (NSB) binding data were simultaneously fitted (Equation 2, see Signal Detection and Data Analysis below), enabling the determination of fluorescent ligand binding affinity.

[0062] Competitive Binding: To determine the affinity of CB2R-specific ligands, the inventors used a simple competitive kinetic binding assay. This approach involves the simultaneous addition of both the fluorescent ligand and the competing substance to the CB2R preparation. 62.5 nM 8-SiR or 900 nM D77, at concentrations that avoid ligand depletion in the assay volume, were added to the CB2R cell membrane (4 μg / well) simultaneously with an increasing concentration of the unlabeled compound in 40 μL of assay buffer in a 384-well plate incubated at room temperature with orbital mixing. The degree of receptor-bound fluorescent ligand was assessed at equilibrium by HTRF detection. Nonspecific binding was determined as the amount of HTRF signal detected in the presence of SR144528 (1 μM) and subtracted from total binding to obtain IC50. 50 Specific bindings were calculated to construct the curve. The kinetic parameters of D77 plus those of the unlabeled compound were determined using a start time of approximately 60 seconds and an interval time of 60 seconds. Nonspecific bindings were determined as the amount of HTRF signal detected in the presence of (SR144, 528, 10 μM) and subtracted from the total bindings to calculate specific bindings (this means that t=0 is always equal to 0).

[0063] Signal detection and data analysis: Signal detection was performed using Pherastar FSX (BMG Labtech, Offenburg, Germany). Terbium donors were continuously excited with eight laser flashes at a wavelength of 337 nm. TR-FRET signals were collected at 665 nm (acceptor) and 620 nm (donor) when using the red acceptor fluorescent ligand 8-SiR. The HTRF ratio was obtained by dividing the acceptor signal by the donor signal and multiplying this value by 10,000. All experiments were analyzed by non-regression using Prism 8.0 (GraphPad Software, San Diego, USA).

[0064] Using GraphPad Prism 8.0, the fluorescent ligand association data was fitted to a global fitting model as follows, and the following equation was used to determine kon and k off These were calculated simultaneously. Y=Y max *(1-exp(-1*k ob *X)) (Formula 1) In the formula, k ob =[L]*k on +k off

[0065] k ob This is equal to the observed rate of ligand association, k on and k off These are the association and dissociation rate constants of the fluorescent ligand, respectively. In this globally fitted model of tracer binding, the tracer concentration [L] is fixed, and k on and k off k is a shared parameter, but obs This can be changed. Here, Y is the level of the tracer bound to the receptor, and Y max is the level of tracer binding in equilibrium, where X is expressed in units of time (e.g., minutes), and k obs This is the rate at which the state approaches equilibrium (for example, min -1 )

number

[0066] Saturated coupling data were analyzed by nonlinear regression following a one-site equation, with global fitting of the overall and NSB. The fluorescent ligand dissociation constant (K) was calculated using the following equation. d Individual estimates for ) were calculated. In the formula, L is the fluorescent ligand concentration:

[0067] By fitting the total dataset and NSB dataset globally (simultaneously) and sharing the slope values, K d and B max A single best fit value is obtained for both.

[0068] We fitted the competitive substitution-joint data to a sigmoid (variable gradient) curve using the "four-parameter logistic equation": Y = Minimum value + (Maximum value - Minimum value) / (1 + 10) (logIC50-X)×ヒル係数 ) (Formula 3)

[0069] The IC2000 (IC2000) was obtained from the inhibition curve using the method of Cheng and Prusoff (C. Yung-Chi, WH. Prusoff, Biochem. Pharmacol. 1973, 22, 3099-3108). 50 The value is K i It was converted to a value.

[0070] The association and dissociation rates of unlabeled antagonists were calculated using the following formula, first described in Motulsky, HJ; Mahan, LCMol.Pharmacol. 1984, 25, 1-9, and modified to account for photobleaching in Schiele, F. et al. Anal. Biochem. 2015, 468, 42-9.

number

[0071] Here, X = time (minutes), Y = specific binding (e.g., CPM or HTRF unit, e.g., HTRF ratio 520nm / 620nm × 10'000), k1 = k on Tracer (M -1 minutes -1 ), k²=k off Tracer (minutes) -1 ), L = concentration of the tracer used (nM), I = concentration of the unlabeled ligand (nM). By fixing the above parameters, it becomes possible to calculate the following: k3 = association rate constant of the unlabeled ligand (M -1 minutes -1 ), k4 = dissociation rate constant of unlabeled ligand (min -1 ), B max = Maximum specific bond of the system at equilibrium (e.g., CPM or HTRF units, e.g., HTRF ratio 520nm / 620nm × 10'000), Kdrift = Signal drift. [Table 1]

[0072] cAMP hCB2R Functional Assay Homogeneous time-resolved fluorescence (HTRF) assay The homogeneous time-resolved fluorescence (HTRF) cAMP assay was performed according to the manufacturer's protocol for the cAMP-Gs Dynamic kit (Cisbio). Briefly, a CHO cell line stably overexpressing the CB2 receptor was maintained in Ham's F12 supplemented with 10% FBS, 100 U / ml penicillin and 100 μg / ml streptomycin (Gibco-ThermoFisher) and 400 μg / ml G418 (ThermoFisher). For the CB2 compound assay, cells were harvested in cell dissociation buffer and 0.4*10 6 Cells were resuspended in F-12 K at a concentration of cells / mL and dispensed into 384-well low-volume plates at a rate of 2000 cells / 5 μL / well. Cells were stimulated at room temperature for 15 minutes with a compound diluted in stimulation buffer (2.5 μL / well). Subsequently, 2.5 μL of 25 μM forsculin was added. After 15 minutes of incubation, the reaction was stopped with 5 μL / well of cAMP-d2 conjugate working solution, followed by 5 μL / well of anti-cAMP cryptotate working solution. After incubation at room temperature for 1 hour, the plates were read with a PerkinElmer Envision reader and time-resolved fluorescence resonance energy transfer detection was performed at 620 nm and 665 nm.

[0073] Quantitative and statistical analysis All HTRF ratio datasets for the test compounds were normalized to the Emax (100%) of CP55940, and the mean ± mean standard error (SEM) of 2-3 independent experiments performed in technically replicated experiments was obtained. [Table 2]

[0074] Use of the compound of the present invention The compound of formula (I) is a modulator of CB2R pharmacology and a fluorescent probe with high affinity for CB2R. The fluorescent probe maintains excellent affinity and specificity for CB2R regardless of the specific fluorophore used, and is therefore an elaborate high-resolution tool for investigating the localization, expression levels, and protein distribution of CB2R in health and disease, structure, kinetics, and function in vitro, in live cells, and in vivo. The inverse agonist functionality of the fluorescent probe promises to investigate the receptor population without inducing receptor activation and associated agonist-mediated internalization events at CB2R. Furthermore, those skilled in the art can select specific fluorophores from reported examples (cell permeability / impermeability, environmental sensitivity / insensitivity, tuned wavelengths of absorption and emission, etc.) to investigate specific receptor-related events and / or target membrane-bound intracellular compartmentalized receptor populations. The probe can also be applied to cell transport studies using flow cytometry fluorescence-activated cell sorting (FACS) experiments or fluorescence confocal live-cell imaging. Certain probes (such as Examples 30 and 31) are particularly well-suited for performing these experiments without disrupting cellular homeostasis due to their functionalization with cleavable motifs that allow ligand dissociation after covalent labeling. Due to the covalent nature of the labeling, these probes are particularly well-suited for imaging low-abundance target proteins. These probes can be used to construct FRET sensors for membrane-bound and intracellular protein targets, which can then be used to investigate ligand-protein interactions in real time via TR-FRET. Novel CB2R modulators exhibit potent responses and possess functionalization profiles ranging from full agonism, partial agonism, antagonistism, and inverse agonism. These compounds promise to deliver finely tuned pharmacological interventions at CB2R that improve disease by addressing underlying dysregulation.

[0075] In one embodiment, the present invention relates to a compound of formula (I) described herein (R) for use as a pharmaceutical. 1The present invention provides a hydroxyl compound (selected from hydroxyl compounds and amino compounds) or a pharmaceutically acceptable salt thereof.

[0076] In one embodiment, the present invention relates to a method for treating or preventing a disease or disorder related to CB2R in a subject requiring treatment or prevention thereof, comprising a therapeutically effective amount of the compound of formula (I) described herein (R 1 The present invention provides a method comprising administering a hydroxyl or amino (selected from hydroxyl and amino) or a pharmaceutically acceptable salt thereof to a subject requiring such administration.

[0077] In one embodiment, the present invention relates to a compound of formula (I) described herein for use in the treatment or prevention of diseases or disorders related to CB2R. 1 The present invention provides a hydroxyl compound (selected from hydroxyl compounds and amino compounds) or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the present invention relates to the treatment or prevention of diseases or disorders related to CB2R, using a compound of formula (I) described herein (R 1 The use of a hydroxyl or amino compound (selected from hydroxyl and amino compounds) or a pharmaceutically acceptable salt thereof is provided.

[0079] In one embodiment, the present invention relates to the manufacture of a pharmaceutical product for the treatment or prevention of a disease or disorder related to CB2R, comprising a compound of formula (I) (R) described herein. 1 The use of a hydroxyl or amino compound (selected from hydroxyl and amino compounds) or a pharmaceutically acceptable salt thereof is provided.

[0080] In preferred embodiments, the disease or disorder associated with CB2R is selected from hypertension, inflammation, peripheral pain, neuropathic pain, gastrointestinal disorders, autoimmune diseases, pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, hepatic fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephritis, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning sensation, hypertrophic scarring, keloids, gingivitis, fever, cirrhosis, tumors, bone density regulation, neurodegeneration, stroke, transient ischemic attack, uveitis, renal fibrosis, arthritis, neuroinflammation, asthma, osteoporosis, mental disorders, psychosis, cancer, encephalitis, malaria, immunodeficiency, rheumatoid arthritis, and allergies.

[0081] In one embodiment, the present invention relates to a compound of formula (I) described herein for use as a fluorescent probe for cannabinoid receptor 2 (CB2R), 1 is the base [ka] X, p and R 4 The present invention provides a pharmaceutically acceptable salt thereof (as described herein).

[0082] In a further embodiment, the present invention relates to a compound of formula (I) described herein as a fluorescent probe or bioorthogonal probe for cannabinoid receptor 2 (CB2R), or a compound of formula (R) described herein. 1 is the base [ka] X, p and R 4 This specification provides for the use of (as described herein) or a pharmaceutically acceptable salt thereof.

[0083] In a further embodiment, the present invention relates to a compound of formula (I) described herein (wherein R 1 is the base [ka] X, p and R 4 The present invention provides a method for imaging cannabinoid receptor 2 (CB2R), comprising contacting it with a pharmaceutically acceptable salt thereof (as described herein).

[0084] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

[0085] In one embodiment, a pharmaceutical composition according to Example 33 or Example 34 is provided.

[0086] Compounds of formula (I) and their pharmaceutically acceptable salts and esters may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injectable solutions).

[0087] Compounds of formula (I) and their pharmaceutically acceptable salts and esters can be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid, or their salts can be used, for example, as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules.

[0088] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0089] Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0090] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0091] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0092] Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances of therapeutic value.

[0093] Dosage can be varied widely and, of course, adapted to the individual requirements of each specific case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), may be appropriately divided into 1 to 3 individual doses, for example, of the same amount. However, it is clear that the upper limits given herein can be exceeded where indicated. [Examples]

[0094] The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0095] If the preparation is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0096] General synthesis methods procedure Unless otherwise specified, all reactions were carried out under a nitrogen atmosphere.

[0097] chemicals All chemicals and solvents were purchased from commercial suppliers and used without further purification. DMF, DMSO, THF, Et2O, MeCN, toluene, benzene, and CH2Cl2 were dried under a dry nitrogen atmosphere using 4Å molecular sieves or an LC Technology Solutions solvent purification system (SP-1). Pyridine and i-Pr2NEt were distilled from KOH under a dry nitrogen atmosphere. Et3N was distilled from CaH2 under a dry nitrogen atmosphere.

[0098] chromatography Thin-layer chromatography (TLC) for analysis uses Merck silica gel 60 F 254 The reaction was performed on TLC glass plates. The reaction products were purified by flash column chromatography (FCC) using Sigma Aldrich silica with a particle size of 230-400 mesh, 60 Å, and an overpressure of 0.3-0.5 bar.

[0099] Nuclear magnetic resonance spectroscopy NMR spectra were acquired using Bruker AVIII HD 600MHz, 500MHz, and 400MHz spectrometers operating at the indicated spectrometer frequencies given in MHz for the specified nuclei. 1 The 1H NMR spectrum is reported with solvent resonances as reference (7.26 ppm CDCl3, 3.31 ppm CD3OD, 5.32 ppm CD2Cl2, 7.16 ppm C6D6, 2.50 ppm DMSO-d6). Peaks are reported as (s=singlet, bs=broad singlet, d=doublet, bt=broad triplet, t=triplet, q=quadruplet, m=multilet or undissolved, coupling constant (Hz), integral). 13 The 13C NMR spectrum is, 1The measurements were recorded using 1H decoupling and reported in ppm, with solvent resonances as the reference (77.16 ppm CDCl3, 49.00 ppm CD3OD, 54.00 ppm CD2Cl2, 128.06 ppm C6D6, and 39.52 ppm DMSO-d6). Service measurements were performed by the NMR service team at the Laboratory for Organische Chemie, ETH Zurich.

[0100] High resolution mass spectrometry High-resolution mass spectrometry data were obtained using Bruker Daltonics maXis ESI-QTOF or Bruker Daltonics maXiS II ESI-QTOF spectrometers at the ETH Zurich Mass Spectrometry Service and reported as (m / z).

[0101] Infrared spectroscopy The infrared (IR) spectrum was measured neatly using a Perkin-Elmer UATR Two FT-IR Spectrometer, and the maximum band value was defined as the wavenumber (cm²). -1 ) will be reported.

[0102] optical rotation Optical rotation ([α] D T The polarity was determined using a Jasco P-2000 Polarimeter (10 cm, 1.5 mL cell).

[0103] X-ray diffraction X-ray diffraction was measured using the XtaLAB Synergy R, HyPix-Arc 150 diffractometer.

[0104] Half-part chiral SFC: Separation was performed using a Prep-SFC-100 half-part system supplied by Daicel, Chiral Technology, with a column (20 × 250 mm, 5 μm) and a flow of solvent A (CO2) and co-solvent B at 90 mL / min, as specified by one of the following methods: Method 1. Column: Chiralpak IC, B=25% i-PrOH Method 2. Column: Chiralpak IK, B=18% i-PrOH Method 3. Column: Chiralcel IK, B=15% MeOH Method 4. Column: Chiralcel IK, B=16% MeOH Method 5. Column: Chiralcel OD-H, B=25% (EtOH:n-heptane, 1:1) Method 6. Column: Chiralcel OD-H, B=20% (EtOH:n-heptane, 1:1)

[0105] When separated by the chiral SFC method described above, for Examples 1 to 12, the absolute stereochemistry of the α C(2') and homobenzyl positions relative to the gem-dimethyl group was arbitrarily assigned as R for the first enantiomer to elute and as S for the second enantiomer to elute.

[0106] When the derivative example 32 was determined by X-ray crystal structure analysis and separated by the chiral SFC method described above, the first enantiomer (A) of racemic mixture F9-A had an absolute stereochemistry of S at the α C(2') position relative to the gem-dimethyl group and at the homobenzyl position. Therefore, Examples 14, 15, 17-31 incorporating F9-A or F9-B have a C(2') configuration assigned as S or R, respectively.

[0107] The alphanumeric sequence determination in the synthesis process described below is based on the alphanumeric sequence determination used in Scheme 1 above.

[0108] Example 1 ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step j) 3-(3,5-dimethoxyphenyl)-1,1,1-trifluoro-3-methylbutan-2-ol To a solution of 2-(3,5-dimethoxyphenyl)-2-methylpropanal (2.00 g, 9.60 mmol, 1.0 equivalent, CAS RN: 120078-30-0) in anhydrous THF (16 mL), Me3SiCF3 (1.85 mL, 12.5 mmol, 1.3 equivalents, CAS RN: 81290-20-2) was added at -78°C, followed by TBAF solution (1.0 M, 960 μL, 960 μmol, 0.1 equivalent in THF). The mixture was warmed to room temperature and stirred overnight. Further Me3SiCF3 (710 μL, 4.80 mmol, 0.5 equivalents) and TBAF solution (1.0 M, 960 μL, 960 μmol, 0.1 equivalent in THF) were added dropwise, and the mixture was stirred for 1 hour to complete the reaction. The mixture was quenched with water (25 mL), extracted with Et2O (3 × 25 mL), and the organic extract was concentrated under vacuum. The crude mixture was dissolved in THF (10 mL) and 1 M aqueous HCl (10 mL) and refluxed for 1 hour. The mixture was cooled to room temperature, extracted with Et2O (3 × 25 mL), and the combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (using SiO2; 0-30% Et2O in hexane) to obtain the final product as a colorless liquid (2.50 g, 94%).

[0109] 1 H NMR(400 MHz,CDCl3)δ 6.55(d,J=2.2 Hz,2H),6.37(t,J=2.2 Hz,1H),4.06(td,J=7.5,5.6 Hz,1H),3.80(s,6H),2.28(d,J=5.6 Hz,1H),1.49-1.42(m,6H). 13 C NMR(101 MHz,CDCl3)δ 160.9,148.0,125.4(q,J=284.4 Hz),105.4,98.0,77.1(q,J=28.1 Hz),55.4,41.2,24.8(q,J=2.4 Hz),23.7(q,J=2.0 Hz). 19 F NMR(377 MHz,CDCl3)δ-71.2.IR(neat,ν max / cm-1 ):3472,2942,2841,1597,1458,1425,1270,1156.HRMS(ESI):m / z=279.1204 [M+H] + (Calculated value C) 13 H 18 F3O3m / z=279.1203)

[0110] Step k) 3-(3,5-dimethoxyphenyl)-1,1,1-trifluoro-3-methylbutan-2-one To a solution of 3-(3,5-dimethoxyphenyl)-1,1,1-trifluoro-3-methylbutan-2-ol (2.70 g, 9.70 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (29 mL), DMP (5.35 g, 12.6 mmol, 1.3 equivalents) was added all at once at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under vacuum, and the residue was polished with pentane (50 mL). The white solid was filtered and washed with pentane (2 × 50 mL). The organic washing solution was concentrated under vacuum, and the crude product was purified by flash column chromatography (using SiO2; 0-15% Et2O in hexane) to obtain the final product as a colorless liquid (2.10 g, 78%).

[0111] 1 H NMR(400 MHz,CDCl3)δ 6.39(t,J=2.2 Hz,1H),6.34(d,J=2.2 Hz,2H),3.78(s,6H),1.58(q,J=0.8 Hz,6H). 13 C NMR(101 MHz,CDCl3)δ 193.8(q,J=31.2 Hz),161.4,142.7,116.2(q,J=295.1 Hz),104.3,99.1,55.4,50.2,24.7(q,J=1.4 Hz). 19 F NMR(377 MHz,CDCl3)δ-71.0.IR(neat,ν max / cm -1 ):2941,2841,1745,1596,1458,1426,1371,1341,1299,1261,1203.HRMS(ESI):m / z=277.1047 [M+H] + (Calculated value C)13 H 16 F3O3m / z = 277.1046).

[0112] Step l) 1,3-dimethoxy-5-(2-methyl-3-(trifluoromethyl)octa-3-en-2-yl)benzene To a suspension of pentyltriphenylphosphonium bromide (1.92 g, 4.63 mmol, 3.2 equivalents) in dry THF (40 mL), n-BuLi (1.6 M in hexane, 2.71 mL, 4.34 mmol, 3.0 equivalents) was added dropwise at -78°C. The solution was stirred at -78°C for 10 minutes, warmed to room temperature, and stirred for another 30 minutes. Subsequently, 3-(3,5-dimethoxyphenyl)-1,1,1-trifluoro-3-methylbutan-2-one (400 mg, 1.45 mmol, 1.0 equivalent) was dissolved in dry THF (1 mL) and added dropwise to the mixture at 0°C. The mixture was stirred overnight at room temperature, quenched with saturated NH4Cl aqueous solution (25 mL), diluted with Et2O (25 mL), and the phases were separated. The aqueous phase was extracted with Et2O (2 × 25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography (using SiO2; hexane with 0-10% Et2O) to obtain separate E-1,3-dimethoxy-5-(2-methyl-3-(trifluoromethyl)octa-3-en-2-yl)benzene (210 mg, 44%) and Z-1,3-dimethoxy-5-(2-methyl-3-(trifluoromethyl)octa-3-en-2-yl)benzene (145 mg, 30%) isomers, each as a pale yellow liquid.

[0113] E-isomer 1 H NMR(500 MHz,CDCl3)δ 6.48(d,J=2.2 Hz,2H),6.30(t,J=2.2 Hz,1H),6.14(tq,J=7.6,2.0 Hz,1H),3.78(s,6H),1.64-1.57(m,2H),1.51(q,J=1.2 Hz,6H),1.13-0.98(m,4H),0.70(t,J=7.1 Hz,3H). 1313C NMR (126 MHz, CDCl3) δ 160.8, 153.5, 138.18 (q, J = 7.7 Hz), 135.30 (q, J = 24.4 Hz), 125.17 (q, J = 274.4 Hz), 104.5, 97.2, 55.4, 41.8, 30.5, 29.91 (q, J = 1.9 Hz), 28.3, 22.4, 13.9. 19 19F NMR (471 MHz, CDCl3) δ -60.9. IR (neat, ν max / cm -1 ): 2958, 2931, 2874, 2838, 1649, 1596, 1457, 1423, 1290. HRMS (ESI): m / z = 331.1882 [M+H] + (Calculated for C 18 H 26 F3O2 m / z = 331.1879).

[0114] Z-isomer 1 1H NMR (500 MHz, CDCl3) δ 6.43 (d, J = 2.2 Hz, 2H), 6.32 (t, J = 2.2 Hz, 1H), 6.04 (t, J = 7.7 Hz, 1H), 3.78 (s, 6H), 2.41 - 2.33 (m, 2H), 1.53 - 1.48 (m, 2H), 1.47 (s, 6H), 1.45 - 1.36 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 160.8, 150.7, 137.4 (q, J = 25.2 Hz), 137.0 (q, J = 3.5 Hz), 124.9 (q, J = 279.4 Hz), 104.1, 97.4, 55.3, 43.1, 31.8, 29.6, 28.5, 22.5, 14.0. 19 19F NMR (471 MHz, CDCl3) δ -53.9. IR (neat, ν max / cm -1 ): 2959, 2933, 2874, 2838, 1652, 1596, 1457, 1424, 1204. HRMS (ESI): m / z = 331.1881 [M+H] + (Calculated for C 18 H 26 F3O2 m / z = 331.1879).

[0115] Step m) 1,3-dimethoxy-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene Note: Pd / C in MeOH can spontaneously combust upon contact with air. Pd (10 wt% above C, 644 mg, 605 μmol, 1.0 equivalent) was placed in a flask, and the atmosphere was changed three times with argon. Then, the catalyst was carefully moistened with MeOH (8 mL), and a solution of 1,3-dimethoxy-5-(2-methyl-3-(trifluoromethyl)octa-3-en-2-yl)benzene (200 mg, 605 μmol, 1.0 equivalent) in MeOH (2.0 mL) was added. The mixture was stirred in an autoclave under a 7 bar H2 pressure for 7 days. The atmosphere was changed to argon, and the suspension was carefully filtered through a Celite pad, washed with ethyl acetate, and concentrated under vacuum. The product was obtained as a pale yellow oily substance (180 mg, yield 89%) by purification by flash column chromatography (SiO2; 0-5% Et2O in hexane).

[0116] 1 H NMR(500 MHz,CDCl3)δ 6.49(d,J=2.2 Hz,2H),6.34(t,J=2.2 Hz,1H),3.80(s,6H),2.37(qdd,J=10.3,7.7,2.7 Hz,1H),1.54-1.43(m,1H),1.41(d,J=2.0 Hz,3H),1.35(s,3H),1.29-1.20(m,1H),1.18-0.97(m,6H),0.78(t,J=7.2 Hz,3H). 13 C NMR(126 MHz,CDCl3)δ 160.7,151.5,129.07(q,J=283.3 Hz),105.0,97.4,55.4,52.50(q,J=22.1 Hz),40.4,31.7,29.4,28.33(q,J=2.5 Hz),26.26(q,J=2.4 Hz),23.80(q,J=1.8 Hz),22.3,14.0. 19 F NMR(471 MHz,CDCl3)δ-62.1.IR(neat,ν max / cm -1):2957,2873,1597,1458,1206,1156.HRMS(ESI):m / z=333.2033 [M+H] + (Calculated value C) 18 H 28 F3O2m / z = 333.2036).

[0117] Step n) 5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol To a solution of 1,3-dimethoxy-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene (100 mg, 301 μmol, 1.0 equivalent) in anhydrous CH2Cl2 (3.0 mL), BBr3 (86 μL, 903 μmol, 3.0 equivalent) was added dropwise at 0°C, and the solution was stirred at 0°C for 2 hours. The mixture was carefully quenched with saturated NaHCO3 aqueous solution (5 mL) and diluted with Et2O (10 mL). The layers were separated, and the aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-30% Â in hexane) yielded the product as a pale red oil (91 mg, 99%). The racemic mixture was divided by chiral SFC method 2 to obtain enantiomer (R)-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol A (38 mg, 42%, %ee>99%) and (S)-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol B (35 mg, 38%, %ee=98%).

[0118] 1 H NMR(400 MHz,CDCl3)δ 6.42(d,J=2.2 Hz,2H),6.23(t,J=2.2 Hz,1H),5.51(s,2H),2.30(qdd,J=10.2,7.5,2.6 Hz,1H),1.51-0.96(m,8H),1.34(q,J=1.9 Hz,3H),1.28(s,3H),0.79(t,J=7.1 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 156.4,152.6,128.93(q,J=283.4 Hz),106.3,100.8,52.52(q,J=22.1 Hz),40.1,31.7,29.4,27.6,26.20(q,J=2.4 Hz),24.3,22.3,14.0. 19 F NMR(376 MHz,CDCl3)δ-62.1.IR(neat,ν max / cm -1 ):3349,2957,2928,2872,1598,1459,1256,1148.HRMS(ESI):m / z=305.1721 [M+H] + (Calculated value C) 16 H 24 F3O2m / z=305.1723).(R)-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol A [α] 25 D = +17.570 ± 0.110 (c=1.0, CHCl3). (S)-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol B [α] 25 D =-16.414±0.153(c=1.0,CHCl3).

[0119] Process o)((1S,4S,5S)-4-(2,6-dihydroxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of (R)-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol A (17.9 mg, 58.8 μmol, 1.0 equivalent) and ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (16.3 mg, 64.7 μmol, 1.1 equivalent, pn=CA3171726A1) in CH2Cl2 (2.3 mL), pTsOH·H2O (3.1 mg, 16.4 μmol, 0.28 equivalent) was added, and the solution was stirred for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (4 mL), and the solution was diluted with Et2O (5 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 0-15% siRNA in hexane) yielded the product as a colorless foam (23.3 mg, 74%).

[0120] 1 H NMR(500 MHz,CDCl3)δ 6.34(s,2H),5.99(dt,J=3.0,1.5 Hz,1H),5.68(bs,2H),4.64(ddd,J=13.5,2.1,1.4 Hz,1H),4.51(ddd,J=13.6,2.4,1.6 Hz,1H),4.04-3.97(m,1H),2.36(dt,J=9.7,5.6 Hz,1H),2.33-2.22(m,3H),1.47(d,J=9.7 Hz,1H),1.45-1.38(m,1H),1.35(s,3H),1.34(s,3H),1.32-1.20(m,2H), 1.28(s,3H),1.23(s,9H),1.14-1.00(m,5H),0.98(s,3H),0.76(t,J=7.1 Hz,3H). 13C NMR(126 MHz,CDCl3)δ 178.7,155.2,149.8,149.3,129.1(q,J=283.3 Hz),120.1,112.5,106.7,66.6,52.4(q,J=22.1 Hz),47.5,44.2,41.1,39.8,39.1,37.9,31.6,29.4,28.1,28.1,27.4,26.1,26.0,23.6,22.2,20.9,14.0. 19 F NMR(471 MHz,CDCl3)δ-62.2.IR(neat,ν max / cm -1 ):3445,2942,2872,1707,1626,1578,1481,1254,1149.HRMS(ESI):m / z=561.3147 [M+Na] + (Calculated value C) 31 H 45 F3NaO4m / z=561.3162).[α] 25 D = +62.961 ± 0.119 (c=1.0, CHCl3).

[0121] Process p)((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate ((1S,4S,5S)-4-(2,6-dihydroxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (23.3 mg, 43.2 μmol, 1.0 equivalent) was dissolved in acetone (0.5 mL), to which (MeO)2SO2 (20.5 μL, 0.216 mmol, 5.0 equivalents) and K2CO3 (35.9 mg, 0.260 mmol, 6.0 equivalents) were added, and the pale purple suspension was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-10% Et2O in hexane) yielded the product as pale red wax (23.1 mg, 94%).

[0122] 1 1H NMR (500 MHz, CDCl3) δ 6.47 (s, 2H), 5.76 (dt, J = 2.9, 1.5 Hz, 1H), 4.61 - 4.54 (m, 1H), 4.51 (ddd, J = 12.2, 1.7, 1.2 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.74 (s, 6H), 2.31 (dddd, J = 20.6, 10.3, 7.4, 2.5 Hz, 1H), 2.20 - 2.10 (m, 2H), 2.02 (tt, J = 5.8, 1.9 Hz, 1H), 1.73 - 1.66 (m, 1H), 1.50 - 1.41 (m, 1H), 1.43 (s, 3H), 1.36 (s, 3H), 1.34 - 1.18 (m, 2H), 1.29 (s, 3H), 1.21 (s, 9H), 1.12 - 0.88 (m, 5H), 0.97 (s, 3H), 0.74 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 178.6, 158.6, 148.1, 137.5, 129.1 (q, J = 283.3 Hz), 126.1, 118.7, 103.1, 67.6, 56.0, 52.7 (q, J = 22.1 Hz), 47.6, 44.0, 41.1, 40.5, 39.0, 37.7, 31.5, 30.5, 29.4, 28.8, 27.6, 27.4, 26.4, 26.2, 22.2, 21.2, 14.0. 19 19F NMR (471 MHz, CDCl3) δ -62.1. IR (neat, ν max / cm -1 ): 2957, 2932, 2870, 1727, 1605, 1575, 1461, 1412, 1150. HRMS (ESI): m / z = 589.3470 [M + Na]<00002^{29}>(Calculated for C 33 H 49 F3NaO4 m / z = 589.3475). [α] 25 D = +73.052 ± 0.280 (c = 1.0, CHCl3).

[0123] Step q)((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (26.1 mg, 46.0 μmol, 1.0 equivalent) in CH2Cl2 (0.4 mL) was cooled to 0°C, and DIBAL (1.0 M in hexane, 97 μL; 96.7 μmol, 2.1 equivalents) was added dropwise. The mixture was stirred at 0°C for 15 minutes, then quenched with saturated Rochelle salt aqueous solution (4 mL), and diluted with Et2O (5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The phases were separated, and the aqueous phase was extracted with Et2O (2 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 5-20% siRNA in hexane) yielded the product as a clear oily substance (18.3 mg, 82%).

[0124] 1 H NMR(500 MHz,CDCl3)δ 6.47(s,2H),5.69(dt,J=2.8,1.4 Hz,1H),4.07(ddd,J=1.9,1.3,0.6 Hz,2H),4.03-3.98(m,1H),3.75(s,6H),2.31(qdd,J=10.3,7.4,2.6 Hz,1H),2.25-2.16(m,2H),2.04(tt,J=5.8,1.9 Hz,1H),1.69(d,J=8.3 Hz,1H),1.50-1.41(m,1H),1.43(s,3H),1.36(s,3H),1.34-1.16(m,2H),1.31(s,3H),1.12-0.89(m,5H),0.97(s,3H),0.74(t,J=7.1 Hz,3H). 13C NMR(126 MHz,CDCl3)δ 158.6,148.1,142.2,129.1(q,J=283.4 Hz),123.6,118.8,103.2,66.8,56.1,52.7(q,J=22.2 Hz),47.6,44.0,41.0,40.5,37.6,31.6,29.4,28.8,28.0,26.4,26.3,23.3,22.2,21.2,14.0. 19 F NMR(471 MHz,CDCl3)δ-62.1.IR(neat,ν max / cm -1 ):3373,2929,2866,1605,1574,1460,1412,1239,1119.HRMS(ESI):m / z=505.2903 [M+Na] + (Calculated value C) 28 H 41 F3NaO3m / z=505.2900).[α] 25 D = +97.242 ± 0.182 (c=1.0, CHCl3).

[0125] Example 2 ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Process o)((1S,4S,5S)-4-(2,6-dihydroxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of (S)-5-(2-methyl-3-(trifluoromethyl)octan-2-yl)benzene-1,3-diol B (16.6 mg, 54.5 μmol, 1.0 equivalent) and ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (15.1 mg, 60.0 μmol, 1.1 equivalent) in CH2Cl2 (2.3 mL), pTsOH·H2O (2.9 mg, 15.2 μmol, 0.28 equivalent) was added, and the solution was stirred for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (4 mL), and the solution was diluted with Et2O (5 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 0-15% siRNA in hexane) yielded the product as a pale yellow foam (23.0 mg, 78%).

[0126] 1 H NMR(500 MHz,CDCl3)δ 6.34(s,2H),6.00(dt,J=3.1,1.6 Hz,1H),5.76(bs,2H),4.64(ddd,J=13.5,2.0,1.4 Hz,1H),4.51(ddd,J=13.5,2.3,1.5 Hz,1H),4.02-3.98(m,1H),2.36(dt,J=9.7,5.6 Hz,1H),2.33-2.22(m,3H),1.46(d,J=9.7 Hz,1H),1.45-1.38(m,1H),1.35(s,3H),1.34(s,3H),1.33-1.19(m,2H), 1.28(s,3H),1.23(s,9H),1.16-0.96(m,5H),0.98(s,3H),0.76(t,J=7.1 Hz,3H). 13C NMR(126 MHz,CDCl3)δ 178.7,155.2,149.8,149.3,129.1(q,J=283.5 Hz),120.1,112.4,106.7,66.6,52.5(q,J=22.2 Hz),47.5,44.2,41.1,39.8,39.1,37.9,31.6,29.4,28.1,28.1,27.4,26.1,26.0,23.6,22.2,20.9,14.0. 19 F NMR(471 MHz,CDCl3)δ-62.2.IR(neat,ν max / cm -1 ):3446,2942,2872,1707,1626,1578,1481,1254,1149.HRMS(ESI):m / z=561.3154 [M+Na] + (Calculated value C) 31 H 45 F3NaO4m / z=561.3162).[α] 25 D = +38.128 ± 0.330 (c=1.0, CHCl3).

[0127] Process p)((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate ((1S,4S,5S)-4-(2,6-dihydroxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (23.0 mg, 42.7 μmol, 1.0 equivalent) was dissolved in acetone (0.5 mL), to which (MeO)2SO2 (20.2 μL, 0.214 mmol, 5.0 equivalents) and K2CO3 (35.4 mg, 0.256 mmol, 6.0 equivalents) were added, and the pale purple suspension was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-10% Et2O in hexane) yielded the product as pale red wax (23.5 mg, 97%).

[0128] 1 H NMR(500 MHz,CDCl3)δ 6.47(s,2H),5.88-5.64(m,1H),4.61-4.55(m,1H),4.51(ddd,J=12.2,1.7,1.3 Hz,1H),4.02-3.95(m,1H),3.74(s,6H),2.31(dddd,J=20.4,10.1,7.2,2.5 Hz,1H),2.19-2.11(m,2H),2.06-1.96(m,1H),1.73-1.64(m,1H),1.49-1.41(m,1H),1.42(s,3H),1.3 6(s,3H),1.35-1.19(m,2H),1.29(s,3H),1.21(s,9H),1.12-0.86(m,5H),0.97(s,3H),0.74(t,J=7.1 Hz,3H). 13 C NMR(126 MHz,CDCl3)δ 178.6,158.6,148.1,137.5,129.1(q,J=283.3 Hz),126.2,118.7,103.1,67.6,56.0,52.7(q,J=22.1 Hz),47.5,43.9,41.0,40.5,39.0,37.7,30.5,29.4,28.8,27.6,27.4,26.4,26.2,23.3,22.1,21.2,14.0. 19 F NMR(471 MHz,CDCl3)δ-62.1.IR(neat,ν max / cm -1 ):2956,2932,2870,1727,1605,1575,1461,1412,1149.HRMS(ESI):m / z=589.3460 [M+Na] + (Calculated value C) 33 H 49 F3NaO4m / z=589.3475).[α] 25 D = +58.259 ± 0.119 (c=1.0, CHCl3).

[0129] Process q)((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (24.0 mg, 42.3 μmol, 1.0 equivalent) in CH2Cl2 (0.4 mL) was cooled to 0°C, and DIBAL (1.0 M in hexane, 89 μL; 88.9 μmol, 2.1 equivalents) was added dropwise. The mixture was stirred at 0°C for 15 minutes, then quenched with saturated Rochelle salt aqueous solution (4 mL), and diluted with Et2O (5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The phases were separated, and the aqueous phase was extracted with Et2O (2 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 5-20% siRNA in hexane) yielded the product as a clear oily substance (16.6 mg, 81%).

[0130] 1 H NMR(400 MHz,CDCl3)δ 6.47(s,2H),5.69(dt,J=2.8,1.4 Hz,1H),4.11-4.04(m,2H),4.04-3.96(m,1H),3.75(s,6H),2.32(qdd,J=10.2,7.4,2.5 Hz,1H),2.25-2.16(m,2H),2.04(tt,J=5.9,1.9 Hz,1H),1.68(d,J=8.2 Hz,1H),1.51-1.45(m,1H),1.43(s,3H),1.36(s,3H),1.34-1.16(m,2H),1.31(s,3H),1.12-0.87(m,5H),0.97(s,3H),0.74(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 158.7,148.1,142.2,129.1(d,J=283.3 Hz),123.6,118.8,103.2,66.8,56.0,52.7(q,J=22.0 Hz),47.6,44.0,41.0,40.5,37.6,31.6,29.4,28.8,28.0,26.4,26.2,23.3,22.2,21.2,14.0. 19F NMR(376 MHz,CDCl3)δ-62.1.IR(neat,ν max / cm -1 ):3371,2929,2866,1605,1574,1459,1412,1239,1119.HRMS(ESI):m / z=505.2902 [M+Na] + (Calculated value C) 28 H 41 F3NaO3m / z=505.2900).[α] 25 D = +78.198 ± 0.132 (c=1.0, CHCl3).

[0131] Example 3 ((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step a) 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one

[0132] A solution of 1-iodopentane (3.82 mL, 29.2 mmol, 1.20 equivalents) in 3:2 pentane-Et2O (300 mL) was cooled to -78°C under an argon atmosphere, and t-BuLi (1.7 M in pentane, 38.0 mL, 64.6 mmol, 2.65 equivalents) was added dropwise. After adding the solution, the mixture was stirred at -78°C for 5 minutes, then allowed to reach room temperature and stand for 1 hour. The reaction mixture was cooled back to the original -78°C, and a solution of 2-(3,5-dimethoxyphenyl)-2-methylpropanenitrile (5.00 g, 24.4 mmol, 1.00 equivalent, CAS RN: 22972-63-0) in pentane (10 mL) was added all at once. The mixture was stirred at -78°C for 5 minutes, warmed to room temperature, and stirred for 1.5 hours. The reaction was quenched by adding 0.5 M HCl aqueous solution (50 mL). The organic solvent was removed under vacuum, and THF (150 mL) and 0.5 M HCl aqueous solution (100 mL) were added. The mixture was vigorously stirred overnight at room temperature. The mixture was diluted with RINKAN (150 mL), the layers were separated, and the aqueous phase was extracted with RINKAN (2 × 150 mL). The combined organic extracts were washed with 5% Na₂S₂O₃ aqueous solution (150 mL), followed by brine, dried over MgSO₄, and concentrated under vacuum. The product was obtained as a pale yellow liquid (6.10 g, 90%) by purification by flash column chromatography (SiO₂; using 0-15% Et₂O in hexane).

[0133] 1 H NMR(400 MHz,CDCl3)δ 6.36(d,J=2.2 Hz,2H),6.33(t,J=2.2 Hz,1H),3.75(s,6H),2.20(t,J=7.4 Hz,2H),1.50-1.43(m,2H),1.42(s,6H),1.23-1.02(m,4H),0.79(t,J=7.2 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 213.0,161.1,146.7,104.6,98.3,55.3,52.4,37.2,31.4,25.1,24.1,22.5,13.9.IR(neat,ν max / cm -1):2956,2932,2872,1708,1594,1456,1423,1205,1155.HRMS(ESI):m / z=279.1955 [M+H] + (Calculated value C) 17 H 27 O3m / z = 279.1955).

[0134] Step b) 2-(3,5-dimethoxyphenyl)-3-ethyl-2-methyloctan-3-ol To a solution of LaCl3·2LiCl (0.6 M in THF, 5.57 mL, 3.34 mmol, 1.0 equivalent), 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one (930 mg, 3.34 mmol, 1.0 equivalent) in dry THF (3.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and EtLi solution (benzene: 0.3 M in cyclohexane, 12.2 mL, 3.68 mmol, 1.1 equivalents) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. The mixture was quenched with saturated NH4Cl solution (10 mL) and H2O (10 mL), and diluted with Et2O (10 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (SiO2; 0-15% ethyl hexane), yielding a colorless oily product (932 mg, 99%).

[0135] 1 H NMR(400 MHz,CDCl3)δ 6.62(d,J=2.3 Hz,2H),6.34(t,J=2.2 Hz,1H),3.76(s,6H),1.60-1.41(m,4H),1.38(s,6H),1.30(s,1H),1.29-1.15(m,6H),0.85(t,J=6.8 Hz,3H),0.81(t,J=7.4 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 160.1,149.7,107.0,97.3,77.0,55.1,46.7,34.9,33.0,27.8,24.8,24.8,24.5,22.6,14.1,9.2.IR(neat,νmax / cm -1 ):3568,2954,2872,1594,1456,1421,1204,1154,1021.HRMS(ESI):m / z=331.2244 [M+Na] + (Calculated value C) 19 H 32 NaO3m / z = 331.2244).

[0136] Steps d and e) 1-(3-ethyl-2-methyloctan-2-yl)-3,5-dimethoxybenzene To a solution of 2-(3,5-dimethoxyphenyl)-3-ethyl-2-methyloctan-3-ol (932 mg, 3.02 mmol, 1.0 equivalent) in dried pyridine (12.0 mL), DMAP (73.8 mg, 604 μmol, 0.2 equivalents) was added. The mixture was cooled to 0°C, SOCl2 (661 μL, 9.07 mmol, 3.0 equivalents) was added dropwise, and the solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding 1 M aqueous HCl (30 mL) and diluted with HCl (50 mL). The phases were separated, and the aqueous phase was extracted with HCl (50 mL). The combined organic phases were washed with 0.5 M HCl (2 × 20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was dissolved in dry ethyl acetate (6.0 mL), and Pd (10% by weight above C, 161 mg, 151 μmol, 0.05 equivalents) was added. The resulting mixture was stirred in an autoclave at room temperature for 16 hours under an H2 pressure of 55 bar. The reaction mixture was then filtered through Celite, and the crude material was purified by flash column chromatography (SiO2; 0-10% ethyl acetate in hexane) to obtain the product as a colorless oil (830 mg, 94%).

[0137] 1 H NMR(400 MHz,CDCl3)δ 6.54(d,J=2.2 Hz,2H),6.32(t,J=2.2 Hz,1H),3.81(s,6H),1.47-1.00(m,11H),1.23(s,6H),0.86(t,J=7.2,3H),0.86(t,J=6.2 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 160.4,153.7,105.2,96.6,55.3,50.9,42.1,32.5,31.5,30.0,25.9,25.3,24.6,22.7,14.6,14.2.IR(neat,ν max / cm -1 ):2957,2932,2872,1595,1457,1421,1205,1155,1055.HRMS(ESI):m / z=315.2294 [M+Na] + (Calculated value C) 19 H 32 NaO2m / z = 315.2295).

[0138] Step f) 5-(3-ethyl-2-methyloctan-2-yl)benzene-1,3-diol To a solution of 1-(3-ethyl-2-methyloctan-2-yl)-3,5-dimethoxybenzene (890 mg, 3.04 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (30 mL), BBr3 (866 μL, 9.13 mmol, 3.0 equivalent) was added dropwise at 0°C, and the green solution was stirred at 0°C for 3 hours. The mixture was diluted with CH2Cl2 (30 mL) and carefully quenched with saturated NaHCO3 aqueous solution (30 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-40% Â in hexane) yielded the product as a golden oil (777 mg, 97%).

[0139] 1 H NMR(400 MHz,CDCl3)δ 6.43(d,J=2.2 Hz,2H),6.19(t,J=2.2 Hz,1H),5.38(bs,2H),1.37-1.10(m,9H),1.15(s,3H),1.14(s,3H),1.07-0.95(m,2H),0.84(t,J=7.1 Hz,3H),0.80(t,J=7.3 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 156.1,154.8,106.5,100.0,50.8,41.9,32.6,31.4,30.0,25.9,25.1,24.6,22.7,14.5,14.2.IR(neat,ν max / cm -1 ):3322,2959,2931,2873,1596,1465,1325,1150,991.HRMS(ESI):m / z=265.2164 [M+H] + (Calculated value C) 17 H 29 O2m / z = 264.2162.

[0140] Process o)((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of 5-(3-ethyl-2-methyloctan-2-yl)benzene-1,3-diol (52.0 mg, 197 μmol, 1.0 equivalent) and ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (54.6 mg, 216 μmol, 1.1 equivalent) in CH2Cl2 (6.7 mL), pTsOH·H2O (10.5 mg, 55.0 μmol, 0.28 equivalent) was added, and the solution was stirred for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (5 mL), and the solution was diluted with Et2O (10 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 0-20% pharmaceutically acceptable ammonium compounds in hexane) yielded the product as a colorless foam (72.0 mg, 73%).

[0141] 1H NMR(400 MHz,CDCl3)δ 6.35(s,2H),6.01(dt,J=3.1,1.7 Hz,1H),5.63(bs,2H),4.63(ddd,J=13.5,2.0,1.2 Hz,1H),4.51(ddd,J=13.5,2.4,1.6 Hz,1H),4.07-3.94(m,1H),2.40-2.33(m,1H),2.32-2.27(m,2H),1.49(d,J=9.6 Hz,1H),1.42-0.79(m,11H),1.34(s,3H),1.23(s,9H),1.15(s,3H),1.14(s,3H),0.98(s,3H),0.83(t,J=6.8 Hz,3H),0.82(t,J=7.3 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 178.6,154.9,151.6,149.5,120.5,111.5,107.0,66.6,50.8,47.5,44.3,41.5,41.1,39.1,3 7.9,32.5,31.3,30.0,28.2,27.4,26.0,25.7,25.2,24.6,22.7,20.9,14.5,14.2.IR(neat,ν max / cm -1 ):3453,2958,2931,2872,1730,1708,1625,1575,1480,1157.HRMS(ESI):m / z=521.3596 [M+Na] + (Calculated value C) 32 H 50 NaO4m / z=521.3601).[α] 25 D = +53.699 ± 0.155 (c=1.0, CHCl3).

[0142] Process p)((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of ((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (43.0 mg, 86.2 μmol, 1.0 equivalent) in acetone (0.9 mL), (MeO)2SO2 (40.9 μL, 431 μmol, 5.0 equivalents) and K2CO3 (71.5 mg, 517 μmol, 6.0 equivalents) were added, and the pale purple suspension was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-5% Et2O in hexane) yielded the product as pale red wax (40.0 mg, 88%).

[0143] 1 H NMR(500 MHz,CDCl3)δ 6.49(s,2H),5.78(dt,J=2.8,1.4 Hz,1H),4.60-4.56(m,1H),4.52-4.49(m,1H),4.02-3.98(m,1H),3.73(s,6H),2.22-2.11(m,2H),2.11-1.99(m,1H),1 .77-1.66(m,1H),1.44-1.00(m,11H),1.29(s,3H),1.22(s,3H),1.21(s,9H),1.21(s,3H),0.97(s,3H),0.84(t,J=7.3 Hz,3H),0.83(t,J=7.1 Hz, 3H). 13 C NMR(126 MHz,CDCl3)δ 178.6,158.4,150.4,137.3,126.6,117.7,103.5,67.7,56.0,51.1,47.5,44.0,42.1,41.0,39. 0,37.7,32.5,31.5,30.0,27.7,27.5,26.5,25.7,25.7,24.7,22.7,21.2,14.6,14.2.IR(neat,ν max / cm -1 ):2957,2930,2871,1728,1605,1573,1461,1410,1151.HRMS(ESI):m / z=549.3917 [M+Na] + (Calculated value C) 34 H 54NaO4m / z=549.3914).[α] 25 D = +67.051 ± 0.163 (c=1.0, CHCl3).

[0144] Process q) ((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (20.0 mg, 37.9 μmol, 1.0 equivalent) in CH2Cl2 (0.3 mL) was cooled to 0°C, and DIBAL (1.0 M in hexane, 80 μL; 79.7 μmol, 2.1 equivalents) was added dropwise. The mixture was stirred at 0°C for 15 minutes, then quenched with saturated Rochelle salt aqueous solution (4 mL), and diluted with Et2O (5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The phases were separated, and the aqueous phase was extracted with Et2O (3 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 5-20% siRNA in hexane) yielded the product as a clear wax (15.0 mg, 89%).

[0145] 1 H NMR(500 MHz,CDCl3)δ 6.50(s,2H),5.71(dt,J=2.8,1.4 Hz,1H),4.08-4.06(m,2H),4.01-3.99(m,1H),3.74(s,6H),2.25-2.17(m,2H),2.06(tt,J=5.8,1.8 Hz,1H),1.71(d,J=8.1 Hz,1H),1.45-0.98(m,11H),1.31(s,3H),1.22(s,3H),1.21(s,3H),0.97(s,3H),0.84(t,J=7.4 Hz,3H),0.83(t,J=7.1 Hz,3H). 13C NMR(126 MHz,CDCl3)δ 158.4,150.4,142.0,124.0,117.7,103.5,66.8,56.0,51.1,47.6,44.0,42.1,41.0,3 7.6,32.5,31.5,30.0,28.0,26.4,25.7,25.6,24.7,22.7,21.2,14.6,14.2.IR(neat,ν max / cm -1 ):3375,2956,2929,2868,1605,1572,1463,1410,1239,1122.HRMS(ESI):m / z=460.3778 [M+NH4] + (Calculated value C) 29 H 50 NO3m / z=460.3785).[α] 25 D = +88.454 ± 0.171 (c=1.0, CHCl3).

[0146] Example 4 ((1S,4S,5S)-4-(4-((R)-3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] A mixture of diastereomers of ((1S,4S,5S)-4-(4-((R)-3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol was purified by chiral SFC method 6 to obtain diastereomer A (4.5 mg, 27%, %ee>99%). [α] 25 D = +54.405 ± 0.207 (c = 1.0, CHCl3).

[0147] Example 5 ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step b) 4-(2-(3,5-dimethoxyphenyl)propan-2-yl)nonan-4-ol

[0148] Preparation of n-propyllithium: To a dry 3:2 pentane-Et2O (42 mL) solution of 1-iodopropane (414 μL, 4.25 mmol, 1.20 equivalents), t-BuLi (1.7 M in pentane, 5.52 mL, 9.38 mmol, 2.65 equivalents) was added dropwise at -78°C. After the addition, the solution was stirred at -78°C for 5 minutes, and then the mixture was allowed to reach room temperature and stand for 1 hour.

[0149] To a solution of LaCl3·2LiCl (0.6 M in THF, 5.90 mL, 3.54 mmol, 1.00 equivalent), 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one (985 mg, 3.54 mmol, 1.00 equivalent) in dry THF (3 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and a pre-prepared n-PrLi solution was added dropwise. The mixture was stirred at 0°C for 30 minutes, and then quenched with saturated NH4Cl solution (15 mL) and H2O (15 mL). The mixture was diluted with Et2O (15 mL), the phases were separated, and the aqueous phase was extracted with Et2O (3 × 15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (SiO2; 0-15% phenyl in hexane), yielding a colorless oily product (1.13 g, 99%).

[0150] 1H NMR(400 MHz,CDCl3)δ 6.62(d,J=2.2 Hz,2H),6.35(t,J=2.2 Hz,1H),3.79(s,6H),1.56-1.40(m,4H),1.37(s,6H),1.31-1.24(m,8H),1.24(s,1H),0.85(t,J=7.1 Hz,3H),0.84(t,J=7.2 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 160.2,149.8,107.1,97.5,77.1,55.4,46.8,38.1,35.6,33.1,24.9,24.6,22.8,18.2,15.2,14.2.IR(neat,ν max / cm -1 ):3572,2957,2871,1595,1457,1421,1205,1156,1054.HRMS(ESI):m / z=245.2405 [M+Na] + (Calculated value C) 20 H 34 NaO3m / z = 345.2400).

[0151] Steps d and e) 1,3-dimethoxy-5-(2-methyl-3-propyloctan-2-yl)benzene To a solution of 4-(2-(3,5-dimethoxyphenyl)propan-2-yl)nonan-4-ol (840 mg, 2.61 mmol, 1.0 equivalent) in dried pyridine (6.5 mL), DMAP (63.6 mg, 521 μmol, 0.2 equivalents) was added. The mixture was cooled to 0°C, SOCl2 (570 μL, 7.81 mmol, 3.0 equivalents) was added dropwise, and the solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding 1 M aqueous HCl (30 mL) and diluted with HCl (50 mL). The phases were separated, and the aqueous phase was extracted with HCl (50 mL). The combined organic phases were washed with 0.5 M HCl (2 × 20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was dissolved in dry SiO2 (7.0 mL), and Pd (10% by weight above C, 278 mg, 261 μmol, 0.1 equivalent) was added. The resulting mixture was stirred in an autoclave at room temperature for 24 hours under a hydrogen pressure of 75 bar. The reaction mixture was then filtered through Celite, and the crude material was purified by flash column chromatography (SiO2; 0-10% SiO2 in hexane) to obtain a colorless oily product (790 mg, 99%).

[0152] 1 H NMR(400 MHz,CDCl3)δ 6.56(d,J=2.3 Hz,2H),6.34(t,J=2.2 Hz,1H),3.81(s,6H),1.51(tt,J=7.4,2.6 Hz,1H),1.47-1.18(m,10H),1.25(s,6H),1.14-1.03(m,2H),0.96-0.78(m,6H). 13 C NMR(101 MHz,CDCl3)δ 160.4,153.5,105.2,96.6,55.1,48.7,41.9,34.5,32.5,32.0,29.8,25.6,25.4,23.1,22.6,14.7,14.1.IR(neat,ν max / cm -1 ):2956,2931,2871,1595,1456,1421,1205,1155,1055.GC-MS(EI):m / z=306.2552 [M] + (Calculated value C) 20 H 34O2m / z = 306.2553).

[0153] Step f) 5-(2-methyl-3-propyloctan-2-yl)benzene-1,3-diol To a solution of 1,3-dimethoxy-5-(2-methyl-3-propyloctan-2-yl)benzene (890 mg, 2.90 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (30 mL), BBr3 (827 μL, 8.71 mmol, 3.0 equivalents) was added dropwise at 0°C, and the green solution was stirred at 0°C for 4 hours. The mixture was diluted with CH2Cl2 (30 mL) and carefully quenched with saturated NaHCO3 aqueous solution (30 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-40% Â in hexane) yielded the product as a golden oily substance (800 mg, 99%).

[0154] 1 H NMR(400 MHz,CDCl3)δ 6.59(bs,2H),6.49(d,J=2.2 Hz,2H),6.23(t,J=2.1 Hz,1H),1.43-1.35(m,1H),1.34-1.16(m,10H),1.12(d,J=2.0 Hz,6H),1.04-0.92(m,2H),0.84(t,J=7.1 Hz,3H),0.78(t,J=6.9 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 155.8,155.0,106.8,100.2,48.6,41.8,34.4,32.5,31.9,29.7,25.6,25.2,23.1,22.7,14.7,14.2.IR(neat,ν max / cm -1 ):3324,2957,2930,2871,1596,1466,1325,1151,992.HRMS(ESI):m / z=279.2318 [M+H] + (Calculated value C) 18 H 31 O2m / z = 279.2319).

[0155] Process o)((1S,4S,5S)-4-(2,6-dihydroxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (60.0 mg, 236 μmol, 1.3 equivalents) was added to a solution of 5-(2-methyl-3-propyloctan-2-yl)benzene-1,3-diol (50.6 mg, 182 μmol, 1.0 equivalent) and pTsOH·H2O (9.7 mg, 50.8 μmol, 0.28 equivalents) in CH2Cl2 (7.0 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by the addition of saturated NaHCO3 aqueous solution (3 mL). The phases were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-10% siRNA in hexane) to obtain a white foamy substance (82.2 mg, 88%).

[0156] 1 H NMR(400 MHz,CDCl3)δ 6.35(s,2H),6.04-5.99(m,1H),5.90-5.51(bs,2H),4.67-4.59(m,1H),4.55-4.4 7(m,1H),4.04-3.99(m,1H),2.40-2.33(m,1H),2.32-2.27(m,2H),1.49(d,J=9.7 Hz,1H),1.35-0.91(m,12H),1.34(s,3H),1.23(s,9H),1.14(s,3H),1.13(s,3H),0.98(s,3H),0.84-0.80(m,1H),0.82(t,J=7.0 Hz, 3H), 0.80(t, J=7.0 Hz, 3H). 13C NMR(101 MHz,CDCl3)δ 178.7,154.9,151.5,149.4,120.6,111.5,107.0,66.6,48.7,47.5,44.3,41.4,41.1,39.1,37. 9,34.4,32.5,31.9,29.8,28.1,27.4,26.0,25.7,25.1,23.1,22.7,20.9,14.8,14.2.IR(neat,ν max / cm -1 ):3458,2956,2929,2870,1730,1708,1625,1574,1479,1462,1429,1366,1282,1232,1159,1026,837,757.HRMS(ESI):m / z=535.375 [M+Na] + (Calculated value C) 33 H 52 NaO4m / z=535.3758).[α] 25 D = +53.675 ± 0.246 (c=1.0, CHCl3).

[0157] Process p)((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate ((1S,4S,5S)-4-(2,6-dihydroxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (82.2 mg, 160 μmol, 1.0 equivalent) and K2CO3 (133 mg, 962 μmol, 6.0 equivalents) were suspended in acetone (1.6 mL). (MeO)2SO2 (76 μL, 80.2 μmol, 5.0 equivalents) was added to the suspension, and the mixture was stirred at room temperature for 19 hours. The suspension was filtered and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-15% Et2O in hexane) to obtain a pale pink oily substance (86.0 mg, 99%).

[0158] 1H NMR(400 MHz,CDCl3)δ 6.49(s,2H),5.81-5.76(m,1H),4.62-4.55(m,1H),4.54-4.48(m,1H),4.03-3.98(m,1H),3.74(s,6H),2.20-2.13(m,2H),2.08-2.01( m,1H),1.75-1.68(m,1H),1.46-0.97(m,12H),1.30(s,3H),1.22(s,12H),1.21(s,3H),0.98(s,3H),0.85-0.80(m,1H),0.82(t,J=7.1 Hz,3H),0.82(t,J=7.0 Hz, 3H). 13 C NMR(101 MHz,CDCl3)δ 178.7,158.4,150.4,137.3,126.6,117.7,103.5,67.7,56.0,48.9,47.6,44.0,42.0,41.0,39.0,3 7.7,34.6,32.5,32.1,29.9,27.7,27.5,26.5,26.0,25.4,23.1,22.7,21.2,14.8,14.2.IR(neat,ν max / cm -1 ):2955,2928,2868,1728,1605,1572,1461,1410,1280,1239,1151,1123.HRMS(ESI):m / z=563.4056 [M+Na] + (Calculated value C) 35 H 56 NaO4m / z=563.4071).[α] 25 D = +65.594 ± 0.383 (c = 1.0, CDCl3).

[0159] Step q) ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (86.0 mg, 159 μmol, 1.0 equivalent) in CH2Cl2 (1.6 mL) was cooled to 0°C, and DIBAL (1.0 M in hexane, 334 μL, 334 μmol, 2.1 equivalents) was added dropwise. The mixture was stirred at 0°C for 20 minutes, then diluted with CH2Cl2 (2 mL), and quenched with saturated Rochelle salt aqueous solution (5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The layers were separated, and the aqueous phase was extracted with Et2O (5 × 3 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (SiO2; 10-20% siRNA in hexane) yielded the product (61.6 mg, 85%) as a pale pink oily substance.

[0160] 1 H NMR(400 MHz,CDCl3)δ 6.50(s,2H),5.73-5.69(m,1H),4.08(s,2H),4.03-3.98(m,1H),3.74(s,6H),2.26-2.17(m,2H),2.09-2.03(m,1H),1.71(d,J=7.9 Hz,1H),1.47-1.39(m,1H),1.38-0.99(m,11 H),1.31(s,3H),1.22(s,3H),1.21(s,3H),0.97(s,3H),0.87-0.83(m,1H),0.83(t,J=7.0 Hz,3H),0.82(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 158.4,150.3,142.0,123.9,117.8,103.5,66.8,56.0,48.8,47.6,43.9,42.0,41.0,37.6 ,34.6,32.5,32.0,29.9,28.0,26.4,25.9,25.4,23.1,22.6,21.2,14.8,14.2.IR(neat,ν max / cm -1):3368,2954,2930,2868,1605,1571,1463,1409,1238,1121,831.HRMS(ESI):m / z=495.3234 [M+K] + (Calculated value C) 30 H 48 KO3m / z=495.3235).[α] 25 D = +92.576 ± 0.103 (c = 1.0, CDCl3).

[0161] Example 6 ((1S,4S,5S)-4-(4-(3-isopropyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step b) 2-(3,5-dimethoxyphenyl)-3-isopropyl-2-methyloctan-3-ol To a solution of LaCl3·2LiCl (0.6 M in THF, 6.00 mL, 3.59 mmol, 1.0 equivalent), 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one (1.00 g, 3.59 mmol, 1.0 equivalent) in dry THF (3.3 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and i-PrMgCl solution (1.4 M in THF, 2.82 mL, 3.95 mmol, 1.1 equivalent) was added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. The mixture was quenched with saturated NH4Cl solution (10 mL) and H2O (10 mL), and diluted with Et2O (10 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. When the crude material was purified by flash column chromatography (SiO2; 0-15% phenylethanol in hexane), the product was obtained as a colorless oil (820 mg, 71%).

[0162] 1H NMR(400 MHz,CDCl3)δ 6.65(d,J=2.3 Hz,2H),6.34(t,J=2.2 Hz,1H),3.78(s,6H),2.07(hept,J=7.0 Hz,1H),1.62(ddd,J=13.9,11.2,4.9 Hz,1H),1.50-1.38(m,1H),1.43(s,1H),1.41(s,3H),1.40(s,3H),1.35-1.12(m,6H),0.90-0.79(m,9H). 13 C NMR(101 MHz,CDCl3)δ 160.2,150.5,107.2,97.4,78.4,55.3,47.9,33.7,33.4,33.2,26.1,25.3,24.7,22.8,20.5,20.2,14.2.IR(neat,ν max / cm -1 ):3573,2955,1594,1457,1421,1204,1155,1052.HRMS(ESI):m / z=345.2398 [M+Na] + (Calculated value C) 20 H 34 NaO3m / z = 345.2400).

[0163] Steps d and e) 1-(3-isopropyl-2-methyloctan-2-yl)-3,5-dimethoxybenzene To a solution of 2-(3,5-dimethoxyphenyl)-3-isopropyl-2-methyloctan-3-ol (550 mg, 1.71 mmol, 1.0 equivalent) in dry pyridine (6.0 mL), DMAP (41.7 mg, 341 μmol, 0.2 equivalents) was added. The mixture was cooled to 0°C, SOCl2 (373 μL, 5.12 mmol, 3.0 equivalents) was added dropwise, and the solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding 1 M aqueous HCl (30 mL) and diluted with HCl (50 mL). The phases were separated, and the aqueous phase was extracted with HCl (50 mL). The combined organic phases were washed with 0.5 M HCl (2 × 20 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was dissolved in dry MeOH (3.0 mL), and Pd (10% by weight above C, 182 mg, 171 μmol, 0.1 equivalent) was added. The resulting mixture was stirred in an autoclave at room temperature for 48 hours under a H2 pressure of 75 bar. The reaction mixture was then filtered through Celite, and the crude material was purified by flash column chromatography (SiO2; 0-10% phenylethylamine in hexane) to obtain the product as a colorless oil (425 mg, 81%).

[0164] 1 H NMR(400 MHz,CDCl3)δ 6.52(d,J=2.2 Hz,2H),6.31(t,J=2.2 Hz,1H),3.80(s,6H),1.76-1.63(m,1H),1.56(ddd,J=7.2,3.9,1.5 Hz,1H),1.34-1.21(m,8H),1.25(s,3H),1.21(s,3H),0.90-0.80(m,9H). 13 C NMR(101 MHz,CDCl3)δ 160.4,154.0,105.1,96.6,55.3,53.5,43.1,32.7,31.4,27.8,27.8,26.3,26.3,24.9,22.7,18.6,14.2.IR(neat,ν max / cm -1 ):2955,2872,1595,1456,1421,1205,1155,1055.GC-MS(EI):m / z=306.2557 [M] + (Calculated value C) 20H 34 O2m / z = 306.2553).

[0165] Step f) 5-(3-isopropyl-2-methyloctan-2-yl)benzene-1,3-diol To a solution of 1-(3-isopropyl-2-methyloctan-2-yl)-3,5-dimethoxybenzene (230 mg, 751 μmol, 1.0 equivalent) in anhydrous CH2Cl2 (7.5 mL), BBr3 (1.0 M in CH2Cl2, 2.25 mL, 2.25 mmol, 3.0 equivalents) was added dropwise at 0°C, and the green solution was stirred at 0°C for 5.5 hours. The mixture was diluted with CH2Cl2 (15 mL) and carefully quenched with saturated NaHCO3 aqueous solution (15 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 20 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-40% Â in hexane) yielded the product as a golden oil (220 mg, 96%).

[0166] 1 H NMR(400 MHz,CDCl3)δ 6.45(d,J=2.2 Hz,2H),6.20(t,J=2.2 Hz,1H),5.78(bs,2H),1.65(heptd,J=7.0,1.3 Hz,1H),1.48(ddd,J=7.2,4.0,1.5 Hz,1H),1.33-1.09(m,8H),1.16(s,3H),1.13(s,3H),0.86(t,J=7.0 Hz,3H),0.83-0.75(m,6H). 13 C NMR(101 MHz,CDCl3)δ 156.0,155.2,106.5,100.1,53.4,40.8,32.7,31.4,27.8,27.8,26.3,26.2,24.7,22.7,18.6,14.2.IR(neat,ν max / cm -1 ):3330,2958,2872,1597,1469,1325,1152,991.HRMS(ESI):m / z=279.2319 [M+H] + (Calculated value C) 18 H 31O2m / z = 279.2319).

[0167] Process o)((1S,4S,5S)-4-(2,6-dihydroxy-4-(3-isopropyl-2-methyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (49.9 mg, 198 μmol, 1.1 equivalents) was added to a solution of 5-(3-isopropyl-2-methyloctan-2-yl)benzene-1,3-diol (50.1 mg, 180 μmol, 1.0 equivalent) and pTsOH·H2O (9.6 mg, 50.4 μmol, 0.28 equivalents) in CH2Cl2 (7.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of saturated NaHCO3 aqueous solution (3 mL) and diluted with Et2O (3 mL). The phases were separated, and the aqueous layer was extracted with Et2O (3 × 3 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (SiO2; 2-8% siRNA in hexane) yielded the product as a colorless foam (58.6 mg, 64%).

[0168] 1 H NMR(400 MHz,CDCl3)δ 6.35(s,2H),6.02(m,1H),5.90-5.47(bs,2H),4.68-4.59(m,1H),4.55-4.47(m,1H) ),4.05-3.99(m,1H),2.42-2.33(m,1H),2.32-2.27(m,2H),1.71(dhept,J=7.0,1.7 Hz,1H),1.49(d,J=1.6 Hz,1H),1.48-1.43(m,1H),1.34(s,3H),1.30-1.05(m,8H),1.23(s,9H),1.18(s,3H),1.14(s,3H),0.98(s,3H),0.85(t,J=5.2 Hz,3H),0.84(d,J=7.2 Hz,3H),0.78(dd,J=6.9,1.2 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.7,154.9,151.9,149.4,120.6,111.5,106.9,66.6,53.4,47.5,44.3,42.4,41.0,39.1,37. 9,32.6,31.4,28.2,28.1,27.7,27.4,27.4,26.2,26.0,25.0,22.7,20.9,18.6,14.2.IR(neat,ν max / cm -1 ):3457,2956,2871,1707,1625,1575,1480,1429,1366,1283,1233,1162,1027,837.HRMS(ESI):m / z=535.3749 [M+Na] + (Calculated value C) 33 H 52 NaO4m / z=535.3758).[α] 25 D = +63.340 ± 0.159 (c = 1.0, CDCl3).

[0169] Process p)((1S,4S,5S)-4-(4-(3-isopropyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate ((1S,4S,5S)-4-(2,6-dihydroxy-4-(3-isopropyl-2-methyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (48.1 mg, 93.8 μmol, 1.0 equivalent) and K2CO3 (77.8 mg, 563 μmol, 6.0 equivalents) were suspended in acetone (1.0 mL) to which (MeO2)SO2 (45 μL, 469 μmol, 5.0 equivalents) was added. The resulting purple suspension was stirred at room temperature for 20 hours. The reaction was quenched by the addition of saturated NaHCO3 aqueous solution (3 mL). The phases were separated, and the aqueous layer was extracted with Et2O (3 × 3 mL). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-15% Et2O in hexane) to obtain a pale pink oily substance (38.2 mg, 75%).

[0170] 1 H NMR(400 MHz,CDCl3)δ 6.49(m,2H),5.82-5.75(m,1H),4.61-4.55(m,1H),4.54-4.47(m,1H), 4.02-3.98(m,1H),3.74(s,6H),2.21-2.12(m,2H),2.08-2.01(m,1H),1 .77-1.65(m,2H),1.55-1.48(m,1H),1.36-1.05(m,8H),1.30(s,3H),1 .25(s,3H),1.21(s,9H),1.20(s,3H),0.98(s,3H),0.86(dd,J=7.1,1.1 Hz,3H),0.85(t,J=7.2 Hz,3H),0.80(d,J=6.9 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 178.6,158.4,150.7,137.3,126.6,117.7,103.3,67.7,55.9,53.7,47.5,44.0,43.1,41.0,39.0,3 7.7,32.7,31.4,27.8,27.7,27.6,27.5,26.5,26.3,25.2,25.1,22.7,21.2,18.6,14.2.IR(neat,ν max / cm -1 ):2946,2870,1728,1605,1572,1461,1410,1365,1280,1239,1151,1122,832.HRMS(ESI):m / z=563.4057 [M+Na] + (Calculated value C) 35 H 56 NaO4m / z=563.4071).[α] 25 D = +89.637 ± 0.233 (c = 1.0, CDCl3).

[0171] Process q) ((1S,4S,5S)-4-(4-(3-isopropyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(4-(3-isopropyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (28.2 mg, 52.1 μmol, 1.0 equivalent) in CH2Cl2 (0.5 mL) was cooled to 0°C, and DIBAL (1.0 M, 110 μL, 110 μmol, 2.1 equivalents) in hexane was added dropwise. The mixture was stirred at 0°C for 20 minutes, then diluted with Et2O (2 mL), and quenched with saturated Rochelle salt aqueous solution (1.5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The layers were separated, and the aqueous phase was extracted with Et2O (4 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-20% Â in hexane) to obtain a pale pink oily substance (18.8 mg, 79%).

[0172] 1 H NMR(400 MHz,CDCl3)δ 6.50(s,2H),5.74-5.69(m,1H),4.09-4.05(m,2H),4.03-3.98(m,1H),3.74(s,6H),2.25-2.16(m,2H),2.09-2.04(m,1H),1 .75-1.66(m,2H),1.55-1.49(m,1H),1.35-1.05(m,8H),1.31(s,3H),1.25(s,3H),1.21(s,3H),0.97(s,3H),0.86(d,J=7.1 Hz,3H),0.84(t,J=7.1 Hz,3H),0.80(dd,J=6.9,1.1 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 158.4,150.7,142.0,123.9,117.8,103.4,66.8,56.0,53.7,47.6,43.9,43.1,41.0,37.6 ,32.7,31.4,28.0,27.8,27.7,26.4,26.3,26.3,25.2,22.7,21.2,18.6,14.2.IR(neat,ν max / cm -1):3363,2953,2930,2869,1604,1572,1464,1409,1238,1121,832.HRMS(ESI):m / z=479.3495 [M+Na] + (Calculated value C) 30 H 48 NaO3m / z = 479.3496).[α] 25 D = +88.948 ± 0.459 (c = 1.0, CDCl3).

[0173] Example 7 ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step b) 2-(3,5-dimethoxyphenyl)-2-methyl-3-phenyloctan-3-ol To a solution of LaCl3·2LiCl (0.6 M in THF, 6.29 mL, 3.77 mmol, 1.0 equivalent), 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one (1.05 g, 3.77 mmol, 1.0 equivalent) in dry THF (3.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and PhLi (1.8 M in dibutyl ether, 3.14 mL, 5.66 mmol, 1.5 equivalents) was added dropwise. The mixture was stirred at 0°C for 30 minutes, and then quenched with saturated NH4Cl aqueous solution (15 mL) and H2O (15 mL). The aqueous phase was diluted with Et2O (20 mL), the phases were separated, and the aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (SiO2; 0-15% phenyl in hexane), yielding a pale yellow oily product (1.33 g, 99%).

[0174] 1H NMR(400 MHz,CDCl3)δ 7.30-7.20(m,5H),6.46(d,J=2.3 Hz,2H),6.37(t,J=2.2 Hz,1H),3.75(s,6H),2.21(ddd,J=14.0,11.6,4.2 Hz,1H),1.81(s,1H),1.60(ddd,J=13.0,11.6,3.6 Hz,1H),1.39(s,3H),1.27(s,3H),1.24-1.09(m,4H),0.94-0.84(m,2H),0.83-0.77(m,3H). 13 C NMR(101 MHz,CDCl3)δ 160.0,148.4,142.5,128.0,127.0,126.4,107.5,98.0,80.5,55.3,46.7,35.7,32.6,25.1,24.8,23.8,22.8,14.2.IR(neat,ν max / cm -1 ):3552,2954,2870,1595,1457,1205,1155.HRMS(ESI):m / z=379.2241 [M+Na] + (Calculated value C) 23 H 32 NaO3m / z = 379.2244).

[0175] Step g)(E)-1,3-dimethoxy-5-(2-methyl-3-phenylocta-3-en-2-yl)benzene To a solution of 2-(3,5-dimethoxyphenyl)-2-methyl-3-phenyloctan-3-ol (2.65 g, 7.43 mmol, 1.0 equivalent) in anhydrous THF (48 mL), KHMDS (1.0 M in THF, 18.6 mL, 18.6 mmol, 2.5 equivalents) and CS2 (6.71 mL, 112 mmol, 15 equivalents) were added at -78°C. The yellow solution was stirred at -78°C for 10 minutes, the cooling bath was removed, and the mixture was stirred for a further 30 minutes. MeI (7.40 mL, 119 mmol, 16 equivalents) was added, and the mixture was stirred first at ambient temperature for 1 hour, then at 40°C overnight. The mixture was diluted with Et2O (50 mL), and saturated NaHCO3 aqueous solution (50 mL) was added. The layers were separated, and the aqueous phase was extracted with Et2O (2 × 50 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 0.5% Et2O in pentane) to obtain an amber-orange liquid (2.35 g, 93%).

[0176] 1 H NMR(400 MHz,CDCl3)δ 7.19-7.11(m,3H),6.75-6.64(m,2H),6.55(d,J=2.3 Hz,2H),6.35(t,J=2.3 Hz,1H),5.71(t,J=7.2 Hz,1H),3.79(s,6H),1.78(q,J=7.1 Hz,2H),1.40(s,6H),1.36-1.18(m,4H),0.83(t,J=7.2 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 160.4,151.2,148.5,140.5,129.7,127.4,126.5,126.1,105.7,97.4,55.3,44.2,32.3,29.1,29.0,22.4,14.1.IR(neat,ν max / cm -1 ):2956,2872,1595,1456,1423,1204,1153.HRMS(ESI):m / z=339.2315 [M+H] + (Calculated value C) 23 H 31 O2m / z = 339.2319).

[0177] Process h)(E)-5-(2-methyl-3-phenylocta-3-en-2-yl)benzene-1,3-diol To a solution of (E)-1,3-dimethoxy-5-(2-methyl-3-phenylocta-3-en-2-yl)benzene (1.70 g, 5.02 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (48 mL), BBr3 (1.43 mL, 15.1 mmol, 3.0 equivalents) was added dropwise at 0°C, and the green solution was stirred at 0°C for 3 hours. The mixture was diluted with CH2Cl2 (100 mL) and carefully quenched with saturated NaHCO3 aqueous solution (50 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 100 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-30% Â in hexane) yielded the product as a golden oil (1.54 g, 99%).

[0178] 1 H NMR(400 MHz,CDCl3)δ 7.18-7.09(m,3H),6.73-6.63(m,2H),6.40(d,J=2.3 Hz,2H),6.19(t,J=2.2 Hz,1H),5.66(t,J=7.3 Hz,1H),4.87(s,2H),1.72(q,J=7.2 Hz,2H),1.33(s,6H),1.32-1.16(m,4H),0.81(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 156.2,152.1,148.2,140.5,129.8,127.4,126.6,126.2,107.2,100.4,43.9,32.3,29.0,28.9,22.5,14.1.IR(neat,ν max / cm -1 ):3337,3054,2960,2928,2872,1598,1492,1465,1439,1322,1149.HRMS(ESI):m / z=311.2013 [M+H] + (Calculated value C) 21 H 27 O2m / z = 311 (2006).

[0179] Step i) 5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol To a solution of (E)-5-(2-methyl-3-phenylocta-3-en-2-yl)benzene-1,3-diol (1.00 g, 3.22 mmol, 1.0 equivalent) in siRNA (27 mL), Pd (10% by weight on C, 3.43 g, 3.22 mmol, 1.0 equivalent) was added, and the mixture was stirred overnight in an autoclave under a H2 pressure of 7 bar. The suspension was filtered through a Celite pad and concentrated under vacuum to obtain the product as a pink foam (960 mg, yield 95%). The racemic mixture was divided by chiral SFC method 1 to obtain (R)-5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A (430 mg, 43%, %ee>99%) and (S)-5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol B (420 mg, 42%, %ee>99%).

[0180] 1 H NMR(400 MHz,CDCl3)δ 7.28-7.14(m,3H),7.11-7.03(m,2H),6.39(d,J=2.2 Hz,2H),6.20(t,J=2.2 Hz,1H),4.69(bs,2H),2.73(dd,J=12.1,2.9 Hz,1H),1.61(dddd,J=13.3,12.1,9.7,4.7 Hz,1H),1.38(dddd,J=13.1,9.6,6.5,2.9 Hz,1H),1.22(s,3H),1.18-1.01(m,4H),1.07(s,3H),1.00-0.79(m,2H),0.74(t,J=6.6 Hz, 3H). 13 C NMR(101 MHz,CDCl3)δ 156.2,153.3,141.8,130.2,127.5,126.2,106.8,100.2,57.1,41.6,31.9,29.4,29.1,28.1,23.5,22.6,14.2.IR(neat,ν max / cm -1):3340,2956,2931,2870,1599,1496,1467,1328,1151,992,704.GC-MS(EI):m / z=312.2084 [M] + (Calculated value C) 21 H 28 O2m / z=312.2084).(R)-5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A [α] 25 D =-38.557±0.179(c=1.0,CHCl3). (S)-5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol B [α] 25 D =+38.058±0.691(c=1.0,CHCl3).

[0181] Process o)((1S,4S,5S)-4-(2,6-dihydroxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of resorcinol(R)-5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A (17.6 mg, 56.3 μmol, 1.0 equivalent) in anhydrous CH2Cl2 (1.4 mL), pTsOH·H2O (3.0 mg, 15.7 μmol, 0.28 equivalents) and a solution of ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (15.6 mg, 61.9 μmol, 1.1 equivalents) in anhydrous CH2Cl2 (0.7 mL) were added. The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched by adding saturated NaHCO3 aqueous solution (2 mL). The phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL) and siRNA (3 × 15 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2, 5-10% siRNA in hexane) yielded the product (23.5 mg, 76%) as a pale yellow foam.

[0182] 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.14 (m, 3H), 7.12 - 7.05 (m, 2H), 6.36 (s, 2H), 6.04 (dt, J = 3.1, 1.5 Hz, 1H), 5.69 (s, 2H), 4.65 (dt, J = 13.3, 1.6 Hz, 1H), 4.53 (dt, J = 13.5, 1.9 Hz, 1H), 4.03 (s, 1H), 2.72 (dd, J = 12.1, 2.9 Hz, 1H), 2.43 - 2.35 (m, 1H), 2.35 - 2.28 (m, 2H), 1.68 - 1.54 (m, 1H), 1.51 (d, J = 9.6 Hz, 1H), 1.41 - 1.33 (m, 1H), 1.36 (s, 3H), 1.24 (s, 9H), 1.19 (s, 3H), 1.13 - 1.00 (m, 4H), 1.02 (s, 3H), 1.00 (s, 3H), 0.98 - 0.82 (m, 2H), 0.74 (t, J = 6.5 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 178.7, 154.9, 150.4, 149.5, 142.0, 130.2, 127.5, 126.1, 120.5, 111.8, 107.3, 66.6, 56.9, 47.5, 44.3, 41.2, 41.1, 39.1, 37.9, 31.8, 29.4, 29.3, 28.2, 28.0, 27.4, 26.0, 22.8, 22.5, 20.9, 14.2. IR (neat, ν max / cm -1 ): 3455, 2957, 2932, 2871, 1728, 1707, 1625, 1575, 1479, 1465, 1452, 1429, 1367, 1283, 1230, 1163, 1040, 1029, 748, 704. HRMS (ESI): m / z = 569.3603 [M + Na] + (calculated for C 36 H 50 NaO4 m / z = 569.3601). [α] 25 D = +19.921 ± 0.144 (c = 1.0, CHCl3).

[0183] Process p)((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of ((1S,4S,5S)-4-(2,6-dihydroxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (23.5 mg, 42.9 μmol, 1.0 equivalent) in acetone (0.5 mL), (MeO)2SO2 (12.2 μL, 129 μmol, 3.0 equivalents) and K2CO3 (20.8 mg, 0.150 mmol, 3.5 equivalents) were added, and the pale red suspension was stirred overnight at room temperature. Then, (MeO)2SO2 (12.2 μL, 0.129 mmol, 3.0 equivalents) was added, and the solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with Et2O (5 mL) and water (5 mL). The layers were separated, and the aqueous layer was extracted with Et2O (2 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 0-5% Et2O in hexane) yielded the product as a pale red wax (21.8 g, 88%).

[0184] 1H NMR(500 MHz,CDCl3)δ 7.25-7.15(m,3H),7.07-6.98(m,2H),6.42(s,2H),5.79(dt,J=2.7,1.4 Hz,1H),4.65-4.55(m,1H),4.55-4.46(m,1H),4.05-3.97(m,1H),3.69(s,6H),2.72(dd,J=12.1,2.9 Hz,1H),2.21-2.13(m,2H),2.09-2.02(m,1H),1.73(d,J=7.8 Hz,1H),1.61(dddd,J=13.5,11.9,9.5,4.6 Hz,1H),1.50-1.40(m,1H),1.31(s,3H),1.27(s,3H),1.22(s,9H),1.14( s,3H),1.13-1.02(m,4H),0.98(s,3H),0.97-0.84(m,2H),0.75(t,J=7.0 Hz,3H). 13 C NMR(126 MHz,CDCl3)δ 178.6,158.3,148.7,142.0,137.4,130.2,127.4,126.5,126.1,118.0,104.0,67.6,57.3,56.0,47.6,4 4.0,41.8,41.0,39.0,37.7,31.9,29.3,28.8,28.1,27.7,27.5,26.5,24.1,22.6,21.2,14.2.IR(neat,ν max / cm -1 ):2932,2870,1727,1604,1573,1453,1411,1151,1122.HRMS(ESI):m / z=597.3915 [M+Na] + (Calculated value C) 38 H 54 NaO4m / z=597.3914).[α] 25 D = +38.804 ± 0.225 (c=1.0, CHCl3).

[0185] Step q) ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (22.0 mg, 38.2 μmol, 1.0 equivalent) in CH2Cl2 (0.4 mL) was cooled to 0°C, and DIBAL (1.0 M in hexane, 81 μL; 80.7 μmol, 2.1 equivalents) was added dropwise. The mixture was stirred at 0°C for 15 minutes, then quenched with saturated Rochelle salt aqueous solution (4 mL), and diluted with Et2O (5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The phases were separated, and the aqueous phase was extracted with Et2O (2 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 10-15% siRNA in hexane) to obtain a white foamy substance (16.0 mg, 85%).

[0186] 1 H NMR(400 MHz,CDCl3)δ 7.25-7.14(m,3H),7.08-6.96(m,2H),6.43(s,2H),5.76-5.68(m,1H),4.08(s,2H),4.05-3.98(m,1H),3.70(s,6H),2.73(dd,J=12.0,2.9 Hz,1H),2.28-2.18(m,2H),2.11-2.00(m,1H),1.78-1.69(m,1H),1.68-1.54(m,1H),1.52-1.39(m,1H), 1.32(s,3H),1.27(s,3H),1.15(s,3H),1.13-1.02(m,4H),0.98(s,3H),0.96-0.81(m,2H),0.75(t,J=6.8 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 158.3,148.7,142.1,142.0,130.2,127.4,126.1,123.9,118.1,104.0,66.8,57.3,56.0,47.6 ,44.0,41.8,41.0,37.6,31.9,29.4,28.9,28.1,28.0,26.4,24.1,22.6,21.2,14.2.IR(neat,ν max / cm-1 ):3398,2931,2866,1604,1573,1410,1122.HRMS(ESI):m / z=513.3335 [M+Na] + (Calculated value C) 33 H 46 NaO3m / z=513.3339).[α] 25 D = +57.735 ± 0.424 (c = 1.0, CHCl3).

[0187] Example 8 ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Process o)((1S,4S,5S)-4-(2,6-dihydroxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of resorcinol(S)-5-(2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol B (18.3 mg, 58.5 μmol, 1.0 equivalent) in anhydrous CH2Cl2 (1.7 mL), pTsOH·H2O (3.1 mg, 16.4 μmol, 0.28 equivalents) and a solution of ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (16.3 mg, 64.4 μmol, 1.1 equivalents) in anhydrous CH2Cl2 (0.5 mL) were added. The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched by adding saturated NaHCO3 aqueous solution (2 mL). The phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL) and siRNA (3 × 15 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2, 5-10% siRNA in hexane) yielded the product (24.3 mg, 76%) as a pale yellow foam.

[0188] 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.14 (m, 3H), 7.10 - 6.98 (m, 2H), 6.36 (s, 2H), 6.04 (dt, J = 3.3, 1.6 Hz, 1H), 5.68 (bs, 2H), 4.65 (dt, J = 13.3, 1.7 Hz, 1H), 4.52 (dt, J = 13.5, 2.0 Hz, 1H), 4.08 - 3.97 (m, 1H), 2.71 (dd, J = 12.1, 2.9 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.34 - 2.28 (m, 2H), 1.69 - 1.56 (m, 1H), 1.52 (d, J = 9.7 Hz, 1H), 1.44 - 1.33 (m, 1H), 1.36 (s, 3H), 1.24 (s, 9H), 1.19 (s, 3H), 1.16 - 1.00 (m, 4H), 1.03 (s, 3H), 0.99 (s, 3H), 0.96 - 0.82 (m, 2H), 0.74 (t, J = 6.5 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 178.7, 154.9, 150.3, 149.6, 142.0, 130.2, 127.5, 126.1, 120.5, 111.8, 107.3, 66.6, 57.0, 47.5, 44.3, 41.2, 41.1, 39.1, 37.9, 31.9, 29.4, 29.4, 28.2, 28.0, 27.4, 26.0, 22.9, 22.5, 20.9, 14.2. IR (neat, ν max / cm -1 ): 3459, 2957, 2932, 2871, 1729, 1707, 1625, 1575, 1480, 1465, 1452, 1429, 1367, 1326, 1283, 1230, 1163, 1029, 759, 704. HRMS (ESI): m / z = 569.3592 [M + Na] + (Calculated for C 36 H 50 NaO4 m / z = 569.3601). [α] 25 D = +82.985 ± 0.109 (c = 1.0, CHCl3).

[0189] Process p)((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of ((1S,4S,5S)-4-(2,6-dihydroxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (24.3 mg, 44.4 μmol, 1.0 equivalent) in acetone (0.5 mL), (MeO)2SO2 (12.6 μL, 0.133 mmol, 3.0 equivalents) and K2CO3 (21.5 mg, 0.155 mmol, 3.5 equivalents) were added, and the pale red suspension was stirred overnight at room temperature. Then, (MeO)2SO2 (12.6 μL, 0.133 mmol, 3.0 equivalents) was added, and the solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with Et2O (5 mL) and water (5 mL). The layers were separated, and the aqueous layer was extracted with Et2O (2 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. Purification by flash column chromatography (using SiO2; 0-5% Et2O in hexane) yielded the product as a pale red wax (23.4 g, 92%).

[0190] 1 H NMR(400 MHz,CDCl3)δ 7.25-7.15(m,3H),7.06-6.99(m,2H),6.42(s,2H),5.80(dt,J=2.8,1.4 Hz,1H),4.61-4.56(m,1H),4.54-4.49(m,1H),4.03-3.98(m,1H),3.69(s,6H),2.72(dd,J=12.0,2.9 Hz,1H),2.23-2.13(m,2H),2.06(ddt,J=5.4,3.6,1.8 Hz,1H),1.75-1.54(m,2H),1.51-1.39(m,1H),1.31(s,3H),1.27(s,3H),1.22(s,9) H),1.15(s,3H),1.12-1.03(m,4H),0.99(s,3H),0.96-0.83(m,2H),0.75(t,J=6.9 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.6,158.2,148.7,142.0,137.3,130.2,127.4,126.6,126.1,118.0,103.9,67.7,57.3,55.9,47.6,4 4.0,41.8,41.1,39.1,37.7,31.9,29.4,28.9,28.1,27.7,27.5,26.5,24.1,22.6,21.2,14.2.IR(neat,ν max / cm -1 ):2931,2869,1727,1604,1573,1452,1411,1151,1122.HRMS(ESI):m / z=597.3911 [M+Na] + (Calculated value C) 38 H 54 NaO4m / z=597.3914).[α] 25 D = +86.208 ± 0.243 (c=1.0, CHCl3).

[0191] Process q)((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol A solution of ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (23.4 mg, 40.7 μmol, 1.0 equivalent) in CH2Cl2 (0.4 mL) was cooled to 0°C, and DIBAL (1.0 M in hexane, 86 μL; 85.4 μmol, 2.1 equivalents) was added dropwise. The mixture was stirred at 0°C for 15 minutes, then quenched with saturated Rochelle salt aqueous solution (4 mL), and diluted with Et2O (5 mL). The mixture was stirred vigorously at room temperature until the phases were cleanly separated. The phases were separated, and the aqueous phase was extracted with Et2O (2 × 5 mL). The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 10-15% phenyl in hexane) to obtain a white foamy substance (17.3 mg, 87%).

[0192] 1 H NMR(400 MHz,CDCl3)δ 7.26-7.13(m,3H),7.06-6.99(m,2H),6.43(s,2H),5.79-5.68(m,1H),4.08(s,2H),4.03-4.00(m,1H),3.70(s,6H),2.73(dd,J=12.1,2.9 Hz,1H),2.28-2.18(m,2H),2.10-2.05(m,1H),1.76-1.67(m,1H),1.67-1.54(m,1H),1.50-1.39(m,1H), 1.32(s,3H),1.27(s,3H),1.15(s,3H),1.13-1.03(m,4H),0.98(s,3H),0.96-0.84(m,2H),0.75(t,J=6.7 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 158.3,148.7,142.0,142.0,130.2,127.4,126.1,123.9,118.0,104.0,66.8,57.3,56.0,47.6 ,44.0,41.8,41.0,37.6,31.9,29.4,28.9,28.1,28.0,26.4,24.1,22.6,21.2,14.2.IR(neat,ν max / cm -1 ):3369,2931,2867,1604,1573,1410,1122.HRMS(ESI):m / z=513.3335 [M+Na] + (Calculated value C) 33 H 46 NaO3m / z=513.3339).[α] 25 D =+123.317±0.334(c=1.0,CHCl3).

[0193] Example 9 ((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step b) 2-(3,5-dimethoxyphenyl)-3-(4-fluorophenyl)-2-methyloctan-3-ol Preparation of 4-fluorophenyllithium: To a solution of 4-fluoroiodobenzene (853 μL, 7.40 mmol, 2.0 equivalents) in dry Et2O (8.0 mL), n-BuLi (1.6 M in hexane, 3.47 mL, 5.55 mmol, 1.5 equivalents) was added dropwise at -78°C, and the solution was stirred at -78°C for 30 minutes.

[0194] To a solution of LaCl3·2LiCl (0.6 M in THF, 6.17 mL, 3.70 mmol, 1.0 equivalent), 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one (1.03 g, 3.70 mmol, 1.0 equivalent) in dry THF (3.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and a pre-prepared solution of 4-fluorophenyllithium was added dropwise. The mixture was stirred at 0°C for 30 minutes, and then quenched with saturated NH4Cl aqueous solution (15 mL) and H2O (15 mL). The aqueous phase was diluted with Et2O (15 mL), the phases were separated, and the aqueous phase was extracted with Et2O (3 × 15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (SiO2; 0-15% phenyl in hexane), yielding a colorless oily product (1.36 g, 98%).

[0195] 1 H NMR(400 MHz,CDCl3)δ 7.19(bs,2H),6.94(t,J=8.8 Hz,2H),6.44(d,J=2.0 Hz,2H),6.36(t,J=2.2 Hz,1H),3.75(s,6H),2.21-2.09(m,1H),1.79(s,1H),1.58(ddd,J=15.1,11.7,3.5 Hz,1H),1.35(s,3H),1.24(s,3H),1.21-1.04(m,4H),0.92-0.74(m,2H),0.79(t,J=6.9 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 161.64(d,J=244.7 Hz),160.1,148.2,138.14(d,J=3.1 Hz),129.54(d,J=7.8 Hz),113.69(d,J=20.9 Hz),107.5,97.9,80.3,55.3,46.7,35.8,32.5,24.9,24.8,23.8,22.7,14.1. 19 F NMR(377 MHz,CDCl3)δ-117.8.IR(neat,ν max / cm -1 ):3559,2955,2872,1595,1508,1457,1421,1205,1156,1054.HRMS(ESI):m / z=397.2156 [M+Na] + (Calculated value C) 23 H 31 FNaO3m / z = 397.2149).

[0196] Step g)(E)-1-(3-(4-fluorophenyl)-2-methylocta-3-en-2-yl)-3,5-dimethoxybenzene To a solution of 2-(3,5-dimethoxyphenyl)-3-(4-fluorophenyl)-2-methyloctan-3-ol (1.32 g, 3.53 mmol, 1.0 equivalent) in anhydrous THF (22 mL), KHMDS (0.5 M in toluene, 17.6 mL, 8.81 mmol, 2.5 equivalents) and CS2 (3.20 mL, 52.9 mmol, 15 equivalents) were added at -78°C. The yellow solution was stirred at -78°C for 10 minutes, the cooling bath was removed, and the mixture was stirred for a further 30 minutes. MeI (3.51 mL, 56.4 mmol, 16 equivalents) was added, and the mixture was stirred first at ambient temperature for 1 hour, then at 40°C overnight. The mixture was diluted with Et2O (25 mL), and saturated NaHCO3 aqueous solution (25 mL) was added. The layers were separated, and the aqueous phase was extracted with Et2O (2 × 25 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-1.5% Et2O in hexane) to obtain an amber-orange liquid (1.25 g, 99%).

[0197] 1 H NMR(400 MHz, CDCl3)δ 6.87-6.77(m,2H),6.63-6.57(m,2H),6.49(d,J=2.3 Hz,2H),6.32(t,J=2.3 Hz,1H),5.72(t,J=7.3 Hz,1H),3.77(s,6H),1.79-1.68(m,2H),1.36(s,6H),1.31-1.19(m,4H),0.80(t,J=7.1 Hz,3H). 13 C NMR(101 MHz, CDCl3)δ 161.5(d,J=244.1 Hz),160.5,150.8,147.5,136.2(d,J=3.4 Hz),131.2(d,J=7.6 Hz),126.9,114.3(d,J=20.9 Hz),105.7,97.4,55.4,44.2,32.2,29.0,28.9,22.4,14.1. 19 F NMR(377 MHz, CDCl3)δ-117.2.IR(neat,ν max / cm -1 ):2958,2933,2867,1600,1508,1458,1422,1205,1155,1059.HRMS(ESI):m / z=379.2043 [M+Na] + (calculated value C 23 H 29 FNaO2m / z=379.2044).

[0198] Engineering h) (E)-5-(3-(4-フルオロフェニル)-2-メチルオクタ-3-エン-2-イル)ベンゼン-1,3-ジオール To a solution of (E)-1-(3-(4-fluorophenyl)-2-methylocta-3-en-2-yl)-3,5-dimethoxybenzene (1.25 g, 3.51 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (30 mL), BBr3 (1.0 M in CH2Cl2, 10.5 mL, 10.5 mmol, 3.0 equivalents) was added dropwise at 0°C, and the green solution was stirred at 0°C for 5.5 hours. The mixture was diluted with CH2Cl2 (25 mL) and carefully quenched with saturated NaHCO3 aqueous solution (25 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 30 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-50% Â in hexane) yielded the product as a golden oil (1.14 g, 99%).

[0199] 1 H NMR(400 MHz,CDCl3)δ 6.86-6.78(m,2H),6.64-6.57(m,2H),6.38(d,J=2.2 Hz,2H),6.20(t,J=2.2 Hz,1H),5.68(t,J=7.2 Hz,1H),5.19(bs,2H),1.75-1.65(m,2H),1.32(s,6H),1.29-1.17(m,4H),0.81(t,J=7.2 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 161.5(d,J=244.2 Hz),156.3,151.8,147.2,136.1(d,J=3.5 Hz),131.2(d,J=7.6 Hz),127.0,114.3(d,J=20.8 Hz),107.1,100.5,43.9,32.2,29.0,28.8,22.5,14.1. 19 F NMR(377 MHz,CDCl3)δ-117.0.IR(neat,ν max / cm -1 ):3311,2961,2929,2872,1599,1507,1466,1324,1220,1153,993,835.HRMS(ESI):m / z=351.1729 [M+Na] + (Calculated value C) 21 H 25 FNaO2m / z = 351.1731).

[0200] Step i) 5-(3-(4-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol To a solution of (E)-5-(3-(4-fluorophenyl)-2-methylocta-3-en-2-yl)benzene-1,3-diol (800 mg, 2.44 mmol, 1.0 equivalent) in siRNA (20 mL), Pd (10% by weight on C, 2.59 g, 2.44 mmol, 1.0 equivalent) was added, and the mixture was stirred in an autoclave at room temperature for 48 hours under a H2 pressure of 35 bar. The suspension was filtered through a Celite pad and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 20-30% siRNA in hexane) yielded the product as a golden foam (550 mg, yield 68%). The racemic mixture was divided by chiral SFC method 3 to obtain (R)-5-(3-(4-fluorophenyl)-2-methyloctane-2-yl)benzene-1,3-diol A (170 mg, 21%, %ee>99%) and (S)-5-(3-(4-fluorophenyl)-2-methyloctane-2-yl)benzene-1,3-diol B (160 mg, 20%, %ee>99%).

[0201] 1 H NMR(400 MHz,CDCl3)δ 7.02-6.95(m,2H),6.95-6.88(m,2H),6.36(d,J=2.2 Hz,2H),6.21(t,J=2.2 Hz,1H),5.03(bs,2H),2.71(dd,J=12.1,3.0 Hz,1H),1.62-1.50(m,1H),1.47-1.37(m,1H),1.20(s,3H),1.15-1.01(m,4H),1.07(s,3H),0.96-0.83(m,2H),0.75(t,J=6.7 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 161.5(d,J=243.7 Hz),156.2,153.0,137.4(d,J=3.2 Hz),131.3(d,J=7.6 Hz),114.3(d,J=20.8 Hz),106.8,100.3,56.4,41.6,31.8,29.5,28.6,28.0,23.8,22.6,14.1. 19 F NMR(377 MHz,CDCl3)δ-117.4.IR(neat,ν max / cm -1 ):3345,2961,2932,2863,1600,1509,1225,1157,993,842.HRMS(ESI):353.1889 [M+Na] + (Calculated value C) 21 H 27 FNaO2m / z=353.1887).(R)-5-(3-(4-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol A [α] 25 D =-40.068±0.134(c=1.0,CHCl3). (S)-5-(3-(4-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol B [α] 25 D =+40.982±0.175(c=1.0,CHCl3).

[0202] Process o)((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of (R)-5-(3-(4-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol A (24.0 mg, 72.6 μmol, 1.0 equivalent) and ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (20.2 mg, 79.8 μmol, 1.1 equivalent) in CH2Cl2 (3.0 mL), pTsOH·H2O (3.8 mg, 20.3 μmol, 0.28 equivalent) was added, and the solution was stirred for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (3 mL), and the solution was diluted with Et2O (5 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 0-10% siRNA in hexane) to obtain a white foamy substance (32.3 mg, 79%).

[0203] 1 H NMR(400 MHz,CDCl3)δ 7.04-6.94(m,2H),6.94-6.87(m,2H),6.31(s,2H),6.03(dt,J=3.1,1.6 Hz,1H),5.69(bs,2H),4.65(dt,J=13.4,1.5 Hz,1H),4.52(ddd,J=13.5,2.4,1.6 Hz,1H),4.05-4.00(m,1H),2.69(dd,J=12.0,3.0 Hz,1H),2.39(dt,J=9.6,5.6 Hz,1H),2.35-2.24(m,2H),1.59-1.48(m,1H),1.50(d,J=9.7 Hz,1H),1.47-1.38(m,1H),1.35(s,3H),1.24(s,9H),1.17(s,3H),1.15- 1.05(m,4H),1.03(s,3H),0.99(s,3H),0.94-0.83(m,2H),0.75(t,J=6.7 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.7,161.5(d,J=243.6 Hz),154.9,149.8,149.6,137.6(d,J=3.2 Hz),131.3(d,J=7.5 Hz),120.4,114.2(d,J=20.8 Hz),111.9,107.3,66.6,56.3,47.5,44.3,41.2,41.1,39.1,37.9,31.8,29.5,28.9,28.2,28.0,27.4,26.0,23.4,22.6,20.9,14.1. 19 F NMR(377 MHz,CDCl3)δ-117.6.IR(neat,ν max / cm -1 ):3453,2956,2928,2871,2857,1729,1707,1625,1575,1509,1225,1160.HRMS(ESI):m / z=587.3509 [M+Na] + (Calculated value C) 36 H 49 FNaO4m / z=587.3507).[α] 25 D = +28.542 ± 0.383 (c=1.0, CHCl3).

[0204] Process p)((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a suspension of the diol ((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (32.3 mg, 57.1 μmol, 1.0 equivalent) and K2CO3 (47.4 mg, 343 μmol, 6.0 equivalents) in acetone (1.0 mL), (MeO)2SO2 (27.1 μL, 286 μmol, 5.0 equivalents) was added, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-5% ethylethanol in hexane) to obtain the product as a white foam (28.9 mg, 85%).

[0205] 1 H NMR(400 MHz,CDCl3)δ 7.00-6.80(m,4H),6.39(s,2H),5.78(dt,J=2.8,1.4 Hz,1H),4.62-4.55(m,1H),4.54-4.48(m,1H),4.01(s,1H),3.69(s,6H),2.71(dd,J=11.6,3.4 Hz,1H),2.18(dd,J=7.2,5.6 Hz,2H),2.05(td,J=6.0,2.9 Hz,1H),1.72(d,J=7.4 Hz,1H),1.63-1.45(m,2H),1.31(s,3H),1.26(s,3H),1.22(s,9H),1.15( s,3H),1.14-1.02(m,4H),0.98(s,3H),0.94-0.81(m,2H),0.76(t,J=6.8 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 178.6,161.5(d,J=243.7 Hz),158.3,148.3,137.6(d,J=3.3 Hz),137.4,131.3(d,J=7.5 Hz),126.4,118.1,114.2(d,J=20.8 Hz),103.9,67.6,56.6,55.9,47.6,44.0,41.8,41.1,39.0,37.7,31.8,29.5,28.4,28.0,27.7,27.5,26.5,24.4,22.6,21.2,14.1.19 F NMR(376 MHz,CDCl3)δ-117.6.IR(neat,ν max / cm -1 ):2955,2930,2869,1726,1658,1604,1572,1508,1479,1462,1410,1381,1365,1339,1280,1239,1 224,1152,11122,1032,1015,957,938,907,841,770,742,702,670,546.HRMS(ESI):m / z=615.3808 [M+Na] + (Calculated value C) 38 H 53 FNaO4m / z=615.3820).[α] 25 D = +50.994 ± 0.086 (c = 1.0, CDCl3).

[0206] Process q)((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol ((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (28.9 mg, 48.7 μmol, 1.0 equivalent) was dissolved in CH2Cl2 (0.55 mL), to which DIBAL (102 μL, 102 μmol, 2.1 equivalents) was added at 0°C. After stirring the reaction mixture at 0°C for 15 minutes, saturated NH4Cl aqueous solution (3 mL) was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-20% siRNA in hexane) yielded the product as a colorless oil (21.3 mg, 86%).

[0207] 11H NMR (400 MHz, CDCl3) δ 7.02 - 6.84 (m, 4H), 6.39 (s, 2H), 5.71 (dt, J = 3.0, 1.4 Hz, 1H), 4.08 (s, 2H), 4.01 (t, J = 2.3 Hz, 1H), 3.69 (s, 6H), 2.71 (dd, J = 11.5, 3.5 Hz, 1H), 2.27 - 2.17 (m, 2H), 2.10 - 2.03 (m, 1H), 1.72 (d, J = 6.9 Hz, 1H), 1.62 - 1.45 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H), 1.13 - 1.01 (m, 4H), 0.98 (s, 3H), 0.94 - 0.82 (m, 2H), 0.76 (t, J = 6.6 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 161.5 (d, J = 243.7 Hz), 158.3, 148.3, 142.1, 137.6 (d, J = 3.3 Hz), 131.3 (d, J = 7.5 Hz), 123.8, 118.2, 114.2 (d, J = 20.8 Hz), 104.0, 66.8, 56.6, 56.0, 47.6, 44.0, 41.8, 41.0, 37.6, 31.8, 29.5, 28.4, 28.0, 28.0, 26.4, 24.4, 22.6, 21.2, 14.1. 19 19F NMR (376 MHz, CDCl3) δ -117.6. IR (neat, ν max / cm -1 ): 3378, 2928, 2863, 1655, 1604, 1572, 1508, 1461, 1410, 1380, 1364, 1340, 1301, 1238, 1224, 1184, 1160, 1120, 1049, 1014, 986, 908, 840, 743, 701, 669, 563, 547, 525. HRMS (ESI): m / z = 531.3238 [M+Na] + (Calculated for C 33 H 45 FNaO3 m / z = 531.3245). [α] 25 D = +43.736 ± 0.139 (c = 1.0, CDCl3).

[0208] Example 10 ((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Process o)((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of (S)-5-(3-(4-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol B (26.6 mg, 80.5 μmol, 1.0 equivalent) and ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (22.4 mg, 88.5 μmol, 1.1 equivalent) in CH2Cl2 (3.3 mL), pTsOH·H2O (4.3 mg, 22.5 μmol, 0.28 equivalent) was added, and the solution was stirred for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (3 mL), and the solution was diluted with Et2O (5 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 0-10% siRNA in hexane) to obtain a white foamy substance (38.5 mg, 85%).

[0209] 11H NMR (500 MHz, CDCl3) δ 7.03 - 6.96 (m, 2H), 6.96 - 6.87 (m, 2H), 6.32 (s, 2H), 6.03 (dt, J = 3.1, 1.5 Hz, 1H), 5.70 (bs, 2H), 4.65 (ddd, J = 13.5, 2.0, 1.4 Hz, 1H), 4.52 (ddd, J = 13.5, 2.4, 1.6 Hz, 1H), 4.09 - 3.96 (m, 1H), 2.69 (dd, J = 12.1, 3.0 Hz, 1H), 2.39 (dt, J = 9.7, 5.6 Hz, 1H), 2.35 - 2.25 (m, 2H), 1.58 - 1.48 (m, 1H), 1.50 (d, J = 9.8 Hz, 1H), 1.45 - 1.38 (m, 1H), 1.35 (s, 3H), 1.24 (s, 9H), 1.17 (s, 3H), 1.14 - 1.05 (m, 4H), 1.02 (s, 3H), 0.99 (s, 3H), 0.95 - 0.81 (m, 2H), 0.74 (t, J = 6.6 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 178.7, 161.5 (d, J = 243.6 Hz), 154.9, 149.9, 149.6, 137.6 (d, J = 3.2 Hz), 131.3 (d, J = 7.5 Hz), 120.4, 114.3 (d, J = 20.8 Hz), 111.9, 107.3, 66.6, 56.2, 47.5, 44.3, 41.2, 41.1, 39.1, 37.9, 31.8, 29.4, 28.8, 28.2, 28.0, 27.4, 26.0, 23.2, 22.6, 20.9, 14.1. 19 19F NMR (471 MHz, CDCl3) δ -117.6. IR (neat, ν max / cm -1 ): 3453, 2956, 2929, 2871, 1728, 1707, 1625, 1575, 1509, 1225, 1160. HRMS (ESI): m / z = 587.3495 [M+Na] + (Calculated for C 36 H 49 FNaO4 m / z = 587.3507). [α] 25 D = +77.406 ± 0.191 (c = 1.0, CHCl3).

[0210] Process p)((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a suspension of the diol ((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (38.5 mg, 68.1 μmol, 1.0 equivalent) and K2CO3 (56.5 mg, 409 μmol, 6.0 equivalents) in acetone (1.0 mL), (MeO)2SO2 (32.3 μL, 341 μmol, 5.0 equivalents) was added, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-5% ethylethanol in hexane) to obtain the product as a white foam (35.5 mg, 88%).

[0211] 1 H NMR(400 MHz,CDCl3)δ 6.99-6.85(m,4H),6.39(s,2H),5.79(dt,J=2.9,1.4 Hz,1H),4.62-4.56(m,1H),4.55-4.48(m,1H),4.01(s,1H),3.69(s,6H),2.71(dd,J=11.7,3.4 Hz,1H),2.22-2.14(m,2H),2.10-2.02(m,1H),1.70(d,J=7.8 Hz,1H),1.63-1.45(m,2H),1.31(s,3H),1.26(s,3H),1.22(s,9H),1.15( s,3H),1.14-1.02(m,4H),0.99(s,3H),0.94-0.81(m,2H),0.76(t,J=6.8 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.6,161.5(d,J=243.7 Hz),158.3,148.3,137.6(d,J=3.2 Hz),137.4,131.3(d,J=7.3 Hz),126.5,118.1,114.2(d,J=20.8 Hz),103.9,67.6,56.6,55.9,47.6,44.0,41.8,41.1,39.0,37.7,31.8,29.5,28.4,28.0,27.7,27.5,26.5,24.4,22.6,21.2,14.1. 19 F NMR(376 MHz,CDCl3)δ-117.6.IR(neat,ν max / cm -1 ):2931,2869,1726,1658,1604,1572,1508,1479,14623,1410,1397,1381,1364,1339,1280,1239,1224 ,1151,1121,1042,1031,1015,957,938,907,841,769,757,702,562,547,525.HRMS(ESI):m / z=615.3818 [M+Na] + (Calculated value C) 38 H 53 FNaO4m / z=615.3820).[α] 25 D = +96.771 ± 0.079 (c = 1.0, CDCl3).

[0212] Process q)((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol ((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (35.5 mg, 59.8 μmol, 1.0 equivalent) was dissolved in CH2Cl2 (0.55 mL), to which DIBAL (126 μL, 126 μmol, 2.1 equivalents) was added at 0°C. After stirring the reaction mixture at 0°C for 15 minutes, saturated NH4Cl aqueous solution (3 mL) was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-20% siRNA in hexane) yielded the product as a colorless oil (29.1 mg, 96%).

[0213] 1 H NMR(400 MHz,CDCl3)δ 6.98-6.83(m,4H),6.39(s,2H),5.72(dt,J=2.9,1.4 Hz,1H),4.08(s,2H),4.01(s,1H),3.70(s,6H),2.71(dd,J=11.7,3.3 Hz,1H),2.26-2.18(m,2H),2.11-2.05(m,1H),1.70(d,J=7.6 Hz,1H),1.63-1.45(m,2H),1.32(s,3H),1.26(s,3H),1.15(s,3H),1.14-1.02(m,4H),0.98(s,3H),0.94-0.80(m,2H),0.76(t,J=6.7 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 161.5(d,J=243.7 Hz),158.3,148.3,142.1,137.6(d,J=3.2 Hz),131.3(d,J=7.5 Hz),123.7,118.2,114.2(d,J=20.8 Hz),103.9,66.8,56.6,56.0,47.6,44.0,41.8,41.0,37.6,31.8,29.5,28.4,28.0,28.0,26.4,24.4,22.6,21.2,14.1. 19 F NMR(376 MHz,CDCl3)δ-117.6.IR(neat,νmax / cm -1 ):3379,2929,2864,1655,1604,1572,1508,1462,1410,1381,1364,1340,1301,1238,1224,1 184,1160,1120,1049,1014,986,908,841,742,701,670,563,525.HRMS(ESI):m / z=531.3248 [M+Na] + (Calculated value C) 33 H 45 FNaO3m / z=531.3245).[α] 25 D =+109.233±0.100(c=1.0,CDCl3).

[0214] Example 11 ((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Step b) 2-(3,5-dimethoxyphenyl)-3-(3-fluorophenyl)-2-methyloctan-3-ol Preparation of 3-fluorophenyllithium: To a solution of 3-fluoroiodobenzene (861 μL, 7.33 mmol, 2.0 equivalents) in dry Et2O (8.0 mL), n-BuLi (1.6 M in hexane, 3.43 mL, 5.50 mmol, 1.5 equivalents) was added dropwise at -78°C, and the solution was stirred at -78°C for 30 minutes.

[0215] To a solution of LaCl3·2LiCl (0.6 M in THF, 6.11 mL, 3.66 mmol, 1.0 equivalent), 2-(3,5-dimethoxyphenyl)-2-methyloctan-3-one (1.02 g, 3.66 mmol, 1.0 equivalent) in dry THF (3.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and a pre-prepared solution of lithium 3-fluorophenyl was added dropwise. The mixture was stirred at 0°C for 30 minutes, and then quenched with saturated aqueous NH4Cl (15 mL) and H2O (15 mL). The mixture was diluted with Et2O (15 mL), the phases were separated, and the aqueous phase was extracted with Et2O (3 × 15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (SiO2; 0-15% phenylethylamine in hexane), yielding a colorless oily product (1.26 g, 99%).

[0216] 1 H NMR(400 MHz,CDCl3)δ 7.29-7.20(m,1H),7.11-6.99(m,2H),6.98-6.91(m,1H),6.51(d,J=2.3 Hz,2H),6.41(t,J=2.2 Hz,1H),3.78(s,6H),2.27-2.14(m,1H),1.88(s,1H),1.70-1.56(m,1H),1.41(s,3H),1.29(s,3H),1.20(d,J=4.2 Hz,4H),0.94-0.77(m,2H),0.82(t,J=6.8 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 162.33(d,J=243.6 Hz),160.1,148.0,145.58(d,J=6.6 Hz),128.15(d,J=8.0 Hz),123.54(d,J=2.7 Hz),115.22(d,J=22.4 Hz),113.11(d,J=21.1 Hz),107.5,98.0,80.3,55.3,46.6,35.8,32.5,25.0,24.7,23.7,22.7,14.1. 19 F NMR(377 MHz,CDCl3)δ-114.5.IR(neat,ν max / cm -1):3554,2955,2871,1594,1457,1422,1205,1156,1059.HRMS(ESI):m / z=397.2144 [M+Na] + (Calculated value C) 23 H 31 FNaO3m / z = 397.2149).

[0217] Step g)(E)-1-(3-(3-fluorophenyl)-2-methylocta-3-en-2-yl)-3,5-dimethoxybenzene To a solution of 2-(3,5-dimethoxyphenyl)-3-(3-fluorophenyl)-2-methyloctan-3-ol (1.40 g, 3.74 mmol, 1.0 equivalent) in anhydrous THF (24 mL), KHMDS (0.5 M in toluene, 18.7 mL, 9.35 mmol, 2.5 equivalents) and CS2 (3.39 mL, 56.1 mmol, 15 equivalents) were added at -78°C. The yellow solution was stirred at -78°C for 10 minutes, the cooling bath was removed, and the mixture was stirred for a further 30 minutes. MeI (3.72 mL, 59.8 mmol, 16 equivalents) was added, and the mixture was stirred first at ambient temperature for 1 hour, then at 40°C overnight. The mixture was diluted with Et2O (25 mL), and saturated NaHCO3 aqueous solution (25 mL) was added. The layers were separated, and the aqueous phase was extracted with Et2O (2 × 25 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-1.2% Et2O in hexane) to obtain an amber-orange liquid (1.09 g, 82%).

[0218] 1H NMR(400 MHz, CDCl3)δ 7.10(ddd,J=8.4,7.6,6.1 Hz,1H),6.89-6.82(m,1H),6.52(d,J=2.3 Hz,2H),6.50-6.46(m,1H),6.41(ddd,J=10.2,2.7,1.5 Hz,1H),6.35(t,J=2.2 Hz,1H),5.73(t,J=7.3 Hz,1H),3.79(s,6H),1.82-1.73(m,2H),1.39(s,6H),1.37-1.20(m,4H),0.83(t,J=7.2 Hz,3H). 13 C NMR(101 MHz, CDCl3)δ 162.2(d,J=244.9 Hz),160.5,150.7,147.4(d,J=1.6 Hz),142.8(d,J=7.5 Hz),128.7(d,J=8.4 Hz),127.0,125.57(d,J=2.8 Hz),116.6(d,J=20.8 Hz),113.0(d,J=20.9 Hz),105.6,97.5,55.3,44.1,32.2,29.0,29.0,22.4,14.0. 19 F NMR(377 MHz,CDCl3)δ-114.6.IR(neat,ν max / cm -1 ):2957,2933,2873,1598,1458,1423,1205,1155,1058.HRMS(ESI):m / z=379.2041 [M+Na] + (calculated value C 23 H 29 FNaO2m / z=379.2044).

[0219] Engineering h) (E)-5-(3-(3-フルオロフェニル)-2-メチルオクタ-3-エン-2-イル)ベンゼン-1,3-ジオール To a solution of (E)-1-(3-(3-fluorophenyl)-2-methylocta-3-en-2-yl)-3,5-dimethoxybenzene (1.01 g, 2.83 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (25 mL), BBr3 (1.0 M in CH2Cl2, 8.50 mL, 8.50 mmol, 3.0 equivalents) was added dropwise at 0°C, and the green solution was stirred at 0°C for 5.5 hours. The mixture was diluted with CH2Cl2 (25 mL) and carefully quenched with saturated NaHCO3 aqueous solution (25 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 30 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-50% Â in hexane) yielded the product as a golden oil (920 mg, 99%).

[0220] 1 H NMR(400 MHz,CDCl3)δ 7.08(dd,J=8.0,6.1 Hz,1H),6.83(ddd,J=8.5,2.6,1.0 Hz,1H),6.46(dd,J=7.6,1.2 Hz,1H),6.40(d,J=2.1 Hz,2H),6.39(dd,J=2.7,1.7 Hz,1H),6.20(t,J=2.2 Hz,1H),5.67(t,J=7.3 Hz,1H),5.27(bs,2H),1.75-1.68(m,2H),1.31(s,6H),1.29-1.17(m,4H),0.81(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,CDCl3)δ 162.2(d,J=244.7 Hz),156.2,151.8,147.1(d,J=1.7 Hz),142.7(d,J=7.5 Hz),128.8(d,J=8.4 Hz),127.1,125.6(d,J=2.7 Hz),116.6(d,J=20.8 Hz),113.1(d,J=20.9 Hz),107.1,100.6,43.8,32.1,29.0,28.8,22.4,14.1. 19 F NMR(377 MHz,CDCl3)δ-114.3.IR(neat,ν max / cm -1):3341,2961,2930,2872,1599,1580,1466,1434,1423,1324,1151,993.HRMS(ESI):m / z=351.1732 [M+Na] + (Calculated value C) 21 H 25 FNaO2m / z = 351.1731).

[0221] Step i) 5-(3-(3-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol To a solution of (E)-5-(3-(3-fluorophenyl)-2-methylocta-3-en-2-yl)benzene-1,3-diol (850 mg, 2.59 mmol, 1.0 equivalent) in siRNA (25 mL), Pd (10% by weight on C, 2.75 g, 2.59 mmol, 1.0 equivalent) was added, and the mixture was stirred in an autoclave at room temperature for 48 hours under a H2 pressure of 35 bar. The suspension was filtered through a Celite pad and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 20-30% siRNA in hexane) yielded the product as a golden foam (560 mg, yield 65%). The racemic mixture was divided by chiral SFC method 4 to obtain (R)-5-(3-(3-fluorophenyl)-2-methyloctane-2-yl)benzene-1,3-diol A (200 mg, 23%, %ee>99%) and (S)-5-(3-(3-fluorophenyl)-2-methyloctane-2-yl)benzene-1,3-diol B (190 mg, 22%, %ee>99%).

[0222] 1 H NMR(400 MHz,CDCl3)δ 7.21-7.11(m,1H),6.92-6.74(m,3H),6.43(d,J=2.2 Hz,2H),6.26(t,J=2.1 Hz,1H),6.08(bs,2H),2.73(dd,J=12.1,2.8 Hz,1H),1.61-1.49(m,1H),1.48-1.34(m,1H),1.21(s,3H),1.15-1.00(m,4H),1.05(s,3H),0.95-0.84(m,2H),0.74(t,J=6.9 Hz,3H).13 C NMR(101 MHz,CDCl3)δ 162.5(d,J=243.9 Hz),156.1,153.1,144.7(d,J=6.7 Hz),128.8(d,J=8.3 Hz),126.0(d,J=1.2 Hz),116.6(d,J=20.8 Hz),113.0(d,J=21.0 Hz),106.9,100.5,56.9,41.5,31.8,29.4,28.7,28.0,23.6,22.5,14.1. 19 F NMR(377 MHz,CDCl3)δ-114.4.IR(neat,ν max / cm -1 ):3342,2960,2933,2862,1595,1486,1466,1445,1326,1150,992,704.HRMS(ESI):353.1882 [M+Na] + (Calculated value C) 21 H 27 FNaO2m / z=353.1887).(R)-5-(3-(3-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol A [α] 25 D =-40.385±0.408(c=1.0,CHCl3). (S)-5-(3-(3-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol B [α] 25 D =+42.357±0.102(c=1.0,CHCl3).

[0223] Process o)((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of resorcinol(R)-5-(3-(3-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol A (25.5 mg, 77.1 μmol, 1.0 equivalent) and pTsOH·H2O (4.1 mg, 21.6 μmol, 0.28 equivalents) in CH2Cl2 (3.0 mL), ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (21.4 mg, 84.8 μmol, 1.1 equivalents) was added, and the solution was stirred at room temperature for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (3 mL), the layers were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-15% GaN in hexane) yielded the product as a colorless foam (33.6 mg, 77%).

[0224] 1 H NMR(400 MHz,CDCl3)δ 7.17(td,J=8.0,6.2 Hz,1H),6.91-6.82(m,2H),6.75(dt,J=10.4,2.1 Hz,1H),6.33(s,2H),6.03(dt,J=3.2,1.6 Hz,1H),5.72(bs,2H),4.65(dt,J=13.5,1.7 Hz,1H),4.52(dt,J=13.5,2.0 Hz,1H),4.06-4.01(m,1H),2.71(dd,J=12.0,2.9 Hz,1H),2.39(dt,J=9.7,5.6 Hz,1H),2.35-2.28(m,2H),1.62-1.53(m,1H),1.51(d,J=9.7 Hz,1H),1.45-1.38(m,1H),1.35(s,3H),1.24(s,9H),1.20(s,3H),1.16- 1.05(m,4H),1.04(s,3H),0.99(s,3H),0.96-0.82(m,2H),0.75(t,J=6.7 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.7,162.5(d,J=244.0 Hz),155.0,149.8,149.6,145.0(d,J=6.7 Hz),128.7(d,J=8.3 Hz),126.0,120.4,116.6(d,J=20.8 Hz),113.0(d,J=21.0 Hz),112.0,107.3,66.6,56.9,47.5,44.3,41.2,41.1,39.1,37.9,31.8,29.4,28.9,28.1,28.0,27.4,26.0,23.3,22.5,20.9,14.1. 19 F NMR(376 MHz,CDCl3)δ-114.7.IR(neat,ν max / cm -1 ):3451,2956,2931,2870,1728,1707,1624,1613,1586,1577,1510,1480,1464,1445,1429,1398,1384,1366,1328,1283,1 230,1159,1111,1073,1040,1027,963,935,916,876,783.,758,724,700,672,587,569,545,521.HRMS(ESI):m / z=587.3499 [M+Na] + (Calculated value C) 36 H 49 FNaO4m / z=587.3507).[α] 25 D = +14.014 ± 0.249 (c=1.0, CHCl3).

[0225] Process p)((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (MeO)2SO2 (28.2 μL, 298 μmol, 5.0 equivalents) was added to a suspension of the diol ((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (33.6 mg, 59.4 μmol, 1.0 equivalent) and K2CO3 (49.3 mg, 357 μmol, 6.0 equivalents) in acetone (0.7 mL), and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-5% ethyl hexane) to obtain a white foamy substance (28.3 mg, 80%).

[0226] 1 H NMR(400 MHz,CDCl3)δ 7.21-7.12(m,1H),6.91-6.84(m,1H),6.79(d,J=7.7 Hz,1H),6.75-6.66(m,1H),6.40(s,2H),5.78(dt,J=2.8,1.4 Hz,1H),4.61-4.55(m,1H),4.55-4.48(m,1H),4.01(s,1H),3.69(s,6H),2.72(dd,J=11.8,3.2 Hz,1H),2.23-2.14(m,2H),2.08-2.02(m,1H),1.72(d,J=7.6 Hz,1H),1.62-1.44(m,2H),1.30(s,3H),1.28(s,3H),1.22(s,9H),1.16( s,3H),1.15-1.03(m,4H),0.98(s,3H),0.94-0.84(m,2H),0.76(t,J=6.8 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.6,162.5(d,J=244.1 Hz),158.3,148.3,145.0(d,J=6.7 Hz),137.4,128.6(d,J=8.3 Hz),126.4,126.0,118.2,116.6(d,J=21.2 Hz),112.9(d,J=21.0 Hz),103.9,67.6,57.2,56.0,47.6,44.0,41.8,41.1,39.0,37.7,31.8,29.4,28.5,28.0,27.7,27.5,26.5,24.3,22.6,21.2,14.1. 19 F NMR(376 MHz,CDCl3)δ-114.8.IR(neat,ν max / cm -1 ):2955,2930,2869,1726,1656,1604,1586,1573,1480,1455,1410,1397,1382,1365,1338,1280,12 39,1149,1120,1032,957,928,904,871,852,832,782,724,699,585,520.HRMS(ESI):m / z=615.3806 [M+Na] + (Calculated value C) 38 H 53 FNaO4m / z=615.3820).[α] 25 D = +25.224 ± 0.173 (c=1.0, CHCl3).

[0227] Process o)((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol ((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (30.2 mg, 50.1 μmol, 1.0 equivalent) was dissolved in CH2Cl2 (0.55 mL), to which DIBAL (107 μL, 107 μmol, 2.1 equivalents) was added at 0°C. After stirring the reaction mixture at 0°C for 15 minutes, saturated NH4Cl aqueous solution (3 mL) was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-20% siRNA in hexane) yielded the product as a colorless oil (21.8 mg, 84%).

[0228] 1 H NMR(400 MHz,CDCl3)δ 7.22-7.10(m,1H),6.93-6.83(m,1H),6.79(d,J=7.7 Hz,1H),6.71(d,J=10.5 Hz,1H),6.41(s,2H),5.71(dt,J=2.7,1.4 Hz,1H),4.08(s,2H),4.03-3.99(m,1H),3.70(s,6H),2.72(dd,J=11.7,3.2 Hz,1H),2.26-2.19(m,2H),2.09-2.05(m,1H),1.72(d,J=7.9 Hz,1H),1.65-1.41(m,2H),1.32(s,3H),1.28(s,3H),1.16(s,3H),1.14-1.02(m,4H),0.98(s,3H),0.96-0.82(m,2H),0.76(t,J=6.9 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 162.4(d,J=244.1 Hz),158.2,148.1,144.8(d,J=6.7 Hz),142.0,128.5(d,J=8.2 Hz),125.9,123.6,118.2,116.5(d,J=21.1 Hz),112.8(d,J=21.0 Hz),103.8,66.7,57.1,55.9,47.5,43.8,41.6,40.9,37.5,31.7,29.3,28.4,27.8,27.8,26.3,24.2,22.4,21.1,14.0. 19 F NMR(376 MHz,CDCl3)δ-114.8.IR(neat,ν max / cm -1 ):3381,2928,2862,1656,1605,1586,1572,1487,1463,1449,1410,1380,1364,1340,1302,1238, 1184,1160,1119,1049,986,927,871,832,782,724,699,671,654,578.HRMS(ESI):m / z=531.3245 [M+Na] + (Calculated value C) 33 H 45 FNaO3m / z=531.3245).[α] 25 D = +55.004 ± 0.309 (c = 1.0, CHCl3).

[0229] Example 12 ((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Process o)((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate To a solution of resorcinol(S)-5-(3-(4-fluorophenyl)-2-methyloctan-2-yl)benzene-1,3-diol B (25.5 mg, 77.1 μmol, 1.0 equivalent) and pTsOH·H2O (4.1 mg, 21.6 μmol, 0.28 equivalents) in CH2Cl2 (3.0 mL), ((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (21.4 mg, 84.8 μmol, 1.1 equivalents) was added, and the solution was stirred at room temperature for 30 minutes. The reaction was stopped by adding saturated NaHCO3 aqueous solution (3 mL), the layers were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-15% phenylethylamine in hexane) yielded the product as a colorless foam (31.6 mg, 73%).

[0230] 1 H NMR(400 MHz,CDCl3)δ 7.23-7.14(m,1H),6.94-6.82(m,2H),6.76(ddd,J=10.7,2.6,1.6 Hz,1H),6.33(s,2H),6.03(dt,J=3.2,1.6 Hz,1H),5.73(bs,2H),4.68-4.61(m,1H),4.52(ddd,J=13.5,2.3,1.6 Hz,1H),4.03(s,1H),2.71(dd,J=12.0,2.9 Hz,1H),2.43-2.35(m,1H),2.33-2.29(m,2H),1.61-1.52(m,1H),1.50(d,J=9.7 Hz,1H),1.45-1.37(m,1H),1.35(s,3H),1.24(s,9H),1.20(s,3H),1.19- 1.05(m,4H),1.04(s,3H),0.99(s,3H),0.96-0.80(m,2H),0.75(t,J=6.6 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.7,162.5(d,J=244.1 Hz),155.0,149.9,149.6,145.0(d,J=6.7 Hz),128.7(d,J=8.2 Hz),126.0,120.4,116.6(d,J=20.7 Hz),113.0(d,J=21.0 Hz),112.0,107.2,66.6,56.9,47.5,44.3,41.2,41.1,39.1,37.9,31.8,29.4,28.9,28.2,28.0,27.4,26.0,23.2,22.5,20.9,14.1. 19 F NMR(376 MHz,CDCl3)δ-114.7.IR(neat,ν max / cm -1 ):3449,2956,2930,2870,1726,1707,1625,1613,1586,1577,1480,1464,1445,1428,1398,1384,1366,1337,1326,1283,1 229,1157,1111,1073,1040,1028,962,935,916,876,783,756,724,700,668,587,569,545,521.HRMS(ESI):m / z=587.3498 [M+Na] + (Calculated value C) 36 H 49 FNaO4m / z=587.3507).[α] 25 D = +69.607 ± 0.141 (c=1.0, CHCl3).

[0231] Process p)((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (MeO)2SO2 (26.5 μL, 280 μmol, 5.0 equivalents) was added to a suspension of the diol ((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctane-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (31.6 mg, 55.9 μmol, 1.0 equivalent) and K2CO3 (46.4 mg, 336 μmol, 6.0 equivalents) in acetone (0.7 mL), and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. The product was obtained as a white foam (30.2 mg, 91%) by purification by flash column chromatography (SiO2; 0-5% ethyl hexane).

[0232] 1 H NMR(400 MHz,CDCl3)δ 7.20-7.12(m,1H),6.91-6.83(m,1H),6.80(d,J=7.9 Hz,1H),6.71(d,J=10.5 Hz,1H),6.41(s,2H),5.79(s,1H),4.61-4.55(m,1H),4.55-4.48(m,1H),4.01(s,1H),3.70(s,6H),2.72(dd,J=11.7,3.2 Hz,1H),2.23-2.13(m,2H),2.09-2.01(m,1H),1.70(d,J=7.5 Hz,1H),1.63-1.43(m,2H),1.31(s,3H),1.28(s,3H),1.22(s,9H),1.17( s,3H),1.15-1.04(m,4H),0.98(s,3H),0.94-0.85(m,2H),0.76(t,J=6.4 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 178.6,162.5(d,J=244.1 Hz),158.3,148.2,145.0(d,J=6.8 Hz),137.4,128.7(d,J=8.2 Hz),126.4,126.0,118.2,116.6(d,J=20.0 Hz),112.9(d,J=21.0 Hz),103.9,67.6,57.2,55.9,47.6,44.0,41.8,41.1,39.0,37.7,31.8,29.4,28.6,28.0,27.7,27.5,26.5,24.3,22.6,21.2,14.1. 19 F NMR(376 MHz,CDCl3)δ-114.8.IR(neat,ν max / cm -1 ):2955,2930,2869,1725,1657,1635,1604,1586,1573,1508,1480,1463,1450,1410,1382,1365,1337,1281 ,1260,1239,1150,1120,1031,957,928,904,871,832,782,756,669,654,584,521.HRMS(ESI):m / z=615.3804 [M+Na] + (Calculated value C) 38 H 53 FNaO4m / z=615.3820).[α] 25 D = +73.779 ± 0.081 (c=1.0, CHCl3).

[0233] Process o)((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol ((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl pivalate (27.3 mg, 46.0 μmol, 1.0 equivalent) was dissolved in CH2Cl2 (0.55 mL), to which DIBAL (97.0 μL, 97.0 μmol, 2.1 equivalents) was added at 0°C. After stirring the reaction mixture at 0°C for 15 minutes, saturated NH4Cl aqueous solution (3 mL) was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-20% siRNA in hexane) yielded the product as a colorless oil (21.5 mg, 92%).

[0234] 1 H NMR(400 MHz,CDCl3)δ 7.19-7.13(m,1H),6.91-6.83(m,1H),6.79(d,J=7.7 Hz,1H),6.71(d,J=10.2 Hz,1H),6.41(s,2H),5.72(dt,J=2.8,1.4 Hz,1H),4.08(d,J=4.4 Hz,2H),4.03-3.96(m,1H),3.70(s,6H),2.72(dd,J=11.8,3.2 Hz,1H),2.27-2.18(m,2H),2.11-2.05(m,1H),1.70(d,J=7.7 Hz,1H),1.61-1.40(m,2H),1.32(s,3H),1.27(s,3H),1.16(s,3H),1.15-1.02(m,4H),0.98(s,3H),0.96-0.81(m,2H),0.76(t,J=6.5 Hz,3H). 13C NMR(101 MHz,CDCl3)δ 162.5(d,J=244.1 Hz),158.3,148.2,145.0(d,J=6.7 Hz),142.1,128.7(d,J=8.3 Hz),126.0,123.7,118.3,116.6(d,J=21.2 Hz),112.9(d,J=21.0 Hz),103.9,66.8,57.2,56.0,47.6,44.0,41.8,41.0,37.6,31.8,29.4,28.6,28.0,28.0,26.4,24.3,22.6,21.2,14.1. 19 F NMR(376 MHz,CDCl3)δ-114.8.IR(neat,ν max / cm -1 ):3373,2927,2862,1661,1604,1586,1572,1508,1487,1463,1450,1410,1380,1364,1341,1302,1239, 1183,1160,1119,1072,1049,987,927,871,832,782,724,699,671,578,522.HRMS(ESI):m / z=531.3245 [M+Na] + (Calculated value C) 33 H 45 FNaO3m / z=531.3245).[α] 25 D =+107.650±0.171(c=1.0,CHCl3).

[0235] Example 13 ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-(1-methyl-1H-pyrazole-3-yl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol [ka] Example 13 can be accessed in the same format as described for Examples 1 to 12.

[0236] Example 14 ((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine [ka] Step c) 8-Chloro-2-(3,5-dimethoxyphenyl)-2-methyl-3-phenyloctan-3-ol A solution of 1-chloro-5-iodopentane (1.42 mL, 10.1 mmol, 1.2 equivalents, CAS RN: 60274-60-4) in a 3:2 pentane-Et2O (100 mL) was cooled to -78°C under an argon atmosphere, and t-BuLi (1.7 M in pentane, 11.9 mL, 20.3 mmol, 2.4 equivalents) was added dropwise. The solution was stirred at -78°C for 20 minutes. To this solution, 2-(3,5-dimethoxyphenyl)-2-methyl-1-phenylpropan-1-one (2.40 g, 8.44 mmol, 1.0 equivalent, CAS RN: 208349-21-7) (in Et2O (2.0 mL)) was added all at once. The mixture was stirred at -78°C for 5 minutes, then the cooling bath was removed, and the mixture was stirred for a further 30 minutes. The reaction was quenched by adding saturated NH4Cl aqueous solution (50 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 100 mL). The combined organic extract was washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 5-35% Et2O in hexane) to obtain a colorless viscous liquid (2.75 g, 83%).

[0237] 1H NMR(400 MHz,CDCl3)δ 7.31-7.18(m,5H),6.43(d,J=2.3 Hz,2H),6.36(t,J=2.2 Hz,1H),3.74(s,6H),3.42(t,J=6.7 Hz,2H),2.21(ddd,J=13.9,12.0,4.3 Hz,1H),1.81(s,1H),1.70-1.53(m,3H),1.37(s,3H),1.36-1.28(m,2H),1.24(s,3H),1.22-1.09(m,1H),0.95-0.78(m,1H). 13 C NMR(101 MHz,CDCl3)δ 160.1,148.2,142.2,127.9,127.1,126.5,107.5,98.0,80.4,55.4,46.7,45.2,35.7,32.7,27.6,25.1,24.8,23.5.IR(neat,ν max / cm -1 ):3558,2937,2868,2836,1594,1456,1421,1386,1204,1154,707.HRMS(ESI):m / z=413.1850 [M+Na] + (Calculated value C) 23 H 31 ClNaO3m / z = 413.1854).

[0238] Step g)(E)-1-(8-chloro-2-methyl-3-phenylocta-3-en-2-yl)-3,5-dimethoxybenzene To a solution of 8-chloro-2-(3,5-dimethoxyphenyl)-2-methyl-3-phenyloctan-3-ol (2.70 g, 6.91 mmol, 1.0 equivalent) in anhydrous THF (40 mL), KHMDS (1.0 M in THF, 17.3 mL, 17.3 mmol, 2.5 equivalents) and CS2 (6.26 mL, 104 mmol, 15.0 equivalents) were added at -78°C. The yellow solution was stirred at -78°C for 10 minutes, the cooling bath was removed, and the mixture was stirred for a further 30 minutes. MeI (6.88 mL, 111 mmol, 16.0 equivalents) was added, and the mixture was stirred at ambient temperature for 1 hour, then at 40°C overnight. The mixture was diluted with Et2O (40 mL), and saturated NaHCO3 aqueous solution (40 mL) was added. The layers were separated, and the aqueous phase was extracted with Et2O (2 × 40 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by flash column chromatography (using SiO2; 0-2% Et2O in hexane) to obtain an amber-orange liquid (2.45 g, 95%).

[0239] 1 H NMR(400 MHz,CDCl3)δ 7.17-7.11(m,3H),6.70-6.63(m,2H),6.50(d,J=2.3 Hz,2H),6.33(t,J=2.3 Hz,1H),5.65(t,J=7.2 Hz,1H),3.78(s,6H),3.42(t,J=6.8 Hz,2H),1.82-1.74(m,2H),1.72-1.64(m,2H),1.50-1.41(m,2H),1.37(s,6H). 13 C NMR(101 MHz,CDCl3)δ 160.4,150.9,149.5,140.2,129.7,127.5,126.3,125.6,105.8,97.4,55.4,45.0,44.3,32.2,29.0,28.5,27.2.IR(neat,ν max / cm -1 ):2947,2933,2835,1598,1457,1422,1204,1155,1059,706.HRMS(ESI):m / z=395.1745 [M+Na] + (Calculated value C) 23 H 29ClNaO2m / z = 395.1748).

[0240] Process h)(E)-5-(8-chloro-2-methyl-3-phenylocta-3-en-2-yl)benzene-1,3-diol To a solution of (E)-1-(8-chloro-2-methyl-3-phenylocta-3-en-2-yl)-3,5-dimethoxybenzene (2.50 g, 6.70 mmol, 1.0 equivalent) in anhydrous CH2Cl2 (50 mL), BBr3 (1.0 M in CH2Cl2, 20.1 mL, 20.1 mmol, 3.0 equivalents) was added dropwise at 0°C, and the green solution was stirred at 0°C for 5.5 hours. The mixture was diluted with CH2Cl2 (40 mL) and carefully quenched with saturated NaHCO3 aqueous solution (40 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 40 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 0-50% Â in hexane) yielded the product as a golden oil (2.25 g, 97%).

[0241] 1 H NMR(400 MHz,CDCl3)δ 7.18-7.10(m,3H),6.76-6.66(m,2H),6.46(d,J=2.2 Hz,2H),6.25(t,J=2.1 Hz,1H),5.90(bs,2H),5.64(t,J=7.2 Hz,1H),3.42(t,J=6.7 Hz,2H),1.82-1.71(m,2H),1.71-1.61(m,2H),1.51-1.38(m,2H),1.33(s,6H). 13 C NMR(101 MHz,CDCl3)δ 156.0,151.8,149.0,140.1,129.6,127.4,126.2,125.7,107.1,100.5,45.2,43.8,32.0,28.8,28.3,26.9.IR(neat,ν max / cm -1 ):3356,2966,2944,2867,1599,1440,1323,1151,993,705.HRMS(ESI):m / z=367.1432 [M+Na] + (Calculated value C)21 H 25 ClNaO2m / z = 367.1435).

[0242] Step i) 5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol To a solution of (E)-5-(8-chloro-2-methyl-3-phenylocta-3-en-2-yl)benzene-1,3-diol (1.80 g, 5.22 mmol) in dry siRNA (30 mL), Pd (10% by weight on C, 5.55 g, 5.22 mmol, 1.0 equivalent) was added, and the resulting mixture was hydrogenated at 60 bar at room temperature for 48 hours. The mixture was then filtered through a Celite pad, and the crude material was purified by flash column chromatography (SiO2, hexane, 15-30% siRNA) to obtain the product as a dark red oil (1.75 g, 97%). The racemic mixture was divided by chiral SFC method 5 to obtain (S)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A (450 mg, 25%, %ee>99%) and (R)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol B (360 mg, 20%, %ee=96%).

[0243] 1 H NMR(400 MHz,CDCl3)δ 7.30-7.17(m,3H),7.11-7.03(m,2H),6.42(d,J=2.2 Hz,2H),6.22(t,J=2.2 Hz,1H),5.18(bs,2H),3.38(td,J=6.7,2.0 Hz,2H),2.74(dd,J=12.2,2.9 Hz,1H),1.70-1.59(m,1H),1.58-1.49(m,2H),1.45-1.34(m,1H),1.32-1.18(m,2H),1.22(s,3H),1.06(s,3H),1.02-0.83(m,2H). 13C NMR(101 MHz,CDCl3)δ 156.2,153.2,141.5,130.1,127.6,126.3,106.8,100.3,56.8,45.4,41.6,32.4,29.2,29.1,27.5,26.7,23.2.IR(neat,ν max / cm -1 ):3345,2936,2867,1599,1453,1320,1151,992,705.HRMS(ESI):m / z=369.1590 [M+Na] + (Calculated value C) 21 H 27 ClNaO2m / z=369.1592).(S)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A [α] 25 D =-34.683±0.163(c=1.0,CHCl3). (R)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol B [α] 25 D =+33.913±0.053(c=1.0,CHCl3).

[0244] Process o)2-(((1S,4S,5S)-4-(4-((S)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of (S)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A (51.0 mg, 147 μmol, 1.0 equivalent) and pTsOH·H2O (8.0 mg, 42.0 μmol, 0.28 equivalents) in CH2Cl2 (6.0 mL), 2-(((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindorin-1,3-dione (48.0 mg, 162 μmol, 1.1 equivalents, Chem. Eur. J., 2020, 26, 1380-1387) was added, and the pale yellow solution was stirred at room temperature for 1.5 hours. Further 2-(((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (10.9 mg, 36.7 μmol, 0.25 equivalents) was added, and the reaction mixture was stirred for 1 hour. The reaction was stopped by adding saturated NaHCO3 aqueous solution (3 mL), the layers were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 5-30% ethyl hexane) yielded the product as a colorless foam (62.0 mg, 67%).

[0245] 1 H NMR(400 MHz,CDCl3)δ 7.93-7.86(m,2H),7.76-7.70(m,2H),7.28-7.14(m,3H),7.11-7.03(m,2H),6 .49-6.31(s,2H),6.05-5.98(m,1H),5.90(bs,2H),4.47(ddd,J=15.5,3.0,1.9 Hz,1H),4.27-4.19(m,1H),4.05-3.98(m,1H),3.35(t,J=6.8 Hz,2H),2.71(dd,J=12.1,2.9 Hz,1H),2.37-2.21(m,3H),1.66-1.15(m,7H),1.32(s,3H),1.17(s,3H),1.01(s,3H),1.00(s,3H),0.98-0.82(m,2H). 13C NMR(101 MHz,CDCl3)δ 168.5,154.9,149.9,148.1,141.8,134.3,132.0,130.1,127.6,126.2,123.7,120.7,111.9,107.4,56.8, 47.3,45.3,44.3,43.3,41.3,41.2,37.8,32.4,29.6,29.2,28.2,27.5,26.7,26.0,22.6,20.7.IR(neat,ν max / cm -1 ):3454,2933,1770,1711,1623,1574,1426,1393,754,729,705.HRMS(ESI):m / z=648.2844 [M+Na] + (Calculated value C) 39 H 44 ClNNaO4m / z=648.2851).[α] 25 D = +72.790 ± 0.118 (c=1.0, CHCl3).

[0246] Step p)2-(((1S,4S,5S)-4-(4-((S)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a suspension of 2-(((1S,4S,5S)-4-(4-((S)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (57.0 mg, 91.0 μmol, 1.0 equivalent) and K2CO3 (75.5 mg, 546 μmol, 6.0 equivalents) in acetone (0.9 mL), (MeO)2SO2 (43 μL, 455 μmol, 5.0 equivalents) was added, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2; 0-15% acetone in hexane) to obtain a white foamy substance (49 mg, 82%).

[0247] 1 1H NMR (400 MHz, CDCl3) δ 7.89 - 7.82 (m, 2H), 7.75 - 7.67 (m, 2H), 7.25 - 7.12 (m, 3H), 7.05 - 6.98 (m, 2H), 6.39 (s, 2H), 5.62 - 5.56 (m, 1H), 4.35 - 4.28 (m, 1H), 4.24 (ddd, J = 15.4, 2.3, 1.6 Hz, 1H), 3.98 - 3.94 (m, 1H), 3.68 (s, 6H), 3.36 (t, J = 6.7 Hz, 2H), 2.71 (dd, J = 12.0, 2.9 Hz, 1H), 2.23 - 2.12 (m, 2H), 2.05 - 1.97 (m, 1H), 1.74 (d, J = 8.0 Hz, 1H), 1.68 - 1.38 (m, 4H), 1.34 - 1.14 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.12 (s, 3H), 1.02 - 0.83 (m, 2H), 0.94 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 168.3, 158.3, 148.4, 141.7, 136.2, 133.9, 132.4, 130.1, 127.5, 126.2, 123.9, 123.3, 117.9, 103.7, 57.2, 55.9, 47.6, 45.2, 44.4, 42.6, 41.8, 41.2, 37.5, 32.5, 29.2, 29.0, 27.6, 27.6, 26.8, 26.4, 23.9, 20.9. IR (neat, ν max / cm -1 ): 2930, 2863, 1772, 1715, 1603, 1572, 1390, 1239, 1117, 729, 704, 671. HRMS (ESI): m / z = 676.3152 [M + Na] + (Calculated for C 41 H 48 ClNNaO4 m / z = 676.3164). [α] 25 D = +33.551 ± 0.235 (c = 1.0, CHCl3).

[0248] Process r)2-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of 2-(((1S,4S,5S)-4-(4-((S)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (42.0 mg, 64.1 μmol, 1.0 equivalent) in DMF (0.35 mL), NaN3 (41.7 mg, 642 μmol, 10 equivalents) was added, and the reaction mixture was stirred at 50°C for 24 hours. The mixture was cooled to room temperature and diluted with 5% LiCl aqueous solution (3 mL) and Et2O (3 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 3 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2, hexane with 0-10% siRNA) to obtain a white foamy substance (38.0 mg, 90%).

[0249] 1 H NMR(400 MHz,CDCl3)δ 7.88-7.82(m,2H),7.74-7.66(m,2H),7.25-7.13(m,3H),7.05-6.98(m,2H),6 .39(s,2H),5.63-5.56(m,1H),4.36-4.28(m,1H),4.24(ddd,J=15.4,2.3,1.6 Hz,1H),3.99-3.94(m,1H),3.68(s,6H),3.09(t,J=6.9 Hz,2H),2.70(dd,J=12.0,2.9 Hz,1H),2.24-2.11(m,2H),2.04-1.98(m,1H),1.74(d,J=8.0 Hz,1H),1.68-1.08(m,6H),1.27(s,3H),1.25(s,3H),1.12(s,3H),1.02-0.83(m,2H),0.94(s,3H). 13C NMR(101 MHz,CDCl3)δ 168.3,158.3,148.4,141.7,136.2,133.9,132.4,130.1,127.5,126.2,123.9,123.3,117.9,103.6,57.2,55 .8,51.5,47.6,44.3,42.6,41.8,41.2,37.5,29.3,29.0,28.7,27.9,27.6,26.6,26.4,23.9,20.9.IR(neat,ν max / cm -1 ):2933,2865,2094,1772,1716,1603,1572,1390,1240,1119.(ESI):m / z=661.3746 [M+H] + (Calculated value C) 41 H 49 N4O4m / z=661.3748).[α] 25 D = +32.189 ± 0.150 (c=1.0, CHCl3).

[0250] Process s)((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine To a solution of 2-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (36.0 mg, 54.4 μmol, 1.0 equivalent) in EtOH (1.1 mL), N2H4·H2O (27 μL, 544 μmol, 10 equivalents) and (E) / (Z)-clotyl alcohol (70 μL, 817 μmol, 15 equivalents) were added, and the solution was heated to 75°C and stirred for 2 hours. A white solid precipitate formed, and the mixture was filtered through cotton and rinsed with EtOH. The filtrate was concentrated under vacuum. The product was purified by flash column chromatography (1% 7.0 M NH3 in SiO2;MeOH, 1-4% MeOH in CH2Cl2) to obtain a white foamy substance (25.5 mg, 88%).

[0251] 1 H NMR(400 MHz,CDCl3)δ 7.25-7.15(m,3H),7.06-7.00(m,2H),6.43(s,2H),5.58-5.54(m,1H),4.03-3.97(m,1H),3.70(s,6H),3.24(t,J=1.8 Hz,2H),3.11(t,J=6.9 Hz,2H),2.72(dd,J=12.1,2.9 Hz,1H),2.23-2.17(m,1H),2.14(td,J=5.6,1.4 Hz,1H),2.06(ddt,J=5.8,3.9,1.9 Hz,1H),1.72(d,J=8.4 Hz,1H),1.69-1.32(m,4H),1.31(s,3H),1.27(s,3H),1.24-1.16(m,2H),1.14(s,3H),1.02-0.88(m,2H),0.97(s,3H). 13 C NMR(101 MHz,CDCl3)δ 158.4,148.4,143.6,141.7,130.1,127.5,126.3,121.0,118.5,104.0,57.3,56.0,51.5,47.7 ,47.6,44.7,41.8,41.0,37.6,29.3,28.9,28.7,28.1,27.9,26.7,26.5,24.0,21.2.IR(neat,ν max / cm -1 ):2932,2864,2094,1604,1572,1452,1410,1240,1120.HRMS(ESI):m / z=531.3690 [M+H] + (Calculated value C) 33 H 47 N4O2m / z=531.3694).[α] 25 D = +44.526 ± 0.423 (c = 1.0, CHCl3).

[0252] Example 15 ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine [ka] Process o)2-(((1S,4S,5S)-4-(4-((R)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of (R)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol B (56.2 mg, 162 μmol, 1.0 equivalent) and pTsOH·H2O (8.6 mg, 45.3 μmol, 0.28 equivalents) in CH2Cl2 (7.0 mL), 2-(((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindorin-1,3-dione (53.0 mg, 178 μmol, 1.1 equivalents) was added, and the pale yellow solution was stirred at room temperature for 1.5 hours. Further 2-(((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (12.0 mg, 40.5 μmol, 0.25 equivalents) was added, and the reaction mixture was stirred for 1 hour. The reaction was stopped by adding saturated NaHCO3 aqueous solution (3 mL), the layers were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; using 5-30% SiO2 in hexane) yielded the product as a colorless foam (72.0 mg, 71%).

[0253] 1H NMR(400 MHz,CDCl3)δ 7.92-7.86(m,2H),7.76-7.71(m,2H),7.27-7.16(m,3H),7.12-7.06(m,2H) ,6.41(s,2H),6.05-5.99(m,1H),5.88(bs,2H),4.47(ddd,J=15.5,3.0,1.9 Hz,1H),4.27-4.18(m,1H),4.05-3.99(m,1H),3.36(t,J=6.7 Hz,2H),2.72(dd,J=12.1,2.9 Hz,1H),2.36-2.22(m,3H),1.70-1.44(m,4H),1.40-1.13(m,3H),1.32(s,3H),1.17(s,3H),1.00(s,3H),0.99(s,3H),0.97-0.81(m,2H). 13 C NMR(101 MHz,CDCl3)δ 168.5,155.0,150.1,148.1,141.7,134.3,132.1,130.1,127.6,126.2,123.7,120.8,111.9,107.3,56.7, 47.4,45.3,44.3,43.3,41.3,41.2,37.8,32.4,29.6,29.1,28.2,27.5,26.7,26.0,22.5,20.7.IR(neat,ν max / cm -1 ):3454,2931,2867,1770,1710,1623,1574,1426,1392,1340,1112,1024,946,764,728,705.HRMS(ESI):m / z=626.3030 [M+H] + (Calculated value C) 39 H 45 ClNO4m / z=626.3032).[α] 25 D =+114.140±0.504(c=1.0,CHCl3).

[0254] Step p)2-(((1S,4S,5S)-4-(4-((R)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a suspension of 2-(((1S,4S,5S)-4-(4-((R)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (70.0 mg, 118 μmol, 1.0 equivalent) and K2CO3 (92.7 mg, 671 μmol, 6.0 equivalents) in acetone (1.0 mL), (MeO)2SO2 (53 μL, 559 μmol, 5.0 equivalents) was added, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. The product was obtained as a white foam (59 mg, 81%) by purification by flash column chromatography (SiO2; 0-15% acetone in hexane).

[0255] 1 H NMR(400 MHz,CDCl3)δ 7.88-7.83(m,2H),7.74-7.68(m,2H),7.25-7.15(m,3H),7.06-7.00(m,2H),6.39(s,2H),5.62-5.58(m,1H),4.32(ddd,J=15.4,2.2,1.6 Hz,1H),4.24(ddd,J=15.4,2.3,1.6 Hz,1H),3.99-3.94(m,1H),3.68(s,6H),3.37(t,J=6.8,2H),2.71(dd,J=12.1,2.9 Hz,1H),2.22-2.11(m,2H),2.05-1.99(m,1H),1.72(d,J=8.1 Hz,1H),1.66-1.38(m,4H),1.34-1.15(m,2H),1.27(s,3H),1.25(s,3H),1.11(s,3H),1.02-0.84(m,2H),0.94(s,3H). 13C NMR(101 MHz,CDCl3)δ 168.3,158.3,148.5,141.7,136.1,133.9,132.4,130.1,127.5,126.2,123.9,123.3,117.9,103.6,57.1,55 .8,47.6,45.2,44.3,42.6,41.8,41.2,37.5,32.4,29.2,29.0,27.6,27.6,26.8,26.4,23.8,20.9.IR(neat,ν max / cm -1 ):2933,2865,1772,1715,1603,1572,1390,1239,1117,730,704.HRMS(ESI):m / z=676.3163 [M+Na] + (Calculated value C) 41 H 48 ClNNaO4m / z=676.3164).[α] 25 D = +71.187 ± 0.169 (c=1.0, CHCl3).

[0256] Process r)2-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of 2-(((1S,4S,5S)-4-(4-((R)-8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (57.0 mg, 87.1 μmol, 1.0 equivalent) in DMF (0.40 mL), NaN3 (56.6 mg, 871 μmol, 10 equivalents) was added, and the reaction mixture was stirred at 50°C for 24 hours. The mixture was cooled to room temperature and diluted with 5% LiCl aqueous solution (3 mL) and Et2O (3 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 × 3 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2, hexane with 0-10% siRNA) to obtain a white foamy substance (50.5 mg, 88%).

[0257] 1 H NMR(400 MHz,CDCl3)δ 7.89-7.81(m,2H),7.75-7.67(m,2H),7.25-7.15(m,3H),7.06-6.99(m,2H),6.39(s,2H),5.63- 5.5(m,1H),4.35-4.29(m,1H),4.28-4.20(m,1H),4.00-3.93(m,1H),3.68(s,6H),3.09(t,J=6.9 Hz,2H),2.71(dd,J=12.1,2.9 Hz,1H),2.23-2.10(m,2H),2.06-1.98(m,1H),1.72(d,J=8.1 Hz,1H),1.68-1.53(m,1H),1.47-1.09(m,5H),1.27(s,3H),1.25(s,3H),1.11(s,3H),1.03-0.85(m,2H),0.94(s,3H). 13C NMR(101 MHz,CDCl3)δ 168.3,158.3,148.5,141.7,136.1,133.9,132.4,130.1,127.5,126.2,124.0,123.3,117.9,103.6,57.2,55 .8,51.5,47.6,44.3,42.6,41.8,41.2,37.5,29.2,29.0,28.7,27.9,27.6,26.6,26.4,23.8,20.9.IR(neat,ν max / cm -1 ):2933,2864,2094,1772,1715,1603,1572,1424,1410,1390,1239,1118,730,711.HRMS(ESI):m / z=683.3565 [M+Na] + (Calculated value C) 41 H 48 N4NaO4m / z=683.3568).[α] 25 D = +73.648 ± 0.128 (c=1.0, CHCl3).

[0258] Process s)((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine To a solution of 2-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (37.0 mg, 55.9 μmol, 1.0 equivalent) in EtOH (1.1 mL), N2H4·H2O (28 μL, 559 μmol, 10 equivalents) and (E) / (Z)-clotyl alcohol (72 μL, 840 μmol, 15 equivalents) were added, and the solution was heated to 75°C and stirred for 2 hours. A white solid precipitate formed, and the mixture was filtered through cotton and rinsed with EtOH. The filtrate was concentrated under vacuum. The product was purified by flash column chromatography (1% 7.0 M NH3 in SiO2;MeOH, 1-4% MeOH in CH2Cl2) to obtain a white foamy substance (28.0 mg, 94%).

[0259] 1 H NMR(400 MHz,CDCl3)δ 7.26-7.15(m,3H),7.03(dt,J=6.0,1.6 Hz,2H),6.43(s,2H),5.58-5.55(m,1H),4.01-3.98(m,1H),3.71(s,6H),3.23(t,J=1.8 Hz,2H),3.11(t,J=6.9 Hz,2H),2.72(dd,J=12.1,2.9 Hz,1H),2.20(dt,J=8.3,5.5 Hz,1H),2.13(td,J=5.6,1.4 Hz,1H),2.10-2.05(m,1H),1.70(d,J=8.3 Hz,1H),1.68-1.57(m,1H),1.53-1.33(m,3H),1.31(s,3H),1.27(s,3H),1.25-1.17(m,2H),1.14(s,3H),1.01-0.86(m,2H).0.97(s,3H). 13C NMR(101 MHz,CDCl3)δ 158.4,148.4,143.7,141.7,130.1,127.5,126.2,120.9,118.5,104.0,57.2,56.0,51.5,47.7 ,47.7,44.7,41.8,41.0,37.5,29.3,28.9,28.7,28.1,27.9,26.7,26.5,23.9,21.2.IR(neat,ν max / cm -1 ):2933,2864,2094,1604,1572,1452,1410,1240,1120.HRMS(ESI):m / z=531.3690 [M+H] + (Calculated value C) 33 H 47 N4O2m / z=531.3694).[α] 25 D =+101.994±0.218(c=1.0,CHCl3).

[0260] Example 16 6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)-1-(6-((((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)pyridine-1-ium-3-sulfonate [ka] 2-(3,5-bis(methoxymethoxy)phenyl)-2-methyl-1-phenylpropan-1-one

[0261] To a solution of 2-(3,5-dimethoxyphenyl)-2-methyl-1-phenylpropan-1-one (3.45 g, 12.1 mmol, 1.0 equivalent) in CH2Cl2 (40 mL), BBr3 (3.44 mL, 36.4 mmol, 3.0 equivalent) was added at -78 °C. The solution was brought to 0 °C in an ice bath and stirred at 0 °C for 3.5 hours. The reaction was stopped by the addition of saturated NaHCO3 aqueous solution, and the mixture was extracted with CH2Cl2. The combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (dry loading on SiO2, silica; using 20-40% siRNA in hexane). The resorcinol intermediate was dissolved in anhydrous DMF (40 mL), and the solution was cooled to 0 °C. NaH (50% on mineral oil, 1.75 g, 36.4 mmol, 3.0 equivalents) was added, and the suspension was stirred at 0°C for 15 minutes. Freshly distilled MOMCl (2.76 mL, 36.4 mmol, 3.0 equivalents) was added by syringe, and the mixture was warmed to ambient temperature. After 2 hours, TLC (20% siRNA in hexane) showed complete conversion of the resorcinol intermediate, and the reaction was stopped by the addition of water. The mixture was extracted with Et2O, the combined organic extract was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; using 10-20% Et2O in hexane) yielded the product as a yellow oil (4.20 g, quantitative yield).

[0262] 1 H NMR(400 MHz,CDCl3)δ=7.56-7.51(m,2H),7.37(ddt,J=8.6,7.0,1.3 Hz,1H),7.26-7.20(m,2H),6.67(t,J=2.2 Hz,1H),6.64(d,J=2.2 Hz,2H),5.12(s,4H),3.44(s,6H),1.57(s,6H). 13 C NMR(101 MHz,CDCl3)δ=203.5,158.9,148.0,136.4,131.8,129.7,128.1,108.0,102.8,94.8,56.3,51.6,27.9.lR(neat,ν max / cm -1)2934,1677,1594,1446,1399,1145,1027.ESI-HRMS Calculated value C 20 H 25 O5[M+H] + 345.1697; Measured value: 345.1695.

[0263] 2-(3,5-bis(methoxymethoxy)phenyl)-8-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenyloctan-3-ol To a solution of tert-butyl((5-iodopentyl)oxy)dimethylsilane (1.14 g, 3.48 mmol, 1.2 equivalents) in 3:2 pentane-Et2O (30 mL), t-BuLi (1.6 M in pentane, 4.54 mL, 7.26 mmol, 2.5 equivalents) was added at -78°C. After addition, the solution was stirred at -78°C for 5 minutes, and then the mixture was allowed to reach ambient temperature and stirred for 1 hour. The reaction mixture was cooled to the original -78°C, and a solution of 2-(3,5-bis(methoxymethoxy)phenyl)-2-methyl-1-phenylpropan-1-one (1.00 g, 2.90 mmol, 1.0 equivalent) was added very slowly by syringe. The cooling bath was then removed, and the mixture was warmed to ambient temperature. The reaction was stopped by adding saturated NH4Cl aqueous solution. After separating the organic layer, the aqueous phase was extracted with Et2O, the combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (using SiO2; 5-10% Et2O in hexane) yielded the product as a yellow oily substance (1.03 g, 64%).

[0264] 1H NMR(500 MHz,CDCl3)δ=7.26-7.17(m,5H),6.64(t,J=2.1 Hz,1H),6.62(d,J=2.2 Hz,2H),5.10(s,4H),3.51-3.48(m,2H),3.47(s,6H),2.19(ddd,J=13.9,12.0,4.2 Hz,1H),1.58(ddd,J=16.3,9.8,4.4 Hz,1H),1.41-1.33(m,2H),1.35(s,3H),1.27-1.18(m,2H),1.23(s,3H)1.16-1.07(m,1H),0.87-0.84(m,1H),0.86(s,9H),-0.01(s,6H). 13 C NMR(126 MHz, CDCl3)δ=157.5,148.5,142.3,127.9,127.0,126.4,111.0,102.6,94.8,80.5 ,63.3,56.2,46.7,35.8,32.9,26.5,26.1,25.0,24.8,23.9,18.5,-5.1.lR(neat,ν max / cm -1 )3569,2953,2931,2857,1595,1472,1145,1084,1031.ESI-HRMS calculation value C 31 H 50 NaO6Si [M+Na] + 569.3269; Measured value: 569.3270.

[0265] (E)-7-(3,5-bis(methoxymethoxy)phenyl)-7-methyl-6-phenylocta-5-en-1-ol To a solution of 2-(3,5-bis(methoxymethoxy)phenyl)-8-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenyloctan-3-ol (3.1 g, 5.6 mmol, 1.0 equivalent) in THF (56 mL), KHMDS (1.0 M in THF, 0.014 L, 0.014 mol, 2.5 equivalents) and CS2 (5.1 mL, 0.084 mol, 15 equivalents) were added at -78 °C. The yellow solution was stirred at -78 °C for 30 minutes, then warmed to ambient temperature. After stirring for another 30 minutes, MeI (5.6 mL, 0.090 mol, 16 equivalents) was added, and the mixture was stirred first at ambient temperature for 1 hour, then at 50 °C overnight. Saturated aqueous NaHCO3 solution was added, and the mixture was extracted with Et2O. The combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was dissolved in THF (21 mL), and TBAF (1.0 M, 0.017 L, 0.017 mol, 3.0 equivalents in THF) was added. After stirring for 4 hours, the reaction was stopped by adding saturated NaHCO3 aqueous solution. The mixture was extracted with siRNA, the combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; using 10-30% siRNA in hexane) yielded the product as a yellow oily substance and a single olefin isomer (1.5 g, 64% in 2 steps).

[0266] 1 H NMR(500 MHz,CDCl3)δ=7.15-7.12(m,3H),6.69-6.64(m,4H),6.60(t,J=2.2 Hz,1H),5.66(t,J=7.3 Hz,1H),5.13(s,4H),3.53-3.50(m,2H),3.47(s,6H),1.76(q,J=7.2 Hz,2H),1.51-1.44(m,2H),1.41-1.34(m,8H). 13 C NMR(126 MHz, CDCl3)δ=157.9,151.2,149.0,140.4,129.8,127.4,126.2,126.2,109.2,102.2,94.7,63.0,56.2,44.2,32.4,29.0,28.9,26.0.ESI-HRMS calculated value C 25 H34 NaO5[M+Na] + 437.2298; measured value 437.2296.

[0267] Step f) 5-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol To a solution of (E)-7-(3,5-bis(methoxymethoxy)phenyl)-7-methyl-6-phenylocta-5-en-1-ol (1.5 g, 3.6 mmol, 1.0 equivalent) in siRNA (36 mL), Pd (10% by weight on C, 3.9 g, 3.6 mmol, 1.0 equivalent) was added, and the mixture was stirred in an autoclave under 5 bar of hydrogen for 7 hours. The suspension was filtered through a Celite pad and concentrated under reduced pressure to obtain the product as a slightly yellowish oily substance (0.60 g, yield 61%).

[0268] 1 H NMR(400 MHz,CD3OD)δ=7.26-7.21(m,2H),7.20-7.10(m,3H),6.35(d,J=2.2 Hz,2H),6.12(t,J=2.1 Hz,1H),3.39(t,J=6.6 Hz,2H),2.80(dd,J=12.1,2.8 Hz,1H),1.68(dddd,J=13.7,12.1,9.4,4.7 Hz,1H),1.48-1.38(m,1H),1.36-1.24(m,2H),1.20(s,3H),1.16-1.06(m,2H),1.03(s,3H),0.92(m,2H). 13 C NMR(101 MHz,CD3OD)δ=158.9,153.5,143.1,131.2,128.5,127.1,106.5,100.8,62.9,58.1,42.3,33.4,30.4,30.0,29.2,26.6,23.4.lR(neat,ν max / cm -1 )3307,2935,2488,1705,1598,1436,1328,1153.ESI-HRMS calculated value C 21 H 28 NaO3[M+Na] + 351.1931; measured value 351.1928.

[0269] Step o)2-(((1S,4S,5S)-4-(2,6-dihydroxy-4-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of 5-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol (0.38 g, 1.2 mmol, 1.0 equivalent) and 2-(((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindorin-1,3-dione (0.36 g, 1.2 mmol, 1.05 equivalent) in CH2Cl2 (46 mL), pTsOH·H2O (0.062 g, 0.32 mmol, 0.28 equivalent) was added, and the yellow solution was stirred for 3 hours. The reaction was stopped by adding saturated NaHCO3 aqueous solution, and the aqueous layer was extracted with CH2Cl2. The combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (using SiO2; 10-50% phenyl in hexane) yielded the product as a yellowish foamy substance in a 1:1 mixture of diastereomers (0.42 g, 59%).

[0270] 1:1 mixture of diastereomers - all reported signals: 1H NMR (500 MHz, CDCl3) δ=7.89(ddd,J=5.4,3.0,0.9 Hz,2H),7.73(dd,J=5.5,3.0 Hz,2zH),7.23(ddd,J=7.6,6.4,3.7 Hz,2jH),7.20-7.16(m,1H),7.13-7.08(m,2H),6.42(br,2H),6.03-5.99(m,1H),4.46(ddd,J=15.5,3.0,1.9 Hz,1H),4.23(dt,J=15.5,1.3 Hz,1H),4.05-4.01(m,1H),3.58-3.45(m,2H),2.79(ddd,J=15.1,12.1,2.7 Hz,1H),2.33-2.21(m,3H),1.60(tp,J=13.2,6.4,5.9 Hz,2H),1.50-1.45(m,1H),1.36(ddd,J=13.9,7.5,3.2 Hz,2H),1.31(s,3H),1.29-1.24(m,1H),1.20-1.13(m,2H),1.16(d,J=2.4 Hz,3H),0.99(s,3H),0.97(d,J=9.0 Hz, 3H), 0.95-0.87 (m, 2H). 13 C NMR(126 MHz, CDCl3)δ=168.5,168.5,155.1,150.2,150.0,148.0,148.0,141.8,141.8,134.3,1 32.1,130.3,127.6,127.6,126.2,123.7,120.9,120.8,112.0,112.0,107.3,63.2,63. 2,56.2,55.8,47.4,47.4,44.4,43.3,41.3,41.3,41.2,37.9,32.2,32.1,30.0,29.9,2 8.8,28.6,28.2,28.2,27.6,27.4,26.0,26.0,25.1,25.0,22.4,22.2,20.7.lR(neat,ν max / cm -1 )3462,2932,1771,1713,1427,1394. ESI-HRMS Calculation Value C 39 H 45 NNaO5[M+Na] + 630.3190; measured value 630.3196.[α] 25 D= +90.727 ± 0.124 (c=2.0, CHCl3).

[0271] Step p)2-(((1S,4S,5S)-4-(4-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of 2-(((1S,4S,5S)-4-(2,6-dihydroxy-4-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (0.42 g, 0.68 mmol, 1.0 equivalent) in acetone (6.8 mL), (MeO)2SO2 (0.2 mL, 2.0 mmol, 3.0 equivalents) and K2CO3 (0.33 g, 2.4 mmol, 3.5 equivalents) were added, and the resulting purple solution was stirred overnight. The reaction mixture was then diluted with ether, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (using SiO2; 10-30% acetone in hexane) yielded the product as a 1:1 mixture of diastereomers in a white foamy substance (0.34 g, 77%).

[0272] 1:1 mixture of diastereomers - all reported signals: 11H NMR (400 MHz, CDCl3) δ = 7.85 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.1 Hz, 2H), 7.19 (dtt, J = 9.1, 5.1, 2.2 Hz, 3H), 7.02 (ddd, J = 7.8, 3.5, 1.6 Hz, 2H), 6.39 (s, 2H), 5.60 (tt, J = 3.1, 1.5 Hz, 1H), 4.28 (qt, J = 15.4, 1.9 Hz, 2H), 3.96 (p, J = 2.2 Hz, 1H), 3.68 (d, J = 0.9 Hz, 6H), 3.51 - 3.44 (m, 2H), 2.71 (dt, J = 12.1, 2.9 Hz, 1H), 2.21 - 2.11 (m, 2H), 2.01 (dtt, J = 5.9, 4.0, 1.7 Hz, 1H), 1.72 (t, J = 7.8 Hz, 1H), 1.66 - 1.55 (m, 1H), 1.43 (dtt, J = 9.2, 6.1, 3.1 Hz, 1H), 1.38 - 1.29 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.19 (tt, J = 9.0, 4.6 Hz, 2H), 1.11 (d, J = 2.7 Hz, 3H), 0.98 - 0.87 (m, 2H), 0.94 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ = 168.3, 158.3, 148.6, 148.5, 141.9, 141.8, 136.2, 136.2, 133.9, 132.4, 130.2, 127.5, 127.5, 126.2, 124.0, 123.3, 117.9, 103.7, 103.7, 63.0, 57.2, 57.2, 55.9, 47.6, 47.6, 44.4, 44.3, 42.6, 41.8, 41.2, 37.5, 37.5, 32.6, 29.3, 29.0, 28.1, 27.7, 26.4, 25.6, 23.9, 23.8, 20.9. IR (neat, ν max / cm -1 ) 3467, 2932, 2865, 1771, 1712, 1603, 1572, 1466, 1410, 1390, 1239, 1117. ESI - HRMS calculated for C 41 H 49 NNaO5 [M + Na] + 658.3503; found 658.3496. [α] 25 D=+55.530±0.075(c=3.0,CHCl3,).

[0273] Process r)2-(((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of I2 (0.036 g, 0.14 mmol, 1.5 equivalents) in CH2Cl2 (0.5 mL) at 0°C, PPh3 (0.042 g, 0.16 mmol, 1.7 equivalents) was added, and the resulting solution was stirred at 0°C for 20 minutes. Imidazole (0.019 g, 0.28 mmol, 3.0 equivalents) was added, and stirring at 0°C was continued for 10 minutes. Then, 2-(((1S,4S,5S)-4-(4-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (0.060 g, 0.09 mmol, 1.0 equivalent) (in CH2Cl2 (0.5 mL)) was added. The reactants were slowly heated to ambient temperature, and after 1 hour, TLC analysis (20% acetone in hexane) showed complete consumption of the starting materials. The reaction was stopped by the addition of saturated aqueous Na2S2O3, and the mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; using 10% acetone in hexane) yielded an alkyl iodide intermediate as a pale yellow oil (0.070 g, quantitative yield). Alkyl iodide (0.070 g, 0.09 mmol, 1.0 equivalent) was dissolved in toluene (1.0 mL), and AIBN (0.012 g, 0.08 mmol, 0.8 equivalent) and Bu3SnH (0.15 mL, 0.56 mmol, 6.0 equivalent) were added. The reaction solution was heated to 70°C and stirred for 1 hour. After TLC (20% acetone in hexane) showed complete consumption of alkyl iodide, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; using 5-10% acetone in hexane) yielded the product as a colorless oil, consisting of a 1:1 mixture of diastereomers (0.040 g, 68%) and a small amount of stannane impurities.

[0274] Alkyl iodide, 1:1 mixture of diastereomers - all reported signals: 1H NMR(400 MHz,CDCl3)δ=7.85(ddd,J=5.4,3.0,0.6 Hz,2H),7.74-7.67(m,2H),7.24-7.14(m,3H),7.01(ddd,J=7.7,4.0,1.6 Hz,2H),6.38(s,2H),5.59(ddt,J=4.5,3.0,1.5 Hz,1H),4.27(qt,J=15.4,2.0 Hz,2H),3.96(s,1H),3.68(d,J=0.9 Hz,6H),3.02(tt,J=7.0,1.6 Hz,2H),2.70(dt,J=12.1,2.9 Hz,1H),2.20-2.12(2H,assigned by HSQC),2.02(d,J=6.3 Hz,1H),1.72(t,J=7.7 Hz,1H),1.65-1.56(m,3H),1.46-1.37(m,1H),1.34-1.21(m,10H),1.11(s,1.5H),1.10(s,1.5H),0.93(s,3H).ESI-HRMS calculated value C 41 H 48 INNaO4[M+Na] + 768.2520; Measured value: 768.2516.

[0275] 2-(((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione, a 1:1 mixture of diastereomers - all reported signals: 1H NMR (400 MHz, CDCl3) δ=7.90-7.81(m,2H),7.71(dddd,J=5.5,4.3,2.7,1.2 Hz,2H),7.23-7.11(m,3H),7.01(dddd,J=7.7,3.4,1.6 Hz,2H),6.39(s,2H),5.60(ddt,J=5.8,2.9,1.5 Hz,1H),4.28(qt,J=15.4,1.9 Hz,2H),3.96(q,J=2.3 Hz,1H),3.68(s,6H),f2.71(dt,J=12.0,3.1 Hz,1H),2.23-2.10(m,2H),2.01(qd,J=3.7,1.7 Hz,1H),1.76-1.70(m,1H),1.68-1.60(m,1H),1.58(s,1H),1.45-1.40(m,1H),1. 27(s,3H),1.24(s,3H),1.12(s,1.5H),1.11(s,1.5H),1.07(ddd,J=11.0,6.0,2.5 Hz,4H),0.94(s,3H),0.92-0.88(m,1H),0.73(dt,J=7.3,3.7 Hz,3H). 13 C NMR(101 MHz, CDCl3)δ=168.3,158.3,148.6,148.6,142.0,142.0,136.1,136.1,133.9 ,132.4,130.2,127.4,127.4,126.1,124.0,124.0,123.3,117.9,117.8,103.8 ,103.7,57.3,57.2,55.9,55.8,47.6,44.4,42.7,41.8,41.2,37.5,37.5,31. 8,29.3,29.0,28.0,27.7,26.4,24.0,24.0,22.6,22.5,20.9,14.1.lR(neat,ν max / cm -1 )2930,1772,1715,1604,1573,1390,1120. ESI-HRMS Calculated Value C 41 H 49 NNaO4[M+Na] + 642.3554; measured value 642.3551.[α] 24 D =+46.179±0.165 (c=2.0, CHCl3).

[0276] Process s)((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine To a solution of 2-(((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (0.040 g, 0.065 mmol, 1.0 equivalent) in EtOH (1.3 mL), N2H4·H2O (0.032 mL, 0.65 mmol, 10 equivalents) and (E) / (Z)-clotyl alcohol (0.083 mL, 0.97 mmol, 15 equivalents) were added, and the solution was heated to 75°C and stirred for 3 hours. A white solid precipitate formed, and the mixture was filtered through a Celite pad and rinsed with EtOH. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography (using SiO2;CH2Cl2 with 1-10% MeOH and 1% 7N NH3 in MeOH) yielded the product as a slightly brownish oily substance in a 1:1 mixture of diastereomers (0.030 g, 95%).

[0277] 1:1 mixture of diastereomers - all reported signals: 11H NMR (400 MHz, CDCl3) δ = 7.24 - 7.15 (m, 3H), 7.02 (dt, J = 7.9, 1.7 Hz, 2H), 6.42 (s, 2H), 5.69 (p, J = 1.8 Hz, 1H), 4.01 (s, 1H), 3.70 (s, 6H), 3.35 (s, 2H), 2.72 (dd, J = 12.0, 2.9 Hz, 1H), 2.25 - 2.17 (m, 2H), 2.06 (qd, J = 4.6, 3.9, 2.1 Hz, 1H), 1.72 (td, J = 6.9, 1.9 Hz, 1H), 1.59 (tt, J = 10.2, 2.7 Hz, 1H), 1.45 (dtd, J = 12.9, 6.8, 4.0 Hz, 1H), 1.32 (s, 3H), 1.27 (s, 3H), 1.14 (d, J = 1.5 Hz, 3H), 1.09 (tt, J = 9.5, 3.7 Hz, 4H), 0.99 (s, 3H), 0.96 - 0.86 (m, 2H), 0.78 - 0.72 (m, 3H). 13 13C NMR (101 MHz, CDCl3) δ = 158.3, 148.7, 148.6, 142.0, 140.6, 130.2, 127.4, 126.1, 123.8, 118.1, 118.0, 104.0, 103.9, 57.3, 56.0, 56.0, 47.6, 46.8, 44.5, 41.8, 41.1, 37.6, 31.9, 29.4, 28.9, 28.1, 28.1, 28.0, 26.4, 24.1, 24.1, 22.6, 21.3, 14.2. IR (neat, ν max / cm -1 ) 2931, 1604, 1572, 1464, 1452, 1410, 1239, 1121. ESI - HRMS calculated for C 33 18 47 21NNaO2 [M + Na] + 512.3499; found 512.3502. [α] 26 D = +57.496 ± 0.142 (c = 1.0, CHCl3).

[0278] Process t)6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)-1-(6-((((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)pyridine-1-ium-3-sulfonate ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine (5.0 mg, 0.010 mmol, 1.0 equivalent) was dissolved in CH2Cl2 (0.1 mL) to which Fluorescence Red Mega 480 succinimidyl ester (6.2 mg, 0.010 mmol, 1.0 equivalent, CAS RN: 1034442-03-9) was added. The deep red solution was stirred overnight at ambient temperature in the light-free zone, and then volatile substances were removed by N2 flow. Purification by flash column chromatography (using ultra-neutral SiO2; 1-5% MeOH in CH2Cl2) yielded the product as a dark red wax in a 1:1 mixture of diastereomers (6.0 mg, 59%). Residual N-hydroxysuccinimide was separated by preparative reverse-phase HPLC (Reprosil Gold 120 C18 125×20 mm column, flow rate 26.5 mL / min) to obtain an analytically clean product (2.0 mg, 19%).

[0279] ESI-HRMS calculated value C 59 H 75 N3NaO8S [M+Na] + 1008.5167;Actual value 1008.5167.Preparative HPLC H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=10:90(t=0.0 min)→10:90(t=15.0 min), t R =5.0 minutes.

[0280] Example 17 N-(((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide [ka] Process o)2-(((1S,4S,5S)-4-(4-(8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of 5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol (69.3 mg, 200 μmol, 1.0 equivalent) and pTsOH·H2O (10.6 mg, 56.0 μmol, 0.28 equivalents) in CH2Cl2 (10 mL), 2-(((1S,4R,5R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindorin-1,3-dione (65.3 mg, 220 μmol, 1.1 equivalents) was added, and the pale yellow solution was stirred at room temperature for 1.5 hours. The reaction was stopped by adding saturated NaHCO3 aqueous solution (5 mL), the layers were separated, and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum. Purification by flash column chromatography (SiO2; 0-20% siRNA in hexane) yielded the product as a colorless foam (80.0 mg, 64%).

[0281] 1:1 mixture of diastereomers - all reported signals: 1H NMR(400 MHz,CDCl3)δ 7.95-7.85(m,2H),7.80-7.67(m,2H),7.29-7.14(m,3H),7.12-7.03(m,2H) ,6.55-5.14(bs,2H),6.40(bs,2H),6.02(s,1H),4.47(ddd,J=15.5,3.0,1.9 Hz,1H),4.29-4.18(m,1H),4.01(s,1H),3.42-3.31(m,2H),2.71(dd,J=12.1,3.5 Hz,1H),2.37-2.20(m,3H),1.74-1.34(m,5H),1.32(s,3H),1.30-1.20(m,2H),1.17(s,3H),1.01(s,3H),1.00(s,3H),0.96-0.80(m,2H). 13 C NMR(101 MHz,CDCl3)δ 168.5,154.9,150.2,148.2,141.8,134.3,132.1,130.2,127.6,126.3,123.7,120.7,111.9,107.3,56.9, 47.4,45.3,44.3,43.3,41.3,41.2,37.9,32.5,29.8,29.2,28.2,27.5,26.8,26.0,22.7,20.7.IR(neat,ν max / cm -1 ):3460,2931,2867,1771,1714,1624,1574,1426,1393,1341,1025,729,705.HRMS(ESI):m / z=648.2834 [M+Na] + (Calculated value C) 39 H 44 ClNNaO4m / z=648.2851).[α] 25 D =+80.468±0.199(c=0.66,CHCl3).

[0282] Step p) 2-(((1S,4S,5S)-4-(4-(8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a suspension of 2-(((1S,4S,5S)-4-(4-(8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dihydroxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (30.0 mg, 47.9 μmol, 1.0 equivalent) and K2CO3 (39.7 mg, 287 μmol, 6.0 equivalents) in acetone (0.4 mL), (MeO)2SO2 (23 μL, 240 μmol, 5.0 equivalents) was added, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with Et2O (5 mL), filtered, and concentrated under vacuum. Purification by flash column chromatography (SiO2; 0-20% acetone in hexane) yielded the product as a pale yellow oil (24.5 mg, 78%).

[0283] 1:1 mixture of diastereomers - all reported signals: 1 H NMR(400 MHz,CDCl3)δ 7.89-7.81(m,2H),7.75-7.67(m,2H),7.24-7.13(m,3H),7.05-6.99(m,2H),6.39(s,2H),5.62-5.57(m,1H),4 .34-4.29(m,1H),4.27-4.20(m,1H),3.98-3.94(m,1H),3.68(s,6H),3.39-3.32(m,2H),2.70(dd,J=12.1,2.8 Hz,1H),2.21-2.12(m,2H),2.05-1.98(m,1H),1.72(d,J=7.9 Hz,1H),1.66-1.35(m,4H),1.30-1.21(m,2H),1.27(s,3H),1.24(s,3H),1.11(s,3H),0.94(s,3H),0.98-0.84(m,2H). 13C NMR(101 MHz,CDCl3)δ 168.3,158.3,148.4,141.8,136.1,133.9,132.4,130.2,127.5,126.2,124.0,123.3,118.0,103.6,57.2,55 .9,47.6,45.2,44.4,42.6,41.8,41.2,37.5,32.5,29.2,29.0,27.7,27.6,26.8,26.4,23.9,20.9.IR(neat,ν max / cm -1 ):2932,2864,1771,1714,1603,1572,1465,1451,1389,1239,1116,956,730,704.HRMS(ESI):m / z=676.3144 [M+Na] + (Calculated value C) 41 H 48 ClNNaO4m / z=676.3164).[α] 25 D =+57.601±0.343(c=0.75,CHCl3).

[0284] Process r)2-(((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione To a solution of 2-(((1S,4S,5S)-4-(4-(8-chloro-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)isoindoline-1,3-dione (15.2 mg, 23.2 μmol, 1.0 equivalent) in DMF (0.10 mL), NaN3 (15.1 mg, 232 μmol, 10 equivalents) was added, and the reaction mixture was stirred at 80°C for 24 hours. The mixture was cooled to room temperature and diluted with 5 mL of 5% LiCl aqueous solution and 5 mL of Et2O. The layers were separated, and the aqueous phase was extracted with 4 × 5 mL of Et2O. The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2, hexane with 0-10% siRNA) to obtain a pale pink foamy substance (14.7 mg, 96%).

[0285] 1:1 mixture of diastereomers - all reported signals: 1 H NMR(400 MHz,CDCl3)δ 7.92-7.82(m,2H),7.76-7.68(m,2H),7.24-7.14(m,3H),7.06-6.98(m,2H),6.38(s,2H),5.66-5 .55(m,1H),4.35-4.28(m,1H),4.27-4.20(m,1H),4.00-3.93(m,1H),3.68(s,6H),3.09(t,J=6.9 Hz,2H),2.78-2.66(m,1H),2.26-2.11(m,2H),2.08-1.97(m,1H),1.72(d,J=7.7 Hz,1H),1.68-1.54(m,1H),1.50-1.29(m,3H),1.27(s,3H),1.26-1.23( m,3H),1.23-1.13(m,2H),1.12(s,3H),0.94(s,3H),1.02-0.82(m,2H). 1313C NMR (101 MHz, CDCl3) δ 168.34, 158.30, 148.51, 141.74, 136.16, 133.93, 132.42, 130.14, 127.53, 126.24, 123.94, 123.27, 117.94, 103.60, 57.19, 55.85, 51.49, 47.62, 44.36, 42.64, 41.78, 41.20, 37.51, 29.26, 28.98, 28.73, 27.88, 27.66, 26.65, 26.43, 23.92, 20.93. IR (neat, ν max / cm -1 ): 2931, 2864, 2094, 1772, 1715, 1603, 1572, 1466, 1451, 1389, 1239, 1117, 956, 729, 704. HRMS (ESI): m / z = 683.3563 [M+Na] + (calculated for C 41 H 48 N4NaO4 m / z = 683.3568). [α] 25 D = +43.225 ± 0.114 (c = 1.0, CHCl3).

[0286] Step s) ((1S,4S,5S)-4-(4-(8-Azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanamine A solution of 2-(((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)isoindoline-1,3-dione (44.0 mg, 67.0 μmol, 1.0 eq) in EtOH (1.3 mL) was added with N2H4·H2O (33 μL, 670 μmol, 10 eq) and (E) / (Z)-crotyl alcohol (85 μL, 1.0 mmol, 15 eq). The solution was heated to 75 °C and stirred for 3 h. A precipitate of white solid formed, and the mixture was filtered through cotton and rinsed with EtOH. The filtrate was concentrated in vacuo. Purification by flash column chromatography (SiO2; 1% 7.0 M NH3 in MeOH, 1 - 4% MeOH in CH2Cl2) afforded the product as a white foam (27.0 mg, 76%).

[0287] 1:1 mixture of diastereomers - all signals reported: 1 H NMR (400 MHz, CDCl3) δ = 7.28 - 7.14 (m, 3H), 7.03 (dt, J = 7.8, 1.6 Hz, 2H), 6.43 (s, 2H), 5.57 (s, 1H), 4.02 - 3.97 (m, 1H), 3.70 (s, 6H), 3.24 (t, J = 1.7 Hz, 2H), 3.11 (td, J = 6.9, 1.1 Hz, 2H), 2.72 (dd, J = 12.1, 2.9 Hz, 1H), 2.20 (dtd, J = 8.3, 5.4, 1.2 Hz, 1H), 2.16 - 2.12 (m, 1H), 2.07 (tq, J = 5.5, 1.9 Hz, 1H), 1.71 (dd, J = 8.3, 5.9 Hz, 1H), 1.67 - 1.57 (m, 1H), 1.50 - 1.43 (m, 1H), 1.39 (dtd, J = 8.8, 6.2, 5.7, 1.3 Hz, 2H), 1.31 (s, 3H), 1.27 (s, 3H), 1.24 - 1.17 (m, 2H), 1.14 (d, J = 1.2 Hz, 3H), 1.00 - 0.88 (m, 2H), 0.97 (s, 3H). 13C NMR(101 MHz, CDCl3)δ=158.4,148.4,148.4,143.5,143.5,141.7,130.1,127.5,127.5,126.3,121.1,118.5,118.5,104.0,104.0,57.3,56. 0,56.0,51.5,47.7,47.6,44.7,41.8,41.0,37.6,29.3,29.3,28.9,28.7,28.1,27.9,27.9,26.7,26.5,24.0,24.0,21.2.lR(neat,ν max / cm -1 )2934,2865,2095,1604,1572,1452,1411,1240,1120.HRMS(ESI):m / z=553.3510 [M+Na] + (Calculated value C) 33 H 46 N4NaO2m / z=553.3513).[α] 25 D = +71.916 ± 0.163 (c = 0.7, CHCl3).

[0288] Process t)N-(((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide To a solution of 4-pentic acid (0.6 mg, 6.3 μmol, 1.3 equivalents, CAS RN: 6089-09-4) in DMF (50 μL), HATU (2.8 mg, 7.2 μmol, 1.5 equivalents) and i-Pr2NEt (3.5 μL, 20 μmol, 4.0 equivalents) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then added to a mixture of ((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine (2.6 mg, 4.8 μmol, 1.0 equivalent) in DMF (50 μL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. Purification of the crude product by preparative TLC (SiO2, 35% siRNA in hexane) yielded the title product as a colorless, waxy solid (2.7 mg, 90%).

[0289] 1:1 mixture of diastereomers - all reported signals: 1 H NMR(500 MHz,CD2Cl2)δ 7.26-7.16(m,3H),7.11-7.05(m,2H),6.46(s,2H),5.63(ddt,J=5.3,2.9,1.5 Hz,1H),5.53(bt,J=5.4 Hz,1H),4.00-3.94(m,1H),3.87-3.81(m,2H),3.70(s,3H),3.69(s,3H),3.11(t,J=6.9 Hz,2H),2.80-2.75(m,1H),2.54-2.48(m,2H),2.39(t,J=7.1 Hz,2H),2.18(dddd,J=8.4,5.5,4.6,1.3 Hz,1H),2.10(td,J=5.6,1.4 Hz,1H),2.05-1.99(m,2H),1.72-1.57(m,3H),1.48-1.30(m,4H),1.29(s,3H),1.26(s,3H),1.12(s,3H),0.96(s,3H),0.93(m,2H). 13C NMR(126 MHz,CD2Cl2)δ 170.86,158.79,149.39,142.33,138.98,130.62,127.94,126.61,124.18,118.36,104.28,83.84,69.41,57.46,56.32,51.97 ,48.03,44.93,42.23,41.29,38.05,36.01,29.74,29.20,29.14,28.33,28.09,27.06,26.57,24.01,21.27,15.37.IR(neat,ν max / cm -1 )3310,2927,2857,2094,1650,1604,1572,1452,1411,1365,1302,1261,1239,1184,1120.HRMS(ESI):m / z=633.3767 [M+Na] + (Calculated value C) 38 H 50 N4NaO3m / z = 633.3775).

[0290] Example 18 N-(((1S,4S,5S)-4-(4((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide [ka] Process t)N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide To a solution of 4-pentic acid (0.5 mg, 5.3 μmol, 1.3 equivalents) in DMF (50 μL), HATU (2.4 mg, 6.2 μmol, 1.5 equivalents) and i-Pr2NEt (2.9 μL, 17 μmol, 4.0 equivalents) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then added to a mixture of ((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine (2.2 mg, 4.1 μmol, 1.0 equivalent) in DMF (50 μL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. Purification of the crude product by preparative TLC (SiO2, 35% siRNA in hexane) yielded the title product as a colorless, waxy solid (2.3 mg, 91%).

[0291] 1 H NMR(400 MHz,CDCl3)δ 7.25-7.14(m,3H),7.06-6.98(m,2H),6.42(s,2H),5.68-5.62(m,1H),5.54(t,J=4.8 Hz,1H),4.02-3.95(m,1H),3.89(d,J=5.4 Hz,2H),3.70(s,6H),3.11(t,J=6.9 Hz,2H),2.72(dd,J=12.0,2.9 Hz,1H),2.55(tdd,J=7.0,2.7,0.9 Hz,2H),2.43(td,J=7.1,1.0 Hz,2H),2.24-2.14(m,1H),2.11(td,J=5.6,1.4 Hz,1H),2.10-2.02(m,1H),1.99(t,J=2.6 Hz,1H),1.70(d,J=8.4 Hz,1H),1.69-1.11(m,6H),1.29(s,3H),1.27(s,3H),1.14(s,3H),1.01-0.79(m,2H),0.97(s,3H). 13C NMR(101 MHz,CDCl3)δ 170.8,158.3,148.6,141.7,138.3,130.1,127.6,126.3,124.2,118.0,103.9,83.3,69.5,57.3,56.0,51.5,47.5 ,44.8,44.5,41.8,41.0,37.6,35.8,29.9,29.3,28.9,28.7,27.9,27.9,26.7,26.4,24.0,21.2,15.1.IR(neat,ν max / cm -1 )3308,2925,2853,2094,1652,1603,1571,1452,1410,1261,1120.HRMS(ESI):m / z=611.3947 [M+H] + (Calculated value C) 38 H 51 N4O3m / z = 611.3956).

[0292] Example 19 N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide [ka] Process t)N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide To a solution of 4-pentic acid (0.9 mg, 9.0 μmol, 1.3 equivalents) in DMF (50 μL), HATU (4.0 mg, 10 μmol, 1.5 equivalents) and i-Pr2NEt (4.9 μL, 28 μmol, 4.0 equivalents) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then added to a mixture of ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine (3.7 mg, 6.9 μmol, 1.0 equivalent) in DMF (50 μL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. Purification of the crude product by preparative TLC (SiO2, 35% siRNA in hexane) yielded the title product as a colorless, waxy solid (4.1 mg, 96%).

[0293] 1 H NMR(400 MHz,CDCl3)δ 7.25-7.15(m,3H),7.06-6.99(m,2H),6.42(s,2H),5.66(dt,J=3.0,1.5 Hz,1H),5.54(s,1H),4.04-3.93(m,1H),3.89(d,J=5.4 Hz,2H),3.70(s,6H),3.11(t,J=6.9 Hz,2H),2.72(dd,J=12.1,2.9 Hz,1H),2.55(tdd,J=7.0,2.6,1.0 Hz,2H),2.43(td,J=7.1,1.0 Hz,2H),2.26-2.14(m,1H),2.11(td,J=5.7,1.4 Hz,1H),2.09-2.03(m,1H),1.99(t,J=2.6 Hz,1H),1.69(d,J=8.4 Hz,1H),1.67-1.12(m,6H),1.29(s,3H),1.27(s,3H),1.14(s,3H),0.99-0.79(m,2H),0.97(s,3H). 13C NMR(101 MHz,CDCl3)δ 170.8,158.3,148.6,141.7,138.3,130.1,127.6,126.3,124.2,118.0,103.9,83.3,69.5,57.3,56.0,51.5,47.5 ,44.8,44.5,41.8,41.0,37.6,35.8,29.9,29.3,28.9,28.7,28.0,27.9,26.7,26.4,24.0,21.2,15.1.IR(neat,ν max / cm -1 )3308,2925,2853,2095,1652,1603,1572,1452,1411,1261,1120.HRMS(ESI):m / z=611.3947 [M+H] + (Calculated value C) 38 H 51 N4O3m / z = 611.3956).

[0294] Example 20 1-(6-((((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate [ka] Process t) 1-(6-((((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate To a solution of ((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine (9.0 mg, 17.0 μmol, 1.0 equivalent) in DMF (50 μL), Fluorescence Red Mega 480 succinimidyl ester (10.0 mg, 17.0 μmol, 1.0 equivalent, CAS RN: 1034442-03-9) (in DMF (30 μL)) was added. The deep red solution was stirred overnight at ambient temperature in the light-free zone, and then the mixture was concentrated in vacuum. The product was purified by flash column chromatography (ultra-neutral SiO2, CH2Cl2 with 1-5% MeOH) to obtain a dark red waxy solid (15.0 mg, 86%).

[0295] 1:1 mixture of diastereomers - all reported signals: 1H NMR(500 MHz,CD2Cl2)δ=9.02(d,J=1.8 Hz,1H),8.62(dd,J=8.6,1.7 Hz,1H),8.14(d,J=8.6 Hz,1H),8.10(d,J=15.3 Hz,1H),7.94(s,1H),7.51(d,J=15.2 Hz,1H),7.44(d,J=9.0 Hz,1H),7.25-7.19(m,2H),7.20-7.15(m,1H),7.09-7.05(m,2H),6.69(dd,J=9.0,2.5 Hz,1H),6.50(d,J=2.4 Hz,1H),6.44(s,2H),6.12(t,J=5.7 Hz,1H),5.61(ddd,J=4.5,3.0,1.5 Hz,1H),4.64-4.56(m,2H),3.94(q,J=2.1 Hz,1H),3.89-3.79(m,2H),3.68(s,6H),3.68(s,4H),3.46(q,J=7.1 Hz,4H),3.09(t,J=6.9 Hz,2H),2.76(dt,J=11.8,2.3 Hz,1H),2.28(t,J=7.5 Hz,2H),2.18-2.13(m,1H),2.12-2.04(m,3H),2.00(dtt,J=5.8,3.9,1.9 Hz,1H),1.76(q,J=7.5 Hz,2H),1.68(t,J=8.2 Hz,2H),1.64-1.56(m,2H),1.47-1.39(m,1H),1.38-1.31(m,2H),1.27(s,3H),1.25(s,3H),1.23(t,J=7.1 Hz,6H),1.20-1.12(m,2H),1.09(s,3H),0.97-085(m,2H),0.94(s,3H). 13C NMR(126 MHz,CD2Cl2)δ=172.7,172.6,172.6,160.6,158.7,157.4,153.4,153.1,149.2,147.8,145.0,143.0 ,142.2,141.3,139.1,131.2,130.5,127.8,126.4,124.8,123.7,118.4,115.9,113.8,110.7,109.4, 104.2,97.1,59.2,57.3,56.2,56.2,51.8,48.0,45.6,44.8,44.7,44.5,42.1,41.1,37.9,36.3,36.3 ,29.8,29.6,29.1,29.0,28.2,27.9,26.9,26.9,26.5,26.2,25.9,25.1,23.9,21.2,12.7.IR(neat,ν max / cm -1 ):2933,2866,2095,1713,1578,1504,1417,1272,1134,1041.HRMS(ESI):m / z=1027.5356 [M+H] + (Calculated value C) 59 H 75 N6O8S (m / z = 1027.5362)

[0296] Example 21 1-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate [ka] Process t) 1-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate To a solution of ((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine (2.3 mg, 4.3 μmol, 1.0 equivalent) in DMF (50 μL), Fluorescence Red Mega 480 succinimidyl ester (2.7 mg, 4.3 μmol, 1.0 equivalent) and i-Pr2NEt (0.8 μL, 4.3 μmol, 1.0 equivalent) in DMF (30 μL) were added. The deep red solution was stirred overnight at ambient temperature in the light-free zone, and then the mixture was concentrated under vacuum. Purification by preparative TLC (5% MeOH in SiO2, CH2Cl2) yielded the product as a dark red, waxy solid (4.3 mg, 97%).

[0297] 11H NMR (500 MHz, CD2Cl2) δ 8.89 (s, 1H), 8.66 (d, J = 8.5 Hz, 1H), 8.20 - 8.04 (m, 2H), 7.88 (s, 1H), 7.48 - 7.40 (m, 2H), 7.26 - 7.21 (m, 2H), 7.20 - 7.16 (m, 1H), 7.09 - 7.04 (m, 2H), 6.69 (dd, J = 9.0, 2.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.45 (s, 2H), 5.83 (t, J = 4.8 Hz, 1H), 5.67 - 5.56 (m, 1H), 4.58 - 4.50 (m, 2H), 3.97 - 3.94 (m, 1H), 3.91 - 3.77 (m, 2H), 3.68 (s, 6H), 3.47 (q, J = 7.1 Hz, 4H), 3.10 (t, J = 6.9 Hz, 2H), 2.77 (dd, J = 12.0, 2.8 Hz, 1H), 2.32 - 1.94 (m, 7H), 1.81 - 1.51 (m, 6H), 1.48 - 1.30 (m, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H), 1.20 - 1.12 (m, 2H), 1.11 (d, J = 3.5 Hz, 3H), 1.00 - 0.85 (m, 2H), 0.95 (s, 3H). 13 13C NMR (126 MHz, CD2Cl2) δ 172.3, 158.8, 157.6, 153.6, 149.4, 148.1, 142.6, 142.3, 139.3, 131.4, 130.6, 127.9, 126.6, 124.8, 123.8, 118.5, 115.9, 113.8, 110.9, 109.5, 104.3, 97.3, 59.4, 57.4, 56.4, 52.0, 48.1, 45.8, 44.9, 44.8, 42.2, 41.3, 38.1, 36.5, 32.5, 30.0, 29.7, 29.2, 29.1, 28.3, 28.1, 27.0, 26.6, 26.4, 25.4, 25.1, 24.0, 23.3, 21.3, 12.8. IR (neat, ν max / cm -1 ): 2917, 2851, 2094, 1717, 1578, 1504, 1416, 1272, 1134, 1043. HRMS (ESI): m / z = 1027.5357 [M + H] + (Calculated for C 59 H 75 N6O8S m / z = 1027.5362).

[0298] Example 22 1-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate [ka] Process t) 1-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate To a solution of ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine (2.2 mg, 4.1 μmol, 1.0 equivalent) in DMF (50 μL), Fluorescence Red Mega 480 succinimidyl ester (2.5 mg, 4.1 μmol, 1.0 equivalent) and i-Pr2NEt (0.7 μL, 4.1 μmol, 1.0 equivalent) in DMF (30 μL) were added. The deep red solution was stirred overnight at ambient temperature in the light-free zone, and then the mixture was concentrated under vacuum. Purification by preparative TLC (SiO2;CH2Cl2 with 5% MeOH) yielded the product as a dark red, waxy solid (3.7 mg, 87%).

[0299] 11H NMR (500 MHz, CD2Cl2) δ 8.89 (s, 1H), 8.66 (d, J = 8.9 Hz, 1H), 8.18 - 8.05 (m, 2H), 7.88 (s, 1H), 7.49 - 7.40 (m, 2H), 7.26 - 7.20 (m, 2H), 7.20 - 7.16 (m, 1H), 7.07 (dt, J = 8.0, 1.4 Hz, 2H), 6.70 (dd, J = 9.0, 2.5 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.45 (s, 2H), 5.83 (t, J = 5.8 Hz, 1H), 5.65 - 5.56 (m, 1H), 4.60 - 4.48 (m, 2H), 4.01 - 3.91 (m, 1H), 3.90 - 3.79 (m, 2H), 3.68 (s, 6H), 3.47 (q, J = 7.1 Hz, 4H), 3.10 (td, J = 7.0, 1.8 Hz, 2H), 2.76 (dd, J = 12.1, 3.0 Hz, 1H), 2.25 (t, J = 7.5 Hz, 2H), 2.22 - 1.98 (m, 5H), 1.80 - 1.50 (m, 6H), 1.46 - 1.30 (m, 3H), 1.28 (s, 3H), 1.26 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H), 1.19 - 1.12 (m, 2H), 1.10 (s, 3H), 1.00 - 0.84 (m, 2H), 0.95 (s, 3H). 13 13C NMR (126 MHz, CD2Cl2) δ 172.3, 160.7, 158.8, 157.6, 153.6, 153.1, 149.4, 148.0, 142.7, 142.3, 141.4, 139.3, 131.3, 130.6, 127.9, 126.6, 124.8, 123.8, 118.4, 115.9, 113.8, 110.9, 109.5, 104.3, 97.3, 59.4, 57.4, 56.3, 52.0, 48.1, 45.8, 44.9, 44.8, 42.2, 41.3, 38.1, 36.5, 30.0, 29.7, 29.2, 29.1, 28.3, 28.1, 27.1, 26.6, 26.4, 25.1, 24.0, 21.3, 12.8. IR (neat, ν max / cm -1 ): 2918, 2851, 2094, 1714, 1579, 1504, 1415, 1240, 1042. HRMS (ESI): m / z = 1027.5357 [M + H] + (Calculated value C 59 H75 N6O8S m / z = 1027.5362).

[0300] Example 23 N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide [ka] Process t)N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide To a solution of 7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanoic acid (2.5 mg, 8.1 μmol, 1.5 equivalents) in DMF (50 μL), HATU (3.1 mg, 8.1 μmol, 1.5 equivalents) and i-Pr2NEt (3.8 μL, 22 μmol, 4.0 equivalents) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then added to a mixture of ((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine (2.9 mg, 5.4 μmol, 1.0 equivalent) in DMF (50 μL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative TLC (SiO2;CH2Cl2 with 2% MeOH) to obtain the title product as a yellow amorphous solid (2.8 mg, 62%).

[0301] 1H NMR(500 MHz, CD3OD)δ 8.41(d,J=8.9 Hz,1H),7.25-7.19(m,2H),7.19-7.14(m,1H),7.12-7.03(m,2H),6.50(s,2H),6.25(d,J=8.9 Hz,1H),5.62-5.55(m,1H),4.00-3.92(m,1H),3.82-3.71(m,2H),3.69(s,6H),3.48(bs,2H),3.09(dt,J=6.9,1.2 Hz,2H),2.81(dd,J=12.0,2.7 Hz,1H),2.24(t,J=7.2 Hz,2H),2.19-2.05(m,2H),1.95(td,J=5.8,2.9 Hz,1H),1.82-1.61(m,6H),1.55-1.38(m,4H),1.36-1.12(m,5H),1.27(s,3H),1.25(s,3H),1.10(s,3H),1.03-0.86(m,2H),0.95(s,3H). 13 C NMR(126 MHz,CD3OD)δ 175.8,159.6,150.1,143.0,139.9,131.2,128.5,127.2,123.9,119.0,104.8,58.1,56.3,52.3,45.5,44.9,4 2.8,41.8,38.7,37.1,30.8,30.1,29.8,29.5,29.3,28.6,28.4,27.8,27.3,27.1,26.8,24.0,21.4.IR(neat,ν max / cm -1 )3303,2919,2852,2094,1650,1579,1300,1121.HRMS(ESI):m / z=821.4703 [M+H] + (calculated value C 46 H 61 N8O6m / z=821.4709).

[0302] Example 24 N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide [ka] Process t)N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide To a solution of 7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanoic acid (2.4 mg, 7.6 μmol, 1.5 equivalents) in DMF (50 μL), HATU (2.9 mg, 7.6 μmol, 1.5 equivalents) and i-Pr2NEt (3.5 μL, 20 μmol, 4.0 equivalents) were added. The reaction mixture was stirred at room temperature for 5 minutes, and then added to a mixture of ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine (2.7 mg, 5.0 μmol, 1.0 equivalent) in DMF (50 μL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative TLC (SiO2;CH2Cl2 with 2% MeOH) to obtain the title product as a yellow amorphous solid (2.5 mg, 60%).

[0303] 1H NMR(500 MHz, CD3OD)δ 8.42(d,J=8.8 Hz,1H),7.27-7.20(m,2H),7.19-7.14(m,1H),7.12-7.07(m,2H),6.50(s,2H),6.25(d,J=8.9 Hz,1H),5.61-5.56(m,1H),4.00-3.93(m,1H),3.84-3.71(m,2H),3.69(s,6H),3.45(bs,2H),3.08(dt,J=6.8,1.0 Hz,2H),2.81(dd,J=12.0,2.8 Hz,1H),2.24(t,J=7.2 Hz,2H),2.16-2.06(m,2H),2.00-1.94(m,1H),1.81-1.62(m,6H),1.52-1.40(m,4H),1. 40-1.11(m,5H),1.26(s,3H),1.25(s,3H),1.11(s,3H),1.03-0.85(m,2H),0.95(s,3H). 13 C NMR(126 MHz,CD3OD)δ 175.8,159.6,150.1,143.0,139.9,131.3,128.5,127.2,123.8,119.0,104.7,58.0,56.2,52.3,45.5,44.9 ,42.8,41.8,38.7,37.1,30.1,29.8,29.5,29.4,28.6,28.4,27.8,27.3,27.1,26.8,24.0,21.4.IR(neat,ν max / cm -1 )3319,2924,2853,2095,1579,1300,1121.HRMS(ESI):m / z=821.4697 [M+H] + (calculated value C 46 H 61 N8O6m / z=821.4709).

[0304] Example 25 N-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxamide [ka] Process u)tert-butyl(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamate To a solution of 6-(Boc-amino)hexanoic acid (9.9 mg, 42.6 μmol, 1.3 equivalents) in DMF (0.1 mL), HATU (13.7 mg, 36.0 μmol, 1.1 equivalents) and i-Pr2NEt (20 μL, 115 μmol, 3.5 equivalents) were added. The reaction mixture was stirred at 0°C for 5 minutes, and then added to a mixture of ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine (17.4 mg, 32.7 μmol, 1.0 equivalent) in DMF (0.1 mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with SiO2 (15 mL), and quenched with water (10 mL). The phases were separated, and the aqueous layer was extracted with SiO2 (2 × 15 mL). The combined organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (SiO2; in hexane, 0-15% (3 × CV), 15-25% (5 × CV), 25% (5 × CV), 25-40% (5 × CV), (SiO2:EtOH 3:1)) to obtain the title product as a pale yellow waxy solid (21.0 mg, 86%).

[0305] 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.14 (m, 3H), 7.08 - 6.99 (m, 2H), 6.42 (s, 2H), 5.63 (dt, J = 2.9, 1.4 Hz, 1H), 5.34 (t, J = 5.5 Hz, 1H), 4.53 (s, 1H), 4.01 - 3.94 (m, 1H), 3.94 - 3.80 (m, 2H), 3.70 (s, 6H), 3.10 (t, J = 6.9 Hz, 4H), 2.72 (dd, J = 12.1, 2.9 Hz, 1H), 2.24 - 2.14 (m, 3H), 2.13 - 2.01 (m, 2H), 1.74 - 1.57 (m, 5H), 1.55 - 1.11 (m, 8H), 1.44 (s, 9H), 1.29 (s, 3H), 1.27 (s, 3H), 1.14 (s, 3H), 1.02 - 0.87 (m, 2H), 0.96 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 172.7, 158.3, 156.1, 148.6, 141.7, 138.6, 130.1, 127.5, 126.3, 124.0, 118.0, 103.9, 79.2, 57.2, 56.0, 51.5, 47.5, 44.6, 44.5, 41.8, 40.9, 40.5, 37.6, 36.9, 30.0, 29.3, 28.9, 28.7, 28.6, 27.9, 27.9, 26.7, 26.6, 26.4, 25.6, 23.9, 21.2. IR (neat, ν max / cm -1 ) 3323, 2932, 2864, 2095, 1698, 1650, 1604, 1572, 1518, 1452, 1240, 1121. HRMS (ESI): m / z = 744.5057 [M + H] + (Calculated for C 44 H 66 N5O5 m / z = 744.5058).

[0306] Step v) N-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxamide To a solution of tert-butyl(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamate (3.0 mg, 4.0 μmol, 1.0 equivalent) in Et2O (50 μL), HCl (2.0 M in Et2O, 50 μL) was added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the hydrochloride salt was used immediately in the next step without further purification.

[0307] To 5-carboxytetramethylrhodamine (2.2 mg, 5.0 μmol, 1.25 equivalents, CAS RN: 150322-05-7), i-Pr2NEt (3.5 μL, 20 μmol, 5.0 equivalents) and anhydrous DMF (20 μL) were added, and the mixture was stirred for 1 minute. Then, a solution of crude hydrochloride (2.7 mg, 4.0 μmol, 1.0 equivalent) in anhydrous DMF (50 μL) and HATU (1.9 mg, 5.0 μmol, 1.25 equivalents) were added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and subjected to preparative reverse-phase HPLC (Dr. Maisch Reprosil Gold 120 C4 150 × 20 mm, flow rate 26.5 mL). -1 Purification by a gradient of 50% to 90% acetonitrile (+0.1% HCOOH) in water (+0.1% HCOOH) over 30 minutes (column temperature 25°C) yielded the title compound as a red lyophilized powder (1.8 mg, 43%).

[0308] HRMS(ESI):m / z=1056.5958 [M+H] + (Calculated value C) 64 H78 N7O7m / z=1056.5957).Preparative reverse phase HPLC: (Dr.Maisch Reprosil Gold 120 C4 150×20mm, flow rate 26.5mL / min, column temperature 25℃, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=50:50(t=0.0min)→50:50(t=1.0min)→10:90(t=24.0min)→10:90(t=26.0min)→50:50(t=30.0min), R =9.20 minutes. Analytical UPLC:(Acquity UPLC (登録商標) BEH C18 1.7μm 2.1×50mm, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=98:2(t=0.0min)→98:2(t=0.5min)→2:98(t=4.0min)→2:98(t=5.0min)→98:2(t=6.5min), t R =4.18 minutes.

[0309] Example 26 N-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-6-carboxamide [ka] Step v) N-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-6-carboxamide To a solution of tert-butyl(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamate (3.0 mg, 4.0 μmol, 1.0 equivalent) in Et2O (50 μL), HCl (2.0 M in Et2O, 50 μL) was added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the hydrochloride salt was used immediately in the next step without further purification.

[0310] To 6-carboxyfluorescein (1.9 mg, 5.0 μmol, 1.25 equivalents, CAS RN: 3301-79-9), i-Pr2NEt (3.5 μL, 20 μmol, 5.0 equivalents) and anhydrous DMF (20 μL) were added, and the mixture was stirred for 5 minutes. Then, a solution of crude hydrochloride (2.7 mg, 4.0 μmol, 1.0 equivalent) in anhydrous DMF (50 μL) and HATU (1.9 mg, 5.0 μmol, 1.25 equivalents) were added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and purified by preparative TLC (SiO2;CH2Cl2 with 1% AcOH and 7% MeOH) and further preparative reverse-phase HPLC (Dr. Maisch Reprosil Gold 120 C4 150×20mm, flow rate 26.5 mL / min, gradient of 60% to 90% acetonitrile (+0.1% HCOOH) in water (+0.1% HCOOH) over 30 minutes, column temperature 25°C) to obtain the title compound as a yellow lyophilized powder (1.5 mg, 37%).

[0311] HRMS(ESI): m / z = 1002.5012 [M+H] + (Calculated value C) 60 H 68N5O9m / z=1002.5012).Preparative reverse phase HPLC: (Dr.Maisch Reprosil Gold 120 C4 150×20mm, flow rate 26.5mL / min, column temperature 25℃, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=40:60(t=0.0 min)→40:60(t=1.0 min)→10:90(t=24.0 min)→10:90(t=26.0 min)→40:60(t=30.0 min),t R =10.81 minutes. Analytical UPLC:(Acquity UPLC (登録商標) BEH C18 1.7μm 2.1×50mm, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=98:2(t=0.0min)→98:2(t=0.5min)→2:98(t=4.0min)→2:98(t=5.0min)→98:2(t=6.5min), t R =4.70 minutes.

[0312] Example 27 1-(6-((6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)amino)-6-oxohexyl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)indoline-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-3-(4-sulfobutyl)-3H-indole-1-ium-5-sulfonate [ka] Step v) 1-(6-((6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)amino)-6-oxohexyl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)indoline-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-3-(4-sulfobutyl)-3H-indole-1-ium-5-sulfonate To a solution of tert-butyl(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamate (7.0 mg, 9.4 μmol, 1.8 equivalents) in Et2O (100 μL), HCl (2.0 M, 100 μL in Et2O) was added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the hydrochloride salt was used immediately in the next step without further purification.

[0313] To AlexaFluor647-OSu (5.0 mg, 5.2 μmol, 1.0 equivalent, Jena Bioscience), a solution of crude hydrochloride (6.5 mg, 9.4 μmol, 1.8 equivalents) in anhydrous DMF (100 μL) and i-Pr2NEt (2.7 μL, 16 μmol, 3.0 equivalents) was added, and the deep blue solution was stirred at room temperature for 16 hours. To achieve complete conversion of the hydrolyzed OSu-ester, HATU (0.5 mg, 1.3 μmol, 0.25 equivalents) and i-Pr2NEt (1.0 μL, 5.7 μmol, 1.1 equivalents) were added, and the solution was stirred for a further 30 minutes, at which point complete conversion was confirmed. The mixture was concentrated under vacuum and purified directly by preparative TLC (SiO2, 20% H2O in SiO2, 40% i-PrOH), followed by a second filtration (8-15% MeOH in CH2Cl2) to remove co-eluted HOAt contaminants. The product was obtained as a deep blue wax (5.2 mg, 70%).

[0314] 1 H NMR(500 MHz,CD3OD)δ 8.55(s,1H),8.41-8.28(m,2H),7.92-7.87(m,4H),7.42(d,J=8.3 Hz,1H),7.33(d,J=8.3 Hz,1H),7.25-7.20(m,2H),7.20-7.14(m,1H),7.13-7.08(m,2H),6.73(t,J=12.4 Hz,1H),6.54-6.52(m,1H),6.52(s,2H),6.37(d,J=13.8 Hz,1H),5.60-5.57(m,1H),4.35(t,J=8.1 Hz,2H),4.13(t,J=7.4 Hz,2H),3.99-3.96(m,1H),3.84-3.71(m,2H),3.69(s,6H),3.66-3.63(m,2H),3.16-3.06(m,4H),3.00(t,J=6.6 Hz,2H),2.83(dd,J=12.0,2.5 Hz,1H),2.65-2.60(m,2H),2.23(t,J=7.4 Hz,4H),2.20-2.12(m,5H),2.09(t,J=5.6 Hz,1H),2.03-1.96(m,1H),1.86-1.80(m,1H),1.77(s,3H),1.76(s,3H),1.73(s,3H),1.72-1.41(m,8H),1.39-1.15(m,12H),1.29(s,3H),1.28(s,3H),1.12(s,3H),1.04-0.97(m,2H),0.95(s,3H). 13C NMR(126 MHz,CDCl3)δ 175.8,170.3,159.6,155.2(HSQC),131.3,128.5,128.3,127.2,123.9,121.4,111.4(HSQC),11 1.1(HSQC),105.6(HSQC),104.8,71.3,58.0,56.3,52.3,52.1(HSQC),48.9(HSQC),48.6(HSQC), 45.5,44.9,44.7(HSQC),43.7(HSQC),42.8,41.8,40.2,39.4,38.7,37.1,36.8,33.1,30.8,30. 5,30.1,29.5,28.6,28.4,28.2,27.9,27.6,27.3,26.9,26.6,26.0,24.0,23.7,21.4.IR(neat,ν max / cm -1 )3424,2923,2853,2095,1642,1602,1572,1492,1464,1382,1330,1180.HRMS(ESI):m / z=1520.6240 [M+Na] + (Calculated value C) 76 H 103 N7NaO 16 S4m / z = 1520.6236).

[0315] Example 28 N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-6-(3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5l4,6l4-dipyrrole[1,2-c:2',1'-f][1,3,2]diazabolinin-3-yl)propanamide)hexanamide [ka] Process v) N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-6-(3(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5l4,6l4-dipyrrole[1,2-c:2',1'-f][1,3,2]diazabolinin-3-yl)propanamide)hexanamide To a solution of tert-butyl(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamate (7.3 mg, 9.8 μmol, 1.2 equivalents) in Et2O (100 μL), HCl (2.0 M in Et2O, 100 μL) was added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the hydrochloride salt was used immediately in the next step without further purification.

[0316] To BODIPY 576 / 589-COOH (2.7 mg, 8.2 μmol, 1.0 equivalent, CAS RN: 150173-78-7), a solution of crude hydrochloride (6.3 mg, 9.8 μmol, 1.2 equivalents) in anhydrous DMF (100 μL), followed by i-Pr2NEt (7.2 μL, 41 μmol, 5.0 equivalents) and HATU (3.9 mg, 10 μmol, 1.25 equivalents), and the deep purple solution was stirred at room temperature for 45 minutes. The mixture was concentrated under vacuum and purified directly by preparative TLC (SiO2; 2% MeOH in CH2Cl2), followed by a second purification (SiO2; 7.5% EtOH in hexane, 22.5% SiO2), yielding the product as a dark purple solid (4.7 mg, 60%).

[0317] 1H NMR(500 MHz,CD2Cl2)δ 10.38(s,1H),7.27-7.21(m,2H),7.20-7.16(m,2H),7.11-7.06(m,3H),7.05(s,1H),7.01(ddd,J=3.9,2.5,1.4 Hz,1H),6.90(d,J=4.6 Hz,1H),6.89(d,J=4.0 Hz,1H),6.46(s,2H),6.41-6.36(m,1H),6.31(d,J=4.0 Hz,1H),5.70(t,J=5.5 Hz,1H),5.59(dt,J=2.9,1.5 Hz,1H),5.39(t,J=5.7 Hz,1H),3.99-3.91(m,1H),3.89-3.75(m,2H),3.69(s,6H),3.28(t,J=7.7 Hz,2H),3.21(td,J=7.0,5.8 Hz,2H),3.10(t,J=6.9 Hz,2H),2.77(dd,J=11.9,2.7 Hz,1H),2.59(dd,J=8.2,7.1 Hz,2H),2.20-2.11(m,3H),2.08(td,J=5.6,1.4 Hz,1H),2.02(tt,J=5.8,1.9 Hz,1H),1.70-1.20(m,12H),1.67(d,J=8.3 Hz,1H),1.28(s,3H),1.26(s,3H),1.11(s,3H),1.00-0.91(m,2H).0.95(s,3H). 13 C NMR(126 MHz,CD2Cl2)δ 172.8,171.6,158.8,156.5,150.8,149.4,142.3,139.3,137.8,134.1,132.2,130.6,127.9,127.2,126.6,126.2,124.1,123.9,120.8,118.4,118.2,117.3,112.0,104.3,57.4,56.3,52.0,48.0,44.9,44.7,42.2,41.3,39.7,38.1,37.1,36.0,29.8,29.2,29.1,28.3,28.1,27.1,26.9,26.6,25.8,25.2,24.0,21.3. 19 F NMR(471 MHz,CD2Cl2)δ-140.3(d,J=36.3 Hz),-140.5(d,J=36.1 Hz). 11B NMR(160 MHz,CD2Cl2)δ 1.54(t,J=36.3 Hz).IR(neat,ν max / cm -1 )3301,2926,2855,2094,1648,1604,1574,1484,1462,1107.HRMS(ESI):m / z=955.5567 [M+H] + (Calculated value C) 55 H 70 BF2N8O4m / z=955.5576).

[0318] Example 29 3',6'-diamino-5-((6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid [ka] Step v) 3',6'-diamino-5-((6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid To a solution of tert-butyl(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamate (9.0 mg, 12.1 μmol, 1.3 equivalents) in Et2O (100 μL), HCl (2.0 M in Et2O, 100 μL) was added, and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the hydrochloride salt was used immediately in the next step without further purification.

[0319] To AZDye488-COOH (5.0 mg, 9.3 μmol, 1.0 equivalent, Fluoroprobes catalog number 1012-5), a solution of crude hydrochloride (8.3 mg, 12.1 μmol, 1.3 equivalents) in anhydrous DMSO (200 μL), followed by i-Pr2NEt (8.2 μL, 47 μmol, 5.0 equivalents) and HATU (4.3 mg, 11.2 μmol, 1.2 equivalents), was added, and the deep red solution was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and purified directly by preparative TLC (SiO2, 40% i-PrOH, 20% H2O), and preparative reverse-phase HPLC (Dr. Maisch Reprosil Gold 120 C4 150 × 20 mm, flow rate 26.5 mL / min). -1 The first step involved a second step using a gradient of 50% to 90% acetonitrile (+0.1% HCOOH) in water (+0.1% HCOOH) over 30 minutes (column temperature 25°C), to obtain the title compound as a red lyophilized powder (2.7 mg, 25%).

[0320] 11H NMR (600 MHz, (CD3)2SO) δ 8.79 (s, 1H), 8.44 (bs, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.80 (t, J = 6.1 Hz, 1H), 7.34 (bs, 1H), 7.27 - 7.22 (m, 2H), 7.21 - 7.13 (m, 3H), 6.81 (bs, 2H), 6.54 (s, 2H), 6.42 (bs, 2H), 5.45 (dt, J = 3.3, 1.6 Hz, 1H), 3.89 - 3.83 (m, 1H), 3.74 - 3.69 (m, 1H), 3.68 (s, 6H), 3.62 (dd, J = 15.2, 5.8 Hz, 1H), 3.51 (t, J = 1.2 Hz, 2H), 3.12 (td, J = 6.8, 1.7 Hz, 2H), 2.87 (dd, J = 11.9, 2.7 Hz, 1H), 2.15 - 2.07 (m, 3H), 2.07 - 2.01 (m, 1H), 1.93 (t, J = 5.6 Hz, 1H), 1.63 (d, J = 8.1 Hz, 1H), 1.60 - 1.52 (m, 4H), 1.37 - 1.18 (m, 6H), 1.24 (s, 3H), 1.20 (s, 3H), 1.16 - 1.04 (m, 2H), 1.01 (s, 3H), 0.91 (s, 3H), 0.88 - 0.77 (m, 2H). 13 13C NMR (151 MHz, (CD3)2SO) δ 174.5, 171.8, 164.5, 157.8, 148.8, 141.5, 139.3, 136.1, 129.9, 127.4, 126.0, 121.1, 117.1, 103.6, 69.8, 55.9, 55.3, 50.5, 47.0, 43.4, 42.8, 41.3, 40.4, 40.2, 36.9, 35.5, 29.1, 28.9, 28.3, 27.9, 27.2, 27.1, 26.2, 26.2, 25.6, 25.3, 22.6, 20.8. IR (neat, ν max / cm -1 ) 3410, 3304, 3192, 2922, 2852, 2096, 1737, 1598, 1556, 1424, 1242. HRMS (ESI): m / z = 1182.4283 [M+Na] + (Calculated for C 60 H 69 N7NaO 13S2m / z=1182.4287).Preparative reverse phase HPLC (Dr.Maisch Reprosil 100 C4, 5μm, 150×20mm, flow rate 26.5mL / min, column temperature 25℃, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=50:50(t=0.0min)→50:50(t=1.0min)→10:90(t=24.0min)→10:90(t=26.0min)→50:50(t=30.0min), R =9.60 minutes. Analytical HPLC (Dr.Maisch Reprosil 100 C4,5μm, 150×4.6mm, flow rate 1.4mL / min, column temperature 25℃, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=50:50(t=0.0min)→50:50(t=1.0min)→10:90(t=12.0min)→10:90(t=14.0min)→50:50(t=15.0min), R =8.22 minutes.

[0321] Example 30 N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)oxy)heptanamide [ka] Process t)N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)oxy)heptanamide ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanamine (2.9 mg, 5.4 μmol, 1.0 equivalent) and i-Pr2NEt (2.9 μL, 16.3 μmol, 3.0 equivalents) in anhydrous CH2Cl2 After stirring in 50 μL of water at room temperature for 15 minutes, the solutions of each acid, 7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)oxy)heptanoic acid (2.2 mg, 7.1 μmol, 1.3 equivalents, EP22192302.2), in anhydrous DMF (50 μL) were pre-stirred at 0°C for 15 minutes, and HATU (3.1 mg, 8.1 μmol, 1.5 equivalents) was added all at once. The combined reaction mixture was stirred at room temperature for 45 minutes, followed by concentration under vacuum. The crude product was purified by preparative TLC (SiO2, 70% SiO2 in hexane) to obtain the product as a pale yellow wax.

[0322] 1 H NMR(600 MHz,C6D6)δ 7.67(d,J=8.3 Hz,1H),7.20-7.17(m,2H),7.13-7.09(m,1H),7.08-7.04(m,2H),6.58(s,2H),5.74(dt,J=2.9,1.5 Hz,1H),5.35(d,J=8.3 Hz,1H),4.73(t,J=6.0 Hz,1H),4.42-4.35(m,1H),3.98-3.90(m,2H),3.52(s,6H),3.47(t,J=6.4 Hz,2H),2.83(dd,J=12.1,2.9 Hz,1H),2.51(td,J=6.7,2.3 Hz,2H),2.39(tt,J=6.4,2.1 Hz,1H),2.26(dt,J=8.5,5.6 Hz,1H),2.17(td,J=5.7,5.3,1.4 Hz,1H),2.05(d,J=8.5 Hz,1H),1.93-1.81(m,2H),1.70-1.58(m,3H),1.54-1.47(m,3H),1.31(s,3H) ,1.30(s,3H),1.29-1.24(m,4H),1.21(s,3H),1.15(s,3H),0.99-0.78(m,6H). 13C NMR(151 MHz,C6D6)δ 171.3,159.0,154.3,149.0,145.4,144.3,141.9,139.6,133.2,130.4,130.0,127.9,126.7,123.0,118.4,103.9,103.9,70.5,57.5,5 5.6,51.2,48.1,44.8,44.4,42.0,41.0,38.2,36.3,29.6,29.4,28.8,28.7,28.3,28.1,26.7,26.5,25.7,25.5,23.8,21.4.IR(neat,ν max / cm -1 )3310,2932,2861,2094,1642,1547,1452,1319,1103.HRMS(ESI):m / z=844.4364 [M+Na] + (Calculated value C) 46 H 59 N7NaO7m / z = 844.4368).

[0323] Example 31 1-(6-((2-(2-(4-(3-((4-((7-((((1S,4S,5S)-4-(4-(((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-7-oxoheptyl)carbamoyl)-N-(cyanomethyl)phenyl)sulfonamide)-3-oxopropyl)-1H-1,2,3-triazole-1-yl)ethoxy)ethyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate [ka] Process t) 1-(6-((2-(2-(4-(3-((4-((7-((((1S,4S,5S)-4-(4-(((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-7-oxoheptyl)carbamoyl)-N-(cyanomethyl)phenyl)sulfonamide)-3-oxopropyl)-1H-1,2,3-triazole-1-yl)ethoxy)ethyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate To a solution of (E)-1-(6-((2-(2-(4-(3-((4-((7-(tert-butoxy)-7-oxoheptyl)carbamoyl)-N-(cyanomethyl)phenyl)sulfonamide)-3-oxopropyl)-1H-1,2,3-triazole-1-yl)ethoxy)ethyl)amino)-6-oxohexyl)-6-(2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate (3.0 mg, 2.6 μmol, 1.0 equivalent, EP22192302.2) in dry CH2Cl2 (200 μL), TFA (100 μL) was added, and the resulting plum-colored reaction mixture was stirred at room temperature for 30 minutes. Next, the solvent was removed under vacuum, the residue was redissolved in CH2Cl2, and co-evaporated (×3). The residue was then dissolved in dry DMF (50 μL). TFA (0.5 M solution in dry DMF, 17.5 μL, 8.7 μmol, 3.3 equivalents) and i-Pr2NEt (0.5 M solution in dry DMF, 28.1 μL, 14.0 μmol, 5.3 equivalents) were added, and the resulting colorless solution was cooled to 0°C. Next, HATU (0.1 M solution in DMF, 29.2 μL, 2.9 μmol, 1.1 equivalents) was added, and the reaction mixture was stirred at 0°C for 15 minutes. Next, amine ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine (1.5 mg, 2.7 μmol, 1.1 equivalents) (in 50 μL of CH2Cl2) was added. The reaction mixture was heated to ambient temperature and stirred for a further 30 minutes. The reaction mixture was then concentrated under vacuum, the residue was dissolved in CH2Cl2, and loaded directly onto a silica plate. Purification by preparative TLC (SiO2, 6% MeOH in CH2Cl2) yielded the product (2.5 mg, 59%) as a red solid.

[0324] HRMS(ESI):m / z=1586.7561 [M+H] + (Calculated value C) 84 H 108 N 13 O 14S2m / z=1586.7575).Analytical UPLC:(Acquity UPLC (登録商標) BEH C18 1.7μm 2.1×50mm, H2O(+0.1% HCOOH):MeCN(+0.1% HCOOH)=98:2(t=0.0min)→98:2(t=0.5min)→2:98(t=4.0min)→2:98(t=5.0min)→98:2(t=6.5min), t R =4.65 minutes.

[0325] Example 32 (S)-5-(2-methyl-8-((4-nitrobenzoyl)oxy)-3-phenyloctan-2-yl)-1,3-phenylenebis(4-nitrobenzoate) [ka] Step b) (S)-5-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol A suspension of (S)-5-(8-chloro-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol (32.0 mg, 92.2 μmol, 1.0 equivalent) in H2O (2.0 mL) was heated at 150°C for 3 hours under microwave irradiation. The vial was washed with ELISA (10 mL) and CH2Cl2 (10 mL) in a separatory funnel. The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain (S)-5-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol (30.1 mg, 91.6 μmol, 99%) as an off-white foam.

[0326] 1H NMR(400 MHz,CDCl3)δ 7.25-7.16(m,3H),7.15-7.08(m,2H),6.48(d,J=2.0 Hz,2H),6.25(t,J=2.1 Hz,2H),3.52(tdd,J=10.5,6.6,4.0 Hz,2H),2.80(d,J=12.0 Hz,1H),1.69-1.52(m,1H),1.40-1.09(m,10H),0.99(s,3H),0.96-0.81(m,2H). 13 C NMR(101 MHz,CDCl3)δ 156.5,153.5,141.6,130.3,127.7,126.3,106.7,100.5,63.3,55.8,41.6,31.8,30.1,28.5,27.2,24.7,22.2.IR(neat,ν max / cm -1 ):3307,2935,2488,1705,1598,1436,1328,1153.HRMS(ESI):m / z=351.1928 [M+Na] + (Calculated value C) 21 H 28 NaO3m / z=351.1931).[α] 25 D = -32.414 ± 0.253 (c = 0.5, CHCl3).

[0327] Step c) (S)-5-(2-methyl-8-((4-nitrobenzoyl)oxy)-3-phenyloctan-2-yl)-1,3-phenylenebis(4-nitrobenzoate) (S)-5-(8-hydroxy-2-methyl-3-phenyloctan-2-yl)benzene-1,3-diol (17.5 mg, 53.3 μmol, 1.0 equivalent), NEt3 (37.7 mg, 52.0 μL, 373.0 μmol, 7.0 equivalents), and DMAP (1.3 mg, 10.7 μmol, 0.2 equivalents) were dissolved in dry CH2Cl2 (0.8 mL) to which solid 4-nitrobenzoyl chloride (49.4 mg, 266.0 μmol, 5.0 equivalents) was added all at once. The yellow reaction mixture was stirred at room temperature for 14 hours and then loaded directly onto silica. Purification by flash column chromatography (SiO2; 15% Â in hexane) yielded (S)-17 (35.0 mg, 45.1 μmol, yield 85%) as a white solid. Acine-shaped crystals suitable for X-ray crystallography were obtained by slow evaporation from a solution of cyclohexane, sorbate, and Et2O.

[0328] 1 H NMR(500 MHz,CDCl3)δ 8.41-8.35(m,8H),8.27-8.23(m,2H),8.15-8.12(m,2H),7.28-7.17(m,3H),7.13(d,J=2.1 Hz,2H),7.10-7.06(m,3H),4.24(t,J=6.7 Hz,2H),2.80(dd,J=12.1,2.8 Hz,1H),1.78-1.69(m,1H),1.66-1.58(m,2H),1.54-1.46(m,1H),1.40-1.31(m,4H),1.30-1.23(m,1H),1.20(s,3H),1.13-0.98(m,2H). 13 C NMR(126 MHz,CDCl3)δ 164.8,163.2,153.1,151.2,150.7,140.9,136.0,134.8,131.5,130.8,130.0,127.9,126.6, 124.0,123.6,118.1,112.8,66.1,57.3,42.1,29.4,28.7,28.5,28.0,26.0,23.8.IR(neat,ν max / cm -1):3112,2937,2862,1744,1722,1608,1526,1467,1432,1410,1348,1319,1256,1171 ,1127,1104,1073,1014,959,906,872,855,839,779,714.HRMS(ESI):m / z=798.2270 [M+Na] + (Calculated value C) 42 H 37 N3NaO 12 m / z = 798.2269). [Table 3] Correction method = # Reported T limits: Tmin = 0.779 Tmax = 1.000 AbsCorr=GAUSSIAN [Table 4] CCDC Registration Number: 2310248

[0329] Example 33 The compound of formula (I) can be used as an active ingredient in a manner known to itself to manufacture tablets of the following composition: per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropylmethylcellulose 20mg 425mg

[0330] Example 34 The compound of formula (I) can be used as an active ingredient in a manner known to itself to produce capsules of the following composition: per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5mg 220.0 mg

Claims

1. Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, R １ hydroxy, amino and group 【Chemistry 2】 Selected from; X is selected from a covalent bond, -O-, -NR ｘ -, -NR ｘ C(O)-(CH ２ ) ｑ -, -C(O)NR ｘ -, -C(O)-(CH ２ ) ｑ -, -C(O)-(CH ２ ) ｑ -NR ｘ C(O)-, -C(O)-CH ２ -(CH ２ ) ｑ -C(O)O-, -C(O)-CH ２ -O-, and -C(O)-CH ２ -S-; R ｘ It is selected from hydrogen and methyl; p is an integer selected from 1, 2, 3, 4, 5, and 6; q is an integer selected from 0, 1, 2, 3, 4, and 5; R ２ and R ３ Each of them is independent of C １ -C ６ - Alkyl, Halo C １ ~C ６ Alkyl, C １ -C ６ - Alkoxy, Halo-C １ -C ６ - Alkoxy, C ６ -C １０ - Selected from aryls and 5- to 14-membered heteroaryls; the C ６ -C １０ - Aryl and 5- to 14-membered heteroaryls include halogen, cyano, hydroxy, amino, and C. １ -C ６ - Alkyl, Halo C １ ~C ６ Alkyl, C １ -C ６ - Alkoxy and halo-C １ -C ６ - Optionally substituted with 1 to 3 substituents independently selected from the alkoxy; R ４ The following can be selected: 【Transformation 3】 ， 【Chemistry 4】 ， 【Transformation 5】 ， 【Transformation 6】 ， 【Transformation 7】 ， 【Transformation 8】 ， 【Chemistry 9】 ， 【Chemistry 10】 ， 【Chemistry 11】 ， 【Chemistry 12】 ， 【Chemistry 13】 ， 【Chemistry 14】 ， 【Chemistry 15】 ， 【Chemistry 16】 ， 【Chemistry 17】 ， [Chemistry 18] ， 【Chemistry 19】 ， 【Chemistry 20】 ， 【Chemistry 21】 ， 【Chemistry 22】 ， 【Chemistry 23】 ， 【Chemistry 24】 and 【Chemistry 25】 ； R ４ａ and R ４ｂ Each is independently selected from hydroxy, amino, dimethylamino, and azetidinyl; R ４ｃ and R ４ｄ These are, independently, hydrogen and -SO4. ３ Selected from H; R ４ｅ , R ４ｆ and R ４ｇ Each is independently selected from hydrogen and halogen; Y is Se, S, O, C (CH ３ ) ２ , C (CD ３ ) ２ NCH ２ Selected from C≡CH; and Z is O, S and Si (CH ３ ) ２ Selected from, A compound, or a pharmaceutically acceptable salt thereof.

2. R １ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is selected from hydroxyl and amino.

3. A compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, R １ is, 【Chemistry 26】 And; R ４ The following can be selected: 【Chemistry 27】 ， 【Chemistry 28】 ， 【Chemistry 29】 ， 【Transformation 30】 ， 【Chemistry 31】 ， 【Chemistry 32】 ， 【Transformation 33】 , and 【Transformation 34】 ； p is an integer selected from 2, 3, 4, 5, and 6; R ４ａ and R ４ｂ Each is independently selected from hydroxy, amino, and dimethylamino; R ４ｃ and R ４ｄ These are, independently, hydrogen and -SO4. ３ Selected from H; and Y is O. A compound, or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, R １ is, 【Chemistry 35】 And; R ４ The following can be selected: 【Transformation 36】 ， 【Chemistry 37】 ， 【Transformation 38】 , and 【Chemistry 39】 ; and p is an integer selected from 2 and 5. A compound, or a pharmaceutically acceptable salt thereof.

5. R １ However, a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof, selected from the following: 【Chemistry 40】 ， 【Chemistry 41】 ， 【Chemistry 42】 , and 【Chemistry 43】 。

6. R ２ However, C １ -C ６ - Alkyl, Halo C １ ~C ６ Alkyl, C ６ -C １０ - Selected from aryls and 5- to 14-membered heteroaryls; the C ６ -C １０ - Aryl and 5- to 14-membered heteroaryls, halogens and C １ -C ６ - A compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, optionally substituted with one substituent selected from alkyl groups.

7. R ２ However, C １ -C ６ - Alkyl, Halo C １ ~C ６ Selected from alkyl, phenyl, and 5-6 membered heteroaryls comprising 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon; the phenyl and 5-6 membered heteroaryls are halogens and C １ -C ６ - A compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt thereof, optionally substituted with one substituent selected from alkyl groups.

8. R ２ However, ethyl, 1-propyl, 2-propyl, CF ３ A compound of formula (I) according to claim 7, selected from phenyl, 4-fluorophenyl, 3-fluorophenyl, and 1-methylpyrazole-3-yl, or a pharmaceutically acceptable salt thereof.

9. R ２ C ６ -C １０ - A compound of formula (I) according to claim 8, which is an aryl compound or a pharmaceutically acceptable salt thereof.

10. R ２ The compound of formula (I) according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R is phenyl.

11. R ３ C １ -C ６ -Alkyl and azido-C １ -C ６ - A compound of formula (I) according to any one of claims 1 to 10, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

12. R ３ A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein is selected from pentyl and 5-azidopentyl.

13. A compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, R １ is hydroxy, amino and group 【Chemistry 44】 Selected from; R ２ C １ -C ６ - Alkyl, Halo C １ ~C ６ Selected from alkyl, phenyl, and 5-6 membered heteroaryls comprising 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon; the phenyl and 5-6 membered heteroaryls are halogens and C １ -C ６ - Optionally substituted with one substituent selected from alkyl groups; R ３ C １ -C ６ -Alkyl and azido-C １ -C ６ - Selected from alkyl groups; R ４ The following can be selected: 【Chemistry 45】 ， 【Chemistry 46】 ， 【Chemistry 47】 ， 【Chemistry 48】 ， 【Chemistry 49】 ， [Transformation 50] ， 【Chemistry 51】 , and 【Chemistry 52】 ； p is an integer selected from 2, 3, 4, 5, and 6; R ４ａ and R ４ｂ Each is independently selected from hydroxy, amino, and dimethylamino; R ４ｃ and R ４ｄ These are, independently, hydrogen and -SO4. ３ Selected from H; and Y is O. A compound, or a pharmaceutically acceptable salt thereof.

14. A compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt thereof, R １ hydroxy, amino and group 【Chemistry 53】 Selected from; R ２ ethyl, 1-propyl, 2-propyl, CF ３ Selected from phenyl, 4-fluorophenyl, 3-fluorophenyl, and 1-methylpyrazole-3-yl; R ３ It is selected from pentyl and 5-azidopentyl; R ４ The following can be selected: 【Chemistry 54】 ， 【Transformation 55】 ， 【Transformation 56】 ， 【Chemistry 57】 ， 【Chemistry 58】 ， 【Chemistry 59】 ， 【Transformation 60】 , and 【Chemistry 61】 ； p is an integer selected from 2, 3, 4, 5, and 6; R ４ａ and R ４ｂ Each is independently selected from hydroxy, amino, and dimethylamino; R ４ｃ and R ４ｄ These are, independently, hydrogen and -SO4. ３ Selected from H; and Y is O. A compound, or a pharmaceutically acceptable salt thereof.

15. A compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt thereof, R １ is, 【Transformation 62】 And; R ２ C ６ -C １０ - is an allele; R ３ C １ -C ６ -Alkyl and azido-C １ -C ６ - Selected from alkyl groups; R ４ The following can be selected: 【Transformation 63】 ， 【Chemistry 64】 ， 【Transformation 65】 , and 【Chemical Formula 66】 ; and p is an integer selected from 2 and 5. A compound, or a pharmaceutically acceptable salt thereof.

16. A compound of formula (I) according to claim 15 or a pharmaceutically acceptable salt thereof, R １ The following can be selected: 【Transformation 67】 ， 【Transformation 68】 ， 【Transformation 69】 , and 【Transformation 70】 ； R ２ is phenyl; and R ３ This is selected from pentyl and 5-azidopentyl. A compound, or a pharmaceutically acceptable salt thereof.

17. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is selected from the following: 1-(6-((((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate; 6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)-1-(6-((((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)pyridine-1-ium-3-sulfonate; N-(((1S,4S,5S)-4-(4-(8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide; ((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine; ((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methaneamine; N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)amino)heptanamide; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)aminoheptanamide; N-(((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)penta-4-inamide; 1-(6-((((1S,4S,5S)-4-(4-((R)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate; 1-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate; N-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-bis(dimethylamino)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxamide; N-(6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-6-carboxamide; 1-(6-((6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)amino)-6-oxohexyl)-2-((1E,3E)-5-((E)-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)indoline-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-3-(4-sulfobutyl)-3H-indole-1-ium-5-sulfonate; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-6-(3-(5,5-difluoro-7-(1H-pyrrole-2-yl)-5H-5l4,6l4-dipyrrole[1,2-c:2',1'-f][1,3,2]diazabolinin-3-yl)propanamide)hexanamide; 3',6'-diamino-5-((6-((((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-6-oxohexyl)carbamoyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-4',5'-disulfonic acid; ((1S,4S,5S)-4-(4-((R)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((S)-3-(4-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((R)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((S)-3-(3-fluorophenyl)-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-((R)-3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-(3-ethyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-propyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(4-(3-isopropyl-2-methyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-(trifluoromethyl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((R)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-((S)-2-methyl-3-phenyloctan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; ((1S,4S,5S)-4-(2,6-dimethoxy-4-(2-methyl-3-(1-methyl-1H-pyrazole-3-yl)octan-2-yl)phenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methanol; N-(((1S,4S,5S)-4-(4-((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)-7-((7-nitrobenzo[c][1,2,5]oxadiazole-4-yl)oxy)heptanamide; and 1-(6-((2-(2-(4-(3-((4-((7-((((1S,4S,5S)-4-(4-((((S)-8-azido-2-methyl-3-phenyloctan-2-yl)-2,6-dimethoxyphenyl)-6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl)methyl)amino)-7-oxoheptyl)carbamoyl)-N-(cyanomethyl)phenyl)sulfonamide)-3-oxopropyl)-1H-1,2,3-triazole-1-yl)ethoxy)ethyl)amino)-6-oxohexyl)-6-((E)-2-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)vinyl)pyridine-1-ium-3-sulfonate.

18. A compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

19. A pharmaceutical composition comprising a compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

20. CB ２ A method for treating or preventing a disease or disorder related to R in a subject requiring treatment or prevention, comprising administering a therapeutically effective amount of the compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof to the subject requiring treatment or prevention.

21. A compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, for use in the method according to claim 20.

22. The method according to claim 20, comprising the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 2.

23. CB ２ Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 2 in the manufacture of a medicament for treating or preventing a disease or disorder related to R.

24. CB ２ The diseases or disorders associated with R include hypertension, inflammation, peripheral pain, neuropathic pain, gastrointestinal disorders, autoimmune diseases, pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, hepatic fibrosis, pulmonary fibrosis, renal fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephritis, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, heat injury, burning sensation, hypertrophic scarring, keloids, and gingivitis. The method according to claim 20, the compound for use according to claim 21, or the use according to claims 22 and 23, selected from fever, cirrhosis, tumor, bone density regulation, neurodegeneration, stroke, transient ischemic attack, uveitis, renal fibrosis, arthritis, neuroinflammation, asthma, osteoporosis, mental disorder, psychosis, cancer, encephalitis, malaria, immunodeficiency, rheumatoid arthritis, and allergy.

25. Cannabinoid receptor 2 (CB ２ A compound of formula (I) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for use as a fluorescent probe of R).

26. Cannabinoid receptor 2 (CB ２ Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 17 as a fluorescent probe of R).

27. Cannabinoid receptor 2 (CB ２ A method for imaging R), wherein the cannabinoid receptor 2 (CB ２ A method comprising contacting R) with a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 17.

28. The invention as described above.

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